Lights and Shadows of Bacillus Calmette-Guérin (BCG)-exposed and BCG-unresponsive Definitions: A Practical Overview.

According to the current definitions of recurrence of non-muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG), patients in the BCG-exposed and late relapse categories might benefit from further instillations. Patients with BCG-unresponsive disease could be included in clinical trials, but otherwise radical cystectomy is the preferred treatment. BCG-intolerant disease still represents an area of debate, with limited evidence regarding the best treatment for these patients.

Cut-offs for relapse detection in men with stage I testicular germ cell tumors during active surveillance within a prospective multicentre cohort study using either raw or housekeeper normalized miR-371a-3p serum levels.

PURPOSE: MiR-371a-3p represents a novel liquid biomarker that detects all histologies of germ-cell tumors (GCT) except teratoma. However, it is currently unclear whether miR-371a-3p results obtained directly from RT-PCR (raw Cq) or normalized for housekeeper genes and transformed into the relative quantity (RQ) value should be used and at what cut-off level. The purpose of this research was to evaluate, which values should be used, and a potential cut-off level for relapse-detection to inform subsequent studies. MATERIALS AND METHODS: We applied a CE-certified qRT-PCR test to measure miR-371a-3p at each follow-up visit during active surveillance in 34 men with stage I testicular GCT. MiR-371a-3p levels were calculated by the ΔΔ method. RESULTS: About 18 Patients had pure seminoma and 16 had mixed or nonseminomatous testicular GCT. Recurrences were detected in 10 patients and were correctly identified by both raw and housekeeper-normalized miR-371a-3p serum levels. The raw Cq, with a cut-off value of <28, resulted in only 1 false positive (3%), whereas RQ, with a cut-off value of >15, produced 6 false positive results (17%). Most of these false positive results normalized in subsequent measurements. The RQ approach detected recurrence in 1 patient 6 months earlier than the raw Cq approach. CONCLUSION: Our preliminary data suggest that this CE-certified assay, using previously suggested cut-off values, is a promising method for detecting disease recurrence, provided a confirmatory second test is conducted to identify false positive results. To avoid unnecessary scans or overtreatment, we are currently validating this assay and cut-offs in a prospective cohort study.

Observation With or Without Subsequent Salvage Therapy for Pathologically Node-positive Prostate Cancer With Negative Conventional Imaging: Results From a Large Multicenter Cohort.

Background and objective: More than 10% of patients with negative clinical metastatic status (cN0M0) on conventional imaging for prostate cancer (PCa) harbor lymph node involvement (pN+) at final pathology following radical prostatectomy (RP) and lymphadenectomy. Our aim was to assess outcomes of initial observation for cN0M0 pN+ PCa and identify prognostic factors that may help in clinical decision-making. Methods: We performed a retrospective multicenter study of patients with cN0M0 PCa on conventional imaging (computed tomography and/or magnetic resonance imaging, and a bone scan) who were found to have pN+ disease at RP between 2000 and 2021. Biochemical recurrence (BCR) and systemic progression/recurrence were the primary outcomes. Kaplan-Meier curves and Cox proportional hazards model were used for survival and multivariate analysis. Key findings and limitations: A total of 469 men were included in this retrospective multicenter trial. Median prostate-specific antigen (PSA) was 10.1 ng/ml (interquartile range [IQR] 6.6-18.0). Among these patients, 56% had grade group ≥4, 53.7% had stage ≥pT3b, 42.6% had positive margins, and 19.6% had PSA persistence. The median number of positive nodes and of nodes removed were 1 (IQR 1-3) and 20 (14-28), respectively. At median follow-up of 41 mo, 48.5% experienced BCR. The 5-yr BCR-free survival rate was 31.7% (95% confidence interval [CI] 26.33-37.1%). Salvage treatments were needed in 211 patients and included radiotherapy (RT; n = 53), RT + androgen deprivation therapy (ADT; n = 88), ADT alone (n = 68), and salvage lymphadenectomy (n = 2). The 5-yr estimated survival rates were 66.3% (95% CI 60.4-72.1) for metastasis-free survival, 97.7% (95% CI 95.5-99.8%) for cancer-specific survival, and 95.3% (95% CI 92.4-98.1%) for overall survival. On multivariable analysis, PSA persistence was an independent predictor of BCR (odds ratio [OR] 51.8, 95% CI 12.2-219.2), exit from observation (OR 8.5, 95% CI 4.4-16.5), and systemic progression (OR 3.0, 95% CI 1.771-4.971). Conclusions: Initial observation in the management of pN+ cN0M0 PCa is feasible and has excellent survival rates in the intermediate term. Patients with worse disease features, especially PSA persistence, have a higher likelihood of recurrence and progression and may be candidates for more aggressive upfront management. Patient summary: We investigated the value of initial observation for men with prostate cancer with negative scan findings for metastasis who were then found to have positive lymph nodes after surgery to remove the prostate. Our results show that initial observation is a good option for patients with less aggressive prostate cancer features.

