Estrous cycle modification of rat mammary tumor induction by a single dose of N-methyl-N-nitrosourea.

The potential of individual stages of the rat estrous cycle to alter the incidence and subsequent behavior of mammary carcinomas induced by a single dose of N-methyl-N-nitrosourea on diestrus, proestrus, or estrus was examined. Mean latencies to first tumor appearance in diestrous, proestrous, and estrous groups were 86, 71, and 69 days, respectively (P less than 0.05 diestrus versus proestrus, estrus). Tumor incidence in diestrous rats given injections (73%) was significantly lower than in proestrous (87%) or estrous (89%) animals given injections, as was the mean number of tumors per rat. However, the number of days required for tumors to reach 1 cm in diameter in diestrous animals given injections (13.0) was significantly lower as compared with tumors in rats given injections during proestrus (19.3) or estrus (22.2). In later growth stages, the diestrous tumor doubling time was one-half that of tumors in proestrous rats given injections. Flow cytometric analysis of tumor tissues during midlog and later growth phases did not reveal any significant changes in ploidy or growth fractions between groups. Further, there was no significant difference in tumor cytosol estrogen receptor incidence, affinity (Kd), or content between groups, although tumor cell nuclear receptor for estrogen was higher (38.3 fmol/mg DNA; P less than 0.05) in proestrous rats given injections than in diestrous (21.6) or estrous (21.8) animals given injections. These data support the concept that the prevailing hormonal profile of the estrous cycle at the time of tumor initiation modulates the subsequent induction of mammary tumors. Further, the absence of any observed difference in tumor behavior between proestrous and estrous rats given injections suggests that prolactin does not impose an additive or synergistic effect on the initial stage of tumor induction when mammary gland epithelial cell DNA is previously stimulated by estrogen.

Estrous cycle modification of rat mammary gland DNA alkylation by N-methyl-N-nitrosourea.

Virgin Sprague-Dawley rats exhibiting regular estrous cycles were used as a model system to determine whether the level of circulating estrogen modifies the alkylation pattern of mammary gland DNA by a direct-acting carcinogen, N-methyl-N-nitrosourea (NMU). The concentration of 7-methylguanine and O6-methylguanine were similar in mammary epithelial DNA 0.25, 0.50, and 1.0 h after i.v. injection of 50 mg/kg body weight NMU on different days of the rat estrous cycle. However, O6-methylguanine was significantly higher in mammary gland DNA 8 and 24 h after a single i.v. dose of carcinogen on proestrus or estrus, compared to rats receiving carcinogen on diestrus. There was no difference in the 7-methylguanine levels at 8 h in any group, but this adduct was higher in estrous-treated rats at 24 h. The ratio of O6-methylguanine to 7-methylguanine was significantly lower at 8 h in mammary gland DNA from diestrous-injected rats, and this difference reflected the lower level of O6-methylguanine adducts in this group. In contrast, O6-methylguanine concentrations in DNA extracted from the liver of the same animals were virtually identical at all time periods examined. 7-Methylguanine levels were higher in the liver at 0.5, 1, 8, and 24 h post-NMU in proestrus as compared with diestrous-injected rats. The observed adduct clearance suggests that rat mammary epithelium may contain repair systems capable of removing O6-methylguanine. These results also suggest that the initial removal of the O6-methylguanine lesions in mammary epithelial DNA (rather than the initial rate of alkylation) is affected by the hormonal environment during carcinogen exposure. This effect may be tissue specific since removal of O6-methylguanine from liver DNA is apparently not altered by the stage of the estrous cycle at which NMU is administered.

Inhibition of rat mammary gland chemical carcinogenesis by dietary dehydroepiandrosterone or a fluorinated analogue of dehydroepiandrosterone.

