Effect of raloxifene on bone mineral density in premenopausal women at increased risk of breast cancer.

CONTEXT: Raloxifene is a promising breast cancer prevention agent in postmenopausal women at increased risk for breast cancer. The effects of raloxifene in premenopausal women are unknown. OBJECTIVE: We evaluated the effect of raloxifene in premenopausal women at increased risk for breast cancer on bone mineral density (BMD). DESIGN: This was a phase II clinical trial. SETTING: This study was conducted at an academic medical center. PARTICIPANTS: Thirty-seven premenopausal women at increased risk for breast cancer enrolled in the trial. Thirty subjects began treatment and 27 were evaluable. INTERVENTION: Raloxifene (60 mg daily) and elemental calcium (500 mg daily) were given for 2 yr. Subjects were followed up off medications for 1 yr. MAIN OUTCOME MEASURE: The primary end point was the intrasubject percent change in BMD at 1 yr measured by dual-energy x-ray absorptiometry. RESULTS: The mean baseline lumbar spine density was 1.027 g/cm(2). Lumbar spine density decreased 2.3% at 1 yr (P < 0.00001) and 3.5% at 2 yr (P < .00001). Percent change from yr 2 to 3 was +1.4%. The mean baseline total hip bone density was 0.905 g/cm(2). Total hip density decreased 0.3% at 1 yr and 1.0% at 2 yr (P = 0.033). Percent change from yr 2 to 3 was +1.7%. CONCLUSIONS: Raloxifene use is associated with a decrease in BMD in premenopausal women at increased risk for breast cancer. The clinical significance of this decrease is unknown and is attenuated with stopping raloxifene.

All trans-retinoic acid acts synergistically with hydroxytamoxifen and transforming-growth factor beta to stimulate apoptosis in MCF-7 breast cancer cells.

The anti-estrogen 4-hydroxytamoxifen (TAM) and vitamin A-related compounds, the retinoids, in combination act synergistically to inhibit growth of breast cancer cells in vitro and in vivo. To clarify the mechanism of this synergism, the effect of TAM and all trans-retinoic acid (AT) on proliferation of MCF-7 breast cancer cells was studied in vitro. TAM and AT acted synergistically to cause a time-dependent and dose-dependent inhibition of MCF-7 cell growth. In a temporally related manner, TAM+AT acted synergistically to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis. TAM and AT each blocked cell cycle progression throughout 7 days of treatment but without any synergistic or additive effect on this process, indicating a selective synergism for apoptosis. The negative growth factor-transforming growth factor beta (TGFbeta) is secreted by these cells and was studied as a potential mediator of the synergistic effects of TAM+AT on apoptosis. TAM+AT acted synergistically to induce a fivefold increase in TGFbeta1 secretion over 72 h. TGFbeta1 alone had no apoptotic effects on these cells; however, TGFbeta1 in combination with AT acted synergistically to inhibit growth, to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis of these cells in a manner comparable with that noted for TAM+AT. The synergism of both TAM+AT and TGFbeta1+AT for apoptosis was suppressed by estradiol. Co-incubation of TAM+AT with anti-TGFbeta antibody did not block down-regulation of Bcl-2 protein expression or stimulation of apoptosis. The synergistic effects of TAM+AT on apoptosis therefore occur independently of TGFbeta, although TGFbeta may interact with AT in a novel manner to provide another important anti-proliferative mechanism for breast cancer cells.

Weight and body composition changes during and after adjuvant chemotherapy in women with breast cancer.

