Results of surgical treatment of neonatal necrotizing enterocolitis.

In 6 years, 74 neonates were treated for necrotizing enterocolitis, 40 (54 per cent) of whom underwent operation. The early postoperative mortality rate was 23 per cent and there was one late death. Of the 30 postoperative survivors, two have short bowel syndrome, two have chronic respiratory disease, two are partially sighted, and five (17 per cent) have severe developmental delay. Only 15 (50 per cent) survivors enjoy good health.     

Phase I trial of ZD9331, a nonpolyglutamatable thymidylate synthase inhibitor, given as a 5-day continuous infusion to patients with refractory solid malignancies.

PURPOSE: This dose-escalating study investigated the toxicity, pharmacokinetics, and efficacy of the novel direct-acting antifolate ZD9331, given as a 5-day i.v. infusion every 3 weeks. EXPERIMENTAL DESIGN: Forty-five patients with refractory solid malignancies received ZD9331, which was escalated from 0.125 mg/m(2)/day. RESULTS: Dose-limiting grade 4 thrombocytopenia occurred in 3 of 6 patients treated at 8 mg/m(2)/day; other drug-related toxicities, across dose levels, included skin and gastrointestinal toxicity, lethargy, and asymptomatic, reversible, elevated transaminases. The maximum plasma concentration and area under the curve increased with dose. Clearance was dose-dependent and predominantly renal. At doses >/=2.4 mg/m(2)/day, plasma 2'-deoxyuridine levels were elevated consistently indicating inhibition of thymidylate synthase. Two patients had a partial response (breast, 1 patient; ovarian, 1 patient), and 10 patients had stable disease. CONCLUSION: The maximum tolerated dose was defined as 6 mg/m(2)/day, and the toxicity profile for this regimen was considered acceptable and manageable. Administration of ZD9331 lead to elevation of 2'-deoxyuridine levels, signifying thymidylate synthase inhibition, and evidence of antitumor activity was observed.     

A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717

CB3717 is a quinazoline antifolate whose cytotoxic activity is mediated by inhibition of thymidylate synthase (TS). A phase I clinical trial commenced in September 1981 and 99 patients have received 296 treatments. Doses were dissolved in 0.15 mol/L NaHCO3 (pH 9.0) at a concentration of 4 mg/mL infused over one hour or in a total volume of 1 L infused over 12 hours. Doses were repeated every 3 weeks. The starting dose of 140 mg/m2 was escalated to 600 mg/m2. Renal toxicity, detected by a decrease in the 51Cr EDTA clearance, was dose-related and occurred in seven of ten patients receiving greater than 450 mg/m2. Reversible hepatic toxicity often associated with malaise occurred in 223 of 288 assessable courses (77%). Fifty-nine courses (20%) were associated with increases in alanine transaminase (ALT) levels to greater than 2.5 times the upper limit of the normal laboratory range. Increases in alkaline phosphatase levels also occurred, but were less marked. The severity and prevalence of these elevations were unaffected by the duration of the infusion. A self-limiting rash appeared in 12 patients and a radiation recall reaction was seen in two. Leukopenia developed in 17 patients (WBC less than 3 X 10(9)/L), and thrombocytopenia occurred in six patients (platelets less than 100 X 10(9)/L). The mean leucocyte nadir occurred on day 10 and was followed by recovery at 11 to 19 days. Neither the incidence nor the severity of any of these latter toxicities was dose related. The maximum tolerated dose was in the region of 600 mg/m2 with renal toxicity being dose limiting, although the inter-patient variation did not allow a precise definition. Seventy-six patients were evaluable for response. Responses occurred at doses greater than or equal to 200 mg/m2 and were ovary, one complete response (CR), one partial response (PR), seven minor responses (MR) in 30 cases; breast, two PRs and one MR in eight cases; adenocarcinoma of the lung, one MR in 5 cases; mesothelioma, one PR in five cases; and colon, two MRs in four cases. CB3717 has activity in heavily pretreated patients. The recommended phase II dose for good-risk patients is 400 mg/m2 using the one-hour infusion schedule of administration.     

Cohort profile: The QSkin Sun and Health Study

The QSkin Sun and Health Study comprises a cohort of 43 794 men and women aged 40-69 years randomly sampled from the population of Queensland, Australia in 2011. The cohort was established to study the development of skin cancer and melanoma in the population with the highest reported incidence of these diseases in the world. At baseline, besides demographic items and general medical history, information about standard pigmentary characteristics (including hair and eye colour, freckling tendency, tanning ability and propensity to sunburn), past and recent history of sun exposure and sunburns, sun protection behaviours, use of tanning beds and history of skin cancer was collected by self-completed questionnaire. Participants have given their consent for data linkage to the universal national health insurance scheme and for linkage to cancer registries and pathology databases, thus ensuring complete ascertainment of all future skin cancer and melanoma occurrences and medical treatments and other cancer events. Linkage to these registers will occur at predetermined intervals. Approval to access QSkin data can be obtained on application to the study investigators and submission of a formal research plan that has previous approval from the human research ethics committee of the applicant's institution.     

Role of β-Adrenergic Receptor Subtypes in Lipolysis

In vitro lipolysis stimulated by low (-)-isopre-naline concentrations (30 nM) in epididymal white adipo-cytes from Sprague-Dawley rats was inhibited at least 60–80% by the specific ₁-antagonists LK 204-545 and CGP 20712A (1 M), suggesting that at these low (10 nM) concentrations of (-)-isoprenaline lipolysis was primarily (80%) but not solely mediated via ₁-adrenergic receptors. Low concentrations (100 nM) of (-)-noradrenaline and formoterol also confirmed a role for ₁-adrenergic receptors in mediating lipolysis at low concentrations of these agonists. At higher agonist concentrations, ₃-adrenergic receptors were fully activated and were the dominant -adrenergic receptor subtype mediating the maximum lipolytic response, and the maximum response was not affected by the ₁-antagonists, demonstrating that the ₃-receptor is capable of inducing maximum lipolysis on its own. Studies of lipolysis induced by the relatively ₂-selective agonist formoterol in the presence of ₁-blockade (1 M CGP 20712A) demonstrated the inability of the ₂-selective antagonist ICI 118-551 to inhibit the residual lipolysis at concentrations of ICI 118-551 1 M. Higher concentrations of ICI 118-551 inhibited the residual formoterol-induced lipolysis competetively, but with low affinity (500-fold lower than its ₂-adrenergic receptor pA ₂, 7.80 ± 0.21), suggesting that formoterol was not acting via ₂-adrenergic receptors. These data are consistent with ₁-adrenergic receptors playing an important role in lipolysis at physiological but not pharmacological concentrations of catecholamines and that ₂-adrenergic receptors play no obvious direct role in mediating -adrenergic receptor agonist-induced lipolysis in vitro. Finally, racemic-SR 59230A, unlike the pure (S, S)-isomer (a ₃-selective antagonist), was found to be a non-selective antagonist at the three -adrenergic receptor subtypes, showing that the other enantiomers have different selectivity.