Humoral complementomics - exploration of noninvasive complement biomarkers as predictors of renal cancer progression.

Despite the progress of anti-cancer treatment, the prognosis of many patients with solid tumors is still dismal. Reliable noninvasive biomarkers are needed to predict patient survival and therapy response. Here, we propose a Humoral Complementomics approach: a work-up of assays to comprehensively evaluate complement proteins, activation fragments, and autoantibodies targeting complement proteins in plasma, which we correlated with the intratumoral complement activation, and/or local production, focusing on localized and metastatic clear cell renal cell carcinoma (ccRCC). In two prospective ccRCC cohorts, plasma C2, C5, Factor D and properdin were elevated compared to healthy controls, reflecting an inflammatory phenotype that correlated with plasma calprotectin levels but did not associate with CRP or with patient prognosis. Conversely, autoantibodies against the complement C3 and the reduced form of FH (a tumor neo-epitope reported in lung cancer) correlated with a favorable outcome. Our findings pointed to a specific group of patients with elevated plasma C4d and C1s-C1INH complexes, indicating the initiation of the classical pathway, along with elevated Ba and Bb, indicating alternative pathway activation. Boostrapped Lasso regularized Cox regression revealed that the most predictive complement biomarkers were elevated plasma C4d and Bb levels at the time of surgery, which correlated with poor prognosis. In conclusion, we propose Humoral Complementomics as an unbiased approach to study the global state of the complement system in any pathological plasma sample and disease context. Its implementation for ccRCC revealed that elevated C4d and Bb in plasma are promising prognostic biomarkers, correlating with shorter progression-free survival.

Urinary Symptoms Change and Quality of Life After Robotic Radical Prostatectomy: A Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: To present the patient-reported quality of life (QoL) outcomes from a prospective, randomized controlled trial comparing the use of pelvic floor muscle training (PFMT) and duloxetine after robot-assisted radical prostatectomy (RARP). METHODS: We identified 213 men with organ-confined disease having post-RARP urinary incontinence who were randomly assigned to received PFMT, duloxetine, combined PFMT-duloxetine and pelvic floor muscle home exercises. Urinary symptoms burden was measured by marked clinical important difference improvement (MCID) defined by using the International Prostate Symptom Score (IPSS) difference of - 8 points (ΔIPSS ≤-8). QoL was assessed according to Visual Analog Scale (VAS), King's Health Questionnaire (KQH), and International Index of Erectile Function (IIEF-5). Multivariable regression analyses aimed to predict MCID, burden of urinary symptoms (IPSS ≥8), and patients reporting to be satisfied (IPSS QoL ≤2) or comfortable (VAS ≤1) post-RARP. RESULTS: Moderate to severe urinary symptoms decreased from 48% preoperatively to 40%, 34%, and 23% at 3, 6, and 12months post-RARP. After surgery, MCID improvement was observed in 19% of patients, and deterioration in 3.3%. Large prostate was the only factor associated to MCID (OR 1.03 [95%CI 1.01-1.05], P = .005). At 6months, patients reached the same degree of preoperative satisfaction. Neurovascular bundle preservation was the only predictor of being comfortable regarding urinary symptoms postoperatively (OR 12.8 [CI95% 1.47-111.7], P = .02 at 3months) and was also associated to higher median postoperative IIEF-5. CONCLUSION: Despite urinary incontinence following RARP, patients with larger prostates experience a reduction of lower urinary tract symptoms within a year, which subsequently elevates QoL. Furthermore, nerve-sparing surgery augments erectile function and urinary outcomes, shaping postoperative QoL.

Assessing the efficacy of pelvic floor muscle training and duloxetine on urinary continence recovery following radical prostatectomy: A randomized clinical trial.

