Cisplatin, continuous-infusion 5-fluorouracil, and intermediate-dose methotrexate in the treatment of unresectable non-small cell carcinoma of the lung.

Forty-one patients with unresectable non-small cell carcinoma of the lung (NSCCL) were treated with cisplatin 20 mg/m2/d for 5 days as a daily bolus injection, 5-fluorouracil 800 mg/m2/d by continuous infusion for 5 days, and intermediate-dose methotrexate 200 mg/m2 on days 15 and 22 of a 28-day cycle (PFM). One complete and 23 partial responses were observed, yielding an overall response rate of 60%. There was no significant difference in response rates based on histologic subtype or extent of disease (locally unresectable versus metastatic). Median duration of response was 6 months, and the median survival of all patients was 10 months. Two patients with unresectable disease at presentation became resectable after chemotherapy and remain disease-free at 46+ and 53+ months. Toxicity was modest, with oral mucositis the major adverse effect. Clinically important neutropenia was uncommon. PFM is an active regimen in NSCCL and deserves further study in the "neoadjuvant" setting.     

2-Nitroimidazole potentiation of nitrosourea induced cytotoxicity in subcutaneous implants of rat 9L brain tumor cells

Summary To determine if the 2-nitroimidazole (2-NI) and the nitrosourea (NU) in a brain tumor chemopotentiation trial should be selected on the basis of known structure-activity relationships (electron affinity, lipophilicity, alkylating activity, carbamoylating activity), s.c. implants of rat 9L brain tumor cells were treated with combinations of misonidazole (MISO) or etanidazole (SR-2508) administered under oxic and hypoxic conditions, and BCNU, CCNU or chlorozotocin (CLZ) administered under oxic conditions. Cell kill was assessed by an in vivo to in vitro colony formation assay. To mimic the preincubation effect, the 2-NI was injected i.p., and 30min later the tumor was clamped. After 2hr, the clamp was released, and the NU administered immediately. MISO (2.5 mmole/kg) and SR-2508 (3.75 mmole/kg) reached the same peak tumor concentration in 30 min. Both 2-NIs were metabolized at the same rate in the clamped tumors; however, metabolism of the 2-NIs by hypoxic cells over the 2hr clamping period did not produce any measurable s.c. 9L cell kill. The relative effectiveness of the NUs for killing oxic s.c. 9L tumor cells was: BCNU > CCNU > CLZ. Clamping the tumor prior to NU administration did not change the NU cytotoxicity. No potentiation of the NU cytotoxicity by the 2-NIs was observed in oxic tumors. Although metabolism of MISO by hypoxic cells did not result in potentiation of CLZ cytotoxicity at any dose, it resulted in potentiation of BCNU cytotoxicity at all doses and CCNU cytotoxicity at high doses. Metabolism of SR-2508 by hypoxic cells did not result in potentiation of BCNU, CCNU or CLZ cytotoxicity at any dose. These in situ data indicate that, 1) MISO is superior to SR-2508 for potentiating NU cytotoxicity, and 2) the NU in a brain tumor chemopotentiation trial should be selected on the basis that it is the most effective potentiable NU against a particular type of brain tumor.     

A phase I trial of continuous-infusion cyclophosphamide in refractory cancer patients

Summary Cyclophosphamide demonstrates enhanced tumoricidal activity with decreased bone marrow toxicity when given on a divided-dose schedule in certain animal models. A total of 22 patients presenting with refractory metastatic cancer were treated in a phase I trial of continuous infusion of cyclophosphamide over 96 h. Granulocytopenia of <500/l that lasted for > 14 days or thrombocytopenia of <25,000/l that lasted for > 14 days was the target dose-limiting toxicity in the absence of nonhematologic grade 4 toxicity. The maximal tolerated dose was 7 g/m². Three patients died. Of 21 evaluable patients, 9 responded, including 8/9 who had experienced disease progression during prior oxazaphosphorine-containing combination chemotherapy. Clinically meaningful responses were observed in patients who had demonstrated clinical resistance to an oxazaphosphorine drug given at lower doses.Supported in part by U.S. Public Health Service grant P01CA-38493 and by a grant from the Mather's Foundation. Two of the authors (J. P. E. and A. D. E.) are recipients of Career Development awards from the American Cancer Society, and one (T. C. S.) is a recipient of a Faculty Development Award from the Pharmaceutical Manufacturer's Association Foundation     

Antibiotics and surgery for vesicoureteric reflux: a meta-analysis of randomised controlled trials.

