Older patients with low Charlson score and high-risk prostate cancer benefit from radical prostatectomy.

INTRODUCTION: The aim of the study was to identify the appropriate level of Charlson comorbidity index (CCI) in older patients (>70 years) with high-risk prostate cancer (PCa) to achieve survival benefit following radical prostatectomy (RP). METHODS: We retrospectively analyzed 1008 older patients (>70 years) who underwent RP with pelvic lymph node dissection for high-risk prostate cancer (preoperative prostate-specific antigen >20 ng/mL or clinical stage ≥T2c or Gleason ≥8) from 14 tertiary institutions between 1988 and 2014. The study population was further grouped into CCI < 2 and ≥2 for analysis. Survival rate for each group was estimated with Kaplan-Meier method and competitive risk Fine-Gray regression to estimate the best explanatory multivariable model. Area under the curve (AUC) and Akaike information criterion were used to identify ideal 'Cut off' for CCI. RESULTS: The clinical and cancer characteristics were similar between the two groups. Comparison of the survival analysis using the Kaplan-Meier curve between two groups for non-cancer death and survival estimations for 5 and 10 years shows significant worst outcomes for patients with CCI ≥ 2. In multivariate model to decide the appropriate CCI cut-off point, we found CCI 2 has better AUC and p value in log rank test. CONCLUSION: Older patients with fewer comorbidities harboring high-risk PCa appears to benefit from RP. Sicker patients are more likely to die due to non-prostate cancer-related causes and are less likely to benefit from RP.

MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer.

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.

The role of exenterative surgery and urinary diversion in persistent or locally recurrent gynecological malignancy: complications and survival.

OBJECTIVE: Treatment options in patients with persistent or locally recurrent cervical cancer are limited. The aim of this study was to determine the chance of cure and associated morbidity following pelvic exenteration. PATIENTS AND METHODS: Consecutive patients who underwent pelvic exenteration between January 1992 and December 2006 at the University Hospital of Bern or the Karlsruhe Medical Center were evaluated. Time to recurrence, type of exenteration and urinary diversion, pathological stage, postoperative complications and survival were assessed. RESULTS: Initial therapy prior to diagnosis of persistent or locally recurrent disease included radiation therapy in 51%. Anterior exenteration was performed in 37 (86%) and total exenteration in 6 (14%). Half of the women underwent additional procedures. A continent urinary diversion was constructed in 16 and an ileal conduit in 27 patients. Early postoperative complications were generally minor and only 2 patients required surgical intervention. Four intestinal fistulas were successfully treated conservatively. Late complications were mainly tumor-related. Complication rates associated with the urinary diversion were low and there was no difference in complications between continent and incontinent diversions. The overall disease-specific 5-year survival rate after exenteration was 36.5%. Survival correlated significantly with surgical margin status. CONCLUSION: In patients with persistent or locally recurrent gynecological malignancy of the pelvis, exenteration is a viable option with long-term survival in over one third of patients. Continent urinary diversion did not show higher complication rates than an ileal conduit and should be considered even in irradiated patients. This may be of greater significance in younger patients in whom an intact body image can play an important role in quality of life.

[Calcium oxalate stone formation. New pathogenetic aspects of an old disease]. / Kalziumoxalatsteinbildung. Neue pathogenetische Aspekte einer alten Erkrankung.

Calcium oxalate (CaOx) urolithiasis is a very common disorder. Surprisingly, the pathogenetic mechanisms leading to CaOx stone formation have been largely unknown so far. The long-accepted simple explanation by an exceeding of the solubility product of lithogenic substances in the urine cannot sufficiently describe the complex processes. Deviating from the hypothesis that proclaims that the initial crystal deposition takes place in the lumens of renal tubules, new insights suggest a primary plaque formation in the interstitial space of the renal papilla. Initially, calcium phosphate (CaPh) crystals and organic matrix are deposited along the basement membranes of the thin loops of Henle and extend further in the interstitial space to the urothelium, constituting the so-called Randall's plaques that can be regularly found during endoscopy of CaOx-stone-forming patients. These CaPh crystals seem to be the origin for the development of future CaOx stones, which form by the attachment of further matrix molecules and CaOx from the urine to the plaque. The driving forces, the exact pathogenetic mechanisms, and the involved matrix molecules remain largely unknown. Possibly, completely different pathomechanisms lead to the common clinical diagnosis of"CaOx stone former."