BACKGROUND: Urinary incontinence (UI) can negatively impact quality of life (QoL) after robot-assisted radical prostatectomy (RARP). Pelvic floor muscle training (PFMT) and duloxetine are used to manage post-RARP UI, but their efficacy remains uncertain. We aimed to investigate the efficacy of PFMT and duloxetine in promoting urinary continence recovery (UCR) after RARP. METHODS: A randomized controlled trial involving patients with urine leakage after RARP from May 2015 to February 2018. Patients were randomized into 1 of 4 arms: (1) PFMT-biofeedback, (2) duloxetine, (3) combined PFMT-biofeedback and duloxetine, (4) control arm. PFMT consisted of pelvic muscle exercises conducted with electromyographic feedback weekly, for 3 months. Oral duloxetine was administered at bedtime for 3 months. The primary outcome was prevalence of continence at 6 months, defined as using ≤1 security pad. Urinary symptoms and QoL were assessed by using a visual analogue scale, and validated questionnaires. RESULTS: From the 240 patients included in the trial, 89% of patients completed 1 year of follow-up. Treatment compliance was observed in 88% (92/105) of patients receiving duloxetine, and in 97% (104/107) of patients scheduled to PFMT-biofeedback sessions. In the control group 96% of patients had achieved continence at 6 months, compared with 90% (p = 0.3) in the PMFT-biofeedback, 73% (p = 0.008) in the duloxetine, and 69% (p = 0.003) in the combined treatment arm. At 6 months, QoL was classified as uncomfortable or worse in 17% of patients in the control group, compared with 44% (p = 0.01), 45% (p = 0.008), and 34% (p = 0.07), respectively. Complete preservation of neurovascular bundles (NVB) (OR: 2.95; p = 0.048) was the only perioperative intervention found to improve early UCR. CONCLUSIONS: PFMT-biofeedback and duloxetine demonstrated limited impact in improving UCR after RP. Diligent NVB preservation, along with preoperative patient and disease characteristics, are the primary determinants for early UCR.

The Prognostic Role of Preoperative PSMA PET/CT in cN0M0 pN+ Prostate Cancer: A Multicenter Study.

CONTEXT: Despite negative preoperative conventional imaging, up to 10% of patients with prostate cancer (PCa) harbor lymph-node involvement (LNI) at radical prostatectomy (RP). The advent of more accurate imaging modalities such as PET/CT improved the detection of LNI. However, their clinical impact and prognostic value are still unclear. We aimed to investigate the prognostic value of preoperative PET/CT in patients node positive (pN+) at RP. EVIDENCE SYNTHESIS: We retrospectively identified cN0M0 patients at conventional imaging (CT and/or MRI, and bone scan) who had pN+ PCa at RP at 17 referral centers. Patients with cN+ at PSMA/Choline PET/CT but cN0M0 at conventional imaging were also included. Systemic progression/recurrence was the primary outcome; Cox proportional hazards models were used for multivariate analysis. EVIDENCE ACQUISITION: We included 1163 pN+ men out of whom 95 and 100 had preoperative PSMA and/or Choline PET/CT, respectively. ISUP grade ≥4 was detected in 66.6%. Overall, 42% of patients had postoperative PSA persistence (≥0.1 ng/mL). Postoperative management included initial observation (34%), ADT (22.7%) and adjuvant RT+/-ADT (42.8%). Median follow-up was 42 months. Patients with cN+ on PSMA PET/CT had an increased risk of systemic progression (52.9% vs. 13.6% cN0 PSMA PET/CT vs. 21.5% cN0 at conventional imaging; P < .01). This held true at multivariable analysis: (HR 6.184, 95% CI: 3.386-11-295; P < .001) whilst no significant results were highlighted for Choline PET/CT. No significant associations for both PET types were found for local progression, BCR, and overall mortality (all P > .05). Observation as an initial management strategy instead of adjuvant treatments was related with an increased risk of metastases (HR 1.808; 95% CI: 1.069-3.058; P < .05). CONCLUSIONS: PSMA PET/CT cN+ patients with negative conventional imaging have an increased risk of systemic progression after RP compared to their counterparts with cN0M0 disease both at conventional and/or molecular imaging.

Development, multi-institutional external validation, and algorithmic audit of an artificial intelligence-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA) for patients undergoing radical prostatectomy: a retrospective cohort study.

