Immune-Related Adverse Events Can Predict Progression-Free and Overall Survival In Patients With Metastatic Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Different combination therapies using anti - PD-1 / PD-L1 or CTLA-4 immune checkpoint inhibition (ICI) are widely used in patients with metastatic renal cell carcinoma (mRCC). In the absents of established biomarkers, immune-related adverse events (irAEs) have been discussed as potential predictors of response. METHODS: In this retrospective cohort study, data of 134 patients with mRCC undergoing ICI treatment (Nivolumab, Ipilimumab and Nivolumab, Pembrolizumab and Axitinib or Avelumab and Axitinib) between 2015 and 2021 were analyzed. To examine the utility of irAEs as predictors of overall survival (OS) and progression-free survival (PFS), separate Kaplan-Meier analyses and Cox proportional regression analyses were applied. Landmark analysis was conducted after 12 weeks to reduce immortal time bias. RESULT: irAEs were observed in 85 patients (63.4%). Cutaneous (n = 52, 38.8%), endocrine (n = 33, 24.6%) and hepatic (n = 19, 14.2%) irAEs were most commonly observed. In Kaplan-Meier analysis, patients experiencing irAEs showed favorable median PFS (15 months, 95% CI, 9.91-20.09) compared to the non-irAE group (5 months, 95% CI, 3.56-6.44, P < .001). The median OS was 25 months (95% CI, 16.79-33.21) in the non-irAE group, while it was not reached in the irAE group (P = .002). In multivariable analysis, the presence of any irAE was associated with favorable PFS (HR 0.46 [95% CI, 0.26-0.82] P = .008) and OS (HR: 0.28 [95% CI, 0.12-0.63] P = .002), respectively. Landmark analysis after 12 weeks showed mixed results depending on the classification of the irAE group at the landmark time. CONCLUSION: The presence of irAEs under ICI therapy in patients with mRCC is associated with better PFS and OS. Thus, manageable irAEs should not be cause for premature discontinuation of ICI therapy, as they seem to indicate favorable outcomes. Considering the time-dependent nature of irAEs is crucial estimating their value as predictive markers.

Establishment of primary prostate epithelial and tumorigenic cell lines using a non-viral immortalization approach.

BACKGROUND: Research on prostate cancer is mostly performed using cell lines derived from metastatic disease, not reflecting stages of tumor initiation or early progression. Establishment of cancer cell lines derived from the primary tumor site has not been described so far. By definition, cancer cells are able to be cultured indefinitely, whereas normal epithelial cells undergo senescence in vitro. Epithelial cells can be immortalized, accomplished by using viral integration of immortalization factors. Viral approaches, however, might be impaired by regulatory and safety issues as well as random integration into regulatory genetic elements, modifying precise gene expression. We intend to use surgical specimen of prostate cancer patients to (i) prove for establishment of cancer cell lines, and (ii) perform non-viral, Sleeping Beauty (SB) transposase-based immortalization of prostate epithelial cells. METHODS: Radical prostatectomy samples of prostate cancer patients (n = 4) were dissociated and cultured in vitro. Cells were cultivated either without or after non-viral, Sleeping-Beauty transposase-based stable transfection with immortalization factors SV40LT and hTERT. Established cell lines were analyzed in vitro and in vivo for characteristics of prostate (cancer) cells. RESULTS: Initial cell cultures without genetic manipulation underwent senescence within ≤ 15 passages, demonstrating inability to successfully derive primary prostate cancer cell lines. By using SB transposase-based integration of immortalization factors, we were able to establish primary prostate cell lines. Three out of four cell lines displayed epithelial characteristics, however without expression of prostate (cancer) characteristics, e.g., androgen receptor. In vivo, one cell line exhibited tumorigenic potential, yet characteristics of prostate adenocarcinoma were absent. CONCLUSION: Whereas no primary prostate cancer cell line could be established, we provide for the first-time immortalization of primary prostate cells using the SB transposase system, thereby preventing regulatory and molecular issues based on viral immortalization approaches. Although, none of the newly derived cell lines demonstrated prostate cancer characteristics, tumor formation was observed in one cell line. Given the non-prostate adenocarcinoma properties of the tumor, cells have presumably undergone oncogenic transformation rather than prostate cancer differentiation. Still, these cell lines might be used as a tool for research on prostate cancer initiation and early cancer progression.

