Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice.

Converging evidence suggests that folate-mediated one-carbon metabolism may modulate cognitive functioning throughout the lifespan, but few studies have directly tested this hypothesis. This study examined the separate and combined effects of dietary and genetic manipulations of folate metabolism on neocortical functions in mice, modeling a common genetic variant in the MTHFD1 gene in humans. Mutant (Mthfd1(gt/+)) and wildtype (WT) male mice were assigned to a folate sufficient or deficient diet at weaning and continued on these diets throughout testing on a series of visual attention tasks adapted from the 5-choice serial reaction time task. WT mice on a deficient diet exhibited impulsive responding immediately following a change in task parameters that increased demands on attention and impulse control, and on trials following an error. This pattern of findings indicates a heightened affective response to stress and/or an inability to regulate negative emotions. In contrast, Mthfd1(gt/+) mice (regardless of diet) exhibited attentional dysfunction and a blunted affective response to committing an error. The Mthfd1(gt/+) mice also showed significantly decreased expression levels for genes encoding choline dehydrogenase and the alpha 7 nicotinic cholinergic receptor. The effects of the MTHFD1 mutation were less pronounced when combined with a deficient diet, suggesting a compensatory mechanism to the combined genetic and dietary perturbation of folate metabolism. These data demonstrate that common alterations in folate metabolism can produce functionally distinct cognitive and affective changes, and highlight the importance of considering genotype when making dietary folate recommendations.

Gestational weight gain and postpartum behaviors associated with weight change from early pregnancy to 1 y postpartum.

OBJECTIVES: (1) To describe the relative importance of gestational weight gain, postpartum exercise, food intake and breastfeeding to weight change from early pregnancy to 1 y postpartum; and (2) to identify subgroups of women at greatest risk for major weight gain surrounding childbearing. DESIGN: A prospective cohort study of women who registered for obstetrical care in a hospital and primary care clinic system serving a 10 county area of upstate New York. SUBJECTS: A total of 540 healthy adult women who gave birth to full-term singleton infants. MEASUREMENTS: Sociodemographic characteristics, exercise, food-related behaviors and breastfeeding were assessed using the medical record and a mailed questionnaire. Body weight was measured at prenatal visits and 1 y postpartum. Weight retained and major weight gain (4.55 kg) at 1 y postpartum were the main outcomes. ANALYSIS: Linear and logistic regression analyses were conducted. RESULTS: Women were on average 1.51+/-5.95 kg heavier at 1 y postpartum than they were in early pregnancy. Nearly 25% of women experienced a major weight gain of 4.55 kg or more at 1 y postpartum. Gestational weight gain, exercise frequency, change in food intake and breastfeeding were each significantly related to postpartum weight retention. With the exception of breastfeeding, all of these factors were also associated with major weight gain. Women under 20 y or over 40 y at delivery, and single women retained significantly more weight. Lower income women with gestational weight gains above the Institute of Medicine (IOM) range retained 3.73 kg more than lower income women who gained within the range. They were also 4.7 times more likely to experience major weight gain with childbearing. The impact of exceeding the IOM gestational weight gain guidelines was three times greater in lower income women than it was in higher income women. CONCLUSION: Gestational weight gain, postpartum exercise frequency, and food intake are significantly associated with weight change from early pregnancy to 1 y postpartum and major weight gain with childbearing. Lower income women who gain more weight in pregnancy than the IOM recommends are at high risk for major weight gain with childbearing.

Proliferation index is related to patient age in glioblastoma.

Younger patients with glioblastomas have a significantly better prognosis than do older patients. To determine whether patient age might be related to proliferation of glioblastoma cells, glioblastomas from patients of different ages were stained with the Molecular Immunology Borstel number 1 antibody to detect proliferating cells. Younger patient age was a significant predictor of a low Molecular Immunology Borstel number 1 proliferation index (p = 0.0001). This previously unreported association favors an intrinsic difference in the type of glioblastomas that afflict younger patients.

