Radioenhancement by cisplatin with accelerated fractionated radiotherapy in a human tumour xenograft

The aim of the present study was to investigate whether cisplatin would enhance the radioresponse of a human tumour xenograft when given in different schedules combined with accelerated fractionated radiation therapy. A human squamous carcinoma of the hypopharynx, FaDu, was grown in the thigh of athymic nude mice. Tumours were exposed to twice-daily 2-Gy fractions, applied 6 h apart over 2 weeks, 5 days a week, alone or combined with cisplatin given at maximally tolerated doses in three different schedules: (1) i.p. as a single bolus (SB) or (2) i.p. as a daily bolus at 30 min before the first daily radiation fraction or (3) s.c. as a continuous infusion through a mini-osmotic pump over 13 days, commencing 24 h prior to the first daily radiation fraction. The end point for the study was tumour growth delay (TGD), calculated as the difference between the delay in regrowth to 200% of the initial tumour size in treated versus control mice. SB cisplatin plus radiation showed only an additive effect on TGD, whereas daily-bolus and continuous-infusion cisplatin demonstrated a greater than additive effect when combined with accelerated fractionated radiation in this human tumour model. Cisplatin appears to be especially beneficial as a radiation enhancer when given throughout the course of radiation. Received: 15 December 1996 / Accepted: 25 March 1997     

Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.     

Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805.

PURPOSE: Flavopiridol has in vitro activity in chronic lymphocytic leukemia (CLL) and promotes apoptosis independent of p53 function or prior fludarabine exposure. We sought to determine if flavopiridol has activity in previously treated CLL using two schedules of administration. PATIENTS AND METHODS: Patients with previously treated CLL were enrolled in two sequentially done phase II studies. Patients in the first trial received flavopiridol (50 mg/m(2)/d) as a continuous infusion (CI) for 72 hours every 2 weeks. Patients in the second trial received flavopiridol 50 mg/m(2) as a 1-hour bolus (IVB) daily for 3 days repeated every 3 weeks. Patients received up to 12 (CI cohort) or 8 (IVB cohort) cycles of therapy. RESULTS: Fifteen patients were enrolled in the 72-hour CI phase II trial; 6 (40%) had intermediate-risk (Rai stage I or II) and 9 (60%) had high-risk (Rai stage III and IV) stages. No responses were noted in this group; 27% had stable disease and 73% had progressive disease. Thirty-six patients were enrolled in the second IVB trial, with 13 (36%) having intermediate and 23 (64%) having high-risk disease. Four patients (11%) had partial responses, 19 (53%) had stable disease, and 13 (36%) had progressive disease. The progression-free survival for responders in the IVB trial was 3, 3, 9, and 19 months. The median progression-free survival was 2 months [95% confidence interval (95% CI), 1.8-3.8] for patients in the CI trial and 3 months (95% CI, 2.5-7.4) for the IVB trial. The median overall survival was 27 months (95% CI, 20-42) for the CI trial and 24 months (95% CI, 18-31) for the IVB trial. Toxicity was manageable and included mainly myelosuppression, infections, diarrhea, and fatigue. CONCLUSIONS: Flavopiridol has modest, schedule-dependent clinical activity in relapsed CLL and warrants future investigation utilizing alternative schedules of administration.     

Bilobed oblong porous coated acetabular components in revision total hip arthroplasty

Thirty-eight oblong bilobed noncustom uncemented, porous-coated titanium acetabular components were used to reconstruct failed hip arthroplasties with large superior segmental acetabular bone deficiencies. No structural bone grafts were used. All patients were followed up for 2 to 5 years (mean, 3 years) after the operation. One patient (whose socket rested primarily on a structural bone graft from a previous procedure) had revision surgery for acetabular loosening. No other patients have had revision surgery or had another ipsilateral hip operation. At latest followup, 35 patients had no or mild pain and two patients had moderate pain. Two implants migrated more than 2 mm in the first year, then stabilized. On the latest radiographs, two implants had bead shedding, but there was no measurable migration or change in position. For selected patients with large superolateral acetabular bone deficiencies, this implant facilitated a complex reconstruction, provided good clinical results, and showed satisfactory stability at early to midterm followup in most patients.     

Liquid Guayule Natural Rubber,a Sustainable Processing Aid,Enhances the Processability,Durability and Dynamic Mechanical Properties of Rubber Composites

Petroleum-based oils are widely used as processing aids in rubber composites to improve processability but can adversely affect rubber composite performance and increase carbon footprint. In this research, liquid guayule natural rubber (LGNR), produced from guayule natural rubber, was used as a renewable processing aid to replace naphthenic oil (NO) in Hevea natural rubber, styrene-butadiene rubber (SBR) and guayule natural rubber (GNR) composites. The rheological properties, thermal stability, glass transition temperature, dynamic mechanical properties, aging, and ozone resistance of rubber composites with and without NO or LGNR were compared. Natural and synthetic rubber composites made with LGNR had similar processability to those made with NO, but had improved thermal stability, mechanical properties after aging, and ozone resistance. This was due to the strong LGNR–filler interaction and additional crosslinks formed between LGNR and the rubber matrices. The glass transition temperature of SBR composites was reduced by LGNR because of its increased molecular mobility. Thus, unlike NO, LGNR processing aid can simultaneously improve rubber composite durability, dynamic performance and renewability. The commercialization of LGNR has the potential to open a new sustainable processing-aid market.     

Cost-effectiveness analysis of endometrial cancer prevention strategies for obese women

OBJECTIVE: It is unknown whether obese women would benefit from oral contraceptives or screening as endometrial cancer prevention strategies. We estimated the net health benefits and cost-effectiveness of these strategies in a hypothetical cohort of obese women. METHODS: A Markov decision-analytic model evaluated 4 strategies: 1) no prevention (reference strategy); 2) oral contraceptive pills (OCPs) for 5 years; 3) annual screening with endometrial biopsy from age 30; 4) biennial screening from age 30. Net health benefit was life expectancy and primary outcome was the incremental cost-effectiveness ratio. Baseline and transition probabilities were obtained from published literature and the Surveillance Epidemiology and End Results database, and costs were from the U.S. Department of Health and Human Services and Agency for Healthcare Research and Quality. Sensitivity analyses were performed for uncertainty around various measures. RESULTS: Average life expectancy for all strategies ranged from 74.52 to 74.60 years. None of the strategies had an incremental cost-effectiveness ratio less than $50,000 per year of life saved relative to the next best strategy. Endometrial cancer risk in obese women had to be 13 times greater than the general population risk before OCPs were a cost-effective intervention. CONCLUSION: Oral contraceptives and current screening methods are not cost-effective endometrial cancer prevention strategies for obese women. Risk factors such as morbid obesity and longstanding anovulation may define a subgroup at highest risk of endometrial cancer for whom OCPs may be a cost-effective strategy. Interventions that reduce endometrial cancer risk further or those with additional health benefits are needed in this population. LEVEL OF EVIDENCE: III.