Successful Treatment of Kaposi Sarcoma-Associated Herpesvirus Inflammatory Cytokine Syndrome After Kidney-Liver Transplant: Correlations With the Human Herpesvirus 8 miRNome and Specific T Cell Response.

After transplant, patient infection with human herpesvirus 8 (HHV-8) and Kaposi sarcoma-associated herpesvirus (KSHV) is known to cause aggressive tumors and severe nonneoplastic complications. These latter syndromes are driven by HHV-8/KSHV lytic reactivations and related hyperinflammatory host responses typically characterized by high viral loads, elevated levels of cytokines and other inflammation biomarkers, cytopenia, organ failure, high fever, and worsening conditions (with no evidence of B cell neoplasias). These disorders are associated with a high mortality rate, often due to lack of prompt diagnosis, effective therapeutic approaches, and adequate follow-up. These features resemble most of those defining the so-called KSHV-associated inflammatory cytokine syndrome (KICS), which was recently recognized in patients positive for human immunodeficiency virus (HIV). In this report, we describe-for the first time-a case of a KICS-like nonneoplastic recurrent complication occurring after transplant in an HIV-negative patient that was successfully treated by a combination of anti-CD20 monoclonal therapy, antivirals, and modification of the immunosuppressive regimen. In addition to clinical and laboratory findings collected during 3-year follow-up, we report novel experimental data on HHV-8-specific T cell dynamics and circulating microRNA profile, showing correlations with clinical course and other laboratory markers (including viral load, C-reactive protein, and cytokine levels), providing useful information about abnormal cellular and cytokine dynamics underlying HHV-8-associated inflammatory disorders in posttransplant patients.

Fully covered metallic stents in biliary stenosis after orthotopic liver transplantation.

BACKGROUND AND STUDY AIMS: Data from a preliminary study suggested that the placement of a fully covered metal stent may be a valid alternative to surgery in patients who do not respond to standard endoscopic treatment. The aims of the current study were to evaluate the clinical success of self-expandable metallic stents (SEMS) in a large cohort of patients and with a long followup,and the effectiveness of SEMS placement as a first-line procedure. MATERIALS AND METHODS: Between January 2008 and August 2010, 54 consecutive patients with biliary complications following orthotopic liver transplantation were treated with SEMS placement:39 after failure of conventional endoscopic therapy (Group I), and 15 with no previous endoscopic treatment who were undergoing SEMS placement as first-line treatment for complications(Group II). RESULTS: In Group I, resolution after SEMS removal was observed in 71.8% of patients. Mean followup after resolution was 22.1 ±10 months. Recurrence of the complication was observed in 14.3%of patients after a mean of 8.5 months and SEMS migration was observed in 33.3% of patients. In Group II, resolution was observed in 53.3% of patients.Mean follow-up after resolution was 14.4±2.2 months. Recurrence was observed in 25% of patients and SEMS migration was observed in 46.7 %. CONCLUSIONS: For endotherapy of biliary complications after orthotopic liver transplantation, metallic stents should not be used as the primary modality. In patients in whom the standard approach fails, treatment with temporary SEMS placement can solve biliary complications in almost three-quarters of cases; however stent migration(33 %) remains a problem.

Pharmacokinetics and efficacy of intravenous or intramuscular hepatitis B immunoglobulins in prophylaxis of hepatitis B after liver transplantation.

AIM: The use of hepatitis B immunoglobulin (HBIg) combined with nucleos(t)ide analogues (NUCs) has improved outcomes in post-hepatitis B (PHB) liver transplant (LT), reducing the 1-year recurrence rate below 10%. The aim of this study was to evaluate efficacy and pharmacokinetics of prophylaxis with NUC(s) and intravenous (iv-) or intramuscular (im-) HBIg in 33 PHBLTs, transplanted for more than 1 year. METHODS: During the first six months of the study, 18 subjects received 5000 IU of iv-HBIg every four weeks and 15 patients 2160 IU/12 mL of im-HBIg every two weeks. In the following six months, 31 subjects were switched to two different concentrations of im-HBIg, 2160/12 mL (16 patients) or 2000 IU/6 mL every two weeks (15 patients). RESULTS: All patients remained HBsAg-negative and 30/31 maintained anti-HBs >100 IU/L. Overall mean anti-HBs titer during treatment was 363 IU/mL. Mean HBIg half-life was 21.4, 27.3 and 26 days with intravenous, diluted or concentrated im-preparations, respectively. CONCLUSION: These results confirm an analogue efficacy and tolerance of iv- and im-HBIg combined with antivirals in prophylaxis of hepatitis B after LT. Anti-HBs titers three times higher than aimed and four weeks mean half-life could suggest the reduction of doses and the elongation of the interval of administration of im-HBIg.

