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Immune checkpoint inhibitors (ICIs) have reported unprecedented results in the treatment of metastatic renal cell carcinoma (mRCC) patients, as monotherapy or in combination with other anticancer agents. However, little information is available regarding the association between different clinicopathological features and survival in this setting.We performed a meta-analysis aimed at exploring the predictive value of routinely collected clinicopathological data in randomized controlled trials (RCTs) evaluating ICIs plus tyrosine kinase inhibitors (TKIs) in treatment-naïve patients with mRCC.We retrieved all the relevant RCTs through PubMed/Medline, Cochrane Library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible studies included RCTs assessing first-line ICI-TKI versus sunitinib in treatment-naïve mRCC patients; the primary endpoint was overall survival (OS), measured as hazard ratio (HR) with corresponding 95% confidence interval (CI).Overall, three phase III RCTs involving 1769 patients with advanced or metastatic RCC were included. Compared with sunitinib, the ICI-TKI combination significantly decreased the risk of death in patients with Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 (HR, 0.66; 95% CI, 0.57-0.76) and ECOG-PS 1 (HR, 0.64; 95% CI, 0.54-0.77). Similarly, the combination was associated with prolonged OS in patients who were65 yr old (HR, 0.57; 95% CI, 0.49-0.67), in mRCC patients ≥65 yr old (HR, 0.75; 95% CI, 0.61-0.90), as well as in male (HR, 0.66; 95% CI, 0.56-0.78) and female (HR, 0.66; 95% CI, 0.52-0.83) patients.According to our results, the magnitude of benefit of the ICI-TKI combination over sunitinib monotherapy in treatment-naïve mRCC patients was consistent across the clinicopathological subgroups. Despite the limitations affecting the analysis, we believe that the results of the current meta-analysis could assist clinicians and researchers in the design and interpretation of future clinical trials on combination therapies in this setting.First-line combinations of an immune checkpoint inhibitor plus a tyrosine kinase inhibitor improved survival in metastatic renal cell carcinoma (mRCC) patients. This survival benefit was consistent across all subgroups of mRCC patients irrespective of clinicopathological features such as patient performance status, age65 and ≥65 yr, and male and female gender.

Context Immune checkpoint inhibitors (ICIs) have reported durable responses in selected groups of patients with metastatic urothelial carcinoma (mUC). However, identification of biomarkers predictive of response to ICIs remains an unmet need in mUC management, and the role of programmed cell death ligand 1 (PD-L1) expression remains controversial. Objective In this systematic review and meta-analysis, we aimed at assessing the predictive value of PD-L1 in mUC patients receiving first-line ICIs as monotherapy or in combination with other anticancer agents across randomized controlled clinical trials (RCTs). Evidence acquisition We retrieved all the relevant RCTs through PubMed/Medline, Cochrane library, and EMBASE; proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible studies included RCTs evaluating ICIs versus chemotherapy in PD-L1–positive mUCs; the primary endpoint was overall survival (OS). Evidence synthesis Three phase III trials matched our eligibility criteria; a total of 2237 PD-L1–positive mUC patients (ICIs: 1125; chemotherapy: 1112) were included in the analysis. Compared with chemotherapy, ICIs were associated with higher OS in PD-L1–positive patients (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.78–0.96; p = 0.007); conversely, no differences were observed in the PD-L1–negative patient population (HR 1.03, 95% CI 0.89–1.19; p Conclusions Compared with standard chemotherapy, our results suggested a survival benefit in PD-L1–positive mUC patients receiving ICIs; conversely, no benefit was observed in patients with PD-L1–negative disease. Although this systematic review and meta-analysis should be interpreted with caution due to several issues, our results highlight the need for reliable predictive biomarkers of response to ICIs, providing a benchmark for future studies in this setting. Patient summary Despite immune checkpoint inhibitors (ICIs) having revolutionized the treatment landscape of metastatic urothelial carcinoma (mUC), an important percentage of patients do not experience clinical benefit or durable responses. Identification of reliable biomarkers of response to ICIs remains a mandatory need in mUC management, and further efforts are needed to standardize the assessment of programmed cell death ligand 1 in urothelial carcinoma.

