Immune phenotype-genotype associations in primary clear cell renal cell carcinoma and matched metastatic tissue.

Adjuvant immunotherapy has been recently recommended for patients with metastatic ccRCC, but there are no tissue biomarkers to predict treatment response in ccRCC. Potential predictive biomarkers are mainly assessed in primary tumor tissue, whereas metastases remain understudied. To explore potential differences between genomic alterations and immune phenotypes in primary tumors and their matched metastases, we analyzed primary tumors (PTs) of 47 ccRCC patients and their matched distant metastases (METs) by comprehensive targeted parallel sequencing, whole-genome copy number variation (CNV) analysis, determination of microsatellite instability (MSI) and tumor mutational burden (TMB). We quantified the spatial distribution of tumor-infiltrating CD8+ T cells, and co-expression of the T-cell-exhaustion marker TOX by digital immunoprofiling and quantified tertiary lymphoid structures (TLS). Most METs were pathologically "cold". Inflamed, pathologically "hot" PTs were associated with a decreased disease-free survival (DFS), worst for patients with high levels of CD8+TOX+ T cells. Interestingly, inflamed METs showed a relative increase of exhausted CD8+TOX+ T cells and increased accumulative size of TLS compared to PTs. Integrative analysis of molecular and immune phenotypes revealed BAP1 and CDKN2A/B deficiency to be associated with an inflamed immune phenotype. Our results highlight the distinct spatial distribution and differentiation of CD8+ T cells at metastatic sites, and the association of an inflamed microenvironment with specific genomic alterations.

Comparison of Primary and Metastatic Fumarate Hydratase-Deficient Renal Cell Carcinomas Documents Morphologic Divergence and Potential Diagnostic Pitfall With Peritoneal Mesothelioma.

Fumarate hydratase (FH)-deficient renal cell carcinomas are rare neoplasms characterized by wide morphologic heterogeneity and pathogenetic mutations in the FH gene. They often show aggressive behavior with rapid diffusion to distant organs, so novel therapeutic scenarios have been explored, including EGFR inhibitors and PD-L1 expression for targeted immunotherapy. Herein, we investigated a series of 11 primary FH-deficient renal cell carcinomas and 7 distant metastases to evaluate tumor heterogeneity even in metastatic sites and estimate the specific spread rates to various organs. Furthermore, the tumors were tested for immunohistochemical PD-L1 expression and EGFR mutations. Most metastatic cases involved the abdominal lymph nodes (4/7; 57%), followed by the peritoneum (3/7; 42%), the liver (2/7; 29%), and the lungs (1/7; 14%). Six metastatic localizations were histologically documented, revealing a morphologic heterogeneous architecture often differing from that of the corresponding primary renal tumor. Peritoneal involvement morphologically resembled a benign reactive mesothelial process or primary peritoneal mesothelioma, thus advocating to perform an accurate immunohistochemical panel, including PAX8 and FH, to reach a proper diagnosis. A pure low-grade succinate dehydrogenase-looking primary FH-deficient renal cell carcinoma was also recorded. As for therapy, significant PD-L1 labeling was found in 60% of primary renal tumors, whereas none of them carried pathogenetic EGFR mutations. Our data show that FH-deficient renal cell carcinoma may be morphologically heterogeneous in metastases as well, which involve the lymph nodes, the liver, and the peritoneum more frequently than other renal tumors. Due to the high frequency of this latter (42%), pathologists should always be concerned about ruling out mesothelial-derived mimickers, and the occurrence of rarer, primary, low-grade-looking types. Finally, contrary to EGFR mutations, PD-L1 expression could be a possible predictive biomarker for the therapy of these tumors.

Sarcoidosis-like reactions in metastatic renal cell carcinoma patients treated with immune-based combinations.