BACKGROUND: Accurate prediction of side-specific extraprostatic extension (ssEPE) is essential for performing nerve-sparing surgery to mitigate treatment-related side-effects such as impotence and incontinence in patients with localised prostate cancer. Artificial intelligence (AI) might provide robust and personalised ssEPE predictions to better inform nerve-sparing strategy during radical prostatectomy. We aimed to develop, externally validate, and perform an algorithmic audit of an AI-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA). METHODS: Each prostatic lobe was treated as an individual case such that each patient contributed two cases to the overall cohort. SEPERA was trained on 1022 cases from a community hospital network (Trillium Health Partners; Mississauga, ON, Canada) between 2010 and 2020. Subsequently, SEPERA was externally validated on 3914 cases across three academic centres: Princess Margaret Cancer Centre (Toronto, ON, Canada) from 2008 to 2020; L'Institut Mutualiste Montsouris (Paris, France) from 2010 to 2020; and Jules Bordet Institute (Brussels, Belgium) from 2015 to 2020. Model performance was characterised by area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), calibration, and net benefit. SEPERA was compared against contemporary nomograms (ie, Sayyid nomogram, Soeterik nomogram [non-MRI and MRI]), as well as a separate logistic regression model using the same variables included in SEPERA. An algorithmic audit was performed to assess model bias and identify common patient characteristics among predictive errors. FINDINGS: Overall, 2468 patients comprising 4936 cases (ie, prostatic lobes) were included in this study. SEPERA was well calibrated and had the best performance across all validation cohorts (pooled AUROC of 0·77 [95% CI 0·75-0·78] and pooled AUPRC of 0·61 [0·58-0·63]). In patients with pathological ssEPE despite benign ipsilateral biopsies, SEPERA correctly predicted ssEPE in 72 (68%) of 106 cases compared with the other models (47 [44%] in the logistic regression model, none in the Sayyid model, 13 [12%] in the Soeterik non-MRI model, and five [5%] in the Soeterik MRI model). SEPERA had higher net benefit than the other models to predict ssEPE, enabling more patients to safely undergo nerve-sparing. In the algorithmic audit, no evidence of model bias was observed, with no significant difference in AUROC when stratified by race, biopsy year, age, biopsy type (systematic only vs systematic and MRI-targeted biopsy), biopsy location (academic vs community), and D'Amico risk group. According to the audit, the most common errors were false positives, particularly for older patients with high-risk disease. No aggressive tumours (ie, grade >2 or high-risk disease) were found among false negatives. INTERPRETATION: We demonstrated the accuracy, safety, and generalisability of using SEPERA to personalise nerve-sparing approaches during radical prostatectomy. FUNDING: None.

Diagnostic accuracy and clinical utility of micro-ultrasound guided biopsies in patients with suspected prostate cancer.

Introduction: New technologies to improve quality of prostate biopsies are appearing in clinical practice.We evaluate the performance of a micro-ultrasound device and the Prostate Risk Identification using MicroUltraSound (PRI-MUS) score in detecting clinically significant prostate cancer (csPCa). Material and methods: We retrospectively reviewed data of 139 biopsy- naïve patients with suspicion of prostate cancer, who underwent diagnostic MRI and micro-ultrasonography (microUS), followed by transrectal prostatic biopsy (systematic ±targeted) under local anesthetic. The main objective was to evaluate the performance of the Prostate Risk Identification using MicroUltraSound (PRI-MUS) score in detecting csPCa, defined as International Society of Urological Pathology (ISUP) ≥2. Results: Of all patients, 97 (70%) were found to have PCa, and 62 (45%) having csPCa.Among 100 patients with positive microUS (PRI-MUS score ≥3), 23 (23%) had ncsPCa and 57 (57%) were diagnosed with csPCa (ISUP ≥2); and in 39 patients with negative microUS, 12 (31%) were diagnosed with ncsPCa and 5 (13%) with csPCa.A PRI-MUS score ≥3 presented a sensitivity, specificity, positive predictive value and negative predictive value of 92%, 44%, 57% and 95%, respectively, for the detection of csPCa.The PRI-MUS score had higher areas under the curve than Prostate Imaging Reporting & Data System (PI-RADS) both for targeted (AUC 0.801 vs 0.733) and systematic + targeted (AUC 0.776 vs 0.694) biopsies for csPCa detection. Conclusions: In our cohort, microUS performed well as a diagnostic tool through an easily implementable scale. MicroUS presented similar sensitivity and higher specificity than MRI in detecting csPCa. Further multicenter prospective studies may clarify its role in prostate cancer diagnosis.

Accuracy of PET-choline in nodal staging of localized very high-risk prostate cancer.

