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.

Robot-assisted Surgery in the Field of Urology: The Most Pioneering Approaches 2015-2023.

Robot-assisted surgery has emerged as a transformative technology, revolutionizing surgical approaches and techniques that decades ago could barely be imagined. The field of urology has taken charge in pioneering a new era of minimally invasive surgery with the ascent of robotic systems which offer enhanced visualization, precision, dexterity, and enabling surgeons to perform intricate maneuvers with improved accuracy. This has led to improved surgical outcomes, including reduced blood loss, lower complication rates, and faster patient recovery. The aim of our review is to present an evidence-based critical analysis on the most pioneering robotic urologic approaches described over the last eight years (2015-2023).

BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets.

Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most common cancers among UCs (90-95%). BC is the most common cancer and can be a highly heterogeneous disease, including both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) forms with different oncologic outcomes. Approximately 80% of new BC diagnoses are classified as NMIBC after the initial transurethral resection of the bladder tumor (TURBt). In this setting, intravesical instillation of Bacillus Calmette-Guerin (BCG) is the current standard treatment for intermediate- and high-risk patients. Unfortunately, recurrence occurs in 30% to 40% of patients despite adequate BCG treatment. Radical cystectomy (RC) is currently considered the standard treatment for NMIBC that does not respond to BCG. However, RC is a complex surgical procedure with a recognized high perioperative morbidity that is dependent on the patient, disease behaviors, and surgical factors and is associated with a significant impact on quality of life. Therefore, there is an unmet clinical need for alternative bladder-preserving treatments for patients who desire a bladder-sparing approach or are too frail for major surgery. In this review, we aim to present the strategies in BCG-unresponsive NMIBC, focusing on novel molecular therapeutic targets.

Effect of smoking, hypertension and lifestyle factors on kidney cancer - perspectives for prevention and screening programmes.

Renal cell carcinoma (RCC) incidence has doubled over the past few decades. However, death rates have remained stable as the number of incidental renal mass diagnoses peaked. RCC has been recognized as a European health care issue, but to date, no screening programmes have been introduced. Well-known modifiable risk factors for RCC are smoking, obesity and hypertension. A direct association between cigarette consumption and increased RCC incidence and RCC-related death has been reported, but the underlying mechanistic pathways for this association are still unclear. Obesity is associated with an increased risk of RCC, but interestingly, improved survival outcomes have been reported in obese patients, a phenomenon known as the obesity paradox. Data on the association between other modifiable risk factors such as diet, dyslipidaemia and physical activity with RCC incidence are conflicting, and potential mechanisms underlying these associations remain to be elucidated.

The Utility of Inflammatory Serum Markers in the Assessment of Perioperative Morbidity after Radical Cystectomy for Bladder Cancer.

Background and Objectives: To date, sparse evidence exists about the impact of inflammatory serum markers in predicting perioperative complications after radical cystectomy (RC) for bladder cancer (BC). Here, we evaluated the role of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), C-reactive protein (CRP), and plasma fibrinogen in predicting perioperative morbidity and unplanned 30-days readmission after RC for BC. Materials and methods: We relied on a collaborative database of 271 patients who underwent open RC for cT1-4a N0 M0 BC between January 2012 and December 2022. Univariable and multivariable binomial logistic regression analyses were performed to assess the odds ratio (OR) with 95% confidence intervals (CI) testing the ability of each serum marker to predict postoperative complications (any-grade and major complications), and 30-days unplanned readmission. Results: The median age at RC was 73 yr (IQR 67-79). A total of 182 (67.2%) patients were male and the median BMI was 25.2 (IQR 23.2-28.4). Overall, 172 (63.5%) patients had a Charlson Comorbidity Index (CCI) greater than 2 points and 98 (36.2%) were current smokers at the time of RC. Overall, 233 (86.0%) patients experienced at least one complication after RC. Of these, 171 (63.1%) patients had minor complications (Clavien-Dindo grade 1-2) while 100 (36.9%) experienced major complications (Clavien-Dindo grade ≥ 3). According to multivariable analysis, current smoking status, high plasma fibrinogen, and preoperative anemia were independently associated with major complications (OR 2.10, 95%CI 1.15-4.90, p = 0.02), (OR 1.51, 95%CI 1.26-1.98, p = 0.09), and (OR 1.35, 95%CI 1.17-2.57, p = 0.03), respectively. Overall, 56 (20.7%) patients experienced a 30-days unplanned readmission. According to univariable analysis, high preoperative CRP and hyperfibrinogenemia were significantly associated with an increased risk of unplanned readmission (OR 2.15, 95%CI 1.15-4.16, p = 0.02; OR 2.18, 95%CI 1.13-4.44, p = 0.02, respectively). Conclusions: In our study, the preoperative immune-inflammation signature described by NLR, PLR, LMR, SII, and CRP showed a low reliability in predicting perioperative course after RC. Preoperative anemia and hyperfibrinogenemia were independent predictors of major complications. Further studies are pending in order to draw definitive conclusions.