Aim: The incidence of drug-induced sarcoidosis-like reactions (DISR) in patients treated with immune checkpoint inhibitors (ICIs) is rising. We determine the incidence and characteristics of DISR in a metastatic renal cell carcinoma (mRCC) population. Methods: We retrospectively reviewed clinico-radiological data of 83 mRCC patients treated at a single institution with immune-based combinations. Results: 15 patients received immune-doublet (ipilimumab-nivolumab), while 68 patients received other immune-based combinations. Two cases of DISR (2.4%) were evidenced, with enlargement of mediastinal lymph nodes that mimicked disease progression, thus requiring a biopsy which showed histological features of DISR. Conclusion: In our series of the incidence of DISR, radiological and clinical features, are in line with literature. DISR diagnosis is often only radiological, and its occurrence is possibly associated with a better outcome.

The development of sarcoidosis-like lesions (DISR) is a rare event observed in cancer patients receiving immunotherapy. DISR occurrence represents a huge diagnostic issue, because its clinical and radiological features simulate disease progression. We present a series of 83 patients with kidney cancer receiving immunotherapy. During the therapy, two of these patients showed enlargement of chest lymph nodes that could be interpreted as disease progression. However, the microscopic analysis of these lymph nodes showed evidence of DISR. In conclusion, DISR should be adequately recognized to correctly manage patients who receive immunotherapy.

Briganti's 2012 nomogram is an independent predictor of prostate cancer progression in EAU intermediate-risk class: results from 527 patients treated with robotic surgery.

ABSTRACT: The study aimed to test if Briganti's 2012 nomogram could be associated with the risk of prostate cancer (PCa) progression in European Association of Urology (EAU) intermediate-risk patients treated with robotic surgery. From January 2013 to December 2021, 527 consecutive patients belonging to the EAU intermediate-risk class were selected. Briganti's 2012 nomogram, which predicts the risk of pelvic lymph node invasion (PLNI), was assessed as a continuous and dichotomous variable that categorized up to the median of 3.0%. Disease progression defined as biochemical recurrence and/or metastatic progression was evaluated by Cox proportional hazards (univariate and multivariate analysis). After a median follow-up of 95.0 months (95% confidence interval [CI]: 78.5-111.4), PCa progression occurred in 108 (20.5%) patients who were more likely to present with an unfavorable nomogram risk score, independently by the occurrence of unfavorable pathology including tumor upgrading and upstaging as well as PLNI. Accordingly, as Briganti's 2012 risk score increased, patients were more likely to experience disease progression (hazard ratio [HR] = 1.060; 95% CI: 1.021-1.100; P = 0.002); moreover, it also remained significant when dichotomized above a risk score of 3.0% (HR = 2.052; 95% CI: 1.298-3.243; P < 0.0001) after adjustment for clinical factors. In the studied risk population, PCa progression was independently predicted by Briganti's 2012 nomogram. Specifically, we found that patients were more likely to experience disease progression as their risk score increased. Because of the significant association between risk score and tumor behavior, the nomogram can further stratify intermediate-risk PCa patients, who represent a heterogeneous risk category for which different treatment paradigms exist.

Analyses of tumor microenvironment in patients with advanced renal cell carcinoma receiving immunotherapy (Meet-URO 18 study).

Introduction: The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as responders (progression-free survival ≥ 12 months) and non-responders (progression-free survival < 3 months). Areas covered: The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. Responders' tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (p = 0.014), higher CD56 expression (p = 0.046) and higher CD8/CD4 ratio (p = 0.030). Expert opinion/commentary: The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy.

High-volume surgeons decrease operating time in robot-assisted radical prostatectomy: results in 1229 patients.

BACKGROUND: The aim is to evaluate factors impacting operating time (OT) during robot-assisted radical prostatectomy (RARP) with or without extended pelvic lymph node dissection (ePLND) for prostate cancer. METHODS: Overall, 1289 patients underwent RARP from January 2013 to December 2021. ePLND was performed in 825 cases. Factors potentially associated with OT variations were assessed. Three low-volume (LVS) and two high-volume surgeons (HVS) performed the procedures. A linear regression model was computed to assess associations with OT variations. RESULTS: When RARP was performed by HVS an OT decrease was observed independently by significant clinical (Body Mass Index [BMI]; prostate volume [PV]) and anatomical/perioperative features (prostate weight [PW]; intraoperative blood loss [BL]) both in clinical (change in OT: -42.979 minutes; 95% CI: -51.789; -34.169; P<0.0001) and anatomical/perioperative models (change in OT: -40.020 minutes; 95% CI: -48.494; -31.587; P<0.0001). A decreased OT was observed in clinical (change in OT: -27.656 minutes; 95% CI: -33.449; -21.864; P<0.0001) and anatomical/perioperative (change in OT: -24.935 minutes; 95% CI: -30.562; -19.308; P<0.0001) models also in case of RARP with ePLND performed by HVS, independently by BMI, PV, PSA as well as for PW, seminal vesicle invasion, positive surgical margins, and BL. CONCLUSIONS: In a tertiary academic referral center, OT decreased when RARP was performed by HVS, independently of adverse clinical and anatomical/perioperative factors. Available OT loads can be planned to optimize waiting lists, teaching tasks, operative costs, and surgeon's volume.

