Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model

The chemopreventive activity of the highly specific nonsteroidal aromatase inhibitor, vorozole, was examined in the methylnitrosourea (MNU)-induced rat model of mammary carcinogenesis. Various doses of vorozole (0.08-1.25 mg/kg body wt/day) were administered daily (by gavage) to female Sprague-Dawley rats starting at 43 days of age. Seven days later, the rats were given a single i.v. dose of MNU (50 mg/kg body wt). Rats were continually treated with vorozole until the end of the experiment (120 days post-MNU). Vorozole caused a dose dependent inhibition of mammary cancer multiplicity. The highest dose of vorozole (1.25 mg/kg body wt/day) decreased cancer multiplicity by approximately 90%, and simultaneously decreased cancer incidence from 100 to 44%. The next two highest doses of vorozole (0.63 and 0.31 mg/kg body wt/day) inhibited MNU-induced mammary cancer multiplicity by 70-80%. Even the two lowest doses of vorozole (0.16 and 0.08 mg/kg body wt/ day) decreased cancer multiplicity -50%. Serum level determinations were performed on a variety of endpoints at either 4 or 24 h following the last dose of vorozole. Insulin-like growth factor (IGF)-1 levels were slightly, but significantly, increased by vorozole treatment. Vorozole induced striking increases in serum testosterone levels at 4 h at all the dose levels employed. Testosterone levels were significantly elevated over controls at 24 h in rats given the lower doses of vorozole (0.08-0.31 mg/kg body wt/day), but were significantly lower than in rats administered the higher doses of vorozole (0.63 or 1.25 mg/kg body wt/ day). This result presumably reflects the limited half- life of vorozole in rats. In a second series of experiments, the effects of limited duration of dosing with vorozole (2.5 mg/kg body wt/day) or intermittent dosing with vorozole were determined. Treatment of rats with vorozole for limited time periods, from 3 days post-MNU administration until 30 or 60 days post-MNU treatment, resulted in significant delays in the time to appearance of palpable cancers. However, these limited treatments did not greatly affect the overall incidence or multiplicity of mammary cancers when compared with the MNU controls at the end of the study (150 days post-MNU). Finally, the effects of intermittent dosing with vorozole (2.5 mg/kg body wt/day) were examined. Rats were administered cycles of vorozole daily for a period of 3 weeks followed by treatment with the vorozole vehicle for the next 3 weeks (total of four cycles). Although this intermittent treatment did inhibit the appearance of new tumors during each of the periods that vorozole was administered, it did not cause regression of palpable cancers.      

SAFETY,EFFECTIVENESS AND COST EFFICACY OF DIAGNOSTIC ELECTROPHYSIOLOGY AND RADIOFREQUENCY ABLATION IN A DISTRICT GENERAL HOSPITAL

Electrophysiological studies (EPS) are now being performed in district general hospitals (DGH) in the UK. In order to audit our results, a prospective database was established for all patients undergoing EPS and radiofrequency (RF) ablation at Eastbourne District General Hospital, East Sussex. Between 1 January 1997 and 1 July 2000, 300 EPS procedures were performed, resulting in 155 RF ablations. The average RF ablation procedure time was 119.3 minutes with an average fluoroscopy time of 19.1 minutes. Cost per RF ablation procedure was £1166.79 excluding use of facilities, pacemaker devices, medical nursing and radiography staffing costs. The overall success rate for RF ablation was 93.6% with a major complication rate of 0.6%, a total complication rate of 3.9% and no associated mortality. We have shown that RF ablation can be performed safely, effectively and economically in a DGH setting with a high rate of success and a low complication rate.     