Resection Techniques During Robotic Partial Nephrectomy: A Systematic Review.

Context: The resection technique used to excise tumor during robotic partial nephrectomy (RPN) is of paramount importance in achieving optimal clinical outcomes. Objective: To provide an overview of the different resection techniques used during RPN, and a pooled analysis of comparative studies. Evidence acquisition: The systematic review was conducted according to established principles (PROSPERO: CRD42022371640) on November 7, 2022. A population (P: adult patients undergoing RPN), intervention (I: enucleation), comparator (C: enucleoresection or wedge resection), outcome (O: outcome measurements of interest), and study design (S) framework was prespecified to assess study eligibility. Studies reporting a detailed description of resection techniques and/or evaluating the impact of resection technique on outcomes of surgery were included. Evidence synthesis: Resection techniques used during RPN can be broadly classified as resection (non-anatomic) or enucleation (anatomic). A standardized definition for these is lacking. Out of 20 studies retrieved, nine compared "standard" resection versus enucleation. A pooled analysis did not reveal significant differences in terms of operative time, ischemia time, blood loss, transfusions, or positive margins. Significant differences favoring enucleation were found for clamping management (odds ratio [OR] for renal artery clamping 3.51, 95% confidence interval [CI] 1.13-10.88; p = 0.03), overall complications (OR for occurrence 0.55, 95% CI 0.34-0.87; p = 0.01) major complications (OR for occurrence 0.39, 95% CI 0.19-0.79; p = 0.009), length of stay (weighted mean difference [WMD] -0.72 d, 95% CI -0.99 to -0.45; p < 0.001), and decrease in estimated glomerular filtration rate (WMD -2.64 ml/min, 95% CI -5.15 to -0.12; p = 0.04). Conclusions: There is heterogeneity in the reporting of resection techniques used during RPN. The urological community must improve the quality of reporting and research produced accordingly. Positive margins are not specifically related to the resection technique. Focusing on studies comparing standard resection versus enucleation, advantages with tumor enucleation in terms of avoidance of artery clamping, overall/major complications, length of stay, and renal function were found. These data should be considered when planning the RPN resection strategy. Patient summary: We reviewed studies on robotic surgery for partial kidney removal using different techniques to cut away the kidney tumor. We found that a technique called "enucleation" was associated with similar cancer control outcomes in comparison to the standard technique and had fewer complications, better kidney function after surgery, and a shorter hospital stay.

Safety, Tolerability, and Preliminary Efficacy of TAR-200 in Patients With Muscle-invasive Bladder Cancer Who Refused or Were Unfit for Curative-intent Therapy: A Phase 1 Study.

