Health-related quality of life in bladder cancer patients: general and cancer-specific instruments. Part 1.

PURPOSE OF REVIEW: Although survival outcomes are the primary outcomes to determine the effectiveness of treatment options, quality of life (QoL) is gaining in importance in addition to classic oncological outcomes. The present review aims to state and critically assess the challenges in health-related QoL (HRQoL) assessment especially in bladder cancer (BC) patients. RECENT FINDINGS: General QoL-instruments do not address concerns specific to cancer patients or BC patients. Domains, such as sexual functioning, embarrassment, self-consciousness, psychological distress, and urinary incontinence, are not adequately covered by any of the available instruments. With these QoL-instruments becoming increasingly specialized, the general aspects of QoL and possible unanticipated adverse effects are no longer likely to be accurately assessed. Sex-specific requirements have not been properly addressed by these QoL-instruments. HRQoL is reported to be lower in the elderly population, which may be due to their associated comorbidities and limitations, rather than treatment-related issues. SUMMARY: Due to their specifications, BC-specific instruments need to be used together with general QoL instruments to assess overall well being and disease- and treatment-specific QoL. Assessment of age-specific HRQoL is essential to understanding the QoL burden in each age group. QoL assessment calls for more detailed sex-specific questions to accurately address the HRQoL dimensions in men and women alike.

Health-related quality of life in bladder cancer patients: bladder cancer-specific instruments and domains. Part 2.

PURPOSE OF REVIEW: Several instruments have been designed to evaluate health-related quality of life (HRQoL) in patients with bladder cancer (BC). However, they vary in purpose, domains, and quality. To identify QoL instruments that have been validated for BC patients and to critically assess their domains and limitations. RECENT FINDINGS: Of the 11 instruments identified, seven have been externally validated. Of these, four can be used across all disease states; two are available for QoL assessment in patients with non-muscle invasive bladder cancer (NMIBC); and the European Organisation for Research and Treatment of Cancer (EORTC) module is intended for use together with a generic cancer-specific tool. Of the three instruments available to assess QoL in patients with muscle invasive bladder cancer (MIBC), EORTC Quality of Life Questionnaire-Bladder Cancer Muscle Invasive30 (QLQ-BLM30) and Functional Assessment of Cancer Therapy-Bladder-Cystectomy (FACT-Bl-Cys) need to be used each with their respective generic core questionnaire, whereas Ileal Orthotopic Neobladder-Pro Questionnaire is intended only to evaluate patients who have received an orthotopic neobladder.The core domains assessed by these instruments include social functioning, mental health, physical function, urinary function and sexual function. SUMMARY: No optimal BC-specific QoL instruments exist. Multiple cancer- and BC-specific instruments are required to cover each of the relevant domains. Selected tools should be reviewed within the context of specific research objectives.

Diagnostic accuracy of third-generation dual-source dual-energy CT: a prospective trial and protocol for clinical implementation.

PURPOSE: Uric acid (UA) calculi can be referred to chemolitholysis rather than invasive treatment. Dual-energy computed tomography (DECT) may be able to distinguish between UA and non-UA (NUA) calculi. The aim of this study was to evaluate the validity of third-generation DECT for the first time and to investigate whether combining DECT with clinical parameters can increase its predictive accuracy. MATERIALS AND METHODS: All patients who presented to our emergency department between January 2015 and March 2017 with urinary stones were prospectively included in this observational study and underwent DECT with subsequent interventional stone removal. Stone composition was analyzed using infrared spectrometry as the gold standard. Predictive accuracy of DECT and clinical covariates was computed by assessing univariate and multivariate areas under the curve (AUCs). RESULTS: Of 84 patients with 144 urinary stones, 10 (11.9%) patients had UA stones according to infrared spectrometry, and the remaining stones were NUA or mixed stones. DECT had a positive predictive value of 100% and a negative predictive value of 98.5% for UA stones. The AUC for urine pH alone was 0.71 and 0.97 for DECT plus urine pH. No UA stones were found in patients with a urine pH above > 5.5. Mean DLP was 225.15 ± 128.60 mGy*cm and mean effective dose was 3.38 ± 1.93 mSv. CONCLUSIONS: DECT is a safe method for assigning patients to oral chemolitholysis. Clinical preselection of patients based on urinary pH (< 6.0) leads to a more liable use of DECT. Third-generation DECT needs significant lower radiation doses compared to previous generations.