The survival impact of neoadjuvant hormonal therapy before radical prostatectomy for treatment of high-risk prostate cancer.

BACKGROUND: Several randomized controlled trials assessed the outcomes of patients treated with neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP). The majority of them included mainly low and intermediate risk prostate cancer (PCa) without specifically assessing PCa-related death (PCRD). Thus, there is a lack of knowledge regarding a possible effect of NHT on PCRD in the high-risk PCa population. We aimed to analyze the effect of NHT on PCRD in a multicenter high-risk PCa population treated with RP, using a propensity-score adjustment. METHODS: This is a retrospective multi-institutional study including patients with high-risk PCa defined as: clinical stage T3-4, PSA >20 ng ml-1 or biopsy Gleason score 8-10. We compared PCRD between RP and NHT+RP using competing risks analysis. Correction for group differences was performed by propensity-score adjustment. RESULTS: After application of the inclusion/exclusion criteria, 1573 patients remained for analysis; 1170 patients received RP and 403 NHT+RP. Median follow-up was 56 months (interquartile range 29-88). Eighty-six patients died of PCa and 106 of other causes. NHT decreased the risk of PCRD (hazard ratio (HR) 0.5; 95% confidence interval (CI) 0.32-0.80; P=0.0014). An interaction effect between NHT and radiotherapy (RT) was observed (HR 0.3; 95% CI 0.21-0.43; P<0.0008). More specifically, of patients who received adjuvant RT, those who underwent NHT+RP had decreased PCRD rates (2.3% at 5 year) compared to RP (7.5% at 5 year). The retrospective design and lack of specific information about NHT are possible limitations. CONCLUSIONS: In this propensity-score adjusted analysis from a large high-risk PCa population, NHT before surgery significantly decreased PCRD. This effect appeared to be mainly driven by the early addition of RT post-surgery. The specific sequence of NHT+RP and adjuvant RT merits further study in the high-risk PCa population.

[Urinary diversion in elderly patients]. / Harnableitung beim älteren Patienten.

BACKGROUND: Bladder cancer represents one of the ten most prevalent cancers worldwide. More than 400,000 people worldwide are newly diagnosed every year. Within 2 years after diagnosis, 80% of patients with muscle invasive bladder cancer without treatment die. METHODS: The aggressive local surgical approach with a cystectomy is the therapy of choice. The median age of patients with de novo bladder cancer is 70 years. Thus bladder cancer is a cancer of the elderly. For demographical reasons, the number of eldery patients undergoing radical cystectomy will rise in the next few years. The type of urinary diversion is a major factor influencing perioperative morbidity and quality of life in these patients. Incontinent urinary diversions are preferentially used in daily practice. CONCLUSIONS: There are only a few contraindications for orthotopic neobladder; however, age alone is not a contraindication. Patient selection and a nerve sparing approach are crucial in men and women to achieve excellent functional results with orthotopic neobladder in elderly patients.

Predicting prostate cancer-specific outcome after radical prostatectomy among men with very high-risk cT3b/4 PCa: a multi-institutional outcome study of 266 patients.

