Effect of ischaemic preconditioning on recurrence of hepatocellular carcinoma in an experimental model of liver steatosis.

BACKGROUND: Livers with parenchymal abnormalities tolerate ischaemia-reperfusion (IR) injury poorly. IR injury is a risk factor for hepatocellular carcinoma (HCC) recurrence. This study assessed the link between liver parenchymal abnormalities and HCC recurrence, and evaluated the protective effect of ischaemic preconditioning. METHODS: C57BL/6 mice were fed a choline-deficient diet for 6 and 12 weeks, or standard chow. Hepatic IR and ischaemic preconditioning were achieved by clamping liver blood inflow. Hepa 1-6 HCC cells were inoculated through the spleen. Thereafter, tumour burden, serum α-fetoprotein and cancer cell aggressiveness were compared among groups. RESULTS: Hepatocellular damage and expression of inflammatory genes (encoding interleukin 6, tumour necrosis factor α, hypoxia inducible factor 1α and E-selectin) were exacerbated after IR injury in mice with severe steatosis. Compared with control livers or those with minimal steatosis, livers exposed to a prolonged choline-deficient diet developed larger tumour nodules and had higher serum α-fetoprotein levels. Non-ischaemic liver lobes from mice with steatosis were not protected from accelerated tumour growth mediated by IR injury. This remote effect was linked to promotion of the aggressiveness of HCC cells. Ischaemic preconditioning before IR injury reduced the tumour burden to the level of that in non-ischaemic steatotic controls. This protective effect was associated with decreased cancer cell motility. CONCLUSION: Livers with steatosis tolerated IR poorly, contributing to more severe HCC recurrence patterns in mice with increasingly severe steatosis. IR injury also had a remote effect on cancer cell aggressiveness. Ischaemic preconditioning before IR injury reduced tumour load and serum α-fetoprotein levels. SURGICAL RELEVANCE: Liver ischaemia-reperfusion (IR) injury is associated with organ dysfunction and surgical morbidity. Livers with steatosis tolerate IR injury poorly in the setting of both liver resection and liver transplantation. Ischaemic preconditioning is a simple method to mitigate IR injury. This study shows that ischaemic preconditioning of mouse livers with steatosis reduces ischaemia-mediated tumour growth acceleration. Liver parenchymal abnormalities such as warm IR injury and liver steatosis should be taken into account to predict accurately the risk of liver cancer recurrence after surgical management. Ischaemic preconditioning strategies may hold therapeutic potential not only to mitigate surgical morbidity but also to reduce postoperative recurrence of liver cancer.

Donor characteristics and risk of hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND: To date, studies assessing the risk of post-transplant hepatocellular carcinoma (HCC) recurrence have focused on tumour characteristics. This study investigated the impact of donor characteristics and graft quality on post-transplant HCC recurrence. METHODS: Using the Scientific Registry of Transplant Recipients patients with HCC who received a liver transplant between 2004 and 2011 were included, and post-transplant HCC recurrence was assessed. A multivariable competing risk regression model was fitted, adjusting for confounders such as recipient sex, age, tumour volume, α-fetoprotein, time on the waiting list and transplant centre. RESULTS: A total of 9724 liver transplant recipients were included. Patients receiving a graft procured from a donor older than 60 years (adjusted hazard ratio (HR) 1.38, 95 per cent c.i. 1.10 to 1.73; P = 0.006), a donor with a history of diabetes (adjusted HR 1.43, 1.11 to 1.83; P = 0.006) and a donor with a body mass index of 35 kg/m(2) or more (adjusted HR 1.36, 1.04 to 1.77; P = 0.023) had an increased rate of post-transplant HCC recurrence. In 3007 patients with documented steatosis, severe graft steatosis (more than 60 per cent) was also linked to an increased risk of recurrence (adjusted HR 1.65, 1.03 to 2.64; P = 0.037). Recipients of organs from donation after cardiac death donors with prolonged warm ischaemia had higher recurrence rates (adjusted HR 4.26, 1.20 to 15.1; P = 0.025). CONCLUSION: Donor-related factors such as donor age, body mass index, diabetes and steatosis are associated with an increased rate of HCC recurrence after liver transplantation.

[Liver transplantation in swine: a model for tolerance induction]. / Il trapianto di fegato nel suino: considerazioni su un modello per lo studio dell'induzione di tolleranza.

