Direct renin inhibition improves parasympathetic function in diabetes.

AIM: The renin-angiotensin-aldosterone system (RAAS) and autonomic nervous system regulate the cardiovascular system. Blockade of the RAAS may slow the progression of end-organ damage. Direct renin inhibition offers a means for blocking the RAAS. The objective of this study was to examine the effect of direct renin inhibition on cardiovascular autonomic function. METHODS: In this double-blind, placebo-controlled trial, 60 individuals with diabetes were randomly assigned to 300 mg of aliskiren or placebo once daily for 6 weeks. The primary end point was a change in tests of cardiovascular autonomic function. Autonomic function was assessed by power spectral analysis and RR-variation during deep breathing [i.e. mean circular resultant (MCR), expiration/inspiration (E/I) ratio]. The MCR and E/I ratio assess parasympathetic function. Secondary measures included change in biochemical parameters [e.g. plasma renin activity, leptin and interleukin-6]. Change in cardiovascular autonomic function and blood analytes were analysed by a mixed effects model for repeated measures. RESULTS: Baseline characteristics were similar between treatment groups. In response to aliskiren compared with placebo, blood pressure was reduced as well as plasma renin activity [from 2.4 ± 3.8 (mean ± standard deviation) to 0.5 ± 0.4 µg/l/h, p < 0.001]. There was a significant interaction (aliskiren × visit) for MCR (p = 0.003) and E/I ratio (p = 0.003) indicating improvement in MCR and E/I ratio for those on aliskiren. MCR means, baseline vs. follow-up, were 41.8 ± 19.7 vs. 50.8 ± 26.1 (aliskiren) and 38.2 ± 23.6 vs. 37.5 ± 24.1 (placebo). CONCLUSIONS: Parasympathetic function (i.e. MCR and E/I ratio) was enhanced by downregulation of the RAAS.

Glucose challenge test screening for prediabetes and undiagnosed diabetes.

AIMS/HYPOTHESIS: Diabetes prevention and care are limited by lack of screening. We hypothesised that screening could be done with a strategy similar to that used near-universally for gestational diabetes, i.e. a 50 g oral glucose challenge test (GCT) performed at any time of day, regardless of meal status, with one 1 h sample. METHODS: At a first visit, participants had random plasma and capillary glucose measured, followed by the GCT with plasma and capillary glucose (GCTplasma and GCTcap, respectively). At a second visit, participants had HbA(1c) measured and a diagnostic 75 g OGTT. RESULTS: The 1,573 participants had mean age of 48 years, BMI 30.3 kg/m(2) and 58% were women and 58% were black. Diabetes (defined by WHO) was present in 4.6% and prediabetes (defined as impaired glucose tolerance [2 h glucose 7.8-11.1 (140-199 mg/dl) with fasting glucose

Unrecognized glucose intolerance is not associated with depression. Screening for Impaired Glucose Tolerance study 3 (SIGT 3).

AIMS: To understand the metabolic and temporal links in the relationship between diabetes and depression, we determined the association between depressive symptoms and unrecognized glucose intolerance. METHODS: In a cross-sectional study, 1047 subjects without known diabetes were screened for diabetes or pre-diabetes using the oral glucose tolerance test and for depressive symptoms using the Patient Health Questionnaire (PHQ). RESULTS: Mean age was 48 years, body mass index 30 kg/m(2); 63% were female, 54% black, 11% previously treated for depression and 10% currently treated; 5% had diabetes and 34% pre-diabetes. Median PHQ score was 2 (interquartile range 0-5). Depressive symptoms did not increase with worsening glucose tolerance, after adjusting for age, sex, ethnicity, body mass index, family history, exercise, education and depression treatment. CONCLUSIONS: There is no association between depressive symptoms and unrecognized glucose intolerance. However, it remains possible that diagnosed diabetes, with its attendant health concerns, management issues, and/or biological changes, may be a risk for subsequent development of depression. Thus, patients with newly diagnosed diabetes should be counselled appropriately and monitored for the development of depression.

