Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Microencapsulated islet allografts in diabetic NOD mice and nonhuman primates.

OBJECTIVE: Our goal was to assess the efficacy of encapsulated allogeneic islets transplanted in diabetic NOD mice and streptozotocin (STZ)-diabetic nonhuman primates (NHPs). MATERIALS AND METHODS: Murine or NHP islets were microencapsulated and transplanted in non-immunosuppressed mice or NHPs given clinically-acceptable immunosuppressive regimens, respectively. Two NHPs were treated with autologous mesenchymal stem cells (MSCs) and peri-transplant oxygen therapy. Different transplant sites (intraperitoneal [i.p.], omental pouch, omental surface, and bursa omentalis) were tested in separate NHPs. Graft function was monitored by exogenous insulin requirements, fasting blood glucose levels, glucose tolerance tests, percent hemoglobin A1c (% HbA1c), and C-peptide levels. In vitro assessment of grafts included histology, immunohistochemistry, and viability staining; host immune responses were characterized by flow cytometry and cytokine/chemokine multiplex ELISAS. RESULTS: Microencapsulated islet allografts functioned long-term i.p. in diabetic NOD mice without immunosuppression, but for a relatively short time in immunosuppressed NHPs. In the NHPs, encapsulated allo-islets initially reduced hyperglycemia, decreased exogenous insulin requirements, elevated C-peptide levels, and lowered % HbA1c in plasma, but graft function diminished with time, regardless of transplant site. At necropsy, microcapsules were intact and non-fibrotic, but many islets exhibited volume loss, central necrosis and endogenous markers of hypoxia. Animals receiving supplemental oxygen and autologous MSCs showed improved graft function for a longer post-transplant period. In diabetic NHPs and mice, cell-free microcapsules did not elicit a fibrotic response. CONCLUSIONS: The evidence suggested that hypoxia was a major factor for damage to encapsulated islets in vivo. To achieve long-term function, new approaches must be developed to increase the oxygen supply to microencapsulated islets and/or identify donor insulin-secreting cells which can tolerate hypoxia.

PTEN loss in Gleason grade 7 prostate tumors exhibits intratumoral heterogeneity and is associated with unfavorable pathological features

Background: PTEN loss is observed in 20­30% of prostate cancers and is associated with a poor outcome, but clinical details of the impact of this biomarker are unclear for intermediate grade tumors. Methods: We investigated 43 radical prostatectomy-derived grade 7 prostate tumors from the Clinics Hospital of Ribeirão Preto. Tissue microarray (TMA) blocks were constructed and PTEN copy number status was determined for all patients through fluorescence in situ hybridization (FISH). To determine the presence of PTEN protein loss in our study cohort, we performed immunohistochemistry (IHC) in TMA sections. We then developed an automated algorithm in HALO™ to identify regions of PTEN protein loss in whole prostate scanned sections from ten patients with known PTEN deletion status by FISH. Clinical analyses were conducted to determine the associations between PTEN loss and patient outcome. All statistical analyses were conducted in R v3.4.3 with P-values below 0.05 being considered statistically significant. Results: In this study of 43 grade 7 tumors, we found PTEN deletions by FISH in 18.9% of tumors, and PTEN protein loss by IHC in 16.3% of tumors. Both techniques were highly concordant and complementary. Clinical analysis demonstrated that PTEN deletion by FISH was significantly associated with positive margin invasion (P = 0.04) and Gleason score upgrade (P = 0.001). Digital image analysis of ten representative tumors demonstrated distinct intratumoral heterogeneity for PTEN protein loss in four tumors. Conclusions: This study shows that PTEN loss in Gleason grade 7 tumors can be heterogeneous and that a systematic analysis of this biomarker using a combination of FISH, IHC, and digital imaging may identify patients with a greater risk of poor outcome (AU)

In prostate cancer needle biopsies, detections of PTEN loss by fluorescence in situ hybridization (FISH) and by immunohistochemistry (IHC) are concordant and show consistent association with upgrading.