Uncontrolled trials have reported significant weight gain in women with breast cancer during treatment with adjuvant chemotherapy. We prospectively evaluated body composition before (visit 1), immediately after (visit 2), and 6 months after (visit 3) chemotherapy in 20 women with stages I-IIIA breast cancer [body mass index (BMI): 24.1 +/- 3.9 kg/m(2)]. We compared their weight change to 51 age- and BMI-matched healthy controls (BMI: 25.5 +/- 3.8 kg/m(2)). In women with breast cancer, there was no weight change from visit 1-2, or from visit 1-3, but weight increased from visit 2-3 (+1.09 +/- 2.46 kg; P = 0.05). Weight change was not different from controls during either interval. In the breast cancer group, the percentage of body fat assessed by air displacement plethysmography increased, and fat-free mass decreased from visit 1-2 (+2.3 +/- 4% and -2.2 +/- 4%; P = 0.02) and from visit 1-3 (+4.0 +/- 6% and -3.8 +/- 6%; P = 0.01). By dual energy x-ray absorptiometry, the percentage of body fat increased from visit 2-3 (+0.9 +/- 1.6%; P = 0.02). Bone mineral content decreased from visit 2-3 (-0.02 +/- 0.04 kg; P = 0.02) and from visit 1-3 (-0.04 +/- 0.06 kg; P = 0.005). By computed tomography, the visceral adipose to sc adipose tissue ratio decreased from visit 1-3 (-0.02 +/- 0.05 ml; P = 0.02). We conclude that, compared with controls, women with breast cancer receiving modern adjuvant chemotherapy regimens show no significant changes in weight during the first year of their treatment. They do, however, appear to undergo unfavorable changes in body composition.

Noise reduction in oncology FDG PET images by iterative reconstruction: a quantitative assessment.

UNLABELLED: Tumor detection depends on the contrast between tumor activity and background activity and on the image noise in these 2 regions. The lower the image noise, the easier the tumor detection. Tumor activity contrast is determined by physiology. Noise, however, is affected by many factors, including the choice of reconstruction algorithm. Previous simulation and phantom measurements indicated that the ordered-subset expectation maximization (OSEM) algorithm may produce less noisy images than does the usual filtered backprojection (FBP) method, at equivalent resolution. To see if this prediction would hold in actual clinical situations, we quantified noise in clinical images reconstructed with both OSEM and FBP. METHODS: Three patients (2 with colon cancer, 1 with breast cancer) were imaged with FDG PET using a "gated replicate" technique that permitted accurate measurement of noise at each pixel. Each static image was acquired as a gated image sequence, using a pulse generator with a 1-s period, yielding 40 replicate images over the 10- to 15-min imaging time. The images were or were not precorrected for attenuation and were reconstructed with both FBP and OSEM at comparable resolution. From these data, images of pixel mean, SD, and signal-to-noise ratio (S/N) could be produced, reflecting only noise caused by the statistical fluctuations in the emission process. RESULTS: Noise did not vary greatly over each FBP image, even when image intensity varied greatly from one region to the next, causing S/N to be worse in low-activity regions than in high-activity regions. In contrast, OSEM had high noise in hot regions and low noise in cold regions. OSEM had a much better S/N than did FBP in cold regions of the image, such as the lungs (in the attenuation-corrected images), where improvements in S/N averaged 160%. Improvements with OSEM were less dramatic in hotter areas such as the liver (averaging 25% improvement in the attenuation-corrected images). In very hot tumors, FBP actually produced higher S/Ns than did OSEM. CONCLUSION: We conclude that OSEM reconstruction can significantly reduce image noise, especially in relatively low-count regions. OSEM reconstruction failed to improve S/N in very hot tumors, in which S/N may already be adequate for tumor detection.

Iatrogenic gallbladder perforation: conservative management by percutaneous drainage and cholecystostomy.

Gallbladder perforation is an uncommon complication of percutaneous liver biopsy. Diagnosis is usually made clinically and management has traditionally been by cholecystectomy. We report a case of gallbladder perforation secondary to percutaneous liver biopsy diagnosed by dimethyl iminodiacetic acid (HIDA) scan and managed successfully by percutaneous drainage and cholecystostomy. This case illustrates the role of conservative management in selected cases of gallbladder perforation.

Pilot trial of the safety, tolerability, and retinoid levels of N-(4-hydroxyphenyl) retinamide in combination with tamoxifen in patients at high risk for developing invasive breast cancer.

PURPOSE: N-(4-hydroxyphenyl) retinamide (¿4-HPR, Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) have synergistic antitumor and chemopreventive activity against mammary cancer in preclinical studies. We performed a pilot study of this combination in women at high risk for developing breast cancer. PATIENTS AND METHODS: Thirty-two women were treated with four cycles of 4-HPR, 200 mg orally (PO) for 25 days of each 28-day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone. Tolerability, dark adaptometry, tissue biopsies, and retinoid plasma concentrations (Cp) were evaluated. RESULTS: Symptomatic reversible nyctalopia developed in two patients (6%) on 4-HPR, but 16 (73%) of 22 patients had reversible changes in dark adaptation, which correlated with relative decrease in Cp retinol (P

Double-blind, randomized study of the effects of influenza vaccination on the specific antibody response and clinical course of patients with chronic fatigue syndrome.

