Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients

OBJECTIVES: Our aim was to identify prognostic variables for long-term postoperative survival in trimodality management of malignant pleural mesothelioma. METHODS: From 1980 to 1997, 183 patients underwent extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy. RESULTS: Forty-three women and 140 men (age range 31-76 years) had a median follow-up of 13 months. The perioperative mortality rate was 3.8% (7 deaths) and the morbidity, 50%. Survival in the 176 remaining patients was 38% at 2 years and 15% at 5 years (median 19 months). Univariate analysis identified 3 prognostic variables associated with improved survival: epithelial cell type (52% 2-year survival, 21% 5-year survival, 26-month median survival; P =.0001), negative resection margins (44% at 2 years, 25% at 5 years, median 23 months; P =.02), and extrapleural nodes without metastases (42% at 2 years, 17% at 5 years, median 21 months; P =.004). Using the Cox proportional hazards, the relative risk of death was calculated for nonepithelial cell type (OR 3.0, CI 2.0-4.5; P <.0001), positive resection margins (OR 1.7, CI 1.2-2.6; P =.0082), and metastatic extrapleural nodes (OR 2.0, CI 1.3-3.2; P =.0026). Thirty-one patients with 3 positive variables had the best survival (68% 2-year survival, 46% 5-year survival, median 51 months; P =.013). A previously published staging system using these variables stratified survival (P <.05). CONCLUSIONS: (1) Multimodality therapy including extrapleural pneumonectomy is feasible in selected patients with malignant pleural mesotheliomas, (2) pre-resectional evaluation of extrapleural nodes may select patients for radical therapy, (3) microscopic resection margins affect long-term survival, highlighting the need for further investigation of locoregional control, and (4) patients with epithelial, margin-negative, extrapleural node-negative resection had extended survival.     

Cytochrome P450 3A4 activity in premenopausal and postmenopausal women, based on 6-beta-hydroxycortisol:cortisol ratios

STUDY OBJECTIVE: To characterize cytochrome P450 (CYP) 3A4 activity in premenopausal and postmenopausal women by evaluating the urinary 6-beta-hydroxycortisol:cortisol ratio. DESIGN: Prospective study SUBJECTS: Thirteen premenopausal and 13 postmenopausal women who were healthy and not receiving drugs known to affect CYP3A4 activity INTERVENTIONS: Beginning on day 2 of menses, premenopausal women collected first morning urine samples every other day for a complete menstrual cycle. Postmenopausal women collected first morning urine every other day for 28 days. MEASUREMENTS AND MAIN RESULTS: Mean weekly 6-beta-hydroxycortisol:cortisol ratios did not differ during the phase (week) of the menstrual cycle. Daily ratios did not differ in postmenopausal women. No difference between premenopausal and postmenopausal women was found on comparing overall median ratios. CONCLUSION: Cytochrome P450 3A4 activity as measured by 6-beta-hydroxy cortisol:cortisol ratio did not differ by week of menstrual cycle, suggesting no menstrual cycle-related changes. Menopause does not appear to be associated with differences in CYP3A4 activity, compared with premenopause.     

Homology modelling of two subtilisin-like proteases from the hyperthermophilic archaea Pyrococcus furiosus and Thermococcus stetteri

The hyperthermophilic archaeon Pyrococcus furiosus produces an extracellular, glycosylated hyperthermostable subtilisin-like serine protease, termed pyrolysin (Voorhorst,W.G.B., Eggen,R.I.L., Geerling,A.C.M., Platteeuw,C., Siezen,R.J. and de Vos,W.M. (1996) J. Biol. Chem., 271, 20426-20431). Based on the pyrolysin coding sequence, a pyrolysin-like gene fragment was cloned and characterized from the extreme thermophilic archaeon Thermococcus stetteri. Like pyrolysin, the deduced sequence of this serine protease, designated stetterlysin, contains a catalytic domain with high homology with other subtilases, allowing homology modelling starting from known crystal structures. Comparison of the predicted three-dimensional models of the catalytic domain of stetterlysin and pyrolysin with the crystal structure of subtilases from mesophilic and thermophilic origin, i.e. subtilisin BPN' and thermitase, and the homology model of subtilisin S41 from psychrophilic origin, led to the identification of features that could be related to protein stabilization. Higher thermostability was found to be correlated with an increased number of residues involved in pairs and networks of charge-charge and aromatic-aromatic interactions. These highly thermostable proteases have several extra surface loops and inserts with a relatively high frequency of aromatic residues and Asn residues. The latter are often present in putative N-glycosylation sites. Results from modelling of known substrates in the substrate- binding region support the broad substrate range and the autocatalytic activation previously suggested for pyrolysin.      