Tetrahydrobiopterin: a novel antihypertensive therapy.

Tetrahydrobiopterin (BH(4)) is a cofactor for the nitric oxide (NO) synthase enzymes, such that its insufficiency results in uncoupling of the enzyme, leading to release of superoxide rather than NO in disease states, including hypertension. We hypothesized that oral BH(4) will reduce arterial blood pressure (BP) and improve endothelial function in hypertensive subjects. Oral BH(4) was given to subjects with poorly controlled hypertension (BP >135/85 mm Hg) and weekly measurements of BP and endothelial function made. In Study 1, 5 or 10 mg kg(-1) day(-1) of BH(4) (n=8) was administered orally for 8 weeks, and in Study 2, 200 and 400 mg of BH(4) (n=16) was given in divided doses for 4 weeks. Study 1: significant reductions in systolic (P=0.005) and mean BP (P=0.01) were observed with both doses of BH(4). Systolic BP was 15+/-15 mm Hg (P=0.04) lower after 5 weeks and persisted for the 8-week study period. Study 2: subjects given 400 mg BH(4) had decreased systolic (P=0.03) and mean BP (P=0.04), with a peak decline of 16+/-19 mm Hg (P=0.04) at 3 weeks. BP returned to baseline 4 weeks after discontinuation. Significant improvement in endothelial function was observed in Study 1 subjects and those receiving 400 mg BH(4). There was no significant change in subjects given the 200 mg dose. This pilot investigation indicates that oral BH(4) at a daily dose of 400 mg or higher has a significant and sustained antihypertensive effect in subjects with poorly controlled hypertension, an effect that is associated with improved endothelial NO bioavailability.

Intratumor variability in prognostic indicators may be the cause of conflicting estimates of patient survival and response to therapy.

The DNA index, percentage of S-phase cells, proliferation fraction, and glutathione (GSH) content were determined at more than 1100 separate sites in 140 human tumors and 140 normal tissues. The study showed that the variability was so great from site to site within a tumor that there was only a 61% chance of identifying an aneuploid tumor clone (when present) if only a single site sample was analyzed for DNA content. Similar broad variability was observed in the percentage of S-phase cells, proliferation fraction, and glutathione content. Since these tumor characteristics are often used to predict the outcome of therapy and patient survival, the inaccuracy and underestimation of the test results may cause conflicting or erroneous predictions. The probability of finding an aneuploid clone or elevated percentage of S-phase cells proliferation fraction and GSH content increased dramatically as the number of sample sites studied per tumor was increased. Statistical analyses indicated that in order to achieve a 90% probability that the test results for these parameters were representative of the whole tumor: (a) all single site testing should be abandoned; (b) assays should be performed on samples taken from 3-7 different sites within each tumor; or (c) samples from each tumor should be pooled and the analyses run on a thoroughly mixed or homogenized aliquot of the multisite sample.

Epidermal growth factor receptor: an independent predictor of survival in astrocytic tumors given definitive irradiation.

PURPOSE: To determine whether the expression of epidermal growth factor receptor (EGFR) protein was predictive of patient survival independently of other prognostic factors in astrocytic tumors. METHODS AND MATERIALS: Epidermal growth factor receptor protein expression was investigated immunohistochemically in formalin-fixed, paraffin-embedded surgical specimens of 55 glioblastoma multiforme, 14 anaplastic astrocytoma, and 2 astrocytomas given definitive irradiation. We evaluated the relationship of EGFR protein expression and tumor grade, histologic features, age at diagnosis, sex, patient survival, and recurrence-free survival. RESULTS: The percentage of tumor cells which were EGFR positive related to reduced survival by Cox regression analysis in both univariate (p = 0.0424) and multivariate analysis (p = 0.0016). Epidermal growth factor receptor positivity was the only 1 of 11 clinical and histological variables associated with decreased recurrence-free survival by either univariate (p = 0.0353) or multivariate (p=0.0182) analysis. Epidermal growth factor receptor protein expression was not related to patient age, sex, or histologic features. CONCLUSION: Epidermal growth factor receptor positivity was a significant and independent prognostic indicator for overall survival and recurrence-free survival for irradiated patients with astrocytic gliomas.