Prognostic Impact and Clinical Implications of Adverse Tumor Grade in Very Favorable Low- and Intermediate-Risk Prostate Cancer Patients Treated with Robot-Assisted Radical Prostatectomy: Experience of a Single Tertiary Referral Center.

OBJECTIVES: To assess the prognostic impact and predictors of adverse tumor grade in very favorable low- and intermediate-risk prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy (RARP). METHODS: Data of low- and intermediate PCa risk-class patients were retrieved from a prospectively maintained institutional database. Adverse tumor grade was defined as pathology ISUP grade group > 2. Disease progression was defined as a biochemical recurrence event and/or local recurrence and/or distant metastases. Associations were assessed by Cox's proportional hazards and logistic regression model. RESULTS: Between January 2013 and October 2020, the study evaluated a population of 289 patients, including 178 low-risk cases (61.1%) and 111 intermediate-risk subjects (38.4%); unfavorable tumor grade was detected in 82 cases (28.4%). PCa progression, which occurred in 29 patients (10%), was independently predicted by adverse tumor grade and biopsy ISUP grade group 2, with the former showing stronger associations (hazard ratio, HR = 4.478; 95% CI: 1.840-10.895; p = 0.001) than the latter (HR = 2.336; 95% CI: 1.057-5.164; p = 0.036). Older age and biopsy ISUP grade group 2 were independent clinical predictors of adverse tumor grade, associated with larger tumors that eventually presented non-organ-confined disease. CONCLUSIONS: In a very favorable PCa patient population, adverse tumor grade was an unfavorable prognostic factor for disease progression. Active surveillance in very favorable intermediate-risk patients is still a hazard, so molecular and genetic testing of biopsy specimens is needed.

Diagnostic Biomarkers in Renal Cell Tumors According to the Latest WHO Classification: A Focus on Selected New Entities.

The fifth edition of the World Health Organization (WHO) classification for urogenital tumors, released in 2022, introduces some novelties in the chapter on renal epithelial tumors compared to the previous 2016 classification. Significant changes include the recognition of new disease entities and adjustments in the nomenclature for certain pathologies. Notably, each tumor entity now includes minimum essential and desirable criteria for reliable diagnosis. This classification highlights the importance of biological and molecular characterization alongside traditional cytological and architectural features. In this view, immunophenotyping through immunohistochemistry (IHC) plays a crucial role in bridging morphology and genetics. This article aims to present and discuss the role of key immunohistochemical markers that support the diagnosis of new entities recognized in the WHO classification, focusing on critical topics associated with single markers, in the context of specific tumors, such as the clear cell capillary renal cell tumor (CCPRCT), eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), and so-called "other oncocytic tumors", namely the eosinophilic vacuolated tumor (EVT) and low-grade oncocytic tumor (LOT). Their distinctive characteristics and immunophenotypic profiles, along with insights regarding diagnostic challenges and the differential diagnosis of these tumors, are provided. This state-of-the-art review offers valuable insights in biomarkers associated with novel renal tumors, as well as a tool to implement diagnostic strategies in routine practice.

The 2012 Briganti nomogram not only predicts lymph node involvement but also disease progression in surgically treated intermediate-risk prostate cancer patients with PSA <10 ng/mL, ISUP grade group 3, and clinical stage up to cT2b.

