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.

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.

[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.

Spontaneous benign prostatic hyperplasia in the beagle. Age-associated changes in serum hormone levels, and the morphology and secretory function of the canine prostate.

This paper is a cross-sectional study of spontaneous benign prostatic hyperplasia (BPH) in a single canine species. The effects of aging and hormonal changes on the growth, histology, and glandular secretory function of the canine prostate were studied in 42 male beagles ranging in age from 8 mo to 9 yr. The beagle prostate enlarges for at least 6 yr, whether normal or hyperplastic. In contrast, prostatic secretory function, determined by ejaculate volume and total ejaculate protein, declines markedly after 4 yr of age. These reciprocal growth and functional changes in the prostate are closely associated with a progressive increase in the incidence of BPH, which is already apparent in some dogs by age two. With age there is a modest decrease in serum androgen levels with no apparent change in serum 17 beta-estradiol levels. This suggests that the growth and functional changes that are associated with the development of BPH and are initiated very early in life reflect an altered sensitivity of the prostate to serum androgens or a response to the relative decrease in the serum androgen to estrogen ratio.

Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model.

Cohorts of 4- to 5-wk-old female Fischer 344 rats received four biweekly 1.5-mg doses of N-methyl-N-nitrosourea (MNU) intravesically and were sacrificed at various intervals. By 13 wk after initiation of the carcinogen, all animals have flat epithelial atypia and/or papillary transitional cell bladder carcinomas, and 67% of the lesions are histological Grade II or III. By 20 wk, 83% have gross bladder wall muscle-invasive tumors that eventually kill the host. There was no gross evidence of visceral metastases in any animal. This rat model of transitional cell carcinoma of the bladder is useful because: (a) all animals develop progressive neoplastic changes in situ within 4 mo after initiation of MNU treatment; (b) these lesions progress to grossly detectable bladder tumors which invade the bladder wall and kill the host; (c) this full progression of bladder epithelial cells from atypical hyperplasia through flat carcinoma in situ to transitional cell carcinoma occurs at discrete time points; (d) the histology of the grossly detectable tumors is that of invasive transitional cell carcinomas; and (e) no leukemias, breast cancers, lymphomas, or other non-bladder tumors are induced. Six MNU-induced bladder wall-invasive tumors were karyotyped, and all tumors were diploid with 42 chromosomes. Three of the tumors had apparently normal karyotypes, while three tumors had karyotypes containing one or more cytogenetic structural markers. One of these markers (i.e., 8p+) was observed in two of the three tumors. The level of expression of total ras p21 (N-, Ki-, and Ha-ras p21) and codon 12-mutated c-Ha-ras p21 (i.e., glycine to glutamic acid mutation in codon 12) in a series of these MNU-induced bladder tumors was determined by Western blot analysis. No increase in the total ras p21 nor any expression of codon 12-mutated c-Ha-ras p21 was detected in any of these tumors.

Changes in the metabolism of dihydrotestosterone in the hyperplastic human prostate.

It has been well established that hyperplastic human prostatic tissue is characterized by a 3- to 4-fold elevation in the content of dihydrotestosterone (DHT) compared to that in normal prostatic tissue. However, the exact mechanism responsible for DHT accumulation has not been established. One hypothesis for the abnormal elevation of DHT content in hyperplastic prostatic tissue is that changes occur in the tissue itself which shift the overall balance of androgen metabolism favoring the increased accumulation of DHT. To test this hypothesis, the metabolic activities that produce and remove DHT were determined in a series of normal as well hyperplastic human prostates. The results of these studies demonstrated that in each of the eight separate hyperplastic prostatic tissues assayed, there was a significant increase in 5 alpha-reductase activity producing DHT concomitant with significant decreases in the 3 alpha- and 3 beta-hydroxysteroid oxidoreductase reductase and 17 beta-hydroxysteroid oxidoreductase oxidase activities removing DHT. These specific alterations result in a major shift in the overall balance of androgen metabolism which favors an increase in the net formation of DHT in hyperplastic prostatic tissue. Such a shift in androgen metabolism is, therefore, at least one mechanism for the well documented increase in DHT content found in hyperplastic human prostatic tissue.

Characteristics of prostate cancer found with early detection regimens.