The prognostic value of phosphatase and tensin homolog (PTEN) loss in prostate cancer has primarily been evaluated by either fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC). Previously, we found that PTEN loss by IHC was associated with increased risk of upgrading from biopsy (Gleason 3 + 3) to prostatectomy (Gleason 7+). Now, using an evaluable subset of 111 patients with adjacent biopsy sections, we analyzed the association between PTEN deletion in cancer and the odds of upgrading by a highly sensitive and specific four-color FISH assay. We also compared the concordance of PTEN loss by IHC and PTEN deletion by FISH. PTEN deletion was found in 27 % (12/45) of upgraded cases compared with 11 % (7/66) of controls (P = 0.03). Cancers with PTEN deletions were more likely to be upgraded than those without deletions (adjusting for age odds ratio = 3.40, 95 % confidence interval 1.14-10.11). With respect to concordance, of 93 biopsies with PTEN protein detected by IHC, 89 (96 %) had no PTEN deletion by FISH, and of 18 biopsies without PTEN protein by IHC, 15 had homozygous or hemizygous PTEN deletion by FISH. Only 4 biopsies of the 93 (4 %) with PTEN protein intact had PTEN deletion by FISH. When the regions of uncertainty in these biopsies were systematically studied by FISH, intra-tumoral variation of PTEN deletion was found, which could account for variation in immunoreactivity. Thus, FISH provides a different approach to determining PTEN loss when IHC is uncertain. Both FISH and IHC are concordant, showing consistent positive associations between PTEN loss and upgrading.

The safety and feasibility of probiotics in children and adolescents undergoing hematopoietic cell transplantation.

Hematopoietic cell transplantation (HCT) has become a standard treatment for many adult and pediatric conditions. Emerging evidence suggests that perturbations in the microbiota diversity increase recipients' susceptibilities to gut-mediated conditions such as diarrhea, infection and acute GvHD. Probiotics preserve the microbiota and may minimize the risk of developing a gut-mediated condition; however, their safety has not been evaluated in the setting of HCT. We evaluated the safety and feasibility of the probiotic, Lactobacillus plantarum (LBP), in children and adolescents undergoing allogeneic HCT. Participants received once-daily supplementation with LBP beginning on day -8 or -7 and continued until day +14. Outcomes were compliance with daily administration and incidence of LBP bacteremia. Administration of LBP was feasible with 97% (30/31, 95% confidence interval (CI) 83-100%) of children receiving at least 50% of the probiotic dose (median 97%; range 50-100%). We did not observe any case of LBP bacteremia (0% (0/30) with 95% CI 0-12%). There were not any unexpected adverse events related to LBP. Our study provides preliminary evidence that administration of LBP is safe and feasible in children and adolescents undergoing HCT. Future steps include the conduct of an approved randomized, controlled trial through Children's Oncology Group.

Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error.

BACKGROUND: Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation. METHODS: Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high- and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively. RESULTS: Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high- and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error. CONCLUSIONS: Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness.

Curative therapy for bladder cancer in routine clinical practice: a population-based outcomes study.

AIMS: Definitive therapy of bladder cancer involves cystectomy or radiotherapy; controversy exists regarding optimal management. Here we describe the management and outcomes of patients treated in routine practice. MATERIALS AND METHODS: Treatment records were linked to the Ontario Cancer Registry to identify all cases of bladder cancer in Ontario treated with cystectomy or radiotherapy in 1994-2008. Practice patterns are described in three study periods: 1994-1998, 1999-2003, 2004-2008. Logistic regression, Cox model and propensity score analyses were used to evaluate factors associated with treatment choice and survival. RESULTS: In total, 3879 cases (74%) underwent cystectomy and 1380 (26%) were treated with primary radiotherapy. Cystectomy use increased over time (66, 75, 78%), whereas radiotherapy decreased (34, 25, 22%), P < 0.001. There was substantial regional variation in the proportion of cases undergoing radiotherapy (range 16-51%). Five year cancer-specific survival (CSS) and overall survival were 40 and 36% for surgical cases and 35 and 26% for radiotherapy cases (P < 0.001). In multivariate Cox model and propensity score analyses, there was no significant difference in CSS between surgery and radiotherapy (hazard ratio 0.99, 95% confidence interval 0.91-1.08); radiotherapy was associated with slightly inferior overall survival (hazard ratio 1.08, 95% confidence interval 1.00-1.16). CONCLUSION: Utilisation of cystectomy for bladder cancer in routine practice has increased over time with no evidence of a significant difference in CSS between radiotherapy and cystectomy.

The anterior chamber of the eye as a clinical transplantation site for the treatment of diabetes: a study in a baboon model of diabetes.

