Induction therapy with alemtuzumab (campath) in combined liver-kidney transplantation: University of Bologna experience.

BACKGROUND: Combined liver-kidney transplantation (LKT) is considered to be a safe procedure, but the appropriate immunosuppressive regimen is unclear. PATIENTS AND METHODS: Between January 1997 and October 2011, 55 patients were listed for LKT: 45 (82%) were effectively transplanted, 5 (9.2%) died whereon here the waiting list, 3 (5.5%) temporarily out of waiting list, 1 (1.8%) was on waiting list and 1 (1.8%) refused LKT. Five LKTs treated with cyclosporine (CyA) were excluded from the analysis. Mean recipient age was 50.32 ± 10.32 years (14-65), MELD score at time of LKT was 19.22 ± 4.69 (8-29), mean waiting list time was 8.14 ± 9.50 months (0.1-35.76), and follow-up, 4.09 ± 3.02 years (0.01-10.41). Main indications for LKT were policystic disease (n = 15; 37%), hepatitis virus C (HCV)-related cirrhosis (n = 9; 22%) metabolic disease (n = 5; 13%), hepatitis virus B (HBV) cirrhosis (n = 4; 10%), alcoholic cirrhosis (n = 4; 10%), and cholestatic disease (n = 3; 8%). Immunosuppressive regimen was based on tacrolimus and steroids in 40 cases with induction therapy with alemtuzumab (Campath; 0.3 mg/kg) in 13 of 40 instances cases administered on day 0 and day 7. RESULTS: Postoperative mortality was 2.5%. Acute cellular rejection episodes were biopsy-proven in 2 (5%) cases, post-LKT infections developed in 17 cases (42.5%), and de novo cancer developed in 3 (7.5%) cases. Similar 5-year overall survivals were obtained irrespective of the LKT indication: 100% in cholestatic and alcoholic cirrhosis patients, 86% in policystic disease, 75% in metabolic disease and HBV patients, and 66% in HCV cirrhosis. Overall survivals for the alemtuzumab vs without-induction therapy groups at 1, 3, and 5-years were 100%, 85.7%, and 85.7% vs 76%, 76%, and 70%, respectively (P = .04). CONCLUSION: An immunosuppressive regimen based on tacrolimus and steroids with induction therapy with alemtuzumab was safe, with excellent long-term results for combined LKT.

Prognostic significance of disordered calcium metabolism in hormone-refractory prostate cancer patients with metastatic bone disease.

Bone metabolic disruption that occurs in bone metastatic prostate cancer could lead to disturbances of calcium metabolism. The prognostic role of either hypocalcemia or hypercalcemia was assessed in a consecutive series of hormone-refractory bone metastatic prostate cancer patients. Serum calcium was measured in 192 patients. The presence of hypocalcemia and hypercalcemia was related with baseline biochemical and clinical characteristics and the role of these two calcium disturbances in predicting prognosis and adverse skeletal-related events (SREs) was assessed. As compared to normocalcemic patients, hypocalcemic patients (n=51) had higher tumor load in bone (P=0.005), higher plasma chromogranin A (CgA, P=0.01), serum alkaline phosphatase (P=0.01), urinary N-telopeptide (NTX, P=0.002) and lower hemoglobin values (P=0.01), while hypercalcemic patients (n=16) had higher plasma CgA (P=0.001) and serum lactate dehydrogenase values (P=0.001), higher bone pain (P=0.003) and a lower frequency of pure osteoblastic lesions (P=0.001). Hypercalcemia was significantly associated with poor prognosis: hazard ratio (HR), 1.9 (95% confidence Interval (CI) 1.2-3.3) and higher risk to develop SREs HR, 2.5 (95% CI 1.2-5.2, P=0.01), while hypocalcemia was not associated with poor prognosis. The prognostic role of hypercalcemia was maintained in multivariate analysis after adjusting for validated prognostic parameters: HR, 2.72 (95% CI 1.1-6.8, P=0.03). These data suggest that serum calcium levels should be taken into account in the clinical decision-making process of bone metastatic prostate cancer patients. Patients with asymptomatic hypercalcemia could benefit of a strict follow-up and an immediate bisphosphonate treatment. Further prospective clinical trials are needed to confirm this finding.

Predictive factors for skeletal complications in hormone-refractory prostate cancer patients with metastatic bone disease.