OBJECTIVES: Localized very high-risk prostate cancer (VHR PCa) has long suffered from the inex-istence of good lymph node staging methods other than invasive surgery, as computed tomogra-phy has low sensitivity for nodal disease. With the rising use of positron emission tomography (PET), it is clinically meaningful to know its value for these patients. Our goal was to evaluate the real-life diagnostic accuracy of PET Choline in nodal staging, comparing it with the gold standard of extended pelvic lymph node dissection (ePLND). MATERIALS AND METHODS: We reviewed data from a high-volume center, including patients with VHR PCa according to current NCCN guidelines who underwent community 18F-fluorocholine PET/CT; followed by ro-botic assisted laparoscopic prostatectomy (RALP) and ePLND between 2010 and 2021. RESULTS: We included 44 patients and 88 lymph node regions. Among those, 14/44 (31.8%) patients and 20/88 (22.7%) regions had nodal disease present on definitive pathology. In comparison with ePLND, we found a sensitivity of 64.3% (95% CI, 39.2-89.4%), specificity of 83.3% (95% CI, 70.0- 96.7%), PPV of 64.3% (95% CI, 39.2-89.4%), and NPV of 83.3% (95% CI, 70.0-96.7%) for nodal disease on a patient-based analysis; and sensitivity of 35.0% (95% CI, 14.1-60.0%), specificity of 88.2% (95% CI, 80.6-95.9%), PPV of 46.7% (95% CI, 21.4-71.9%), and NPV of 82.2% (95% CI, 73.4-91.0%) on a region-based analysis. CONCLUSIONS: In our view 18F-fluorocholine PET/CT doesn't meet the criteria to be a standard exam for pre-operative staging for patients with VHR PCa, mostly due to its low sensitivity. However, other radiotracers should continue to be investigated in this setting.

Medium-term oncological outcomes of intermediate-risk prostate cancer treated with HIFU or cryotherapy. A single center 10-year experience.

OBJECTIVES: Focal therapies (FTs) are promising techniques for the treatment of localized prostate cancer. We assessed the medium-term oncological outcomes of intermediate-risk prostate cancer (PCa) treated with HIFU or cryotherapy. MATERIALS AND METHODS: One-hundred and fifty consecutive patients with intermediate-risk PCa, treated between 2009 and 2018 at a single center were included. Primary study outcome was failure-free survival (FFS), defined as absence of additional treatment, systemic progression or prostate cancer related death. RESULTS: Thirty-seven (25%) patients underwent cryotherapy and 113 (75%) HIFU. Median age was 69 (IQR 62-72) years, with 36 (24%) presenting palpable disease on rectal examination, and median total PSA of 7.85 (IQR 5.75-10.62) ng/mL. Patients were followed for a median of 61 (IQR 48-82) months. FFS at 2 and 4 years was of 75.6% and 53.6%, respectively. Survival from whole gland or systematic treatment at 2 and 4 years was of 78.9% and 53.9%, respectively. Patients with FFS presented lower total PSA nadir (1.89 vs 3.25 ng/mL, p < 0.001), higher % PSA reduction at 3 months (66.1% vs 49.3%, p < 0.001), and at nadir (75.5% vs 55.8%, p < 0.001). Other characteristics such has the treatment modality, age, prostate size, initial total PSA, cT stage, International Society of Urological Pathology (ISUP), tumor location and biopsy results by region did not differ between patients failing and not failing FT. Complications were uncommon (13%), with only onr (1%) patient having Clavien-Dindo grade > II. No deaths due to treatment were registered. CONCLUSIONS: At medium-term, FTs for intermediate-risk PCa presented good oncological results, with an excellent safety profile.

Focal High-Intensity Focused Ultrasound vs. Active Surveillance for ISUP Grade 1 Prostate Cancer: Medium-Term Results of a Matched-Pair Comparison.

INTRODUCTION/BACKGROUND: Only 1 randomized controlled trial has compared focal therapy and active surveillance (AS) for the low-risk prostate cancer (PCa). We investigated whether focal HIFU (fHIFU) yields oncologic advantages over AS for low-risk PCa. MATERIALS AND METHODS: We included 2 non-randomized prospective series of 132 (fHIFU) and 421 (AS) consecutive patients diagnosed with ISUP 1 PCa between 2008 and 2018. A matched pair analysis was performed to decrease potential bias. Study main outcomes were freedom from radical treatment (RT) or androgen-deprivation therapy (ADT), treatment-free survival (TFS), time to metastasis, and overall survival (OS). RESULTS: Median fHIFU follow-up was 50 months (interquartile range, 29-84 months). Among matched variables, no major differences were recorded except for AS having more suspicious digital rectal examination findings (P = .0074) and recent enrollment year (P = .0005). Five-year intervention-free survival from RT or ADT was higher for the fHIFU cohort (67.4% vs. 53.8%; P = .0158). Time to treatment was approximately 10 months shorter for AS than for fHIFU (time to RT, P = .0363; time to RT or ADT, P = .0156; time to any treatment, P = .0319). No differences were found in any-TFS (fHIFU, 61.4% vs. AS, 53.8%; P = .2635), OS (fHIFU, 97% vs. AS, 97%; P = .9237), or metastasis (n = 0 in fHIFU and n = 2 in AS; P = .4981). Major complications (≥ Clavien 3) were rare (n = 4), although 36.4% of men experienced complications. No relevant changes were noted in continence (P = .3949). CONCLUSION: At a 4-year median follow-up, fHIFU for mainly low-risk PCa (ISUP grade 1) is safe, may decrease the need for radical treatment or ADT and may allow longer time to treatment compared to AS. Nonetheless, no advantages are seen in PCa progression and/or death (OS).