Thromboprophylaxis and the route of administration of chemotherapy in testicular cancer patients in German-speaking countries.

PURPOSE: Due to the excellent cure rates for testicular cancer (TC), focus has shifted towards decreasing therapy-related morbidities. Thrombosis is a frequent complication of cisplatin chemotherapy. Furthermore, the optimal route of administration for chemotherapy is still under debate. The purpose of this study was to assess the patterns of care concerning dosing and duration of thromboprophylaxis currently utilized in TC patients in German-speaking countries as well as the route of chemotherapy administration. METHODS: A standardized questionnaire was sent to all members of the German TC Study Group (GTCSG) and to all the urological university hospitals in Germany. The questionnaire was also sent to the oncologic clinics at those universities where urologists do not administer chemotherapy. RESULTS: The response rate was 87% (55/63). Prophylactic anticoagulation with low-molecular-weight heparin (LMWH) was administered in 94% of the clinics. The dosing of LMWH was prophylactic (85%), high prophylactic (adjusted to bodyweight) (7%), or risk adapted (9%). After completion of chemotherapy, anticoagulation was continued in 15 clinics (33%) for 2 to 24 weeks, while the remainder stopped the LMWH upon cessation of chemotherapy. Chemotherapy was administered via central venous access in 59%, peripheral IV in 27%, or both in 14% of the clinics. CONCLUSIONS: Most of the institutions performed some form of thromboprophylaxis, although the modes of application varied by institution type and amongst the urologists and oncologists. Prospective studies are needed to evaluate the incidence, date of occurrence, and risk factors of venous thrombosis during TC chemotherapy to provide a recommendation concerning prophylactic anticoagulation.

German second-opinion network for testicular cancer: sealing the leaky pipe between evidence and clinical practice.

In 2006, the German Testicular Cancer Study Group initiated an extensive evidence-based national second-opinion network to improve the care of testicular cancer patients. The primary aims were to reflect the current state of testicular cancer treatment in Germany and to analyze the project's effect on the quality of care delivered to testicular cancer patients. A freely available internet-based platform was developed for the exchange of data between the urologists seeking advice and the 31 second-opinion givers. After providing all data relevant to the primary treatment decision, urologists received a second opinion on their therapy plan within <48 h. Endpoints were congruence between the first and second opinion, conformity of applied therapy with the corresponding recommendation and progression-free survival rate of the introduced patients. Significance was determined by two-sided Pearson's χ2 test. A total of 1,284 second-opinion requests were submitted from November 2006 to October 2011, and 926 of these cases were eligible for further analysis. A discrepancy was found between first and second opinion in 39.5% of the cases. Discrepant second opinions led to less extensive treatment in 28.1% and to more extensive treatment in 15.6%. Patients treated within the framework of the second-opinion project had an overall 2-year progression-free survival rate of 90.4%. Approximately every 6th second opinion led to a relevant change in therapy. Despite the lack of financial incentives, data from every 8th testicular cancer patient in Germany were submitted to second-opinion centers. Second-opinion centers can help to improve the implementation of evidence into clinical practice.

Predicting metastasized seminoma using gene expression.