Age-specific distribution of serum prostate-specific antigen in a community-based study of African-American men.

OBJECTIVES: Previous studies have observed higher age-specific serum prostate-specific antigen (PSA) values in African-American (AA) men without prostate cancer compared to white men, leading some to recommend race-specific PSA reference ranges for the early detection of prostate cancer. The primary objective of the Flint Men's Health Study was to determine age-specific PSA reference values in a community-based sample of AA men, aged 40 to 79 years. METHODS: A probability sample of 943 AA men was selected from households in Genesee County, Michigan. Men without a prior history of prostate cancer/surgery were invited to participate in a prostate cancer screening protocol, consisting of measurement of serum total PSA, free/total PSA ratio, and digital rectal examination. Sextant biopsies were recommended, based on total PSA greater than 4.0 ng/mL and/or an abnormal digital rectal examination. RESULTS: From the sample of 943 men, 732 were eligible, 432 had blood drawn for PSA testing, and 374 completed all phases of the clinical examination. The 95th percentile PSA values were estimated to range from 2.36 ng/mL for men in the fifth decade to 5.59 ng/mL for men in the eighth decade. The 95th percentile values for age-specific PSA were comparable to those observed in a similar study of white men in Olmsted County, Minnesota. The median and 5th percentile values for free/total PSA did not vary significantly across age. CONCLUSIONS: The minor differences in PSA reference ranges between AA and white men may not be of sufficient magnitude to recommend the use of race-specific PSA reference ranges for screening.

Relationship and significance of greatest percentage of tumor and perineural invasion on needle biopsy in prostatic adenocarcinoma.

Serum prostate-specific antigen (PSA) levels and the biopsy Gleason sum are used along with clinical staging to predict prostatectomy pathology results for men with localized prostate cancer. The additional predictive value of perineural invasion (PNI) in pretreatment prostate needle biopsies for evaluating tumor stage in this setting is controversial. The current study evaluates the independent predictive value of PNI for tumor staging in a cohort of 632 men who underwent radical retropubic prostatectomies for clinically localized adenocarcinoma of the prostate between the years 1994 and 1998. None of these men received hormonal or radiation therapy before surgery. In addition to the Gleason sum, biopsy results contained detailed information regarding tumor burden: 1) total number of biopsy cores involved by adenocarcinoma, 2) greatest percentage of any single biopsy involved by prostate carcinoma (GPC), and 3) total percentage of cancer added over all cores (TPC). The presence or absence of any PNI was recorded. Pretreatment factors were analyzed in a univariate and multivariate fashion to determine their predictive value using the TNM tumor stage (pT2 vs pT3) and the modified tumor staging system, which includes surgical margin status (pT2 vs pT3 or positive surgical margin) as end points. Univariate analysis revealed a significant association between pT3 disease and several preoperative factors including age, Gleason sum, serum PSA, digital rectal examination, PNI, GPC, TPC, and the total number of positive cores (p <0.01). Multivariate analysis indicated that serum PSA, Gleason sum, age, and GPC contributed significantly to predicting pT3 disease with odds ratios of 2.7 (95% CI, 1.7-4.3), 2.3 (95% CI, 1.7-3.1), 1.7 (95% CI, 1.1-2.7), and 1.7 (95% CI, 1.4-2.1) respectively. PNI was significant in multivariate analysis only when GPC and TPC were not considered, due to a significant interaction between GPC and PNI (p <0.0001, Wilcoxon's rank sum test). These predictive factors showed a similar relationship to adverse pathology when an alternative definition of adverse pathology was used that included positive surgical margins (pT3 or any positive margin). In the interaction between GPC and PNI, GPC was more significant than PNI in predicting pT3 disease. However, PNI added additional information when adverse pathology was defined more broadly as pT3 or any positive margin.

MIB-1 proliferation index predicts survival among patients with grade II astrocytoma.

