University of Modena experience in HIV-positive patients undergoing liver transplantation.

INTRODUCTION: Highly effective antiretroviral therapy in the last decade has increased the survival rates of HIV-positive patients, yielding a greater number of HIV patients suffering from liver-related disease. Liver transplantation (LT) is the only curative treatment for end-stage liver disease (ESLD) associated or not with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: From June 2003 to September 2010, 23 patients underwent cadaveric donor LT for ESLD at our institution. Inclusion criteria followed the Italian Protocol for LT in HIV-positive patients. Immunosuppressive regimens were based on cyclosporine or tacrolimus, eventually switched to Rapamycin. RESULTS: The median CD4 T-cell count was 275/mmc (range=119-924). All patients were affected by ESLD, which was associated with HCC in 14 cases. Ten patients were within the Milan criteria and four patients exceeded them but were within the San Francisco criteria. Conversion from calcineurin inhibitors (CNI) to rapamycin occurred in ten cases. Hepatitis C virus (HCV) recurrence occurred in 13/21 HCV-positive patients. Acute cellular rejection occurred in eight patients with one developing chronic cellular rejection. Overall patient and graft survivals at 80 months were 50% and 45% respectively. DISCUSSION: LT in HIV-positive patients is a feasible procedure, even if in our experience was burdened by a greater incidence of complications including HCV recurrence and infection compared with HIV-negative patients.

FOLFOX6 and bevacizumab in non-optimally resectable liver metastases from colorectal cancer.

BACKGROUND: In patients with colorectal liver metastases (CLM) R0 resection significantly improves overall survival (OS). METHODS: In this report, we present the results of a phase II trial of FOLFOX6+bevacizumab in patients with non-optimally resectable CLM. Patients received six cycles of FOLFOX6+ five of bevacizumab. Patients not achieving resectability received six additional cycles of each. A PET-CT was performed at baseline and again within 1 month after initiating treatment. RESULTS: From September 2005 to July 2009, 21 patients were enrolled (Male/Female: 15/6; median age: 65 years). An objective response (OR) was documented in 12 cases (57.1%; complete responses (CRs): 3, partial response (PR): 9); one patient died from toxicity before surgery. Thirteen patients underwent radical surgery (61.9%). Three (23%) had a pathological CR (pCR). Six patients (46.1%) experienced minor postsurgical complications. After a median 38.8-month follow-up, the median OS was 22.5 months. Patients achieving at least 1 unit reduction in Standard uptake value (SUV)max on PET-CT had longer progression-free survival (PFS) (median PFS: 22 vs 14 months, P=0.001). CONCLUSIONS: FOLFOX6+bevacizumab does not increase postsurgical complications, yields high rates of resectability and pCR. Early changes in PET-CT seem to be predictive of longer PFS.

Pulmonary hypertension as a predictor of postoperative complications and mortality after liver transplantation.

Most transplant centers consider severe pulmonary hypertension (PHT) to be an absolute contraindication for orthotopic liver transplantation (OLT). We retrospectively examined the outcome of 24 patients with PHT (group 1) who underwent OLT compared with 24 matched patients (group 2) without PHT, who also underwent OLT. Based on right cardiac catheterization measurements made after the induction of anesthesia for OLT, PHT was defined as mild or moderate-to-severe if the mean pulmonary arterial pressure exceeded 25 or 35 mm Hg, respectively. The incidence of PHT was 9.8% (24/244); 21/24 PHT patients showed mild and 3/24 moderate PHT. Kaplan-Meier survival analysis did not show a significant difference between the two groups. The incidence of pulmonary infections was significantly greater in group 1 (P < .05). The duration of ventilation and intensive care unit stay was similar in the two groups. Echocardiography detected only the three moderate cases of PHT and not the twenty-one cases of mild PHT. Our analysis suggested that mild PHT was common and did not affect patient outcomes after OLT; moderate or severe PHT was uncommon. The two patients with moderate PHT survived OLT and did not succum to PHT during long-term follow-up.

Novel genetic mutation in apolipoprotein E2 homozygosis and its implication in organ donation: a case report.