["Pressure kills kidneys": protection of the upper urinary tract through neuro-urological management]. / "Pressure kills kidneys": Schutz des oberen Harntrakts durch neuro-urologisches Management.

Low compliance is not an independent disease but a severe manifestation resulting from various disorders of the storage and excretory function of the bladder. Reduced distensibility of the detrusor muscle can lead to a pressure load on the upper urinary tract but also to urge-dominant LUTS and urinary tract infections. Neurogenic causes, especially spinal cord injury/spina bifida but also iatrogenic damage or subvesical obstruction, can contribute to the development. This article is intended to provide information about the epidemiology and complex pathogenetic mechanisms as well as the necessary diagnostic steps. Various medical, interventional and surgical treatment strategies are evaluated on the basis of current scientific findings, thus supporting the reader in the care of this complex patient group.

Establishment of primary prostate epithelial and tumorigenic cell lines using a non-viral immortalization approach

Background Research on prostate cancer is mostly performed using cell lines derived from metastatic disease, not reflecting stages of tumor initiation or early progression. Establishment of cancer cell lines derived from the primary tumor site has not been described so far. By definition, cancer cells are able to be cultured indefinitely, whereas normal epithelial cells undergo senescence in vitro. Epithelial cells can be immortalized, accomplished by using viral integration of immortalization factors. Viral approaches, however, might be impaired by regulatory and safety issues as well as random integration into regulatory genetic elements, modifying precise gene expression. We intend to use surgical specimen of prostate cancer patients to (i) prove for establishment of cancer cell lines, and (ii) perform nonviral, Sleeping Beauty (SB) transposase-based immortalization of prostate epithelial cells. Methods Radical prostatectomy samples of prostate cancer patients (n = 4) were dissociated and cultured in vitro. Cells were cultivated either without or after non-viral, Sleeping-Beauty transposase-based stable transfection with immortalization factors SV40LT and hTERT. Established cell lines were analyzed in vitro and in vivo for characteristics of prostate (cancer) cells. Results Initial cell cultures without genetic manipulation underwent senescence within ≤ 15 passages, demonstrating inability to successfully derive primary prostate cancer cell lines. By using SB transposase-based integration of immortalization factors, we were able to establish primary prostate cell lines. Three out of four cell lines displayed epithelial characteristics, however without expression of prostate (cancer) characteristics, e.g., androgen receptor. In vivo, one cell line exhibited tumorigenic potential, yet characteristics of prostate adenocarcinoma were absent. Conclusion Whereas no primary prostate cancer cell line could be established, we provide for the first-time immortalization of primary prostate cells using the SB transposase system, thereby preventing regulatory and molecular issues based on viral immortalization approaches. Although, none of the newly derived cell lines demonstrated prostate cancer characteristics, tumor formation was observed in one cell line. Given the non-prostate adenocarcinoma properties of the tumor, cells have presumably undergone oncogenic transformation rather than prostate cancer differentiation. Still, these cell lines might be used as a tool for research on prostate cancer initiation and early cancer progression.

Immunohistochemical expression of TROP­2 (TACSTD2) on the urothelial carcinoma of the urinary bladder and other types of cancer.

In metastatic or locally advanced urothelial carcinoma (UC), therapeutic options have been limited to chemotherapy and immune checkpoint inhibitors. Novel targets and drugs such as antibody drug conjugates have been developed, and enfortumab vedotin targeting nectin-4 and sacituzumab govitecan (SG) targeting trophoblast cell surface antigen 2 (TROP-2), the protein product of the TACSTD2 gene, have been approved. The expression of TROP-2 was investigated within UC and other types of carcinomas, and within the tissue of different healthy organs to understand treatment responses and toxicities. The expression of TROP-2 in the tissues of 42 patients with UC, 13 patients with other types of cancer and in the normal tissues of 11 patients was retrospectively analyzed. Immunohistochemical staining of the TROP-2 protein was performed on a BenchMark ULTRA IHC/ISH System (Roche Tissue Diagnostics; Roche Diagnostics, Ltd.) according to accredited staining protocols in a routine immunohistochemistry accredited and certified facility of the laboratory of immunohistochemistry at the Institute of Pathology (Gerhard-Domagk Institute)- University Hospital Muenster (UKM)-Muenster-Germany]. Different expression levels of TROP-2 were observed, and the highest expression rate of TROP-2 was observed in UC, independent of the tumor stage. However, normal urothelial cells had similar expression levels. Except for ductal carcinoma in situ, the expression of TROP-2 was reduced in other types of cancer and in the healthy tissues from other organs, including pancreas, gall bladder, colon and prostate. Given the treatment response based on the expression level of TROP-2, SG would be effective in almost all cases of UC. However, it would also have an effect on the normal urothelium.

