Rucaparib or Physician's Choice in Metastatic Prostate Cancer.

BACKGROUND: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study. METHODS: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review. RESULTS: Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea. CONCLUSIONS: The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).

Adjunctive Surgery Is Often Without Oncological Benefit at Time of Postchemotherapy Retroperitoneal Lymph Node Dissection.

PURPOSE: Postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for advanced nonseminomatous germ cell tumors (GCTs) aims to resect all remaining metastatic tissue. Resection of adjacent visceral or vascular organs is commonly performed for complete resection. Resection of organs harboring only necrosis results in relevant overtreatment. The study aimed to describe the frequency of metastatic involvement of resected organs with teratoma or viable cancer and to analyze perioperative complications and relapse-free survival. MATERIALS AND METHODS: In a 2-center study, we reviewed a cohort of 1204 patients who underwent PC-RPLND between 2008 and 2021 and identified 242 (20%) cases of adjunctive surgery during PC-RPLND. We analyzed the removed adjacent structures and the pathohistological presence of GCT elements in the resected organs: viable GCT, teratoma, or necrosis/fibrosis. Surgery-associated complications were reported according to the Clavien-Dindo classification. RESULTS: Viable GCT, teratoma, and necrosis were present in 54 (22%), 94 (39%), and 94 (39%), respectively, of all patients with adjunctive resection of adjacent organs. Vascular resections or reconstructions (n = 112; viable: 23%, teratoma: 41%, necrosis: 36%) were performed most frequently, followed by nephrectomies (n = 77; viable: 29%, teratoma: 39%, necrosis: 33%). Perioperative complications of grade ≥ IIIa occurred in 6.6% of all patients, with no difference between the viable GCT and teratoma/necrosis groups (P = .1). A total of 76 patients have been followed without a relapse for at least 36 months. Median follow-up of the whole cohort was 22 months (quartile 7 and 48). Patients with viable GCT/teratoma in the resected specimens had a significantly increased risk of recurrence by 5 years compared to patients with only necrosis (19% vs 59% vs 81%, P < .001). CONCLUSIONS: This study shows that 33% to 40% of all resections of adjacent organs do not harbor teratoma or viable GCT. This highlights the need for better patient selection for these complex patients.

Cost-effectiveness analysis of different treatment modalities in BCG-unresponsive NMIBC.

OBJECTIVE: Radical cystectomy (RC) is the standard of care (SOC) in BCG-unresponsive NMIBC and is associated with a significant health-related quality-of-life burden. Recently, promising results have been published on Gemcitabine/Docetaxel, Pembrolizumab, and Hyperthermic Intravesical Chemotherapy (HIVEC) as salvage therapy options trying to increase the rate of bladder preservation. Here, we performed a Cost-Effectiveness-Analysis of those treatment modalities. PATIENTS AND METHODS: We developed a Markov model from a payer's perspective drawing on clinical data of single-arm trials testing intravesical gemcitabine/docetaxel and pembrolizumab in BCG-unresponsive NMIBC, as well as clinical data from patients receiving hyperthermic intravesical chemotherapy HIVEC (n = 29) as intravesical salvage chemotherapy at our uro-oncological centre in Cologne. Costs were simulated utilising a non-commercial diagnosis-related groups grouper, utilities were derived from comparable cost-effectiveness studies. We used a Monte Carlo simulation to identify the optimal treatment, comparing the incremental cost effectiveness ratios (ICERs) at a willingness-to-pay threshold of €50 000 (euro)/quality-adjusted life year (QALY). RESULTS: Over a horizon of 10 years, gemcitabine/docetaxel, HIVEC, and pembrolizumab were associated with costs of €48 353, €64 438, and €204 580, as well as a gain of QALYs of 6.16, 6.48, and 6.00, resulting in an ICER of €26 482, €42 567, and €184 533 respectively, in comparison to RC with total costs of €21 871 and a gain of QALYs of 5.01. Monte Carlo simulation identified HIVEC as the treatment of choice under assumption of a WTP of <€50 000. CONCLUSION: Considering a WTP of <€50 000/QALY, gemcitabine/docetaxel and HIVEC are highly cost-effective therapeutic options in BCG-refractory NMIBC, while RC remains the cheapest option. At its current price, pembrolizumab would only be cost-effective assuming a price reduction of at least 70%.

Trophoblast cell surface antigen-2: a promising new biomarker and potential therapeutic target in penile squamous cell carcinoma.