Tacrolimus (FK506) versus cyclosporin A microemulsion (Neoral) maintenance immunosuppression: effects on graft survival and function,infection, and metabolic profile following kidney transplantation (KT)

We reviewed two groups of kidney transplant patients receiving neoral (Group I, 27 patients) or FK506 (Group II, 25 patients) as maintenance immunosuppression between December 1998 and May 2002. The recipient and donor demographics and induction therapy were comparable in both groups except for more highly sensitized patients in Group II. Acute rejection (AR) rate and timing were similar in both groups except for more steroid resistant AR in Group II (P=0.04). Infections rate was similar in both groups (25.9% in Group I and 36% in Group II; P=N.S.), but there were less viral infections in Group I (0%) than Group II (29%; 4 CMV). CMV infections were related to the presence in Group II of more CMV-negative recipients getting kidneys from CMV-positive donors. The metabolic profile was comparable between the two groups, except for a better HDL in Group II (48.2+/-7.6) versus Group I (45+/-2.2; P=0.021). Mean serum creatinine levels upon discharge, at 1, 3 and 6 months were: 1.62+/-0.32, 1.4+/-0.17, 1.39+/-0.14 and 1.4+/-0.14 in Group I and 2.15+/-0.5, 1.48+/-0.23, 1.41+/-0.21 and 1.23+/-0.11 in Group II, respectively. The 6 months actuarial patient and graft survival were identical in both groups (100 and 100%). Both calcineurin inhibitors are effective and safe in KT. The higher rate of AR in Group II was related to more highly sensitized patients and the higher CMV infections was due to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. The same study will be continued to evaluate the long term effects of both drugs.     

Evaluating patients with renal failure for renal artery stenosis with gadolinium-enhanced magnetic resonance angiography

The incidence and prevalence of end-stage renal disease (ESRD) continues to increase, especially in the elderly population. The role of renovascular disease in contributing to ESRD is still not well defined. The objective of this study was to determine the utility of gadolinium (Gd)-enhanced magnetic resonance angiography (MRA) in evaluating elderly patients with renal insufficiency for renal artery stenosis (RAS). A 7-month prospective study conducted in a tertiary referral center evaluated 40 consecutive patients with progressive renal insufficiency (18 men and 22 women; mean age, 70 +/- 5.6 [standard deviation] years) and high clinical suspicion for renovascular disease with Gd-enhanced MRA. Digital subtraction angiography (DSA) was obtained in only those patients with significant RAS detected by MRA. Twelve patients had significant RAS. Six of these patients had percutaneous transluminal renal angioplasty (PTRA), five patients had renal artery bypass surgery, and one patient had a stent placed after PTRA. Seventy-eight renal arteries were satisfactorily evaluated by MRA. Twenty-two renal arteries were evaluated by both MRA and DSA. Of the 12 significant stenoses detected by the MRA, 11 were confirmed by DSA and 1 was confirmed at the time of surgical revascularization. It is concluded that Gd-enhanced MRA is a useful test for the evaluation of RAS in patients with compromised renal function.     

Temporal sequence of mammary intraductal proliferations, ductal carcinomas in situ and adenocarcinomas induced by 1-methyl-1- nitrosourea in rats

An experimental model for mammary carcinogenesis has been described in which intraductal proliferations, ductal carcinomas in situ and adenocarcinomas can be readily detected and the frequency of their occurrence quantified. The objective of the experiment reported in this study was to determine the latency period between carcinogen administration and the occurrence of each of these types of lesion. A total of 150 female Sprague-Dawley rats were injected i.p. with 50 mg 1- methyl-1-nitrosourea (MNU)/kg body wt at 21 days of age. Groups of 30 rats each were killed at 7, 14, 21, 28 and 35 days post-carcinogen. Mammary intraductal proliferations were the first detected lesions and were observed in 20% of the animals at 14 days following carcinogen administration. At 21 days post-carcinogen ductal carcinomas in situ and adenocarcinomas were observed. The number of each type of lesion increased with time post-carcinogen, but the temporal pattern of occurrence was different among lesion types. The pattern of lesion occurrence was consistent with intraductal proliferations being a precursor lesion for ductal carcinomas in situ and adenocarcinomas. Furthermore, the data imply that ductal carcinomas in situ represent one pathway of morphological progression by which intraductal proliferations evolve into invasive carcinomas, but that this lesion type, as currently defined histologically, may not be an obligatory intermediate in morphologic progression. These findings are consistent with emerging evidence of multiple but distinct pathogenetic pathways leading to mammary carcinomas that display different morphological patterns and biological activities.