E23K, a common single nucleotide polymorphism in K IR 6.2, the pore-forming subunit of pancreatic ␤-cell ATP-sensitive K ؉ channels, significantly enhanced open probability of these channels, thus reducing their sensitivity toward inhibitory ATP 4؊ and increasing the threshold concentration for insulin release. Previous association studies and high allelic frequency suggest this effect to critically inhibit secretion and play a major role in pathogenesis of common type 2 diabetes. Based on evidence for functional relevance of E23K in both the heterozygous (E/K; with E in position 23 of K IR 6.2 in one allele and K in the other) and homozygous (K/K; with K in position 23 of K IR 6.2 in both alleles) genotype, we propose a model in which enhanced susceptibility to type 2 diabetes is associated with evolutionary advantage of the E/K state. Diabetes 51:875-879, 2002 T ype 2 diabetes is generally perceived as a polygenic disorder, with disease development being influenced by both hereditary and environmental factors (1). Genes encoding for key components of insulin secretion and glucose metabolism pathways have been widely considered as targets for defects in type 2 diabetes. However, despite intensive investigations, little progress has been made in identifying the genes that impart susceptibility to the common late-onset forms of the disease (2).In pancreatic ␤-cells, ATP-sensitive K ϩ (K ATP ) channels critically control insulin secretion by coupling metabolism to electrical activity (3). Recent advances resulted in cloning of these channels and elucidation of their subunit composition (4). The ␤-cell channels are assembled, with tetradimeric stoichiometry, from two structurally distinct subunits: an inwardly rectifying K ϩ channel subunit (K IR 6.2), forming the pore, and the regulatory sulfonylurea receptor subunit-1 (SUR1). While hypoglycemic sulfonylureas (e.g., glibenclamide) exert their effects on channel activity by interaction with SUR1, there is strong evidence that the receptor site for inhibitory ATP 4Ϫ is formed by K IR 6.2.Three common missense single nucleotide polymorphisms (SNPs) have been observed in K IR 6.2 (E23K, L270V, and I337V) (5-9), and their potential impact in type 2 diabetes led us to analyze their functional relevance. Whereas L270V and I337V were without effect on the properties of reconstituted human SUR1/K IR 6.2 channels (including expression rate, single channel conductance, spontaneous open probability [P O ], and nucleotide and drug sensitivities [results not shown]), E23K markedly affected channel gating, significantly reducing the time spent in long interburst closed states (17 Ϯ 3% for SUR1/ the mutant isoform of K IR 6.2 with K instead of E in position 23 [K IR 6.2 E23K ] vs. 54 Ϯ 6% for wild-type channels, n ϭ 10 each, P Ͻ 0.001) (Fig. 1A and B), thus producing a 1.6-fold increase of P O (P O ϭ 0.66 Ϯ 0.05 for SUR1/ K IR 6.2 E23K vs. 0.41 Ϯ 0.04 for wild-type channels, n ϭ 10 each, P Ͻ 0.001). The increase of P O was confirmed by noise analysis (patches with 100 -500 chann...

In the European Intergroup EURO-LB02 trial, children and adolescents with lymphoblastic lymphoma underwent the non-Hodgkin lymphoma Berlin-Frankfurt-Münster protocol without prophylactic cranial radiotherapy. The primary aims of this trial were to test whether replacing prednisone with dexamethasone during induction increases event-free survival in the subgroups with T-cell lymphoblastic lymphoma and whether therapy duration could be reduced from 24 to 18 months (factorial design, randomizations). These questions could not be answered due to premature closure of the trial. Here we report on the secondary aims of the trial: whether the results of the NHL-BFM90 study could be reproduced and evaluation of disease features and prognostic factors. Three hundred and nineteen patients (66 with precursor B-cell lymphoblastic lymphoma, 233 with T-cell lymphoblastic lymphoma, 12 with mixed phenotype, 8 not classifiable) were enrolled. In induction, 215 patients received prednisone and 104 patients received dexamethasone. The median follow-up was 6.8 years (range, 3.0–10.3). The 5-year event-free survival was 82±2% [12 toxic deaths, 5 secondary malignancies, 43 non-response/relapse (central nervous system n=9; all received prednisone during induction)]. The event-free survival rate was 80±5% for patients with precursor B-cell lymphoblastic lymphoma, 82±3% for those with T-cell lymphoblastic lymphoma, and 100% for patients with a mixed phenotype. During induction, significantly more grade III/IV toxicities were observed in patients receiving dexamethasone, resulting in significant treatment delays. The number of toxic deaths did not differ significantly. The only variable associated with outcome was performance status at diagnosis. The 90% event-free survival rate for patients with T-cell lymphoblastic lymphoma shown in study NHL-BFM90 was not replicated, mainly due to more toxic deaths and central nervous system relapses. Dexamethasone in induction may prevent central nervous system relapse more effectively than prednisone but produces a higher burden of toxicity. (#NCT00275106).

No abstract

Summary Children with chromosomal instability syndromes have an increased risk of developing lymphoma and leukaemia. The treatment of these malignancies is hampered by therapy‐associated toxicity and infectious complications. This retrospective analysis evaluated the therapy outcome of 38 children with Ataxia teleangiectasia or Nijmegen‐breakage syndrome with acute lymphoblastic leukaemia (ALL, n = 9), Non‐Hodgkin lymphoma (NHL, n = 28) and Hodgkin lymphoma (HL, n = 1). All patients with NHL or ALL were treated in accordance to Berlin‐Frankfurt‐Münster (BFM)‐ or Co‐operative study group for childhood ALL (CoALL)‐oriented chemotherapy schedules. 22 patients received significantly reduced‐intensity chemotherapy. After a median follow‐up of 3·7 years the 10‐year overall survival was 58%. Dosage‐reduction of chemotherapeutic drugs seemed to have no disadvantages and reduced toxic side effects. On the other hand, reduced‐intensity chemotherapy did not prevent second malignancies, which occurred in ten patients with a 10‐year incidence of 25%. After individual treatment approaches three of these patients with second malignancies were in complete clinical remission for more than 5 years. We conclude that BFM‐ or CoALL‐oriented chemotherapy is effective and can be administered in children with AT or NBS. Moreover, we show that even second lymphoid malignancies can successfully be treated in these patients.

Marginal zone lymphomas of MALT type comprise a considerable group of indolent B-cell non-Hodgkin lymphoma (NHL) in adult patients. In childhood, however, these tumors are extremely rare, as nearly all pediatric patients have aggressive NHL. Among 2,703 children and adolescents registered into the prospective multicenter NHL-BFM treatment studies since 1986, only 4 patients (0.1%) displayed features of MALT lymphoma. These tumors were localized in the stomach, breast, lower lid, and conjunctiva, respectively and they were associated with H. pylori infection in two patients. All children are alive but long-term follow-up will be mandatory to assess the behavior of MALT lymphoma in this age group.