An open-label expanded-access trial of bendamustine in patients with rituximab-refractory indolent non-Hodgkin lymphoma or previously untreated chronic lymphocytic leukemia: BEND-ACT.

BACKGROUND: Bendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other agents in its class. Bendamustine is used as monotherapy or in combination with other agents to treat patients with non-Hodgkin lymphoma (nhl) and chronic lymphocytic leukemia (cll). METHODS: The prospective interventional open-label bend-act trial evaluated bendamustine in patients with rituximab-refractory indolent nhl (inhl) and previously untreated cll. Study objectives were to assess the safety and tolerability of bendamustine monotherapy and to provide patients with access to bendamustine before Health Canada approval. The study aimed to enrol up to 100 patients. All patients with inhl received an intravenous dose of bendamustine 120 mg/m(2) over 60 minutes on days 1 and 2 for up to eight 21- or 28-day treatment cycles. All patients with cll received an intravenous dose of bendamustine 100 mg/m(2) over 30 minutes on days 1 and 2 for up to six 28-day treatment cycles. RESULTS: Of 90 patients treated on study (16 with cll and 74 with inhl), 35 completed the study (4 with cll and 31 with inhl). The most common treatment-emergent adverse events (teaes) were nausea (70%), fatigue (57%), vomiting (40%), and diarrhea (33%)-mostly grades 1 and 2. Ondansetron was the most common supportive medication used in the patients (63.5% of those with inhl and 68.8% of those with cll). Neutropenia (32%), anemia (23%), and thrombocytopenia (21%) were the most frequent hematologic teaes, with neutropenia being the most common grade 3 or 4 teae leading to dose modification. Dose delays occurred in 28 patients (31.3%) because of grade 3 or 4 teaes, with a higher incidence of dose delays being observed in inhl patients on the 21-day treatment cycle than in those on the 28-day treatment cycle (50.0% vs. 24.1%). During the study, 33 patients (36.7%) experienced at least 1 serious adverse event, and 4 deaths were reported (all in patients with inhl). CONCLUSIONS: The type and frequency of the teaes reported accorded with observations in earlier clinical trials and post-marketing experiences, thus confirming the acceptable and manageable safety profile of bendamustine.

Phase I/II study of (131)I-MIBG with vincristine and 5 days of irinotecan for advanced neuroblastoma.

BACKGROUND: (131)I-metaiodobenzylguanidine (MIBG) is an active radiopharmaceutical in neuroblastoma. A previous study demonstrated that MIBG could be combined with vincristine and prolonged irinotecan, although 25% of first courses had grade 3 diarrhoea. The current phase I/II study evaluated MIBG with vincristine and 5 days of higher-dose irinotecan. METHODS: Patients 1-30 years old with advanced neuroblastoma were eligible. Patients received cefixime on days -1 to +6, irinotecan (50 mg m(-2) per dose IV) on days 0-4, vincristine (2 mg m(-2)) on day 0, MIBG (555 or 666 MBq kg(-1)) on day 1, and peripheral blood stem cells on day 13. UGT1A1 genotyping was performed in consenting patients. RESULTS: Thirty-two patients (12 phase I ; 20 phase II) received 42 courses. No dose-limiting toxicities were seen during dose escalation and the recommended administered activity was 666 MBq kg(-1). Myelosuppression and diarrhoea were the most common toxicities, with grade 3 diarrhoea in 6% of first courses. Patients homozygous for UGT1A1*28 had more grade 4 thrombocytopenia (80% vs 37%; P=0.14). Responses (five complete and four partial) occurred in 9 out of 32 (28%) patients. CONCLUSIONS: MIBG (666 MBq kg(-1)) with vincristine and this irinotecan schedule is tolerable and active, with less severe diarrhoea compared with a regimen using more protracted irinotecan.

131I-Metaiodobenzylguanidine therapy in children with advanced neuroblastoma.

Neuroblastoma is an aggressive childhood cancer, with a propensity for early widespread metastasis. Approximately 90% of tumors accumulate the norepinephrine analogue metaiodobenzylguanidine (MIBG) avidly, allowing the use of radiolabeled MIBG for targeted imaging and radiotherapy. After preclinical studies demonstrated activity of 131I-MIBG in models of neuroblastoma, clinical development of this agent ensued. Early clinical trials of 131I-MIBG in patients with relapsed or refractory neuroblastoma defined the toxicity profile of this agent, with myelosuppression as the main dose-limiting toxicity. Subsequent trials defined the activity of 131I-MIBG, with response rates of 20-40% in patients with relapsed or refractory disease. More recent clinical trials have tested 131I-MIBG in combination with chemotherapy or as a component of myeloablative therapies. Given the documented activity of 131I-MIBG, future studies will need to evaluate the impact of radiation sensitizers on this activity and define the role of this agent in treating patients with newly diagnosed high-risk neuroblastoma.

Rates and appropriateness of antimicrobial prescribing at an academic children's hospital, 2007-2010.