Clinical burden of screening asymptomatic patients for coronary artery disease prior to liver transplantation.

The aim of this study is to assess the clinical burden of silent coronary artery disease (CAD) in cirrhotic candidates for liver transplantation (LT), and to evaluate the usefulness of a CAD screening approach. Between July 1999 and January 2006, we evaluated 627 LT candidates. All of them underwent a detailed clinical history. Sixteen had a previous diagnosis of CAD or symptoms suggestive (2.5%). The remaining 611 underwent further tests according to a predefined protocol, including EKG, echocardiogram and, on the basis of CAD risk factors, heart stress tests. Selective coronary angiography (SCA) was performed in the 30 patients with positive heart stress test: in only 2 did SCA show any CAD, and in both it was subcritical disease requiring neither intervention nor contraindicating LT. The 611 screened patients continued their follow-up until study closure or death. No coronary events occurred in the study population in a mean follow-up of 32.50 months (+/- 23.67 DS). No perioperative mortality related to CAD occurred in the 233 transplanted patients. In conclusion, no prognostic advantage was achieved by following a strict CAD screening protocol, leading us to believe that the cost-effectiveness of a similar screening can be unacceptably high in our setting.

The role of basiliximab induction therapy in adult-to-adult living-related transplantation and deceased donor liver transplantation: a comparative retrospective analysis of a single-center series.

AIM: The aim of this study was to report our single-center experience with the use of basiliximab, in combination with a steroid and tacrolimus-based regimen in adult to adult living-related liver transplantation (ALRLT) and in deceased donor liver transplantation (DDLT). MATERIALS AND METHODS: Seventy-seven consecutive ALRLT recipients (group 1) and 244 DDLT recipients (group 2) were analyzed. All patients received 2 20-mg doses of basiliximab (days 0 and 4 after transplantation) followed by tacrolimus (0.15 mg/kg/d; 10-15 ng/mL target trough levels) and a dose regimen of steroids. Follow-up ranged from 4-1972 days after transplantation in group 1 and from 1-2741 days in group. RESULTS: In group 1, 89.32% of the patients remained rejection-free during follow-up, with an actuarial rejection-free probability of 93.51% within 3 months. Actuarial patient survival rate at 3 years was 84.49%. In group 2, 86.07% of the patients remained rejection-free during follow-up, with an actuarial rejection-free probability of 93.04% within 3 months. Actuarial patient survival rate at 3 years was 87.69%. We observed 14 cases of hepatitis C virus (HCV) recurrence in group 1 (prevalence of 26.92%) and 80 cases in group 2 (prevalence of 54.05%). CONCLUSION: Basiliximab in association with tacrolimus and steroids is effective in reducing episodes of acute cellular rejection (ACR) and increasing ACR-free survival after ALRLT and DDLT. No difference in patient and graft survival was found between group 1 and 2, nor was there any difference in the incidence of ACR between the 2 groups. However, less risk of HCV recurrence was present in the LRLT group.

Liver transplantation using donors older than 80 years: a single-center experience.

