Systemic therapy in metastatic renal cell carcinoma (mRCC): an evidence-based recommendation of the German interdisciplinary RCC guidelines group.

PURPOSE: The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated current medical treatments and gave recommendations. METHODS: A systematic review of published evidence for medical treatment of mRCC was performed (July 2016-August 2019) to cover the duration from last guideline update in 2016. Evidence was graded according to SIGN ( http://www.sign.ac.uk/pdf/sign50.pdf ). Recommendations were made on the basis of a nominal group work with consensus approach and included patient advocates and shareholder of the German RCC treatment landscape. Each recommendation was graded according to its strength as strong recommendation (A) or recommendation (B). Expert statements were given, where appropriate. RESULTS: Strong first-line recommendations (IA) exist for axitinib + pembrolizumab (all risk categories) and ipilimumab + nivolumab (intermediate or poor risk only). Axitinib + avelumab is a recommended first-line treatment across patients with any risk category (IB). In patients who are not candidates for immune check point inhibitor (ICI) combinations, targeted agents should be offered as an alternative treatment. Subsequent treatment after ICI-based combinations remain ill-defined and no standard of care can be formulated. CONCLUSION: ICI-based combinations are the first-line standard of care and should be considered accordingly. There is an unmet medical need for pivotal studies that define novel standards in patients with failure of ICI-based combinations.

Comparison of adjustable male slings and artificial urinary sphincter in the treatment of male urinary incontinence: a retrospective analysis of patient selection and postoperative continence status.

PURPOSE: To analyze and compare preoperative patient characteristics and postoperative results in men with stress urinary incontinence (SUI) selected for an adjustable male sling system or an artificial urinary sphincter (AUS) in a large, contemporary, multi-institutional patient cohort. METHODS: 658 male patients who underwent implantation between 2010 and 2012 in 13 participating institutions were included in this study (n = 176 adjustable male sling; n = 482 AUS). Preoperative patient characteristics and postoperative outcomes were analyzed. For statistical analysis, the independent T test and Mann-Whitney U test were used. RESULTS: Patients undergoing adjustable male sling implantation were less likely to have a neurological disease (4.5% vs. 8.9%, p = 0.021), a history of urethral stricture (21.6% vs. 33.8%, p = 0.024) or a radiation therapy (22.7% vs. 29.9%, p = 0.020) compared to patients that underwent AUS implantation. Mean pad usage per day (6.87 vs. 5.82; p < 0.00) and the ratio of patients with a prior incontinence surgery were higher in patients selected for an AUS implantation (36.7% vs. 22.7%; p < 0.001). At maximum follow-up, patients that underwent an AUS implantation had a significantly lower mean pad usage during daytime (p < 0.001) and nighttime (p = 0.018). Furthermore, the patients' perception of their continence status was better with a subjective complete dry rate of 57.3% vs. 22.0% (p < 0.001). CONCLUSIONS: Patients selected for an AUS implantation showed a more complex prior history and pathogenesis of urinary incontinence as well as a more severe grade of SUI. Postoperative results reflect a better continence status after AUS implantation, favoring the AUS despite the more complicated patient cohort.

[Lower urinary tract dysfunction in Guillain-Barre syndrome]. / Harntraktfunktionsstörungen bei Guillain-Barré-Syndrom.

BACKGROUND: Guillain-Barré syndrome (GBS) as acute inflammatory demyelinating polyradiculoneuropathy frequently leads to lower urinary tract dysfunction. The available knowledge in the medical literature is limited and good recommendations for diagnosis and therapy are rare. MATERIALS AND METHODS: In this study, 189 patients with GBS were screened for lower urinary tract dysfunction. In symptomatic patients, a urodynamic study was performed. Detrusor contractility, post-void residual, and changes of the symptoms over time were studied. Overall Barthel index and urinary control Barthel index as well as the relationship of time after onset of the disease and post-void residual were studied as possible screening criteria for urodynamic assessment. RESULTS: According to the urinary control Barthel index (BI), 115 of 189 patients (61%) presented lower urinary tract symptoms sometime during the course of disease. In 28 patients, these symptoms were temporary during the acute phase. At the time of urological assessment, 87 patients had lower urinary tract symptoms. At the end of rehabilitation, 37 had no symptoms anymore (BI 10), 20 were able to control micturition to a certain extent (BI 5), and 30 had no lower urinary tract control (BI 0). There was a significant negative correlation between post-void residual volume and overall BI (ρ -0.5823, p < 0.0001) and BI for urinary tract control (ρ -0.6430, p < 0.0001). CONCLUSIONS: Overall BI and BI for urinary tract control are suitable screening criteria for urodynamic assessment.