AIMS/HYPOTHESIS: The aim of this study was to provide evidence that the anterior chamber of the eye serves as a novel clinical islet implantation site. METHODS: In a preclinical model, allogeneic pancreatic islets were transplanted into the anterior chamber of the eye of a baboon model for diabetes, and metabolic and ophthalmological outcomes were assessed. RESULTS: Islets readily engrafted on the iris and there was a decrease in exogenous insulin requirements due to insulin secretion from the intraocular grafts. No major adverse effects on eye structure and function could be observed during the transplantation period. CONCLUSIONS/INTERPRETATION: Our study demonstrates the long-term survival and function of allogeneic islets after transplantation into the anterior chamber of the eye. The safety and simplicity of this procedure provides support for further studies aimed at translating this technology into the clinic.

Long-term survival of nonhuman primate islets implanted in an omental pouch on a biodegradable scaffold.

The aim of this study was to test whether an omental pouch can be used as an alternative site for islet implantation in diabetic monkeys. Here we report the successful engraftment of islets in diabetic cynomolgus monkeys when loaded on a synthetic biodegradable scaffold and placed in an omental pouch. One autologous and five allogeneic diabetic monkey transplants under the cover of steroid-free immune suppression (SFIS) were undertaken. Fasting blood glucose (FBG) and C-peptide (CP), exogenous insulin requirements (EIR), intravenous glucose tolerance test (IVGTT), A1C and histopathology were used to assess islet engraftment and survival. All animals achieved CP levels > 1.0 ng/mL following transplant, a 66-92% posttransplant decrease in EIR and reduced A1C. Following graft removal, CP became negative and histopathological analysis of the explanted grafts demonstrated well-granulated and well-vascularized, insulin-positive islets, surrounded by T-cell subsets and macrophages. Compared to intrahepatic allogeneic islet transplants (n = 20), there was a delayed engraftment for omental pouch recipients but similar levels of CP production were ultimately achieved, with a broad range of IEQ/kg transplanted in both sites. Our results suggest this extrahepatic transplantation site has potential as an alternative site for clinical islet cell transplantation.

Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer.

Cancer cells differentiate along specific lineages that largely determine their clinical and biologic behavior. Distinct cancer phenotypes from different cells and organs likely result from unique gene expression repertoires established in the embryo and maintained after malignant transformation. We used comprehensive gene expression analysis to examine this concept in the prostate, an organ with a tractable developmental program and a high propensity for cancer. We focused on gene expression in the murine prostate rudiment at three time points during the first 48 h of exposure to androgen, which initiates proliferation and invasion of prostate epithelial buds into surrounding urogenital sinus mesenchyme. Here, we show that androgen exposure regulates genes previously implicated in prostate carcinogenesis comprising pathways for the phosphatase and tensin homolog (PTEN), fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), and Wnt signaling along with cellular programs regulating such 'hallmarks' of cancer as angiogenesis, apoptosis, migration and proliferation. We found statistically significant evidence for novel androgen-induced gene regulation events that establish and/or maintain prostate cell fate. These include modulation of gene expression through microRNAs, expression of specific transcription factors, and regulation of their predicted targets. By querying public gene expression databases from other tissues, we found that rather than generally characterizing androgen exposure or epithelial budding, the early prostate development program more closely resembles the program for human prostate cancer. Most importantly, early androgen-regulated genes and functional themes associated with prostate development were highly enriched in contrasts between increasingly lethal forms of prostate cancer, confirming a 'reactivation' of embryonic pathways for proliferation and invasion in prostate cancer progression. Among the genes with the most significant links to the development and cancer, we highlight coordinate induction of the transcription factor Sox9 and suppression of the proapoptotic phospholipid-binding protein Annexin A1 that link early prostate development to early prostate carcinogenesis. These results credential early prostate development as a reliable and valid model system for the investigation of genes and pathways that drive prostate cancer.

Grading melanocytic dysplasia in paraffin wax embedded tissue by the nucleic acid index.

BACKGROUND: Although nucleic acid derangements are the hallmark of melanocytic dysplasia, the gold standard for its diagnosis remains the microscopic evaluation of haematoxylin and eosin stained slides. However, light microscopy is subjective and crucial genomic changes do not always show as changes in histology. AIMS: To introduce the nucleic acid index (NAI) as a means of analysing nucleic acid derangements in histological sections at the level of the individual cell and within the context of its microenvironment. METHODS: Confocal laser scanning microscopy was performed on melanocytic lesions stained with acridine orange (AO), a fluorescent stain for DNA and RNA. The NAI, calculated by measuring the fluorescence intensities of AO in nuclei relative to the surrounding cytoplasm, reflects the concentration of DNA relative to RNA. RESULTS: When applied to benign naevi, dysplastic naevi, and melanoma, a very strong significant association was seen between lower NAI and malignant potential (p < 0.0001). Strong inverse correlations were found between NAI and both mitotic index and Breslow thickness. Interestingly, the NAI for dysplastic naevi is between that of melanoma and most benign naevi, consistent with their intermediate biological behaviour and histological appearance. CONCLUSION: By providing a quantitative measure for melanocytic neoplasia, the NAI may improve the diagnosis of melanocytic lesions and the selection of treatment.