First Indicator of Relapse in Testicular Cancer and Implications for Follow-up: Analysis of the Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS).

Background and objective: Follow-up for patients with testicular cancer should ensure early detection of relapses. Optimal schedules and minimum requirements for cross-sectional imaging are not clearly defined, and guideline recommendations differ. Our aim was to analyse the clinical impact of different imaging modalities for detection of relapse in a large prospective cohort (Swiss Austrian German Testicular Cancer Cohort Study, SAG TCCS). Methods: Patients with seminoma or nonseminoma were prospectively enrolled between January 2014 and February 2023 after initial treatment (n = 1175). Follow-up according to the study schedule was individualised for histology and disease stage. Only patients who had received primary treatment were considered. We analysed the total number of imaging modalities and scans identifying relapse and the timing of relapse. Key findings and limitations: We analysed data for 1006 patients (64% seminoma, 36% nonseminoma); 76% had stage I disease. Active surveillance was the most frequent management strategy (65%). Recurrence occurred in 82 patients, corresponding to a 5-yr relapse-free survival rate of 90.1% (95% confidence interval 87.7-92.1%). Median follow-up for patients without relapse was 38.4 mo (interquartile range 21.6-61.0). Cross-sectional imaging of the abdomen was the most important indicator of relapse 57%, abdominal CT accounting for 46% and MRI for 11%. Marker elevation indicated relapse in 24% of cases. Chest X-ray was the least useful modality, indicating relapse in just 2% of cases. Conclusions and clinical implications: On the basis of findings from our prospective register, we have adapted a follow-up schedules with an emphasis on abdominal imaging and a reduction in chest X-rays. This schedule might provide additional guidance for clinicians and will be prospectively evaluated as SAG TCCS continues to enrol patients. Patient summary: We analysed the value of different types of imaging scans for detection of relapse of testicular cancer. We used our findings to propose an optimum follow-up schedule for patients with testicular cancer.

Follow-up strategies after trimodal treatment for muscle-invasive bladder cancer: a systematic review.

PURPOSE: Optimal follow-up strategies following trimodal treatment for muscle invasive bladder cancer play a crucial role in detecting and managing relapse and side-effects. This article provides a comprehensive summary of the patterns and risk factors of relapse, functional outcomes, and follow-up protocols. METHODS: A systematic literature search on PubMed and review of current guidelines and institutional follow-up protocols after trimodal therapy were conducted. RESULTS: Out of 200 identified publications, 43 studies (28 retrospective, 15 prospective) were selected, encompassing 7447 patients (study sizes from 24 to 728 patients). Recurrence rates in the urinary bladder varied between 14-52%; 3-16% were muscle-invasive while 11-36% were non-muscle invasive. Nodal recurrence occurred at 13-16% and distant metastases at 15-35%. After 5 and 10 years of follow-up, around 60-85% and 45-75% of patients could preserve their bladder, respectively. Various prognostic risk factors associated with relapse and inferior survival were proposed, including higher disease stage (> c/pT2), presence of extensive/multifocal carcinoma in situ (CIS), hydronephrosis, multifocality, histological subtypes, incomplete transurethral resection of bladder tumor (TURBT) and incomplete response to radio-chemotherapy. The analyzed follow-up guidelines varied slightly in terms of the number, timing, and types of investigations, but overall, the recommendations were similar. CONCLUSION: Randomized prospective studies should focus on evaluating the impact of specific follow-up protocols on oncological and functional outcomes following trimodal treatment for muscle-invasive bladder cancer. It is crucial to evaluate personalized adaption of follow-up protocols based on established risk factors, as there is potential for improved patient outcomes and resource allocation.