Evaluation of Gas 6 as a Prognostic Marker in Papillary Renal Cell Carcinoma.

INTRODUCTION: Growth arrest-specific protein 6 (Gas 6) is a ligand that plays a role in proliferation and migration of cells. For several tumor entities, high levels of Gas 6 are associated with poorer survival. We examined the prognostic role of Gas 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), which is still unclear. METHODS: The patients' sample collection is a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Gas 6 was determined by immunohistochemistry. RESULTS: In total, Gas 6 staining was evaluable in 180 of 240 type 1 and 110 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed no significant difference in 5-year overall survival for all pRCC nor either subtype. Also, Gas+ and Gas- groups did not significantly differ in any tumor or patient characteristics. CONCLUSION: Gas 6 was not found to be an independent prognostic marker in pRCC. Future studies are warranted to determine if Gas 6 plays a role as prognostic marker or therapeutic target in pRCC.

Co-expression and clinical utility of AR-FL and AR splice variants AR-V3, AR-V7 and AR-V9 in prostate cancer.

BACKGROUND: Androgen receptor (AR) splice variants (AR-Vs) have been discussed as a biomarker in prostate cancer (PC). However, some reports question the predictive property of AR-Vs. From a mechanistic perspective, the connection between AR full length (AR-FL) and AR-Vs is not fully understood. Here, we aimed to investigate the dependence of AR-FL and AR-V expression levels on AR gene activity. Additionally, we intended to comprehensively analyze presence of AR-FL and three clinically relevant AR-Vs (AR-V3, AR-V7 and AR-V9) in different stages of disease, especially with respect to clinical utility in PC patients undergoing AR targeted agent (ARTA) treatment. METHODS: AR-FL and AR-V levels were analyzed in PC and non-PC cell lines upon artificial increase of AR pre-mRNA using either drug treatment or AR gene activation. Furthermore, expression of AR-FL and AR-Vs was determined in PC specimen at distinct stages of disease (primary (n = 10) and metastatic tissues (n = 20), liquid biopsy samples (n = 422), mCRPC liquid biopsy samples of n = 96 patients starting novel treatment). Finally, baseline AR-FL and AR-V status was correlated with clinical outcome in a defined cohort of n = 65 mCRPC patients undergoing ARTA treatment. RESULTS: We revealed rising levels of AR-FL accompanied with appearance and increase of AR-Vs in dependence of elevated AR pre-mRNA levels. We also noticed increase in AR-FL and AR-V levels throughout disease progression. AR-V expression was always associated with high AR-FL levels without any sample being solely AR-V positive. In patients undergoing ARTA treatment, AR-FL did show prognostic, yet not predictive validity. Additionally, we observed a substantial clinical response to ARTA treatment even in AR-V positive patients. Accordingly, multivariate analysis did not demonstrate independent significance of AR-Vs in neither predictive nor prognostic clinical utility. CONCLUSION: We demonstrate a correlation between AR-FL and AR-V expression during PC progression; with AR-V expression being a side-effect of elevated AR pre-mRNA levels. Clinically, AR-V positivity relies on high levels of AR-FL, making cells still vulnerable to ARTA treatment, as demonstrated by AR-FL and AR-V positive patients responding to ARTA treatment. Thus, AR-FL and AR-V might be considered as a prognostic, yet not predictive biomarker in mCRPC patients.

Expression of nectin-4 in papillary renal cell carcinoma.

