Vinorelbine in bladder-preserving multimodality treatment for muscle-invasive bladder cancer-a valid option for cisplatin-unfit patients?

PURPOSE: Treatment of muscle-invasive bladder cancer (MIBC) remains challenging, especially for elderly and/or comorbid patients. Patients who are unfit for or refuse surgery should receive bladder-preserving multimodality treatment (BPMT), consisting of transurethral resection of the bladder tumor (TURB) followed by combined chemoradiotherapy (CRT). We aimed to investigate the effectiveness of vinorelbine, a chemotherapeutic agent not routinely used for MIBC, in patients referred to CRT who are unfit for standard chemotherapy and would thus rely solely on radiotherapy (RT). METHODS: We retrospectively analyzed 52 consecutive patients with MIBC who received standard CRT with cisplatin (n = 14), CRT with vinorelbine (n = 26), or RT alone (n = 12). Primary endpoints were median overall survival (OS) and median cancer-specific survival (CSS). Secondary endpoints were median local control (LC), median distant control (DC), and OS, CSS, LC, and DC after 1, 2, and 3 years, respectively. RESULTS: Median OS and CSS were significantly higher for patients who received vinorelbine as compared to RT alone (OS 8 vs. 22 months, p = 0.003; CSS 11 months vs. not reached, p = 0.001). Median LC and DC did not differ significantly between groups. Vinorelbine was well tolerated with no reported side effects >grade II. CONCLUSION: Our results suggest that CRT with vinorelbine is well tolerated and superior to RT alone in terms of OS and CSS. Therefore, this treatment regime might constitute a new treatment option for patients with MIBC who are unfit for or refuse surgery or standard chemotherapy. This study encourages a randomized controlled trial to compare this new regime to current standard therapies.

[What should urologists know about SARS-CoV-2? Risk analysis for urological operations and recommendations for action in clinical routine]. / Was sollte ein Urologe zu SARS-Cov-2 wissen? Risikoanalyse für urologische Operationen und Handlungsempfehlungen im klinischen Alltag.

BACKGROUND: COVID-19 poses a challenge to healthcare systems worldwide. Due to the increasing number of cases, surgeons in urology have also been confronted with SARS-CoV­2 infections. Thus, there is an urgent need for clinical guidance and recommendations. AIM: Our work aims to create a widespread assessment of a possible risk for infection with SARS-CoV­2 during surgical procedures. Based on current data and current national and international guidelines, we try to assess the risk of infection when handling human tissue and the necessary hygienic measures that are needed. Finally, recommendations for daily urologic work are derived and explained. MATERIALS AND METHODS: The current literature in PubMed, bioRxiv and medRxiv and data available from the WHO and Robert-Koch-Institut on SARS-CoV­2 and surgical procedures in (potentially) infected patients are reviewed. The endpoint of our research was 21 April 2020. CONCLUSION: Based on our research, general and specific recommendations for clinical urologic praxis can be derived. Although it remains unclear whether SARS-CoV­2 is transmitted via the aerosols produced, current PPE in operating rooms probably does not offer sufficient protection during surgical interventions during the SARS-CoV­2 pandemic. Use of FFP­2 masks, safety goggles and full-body protective suits is crucial. To contain viral spread on surfaces and personnel, complex filter systems (HEPA) should be used as well as closed suction devices during surgery. Combined with consequent disinfection of surfaces and behavioral measures, a safe environment for healthcare workers in urology can be created. Thus, according to current knowledge, we believe that emergency and urgent surgical procedures are not contraindicated, provided that appropriate precautionary safety measures are followed.

ProPSA and the Prostate Health Index as predictive markers for aggressiveness in low-risk prostate cancer-results from an international multicenter study.