Thromboprophylaxis during neoadjuvant chemotherapy for bladder cancer reduces thromboembolism and bleeding.

OBJECTIVES: To assess the risk of venous thromboembolic events (VTEs) and bleeding with or without thromboprophylaxis during neoadjuvant chemotherapy in bladder cancer patients scheduled for radical cystectomy. MATERIALS AND METHODS: We conducted a retrospective cohort study in 4886 patients with non-metastatic bladder cancer undergoing cystectomy across 28 centres in 13 countries between 1990 and 2021. Inverse probability weighting analyses were performed to estimate the effect of thromboprophylaxis on VTE and bleeding. RESULTS: In 147 patients (3%) VTEs were recorded within the first year. These occurred a median (interquartile range [IQR]) of 127 (82-198) days after bladder cancer diagnosis. Bleeding events occurred in 131 patients (3%) within the first year. These occurred a median (IQR) of 101 (83-171) days after cancer diagnosis. In inverse probability weighting analyses, compared to patients without thromboprophylaxis during chemotherapy, patients with thromboprophylaxis had not only a lower risk of VTE (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.12-0.81; P = 0.016) but also a lower bleeding risk (HR 0.03, 95% CI 0.09-0.12; P <0.0001). The retrospective nature of the study was its main limitation. CONCLUSIONS: In this retrospective analysis, the benefit of thromboprophylaxis during neoadjuvant chemotherapy before cystectomy is in line with data from randomised trials in other malignancies. Our data suggest thromboprophylaxis is protective against VTEs and should be the standard of care during neoadjuvant chemotherapy.

Oncological and Functional Outcomes of Penile Shaft Sparing Surgery for Localised Penile Cancer: A Systematic Review.

CONTEXT: Penile shaft sparing (PSS) surgery for localised penile cancer (PeCa) aims to balance oncological and functional outcomes. OBJECTIVE: To summarise the published evidence on different PSS approaches. EVIDENCE ACQUISITION: We performed a systematic review adhering to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The systematic search was performed on PubMed, EMBASE, and Scopus databases up to February 14, 2023. The inclusion criteria encompassed retrospective or prospective studies including patients ≥18 yr of age with localised PeCa treated with different PSS approaches, classified as laser ablation, circumcision, wide local excision, glansectomy with or without split skin graft, glans resurfacing, and mixed technique excision. The risk of bias was assessed using the Newcastle-Ottawa scale. A quantitative synthesis was not performed due to anticipated data heterogeneity and a lack of comparative studies. EVIDENCE SYNTHESIS: Out of 4343 articles identified, 47 met our inclusion criteria, including 10 847 patients. The year of publication ranged between 1983 and 2021. Nine studies were prospective case series, while the remaining studies were retrospective. No comparative studies were identified. Most of the cases included in these studies were Ta and T1. The oncological outcomes were good for all the approaches, with cancer-specific mortality ranging between 0% and 18%. Sexual and cosmetic outcomes, despite being under-reported, were good for all the approaches, with almost all patients being satisfied with their quality of life after surgery. The Newcastle and Ottawa scale revealed a high or severely high risk of bias in all the included studies. CONCLUSIONS: PSS approaches were safe and had good functional outcomes, considering however the overall low quality of the studies on this issue. PATIENT SUMMARY: The perioperative, function, and oncological outcomes of penile shaft sparing approaches are good. However, high-quality studies are needed to determine whether these approaches benefit patients with localised penile cancer.

