Orthotopic Robot-assisted Kidney Transplantation: Surgical Technique and Preliminary Results.

BACKGROUND AND OBJECTIVE: Orthotopic kidney transplantation (KT) has been proposed as an option for patients ineligible for heterotopic KT. In this scenario, orthotopic robot-assisted KT (oRAKT) represents a novel, minimally invasive alternative to the open approach. Here we describe the largest oRAKT series of patients, with a focus on the surgical technique, perioperative surgical outcomes, and functional results. METHODS: We queried prospectively maintained databases from three referral centers to identify patients who underwent oRAKT and evaluated surgical and functional outcomes. KEY FINDINGS AND LIMITATIONS: Overall, 16 oRAKT procedures were performed between January 2020 and August 2023. These involved four donors after cardiovascular death, five donors after brain death, and seven living donors. All oRAKT procedures were carried out in the left renal fossa. The indication for oRAKT was extensive calcification of the external iliac vessels (100%), frequently associated with prior KT (31%). The median operative time was 295 min (interquartile range [IQR] 268-360) and the median rewarming time 48 min (IQR 40-54). Conversion to open surgery occurred in two cases (12%), and delayed graft function was observed in two cases (12%). Postoperative complications occurred in 11 patients (69%) and three (18%) experienced Clavien-Dindo grade >II complications. At median follow-up of 9 mo (IQR 7-17), 14 patients had a functioning graft and median creatinine of 1.49 mg/dl (IQR 1.36-1.72). CONCLUSIONS AND CLINICAL IMPLICATIONS: Although oRAKT is a challenging procedure, it represents a feasible option for individuals ineligible for heterotopic KT and yields favorable perioperative and mid-term functional outcomes. PATIENT SUMMARY: We evaluated outcomes of orthotopic robot-assisted kidney transplantation (KT), in which the native kidney is removed and the donor kidney is transplanted into its place, in patients who are not eligible for heterotopic KT, in which the native kidney is left in place and the donor kidney is transplanted into a new location. We found that robot-assisted surgery is a safe and feasible alternative to traditional open surgery for orthotopic KT.

Apalutamide for prostate cancer: Multicentre and multidisciplinary real-world study of 227 patients.

OBJECTIVE: To evaluate the efficacy and safety of apalutamide prostate cancer compared to the pivotal trials patients and to identify the first subsequent therapy in a real-world setting. METHODS: The study is prospective and observational based on real-world evidence, performed by different medical disciplines and eight academics centres around Barcelona, Spain. It included all patients with metastatic hormone-sensitive prostate cancer (mHSPC) and high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) treated with apalutamide from June 2018 to December 2022. RESULTS: Of 227 patients treated with apalutamide, 10% had ECOG-PS 2, and 41% were diagnosed with new-generation imaging. In the mHSPC group (209 patients), 75 years was the median age, 53% had synchronous metastases, and 22% were M1a. In the nmCRPC (18 patients), 82 years was the median age, and 81% ≤6 months had PSA doubling time. Patients achieved PSA90 in 92% of mHSPC and 50% of nmCRPC and PSA ≤0.2 in 71% of mHSPC and 39% of nmCRPC. Treatment-related adverse events occurred in 40.1% of mHSPC and 44.4% of nmCRPC. After discontinuation of apalutamide due to disease progression, 54.5% in mHSPC and 75% in nmCRPC started chemotherapy, while after discontinuation because of adverse events, 73.3% in mHSPC and 100% in nmCRPC continued with other hormonal-therapies. CONCLUSIONS: The efficacy and safety of apalutamide were similar to that described in the pivotal trials, despite including an older and more comorbid population. Usually, subsequent therapies after apalutamide differed depending on the reason for discontinuation: by disease progression started chemotherapy and by adverse events hormonal sequencing.