The chemopreventive efficacy of p.o. administered dehydroepiandrosterone (DHEA), DHEA plus N-(4-hydroxyphenyl)retinamide (4-HPR), or 16 alpha-fluoro-5-androsten-17-one (DHEA analogue 8354) was examined in rats treated with N-methyl-N-nitrosourea (MNU; 50 mg/kg body weight, i.v.) at 50 days of age. Semipurified diet (AIN-76A) containing each steroid alone, or DHEA plus 4-HPR, was administered during initiation (-1 week to +1 week post-MNU), promotion/progression (+1 week post-MNU to termination), or both phases (-1 week post-MNU to termination) of the carcinogenic process. Neither DHEA nor DHEA analogue 8354 (0.2%, w/w) significantly affected the initiation of mammary cancer when administered alone; however, DHEA (0.2%, w/w) plus 4-HPR (1 mmol/kg diet) significantly reduced cancer multiplicity (26%) when given during initiation. All three treatments were strongly effective when given during promotion/progression, significantly reducing mammary cancer multiplicity by 77% (DHEA), 84% (DHEA/4-HPR), and 66% (DHEA analogue 8354), relative to carcinogen controls. Cancer incidence was significantly inhibited by DHEA (33% inhibition) and DHEA/4-HPR (24% reduction) during promotion/progression. However, the most effective chemopreventive treatment encompassed both phases of carcinogenesis. Thus, under these conditions, DHEA (0.2% or 0.1%, w/w) reduced cancer incidence (52% and 32% reductions, respectively) and multiplicity (91% and 86% reductions, respectively). Further reduction in mammary cancer incidence was observed in animals that received DHEA (both doses) plus 4-HPR (1 and 0.5 mmol/kg diet, respectively). DHEA analogue 8354 (0.2% or 0.1%, w/w) given for the duration of the study reduced only cancer multiplicity (61% and 56% reductions, respectively). Tumor-related mortality was significantly lower in rats that received long-term treatment with DHEA or DHEA/4-HPR, when compared with carcinogen controls. Except for a slight, but significant, postcarcinogen decrease in the mean body weights of rats treated concomitantly with DHEA (plus or minus 4-HPR) and MNU, additional gross manifestations of steroid-induced toxicity were not observed.

Chemopreventive efficacy of combined retinoid and tamoxifen treatment following surgical excision of a primary mammary cancer in female rats.

Dietary N-(4-hydroxyphenyl)retinamide (4-HPR; 3 mmol/kg diet) and s.c. injections of the antiestrogen, tamoxifen (Tx; 10 micrograms or 20 micrograms per rat, thrice weekly) were used together as adjunct chemopreventive therapy in groups of 39-40 female, Sprague-Dawley rats that each received an i.v. injection (50 mg/kg b.w.) of the mammary gland carcinogen N-methyl-N-nitrosourea (MNU). Treatment was started immediately following the surgical excision of the first (primary) mammary carcinoma from each MNU-treated rat and was continued for 180 days. When compared to the effect of treatment with 4-HPR or Tx (30 micrograms/wk) alone, the combination treatments significantly enhanced terminal survival and reduced nonrecurrent mammary cancer incidence and multiplicity. Data showing the incidence of rats bearing the first through fifth additional cancers to appear following surgical resection of a primary lesion demonstrate that combined treatment with 4-HPR/Tx was immediately and consistently more efficacious than either agent per se in suppressing subsequent tumor appearance. This effect was apparently related to the dose of Tx. These results suggest that combined treatment with 4-HPR/Tx is superior to that of either agent alone in blocking progression of incipient neoplastic lesions at both early and later stages of the process.

A paradigm for consensus. The University Hospital Consortium guidelines for the use of albumin, nonprotein colloid, and crystalloid solutions.

OBJECTIVE: To develop contemporary, comprehensive guidelines for the appropriate and efficient use of albumin, nonprotein colloid, and crystalloid solutions. DESIGN: A systematic, literature-based, consensus exercise employing a modified Delphi method. PARTICIPANTS: Thirty-one medical and allied health professionals from 26 University Hospital Consortium (Oak Brook, Ill) member institutions were initially chosen to participate. Participants were selected on the basis of their recognized research in the use of albumin, nonprotein colloid, and crystalloid solutions, and/or experience in the review of appropriateness of such use. A total of 24 participants completed the exercise. MAIN OUTCOME MEASURES: Group responses were statistically analyzed in an iterative consensus development process. Five separate questionnaire rounds were designed to establish criteria for the appropriate use of albumin, nonprotein colloid, and crystalloid solutions. RESULTS: Consensus guidelines were developed outlining the appropriate use of these products for 12 clinical indications, including hemorrhagic shock, nonhemorrhagic (maldistributive) shock, hepatic resection, thermal injury, cerebral ischemia, nutritional intervention, cardiac surgery, hyperbilirubinemia of the newborn, cirrhosis and paracentesis, nephrotic syndrome, organ transplantation, and plasmapheresis. CONCLUSIONS: The Delphi method, a systematic, literature-based consensus process, was shown to be useful in the development of complex clinical practice guidelines for the use of albumin, nonprotein colloid, and crystalloid solutions. It is anticipated that the guidelines will assist health care providers to develop local institutional policies and procedures for the appropriate and efficient use of albumin and albumin alternatives. Institutions reviewing and updating existing local guidelines may use the University Hospital Consortium guidelines as a model for comparison.

Evaluation of ondansetron prescribing in US academic medical centers.