AIM: The shortage of organs for orthotopic liver transplantation (OLT) has forced transplantation centers to expand the donor pool by using donors traditionally labeled as "extended criteria donors." One such example is OLT using a donor with advanced age. MATERIALS AND METHODS: We retrospectively evaluated 10 patients who received a liver graft from cadaveric donors older than 80 years. We analyzed pretransplantation donor and recipient characteristics, as well as the evolution of the recipients. RESULTS: All 10 donors were older than 80 years (median age, 83.5; range, 80-93). No steatosis (>30%) was accepted in the older donor group. Medium follow-up was 19.5 months. The most frequent cause for OLT was hepatitis C virus (HCV) cirrhosis (8/10 patients). We had 1 case of primary nonfunction, 1 patient died immediately after surgery because of extrahepatic complications (cardiac arrest), and 2 other patients had a severe HCV recurrence and died after 1 and 2 years from OLT, respectively. Five patients had HCV recurrence and biliary complications were present in 60% of the patients. No cases of acute or chronic rejection were described. Overall survival rates after 1 and 3 years were 80% and 40%, respectively. CONCLUSIONS: Old donor age is not an absolute contraindication to OLT. Liver grafts from donors older than 80 years can be used knowing that there is a high risk of postoperative complications. Furthermore, the increased risk of developing severe HCV recurrence, related to older donor age, suggests that such livers should be used in HCV-negative recipients.

Adult to adult living-related liver transplant: report on an initial experience in Italy.

INTRODUCTION: Living-related liver transplantation has become the treatment of choice for many liver diseases. We present our initial analysis of 53 cases of adult to adult living-related liver transplantation performed in a single institute in Italy. MATERIALS AND METHODS: From January 2002 to September 2006, we performed 53 adult to adult living-related liver transplantations. The donors (age 18-53) all had genetic or emotional relationships; they were all ABO identical or compatible. Recipients (ages 18-68) suffered from cirrhosis secondary to viral etiology (18), hepatocellular carcinoma with viral cirrhosis (24), cystic fibrosis (2), primary biliary cirrhosis (2), hepatocellular carcinoma with non-viral cirrhosis (2), alcoholic cirrhosis (1), ornithine transcarbamylase deficiency (OTC), (1) criptogenic cryptogenic cirrhosis, (1) primary sclerosing cholangitis, (1) biliary atresia and metastatic carcinoid (1). Donor liver resection resulted in 51 right hepatectomies and two left hepatectomies. Graft body weight ratio was always above 0.8%; graft implantation was performed with the piggy back technique and, in 43 cases, with the use of veno-venous bypass. RESULTS: There was neither donor mortality nor need of blood transfusion. Actuarial recipient survival rate at 3 years was 82.66% and graft survival rate was 75.34%. Six patients underwent retransplantation: in four cases due to hepatic artery thrombosis, and in two, due to graft dysfunction. Three patients had one episode each of acute cellular rejection. CONCLUSION: Adult to adult living-related liver transplantation represents a resource to be used in confronting organ shortage, and is a valuable option for decreasing mortality and drop out from the waiting list.

In situ split liver transplantation for adult and pediatric recipients: an answer to organ shortage.

BACKGROUND: We report our initial experience with in situ split liver transplantation (SLT) for adult and pediatric patients. PATIENTS AND METHODS: From June 2003 to August 2005, 177 liver transplantations in 165 patients, 133 adults (81%) and 32 children (19%), were performed at our institution. Over this period, 45 liver transplantations (25%) were performed with an in situ split liver technique in 44 patients: 17 (39%) were adults and 27 (61%) children. All of the adult split liver recipients were transplanted with an extended right graft (ERG; segments I + IV-VIII), while pediatric recipients received in 23 cases a left lateral segment (LLS; segments II-III) and in 4 cases an ERG from a pediatric donor. The 45 split liver grafts (21 ERGs and 24 LLSs) were generated from 35 donors. In 10 cases we used both grafts generated with an in situ split procedure to transplant our patients, while in 25 cases the procurement procedure was performed in collaboration with other transplant centers. RESULTS: After a median follow-up of 9 months (range, 1-27 months), the overall patient survival rate was 88% for adult patients and 82% for pediatric patients. Graft survivals were 88% and 79%, respectively. Two adult patients (12%) died from sepsis in the early postoperative period. Five children (18%) died after their transplantations. Only one pediatric recipient (2%) of primary SLT underwent retransplantation. Vascular complications were absent in adult recipients, whereas 4 arterial (14%) and 4 venous (14%) complications developed in the pediatric population. The incidence of biliary complications was 23% in adult and 18% in pediatric recipients. CONCLUSIONS: The use of in situ SLT for adult and pediatric populations allowed us to expand the cadaveric donor pool, significantly eliminating pediatric waiting list mortality without penalizing the adult population.