Adiponectin levels do not change with moderate dietary induced weight loss and exercise in obese postmenopausal women.

OBJECTIVE: The purpose of this study was to determine changes in adiponectin levels with moderate weight loss, weight loss plus aerobic exercise, or weight loss plus resistive exercise in overweight and obese, sedentary postmenopausal women. DESIGN: Longitudinal, clinical intervention study of 6-month (3 x /week) program of either weight loss (WL, n=15), weight loss + aerobic exercise (WL+AEX, n=16), or weight loss + resistive exercise (WL+RT, n=9) SUBJECTS: We studied 40 sedentary, overweight and obese (body mass index, BMI=32+/-1 kg/m(2), X+/-s.e.m.) postmenopausal (57+/-1y) women. MEASUREMENTS: Fat mass and fat-free mass (FFM) by dual-energy X-ray absorptiometry, plasma insulin, leptin, and adiponectin by radioimmunoassay. RESULTS: Age, body weight, BMI, waist and hip circumferences, waist-to-hip ratio, VO(2)max, percent fat, total body fat mass, FFM, and fasting plasma glucose, insulin, leptin, and adiponectin concentrations were similar among WL, WL+AEX, and WL+RT groups before the interventions. In all women combined, body weight, BMI, and waist and hip circumferences decreased (P < 0.001). There was a significant absolute decrease in percent body fat from 47 to 44%, representing a 13% decrease in total fat mass and a -1.6% change in FFM. Fasting concentrations of plasma adiponectin did not change (40+/-16%, P=NS), whereas fasting plasma glucose, insulin, and leptin all decreased (P<0.001). CONCLUSIONS: Plasma adiponectin levels do not change with a 6-month moderate weight reduction program even when accompanied by aerobic or resistive exercise training in overweight and obese postmenopausal women.

Genetic variation in the peroxisome proliferator-activated receptor-gamma2 gene (Pro12Ala) affects metabolic responses to weight loss and subsequent weight regain.

This study determined the effects of the peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala variant on body composition and metabolism and the magnitude of weight regain in 70 postmenopausal women (BMI 25-40 kg/m(2)) who completed 6 months of a hypocaloric diet. At baseline, BMI, percent body fat, intra-abdominal and subcutaneous abdominal fat areas, resting metabolic rate, substrate oxidation, and postprandial glucose and insulin responses were not different between genotypes (Pro/Pro = 56, Pro/Ala and Ala/Ala = 14). The intervention similarly decreased body weight by 8 +/- 1% in women homozygous for the Pro allele and by 7 +/- 1% in women with the Ala allele (P < 0.0001). Fat oxidation did not change in Pro/Pro women but decreased 19 +/- 9% in women with the Ala allele (P < 0.05). Changes in glucose area were not different between groups; however, women with the Ala allele decreased their insulin area more than women homozygous for the Pro allele (P < 0.05). Weight regain during follow-up was greater in women with the Ala allele than women homozygous for the Pro allele (5.4 +/- 0.9 vs. 2.8 +/- 0.4 kg, P < 0.01). PPAR-gamma2 genotype was the best predictor of weight regain (r = 0.50, P < 0.01), followed by the change in fat oxidation (partial r = 0.35, P < 0.05; cumulative r = 0.58). Thus, the Pro12Ala variant of the PPAR-gamma2 gene may influence susceptibility for obesity.

The insertion/deletion polymorphism of the ACE gene is related to insulin sensitivity in overweight women.

