The Prevalence of Clinically Significant Prostate Cancer According to Commonly Used Histological Thresholds in Men Undergoing Template Prostate Mapping Biopsies.

PURPOSE: Transrectal prostate biopsies are inaccurate and, thus, the prevalence of clinically significant prostate cancer in men undergoing biopsy is unknown. We determined the ability of different histological thresholds to denote clinically significant cancer in men undergoing a more accurate biopsy, that of transperineal template prostate mapping. MATERIALS AND METHODS: In this multicenter, cross-sectional cohort of men who underwent template prostate mapping biopsies between May 2006 and January 2012, 4 different thresholds of significance combining tumor grade and burden were used to measure the consequent variation with respect to the prevalence of clinically significant disease. RESULTS: Of 1,203 men 17% (199) had no previous biopsy, 38% (455) had a prior negative transrectal ultrasound biopsy, 24% (289) were on active surveillance and 21% (260) were seeking risk stratification. Mean patient age was 63.5 years (SD 7.6) and median prostate specific antigen was 7.4 ng/ml (IQR 5.3-10.5). Overall 35% of the patients (424) had no cancer detected. The prevalence of clinically significant cancer varied between 14% and 83% according to the histological threshold used, in particular between 30% and 51% among men who had no previous biopsy, between 14% and 27% among men who had a prior negative biopsy, between 36% and 74% among men on active surveillance, and between 47% and 83% among men seeking risk stratification. CONCLUSIONS: According to template prostate mapping biopsy between 1 in 2 and 1 in 3 men have prostate cancer that is histologically defined as clinically significant. This suggests that the commonly used thresholds may be set too low.

Rayleigh-Taylor instability of an ultrathin foil accelerated by the radiation pressure of an intense laser.

We report experimental evidence for a Rayleigh-Taylor-like instability driven by radiation pressure of an ultraintense (10(21) W/cm(2)) laser pulse. The instability is witnessed by the highly modulated profile of the accelerated proton beam produced when the laser irradiates a 5 nm diamondlike carbon (90% C, 10% H) target. Clear anticorrelation between bubblelike modulations of the proton beam and transmitted laser profile further demonstrate the role of the radiation pressure in modulating the foil. Measurements of the modulation wavelength, and of the acceleration from Doppler-broadening of back-reflected light, agree quantitatively with particle-in-cell simulations performed for our experimental parameters and which confirm the existence of this instability.

Hypomethylation of WNT5A, CRIP1 and S100P in prostate cancer.

Oligoarray analysis of a matched pair of prostate cancer and normal cell lines derived from the same radical prostatectomy specimen identified 113 candidate hypomethylated genes that were overexpressed in the cancer cells and contained CpG islands. Hypomethylation of wingless-related MMTV integration site 5A (WNT5A), S100 calcium-binding protein P (S100P) and cysteine-rich protein 1(CRIP1) was confirmed in the cancer cells by bisulfite sequencing. Treatment of the corresponding normal prostate epithelial cells 1542-NPTX with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-CdR) induced higher levels of mRNA expression and partial loss of methylation on these genes. Primary prostate cancers were tested using methylation-specific polymerase chain reaction. WNT5A was hypomethylated in 11/17 (65%) tumors, S100P in 8/16 (50%) and CRIP1 in 13/20 (65%). Bisulfite sequencing of a section of the 5' untranslated region (UTR) of WNT5A revealed that three CpG sites (15, 24 and 35) were consistently methylated (93%) in the normal cell line and normal tissues, but not in the prostate cancer cell line and eight primary prostate cancers. Multiple putative binding sites for the transcription factors SP1 and AP-2 were found adjacent to CpG sites 15 and 24. A putative c-Myb binding site was located within the CpG site 35. Anti-c-Myb antibody co-precipitation with WNT5A was methylation-sensitive in 1542-NPTX cells. It is likely that an epigenetic mechanism regulates WNT5A expression in prostate cancer.