Background/aim We performed a systematic review and meta-analysis to investigate the safety of maintenance with olaparib after platinum-based chemotherapy in cancer patients. Materials and methods Eligible studies included randomized controlled trials (RCTs) regarding the clinical role of olaparib maintenance therapy versus placebo in BRCA-mutated, advanced cancers. Safety profile from each selected study was investigated for all-grade and G3-G4 haematological and non-haematological adverse drug events (ADEs). Results Four RTCs that involved 1099 patients were included in the analysis. Overall incidences of all-grade and G3-4 ADEs in olaparib group were 97.6% and 41%, respectively. Patients treated with maintenance olaparib showed higher risk of all-grade and G3-G4 anaemia, all-grade neutropenia and thrombocytopenia. Moreover, all-grade and G3-G4 fatigue, all-grade vomiting, diarrhoea, nausea and decreased appetite were more common in the olaparib group compared to placebo. Conclusion Despite an increased risk and incidence of several haematological and non-haematological toxicities, olaparib is a relatively safe agent for the treatment of advanced solid tumors. Prompt identification of ADEs is mandatory to avoid therapy discontinuation and optimize treatment.

Introduction: In the evolving treatment scenario of metastatic renal cell carcinoma, cabozantinib is gaining increasing attention, presenting as a cornerstone therapy, both as a monotherapy and in combination with immune-checkpoint inhibitors.Areas covered: In this review, the authors explore the role of cabozantinib in the treatment of metastatic clear cell and non-clear cell renal cell carcinoma, presenting data from the most recent clinical trials and investigating ongoing studies. They, furthermore, evaluate the pharmacokinetic, pharmacodynamic, and immunomodulatory effect of cabozantinib, as well as underlining the tolerability profile and patients' quality of life.Expert opinion: Cabozantinib's administration as a single agent is restricted to intermediate- and poor-risk patients (according to IMDC criteria). The further advent of anti-VEGF-receptor tyrosine kinase inhibitors combined with immune checkpoint inhibitor regimens (such as pembrolizumab + axitinib) has allowed to expand the use of cabozantinib, leading to its combination with nivolumab. In the next few years, more information is required to look for the application of cabozantinib-based combinations as a later-line approach in metastatic RCC patients, beside their use in the first-line setting.

Several novel androgen receptor (AR)-inhibitors have been introduced for nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the improvement of survival outcomes which need to be balanced against the risk of adverse events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating enzalutamide, apalutamide and darolutamide in nmCRPC patients, to assess overall survival (OS), incidence and risk of adverse drug events, adverse-events-related death and adverse-events-related treatment discontinuation. We selected three RCTs (SPARTAN, PROSPER and ARAMIS). New hormonal agents administration resulted in better OS, despite the increased risk of several any grade and grade 3-4 adverse events. In the decision-making process, careful evaluation of expected adverse events, patients' comorbidities and maintenance of quality of life are mandatory.

Aim We performed a systematic review and meta-analysis to evaluate the role of platinum-based adjuvant chemotherapy (AC) in upper tract urothelial carcinoma. Materials methods Eligible studies were identified using Pubmed/Medline, Cochrane library, Embase and meeting abstracts. Outcomes of interest included: overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Results Platinum-based AC was associated with improved DFS, while the benefit in OS and CSS was not statistically significant compared to observation. Conversely, platinum-based AC showed a modest OS benefit in an analysis combing multivariable HRs with estimated HRs from Kaplan-Meier curves. Conclusion Our results suggest that platinum-based AC is associated with improved DFS and a modest OS benefit in patients with locally advanced urothelial carcinomas.

Background: Renal cell carcinoma with sarcomatoid differentiation is a highly aggressive form of kidney cancer. Objective: We aimed to analyze the outcomes of patients treated with cabozantinib for metastatic renal cell carcinoma with sarcomatoid features. Methods: We retrospectively collected data from 16 worldwide centers. Overall survival and progression-free survival were analyzed using Kaplan–Meier curves. Cox proportional models were used for univariate and multivariate analyses. Results: We collected data from 66 patients with metastatic sarcomatoid renal cell carcinoma receiving cabozantinib as second-line (51%) or third-line (49%) therapy. The median progression-free survival from the start of cabozantinib was 7.59 months (95% confidence interval [CI] 5.75−17.49) and was longer in male patients (8.81 vs 5.95 months, p = 0.042) and in patients without bone metastases (7.59 vs 5.11 months, p = 0.010); the median overall survival was 9.11 months (95% CI 7.13−23.80). At the multivariate analysis, female sex (hazard ratio = 1.81; 95% CI 1.02−3.37,p = 0.046), bone metastases (hazard ratio = 2.62; 95% CI 1.34−5.10, p = 0.005), and International Metastatic Renal Cell Carcinoma Database Consortium criteria (hazard ratio = 3.04; 95% CI 1.54−5.99, p = 0.001) were significant predictors of worse overall survival. Conclusions: Our data show that cabozantinib is active in pretreated patients with sarcomatoid renal cell carcinoma. Biomarkers are needed in this field to select patients for multi-kinase inhibitors or other options.

