sTRAIL coupled to liposomes improves its pharmacokinetic profile and overcomes neuroblastoma tumour resistance in combination with Bortezomib.

Neuroblastoma (NB), the most common and deadly extracranial solid tumour of childhood, represents a challenging in paediatric oncology. Soluble tumour necrosis factor (TNF)-related apoptosis-inducing ligand (sTRAIL) is a cancer cell-specific molecule exerting remarkable anti-tumour activities against paediatric malignancies both in vitro and in preclinical settings. However, due to its too fast elimination and to the undesired related side effects, the improvement of sTRAIL in vivo bioavailability and the specific delivery to the tumour is mandatory for increasing its therapeutic efficacy. In this manuscript, we developed an innovative pegylated liposomal formulation carrying the sTRAIL at the outer surface (sTRAIL-SL) with the intent to improve its serum half-life and increase its efficacy in vivo, while reducing side effects. Furthermore, the possibility to combine sTRAIL-SL with the proteasome inhibitor Bortezomib (BTZ) was investigated, being BTZ able to sensitize tumour cells toward TRAIL-induced apoptosis. We demonstrated that sTRAIL preserved and improved its anti-tumour activity when coupled to nanocarriers. Moreover, sTRAIL-SL ameliorated its PK profile in blood allowing sTRAIL to exert a more potent anti-tumour activity, which led, upon BTZ priming, to a statistically significant enhanced life spans in two models of sTRAIL-resistant NB-bearing mice. Finally, mechanistic studies indicated that the combination of sTRAIL with BTZ sensitized sTRAIL-resistant NB tumour cells to sTRAIL-induced cell death, both in vitro and in vivo, through the Akt/GSK3/ß-catenin axis-dependent mechanism. In conclusion, our results suggest that sTRAIL-SL might be an efficient vehicle for sTRAIL delivery and that its use in clinic, in combination with BTZ, might represent an adjuvant strategy for the treatment of stage IV, sTRAIL-resistant, NB patients.

Single-center experience in double kidney transplantation.

Use of organs from marginal donors for transplantation is a current strategy to expand the organ donor pool. Its efficacy is universally accepted among data from multicenter studies. Herein, we have reviewed outcomes of double kidney transplantation (DKT) over an 9-year experience in our center. The aim of this study was to evaluate possible important differences between a monocenter versus multicenter studies. Between 1999 and 2008, we performed 59 DKT. Recipient mean age was 63 +/- 5 years. Mean HLA-A, -B, and -DR mismatches were 3.69 +/- 0.922. Donor mean age was 69 +/- 7 years and mean creatinine clearance was 69.8 +/- 30.8 mL/min. Proteinuria was detected in three donors (5%). Mean cold ischemia and warm ischemia times were 1130 +/- 216 and 48 +/- 11 minutes, respectively. The right and left kidney scores were 4.18 +/- 2 and 4.21 +/- 2, respectively. Thirty patients (51%) displayed good postoperative renal function; 22 (37%), acute tubular necrosis with postoperative dialysis; 3 (5%), acute rejection episodes; 4 (7%), single-graft transplantectomy due to vascular thrombosis; 1 (2%), a retransplantation; 5 (8%), a lymphocele; 3 (5%) vescicoureteral reflux or stenosis requiring surgical correction. Cytomegalovirus infection was detected in five patients (8%). In three patients (5%) displayed de novo neoplasia. Three patients showed chronic rejection (5%), whereas we observed a cyclosporine-related toxicity in 7 (12%). Nine patients (15%) developed iatrogenic diabetes. Patient and graft survivals after 3 years from DKT were 93% and 86.3%, respectively. In this study, we applied successfully a widespread score to allocate organs to single kidney transplantation or DKT. In our experience, the score is suitable for the organ allocation but it may be overprotective, excluding potentially suitable organs for a single transplantation.

Alcohol abstinence and orthotopic liver transplantation in alcoholic liver cirrhosis.