BACKGROUND: Nectin-4 contributes to tumor proliferation, lymphangiogenesis and angiogenesis in malignant tumors and is an emerging target in tumor therapy. In renal cell carcinoma (RCC) VEGF-directed tyrosine kinase inhibitors and checkpoint inhibitors are currently treatments of choice. Enfortumab vedotin-ejf (EV) is an antibody drug conjugate that targets Nectin-4. The aim of our study was to investigate the expression of Nectin-4 in a large cohort of papillary RCC specimens. PATIENTS AND METHODS: Specimens were derived from the PANZAR consortium (Erlangen, Heidelberg, Herne, Homburg, Mainz, Mannheim, Marburg, Muenster, LMU Munich, TU Munich, and Regensburg). Clinical data and tissue samples from n = 190 and n = 107 patients with type 1 and 2 pRCC, respectively, were available. Expression of Nectin-4 was determined by immunohistochemistry (IHC). RESULTS: In total, Nectin-4 staining was moderately or strongly positive in of 92 (48.4%) of type 1 and 39 (36.4%) type 2 of pRCC cases. No associations between Nectin-4 expression and age at diagnosis, gender, grading, and TNM stage was found. 5 year overall survival rate was not statistically different in patients with Nectin-4 negative versus Nectin-4 positive tumors for the overall cohort and the pRCC type 2 subgroup, but higher in patient with Nectin-4 positive pRCC type 1 tumors compared to Nectin-4 negative tumors (81.3% vs. 67.8%, p = 0.042). CONCLUSION: Nectin-4 could not be confirmed as a prognostic marker in pRCC in general. Due to its high abundance on pRCC specimens Nectin-4 is an interesting target for therapeutical approaches e.g. with EV. Clinical trials are warranted to elucidate its role in the pRCC treatment landscape.

The Prognostic Impact of PD-L2 in Papillary Renal-Cell Carcinoma.

INTRODUCTION: Programmed death-1 ligand (PD-L1) has been often studied in different types of renal-cell carcinoma (RCC). For example, in clear-cell renal carcinoma it is well established that programmed death-1 receptor and PD-L1 are important prognostic markers. In contrast, the role of programmed death-2 ligand (PD-L2) as prognostic marker remains unclear. The aim of this study was to evaluate if PD-L2 expression could play a role as a prognostic marker for papillary RCC (pRCC). METHODS: The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of PD-L2 was determined by immunohistochemistry. In total, PD-L2 staining was evaluable in 185 of 240 type 1 and 99 of 128 type 2 pRCC cases. RESULTS: PD-L2 staining was positive in 67 (36.2%) of type 1 and in 31 (31.3%) of type 2 pRCC specimens. The prevalence of PD-L2+ cells was significantly higher in high-grade type 1 tumors (p = 0.019) and in type 2 patients with metastasis (p = 0.002). Kaplan-Meier analysis disclosed significant differences in 5-year overall survival (OS) for patients with PD-L2- compared to PD-L2+ in pRCC type 1 of 88.4% compared to 73.6% (p = 0.039) and type 2 of 78.8% compared to 39.1% % (p < 0.001). However, multivariate analysis did not identify the presence of PD-L2+ cells neither in type 1 nor type 2 pRCC as an independent predictor of poor OS. DISCUSSION/CONCLUSION: PD-L2 expression did not qualify as an independent prognostic marker in pRCC. Future studies will have to determine whether anti-PD-L2-targeted treatment may play a role in pRCC and expression can potentially serve as a predictive marker for these therapeutic approaches.

Expression of Prostate-specific Membrane Antigen (PSMA) in Papillary Renal Cell Carcinoma - Overview and Report on a Large Multicenter Cohort.

Prostate specific membrane antigen (PSMA) is an emerging diagnostic and therapeutic target in prostate cancer. 68Ga-PSMA-labeled hybrid imaging is used for the detection of prostate primary tumors and metastases. Therapeutic applications such as Lutetium-177 PSMA radionuclide therapy or bispecific antibodies that target PSMA are currently under investigation within clinical trials. The expression of PSMA, however, is not specific to prostate-tissue. It has been described in the neovascular endothelium of different types of cancer such as breast cancer, and clear cell renal cell carcinoma (ccRCC). The aim of this study was to analyze PSMA expression in papillary RCC (pRCC) type 1 and type 2, the most common non-ccRCC subtypes, and to evaluate the potential of PSMA-targeted imaging and treatment in pRCC. Formalin-fixed, paraffin-embedded tissue samples of primary tumors were analyzed for PSMA expression by immunohistochemistry. Out of n=374 pRCC specimens from the multicenter PANZAR consortium, n=197 pRCC type 1 and n=110 type 2 specimens were eligible for analysis and correlated with clinical data. In pRCC type 1 PSMA staining was positive in 4 of 197 (2.0%) samples whereas none (0/110) of the pRCC type 2 samples were positive for PSMA in this large cohort of pRCC patients. No significant PSMA expression was detected in pRCC. Reflecting current clinical evaluation of PMSA expression in RCC do not encourage further analysis in papillary subtypes.