BACKGROUND: The value of radical prostatectomy (RP) as an approach for very high-risk prostate cancer (PCa) patients is controversial. To examine the risk of 10-year cancer-specific mortality (CSM) and other-cause mortality (OCM) according to clinical and pathological characteristics of very high-risk cT3b/4 PCa patients treated with RP as the primary treatment option. METHODS: In a multi-institutional cohort, 266 patients with very high-risk cT3b/4 PCa treated with RP were identified. All patients underwent RP and pelvic lymph-node dissection. Competing-risk analyses assessed 10-year CSM and OCM before and after stratification for age and Charlson comorbidity index (CCI). RESULTS: Overall, 34 (13%) patients died from PCa and 73 (28%) from OCM. Ten-year CSM and OCM rates ranged from 5.6% to 12.9% and from 10% to 38%, respectively. OCM was the leading cause of death in all subgroups. Age and comorbidities were the main determinants of OCM. In healthy men, CSM rate did not differ among age groups (10-year CSM rate for ⩽64, 65-69 and ⩾70 years: 16.2%, 11.5% and 17.1%, respectively). Men with a CCI ⩾1 showed a very low risk of CSM irrespective of age (10-year CSM: 5.6-6.1%), whereas the 10-year OCM rates increased with age up to 38% in men ⩾70 years. CONCLUSION: Very high-risk cT3b/4 PCa represents a heterogeneous group. We revealed overall low CSM rates despite the highly unfavorable clinical disease. For healthy men, CSM was independent of age, supporting RP even for older men. Conversely, less healthy patients had the highest risk of dying from OCM while sharing very low risk of CSM, indicating that this group might not benefit from an aggressive surgical treatment. Outcome after RP as the primary treatment option in cT3b/4 PCa patients is related to age and comorbidity status.

A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women.

Enhanced 5 alpha-reductase activity has been found in the skin of the majority of women with hirsutism. Finasteride is a specific competitive inhibitor of 5 alpha-reductase, preferentially inhibiting the type 2 isoenzyme. Therefore, we randomly assigned 14 hirsute women in a 2:1 ratio to 1 of 2 treatment arms: 1) finasteride (F) treatment (n = 9; 5 mg, orally, daily), or 2) spironolactone (S) treatment (n = 5; 100 mg, orally, daily). Each group was treated for 6 months. Patients were evaluated at baseline and after 3 and 6 months of treatment. The 2 groups were similar in age, weight, hip/waist ratio, baseline Ferriman-Gallwey score (F, 19 +/- 2; S, 19 +/- 2), and baseline androgen levels. Finasteride treatment resulted in a significant increase in testosterone (T; P < 0.01) and the T/dihydrotestosterone ratio (P < 0.01). Finasteride caused a significant decrease in 5 alpha-androstane-3 alpha,17 beta-diol glucuronide (3 alpha-diolG; P < 0.05), the 3 alpha-diolG/T ratio (P < 0.01), and the 3 alpha-diolG/androstenedione ratio (P < 0.05). All changes were consistent with 5 alpha-reductase inhibition. In contrast, spironolactone treatment did not result in significant changes in serum hormone levels. Both treatments produced a significant decrease in anagen hair diameters [F, -14.0 +/- 6.7% (P < 0.05); S, -13.4 +/- 3.8% (P < 0.05)] and Ferriman-Gallwey scores [F, -2.1 +/- 0.4 (P < 0.05); S, -2.5 +/- 0.7 (P < 0.05)]. In conclusion, despite significantly different effects on androgen levels, finasteride and spironolactone treatment resulted in a similar clinical effect on hirsutism. Both caused significant, but limited, improvement in hirsutism. Although promising, further studies with finasteride are needed to verify its effectiveness as a treatment for hirsutism. Such studies will also provide a better understanding of the relative contribution of 5 alpha-reductase isoenzymes to hirsutism.

Digital radiography with a large-area, amorphous-silicon, flat-panel X-ray detector system.