UNLABELLED: Treatment options for testis cancer depend on the histological subtype as well as on the clinical stage. An accurate staging is essential for correct treatment. The 'golden standard' for staging purposes is CT, but occult metastasis cannot be detected with this method. Currently, parameters such as primary tumour size, vessel invasion or invasion of the rete testis are used for predicting occult metastasis. Last year the association of these parameters with metastasis could not be validated in a new independent cohort. Gene expression analysis in testis cancer allowed discrimination between the different histological subtypes (seminoma and non-seminoma) as well as testis cancer and normal testis tissue. In a two-stage study design we (i) screened the whole genome (using human whole genome microarrays) for candidate genes associated with the metastatic stage in seminoma and (ii) validated and quantified gene expression of our candidate genes (real-time quantitative polymerase chain reaction) on another independent group. Gene expression measurements of two of our candidate genes (dopamine receptor D1 [DRD1] and family with sequence similarity 71, member F2 [FAM71F2]) examined in primary testis cancers made it possible to discriminate the metastasis status in seminoma. The discriminative ability of the genes exceeded the predictive significance of currently used histological/pathological parameters. Based on gene expression analysis the present study provides suggestions for improved individual decision making either in favour of early adjuvant therapy or increased surveillance. OBJECTIVE: To evaluate the usefulness of gene expression profiling for predicting metastatic status in testicular seminoma at the time of first diagnosis compared with established clinical and pathological parameters. PATIENTS AND METHODS: Total RNA was isolated from testicular tumours of metastasized patients (12 patients, clinical stage IIa-III), non-metastasized patients (40, clinical stage I) and adjacent 'normal' tissue (n = 36). The RNA was then converted into cDNA and real-time quantitative polymerase chain reaction was run on 94 candidate genes selected from previous work. Normalised gene expression of these genes and histological variables, e.g. tumour size and rete testis infiltration, were analysed using logistic regression analysis. RESULTS: Expression of two genes (dopamine receptor D1 [DRD1] and family with sequence similarity 71, member F2 [FAM71F2], P = 0.005 and 0.024 in separate analysis and P = 0.004 and 0.016 when combining both genes, respectively) made it possible to significantly discriminate the metastasis status. Concordance increased from 77.9% (DRD1) and 72.3% (FAM71F2) in separate analysis and up to 87.7% when combining both genes in one model. Only primary tumour size in separate analysis (continuous or categorical with tumour size >6 cm) was significantly associated with metastasis (P = 0.039/P = 0.02), but concordance was lower (61%). When we combined tumour size with our two genes in one model there was no further statistical improvement or increased concordance. CONCLUSION: Based on gene expression analysis our study provides suggestions for improved individual decision making either in favour of early adjuvant therapy or increased surveillance.

Testis cancer cells have a genetic determination for a high sensitivity to apoptosis inducing stimuli.

OBJECTIVE: The effect of cytotoxic therapy in testicular tumors (TGCT) has been shown to be mediated mainly by the induction of apoptosis. So far, it is not known which genes play a role for this inherent sensitivity to apoptosis inducing drugs. The aim of this study was to investigate the differential gene expression of apoptosis regulating genes in testicular tumors and in normal testis tissue using a quantitative method. As a premature S-phase entry was shown to induce apoptosis, genes controlling the G1/S-phase checkpoint were also investigated. MATERIAL AND METHODS: Gene expression levels of a representative subset of 19 genes involved in apoptosis and cell cycle control were investigated in vivo in 19 TGCTs using real-time quantitative PCR. Measurements were performed in tumor tissues of both tumor entities, seminomatous and non-seminomatous tumors (SGCT and NSGCT), and in corresponding biopsies from the unaffected site of the resected testis. RESULTS: There was an up-regulation of genes that play a role in facilitating apoptosis, such as FasL, TRAIL, and Bax in both tumor entities. Genes inhibiting apoptosis, such as Bcl-2 were predominantly down-regulated. Regarding cell cycle regulators, a gene expression profile was found that corresponds to a premature S phase entry and subsequent apoptosis induction. CONCLUSION: This study for the first time identified in vivo a panel of genes that give TGCT an inherent sensitivity to apoptotic stimuli after exposure to DNA damaging agents. Studies on these genes in therapy-refractory cancers should provide further insight into the mechanisms of chemotherapy resistance. Furthermore, these genes are promising targets for a future targeted therapy of testis cancer.

Topical treatment of erectile dysfunction with prostaglandin E1 ethyl ester.