The prognostic potential of alkaline phosphatase and lactic acid dehydrogenase in bmCRPC patients without significant PSA response under enzalutamide.

BACKGROUND: In patients with bone metastatic castration-resistant prostate cancer (bmCRPC) on systemic treatment, it is difficult to differentiate between continuous rise of prostate specific antigen (PSA) representing progression, and PSA-surge, which is followed by clinical response or stable disease. The purpose of this study was to evaluate the prognostic value of dynamic changes of alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels as a predictor of clinical efficacy or therapeutic resistance of patients who do not show a sufficient initial PSA decline of ≥50% from baseline during early therapy with Enzalutamide. METHODS: Forty-eight men with bmCRPC on Enzalutamide 07/2010-09/2019 with initially rising PSA were analyzed. We monitored PSA, LDH and ALP at week 0, 2, 4, and every 4 weeks thereafter and analyzed the correlation between ALP rising at 12 weeks with or without LDH-normalization and the association with survival. For this we used Kaplan Meier analysis and uni- and multivariate cox-regression models. RESULTS: In Kaplan-Meier analysis, ALP rising at 12 weeks with or without LDH-normalization was associated with significantly worse median progression-free survival (PFS) of 3 months vs. 5 months (Log rank P = 0.02) and 3 months vs. 5 months (P = 0.01), respectively and overall survival (OS) with 8 months vs. 15 months (P = 0.02) and 8 months vs. 17 months (P < 0.01). In univariate analysis of PFS, ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization and application of Enzalutamide after chemotherapy showed a statistically significant association towards shorter PFS (hazard ratio (HR): 0.51, P = 0.04; HR: 0.48, P = 0.03; HR: 0.48, P = 0.03). Worse OS was significantly associated with ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization, and application of Enzalutamide after chemotherapy (HR: 0.47, P = 0.02; HR: 0.36, P < 0.01; HR: 0.31, P < 0.01). In multivariate analysis only the application of Enzalutamide after chemotherapy remained an independent prognostic factor for worse OS (HR: 0.36, P = 0.01). CONCLUSIONS: Dynamic changes of ALP (non-rise) and LDH (normalization) under therapy with Enzalutamide may be associated with clinical benefit, better PFS, and OS in patients with bmCRPC who do not show a PSA decline.

The prognostic impact of Claudin 6 in papillary renal cell carcinoma.

BACKGROUND: Claudins are promising biomarkers for diagnosis and prognosis or targets for treatment. They play a major role in signal transduction and are important in nearly all aspects of tumorigenesis. Claudin 6 is a member of the claudin family and is part of the tight junction molecule. It is reactivated in several cancer types and serves as prognostic marker in, for example, gastric, breast or non small cell lung cancer. The prognostic role of Claudin 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), is still unclear. PATIENTS AND METHODS: The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Claudin 6 was determined by immunohistochemistry. RESULTS: In total, Claudin 6 staining was positive in 55 of 240 type 1 and 30 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed an overall survival of 84% for Claudin 6- compared to 78% for Claudin 6 + in pRCC type 1 tumors (p = 0.449, log-rank) and 68% for Claudin 6- compared to 65.4% for Claudin 6 + in pRCC type 2 tumors (p = 0.364, log-rank). CONCLUSION: In this study, claudin 6 expression showed no significant association regarding overall survival (OS) and therefore did not qualify as a prognostic marker in pRCC. Future studies will have to determine, whether Claudin 6 plays a prognostic role in other RCC entities. In addition, the function of Claudin 6 as a predictive marker for therapeutic approaches has to be evaluated in future studies.

cMET: a prognostic marker in papillary renal cell carcinoma?