Nomogram based on baseline clinicopathological characteristics for predicting bladder cancer-specific survival to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

PURPOSE: To develop a risk score based on a prognostic model and a nomogram integrating baseline clinicopathological variables to predict bladder cancer-specific survival (BCSS) to neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) patients. METHODS: We retrospectively identified a consecutive sample of 247 MIBC patients treated with cisplatin-based NAC-plus-cystectomy in two Spanish hospitals between 2000 and 2019. Age at MIBC diagnosis, sex, histology, lymphovascular invasion, previous non-MIBC, hydronephrosis, and clinical TNM were included in the initial Cox regression model. A risk score was computed based on the final prognostic model and a nomogram was used to estimate BCSS at 2 and 5 years. RESULTS: Median age was 66 years; 89% were males; 83% had pure urothelial carcinoma; 16.2% had previous non-MIBC. Clinical stage was T2N0, T3-4aN0, and Tx-4N + in 24%, 57%, and 19% of patients, respectively. Complete pathological response was seen in 29.4% and downstaging to non-MIBC (ypT1, ypTa, ypTis) in 12.5% of patients. Overall 5-year BCSS was 59%. Four prognostic factors were identified: variant histology, previous non-MIBC, female sex and hydronephrosis. By adding the points attributed to each of these factors, we categorized patients in three groups: low-risk (0 points); intermediate-risk (1-9 points); high-risk (≥ 10 points). Five-year BCSS was 72%, 53%, and 15%, respectively (p < 0.0001). CONCLUSION: We developed a nomogram and risk score based on four baseline clinicopathological characteristics to predict BCSS to NAC-plus-cystectomy in MIBC patients. If validated in prospective studies, this nomogram can be useful for selecting patients likely to benefit from NAC.

Variant histologies in bladder cancer: Does the centre have an impact in detection accuracy?

OBJECTIVE: To compare the accuracy in detecting variant histologies (VH) at transurethral resection of bladder (TURB) and radical cystectomy (RC) specimen among tertiary referral centres, in order to investigate potential reasons of discrepancies from the pathological point of view. PATIENTS AND METHODS: Clinical and histopathological data of TURB specimen and subsequent cystectomy specimen of 3,445 RC candidate patients have been retrospectively collected from 24 tertiary referral centres between 1980 and 2021. VH considered in the analysis were pure squamous cell carcinoma, urothelial carcinoma with squamous differentiation, pure adenocarcinoma, urothelial carcinoma with glandular differentiation, micropapillary bladder cancer (BCa), neuroendocrine BCa, and other variants. The degree of agreement between TURB and RC concerning the identification of VH was expressed as concordance, classified according to Cohen's kappa coefficient. RESULTS: A VH was reported in 17% of TURB specimens, 45% of which were not confirmed in RC. The lowest concordance rate was reported for micropapillary BCa with 11 out of 18 (61%) centres reporting no agreement, whereas neuroendocrine BCa achieved the highest concordance rate with only 3 centres (17%) reporting no agreement. Our results shows that even among centres with the advantage of a referent uropathologist the micropapillary variant is characterized by scarce accuracy between TURB and RC. Differences in TURB specimen acquisition by the urologist and in sampling methods among different centres are the main limitations of the study. CONCLUSIONS: Accuracy of TURB in detecting VH is poor for certain VH, in particular for micropapillary BCa, with evident variation among centres. Novel diagnostic tools are required to better identify these VH and drive patients toward a personalized treatment.

Taxane-induced Attenuation of the CXCR2/BCL-2 Axis Sensitizes Prostate Cancer to Platinum-based Treatment.