BACKGROUND: Prostaglandin E1 ethyl ester (PGE1-EE) is a prodrug of prostaglandin E1 but with much improved transdermal penetration. PATIENTS AND METHODS: We performed a randomized, double-blind, controlled study in 34 patients to assess the safety and efficacy of transdermally applied PGE1-EE for the treatment of erectile dysfunction. In a first single-blinded titration period the most appropriate PGE1-EE dose (maximum 1000 µg) was determined. PGE1-EE was applied to the shaft of the penis using an adhesive foil patch which contained the drug. For home use, the patients were provided with 4 patches with the appropriate dose and 2 patches with placebo containing a small dose of 5 µg PGE1-EE to use randomly prior to sexual intercourse, waiting three days between each use. RESULTS: The median rigidity score as the primary outcome variable was significantly higher after verum versus placebo applications. Also, concerning the secondary outcome variable satisfactory sexual activity, superiority was shown for verum versus placebo. Although penetrating intercourse could not be performed significantly more frequently, 50 % of patients considered the treatment successful. It was well-tolerated and local side effects were generally mild. CONCLUSIONS: PGE1-EE could be a promising drug formulation in local penile therapy of ED. In further studies higher doses should be investigated in order to potentially achieve a higher level of efficacy.

A critical analysis of nonsurgical treatment of Peyronie's disease.

OBJECTIVE: Because the efficacy of nonsurgical therapy of Peyronie's disease is controversial, this review analyses the current status of conservative therapy of Peyronie's disease. METHOD: A systematic survey on results of studies published as original papers in peer-reviewed journals is provided. RESULTS: Oral drug therapies include potassium para-aminobenzoate (Potaba), vitamin E, colchicine, tamoxifen, propoleum, acetyl-L-carnitine, and propionyl-L-carnitine. Verapamil, interferon-alpha2a and interferon-alpha2b, collagenase, cortisone, hyaluronidase, and superoxide dismutase are considered intralesional therapies that have had various degrees of success. Other treatments include local gels, iontophoresis, extracorporeal shock wave therapy, and radiation. CONCLUSION: This review analyses the current status of the conservative therapy of Peyronie's disease, because the efficacy of the nonsurgical therapy is controversial.

Apoptosis: a key effector mechanism of lymphocyte action in human nonseminomatous testicular carcinoma?

OBJECTIVE: To correlate the number of tumour-infiltrating T lymphocytes (TILs) with the extent of apoptosis in testicular germ cell tumours, as TILs are considered to be a favourable prognostic factor of human testicular tumours, especially of seminomas, but the mechanism by which TIL contribute to an improved outcome is unclear. MATERIALS AND METHODS: Tissue samples from 47 patients with nonseminomatous germ cell tumour (NSGCT) and 15 with seminomatous GCT were investigated immunohistochemically for lymphocyte infiltration and apoptosis. The apoptotic index (AI) was assessed in various categories (DNA condensation and fragmentation) using in-situ end-labelling to identify typical apoptotic DNA strand breaks, and nuclear staining to identify typical apoptotic morphology. RESULTS: In seminomatous GCT there was no correlation between the number of TILs and any AI. In NSGCT there was only a relationship between lymphoid infiltration and those AIs showing morphological criteria of apoptosis in a small subgroup of NSGCT, i.e. metastasized embryonal cell carcinomas. Only 1.2% (AI, chromatin condensation) and 0.8% (AI, fragmentation and condensation) of all tumour cells showed these features of apoptosis. The overall AI in NSGCT was 7.9%. CONCLUSIONS: TILs do not seem to induce apoptosis in testicular tumours. Embryonal cell carcinomas might be susceptible to lymphocyte attack, resulting in apoptosis of the tumour cell. The mechanisms of interaction between lymphocytes and testis tumour cells need further investigation.

Giant multilocular cystadenoma of the prostate: a rare differential diagnosis of benign prostatic hyperplasia.