Selecting the Best Candidates for Cisplatin-based Adjuvant Chemotherapy After Radical Cystectomy Among Patients with pN+ Bladder Cancer.

A trend towards greater benefit from adjuvant chemotherapy (ACT) in pN+ bladder cancer (BCa) has been observed in multiple randomized controlled trials. However, it is still unclear which patients might benefit the most from this approach. We retrospectively analyzed a multicenter cohort of 1381 patients with pTany pN1-3 cM0 R0 urothelial BCa treated with radical cystectomy (RC) with or without cisplatin-based ACT. The main endpoint was overall survival (OS) after RC. We performed 1:1 propensity score matching to adjust for baseline characteristics and conducted a classification and regression tree (CART) analysis to assess postoperative risk groups and Cox regression analyses to predict OS. Overall, 391 patients (28%) received cisplatin-based ACT. After matching, two cohorts of 281 patients with pN+ BCa were obtained. CART analysis stratified patients into three risk groups: favorable prognosis (≤pT2 and positive lymph node [PLN] count ≤2; odds ratio [OR] 0.43), intermediate prognosis (≥pT3 and PLN count ≤2; OR 0.92), and poor prognosis (pTany and PLN count ≥3; OR 1.36). Only patients with poor prognosis benefitted from ACT in terms of OS (HR 0.51; p < 0.001). We created the first algorithm that stratifies patients with pN+ BCa into prognostic classes and identified patients with pTany BCa with PLN ≥3 as the most suitable candidates for cisplatin-based ACT. PATIENT SUMMARY: We found that overall survival among patients with bladder cancer and evidence of lymph node involvement depends on cancer stage and the number of positive lymph nodes. Patients with more than three nodes affected by metastases seem to experience the greatest overall survival benefit from cisplatin-based chemotherapy after bladder removal. Our study suggests that patients with the highest risk should be prioritized for cisplatin-based chemotherapy after bladder removal.

Neoadjuvant chemotherapy does not increase peri-operative morbidity following radical cystectomy.

OBJECTIVE: To determine whether use of neoadjuvant chemotherapy (NAC) is associated with a higher risk of post-operative complications following radical cystectomy (RC) for bladder cancer (BCa). MATERIALS AND METHODS: We retrospectively reviewed records of patients undergoing RC for non-metastatic urothelial BCa at 13 tertiary care centres from 2007-2019. Patients who received NAC ('NAC + RC' group) were compared with those who underwent upfront RC ('RC alone' group) for intra-operative variables, incidence of post-operative complications as per the Clavien-Dindo classification (CDC) and rates of re-admission and re-intervention. Multivariable logistic regression analysis was performed to determine predictors of CDC overall and CDC major (grade III-V) complications. We also analysed the trend of NAC utilization over the study period. RESULTS: Of the 3113 patients included, 968 (31.1%) received NAC while the remaining 2145 (68.9%) underwent upfront RC for BCa. There was no significant difference between the NAC + RC and RC alone groups with regards to 30-day CDC overall (53.2% vs 54.6%, p = 0.4) and CDC major (15.5% vs 16.5%, p = 0.6) complications. The two groups were comparable for the rate of surgical re-intervention (14.6% in each group) and re-hospitalization (19.6% in NAC + RC vs 17.9% in RC alone, p = 0.2%) at 90 days. On multivariable regression analysis, NAC use was not found to be a significant predictor of 90-day CDC overall (OR 1.02, CI 0.87-1.19, p = 0.7) and CDC major (OR 1.05, CI 0.87-1.26, p = 0.6) complications. We also observed that the rate of NAC utilization increased significantly (p < 0.001) from 11.1% in 2007 to 41.2% in 2019, reaching a maximum of 48.3% in 2018. CONCLUSION: This large multicentre analysis with a substantial rate of NAC utilization showed that NAC use does not lead to an increased risk of post-operative complications following RC for BCa. This calls for increasing NAC use to allow patients to avail of its proven oncologic benefit.

Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial.

BACKGROUND: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. METHODS: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. FINDINGS: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. INTERPRETATION: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. FUNDING: Bristol Myers Squibb, ARTIC.

Available evidence on HIFU for focal treatment of prostate cancer: a systematic review

ABSTRACT Purpose: Prostate cancer (PCa) is the second most common oncologic disease among men. Radical treatment with curative intent provides good oncological results for PCa survivors, although definitive therapy is associated with significant number of serious side-effects. In modern-era of medicine tissue-sparing techniques, such as focal HIFU, have been proposed for PCa patients in order to provide cancer control equivalent to the standard-of-care procedures while reducing morbidities and complications. The aim of this systematic review was to summarise the available evidence about focal HIFU therapy as a primary treatment for localized PCa. Material and methods: We conducted a comprehensive literature review of focal HIFU therapy in the MEDLINE database (PROSPERO: CRD42021235581). Articles published in the English language between 2010 and 2020 with more than 50 patients were included. Results: Clinically significant in-field recurrence and out-of-field progression were detected to 22% and 29% PCa patients, respectively. Higher ISUP grade group, more positive cores at biopsy and bilateral disease were identified as the main risk factors for disease recurrence. The most common strategy for recurrence management was definitive therapy. Six months after focal HIFU therapy 98% of patients were totally continent and 80% of patients retained sufficient erections for sexual intercourse. The majority of complications presented in the early postoperative period and were classified as low-grade. Conclusions: This review highlights that focal HIFU therapy appears to be a safe procedure, while short-term cancer control rate is encouraging. Though, second-line treatment or active surveillance seems to be necessary in a significant number of patients.

Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer.

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.

The Cancer of the Bladder Risk Assessment (COBRA) score accurately predicts cancer-specific survival after radical cystectomy: external validation and lymphovascular invasion assessment value to improve its performance.

The Cancer of the Bladder Risk Assessment (COBRA) score is a predictive tool for estimating Cancer Specific Survival (CSS) after Radical Cystectomy (RC) for urothelial carcinoma. COBRA score variables are: age at RC, Tumor stage and Lymph Node Density (LND). We sought to externally validate the COBRA score and to improve its performance in estimating CSS adding Lymphovascular Invasion (LVI) as a further variable (Modified COBRA score). Clinicopathological and survival data from 789 patients who underwent RC and Pelvic Lymph Node Dissection (PLND) between January 2007 and December 2020 in two European referral centers (Paris, France and Badalona, Spain) were analyzed. COBRA score was applied to our cohort and CSS Kaplan-Meier curves were performed. Univariable and Multivariable analysis was performed in order to identify risk factors for Cancer Specific Mortality (CSM) and a score was assigned for any statistically significant risk factor; afterward, c-index calculation was performed and CCS curves have been plotted for the model after having integrated LVI variable to the COBRA score. Finally, we compared both COBRA score and Modified COBRA score models with the established AJCC model. A total of 789 patients underwent RC during the observation period. Complete data were available for 731 patients with a median follow-up of 32 months (8-47). CSM was 27.6% (no. 218 patients) at follow-up. When COBRA score was applied to our cohort, c-index was 0.76. Regression COX analysis has shown HR 0.36, CI 95% (0.16-0.83), P = .016 for patients with COBRA score 1; HR 0, CI 95% (0-1.77), P =.94 for score 2; HR 0.51, CI 95% (0.39 -0.67), P =.001 for score 3; HR 1.67, CI 95% (1.23-2.27), P =.001 for score 4; HR 2.45, CI 95% (1.51-3.99), P =.001 for score 5; HR 2.01, CI 95% (1.42-2.85), P =.001 for score 6 and HR 0.66, CI 95% (0.09-4.73), P =.682 for score 7. When the LVI variable was added to the CSS predictive model the discriminatory power increased to a c-index of 0.78. COBRA score adequately identifies those patients with a higher risk of CSM, with a c-index of 0.76. Moreover, LVI variable further improves its predictive accuracy from c-index of 0.76 to c-index of 0.78. LVI variable could be integrated in the COBRA score to optimizing prognosis stratification for patients who undergo RC.