This article reviews the clinical and pathologic characteristics of nonpalpable (Stage T1c) prostate cancer reported in five studies published to date. Stage T1c tumors more closely resemble palpable prostate cancers (Stage T2) than they do incidental prostate cancers detected in cystoprostatectomy specimens. The mean tumor volume of Stage T1c tumors is about 50 times greater (2.0 mL vs 0.04 mL) than incidental cystoprostate cancers. Only about 20-25% of T1c tumors have a tumor volume < 0.5 mL; tumors > 0.5 mL are considered to have significant biologic potential. Futhermore, 30-50% of T1c tumors have penetrated the prostatic capsule, 20-30% demonstrate positive surgical margins, and 5-10% demonstrate seminal vesicle invasion and/or positive pelvic lymph nodes. Possible reasons for nonpalpability of T1c tumors include tumor location in the central and/or anterior zones of the prostate and increased gland volume due to benign prostatic hyperplasia, making T1c tumors more difficult to palpate. A combination of serum prostate-specific antigen (PSA) density < 0.1 and favorable needle biopsy pathology (no Gleason 4 or 5 pattern in any core, < 3 cores positive for cancer, and < 50% involvement of any single core) will identify about 75% of men with tumors < 0.5 mL who might be followed without immediate treatment. Overall, however, these data indicate that most T1c tumors are significant cancers > 0.5 mL that warrant aggressive treatment in accordance with age and other health considerations.

Management of urinary retention due to benign prostatic hyperplasia using luteinizing hormone-releasing hormone agonist.

A common affliction of older men is bladder outlet obstruction secondary to benign prostatic hyperplasia for which the standard treatment is surgical prostatectomy. We report on six men with urinary retention from benign prostatic hyperplasia who were not medically able to undergo surgical prostatectomy but were successfully treated with the luteinizing hormone-releasing hormone (LH-RH) agonist, leuprolide acetate. This therapy is exemplified by the case of a sixty-six-year-old man with hemophilia B and urinary retention. The patient was treated with daily subcutaneous injections of 1 mg of leuprolide acetate, and prostatic size decreased from 132 g to 42 g, with initiation of spontaneous micturition while on treatment. For patients with symptomatic benign prostatic hyperplasia who are not candidates for surgery, treatment with an LH-RH agonist, such as leuprolide acetate, should be considered as a possible alternative.

Postoperative morbidity is similar in patients anesthetized with epidural and general anesthesia for radical prostatectomy.

OBJECTIVES: To compare the effect of epidural and general anesthesia on the postoperative course and complication rate in patients undergoing radical prostatectomy. METHODS: Ninety-eight men scheduled for radical retropubic prostatectomy (RRP) were randomly assigned to receive epidural anesthesia only (EA, n = 34), combined epidural and general anesthesia (EG, n = 33) or general anesthesia only (GA, n = 31). In the EA group, epidural anesthesia was induced and maintained with bupivacaine. In the EG group, patients received epidural bupivacaine after the induction of general anesthesia. In the GA group, anesthesia was induced with morphine and maintained with isoflurane. In the postoperative period, epidural patient-controlled analgesia (PCA) was maintained in all patients for 3 to 5 days. Patients were evaluated throughout the hospitalization period and at 3, 6, and 12 weeks following surgery. RESULTS: The three groups did not differ with regard to postoperative pain, bleeding, urine output, fever, length of paralytic ileus, or length of hospitalization. No major cardiovascular, pulmonary, or neurologic complications occurred in any of the patients either perioperatively or in the first 3 months postoperatively. CONCLUSIONS: Intraoperative anesthetic technique was not associated with a different postoperative complication rate in patients undergoing RRP. The very low incidence of complications and the uniform postoperative analgesic regimen may have contributed to the similarity between groups.

Intraoperative blood loss during radical retropubic prostatectomy: epidural versus general anesthesia.

OBJECTIVES: There are conflicting reports on the influence of different anesthetic techniques, such as regional versus general anesthesia, on intraoperative blood loss. The purpose of this study was to elucidate the effects of anesthetic technique on intraoperative blood loss in men undergoing radical retropubic prostatectomy (RRP). METHODS: One hundred patients undergoing RRP for prostate cancer were randomly assigned to receive either epidural anesthesia (EA), combined epidural and general anesthesia (EG), or general anesthesia alone (GA). Intraoperative blood loss was calculated by using a formula that accounted for the volume and hematocrit of the fluid suctioned from the surgical field, blood absorbed on surgical pads, and the patient's hematocrit. RESULTS: Mean blood loss in the EA group (1490 +/- 90 mL; mean +/- SEM) was significantly less than mean blood loss in both the EG group (1810 +/- 100 mL) and the GA group (1940 +/- 130 mL) (P = 0.01). Blood loss was not different between the EG and the GA groups (P = 0.7). Significantly less blood was transfused during surgery in the EA group (730 +/- 50 mL) compared with the EG (960 +/- 60 mL) and GA (950 +/- 70 mL) groups (P = 0.02). CONCLUSIONS: Similar blood loss in patients receiving general anesthesia, either alone or when combined with epidural anesthesia, implies that epidural anesthesia did not reduce bleeding, but, rather, that general anesthesia increased blood loss.