The tyrosine-protein kinase c-Met plays a decisive role in numerous cellular processes, as a proto-oncogene that supports aggressive tumor behavior. It is still unknown whether c-Met could be relevant for prognosis of papillary RCC (pRCC). Specimen collection was a collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from 197 and 110 patients with type 1 and 2 pRCC, respectively. Expression of cMET was determined by immunohistochemistry. In total, cMET staining was evaluable in of 97 of 197 type 1 and 63 of 110 type 2 pRCC cases. Five-year overall survival revealed no significant difference in dependence of cMET positivity (cMET- vs. cMET+: pRCC type 1: 84.8% vs. 80.3%, respectively [p = 0.303, log-rank]; type 2: 71.4% vs. 64.4%, respectively [p = 0.239, log-rank]). Interestingly, the subgroup analyses showed a significant difference for cMET expression in T stage and metastases of the pRCC type 2 (p = 0.014, p = 0.022, chi-square). The cMET-positive type 2 collective developed more metastases than the cMET-negative cohort (pRCC type 2 M+: cMET-: 2 [4.3%] vs. cMET+: 12 [19%]). cMET expression did not qualify as a prognostic marker in pRCC for overall survival.

ALP bouncing and LDH normalization in bone metastatic castration-resistant prostate cancer patients under therapy with Enzalutamide: an exploratory analysis.

BACKGROUND: In bone metastatic castration-resistant prostate cancer (bmCRPC) treated with Enzalutamide commonly used prostate-specific antigen (PSA) can be misleading since initial PSA-flares may occur. In other therapies, bouncing of alkaline phosphatase (ALP-bouncing) was shown to be a promising surrogate for survival outcome. Low lactate dehydrogenase (LDH) is usually associated with better outcome. We evaluated the prognostic ability of ALP-bouncing, LDH, PSA, and the combination of these markers after initiation of Enzalutamide. METHODS: Eighty-nine patients with bmCRPC and dynamic changes of PSA, LDH and ALP were analyzed. ALP-bouncing, an increase after therapy start followed by a decline below baseline during the first 8 weeks, LDH-normalization and PSA-decline were analyzed regarding their association with survival using Kaplan-Meier analyses and uni- and multivariate (UV and MV) Cox-regression models. RESULTS: In Kaplan-Meier analysis a PSA-decline >50%, LDH-normalization and ALP-bouncing were associated with longer median progression-free survival (PFS) with 7 [95% confidence interval (CI): 4.2-9.8] vs. 3 (2.3-3.7) months for PSA-decline (log-rank P<0.01), 6 (4.1-8) vs. 2 (1.2-2.8) for LDH-normalization (P<0.01) and 8 (0-16.3) vs. 3 (1.9-4.1) for ALP-bouncing (P=0.01). Analysis of overall survival (OS) showed similar, not for all parameters significant, results with 17 (11.7-22.3) vs. 12 (7.0-17.1) months for PSA (P=0.35), 17 (13.2-20.8) vs. 7 (5.8-8.2) for LDH-normalization (P<0.01) and 19 (7.9-30.1) vs. 12 (7.7-16.3) for ALP-bouncing (P=0.32). In UV analysis, ALP-bouncing [hazard ratio (HR): 0.5 (0.3-1.0); P=0.02], PSA-decline >50% [HR: 0.5 (0.3-0.7); P<0.01] and LDH-normalization [HR: 0.4 (0.2-0.6); P<0.01] were significantly associated with longer PFS. For OS, LDH-normalization significantly prognosticated longer survival [HR: 0.4 (0.2-0.6); P<0.01]. In MV analysis, LDH-normalization was associated with a trend towards better OS [HR: 0.5 (0.2-1.1); P=0.09]. Comparing ALP-bouncing, LDH-normalization and PSA-decline with a PSA-decline alone, Kaplan-Meier analysis showed significantly longer PFS [11 (0.2-21.8) vs. 4 (0-8.6); P=0.01] and OS [20 (17.7-22.3) vs. 8 (0.3-15.7); P=0.02] in favor of the group presenting with the beneficial dynamics of all three markers. In UV analysis, the presence of favorable changes in the three markers was significantly associated with longer PFS [HR: 0.2 (0.1-0.7); P<0.01] and OS [HR: 0.3 (0.1-0.8); P=0.02]. CONCLUSIONS: ALP-bouncing and LDH-normalization may add to identification of bmCRPC-patients with favorable prognosis under Enzalutamide.

