A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial.

BACKGROUND: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. PATIENTS AND METHODS: Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. RESULTS: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. CONCLUSION: The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.

Bevacizumab is equally effective and no more toxic in elderly patients with advanced colorectal cancer: a subgroup analysis from the AGITG MAX trial: an international randomised controlled trial of Capecitabine, Bevacizumab and Mitomycin C.

BACKGROUND: In an ageing population, a greater proportion of geriatric patients will be considered for systemic chemotherapy. Colorectal cancer (CRC) is a common malignancy and will be a major health issue in geriatrics. We used the MAX population to investigate whether age affected the improved outcome found in CRC when bevacizumab is added to capecitabine chemotherapy. PATIENTS AND METHODS: MAX, a three arm study of Capecitabine (C) versus CBevacizumab (CB) versus CBMitomycin C (CBM), found an improvement in progression-free survival (PFS), with addition of B [+/- mitomycin C (MMC)] to C. This analysis assesses the effect of adding B (+/- MMC) to C on PFS, overall survival (OS), response rate (RR), toxicity and dose intensity in geriatric patients (age ≥ 75 years). RESULTS: Ninety-nine patients (21%) were aged 75-86 years. Baseline characteristics were well balanced. Eighty-eight per cent commenced C at the lower optional dose of 2000 mg/m(2)/day; days 1-14, q21 (61% for <75 years) and 88% were Eastern Cooperative Oncology Group 0-1. Co-morbidities were as expected in this population. The addition of B significantly improved PFS in geriatric patients(C 5.8 months versus CB 8.8 months, Hazard ratio (HR) 0.65 and C versus CBM 10.4 months HR 0.38). The interaction test for OS, RR and PFS revealed no impact of age. Dose intensity was maintained >90% in all patients. There were no major differences in toxicity patterns between age cohorts. CONCLUSIONS: Addition of B to C significantly improved PFS in this geriatric population, with similar benefits to those aged <75 years. Treatment was well tolerated with no signal of increased toxicity (including thromboembolism) when compared with those aged <75 years.

Sponges as sentinels: patterns of spatial and intra-individual variation in trace metal concentration.

If sponges are to be effective biomonitors we require a better understanding of the spatial scales over which metals vary in these organisms. We determined how concentration of Cd, Zn, Cu, Pb, Hg and Se varied over four spatial scales for two common estuarine sponge species in the Sydney region. We examined variability with a fully nested sampling design; between coastal lakes, within coastal lakes, between sponges and within sponges. Calculation of variance components confirmed that 'within-sponge' variation in Cd, Zn, Cu, Pb and Se concentrations were low (1-14%) relative to the two largest spatial scales (49-98%) examined. In contrast, Hg concentrations exhibited marked variability 'between-sponges' and were below detection at one location. There was little evidence that sponge size was a good predictor of metal concentration. Taken together, these outcomes confirm that fragments of these sponges could be successfully transplanted and therefore show promise as biomonitors of metal contamination.

The cloning and expression of the cDNA for ovine stem cell factor (kit-ligand) and characterization of its in vitro haematopoietic activity.

The cDNA encoding the soluble form of ovine stem cell factor (SCF) has been cloned and expressed. The soluble protein is predicted to be 165/166 amino acids in length, one more than the human and murine SCFs with which it shares 87% and 81% identity respectively. Ovine SCF has 98.5%, 95% and 91% identity with cattle, pig and dog SCF, respectively. The recombinant ovine (rov) SCF protein has been expressed in Chinese hamster ovary (CHO) cells, purified, and its biological activity on ovine bone marrow cells compared with that of interleukin 3 (rovIL-3), granulocyte-macrophage colony-stimulating factor (rovGM-CSF), interleukin 5 (rovIL-5), human macrophage colony-stimulating factor (M-CSF) and human erythropoietin (epo). On its own rovSCF supported the development of small numbers of neutrophil, macrophage, eosinophil, granulocyte-macrophage, mixed cell phenotype, haemopoietic blast cell and basophilic granular cell colonies in a soft agar clonogenic assay. In combination with each of the above cytokines rovSCF supported an increase in the number and size of the lineage-specific colony types that were stimulated by the other cytokines on their own. In an assay for precursors of multipotential colony-forming cells (multi-CFC), rovSCF in combination with rovIL-3 (but neither cytokine alone) supported the development of these early haematopoietic progenitor cells.

Comparison of injuries in elite senior and junior Australian football.

Three thousand and thirty one AFL and 1034 injuries in the VSFL U/18 competition were recorded by club doctors over the 1992, 1993 and 1994 seasons. Hamstring strains had the highest incidence (86.4 per 10,000 player hours) and prevalence (30.2 hours missed per 1000 hours) of any injury in the AFL, but were significantly less common in the U/18 competition. Other injuries which were common in both competitions were ankle sprains, thigh haematomas, concussion, groin strains and head lacerations. Injury prevalence was higher overall in the AFL, with lower limb muscle strains (hamstring, calf, quadriceps) being significantly more prevalent than in the U/18 competition. Injuries which were significantly more prevalent in the U/18 competition included stress fractures and concussion. Subsequent to this study, coaches and medical staff in the U/18 competition were made aware of the high risk of stress fractures in young footballers with heavy training loads. The AFL injury survey is ongoing and in the process of being computerised; risk factors for specific injuries with high rates are being studied further.

