Sirolimus (SRL) is an mTOR inhibitor that has been shown, in contrast to calcineurin inhibitors (CNI), to inhibit cancers in experimental models. Since February 2005, we introduced SRL in liver transplant patients in group a, in whom the primary disease was hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic or autoimmune liver cirrhosis, and group b, HCC-negative patients who developed posttransplantation cancers de novo. Of 18 patients in group a, 11 received SRL ab initio (subgroup a1), starting for 10 patients at 66.1+/-29.2 days after surgical healing and after 10 days in 1 case; the remaining 7 patients (subgroup a2) received SRL at 31.2+/-24.2 months. Three patients in group b, included 1 with Kaposi's sarcoma, 1 with bladder cancer, and 1 with thyroid cancer. In this group, SRL was introduced at 80.8+/-40.4 months. In all patients but one, who received a single 5 mg loading dose, SRL was started at 2 mg/d and adjusted to 6 to 8 ng/mL blood levels. CNI drugs, present as primary therapy, were gradually tapered to low levels and eventually stopped. The following observations were drawn from this initial experience: (1) 4/21 (19.0%) patients had to discontinue SRL because of early and late side effects: thrombocytopenia (n=2) and headache with leukopenia and leg edema associated with knee joint arthralgia (n=2); (2) 14 patients (11 in group a and 3 in group b) are still on SRL monotherapy; (3) 1 HCC recurrence and 1 de novo pancreatic adenocarcinoma were observed at 14 and 16 months, respectively (at the time of transplantation, both patients were beyond the MIlan HCC criteria), and (4) 1 patient, from subgroup a1, died after 99 days due to pneumonitis and possible relation to SRL lung toxicity. In conclusion, SRL appeared to be an effective immunosuppressant that could be used as monotherapy in liver transplant patients. Any conclusion on SRL anticancer effects can only come from randomized large studies after long follow-up.
[Show abstract][Hide abstract] ABSTRACT: The discovery of patterns of dependency in heterogeneous multivariate dynamic systems is approached with similarity-based neuro-fuzzy networks and evolutionary algorithms. The search space contains general autoregressive non-linear models representing the dependency structure of the process. Examples show that the proposed approach gives better results than the classical statistical one
Neural Networks, 2002. IJCNN '02. Proceedings of the 2002 International Joint Conference on; 02/2002
[Show abstract][Hide abstract] ABSTRACT: Renal transplant recipients have a high risk of developing multiple and invasive urothelial tumors because of long-term immunosuppression and infections with oncogenic viruses in China. However, treatment of renal transplant recipients who developed invasive bladder tumor is challenging. We aimed to evaluate the efficacy and safety of orthotopic ileal neobladder reconstruction following radical cystectomy in renal transplant recipients. Orthotopic ileal neobladder reconstruction and preservation of the transplanted kidney were performed in two patients after one and 36 months of transplantation, respectively. One recipient was lacking a bladder because of prior cystectomy before the transplantation, and the other developed multiple and invasive bladder cancer after the transplantation. During the 14-month and seven-yr follow-up postoperation, no serious complications occurred except slight hydronephrosis in one patient. No rejection and graft dysfunction occurred in both patients with reduced dosage of immunosuppressants, and serum creatinine as a marker of renal function remained stable. Urinary continence was satisfactory during the day and night with voluntary voiding. Our experience showed that radical cystectomy and orthotopic ileal neobladder reconstruction in transplant patients with stable renal function is a safe and effective way to provide better quality of life, satisfactory urinary diversion and preservation of renal function simultaneously.
[Show abstract][Hide abstract] ABSTRACT: The mammalian target of rapamycin inhibitors are immunosuppressive agents with antiproliferative effects and consequent potential application as anticancer agents. The safety and tolerance of calcineurin inhibitor (CNI)-free sirolimus-based immunosuppressant protocols in liver transplant recipients with malignancies or high risk of tumor recurrence has been scarcely evaluated.
Fourteen liver transplant recipients, including 12 men, of overall mean age of 57.4 +/- 12.4 years were distributed into two groups: group I, corresponding to 11 patients with malignant neoplasia, eight de novo neoplasia, and three recurrent hepatocarcinoma and; group II, three patients with high risk of tumor recurrence due to cholangiocarcinoma. Sirolimus was initiated at 2 mg od, with target levels of 3 to 9 ng/mL. Withdrawal of CNI was performed after reaching target levels of sirolimus. Periodic examinations of weight, arterial pressure, liver function tests, serum creatinine, triglycerides, cholesterol, sirolimus blood levels, and creatinine clearance were performed at 30, 60, 90, 180, and 360 days.
After a median follow-up of 221.5 days, eight group I patients (72.7%) were alive, including six with stable disease. All group II patients were alive without evidence of tumor recurrence after a median follow-up of 560 days. CNI was withdrawn in 11 patients (78.6%). Sirolimus was withdrawn in only one case due to severe symptomatic oral ulcers. No vascular complications or rejection episodes were observed.
A sirolimus-based immunosuppressant protocol was well tolerated and safe in liver transplant recipients with malignancies or a high risk of recurrence of neoplastic disease.
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