A safe immunosuppressive protocol in adult-to-adult living related liver transplantation.

BACKGROUND: In this series of 32 adult-to-adult living related liver transplantations, we assessed the efficacy and safety of basiliximab in combination with a tacrolimus-based regimen. Basiliximab, a chimeric monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor (CD25), has been extensively evaluated as induction therapy for cadaveric liver transplant recipients. PATIENTS AND METHODS: Thirty-two adult-to-adult living related liver transplantations were performed in the last 3 years. All patients received two 20 mg doses of basiliximab (days 0 and 4 posttransplantation) followed by tacrolimus (0.15 mg/kg/d; 10-15 ng/mL target trough levels) and steroids (starting with 20 mg IV switched to PO as soon as the patient was able to eat and weaned within 1-2 months). The average follow-up was 395 days after transplantation. RESULTS: Of the patients, 93.75% remained rejection-free during follow-up with an actuarial rejection-free probability of 92.59% within 3 months. Two patients (6%) had one episode of biopsy-proven acute cellular rejection (ACR). Actuarial patient and graft survival rates at 3 years were 86.85% and 81.25%. One patient (3%) experienced one episode of sepsis. There was no evidence of cytomegalovirus infections or side effects related to the basiliximab. We found zero de novo malignancy but we observed two patients with metastatic spread of their primary malignancy during the follow-up. CONCLUSION: Basiliximab in association with tacrolimus and steroids is effective as prophylaxis of ACR among adult living related liver transplant recipients.

Acceptance of marginal liver donors increases the volume of liver transplant: early results of a single-center experience.

To expand the donor pool, clinicians are continually modifying criteria to accept organs, particularly those in the so-called expanded or marginal donor pool. The concept and definition of a marginal donors continues to evolve. The impact of their use is the result of a combination of donor and recipient factors. Most clinicians accept steatosis above 30%, donor age over 60 years, prolonged ischemia time, prolonged intensive care unit stay, hypernatremia, previous cardiac arrest, prolonged episodes of hypotension, large use of inotrope drugs, and elevated liver function tests as criteria for designation of a marginal organ. In June 2003, we started to use marginal donors each year tripling the number of transplants per year at our center.

Pediatric liver transplantation: preliminary results at Istituto Mediterraneo Trapianti e Terapie ad Alta Specializzazione.

Between July 2003 and November 2004 14 pediatric liver transplantations (LTx) have been performed in 12 children using cadaveric donors. The primary diseases were as follows biliary atresia in 9 cases, whereas the other 3 children were affected by cystic fibrosis, Langherans cells histiocytosis, and hepatoblastoma, respectively. Median patient waiting time was 103 days (range, 2-158); no patient died while on the waiting list. Patients who underwent transplantation included 7 boys and 5 girls, ranging in age from 6 months to 14 years (median age, 5 years). Recipient median weight was 16 kg (range, 6-38). Donor median age was 19 years (range, 3-47), whereas donor median weight was 74 kg (range, 15-90). All children who underwent primary LTx were United Network for Organ Sharing (UNOS) status 2B. Of the 12 transplanted patients, 9 received a left lateral segment (LLS) from an in situ split liver, whereas 3 received a whole graft. Two children developed an episode of acute cellular rejection on the seventh postoperative day, which was treated successfully with a course of intravenous steroids for 3 days. After a median follow-up of 245 days, 10 children are alive but 2 children died due to primary nonfunction (PNF) on the second postoperative day and septic shock on the fifth postoperative day after retransplantation for acute hepatic artery thrombosis, respectively. One child who underwent retransplantation for hepatic artery thrombosis on the 31st postoperative day after primary LTx is currently alive. Evaluation of our initial data suggests that the split liver technique has the potential to meet the needs of pediatric LTx allowing grafting early in the course of the original disease and reducing waiting time.