Introduction The incidence of kidney cancer is increasing; it could be counteracted with new ways to predict and detect it. We aimed to implement an artificial neural network in order to predict new cases of renal-cell carcinoma (RCC) in the population using population rate, obesity, smoking incidence, uncontrolled hypertension, and life expectancy data in the United States. Patients and Methods Statistics were collected on US population numbers, life expectancy, obesity, smoking, and hypertension. We used MATLAB R2018 (MathWorks) software to implement an artificial neural network. Data were repeatedly and randomly divided into training (70%) and validation (30%) subsets. Results The number of new RCC cases will grow from 44,400 (2020) to 55,400 (2050), an increase of +24.7%. Our data show that preventing hypertension would have the greatest impact on reduction of the incidence, estimated at −775 and −575 cases per year in 2020 and in 2030, respectively. The prevention of obesity and smoking would have a more limited impact, estimated at −64 and −180 cases per year in 2020 and in 2030, respectively, for obesity, and −173 and −21 cases per year in 2020 and in 2030, respectively, for smoking. Conclusions Our predictions underline the need for accurate studies on RCC-related risk factors to reduce the incidence.

The American Joint Committee of Cancer (AJCC) tumor-node-metastasis (TNM) classification, with its periodical updates and modifications, has represented and still represents the basis of cancer staging. The historical, long-standing limitations of anatomic-based TNM staging have been recently "threatened" by the impressive amount of data derived from molecular analyses, which have led to an unprecedented level of understanding of cancer genomics. In fact, current era of personalized oncology has witnessed important efforts towards the integration between clinical, anatomical and molecular features; however, despite the promises, personalized oncology faces many obstacles, due to the complex relationship between tumor biomarkers, previously unknown cancer subtypes and clinical and anatomical characteristics. With regard to urothelial carcinoma (UC), the characterization of tumors in large cohorts of patients has provided important information concerning genetic alterations, revealing the presence of biologically relevant subtypes of UC. In the current review, we will provide an overview regarding this recent "translation" from the anatomic-based TNM to a novel horizon, aiming at further "tailoring" personalized oncology, especially focusing on recently published data about the molecular landscape of UC with its therapeutic and prognostic implications.

In 1952, renal cell carcinomas had been divided into 2 categories-clear cell or granular cell-depending upon their cytoplasmic staining characteristics. In the following years, the inventory of renal epithelial tumors has expanded by the addition of tumors named by their architectural pattern (i.e., papillary RCC, tubulocystic RCC), anatomic location (i.e., collecting duct carcinoma, renal medullary carcinoma), associated diseases (i.e., acquired cystic disease-associated RCCs). With the extensive application of molecular diagnostic techniques, it becomes possible to detect genetic distinctions between various types of renal neoplasm and discover new entities, otherwise misdiagnosed or diagnosed as unclassified RCC. Some tumors such as ALK rearrangement-associated RCC, MiT family translocation renal carcinomas, SDH-deficient renal cancer or FH-deficient RCC, are defined by their molecular characteristics. The most recent World Health Organization (WHO) classification of renal neoplasms account for more than 50 entities and provisional entities. New entities might be included in the upcoming WHO classification. The aim of this review is to summarise and discuss the newly acquired data and evidence on the clinical, pathological, molecular features and on the prognosis of new RCC entities, which will hopefully increase the awareness and the acceptance of these entities among clinicians and improve prognostication for individual patients.

The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria have been largely adopted in clinical practice. In a recent retrospective study, we assessed that the addition of the first site of metastatic disease to brain, bone, and liver improves prognostic stratification of patients with metastatic renal cell carcinoma (mRCC). Here, we performed an external validation in patients with mRCC. Our aim was to evaluate if the addition of a new independent variable could improve IMDC prognosis prediction and reduce heterogeneity within risk categories.We selected all 1073 patients treated at a single institution for mRCC and included in the Institute Gustave Roussy Renal Cell Carcinoma database. All patients included received at least 1 line of targeted therapy or immune checkpoint inhibitors. Univariate and multivariate analyses (Cox regression model) were performed. Bootstrap validation of the final model was also carried out for internal validation. The IMDC modified classification was defined by the addition of the seventh variable, and we defined the modified IMDC good-risk criteria as 0 risks, intermediate-risk as 1 to 2 risks, and poor-risk as 3 or more risks.The presence of brain, bone, and/or liver as the first site of metastatic disease plus the other variables included in the IMDC score were statistically significant variables associated with overall survival (OS) after univariate and multivariate analysis and bootstrap validation. Finally, 122 (15%) patients had a modification of their initial risk category. The median OS in the poor-, intermediate-, and favorable-risk groups was 10, 26, and 52 months, respectively (P .001). The bias-corrected concordance index in patients receiving immune checkpoint inhibitors (n = 241) was 0.71.The addition of brain, bone, and/or liver metastases as an additional variable to the other IMDC variables improves the prognostic predictive power of the model.