Factors predictive of skeletal-related events (SREs) in bone metastatic prostate cancer patients with hormone-refractory disease were investigated. We evaluated the frequency of SREs in 200 hormone-refractory patients consecutively observed at our Institution and followed until death or the last follow-up. Baseline parameters were evaluated in univariate and multivariate analysis as potential predictive factors of SREs. Skeletal-related events were observed in 86 patients (43.0%), 10 of which (5.0%) occurred before the onset of hormone-refractory disease. In univariate analysis, patient performance status (P=0.002), disease extent (DE) in bone (P=0.0001), bone pain (P=0.0001), serum alkaline phosphatase (P=0.0001) and urinary N-telopeptide of type one collagen (P=0.0001) directly correlated with a greater risk to develop SREs, whereas Gleason score at diagnosis, serum PSA, Hb, serum albumin, serum calcium, types of bone lesions and duration of androgen deprivation therapy did not. Both DE in bone (hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.07-1.25, P=0.000) and pain score (HR: 1.13, 95% CI: 1.06-1.20, P=0.000) were independent variables predicting for the onset of SREs in multivariate analysis. In patients with heavy tumour load in bone and great bone pain, the percentage of SREs was almost twice as high as (26 vs 52%, P<0.02) and occurred significantly earlier (P=0.000) than SREs in patients with limited DE in bone and low pain. Bone pain and DE in bone independently predict the occurrence of SREs in bone metastatic prostate cancer patients with hormone-refractory disease. These findings could help physicians in tailoring the skeletal follow-up most appropriate to individual patients and may prove useful for stratifying patients enrolled in bisphosphonate clinical trials.

Prospective evaluation of high-dose ifosfamide-related nephrotoxicity in young adult patients with recurrent osteosarcoma previously treated with cisplatin, methotrexate and standard-dose ifosfamide.

A prospective evaluation of high-dose ifosfamide (IFO)-related nephrotoxicity in adults and young adults previously treated with cisplatin, methotrexate (MTX) and standard-dose IFO was performed. Eighteen patients (median age 22) with recurrent osteosarcoma were studied: 11 were pretreated with MTX, cisplatin and standard-dose IFO, and seven with MTX and cisplatin. The treatment was comprised of four cycles of high-dose IFO (15 g/m2 over 5 days CI) and mesna at equivalent dose with granulocyte colony stimulating factor support. Renal function was assessed before treatment, after each IFO cycle and after chemotherapy completion. Acute nephrotubular damage was always observed after each IFO cycle with significant changes of renal tubular enzymes N-acetyl-beta-D-glucosaminidase, alanine aminipeptidase, urinary excretion and reduction of tubular reabsorption of phosphate. The appearance of glycosuria was related to the cumulative dose received. Transient and reversible renal tubular acidosis was observed in three patients. WHO grade I renal toxicity was observed in two patients. After chemotherapy completion, persistent mild glomerular and nephrotubular impairment was observed in one patient who had also received aminoglycoside antibiotics due to febrile neutropenia. Persistent and mild glycosuria was documented in another patient. No significant changes compared to baseline values were observed in the remaining patients. We conclude that a chemotherapy regimen with high-dose IFO in young adults pretreated with MTX, cisplatin and standard-dose IFO is feasible with a mild, usually reversible, nephrotoxicity.

Methotrexate-induced pneumonitis in patients with rheumatoid arthritis and psoriatic arthritis: report of five cases and review of the literature.

Pneumonitis is emerging as one of the most unpredictable and potentially serious, adverse effects of treatment with MTX. Its prevalence in rheumatoid arthritis (RA) has been estimated from several retrospective and prospective studies to range from 0.3% to 18%. On the other hand, MTX-induced pneumonitis seems to be very rare in psoriatic arthritis (PsA). Our review of 194 RA patients and 38 PsA patients receiving MTX has identified four RA patients and one PsA patient with MTX-induced pneumonitis, giving a prevalence of 2.1% and 0.03%, respectively. Diagnosis was suggested by clinical history and radiographic findings, but the bronchoalveolar lavage plays an important role both in excluding infectious agents and in providing information for understanding the pathogenesis of lung injury. The presence of a lymphocyte alveolitis with a predominance of CD4+ T cells in 3 RA patients and CD8+ T cells with a concomitant increase in neutrophils in another case suggests that immunologically mediated reactions may be one damage mechanism in MTX-induced pneumonitis. Although risk factors for MTX-induced pulmonary toxicity are poorly understood, the presence in 3 out of 5 of our patients of pre-existing lung disease, represented by diffuse interstitial changes on chest X-ray, and mild bronchial asthma in two RA patients and by pulmonary silicosis in the patient with PsA may account for a predisposition to the development of MTX pneumonitis.