We report a case of giant multilocular cystadenoma of the prostate in a 43-year-old man. This is a rare benign entity of the prostate imitating symptoms of benign prostatic hyperplasia and originates from the prostate with extensive spread into the pelvis. Histologically, prostatic glands and cysts lined by cuboid to columnar epithelial cells with basally located nuclei are characteristic. Immunohistochemical staining is positive for prostate-specific antigen in the epithelial cells. Giant multilocular prostatic cystadenoma should be taken into account in the differential diagnosis in any case of a large cystic mass originating from the prostate.

Extracorporeal shock wave therapy for Peyronie's disease: exploratory meta-analysis of clinical trials.

PURPOSE: Extracorporeal shock wave therapy (ESWT) for the treatment of Peyronie's disease is still controversial. This exploratory meta-analysis of published studies in the international literature investigates its therapeutic effects. MATERIALS AND METHODS: The treatment outcomes from 17 study groups identified by a computerized literature search were compared with natural history outcomes and data from control groups from 2 controlled ESWT studies. An exploratory meta-analysis was performed because a methodologically sound meta-analysis lege artis did not appear appropriate, since treated groups differ considerably in structure, the selection of outcome measures is inconsistent and measurement is not standardized. RESULTS: ESWT seems to have an effect on penile pain during erection and on the improvement of sexual function. Pain seems to resolve faster after ESWT than during the course of the natural history. The effect on plaque size and penile curvature is less impressive. CONCLUSIONS: ESWT in Peyronie's disease at least seems to be effective in regard to penile pain and sexual function compared to natural history. Deducing from these data the effect on plaque size and curvature remains questionable. However, ESWT is not an evidence based therapy at present. A controlled (preferably pairwise matched), single blind, multicenter study with careful, detailed documentation of disease symptoms before intervention and of outcomes is required to evaluate the real effect of ESWT.

Questionable efficacy of extracorporeal shock wave therapy for Peyronie's disease: results of a prospective approach.

PURPOSE: Extracorporeal shock wave therapy (ESWT) for Peyronie's disease is still a topic of debate. We evaluated the effects of ESWT in a large series of patients with Peyronie's disease via a prospective approach. MATERIALS AND METHODS: In a prospective study 114 patients with Peyronie's disease were treated with ESWT. Baseline and followup examinations included ultrasound, and measurement of plaque size and curvature. Symptomatology was evaluated based on a standardized interview. A Minilith SL1 (Storz Medical AG, Kreuzlingen, Switzerland) lithotriptor was used with 4,000 shock waves at a maximum energy level of 0.17 mJ/mm2 applied per session. RESULTS: A total of 96 patients were available for followup. Considering the total study group no significant changes in penile curvature, plaque size or sexual function were observed despite significant improvements in patients with a curvature of 31 to 60 degrees. Penile pain ceased in 76% of the affected patients. CONCLUSIONS: According to our data ESWT does not appear to be significantly effective for decreasing penile curvature and plaque size or improving sexual function in the total population of patients with Peyronie's disease despite improvements in individuals. Penile pain seems to resolve earlier than during the natural course. Regarding the results of this study and previous reports with exact documentation of the clinical findings it can be concluded that ESWT cannot be recommended as a standard procedure for Peyronie's disease. To evaluate the exact efficacy of ESWT a controlled, single-blind, multicenter study with exact documentation of symptoms is urgently required.

Diagnostic value of magnetic resonance imaging in Peyronie's disease--a comparison both with palpation and ultrasound in the evaluation of plaque formation.