[Cytoreductive radical prostatectomy for prostate cancer with minimal osseous metastases: results of a first feasibility and case control study]. / Zytoreduktive radikale Prostatektomie beim Prostatakarzinom mit minimaler ossärer Metastasierung : Ergebnisse einer ersten Machbarkeits- und Fall-Kontroll-Studie.

BACKGROUND: Androgen deprivation therapy (ADT) represents the standard treatment for patients with prostate cancer (PCA) and osseous metastases. We explored the role of cytoreductive radical prostatectomy in PCA with low volume skeletal metastases in terms of a feasibility study. MATERIAL AND METHODS: A total of 23 patients with biopsy proven PCA, minimal osseous metastases (≤3 hot spots on bone scan), absence of visceral or extensive lymph node metastases and a decrease in prostate-specific antigen (PSA) to <1.0 ng/ml after neoadjuvant ADT were included in the feasibility study (group A). The control group (group B) consisted of 38 men with metastatic PCA who were treated by ADT alone. Surgery-related complications, time to castration resistance, symptom-free, cancer-specific and overall survival were analyzed using descriptive statistical analyses. RESULTS: The mean age was 61 years (range 42-69 years) and 64 years (47-83) in groups A and B, respectively, with similar patient characteristics in terms of initial PSA level, biopsy Gleason score, clinical stage and extent of metastatic disease. The median follow-up was 34.5 months (7-75 months) and 47 months (28-96 months) in groups A and B, respectively. Median time to castration resistance was 40 months (9-65 months) and 29 months (16-59 months) in groups A and B, respectively (p=0.04). Patients in group A experienced significantly better clinical symptom-free (38.6 versus 26.5 months, p=0.032) and cancer-specific survival rates (95.6% versus 84.2%, p=0.043) whereas the overall survival was similar. In group A none of the men underwent palliative surgical procedures for locally progressing PCA compared to 29% in group B. CONCLUSIONS: Cytoreductive radical prostatectomy is feasible in well-selected men with metastatic PCA who responded well to neoadjuvant ADT. These men have a long life expectancy and the risk of locally recurrent PCA and local complications are reduced. Cytoreductive radical prostatectomy might be a treatment option in the multimodal management of PCA with minimal osseous metastases.

[Metastasectomy for renal cell cancer]. / Metastasenresektion beim Nierenzellkarzinom.

BACKGROUND: Metastasectomy prior to or after systemic medical cancer treatment is performed within a multimodal therapeutic approach in metastatic renal cell cancer (mRCC) to improve the prognosis. The role of metastasectomy in mRCC is controversially discussed and the potential therapeutic benefit is unquantifiable. The purpose of the current review is to critically discuss the available data. METHODS: A systematic literature search was carried out in the MedLinedatabase to identify original publications, review articles and editorials with respect to metastasectomy in mRCC and the current European guidelines were also taken into consideration. RESULTS: Metastasectomy is one of the approaches for mRCC recommended in the guidelines in cases of stable disease for at least 3 months, complete resectability of all metastatic lesions independent of the anatomic localization and a good performance status of the patient. The median survival time varies between 35 and 55 months. CONCLUSIONS: In mRCC metastasectomy is an indiviudal therapeutic approach which might be considered for limited metastatic disease and the presence of good prognostic risk factors to improve average survival time. Especially in renal cell cancer metastasectomy should be considered early.