BACKGROUND: The study objectives were to characterize the use of the antiemetic ondansetron, a serotonin subtype 3 receptor antagonist, in US academic medical centers, and to assess ondansetron prescribing with consensus-derived prescribing guidelines used as evaluation criteria. METHODS: A multicenter, prospective, observational study was conducted in the inpatient and outpatient care areas of 23 US academic medical centers. A total of 670 patients received ondansetron (508 inpatients and 162 outpatients). The use of ondansetron was compared with consensus-derived prescribing guidelines on the basis of indication for use and dose administered. RESULTS: Only 253 (37.8%) of the 670 patients satisfied for prescribing guidelines for both indication for use and dose administered. The remainder of the patients did not satisfy the guidelines, in whole or in part. If all ondansetron use had met the prescribing guidelines in the patients studied, a reduction in ondansetron use of 31% (16 185/52 260 mg) would have been realized. At an estimated cost of $5 per milligram, this reduction represents a potential cost savings of nearly $81,000, or $121 per patient studied. CONCLUSION: Since its introduction in 1991, ondansetron has become a commonly used antiemetic in US academic medical centers. Although ondansetron is safe and effective in improving patients' tolerance of emetogenic therapies, including cancer chemotherapy, its high cost has added a significant burden to the pharmaceutical budgets of many institutions. The study data suggest that compliance with ondansetron prescribing guidelines, with elimination of indiscriminant use, could result in significant cost savings.

Estrous cycle modification of rat uterine DNA alkylation by N-methyl-N-nitrosourea.

The present study was designed to determine whether the stage of the estrous cycle at the time of N-nitroso-N-methylurea (NMU) presentation altered DNA adduct formation and repair in the rat uterus. In uterus the rate of O6-methylguanine (O6-meGua) and 7-methylguanine (7-meGua) formation and the total yield of adducts was estrous cycle dependent. Uterine DNA from rats injected with NMU on diestrus formed O6-meGua and 7-meGua more rapidly and had significantly higher adduct levels than those rats injected on proestrus or estrus. Repair of O6-meGua and 7-meGua was also significantly faster between 1 and 24 h post-NMU in uterine DNA isolated from rats injected on diestrus compared to those injected on proestrus or estrus.

Interspecies analysis of the chemopreventive efficacy of dietary alpha-difluoromethylornithine.

The anticarcinogenic efficacy of the polyamine biosynthesis inhibitor, alpha-difluoromethylornithine (DFMO), was assessed in three rodent models of human epithelial cancer. In DMBA-induced female, Sprague-Dawley rats, DMFO treatment (3.2 or 6.4 g/kg diet) for 180 days significantly inhibited mammary carcinogenesis and reduced tumor-related intercurrent mortality compared to untreated controls. In male, C57BL/6x DBA/2F1 mice induced with N-butyl-N(4-hydroxybutyl)nitrosamine (OH-BBN), DFMO treatment (2 or 4 g/kg diet) concurrent with the period of carcinogen administration significantly reduced the incidence and severity of urinary bladder carcinomas. In methylnitrosourea (MNU)-induced male Syrian golden hamsters, DFMO (3.2 g/kg diet) numerically reduced the incidence and size of tracheal carcinoma relative to untreated controls. DFMO-mediated toxicity was not evident in any of the animals on study, although a slight reduction in mean body weight gain was evident in rats and mice.

Transmyocardial laser revascularization: a qualitative systematic review.

OBJECTIVE: To evaluate the status of transmyocardial laser revascularization (TMLR) from an evidence-based perspective to help hospitals make resource management decisions. STUDY DESIGN: Qualitative systematic review of the clinical literature. METHODS: We searched the reference databases MEDLINE, BIOSIS, EMBASE, SciSearch, and Current Contents to identify all articles related to TMLR published between January 1985 and March 1997. We collected, analyzed, and summarized clinical studies in evidence tables. RESULTS: The cumulative evidence available in the medical literature regarding the safety and effectiveness of TMLR encompasses approximately 2000 patients treated worldwide, primarily those with medically refractory angina. Preliminary data suggest that TMLR has an acceptable survival rate and effectively relieves angina in approximately 75% of patients. Data showing improved myocardial perfusion, cardiac function, or prognosis are inconclusive. The mechanism by which TMLR relieves angina is not yet known. CONCLUSIONS: Early evidence regarding TMLR suggests it will be useful for treating patients with end-stage coronary artery disease. Definitive recommendations await critical analysis of the results of ongoing randomized clinical trials, post-market surveillance studies, and third-party payer acceptance.

A multicenter drug use surveillance of intravenous immunoglobulin utilization in US academic health centers.

