First-Line Immune Combination Therapies for Nonclear Cell Versus Clear Cell Metastatic Renal Cell Carcinoma: Real-World Multicenter Data From Germany.

INTRODUCTION: The aim was to compare treatment outcomes of clear cell metastatic renal cell carcinoma (ccmRCC) versus non-ccmRCC (nccmRCC) patients who received first-line immune combination therapies. MATERIALS AND METHODS: Within our retrospective multi-institutional consecutive database of eight tertiary-care centers, we identified mRCC patients treated with first-line immune combination therapies between 11/2017 and 12/2022. Using log-rank analysis and multivariable Cox regression, we tested for differences in overall survival (OS) and progression-free survival (PFS) of nccmRCC versus ccmRCC patients. Covariables consisted of age at diagnosis, sex, International Metastatic Renal Cell Carcinoma Database Consortium risk groups, Eastern Cooperative Oncology Group status, and sarcomatoid feature. RESULTS: Of 289 study patients, 39 (13%) patients harbored nccmRCC. Median OS was 37 months versus not reached for ccmRCC versus nccmRCC patients (P = .6). Median PFS was 13 versus 15 months (P = .9). Multivariable Cox regression models did not identify nccmRCC as an independent predictor of higher overall mortality in mRCC patients (hazard ratio [HR]: 1.23; P = .6) or a higher progression rate (HR: 1.0; P = 1.0). CONCLUSION: In our real-world multi-institutional study, no differences in OS and PFS between ccmRCC and nccmRCC patients receiving first-line immune combination treatment were observed, even after adjustment for important patient and tumor characteristics. More prospective trials in nccmRCC patients are needed.

Urology consultants versus large language models: Potentials and hazards for medical advice in urology.

Background: Current interest surrounding large language models (LLMs) will lead to an increase in their use for medical advice. Although LLMs offer huge potential, they also pose potential misinformation hazards. Objective: This study evaluates three LLMs answering urology-themed clinical case-based questions by comparing the quality of answers to those provided by urology consultants. Methods: Forty-five case-based questions were answered by consultants and LLMs (ChatGPT 3.5, ChatGPT 4, Bard). Answers were blindly rated using a six-step Likert scale by four consultants in the categories: 'medical adequacy', 'conciseness', 'coherence' and 'comprehensibility'. Possible misinformation hazards were identified; a modified Turing test was included, and the character count was matched. Results: Higher ratings in every category were recorded for the consultants. LLMs' overall performance in language-focused categories (coherence and comprehensibility) was relatively high. Medical adequacy was significantly poorer compared with the consultants. Possible misinformation hazards were identified in 2.8% to 18.9% of answers generated by LLMs compared with <1% of consultant's answers. Poorer conciseness rates and a higher character count were provided by LLMs. Among individual LLMs, ChatGPT 4 performed best in medical accuracy (p < 0.0001) and coherence (p = 0.001), whereas Bard received the lowest scores. Generated responses were accurately associated with their source with 98% accuracy in LLMs and 99% with consultants. Conclusions: The quality of consultant answers was superior to LLMs in all categories. High semantic scores for LLM answers were found; however, the lack of medical accuracy led to potential misinformation hazards from LLM 'consultations'. Further investigations are necessary for new generations.

Bellmunt risk score as a survival predictor in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: The prognosis of metastatic castration-resistant prostate cancer (mCRPC) is influenced by numerous individual factors. Despite various proposed prognostic models, the clinical application of these remains limited, probably due to complexity. Our study aimed to evaluate the predictive value of the Bellmunt risk score, which is well-known for urothelial carcinoma and easily assessed, in mCRPC patients. METHODS: The Bellmunt risk score was calculated from three risk factors (Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥1, serum hemoglobin <10 g/dL, presence of liver metastases) in 125 patients who received first-line mCRPC treatment between 2005 and 2023. In addition, a modified score was established (one point each for hemoglobin <10 g/dL and the presence of liver metastases added to the ECOG PS). Associations with overall survival (OS) under first- and second-line therapy were tested using Cox regression analyzes, log-rank tests, concordance index (C-index) and time-dependent receiver operating characteristic. RESULTS: There is a significant correlation between the level of the Bellmunt risk score and shorter OS (hazard ratio: 3.23, 95% confidence interval: 2.06-5.05; log-rank p < 0.001; C-index: 0.724). The semi-quantitative modified risk score showed even better prognostic discrimination (log-rank p < 0.001, C-index: 0.764). The score and its dynamics were also predictive in the second-line setting (log-rank p < 0.001 and = 0.01; C-index: 0.742 and 0.595). CONCLUSIONS: The Bellmunt risk score is easy to assess and provides useful prognostic information in mCRPC, and can support physicians in their treatment decisions.

NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer.

PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

Elucidating the need for prostate cancer risk calculators in conjunction with mpMRI in initial risk assessment before prostate biopsy at a tertiary prostate cancer center.

OBJECTIVE: Utilizing personalized risk assessment for clinically significant prostate cancer (csPCa) incorporating multiparametric magnetic resonance imaging (mpMRI) reduces biopsies and overdiagnosis. We validated both multi- and univariate risk models in biopsy-naïve men, with and without the inclusion of mpMRI data for csPCa detection. METHODS: N = 565 men underwent mpMRI-targeted prostate biopsy, and the diagnostic performance of risk calculators (RCs), mpMRI alone, and clinical measures were compared using receiver operating characteristic curve (ROC) analysis and decision curve analysis (DCA). Subgroups were stratified based on mpMRI findings and quality. RESULTS: csPCa was detected in 56.3%. PI-RADS score achieved the highest area under the curve (AUC) when comparing univariate risk models (AUC 0.82, p < 0.001). Multivariate RCs showed only marginal improvement in csPCa detection compared to PI-RADS score alone, with just one of four RCs showing significant superiority. In mpMRI-negative cases, the non-MRI-based RC performed best (AUC 0.80, p = 0.016), with the potential to spare biopsies for 23%. PSA-density and multivariate RCs demonstrated comparable performance for PI-RADS 3 constellation (AUC 0.65 vs. 0.60-0.65, p > 0.5; saved biopsies 16%). In men with suspicious mpMRI, both mpMRI-based RCs and the PI-RADS score predicted csPCa excellently (AUC 0.82-0.79 vs. 0.80, p > 0.05), highlighting superior performance compared to non-MRI-based models (all p < 0.002). Quality-assured imaging consistently improved csPCa risk stratification across all subgroups. CONCLUSION: In tertiary centers serving a high-risk population, high-quality mpMRI provides a simple yet effective way to assess the risk of csPCa. Using multivariate RCs reduces multiple biopsies, especially in mpMRI-negative and PI-RADS 3 constellation.

Key learnings from concordant systematic biopsies in prostate-specific membrane antigen positron emission tomography/computed tomography-guided prostate biopsies: Enhancing targeting accuracy.

BACKGROUND: Prostate cancer (PCa) diagnosis and staging have evolved with the advent of 68Ga-Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT). This study investigates the role of complementary systematic biopsies (SB) during PSMA-PET/CT-guided targeted prostate biopsies (PET-TB) for PCa detection, grading, and distribution. We address the uncertainty surrounding the necessity of SB in conjunction with PET-TB. METHODS: We analyzed PCa grading and distribution in 30 men who underwent PET-TB and SB because of contraindication to magnetic resonance imaging or high clinical suspicion of PCa. Tumor distribution was assessed in relation to the PET-highlighted lesions. Standardized reporting schemes, encompassing SUVmax, PRIMARY score, and miTNM classification, were evaluated. RESULTS: 80% of patients were diagnosed with PCa, with 70% classified as clinically significant (csPCa). SB detected more csPCa cases than PET-TB, but the differences were not statistically significant. Discordant results were observed in 25% of cases, where SB outperformed PET-TB. Spatial analysis revealed that tumor-bearing cores from SB were often located in close proximity to the PET-highlighted region. Reporting schemes showed potential for csPCa detection with significantly increased SUVmax in csPCA patients. Subsequent follow-up data underscored the importance of SB in precise PCa grading and staging. CONCLUSIONS: While PET-TB can simplify prostate biopsy and reduce invasiveness by core number, SB cannot be omitted yet due to potential PET-TB targeting errors. Factors such as limited spatial resolution and fusion inaccuracies contribute to the need for SB. Standardization in reporting schemes currently cannot compensate for targeting errors highlighting the need for refinement.

Delayed symptomatic renal arteriovenous fistula in a 24 years old male following renal biopsy.

We report a case of a 24-year-old male with a history of kidney biopsy at young age due to chronic renal dysfunction and challenging hypertension, who presented with flank pain and hematuria. Initial imaging suggested renal pelvis enlargement, but MRI revealed a massive renal arteriovenous malformation (AVM). Angiographic embolization was abandoned due to extensive effluent flow, followed by successful surgical resection preserving healthy kidney tissue. This case underscores the importance of considering renal AVMs in the differential diagnosis of young patients with gross hematuria or refractory hypertension to prevent complications and improve patient outcomes.