[Organ-limited prostate cancer with positive resection margins. Importance of adjuvant radiation therapy]. / Organbegrenztes Prostatakarzinom mit positivem Resektionsrand. Stellenwert der adjuvanten Radiatio.

For pT3 prostate cancer with positive resection margins, the importance of postoperative radiation therapy is confirmed by a high level of evidence. However, for the pT2,R1 situation prospective, randomized studies concerning this question are lacking. Despite better local tumor control in the pT2 stage the PSA recurrence rate lies between 25% and 40% and positive margins are an independent factor for recurrence. Retrospective studies suggest a positive effect of adjuvant or salvage radiation for the oncological outcome in the pT2,R1 situation. On the other hand the side effects profile, with a potentially negative influence of postoperative continence and various delayed toxicities, is not insignificant despite modern radiation techniques and in the era of ultrasensitive PSA analysis should be considered in the risk-benefit assessment. As long as the optimal initiation of postoperative radiation therapy is unclear, the assessment of indications for adjuvant or salvage radiation for organ-limited prostate cancer with positive resection margins should be made after an individual patient consultation and under consideration of the recurrence risk factors, such as the Gleason grade and the localization and extent of the resection margins.

[Organ-preserving renal tumor surgery for renal cell carcinoma ≥T1b: operative technique, complications and oncological control]. / Organerhaltende Nierentumorchirurgie bei Nierenzellkarzinomen ≥T1b : Operationstechnik, Komplikationen und onkologische Kontrolle.

BACKGROUND: Nephron sparing surgery (NSS) represents the recommended treatment of choice in guidelines for T1a and T1b renal tumors. Current data, however, suggest that approximately 60% of patients with T1b tumors are treated by radical nephrectomy. PATIENTS AND METHODS: We performed a retrospective analysis of 320 patients with renal cell cancer who underwent organ sparing procedures: NSS for renal tumors ≤4 cm (n=196, group 1) and 4.1-7 cm (n=92, group 2) as well as radiofrequency ablation (RFA, n=32, group 3). We analysed the indications, surgical techniques, perioperative complications and oncological outcome of the three groups. RESULTS: There were significant differences between groups 1 and 2 with regard to mean tumor size (2.9 cm versus 8.6 cm, p=0.03), necessity for warm ischemia (15.1% versus 51%, p=0.001), mean time of warm ischemia (3.5 min versus 10.2 min, p=0.002), necessity for endoluminal stenting due to involvement of the renal collecting system (0.5% versus 24.2%, p=0.001) and the number of pT2 (12.7% versus 29.7%, p=0.03) and pT3 tumors (8.7% versus 12%, p=0.05). In group 3 the mean age was 69.2 years and the mean Charlson comorbidity score was 7.7 (range 3-12) as compared to 3.4 (1-6) in groups 1 and 2. After a mean follow-up of 32 (2-71) months, 2 (6.2%) local recurrences developed and 8 patients died, 6 patients due to comorbidities and 2 patients due to metastatic renal cell carcinoma (RCC). CONCLUSIONS: Nephron sparing surgery can be safely performed for T1a to T2a renal cell carcinoma with equivalent oncological outcomes as compared to radical nephrectomy. Nephron sparing surgery should represent the standard surgical approach for localized RCCs independent of size and RFA should be reserved for patients with significant comorbidities.