Allelic imbalance and biochemical outcome after radical prostatectomy.

OBJECTIVE: To compare the incidence of allelic imbalance (AI) in men with rapid disease progression with those who remained disease free after radical prostatectomy, with the aim of identifying genetic markers to predict prognosis and guide further treatment. PATIENTS AND METHODS: Tumour and normal DNA were extracted from two matched groups of 31 men with extracapsular node-negative (pT3N0) prostate cancer who had undergone radical prostatectomy. One group comprised men who developed biochemical recurrence within 2 years of surgery and one group were prostate-specific antigen (PSA) free for at least 3 years. Men were matched for Gleason grade, preoperative PSA and pathological stage. Analysis was performed by genotyping. RESULTS: Allelic imbalance was analysed using 30 markers, and was seen in at least one marker in 57 (92%) of the cases. Deletion at marker D10S211 (10p12.1) was significantly more common in the relapse group than the non-relapse group (35 vs 5%, P=0.03). CONCLUSIONS: This study demonstrates significant association between AI on chromosome 10 and biochemical progression after radical prostatectomy.

Dynamics of cylindrically converging precursor plasma flow in wire-array Z -pinch experiments.

This paper summarizes the present understanding of the processes leading to precursor column formation in cylindrical wire arrays on the 1 MA MAGPIE generator at Imperial College London. Direct experimental measurements of the diameter variation during the collapse and formation phase of the precursor column are presented, along with soft x-ray emission, and quantitative radiography. In addition, data from twisted cylindrical arrays are presented which give additional information on the behavior of coronal plasma generated in wire array z pinches. Three stages in precursor column formation are identifiable from the data: broad initial density profile, rapid contraction to small diameter, and slow expansion after formation. The correlation of emission to column diameter variation indicates the contraction phase is a nonlinear collapse resulting from the increasing on-axis density and radiative cooling rate. The variation in the minimum diameter is measured for several array materials, and data show good agreement with a pressure balance model. Comparison of column expansion rates to analytical models allows an estimate of column temperature variation, and estimates of the current in the column are also made. Formation data are in good agreement with both fluid and kinetic modeling, but highlight the need to include collisionless flow in the early time behavior.

Molecular changes in prostatic cancer.

Prostate cancer is one of the most commonly diagnosed and potentially devastating cancers in men, throughout the world. However, the clinical manifestation of this disease varies greatly, from indolent tumours, requiring little or no treatment, to those aggressive cancers which require radical therapies. Prostate cancer, like all other cancers, develops and progresses as a consequence of an accumulation of genetic changes. While several putative genes have been isolated for the development of breast, ovarian and colon cancer, the aetiology and pathogenesis of prostate cancer remains poorly understood. In this review, we discuss important genetic markers in early, metastatic and hormone refractory prostate cancer which may, in the future, be used as markers for diagnosis and prognosis, as well as targets for therapeutic intervention.

p21WAF1/CIP1 gene is inactivated in metastatic prostatic cancer cell lines by promoter methylation.

INTRODUCTION: p21WAF1/CIP1 may act as a tumour suppressor gene (TSG) and loss of the p21WAF1/CIP1 gene has been reported in several solid tumours. The aim of this study was to see whether p21WAF1/CIP1 was expressed in metastatic prostate cancer cell lines and to determine if there was methylation of the p21WAF1/CIP1 promoter. METHOD: PC3, LNCaP and DU145 metastatic prostate cancer cell lines, 1542NP normal prostate, and RD rhabdomyosarcoma cell lines were cultured in the demethylating agent 5-Aza-2 deoxycytidine (5-Aza-CdR). p21WAF1/CIP1 mRNA expression was analysed by RT-PCR. DNA from untreated cell lines was modified with sodium bisulphite and promoter sequencing was performed. RESULTS: p21WAF1/CIP1 was expressed at low or undetectable levels in metastatic prostate cancer cell lines but expression was reactivated by treatment with 5-Aza-CdR. Sequence analysis of the promoter region revealed several sites of methylation at the 5' end of a CpG island in the PC3, LNCaP and DU145 cell line DNA but not in the normal prostate control DNA. Most notably the Sis-inducible element (SEI)-1-a STAT1-binding site, was methylated. CONCLUSIONS: In this study, we show that p21WAF1/CIP1 expression in metastatic prostate cancer cell lines is enhanced as a result of demethylation of the DNA. Furthermore, several cytosine residues in the promoter region are methylated, including critical binding sites. The inhibition of the STAT1-signalling pathway by methylation of the promoter may inactivate the p21WAF1/CIP1 TSG in prostate cancer.