OBJECTIVE: To evaluate the potential utility of antibody-drug conjugates targeting trophoblast cell surface antigen-2 (TROP-2) in patients with primary penile squamous cell carcinoma (PSCC), patients with recurrence (REC cohort), and patient-matched distant metastases (MET cohort), and to assess the potential use of TROP-2 as a predictive non-invasive biomarker in PSCC. METHODS: A cohort comprising a PRIM (n = 37), REC (n = 5) and MET subcohort (n = 7), with MET including lymph node and lung metastases, was analysed using quantitative real-time PCR, ELISA and immunohistochemical staining with evaluation of H-score. RESULTS: TROP-2 mRNA and serum protein levels were significantly increased in primary and recurrent PSCC compared to cancer-free controls (both P < 0.001). Immunohistochemical analysis revealed that most of the PRIM cohort (n = 34/37, median H-score 260, interquartile range [IQR] 210-300), as well as all patients in the REC (median [IQR] H-score 200 [165-290]) and MET cohorts (median [IQR] H-score 280 [260-300]) exhibited moderate to strong membranous TROP-2 expression. Additionally, The H-score (membranous TROP-2 expression) was positively correlated with TROP-2 mRNA (ρ = 0.69, P < 0.0001, R2 = 0.70) and protein levels (ρ = 0.86, P < 0.0001, R2 = 0.59), indicating its potential as a non-invasive biomarker in PSCC. CONCLUSION: In summary, our results support further studies on TROP-2 as a diagnostic and therapeutic target in primary, recurrent and metastatic PSCC.

Salvage vesiculectomy for local prostate cancer recurrence: surgical technique and early post-operative outcomes.

PURPOSE: Isolated recurrence in remnants of the seminal vesicles (SV) after treatment of primary prostate cancer (PCa) has become a more frequent entity with the widespread use of more sensitive next-generation imaging modalities. Salvage vesiculectomy is hypothesized to be a worthwhile management option in these patients. The primary goal of this study is to describe the surgical technique of this new treatment option. Secondary outcomes are peri- and post-operative complications and early oncological outcomes. METHODS: Retrospective multicenter study, including 108 patients with solitary recurrence in the SV treated between January 2009 and June 2022, was performed. Patients with local recurrences outside the SVs or with metastatic disease were excluded. Both SVs were resected using a robot-assisted or an open approach. In selected cases, a concomitant lymphadenectomy was performed. RESULTS: Overall, 31 patients (29%) reported complications, all but one grade 1 to 3 on the Clavien-Dindo Scale. A median PSA decrease of 2.07 ng/ml (IQR: 0.80-4.33, p < 0.001), translating into a median PSA reduction of 92% (IQR: 59-98%) was observed. At a median follow-up of 14 months, freedom from secondary treatment was 54%. Lymphadenectomy had a significant influence on PSA reduction (p = 0.018). CONCLUSION: Salvage vesiculectomy for PCa recurrence limited to the SV is a safe procedure with excellent PSA response and is a potential curative treatment in a subset of patients. A concomitant lymphadenectomy can best be performed in all patients that did not underwent one at primary treatment.

Importance of magnetic resonance imaging and prostate-specific membrane antigen PET-CT in patients treated with salvage radical prostatectomy for radiorecurrent prostate cancer.

BACKGROUND: Accurate staging and identification of optimal candidates for local salvage therapy, such as salvage radical prostatectomy (SRP), is necessary to ensure optimal care in patients with radiorecurrent prostate cancer (PCa). We aimed to analyze performance of magnetic resonance imaging (MRI) and prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)/computed tomography (CT) for predicting pathologic nonorgan confined disease (pT3) and lymph node involvement (pN+) in patients treated with SRP for radiorecurrent PCa. METHODS: We retrospectively reviewed the institutional database to identify patients who underwent MRI or 68 Ga-PSMA-PET/CT before SRP for radiorecurrent PCa. The diagnostic estimates of MRI and PSMA-PET/CT for pT3 and pN+, were calculated. RESULTS: We identified 113 patients with radiorecurrent PCa who underwent preoperative MRI followed by SRP; 53 had preoperative 68 Ga-PSMA-PET/CT. For the detection of pT3 disease, the overall accuracy of MRI was 70% (95% confidence interval [CI] 61-78), sensitivity 40% (95% CI 26-55) and specificity 94% (95% CI 85-98); PSMA-PET/CT had slightly higher accuracy of 77% (95% CI 64-88), and higher sensitivity of 90% (95% CI 68-99), but lower specificity of 70% (95% CI 51-84). For pN+ disease, MRI had poor sensitivity of 14% (95% CI 3-36), specificity of 50 (95% CI 39-61) and total accuracy of 43% (95% CI 34-53); PSMA-PET/CT had an accuracy of 85% (95% CI 72-93), sensitivity of 27% (95% CI 6-61), and specificity of 100% (95% CI 92-100). CONCLUSION: In patients with radiorecurrent PCa, both, MRI, and 68 Ga-PSMA PET/CT are valuable tools for the pre-SRP staging and should be integrated into the standard workup. For lymph node metastases, 68 Ga-PSMA PET/CT is a strong rule-in test with nearly perfect specificity; in contrast MRI had a low accuracy for lymph node metastases.