Six-year survival after coronary thrombolysis and early revascularization for acute myocardial infarction.

Six-year follow-up was conducted in a consecutive series of 192 patients receiving thrombolytic therapy for acute myocardial infarction (AMI) with ST-segment elevation. Cardiac catheterization was performed within a day, and patients with an open infarct artery routinely had early revascularization: 99 (67%) underwent coronary bypass surgery and 18 (12%) coronary angioplasty. With this treatment strategy, 6-year cardiac mortality was 14.5%, 6% (12 patients) in hospital and 9% (16 patients) for survivors of hospitalization. Multivariate analysis showed that predictors of cardiac death among survivors of hospitalization were a closed infarct artery at catheterization (p less than 0.01), diabetes (p less than 0.01) and anterior myocardial infarction (p = 0.01). A subset of 146 patients underwent radionuclide angiography before hospital discharge; for them, predictors of mortality were a closed infarct artery at catheterization (p less than 0.01), anterior wall AMI (p = 0.02), and Killip class III to IV on admission (p less than 0.06). Left ventricular ejection fraction was not a significant predictor of mortality for this subset of patients.

Wound complications after median sternotomy. Relationship to internal mammary grafting.

Case histories of 2582 patients requiring median sternotomy for coronary artery bypass grafting between January 1982 and August 1986 were retrospectively reviewed. Only saphenous vein grafts were used in 230 patients, one mammary artery graft was used in 1626 patients, and both mammary arteries were used in 726 patients. The relationship of potential risk factors and wound complication was evaluated. The overall incidence of wound complications was 0.81%-0.43% in the saphenous vein graft group, 0.49% in the single mammary group, and 1.65% in the bilateral mammary group. Graft type and a number of potential risk factors were analyzed in a logistic regression analysis to determine significant predictors of wound complications. The results indicated that pneumonia, obesity, reexploration, use of the intraaortic balloon pump, and diabetes were significant risk factors contributing to the probability of wound complications. Bilateral mammary grafting was significantly associated with the increased probability of a wound complication developing. Bilateral mammary grafting increased the chance of wound complication nearly five times that of saphenous vein grafting and three times that of single mammary grafting. Mammary artery grafts have been shown to achieve greater long-term patency than saphenous vein grafts, and their continued use is encouraged. However, the potential for increased wound problems should be considered along with other significant preoperative risk factors such as insulin-dependent diabetes, chronic pulmonary disease, and obesity.

Effect of maternal hydration on fetal renal pyelectasis.

OBJECTIVE: To assess the effect of maternal hydration on fetal pyelectasis. METHODS: Thirteen pregnant women with fetal pyelectasis and 13 controls matched for gestational age were recruited during the same period. Ultrasound and Doppler studies and maternal urine specific gravity measurements were carried out before and after maternal oral hydration. The data were analyzed by either a two- or three-factor analysis of variance. RESULTS: Renal artery Doppler pulsatility index was significantly greater in the study group than in the controls (2.37 versus 1.83; P=.009) and this finding was unaffected by maternal hydration status. After hydration, the maternal urinary specific gravity decreased significantly (1.018 versus 1.009; P < .001), the amniotic fluid index (AFI) increased significantly (14.27 versus 18.24 cm; P < .001), and the fetal renal pelvis diameter increased significantly (0.29 versus 0.46 cm; P=.002) in both the study and control groups. Renal pelvis anteroposterior diameter after hydration did not differ significantly whether the fetal bladder was full or empty (0.7 versus 0.6 cm; P=.1). In this study, each subject served as her own control (ie, from before to after hydration). Three of 13 controls met the diagnostic criteria for pyelectasis after maternal hydration. CONCLUSION: The AFI increases after maternal hydration in both normal fetuses and those with pyelectasis. The fetal renal pelvis anteroposterior diameter increases with maternal hydration in both normal fetuses and those with pyelectasis and is independent of the state of the fetal bladder. The renal artery Doppler pulsatility index is significantly greater in fetuses with pyelectasis than in controls.