BACKGROUND: One of the major challenges in prostate cancer (PCa) treatment is distinguishing insignificant PCa from those forms that need active treatment. We evaluated the impact of PSA isoforms on risk stratification in patients with low-risk PCa as well as in active surveillance (AS) candidates who underwent radical prostatectomy. METHODS: A total of 112 patients with biopsy confirmed Gleason score (GS) 6 PCa of four different international institutions were prospectively enrolled in the study. Blood withdrawal was performed the day before radical prostatectomy. In addition, patients were classified according to the EAU and NCCN criteria for AS candidates. PSA, free PSA (fPSA) and proPSA were measured using dual monoclonal antibody sandwich immunoassays. In addition, the Prostate Health Index (PHI=proPSA/fPSA × âˆšPSA) was calculated. Final histology of the radical prostatectomy specimens was correlated to PSA, its isoforms and PHI. RESULTS: Serum proPSA levels were significantly elevated in those patients with an upgrade in final histology (GS⩾7). In addition, higher proPSA levels were predictive for extraprostatic extension (⩾pT3a) as well as for positive surgical margins. Interestingly, PHI had an even higher predictive power when compared with proPSA alone concerning GS upgrading, extraprostatic extension and surgical margins in both the total and the AS patient group. CONCLUSION: We showed in a multicenter study that proPSA is a valuable biomarker to detect patients with aggressive PCa in a cohort of GS 6 patients, who would benefit from active tumor therapy. Combining proPSA with the standard markers PSA and fPSA using PHI further increases the predictive accuracy significantly. Moreover, our data support the use of PHI for monitoring PCa patients under AS.

[Bevacizumab as first-line therapy in metastatic renal cell carcinoma: Progression-free survival for 3 years]. / Metastasiertes Nierenzellkarzinom unter Bevacizumab als Erstlinientherapie : Progressionsfreies Überleben seit 3 Jahren.

We report the case of a 72-year-old woman who was diagnosed in 2006 with renal cell cancer (RCC) and had undergone consecutive tumor nephrectomy (clear-cell RCC, Fuhrmann grade II, stage pT3a, R0). Over the years, the patient underwent several surgical and radiological interventions due to various metastatic lesions. This case report describes the 3-year progression-free survival in a patient who underwent first-line therapy with the monoclonal antibody bevacizumab. Except for hypertension, the patient does not suffer currently from any other side effects of bevacizumab therapy.

[-2]proPSA is an early marker for prostate cancer aggressiveness.

BACKGROUND: The aim of the study was to evaluate the correlation between preoperative [-2]proPSA, the Gleason Score (GS) and the risk of non-organ-confined (NOC) disease in patients undergoing radical prostatectomy (RP). METHODS: Beckman Coulter Access immunoassay was used to study serum specimens of 381 patients enrolled in a prostate cancer (PCa) early detection program. Inclusion criteria were three or more available serum specimens over 4 years before diagnosis. The values obtained were correlated with the GSs and pathological stages of specimens obtained at RP. RESULTS: [-2]proPSA levels were significantly higher in the cancer group (n=208) than in the benign group (n=173). Already 4 years before diagnosis [-2]proPSA differed significantly between PCa and benign prostate in all measured time points, however, highest prediction value was 2 and 1 years before diagnosis (P<0.001). When stratified [-2]proPSA levels according to GS of RP specimens, [-2]proPSA was highest in patients with ≥GS8 and lowest in those with ≤GS6.The difference in [-2]proPSA values between GS≥8 and GS≤7 was highly significant (P<0.01) already 3 years before diagnosis. Investigating the correlation between extraprostatic extension and the preoperative [-2]proPSA levels we found preoperative [-2]proPSA values significantly higher in men with NOC PCa compared with organ-confined (OC) cancers.The highest predictive value of [-2]proPSA to differ between OC and extraprostatic extension was found 3 and 2 years before RP. CONCLUSIONS: Patients with high [-2]proPSA levels in the years before cancer diagnosis are at a higher risk of having aggressive PCas. Thus, the [-2]proPSA should be included in the treatment decision-making for managing screen-detected PCa.

Distinct ERG rearrangement prevalence in prostate cancer: higher frequency in young age and in low PSA prostate cancer.