OBJECTIVE: To determine whether influenza immunization is associated with early side effects, a deleterious impact on the illness course and depressed antibody response in patients with chronic fatigue syndrome (CFS). DESIGN: Prospective, randomized, double-blind, placebo controlled trial. CFS patients and healthy volunteers filled out a questionnaire on immunization side effects and had hemagglutination-inhibiting (HI) antibody titres measured pre- and three weeks after immunization. CFS patients completed symptom and function questionnaires before and during the six-week, postimmunization period. SETTING: Ambulatory care. POPULATION STUDIED: Convenience sample of 40 CFS patients fulfilling the Centers for Disease Control and Prevention criteria and 21 demographically matched healthy volunteers. INTERVENTIONS: CFS patients were randomly selected to receive commercially available whole virus influenza vaccine (n=19) or an injection of saline placebo (n=21). Healthy volunteers received vaccine only. MAIN RESULTS: As a group, immunized CFS patients had lower geometric mean HI antibody rises than healthy volunteers (P<0.001). However, there was no difference in the rates of fourfold titre rises, and immunization did achieve a probably protective titre (1:32 or greater) in most CFS patients. No difference could be detected between immunized and placebo CFS patients in immunization side effects, although CFS patients as a group reported four times as many side effects as healthy volunteers. Further, in the six weeks following immunization, placebo and immunized CFS patients did not demonstrate any differences in terms of functioning, symptom severity and sleep disturbance. CONCLUSIONS: In patients with CFS, influenza immunization is safe, not associated with any excess early reactions, and stimulates an immunizing response comparable with that of healthy volunteers.

Vascular endothelial growth factor, nitric oxide, and leptin follicular fluid levels correlate negatively with embryo quality in IVF patients.

OBJECTIVE(S): To measure vascular endothelial growth factor (VEGF), nitric oxide (NO) and leptin levels in individual ovarian follicles and to examine their relationships with perifollicular blood flow, follicular metabolic indices, and the developmental potential of the corresponding oocyte and embryo. DESIGN: Prospective study. SETTING: Academic, tertiary care institution. PATIENT(S): Unselected IVF patients. INTERVENTION(S): Color-pulsed Doppler analysis of perifollicular blood flow; determination of partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2), and pH and VEGF, leptin and NO levels in follicular fluid. MAIN OUTCOME MEASURE(S): Fertilization and day 3 embryo morphology and cleavage. RESULT(S): Fifty-five follicular fluid samples from 16 patients were studied. Mean follicular fluid levels were as follows: VEGF, 1,046+/-863.7 pg/mL (range, <63-3,332.7 pg/mL); NO3/NO2, 34.2+/-12 microM (range, 16.4-76.1 microM); and leptin, 20.1+/-12.1 ng/mL (range, 3.3-52.2 ng/mL). Vascular endothelial growth factor had a negative correlation with embryo morphology (r = -0.28, P = .01). Leptin demonstrated a negative correlation with follicular pO2 (r = -0.42, P = .005) and a positive correlation with follicular pCO2 (r = 0.36, P = .02). Follicular leptin levels correlated positively with VEGF levels (r = 0.46, P = .008) and with NO3/NO2 levels (r = 0.39, P =.006). CONCLUSION(S): Vascular endothelial growth factor, NO and leptin appear to be markers of follicular hypoxia and suboptimal embryo development. Whether fluctuations of these regulatory factors determine or reflect changes in the follicular microenvironment affecting oocyte developmental potential remains to be elucidated.

Women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B before a rise in day 3 follicle-stimulating hormone.