Differentially expressed messenger RNA/proteins can distinguish teratoma from necrosis in postchemotherapy retroperitoneal lymph node dissection tissue.

BACKGROUND: Before postchemotherapy retroperitoneal lymph node dissection (pcRPLND), in patients with metastasized germ cell tumors (GCTs), those harboring necrosis (NEC) cannot be distinguished from those who have teratoma (TER), resulting in relevant overtreatment, whereas microRNA-371a-3p may be predictive for viable GCT. The purpose of this study was to explore messenger RNA (mRNA) and proteins to distinguish TER from NEC in pcRPLND tissue. METHODS: The discovery cohort consisted in total of 48 patients, including 16 each with TER, viable GCT, and NEC. Representative areas were microdissected. A NanoString panel and proteomics were used to analyze 770 genes and >5000 proteins. The most significantly and differentially expressed combination of both parameters, mRNA and its associated protein, between TER and NEC was validated using immunohistochemistry (IHC) in an independent validation cohort comprising 66 patients who were not part of the discovery cohort. RESULTS: The authors observed that anterior gradient protein 2 homolog (AGR2) and keratin, type I cytoskeletal 19 (KRT19) were significantly differentially expressed in TER versus NEC in mRNA and protein analyses (proteomics). The technical validation using IHC was successful in the same patients. These proteins were further validated by IHC in the independent patient cohort and exhibited significantly higher levels in TER versus NEC (p < .0001; area under the curve, 1.0; sensitivity and specificity, 100% each). CONCLUSIONS: The current study demonstrated that KRT19 and AGR2 mRNA and protein are overexpressed in TER versus NEC in pcRPLND tissue and might serve as a future diagnostic target to detect TER, for instance, by functional imaging, to avoid overtreatment. PLAIN LANGUAGE SUMMARY: The proteins and the corresponding genes called AGR2 and KRT19 can differentiate between teratoma and necrosis in remaining tumor masses after chemotherapy in patients who have metastasized testicular cancer. This may be a way to improve presurgical diagnostics and to reduce the current overtreatment of patients with necrosis only, who could be treated sufficiently by surveillance.

Outcomes of relapsed clinical stage I versus de novo metastatic testicular cancer patients: an analysis of the IGCCCG Update database.

BACKGROUND: Active surveillance after orchiectomy is the preferred management in clinical stage I (CSI) germ-cell tumours (GCT) associated with a 15 to 30% relapse rate. PATIENTS AND METHODS: In the IGCCCG Update database, we compared the outcomes of gonadal disseminated GCT relapsing from initial CSI to outcomes of patients with de novo metastatic GCT. RESULTS: A total of 1014 seminoma (Sem) [298 (29.4%) relapsed from CSI, 716 (70.6%) de novo] and 3103 non-seminoma (NSem) [626 (20.2%) relapsed from CSI, 2477 (79.8%) de novo] were identified. Among Sem, no statistically significant differences in PFS and OS were found between patients relapsing from CSI and de novo metastatic disease [5-year progression-free survival (5y-PFS) 87.6% versus 88.5%; 5-year overall survival (5y-OS) 93.2% versus 96.1%). Among NSem, PFS and OS were higher overall in relapsing CSI patients (5y-PFS 84.6% versus 80.0%; 5y-OS 93.3% versus 88.7%), but there were no differences within the same IGCCCG prognostic groups (HR = 0.89; 95% CI: 0.70-1.12). Relapses in the intermediate or poor prognostic groups occurred in 11/298 (4%) Sem and 112/626 (18%) NSem. CONCLUSION: Relapsing CSI GCT patients expect similar survival compared to de novo metastatic patients of the same ICCCCG prognostic group. Intermediate and poor prognosis relapses from initial CSI expose patients to unnecessary toxicity from more intensive treatments.