Distribution of very late activation integrins in the human cornea. An immunohistochemical study using monoclonal antibodies.

There is growing evidence that cellular adhesion mechanisms characterized by cell-cell and cell-matrix interactions are a fundamental process in the immunobiology of the cornea. Interactions with various extracellular matrix components are mediated by the very late activation (VLA) subgroup of the integrin superfamily of adhesion molecules. The six different VLA dimers known thus far consist of a common beta 1 subunit and a variable alpha (1 to 6) subunit. They serve as receptors for laminin (alpha 3 and alpha 6), collagen (alpha 2 and alpha 3), and fibronectin (alpha 4 and alpha 5). Using in situ immunohistochemistry and monoclonal antibodies, the distribution of the common beta 1 and the variable alpha-chains of VLA molecules was studied in normal human cornea and in cases with scarring or subepithelial/retrocorneal fibrous tissue. Epithelial cells were VLA-beta 1 and VLA-alpha 2, -alpha 3, -alpha 4, -alpha 5, and -alpha 6 positive. This is consistent with their intercellular adhesion and may aid in their attachment to the basement membrane which is composed of collagen, laminin, and fibronectin. Keratocytes in normal stroma expressed only the common beta 1-chain and no detectable alpha-chains. In regions of scar or fibrous tissue, however, an upregulated expression of the alpha-chains was detected. The VLA- alpha 1, -alpha 3, -alpha 4, and -alpha 5 were expressed in young fibrous tissue; in older lesions, VLA- alpha 1, -alpha 2, -alpha 3, -alpha 4, and -alpha 5 could be detected. The corneal endothelium showed a strikingly strong positivity for all VLA integrins.(ABSTRACT TRUNCATED AT 250 WORDS)

In situ immunohistochemical analysis of cell adhesion molecules on human corneal endothelial cells.

Interaction of leucocytes with human corneal endothelial cells (HCECs) can be observed in several clinicopathological conditions, such as uveitis, keratitis, and corneal graft rejection. Since leucocyte-endothelial cell interactions involve various adhesion receptors we have analysed the expression and distribution pattern of the neural cell adhesion molecule (NCAM), the intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1), the endothelial leucocyte adhesion molecule-1 (ELAM-1), and the cluster of differentiation antigen-44 (CD44) on flat preparations of normal and organ-cultured HCECs. NCAM and ICAM were constitutively expressed on HCECs whereas VCAM-1, ELAM-1, and CD44 were absent from normal HCECs. However flat mounts of HCECs from organ-culture preserved corneas showed a mosaic-like distribution pattern of VCAM-1 and ELAM-1 positive cells and garland-like clusters of CD44 positive cells. We suggest that modulation of ELAM-1, VCAM-1, and CD44 expression on HCECs may contribute to the regulation of leucocytes-HCECs interaction in the case of anterior segment inflammation.

Oral microemulsion cyclosporin to reduce steroids rapidly in chronic active ulcerative colitis.

OBJECTIVE: The list of the therapeutic tools for chronic active ulcerative colitis lacks a potent and reliably absorbed immune modifier to help wean patients from steroids. We investigated whether oral microemulsion cyclosporin (Neoral) can achieve this goal. DESIGN: Retrospective analysis. SETTING: Tertiary care referral centre. PARTICIPANTS: Nine consecutive patients facing colectomy because of steroid-dependent chronic active ulcerative colitis were studied: the disease was left-sided in six of them and had lasted a median of 10 years. Two patients depended on prednisone 12.5 mg/day, six on 25 mg, and one on 35 mg. The median cumulative steroid dose in the month preceding the trial had been 750 mg. INTERVENTIONS: Neoral was started at a dose of 5 mg/kg/day, which was then titrated to reach a whole-blood therapeutic range of 60-240 ng/ml. During the three-month trial, previous drugs were continued but steroids were tapered according to the patient's clinical condition. PRIMARY OUTCOME MEASURES: The number of patients leaving the trial with quiescent disease and a significantly decreased need for steroids. RESULTS: Eight of the nine patients (89%) showed an initial response and commenced tapering steroids. Remission to the end of the 3rd month was observed in five cases treated with < or = 15 mg steroids daily (median cumulative dose 150 mg). Of the remaining four cases, two were partial responders and two failures, with the failure being linked to poor drug absorption in at least one patient. CONCLUSION: Neoral may help wean patients with chronic active ulcerative colitis from steroids, but this novel indication of cyclosporin must be tested in a specifically designed study.