Assessment of prognosis by established prognosis scores and physicians' judgement in mRCC patients: an analysis of the STAR-TOR registry.

BACKGROUND: Temsirolimus is a mTOR inhibitor approved for the first-line treatment of advanced or metastatic renal cell carcinoma (a/mRCC) with poor prognosis. In treatment of a/mRCC several prognostic scoring systems are used. We assessed the prognostic value of these scores in a large temsirolimus treated cohort and compared the results with the physician's prognosis. METHODS: A German multicenter registry (STAR-TOR) for a/mRCC patients (NCT00700258) was established to evaluate the efficacy and safety of temsirolimus 25 mg weekly in a routine clinical setting. These prospective data were systematically analyzed and followed-up by an independent clinical research organization to compare established prognostic scores (MSKCC, IMDC and Hudes) with the risk assessment by treating physicians based on their medical expertise and match them with survival outcomes. RESULTS: This interim analysis included 547 patients between 02/2008 and 05/2015 in 87 centers. Either prognostic tool resulted in significant and clinically meaningful differentiation between good, intermediate and poor prognosis. However, physician's prognosis identified more patients with good prognosis (9.1% vs. 1.3%). In patients with good physician's prognosis and intermediate prognosis by MSKCC, overall survival was nearly doubled compared to consensual intermediate prognosis (26.6 vs. 13.6 months), albeit without reaching statistical significance (P=0.09). For poor prognosis assessed by the physician, MSKCC performed statistically better for differentiation between poor and intermediate prognosis with a median overall survival of 10.3 vs. 5.5 months (P<0.01). CONCLUSIONS: Physician's prognosis may be able to identify a subset of patients treated with temsirolimus with good prognosis when MSKCC-determines intermediate prognosis while the MSKCC score could identify patients which were falsely placed in the poor risk group by physicians.

CTLA4 promoter hypomethylation is a negative prognostic biomarker at initial diagnosis but predicts response and favorable outcome to anti-PD-1 based immunotherapy in clear cell renal cell carcinoma.

BACKGROUND: In metastatic clear cell renal cell carcinoma (ccRCC), different combination therapies, each including anti-PD-1 immune checkpoint blockade (ICB), are applied as first-line treatment. Robust predictive biomarkers for rational upfront therapy decisions are lacking, although they are urgently needed. Recently, we showed that CTLA4 promoter methylation predicts response to ICB in melanoma. Here, we aimed to investigate CTLA4 methylation in ccRCC and its utility to serve as a predictive biomarker for anti-PD-1 based ICB in metastatic ccRCC. METHODS: CTLA4 methylation was analyzed with regard to transcriptional gene activity (mRNA expression), intratumoral immune cell composition, and clinical course in two ccRCC cohorts obtained from The Cancer Genome Atlas (TCGA cohort, n=533) and the University Hospital Bonn (UHB Non-ICB Cohort, n=116). In addition, CTLA4 methylation as well as CD8+ T cell infiltrates and PD-L1 expression were evaluated in pre-treatment samples from a multicenter cohort (RCC-ICB Cohort, n=71). Patients included in the RCC-ICB Cohort were treated with either first line anti-PD-1 based combination therapy (n=25) or monotherapy post-tyrosine kinase inhibition in second line or later. Analyses were performed with regard to treatment response according to RECIST, progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) following treatment initiation. RESULTS: CTLA4 promoter hypomethylation was significantly correlated with CTLA4 mRNA expression, lymphocyte infiltration, and poor OS in both primary ccRCC cohorts (TCGA: HR 0.30 (95% CI 0.18 to 0.49), p<0.001; UHB Non-ICB: HR 0.35 (95% CI 0.16 to 0.75), p=0.007). In contrast, CTLA4 promoter hypomethylation predicted response and, accordingly, favorable outcomes (PFS and OS) in patients with ICB-treated ccRCC, overcompensating the negative prognostic value of CTLA4 hypomethylation at initial diagnosis. Moreover, in multivariable Cox regression, CTLA4 promoter hypomethylation remained an independent predictor of improved outcome in ICB-treated ccRCC after co-adjustment of the International Metastatic Renal Cell Carcinoma Database Consortium score (HR 3.00 (95% CI 1.47 to 6.28), p=0.003). CONCLUSIONS: Our study suggests CTLA4 methylation as a powerful predictive biomarker for immunotherapy response in metastatic RCC.

