Nicola Guglielmo

Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus–infected liver tissue

Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T‐bethighIFN‐γ– “T‐helper (Th)1‐suppressing” phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon‐gamma (IFN‐γ; T‐bet+IFN‐γ+), thus becoming “Th1‐like” cells. OX40‐expressing and Th1‐suppressing Tregs were enriched in the Helios‐positive subset, carrying highly demethylated Treg cell‐specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2‐like monocytes and macrophages, boosted OX40+ Treg proliferation and antagonized the differentiation of Th1‐like Tregs. However, this signal is counteracted in noncirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin‐12 and IFN‐γ, ultimately leading to complete, full Th1‐like Treg differentiation. Conclusion: Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ. (Hepatology 2014;60:1494–1507)

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

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

Laparoscopy in Liver Transplantation: The Future Has Arrived

In the last two decades, laparoscopy has revolutionized the field of surgery. Many procedures previously performed with an open access are now routinely carried out with the laparoscopic approach. Several advantages are associated with laparoscopic surgery compared to open procedures: reduced pain due to smaller incisions and hemorrhaging, shorter hospital length of stay, and a lower incidence of wound infections. Liver transplantation (LT) brought a radical change in life expectancy of patients with hepatic end-stage disease. Today, LT represents the standard of care for more than fifty hepatic pathologies, with excellent results in terms of survival. Surely, with laparoscopy and LT being one of the most continuously evolving challenges in medicine, their recent combination has represented an astonishing scientific progress. The intent of the present paper is to underline the current role of diagnostic and therapeutic laparoscopy in patients waiting for LT, in the living donor LT and in LT recipients.

Does Caval Reconstruction Technique Affect Early Graft Function after Liver Transplantation? A Preliminary Analysis

BACKGROUND In the past decades, the inferior vena cava (IVC) reconstruction technique has undergone several evolutions, such as biopump, piggyback technique (PB), and laterolateral approach (LLPB). Several advantages are reported comparing the PB technique to biopump use. However, comparison between PB and LLPB has not been as well investigated. The aim of this study was to compare the results in terms of immediate graft function and intermediate graft survival among 3 subgroups characterized by distinct caval reconstruction techniques. METHODS We retrospectively analyzed a cohort of 200 consecutive adult patients who underwent liver transplantation from January 2001 to December 2009. The patients were stratified according to 3 caval reconstructive techniques: biopump (n=135), PB (n=32) and LLPB (n=33). RESULTS The LLPB group showed the shortest cold and warm ischemia times and the best immediate postoperative graft function. Survival analysis revealed LLPB patients to present the best 1-year graft survival rates: namely, 90.9% versus 75.0% and 74.1% among the PB and biopump groups, respectively (log-rank tests: LLPB vs biopump: P=.03; LLPB vs PB: P=.05). In our experience, LLPB showed the best graft survivals with an evident reduction in both cold and warm ischemia times. However, it is hard to obtain an irrefutable conclusion owing to the retrospective nature of this study, the small sample, and the different periods in which the groups were transplanted. CONCLUSIONS LLPB technique was a safe procedure that minimized the sequelal of ischemia-reperfusion damage. This technique yielded results superior to venovenous bypass. No definitive conclusions can to be obtained in this study comparing classic PB or LLPB.

Adult Wilms tumor: Case report.

Wilms tumor (WT) occurs infrequently in adults. Even rarer is adult WT with extension by direct intravascular spread into the right side of the heart. The present report describes a WT with intracaval and intracardiac extension in a 38-year-young man. In addition, thrombus extension above the infrahepatic IVC represents a major technical topic for surgeons because of the possible occurrence of uncontrollable hemorrhages and tumor fragmentation. We report the results of a surgical approach to caval thrombosis including the isolation of the IVC from the liver as routinely performed during liver harvesting. The morphologic and immune-histochemical findings confirmed the diagnosis.

Graft macrosteatosis and time of T-tube removal as risk factors for biliary strictures after liver transplantation.

Biliary strictures (BS) remain a significant problem following liver transplantation (LT), representing an important cause of morbidity. The purpose of this follow‐up study was to evaluate the incidence and risk factors associated with BS after LT. From 2001 to 2009, 244 consecutive patients underwent LT at our center. Multiple donor and recipient variables were collected for each patient. Exclusion criteria were hepaticojejunostomy, living‐donor LT, and follow‐up less than three months. We reviewed 177 patients, all of whom underwent an end‐to‐end choledochocholedochostomy and T‐tube placement. BS occurred in 23% of patients. Multivariate analysis revealed that graft macrovesicular steatosis >25% (p = 0.05, OR 3.38) and time of T‐tube removal less than six months (p = 0.02, OR 2.53) were independent risk factors for BS. Biliary strictures did not affect patient and graft survival. Donor macrovesicular steatosis represents a risk factor for BS, contributing to liver damage through a reduction in hepatic blood flow. Time of T‐tube removal seems to play a role in the development of BS, although it is unclear whether it represents the cause or the consequence of the development of BS.

