The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer.

In an effort to develop a new therapy for prostate cancer (PCa) bone metastases, we have created Ad.dcn, a recombinant oncolytic adenovirus carrying the human decorin gene. Infection of PC-3 and DU-145, the human prostate tumor cells, with Ad.dcn or a non-replicating adenovirus Ad(E1-).dcn resulted in decorin expression; Ad.dcn produced high viral titers and cytotoxicity in human prostate tumor cells. Adenoviral-mediated decorin expression inhibited Met, the Wnt/ß-catenin signaling axis, vascular endothelial growth factor A, reduced mitochondrial DNA levels and inhibited tumor cell migration. To examine the antitumor response of Ad.dcn, PC-3-luc cells were inoculated in the left heart ventricle to establish bone metastases in nude mice. Ad.dcn, in conjunction with control replicating and non-replicating vectors were injected via tail vein. The real-time monitoring of mice, once a week, by bioluminescence imaging and X-ray radiography showed that Ad.dcn produced significant inhibition of skeletal metastases. Analyses of the mice at the terminal time point indicated a significant reduction in the tumor burden, osteoclast number, serum tartrate-resistant acid phosphatase 5b levels, osteocalcin levels, hypercalcemia, inhibition of cancer cachexia and an increase in the animal survival. Based on these studies, we believe that Ad.dcn can be developed as a potential new therapy for PCa bone metastasis.

[Age- and occupation-related differences in sick leave due to frequent musculoskeletal disorders. Low back pain and knee osteoarthritis]. / Alters- und berufsgruppenabhängige Unterschiede in der Arbeitsunfähigkeit durch häufige Muskel-Skelett-Erkrankungen. Rückenschmerzen und Gonarthrose.

Musculoskeletal disorders are the leading cause of sick leave. Because of the importance of back pain and knee osteoarthritis (ICD-10 diagnoses M54 and M17), these conditions are considered in detail. The aim of this study was to clarify whether job-specific differences in the incidence of sick leave events due to these disorders vary depending on age. The study was based on a secondary analysis of data on sick leave from almost all statutory health insurances in 2008. The database contains aggregated data on sick leave of approximately 26.2 million insured employees. The occurrence of sick leave events resulting from the M54 and M17 diagnoses was defined as the outcome variable. The assignment of employees to occupational groups (Blossfeld classification) was considered as the exposure variable. We calculated the morbidity ratios (SMR) of sick leave occurrence stratified by sex and age. The risk of sick leave was increased for both genders and for both diagnoses, particularly in the occupational groups of the production and service industries with low and medium skill level, even after stratification according to age. Sick leave due to these disorders is a significant issue in these occupations regardless of age, and must be considered with regard to social and preventive aspects.

[Occupation- and age-related differences in work absence due to frequent cardiovascular diseases using essential hypertension and acute myocardial infarction as examples]. / Berufsgruppen- und altersabhängige Unterschiede in der Arbeitsunfähigkeit durch häufige Herz-Kreislauf-Erkrankungen am Beispiel der essenziellen Hypertonie und des akuten Myokardinfarktes.

Cardiovascular diseases (CVD) are responsible for a major part of morbidity and mortality. Based on two selected diagnoses (ICD-10) "essential hypertension" (I10) and "acute myocardial infarction" (AMI, I21) the occupational- and age-dependent increases in sick leave are described. The secondary data analysis is based on gender-stratified, pooled data (26.2 million legally insured) on sick leave of the German social security workforce in 2008. The number of sick leave cases stratified by sex and age were calculated. Indirectly standardized morbidity ratios (SMR) for the occurrence of sick leave cases stratified by age and occupational groups (according to Blossfeld) with 99.99% confidence intervals are estimated. Age had an influence on the professional group-dependent sick leave. In the youngest age group, a similar risk existed for hypertension and AMI in all occupational groups. In the middle and older age groups, low-skilled service workers and manual occupations had increased risks for both men and women as compared to the occupational group of qualified sales and administrative occupations. Because the workforce is expected to continue to age in the future, primary and secondary prevention of CVD in all age groups is strongly recommended.

Investigation of neuroleptics and other aromatic compounds by laser-based ion mobility mass spectrometry.