BACKGROUND: The TMPRSS2-ERG gene fusion resulting in ERG overexpression has been found in around 50% of prostate cancers (PCa) and is a very early event in tumorigenesis. Most studies have reported on selected surgical cohorts with inconsistent results. We hypothesized that ERG gene rearrangements impact tumor development and investigated the frequency of ERG overexpression in the context of clinicopathological tumor characteristics. METHODS: ERG overexpression (ERG+ or ERG-) was determined by immunohistochemistry (IHC) in 1039 radical prostatectomy (RP) tumors and association with PSA, D'Amico risk score, histopathology, biochemical recurrence, body mass index and age of PCa cases was analyzed. RESULTS: ERG+ was associated with younger age at diagnosis (P<0.0001), lower serum PSA (P=0.002) and lower prostate volume (PV) (P=0.001). It was most frequent in the youngest age quartile (≤55 years, 63.9% ERG+) and decreased constantly with increasing age to 40.8% in the oldest age quartile (≥67 years, P<0.0001). In the PSA range <4 ng ml(-1) the frequency of ERG positivity was 60.2% compared with 47.5 and 49.1% in the PSA ranges 4-10 and ≥10 ng ml(-1), respectively. In the first age quartile, ERG+ patients had lower median serum PSA and fPSA% and smaller PV. In the highest age quartile tumor volume (TV) was increased. Similar differences were observed in the low PSA range. Multivariate analysis identified the first age quartile as a predictor for ERG status (odds ratios (OR) 2.05, P=0.007). No association was found with the D'Amico progression risk score and with biochemical tumor recurrence. CONCLUSIONS: ERG+ tumors manifest clinically at lower PSA levels and their prevalence is age dependent. This suggests acceleration of tumor development by ERG overexpression that results in earlier tumor detection in young patients. Long-term results are warranted to determine the impact of ERG overexpression on disease outcome.

[New ultrasound technologies for the diagnostics of prostate cancer]. / Neue Ultraschalltechnologien für die Diagnostik des Prostatakarzinoms.

CLINICAL/METHODOLOGICAL ISSUE: Prostate cancer is the most common cancer in men. The diagnosis is based on prostate-specific antigen (PSA), digital rectal examination (DRE) and transrectal ultrasound (TRUS) guided biopsy. These techniques have considerable limitations, which result in unnecessary biopsies. Furthermore the biopsies are associated with morbidity and costs. STANDARD RADIOLOGICAL METHODS: Standard gray-scale ultrasound has a low sensitivity and specificity for prostate cancer detection. METHODOLOGICAL INNOVATIONS: New ultrasound technologies, including color- and power Doppler ultrasound, contrast enhanced US and real-time sonoelastography have shown to improve prostate cancer diagnosis. PERFORMANCE: Contrast-enhanced ultrasound has shown a sensitivity of 100% (95% CI, 95%), a negative predictive value (NPV) of 99.8% and a positive predictive value (PPV) of 88.8% for prostate cancer detection. Real-time sonoelastography has shown a sensitivity of 86%, a specificity of 81% and NPV of 91% for prostate cancer diagnosis. ACHIEVEMENTS: Most studies show that these new ultrasound modalities demonstrate a 1.5 to 2.5 times higher detection of prostate cancer per biopsy specimen compared with systematic biopsy. Multicenter studies results are at present lacking but are, however ongoing. PRACTICAL RECOMMENDATIONS: In patients with suspected prostate cancer (elevated PSA, suspicious DRE) these new ultrasound techniques should be used. These techniques can detect prostate cancer and allow a targeted biopsy approach.

Comparison of contrast enhanced color Doppler targeted biopsy to conventional systematic biopsy: impact on Gleason score.