Diagnostic Accuracy of Clinical Lymph Node Staging for Upper Tract Urothelial Cancer Patients: A Multicenter, Retrospective, Observational Study.

PURPOSE: Treatment options for the management of upper tract urothelial cancer are based on accurate staging. However, the performance of conventional cross-sectional imaging for clinical lymph node staging (N-staging) remains poorly investigated. This study aims to evaluate the diagnostic accuracy of conventional cross-sectional imaging for upper tract urothelial cancer N-staging. MATERIALS AND METHODS: This study was a multicenter, retrospective, observational study. We included 865 nonmetastatic (M0) upper tract urothelial cancer patients treated with curative intended surgery and lymph node dissection who had been staged with conventional cross-sectional imaging before surgery. We compared clinical (c) and pathological (p) N-staging results to evaluate the concordance of node-positive (N+) and node-negative (N0) disease and calculate cN-staging's diagnostic accuracy. RESULTS: Conventional cross-sectional imaging categorized 750 patients cN0 and 115 cN+. Lymph node dissection categorized 641 patients pN0 and 224 pN+. The cN-stage was pathologically downstaged in 6.8% of patients, upstaged in 19%, and found concordant in 74%. The sensitivity and specificity of cN-staging were 25% (95% CI 20; 31) and 91% (95% CI 88; 93). Positive and negative likelihood ratios were 2.7 (95% CI 2.0; 3.8) and 0.83 (95% CI 0.76; 0.89). The area under the receiver operating characteristics curve (0.58, 95% CI 0.55; 0.61) revealed low diagnostic accuracy. CONCLUSIONS: Conventional cross-sectional imaging had low sensitivity in detecting upper tract urothelial cancer pN+ disease. However, cN+ increased the likelihood of pN+ by almost threefold. Thus, conventional cross-sectional imaging is a rule-in but not a rule-out test. Lymph node dissection should remain the standard during extirpative upper tract urothelial cancer surgery to obtain accurate N-staging. cN+ could be a strong argument for early systemic treatment.

Concomitant vs Staged Therapeutic Inguinal Lymphadenectomy in Clinically Node Positive Penile Squamous Cell Carcinoma: Does It Make a Difference?

PURPOSE: Inguinal lymph node dissection within 3 months of primary tumor resection in penile cancer has been associated with longer recurrence-free and cancer-specific survival. However, the optimal timing and effect of lymphadenectomy performed concurrently at the time of primary lesion management on oncologic outcomes in clinically lymph node positive penile squamous cell carcinoma remains unknown. MATERIALS AND METHODS: An international, multicenter cohort of 966 penile cancer cases was queried for penile squamous cell carcinoma management after the year 2000, clinically lymph node positive status, and performance of penile surgery and inguinal lymph node dissection. Cohorts were stratified as concomitant if inguinal lymph node dissection and penile surgery occurred on the same date or staged when inguinal lymph node dissection was performed after penile resection. Rates and patterns of penile squamous cell carcinoma recurrence were reported. Distant recurrence-free, cancer-specific, and overall survival were estimated using Kaplan-Meier analyses and groups compared with log-rank testing. RESULTS: Of 253 contemporary men with clinically lymph node positive penile squamous cell carcinoma, 96 (38%) underwent concomitant inguinal lymph node dissection and 157 (62%) had inguinal lymph node dissection performed in a staged manner. Penile cancer was most likely to recur distantly (19%) followed by in the groin (14%) or pelvis (5%). There were no differences in distant recurrence-free, cancer-specific, or overall survival between management strategies. Multivariable analysis adjusting for stage, treatment center, and perioperative chemoradiation also demonstrated no recurrence-free, cancer-specific, or overall survival benefit between management strategies. CONCLUSIONS: Inguinal lymph node dissection performed concurrently with excision of the penile tumor for clinically node positive penile squamous cell carcinoma is not associated with differences in recurrence-free, cancer-specific, or overall survival compared to staged lymph node dissection.

Toxicity of dose-escalated radiotherapy up to 84 Gy for prostate cancer.