[Metastasectomy in renal cell cancer after neoadjuvant therapy with multi-tyrosine kinase inhibitors]. / Metastasenresektion nach neoadjuvanter Systemtherapie mit Multityrosinkinaseinhibitoren beim metastasierten Nierenzellkarzinom.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) still poses a challenge to therapists in spite of the availability of multiple innovative molecular treatment options. Complete remission is rare and in cases of partial remission it is often unclear if necrosis or vital carcinoma tissue persists. We report on a cohort of patients who underwent metastasectomy after neoadjuvant therapy with multi-tyrosine kinase inhibitors (MTKI). METHODS: In 2009 a total of 11 patients (7 male and 4 female) underwent metastasectomy after achievement of ≥ 3 months stable partial remission. All patients received either sunitinib (n=7, mean 5.5 cycles), bevacizumab and interferon (IFN)-α2a (n=2, mean 8.5 months), temsirolimus (n=1, mean 9 months) or a combination of sunitinib followed by temsirolimus (n=1). Of the patients 7 presented with retroperitoneal lymph node metastases with a mean diameter of 3.5-12 cm, 2 patients with pulmonary metastases, 1 patient with lymph node and pancreas tail metastases and 1 female patient showed residual disease in the vena cava. RESULTS: All metastases were completely resected with negative surgical margins. In 82% of the cases histologically active, Ki-67 positive renal cell cancer tissue was identified. The following adjunctive interventions were necessary: vena cava resection with vascular prosthesis and reimplantation of the renal vein (n=3), partial liver resection (n=1), splenectomy (n=1) and pancreas tail resection (n=1). There were no significant perioperative complications but 1 patient developed fascial dehiscence and underwent revision surgery and 1 patient developed clinically insignificant pancreatitis. After a median follow-up of 12 months (range 8-19 months) 5 patients had no recurrence and 6 of the patients showed liver (n=3), lung (n=2) or bone (n=1) recurrences from which 3 patients died. CONCLUSIONS: Metastasectomy of mRCC is associated with a low rate of complications in experienced centers. Surgical resection of metastatic disease is indicated to achieve complete remission with a favorable prognosis because of biologically active kidney cancer tissue. Patients with isolated and resectable metastases are ideal candidates for such a procedure.

[Urgency after successful treatment of prostate cancer. Prospective study on the influence of treatment modality, morbidity, and epidemiological factors on the quality of life]. / Drangsymptomatik nach onkologisch erfolgreicher Prostatakarzinomtherapie. Prospektive Studie zum Einfluss von Therapiemodalität, Morbidität und epidemiologischen Faktoren auf die Lebensqualität.

BACKGROUND: The aim of this prospective study was to investigate factors influencing long-term health-related quality of life (HRQoL) in patients treated for prostate cancer with no signs of tumor relapse. PATIENTS AND METHODS: We included epidemiological and oncological data as well as standardized questionnaires on incontinence and sexual function. Data were analyzed using standard descriptive and explorative statistics. RESULTS: We obtained pre-therapeutic data as well as a complete data set after 36 months for 488 patients. A total of 162 patients (33.2%) in whom we could not exclude a tumor relapse according to the guidelines of the EAU or because of incomplete data were excluded from further analysis. In a univariate analysis as expected stress incontinence, lower urinary tract symptoms (LUTS), overactive bladder (OAB), urgency, pad use, sexual activity as well as perceived pre-therapeutic HRQoL, being privately insured, and a better school education were significantly associated with post-therapeutic long-term HRQoL (p<0.05). In a multivariate analysis of covariance only dry OAB (p=0.0411) and sexual activity (p=0.0046) proved to be independent parameters with a significant impact on HRQoL after 36 months. CONCLUSION: Symptoms of OAB even without urine loss after successful treatment of prostate cancer need to be addressed in clinical practice as well as in research studies.

A limited LCA of bio-adipic acid: manufacturing the nylon-6,6 precursor adipic acid using the benzoic acid degradation pathway from different feedstocks.

A limited life cycle assessment (LCA) was performed on a combined biological and chemical process for the production of adipic acid, which was compared to the traditional petrochemical process. The LCA comprises the biological conversion of the aromatic feedstocks benzoic acid, impure aromatics, toluene, or phenol from lignin to cis, cis-muconic acid, which is subsequently converted to adipic acid through hydrogenation. Apart from the impact of usage of petrochemical and biomass-based feedstocks, the environmental impact of the final concentration of cis, cis-muconic acid in the fermentation broth was studied using 1.85% and 4.26% cis, cis-muconic acid. The LCA focused on the cumulative energy demand (CED), cumulative exergy demand (CExD), and the CO(2) equivalent (CO(2) eq) emission, with CO(2) and N(2) O measured separately. The highest calculated reduction potential of CED and CExD were achieved using phenol, which reduced the CED by 29% and 57% with 1.85% and 4.26% cis, cis-muconic acid, respectively. A decrease in the CO(2) eq emission was especially achieved when the N(2) O emission in the combined biological and chemical process was restricted. At 4.26% cis, cis-muconic acid, the different carbon backbone feedstocks contributed to an optimized reduction of CO(2) eq emissions ranging from 14.0 to 17.4 ton CO(2) eq/ton adipic acid. The bulk of the bioprocessing energy intensity is attributed to the hydrogenation reactor, which has a high environmental impact and a direct relationship with the product concentration in the broth.