RATIONALE AND OBJECTIVES: To investigate the image quality of a digital radiography system with an amorphous-silicon, large-area, digital flat-panel detector. METHODS: A flat-panel detector based on a matrix of amorphous silicon was integrated into a projection radiography system. The scintillator consisted of a layer of structured cesium iodide. The active matrix size of 30002 pixels together with a pixel size of 143 microm provided a large image area of 43 x 43 cm2. Basic image quality parameters such as detective quantum efficiency (DQE) and modulation transfer function (MTF) were measured and compared with those obtained with conventional systems. RESULTS: The measurement of DQE yielded a high value of 70% at zero spatial frequency. At a system dose equivalent to 400 speed, the DQE of the digital system was a factor of two larger than the DQE of a storage phosphor or screen-film system within the entire spatial frequency range between zero and the Nyquist limit of 3.5 line pairs per millimeter. The flat-panel detector furthermore has an MTF that is superior to that in regular screen-film systems and also provides a substantially larger dynamic range. CONCLUSIONS: This new technology demonstrates its potential to provide equal or superior image quality to conventional screen-film systems and to reduce patient exposure to radiation dose. The advantages of digital radiography systems, based on a flat-panel detector as an instant image display, facilitation of work flow in the radiology department, and digital networking and archiving, are well in sight.

Flat-panel x-ray detector using amorphous silicon technology. Reduced radiation dose for the detection of foreign bodies.

RATIONALE AND OBJECTIVES: The authors evaluate a new flat-panel x-ray detector (FD) with respect to foreign body detection and reduction of radiation dose compared with screen-film radiography. METHODS: Flat-panel x-ray detector is based on amorphous silicon technology and uses a 1 k x 1 k photo-detector matrix with a pixel size of 143 x 143 microns and 12-bit digital output. A thallium-dotted cesium iodide scintillation layer converts x-rays into light. An ex vivo experimental model was used to determine the detectability of foreign bodies. Foreign bodies with varying sizes were examined: glass with and without addition of lead, bone, aluminium, iron, copper, gravel fragments, and graphite. Four hundred observation fields were examined using conventional radiography (speed, 400; system dose: 2.5 microGy) as well as FD with a simulated speed of 400, 800, 1200, and 1600, corresponding to a detector dose of 2.5 microGy, 1.25 microGy, 0.87 microGy, and 0.625 microGy, respectively. Four independent radiologists performed receiver operating characteristic analysis of 8000 observations. RESULTS: Flat-panel x-ray detector with a simulated speed of 400 was significantly superior (P = 0.012) to screen-film radiography (speed, 400). At a simulated speed of 800 and 1200 FD yielded results equivalent to screen-film radiography. Flat-panel x-ray detector was significantly inferior to screen-film radiography at a simulated speed of 1600 (P = 0.012). CONCLUSIONS: Flat-panel x-ray detector technology allows significant reduction in radiation dose compared with screen-film radiography without loss of diagnostic accuracy.

Amorphous silicon, flat-panel, x-ray detector versus screen-film radiography: effect of dose reduction on the detectability of cortical bone defects and fractures.

RATIONALE AND OBJECTIVES: The purpose of this phantom study was to assess the diagnostic performance of a self-scanning, solid-state amorphous silicon (a-Si) detector in skeletal radiography using different exposure parameters. METHODS: A flat-panel detector (15 cm x 15 cm), based on a-Si technology with 143 microm x 143 microm pixel size, 1k x 1k matrix, and 12 bit digital output was used. State-of-the-art screen-film radiography (SFR; speed 400, detector dose 2.5 microGy) was compared with a-Si images taken at doses that were equivalent to a speed of 400, 800, 1,250, and 1,600, respectively. A total of 232 segments of long tubular deer-bones (femur, tibia, humerus, radius) had 110 artificial fractures and 112 cortical defects simulating osteolytic lesions. Receiver operating characteristic analysis was performed for 9,280 observations made by four independent observers. Two-tailed Student's paired t test was used for statistical analysis (95% confidence level). RESULTS: Receiver operating characteristic analysis yielded equivalent results of the a-Si and SFR system. Even at the lowest dose there were no statistically significant differences between both imaging modalities with respect to the detectability of fractures and cortical defects. CONCLUSIONS: The results of this study indicate that a-Si detector technology holds promise in terms of dose reduction in skeletal radiography without loss of diagnostic accuracy.

