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A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov].).

Analysis of mitochondrial function is central to the study of intracellular energy metabolism, mechanisms of cell death and pathophysiology of a variety of human diseases, including myopathies, neurodegenerative diseases and cancer. However, important properties of mitochondria differ in vivo and in vitro. Here, we describe a protocol for the analysis of functional mitochondria in situ, without the isolation of organelles, in selectively permeabilized cells or muscle fibers using digitonin or saponin. A specially designed substrate/inhibitor titration approach allows the step-by-step analysis of several mitochondrial complexes. This protocol allows the detailed characterization of functional mitochondria in their normal intracellular position and assembly, preserving essential interactions with other organelles. As only a small amount of tissue is required for analysis, the protocol can be used in diagnostic settings in clinical studies. The permeabilization procedure and specific titration analysis can be completed in 2 h.

Purpose: The pathologic interactions between tumor and host immune cells within the tumor microenvironment create an immunosuppressive network that promotes tumor growth and protects the tumor from immune attack. In this study, we examined the contribution of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) on this phenomenon. Experimental Design: Expression of IDO was analyzed in colorectal cancer cell lines by reverse transcription-PCR and functional enzyme activity was assessed by high-pressure liquid chromatography. Semiquantitative immunohistochemistry was used to evaluate IDO expression in the tissue samples of 143 patients with colorectal carcinoma, and was then correlated with the number of tumor-infiltrating T cells and clinical variables. Results: In vitro IDO expression and functional enzyme activity in colorectal cancer cells was found to be strictly dependent on IFN-g stimulation. Immunohistochemical scores revealed IDOhigh expression in 56 of143 (39.2%) tumor specimens, whereas 87 of143 (60.8%) cases showed low IDO expression levels. IDO-high expression was associated with a significant reduction of CD3+ infiltratingT cells (46.02 F 7.25) as compared with tissue samples expressing low IDO (19.42 F 2.50; P = 0.0003). Furthermore, IDO-high immunoreactivity significantly correlated with the frequency of liver metastases (P = 0.003). Kaplan-Meier analysis showed the crossing of survival curves at 45 months. By multivariate Cox's analysis, IDO-high expression emerged as an independent prognostic variable (<45 months, P = 0.006; >45 months, P = 0.04).Conclusion: IDO-high expression by colorectal tumor cells enables certain cancer subsets to initially avoid immune attack and defeat the invasion of Tcells via local tryptophan depletion and the production of proapoptotic tryptophan catabolites. Thus, IDO significantly contributes to disease progression and overall survival in patients with colorectal cancer.Colorectal cancer is the most common gastrointestinal malignancy and one of the leading causes of cancer-related deaths worldwide (1). Five-year overall survival rates range from 90% for stage I to 75% and 50% for stage II and III

Orthotopic liver transplantation (OLT) has been considered the best treatment option for patients with hepatocellular carcinoma (HCC). Because of a steadily increasing waiting time, a noteworthy proportion of patients are excluded from OLT because of tumor progression. A 20% and more dropout rate from the waiting list has recently been reported. In this prospective study, we evaluated the effect of preoperative transarterial chemoembolization (TACE) on preventing tumor progression while on the waiting list in patients meeting current selection criteria (solitary lesion < 5 cm, three lesions < 3 cm). In addition, we analyzed the outcome of a separate group of patients with advanced-stage HCC outside the selection criteria but with at least 50% tumor reduction after TACE (downstaging) to expand current criteria. Forty-eight patients met the selection criteria and were eligible for this study. Seven patients are still on the waiting list; 41 underwent OLT. None of these patients had to be removed from the list because of tumor progression after a mean waiting time of 178 days (23 patients >180 days). The 1-, 2-, and 5-year intention-to-treat survival was 98%, 98%, and 94%. The outcome after OLT was also excellent with 1-, 2-, and 5-year survival rates of 98%, 98%, and 93%. Tumor recurrence occurred only in 1 patient (2.4%). Fifteen patients with advanced-stage HCC were included in this study. Three developed a tumor progression and had to be removed from the list (20% dropout rate). Despite tumor reduction before OLT, these patients had a significantly less favorable outcome in the intention-to-treat analysis as well as in the posttransplantation survival. Tumor recurrence was seen in 30% of patients after OLT. In conclusion, TACE followed by OLT is associated with an excellent outcome in selected patients. Furthermore, TACE is highly efficacious in preventing tumor progression while waiting for OLT. Although TACE reduced tumor preoperatively, it failed to show a beneficial effect on patient survival in advanced-stage HCCs. (Liver Transpl 2003;9:557-563.)H epatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with an estimated annual incidence of about 1 million cases. 1-4 Liver cirrhosis, in particular caused by hepatitis B and C virus and iron overload states, constitutes the main risk factor for HCC. A variety of therapeutic modalities have been tried in the treatment of HCC, but orthotopic liver transplantation (OLT) has been considered as the only curative treatment option because OLT has been claimed to simultaneously cure the malignant disease and replace the premalignant cirrhotic liver. However, early experiences with OLT in the setting of HCC were disappointing, in particular because of a recurrence rate of up to 80% and consequently dismal long-term survival results. These were well below the survival rates of patients who underwent transplantation for nonmalignant disorders. 5,6 Several small studies, however, showed that early or incidentally found HCCs did not adversely a...

BackgroundWe investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC).MethodsIn a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor–free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor–free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint.ResultsRecurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874).ConclusionsSirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

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19 patients (3.7%). Long-term success was observed in 77% of patients with AS. In patients with NAS, partial long-term responses could be achieved in 63% of patients. Five patients (6.2%) required a percutaneous and 6 (7.4%) patients a surgical approach.In conclusion, the long-term outcome for patients with post-liver transplant biliary strictures after endoscopic treatment is excellent, especially for patients with AS. Development of NAS reduces graft but not patient survival after endoscopic therapy. Liver Transpl 12:718-725, 2006.