Prostate-specific antigen to determine progression-free survival after radiation therapy for localized carcinoma of prostate.

Prostate-specific antigen (PSA) levels after radiation therapy will more precisely and objectively identify the presence of persistent prostate carcinoma. We determined the impact of PSA marker levels on progression-free status for 123 patients treated by interstitial implantation (I-125) and 311 patients treated by external beam therapy (XRT) who have been followed for a median of 109 and 51 months, respectively. Actuarial progression-free survival curves were calculated, using standard clinical criteria, and then recalculated, using PSA marker criteria. Sera obtained twelve months or more after the initiation of XRT and twenty-four months or more after the date of I-125 were used for determination of PSA levels. Using normal PSA level (by Hybritech assay < or = 4.0 ng/mL) as the criterion for progression-free status for patients treated by XRT, 35 percent of patients with Stage A2, 20 percent of patients with Stage B1 or B2, and 10 percent of patients with Stage C tumor were progression-free at ten years. The progression-free survival by clinical criteria for Stage A2 and 65 percent, B1 was 40 percent, B2 was 35 percent, and C was 25 percent. Using undetectable PSA level (< or = 0.5 ng/mL) as the criterion, less than 10 percent of patients were progression-free at ten years, regardless of stage, grade; and treatment modality. This information should not be interpreted as indicating that radiation is ineffective therapy for prostate cancer, since clinical control of the disease among men in their eighth decade is a more practical goal than marker control. However, PSA monitoring after radiation therapy and after any local therapy for prostate cancer will provide more precise information on the success of that therapy in ablating disease.

Role of radionuclide phallogram in therapeutic decision-making for erectile dysfunction.

OBJECTIVE: The purpose of this study is to evaluate the role of radionuclide phallograms in therapeutic decision-making for erectile dysfunction. METHOD: Forty-eight impotent men being considered for pharmacologically-induced penile erection therapy (PIPE) had radionuclide phallograms (RP) as part of their evaluation. RP were performed using 99mTc-labeled autologous red blood cells and provided a measurement of penile blood volume (PBV) change following the intracorporeal injection of 0.25 to 0.3 mL of a papaverine/phentolamine mixture. RESULTS: Thirty-eight patients showed a good response with a mean PBV increase 2.6 times baseline (range 1.2 to 8.9). Ten patients had significantly lower PBV changes (P = 0.001) than the first group, with a mean PBV increase of 1.6 times baseline (range 1.1 to 2.4). These ten patients were dissatisfied with pharmacologically induced penile erection (PIPE) therapy after an unsuccessful treatment trial. CONCLUSION: We conclude that the RP can help to discriminate between patients who will benefit from PIPE therapy and those who will not.

Experience with a novel vaginal progesterone preparation in a donor oocyte program.