Effect of Sex on the Oncological Outcomes in Response to Immunotherapy and Antibody-drug Conjugates in Patients with Urothelial and Kidney Cancer: A Systematic Review and a Network Meta-analysis.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) herald a transformative era in metastatic renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) treatment, amid acknowledged sex-based disparities in these cancers. We conducted a systematic review and network meta-analysis (NMA) to identify sex-specific differences in the efficacy of ICI/ADC monotherapy or combination therapies for RCC and TCC survival, in metastatic and adjuvant settings. METHODS: A systematic search was conducted up to October 2023 for English articles on ICIs and ADCs as systemic therapies (ICIs in first-line and adjuvant treatment for RCC, ICIs and ADCs in first- and second-line treatment for TCC). Randomised clinical trials were considered. The primary objective was overall survival (OS) of ICIs and ADCs between males and females. The secondary outcomes included progression-free survival, overall response rate, disease-free survival, and recurrence-free survival. Treatment efficacy was evaluated by sex via odds ratios (ORs) and confidence intervals compared with controls. Log ORs were used for creating a frequentist NMA. This meta-analysis was registered on PROSPERO (CRD42023468632). KEY FINDINGS AND LIMITATIONS: Eighteen articles met the inclusion criteria. Females had an advantage for RCC-adjuvant treatment for atezolizumab (log OR [SE] = -0.57 ± 0.25, p = 0.024) in OS. Males showed a survival advantage in TCC second-line treatment for ADC-Nectin 4 (log OR [SE] = 0.65 ± 0.28, p = 0.02). No other significant results were shown. CONCLUSIONS AND CLINICAL IMPLICATIONS: The NMA revealed gender-specific variations in ICI and ADC responses for RCC and TCC, offering insights for personalised cancer care and addressing disparities in cancer care and outcomes. PATIENT SUMMARY: In this systematic review, we looked at the sex differences for metastatic renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) for antibody-drug conjugates and immune checkpoint inhibitors. In our analysis, female and male sex has better overall survival for adjuvant and second-line therapies for RCC and TCC, respectively. Urgent research on gender-specific cancer therapies is imperative.

Role of enzalutamide in primary and recurrent non-metastatic hormone sensitive prostate cancer: a systematic review of prospective clinical trials.

INTRODUCTION: Enzalutamide, a second-generation androgen receptor inhibitor, is indicated for the treatment of metastatic disease, as well as in the treatment of non-metastatic castration resistant prostate cancer (PCa). This systematic review aims to determine outcomes and toxicity in patients with non-metastatic castration sensitive prostate cancer (nmCSPC) treated with enzalutamide in the primary or salvage settings. METHOD: We performed a systematic review focusing on the role of Enzalutamide in the treatment of nmCSPC, using the PubMed/Medline database. Articles focusing on androgen receptor inhibitors in nmCSPC were included, while articles discussing exclusively metastatic or castration-resistant PCa were excluded. RESULTS: The initial search retrieved 401 articles, of which 15 underwent a thorough assessment for relevance. Ultimately, 12 studies with pertinent outcomes were meticulously examined. Among these, seven studies were dedicated to the investigation of enzalutamide in the primary setting, while the remaining five publications specifically addressed its use in salvage settings. Regardless of the treatment setting, our data revealed two distinct therapeutic strategies. The first advocates for the substitution of enzalutamide for androgen deprivation therapy (ADT), based on the premise of achieving equivalent, if not superior, oncological outcomes while minimizing treatment-related toxicity. The second, adopting a more conventional approach, entails augmenting the effectiveness of ADT by incorporating enzalutamide. CONCLUSION: Enzalutamide has considerable potential as a therapeutic strategy for nmCSPC, either used alone or in combination with ADT in the primary or in the salvage settings. The use of enzalutamide instead of ADT is an appealing strategy. However, more trials will be required to further understand the efficacy and side-effect profile of enzalutamide monotherapy.

Pectin methylesterification state and cell wall mechanical properties contribute to neighbor proximity-induced hypocotyl growth in Arabidopsis.

Plants growing with neighbors compete for light and consequently increase the growth of their vegetative organs to enhance access to sunlight. This response, called shade avoidance syndrome (SAS), involves photoreceptors such as phytochromes as well as phytochrome interacting factors (PIFs), which regulate the expression of growth-mediating genes. Numerous cell wall-related genes belong to the putative targets of PIFs, and the importance of cell wall modifications for enabling growth was extensively shown in developmental models such as dark-grown hypocotyl. However, the contribution of the cell wall in the growth of de-etiolated seedlings regulated by shade cues remains poorly established. Through analyses of mechanical and biochemical properties of the cell wall coupled with transcriptomic analysis of cell wall-related genes from previously published data, we provide evidence suggesting that cell wall modifications are important for neighbor proximity-induced elongation. Further analysis using loss-of-function mutants impaired in the synthesis and remodeling of the main cell wall polymers corroborated this. We focused on the cgr2cgr3 double mutant that is defective in methylesterification of homogalacturonan (HG)-type pectins. By following hypocotyl growth kinetically and spatially and analyzing the mechanical and biochemical properties of cell walls, we found that methylesterification of HG-type pectins was required to enable global cell wall modifications underlying neighbor proximity-induced hypocotyl growth. Collectively, our work suggests that plant competition for light induces changes in the expression of numerous cell wall genes to enable modifications in biochemical and mechanical properties of cell walls that contribute to neighbor proximity-induced growth.