BACKGROUND: Taxanes are the most active chemotherapy agents in metastatic castration-resistant prostate cancer (mCRPC) patients; yet, resistance occurs almost invariably, representing an important clinical challenge. Taxane-platinum combinations have shown clinical benefit in a subset of patients, but the mechanistic basis and biomarkers remain elusive. OBJECTIVE: To identify mechanisms and response indicators for the antitumor efficacy of taxane-platinum combinations in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Transcriptomic data from a publicly available mCRPC dataset of taxane-exposed and taxane-naïve patients were analyzed to identify response indicators and emerging vulnerabilities. Functional and preclinical validation was performed in taxane-resistant mCRPC cell lines and genetically engineered mouse models (GEMMs). INTERVENTION: Metastatic CRPC cells were treated with docetaxel, cisplatin, carboplatin, the CXCR2 antagonist SB265610, and the BCL-2 inhibitor venetoclax. Gain and loss of function in culture of CXCR2 and BCL-2 were achieved by overexpression or siRNA silencing. Preclinical assays in GEMM mice tested the antitumor efficacy of taxane-platinum combinations. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Proliferation, apoptosis, and colony assays measured drug activity in vitro. Preclinical endpoints in mice included growth, survival, and histopathology. Changes in CXCR2, BCL-2, and chemokines were analyzed by reverse transcriptase quantitative polymerase chain reaction and Western blot. Human expression data were analyzed using Gene Set Enrichment Analysis, hierarchical clustering, and correlation studies. GraphPad Prism software and R-studio were used for statistical and data analyses. RESULTS AND LIMITATIONS: Transcriptomic data from taxane-exposed human mCRPC tumors correlate with a marked negative enrichment of apoptosis and inflammatory response pathways accompanied by a marked downregulation of CXCR2 and BCL-2. Mechanistically, we show that docetaxel inhibits CXCR2 and that BCL-2 downregulation occurs as a downstream effect. Further, we demonstrated in experimental models that the sensitivity to cisplatin is dependent on CXCR2 and BCL-2, and that targeting them sensitizes prostate cancer (PC) cells to cisplatin. In vivo taxane-platinum combinations are highly synergistic, and previous exposure to taxanes sensitizes mCRPC tumors to second-line cisplatin treatment. CONCLUSIONS: The hitherto unappreciated attenuation of the CXCR2/BCL-2 axis in taxane-treated mCRPC patients is an acquired vulnerability with potential predictive activity for platinum-based treatments. PATIENT SUMMARY: A subset of patients with aggressive and therapy-resistant prostate cancer benefits from taxane-platinum combination chemotherapy; however, we lack the mechanistic understanding of how that synergistic effect occurs. Here, using patient data and preclinical models, we found that taxanes reduce cancer cell escape mechanisms to chemotherapy-induced cell death, hence making these cells more vulnerable to additional platinum treatment.

PSA Kinetics as Prognostic Markers of Overall Survival in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate.

BACKGROUND: Abiraterone acetate (AA) is widely used in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, a significant percentage of patients will still progress, highlighting the need to identify patients more likely to benefit from AA. Parameters linked to prostate-specific antigen (PSA) kinetics are promising prognostic markers. We have examined clinical and PSA-related factors potentially associated with overall survival (OS) in patients treated with AA. METHODS: Between 2011 and 2014, 104 patients with mCRPC treated with AA after progression to docetaxel at centers of the Catalan Institute of Oncology were included in this retrospective study. Patients were assessed monthly. Baseline characteristics and variables related to PSA kinetics were included in univariate and multivariate analyses of OS. RESULTS: Median OS was 16.4 months (range 12.4-20.6) for all patients. The univariate analysis identified the following baseline characteristics as significantly associated with OS: ECOG PS, location of metastases, time between starting androgen deprivation therapy and starting AA, time between stopping docetaxel treatment and starting AA, neutrophil-lymphocyte ratio (NLR), alkaline phosphatase levels, and PSA levels. Factors related to PSA kinetics associated with longer OS were PSA response >50%, early PSA response (>30% decline at four weeks), PSA decline >50% at week 12, PSA nadir <2.4ng/mL, time to PSA nadir >140 days, the combination of PSA nadir and time to PSA nadir, and low end-of-treatment PSA levels. The multivariate analysis identified ECOG PS (HR 37.46; p<0.001), NLR (HR 3.7; p<0.001), early PSA response (HR 1.22; p=0.002), and time to PSA nadir (HR 0.39; p=0.002) as independent prognostic markers. CONCLUSION: Our results indicate an association between PSA kinetics, especially early PSA response, and outcome to AA after progression to docetaxel. Taken together with other factors, lack of an early PSA response could identify patients who are unlikely to benefit from AA and who could be closely monitored with a view to offering alternative therapies.

Moving towards Personalized Medicine in Muscle-Invasive Bladder Cancer: Where Are We Now and Where Are We Going?

Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the recommended treatment, with the highest level of evidence, for patients with muscle-invasive bladder cancer (MIBC). However, only a minority of patients receive this treatment, mainly due to patient comorbidities, the relatively small survival benefit, and the lack of predictive biomarkers to select those patients most likely to benefit from this multimodal approach. In addition, adjuvant chemotherapy has been recommended for patients with high-risk MIBC, although randomized trials have not provided conclusive evidence on the impact of this approach. At present, however, this situation is changing, largely due to our improved knowledge of the molecular biology of bladder cancer, which has enabled us to identify new prognostic and predictive biomarkers that can be used to select the most appropriate treatment for each patient. Moreover, new active treatments, especially immunotherapy, have shown promising results in the neoadjuvant setting. In addition, the gene expression profile of bladder tumors can be used to classify them into different subtypes, which correlate with specific clinical-pathological characteristics and with treatment response or resistance. Therefore, the main objective for the near future is to introduce these translational breakthroughs into routine clinical practice in order to personalize treatment for each patient.

