An analysis of men with clinically localized prostate cancer who deferred definitive therapy

PURPOSE: We evaluated expectant management of prostate cancer with definitive treatment deferred until evidence of cancer progression in men with low risk, localized cancers. MATERIALS AND METHODS: We retrospectively reviewed prospectively entered data base records. Patients with low risk cancer who were eligible for definitive therapy but chose deferred management between 1984 and 2001 composed the cohort. Followup included regular evaluations to detect progression by prostate specific antigen (PSA), digital rectal examination, transrectal ultrasound and prostate biopsy. Objective progression was defined by a point scale of changes in prognostic factors. Definitive treatment was recommended in patients with objective progression. RESULTS: The cohort comprised 88 patients with clinical stages T1-2, NX0, M0 prostate cancer, a mean age of 65.3 years and a mean initial PSA of 5.9 ng/ml. Systematic biopsy, which was repeated after the initial diagnostic biopsy, showed no cancer in 61% of cases. During a median followup of 44 months 22 patients had progression. Factors that predicted progression were repeat biopsy showing cancer (p = 0.004) and initial PSA (p = 0.014). Actuarial 5 and 10-year progression-free probabilities were 67% and 55%, respectively. Of the 31 patients treated 17 underwent radical prostatectomy, 13 received radiation therapy and 1 received androgen ablation. Seven men who did not show objective progression were treated because of anxiety. Only 1 patient, who was treated with radiation therapy, had biochemical recurrence. CONCLUSIONS: Deferred therapy may be a feasible alternative to curative treatment in select patients with favorable, localized prostate cancer. About half of these patients remain free of progression at 10 years and definitive treatment appeared effective in those with progression. Absent cancer on repeat needle biopsy identified cases highly unlikely to progress.     

Prevalence and significance of anaemia in patients receiving long‐course neoadjuvant chemoradiotherapy for rectal carcinoma

Aim The study aimed to assess the prevalence and significance of anaemia during long‐course neoadjuvant radiotherapy for rectal cancer at our centre. Method Hospital coding and a prospective oncology database were used to identify all patients undergoing long‐course neoadjuvant radiotherapy for rectal cancer at our centre between 2004 and 2009. A retrospective review of computerized records was used to extract individual patient data. Anaemia was defined as a haemoglobin level of < 11.5 g/dl for women and of < 13 g/dl for men. Downstaging was assessed by comparing radiological stage (rTNM) with histological stage (ypTNM). Tumour regression after radiotherapy was assessed using the Rectal Cancer Regression Group (RCRG) scores of 1–3. The results were analysed using Gnu PSPP statistical software. Results There were 70 patients (51 men) of median age 66 (interquartile range 60–72.75) years. Of these, 24 were anaemic. Two (3%) had no haemoglobin level recorded and were excluded. Forty‐two per cent of anaemic patients demonstrated mural (T) downstaging compared with 68% of nonanaemic patients (P = 0.03). There was no difference in nodal downstaging between the groups. The RCRG scores showed more tumour regression in nonanaemic patients than in anaemic patients, as follows: RCRG 1, 59%vs 30%; RCRG 2, 11%vs 17%; and RCRG 3, 38%vs 46% (P < 0.001). Conclusion The prevalence of anaemia in patients undergoing long‐course neoadjuvant radiotherapy was 35%. Anaemia during long‐course neoadjuvant radiotherapy was associated with significant reductions in tumour downstaging and regression.     

Association of Body Composition and Physical Activity with Proximal Femur Geometry in Middle-Aged and Elderly Afro-Caribbean Men:

Osteoporotic fractures are less prevalent in African Americans than in caucasians, possibly because of differences in bone structural strength. Bone structural adaptation can be attributed to changes in load, crudely measured as lean and fat mass throughout life. The purpose of this analysis was to describe the associations of leg lean mass, total body fat mass, and hours walked per week with femoral bone mineral density (BMD) and bone geometry in a cross-sectional sample of 1,748 men of African descent between the ages of 40 and 79 years. BMD, section modulus (Z), cross-sectional area (CSA), and subperiosteal width were measured from dual energy X-ray absortiometry (DXA) scans using the hip structural analysis (HSA) program. Multiple linear regression models explained 35% to 48% of the variance in bending (Z) and axial (CSA) strength at the femoral neck and shaft. Independent of all covariates including total body fat mass, one standard deviation increase in leg lean mass was significantly associated with a 5% to 8% higher Z, CSA, and BMD (P < 0.010) at the neck and shaft. The number of hours walked per week was not a strong or consistent independent predictor of bone geometry or BMD. We have shown that weight is the strongest independent predictor of femur BMD and geometric strength although the effect appears to be mediated by lean mass since leg lean mass fraction and total body fat mass fraction had significant and opposing effects at the narrow neck and shaft in this group of middle aged and elderly men.     