OBJECTIVE: To test the hypothesis that women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B levels before a rise in day 3 serum FSH levels. DESIGN: Case-control study. SETTING: Tertiary care fertility center. PATIENT(S): One hundred nine women with nonovarian infertility (tubal factor or male factor) and 47 women with declining ovarian reserve who underwent assisted reproductive techniques. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum inhibin B and FSH levels, number of ampules of gonadotropins administered, E2 levels on the day of hCG administration, number of oocytes retrieved, clinical pregnancy rate, and cycle cancellation rate. RESULT(S): Women who had declining ovarian reserve as demonstrated by an increased gonadotropin requirement, a decreased E2 response, fewer retrieved oocytes, a lower clinical pregnancy rate, and a higher cycle cancellation rate had lower day 3 serum inhibin B levels despite having nonelevated day 3 FSH levels similar to those of women with nonovarian infertility. CONCLUSION(S): Women with declining ovarian responsiveness and clinical outcomes consistent with declining ovarian reserve had decreased day 3 serum inhibin B levels despite having nonelevated day 3 serum FSH concentrations. Declining ovarian reserve may be demonstrated by a decrease in day 3 inhibin B levels before a rise in day 3 FSH levels.

Enterocutaneous fistula in cancer patients: etiology, management, outcome, and impact on further treatment.

Enterocutaneous fistulae that develop in patients with cancer represent a difficult management situation, which is often complicated by prior treatment including surgery, radiation therapy, and chemotherapy. A fistula may in turn delay potentially beneficial treatment of the underlying malignancy. To provide a better understanding of this problem, we reviewed the National Institutes of Health experience with enterocutaneous fistulae in adult patients with cancer. The medical records of patients with cancer who developed a fistula from the gastrointestinal tract during the period 1980 through 1994 were reviewed. Etiology, management, outcome, and impact on further treatment were assessed. Twenty-five patients with gastrointestinal fistulae were identified. The most common primary tumor site was the colon/rectum in males and the ovary in women. The majority of patients had metastatic disease at diagnosis and a history of prior therapy and presented with anorexia and weight loss. The fistula was usually single, most commonly developed from the jejunum/ileum (13 patients) or colon/rectum (6 patients), and occurred postoperatively after procedures on the small bowel (10 patients) or colon (8 patients). Malnutrition and sepsis developed in 60 per cent of patients. Thirty-day mortality was 16 per cent and correlated with prior radiation therapy, location and output from the fistula, and hypoalbuminemia. An enterocutaneous fistula negatively impacted on the provision of further therapy for the majority of patients (63%). Enterocutaneous fistula in the patient with cancer occurs most frequently in the setting of extensive prior therapy and is associated with prolonged morbidity. Identification of high-risk patients and early management of fistulas once they develop may prevent delays in subsequent cancer therapy and decrease morbidity.

Elevated level of follicular fluid vascular endothelial growth factor is a marker of diminished pregnancy potential.

OBJECTIVE: To evaluate whether differences in follicular fluid vascular endothelial growth factor (FF VEGF) concentrations are observed between women achieving a clinical pregnancy and those failing to conceive. DESIGN: Retrospective chart review and analysis of FF VEGF concentrations. SETTING: University teaching center. PATIENT(S): Fifty-seven women < or =42 years of age undergoing follicular aspiration in preparation for IVF or GIFT. INTERVENTION(S): Analysis of FF VEGF concentrations and chart review of a single IVF or GIFT cycle. MAIN OUTCOME MEASURE(S): Follicular fluid VEGF concentrations, clinical pregnancy rate, age, ampules of gonadotropins used, oocytes retrieved, peak estradiol serum concentrations, day 3 FSH levels, and fertilization rate. RESULT(S): Women who did not conceive had higher FF VEGF concentrations than women achieving a clinical pregnancy (4.409 + 2,387 versus 2.793 +/- 1,180 pg/mL: P < .001). A negative correlation was observed between FF VEGF concentrations and peak estradiol levels and number of oocytes retrieved. A positive correlation was found for FF VEGF and patient's age and ampules of gonadotropins used. CONCLUSION(S): Elevated FF VEGF concentrations are associated with poor conception rates after IVF or GIFT.

Dimeric inhibin: a direct marker of ovarian aging.