PURPOSE: The outcome of radiotherapy (RT) for prostate cancer (PCA) depends on the delivered dose. While the evidence for dose-escalated RT up to 80 gray (Gy) is well established, there have been only few studies examining dose escalation above 80 Gy. We initiated the present study to assess the safety of dose escalation up to 84 Gy. METHODS: In our retrospective analysis, we included patients who received dose-escalated RT for PCA at our institution between 2016 and 2021. We evaluated acute genitourinary (GU) and gastrointestinal (GI) toxicity as well as late GU and GI toxicity. RESULTS: A total of 86 patients could be evaluated, of whom 24 patients had received 80 Gy and 62 patients 84 Gy (35 without pelvic and 27 with pelvic radiotherapy). Regarding acute toxicities, no > grade 2 adverse events occurred. Acute GU/GI toxicity of grade 2 occurred in 12.5%/12.5% of patients treated with 80 Gy, in 25.7%/14.3% of patients treated with 84 Gy to the prostate only, and in 51.9%/12.9% of patients treated with 84 Gy and the pelvis included. Late GU/GI toxicity of grade ≥ 2 occurred in 4.2%/8.3% of patients treated with 80 Gy, in 7.1%/3.6% of patients treated with 84 Gy prostate only, and in 18.2%/0% of patients treated with 84 Gy pelvis included (log-rank test p = 0.358). CONCLUSION: We demonstrated that dose-escalated RT for PCA up to 84 Gy is feasible and safe without a significant increase in acute toxicity. Further follow-up is needed to assess late toxicity and survival.

German specialists treating testicular cancer follow different guidelines with resulting inconsistency in assessment of retroperitoneal lymph-node metastasis: clinical implications and possible corrective measures.

BACKGROUND: Testicular germ cell tumors (GCTs) are aggressive but highly curable tumors. To avoid over/undertreatment, reliable clinical staging of retroperitoneal lymph-node metastasis is necessary. Current clinical guidelines, in their different versions, lack specific recommendations on how to measure lymph-node metastasis. OBJECTIVE: We aimed to assess the practice patterns of German institutions frequently treating testicular cancer for measuring retroperitoneal lymph-node size. METHODS: An 8-item survey was distributed among German university hospitals and members of the German Testicular Cancer Study Group. RESULTS: In the group of urologists, 54.7% assessed retroperitoneal lymph nodes depending on their short-axis diameter (SAD) (33.3% in any plane, 21.4% in the axial plane), while 45.3% used long-axis diameter (LAD) for the assessment (42.9% in any plane, 2.4% in the axial plane). Moreover, the oncologists mainly assessed lymph-node size based on the SAD (71.4%). Specifically, 42.9% of oncologists assessed the SAD in any plane, while 28.5% measured this dimension in the axial plane. Only 28.6% of oncologists considered the LAD (14.3% in any plane, 14.3% in the axial plane). None of the oncologists and 11.9% of the urologists (n = 5) always performed an MRI for the initial assessment, while for follow-up imaging, the use increased to 36.5% of oncologists and 31% of urologists. Furthermore, only 17% of the urologists, and no oncologists, calculated lymph-node volume in their assessment (p = 0.224). CONCLUSION: Clear and consistent measurement instructions are urgently needed to be present in all guidelines across different specialistic fields involved in testicular cancer management.

Cytoreductive radical prostatectomy: who benefits from the surgical approach?

PURPOSE OF REVIEW: Local treatment in oligometastatic prostate cancer patients is associated with improved survival. Nevertheless, in term of surgery, cytoreductive radical prostatectomy has no level of evidence 1 and is an individual treatment approach. We reviewed the recent literature to highlight parameters for selecting patients for a surgical approach. RECENT FINDINGS: Retrospective data on oncologic outcome for cytoreductive prostatectomy are confirmed. We identified several parameters that help to select patients for surgery. Patients with a favorable prostate-specific antigen (PSA) decline after androgen deprivation therapy (ADT) have excellent oncologic long-term control. Circulating tumor cells (CTC's) are frequently analyzed in more advanced prostate cancer. In case of C-reactive protein (CRP) at least a longer interval to develop castration resistant prostate cancer (CRPC) is shown in case of low CTC count at time of surgery. Nutrition status analyzed as the hemoglobin, albumin, lymphocyte, and platelet (HALP)-score is of significant value in demonstrating an effect of CRP. SUMMARY: From retrospective findings we have several clinical and basic science parameters to select patients for CRP. PSA at the time of surgery is the most frequently analyzed one, whereas CTC and HALP-score are promising tools to select patients that need to be validated.