PURPOSE: Half of patients with muscle-invasive bladder cancer worldwide may not receive curative-intent therapy. Elderly or frail patients are most affected by this unmet need. TAR-200 is a novel, intravesical drug delivery system that provides sustained, local release of gemcitabine into the bladder over a 21-day dosing cycle. The phase 1 TAR-200-103 study evaluated the safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who either refused or were unfit for curative-intent therapy. MATERIALS AND METHODS: Eligible patients had cT2-cT3bN0M0 urothelial carcinoma of the bladder. TAR-200 was inserted for 4 consecutive 21-day cycles over 84 days. The primary end points were safety and tolerability at 84 days. Secondary end points included rates of clinical complete response and partial response as determined by cystoscopy, biopsy, and imaging; duration of response; and overall survival. RESULTS: Median age of the 35 enrolled patients was 84 years, and most were male (24/35, 68.6%). Treatment-emergent adverse events related to TAR-200 occurred in 15 patients. Two patients experienced treatment-emergent adverse events leading to removal of TAR-200. At 3 months, complete response and partial response rates were 31.4% (11/35) and 8.6% (3/35), respectively, yielding an overall response rate of 40.0% (14/35; 95% CI 23.9-57.9). Median overall survival and duration of response were 27.3 months (95% CI 10.1-not estimable) and 14 months (95% CI 10.6-22.7), respectively. Progression-free rate at 12 months was 70.5%. CONCLUSIONS: TAR-200 was generally safe, well tolerated, and had beneficial preliminary efficacy in this elderly and frail cohort with limited treatment options.

Estimating Postoperative Renal Function After Surgery for Nonmetastatic Renal Masses: A Systematic Review of Available Prediction Models.

CONTEXT: A variety of models predicting postoperative renal function following surgery for nonmetastatic renal tumors have been reported, but their validity and clinical usefulness have not been formally assessed. OBJECTIVE: To summarize prediction models available for estimation of mid- to long-term (>3 mo) postoperative renal function after partial nephrectomy (PN) or radical nephrectomy (RN) for nonmetastatic renal masses that include only preoperative or modifiable intraoperative variables. EVIDENCE ACQUISITION: A systematic review of the English-language literature was conducted using the MEDLINE, Embase, and Web of Science databases from January 2000 to March 2022 according to the PRISMA guidelines (PROSPERO ID: CRD42022303492). Risk of bias was assessed according to the Prediction Model Study Risk of Bias Assessment Tool. EVIDENCE SYNTHESIS: Overall, 21 prediction models from 18 studies were included (nine for PN only; eight for RN only; four for PN or RN). Most studies relied on retrospective patient cohorts and had a high risk of bias and high concern regarding the overall applicability of the proposed model. Patient-, kidney-, surgery-, tumor-, and provider-related factors were included among the predictors in 95%, 86%, 100%, 61%, and 0% of the models, respectively. All but one model included both patient age and preoperative renal function, while only a few took into account patient gender, race, comorbidities, tumor size/complexity, and surgical approach. There was significant heterogeneity in both the model building strategy and the performance metrics reported. Five studies reported external validation of six models, while three assessed their clinical usefulness using decision curve analysis. CONCLUSIONS: Several models are available for predicting postoperative renal function after kidney cancer surgery. Most of these are not ready for routine clinical practice, while a few have been externally validated and might be of value for patients and clinicians. PATIENT SUMMARY: We reviewed the tools available for predicting kidney function after partial or total surgical removal of a kidney for nonmetastatic cancer. Most of the models include patient and kidney characteristics such as age, comorbidities, and preoperative kidney function, and a few also include tumor characteristics and intraoperative variables. Some models have been validated by additional research groups and appear promising for improving counseling for patients with nonmetastatic cancer who are candidates for surgery.

Impact of the controlling nutritional status (CONUT) score on perioperative morbidity and oncological outcomes in patients with bladder cancer treated with radical cystectomy.