OBJECTIVE: The ACE insertion/deletion (I/D) polymorphism has been identified as a genetic risk factor for coronary heart disease (CHD). The deletion (D) allele of the ACE gene may be associated with higher insulin sensitivity. Individuals who are homozygous for the DD allele have higher ACE levels and possibly more angiotensin II, which, when infused exogenously, causes an increase in insulin sensitivity. The purpose of this study was to investigate the association of the I/D polymorphism of the ACE gene with insulin sensitivity and CHD risk factors. RESEARCH DESIGN AND METHODS: The study included 66 women (ages 57 +/- 1 years) who were overweight or obese (means +/- SEM, BMI = 33 +/- 1 kg/m(2)) and sedentary (VO(2max) = 19.6 +/- 0.4 ml. kg(-1). min(1)). Total body fat mass and percent fat were determined by dual-energy X-ray absorptiometry, and abdominal fat was by computed tomography. Insulin sensitivity was measured during the last 30 min of 3-h hyperinsulinemic-euglycemic clamps (40 mU. m(-2). min(-1)). Comparisons were made among women with the II (n = 9), ID (n = 36), and DD (n = 21) genotypes. RESULTS: Age, percent body fat, waist-to-hip ratio, visceral and subcutaneous abdominal fat areas, plasma lipid levels, and systolic and diastolic blood pressures did not differ by ACE genotype. Fasting glucose and 2-h glucose levels were similar among genotypes, but fasting plasma insulin levels were lower in DD women than in ID women (P < 0.05). Glucose utilization was higher in women with the DD genotype than in women with the II genotype (53.1 +/- 3.9 vs. 36.0 +/- 3.8 micromol. kg(-1) FFM. min(-1), P = 0.01) and was higher in ID women than in II women (48.5 +/- 2.5 micromol. kg(-1) FFM. min(-1), P = 0.04). CONCLUSIONS: These data suggest that the I/D polymorphism is not associated with risk factors for CHD in overweight sedentary women; however, women who are homozygous for the D allele of the ACE gene are more insulin sensitive, whereas women who are homozygous for the I allele of the ACE gene have greater insulin resistance and potential risk for type 2 diabetes.

Racial disparities in metabolism, central obesity, and sex hormone-binding globulin in postmenopausal women.

Increased total and intraabdominal fat (IAF) obesity as well as other metabolic conditions associated with the insulin resistance syndrome (IRS) are related to low levels of sex hormone-binding globulin (SHBG) in young and older Caucasian (CAU) and young African-American (AA) women. We examined whether postmenopausal AA women, a population with a high incidence of obesity and IRS despite low IAF, would have higher levels of circulating SHBG compared with CAU women, and whether there would be negative relationships between indexes of obesity and risk factors associated with IRS and SHBG levels. We measured body composition, SHBG, free testosterone, leptin, glucose tolerance, insulin, and lipoprotein lipids in 55 CAU (mean +/- SD, 59 +/- 7 yr) and 35 AA (57 +/- 6 yr) sedentary women of comparable obesity (48% body fat, by dual energy x-ray absorptiometry). Compared with CAU women, AA women had larger waist (101 vs. 96 cm), larger fat mass (44.9 +/- 8.8 vs. 39.9 +/- 8.1 kg), larger sc fat area (552 +/- 109 vs. 452 +/- 109 cm(2)), and lower IAF/SC ratio (0.28 +/- 0.12 vs. 0.38 +/- 0.15; P < 0.01), but similar waist to hip ratio (0.83). Both groups had similar SHBG (117 vs. 124 nmol/L) and free testosterone (3.7 vs. 3.4 pmol/L) levels, but AA women had a 35% higher leptin, 34% higher fasting insulin, and 39% greater insulin response to a glucose load (P < 0.05) compared with CAU women. In CAU, but not AA, women SHBG correlated negatively with body mass index (r = -0.28; P < 0.05), waist (r = -0.36; P = 0.01), IAF (r = -0.34; P = 0.01), and insulin response to oral glucose (r = -0.37; P < 0.05) and positively with high density lipoprotein cholesterol (r = 0.30; P = 0.03). The relationship between insulin area and SHBG in CAU women disappeared after adjusting for IAF, whereas the relationship between high density lipoprotein cholesterol and SHBG persisted after adjusting for IAF, but not for fat mass. Leptin was positively related to fat mass (P < 0.05) in both groups, but it was related to insulin only in the Caucasian women (P< 0.01). There was a racial difference in the slopes (P< 0.05) of the relationships of leptin to fat mass (P < 0.05). Racial differences in leptin disappeared after adjustment for fasting insulin. These results suggest that the metabolic relationships between total and regional obesity, glucose, and lipid metabolism with SHBG in CAU women are different from those in postmenopausal obese AA women.

Reductions in visceral fat during weight loss and walking are associated with improvements in VO(2 max).