Disorders in lipoprotein metabolism do not contraindicate liver procurement and transplantation (LT). In this circumstance, LT provides an intriguing opportunity to assess the in vivo contribution of the liver to the synthesis and degradation of genetically polymorphic plasma proteins. Apolipoprotein (APO) E exists with several common phenotypic differences due to gene polymorphism. Some authors have shown that the APOE phenotype of the recipient was virtually completely converted to that of the donor, providing evidence that >90% of plasma APOE arises from the liver. Homozygosis for APOE2 (E2-E2) is related to an increased incidence of type III hyperlipoproteinemia (HLP). Recently, some authors have identified 4 new APOE mutations that are strongly linked to a unique entity of renal lipidosis called lipoprotein glomerulopathy (LPG). At present, 65 cases of LPG have been reported worldwide, although most patients have been discovered in Japan and other East Asian countries. We have herein reported a case of LT in a patient with advanced hepatocarcinoma who received a liver from a caucasian donor affected by type III HLP due to homozygous E2-E2. The LPG was due to a novel genetic mutation in APOE. After the LT, the recipient, developed de novo severe lipid abnormalities despite good graft function. To our knowledge this is the first report of an LT using a graft from a non Asian donor with homozygous E2-E2 with the presence of a novel APOE mutation.

Liver transplantation due to iatrogenic injuries: two case reports.

The transjugular intrahepatic portosystemic shunt (TIPS) is an acceptable procedure that has proven benefits in the treatment of patients who have complications from portal hypertension due to liver cirrhosis. In the literature few reports have described complications after TIPS placement. Initial surgery and local hemostasis have been needed to manage abdominal bleeding: if this treatment is insufficient, it may be necessary to perform a liver transplantation. This report describes the role of liver transplantation to manage dangerous complications in 2 patients after TIPS placement, when surgical procedures and hemostasis were unable to stop the bleeding.

[Is there an age limit for radical surgery in case of tumors infiltrating the duodenum?]. / Per le neoplasie infiltranti il duodeno esiste un limite di età per una chirurgia radicale?

AIM: Radical resection is the only potential cure for pancreatic malignancies and a useful treatment for other benign diseases, such as pancreatitis. Over the last two decades, medical and surgical improvements have drastically changed the postoperative outcome of elderly patients undergoing pancreatic resection, and appropriate treatment for elderly potential candidates for pancreatic resection has become an important issue. METHODS: A hundred and five consecutive patients undergoing radical pancreatic resection between 2003 and 2007 at the Surgery Unit of the University of Modena, Italy, were considered and divided into two groups according to their age, i.e., over 75-year olds (group 1, 25 patients) and under 75-year-olds (group 2, 80 patients). The two groups were compared as regards to demographic features, American Society of Anesthesiologists scores, comorbidities, previous major surgery, surgical procedure, postoperative mortality, and morbidity. RESULTS: There were no significant differences between the two groups concerning postoperative mortality, and the duration of hospital stay and days in the postoperative Intensive Care Unit were also similar. Complications such as pancreatic fistulas, wound infections, and pneumonia were more frequent in the older group, but the differences were not statistically significant. CONCLUSION: In the light of these findings and as reported for other series, old age is probably not directly related with any increase in the rate of postoperative complications, but comorbidities (which are naturally related to the patients' previous life) may have a key role in the postoperative course.

Prevalence of human herpesvirus-6 chromosomal integration (CIHHV-6) in Italian solid organ and allogeneic stem cell transplant patients.

The unique phenomenon of human herpesvirus-6 (HHV-6) chromosomal integration (CIHHV-6) may account for clinical drawbacks in transplant setting, being misinterpreted as active infection and leading to unnecessary and potentially harmful treatments. We have investigated the prevalence of CIHHV-6 in 205 consecutive solid organ (SO) and allogeneic stem cell transplant (alloSCT) Italian patients. Fifty-two (38.5%) of 135 solid organ transplant (SOT) and 16 (22.8%) of 70 alloSCT patients resulted positive for plasma HHV-6 DNA by real-time polymerase chain reaction. Seven SOT and three alloSCT patients presented HHV-6-related diseases, requiring antivirals. Two further patients (0.9%) were identified, presenting high HHV-6 loads. The quantification of HHV-6 on hair follicles disclosed the integrated state, allowing the discontinuation of antivirals. Before starting specific treatments, CIHHV-6 should be excluded in transplant patients with HHV-6 viremia by the comparison of HHV-6 loads on different fluids and tissues. Pretransplantation screening of donors and recipients may further prevent the misdiagnosis of CIHHV-6.