OBJECTIVE: To compare the efficacy of a vaginal progesterone preparation with our standard IM preparation within a donor egg program. DESIGN: Prospective randomized trial. SETTING: Donor egg program at a university assisted reproductive therapy program (Jones Institute for Women's Health). PATIENT(S): Couples accepted into the donor egg program because of either premature ovarian failure or evidence of diminished ovarian reserve. INTERVENTION(S): Women were randomized into either a group receiving IM progesterone replacement or a group receiving vaginal progesterone replacement. Both groups underwent Estraderm patch/progesterone treatment in a mock cycle leading to an endometrial biopsy on day 26 followed by a second cycle in which ET was performed. Subjects with residual ovarian function received a GnRH agonist. In the IM treatment group, 100 mg was administered from cycle days 15 to 27. In the vaginal treatment group, Crinone 8%, a polycarbophil-based gel preparation containing 90 mg of micronized progesterone, was administered twice daily from the evening of day 14. MAIN OUTCOME MEASURE(S): Endometrial histology, serum levels of progesterone (on days 13, 17, 20, 24, and 26), the occurrence of pregnancy, implantation rate, and pregnancy outcome. RESULT(S): Fifty-four women randomized into the vaginal progesterone treatment group and 18 women in the IM treatment group achieved ET. Mean serum progesterone levels were higher in the IM treatment group than in the Crinone group. Endometrial histology was "in phase" for all subjects in both groups. Clinical pregnancies were observed in 26 of 54 women and 5 of 18 women in the Crinone and IM progesterone groups, respectively. The ongoing pregnancy rate (PR) of 31% (17/54) and implantation rate of 23% in the subjects receiving Crinone was not statistically different from the IM progesterone group's ongoing PR of 22% (4/18) and implantation rate of 18%. CONCLUSION: Vaginal progesterone replacement with the polycarbophil gel preparation was as effective as IM progesterone in producing clinical and ongoing pregnancies within our donor egg program in the dosages administered.

Clinical significance of human sperm-zona pellucida binding.

OBJECTIVE: To assess the relationship between sperm morphology and motion parameters and sperm-zona pellucida (ZP) binding capacity under hemizona assay (HZA) conditions and to determine the discriminatory power of the HZA for the prediction of in vitro sperm fertilizing ability. DESIGN: Prospectively designed study. SETTING: Academic tertiary centers. PATIENT(S): One hundred ninety-six couples undergoing IVF therapy participated in this study. INTERVENTION(S): Hemizona assay and IVF results were determined for each couple. MAIN OUTCOME MEASURE(S): Computerized sperm motion analysis, sperm morphology (strict) criteria), and HZA results were correlated with fertilization outcome. RESULT(S): Among sperm parameters from the original ejaculates, morphology was the best predictor of sperm-ZP binding ability; hyperactivated motility was the best predictor of HZA results after swim-up separation of the motile sperm fractions. The HZA index provided the highest discriminatory power for fertilization success/failure, with an overall accuracy of 86%. CONCLUSION(S): Sperm morphology and hyperactivated motility showed a high correlation with the capacity of sperm to achieve tight binding to the ZP. The excellent positive and negative predictive values of the HZA for fertilization outcome provide additional support for the use of this functional bioassay in the decision-making process within the assisted reproduction setting.

Embryo implantation in in vitro fertilization and intracytoplasmic sperm injection: impact of cleavage status, morphology grade, and number of embryos transferred.

OBJECTIVE: The aims of this study were to compare preimplantation embryo quality in intracytoplasmic sperm injection (ICSI) with standard IVF and to examine the impact of age and number and quality of embryos transferred on implantation and pregnancy. DESIGN: Retrospective, controlled clinical study. SETTING: Academic tertiary center. PATIENT(S): We examined 211 consecutive couples undergoing ICSI who were matched with 211 couples undergoing IVF therapy during the same time frame. INTERVENTION(S): In vitro embryo culture. MAIN OUTCOME MEASURE(S): Day 3 embryo quality as judged by the number of blastomeres and morphology scoring. RESULT(S): Patients undergoing ICSI had a significantly reduced number of embryos with good morphology and cleavage compared with IVF cases. Nevertheless, pregnancy and abortion rates were similar when adjusted by age and number of embryos transferred. Average cleavage status and age were significant predictors of implantation. Women of advanced age had significantly lower embryo cleavage and implantation rates. CONCLUSION(S): [1] The cleaving status of day 3 embryos is a valuable, although limited, indicator of implantation outcome. [2] In vitro fertilization-derived embryos had better cleavage rates and morphology scores than ICSI-derived embryos; however, the implantation potential was similar for both groups. [3] The age-related decline in implantation rate was associated with impaired embryo growth rates.