Impact of teratoma on survival probabilities of patients with metastatic non-seminomatous germ cell cancer: Results from the IGCCCG Update Consortium.

AIMS: To resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT). PATIENTS AND METHODS: Using the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method. RESULTS: Among 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS [54.3% in TER patients versus 55.4% (p = 0.7472) in NTER], nor in 5y-OS [69.4% versus 67.7% (p = 0.3841)]. NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001). CONCLUSION: Teratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups.

Why Do Men Reject Adjuvant Radiotherapy following Radical Prostatectomy? A Systematic Survey.

INTRODUCTION: The aim of this study was to investigate non-adherence rates to adjuvant radiotherapy (aRT) after radical prostatectomy (RP) and to obtain patient reported reasons for rejecting aRT despite recommendation by a multidisciplinary team discussion (MTD). METHODS: In a retrospective monocentric analysis, we identified 1,197 prostate cancer patients who underwent RP between 2014 and 2022 at our institution, of which 735 received a postoperative MTD recommendation. Patients with a recommendation for aRT underwent a structured phone interview with predefined standardised qualitative and quantitative questions and were stratified into "adherent" (aRT performed) and "non-adherent" groups (aRT not performed). RESULTS: Of 55 patients receiving a recommendation for aRT (7.5% of all RP patients), 24 (44%) were non-adherent. Baseline tumour characteristics were comparable among the groups. "Fear of radiation damage" was the most common reason for rejection, followed by "lack of information," "feeling that the treating physician does not support the recommendation" and "the impression that aRT is not associated with improved oncological outcome." Salvage radiotherapy was performed in 25% of non-adherent patients. CONCLUSION: High rates of non-adherence to aRT after RP were observed, and reasons for this phenomenon are most likely multifactorial. Multidisciplinary and individualized patient counselling might be a key for increasing adherence rates.

An updated model for predicting side-specific extraprostatic extension in the era of MRI-targeted biopsy.

PURPOSE: Accurate prediction of extraprostatic extension (EPE) is pivotal for surgical planning. Herein, we aimed to provide an updated model for predicting EPE among patients diagnosed with MRI-targeted biopsy. MATERIALS AND METHODS: We analyzed a multi-institutional dataset of men with clinically localized prostate cancer diagnosed by MRI-targeted biopsy and subsequently underwent prostatectomy. To develop a side-specific predictive model, we considered the prostatic lobes separately. A multivariable logistic regression analysis was fitted to predict side-specific EPE. The decision curve analysis was used to evaluate the net clinical benefit. Finally, a regression tree was employed to identify three risk categories to assist urologists in selecting candidates for nerve-sparing, incremental nerve sparing and non-nerve-sparing surgery. RESULTS: Overall, data from 3169 hemi-prostates were considered, after the exclusion of prostatic lobes with no biopsy-documented tumor. EPE was present on final pathology in 1,094 (34%) cases. Among these, MRI was able to predict EPE correctly in 568 (52%) cases. A model including PSA, maximum diameter of the index lesion, presence of EPE on MRI, highest ISUP grade in the ipsilateral hemi-prostate, and percentage of positive cores in the ipsilateral hemi-prostate achieved an AUC of 81% after internal validation. Overall, 566, 577, and 2,026 observations fell in the low-, intermediate- and high-risk groups for EPE, as identified by the regression tree. The EPE rate across the groups was: 5.1%, 14.9%, and 48% for the low-, intermediate- and high-risk group, respectively. CONCLUSION: In this study we present an update of the first side-specific MRI-based nomogram for the prediction of extraprostatic extension together with updated risk categories to help clinicians in deciding on the best approach to nerve-preservation.