PURPOSE: Prostate cancer grading with Gleason score is an important prognostic factor. This prospective randomized study compares ultrasound systematic biopsy vs contrast enhanced color Doppler targeted biopsy for the impact on Gleason score findings. MATERIALS AND METHODS: We examined 690 men (mean age 56 years, range 41 to 77) with a serum total prostate specific antigen of 1.25 ng/ml or greater, a free-to-total prostate specific antigen ratio less than 18% and/or a suspicious digital rectal examination. Contrast enhanced color Doppler targeted biopsies with a limited number of cores (5 or less) were performed in hypervascular areas of the peripheral zone during administration of the ultrasound contrast agent Sonovuetrade mark (Bracco, Milano, Italy). Ten systematic biopsies were obtained in a standard spatial distribution. Cancer detection rates and Gleason score were compared. RESULTS: Prostate cancer was identified in 221 of 690 subjects (32%) with a mean prostate specific antigen of 4.6 ng/ml (range 1.4 to 35.0). Prostate cancer was detected in 180 of 690 subjects (26%) with contrast enhanced color Doppler targeted biopsy and in 166 of 690 patients (24%) with systematic ultrasound biopsy. The Gleason score of all 180 cancers detected on contrast enhanced color Doppler targeted biopsy was 6 or higher (mean 6.8). The Gleason score of all 166 cancers detected on systematic biopsy ranged from 4 to 6 and mean Gleason score was 5.4. Contrast enhanced color Doppler targeted biopsy detected significantly higher Gleason scores compared to systematic biopsy (Wilcoxon rank sum test p <0.003). CONCLUSIONS: Contrast enhanced color Doppler targeted biopsy detected cancers with higher Gleason scores and more cancer than systematic biopsy. Therefore, contrast enhanced color Doppler seems to be helpful in the grading of prostate cancer, which is important for defining prognosis and deciding treatment.

[Ultrasound contrast agents and prostate cancer]. / Ultraschallkontrastmittel und Prostatakarzinom.

Prostatic carcinoma is the most frequent malignant disease in men and associated with very high mortality. The diagnostic work-up of prostatic carcinoma is based on tests to determine the level of prostate-specific antigen (PSA), digital rectal examination, and transrectal sonography. Due to diagnostic limitations, ultrasound-guided prostate biopsy is the method of choice for diagnosis of prostatic carcinoma. New imaging technologies allow detection of prostatic carcinoma, thus facilitating removal of specific biopsy specimens from these regions. Introduction of ultrasound contrast agents ("echo signal enhancers") significantly increased the diagnostic potential of this method, making it possible to visualize tumor vascularization.

Vascular damage induced by type 2 diabetes mellitus as a risk factor for benign prostatic hyperplasia.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the relationship between benign prostatic hyperplasia (BPH) and arteriosclerosis shown in a model of type 2 diabetes in a trans-sectional population study using contrast-enhanced colour Doppler ultrasound for exact assessment of prostatic blood flow. METHODS: Contrast-enhanced transrectal colour Doppler ultrasound was performed using a microbubble-based ultrasound enhancer SonoVue for evaluating prostate vascularity (transitional zone [TZ] and peripheral zone [PZ]) in diabetic BPH patients, non-diabetic BPH patients and healthy subjects. Computer-assisted quantification of colour pixel intensity (CPI) was used to objectively evaluate the prostate vascularity. Resistive index measurements were obtained in the TZ and the PZ. Findings were compared between these three groups. RESULTS: TZ-CPI was significantly lower in diabetic patients than in non-diabetic BPH men (p=0.001), whereas the CPI of the PZ showed no difference between these two groups (p=0.978). TZ-CPI of patients with diabetic and non-diabetic BPH were significantly lower than in controls (p<0.001), but no difference was found between diabetic and healthy patients in the PZ (p=0.022) and borderline significance was seen when comparing patients of the BPH group with the control patients (p=0.019). Resistive index values of the TZ in diabetic patients showed significantly higher values (p<0.001) than the BPH and control groups. CONCLUSIONS/INTERPRETATION: The significantly lower CPI and higher resistive index values of the TZ in diabetic patients compared with patients with non-diabetic BPH and healthy subjects indicate considerable vascular damage in the TZ of these patients. Diabetic vascular damage may cause hypoxia and may contribute to the pathogenesis of BPH.

Three-dimensional transrectal ultrasound of the male urethral rhabdosphincter.