Characterization of PD-1 and PD-L1 Expression in Papillary Renal Cell Carcinoma: Results of a Large Multicenter Study.

BACKGROUND: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) play a decisive role as prognostic markers in clear-cell renal cell carcinoma (RCC). To date, the role of PD-1/PD-L1 as a prognostic marker in papillary RCC (pRCC) remains scarce. PATIENTS AND METHODS: Patients' sample collection was a joint collaboration of the nationwide PANZAR consortium - a multicenter study. Medical history and tumor specimens were collected from 245 and 129 patients with pRCC types 1 and 2, respectively. Expression of PD-1 and PD-L1 was determined by immunohistochemistry in pRCC and tumor-infiltrating mononuclear cells. RESULTS: Of 374 pRCC specimens, 204 type 1 and 97 type 2 were evaluable for PD-1 and PD-L1 expression analysis. In total, PD-1 and PD-L1 expression were found in 8 (4.9%) of 162 and 12 (7.2%) of 166 evaluable pRCC type 1 specimens. Comparably, PD-1 and PD-L1 expression were found in 2 (2.4%) of 83 and 5 (6.2%) of 81 evaluable pRCC type 2 specimens. Hardly any clinically relevant associations between PD-1 and PD-L1 positivity and clinicopathologic or clinical courses were observed, neither in pRCC type 1 nor type 2. CONCLUSION: The analysis of a large pRCC cohort from a multicenter consortium revealed no impact of PD-1/PD-L1 expression on prognosis in patients with pRCC with predominantly limited disease status, neither for type 1 nor type 2. However, the impact of PD-1 and PD-L1 in more advanced pRCC disease needs further elucidation.

A prognostic score for overall survival in patients treated with abiraterone in the pre- and post-chemotherapy setting.

Background: Therapy resistance remains a serious dilemma in metastatic castration-resistant prostate cancer (mCRPC) with primary or secondary resistance frequently occurring against any given therapy. Available prognostic models for Abiraterone Acetate (AA) are specifically designed for either pre- or post-chemotherapy settings and mostly based on trial datasets not necessarily reflecting real-life. Results: A score of 0-2 (low-risk) is associated with an OS-probability of 80.0% (95%CI: 71.3-90.6) and 50.5% (95%CI: 38.7-66.0) after 1 and 2 years while a score of 3-4 (high risk) is associated with an OS-probability of 35.3% (95%CI: 22.3-55.8) and 5.7% (95%CI: 1.5-21.8), respectively. The bootstrapping survival analysis of the scoring-system revealed a median c-index of 0.80 (IQR: 0.79-0.82). Material and Methods: We developed a scoring-system using four real-life parameters 117 mCRPC patients treated with AA either pre- or post-chemotherapy. These parameters were evaluated using COX regression analysis. The scoring-system consists of binary-categorized parameters; when any of these exceeds the given cut-off, one point is added up to a final score ranging between 0-4 points. The final score was stratified by a median threshold of 2 into low- and high-risk groups. We evaluated the discriminative ability of our scoring-system using concordance probability (C-index) and Kaplan-Meier-analysis and applied a 100-times bootstrap for survival analysis. Conclusions: Our study introduces a novel prognostic scoring-system for OS of real-life mCRPC patients receiving AA treatment irrespective of the line of therapy. The scoring-system is simple and can be easily utilized based on PSA and LDH values, neutrophil to lymphocyte ratio, and ECOG performance status.

[Radical prostatectomy through the years]. / Die radikale Prostatektomie im Wandel der Zeit.

The operative aspect of radical prostatectomy has changed dramatically in the past 200 years as significant technological advances have been made, particularly during the past 50 years. The work of Dr. Walsh in the late 1970 s and early 1980 s led to a significant reduction in surgical morbidity and is considered an important milestone of radical prostatectomy, as is the introduction of minimally-invasive (robotic-assisted) surgical techniques. Yet there is no absolute gold standard regarding surgical approaches. Innovative tools, e. g. the addition of "augmented reality", are currently under investigation. This review article for the anniversary issue of "Der Urologe" aims to cover the milestones of the evolution of this "signature" surgery in the field of urology.