Ring Finger Protein 34 (RNF34) as a Prognostic Biomarker for Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Ring finger proteins play pivotal roles in diverse cellular processes and are implicated in contribution to cancer. Ring finger protein 34 (RNF34) has antiapoptotic and oncogenic properties. RNF34 is upregulated during carcinogenesis and tumor progression in the colorectal adenoma-carcinoma sequence and was already described to mediate chemoresistance. In clear cell renal cell carcinoma (ccRCC), however, the role and expression patterns of RNF34 are unknown. METHODS: First, we investigated the association of RNF34 mRNA expression with clinicopathological parameters and survival using data obtained from The Cancer Genome Atlas (TCGA) ccRCC cohort (N = 533). To assess RNA34 protein expression, we performed immunohistochemical (IHC) staining of an established ccRCC cohort (University of Bonn) in a tissue microarray (TMA) format. This validation cohort contains 109 primary ccRCC samples. IHC data were associated with clinicopathological parameters and overall survival (Kaplan-Meier analysis). Adjustment for covariables was done using the Cox regression model. RESULTS: RNF34 expression is correlated with adverse clinicopathological parameters. Survival analysis revealed an association between RNF34 expression and shortened survival. Cox regression analysis confirmed RNF34 expression as an independent prognostic parameter. CONCLUSION: Our study provides evidence for RNF34 as a prognostic biomarker in ccRCC and points toward a major role of this protein in renal cell carcinoma carcinogenesis.

Expression of the microtubule-associated protein 2 (MAP2) as a potential independent prognostic marker in prostate cancer.

PURPOSE: Investigation of Microtubuli-associated Protein 2 (MAP2) expression and its clinical relevance in prostate cancer. MATERIAL AND METHODS: MAP2 expression was immunohistochemically analysed on radical prostatectomy specimens using whole block sections (n = 107) and tissue microarrays (TMA; n = 310). The staining intensity was evaluated for carcinoma, benign tissue and prostatic intraepithelial neoplasia. Expression data were correlated with clinicopathological parameters and biochemical recurrence-free survival. Additionally, MAP2 protein expression was quantitatively analysed in the serum of histologically confirmed prostate carcinoma patients and the control group using a commercial enzyme-linked immunosorbent assay. RESULTS: MAP2 staining was significantly stronger in neoplastic tissue than in non-neoplastic prostatic glands, both in whole block sections (p < 0.01) and in TMA sections (p < 0.05). TMA data revealed significantly stronger MAP2 staining in high-grade tumors. Survival analysis showed a significant correlation between strong MAP2 staining in carcinoma and shortened biochemical recurrence-free survival after prostatectomy (p < 0.001). Multivariate Cox regression analysis confirmed MAP2 as an independent predictor for an unfavourable course. Mean MAP2 serum levels for non-PCA vs. PCA patients differed significantly (non-PCA = 164.7 pg/ml vs. PCA = 242.5 pg/ml, p < 0.001). CONCLUSION: The present data support MAP2 as a novel biomarker in PCA specimens. MAP2 is correlated with tumor grade and MAP2 high-expressing PCA is associated with an increased risk of biochemical recurrence after radical prostatectomy. Future studies are necessary to evaluate MAP2 as a valuable immunohistochemical biomarker in preoperative PCA diagnostic procedures, in particular with regard to treatment modalities.

Integration of on-treatment modified Glasgow prognostic score (mGPS) to improve imaging-based prediction of outcomes in patients with non-small cell lung cancer on immune checkpoint inhibition.

INTRODUCTION: A large number of patients with non-small cell lung cancer (NSCLC) on immune checkpoint inhibition (ICI) achieve stable disease (SD) as the best overall response, which is associated with heterogeneous outcomes. In this context, complementary biomarkers that improve outcome prediction are needed. We have recently demonstrated that measuring the on-treatment modified Glasgow prognostic score (mGPS), which is based on the two serum markers C-reactive protein (CRP) and albumin, can improve outcome prediction complementary to radiological staging in metastatic renal cell carcinoma. However, this concept has not been assessed for patients with NSCLC on ICI. METHODS: We assessed the prognostic and predictive value of on-treatment mGPS at week six in patients with NSCLC treated with atezolizumab or docetaxel in the phase 3 OAK trial (NCT02008227) comprising n = 750 patients and validated the findings in the phase 2 BIRCH (NCT02031458, n = 560). RESULTS: On-treatment mGPS assessed at week six demonstrated valuable prognostic information (Hazard Ratio (HR) for mGPS low-risk vs intermediate risk 2.34 (95 % CI 1.76-3.11, p < 0.001) and vs high risk 3.56, (95 % CI 2.57-4.91, p < 0.001) in the atezolizumab-treated subgroup. On-treatment mGPS predicted overall survival more accurately than imaging using RECIST criteria (concordance index: on-treatment mGPS 0.646 (95 % CI 0.615-0.677) vs RECIST 0.606 (95 % CI 0.575-0.637)). On-treatment mGPS provides additional prognostic information to imaging-assessed treatment response at first staging, especially for the patient subgroup with SD. These findings were validated in the BIRCH trial. CONCLUSIONS: We highlight the novel concept of integrating on-treatment mGPS for improved outcome prediction in conjunction with radiological imaging for patients with NSCLC on ICI.