Laser-based ion mobility (IM) spectrometry was used for the detection of neuroleptics and PAH. A gas chromatograph was connected to the IM spectrometer in order to investigate compounds with low vapour pressure. The substances were ionized by resonant two-photon ionization at the wavelengths λ = 213 and 266 nm and pulse energies between 50 and 300 µJ. Ion mobilities, linear ranges, limits of detection and response factors are reported. Limits of detection for the substances are in the range of 1-50 fmol. Additionally, the mechanism of laser ionization at atmospheric pressure was investigated. First, the primary product ions were determined by a laser-based time-of-flight mass spectrometer with effusive sample introduction. Then, a combination of a laser-based IM spectrometer and an ion trap mass spectrometer was developed and characterized to elucidate secondary ion-molecule reactions that can occur at atmospheric pressure. Some substances, namely naphthalene, anthracene, promazine and thioridazine, could be detected as primary ions (radical cations), while other substances, in particular acridine, phenothiazine and chlorprothixene, are detected as secondary ions (protonated molecules). The results are interpreted on the basis of quantum chemical calculations, and an ionization mechanism is proposed.

Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia.

Identification of the signalling cascades that are differentially activated during prostatic tumourigenesis is a crucial step in the search for future molecular targets in this disease. The stress-activated protein kinase (SAPK) signalling cascade culminates in the phosphorylation of the JNK and p38 mitogen-activated protein kinases (MAPKs). Recently, the upstream activators of these proteins, the MAPK kinases (MKKs), have been implicated as inhibitors of tumour progression in a variety of clinical and experimental tumour models. This study evaluates MKK4, MKK6 and MKK7 expression during prostate cancer progression in humans and in the transgenic adenocarcinoma of a mouse prostate (TRAMP) model of prostate tumourigenesis. Benign prostate, prostatic intraepithelial neoplasia (PIN) lesions and tumour tissues were collected from 37 TRAMP mice. Additionally, six tissue microarrays were constructed with tumours from a matched group of 102 men who underwent radical prostatectomy. Tissues from 20 patients with extensive high-grade prostatic intraepithelial neoplasia (HGPIN) were also analysed. For all samples, immunohistochemical staining for MKK4, MKK6 and MKK7 was scored in normal and neoplastic glands. Staining intensities of MKK4, MKK6 and MKK7 were significantly increased in HGPIN and prostate cancer compared to surrounding normal glands in both the TRAMP and human samples (p < 0.0001 for all markers). Increased levels of MKK4 or MKK7 correlated with higher pathological stage at prostatectomy (p = 0.01 and p = 0.04). Using multivariate analysis, there was no association between protein levels and time to biochemical recurrence in the human samples. The up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression in both TRAMP and human tissues highlights an important role for the SAPK signalling cascade in prostatic neoplasia. The finding that higher MKK4 and MKK7 expression is associated with higher-stage prostatic tumours underscores the dynamic regulation of these proteins during prostatic tumourigenesis.

Alpha-methylacyl-CoA racemase: a multi-institutional study of a new prostate cancer marker.

AIM: To test whether alpha-methylacyl-CoA racemase (AMACR) is a sensitive and specific marker of prostate cancer. METHODS AND RESULTS: The expression levels of AMACR mRNA were measured by real-time polymerase chain reaction. A total of 807 prostatic specimens were further examined by immunohistochemistry specific for AMACR. Quantitative immunostaining analyses were carried out by using the ChromaVision Automated Cellular Imaging System and the Ariol SL-50 Imaging System, respectively. AMACR mRNA levels measured in prostatic adenocarcinoma were 55 times higher than those in benign prostate tissue. Of 454 cases of prostatic adenocarcinoma, 441 were positive for AMACR, while 254 of 277 cases of benign prostate were negative for AMACR. The sensitivity and specificity of AMACR immunodetection of prostatic adenocarcinomas were 97% and 92%, respectively. Both positive and negative predictive values were 95%. By automatic imaging analyses, the AMACR immunostaining intensity and percentage in prostatic adenocarcinomas were also significantly higher than those in benign prostatic tissue (105.9 versus 16.1 for intensity, 45.7% versus 0.02% and 35.03% versus 4.64% for percentage, respectively). CONCLUSIONS: We have demonstrated the promising features of AMACR as a biomarker for prostate cancer in this large series and the potential to develop automated quantitative diagnostic tests.