AIMS: To evaluate the benefits and harms of treatments for vesicoureteric reflux in children. METHODS: Meta-analyses of randomised controlled trials using a random effects model. Main outcome measures were incidence of urinary tract infection (UTI), new or progressive renal damage, renal growth, hypertension, and glomerular filtration rate. RESULTS: Eight trials involving 859 evaluable children comparing long term antibiotics with surgical correction of reflux (VUR) and antibiotics (seven trials) and antibiotics compared with no treatment (one trial) were identified. Risk of UTI by 1-2 and 5 years was not significantly different between surgical and medical groups (relative risk (RR) by 2 years 1.07; 95% confidence interval (CI) 0.55 to 2.09, RR by 5 years 0.99; 95% CI 0.79 to 1.26). Combined treatment resulted in a 60% reduction in febrile UTI by 5 years (RR 0.43; 95% CI 0.27 to 0.70) but no concomitant significant reduction in risk of new or progressive renal damage at 5 years (RR 1.05; 95% CI 0.85 to 1.29). In one small study no significant differences in risk for UTI or renal damage were found between antibiotic prophylaxis and no treatment. CONCLUSION: It is uncertain whether the identification and treatment of children with VUR confers clinically important benefit. The additional benefit of surgery over antibiotics alone is small at best. Assuming a UTI rate of 20% for children with VUR on antibiotics for five years, nine reimplantations would be required to prevent one febrile UTI, with no reduction in the number of children developing any UTI or renal damage.     

Disposition and metabolic fate of atomoxetine hydrochloride: pharmacokinetics, metabolism, and excretion in the Fischer 344 rat and beagle dog.

These studies were designed to characterize the disposition and metabolism of atomoxetine hydrochloride [(-)-N-methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride; formerly know as tomoxetine hydrochloride] in Fischer 344 rats and beagle dogs. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the majority of its metabolites being excreted into the urine, 66% of the total dose in the rat and 48% in the dog. Fecal excretion, 32% of the total dose in the rat and 42% in the dog, appears to be due to biliary elimination and not due to unabsorbed dose. Nearly the entire dose was excreted within 24 h in both species. In the rat, low oral bioavailability was observed (F = 4%) compared with the high oral bioavailability in dog (F = 74%). These differences appear to be almost purely mediated by the efficient first-pass hepatic clearance of atomoxetine in rat. The biotransformation of atomoxetine was similar in the rat and dog, undergoing aromatic ring hydroxylation, benzylic oxidation (rat only), and N-demethylation. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming O-glucuronide and O-sulfate (dog only) metabolites. Although subtle differences were observed in the excretion and biotransformation of atomoxetine in rats and dogs, the primary difference observed between these species was the extent of first-pass metabolism and the degree of systemic exposure to atomoxetine and its metabolites.     

Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126.