The rhabdosphincter of the male urethra is an omega-shaped loop of striated muscle fibers that surrounds the membranous urethra at its lateral and anterior aspects. We investigated whether this muscle can be visualized by means of three-dimensional ultrasound to define morphological and dynamic ultrasound criteria. We examined the rhabdosphincter of the male urethra in 77 patients by means of this new imaging technique; 37 patients presented with urinary stress incontinence after transurethral resection of the prostate or radical prostatectomy while 40 were fully continent after radical prostatectomy and served as a control group. Contractility of the muscle was quantified by a specially defined parameter (rhabdosphincter-urethra distance). The anatomical arrangement and the contractions of the rhabdosphincter-loop could be clearly visualized in three-dimensional transrectal and transurethral ultrasound; during contraction the rhabdosphincter retracts the urethra, pulling it towards the rectum. We detected defects and postoperative scarrings in the majority of the patients with postoperative urinary stress incontinence. Furthermore, the patients presented with thinnings in parts of the muscle and atrophies of the rhabdosphincter. The rhabdosphincter-urethra distance was significantly lower in the incontinent group than in the continent group (59 vs. 1.42 mm). Our study shows that the rhabdosphincter of the male urethra can be visualized by means of three-dimensional transrectal ultrasound. The sonographic pathomorphological findings of postoperative urinary stress incontinence are well correlated well with the clinical symptoms.

[The value of ultrasound (US) in the diagnosis of prostate cancer]. / Sonographie des Prostatakarzinoms. Derzeitiger Stand und Zukunftsperspektiven.

The value of ultrasound (US) in the diagnosis of prostate cancer has increased in importance in the past decade, which is mainly related due to the increasing incidence of prostate cancer, the most common malignancy in men. The value of conventional gray-scale US for prostate cancer detection has been extensively investigated. The introduction of US contrast agents has dramatically changed the role of US for prostate cancer detection. Advances in US techniques were introduced to further increase the role of US contrast agents. Although most of these advances in US techniques, which use the interaction of the contrast agent with the transmitted US waves are very sensitive for the detection of microbubbles, are mostly unexplored, in particular for prostate applications. First reports of contrast-enhanced US investigations of blood flow of the prostate have shown that contrast-enhanced US adds important information to the conventional US technique. We present a critical evaluation of the current status of transrectal US imaging for prostate cancer detection. Furthermore, we give background information on US contrast agents and imaging modalities. Early results of contrast-enhanced US suggest the feasibility of the use of US contrast agents to enhance US imaging of the prostate. The application of US contrast agents for the detection and clinical staging of prostate cancer is promising. However, future clinical trials will be needed to determine the promise of contrast-enhanced US of the prostate evolves into clinical application.

[Drug therapy of benign prostatic hyperplasia. Is combination therapy with 5 alpha-reductase inhibitors and alpha-receptor blockers effective?]. / Medikamentöse Therapie der BPH. Ist eine Kombinationstherapie mit 5 alpha-Reduktasehemmern und alpha-Rezeptorenblockern sinnvoll?

5 alpha-reductase inhibitors and alpha 1-receptor blockers are the two main drug therapies used in the management of symptomatic benign prostatic hyperplasia. As alpha-reductase inhibitors and alpha 1-receptor blockers act through different mechanisms, a combination of the two agents might be promising. The potential benefits of combination therapy with selective alpha 1-receptor blockers and finasteride, a 5 alpha-reductase inhibitor, are currently being evaluated in several placebo-controlled prospective multicenter studies (VA Study, ALFIN Study, PREDICT Study, and MTOPS Study). The data from these studies available so far demonstrate a statistically significant benefit for the study groups receiving alpha 1-receptor blockers and combination therapy vs placebo and finasteride monotherapy in terms of symptom scores and peak urine flow rates. However, none of the studies yielded a statistically significant advantage of combination therapy over treatment with alpha 1-receptor blockers. These results should be interpreted with reference to the prostatic volume, which in the studies mentioned above was relatively low. From the results of all these studies, it can be concluded that in symptomatic patients with prostate volumes of up to 40-45 ml a combination of 5 alpha-reductase inhibitors with alpha 1-receptor blockers does not appear to provide any benefit. Yet, it can be assumed that in symptomatic patients with prostate volumes of more than 60 ml combination therapy may indeed prove more effective.

Contrast-enhanced transrectal color doppler ultrasonography (TRCDUS) for assessment of angiogenesis in prostate cancer.