OBJECTIVE AND DESIGN: Antimicrobial use in hospitalized children has not been well described. To identify targets for antimicrobial stewardship interventions, we retrospectively examined pediatric utilization rates for 48 antimicrobials from 2007 to 2010 as well as appropriateness of vancomycin and cefepime use in 2010. PATIENTS AND SETTING: All children hospitalized between 2007 and 2010 at the Mayo Clinic Children's Hospital, a 120-bed facility within a larger adult hospital in Rochester, Minnesota. METHODS: We calculated antimicrobial utilization rates in days of therapy per 1,000 patient-days. Details of vancomycin and cefepime use in 2010 were abstracted by chart review. Two pediatric infectious disease physicians independently assessed appropriateness of antibiotic use. RESULTS: From 2007 to 2010, 9,880 of 17,242 (57%) hospitalized children received 1 or more antimicrobials. Antimicrobials (days of therapy per 1,000 patient-days) used most frequently in 2010 were cefazolin (97.8), vancomycin (97.1), fluconazole (76.4), piperacillin-tazobactam (70.7), and cefepime (67.6). Utilization rates increased significantly from 2007 to 2010 for 10 antimicrobials, including vancomycin, fluconazole, piperacillin-tazobactam, cefepime, trimethoprim-sulfamethoxazole, caspofungin, and cefotaxime. In 2010, inappropriate use of vancomycin and cefepime was greater in the pediatric intensive care unit than ward (vancomycin: 17.8% vs 6.4%, P = .001; cefepime: 9.2% vs 3.9%, P = .142) and on surgical versus medical services (vancomycin: 20.5% vs 8.0%, P = .001; cefepime: 19.4% vs 3.4%, P ≤ .001). The most common reason for inappropriate antibiotic use was failure to discontinue or de-escalate therapy. CONCLUSIONS: In our children's hospital, use of 10 antimicrobials increased during the study period. Inappropriate use of vancomycin and cefepime was greatest on the critical care and surgical services, largely as a result of failure to de-escalate therapy, suggesting targets for future antimicrobial stewardship interventions.

Up-regulation of liver glucose-6-phosphatase in x-linked hypophosphatemic mice.

We previously showed that a phosphate-deficient diet resulting in hypophosphatemia upregulated the catalytic subunit p36 of rat liver glucose-6-phosphatase, which is responsible for hepatic glucose production. A possible association between phosphate and glucose homeostasis was now further evaluated in the Hyp mouse, a murine homologue of human X-linked hypophosphatemia. We found that in the Hyp mouse as in the dietary Pi deficiency model, serum insulin was reduced while glycemia was increased, and that liver glucose-6-phosphatase activity was enhanced as a consequence of increased mRNA and protein levels of p36. In contrast, the Hyp model had decreased mRNA and protein levels of the putative glucose-6-phosphate translocase p46 and liver cyclic AMP was not increased as in the phosphate-deficient diet rats. It is concluded that in genetic as in dietary hypophosphatemia, elevated glucose-6-phosphatase activity could be partially responsible for the impaired glucose metabolism albeit through distinct mechanisms.

Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival.

PURPOSE: The goal of this study was to determine the incidence of metastatic sites in neuroblastoma and the extent to which metastatic sites correlate with age, tumor biology, and survival. PATIENTS AND METHODS: All 648 patients with stage IV and IVS neuroblastoma registered on Children's Cancer Group protocols 3881 and 3891 were analyzed. Metastatic site data were provided by treating institutions and reviewed in patients with central nervous system (CNS), intracranial, lung, or "other" metastases. RESULTS: The incidence of metastatic sites at diagnosis was 70.5% in bone marrow, 55.7% in bone, 30.9% in lymph nodes, 29.6% in liver, 18.2% in intracranial and orbital sites, 3.3% in lung, and 0.6% in CNS. Event-free survival (EFS) was decreased in patients with bone, bone marrow, CNS, intracranial/ orbital, lung, and pleural metastases, and improved in those with liver and skin metastases. In infants, MYCN amplification and unfavorable Shimada histopathology correlated with increased frequencies of bone and intracranial or orbital metastases. In older patients, MYCN amplification correlated with increased frequencies of intracranial or orbital, liver, and lung metastases. Multivariate analysis revealed that metastatic site is not an independent prognostic factor. CONCLUSIONS: Metastatic pattern in neuroblastoma differs with age and correlates with tumor biological features and EFS. These correlations could reflect changes in host or tumor biological features with age resulting in differences in metastatic capacity or tumor affinity for specific sites.

Alteration of human UDP-glucuronosyltransferase UGT2B17 regio-specificity by a single amino acid substitution.

The glucuronidation of steroid hormones is catalyzed by a family of UDP-glucuronosyltransferase (UGT) enzymes. Previously, two cDNA clones, UGT2B15 and UGT2B17, which encode UGT enzymes capable of glucuronidating C19steroids, were isolated and characterized. These proteins are 95% identical in primary structure; however, UGT2B17 is capable of conjugating C19steroid molecules at both the 3alpha and 17beta-OH positions, whereas UGT2B15 is only active at the 17beta-OH position. To identify the amino acid residue(s) which may account for this difference in substrate specificity, a comprehensive study on the role of 15 residues which differ between UGT2B15 and UGT2B17 was performed by site-directed mutagenesis. The stable expression of UGT2B17 mutant proteins into HK293 cells demonstrated that the mutation of isoleucine 125, valine 181 and valine 455 to the residues found in UGT2B15 did not alter enzyme activity nor substrate specificity. Furthermore, mutation of the variant residues in UGT2B15 (serine 124, asparagine 125, phenylalanine 165) to the amino acid residues found in UGT2B17 did not alter enzyme activity nor substrate specificity. However, mutation of the serine residue at position 121 of UGT2B17 to a tyrosine, as found in UGT2B15, abolished the ability of UGT2B17 to conjugate androsterone at the 3alpha position, but still retained activity for dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol, which have an OH-group at the 17beta position. Interestingly, mutation of tyrosine 121 in UGT2B15 to a serine abolished activity for C19steroids. It is suggested that the serine residue at position 121 in UGT2B17 is required for activity towards the 3alpha and not for the 17beta position of C19steroids, whereas the tyrosine 121 in UGT2B15 is necessary for UGT activity. Despite the high homology between UGT2B15 and UGT2B17, it is apparent that different amino acid residues in the two proteins are required to confer conjugation of C19steroid molecules.