The pharmacokinetic and pharmacodynamic properties of biphasic insulin Aspart 70 (BIAsp 70) are significantly different from those of biphasic insulin Aspart 30 (BIAsp 30).

AIMS: To evaluate the pharmacokinetic and pharmacodynamic properties of two different formulations of premixed analogue (mixed biphasic insulin aspart [BIAsp]), BIAsp 30 (30 % soluble insulin aspart [IAsp] and 70 % protaminated IAsp) and BIAsp 70 (70 % soluble IAsp and 30 % protaminated IAsp), in patients with type 1 diabetes using a 12-hour euglycaemic clamp technique. METHODS: In this randomised, double-blind, two-period crossover trial, 27 patients with type 1 diabetes received 7 days of treatment with BIAsp 30 three times daily (TID) and 7 days of treatment with BIAsp 70 TID, with a 2 - 6 week washout period between treatment periods. At the start (day 1) and end (day 8) of each treatment period, 12-hour serum IAsp profiles and glucose infusion rate (GIR) profiles were determined during an overnight euglycaemic clamp following subcutaneous (sc) administration of a single 0.3 U/kg dose of trial insulin. All pharmacokinetic and pharmacodynamic endpoints were derived from individual serum IAsp and GIR profiles. RESULTS: The larger fraction of soluble IAsp in BIAsp 70 compared with BIAsp 30 resulted in greater metabolic effect during the initial post-dosing phase (0 - 6 hours) and decreased activity during the late phase (6 - 12 hours). On day 8, AUC (GIR 0 - 6 hours) was 16 % greater for BIAsp 70 than for BIAsp 30 (p = 0.016) and AUC (GIR 6 - 12 hours) was 90 % (p < 0.001) greater for BIAsp 30 relative to BIAsp 70, reflecting the increased proportion of intermediate-acting (protamine co-crystallised) IAsp in BIAsp 30. Overall metabolic effect (AUC (GIR 0 - 12 hours)) was similar for both insulin formulations on day 8 (Ratio, BIAsp 30:BIAsp 70 = 1.04, p = 0.538). Likewise, the larger fraction of soluble IAsp in BIAsp 70 compared with BIAsp 30 resulted in greater exposure to IAsp during the initial post-dosing phase (0 - 6 hours) and a smaller exposure to IAsp during the late phase (6 - 12 hours). On day 8, AUC (IAsp 0 - 6 hours) was 59 % (p < 0.001) greater for BIAsp 70 than for BIAsp 30, and AUC (IAsp 6 - 12 hours) was 61 % (p < 0.001) greater for BIAsp 30 than for BIAsp 70, reflecting the increased proportion of intermediate-acting (protamine co-crystallised) IAsp in BIAsp 30. However, the overall IAsp exposure (AUC 0 - 12 hours) on day 8 was significantly greater for BIAsp 70 than for BIAsp 30 (Ratio, BIAsp 30:BIAsp 70 = 0.73, p < 0.001). The GIR profiles on day 8 were similar to those on day 1. Serum IAsp profiles on day 8 showed a slight increase compared with day 1. CONCLUSIONS: The different proportions of soluble and protaminated IAsp result in differences in the pharmacokinetic and pharmacodynamic properties of BIAsp 30 and BIAsp 70. The pharmacokinetic and pharmacodynamic differences observed may allow for flexibility and individualised treatment regimens in patients with diabetes, while maintaining a limited number of daily injections.