Liver transplantation utilizing grafts from donors with genitourinary cancer detected prior to liver implantation.

Expansion of the donor pool has led to reconsideration of selection criteria to obtain the largest number of grafts without compromising recipient outcomes. This reconsideration concerns the utilization of donors with malignancies. Herein we have analyzed the outcomes, survivals, and risks of cancer transmission among patients who received a liver transplant from a donor with a genitourinary malignancy. Six of 363 patients (1.5%) who underwent transplantation at our center received an organ from a donor with a genitourinary cancer which was detected prior to the surgical harvest. Donors affected by low-grade renal cell carcinoma (Fuhrman grade 1 or 2) or low-grade intraprostatic prostate carcinoma (Gleason score

Usutu virus infection in a patient who underwent orthotropic liver transplantation, Italy, August-September 2009.

We report a case of Usutu virus (USUV)-related illness in a patient that underwent an orthotropic liver transplant (OLT). Post transplant, the patient developed clinical signs of a possible neuroinvasive disease with a significant loss of cerebral functions. USUV was isolated in Vero E6 cells from a plasma sample obtained immediately before the surgery, and USUV RNA was demonstrated by RT-PCR and sequencing. This report enlarges the panel of emerging mosquito-borne flavivirus-related disease in humans.

Effects of everolimus monotherapy on hematological parameters and iron homeostasis in de novo liver transplant recipients: preliminary results.

INTRODUCTION: Anemia after orthotopic liver transplantation (OLT) is a common complication due to several reasons. Immunosuppressive drugs play an important role in anemia occurring at 1 month or more after OLT. Several studies describe myelosuppression immunosuppressants such as the mammalian target of rapamycin inhibitors. METHODS: We performed a single-center, prospective trial consisting of a short 30-day course of cyclosporine (CsA) associated with everolimus (EVL) from postoperative day 10 (Group EVL) versus a CsA immunosuppressive regimen (Group CsA) in de novo OLT patients. We explored the influence of immunosuppressive drugs on hematological parameters comparing EVL versus CsA. RESULTS: Twenty-eight patients were enrolled in the EVL and 12 in the CsA Groups. After OLT, hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), white blood cell (WBC), platelets (PLT), transferrin saturation (TSAT), iron, ferritin, and transferrin did not differ significantly between the 2 groups at any time point. Among the patients who reached 6-months of follow-up, 5 (41.7%) EVL and 4 (80%) CsA subjects were anemic (P=not significant [NS]). Only anemia in patients enrolled in Group EVL showed a trend toward the features of microcytic, hypochromic anemia. DISCUSSION: Our results demonstrated that de novo anemia in OLT patients treated with EVL monotherapy showed the same incidence as in patients treated with CsA. Hb values remained similar during the entire follow-up. Moreover, overall myelosuppression in the EVL Group was not significantly different from patients in the CsA Group.

Human immunodeficiency virus and liver transplantation: our point of view.

INTRODUCTION: Highly active antiretroviral therapy (HAART) has been able to improve the immune system function and survival of HIV patients with a consequent increase in the number of HIV patients affected by end-stage liver disease (ESLD). Between June 2003 and October 2006, 10 HIV-positive patients underwent liver transplantations in our center. METHODS: All patients were treated with HAART before transplantation; treatment was interrupted on transplantation day and was restarted once the patients' conditions stabilized. Five patients were hepatitis C virus (HCV)-positive, 3 were hepatitis B virus (HBV)-positive, and 2 were HBV-HCV coinfected. HIV viral load before transplantation was <50 copies/mL in all cases. CD4+ cell count before transplantation ranged between 144 and 530 c/microL. Immunosuppression was based on Cyclosporine (CyA) and steroid weaning for 8 patients, and on Tacrolimus and steroid weaning for 2 patients. RESULTS: Five patients were cytomegalovirus (CMV)-positive pp65 antigenemia posttransplantation, and 1 patient was EBV-positive; 2 patients had a coinfection with HHV6. Four patients suffered from a cholestatic HCV recurrent hepatitis treated with antiviral therapy (peginterferon and Ribavirin). Three patients died after transplantation. DISCUSSION: The outcome of liver transplantation in HIV patients was influenced by infections (HCV, CMV, and EBV) and Kaposi's Sarcoma. HCV recurrence was more aggressive, showing a faster progression in this patient population. Drug interaction between HAART and immunosuppressants occurs; longer follow-up and better experience may improve the management of these drug interactions.