Perifollicular blood flow Doppler indices, but not follicular pO2, pCO2, or pH, predict oocyte developmental competence in in vitro fertilization.

OBJECTIVE: To assess the relationships among perifollicular blood flow; follicular fluid pO2, pCO2, and pH; oocyte developmental capacity; preimplantation embryo quality. DESIGN: Prospective study. SETTING: Academic, tertiary care institution. PATIENT(S): Unselected, gonadotropin-stimulated IVF cycles. INTERVENTION(S): Color, pulsed Doppler analysis of perifollicular blood flow, and follicular pO2, pCO2, and pH determinations of randomly designated, mapped ovarian follicles. MAIN OUTCOME MEASURE(S): Fertilization and day 3 embryo cleavage and morphology. RESULT(S): Perifollicular vascularity indices were significantly and negatively correlated with day 3 embryo cleavage. Pulsatility index and S-D ratio also were significantly and negatively correlated with follicular pO2. The same correlation was found between resistance index and the fertilization rate of preovulatory oocytes. No relationship existed between follicular metabolic analysis and fertilization or embryo quality. The resistance index had a sensitivity of 0.57 and a specificity of 0.71 for the prediction of advanced embryo cleavage status. CONCLUSION(S): Results confirm and extend previous reports demonstrating that color, pulsed Doppler ultrasound analysis of individual preovulatory follicles during IVF therapy may provide an indirect index of the developmental competence of the corresponding oocyte. Although these methods may provide means to select embryos for transfer with the highest implantation potential, the moderate predictive power showed so far may limit their clinical applicability.

Fertilization efficiency of morphologically abnormal spermatozoa in assisted reproduction is further impaired by antisperm antibodies on the male partner's sperm.

OBJECTIVE: To investigate the influence of antisperm antibodies on the sperm surface on the outcome of IVF and GIFT. DESIGN: Matched controlled retrospective review of two large series. SETTING: Reproductive endocrine divisions of two level-three academic centers. PATIENTS: Twenty-nine male factor patients (38 IVF cycles) showing positive antisperm antibodies on the sperm by immunobead test treated by IVF at the Norfolk program and 56 similar patients (57 cycles) treated by GIFT at the Tygerberg program. Twenty-nine male factor patients (29 IVF cycles) with negative antisperm antibodies screening matched by wife's stimulation protocol and baseline semen analysis characteristics were used as controls in Norfolk; 56 GIFT patients (56 GIFT cycles) matched similarly were the Tygerberg controls. Study and control groups were divided according to sperm morphology pattern in normal, good, and poor prognosis subgroups for comparison. MAIN OUTCOME MEASURES: Fertilization rate of preovulatory oocytes used in IVF in Norfolk and of GIFT supernumerary preovulatory oocytes in Tygerberg; total and term pregnancy rates (PRs) and abortion rates. RESULTS: Fertilization rate was significantly lower in the IVF (41.9% +/- 2.8%) as well as in the GIFT (26.8% +/- 3.8%) (mean +/- SE) study groups than in the respective control groups (73.1% +/- 3.9% and 61.8% +/- 3.9%). Total and term PRs in IVF per cycle (21.1% +/- 6.6%; 13.2% +/- 5.5%) and per transfer (23.5% +/- 7.4%; 14.7% +/- 6.1%), and in GIFT (25.0% +/- 5.8%; 19.6% +/- 5.3%) in the study groups were also lower when compared with their control counterparts (IVF per cycle: 62.1% +/- 6.2% and 41.4% +/- 6.0%; IVF per transfer: 41.9% +/- 2.0% and 27.9% +/- 1.9%; GIFT: 31.6% +/- 6.2% and 28.1% +/- 6.0%), but the difference did not reach statistical significance. Abortion rates were similar in the IVF study group (37.5% +/- 17.1%) and its control groups (39.9% +/- 11.5%). The abortion rate in the GIFT study group was 14.3% +/- 9.4%, and no abortions were recorded in the control group (not significant). CONCLUSIONS: The presence of antisperm antibodies on the sperm surface per se impairs the outcome of assisted reproduction, mainly in terms of fertilization rate of preovulatory oocytes, and possibly in terms of total and term PRs. This holds true regardless of the impact of other semen parameters, particularly the morphology of the sperm within the semen sample.