Implementing a community initiative for the prevention of injury on farms in New Zealand.

Among New Zealand occupational injuries, farm-related injuries are second only to forestry in importance. A three-year Farm Safety Study, funded by the Accident Rehabilitation and Compensation Insurance Corporation, researched the epidemiology of farm injury in New Zealand, the safety behaviour and attitudes of people living on farms and the international literature on farm safety strategies. The Farm Safety Study made funds and regional injury information available to a local farm women's network in Southland to initiate work on farm safety through a series of workshops. Evaluation indicated effective coverage of farm types and localities. Outcomes included increased safety awareness, suggestions for a range of individual, community and institutional strategies and proposals for a local fieldworker. Over half the women responding to an evaluation questionnaire reported taking specific action to make their own farm safer. This project indicates that linking integrated, locally based research with action by community groups can be an effective mechanism to advance change.

Trypsin fails as Australian snake bite cure.

Trypsin has been claimed a new and effective treatment for venomous snake bite. We found that significant inactivation of snake venom lethal potency occurred in vitro when trypsin was incubated with venom and subsequently injected into mice. Premixing of tiger snake venom (TSV) and trypsin just before injection did not significantly increase the survival rate of mice over that of controls injected with TSV alone. Trypsin injected 10 to 30 minutes after TSV injection did not increase the survival rate of mice compared with controls. Specific antivenom was effective as an antidote when there was a 10 minute delay after venom injection. There was varying susceptibility of different venoms to trypsin inactivation in vivo.

Effects of Australian Eastern brown snake (Pseudonaja textilis) venom on the ultrastructure of nerve terminals on the rat diaphragm.

Isolated rat phrenic nerve diaphragm preparations were exposed to the venom of the Eastern brown snake (Pseudonaja textilis). The venom increased the number of 'coated omega figures' in the axolemma of the nerve terminals. The number of synaptic vesicles appeared to be decreased. The increase in coated omega figures in the axolemma is either caused by neurotoxins in the venom slowing down synaptic vesicle recycling or, after binding to axolemmal receptor, being internalized by receptor-mediated endocytosis. Synaptic vesicle recycling and receptor-mediated endocytosis may be related processes in motor nerve terminals.

Ultrastructural effects of the venom of the small-scaled snake (Parademansia microlepidotus) on the nerve terminals of the rat diaphragm.

Venom of the small-scaled snake (Parademansia microlepidotus) causes a large increase in the number of coated omega figures inserted in the axolemma of nerve terminals. It also causes both a loss of synaptic vesicles and an increase in the number of neurofilaments in the nerve terminals. The actions of the venom are very similar to taipoxin, a pre-synaptic neurotoxin from the venom of the taipan (Oxyuranus scutellatus). The morphological changes in the nerve terminals caused by the small-scaled snake venom are not unusual and do not explain the extreme lethality of the venom.

Australia's potentially most venomous snake: Parademansia microlepidotus.

Studies on the venom of the small-scaled or fierce snake, Parademansia microlepidotus, suggested that its combination of high toxicity and relatively large venom yield make it the most venomous snake in Australia. The species is distinct from the taipan, but its venom is neutralized by taipan antivenom but not other monospecific antivenoms.

Pilocarpine delivery by hydrophilic lens in the management of acute glaucoma.

Patients with acute closed-angle glaucoma were treated with a hydrophilic contact lens saturated in 1, 4, or 8 per cent. pilocarpine or bt intensive 4 per cent. pilocarpine drops. The greatest hypotensive response was produced by the 1 per cent. presoaked lens and increased strength of soaking solution gave reduced response. Intensive drops gave the least response. In vitro studies show that the lens is effectively saturated after 2 hrs' soaking holds c. 700 mug. pilocarpine and yields almost all of the contained pilocarpine after 2 hrs' elution. The method of lens preparation is described and pharmaceutical studies confirm a shelf life of 4 months in a domestic refrigerator.

Human snake bite victims: the successful detection of circulating snake venom by radiommunoassay,.

A new solid-phase radioimmunoassay has been developed which allows positive identification of the type of snake venom in human tissue and fluids and its accurate quantitation. Tiger snake venom at a level of 210 ng/ml was detected post mortem in the serum of a child, and brown snake venom was detected in two adults bitten by unidentified snakes. Apart from forensic applications, the assay will be useful in studying clinical aspects of envenomation and the use of antivenenes.

A further study on the dietary-regulated biosynthesis of high-sulphur wool proteins.

When the diet of sheep is supplemented by the infusion of sulphur-containing amino acids or casein into the abomasum, the newly synthesized wool shows characteristic changes in its amino acid composition, with significant increases in cystine, proline and serine and decreases in aspartic acid and phenylalanine. This modification seems to be due entirely to an alteration in the overall composition of the high-sulphur proteins and to an increase in their proportion in the fibre. These variations are not the result of a change in the composition of individual proteins, but are due to alterations in their relative proportions and to the initiation of the synthesis of ;new' proteins, many of which are extremely rich in cystine. It is suggested that the heterogeneity of the high-sulphur proteins may be due, in part, to similar changes in composition caused by natural variations in the nutrition of sheep.