OBJECTIVE: To compare the value of magnetic resonance imaging (MRI) with palpation and ultrasound in the evaluation of plaque formation in Peyronie's disease. METHODS: 57 patients underwent a standardized diagnostic procedure to evaluate plaque formation consisting of palpation and ultrasonography (7.5 MHz). MRI was performed during flaccidity and during erection induced by Prostaglandin E(1) including intravenous application of Gadolinium-diethylenetriaminepentaacetic acid (Gd-DPTA). RESULTS: With all methods, 93 plaques have been detected in 57 patients. 85 plaques (91.4%) have been evaluated by palpation alone. Using ultrasound, 52 of these 93 plaques (55.9%) were detectable. This is equivalent to 61.1% of the palpable plaques. MRI confirmed 58 of the palpated plaques (68.2%) and exposed 8 primarily not palpable plaques at the penile basis. MRI revealed more palpable plaques than ultrasound, but this finding was not significant (p = 0.083). By means of sonography, calcification was evident in 14 plaques. MRI failed in revealing any calcification. After application of Gd-DPTA, 5 of 57 patients (9%) demonstrated contrast enhancement indicating local inflammation. None of these patients reported on penile pain. CONCLUSIONS: Penile palpation in combination with ultrasound represents the method of choice to diagnose plaque formation in Peyronie's disease. MRI provides better information on plaque formation at the penile basis. Calcification can only be proven by ultrasound, not by MRI. There may be additional information by MRI about local inflammation. A prospective study comparing the histological and MRI findings should be performed to answer the question, if pain is really associated with inflammation.

Prospective analysis of single nucleotide polymorphisms of the transforming growth factor beta-1 gene in Peyronie's disease.

PURPOSE: The detection of increased expression of transforming growth factor beta-1 (TGF-beta1) in Peyronie's disease plaques and the possibility of initiating a Peyronie's disease-like condition by intratunical injection of a synthetic heptopeptide with TGF-beta-like activity in an animal model has provided evidence for the central role of this cytokine in the pathogenesis of this entity. Recently 2 defined single nucleotide polymorphisms in the coding region of the TGF-beta1 gene have been described that are associated with different levels of TGF-beta1 production. Based on these data we prospectively investigated the genetic association of distinct TGF-beta1 genotypes with Peyronie's disease. MATERIALS AND METHODS: DNA samples from 111 consecutive patients with idiopathic Peyronie's disease and 100 controls were genotyped for the 2 defined dimorphic single nucleotide polymorphisms T869C and G915C in the coding region of the TGF-beta1 gene using allele specific polymerase chain reaction. RESULTS: We found an increased frequency of the homozygous genotype of the single nucleotide polymorphism G915C in patients with Peyronie's disease compared with healthy controls (89.2% versus 79%, p = 0.04). However, there were no significant differences in allele frequencies of the single nucleotide polymorphism T869C. CONCLUSIONS: Experimental data from other investigators have shown that TGF-beta1 has an important role in the etiopathology of Peyronie's disease. Our results indicate that the homozygous wild type of the G915C single nucleotide polymorphism in the coding region of the TGF-beta1 gene, which was recently associated with elevated TGF-beta1 production and pulmonary fibrosis, may influence the predisposition to Peyronie's disease. However, it does not represent a major genetic risk factor.

Fas/Fas ligand system and apoptosis induction in testicular carcinoma.

BACKGROUND: Tumor-infiltrating, Fas ligand (FasL)-expressing lymphocytes are able to eliminate Fas-bearing tumor cells by apoptosis induction. Activated cytotoxic T-cells that express Fas may enter apoptosis in the presence of FasL tumor cells. To date, no studies of patients with testicular carcinoma have correlated the differential expression of Fas and FasL in both cell types with the corresponding apoptotic index (AI). METHODS: Fas and FasL were investigated immunohistochemically in paraffin embedded tissue sections from 25 patients with nonseminomatous testicular tumors. The percentages of positive cells and the ratios of Fas cells to FasL cells were correlated with the AI of tumor cells and lymphocytes, respectively, using Spearman correlations. RESULTS: No association was found between the rate of FasL positive cells and AI of the other cell type or between the rate of Fas positive cells and the AI of the same cell type. Ratios between Fas positive cells and FasL positive cells were not correlated with the AI; however, a significant positive correlation was found between the AI of tumor cells and the AI of lymphocytes. CONCLUSIONS: It seems unlikely that the Fas/FasL system is responsible for immune escape of the tumor in testicular carcinoma. Rather, the significant positive correlation between the AIs of tumor cells and lymphocytes implicate a previously unknown mechanism of apoptosis induction in both cell types.