Patients diagnosed with acute alcoholic hepatitis (AAH) are routinely managed medically and not considered suitable for orthotopic liver transplantation (OLT). The eligibility for OLT in these patients has been questioned due to the social stigma associated with alcohol abuse, based on the fact that AAH is "self-induced" with an unacceptably high recidivism rate. Many centers in Europe and the United States require abstinence periods between 6 and 12 months before OLT listing. AAH outcomes in the literature are poor, in particular due to patient noncompliance during the immediate 3 months preceeding OLT. Between January 1997 and December 2007, 246 patients were evaluated in our center for alcoholic liver disease: 133 (54%) were listed for OLT (I-OLT), including 110 (83%) who underwent transplantation and 8 (6%) still listed as well as 15 (11%) removed from consideration. One hundred thirteen (46%) patients had no indication for OLT (NO I-OLT), including 18 (16%) who died, 81 (71%) still monitored, and 14 (12%) lost to follow-up. Patient survival rates post-OLT were 79%, 74%, 68%, and 64% at 1, 3, 5, and 10 years, respectively. Explant (native liver) pathologic examination revealed AAH in 8 (7.2%) patients who underwent OLT. In this group, patient survival and the post-OLT recidivism rate were statistically identical to the overall group of transplant recipients.

Torque Teno Virus--cause of viral liver disease following liver transplantation: a case report.

Torque Teno Virus (TTV), a nonenveloped human virus of the Circoviridae family, is hepatotropic, causing liver damage, cirrhosis, and, rarely, fulminant hepatitis. It prevails in 10% to 75% of blood donors due to environmental differences, independent of chronic hepatitis B virus (HBV)/HCV hepatitis, cryptogenic cirrhosis, alcoholic cirrhosis, and in fulminant hepatitis non-A-G. Reports about the efficacy of clinical alpha interferon are rare. In July 2007, a 65-year-old man who was serologically negative for A-E viruses presented with acute liver failure due to a ruptured hepatic artery aneurysm and underwent orthotopic liver transplantation (OLT). Immunosuppression was based on cyclosporine and steroids. At postoperative day 20, there was persistent hypertransaminasemia with otherwise normal liver function. A percutaneous hepatic biopsy documented pattern suggestive of a viral etiology. Multiple tests for hepatotropic viruses in the donor and the recipient from the pre- and post-OLT periods remained negative. Only the TTV qualitative test, assessed by polymerase chain reaction (PCR) on patient sera, was positive. Immunosuppressive therapy was not changed; no antiviral therapy was undertaken. At 6 months posttransplantation, transaminase levels spontaneously normalized and the clinical situation was unchanged. No complications were observed; the patient is in good clinical condition. No graft rejection was observed. In histologically proven non-A-E viral hepatitis, it is important to consider TTV as an incidental pathogenic agent. It may be useful to extend virological tests to TTV among transplant recipients and donors and to gain further knowledge about this virus.

Renal transplant compartment syndrome: a case report.

An unusual case of early double kidney transplant dysfunction due to abdominal compartment syndrome is herein reported. A 62-year-old woman on peritoneal dialysis underwent dual kidney transplantation. The grafts were positioned extraperitoneally in both iliac possae using standard techniques. Surgical procedures and immediate postoperative period were uneventful. The urine output was immediate and the creatinine decreased, but in a few days she developed severe ascites with reduced urine output, increased creatinine, and progressive changes on Doppler ultrasound. The patient underwent paracentesis: the kidney function recovered as well as the Doppler ultrasound. Kidney biopsy was negative for rejection or renal pathology. Graft dysfunction was related to the presence of ascites. A catheter inserted in the abdomen measured intra-abdominal pressure (IAP) of 14 mm Hg. IAP correlated with renal function showing that IAP probably explained renal flow modifications.

Introducing ultrasound-guided vein catheterization into clinical practice: A step-by-step guide for organizing a hands-on training program with inexpensive handmade models.

INTRODUCTION: Central vein catheterization (CVC) plays a central role in hospital patient management. Compared with the use of traditional anatomical landmarks, ultrasound-guidance is associated with higher CVC success rates, fewer complications, and more rapid central venous access. The use of US-guided CVC in clinical practice has not become widespread, largely because anesthesiology and general surgery residents receive limited training in this technique. To increase the use of US-guided CVC in our surgical department, we organized a hands-on training program based on the use of handmade models. METHODS: Three different models were constructed using plastic food-storage containers, segments of rubber tourniquet and silastic tubing (to simulate vessels), and agar gelatin. RESULTS: The hands-on training course allowed progressive acquisition of the basic hand-eye coordination skills necessary for performing US-guided venipuncture. The overall cost for each model was less than €5.00. DISCUSSION: The models described in this report are useful tools for teaching US-guided CVC. Thanks to their low-cost, they can be widely used to facilitate the introduction of this technique in clinical practice.