Management of hepatitis C virus infection in liver transplantation with adacolumn apheresis.

Recurrent hepatitis C virus (HCV) is a major cause of liver transplant loss, hepatic failure, and retransplantation need. Posttransplantation antiviral therapy in patients with evidence of recurrent disease is the mainstay of management. Although HCV is a hepatocellular pathogen, there is increasing evidence that the virus can infect and persist in other cells. In particular, granulocytes and monocytes/macrophages are known to constitute extrahepatic sites for HCV replication and dissemination. The aim of this study was to apply Adacolumn apheresis as a possible therapeutic alternative to conventional drug therapy to manage HCV infections. Seven patients who underwent liver transplantation for HCV-related cirrhosis were eligible for the study. The patients underwent 5 1-hour sessions for 5 consecutive days. The first treatment was performed in the anhepatic phase of liver transplantation with the intent to early reduce infected granulocytes and monocytes/macrophages. The patients were evaluated over the 5 days after inclusion with 3- and 6-months follow-ups. Early apheresis treatments in the anhepatic phase and over the following 4 days after transplantation produced low viral loads in 4 patients, negative viral loads in 2 patients, and increased viremia in 1 patient. At follow-up, the viremia load was stable in 6 patients without increased transaminase levels. At the end of the treatment cycle, almost all immune cells of the 6 patients maintained CD4+/CD8+ T-cell ratios. The optimal timing of treatment initiation is unknown, but early preemptive therapy is recommended to decrease the risk for recurrent infection. Although this study investigated the responses among a small number of patients, it documented that the Adacolumn changed cellular immunity, promoting early virologic responses.

Bilateral ex vivo repair and kidney autotransplantation for complex renal artery aneurysms: A case report and literature review

We report the surgical management of a bilateral renal artery aneurysm diagnosed in a 41‐year‐old patient with a history of recurrent abdominal pain. The preoperative contrast‐enhanced computed tomography showed a complex saccular aneurysm on both renal arteries within the renal hilum. The characteristics of aneurysms precluded endovascular procedures, and a double‐step bilateral ex vivo reconstruction with kidney autotransplantation was planned. The intra‐ and postoperative period was uneventful. Imaging and laboratory examinations show preservation of renal function, and patient is symptom‐free at 10‐month follow up.

Donor Quality Scoring Systems and Early Renal Function Measurements in Kidney Transplantation

Over the last years, an extensive improvement in the use of non-standard kidney allografts from deceased donors has been observed due to a chronic scarcity in the number of available donors. However, use of these donors seems to give worse results, higher delayed graft function (DGF) and rejection rates and briefer graft survivals. Nevertheless, a standardized definition of non-standard donor is still under debate. On these grounds, several studies have focalized on the importance of events immediately before or early post-transplant in determining allograft outcome: introduction of scores based on peri-operative features capable to predict graft function may yield huge implications for organ allocation policies, as well as for immediate and late clinical and immunological management of recipients. In fact, if pre-KT information could accurately predict suboptimal early graft function, the success of various mechanical, immunosuppressive and organ allocation strategies may be improved. The aim of this review is to analyze the different preand post-transplant score systems, detecting their role in the clinical practice and comparing them in terms of prognostic ability.

Effectiveness and versatility of biological prosthesis in transplanted patients

AIM To emphasize the effectiveness and versatility of prosthesis, and good tolerance by patients with incisional hernia (IH). METHODS From December 2001 to February 2016, 270 liver transplantations were performed at San Camillo Hospital. IH occurred in 78 patients (28.8%). IH usually appeared early within the first year post-orthotopic liver transplantation. In the first era, fascial defect was repaired by primary closure for defects smaller than 2.5 cm or with synthetic mesh for greater defects. Recently, we started using biological mesh (Permacol™, Covidien). We present a series of five transplanted patients submitted to surgery for abdominal wall defect correction repaired with biological mesh (Permacol™, Covidien). RESULTS In our cases, the use of biological prosthesis (Permacol™, Covidien) have proven to be effective and versatile in repairing hernia defects of different kinds; patients did not suffer infections of the prosthesis and no recurrence was observed. Furthermore, the prosthesis remains intact even in the years after surgery. CONCLUSION The cases that we presented show that the use of biological mesh (Permacol™, Covidien) in transplanted patients may be safe and effective, being careful in the management of perioperative immunosuppression and renal and graft function, although the cost of the product itself has been the main limiting factor and there is need for prospective studies for further evaluations.