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.

Evaluation of erectile function in men with sickle cell disease.

OBJECTIVES: To evaluate and characterize erectile manifestations associated with sickle cell disease using nocturnal penile tumescence testing with polysomnography (NPT/PSG) and magnetic resonance imaging (MRI) of the penis. METHODS: Six variably potent men with sickle cell disease, of whom 5 reported a history of priapism, underwent comprehensive evaluations of erectile function. Evaluations involved a medical history and physical examination with completion of priapism and sexual function questionnaires, followed by NPT/PSG and MRI of the penis. RESULTS: Many different erectile abnormalities were identified in this group using NPT/PSG, although nocturnal erection durations as well as detumescence times were uniformly prolonged. Various axial rigidity measurements were obtained, which correlated fairly well with individual reports of erectile function. MRI findings ranged from normal corporeal anatomy to corporeal destruction with intracorporeal fibrosis and hemosiderin deposition. CONCLUSIONS: In sickle cell disease, the erectile dysfunction that commonly occurs may be markedly different among men with this disease and may not always be predicted on the basis of clinical history of priapism. Generally, clinical assessments of erectile function may be derived from clinical histories and physical examinations. NPT/PSG and MRI of the penis are in accord with these assessments, obviating their routine use, although they may be valuable management adjuncts in certain situations.

Selection of men at high risk for disease recurrence for experimental adjuvant therapy following radical prostatectomy.

OBJECTIVES: Following surgery, men with recurrent prostate cancer have an isolated elevation in serum prostate-specific antigen (PSA) well in advance of measurable metastatic disease. Rational patient selection for new forms of adjuvant therapy, for example, gene therapy, is imperative. METHODS: In a retrospective study of two cohorts, we used proportional hazards regression analysis to develop and validate a multifactor model for identifying men who are at high risk of cancer recurrence. The model cohort consisted of 216 men with clinical Stage T2b and T2c treated by 1 urologist. The validation cohort consisted of 214 men with Stage T2b and T2c disease. RESULTS: A model for log relative risk, Rw, used serum PSA with a sigmoidal transformation (PSAST), radical prostatectomy Gleason score (GS), and pathologic stage (PS) as specimen confined or nonspecimen confined: Rw = (PSAST x 0.06) + (GS x 0.54) + (PS x 1.87). Recurrence risk categories were determined as low risk if Rw is less than 4.0, intermediate risk if it is 4.0 to less than 5.75, and high risk if Rw is more than 5.75. The observed Kaplan-Meier actuarial analysis of the three risk groups correlated well with the predictions determined for the model cohort. We then validated this model independently using a second cohort of 214 men with similar age, stage, and grade treated by 3 different urologists at two different institutions. CONCLUSIONS: The recurrence rates for men in the high-risk group are similar to those for men with positive lymph nodes and justifies exploration of experimental adjuvant therapy within this group using this model of patient selection.

Molecular biology of bladder cancer.

Recent studies have provided the first clues as to the molecular mechanisms responsible for bladder carcinogenesis. Cytogenetic and molecular studies have demonstrated nonrandom changes of chromosomes 1, 5, 7, 9, 11, and 17. The finding of monosomy of chromosome 9 in early noninvasive lesions has initiated a search for a bladder-specific gene responsible for bladder oncogenesis. Activation of ras and erbB oncogenes has been reported, although the role that these changes play in bladder cancer is not yet understood. Inactivation of two well-characterized tumor suppressor genes, p53 and Rb, also appears to be important in the pathogenesis of bladder cancer, and evidence suggests that inactivation of p53 correlates with the acquisition by bladder cancer cells of the invasive phenotype. Although the picture is far from complete, it is clear that for the first time an understanding of the molecular events responsible for bladder cancer is possible, and that this information will have clinical impact on patients in the near future.

Anatomic radical cystoprostatectomy.

Radical cystoprostatectomy is considered one of the most difficult urologic operations. The nerve-sparing modifications that have allowed preservation of potency have resulted from an improved understanding of pelvic anatomy. This knowledge is not only important for preservation of potency; it also allows the entire operation to be done more precisely with increased exposure and decreased perioperative morbidity. Although many of the steps described above may seem routine to the urologist who does this operation frequently, we hope that this step-by-step guide proves useful to the practicing urologist who does only a few each year and to the resident who is learning the procedure.

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.