The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function.

Precursor T-cell acute lymphoblastic leukemia (T-ALL) remains an important challenge in pediatric oncology. Because of the particularly poor prognosis of relapses, it is vital to identify molecular risk factors allowing early and effective treatment stratification. Activating NOTCH1 mutations signify a favorable prognosis in patients treated on ALL-BFM protocols. We have now tested if NOTCH pathway activation at different steps has similar clinical effects and if multiple mutations in this pathway function synergistically. Analysis of a validation set of 151 T-ALL patients and of the total cohort of 301 patients confirms the low relapse rate generally and the overall favorable effect of activating NOTCH1 mutations. Subgroup analysis shows that the NOTCH1 effect in ALL-BFM is restricted to patients with rapid early treatment response. Inactivation of the ubiquitin ligase FBXW7 is associated with rapid early treatment response and synergizes with NOTCH1 receptor activation. However, the effect of FBXW7 inactivation is separable from NOTCH1 activation by not synergizing with NOTCH1 mutations in predicting favorable long-term outcome, which can probably be explained by the interaction of FBXW7 with other clients. Finally, the comparison with other European protocols suggests that the NOTCH effect is treatment dependent generally and may depend on the intensity of central nervous system-directed therapy specifically.

Hand-assisted laparoscopic donor nephrectomy. Ascending the learning curve.

BACKGROUND: The hand-assisted approach to laparoscopic donor nephrectomy (LDN) might minimize the learning curve and shorten both the operation and the warm ischemia time. Our initial results from hand-assisted LDN are presented and compared with data from the literature. METHODS: From January to September 2000, ten hand-assisted LDNs of the right kidney were performed. RESULTS: The median operation time was 140 min (range, 120-400 min), and the warm ischemia time was 2.5 min (range, 1-4 min). There were no conversions. Postoperative morbidity included one urinary tract infection. All but one patient returned to a normal diet within 48 h. Opiates were needed a maximum of 48 h. One recipient experienced initial loss of graft function as a result of unknown causes. CONCLUSIONS: Even at the beginning of the learning curve, operation time and warm ischemia time are significantly reduced by the hand-assisted approach, as compared with conventional LDN.

Peritoneal sclerosis in chronic peritoneal dialysis patients: analysis of clinical presentation, risk factors, and peritoneal transport kinetics.

OBJECTIVE: To analyze clinical features of peritoneal sclerosis (PS) in a group of peritoneal dialysis (PD) patients, and to compare potential risk factors and peritoneal transport characteristics with a control group matched for duration of PD. DESIGN: Study 1: Retrospective study of 16 PD patients with PS. Study 2: Case-control study comparing 10 patients with evident PS to 30 control patients who were matched for duration of PD. SETTING: Continuous Ambulatory Peritoneal Dialysis unit in the Academic Medical Centre in Amsterdam. RESULTS: The incidence of PS was 3.5 per 1000 patient years. PS was diagnosed either during PD (n = 10), in patients on hemodialysis (n = 2), or after successful transplantation (n = 4). Presenting symptoms were bowel obstruction, ascites, blood-stained effluent, and impaired net ultrafiltration. Macroscopic confirmation of the diagnosis was possible in 13 patients. Sclerotic encapsulation was present in 8 of them. Patients with PS were divided into three groups based on clinical symptoms and typical macroscopical findings. In category I the diagnosis PS was obvious (10 patients), in category II the diagnosis was highly suggestive (3 patients), and in category III it was doubtful (3 patients). Treatment was conservative in most patients. Surgical treatment was only possible in four and immunosuppressive therapy was given in 5 patients. Peritoneal sclerosis was the direct cause of death in 1 patient. Five patients died during follow-up due to other causes. At present, 7 patients are well and 3 patients (all from category I) still have recurrent bowel obstruction. Compared to matched controls, no difference existed in peritonitis incidence, or in the percentage of patients with former renal transplantations. The number of patients treated with beta-blocking agents and the number of previous abdominal surgeries were not different. The number of catheter-related surgical procedures was higher in the PS patients than in the control group. The mass transfer area coefficient (MTAC) of creatinine was higher in PS patients and net ultrafiltration with 1.36% glucose was lower. The estimated cumulative glucose exposure until the diagnosis of PS was made was larger in PS patients than in their controls. This difference was already present in the first year of PD treatment in 8 of 10 patients. The initial values for the MTAC creatinine were similar in both groups. CONCLUSIONS: The presenting symptoms of PS were bowel obstruction, ascites, and blood-stained effluent, often in combination with loss of net ultrafiltration. Peritoneal sclerosis is a complication of long-duration PD and could also become manifest after a successful renal transplant. Treatment should be conservative unless complications require surgical intervention. Patients with PS had lower net ultrafiltration and higher transport rates compared to controls who were matched for duration of PD. Although peritonitis incidence was similar, a relation of PS with severe peritonitis may be present in some patients. Glucose exposure is likely to be an important risk factor for PS.