Transforming growth factor-β (TGF-β) activity in urine of patients with glomerulonephritis is related to their renal functional and structural changes

SUMMARY: Transforming growth factor-β (TGF-β) has been considered the principal cytokine involved in the pathogenesis of renal fibrosis. In the present study, we evaluated TGF-β activity in occasional samples from 22 normal individuals and 29 patients (11 with focal glomerulosclerosis, 11 with membranous nephropathy, five with Berger disease, one with type I membranoproliferative glomerulonephritis and one with postinfectious glomerulonephritis) using a CCL-64 mink lung cell growth inhibition assay.
A significantly increased urinary TGF-β activity (reported in relation to urine creatinine, Ucreat, and median) was observed in patients with glomerulonephritis compared with normal individuals ( P <0.01). the patients with Berger disease [median (Md) = 9.96/10 μg Ucreat.], membranous glomerulonephritis (Md = 7.23/10 μg Ucreat.) and focal glomerulosclerosis (Md = 16.6/10 μg Ucreat.) showed higher urinary TGF-β than normal individuals (Md = 1.09/10 μg Ucreat.) ( P <0.01). We found a positive correlation between the TGF-β activity in the urine of these patients and the incidence of segmental glomerulosclerosis ( r = 0.45, P <0.05) and their plasma creatinine levels ( r = 0.87, P <0.01). A negative correlation was observed between the TGF-β activity in the urine of these patients and their creatinine clearance ( r =−0.75, P <0.01).
Our data suggest that measurement of urinary TGF-β activity could be a useful non-invasive procedure for the evaluation of renal TGF-β production, permitting the assessment of prognosis and the evaluation of therapeutic efficacy in patients with renal disease.     

One-year outcomes of tension-free vaginal tape (TVT) mid-urethral slings in overweight and obese women

Introduction  The purpose of this study was to assess the impact of body mass index (BMI) on tension-free vaginal tape (TVT) success rates, patient satisfaction, and complications 1 year following surgery. Methods  Baseline and 1-year postsurgery outcomes were abstracted, including Urogenital Distress Inventory (UDI-6) scores, Incontinence Impact Questionnaire (IIQ-7) scores, and patient satisfaction ratings. Multivariable logistic and linear regression analyses were performed to examine relationships between outcomes and BMI. Results  Subjects (N = 195) with a mean age of 59.3 ± 12.6 were included. There was significant improvement within each group (all p values <0.01) in total UDI-6 and IIQ-7 scores from baseline to 1 year postsurgery; all groups had high patient satisfaction. No differences in improvement or complications rates were observed among the BMI cohorts (all p values >0.05). Conclusion  Differential counseling of overweight or obese women regarding outcomes of the TVT procedure is not supported by these results; longer follow-up is warranted. Poster presentation Annual Meeting of the Society of Gynecologic Surgeons, April 2009. Partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases DK068389 to HER.     

Diagnosis of breast cancer in women age 40 and younger: delays in diagnosis result from underuse of genetic testing and breast imaging

Background

The impact of newer breast imaging technologies and genetic testing on the detection of breast cancer in women age 40 and younger remains unknown.

Methods

A records review identified 628 women age 40 and younger diagnosed with breast cancer from 1996 to 2008. Patient and tumor characteristics, means of diagnosis, imaging results, and genetic testing were examined.

Results

Tumors were first detected by self-examination in 71%, with a median invasive tumor size of 2.0 cm. Imaging performed at or after diagnosis visualized most tumors; mammography visualized 86%, magnetic resonance imaging (MRI) visualized 96%, and mammography plus MRI visualized more than 98% of tumors. For 81% of patients, the mammogram at diagnosis was their first mammogram. Although 50% had a family history of breast or ovarian cancer, few underwent genetic testing before their cancer diagnosis; 61 of 247 (25%) ultimately tested had a BRCA mutation.

Conclusions

Better use of genetic testing, mammography, and MRI could improve breast cancer detection in young women.     

Regional and systemic cytokine responses to acute inflammation of the vermiform appendix

OBJECTIVE: To measure local (peritoneal fluid) and systemic (plasma) cytokine profiles in patients with infection-inflammation of the vermiform appendix, a relatively mild, localized inflammatory process. SUMMARY BACKGROUND DATA: The systemic host response to invading microorganisms, often termed the systemic inflammatory response syndrome (SIRS), includes changes in heart rate, respiratory rate, body temperature, and circulating white blood cell numbers. Although these changes can be induced experimentally by administering proinflammatory cytokines, the mediators that appear in the bloodstream during early, localized infection in humans have not been defined. METHODS: The authors studied 56 patients with pathologically proven appendicitis. Blood was obtained before the induction of anesthesia, when 82% of the patients met the criteria for SIRS. Peritoneal fluid (PF) was obtained by intraoperative lavage. Cytokines were measured by immunoassay. To assess the net impact of the mediators within plasma, the authors studied the ability of patient plasma to augment or suppress bacterial lipopolysaccharide (LPS) stimulation of monocytes in vitro. RESULTS: Of the proinflammatory cytokines, tumor necrosis factor-alpha was present in PF but not in plasma, interleukin (IL)-1beta and interferon-gamma were found in low concentrations in both PF and plasma, and IL-12 (p70) was detectable in plasma but not PF. In contrast, IL-6 and IL-1 receptor antagonist (IL-1ra) were the most abundant cytokines in the PF and plasma, and the concentrations of IL-4 and IL-10 were also elevated in both compartments. Patients with more severe appendicitis had higher plasma levels of IL-6 and IL-10 and lower plasma levels of IL-12 and interferon-gamma than did those with uncomplicated disease. Patient plasma inhibited LPS-induced stimulation of a monocyte cell line, and this inhibition was accentuated by complicated disease. CONCLUSIONS: As judged from the pattern of soluble cytokines in plasma and the effect of the plasma on monocyte activation by LPS, mild, localized infection can induce a systemic response that is predominantly anti-inflammatory.     