Hypermethylated SHOX2 in circulating cell-free DNA post renal cell carcinoma surgery as TNM-independent biomarker for recurrence risk.

INTRODUCTION: Adjuvant immune checkpoint inhibitor trials in renal cell carcinoma (RCC) call for improved recurrence risk stratification. Due to limitations of circulating tumor DNA (ctDNA) use in RCC, the use of hypermethylated SHOX2 gene (mSHOX2) in circulating cell-free DNA is explored as a surrogate marker for identifying high-risk patients after RCC surgery. METHODS: Liquid biopsies were collected post-surgery from 45 RCC patients (mean duration 4.3 days). Real-time polymerase chain reaction was used to analyze SHOX2 methylation in circulating cell-free DNA. Patients were categorized as mSHOX2 positive or negative by cut-off. Metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were assessed using Cox regression and Log-rank analyses (median follow-up time: 60 months). RESULTS: 17 patients were mSHOX2 positive, showing unfavorable OS/CSS (Log-rank P = 0.004 and 0.02) and nearly 6-fold higher recurrence risk (hazard ratio 5.89, 95% CI 1.46-23.8). Multivariable Cox analysis confirmed mSHOX2 as an independent recurrence risk factor, disregarding TNM-based stratification. CONCLUSIONS: mSHOX2 effectively identifies high-risk RCC patients post-surgery, indicating minimal residual disease. This easy to implement biomarker has potential for guiding of adjuvant therapy decisions.

Feasibility of Monitoring Response to Metastatic Prostate Cancer Treatment with a Methylation-Based Circulating Tumor DNA Approach.

BACKGROUND: Metastatic prostate cancer (mPCA) poses challenges in treatment response assessment, particularly in cases where prostate-specific antigen (PSA) levels do not reliably indicate a response. Liquid biopsy, focusing on circulating cell-free DNA (ccfDNA) methylation analysis as a proxy for circulating tumor DNA, offers a non-invasive and cost-effective approach. This study explores the potential of two methylation markers, short stature homeobox 2 (SHOX2) and Septin 9 (SEPT9), as on-mPCA-treatment biomarkers. METHODS: Plasma samples were collected from 11 mPCA patients undergoing various treatments. Quantitative assessment of hypermethylated SHOX2 (mSHOX2) and SEPT9 (mSEPT9) levels in ccfDNA was conducted through methylation-specific real-time PCR. Early and overall dynamics of PSA, mSHOX2, and mSEPT9 were analyzed. Statistical evaluation employed Wilcoxon tests. RESULTS: mSHOX2 demonstrated a significant decline post-treatment in patients with a radiographic treatment response as well as in an early treatment setting. mSEPT9 and PSA exhibited non-significant declines. In individual cases, biomarker dynamics revealed unique patterns compared to PSA. DISCUSSION: mSHOX2 and mSEPT9 exhibit dynamics on mPCA treatment. This proof-of-concept study lays the groundwork for further investigation into these markers as valuable additions to treatment response monitoring in mPCA. Further validation in larger cohorts is essential for establishing clinical utility.

Emotion-centered versus fact-centered medical information to alleviate pain and anxiety in prostate biopsy: A randomized trial.

BACKGROUND: To test the efficacy of emotion-centered (EC) versus fact-centered (FC) written medical information for prostate biopsy to alleviate pain and anxiety in a randomized controlled trial. METHODS: In a single-center, single-blinded study participants were randomized to receive FC or EC (DRKS00022361; 2020). In the EC, the focus was on possible stress reactions and stress-reducing strategies. Participants were asked to complete questionnaires on the day of MRI acquisition (T0) directly before (T1) and after the procedure (T2). The primary outcome measure was the assessment of worst pain in the last 2 h measured by the adapted brief pain inventory. Secondary outcome measures included state anxiety measured by the state-trait anxiety inventory and the subjective evaluation of the impact of the written medical information at T2. For statistical analysis, mixed models were calculated. RESULTS: Of 137 eligible patients, 108 (79%) could be recruited and were randomized. There was a significant effect for time for the outcome variables pain and anxiety. Regarding the comparison for the primary outcome variable worst pain there was a significantly lower increase from T1 to T2 after FC compared to EC (p < 0.004). The course of anxiety displayed no overall group differences. The FC was evaluated as significantly more helpful regarding stress, pain, and anxiety with moderate effect sizes. CONCLUSIONS: FC was favorable with regard to worst experienced pain, assuming that the brief introduction of emotional issues such as stress and coping in written information might be counterproductive particularly in men not used to these subjects.