PURPOSE: We assessed the prognostic impact of the 2012 Briganti nomogram on prostate cancer (PCa) progression in intermediate-risk (IR) patients presenting with PSA <10ng/mL, ISUP grade group 3, and clinical stage up to cT2b treated with robot assisted radical prostatectomy eventually associated with extended pelvic lymph node dissection. MATERIALS AND METHODS: From January 2013 to December 2021, data of surgically treated IR PCa patients were retrospectively evaluated. Only patients presenting with the above-mentioned features were considered. The 2012 Briganti nomogram was assessed either as a continuous and a categorical variable (up to the median, which was detected as 6%, vs. above the median). The association with PCa progression, defined as biochemical recurrence, and/or metastatic progression, was evaluated by Cox proportional hazard regression models. RESULTS: Overall, 147 patients were included. Compared to subjects with a nomogram score up to 6%, those presenting with a score above 6% were more likely to be younger, had larger/palpable tumors, presented with higher PSA, underwent tumor upgrading, harbored non-organ confined disease, and had positive surgical margins at final pathology. PCa progression, which occurred in 32 (21.7%) cases, was independently predicted by the 2012 Briganti nomogram both considered as a continuous (Hazard Ratio [HR]:1.04, 95% Confidence Interval [CI]:1.01-1.08;p=0.021), and a categorical variable (HR:2.32; 95%CI:1.11-4.87;p=0.026), even after adjustment for tumor upgrading. CONCLUSIONS: In IR PCa patients with PSA <10ng/mL, ISUP grade group 3, and clinical stage up to cT2b, the 2012 Briganti nomogram independently predicts PCa progression. In this challenging subset of patients, this tool can identify prognostic subgroups, independently by upgrading issues.

2012 Briganti nomogram predict prostate cancer progression in EAU intermediate risk with unfavorable tumor grade: A single center experience.

BACKGROUND: To investigate the potential prognostic impact of Briganti's 2012 nomogram in EAU intermediate-risk patients presenting with an unfavorable tumor grade and treated with robot-assisted radical prostatectomy, eventually associated with extended pelvic lymph node dissection. MATERIALS AND METHODS: From January 2013 to December 2021, the study included 179 EAU intermediate-risk patients presenting with an unfavorable tumor grade (ISUP 3), eventually associated with a PSA of 10-20 ng/ml and/or cT-2b. Briganti's 2012 nomogram was assessed as both a continuous and dichotomous variable, categorized according to the median (risk score ⩾7% vs <7%). Disease progression, defined as biochemical recurrence and/or metastatic progression, was evaluated using Cox proportional hazards in both univariate and multivariate analyses. RESULTS: Disease progression occurred in 43 (24%) patients after a median (95% CI) follow-up of 78 (65.7-88.4) months. The nomogram risk score predicted disease progression, evaluated both as a continuous variable (hazard ratio, HR = 1.064; 95% CI: 1.035-1.093; p < 0.0001) and as a categorical variable (HR = 3.399; 95% CI: 1.740-6.638; p < 0.0001). This association was confirmed in multivariate analysis, where hazard ratios remained consistent even after adjusting for clinical and pathological factors. CONCLUSIONS: In EAU intermediate-risk PCa cases presenting with an unfavorable tumor grade and treated surgically, Briganti's 2012 nomogram was associated with disease progression after surgery. Consequently, as the nomogram risk score increased, patients were more likely to experience PCa progression, facilitating the stratification of the patient population into distinct prognostic subgroups.

Forensic value of soft tissue detachments from the hyoid bone in death due to strangulation asphyxia.

