A phase I study of SR-4554 via intravenous administration for noninvasive investigation of tumor hypoxia by magnetic resonance spectroscopy in patients with malignancy.

PURPOSE: To perform a Phase I study of SR-4554, a fluorinated 2-nitroimidazole noninvasive probe of tumor hypoxia detected by (19)F magnetic resonance spectroscopy (MRS). EXPERIMENTAL DESIGN: SR-4554 administration, on days 1 and 8, was followed by plasma sampling for pharmacokinetic studies and by three MRS studies performed over 24 h on days 8 and 9. Unlocalized MR spectra were acquired from tumor (10- or 16-cm dual resonant 1H/19F surface coil; 1.5 T Siemens Vision MR system; 2048 transients acquired over 34 min; 1.28-ms adiabatic pulse; repetition time, 1 s). Plasma drug concentrations were measured with a validated high-performance liquid chromatography method. Noncompartmental pharmacokinetic analysis was performed. RESULTS: Eight patients underwent pharmacokinetic studies, receiving doses of SR-4554 of 400-1600 mg/m(2). Peak plasma concentrations increased linearly with the SR-4554 dose (r(2) = 0.80; P = 0.0002). The plasma elimination half-life was relatively short (mean +/- SD, 3.28 +/- 0.59 h), and plasma clearance was quite rapid (mean +/- SD, 12.8 +/- 3.3 liters/h). Urinary recovery was generally high. SR-4554 was well tolerated. A single patient experienced dose-limiting toxicity (nausea and vomiting) at 1600 mg/m(2). The maximum tolerated dose was 1400 mg/m(2). SR-4554 was detected spectroscopically in tumors immediately after infusion at doses of 400-1600 mg/m(2). At the highest dose (1600 mg/m(2)), SR-4554 was detectable in tumor at 8 h, but not at 27 h. CONCLUSIONS: SR-4554 has plasma pharmacokinetic and toxicity profiles suitable for use as a hypoxia probe. It can be detected in tumors by unlocalized MRS. Additional clinical studies are warranted.     

Molecular Genetics in the Diagnosis and Prognosis of Solid Pediatric Tumors

The field of molecular genetics continues to see an ever increasing number of applications to pediatric tumor analysis. Studies in pediatric tumors have identified novel genes and other genetic changes, a large number of which reflect one of the following mechanisms: (1) activation of proto-oncogenes; (2) loss of tumor suppressor genes; or (3) creation of novel fusion proteins. At least one of these mechanisms is operational in each of the following pediatric tumors: neuroblastoma, Ewing sarcoma and peripheral primitive neuroectodermal tumor (pPNET), intra-abdominal desmoplastic small-cell tumor, rhabdomyosarcoma, synovial sarcoma, and Wilms tumor. Out of this research has come not only an increased understanding of oncogenesis but also, for each of the tumors listed above, diagnostic and/or prognostic markers that can be used by the pathologist and oncologist to improve overall patient management. Received November 20, 1997; accepted April 20, 1998.     

The validity of continuous automated fluid monitoring during endometrial surgery: luxury or necessity?

Thirty-four consecutive women undergoing endometrial laser ablation, as a treatment of menorrhagia, were recruited to assess the validity of fluid absorption monitoring by a new continuous automated system (AquaSens). The same group of women also had monitoring of fluid absorption carried out by our standard technique of weighing. The intra-class correlation coefficient for the fluid deficit estimated by AquaSens compared to our standard technique of manually weighing the irrigation bags was 0.98 (95% CI 0.96–0.99). Aquasens therefore provides a valid and non-invasive method of continuously monitoring fluid deficit amongst patients undergoing operative hysteroscopy procedures, thereby reducing the risk of unexpected fluid absorption and its potentially fatal sequelae.     

Serial Transvaginal Ultrasonography Following McDonald Cerclage and Repeat Suture Insertion

Summary: The aim of this study was to explore the hypothesis that serial transvaginal ultrasonography identifies early evidence of suture failure and that repeat cerclage delays delivery. We undertook a review of our policy of transvaginal ultrasonographic cervical surveillance after McDonald cerclage and of repeat suture insertion if persistent cervical effacement developed. Data from 26 pregnancies in 26 women are analyzed. The women had had a total of 57 mid-trimester miscarriages with a median of 2 (1–6) mid-trimester losses per woman. Twelve (46%) of the 26 women developed cervical changes at scan and underwent repeat cerclage. All 14 women who had a single suture inserted progressed to live births but 1 of the 13 women who had repeat cerclage had a mid-trimester miscarriage (p>0.05). The median gestation at delivery for the women who had repeat cerclage was 35 (22–39) weeks compared with 38 (36–40) weeks for those who had a single suture (p>0.05). The median interval from the detection of cervical changes at scan to delivery was 13 (4–19) weeks. Serial transvaginal ultrasonography after cervical cerclage identifies a group of women who are more likely to deliver preterm, and provides an opportunity for intervention (repeat cerclage) which appears to delay delivery by an average of 7 weeks.     