INTRODUCTION AND OBJECTIVES: To evaluate the impact of the Controlling Nutritional Status (CONUT) score on perioperative morbidity and oncological outcomes of bladder cancer (BC) patients treated with radical cystectomy (RC). MATERIALS AND METHODS: We retrospectively analyzed a multi-institutional cohort of 347 patients treated with RC for clinical-localized BC between 2005 and 2019. The CONUT-score was defined as an algorithm including serum albumin, total lymphocyte count, and cholesterol. Multivariable logistic regression analyses were performed to evaluate the ability of the CONUT-score to predict any-grade complications, major complications and 30 days readmission. Multivariable Cox' regression models were performed to evaluate the prognostic effect of the CONUT-score on recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS). RESULTS: A cut-off value to discriminate between low and high CONUT-score was determined by calculating the receiver operating characteristic (ROC) curve. The area under the curve was 0.72 hence high CONUT-score was defined as ≥3 points. Overall, 112 (32.3%) patients had a high CONUT. At multivariable logistic regression analyses, high CONUT was associated with any-grade complications (OR 3.58, P = 0.001), major complications (OR 2.56, P = 0.003) and 30 days readmission (OR 2.39, P = 0.01). On multivariable Cox' regression analyses, high CONUT remained associated with worse RFS (HR 2.57, P < 0.001), OS (HR 2.37, P < 0.001) and CSS (HR 3.52, P < 0.001). CONCLUSIONS: Poor nutritional status measured by the CONUT-score is independently associated with a poorer postoperative course after RC and is predictive of worse RFS, OS, and CSS. This simple index could serve as a comprehensive personalized risk-stratification tool identifying patients who may benefit from an intensified regimen of supportive cares.

External validation of yonsei nomogram predicting chronic kidney disease development after partial nephrectomy: An international, multicenter study.

OBJECTIVE: To externally validate Yonsei nomogram. METHODS: From 2000 through 2018, 3526 consecutive patients underwent on-clamp PN for cT1 renal masses at 23 centers were included. All patients had two kidneys, preoperative eGFR ≥60 ml/min/1.73 m2, and a minimum follow-up of 12 months. New-onset CKD was defined as upgrading from CKD stage I or II into CKD stage ≥III. We obtained the CKD-free progression probabilities at 1, 3, 5, and 10 years for all patients by applying the nomogram found at https://eservices.ksmc.med.sa/ckd/. Thereafter, external validation of Yonsei nomogram for estimating new-onset CKD stage ≥III was assessed by calibration and discrimination analysis. RESULTS AND LIMITATION: Median values of patients' age, tumor size, eGFR and follow-up period were 47 years (IQR: 47-62), 3.3 cm (IQR: 2.5-4.2), 90.5 ml/min/1.73 m2 (IQR: 82.8-98), and 47 months (IQR: 27-65), respectively. A total of 683 patients (19.4%) developed new-onset CKD. The 5-year CKD-free progression rate was 77.9%. Yonsei nomogram demonstrated an AUC of 0.69, 0.72, 0.77, and 0.78 for the prediction of CKD stage ≥III at 1, 3, 5, and 10 years, respectively. The calibration plots at 1, 3, 5, and 10 years showed that the model was well calibrated with calibration slope values of 0.77, 0.83, 0.76, and 0.75, respectively. Retrospective database collection is a limitation of our study. CONCLUSIONS: The largest external validation of Yonsei nomogram showed good calibration properties. The nomogram can provide an accurate estimate of the individual risk of CKD-free progression on long-term follow-up.

Assessing Trifecta Achievement after Percutaneous Cryoablation of Small Renal Masses: Results from a Multi-Institutional Collaboration.

Background and Objectives: To assess efficacy and safety of Percutaneous Cryoablation (PCA) of small renal masses (SRMs) using Trifecta outcomes in a large cohort of patients who were not eligible for surgery. Materials and methods: All PCAs performed in four different centers between September 2009 and September 2019 were retrospectively evaluated. Patients were divided in two different groups depending on masses dimensional criteria: Group-A: diameter ≤ 25 mm and Group-B: diameter > 25 mm. Complications rates were reported and classified according to the Clavien−Dindo system. The estimate glomerular filtration rate (eGFR) was calculated before PCA and during follow-up schedule. Every patient received a Contrast Enhanced Ultrasound (CEUS) evaluation on the first postoperative day. Radiological follow-up was taken at 3, 6, and 12 months for the first year, then yearly. Radiological recurrence was defined as a contrast enhancement persistence and was reported in the study. Finally, Trifecta outcome, which included complications, RFS, and preservation of eGFR class, was calculated for every procedure at a median follow-up of 32 months. Results: The median age of the patients was 74 years. Group-A included 200 procedures while Group-B included 140. Seventy-eight patients were eligible for Trifecta evaluation. Trifecta was achieved in 69.6% of procedures in Group-A, 40.6% in Group-B (p = 0.02). We observed an increased rate of complication in Group-B (13.0% vs. 28.6; p < 0.001). However, 97.5% were

Reliable Prediction of Post-Operative Complications' Rate Using the G8 Screening Tool: A Prospective Study on Elderly Patients Undergoing Surgery for Kidney Cancer.