Peroxisome proliferator-activated receptor-alpha agonist treatment in a transgenic model of type 2 diabetes reverses the lipotoxic state and improves glucose homeostasis

Abnormalities in insulin action are the characteristics of type 2 diabetes. Dominant-negative muscle-specific IGF-I receptor (MKR) mice exhibit elevated lipid levels at an early age and eventually develop type 2 diabetes. To evaluate the role of elevated lipids in the progression of the diabetic state, MKR mice were treated with WY14,643, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist. WY14,643 treatment markedly reduced serum fatty acid and triglyceride levels within a few days, as well as muscle triglyceride levels, and subsequently normalized glucose and insulin levels in MKR mice. Hyperinsulinemic-euglycemic clamp analysis showed that WY14,643 treatment enhanced muscle and adipose tissue glucose uptake by improving whole-body insulin sensitivity. Insulin suppression of endogenous glucose production by the liver of MKR mice was also improved. The expression of genes involved in fatty acid oxidation was increased in liver and skeletal muscle, whereas gene expression levels of hepatic gluconeogenic enzymes were decreased in WY14,643-treated MKR mice. WY14,643 treatment also improved the pattern of glucose-stimulated insulin secretion from the perfused pancreata of MKR mice and reduced the beta-cell mass. Taken together, these findings suggest that the reduction in circulating or intracellular lipids by activation of PPAR-alpha improved insulin sensitivity and the diabetic condition of MKR mice.     

The incidence and causes of permanent stoma after anterior resection

Aims Defunctioning stomas are used following anterior resection to guard against the serious consequences of anastomotic leak such as pelvic sepsis and generalized peritonitis. This study aims to determine what proportion of patients undergoing anterior resection have a defunctioning stoma, how many of these patients do not have their stoma closed, and the reasons for this. Methods All patients undergoing a resection for rectal cancer in our institution in a five year period (January 1995 to December 1999) are included in the study. Anterior resection was performed on 154 patients, divided into 76 anterior resections (AR) and 78 low anterior resections (defined as the anastomosis within 6 cm of the anal verge). The data from these patients were analysed retrospectively. Results Of the total of 154 patients undergoing anterior resection, 59 (38%) were defunctioned, divided into 33 with loop ileostomy and 26 with loop colostomy. Five of these patients had not had their stoma closed at a median follow up of four years (range 1.5–6.5 years). The reasons for non closure were anastomotic stricture (2), metastatic disease (2), and patient choice (1). When comparing AR and LAR, 16% of patients had a defunctioning stoma after AR, compared with 60% after LAR (P < 0.01). Conclusion Anterior resection is being performed for very low rectal tumours in order to avoid a permanent stoma. However we have found that 8% of patients who are defunctioned with a stoma at anterior resection will not have their stoma closed, and conclude that patients should be warned of this pre‐operatively.     

Glucagon-like peptide-1 receptor activation antagonizes voltage-dependent repolarizing K(+) currents in beta-cells: a possible glucose-dependent insulinotropic mechanism

Glucagon-like peptide-1 (GLP-1) acts through its G-protein-coupled receptor to enhance glucose-stimulated insulin secretion from pancreatic beta-cells. This is believed to result from modulation of at least two ion channels: ATP-sensitive K(+) (K(ATP)) channels and voltage-dependent Ca(2+) channels. Here, we report that GLP-1 receptor signaling also regulates the activity of beta-cell voltage-dependent K(+) (K(V)) channels, themselves potent glucose-dependent regulators of insulin secretion. GLP-1 receptor activation with exendin 4 (10(-8) mol/l) in rat beta-cells antagonized K(V) currents by 43.3 +/- 6.3%, whereas the GLP-1 receptor antagonist exendin 9-39 had no effect. The effect of GLP-1 receptor activation on K(V) currents could be replicated (current reduction of 55.7 +/- 6.0%) by G-protein activation with GMP-PNP (10 nmol/l). The cAMP pathway antagonist Rp-cAMPS (100 micro mol/l) prevented current inhibition by exendin 4, implicating cAMP signaling in GLP-1 receptor modulation of beta-cell K(V) currents. Finally, exendin 4 (10(-8) mol/l) increased the amplitude (130 +/- 5.7%) and duration (285 +/- 15.9%) of the beta-cell depolarization response to current injection, independent of any effect on K(ATP) or Ca(2+) channels. The present results demonstrate that GLP-1 receptor signaling can antagonize beta-cell repolarization by reducing voltage-dependent K(+) currents, an effect likely to contribute to GLP-1's glucose-dependent insulinotropic effect.