Genome-wide association study identifies new prostate cancer susceptibility loci

Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P= 0.72 and P= 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.     

Annals Journal Club: Cumulative Incidence of False-Positive Results in Repeated,Multimodal Cancer Screening

PURPOSE Multiple cancer screening tests have been advocated for the general population; however, clinicians and patients are not always well-informed of screening burdens. We sought to determine the cumulative risk of a false-positive screening result and the resulting risk of a diagnostic procedure for an individual participating in a multimodal cancer screening program.METHODS Data were analyzed from the intervention arm of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomized controlled trial to determine the effects of prostate, lung, colorectal, and ovarian cancer screening on disease-specific mortality. The 68,436 participants, aged 55 to 74 years, were randomized to screening or usual care. Women received serial serum tests to detect cancer antigen 125 (CA-125), transvaginal sonograms, posteroanterior-view chest radiographs, and flexible sigmoidoscopies. Men received serial chest radiographs, flexible sigmoidoscopies, digital rectal examinations, and serum prostate-specific antigen tests. Fourteen screening examinations for each sex were possible during the 3-year screening period.RESULTS After 14 tests, the cumulative risk of having at least 1 false-positive screening test is 60.4% (95% CI, 59.8%–61.0%) for men, and 48.8% (95% CI, 48.1%–49.4%) for women. The cumulative risk after 14 tests of undergoing an invasive diagnostic procedure prompted by a false-positive test is 28.5% (CI, 27.8%–29.3%) for men and 22.1% (95% CI, 21.4%–22.7%) for women.CONCLUSIONS For an individual in a multimodal cancer screening trial, the risk of a false-positive finding is about 50% or greater by the 14th test. Physicians should educate patients about the likelihood of false positives and resulting diagnostic interventions when counseling about cancer screening.     

EFFECT OF EXERCISE ON GLUTAMINE SYNTHESIS AND TRANSPORT IN SKELETAL MUSCLE FROM RATS

• 1 Reductions in plasma glutamine are observed after prolonged exercise. Three hypotheses can explain such a decrease: (i) high demand by the liver and kidney; (ii) impaired release from muscles; and (iii) decreased synthesis in skeletal muscle. The present study investigated the effects of exercise on glutamine synthesis and transport in rat skeletal muscle.
• 2 Rats were divided into three groups: (i) sedentary (SED; n = 12); (ii) rats killed 1 h after the last exercise bout (EX‐1; n = 15); and (iii) rats killed 24 h after the last exercise bout (EX‐24; n = 15). Rats in the trained groups swam 1 h/day, 5 days/week for 6 weeks with a load equivalent to 5.5% of their bodyweight.
• 3 Plasma glutamine and insulin were lower and corticosterone was higher in EX‐1 compared with SED rats (P < 0.05 and P < 0.01, respectively). Twenty‐four hours after exercise (EX‐24), plasma glutamine was restored to levels seen in SED rats, whereas insulin levels were higher (P < 0.001) and costicosterone levels were lower (P < 0.01) than in EX‐1. In the soleus, ammonia levels were lower in EX‐1 than in SED rats (P < 0.001). After 24 h, glutamine, glutamate and ammonia levels were lower in EX‐24 than in SED and EX‐1 rats (P < 0.001). Soleus glutamine synthetase (GS) activity was increased in EX‐1 and was decreased in EX‐24 compared with SED rats (both P < 0.001).
• 4 The decrease in plasma glutamine concentration in EX‐1 is not mediated by GS or glutamine transport in skeletal muscle. However, 24 h after exercise, lower GS may contribute to the decrease in glutamine concentration in muscle.

     

Evaluation of a novel precision template-guided biopsy system for detecting prostate cancer

OBJECTIVE

To explore the ability of a novel transrectal ultrasonography (TRUS) device (TargetScan^TM, Envisioneering Medical Technologies, St. Louis MO) that creates a three‐dimensional map of the prostate and calculates an optimal biopsy scheme, to accurately sample the prostate and define the true extent of disease, as standard TRUS‐guided prostate biopsy relies on the operator to distribute the biopsy sites, often resulting in under‐ and oversampling regions of the gland.

PATIENTS AND METHODS

In a multicentre retrospective chart review evaluating patients who had a TargetScan prostate biopsy between January 2006 and June 2007, we determined the overall cancer detection rate in all patients and in subgroups based on prostate specific antigen level, digital rectal examination, and indication for biopsy. We assessed the pathological significance of cancer detected, defined as a Gleason score of ≥7, positive margins, extracapsular disease or >20% tumour volume in the prostatectomy specimen. We also evaluated the concordance in Gleason score between the biopsy and prostatectomy specimen.