Use of a specific zona pellucida (ZP) protein 3 antiserum as a clinical marker for human ZP integrity and function.

OBJECTIVE: To evaluate binding characteristics of a specific zona pellucida (ZP) protein 3 (ZP3) antiserum to human oocytes in order to determine its usefulness as a clinical marker for human ZP integrity and function and its correlation with IVF outcome. DESIGN: Prospectively designed, blinded, internally controlled study. SETTING: Tertiary care academic center. PATIENTS: Patients undergoing IVF therapy who had either total failed fertilization or partial fertilization were studied. INTERVENTIONS: Metaphase II oocytes showing absence of pronuclear formation were salt stored 48 hours after insemination and bisected into matching hemizonae using micromanipulation. One hemizona was incubated with AS ZP3-6 (an antiserum generated against a synthetic ZP3 peptide derived from an amino acid sequence that is highly conserved in the structure of ZP3), whereas the matching hemizona was incubated with AS ZP3-7, an antiserum detecting exclusively mouse ZP3 (internal, negative control). Antibody binding was visualized using the peroxidase-antiperoxidase method and diaminobenzidine as color reagent. RESULTS: A total of 104 unfertilized oocytes were evaluated. Analysis of variance showed a significant interaction between gamete factor groups (sperm and oocyte) and antiserum factor. Patients with oocyte factor had significantly lower mean staining scores for the AS ZP3-6-treated hemizonae than patients with sperm factor. CONCLUSIONS: These results demonstrate that anomalies of human ZP3 can be identified with AS ZP3-6 and that these ZP abnormalities correlate with fertilization failure during IVF treatment. Thus, this newly developed biomarker may be of clinical significance in the identification of oocyte defects that are associated with fertilization disorders and may help in the decision-making process in the IVF-assisted fertilization setting.

Parameters that predict nipple involvement in breast cancer.

BACKGROUND: Breast conservation therapy has been shown to produce survival rates equivalent to those seen with modified radical mastectomy. Synchronous occult neoplastic involvement of the nipple may lead to incomplete excision of the tumor in patients undergoing breast conservation therapy, possibly leading to recurrence. STUDY DESIGN: The charts of 803 breast cancer patients treated between 1990 and 1995 at two teaching hospitals were retrospectively reviewed. The patients were divided into three groups: nipple-positive for malignancy (n = 54), nipple-negative for malignancy (n = 404), and nipple-not-removed (n = 345). Ten different clinical and tumor parameters including age, race, primary tumor location, histologic grade, primary tumor size, nodal involvement, TNM stage, estrogen receptor status, DNA ploidy, and S-phase were examined for the ability to predict cancerous nipple involvement. RESULTS: Overall, the rate of nipple positivity was 12%. In univariate analysis pathologic stage, tumor size, lymph node status, histologic grade, and tumor location were significant predictors of positive nipple involvement. Patients with tumors that were stage III or higher were nearly ten times (odds ratio [OR] = 9.8, 95% confidence interval [CI] = 5.5 to 17.7) more likely to have nipple involvement than patients with early-stage tumors. Patients with a tumor size of 4 cm or greater were nearly eight times (OR = 7.8, 95% CI = 4.2 to 14.5) more likely to have nipple involvement than patients with tumor size less than 4 cm. Patients with positive lymph nodes were five times (OR = 5.0, 95% CI = 2.7 to 9.1) more likely to have nipple involvement than patients with negative lymph nodes. Patients with tumors in a central location or that overlapped quadrants were nearly four times (OR = 3.8, 95% CI = 2.2 to 6.8) more likely to have nipple involvement than patients with tumors in other locations. Patients with grade 3 or undifferentiated tumors were three times (OR = 3.0, 95% CI = 1.4 to 6.4) more likely to have nipple involvement than patients with lower grade tumors. In multivariable analysis, stage > or = 3 (OR = 9.2, 95% CI = 4.2 to 20.3) central/ overlap location (OR = 4.1, 95% CI = 2.0 to 8.7) and grade 3 or undifferentiated (OR = 3.1, 95% CI = 1.3 to 7.5) were the only variables that remained significant predictors of nipple involvement. CONCLUSIONS: The decision to perform breast conservation surgical procedures with nipple preservation can be difficult, particularly in patients with larger, more centrally located tumors. The multivariable model developed in this study may be useful in predicting the risk of cancerous nipple involvement and selecting appropriate breast conservation patients for nipple preservation.