The purpose of this study was to determine whether a relationship existed between MIB-1 labeling index (LI) percentages and survival in patients with grade II astrocytomas. From archival paraffin-embedded surgical specimens of 50 patients of the University of Michigan Medical Center with World Health Organization grade II astrocytomas, 22 patients had a Ki-67 LI of less than or equal to 2.0; and 28 patients had a MIB-1 LI of more than 2.0. Over a median follow-up interval of 10 years, ranging up to 16 years, 23% (n = 5) died of tumor in the first group while 82% (n = 23) died in the second group, a distinct difference in survival between these groups. Univariate analysis showed that a high MIB-1 predicted shorter survival (p < 0.0001), and that increased age was associated with shorter survival (p = 0.007). Gender, tumor location and radiotherapy had no significant association with survival. When adjusting for these (excluding tumor location) in the Cox proportional hazards model simultaneously, MIB-1 and age were independently prognostic. The hazard ratios were 1.301 per 1% MIB-1 LI (p = 0.0001), and 1.045 per year of age (p = 0.0028). From other studies, we know that histopathologic grade and age predict survival for glioma patients. However, even within grade II astrocytomas there is still a wide heterogeneity in how long a patient survives. We conclude that among grade II astrocytomas older patients and, independently, patients with higher MIB-1 labeling index have shorter survival.

Change in serum prostate-specific antigen as a marker of response to cytotoxic therapy for hormone-refractory prostate cancer.

PURPOSE: Prostate-specific antigen (PSA) has been used as a marker of advanced prostate cancer but remains controversial. To evaluate PSA as a predictor of survival, we analyzed data from sequential phase II trials of estramustine and etoposide. METHODS: A landmark analysis that used data from 62 men with PSA levels at baseline and 8 weeks was conducted. The best PSA measure (of six evaluated) was incorporated into a multiple regression model with performance status (PS); relative change in PSA level; and pretreatment PSA, alkaline phosphatase, and hemoglobin values. RESULTS: A decrease in PSA of 50% or greater at 8 weeks was associated with a significantly increased survival (P=.0005, two-sided log-rank test). Median survival from the landmark was 91 weeks in patients with a 50% or greater decrease at 8 weeks versus 38 weeks in those without this decrease. Modeling showed that PS, pretreatment hemoglobin level, and relative change in PSA level were significant prognostic factors, with a significant interaction between PS and pretreatment hemoglobin level. In the final model, a relative change in PSA level at 8 weeks of less than 50% had an adjusted relative risk of 2.20 (95% confidence interval, 1.21 to 4.00). A decrease in PSA level of 50% or greater at any time during therapy was associated with a response in measurable disease (P=.0369, two-sided Fisher's exact test). CONCLUSION: The PSA value after 8 weeks of this cytotoxic regimen does predict survival. A decrease in PSA level is associated with both survival and response in soft tissue lesions and should be incorporated into the response criteria and reporting of trials of cytotoxic agents in prostate cancer.

A comparison of the predictive power for survival in gliomas provided by MIB-1, bromodeoxyuridine and proliferating cell nuclear antigen with histopathologic and clinical parameters.

The purpose of this prospective study of 65 patients was to compare side-by-side the predictive power for survival of (a) MIB-1, (b) bromodeoxyuridine (BUDR), and (c) proliferating cell nuclear antigen (PCNA). They were compared (a) with each other, (b) with several clinical predictors, and (c) with histopathologic grade under actual clinical biopsy conditions in a study of 1993 World Health Organization (WHO) grade II to IV adult supratentorial gliomas. There was a strong positive relationship between MIB-1 and BUDR by Spearman Rank correlation. In univariate analysis, MIB-1 (logrank p = 0.06) was more predictive of survival than BUDR or PCNA. Longer survivors were distinguished from others by the lowest MIB-1 labeling indices (LI < or = 2.5%) better than by the lowest histopathologic grade. However, histopathologic grades were highly predictive among the entire group (logrank p < 0.0001). Young age (p < 0.0001) and high Karnofsky performance status (p < 0.0001) were the clinical factors most predictive of longer survival. Female gender correlated with longer survival (logrank p = 0.02). In multivariate Cox proportional hazards models, age, Karnofsky performance status, and histopathologic grading remained statistically significant after full reduction of the model. We conclude that Ki-67 measured by MIB-1 monoclonal antibody was superior to other markers of proliferation. When all factors are considered simultaneously over all 3 grades of malignancy, greatest predictive power resides in histopathologic grade and clinical variables. MIB-1 is expected to be most important in cases where clinical or histopathologic factors are ambiguous or where they cannot be fully assessed.