Some conclusions with regard to the safety assessment of cracked components drawn from the research programme “integrity of components” (FKS II) atthe present state

The continuation of the research program “Integrity of Components”, Phase II, mainly deals with further evaluation and assessment of material properties and the application of data from small standard specimens to large scale specimens and components. This includes the use of advanced numerical methods to check the transferability of fracture mechanics parameters with regard to the type of load and degree of multiaxiality on the failure behaviour of fracture mechanics specimens with component-like dimensions. Further points of interest are the relationship between upper shelf toughness and load-bearing capacity, the influence of neutron irradiation on the properties, and the effect of corrosion on cyclic crack growth.     

Environmentally assisted crack growth in a low alloy boiler steel in high temperature water containing oxygen

The crack growth behaviour of the higher strength steel 17 MnMoV 6 4 in deionized high temperature water containing oxygen was investigated with respect to static loading. The tests were performed in an autoclave testing facility at an oxygen content of 8 ppm, a pressure of 70 bar and a temperature of 240°C under quasi-stagnant flow conditions. The stress intensities at the beginning of the tests were 17, 20, 27, 34, 40 and 58 MPa√m. In contrast to the higher loaded specimens no evidence of environmentally assisted cracking was found at stress intensities of 17 and 20 MPa√m.The maximum crack growth rate in the range where only environmetally assisted cracking occured amounted to about 4 x 10^-5 mm/s. The critical stress intensity K_IJ for the onset of stable ductile crack growth in air is 100 MPa√m. On the basis of fractographic studies the crack development found can be ascribed to the “Strain Induced Corrosion Cracking (SICC)” mechanism. This mechanism, used as a working hypothesis, gives a satisfactory explanation for the occurence of stress corrosion cracking of unalloyed and low alloyed steels in high temperature water. SICC is particularly characterized by aggravated corrosive attack occuring as soon as the magnetite/haematite protective layer has been locally disturbed. The stress concentration then just becomes so great that in the region of the resulting crack tips, yield/creep deformation within the critical range of strain rates occurs.     

Development of alarm-call responses in Belding's ground squirrels: the role of dams

Experiences with adult conspecifics can influence the ontogeny of species-typical behaviours in naive young of many species. Two processes of influence, direct and indirect, are proposed to describe the effect of adult behaviours on juvenile development. In Belding's ground squirrels, Spermophilus beldingiexposure to adults experienced with responding to alarm calls may affect how juveniles respond to calls and/or the rate at which juveniles acquire adult-like responses to calls. Because dams and their juvenile offspring interact extensively during early development, the influence of dams on the ontogeny of juvenile alarm-call responses was investigated by conducting playbacks of alarm calls and non-alarm calls to captive ground squirrels. Juveniles were more likely to respond to auditory stimuli if their dam responded, but the responses of unrelated adult females did not influence juveniles. A dam's presence at the time of a playback had no consistent effect, however, on the type of initial response made by her juvenile, its response duration or the vigilance of its postures. The permanent absence of adult models (dams) after weaning appeared to delay the rate at which juveniles developed a discrimination between alarm calls and non-alarm calls, but had no long-term influence on juveniles' expression of responses. Thus, dams indirectly influenced juvenile response development by acting as models of species-typical responses. The outcome of dams' influence was facilitative rather than inductive, because exposure to dams affected the rate of response development but was not necessary for juveniles to acquire alarm-call responses.1997The Association for the Study of Animal Behaviour