The accumulation of visceral fat is independently associated with an increased risk for cardiovascular disease. The aim of this study was to determine whether the loss of visceral adipose tissue area (VAT; computed tomography) is related to improvements in maximal O(2) uptake (VO(2 max)) during a weight loss (250-350 kcal/day deficit) and walking (3 days/wk, 30-40 min) intervention. Forty obese [body fat 47 +/- 1 (SE) %], sedentary (VO(2 max) 19 +/- 1 ml. kg(-1). min(-1)) postmenopausal women (age 62 +/- 1 yr) participated in the study. The intervention resulted in significant declines in body weight (-8%), total fat mass (dual-energy X-ray absorptiometry; -17%), VAT (-17%), and subcutaneous adipose tissue area (-17%) with no change in lean body mass (all P < 0.001). Women with an average 10% increase in VO(2 max) reduced VAT by an average of 20%, whereas those who did not increase VO(2 max) decreased VAT by only 10%, despite comparable reductions in body fat, fat mass, and subcutaneous adipose tissue area. The decrease in VAT was independently related to the change in VO(2 max) (r(2) = 0.22; P < 0. 01) and fat mass (r(2) = 0.08; P = 0.05). These data indicate that greater improvements in VO(2 max) with weight loss and walking are associated with greater reductions in visceral adiposity in obese postmenopausal women.

Responses of adipose tissue lipoprotein lipase to weight loss affect lipid levels and weight regain in women.

This study determines whether changes in abdominal (ABD) and gluteal (GLT) adipose tissue lipoprotein lipase (LPL) activity in response to a 6-mo weight loss intervention, comprised of a hypocaloric diet and low-intensity walking, affect changes in body composition, fat distribution, lipid metabolism, and the magnitude of weight regain in 36 obese postmenopausal women. Average adipose tissue LPL activity did not change with an average 5.6-kg weight loss, but changes in LPL activity were inversely related to baseline LPL activity (ABD: r = -0.60, GLT: r = -0.48; P < 0.01). The loss of abdominal body fat and decreases in total and low-density lipoprotein cholesterol were greater in women whose adipose tissue LPL activity decreased with weight loss despite a similar loss of total body weight and fat mass. Moreover, weight regain after a 6-mo follow-up was less in women whose adipose tissue LPL activity decreased than in women whose LPL increased (ABD: 0.9 +/- 0.5 vs. 2.8 +/- 0.6 kg, P < 0.05; GLT: 0.2 +/- 0.5 vs. 2.8 +/- 0.5 kg, P < 0.01). These results suggest that a reduction in adipose tissue LPL activity with weight loss is associated with improvements in lipid metabolic risk factors with weight loss and with diminished weight regain in postmenopausal women.

Dietary restriction and walking reduce fat deposition in the midthigh in obese older women.

BACKGROUND: It is suggested that fat deposition within midthigh muscle, represented by low-density lean tissue, increases with deconditioning and obesity and is associated with risk factors for cardiovascular disease (CVD) in women. OBJECTIVE: We determined the effects of a 6-mo weight loss and walking (3 times/wk) program (WL+AEX) on midthigh low-density lean tissue and glucose and lipid metabolism in 24 sedentary, obese [body mass index (kg/m(2)): 32 +/- 1 (mean +/- SEM)] postmenopausal women aged 58 +/- 1 y. DESIGN: Total body fat and fat-free mass were measured by using dual-energy X-ray absorptiometry. Intraabdominal fat (IAF), subcutaneous abdominal fat (SAF), midthigh fat, midthigh muscle, and midthigh low-density lean tissue areas were measured by using computed tomography. Glucose and insulin responses were determined with a 3-h oral-glucose-tolerance test. RESULTS: Body weight decreased 8% (P: < 0.001) and maximal aerobic capacity increased 8% (P: < 0.001) with the weight loss and walking program. Total body fat decreased by 15% (P: < 0.001) whereas fat-free mass did not change. IAF and SAF decreased by 18% and 16%, respectively (P: < 0. 001). Midthigh fat and midthigh low-density lean tissue decreased by 16% and 18%, respectively (P: < 0.001), and midthigh muscle area increased by 7% (P: < 0.05). Fasting plasma insulin decreased by 12% and total glucose and insulin areas under the curve decreased by 6% and 24%, respectively (P: < 0.05). HDL-cholesterol concentrations increased 8% (P: < 0.05) and triacylglycerol concentrations decreased 19% (P: < 0.001). CONCLUSION: Increased physical fitness and weight loss reduce midthigh low-density lean tissue and improve glucose and lipid metabolic risk factors for CVD in obese postmenopausal women.