Role of Inflammation in the Perioperative Management of Urothelial Bladder Cancer With Squamous-Cell Features: Impact of Neutrophil-to-Lymphocyte Ratio on Outcomes and Response to Neoadjuvant Chemotherapy.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) might reflect an increased neutrophilic inflammatory response, and urothelial tumors with squamous-cell features (SqD) have been linked to inflammation. We hypothesized that NLR could be prognostic in these patients. PATIENTS AND METHODS: In patients with SqD muscle-invasive bladder cancer treated with curative intent, NLR and relationships with outcomes were analyzed by Cox regression, log-rank, and Kaplan-Meier analysis. RESULTS: Fifty patients presented SqD (median follow-up, 29 months). The ideal NLR cutoff (by receiver operating characteristic curves) was 5. Thirty-seven patients had NLR < 5 and 13 had NLR ≥ 5. The 5-year progression-free survival, cancer-specific survival (CSS), and overall survival were 46.8%, 48.4%, and 45% for NLR < 5 cases, and 10.3%, 10.3%, and 11.7% for NLR ≥ 5 cases (all P < .05). On multivariate analysis, NLR was prognostic (hazard ratio = 4.26, 6.21, and 4.08 for progression-free survival, CSS, and overall survival). Neoadjuvant chemotherapy (NAC) was of significant benefit in NLR < 5 patients, with a CSS of 91.2 months (n = 3) versus 38.1 months (n = 24) for those treated with up-front radical cystectomy (P = .009); Kaplan-Meier curves were also significantly different. These differences did not reach statistical significance for patients with NLR ≥ 5. For the 19 patients treated with NAC, NLR was also predictive of response to NAC. CONCLUSION: Inflammation, measured by NLR, is potentially prognostic in the perioperative management of SqD. NLR identifies 2 risk groups. Patients displaying low NLR had a 4-fold survival improvement and were highly responsive to NAC. NLR might be a good prognostic tool. Its role as a predictor of response to NAC deserves future study, along with its role as a selection criterion for therapies other than chemotherapy.

Low Pretreatment Neutrophil-to-Lymphocyte Ratio Predicts for Good Outcomes in Patients Receiving Neoadjuvant Chemotherapy Before Radical Cystectomy for Muscle Invasive Bladder Cancer.

PURPOSE: The pretreatment neutrophil-to-lymphocyte ratio (NLR) has been associated with cancer prognosis, influencing progression and chemosensitivity. We aimed to define the role of the NLR in predicting the outcomes to neoadjuvant chemotherapy (NAC) in patients with muscle invasive bladder cancer (MIBC). PATIENTS AND METHODS: The data from patients treated with NAC and radical cystectomy for MIBC from 2007 to 2015 at a tertiary care center were reviewed. The clinicopathologic pretreatment, including the NLR, and post-treatment predictors were documented. The NLR was evaluated as a continuous variable on uni- and multivariate analysis and dichotomized in Kaplan-Meier curves. The relationships with outcomes (progression-free survival [PFS], cancer-specific survival [CSS], and overall survival [OS]) were analyzed using Cox regression analysis and log-rank tests. The pathologic response (PR) included any downstaging from the baseline clinical stage to the final pathologic stage. RESULTS: Of 205 patients with MIBC, 75 underwent NAC (median follow-up, 31 months) with a 5-year PFS, CSS, and OS rate of 56%, 60%, and 52%, respectively, and a PR of 38.6%. On multivariate analysis, the PR, PFS, CSS, and OS were predicted by the NLR (hazard ratio > 0.8, 1.25, 1.27, and 1.12, respectively; P < .05 for all). The NLR with age and clinical stage predicted the PR. A NLR threshold of 2.26 better predicted CSS (P < .05) and OS (P = .055). The limitations included the retrospective design and modest number of cases. CONCLUSION: We have provided initial evidence that a low NLR helps understand the value of the underlying immune system in predicting a good outcome to NAC. The NLR is a simple and accessible biomarker that is easy to implement in clinical practice. In addition to established prognosticators and newer genomic predictors, the NLR could improve therapeutic algorithms and help in decision-making regarding the need for NAC, which is currently underused, in MIBC patients.