Synthesis and evaluation of radioiodinated estrogens for diagnosis and therapy of male urogenital tumours.

The preparation of 24 estrogens, their estrogen receptor (ER) affinity and studies of radioiodinated estrogen binding to ER-positive male bladder tumor cells (HTB9) are described. The estrogens with the highest affinity were selected using fluorescence anisotropy assays. A 2,2,2-trifluoroethyl group at the 11ß-position caused particularly promising affinity. (Radio)iodination was performed on the 17α-vinyl group. Binding studies on HTB9 cells revealed picomolar affinities of radioconjugates 19 and 31, indicating promising ability for targeting of urogenital tumors.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

BACKGROUND: Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma (RCC) has changed fundamentally. Today, combined therapies from different drug categories have a firm place in a complex first-line therapy. Due to the large number of drugs available, it is necessary to identify the most effective therapies, whilst considering their side effects and impact on quality of life (QoL). OBJECTIVES: To evaluate and compare the benefits and harms of first-line therapies for adults with advanced RCC, and to produce a clinically relevant ranking of therapies. Secondary objectives were to maintain the currency of the evidence by conducting continuous update searches, using a living systematic review approach, and to incorporate data from clinical study reports (CSRs). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings and relevant trial registries up until 9 February 2022. We searched several data platforms to identify CSRs. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating at least one targeted therapy or immunotherapy for first-line treatment of adults with advanced RCC. We excluded trials evaluating only interleukin-2 versus interferon-alpha as well as trials with an adjuvant treatment setting. We also excluded trials with adults who received prior systemic anticancer therapy if more than 10% of participants were previously treated, or if data for untreated participants were not separately extractable. DATA COLLECTION AND ANALYSIS: All necessary review steps (i.e. screening and study selection, data extraction, risk of bias and certainty assessments) were conducted independently by at least two review authors. Our outcomes were overall survival (OS), QoL, serious adverse events (SAEs), progression-free survival (PFS), adverse events (AEs), the number of participants who discontinued study treatment due to an AE, and the time to initiation of first subsequent therapy. Where possible, analyses were conducted for the different risk groups (favourable, intermediate, poor) according to the International Metastatic Renal-Cell Carcinoma Database Consortium Score (IMDC) or the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Our main comparator was sunitinib (SUN). A hazard ratio (HR) or risk ratio (RR) lower than 1.0 is in favour of the experimental arm. MAIN RESULTS: We included 36 RCTs and 15,177 participants (11,061 males and 4116 females). Risk of bias was predominantly judged as being 'high' or 'some concerns' across most trials and outcomes. This was mainly due to a lack of information about the randomisation process, the blinding of outcome assessors, and methods for outcome measurements and analyses. Additionally, study protocols and statistical analysis plans were rarely available. Here we present the results for our primary outcomes OS, QoL, and SAEs, and for all risk groups combined for contemporary treatments: pembrolizumab + axitinib (PEM+AXI), avelumab + axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), CAB, and pazopanib (PAZ). Results per risk group and results for our secondary outcomes are reported in the summary of findings tables and in the full text of this review. The evidence on other treatments and comparisons can also be found in the full text. Overall survival (OS) Across risk groups, PEM+AXI (HR 0.73, 95% confidence interval (CI) 0.50 to 1.07, moderate certainty) and NIV+IPI (HR 0.69, 95% CI 0.69 to 1.00, moderate certainty) probably improve OS, compared to SUN, respectively. LEN+PEM may improve OS (HR 0.66, 95% CI 0.42 to 1.03, low certainty), compared to SUN. There is probably little or no difference in OS between PAZ and SUN (HR 0.91, 95% CI 0.64 to 1.32, moderate certainty), and we are uncertain whether CAB improves OS when compared to SUN (HR 0.84, 95% CI 0.43 to 1.64, very low certainty). The median survival is 28 months when treated with SUN. Survival may improve to 43 months with LEN+PEM, and probably improves to: 41 months with NIV+IPI, 39 months with PEM+AXI, and 31 months with PAZ. We are uncertain whether survival improves to 34 months with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. Quality of life (QoL) One RCT measured QoL using FACIT-F (score range 0 to 52; higher scores mean better QoL) and reported that the mean post-score was 9.00 points higher (9.86 lower to 27.86 higher, very low certainty) with PAZ than with SUN. Comparison data were not available for PEM+AXI, AVE+AXI, NIV+CAB, LEN+PEM, NIV+IPI, and CAB. Serious adverse events (SAEs) Across risk groups, PEM+AXI probably increases slightly the risk for SAEs (RR 1.29, 95% CI 0.90 to 1.85, moderate certainty) compared to SUN. LEN+PEM (RR 1.52, 95% CI 1.06 to 2.19, moderate certainty) and NIV+IPI (RR 1.40, 95% CI 1.00 to 1.97, moderate certainty) probably increase the risk for SAEs, compared to SUN, respectively. There is probably little or no difference in the risk for SAEs between PAZ and SUN (RR 0.99, 95% CI 0.75 to 1.31, moderate certainty). We are uncertain whether CAB reduces or increases the risk for SAEs (RR 0.92, 95% CI 0.60 to 1.43, very low certainty) when compared to SUN. People have a mean risk of 40% for experiencing SAEs when treated with SUN. The risk increases probably to: 61% with LEN+PEM, 57% with NIV+IPI, and 52% with PEM+AXI. It probably remains at 40% with PAZ. We are uncertain whether the risk reduces to 37% with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. AUTHORS' CONCLUSIONS: Findings concerning the main treatments of interest comes from direct evidence of one trial only, thus results should be interpreted with caution. More trials are needed where these interventions and combinations are compared head-to-head, rather than just to SUN. Moreover, assessing the effect of immunotherapies and targeted therapies on different subgroups is essential and studies should focus on assessing and reporting relevant subgroup data. The evidence in this review mostly applies to advanced clear cell RCC.