Relationship of erythrocyte membrane polyunsaturated fatty acids and prostate-specific antigen levels in Jamaican men.

OBJECTIVE: To investigate the relationship between erythrocyte membrane polyunsaturated fatty acid (PUFA) and serum prostate- specific antigen (PSA) levels in Jamaican men, as there may be an association between prostate cancer incidence and dietary fatty acids, and prostate cancer incidence in Jamaica is among the highest in the world. PATIENTS AND METHODS: Blood from 107 Jamaican men was analysed for 32 individual fatty acids and PSA levels. Special attention was given to correlations between Omega3 and Omega6 PUFAs and PSA. Data were analysed using standard linear regression methods. RESULTS: The mean PSA was 18.6 ng/mL (normal 0-4.0); for age groups of 51-60, 61-70 and 71-80 years the levels were 14, 26 and 23 ng/mL, respectively. Eicosapentaenoic acid (Omega3) levels decreased as PSA exceeded 10 ng/mL (P = 0.02). Arachidonic acid (Omega6) levels decreased as PSA was < 2 ng/mL (P = 0.02). Linoleic acid (Omega6) levels decreased in men with PSA levels of 2-10 ng/mL (P = 0.04). In men with a PSA of > 10 ng/mL there was a positive correlation between the ratio of Omega6 to Omega3 PUFAs and PSA (P = 0.036); there was also a negative correlation between the ratio of Omega3 to Omega6 PUFAs and PSA (P = 0.08). When the ratio of Omega3 PUFAs over the products of Omega6 PUFAs were used, this trend was significant (P= 0.03). CONCLUSIONS: Increased levels of Omega6 PUFAs and the ratio of Omega6/Omega3 PUFAs in Jamaican men are associated with an increased mean PSA level and risk of prostate cancer. Additional studies are needed to establish a causal link between dietary fatty acid intake and the development of prostate cancer in Jamaican men.

Characterizing prostatic adenocarcinomas in men with a serum prostate specific antigen level of < 4.0 ng/mL.

OBJECTIVE: To characterize prostate cancer in men undergoing radical prostatectomy who have a prostate-specific antigen (PSA) level of < 4.0 ng/mL, hypothesizing that a low PSA is not caused by diminished tumour production of PSA, nor does it signify clinically insignificant disease. PATIENTS AND METHODS: Seventy-nine men (mean age 59.3 years, range 43-77) with a PSA level of < 4.0 ng/mL were identified from 702 who had a radical prostatectomy between 1994 and 2000. Demographic and clinical data were analysed; pathological specimens were evaluated by routine haematoxylin and eosin staining and immunohistochemistry with anti-PSA antibody, for both pathological staging and grading, and for the presence of PSA production. Tumours were classified as 'clinically insignificant' if the tumour volume was < 0.5 mL and the Gleason score < 7. RESULTS: The mean (SD, range) preoperative PSA level was 3.04 (0.85, 0.8-3.8) ng/mL Indications for biopsy included an abnormal digital rectal examination (61%), a PSA velocity of > 0.75 ng/mL/year (12%), a strong family history of prostate cancer (3%), obstructive urinary symptoms (2%), or no obvious indication (23%). Thirty-eight (48%) tumours were clinically insignificant. Of 41 clinically significant cancers, 13 had a final Gleason score of > or = 7, 20 had extraprostatic extension and 11 had a tumour volume of > or = 10 mL Of the 79 prostate cancer specimens 78 stained strongly for PSA; the exception was a Gleason 9 tumour. With a mean (range) follow-up of 3.5 (0.18-6) years only one patient had a biochemical recurrence (PSA > or = 0.1 ng/mL). CONCLUSIONS: Most prostate cancers in men with a PSA level of < 4.0 ng/mL are clinically significant and PSA-producing. Many of these tumours are high-grade, high-volume and extraprostatic. We are currently exploring factors to explain why serum PSA is not elevated in these men, including tumour location, pattern of invasion and microvessel density.

Indications and contraindications for nerve-sparing radical prostatectomy.