OBJECTIVE: To investigate whether luteal secretion of inhibin-a is altered in the perimenopausal transition and to evaluate whether luteal inhibin secretion is correlated with other markers of ovarian reserve such as FSH and inhibin-b. DESIGN: Prospective study. SETTING: Reproductive Endocrinology Laboratories at The Ohio State University. PATIENT(S): Twenty-five women 39-52 years of age with regular menstrual cycles. INTERVENTION(S): Daily urine samples were monitored (LH predictor kit) to identify the day of ovulation. Blood samples obtained on days 6 and 8 after the LH surge and on day 3 of the subsequent follicular phase were assayed for FSH, E2, progesterone. inhibin-a, and inhibin-b. MAIN OUTCOME MEASURE(S): Serum levels of inhibin-a, inhibin-b, FSH, E2, and progesterone. RESULT(S): Luteal phase inhibin-a and follicular phase inhibin-b were correlated inversely with age in perimenopausal women. In addition, luteal phase inhibin-a and follicular phase inhibin-b levels were correlated inversely with follicular phase FSH levels. CONCLUSION(S): Both luteal phase inhibin-a and follicular phase inhibin-b levels are correlated inversely with age during the fifth decade of life. These findings suggest that corpus luteum function is altered during the perimenopausal transition. Moreover, these direct measures of ovarian function may be more sensitive indicators of "ovarian reserve" than indirect indicators such as pituitary FSH secretion.

Selection of local therapy after neoadjuvant chemotherapy in patients with stage IIIA,B breast cancer.

BACKGROUND: Stage IIIA,B breast cancer is commonly treated with neoadjuvant chemotherapy because of high objective response rates and improved operability. Criteria for subsequent selection of local therapy--mastectomy, radiotherapy, or both--are not well defined. We adopted a policy of selective local therapy based on rebiopsy of the breast and clinical axillary lymph node status at the time of best response to chemotherapy. METHODS: Between 1980 and 1993, 126 patients with stage IIIA,B breast cancer were treated with neoadjuvant chemotherapy and definitive local therapy. The long-term incidence of locoregional failure (in-breast, chest wall, axilla, supraclavicular, neck), relapse-free survival, and overall survival was determined. RESULTS: The overall clinical objective response rate to chemotherapy was 95.2%. Eighty-three patients underwent mastectomy, with negative margins achieved in 91.6%. Forty-two patients had breast preservation; the overall in-breast recurrence rate was 19.0% (8 of 42 patients). The overall locoregional recurrence rate by site was: chest wall-8.7% (11 of 126 patients), axilla-8.7% (11 of 126 patients), supraclavicular-5.6% (7 of 126 patients), and neck-4.0% (5 of 126 patients). The axillary recurrence rate was 6.6% (5 of 76 patients) for clinically negative axilla treated with radiotherapy only, and 12.0% (6 of 50 patients) for clinically positive axilla treated with surgery only. The overall long-term survival probabilities (6 years) according to stage were: stage IIIA-58.0%, stage IIIB(noninflam)-58.0%, stage IIIB(inflam)-36.0%. CONCLUSIONS: These findings support a selective approach to local therapy in patients with stage IIIA,B breast cancer. This approach provides local control in most patients, and allows for breast preservation and elimination of axillary dissection in selected patients.

Inhibin-B: the physiologic basis of the clomiphene citrate challenge test for ovarian reserve screening.

OBJECTIVE: To determine inhibin-B concentrations during ovarian reserve screening in women with normal and diminished ovarian reserve as determined by the clomiphene citrate challenge test. DESIGN: Retrospective. SETTING: Tertiary fertility center. PATIENT(S): Women undergoing ovarian reserve screening for a routine fertility evaluation. INTERVENTION(S): Clomiphene citrate challenge test. MAIN OUTCOME MEASURE(S): Inhibin-B concentrations on menstrual days 3 and 10. RESULT(S): Nineteen patients with normal ovarian reserve and 15 with diminished ovarian reserve had serum inhibin-B concentrations determined during ovarian reserve screening. For all patients, day 10 inhibin-B concentrations were higher than day 3. Women with normal ovarian reserve had higher inhibin-B concentrations on both days 3 and 10 than women with diminished ovarian reserve. Inhibin-B concentrations demonstrated a negative correlation with FSH levels on both cycle days 3 and 10 and a positive correlation with E2 on cycle day 10. CONCLUSION(S): Women with diminished ovarian reserve during ovarian reserve screening had reduced granulosa cell inhibin-B production compared with women with normal ovarian reserve. The lower inhibin-B concentrations may be responsible for the elevated FSH concentrations and may be indicative of the aging follicular apparatus.

Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity.