Results of 3D conformal radiotherapy in the treatment of localized prostate cancer.

PURPOSE: 3D conformal radiotherapy (3D CRT) has been shown to decrease acute morbidity in the treatment of prostate cancer. Therapeutic outcome and late morbidity data have been accumulating. To evaluate the results of 3D CRT for the treatment of prostate cancer, we analyzed the outcome of a large series of patients treated with conformal techniques. MATERIAL AND METHODS: From January 1987 through June 1994, 707 patients with localized prostate cancer were treated with 3D CRT. Patients with pathologically-confirmed pelvic lymph node metastasis, treated with pre-irradiation (preRT) androgen ablation, or treated post-prostatectomy were excluded. All had CT obtained specifically for treatment planning, multiple structures contoured on the axial images, and beam's-eye view conformal beams edited to provide 3D dose coverage. Median follow-up is 36 mos; 70 patients have been followed longer than 5.5 years. Six hundred three had T1-T2 tumors. PreRT prostate specific antigen (PSA) was available for 649 patients: median preRT PSA was 12.9 ng/ml, 209 patients had preRT PSA > 20 ng/ml. The median dose of radiation was 69 Gy; 102 patients received > or = 69 Gy. Biochemical failure was defined as: 1) two consecutive PSA rises over 2.0 ng/ml if nadir PSA < or = 2.0 ng/ml, 2) two consecutive PSA rises over nadir if nadir PSA > 2.0 ng/ml, or 3) initiation of hormonal therapy after RT. Complications were graded using the RTOG system. RESULTS: PreRT PSA and Gleason score emerged as independent indicators of biochemical control (bNED). Patients with preRT PSA > 10 had a significantly worse bNED at 5 years than patients with preRT PSA < or = 10. Five-year bNED was determined according to preRT PSA: PSA < or = 4, 88%; PSA > 4 < or = 10, 72%; PSA > 10 < or = 20, 43%; and PSA > 20, 30%. Patients with Gleason score > or = 7 also had a significantly worse bNED than patients with Gleason score < 7. Patients were divided into two prognostic groups: a favorable group with PSA < or = 10, Gleason score < 7, and T1-T2 tumors, and an unfavorable group with PSA > 10, Gleason score > or = 7 or T3-T4 tumors and studied for the effect of dose on bNED status. The bNED at 5 years was 75% for the favorable group and 37% for the unfavorable group. In addition, a group that might be considered a surgical subset was reviewed: patients with PSA < or = 10, Gleason score < or = 7, and T1-T2 tumors who were < 70 years old. This subset had an 84% 5-year bNED rate and 98% 5-year overall survival. Complications with the techniques used here are very low: 3% risk at 7 years of Grade 3-4 complications and 1% risk at 7 years of Grade 3 bladder complications (no Grade 4). CONCLUSION: 3D CRT allows for treatment of prostate cancers with a very low risk of complications. Patients with relatively early disease as defined by preRT PSA, Gleason score < 7, and T1-2 tumors and patients who are candidates for radical prostatectomy have excellent 5-year bNED rates. Patients with adverse prognostic factors have a high risk of biochemical recurrence and are candidates for innovative therapy.