Nerve-sparing radical prostatectomy can be performed safely in most men undergoing radical prostatectomy. As is true in many aspects of prostate cancer diagnosis and therapy, the key element is patient selection. With many prostate tumors diagnosed at an earlier stage, the authors have seen a shift toward more favorable pathologic findings at the time of surgery. Concomitant with the success of early detection of prostate cancer is the realization that men are younger at the time of diagnosis and more interested in preserving sexual function. This article has described factors associated with an increased risk for extraprostatic tumor and, subsequently, an increased possibility of postprostatectomy cancer recurrence. Except for the previously mentioned absolute contraindications, none of these factors, by themselves, should be used to exclude a patient from nerve-sparing prostatectomy. Instead, meticulous attention must be given to the surgical dissection. If any doubt remains regarding residual tumor, the surgeon should err on the side of caution and remove the neurovascular bundle. The use of standardized intraoperative frozen-section analysis can help guide these decisions. The patient must be informed before surgery regarding the risks of nerve-sparing surgery, the potency rates of the surgeon, and the possibility that, to ensure adequate cancer control, the nerves may be sacrificed despite any preoperative optimism favoring the potential for their salvage.

High-grade prostatic intraepithelial neoplasia with adjacent atypia is associated with a higher incidence of cancer on subsequent needle biopsy than high-grade prostatic intraepithelial neoplasia alone.

OBJECTIVES: High-grade prostatic intraepithelial neoplasia (HGPIN) is often considered a premalignant lesion of the prostate. Its incidence ranges from 0.7% to 20% in all prostate biopsies, and patients with HGPIN on initial biopsy are reportedly found to have a higher risk of cancer on subsequent biopsy. The purpose of our study was to determine the incidence of HGPIN in our patients who underwent prostate biopsy and to determine whether a further pathologic subclassification of HGPIN between HGPIN alone and HGPIN with adjacent atypical glands has any prognostic value in predicting the rate of prostate cancer on subsequent prostate biopsy. METHODS: A total of 485 patients who underwent prostate biopsy between January 1998 and October 1999 were included in the study. Each set of slides was reviewed by a single urologic pathologist to determine the presence of HGPIN alone or HGPIN with adjacent atypical glands. If any HGPIN was identified, a repeat biopsy was performed, and the presence of cancer was recorded. RESULTS: The overall incidence of HGPIN alone and HGPIN with adjacent atypical glands on initial biopsy was 33 (6.8%) of 485. Of these 33 patients, 21 (64%) had HGPIN alone and 12 (36%) had HGPIN with adjacent atypical glands. Three (14%) of 21 patients with HGPIN alone were found to have cancer on subsequent biopsy compared to 9 (75%) of 12 patients with HGPIN with adjacent atypia on initial biopsy. This difference is statistically significant (P <0.005). CONCLUSIONS: The incidence of HGPIN alone in our experience is 4.3% (21 of 485). Patients with HGPIN with adjacent atypical glands suspicious for cancer have a significantly higher incidence of cancer on subsequent biopsy than patients with HGPIN alone.

Does the CaverMap device help preserve potency?

Erectile dysfunction remains a common complication following radical prostatectomy. The CaverMap Surgical Aid (UroMed, Boston, MA) was designed to aid the surgeon in identifying and preserving neurovascular bundles (NVBs). However, the size of the CaverMap nerve stimulator may make it difficult to trace the cavernous nerves before the prostate is removed, particularly in obese men or in patients who have a large prostate or a narrow pelvis. In a randomized, controlled study, the use of the CaverMap during radical prostatectomy resulted in improved nocturnal erections, but did not lead to improved overall sexual function. The CaverMap device, however, may be useful as a research tool in that it helps determine whether the NVBs have been successfully preserved after removing the prostate. However, preservation of the NVB does not guarantee recovery of potency, which may be prolonged despite successful stimulation of the cavernous nerves intraoperatively. This suggests that erectile dysfunction following radical prostatectomy is multifactorial.

A positive caver map response poorly predicts recovery of potency after radical prostatectomy.