Hepatocellular carcinoma in a non-cirrhotic liver. Two case reports and literature review.

Hepatocellular carcinoma (HCC) is closely associated with cirrhosis, but it also develops, although much less frequently, in a non-cirrhotic liver. It is suspected that hepatocellular carcinoma has a different etiology when associated and not associated with chronic liver disease. We report two cases of patients with hepatocellular carcinoma that developed in a non-cirrhotic liver. In the first case we describe an incidental liver nodular lesion containing multiple foci of HCC including pseudogland or trabecular formation and areas of sclerosis. The non-cancerous parenchyma of the liver was histologically unremarkable except for mild fatty changes of hepatocytes and minimal dysplasia. The second case describes a combined hepatocellular carcinoma and cholangiocellular carcinoma (CCC) (mixed carcinoma) in a patient who was serologically negative for both hepatitis B and C viruses. The adjacent liver parenchyma showed mild piecemeal necrosis and mild lobular activity compatible with chronic viral hepatitis, but cirrhosis was not established. This case appears to indicate that mixed type carcinoma can develop in a non-cirrhotic liver, with CCC being far more dominant than HCC; such a finding is extremely unusual, based on previously published reports.

Anti-alpha interferon antibodies after alpha interferon treatment in patients with chronic viral hepatitis.

Thirty-five patients with chronic viral hepatitis (B, D or non A, non B), treated with alpha interferon were evaluated by a highly sensitive enzyme immunoassay for the presence of alpha interferon neutralizing antibodies before and after three months of treatment. Although 4 subjects (11.4%) became immunized against alpha interferon, treatment with the drug was successful in inhibiting viral replication in 3 of them. We conclude that the appearance of anti alpha interferon antibodies does not affect the effectiveness of the drug, and is therefore not worth monitoring.

[Cyclosporin for steroid refractory ulcerative colitis. Results of a study conducted at Turin General Hospital between 1990 and 1997]. / La ciclosporina nel trattamento della rettocolite ulcerosa refrattaria al cortisone. Risultati dello studio condotto dal 1990 al 1997 all'Ospedale San Giovanni Battista di Torino.

BACKGROUND: Four every ten patients receiving high-dose parenteral steroids for severe ulcerative colitis fail and may have their colon removed. Intravenous followed by oral cyclosporin has been shown to initially rescue approx. 70% of these non-responder patients, but dosages and long term-efficacy are still debated. We reviewed the clinical outcomes of patients treated with cyclosporin for refractory ulcerative colitis at our Center in the last 7 years. METHODS: Fifty-four patients destined to colectomy because of refractory ulcerative colitis (previous failure to respond to 7 days of 1 mg/kg/day steroids) were enrolled to initially receive a two-week continuous infusion of 2 mg/kg/day cyclosporin. Responders (showing at least a 50% reduction of activity) were meant to be treated with oral drug at 6-8 mg/kg/day for 6 months with the maintenance of remission and the spare of steroids being the end-points. RESULTS: Data are available for 47 patients followed-up for a minimum of 6 months up to 6 years. Of these 47, 14 did not respond to the intravenous drug and were submitted to surgery; of the remaining 33 responders (70%) entering the oral 6-month phase, 17 relapsed before end or on leaving the drug and were considered as failures. The remaining 16 (34% of the 47) left cyclosporin in remission and in need of less than 20 mg steroids daily. Of them, 12 avoided colectomy in a follow-up of 6 months-6 years. CONCLUSIONS: Intravenous cyclosporin may be rapidly effective in 7 every 10 patients whose acute ulcerative colitis fails a full-dose steroid course. However, only 3 of the initial 10 may maintain remission over a 6-month oral course. Further efforts should concentrate on improving the long term efficacy of cyclosporin.