BACKGROUND: There are no unequivocal histopathological findings for the diagnosis of fatal asphyxia due to neck compression. From the observation of a series of asphyxiation cases, we noted, during microscopic analysis, a high frequency of "detachment" of soft tissues from the hyoid bone. This specifically refers to the presence of an optical space between the surface of the hyoid bone and soft tissues. OBJECTIVES: We aimed to evaluate the detachment of soft tissues from the hyoid bone as specific histological evidence of death due to strangulation asphyxia. MATERIAL AND METHODS: Ten blocks were taken from deaths due to external mechanical compression of the neck (strangulation asphyxia, group A), 22 blocks were taken from deaths for other causes without trauma to the neck (group B), and 38 blocks were obtained from living subjects that have undergone laryngectomies (group C). The presence/absence of detachments were compared between the 3 groups (A, B and C) using Fisher's exact test. RESULTS: The detachment of soft tissues from the hyoid bone was observed in 5 cases (50%) in group A, 6 cases (27.2%) in group B, and 17 cases (44.3%) in group C. The sensitivity and specificity of the presence of the detachment in group A were 0.5 (95% confidence interval (95% CI): 0.38-0.62) and 0.57 (95% CI: 0.45-0.69), respectively. The comparison between the 3 groups and the presence/absence of soft tissue detachment showed no statistically significant differences between the groups (p = 0.329), clarifying that soft tissue detachment is a nonspecific variable for all 3 situations. CONCLUSIONS: Detachment of soft tissues has poor value as a single element to favor the diagnosis of asphyxia due to violent compression of the neck and should be interpreted as an artifactual finding, unrelated to the neck injury or injury vitality.

Analyses of tumor microenvironment in patients with advanced renal cell carcinoma receiving immunotherapy (Meet-URO 18 study).

Introduction: The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as responders (progression-free survival ≥ 12 months) and non-responders (progression-free survival < 3 months). Areas covered: The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. Responders' tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (p = 0.014), higher CD56 expression (p = 0.046) and higher CD8/CD4 ratio (p = 0.030). Expert opinion/commentary: The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy.

[Box: see text].

The 2012 Briganti nomogram predicts disease progression in surgically treated intermediate-risk prostate cancer patients with favorable tumor grade group eventually associated with some adverse factors.

To evaluate the prognostic potential of the 2012 Briganti nomogram for pelvic lymph node invasion on disease progression after surgery in intermediate-risk (IR) prostate cancer (PCa) patients with favorable tumor grade (International Society of Urological Pathology grade group 1 or 2), eventually associated with adverse clinical features as PSA between 10 and 20 ng/mL and/or clinical stage T2b. All IR PCa patients treated with robot-assisted radical prostatectomy and eventually extended pelvic lymph node dissection at the Department of Urology of the Integrated University Hospital of Verona between 2013 and 2021, with the abovementioned features, and available follow-up were considered. The 2012 Briganti nomogram score was assessed both as a continuous and dichotomous variable, where a mean risk score of 4% was used a threshold. The independent predictor status of the nomogram score on disease progression defined as the occurrence of biochemical recurrence and/or metastatic progression was evaluated using the Cox regression analysis. Overall, 348 patients were enrolled in the study. Median (interquartile range) follow-up was 98 (83.5-112.4) months. At multivariable Cox regression analysis, PCa progression, which occurred in 65 (18.7%) cases, was independently predicted only by the 2012 Briganti nomogram score evaluated as a continuous variable, among all considered clinical features (HR 1.16; 95%CI 1.08-1.24; p < 0.001). In addition, patients presenting with a nomogram score ≥ 4% were more likely to experience disease progression even after adjustment for clinical (HR 2.22, 95%CI 1.02-4.79; p = 0.043) and pathological (HR 1.80; 95%CI 1.06-3.05; p = 0.031) factors. In the examined patient population, the 2012 Briganti nomogram predicted PCa progression after surgery. Accordingly, as the risk score increased, patients were more likely to progress, independently by the occurrence of adverse pathology in the surgical specimen. The 2012 Briganti nomogram score categorized according to the mean value allowed to identify prognostic subgroups.

Optomechanical realization of the bosonic Kitaev chain.

The fermionic Kitaev chain is a canonical model featuring topological Majorana zero modes1. We report the experimental realization of its bosonic analogue2 in a nano-optomechanical network, in which the parametric interactions induce beam-splitter coupling and two-mode squeezing among the nanomechanical modes, analogous to hopping and p-wave pairing in the fermionic case, respectively. This specific structure gives rise to a set of extraordinary phenomena in the bosonic dynamics and transport. We observe quadrature-dependent chiral amplification, exponential scaling of the gain with system size and strong sensitivity to boundary conditions. All these are linked to the unique non-Hermitian topological nature of the bosonic Kitaev chain. We probe the topological phase transition and uncover a rich dynamical phase diagram by controlling interaction phases and amplitudes. Finally, we present an experimental demonstration of an exponentially enhanced response to a small perturbation3,4. These results represent the demonstration of a new synthetic phase of matter whose bosonic dynamics do not have fermionic parallels, and we have established a powerful system for studying non-Hermitian topology and its applications for signal manipulation and sensing.