PURPOSE: ZD6126 is a novel vascular targeting agent currently undergoing clinical evaluation. It acts by destabilizing the microtubulin of fragile and proliferating neoendothelial cells in tumors. The drug leads to blood vessel congestion, the selective destruction of the vasculature, and extensive necrosis in experimental tumors. The aim of the study reported here was to assess the ability of dynamic contrast enhanced magnetic resonance imaging (MRI) to measure the antivascular effects of ZD6126 in tumors. EXPERIMENTAL DESIGN: The work was carried out in mice bearing C38 colon adenocarcinoma and in patients with advanced cancers. MRI was performed before and 6 h (human tumors) or 24 h (C38 tumors) after i.v. drug administration. Contrast agent (gadolinium diethylenetriaminepentaacetate) enhancement was characterized by the initial area under the gadolinium diethylenetriaminepentaacetate uptake versus time curve (IAUC). IAUC reflects blood flow, vascular permeability, and the fraction of interstitial space. RESULTS: The median IAUC was reduced in all C38 tumors after ZD6126 administration [by 6-48% at 50 mg/kg (n = 3)], 58-91% at 100 mg/kg (n = 4), and 11-93% at 200 mg/kg (n = 6). In contrast, the administration of vehicle only led to no consistent change in median IAUC (n = 4). The ZD6126-induced changes in median IAUC appeared to be dose dependent (P = 0.045). No ZD6126-induced changes were apparent in murine muscle. Similar effects were seen in preliminary data from human tumors (11 tumors studied, 9 patients). At doses of 80 mg/m(2) and higher, the median IAUC post-ZD6126 treatment was reduced in all of the tumors studied (8 tumors, 6 patients) to 36-72% from the baseline value. There was a significant trend of increasing reductions with increasing exposure (P < 0.01). No drug-induced changes in human muscle or spleen IAUC were apparent. The reproducibility of the median IAUC parameter was investigated in patients. In 19 human tumors (measured in 19 patients) inter- and intratumor coefficients of variation were 64 and 18%. CONCLUSIONS: The contrast enhanced-MRI measured median IAUC is a useful end point for quantifying ZD6126 antivascular effects in human tumors.     

Mechanical strength of fracture callus in osteopenic bone at different phases of healing

OBJECTIVES: To quantify and compare peak bending force and stiffness of fractured femurs during healing of ovariectomized (OVX) and sham-operated (SHAM) rats. DESIGN: Temporal biomechanical animal study. SETTING: Rat femurs were fractured and surgically fixed by a qualified surgeon. The inherent instability of the fixation system employed produced delayed union of the fracture. All biomechanical assessments were performed with servohydraulic test machines (Instron Inc., Canton, MA, U.S.A.; and MTS Corp., Eden Prairie, MN, U.S.A.). INTERVENTION: OVX was performed sixteen weeks before femur fracture, and the effect of OVX on healing fractures was determined. MAIN OUTCOMES: Peak bending force and stiffness of the healing femurs at four, six, and eight weeks after fracture. RESULTS: Peak bending loads of the healing fractured femurs in the OVX and SHAM animals were not significantly different. Peak bending loads for the OVX animals at four and six weeks were significantly lower than the peak load at eight weeks (p < 0.05), whereas no difference was found in the peak load with respect to time for the SHAM animals. Both SHAM and OVX animals had greater bending stiffness of the healing fractured femur after eight weeks of healing than at four weeks (p < 0.05). CONCLUSIONS: OVX is known to reduce cancellous bone mass and strength, but the effect of OVX on healing of fractures in cortical bone is controversial. This study, using a delayed-union model, found no significant differences between OVX and SHAM animals in the breaking strength of healing fractures.     

Thymic Function and Output of Recent Thymic Emigrant T Cells During Intracranial Glioma Progression

One of the hallmarks of patients with glioblastoma multiforme (GBM) is profound lymphopenia mostly confined to the T cell lineage. A deficiency in the production of naïve T cells from the thymus could contribute to the lymphopenia seen in GBM patients. In this study we asked whether thymic function and the production of recent thymic emigrant (RTE) T cells from the thymus was influenced by intracranial (i.c.) glioma progression. We found significant thymic involution in animals with progressive i.c. gliomas. Involuted thymi from animals with progressive i.c. T9.F gliomas showed dramatic losses of CD4⁺CD8⁺ (DP) thymocytes. Microscopic analysis complemented those findings by demonstrating a reversal of the typical cortico-medullary structure. Significant increases in apoptosis accompanied the rapid loss of viable thymocytes, which was prevented in part by adrenalectomy, suggesting a dominant role for endogenous glucocorticoids. This thymic involution was also associated with a significant decrease in peripheral RTE T cells, reflecting the diminished thymic function. Finally, we found that CD8⁺ RTE T cells were enriched in progressively growing T9 gliomas, which points to an immunological role for RTE's in anti-glioma immunity. Our findings may shed light on the significance of thymic function for anti-glioma immunity and the response to immunotherapeutic treatment paradigms.