Subcutaneous leiomyosarcoma of the frenulum.

Leiomyosarcomas of the penis are rare, with only 29 reported cases to date. We record the case of a patient who presented with a 2-year history of a seemingly indolent penile skin lesion. On histopathology of the local resection, a diagnosis of subcutaneous leiomyosarcoma was made. Specifically, leiomyosarcoma of the penile frenulum has not been clearly reported previously. The patient underwent a further excision to ensure an adequate resection margin and has had no disease recurrence at subsequent follow-up. Our case was of a lesion that, although clinically benign, was malignant and this possibility should be borne in mind when assessing patients.

De novo lipogenesis during controlled overfeeding with sucrose or glucose in lean and obese women.

BACKGROUND: The results of previous studies suggest that de novo lipogenesis may play an important role in the etiology of obesity, particularly during overconsumption of different carbohydrates. OBJECTIVE: We hypothesized that de novo lipogenesis would increase during overfeeding, would vary depending on the type of carbohydrate consumed, and would be greater in obese than in lean women. DESIGN: De novo lipogenesis was measured during 96 h of overfeeding by 50% with either sucrose or glucose and during an energy balance treatment (control) in 8 lean and 5 obese women. De novo lipogenesis was determined by measuring the amount of deuterium incorporation into plasma triacylglycerols. Fat and carbohydrate balance were measured simultaneously by continuous whole-body calorimetry. RESULTS: De novo lipogenesis did not differ significantly between lean and obese subjects, except with the control treatment, for which de novo lipogenesis was greater in the obese subjects. De novo lipogenesis was 2- to 3-fold higher after overfeeding by 50% than after the control treatment in all subjects. The type of carbohydrate overfeeding (sucrose or glucose) had no significant effect on de novo lipogenesis in either subject group. Estimated amounts of absolute VLDL production ranged from a minimum of 2 g/d (control) to a maximum of 10 g/d after overfeeding. This compares with a mean fat balance of approximately 275 g after 96 h of overfeeding. Individual subjects showed characteristic amounts of de novo lipogenesis, suggesting constitutive (possibly genetic) differences. CONCLUSION: De novo lipogenesis increases after overfeeding with glucose and sucrose to the same extent in lean and obese women but does not contribute greatly to total fat balance.

Incidental findings in pelvic lymph nodes at radical prostatectomy.

AIMS: To assess the frequency and cause of incidental (non-metastatic) lymph node pathology discovered before or at radical prostatectomy. METHODS: Eight hundred and fifty four consecutive lymphadenectomies received between 1988 and 2001 were reviewed. All had been processed and stained routinely. Additional techniques, indicated by morphology, were then performed. RESULTS: Incidental pathology was found in 15 cases: florid sinus histiocytosis following prosthetic joint replacement (eight), non-caseating granulomas (three), small lymphocytic cell lymphoma (two), follicular lymphoma (one), and foreign body reaction (one). Incidental pathology was present in 1.8% of 854 patients who underwent pelvic lymphadenectomy during radical prostatectomy. CONCLUSION: Awareness of possible non-metastatic lymph node pathology aids histological diagnosis and may be clinically relevant.

Management of recurrent disease after radical prostatectomy.

Prostate cancer has undergone a stage migration since the advent of widespread PSA testing, yet still a significant number of men develop PSA recurrence following radical prostatectomy. This causes anxiety to the patient and the urologist. This review examines the clinical significance of biochemical relapse and the role of imaging modalities and anastomotic biopsies. The importance of the radical prostatectomy pathological features and the PSA kinetics in determining the site of recurrence and the best treatment modality is emphasised. The optimal timing and dose of salvage radiotherapy and the role of hormonal therapy is discussed.

Avoidance and management of positive surgical margins before, during and after radical prostatectomy.