BACKGROUND: The role of intravenous immunoglobulin (IVIG) in treating a variety of diseases is controversial and under active investigation for at least two reasons: first, a severe shortage of IVIG products exists in the US; second, numerous off-label (not specified in the Food and Drug Administration [FDA]-approved label) uses for IVIG have been, and continue to be, described in the literature. However, most off-label uses are not supported by evidence from properly designed clinical trials. OBJECTIVE: To assess inpatient use of IVIG in a sample of US academic health centers and to compare it with published evidence-based model guidelines for IVIG use. METHODS: Data on the use of IVIG and subsequent clinical outcomes in 251 patients were collected prospectively from 12 institutions. Recommendations from consensus guidelines were used to categorize patients who received IVIG into one of four groups: labeled uses; off-label, recommended; off-label, recommended as alternative; and off-label, not recommended. Outcomes were scored according to guideline criteria. RESULTS: One hundred seven patients (43%) received IVIG for indications contained in the FDA-approved product label, 130 patients (52%) received IVIG for off-label indications, and 14 (5%) received undefined treatment. Among all patients administered IVIG, 31 (12%) were treated for off-label recommended reasons; 64 (26%) received off-label recommended as alternative therapy; and 35 (14%) received off-label not recommended therapy, as defined by model guidelines. Outcomes were not significantly different between the groups. CONCLUSIONS: Our findings suggest that IVIG continues to be used to treat a wide variety of conditions not specified in the product label. Furthermore, a substantial proportion of the reported off-label uses are not recommended according to evidence-based guidelines.

Recommendations for off-label use of intravenously administered immunoglobulin preparations. University Hospital Consortium Expert Panel for Off-Label Use of Polyvalent Intravenously Administered Immunoglobulin Preparations.

OBJECTIVE: To summarize consensus recommendations for off-label uses of standard intravenous immunoglobulin (IVIG), as developed by a University Hospital Consortium (UHC) Expert Panel. These findings are intended to help guide clinicians in the appropriate and efficient use of IVIG. PARTICIPANTS: The UHC-sponsored panel included eight physicians (board certified in critical care, hematology, immunology, neurology, oncology, pediatrics, or rheumatology) and two hospital pharmacists. EVIDENCE: MEDLINE and EMBASE were searched to identify all English-language review articles (n = 201) and original reports (n = 1904) on IVIG (human use only, excluding editorials, letters, and comments) published between January 1982 and March 1994. Relevant original reports (250) and review articles (87) were evaluated by the first author (T.A.R.). Extracted data included laboratory and clinical findings, objective measures, or clinical impressions. The evidence quality was graded by study design according to the US Preventive Services Task Force. CONSENSUS PROCESS: Before the panel meeting, a draft literature review and recommendations were produced by one of the authors (T.A.R.). The recommendations herein represent consensus (100% agreement) based on the published evidence. CONCLUSIONS: The UHC Expert Panel made specific recommendations for 53 off-label indications and the following general recommendations: (1) Usually IVIG is indicated only if standard approaches have failed, become intolerable, or are contraindicated; (2) IVIG products should be considered therapeutically equivalent and interchangeable; (3) interproduct pharmaceutical differences should be considered with the patient's clinical and physiological status when selecting an IVIG product; and (4) currently, IVIG manufacturers cannot guarantee freedom from viral contamination in the finished product.

Surveillance of colony-stimulating factor use in US academic health centers.

OBJECTIVE: To characterize and evaluate hematopoietic colony-stimulating factor (CSF) use, including cost implications, in US academic health centers. DESIGN: An observational study of patients who received granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) from September 1 to October 15, 1993. SETTING: Thirty academic health centers in the US. PARTICIPANTS: Five hundred sixty-five patients were evaluated. MAIN OUTCOME MEASURES: The appropriateness of CSF use was assessed, based on consensus-derived indication guidelines and the Food and Drug Administration-approved product labeling. Indication, type of CSF, and dosage were considered in determining the appropriateness of CSF therapy. RESULTS: Based on indication evaluation criteria, 71% of CSF use was appropriate, 7% was inappropriate, and 22% was unproven, although the majority of unproven use was deemed promising by the expert panel. Based on dosage evaluation criteria, 51% of CSF use was appropriate, 27% was inappropriate, and 22% was for promising and other unproven indications. More than 90% of the patients studied received G-CSF. Approximately 3.4% of patients who received G-CSF had an adverse event, compared with 22% of those who received GM-CSF. Approximately $791,000 was spent on CSF therapy in the 565 patients: $401,000 (51%) on appropriate indications and doses, $160,000 (20%) on inappropriate doses for appropriate indications, $124,000 (16%) on promising indications, and $106,000 (13%) on unproven or inappropriate indications. CONCLUSIONS: Substantial costs are incurred currently for CSF therapy without adequate literature support. Further studies are warranted to justify promising but unproven uses of CSFs, as well as to clarify proper dosing, monitoring, and relative safety of CSFs.