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.

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.

[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.

[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.

[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.

[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.

'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.

[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.

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.

Are age-specific reference ranges for prostate specific antigen population specific?

INTRODUCTION: At present PSA is Considered to be the leading screening test for prostate cancer. We determined whether in men 60 to 79 year old with a serum prostate specific antigen (PSA) within age specific PSA reference ranges prostate biopsy could be safely eliminated. METHODS: We retrospectively analysed all 60-79 year old men who had undergone radical perineal prostatectomy (RPP) for prostate cancer (CaP) at our institution. All patients had undergone prostate biopsy following an abnormal rectal examination and/or PSA greater than 4.0 ng/ml. We compared our results using the standard reference range of 0 to 4.0 ng/ml with those we had obtained using the age specific PSA reference ranges of Oesterling et al. RESULTS: 204 men between 60-69 years and 67 men between 70-76 years had undergone RPP for CaP. Applying age specific PSA reference ranges 56 CaP would have been overlooked. Of those 46% had a favourable histology. Taken together 54% of the cancers overlooked had an unfavourable histology. CONCLUSION: In contrast to previous reports of unfavourable histological characteristics in only 5-24% of missed cancers, applying age specific PSA reference ranges, 54% of missed cancers in our patients exhibited an unfavourable histology. We therefore conclude that age specific PSA reference ranges did not safely eliminate the need for prostate biopsy in our study population.

Cytokeratin markers in patients with prostatic diseases.

OBJECTIVES: Recently tissue polypeptide specific antigen (TPS), a cytokeratin 18 marker, was described to be discriminative between cancer of the prostate (CaP) and benign prostatic hyperplasia (BPH). Cyfra 8/18, a marker which recognizes both cytokeratin 8 and 18 fragments, is thought to improve sensitivity and specificity of TPS. In our study we investigated the ability of the TPS and cyfra 8/18 serum concentration to discriminate between patients with clinically localized CaP and BPH. METHODS: Serum levels of TPS and Cyfra 8/18 were determined in patients with untreated CaP (pT1-3pNoMo: n = 11) and BPH (n = 22). The TPS and the Cyfra 8/18 concentrations were correlated to the prostate specific antigen (PSA) serum concentration. RESULTS: Median TPS concentration was 45.3 U/L in CaP-patients and 54.8 U/L in BPH-patients. This difference is statistically not significant (p = 0.2). Median Cyfra 8/18 level was 0.64 ng/mL in CaP-patients and 0.57 ng/mL in BPH-patients. This difference is statistically not significant (p = 0.91). Furthermore no correlation with PSA levels could be established (TPS: r = -0.13; Cyfra 8/18: r = 0.17). CONCLUSION: In contrast to recent reports we found both cytokeratin markers, TPS as well as Cyfra 8/18, to be non-discriminative parameters in CaP and BPH.

Dynamic decision making: human control of complex systems.

This paper reviews research on dynamic decision making, i.e., decision making under conditions which require a series of decisions, where the decisions are not independent, where the state of the world changes, both autonomously and as a consequence of the decision maker's actions, and where the decisions have to be made in real time. It is difficult to find useful normative theories for these kinds of decisions, and research thus has to focus on descriptive issues. A general approach, based on control theory, is proposed as a means to organize research in the area. An experimental paradigm for the study of dynamic decision making, that of computer simulated microworlds, is discussed, and two approaches using this paradigm are described: the individual differences approach, typical of German work in the tradition of research on complex problem solving, and the experimental approach. In studies following the former approach, the behaviour of groups differing in performance is compared, either with respect to strategies or with respect to performance on psychological tests. The results show that there are wide interindividual differences in performance, but no stable correlations between performance in microworlds and scores on traditional psychological tests have been found. Experimental research studying the effects of system characteristics, such as complexity and feedback delays, on dynamic decision making has shown that decision performance in dynamic tasks is strongly affected by feedback delays and whether or not the decisions have side effects. Although neither approach has led to any well-developed theory of dynamic decision making so far, the results nevertheless indicate that we are now able to produce highly reliable experimental results in the laboratory, results that agree with those found in field studies of dynamic decision making. This shows that an important first step towards a better understanding of these phenomena has been taken.

Road safety improvement in large companies. An experimental comparison of different measures.

Road accidents among professional drivers are a major problem in many companies. There are several traditional measures for improving safety, but knowledge about what measures are most effective is rather limited. The aim of the study is to compare four different measures for reducing accident involvement through changed driver behaviour. The measures are driver training, group discussions, campaigns and bonuses for accident free driving. Five groups of approximately 900 drivers each employed by the Swedish telephone company "Televerket" have been used in the experiment. Four of the groups were test groups, where each took part in one of the measures. The fifth group was a control group. The effect on accident risk (accidents in relation to mileage) and accident costs have been calculated for a period of 2 years after the measures were applied. The results show that group discussions and driver training with the rather unusual design used in the experiment succeeded in improving the accident risk compared to the control group. Accident costs were reduced in all four test groups, but not in the control group.