Positive surgical margins after radical prostatectomy lead to an increased risk of progression and reduced disease free survival. Earlier detection of prostate cancer, appropriate patient selection and improved operative techniques can reduce the incidence of positive margins, though the risk can not be eliminated as pre-operative staging techniques are not sufficiently sensitive. Nerve sparing and bladder neck sparing do not adversely affect margin status in appropriately selected men. Once positive margins have been diagnosed the optimal management and the timing of treatment remains controversial. Adjuvant radiotherapy or salvage radiotherapy in men with a low PSA may improve local control and PSA free survival in some individuals, a survival benefit has not yet been established.

Integrating systematic screening for gender-based violence into sexual and reproductive health services: results of a baseline study by the International Planned Parenthood Federation, Western Hemisphere Region.

Three Latin American affiliates of the International Planned Parenthood Federation, Western Hemisphere Region, Inc. (IPPF/WHR) have begun to integrate gender-based violence screening and services into sexual and reproductive health programs. This paper presents results of a baseline study conducted in the affiliates. Although most staff support integration and many had already begun to address violence in their work, additional sensitization and training, as well as institution-wide changes are needed to provide services effectively and to address needs of women experiencing violence.

Testicular torsion unravelled.

Testicular torsion is a true vascular emergency-prompt diagnosis and surgical management is critical. If treatment is not instigated within 4-6 hours of the onset of pain, irreversible testicular infarction may result, necessitating orchidectomy. This review presents the key features, management principles and medicolegal considerations of this serious condition.

Pathological changes in the TMJ and the length of the ramus in patients with confirmed juvenile idiopathic arthritis.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is characterized by a progressive destruction of the joints. The temporomandibular joints (TMJ) are especially likely to be affected. The often undetected arthritis in the TMJ in particular can cause significant destruction and craniofacial developmental abnormalities. The aim of this study was to analyze the destructive impact of JIA on TMJ and mandibular development. MATERIAL AND METHODS: We analyzed a total of 92 joints and mandibular rami using digital cone-beam tomography (CBT) and compared 23 consecutively treated JIA patients with 23 healthy controls, matched for age and gender. We evaluated ramus length, vertical depth of the articular fossa, anterior-posterior dimensions of the mandibular head and condylar process. The statistical analysis was performed using non-parametric Wilcoxon and Kruskal-Wallis Rank Sum tests. RESULTS: The JIA patients exhibited significantly more pronounced asymmetries. However, we were unable to detect significant differences in the metric measuring distances. The different JIA subtypes exerted no statistically significant influence. CONCLUSIONS: The possible destruction arising as a result of JIA concerns the TMJ and the length of the mandibular ramus. These craniofacial anomalies demonstrate the central importance of sufficiently early detection and timely treatment in the prevention of such growth disturbances.

Root exudation and root development of lettuce (Lactuca sativa L. cv. Tizian) as affected by different soils.

Development and activity of plant roots exhibit high adaptive variability. Although it is well-documented, that physicochemical soil properties can strongly influence root morphology and root exudation, particularly under field conditions, a comparative assessment is complicated by the impact of additional factors, such as climate and cropping history. To overcome these limitations, in this study, field soils originating from an unique experimental plot system with three different soil types, which were stored at the same field site for 10 years and exposed to the same agricultural management practice, were used for an investigation on effects of soil type on root development and root exudation. Lettuce (Lactuca sativa L. cv. Tizian) was grown as a model plant under controlled environmental conditions in a minirhizotrone system equipped with root observation windows (rhizoboxes). Root exudates were collected by placing sorption filters onto the root surface followed by subsequent extraction and GC-MS profiling of the trapped compounds. Surprisingly, even in absence of external stress factors with known impact on root exudation, such as pH extremes, water and nutrient limitations/toxicities or soil structure effects (use of sieved soils), root growth characteristics (root length, fine root development) as well as profiles of root exudates were strongly influenced by the soil type used for plant cultivation. The results coincided well with differences in rhizosphere bacterial communities, detected in field-grown lettuce plants cultivated on the same soils (Schreiter et al., this issue). The findings suggest that the observed differences may be the result of plant interactions with the soil-specific microbiomes.