Pelvic lymph node dissection in high-risk prostate cancer

ABSTRACT Introduction: The therapeutic role of pelvic lymph node dissection (PLND) in prostate cancer (PCa) is unknown due to absence of randomized trials. Objective: to present a critical review on the therapeutic benefits of PLND in high risk localized PCa patients. Materials and Methods: A search of the literature on PLND was performed using PubMed, Cochrane, and Medline database. Articles obtained regarding diagnostic imaging and sentinel lymph node dissection, PLND extension, impact of PLND on survival, PLND in node positive "only" disease and PLND surgical risks were critically reviewed. Results: High-risk PCa commonly develops metastases. In these patients, the possibility of presenting lymph node disease is high. Thus, extended PLND during radical prostatectomy may be recommended in selected patients with localized high-risk PCa for both accurate staging and therapeutic intent. Although recent advances in detecting patients with lymph node involvement (LNI) with novel imaging and sentinel node dissection, extended PLND continues to be the most accurate method to stage lymph node disease, which may be related to the number of nodes removed. However, extended PLND increases surgical time, with potential impact on perioperative complications, hospital length of stay, rehospitalization and healthcare costs. Controversy persists on its therapeutic benefit, particularly in patients with high node burden. Conclusion: The impact of PLND on biochemical recurrence and PCa survival is unclear yet. Selection of patients may benefit from extended PLND but the challenge remains to identify them accurately. Only prospective randomized study would answer the precise role of PLND in high-risk pelvis confined PCa patients.

Molecular biomarkers in the context of focal therapy for prostate cancer: recommendations of a Delphi Consensus from the Focal Therapy Society.

BACKGROUND: Focal therapy (FT) for prostate cancer (PCa) is promising. However, long-term oncological results are awaited and there is no consensus on follow-up strategies. Molecular biomarkers (MB) may be useful in selecting, treating and following up men undergoing FT, though there is limited evidence in this field to guide practice. We aimed to conduct a consensus meeting, endorsed by the Focal Therapy Society, amongst a large group of experts, to understand the potential utility of MB in FT for localized PCa. METHODS: A 38-item questionnaire was built following a literature search. The authors then performed three rounds of a Delphi Consensus using DelphiManager, using the GRADE grid scoring system, followed by a face-to-face expert meeting. Three areas of interest were identified and covered concerning MB for FT, 1) the current/present role; 2) the potential/future role; 3) the recommended features for future studies. Consensus was defined using a 70% agreement threshold. RESULTS: Of 95 invited experts, 42 (44.2%) completed the three Delphi rounds. Twenty-four items reached a consensus and they were then approved at the meeting involving (N.=15) experts. Fourteen items reached a consensus on uncertainty, or they did not reach a consensus. They were re-discussed, resulting in a consensus (N.=3), a consensus on a partial agreement (N.=1), and a consensus on uncertainty (N.=10). A final list of statements were derived from the approved and discussed items, with the addition of three generated statements, to provide guidance regarding MB in the context of FT for localized PCa. Research efforts in this field should be considered a priority. CONCLUSIONS: The present study detailed an initial consensus on the use of MB in FT for PCa. This is until evidence becomes available on the subject.

Available evidence on HIFU for focal treatment of prostate cancer: a systematic review.

PURPOSE: Prostate cancer (PCa) is the second most common oncologic disease among men. Radical treatment with curative intent provides good oncological results for PCa survivors, although definitive therapy is associated with significant number of serious side-effects. In modern-era of medicine tissue-sparing techniques, such as focal HIFU, have been proposed for PCa patients in order to provide cancer control equivalent to the standard-of-care procedures while reducing morbidities and complications. The aim of this systematic review was to summarise the available evidence about focal HIFU therapy as a primary treatment for localized PCa. MATERIAL AND METHODS: We conducted a comprehensive literature review of focal HIFU therapy in the MEDLINE database (PROSPERO: CRD42021235581). Articles published in the English language between 2010 and 2020 with more than 50 patients were included. RESULTS: Clinically significant in-field recurrence and out-of-field progression were detected to 22% and 29% PCa patients, respectively. Higher ISUP grade group, more positive cores at biopsy and bilateral disease were identified as the main risk factors for disease recurrence. The most common strategy for recurrence management was definitive therapy. Six months after focal HIFU therapy 98% of patients were totally continent and 80% of patients retained sufficient erections for sexual intercourse. The majority of complications presented in the early postoperative period and were classified as low-grade. CONCLUSIONS: This review highlights that focal HIFU therapy appears to be a safe procedure, while short-term cancer control rate is encouraging. Though, second-line treatment or active surveillance seems to be necessary in a significant number of patients.