[Optimizing treatment of advanced testicular germ cell tumors]. / Behandlungsoptimierung fortgeschrittener testikulärer Keimzelltumoren.

Testicular germ cell cancer represents the most frequent solid neoplasm in young men aged 20-40 years. Depending on the prognosis according to the IGCCCG classification, the treatment of choice for advanced germ cell tumors consists in three to four cycles of bleomycin, etoposide, and cisplatin (BEP) in accordance with the current European Consensus Guidelines. Although residual tumor resection (RTR) adheres to guidelines as the treatment for residual metastatic lesions, numerous questions remain unresolved, which we intend to systematically answer within the scope of our research group by conducting prospective/retrospective and clinical/molecular investigations in cooperation with national and international project groups.

[Virilizing adrenal ganglioneuroma : A rare differential diagnosis in testosterone secreting adrenal tumours]. / Virilisierendes Ganglioneurom der Nebenniere : Eine seltene Differenzialdiagnose testosteronproduzierender Nebennierentumoren.

Testosterone secreting tumours of the adrenal glands are usually adrenal carcinomas or adenomas. Here we report the rare case of an adrenal ganglioneuroma with ectopic Leydig cells, a so-called virilizing adrenal ganglioneuroma. Clinically it is characterized by symptoms of virilization, histologically by the occurrence of a population of eosinophilic cells. In the absence of crystalloids of Reinke this cell population can be identified as Leydig cells based on positive immunohistochemical staining of inhibin and calretinin.

[Solitary peritoneal carcinomatosis in prostate cancer]. / Solitäre Peritonealkarzinose eines Prostatakarzinoms.

INTRODUCTION: Peritoneal carcinomatosis is a rare finding in metastatic prostate cancer. In the literature peritoneal carcinomatosis is usually reported in its final stages with multiple metastases. A single peritoneal carcinomatosis with no further metastases is a very rare finding. CASE REPORT: We report the case of a 75-year-old patient with initial ischuria. A prostate cancer could be confirmed and the further diagnostics showed no metastasis. In a transperitoneal approach for laparoscopic pelvic lymphadenectomy a peritoneal carcinomatosis from prostate cancer was proven. A complete antiandrogen therapy was started and PSA decreased for more than 14 months to a stable level of < 1 microg/L. CONCLUSION: An isolated peritoneal carcinomatosis from prostate cancer is a very rare finding. The complete antiandrogen therapy is effective.

[Nephron-sparing therapy for renal tumors]. / Die organerhaltende Nierentumor-Therapie.

In this article up-to-date, nephron-sparing therapy for renal cell cancer such as radical tumor nephrectomy, partial resection or enucleation is summarised. The results of open and laparoscopic partial nephrectomy and tumor enucleation are presented. Problems and complications associated with the techniques are reviewed. There are as yet no randomized, controlled trials and most published studies show retrospective data. Further new alternative techniques in nephron-sparing therapy like cryosurgery and radiofrequency ablation are presented.

'UroMaix' scaffolds: novel collagen matrices for application in tissue engineering of the urinary tract.