Classification of temporomandibular joint erosion, arthritis, and inflammation in patients with juvenile idiopathic arthritis.

INTRODUCTION: Juvenile idiopathic arthritis is the most common disease in pediatric rheumatology. It is characterized by chronically progressive joint destruction. The temporomandibular joints (TMJs) are involved in up to 87% of patients and may take an asymptomatic course in 69% of cases. Other than contrast-enhanced magnetic resonance imaging (MRI), there are no reliable screening symptoms or non-invasive procedures available to diagnose the inflammation in its acute form. The goal of this study was to establish an imaging-based classification system for TMJ erosion via MRI and cone-beam computed tomography (CBCT) in an effort to improve indication-specific treatment approaches and to facilitate the comparison of findings. MATERIALS AND METHODS: A total of 46 patients were included. Contrast-enhanced MRI and CBCT images obtained during treatment by pediatric rheumatologists and orthodontists were available from 23 patients with juvenile idiopathic arthritis. We devised a classification system combining the findings of both imaging techniques based on this patient sample in comparison with CBCT findings from an age- and gender-matched group of 23 non-arthritis patients, taking into consideration the available literature and administration of contrast medium. RESULTS: Our cohort of 46 patients comprised 60% female and 40% male patients with a mean age of 14 years, providing a total of 92 TMJs for evaluation. We were able to apply the findings efficiently and conveniently to this classification system with no relevant interobserver differences. Mild structural abnormalities were noted in 21% of TMJs in the control group, whereas 83% of TMJs in the arthritis group exhibited severe anomalies, including cases of extreme destruction. Age and gender did not affect the degree of destruction significantly. CONCLUSION: This is the first classification system to link CBCT and MRI with the use of contrast medium. Contrast-enhanced MRI is an internationally recognized technique that permits acute inflammation to be unequivocally diagnosed. Although structural erosion of the TMJs in our arthritis group was generally severe and significant, we were surprised to observe some cases that were clinically asymptomatic.

MAPPED study design: a 6 month randomised controlled study to evaluate the effect of dutasteride on prostate cancer volume using magnetic resonance imaging.

OBJECTIVE: To evaluate the percentage change in volume of prostate cancer, as assessed by T2-weighted MRI, following exposure to dutasteride (Avodart) 0.5mg daily for six months. PATIENTS AND METHODS: MRI in Primary Prostate cancer after Exposure to Dutasteride (MAPPED) is a double-blind, placebo-controlled trial, supported by GlaxoSmithKline (GSK). Men with prostate cancer suitable for active surveillance (low-intermediate risk prostate cancer on biopsy), and a visible lesion on T2-weighted MRI of at least 0.2 cc, were eligible for consideration. Forty-two men were randomised to 6 months of daily dutasteride 0.5mg or placebo. Multi-parametric MRI (mpMRI) scans were performed at baseline, 3 and 6 months. The percentage changes in cancer volume over time will be compared between the dutasteride and placebo groups. Planned analyses will examine the association between tumour volume and characteristics (perfusion and contrast washout) as seen on mpMRI, HistoScan ultrasound and biopsy histopathology in both groups. DISCUSSION: MAPPED is the first randomised controlled trial to use mpMRI to look at the effect of dutasteride on the volume of prostate cancer. If dutasteride is shown to reduce the volume of prostate cancer, it might be considered as an adjunct for men on active surveillance. Analysis of the placebo arm will allow us to comment on the short-term natural variability of the MR appearance in men who are not receiving any treatment. CONCLUSION: MAPPED will evaluate the short-term effect of dutasteride on prostate cancer volume, as assessed by mpMRI, in men undergoing active surveillance for low or intermediate risk prostate cancer. The study completed recruitment in January 2012.