Pelvic lymph node dissection in high-risk prostate cancer.

INTRODUCTION: The therapeutic role of pelvic lymph node dissection (PLND) in prostate cancer (PCa) is unknown due to absence of randomized trials. OBJECTIVE: to present a critical review on the therapeutic benefits of PLND in high risk localized PCa patients. MATERIALS AND METHODS: A search of the literature on PLND was performed using PubMed, Cochrane, and Medline database. Articles obtained regarding diagnostic imaging and sentinel lymph node dissection, PLND extension, impact of PLND on survival, PLND in node positive "only" disease and PLND surgical risks were critically reviewed. RESULTS: High-risk PCa commonly develops metastases. In these patients, the possibility of presenting lymph node disease is high. Thus, extended PLND during radical prostatectomy may be recommended in selected patients with localized high-risk PCa for both accurate staging and therapeutic intent. Although recent advances in detecting patients with lymph node involvement (LNI) with novel imaging and sentinel node dissection, extended PLND continues to be the most accurate method to stage lymph node disease, which may be related to the number of nodes removed. However, extended PLND increases surgical time, with potential impact on perioperative complications, hospital length of stay, rehospitalization and healthcare costs. Controversy persists on its therapeutic benefit, particularly in patients with high node burden. CONCLUSION: The impact of PLND on biochemical recurrence and PCa survival is unclear yet. Selection of patients may benefit from extended PLND but the challenge remains to identify them accurately. Only prospective randomized study would answer the precise role of PLND in high-risk pelvis confined PCa patients.

Long-term Outcomes of Focal Cryotherapy for Low- to Intermediate-risk Prostate Cancer: Results and Matched Pair Analysis with Active Surveillance.

BACKGROUND: To date, only one trial compared focal therapy and active surveillance (AS) for low-risk prostate cancer (PCa). In addition, long-term outcomes of focal cryotherapy (FC) are lacking. OBJECTIVE: Our aim was to evaluate long-term outcomes of FC and compare them with AS. DESIGN, SETTING, AND PARTICIPANTS: We included two prospective series of 121 (FC) and 459 (AS) consecutive patients (2008-2018) for low- to intermediate-risk PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Study outcomes were radical therapy-free or androgen deprivation therapy (ADT)-free, any treatment-free, metastasis-free, and overall survival. A matched pair analysis was performed using seven covariates. RESULTS AND LIMITATIONS: The median FC follow-up was 85 mo (interquartile range 58-104); 92 (76%) men had International Society of Urological Pathology (ISUP) grade 1. Among matched variables, no significant differences were present except for cT stage and year of entry (both p < 0.01). Ten-year radical therapy-free or ADT-free, any treatment-free, metastasis-free, and overall survival were 51%, 40.2%, 93.9%, and 97%, respectively for FC. No differences were noted with AS (all p > 0.05), with the exception of time to radical therapy, time to radical therapy and ADT, and time to any treatment, all being shorter for AS (all p < 0.01). Freedom from radical treatment or ADT was higher for FC (AS 10 yr 39.3%; p = 0.04). Complications were relatively rare (26.5%) and mainly of low grade (Clavien >2, n = 3); three men developed incontinence (p = 0.0814), while both International Index of Erectile Function 5 and International Prostate Symptom Score scores increased (p = 0.0287 and p = 0.0165, respectively). Limitations include absence of randomization. CONCLUSIONS: At an early long-term follow-up, FC in the context of mainly low-risk PCa is safe and increases time to radical therapy but does not provide meaningful oncological advantages compared with AS. PATIENT SUMMARY: We compared focal cryotherapy with active surveillance mainly for low-risk prostate cancer. Focal cryotherapy, despite having fewer complications, did not yield meaningful advantages over active surveillance at 10 yr. Active surveillance should be preferred to focal cryotherapy for these patients.