OBJECTIVES: To determine whether preservation of the neurovascular bundles (NVBs), defined by a positive CaverMap response, correlates with the recovery of potency after radical prostatectomy. METHODS: We studied a group of 60 men who were potent preoperatively who underwent radical retropubic prostatectomy by one surgeon. The CaverMap was used after removal of the prostate to assess the integrity of the NVBs. Postoperative potency was assessed by a postal questionnaire and telephone interview, administered independently of the treating surgeon. Men were considered potent if they reported postoperative erections consistently sufficient for vaginal penetration with or without the use of sildenafil. RESULTS: The mean patient age was 59 years, and the median follow-up was 365 days. A positive CaverMap response was obtained in 73 (77%) of the 95 NVBs tested. The overall potency rate was 18%. No patients with a bilateral negative CaverMap response were potent, and 2 (22%) of 9 with a unilateral CaverMap response (negative versus unilateral response, P = 0.46) and 6 (27%) of 22 with bilateral CaverMap responses (negative versus bilateral response, P = 0.32) were potent. CONCLUSIONS: A positive CaverMap response, suggesting that a successful nerve-sparing prostatectomy had been performed, was obtained in 77% of the NVBs tested. Nevertheless, with a median follow-up of 12 months, most patients with a positive CaverMap response remained impotent. This suggests that other factors are critical to the recovery of sexual function after radical prostatectomy.

Effect of preoperative biofeedback/pelvic floor training on continence in men undergoing radical prostatectomy.

OBJECTIVES: To determine whether preoperative biofeedback training improves urinary continence overall or the rate of return of continence in men undergoing radical prostatectomy. METHODS: One hundred men scheduled to undergo radical prostatectomy were randomized to receive graded pelvic muscle exercise training with biofeedback 2 to 4 weeks before surgery or to a control group performing pelvic muscle exercises without biofeedback. The biofeedback group was instructed to continue exercises four times per day until surgery and to resume exercises when the urethral catheter was removed following surgery. The control group received written and brief verbal instructions in pelvic muscle exercises before surgery and again after catheter removal. Urinary continence was assessed by personal or phone interviews. RESULTS: Six months following surgery, the continence rates, as defined by the use of one pad or less per day, were 94% (44 of 47) and 96% (48 of 50) in the biofeedback and control groups, respectively (P = 0.596). Also, the rate of return as determined at time points 1, 2, 3, and 4 months after surgery was not significantly different between the two groups. CONCLUSIONS: Preoperative biofeedback training did not improve the outcome of pelvic muscle exercises on overall continence or the rate of return of urinary control in men undergoing radical prostatectomy.

Sildenafil in the treatment of erectile dysfunction after radical prostatectomy.

OBJECTIVES: To evaluate the efficacy of sildenafil for the treatment of erectile dysfunction after radical prostatectomy and to determine whether age, preservation of the neurovascular bundles (NVBs), or the interval between surgery and the initiation of sildenafil therapy influences the response to sildenafil. METHODS: We began this study in April 1998, immediately after the Food and Drug Administration approved sildenafil. We surveyed 170 men who had undergone radical retropubic prostatectomy, had not recovered natural erections sufficient for intercourse, and subsequently received sildenafil between 3 and 24 months postoperatively. The data were collected through a confidential mail survey conducted by a clinical nurse. The men used a dose of 50 mg sildenafil and increased this to 100 mg if they did not obtain an adequate response. RESULTS: In the 120 men who began taking sildenafil at least 12 months after surgery, the overall response rate was 29%. Results varied markedly by patient age and number of NVBs preserved. In men younger than 55 years in whom both NVBs had been preserved, the response rate was 80%. In contrast, no patient older than 55 years in whom only one NVB had been preserved reported an adequate response. Regardless of age, no patient in whom both NVBs had been excised reported success with sildenafil. Of the 50 patients who began taking sildenafil less than 9 months after surgery and who had not recovered natural sexual function, none reported erections adequate for intercourse using sildenafil. CONCLUSIONS: Sildenafil is an effective treatment for men with erectile dysfunction after radical retropubic prostatectomy, particularly in younger men in whom both NVBs have been preserved. It is ineffective in men in whom both NVBs have been excised, and it is also ineffective in older men in whom only one NVB has been preserved. Sildenafil appears ineffective in the first 9 months after prostatectomy.

A new technique for securing a foley catheter.

We describe a new technique to secure a urethral catheter using a horizontal drain tube stabilizer. This device is reliable, inexpensive, and more comfortable for patients than either adhesive tape or leg straps.