Reconstruction of bladder and ureter tissue is indicated in cases of injury, stenosis, infection or tumor. Substitution by ileum, colon or pure synthetic polymers generates a variety of complications. Biohybrid tissue mimicking structural and functional attributes of the multilayered wall architecture of the urinary conduit may be the solution to current problems. This study reports on porcine urinary tract cells isolated and placed on UroMaix matrices with different degrees of cross-linking produced from highly purified type I collagen from medically approved porcine tissue. A patented procedure revealed membrane structures composed of a dense fibrous side and an open fibrous side. These scaffolds with the porcine urinary tract cells were incubated in a batch culture system for up to 14 days. Cell growth and topographical orientation were examined. Urothelial cells showed maximum attachment and a significant increase of living cells on the dense fiber layer of UroMaix-1. No attachment of urothelial cells occurred on the other prototypes. Smooth muscle cells showed similar behavior within the open fiber layer of all UroMaix matrices. Both urothelial and smooth muscle cells retained their phenotypes as demonstrated by the immunostaining of epithelial cytokeratin 18 and the smooth muscle myosin heavy chain respectively. Thus we could show that UroMaix scaffolds support the attachment and proliferation of urinary tract cells. The elastomeric properties of the collagenous matrices promise attractive applications in the tissue engineering of the urinary tract with its high mechanical demands.

Expression of matrix metalloproteinases (MMP-2 and -9) and their inhibitors (TIMP-1 and -2) in prostate cancer tissue.

Matrix metalloproteinases (MMPs) have been implicated in progression and metastases of different tumours. The balance between the MMPs and their natural inhibitors (tissue inhibitors of matrix metalloproteinases; TIMP) seems to be an important factor related to this role. Here, the expression of MMP-2 and -9 along with TIMP-1 and -2 was examined in prostate cancer tissue. A total of 40 radical prostatectomy specimens were embedded in paraffin and immunohistochemical staining was performed to detect MMP-2 and -9, and TIMP-1 and -2. The immunoreactivity was assessed semiquantitively using routine light microscopy. The intensity of staining was correlated to preoperative PSA, T category, Gleason score and clinical parameters of the specimens. The imbalance of MMPs and TIMPs was recognised as a significant loss of TIMP-1 in malignant epithelium and an upregulation of MMPs. Palpable tumours (T2, T3) expressed significantly more MMP-2 and significantly less MMP-9 than T1c tumours. Our data are in accordance with other literature reports in that an imbalance of MMPs and TIMPs is found in malignant tumours. The observed imbalance of MMP and TIMP is mainly caused by a loss of TIMP-1. Furthermore, palpable tumours demonstrated significantly more MMP-2 and significantly less MMP-9 expression than nonpalpable tumours.

[Potency-sparing radical perineal prostatectomy]. / Potenzerhaltende radikale perineale Prostatektomie.

We evaluated the results of a unilateral nerve-sparing radical perineal prostatectomy in a prospective study. Thirty patients with histologically confirmed unilateral prostate cancer and adequate erectile function preoperatively underwent a nerve-sparing procedure. The criteria were a PSA of <10 ng/ml, prostate volume of <60 ml, and a Gleason score <7. In 29 patients the procedure was technically feasible. In one patient significant damage to the neurovascular bundle was seen at the end of the procedure. Bilateral tumors were present in 18 patients on final pathology. Positive surgical margins were observed in five patients (pT2: 2/20; pT3: 3/10). After a follow-up of 3-12 months, 15 of 29 patients (51%) reported some erectile function without additional medication. Of 14 patients, 2 had enough rigidity for penetration within 3 months.The short-term results after unilateral nerve-sparing perineal prostatectomy are encouraging. Since the neurovascular bundle can be exposed very well, interposition of sural nerve should be considered.

Radical prostatectomy in patients with previous groin hernia repair using synthetic nonabsorbable mesh.

OBJECTIVE: Identification of patients in whom the perineal route is the optimal approach to perform radical prostatectomy. MATERIAL AND METHODS: During 1992-1999, 376 patients with prostate cancer underwent radical perineal prostatectomy. Four patients were identified in whom the perineal approach was indicated because of previous bilateral groin hernia repair using synthetic meshes. In addition, 1 patient underwent perineal prostatectomy elsewhere for similar reasons. RESULTS: The perineal approach offered an uneventful surgical solution for an adequate and straightforward radical perineal prostatectomy without complications and without biochemical recurrence during the follow-up. CONCLUSION: Radical perineal prostatectomy is suggested to be the optimal approach in patients with previous bilateral groin hernia repair using synthetic, nonabsorbable meshes.