Use of recombinant factor IX and thromboelastography in a patient with hemophilia B undergoing liver transplantation: a case report.

Hemophilia B is a congenital recessive disorder caused by deficiency of coagulation factor IX (FIX). Surgical procedures can be performed in patients with hemophilia using high-purity and/or recombinant FIX, which has been shown to be safe and effective in surgical hemostasis. Liver transplantation is the only potentially curative treatment available for these patients, providing a long-term phenotypic cure for hemophilia. End-stage liver disease together with hemophilia exposes patients to greater risks of bleeding complications during the perioperative period with consequent difficulties in managing coagulopathy. The limited experiences reported by different investigators and the various strategies for clotting factor replacement make it difficult to define a single approach with respect to the optimal dose and method of administering FIX to achieve perioperative hemostasis. The limits of plasma-based coagulation tests--prothrombin time, activated partial thromboplastin time--have made thromboelastography a valid alternative in this kind of surgery. It has been demonstrated to be a useful tool for real-time analysis of clot formation using a whole-blood assay format. Further, it accurately illustrates the clinical effects of procoagulant or anticoagulant interventions. In this article, we have described the usefulness of thromboelastography to monitor the ability of high-purity FIX supplementation to restore a normal coagulation state and to guide the perioperative administration of blood products in a successful orthotopic liver transplantation in a hemophilic patient with deficiencies of factors IX and X, presenting with hepatitis C virus-related cirrhosis and hepatocellular carcinoma.

Hepatocellular carcinoma in HIV patients treated by liver transplantation.

INTRODUCTION: Several reports have shown the effectiveness of liver transplantation (LT) as a therapeutic option in HIV-patients affected by end-stage liver disease. HCC on cirrhosis is another major indication for LT. However, no reports, to our knowledge, have been published as yet addressing the important questions of indications and outcome of LT in HIV-patients with HCC, mainly because of concerns regarding a more aggressive course of HCC with respect to HCC seen in HIV-negative individuals. METHODS: The aim of this report is to focus on indications, preliminary results and complications of LT in a group of 7 HIV-patients who underwent LT at our department for HCC on cirrhosis. RESULTS: Indications to listing HIV-patients were HCC using the internationally accepted Milan criteria. All patients were HBV-and/or HCV-infected. The mean CD4+ cell-count was 249 (range 144-353), and the HIV-RNA load was undetectable in all but one case. After a mean follow-up period of 232days (range 33-774), no recurrence of HCC was seen; one patient died. CONCLUSION: Characteristics of the study protocol, the patients, virological and immunological features, tumor stage and pre-transplantation treatment, complications and survival are herein described in an effort to provide new insights into methodology for an aggressive management of HCC in HIV patients, and possibly give a greater chance of cure.

Sirolimus monotherapy in liver transplantation.