PURPOSE: This randomized, prospective study assesses the impact of postoperative external-beam radiation therapy on local recurrence (LR), overall survival (OS), and quality of life after limb-sparing resection of extremity sarcomas. PATIENTS AND METHODS: Patients with extremity tumors and a limb-sparing surgical option were randomized to receive or not receive postoperative adjuvant external-beam radiotherapy. Patients with high-grade sarcomas received postoperative adjuvant chemotherapy whereas patients with low-grade sarcomas or locally aggressive nonmalignant tumors were randomized after surgery alone. RESULTS: Ninety-one patients with high-grade lesions were randomized; 47 to receive radiotherapy (XRT) and 44 to not receive XRT. With a median follow-up of 9.6 years, a highly significant decrease (P2 = .0028) in the probability of LR was seen with radiation, but no difference in OS was shown. Of 50 patients with low-grade lesions (24 randomized to resection alone and 26 to resection and postoperative XRT), there was also a lower probability of LR (P2 = .016) in patients receiving XRT, again, without a difference in OS. A concurrent quality-of-life study showed that extremity radiotherapy resulted in significantly worse limb strength, edema, and range of motion, but these deficits were often transient and had few measurable effects on activities of daily life or global quality of life. CONCLUSION: This study indicates that although postoperative external-beam radiotherapy is highly effective in preventing LRs, selected patients with extremity soft tissue sarcoma who have a low risk of LR may not require adjuvant XRT after limb-sparing surgery (LSS).

A double-blind, randomized study of three antimicrobial regimens in the prevention of infections after elective colorectal surgery.

The objective of this study was to assess the prophylactic efficacy of cefoxitin, ceftizoxime, and metronidazole-gentamicin in colorectal surgery. A double-blind, randomized prospective clinical trial design was used in a Canadian tertiary care teaching hospital. Patients were randomized to one of three treatment groups and received three doses of a study drug (30 min preoperative and 2 postoperative doses at 12 and 24 h). Cefoxitin and ceftizoxime were given as 1000-mg doses. Metronidazole-gentamicin was given as 500 mg of metronidazole plus 120 mg of gentamicin in a minibag. High-risk patients (bowel ischemia, diabetic, current steroid use, etc.) received 10 postoperative doses. Patients with infections, prior antibiotics, or study drug allergies were excluded. Over 30 months, 153 patients were enrolled. Thirty-one patients were excluded for protocol violations. Of the 122 evaluable patients (38 ceftizoxime, 45 metronidazole-gentamicin, 39 cefoxitin), there was no difference across groups regarding sex, age, weight, preoperative Apache II score, and prior history of bowel surgery. Groups were equivalent regarding surgeon, nursing unit, high-risk status (six ceftizoxime, seven metronidazole-gentamicin, seven cefoxitin), bowel preparation, and procedure (including blood loss, drains, organ injury, intraoperative complications). Clinically significant infection requiring systemic antibiotics (7-day hospital and 30-day follow-up) was identified in 0% of ceftizoxime, 15% of metronidazole-gentamicin, and 26% of cefoxitin receiving patients (p = 0.005). Mean ASEPSIS scores for each group were 2.3 (range 0-15) for ceftizoxime, 9.2 (range 0-45) for metronidazole-gentamicin, and 10.4 (range 0-75) for cefoxitin (p = 0.01). Ceftizoxime patients tended to have a shorter total hospital stay (12.2 days versus 19.7 days for cefoxitin versus 13.9 days for metronidazole-gentamicin; p = 0.04), although the procedure to discharge interval was not significantly different (p = 0.09). There was no difference in clinical outcome according to risk status. Anaerobic bacteria were observed more commonly in the ceftizoxime and cefoxitin groups, whereas enteric Gram-negative aerobes were observed most often in the metronidazole-gentamicin group. The study regimens were generally well tolerated. Drug costs were equivalent between ceftizoxime and cefoxitin and lowest with the metronidazole-gentamicin regimen. Ceftizoxime appears to be more effective for the prevention of infection in colorectal surgery than either cefoxitin or metronidazole-gentamicin in the dosage regimens studied.

Follicular fluid vascular endothelial growth factor concentrations are elevated in women of advanced reproductive age undergoing ovulation induction.