General dental practitioners' evaluation of the need for extraction of asymptomatic mandibular third molars.

Thirty general dental practitioners were asked to evaluate the need for extraction of asymptomatic mandibular third molars. Thirty-six mandibular third molars with equal distribution of angular positions, impaction status, males and females and age groups were selected. To estimate the consistency of the evaluation, the 36 cases were duplicated so that, in all, 72 teeth were evaluated. The number of molars proposed to be extracted by the observers varied from 0 to 26. There was no third molar which all observers agreed should be extracted. The two molars which most observers, 25 and 23 of altogether 30 observers, proposed to be extracted were partially covered by soft tissue. The decision not to extract two molars was unanimous. Both of these were completely covered by bone tissue and positioned vertically. The mean overall intra-observer agreement for the therapeutical decision was 92%, with a range of 69-100%. The length of professional experience of the observer did not influence the evaluation whether or not to extract. We conclude that there is a great variation among general dental practitioners regarding their evaluation on the need for removal of asymptomatic mandibular third molars.

Pathoses associated with mandibular third molars subjected to removal.

OBJECTIVES: To measure the prevalence of disease of mandibular third molars referred for removal and to estimate the risk for development of pathoses for two cues. STUDY DESIGN: A prospective cohort study on molars subjected to removal was performed. The prevalence of different diseases and the patient's age, angular position, and degree of impaction of the molars were registered. Odds ratio for molars with different positions and impaction states were estimated. RESULTS: Pericoronitis was found in 64% of cases, caries in the third molar in 31%, periodontitis in association with 8%, caries in the second molar in 5%, and root resorption of the second molar with 1% of the molars with pathoses. Odds ratio was highest for distoangular molars (5.8) and for molars partially covered by soft tissue (6.7). CONCLUSIONS: The odds ratio is about 22 and 34 times higher for molars partially covered by soft tissue than for molars completely covered by soft or bone tissue. For distoangular molars the odds ratio is 5 to 12 times higher than for molars in other positions.

[Ureteroureterostomies: indications and results (author's transl)]. / Uretero-Ureterostomien: Indikationen und Ergebnisse.

Thirteen unilateral ureteroureterostomies and twenty-five transureteroureterostomies (TUU) were performed since 1968. In 22 of these, a transureteroureterocutaneostomy (TUUC) was done. Indications, operative procedures, results and complications are discussed. No complications due to the anastomosis were found. In six cases stenosis of the ureterocutaneostomy was demonstrated which, in four instances, made another form of urinary diversion necessary. Ureteroureterostomies should only be performed with well functioning kidneys and with one well preserved ureter. TUUC is recommended in cases with at least one dilated ureter.

[The diagnostic and therapeutic value of second look operation in patients with testicular germinal cell tumors (author's transl)]. / Der diagnostische und therapeutische Stellenwert der Second-look-Operation bei Patienten mit malignen Hodentumoren.

We report on 32 patients with testicular tumor who--after earlier retroperitoneal lymph node dissection--underwent a second-look operation. Whereas in 16 patients vital tumor tissue was found in the retroperitoneum 9 patients had only degenerative changes with fibrosis and necrosis. In 7 patients the retroperitoneum showed no evidence of disease. It is our conclusion that an extensive pre-operative diagnostic workup, including tumor-markers, ultrasound and CT in patients treated with chemo- and radiotherapy cannot determine whether viable tumor tissue is present in the retroperitoneum. In 13 patients with non-seminomatous germinal cell tumors where viable tumor tissue was found at second-look operation 61,5% had normal tumor-markers. Those patients in whom at second-look operation no viable tumor tissue was found benefit from that approach because of the possibility of terminating aggressive chemotherapy. On the other hand patients with vital tumor tissue had a poor prognosis.

[Combined surgical and cytostatic therapy in patients with advanced metastatic nonseminomatous testicular cancer (author's transl)]. / Kombinierte operative und zytostatische Therapie bei Patienten mit fortgeschritten metastasierten nicht-seminomatösen Hodentumoren.

Lymphadenectomy and chemotherapy were carried out on 18 patients with grossly disseminated nonseminomatous testicular cancer. Of the 14 patients so far evaluable, remission was obtained in 13 (92%), complete remission in 7 (50%). Results suggest that even when the disease is advanced, lymphadenectomy is of diagnostic, therapeutic, and palliative value.

[Differential diagnosis of acute scrotum by nuclear medicine study]. / Differentialdiagnose des akuten Skrotums durch nuklearmedizinische Untersuchung.

Sixty-four patients with acute scrotal pain were examined by radionuclide scrotal scanning. We compared clinical, surgical and radionuclide findings. The scrotal scanning is a rapid, non invasive and painless examination with high accuracy in inflammatory disease. But two falsely negative scans in acute testicular torsion warn against this simple method. Torsion of the appendix testis were not recognized by scanning.