AIM: The liver as a solid graft has a known immunological privilege. Its tolerogenic property has been demonstrated in rodents. In humans the onset of chronic rejection and the severity of such complication is less frequent after liver transplantation compared to other organs. The underlying events whose effect is graft acceptance instead of rejection should be further investigated. Their control could open new ways to decrease the need for long-term immunosuppression after transplantation of other organs. Aim of this study is to evaluate a model of liver transplantation in swine as a preliminary step for immunological studies. METHODS: Ten outbred Landrace/Large White mismatched swine underwent to liver transplantation with a simple passive portocaval jugular bypass. The onset of rejection was monitored daily by liver function test. After death or sacrifice the liver parenchyma was studied to evaluate tissue damage and inflammatory infiltrate. RESULTS: The postoperative liver function showed a critical period for organ rejection about postoperative day 5. The animals that survived longer were sacrificed with a normal biochemical hepatic function. However, histology consistently showed a pattern of mild rejection in a still preserved architecture. CONCLUSIONS: The evidence of a prolonged liver function in a rejecting model of liver transplantation makes this model suitable for studies of tolerance induction.

[Blockade of B7:CD28 costimulatory pathway reduces the vascular damage in an experimental model of chronic rejection]. / Riduzione del danno vascolare in un modello sperimentale de rigetto cronico mediante blocco selettivo della via di costimolazione B7:CD28.

AIM: Costimulatory blockade and donor specific transfusion (DST) can catalyze tolerance of transplanted organs through a multistep adaptation between the recipient and donor immune systems. Such an in vivo process may prolong graft survival. Aim of this study was to evaluate the outcome of aortic transplantation under CTLA4Ig and DST in a mismatched model in rats. METHODS: Orthotopic aortic transplantation was performed in recipients Lewis from Wistar-Furth rats. The animals were stratified into 3 groups, according to the postoperative treatment. Group 1 had aortic transplantation only (controls, n=6), while group 2 (n=7) had a load of donor splenocytes (DST). Group 3 was treated with DST and CTLA4Ig. All the animals were sacrificed at the 60th postoperative day and the aortic specimens were prepared for histology. Intimal cells, muscular cells and lymphocyte cell infiltration were evaluated by serial counts. RESULTS: In Group 1 there was a severe chronic rejection, while group 2 showed a slower onset of chronic rejection with less inflammatory infiltrate than group 1 (P<0.05). Group 3 had the best overall outcome with lower infiltration and minimal alterations compared with groups 1 and 2. CONCLUSIONS: Costimulatory blockade and DST load can prevent the onset of chronic rejection in this experimental setting. Despite the wide availability of immunosuppressors, which makes transplantation a today's clinical routine, the solution to chronic rejection is still elusive. The synergistic role of splenocytes and costimulatory blockade raises interesting perspectives about the immunomodulatory role of spleen in tolerance induction.

Encrustation and stone formation: complication of indwelling ureteral stents.

Severe encrustation and stone formation on indwelling ureteral stents in 2 patients with a lithogenic history are reported. In both cases this complication occurred in the presence of sterile urine and treatment required pyelolithotomy in one and renal pelvic irrigation with urologic G solution in the other. Analyses of these stones revealed struvite and apatite, respectively. Dissolution of encrustations and stones via renal pelvic irrigation is suggested as a viable alternative to surgical intervention for this problem. A review of the literature shows a correlation between chronic stone formers and stent encrustation, rather than from bacteriuria alone. Long-term antibiotic suppression, more frequent followup with abdominal roentgenograms, and shorter periods of internal stenting are suggested for patients with a lithogenic history.

Case against routine 2-stage cystectomy for carcinoma of the bladder.

A total of 25 patients with carcinoma of the bladder was subjected to urinary diversion, staged irradiation and total cystectomy. Of these 25 patients 1 died after cystectomy, for a mortality rate of 4 per cent. Complications occurred in 60 per cent of the patients. The projected 5-year survival rate is 49 per cent. We conclude that this protocol offers no advantages over radiation followed by cystectomy and diversion, and we believe that the procedure is unwarranted except in individualized instances.

Computer-assisted analysis of transrectal ultrasound images.

We have developed a microcomputer based system with an application specific software package which permits the direct digitization and analysis of transrectal ultrasound (TRUS) images. The system is highly flexible and enables access to a wide range of image analysis tools through relatively simple software modifications, which cannot be implemented using a standard ultrasound instrument. We have demonstrated the capability of the system by an analysis of a number of morphometric parameters and by a correlation of these measurements with the presence of prostatic cancer. We found that the measurement of the ratio of the anterior-posterior axis to transverse axis and the presumed circular area ratio (PCAR) were significant predictors of prostatic cancer. The sensitivity of the PCAR measurement was 93%, the specificity was 50%, the positive predictive value was 57%, and the negative predictive value was 91%. The high negative predictive values of these parameters may provide objective criteria to allow for selective biopsy of patients. This system provides researchers with an efficient, economical, and flexible method to aid in the analysis of TRUS images in a quantitative manner.