Comparison of oral morbidity and mid-term efficacy of anterior urethroplasty using an autologous tissue-engineered graft (MukoCell®) versus native oral mucosa graft.

OBJECTIVE: Our study aimed to compare surgical success rate (SR) and oral morbidity of augmentation urethroplasty for anterior urethral strictures using autologous tissue-engineered oral mucosa graft (TEOMG) named MukoCell® versus native oral mucosa graft (NOMG). METHODS: We conducted a single-institution observational study on patients undergoing TEOMG and NOMG urethroplasty for anterior urethral strictures >2 cm in length from January 2016 to July 2020. SR, oral morbidity, and potential risk factors of recurrence were compared between groups were analyzed. A decrease of maximum uroflow rate < 15 mL/s or further instrumentation was considered a failure. RESULTS: Overall, TEOMG (n = 77) and NOMG (n = 76) groups had comparable SR (68.8% vs. 78.9%, p = 0.155) after a median follow-up of 52 (interquartile range [IQR] 45-60) months for TEOMG and 53.5 (IQR 43-58) months for NOMG. Subgroup analysis revealed comparable SR according to surgical technique, stricture localization, and length. Only following repetitive urethral dilatations, TEOMG achieved lower SR (31.3% vs. 81.3%, p = 0.003). Surgical time was significantly shorter by TEOMG use (median 104 vs. 182 min, p < 0.001). Oral morbidity and the associated "burden" in patients' quality of life were significantly less at 3 weeks following the biopsy required for TEOMG manufacture, compared to NOMG harvesting and totally absent at 6 and 12 months postoperatively. CONCLUSIONS: The SR of TEOMG urethroplasty appeared to be comparable to NOMG at a mid-term follow-up but taking into account the uneven distribution of stricture site and the surgical techniques used in both groups. Surgical time was significantly shortened, since no intraoperative mucosa harvesting was required, and oral complications were diminished through the preoperative biopsy for MukoCell® manufacture.

Distinct distribution patterns of exercise-induced natural killer cell mobilization into the circulation and tumor tissue of patients with prostate cancer.

The mobilization and activation of natural killer (NK) cells have been proposed as key mechanisms promoting anti-oncogenic effects of physical exercise. Although mouse models have proven that physical exercise recruits NK cells to tumor tissue and inhibits tumor growth, this preclinical finding has not been transferred to the clinical setting yet. In this first-in-human study, we found that physical exercise mobilizes and redistributes NK cells, especially those with a cytotoxic phenotype, in line with preclinical models. However, physical exercise did not increase NK cell tumor infiltrates. Future studies should carefully distinguish between acute and chronic exercise modalities and should be encouraged to investigate more immune-responsive tumor entities.

Transcriptome analysis reveals upregulation of immune response pathways at the invasive tumour front of metastatic seminoma germ cell tumours.