RESULTS

Cancer was detected in 50 (35.7%) of the 140 patients biopsied, including 39 (47.6%) with no previous biopsies. Of 23 prostatectomy specimens, 20 (87%) had pathologically significant disease. The biopsy predicted the prostatectomy Gleason score in 12 patients (52%), overestimated in two (9%), underestimated in eight (35%), and biopsy Gleason score could not be assigned in one (4%).

CONCLUSIONS

Template‐guided biopsy potentially produces a higher cancer detection rate and more accurate assessment of grade. Prostatectomy specimens did not have a high rate of pathologically insignificant disease.     

Design and implementation of a picture archiving and communication system: The second time

This report describes the authors' experience in the design and implementation of two large scale picture archiving and communication systems (PACS) during the past 10 years. The first system, which is in daily clinical operation was developed at University of California, Los Angeles from 1983 to 1992. The second system, which continues evolving, has been in development at University of California, San Francisco (UCSF) since 1992. The report highlights the differences between the two systems and points out the gradual change in the PACS design concept during the past 10 years from a closed architecture to an open hospital-integrated system. Both systems focus on system reliability and data integrity, with 24-hour on-line service and no loss of images. The major difference between the two systems is that the UCSF PACS infrastructure design is a completely open architecture and the system implementation uses more advanced technologies in computer software, digital communication, system interface, and stable industry standards. Such a PACS can withstand future technology changes without rendering the system obsolete, an essential criterion in any PACS design.     

Testicular circulatory isolation: a Phase I study

Antineoplastic agents may damage germinal epithelium. Testicular circulatory isolation (TCI) is a regional drug exclusion technique designed to minimize this. We evaluated the technical and anaesthetic aspects of TCI in 10 patients who underwent bilateral orchiectomy immediately thereafter. A modified aortic clamp was placed trans-scrotally across the left testicular pedicle without pre-medication or anaesthesia and left in place for 1 h, occluding testicular blood flow. Minimal pain and anxiety were reported during the procedure. There were no complications related to TCI in any patient. This study supports the institution of trials of TCI in young men about to receive fertility-threatening chemotherapy.     

Activity of LY146032 in vitro and in experimental enterococcal pyelonephritis.

The efficacy of LY146032 (LY), a new lipopeptide antibiotic, was compared with that of vancomycin, ciprofloxacin, ceftriaxone, imipenem, and gentamicin and combinations of LY-ceftriaxone, LY-imipenem, and LY-gentamicin against 15 strains of Streptococcus (Enterococcus) faecalis by microtiter dilution and checkerboard techniques. LY was effective within a very narrow range of drug concentrations (from 0.125 to 2.0 micrograms/ml) and was more active than other agents tested against S. faecalis. Enhanced inhibition of S. faecalis was seen more frequently with combinations of either penicillin or ampicillin and an aminoglycoside than with combinations of LY and gentamicin, imipenem, or ceftriaxone. The in vivo efficacy of LY was compared with that of vancomycin and ampicillin alone and combinations of vancomycin-gentamicin, ampicillin-gentamicin, and LY-gentamicin in a rat model of chronic enterococcal pyelonephritis. At a dose of 10 mg/kg given twice daily, LY reduced the number of organisms per kidney significantly compared with that in infected untreated controls within 48 h after the initiation of therapy. At 20 mg/kg given once a day, LY was less effective but reduced colony counts significantly after 4 days of therapy, and its activity was comparable to that of vancomycin or vancomycin-gentamicin given twice daily. LY may be a promising agent for the treatment of enterococcal infections.     

Antimicrobial Activities of BMS-284756 Compared with Those of Fluoroquinolones and β-Lactams against Gram-Positive Clinical Isolates

The in vitro antibacterial activity of BMS-284756 was compared to those of ciprofloxacin, gatifloxacin, moxifloxacin, ceftriaxone, imipenem, piperacillin-tazobactam, and amoxicillin-clavulanic acid against 492 gram-positive clinical isolates. BMS-284756 was the most-active agent against Streptococcus pneumoniae, Streptococcus viridans, beta-hemolytic streptococci, methicillin-sensitive and -resistant Staphylococcus aureus, methicillin-sensitive and -resistant coagulase-negative staphylococci, and enterococci.