In the last years the incidence of renal neoplasms has been steadily increasing, along with the average age of patients at the time of diagnosis. Surgical management for localized disease is becoming more challenging because of patients' frailty. We conducted a multi-center prospective study to evaluate the role of the G8 as a screening tool in the assessment of intra and post-operative complications of elderly patients (≥70 y.o.) undergoing surgery for kidney cancer. A total of 162 patients were prospectively enrolled between January 2015 to January 2019 and divided into two study groups (frail vs. not-frail) according to their geriatric risk profile based on G8 score. Several factors (i.e., age, CCI, ASA score, preoperative anemia, RENAL score, surgical procedures, and techniques) were analyzed to identify whether any of them would configure as a statistically significant predictor of surgical complications. According to the G8 Score, 90 patients were included in the frail group. A total of 52 frail patients vs. 4 non-frail patients developed a postoperative complication of any kind (p < 0.001). Of these, 11 were major complications and all occurred in the frail group. Our results suggest that the G8 screening tool is an effective and useful instrument to predict the risk of overall complications in elderly patients prior to renal surgery.

Molecular markers of systemic therapy response in urothelial carcinoma.

Identification of reliable molecular biomarkers that can complement clinical practice represents a fascinating challenge in any cancer field. Urothelial carcinoma is a very heterogeneous disease and responses to systemic therapies, and outcomes after radical cystectomy are difficult to predict. Advances in molecular biology such as next generation sequencing and whole genome or transcriptomic analysis provide promising platforms to achieve a full understanding of the biology behind the disease and can identify emerging predictive biomarkers. Moreover, the ability to categorize patients' risk of recurrence after curative treatment, or even predict benefit from a conventional or targeted therapies, represents a compelling challenge that may reshape both selection for tailored treatment and disease monitoring. Progress has been made but currently no molecular biomarkers are used in the clinical setting to predict response to systemic agents in either neoadjuvant or adjuvant settings highlighting a relevant unmet need. Here, we aim to present the emerging role of molecular biomarkers in predicting response to systemic agents in urothelial carcinoma.

Management of local recurrence after radical nephrectomy: surgical removal with or without systemic treatment is still the gold standard. Results from a multicenter international cohort.

OBJECTIVE: To evaluate the survival outcomes of patients with local recurrence after radical nephrectomy (RN) and to test the effect of surgery, as monotherapy or in combination with systemic treatment, on cancer-specific mortality (CSM). METHODS: Patients with local recurrence after RN were abstracted from an international dataset. The primary outcome was CSM. Cox's proportional hazard models tested the main predictors of CSM. Kaplan-Meier method estimates the 3-year survival rates. RESULTS: Overall, 96 patients were included. Of these, 44 (45.8%) were metastatic at the time of recurrence. The median time to recurrence after RN was 14.5 months. The 3-year cancer-specific survival rates after local recurrence were 92.3% (± 7.4%) for those who were treated with surgery and systemic therapy, 63.2% (± 13.2%) for those who only underwent surgery, 22.7% (± 0.9%) for those who only received systemic therapy and 20.5% (± 10.4%) for those who received no treatment (p < 0.001). Receiving only medical treatment (HR: 5.40, 95% CI 2.06-14.15, p = 0.001) or no treatment (HR: 5.63, 95% CI 2.21-14.92, p = 0.001) were both independently associated with higher CSM rates, even after multivariable adjustment. Following surgical treatment of local recurrence 8 (16.0%) patients reported complications, and 2/8 were graded as Clavien-Dindo ≥ 3. CONCLUSIONS: Surgical treatment of local recurrence after RN, when feasible, should be offered to patients. Moreover, its association with a systemic treatment seems to warrantee adjunctive advantages in terms of survival, even in the presence of metastases.