Self-normalizing method to measure the detective quantum efficiency of a wide range of x-ray detectors.

The detective quantum efficiency (DQE) is widely accepted as the most relevant parameter to characterize the image quality of medical x-ray systems. In this article we describe a solid method to measure the DQE. The strength of the method lies in the fact that it is self-normalizing so measurements at very low spatial frequencies are not needed. Furthermore, it works on any system with a response function which is linear in the small-signal approximation. We decompose the DQE into several easily accessible quantities and discuss in detail how they can be measured. At the end we lead the interested reader through an example. Noise equivalent quanta and normalized contrast values are tabulated for standard radiation qualities.

SCEs are induced by replication of BrdU-substituted DNA templates, but not by incorporation of BrdU into nascent DNA.

After 3 rounds of DNA replication in the presence of BrdU, third-division metaphase cells can be scored for the frequencies of SCEs that occurred during cycles 1 and 2, and also for the frequency of SCE during cycle 3. This procedure was used to resolve the issue of SCE induction by replication of BrdU-substituted DNA templates versus induction by BrdU incorporation into nascent DNA. It was observed that third-cycle SCE frequencies in CHO are dependent upon the amount of BrdU that was present during cycles 1 and 2 and are independent of the BrdU concentration during the third cycle. It is therefore BrdU serving as a template, rather than BrdU being incorporated, that initiates the SCE event. A model is proposed that produces reasonable fits to the observed data. It also predicts a true background or spontaneous SCE frequency of 3 per cell per cycle as previously reported by Heartlein et al. (Mutation Res., 107 (1983) (103-109). The predicted single twin ratio is higher than that reported by Wolff and Perry (Exp. Cell Res., 93 (1975) 23-30), and possible explanations for this discrepancy are discussed.

[Vascular surgery, implant surgery and vacuum erectile aids. Review-overview-prospects of 3 therapy options in erectile dysfunction]. / Gefässchirurgie, Implantationschirurgie und Vakuumerektionshilfe. Rückblick-Uberblick-Ausblick dreier Therapieoptionen bei erektiler Dysfunktion.

Vascular surgery or penile prosthesis implantation are the main surgical options for erectile dysfunction. In this category, penile revascularization is the only causal therapy for selected patients: males younger than 50 years of age at time of surgery, maximum of two risk factors, exclusion of diabetes mellitus. Long-term success decreased to 53% to 55% in comparison to first encouraging reports of 80% success. Venous surgery resulted in an even more distinct decline of success the longer the elapse of time after surgery. Long-term success dropped under 40%, leaving only a few indications for penile venous ligation. In contrast, penile prosthesis implantation results in high satisfaction rates. Despite this, it is not generally recommended as first choice surgical management as it is linked to irreversible damage of the cavernosal bodies. Among numerous types of penile implants, preference is nowadays mostly given to the three-piece hydraulic models. However, such complications as defective or perforated cylinders in up to 35% after 5 years have arisen, depending on the type of implant. In a selected patient group, vacuum constriction devices with a mean patient acceptance of 75% (50% to 90%) seldom result in complications and are thus considered to be a well-established therapeutical option.

[Fibromyxoid pseudosarcoma of the urinary bladder. Case report and review of the literature of a rare disease]. / Das fibromyxoide Pseudosarkom der Harnblase. Fallbericht und Literaturübersicht einer seltenen Erkrankung.

Pseudosarcomatous fibromyxoidtumors (PSF) of the bladder are rare, benign tumors consisting of myofibroblastoid bladder wall proliferations of unknown etiology. Misinterpretation as a sarcoma is common and due to infiltrative growth and cellular pleomorphism and may leaed to false radical treatment. We present a 27 year old man with PSF presenting with microhematuria. Results of clinical, radiological and histopathological examinations and therapy are presented. A. review of the literature data of the to our knowledge 73 cases that have been reported in the literature is given.