Effects of conjugated linoleic acid supplementation on blood lipids and adiposity of rats fed diets rich in saturated versus unsaturated fat

Conjugated linoleic acid (CLA) may decrease adiposity and improve blood lipid profiles under some conditions. The goal of this study was to determine the effects of CLA supplementation on blood lipid profiles and adiposity of rats fed a diet containing a primarily saturated fat versus a diet containing a primarily unsaturated fat. Twenty-eight male Sprague-Dawley rats were randomly assigned to one of four diets containing coconut oil, coconut oil with CLA, corn oil or corn oil with CLA. After 28 days, blood was collected and serum concentrations of total cholesterol (TC), HDL-cholesterol (HDL-C), and triacylglycerols (TG) were assessed. Food intake, body weights, and epididymal fat pads were measured. No significant differences (p>0.05) were noted among groups for amount of food consumed, weight gained, food efficiency ratio or serum TG concentrations. TC concentrations were lower (p<0.05) in the CLA-supplemented rats that were fed coconut oil but not those consuming corn oil. Serum HDL-C was lower (p<0.05) in rats consuming corn oil but was not significantly different (p>0.05) for CLA supplemented groups. Epididymal fat pads weighed significantly more (p<0.05) in the coconut oil fed group compared to the corn oil fed group, but there was no significant difference (p>0.05) between the corn oil and coconut oil + CLA group. Overall, this study suggests that CLA is more beneficial for control of blood lipids and adiposity when supplemented to a diet rich in saturated versus unsaturated fat.     

Randomized trial of two intravenous schedules of the topoisomerase I inhibitor liposomal lurtotecan in women with relapsed epithelial ovarian cancer: a trial of the national cancer institute of Canada clinical trials group.

PURPOSE: Liposomal lurtotecan (OSI-211) is a liposomal formulation of the water-soluble topoisomerase I inhibitor lurtotecan (GI147211), which demonstrated superior levels of activity compared with topotecan in preclinical models. We studied two schedules of OSI-211 in a randomized design in relapsed ovarian cancer to identify the more promising of the two schedules for further study. PATIENTS AND METHODS: Eligible patients had measurable epithelial ovarian, fallopian, or primary peritoneal cancer that was recurrent after one or two prior regimens of chemotherapy. Patients were randomly assigned to receive either arm A (OSI-211 1.8 mg/m(2)/d administered by 30-minute intravenous infusion on days 1, 2, and 3 every 3 weeks) or arm B (OSI-211 2.4 mg/m(2)/d administered by 30-minute intravenous infusion on days 1 and 8 every 3 weeks). The primary outcome measure was objective response, which was confirmed by independent radiologic review, and a pick the winner statistical design was used to identify the schedule most likely to be superior. RESULTS: Eighty-one patients were randomized between October 2000 and September 2001. The hematologic toxic effects were greater on arm A than on arm B (grade 4 neutropenia, 51% v 22%, respectively), as was febrile neutropenia (26% v 2.4%, respectively). Of the 80 eligible patients, eight patients (10%) had objective responses; six responders (15.4%; 95% CI, 6% to 30%) were in arm A and two responders (4.9%; 95% CI, 1% to 17%) were in arm B. CONCLUSION: The OSI-211 daily for 3 days intravenous schedule met the statistical criteria to be declared the winner in terms of objective response. This schedule was also associated with more myelosuppression than the schedule of OSI-211 administered in arm B.     

18F]fluorodeoxyglucose uptake by positron emission tomography predicts outcome of non-small-cell lung cancer.

PURPOSE: To determine whether the standardized uptake value (SUV) of [(18)F]fluorodeoxyglucose uptake by positron emission tomography could be a prognostic factor for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: One hundred sixty-two patients with stage I to IIIb NSCLC were analyzed. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and local-regional control (LRC) were calculated by the Kaplan-Meier method and evaluated with the log-rank test. The prognostic significance was assessed by univariate and multivariate analyses. RESULTS: There were 93 patients treated with surgery and 69 patients treated with radiotherapy. A cutoff of 5 for the SUV for the primary tumor showed the best discriminative value. The SUV for the primary tumor was a significant predictor of OS (P = .02) in both groups. Low SUVs ( 5.0; surgery group, P = .02; radiotherapy group, P = .0005). Low SUVs ( 5.0; stage I or II, P = .02; stage IIIa or IIIb, P = .004). However, using the same cutoff point of 5, the SUV for regional lymph nodes was not a significant indicator for DFS (P = .19), LRC (P = .97), or DMFS (P = .17). The multivariate analysis showed that the SUV for the primary tumor was a significant prognostic factor for OS (P = .03) and DFS (P = .001). CONCLUSION: The SUV of the primary tumor was the strongest prognostic factor among the patients treated by curative surgery or radiotherapy.