Racial pigmentation and the cutaneous synthesis of vitamin D.

The varying epidermal melanin content that produces racial pigmentation determines the number of photons that reach the lower (malpighian) cellular layers, where vitamin D3 synthesis takes place. We investigated the effect of racial pigmentation on vitamin D3 formation, stimulating the process with a fixed dose of UVB radiation (wavelengths, 290 to 320 nm). Vitamin D nutritional status was further assessed measuring serum 25-hydroxyvitamin D and the most active serum metabolite, 1,25-dihydroxyvitamin D. Experimental subjects were young (third decade of life) and healthy, representing the white, Oriental (East Asian), Indian (South Asian), and black races. Basal serum vitamin D3 levels were similar among groups, ranging from 2.3 +/- 0.6 nmol/L (mean +/- SEM) for blacks to 3.4 +/- 1.0 nmol/L for Indians. Following whole-body exposure to 27 mJ/cm2 of UVB, there was a significant racial group effect on serum vitamin D3 levels. Post-UVB levels were significantly higher in whites (31.4 +/- 4.4 nmol/L) than in Indians or blacks (12.8 +/- 2.9 and 9.1 +/- 2.1 nmol/L, respectively), while the levels in Orientals (27.8 +/- 4.4 nmol/L) differed significantly from those in blacks and Indians but not in whites. Race had only a marginal effect on serum 25-hydroxyvitamin D, with higher levels in whites than in blacks (69.9 +/- 12.7 vs 29.7 +/- 6.2 nmol/L). Serum 1,25-dihydroxyvitamin D and vitamin D binding protein levels were similar in all groups. We conclude that while racial pigmentation has a photoprotective effect, it does not prevent the generation of normal levels of active vitamin D metabolites.

PSA response to secondary androgen deprivation following failed treatment of metastatic prostate cancer with the antiandrogen casodex.

Casodex™ (ZENECA Limited) is a new antiandrogen presently under investigation for the treatment of metastatic prostate cancer. This study was designed to analyze response and possible prognostic significance of prostate specific antigen (PSA) monitoring when secondary androgen deprivation is administered at disease progression after treatment with a once-daily dose of Casodex 50 mg. Of the 31 patients receiving Casodex, 28 progressed and were treated with either orchiectomy or a luteinizing hormone releasing hormone agonist. Of the 23 patients who had follow-up PSA determinations, 19 (83%) showed a subsequent PSA decline. Median survival following secondary therapy was 22 months in the 14 patients whose decline was 50% or greater; survival was 17 months in the 9 patients whose PSA either rose or declined by less than 50% (p = 0.1711). In this small study, reduction in PSA with medical or surgical castration following initial monotherapy with Casodex, 50 mg suggests incomplete androgen blockade with this dose of Casodex. While a trend suggesting a predictive value to PSA decline following secondary androgen deprivation was demonstrated, the change was not statistically significant.