INTRODUCTION: Since 1999, a new immunosuppressive drug was administered to renal transplant patients. The SRL molecule acts by blocking post-receptor signal transduction of interleukin-2 (IL-2) interacting with a family of intracellular binding proteins termed immunophilins FKBPs. Among these FKBPs, FK506 12-kd binding protein is the most relevant. SRL is an immunosuppressive drug. Therefore it can inhibit the immune system; at the same time the drug is not nephrotoxic, neurotoxic, and without diabetogenic effects. METHODS: Among 285 patients who underwent liver transplantation, 27 took Sirolimus as monotherapy. Immunosuppressive treatment upto cyclosporine (CsA) or tacrolimus (FK) associated with steroids (methylprednisolone) and mycophenolate Mofetil (MMF) was initiated among subjects with pre-transplant renal failure. SRL was administered as monotherapy for patients who developed nephrotoxicity, or neurotoxicity, or diabetes. Moreover, patients affected by multifocal HCC who did not meet the Milan criteria or patients who developed Kaposi's Sarcoma were prescribed SRL monotherapy. RESULTS: Nephrotoxicity occurred in 14 patients with mean serum creatinine level 2.2 mg/dl. Eleven patients with real failure showed significant improvements after a mean period of 28 days of SRL monotherapy (range: 6-45 days). The mean creatinine serum level after treatment with SRL monotherapy was 1.0 mg/dl (range: 0.7-1.2 mg/dl). Neurotoxicity occurred in 4 patients with tremor, confusion, and agitation. Each patient had complete improvement of symptoms after a few days of Sirolimus monotherapy. Among Three patients who developed Kaposi's Sarcoma, two underwent remission. One patient had diabetes due to calcineurin inhibitors, and one showed arterial hypertension not treatable with drugs. After the switch, we treated these patients with medications. Another important indication was HCC not meeting the Milan criteria. CONCLUSION: SRL monotherapy may be used to manage complication of calcineurin inhibitors or Kaposi's Sarcoma.

Role of therapeutic drug monitoring in a patient with human immunodeficiency virus infection and end-stage liver disease undergoing orthotopic liver transplantation.

Pharmacological interactions between protease inhibitors and tacrolimus require careful monitoring to prevent toxicity in the posttransplantation period. A 42-year-old man with human immunodeficiency virus (HIV) infection and end-stage liver disease due to hepatitis C virus (HCV) received an orthotopic liver transplant. At the time of surgery the patient was on triple antiretroviral therapy (tenofovir, lamivudine, and lopinavir/ritonavir) with a stable CD4(+) count (>500 cells/mm(3)) and HIV-1 RNA (<50 copies/mL). Immunosuppression was maintained with tacrolimus (0.5 mg at a single dose once per week). One month after surgery HCV recurrence was documented. Pharmacokinetic evaluation of lopinavir/ritonavir showed a rapid increase in the area under the curve. Drug concentrations returned to normal levels, with reduction in liver enzymes. At the same time, tacrolimus dosages were reduced to a maintenance dose of 0.5 mg every 2 weeks. The patient, at 17 months postoperatively, is alive in good health with normal liver function and HCV RNA load levels. This is the first case in which a profound change in the pharmacokinetics of a protease inhibitor caused by a drug-drug interaction was observed during transient liver damage. Because this clinical event is particularly common in HIV-infected patients, our findings suggest that therapeutic drug monitoring should be performed to determine the impact of potential drug interactions in the early posttransplantation period, at the time of resumption of therapy or introduction of new anti-retroviral therapy and during HCV recurrence in order to optimize both tacrolimus and protease inhibitor treatment.

Rituximab as treatment of posttransplant lymphoproliferative disorder in patients who underwent small bowel/multivisceral transplantation: report of three cases.

This report describes three cases of posttransplant lymphoproliferative disorder (PTLD) in multivisceral/small bowel transplant patients treated with rituximab (anti-CD20 monoclonal antibodies). In two cases (one of which was a B-cell lymphoma) a good response to therapy was achieved. A third case (with polymorphic PTLD with low CD20 expression) developed a refractory rejection and PTLD was still documented on graftectomy. Rituximab was well tolerated, and a reduction of Epstein-Barr virus (EBV) viral load was documented by quantitive competitive-EBV polymerase chain reaction. Efficacy of therapy needs to be assessed in controlled studies.

[Endoscopic approach to biliary stones: experience acquired in a general surgery unit. Comparison of 2 periods]. / L'approccio endoscopico alla calcolosi della via biliare: acquisizione e sviluppo dell'esperienza in una unità operativa di chirurgia generale. Due periodi a confronto.

The outcome of the laparoscopic technique, that in the first years needed to be applied in non complicated situations, imposed a more frequent use of ERCP preoperatively; this procedure was originally confined to a handful of European and American centers, but later spread to almost all large hospitals. Improvements in the techniques and materials have gone side by side with more specific indications and the assessment of complications. The purpose of the present study was to analyze the experience of a General Surgery Unit in terms of acquiring and developing skills in treating biliary stones by ERCP.