BACKGROUND: The clinical relevance of tumor angiogenesis has been investigated in several human tumors, including prostate carcinoma (PC). Previously, we found angiogenesis, measured as microvessel density (MVD), to be an independent prognostic factor in PC. Therefore, we evaluated contrast-enhanced Transrectal Color Doppler Ultrasonography (TRCDUS) for assessment of angiogenesis in PC. MATERIALS AND METHODS: We investigated 15 patients with PC before radical prostatectomy (RP) and 3 control patients before radical cystoprostatectomy. TRCDUS was performed using a micro-bubble-based ultrasound enhancer Levovist for identifying hypervascularized areas within the prostate. Computer-assisted quantification of color pixel intensity (PI) was used to evaluate objectively the hypervascularized areas; resistive index (RI) measurements were also obtained in these areas. After histopathological examination of the entire prostate gland for tumor confirmation, immunohistochemical evaluation of MVD using a polyclonal antibody against factor VIII was performed as described by Weidner et al. (N Engl J Med 324: 1-8, 1991). TRCDUS findings were correlated with the immunohistochemical data. RESULTS: All patients showed hypervascularized areas (range: 1-9) on contrast-enhanced TRCDUS. Hypervascularized areas showed a sensitivity of 50.8% and a specificity of 95.2% for detecting PC. Analysis of TRCDUS data and immunohistochemistry revealed a significant correlation between PI and MVD in PC specimens, demonstrating a correlation coefficient of r2 = 0.977 (p<0.001). RI did not correlate with MVD. CONCLUSION: Contrast-enhanced TRCDUS showed a high specificity in identifying PC. PI correlated significantly with MVD. Therefore, quantification of color Doppler signals seems to be helpful for assessment of angiogenesis in PC.

Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria.

OBJECTIVES: To monitor the impact of screening in a natural experiment by comparing prostate cancer mortality in Tyrol, where prostate-specific antigen (PSA) testing was introduced at no charge, with the rest of Austria, where it was not introduced. METHODS: In 1993, PSA testing was made freely available to men aged 45 to 75 years in the Federal State of Tyrol, Austria. At least two thirds of all men in this age range have been tested at least once during the first 5 years of the study. Initially, only total PSA was measured, but free PSA measurement was added in 1995. The IMX assay was used. Digital rectal examination was not part of the screening examination. RESULTS: Significant migration to lower stages has been observed since the introduction of this screening program. A reduction in mortality rates in the rest of Austria from 1993 onward has occurred, with the reduction in Tyrol much greater; the mortality remained fairly constant between 1993 and 1995 and subsequently fell. The trends in prostate cancer mortality rates since 1993 differ significantly between Tyrol (P = 0.006) and the rest of Austria. On the basis of the age-specific death rates averaged from 1986 to 1990, the difference between the number of expected and observed deaths from prostate cancer in Tyrol was 22 in the group aged 40 to 79 years in 1998 and 18 the following year. CONCLUSIONS: These findings are consistent with the hypothesis that the policy of making PSA testing freely available, and the wide acceptance by men in the population, is associated with a reduction in prostate cancer mortality in an area in which urology services and radiotherapy are available freely to all patients. It is our opinion that most of this decline is likely to be due to aggressive downstaging and successful treatment and that any contribution from detecting and treating early cancers will only become apparent in the years to come.

Detection of prostate cancer with a microbubble ultrasound contrast agent.

The diagnosis of prostate cancer is currently limited by the low sensitivity and specificity of systematic conventional grey-scale ultrasonography. We assessed contrast-enhanced colour Doppler ultrasonography by means of a microbubble ultrasound contrast agent to detect tumour vascularity and improve the diagnosis of prostate cancer. The use of a microbubble ultrasound contrast agent for transrectal colour Doppler targeted biopsy significantly improved the detection of prostate cancer compared with systematic biopsy following conventional grey-scale ultrasonography (p<0.001). Contrast-agent enhanced colour Doppler imaging may allow for limited targeted biopsies (five or less), which reduces costs and morbidity.