[Penile fractures: controversy of surgical vs. conservative treatment]. / Konservative vs. operative Therapie der Penisfrakturen.

This paper reviews the current status of information on diagnostic and therapeutic management of penile fractures, focusing on the controversy between surgical vs. conservative treatment of this uncommon injury. Penile fracture, commonly defined as a rupture of the tunica albuginea and corpus cavernosum, is a serious urological disorder demanding surgical management. The diagnostic procedure classically consists of history taking, physical examination and urinary status. Determination of the extent of severity and location of the rupture in the tunica albuginea takes foremost priority and requires additional imaging procedures, such as ultrasound or cavernosography, which will impart enough diagnostic information for the correct choice of treatment. In some cases, the urethra is injured as well. Immediate surgical repair offers complete recovery for patients with penile fracture in most cases, even in the presence of urethral injury. Although penile fracture is easily recognized and can therefore be classified as a "first-look diagnosis", therapy remains controversial to date. The correct therapeutical approach is a vital factor in management, as the associated significant morbidity can result in complete loss of erectile function, painful erections or penis deviation. Early surgical treatment is strongly recommended because of the excellent results, shorter hospitalization, less morbidity and an early return to sexual activity.

Development of professional competence via self-instructional units.

In recent years, self-instructional teaching methods have come under criticism from educators, much of it warranted. But when self-instructional materials are written by experienced educators who teach the topic and are developed within a versatile process using a proven format, they are extremely valuable teaching aids. We discuss here the results of a grant project funded by W. K. Kellogg Foundation and describe the process used at Kettering Medical Center's School of Medical Technology to develop and produce over 100 self-instructional units. We also discuss potential uses of self-instructional units in professional continuing education programs and suggest ways self-instructional units might be used to promote interdisciplinary health care and expansion of professional knowledge banks. This project confirmed that professions can create their own educational materials through the independent efforts of their members.

[Approach to prostate cancer in men older than 75 years: active or passive?]. / Umgang mit dem Prostatakarzinom bei über 75-jährigen Männern : Aktiv oder passiv?

Based on the exponential aging of the population and the increasing life expectancy in industrialized western countries, prostate cancer (PCa) in elderly men is becoming a disease of increasing significance. Consensus exists that men over the age of 75 years should not be screened for PCa; however, higher age as a single parameter should not exclude men from being diagnosed with prostate cancer and treated accordingly. It is well-known that overdiagnosis and overtreatment are frequent in this age group. Competing mortality risks of men older than 75 years may supersede the risk of dying from PCa several fold. Both the treating physician and the patient himself should therefore balance the possible risks and benefits of diagnosing and treating prostate cancer concerning the impact on quality of life. This is of special importance when taking into account that the complication rates of curative treatment modalities are higher in older patients than in younger men and that hormonal treatment might have negative effects especially in older men.Age, existing comorbidities, cognitive and physical status in combination with specific tumor parameters are useful tools for an individualized treatment.Therapy should be considered for healthy, active men aged 75 years or older who present with high-risk PCa and/or with a PSA doubling time <12 months. Elderly men who are unfit or have low to intermediate risk PCa will most likely not benefit from treatment.

[How should hormone therapy for castration-resistant prostate cancer be continued?]. / Wie soll die Hormontherapie beim kastrationsresistenten Prostatakarzinom fortgeführt werden?

After an average of 18-36 months under androgen suppression therapy by surgical castration, LHRH, and steroidal or non-steroidal antiandrogens, almost all patients with metastatic prostate cancer show PSA progression as a sign of androgen-independent but still androgen-sensitive tumor growth. Our understanding and the treatment of such castration-resistant prostate cancer has changed markedly. The introduction of new drugs like abiraterone and MDV3100 has shown that prostate cancer progression even in the"hormone-refractory" stage is driven by androgen receptor signaling. Based on this information the question of whether androgen deprivation therapy in castration-resistant prostate cancer should be continued or not is still of relevance. This review gives a critical overview of the literature and current guideline recommendations.