BACKGROUND: Testicular germ cell tumours (TGCTs) have a high metastasis rate. However, the mechanisms related to their invasion, progression and metastasis are unclear. Therefore, we investigated gene expression changes that might be linked to metastasis in seminomatous testicular germ cell tumour (STGCT) patients. METHODS: Defined areas [invasive tumour front (TF) and tumour centre (TC)] of non-metastatic (with surveillance and recurrence-free follow-up >2 years) and metastatic STGCTs were collected separately using laser capture microdissection. The expression of 760 genes related to tumour progression and metastasis was analysed using nCounter technology and validated with quantitative real-time PCR and enzyme-linked immunosorbent assay. RESULTS: Distinct gene expression patterns were observed in metastatic and non-metastatic seminomas with respect to both the TF and TC. Comprehensive pathway analysis showed enrichment of genes related to tumour functions such as inflammation, angiogenesis and metabolism at the TF compared to the TC. Remarkably, prominent inflammatory and cancer-related pathways, such as interleukin-6 (IL-6) signalling, integrin signalling and nuclear factor-κB signalling, were significantly upregulated in the TF of metastatic vs non-metastatic tumours. CONCLUSIONS: IL-6 signalling was the most significantly upregulated pathway in metastatic vs non-metastatic tumours and therefore could constitute a therapeutic target for future personalised therapy. In addition, this is the first study showing intra- and inter-tumour heterogeneity in STGCT.

Contemporary options and future perspectives: three examples highlighting the challenges in testicular cancer imaging.

PURPOSE: One of the main issues in testicular germ cell tumors (TGCTs) management is to reduce the necessary amount of treatment to achieve cure. Excess treatment burden may arise from late diagnosis of the primary as well as from false positive or negative staging results. Correct imaging is of paramount importance for successful management of TGCT. The aim of this review is to point out the current state of the art as well as innovative developments in TGCT imaging on the basis of three common challenging clinical situations. METHODS: A selective literature search was performed in PubMed, Medline as well as in recent conference proceedings. RESULTS: Regarding small testicular lesions, recent studies using elastography, contrast-enhanced ultrasound or magnetic resonance imaging (MRI) showed promising data for differentiation between benign and malignant histology. For borderline enlarged lymph nodes FDG-PET-CT performance is unsatisfactory, promising new techniques as lymphotropic nanoparticle-enhanced MRI is the subject of research in this field. Regarding the assessment of postchemotherapeutic residual masses, the use of conventional computerized tomography (CT) together with serum tumor markers is still the standard of care. To avoid overtreatment in this setting, new imaging modalities like diffusion-weighted MRI and radiomics are currently under investigation. For follow-up of clinical stage I TGCTs, the use of MRI is non-inferior to CT while omitting radiation exposure. CONCLUSION: Further efforts should be made to refine imaging for TGCT patients, which is of high relevance for the guidance of treatment decisions as well as the associated treatment burdens and oncological outcomes.

Peritoneal carcinosis in male germ cell tumor patients: a registry study compiled by the German Testicular Cancer Study Group (GTCSG).

PURPOSE: To report on the clinical characteristics, outcome, and frequency of peritoneal carcinosis (PC) in patients with advanced germ cell tumors (GCT), a multicenter registry analysis was carried out. METHODS: A multicenter registry analysis was conducted by the German Testicular Cancer Study Group (GTCSG) with international collaborators. Data was collected and analyzed retrospectively. Patients were eligible for inclusion if PC was diagnosed either by radiologic or histopathologic finding during the course of disease. Descriptive and explorative statistical analysis was carried out with cancer-specific survival (CSS) as primary study endpoint. RESULTS: Collaborators from ten GCT expert centers identified 28 GCT (0.77%) patients with PC after screening approximately 3767 GCT patient files and one case was contributed from a cancer registry request. Patients were diagnosed from 1997 to 2019 at a median age of 37 years (interquartile range, 13). Two patients (7%) presented with stage I and 27 patients (93%) with synchronous metastatic disease at first diagnosis. The primary histology was seminoma in seven (27%) and non-seminoma in 21 patients (72%). PC was detected after a median of 15.3 months from primary diagnosis (range 0-177) and two consecutive treatment lines (range 0-5), respectively. The median CSS from the time of detection of PC was 10.5 months (95%Confidence Interval 0.47-1.30) associated with an overall 2-year CSS rate of 30%. CONCLUSION: PC represents a rare tumor manifestation in GCT patients and was primarily associated with the occurrence of advanced cisplatin-refractory disease conferring to a dismal prognosis.