A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia ofinfancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose <0 5 mmolIl). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95°/0 pancreatectomy was performed and histological 'nesidioblastosis' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic 1 cells characterised the ionic basis for insulin secretion in nesidioblastosis. The 1 cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3-5 to 4-8 mmoVI and increased in duration the child's tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control ofinsulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.

The purpose of this study was to investigate whether detectable protein biomarker overexpression is a prerequisite for the presence of increased gene copy number or activating mutations and responsiveness to the epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib in patients with lung adenocarcinomas. EGFR status was prospectively analyzed in tumor biopsy samples by three methods: protein expression (n = 117) by standardized immunohistochemistry (IHC), gene copy number (n = 97) by fluorescent in situ hybridization (FISH), and mutation analysis by sequencing (n = 126). Fifty-nine percent of the samples were positive by IHC, 40% were positive by FISH, and 13.5% contained activating kinase domain mutations. Thirty-four percent of the FISH-positive and 27% of the mutant samples were also IHC-negative. All EGFR mutant patients had major clinical responses (five complete response and five partial response) to gefitinib or erlotinib treatment, although three of these tumors were IHC-negative and four were FISH-negative. In a retrospective analysis of samples from nine patients with excellent therapeutic responses (three complete response, five partial response, one stable disease) to erlotinib or gefitinib, mutations were identified in eight cases, but IHC was negative in four of these tumors. These results indicate that molecular diagnostic methods appear to be most important for the identification of lung adenocarcinoma patients who may benefit from EGFR inhibitor treatments.

Cancer chemotherapy started with the discovery of the cytostatic effect of N-mustard and its derivatives more than five decades ago. This observation opened the way for the synthesis of various alkylating agents, antimetabolites and antimitotics expliciting antitumour activity against several human malignancies. The considerable toxicity of these drugs however, limited their application and only hormone-active products were relatively well tolerated. Besides, the majority of human malignant tumours proved to be chemoresistant. Consequently, there was still an urgent need for finding less toxic compounds possessing broader antitumour spectrum. Therefore, it became obvious that better understanding of the cellular metabolism - due to revolution in molecular biology - yielded new targets for cancer chemotherapeutic agents. Key enzymes active in signal transduction pathways could be blocked by new substances. Cell cycle control could be influenced by apoptosis inducers. Mitotic division could be inhibited by antitubulin agents. Multidrug resistance (MDR) could be modified by revertants. New concepts also emerged: a) chemoprevention, which is based on the principle, that since carcinogenesis is a genetically determined, progressive multistep process it can timely be reconverted into the direction of normal cellular metabolism by redifferentiating agents; b) antimetastatic therapy: originally performed postoperatively as an adjuvant therapy nowadays before surgical intervention, in order to block vascular dissemination of tumor cells (neoadjuvant therapy); c) antiangiogenic therapy: substances capable to hinder the vessel production essential for the development of metastasis; d) antitelomerase molecules inhibiting the immortal division capacity of DNA in malignant cells. All these new research approaches necessitate to review the existing drugs which are in clinical use or are investigational agents against human malignancies.

A boy aged 21 months who was being investigated for developmental delay and failure to thrive was found to have punctate epiphyseal calcification. He had no evidence of rhizomelic shortening of the limbs or cataracts. Investigation revealed defective plasmalogen synthesis due to isolated deficiency of dihydroxyacetonephosphate acyltransferase (DHAP-AT). The parents were consanguineous and a sister was similarly affected, suggesting autosomal recessive inheritance. Hitherto, recessively inherited isolated DHAP-AT deficiency has only been described in patients with a phenotype similar to that of rhizomelic chondrodysplasia punctata. This report indicates that the same biochemical disorder can be associated with a less severe phenotype.

DLTs included neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The MTD was 4.8 mg/m(2). The recommended phase II study dose of TZT-1027 is 4.8 mg/m(2) administered every 3-4 weeks.