OBJECTIVE(S): To determine whether follicular fluid (FF) from women of advanced reproductive age had a relative deficiency of the angiogenic cytokine vascular endothelial growth factor/vascular permeability factor. Furthermore, we sought to determine whether luteinized granulosa cells secrete vascular endothelial growth factor/vascular permeability factor in response to hypoxia. DESIGN: Retrospective cohort study. SETTING: University teaching hospital. PATIENTS: Women undergoing follicular aspiration after superovulation in preparation for IVF-ET. Women of advanced reproductive age consisted of 21 women > or = 38 years old (range, 38 to 46 years); 15 subjects < or = 30 years served as the control population. INTERVENTION(S): Granulosa cells and FF were collected by transvaginal aspiration 35 hours after hCG. Granulosa cells from two women were cultured for 24 and 48 hours in M199 + 10% fetal bovine serum in 1% O2-5% CO2-94% N2 (hypoxic) or 95% air-5% CO2 (normoxic) without or with 0.1 mol/L cobalt chloride. MAIN OUTCOME MEASURE(S): Pooled FF vascular endothelial growth factor/vascular permeability factor concentrations and media vascular endothelial growth factor/vascular permeability factor accumulation at 24 and 48 hours were determined. RESULT(S): Follicular fluid vascular endothelial growth factor/vascular permeability factor concentrations were higher in advanced reproductive age women compared with younger women (3,735 +/- 2,155 versus 2,205 +/- 952 pg/mL, mean +/- SD). Accumulation of vascular endothelial growth factor/vascular permeability factor at 24 and 48 hours was 391 +/- 54 and 744 +/- 2 pg/mL in media maintained in 5% CO2 and air. Cobalt chloride induced a marked increase in vascular endothelial growth factor/vascular permeability factor (2,008 +/- 52 pg/mL at 24 hours and 3,630 +/- 519 pg/mL at 48 hours). An intermediate but significant increase in vascular endothelial growth factor/vascular permeability factor (733 +/- 35 pg/mL at 24 hours and 2,675 +/- 864 pg/mL at 48 hours) was observed with 1% O2 compared with normoxic controls. CONCLUSION(S): After hMG and hCG administration the FF from women of advanced reproductive age showed increased vascular endothelial growth factor/vascular permeability factor concentrations compared with younger women. Increased vascular endothelial growth factor/vascular permeability factor concentrations could be consistent with a hypoxic environment within follicles of older women.

Interleukin-1 beta modulates prostaglandin and progesterone production by primate luteal cells in vitro.

Increasing evidence suggests that cytokine products of the immune system may play a regulatory role in corpus luteum regulation in several species. The role of cytokines in primate luteal function, however, remains unclear. In the present study we examined the effects of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), and interferon-gamma (IFN-gamma) on progesterone and prostaglandin (PGE2, PGF2 alpha) production by primate luteal cells in vitro. Specifically, corpora lutea were removed from normally cycling cynomolgus monkeys (n = 30 corpora lutea) during either the early (Days 3-5 after the estimated LH surge), mid (Days 8-10), or late (Days 12-14) luteal phase of the menstrual cycle. The corpora lutea were dispersed into individual cells using collagenase, DNase, and hyaluronidase. Approximately 50,000 viable luteal cells per tube were incubated in Ham's F-10 medium with increasing concentrations of IL-1 beta (0.1-10 ng/ml), TNF alpha (1-100 ng/ml), or IFN-gamma (10-1000 U/ml) in the presence and absence of hCG for 8 h at 37 degrees C. TNF alpha and IFN-gamma had no effect on progesterone PGE2, or PGF2 alpha production during any phase of the cycle at the doses tested. In contrast, IL-1 beta significantly stimulated PGF2 alpha production in a dose-dependent manner during the mid and late luteal phases (p < 0.05). Human CG alone had no effect on PGE2 or PGF2 alpha production by dispersed luteal cells in vitro but inhibited IL-1 beta-stimulated PGF2 alpha production. As expected, hCG stimulated progesterone production by primate luteal cells in vitro. Interestingly, IL-1 beta inhibited this hCG stimulation of progesterone production. In summary, these date suggest that IL-1 beta is a potentially important modulator of prostaglandin production by the primate corpus luteum. In view of this, cytokine-mediated changes in prostaglandin production by the primate corpus luteum may participate in the physiological regulation of luteal function.