Avelumab Plus Intermittent Axitinib in Previously Untreated Patients with Metastatic Renal Cell Carcinoma. The Tide-A Phase 2 Study.

BACKGROUND: Combinations of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitor (ICI) against PD1/PD-L1 are the standard first-line therapy for patients with metastatic renal cell carcinoma (mRCC), irrespective of the prognostic class. OBJECTIVE: To investigate the feasibility and safety of withdrawing VEGFR-TKI but continuing anti-PD1/PD-L1 in patients who achieve a response to their combination. DESIGN, SETTING, AND PARTICIPANTS: This was a single-arm phase 2 trial in patients with treatment-naïve mRCC with prior nephrectomy, without symptomatic/bulky disease and no liver metastases. INTERVENTION: Enrolled patients received axitinib + avelumab; after 36 wk of therapy those who achieved a tumour response interrupted axitinib and continued avelumab maintenance until disease progression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the rate of patients without progression 8 wk after the axitinib interruption. The secondary endpoints were the median value for progression-free (mPFS) and overall (mOS) survival and the safety in the overall population. RESULTS AND LIMITATIONS: Seventy-nine patients were enrolled and 75 were evaluated for efficacy. A total of 29 (38%) patients had axitinib withdrawn, as per the study design, with 72% of them having no progression after 8 wk and thus achieving the primary endpoint. The mPFS of the overall population was 24 mo, while the mOS was not reached. The objective response rate was 76% (12% complete response and 64% partial response), with 19% of patients having stable disease. In the patients who discontinued axitinib, the incidence of adverse events of any grade was 59% for grade 3 and 3% for grade 4. This study was limited by the lack of a comparative arm. CONCLUSIONS: The TIDE-A study demonstrates that the withdrawal of VEGFR-TKI with ICI maintenance is feasible for selected mRCC patients with evidence of a response to the VEGFR-TKI + ICI combination employed in first-line therapy. Axitinib interruption with avelumab maintenance leads to decreased side effects and should be investigated further as a new strategy to delay tumour progression. PATIENT SUMMARY: We evaluated whether certain patients with advanced kidney cancer treated with the fist-line combination of axitinib plus avelumab can interrupt the axitinib in case of a tumour response after 36 wk of therapy. We found that axitinib interruption improved the safety of the combination, while the maintenance with avelumab might delay tumour progression.

Tumor upgrading among very favorable intermediate-risk prostate cancer patients treated with robot-assisted radical prostatectomy: how can it impact the clinical course?

PURPOSE: We sought to investigate predictors of unfavorable tumor upgrading in very favorable intermediate-risk (IR) prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy, in addition to evaluate how it may affect the risk of disease progression. METHODS: A very favorable subset of IR PCa patients presenting with prostate-specific antigen (PSA) < 10 ng/mL, percentage of biopsy positive cores (BPC) < 50%, and either International Society of Urological Pathology (ISUP) grade group 1 and clinical stage T2b or ISUP grade group 2 and clinical stage T1c-2b was identified. Unfavorable pathology at radical prostatectomy was defined as the presence of ISUP grade group > 2 (unfavorable tumor upgrading), extracapsular extension (ECE), and seminal vesicle invasion (SVI). Disease progression was defined as the event of biochemical recurrence and/or local recurrence and/or distant metastases. Associations were evaluated by Cox regression and logistic regression analyses. RESULTS: Overall, 210 patients were identified between January 2013 and October 2020. Unfavorable tumor upgrading was detected in 71 (33.8%) cases, and adverse tumor stage, including ECE or SVI in 18 (8.6%) and 11 (5.2%) patients, respectively. Median (interquartile range) follow-up was 38.5 (16-61) months. PCa progression occurred in 24 (11.4%) patients. Very favorable IR PCa patients with unfavorable tumor upgrading at final pathology showed a persistent risk of disease progression, which hold significance after adjustment for all factors (Hazard Ratio [HR]: 5.95, 95% Confidence Interval [CI]: 1.97-17.92, p = 0.002) of which PSA was an independent predictor (HR: 1.52, 95% CI 1.12-2.08, p = 0.008). Moreover, these subjects were more likely to belong to the biopsy ISUP grade group 2. CONCLUSIONS: Very favorable IR PCa patients hiding unfavorable tumor upgrading were more likely to experience disease progression. Unfavorable tumor upgrading involved about one-third of cases and was less likely to occur in patients presenting with biopsy ISUP grade group 1. Tumor misclassification is an issue to discuss, when counseling this subset of patients for active surveillance because of the risk of delayed active treatment.

TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma.

Introduction: The surface protein TROP-2/TACSTD2 and the cell adhesion protein NECTIN-4/NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC. Aims: In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways. Results: Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2, FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC. Conclusion: Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC.

The impact of prognostic group classification on prostate cancer progression in intermediate-risk patients according to the European Association of Urology system: results in 479 patients treated with robot-assisted radical prostatectomy at a single tertiary referral center.

Background: Treatment outcomes in intermediate-risk prostate cancer (PCa) may be impaired by adverse pathology misclassification including tumor upgrading and upstaging. Clinical predictors of disease progression need to be improved in this category of patients. Objectives: To identify PCa prognostic factors to define prognostic groups in intermediate-risk patients treated with robot-assisted radical prostatectomy (RARP). Design: Data from 1143 patients undergoing RARP from January 2013 to October 2020 were collected: 901 subjects had available follow-up, of whom 479 were at intermediate risk. Methods: PCa progression was defined as biochemical recurrence and/or local recurrence and/or distant metastases. Study endpoints were evaluated by statistical methods including Cox's proportional hazards, Kaplan-Meyer survival curves, and binomial and multinomial logistic regression models. Results: After a median (interquartile range) of 35 months (15-57 months), 84 patients (17.5%) had disease progression, which was independently predicted by the percentage of biopsy-positive cores ⩾ 50% and the International Society of Urological Pathology (ISUP) grade group 3 for clinical factors and by ISUP > 2, positive surgical margins and pelvic lymph node invasion for pathological features. Patients were classified into clinical and pathological groups as favorable, unfavorable (one prognostic factor), and adverse (more than one prognostic factor). The risk of PCa progression increased with worsening prognosis through groups. A significant positive association was found between the two groups; consequently, as clinical prognosis worsened, the risk of detecting unfavorable and adverse pathological prognostic clusters increased in both unadjusted and adjusted models. Conclusion: The study identified factors predicting disease progression that allowed the computation of highly correlated prognostic groups. As the prognosis worsened, the risk of PCa progression increased. Intermediate-risk PCa needs more prognostic stratification for appropriate management.

A study on 479 patients looked at how prognostic group classification affects progression in patients with intermediate-risk prostate cancer treated with robot-assisted radical prostatectomy Prostate cancer is a serious health concern in men, and those with intermediate-risk prostate cancer may experience disease progression. Urologists use various methods to predict the risk of progression in these patients. However, sometimes the predictions are not accurate. Therefore, researchers conducted a study to identify factors that could help predict disease progression in patients with intermediate-risk prostate cancer who underwent robot-assisted surgery. This study on 479 patients found that a percentage of biopsy-positive cores ⩾ 50% and the International Society of Urological Pathology (ISUP) grade group 3 were predictive factors of disease progression. Additionally, factors like ISUP > 2, positive surgical margins, and pelvic lymph node invasion also predicted disease progression. Patients were classified into three groups based on their clinical and pathological features: favorable, unfavorable (one negative prognostic factor), and adverse (more than one negative prognostic factor). The risk of prostate cancer progression increased as the prognosis worsened through these groups. The study concluded that a more accurate stratification of intermediate-risk prostate cancer patients is needed to manage the disease effectively.

External validation of a red cell-based blood prognostic score in patients with metastatic renal cell carcinoma treated with first-line immunotherapy combinations.

Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47-0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39-0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling.