Concurrent cisplatin, prolonged oral etoposide, and vincristine plus chest and brain irradiation for limited small cell lung cancer: a phase II study of the Southwest Oncology Group (SWOG-9229)

PURPOSE: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. METHODS AND MATERIALS: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m2 (days 1-14, 29-42, and 57-70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. RESULTS: Among 56 eligible patients, 93% had SWOG performance status 0-1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimum follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3). CONCLUSION: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.     

25 years of aortic valve replacement using mechanical valves. Risk factors for early and late mortality

This study describes the changes that have taken place in patient characteristics in 25 years of aortic valve replacement using mechanical valves, and looks for risk factors for early and late mortality. During this period, 1449 mechanical valves were implanted. Overall early mortality (< 30 days) was 5.3% and for aortic valve replacement without concomitant procedures 3.9%. Overall survival rates at 5, 10 and 15 years were 80%, 63% and 49%, respectively. Despite an increased proportion of higher risk patients (older age, more reoperations, more concomitant coronary bypass surgery) survival rates improved throughout the study period. Early mortality was related to an early year of operation, urgency, reoperation and concomitant surgery to the tricuspid valve or ascending aorta. Late mortality was higher for patients of older age, with an early year of operation, male gender, concomitant coronary bypass surgery, mitral valve surgery or replacement of the ascending aorta. Aortic regurgitation did not have a major influence on early nor late mortality. The improvement in early and late mortality in more recent years was largely the result of the introduction of cardioplegia. A changing, non-proportional effect was observed for several risk factors during the follow-up period. This study illustrates the changes and improvements in medical care that have taken place in patients requiring aortic valve replacement.     

Human liver CYP2B6-catalyzed hydroxylation of RP 73401

RP 73401 is a potent inhibitor of cyclic nucleotide phosphodiesterase type IV. RP 73401 is metabolized by human liver microsomes almost exclusively by transhydroxylation of the cyclopentyl group to RPR 113406. Liquid chromatography/mass spectrometry/mass spectrometry analysis of plasma from patients given RP 73401 also revealed a molecular ion and fragmentation consistent with RPR 113406. Thus, the objective was to determine the oxidative enzyme(s) responsible for RP 73401 hydroxylation. Kinetic constants of RP 113406 formation ranged from 8 to 26 MM and 0.83 to 5.99 nmol/min/mg protein for K(m) and V(max), respectively (n = 3). Enzyme activity varied 23-fold among 15 human liver microsome samples and correlated with CYP2A6-catalyzed coumarin hydroxylase (r2 = 0.85, P < .01) and CYP2B6-catalyzed 7-ethoxytrifluoromethylcoumarin O-deethylase (r2 = 0.82, P < .01) activities. Chemical inhibition studies showed a 63% decrease in RP 73401 hydroxylation by 500 microM orphenadrine. Coumarin (10 microM), however, did not inhibit RP 73401 hydroxylation. Also, anti-CYP2B1 IgG produced 85% inhibition of RP 73401 hydroxylation, but only a negligible decline in coumarin hydroxylase activity. Of the 10 expressed P450 forms studied, only CYP2B6 catalyzed RP 73401 hydroxylation. Finally, expressed CYP2B6 showed a high affinity (K(m) = 22.5 microM) for RP 73401 hydroxylation, similar to the human liver microsome studies.     

Phylogenetic relationships of Australian strongyloid nematodes inferred from ribosomal DNA sequence data

The sequence of the second internal transcribed spacer of the ribosomal DNA was determined for the following strongyloid nematodes: Cylicocyclus insignis, Chabertia ovina, Oesophagostomum venulosum, Cloacina communis, Cloacina hydriformis, Labiostrongylus labiostrongylus, Parazoniolaimus collaris, Macropostrongylus macropostrongylus, Macropostrongylus yorkei, Rugopharynx australis, Rugopharynx rosemariae, Macropostrongyloides baylisi, Oesophagostomoides longispicularis and Paramacropostrongylus toraliformis, and compared with published sequences for species of Strongylus and for Hypodontus macropi. The resultant phylogenetic trees supported current hypotheses based on morphological evidence for the separation of the families Strongylidae and Chabertiidae, but did not support the separation of the endemic Australian genera as a distinctive clade within the Chabertiidae. The implications of this finding for the phylogenetic origins of the Australian strongyloids are discussed.     

Comparison of RDC, DSM-III, DSM-III-R diagnostic criteria for generalized anxiety disorder

The aim of the present study is to conduct an observation of a time series of job-event/life event and depressive symptoms, prospectively. Ten male computer software engineers were observed every two weeks for five months and every following week for two months. In total, one hundred and eighty-one observations were made. A semi-structured interview was conducted to survey the week-unit job-events on each sampling day. The depressive symptoms were measured using Zung's Self-reporting Depressive Scale (SDS). It was found that the events had a significant effect on the SDS raw score. It also showed that the effective time period of the events on depression is within two weeks. With a week-based analysis in a prospective approach, the present study showed the immediate effects of job events or life events on depressive symptoms.     

The influence of knowledge and attitudes about breast cancer on mammography use among Latinas and Anglo women

We conducted a telephone survey of randomly selected Latinas (n = 208) and Anglo women (n = 222) to determine predictors of mammography use. The cooperation rate was 78.5%. Relatively high proportions of Latinas (61%) and Anglo women (79%) reported mammography use within the past 2 years. A logistic regression analysis revealed that knowledge and attitudes did not independently predict use. On the other hand, having health insurance, being married, and being Latino were consistent independent predictors. We conclude that mammography use among Latinas and Anglo women is increasing. However, further gains in use must address difficult barriers such as lack of health insurance.