Immune checkpoint inhibitors have radically changed the treatment approach to metastatic renal cell carcinoma (mRCC). In the present article, we reported and discussed the available data with immunocombinations in mRCC, offering new perspectives in the treatment landscape of these patients. We discussed the main results of pivotal clinical trials of immune checkpoint inhibitors in the treatment of mRCC. Moreover, we discussed novel immuno-based treatments currently under investigation in ongoing clinical trials. Renal cell carcinoma is a particularly immunogenic tumor and immunotherapy is a pivotal treatment approach. A wide series of clinical trials is exploring novel promising immunocombinations in patients with renal cell carcinoma.

Background:The management of renal cell carcinoma is rapidly evolving and immunotherapy, mostly consisting of immune checkpoint inhibitors, is revolutionizing the treatment scenario of metastatic patients. Novel fractionation schedules of radiotherapy, consisting of high doses in few fractions, can overcome the radioresistance of this tumor. Localized radiotherapy is associated with a systemic effect, known as the abscopal effect. This effect mediated by the immune system can be enhanced associating radiotherapy with immunotherapy.Objective:In this review, we explore the role of radiotherapy and immunotherapy in RCC, the rationale of combining these strategies and the on-going clinical trials investigating combinations of these two treatment modalities.Conclusion:Combining immunotherapy and radiotherapy has a strong rationale and pre-clinical studies support their association because it can overcome the immunosuppression of the tumor microenvironment and increase the anti-tumor immune response. More clinical evidence, deriving from onclinical trials, are needed to prove the efficacy and safety of these treatments combined.

Immune-based combinations, including nivolumab plus ipilimumab, pembrolizumab plus axitinib, and (at a lesser extent) avelumab plus axitinib, should be regarded among the new standards of care for first line therapy of metastatic renal cell carcinoma. Toxicity profiles are different among all these above combinations, as well as between them and targeted agents monotherapies, including sunitinib (i.e. the control arm of all the above studies). We performed a systematic review and meta-analysis with the aim to compare adverse events from immune-based combinations versus sunitinib monotherapy across four recent randomized controlled trials (CheckMate-214, Keynote-426, IMmotion-151, and JAVELIN Renal 101) of front-line treatment for metastatic renal cell carcinoma, with particular attention to those from the ipilimumab plus nivolumab combination. Beyond efficacy and activity, the ipilimumab plus nivolumab combination appears feasible, being endowed by an acceptable safety profile, in line with that of the other available options for the treatment of metastatic RCC. The different patterns of toxicities emerging from this systematic review and meta-analysis need to be kept in mind while choosing the appropriate treatment for each individual patient. Furthermore, prevention, prompt identification, and treatment of immune-related adverse events remains an area to be improved.

Introduction: Despite significant advances in the treatment of metastatic urothelial carcinoma, including the advent of immune checkpoint inhibitors, this disease is still challenging to treat and associated poor outcomes remain. Genomic characterization of advanced-stage urothelial carcinoma is widening the field of potential treatments due to the identification of novel biologic drivers. Areas covered: In this review, we explore the role of PARP, HER-2, and mTOR inhibitors in the therapeutic scenario of advanced urothelial carcinoma, as these pathways are frequently altered in urothelial carcinoma. We report ongoing clinical trials involving these agents, either in monotherapy or in combination with other compounds, highlighting the dynamic scenario of metastatic urothelial carcinoma treatment. Expert opinion: Several challenges need to be faced in the development of new potential therapeutic strategies, such as inter/intratumoral heterogeneity and the lack of validated biomarkers.

Background Several models are adopted in clinical practice to estimate prognosis of patients with metastatic renal cell carcinoma (mRCC); however, none of these models have evaluated patients treated by immune-checkpoint inhibitors. The aim of this study was to investigate if the site of initial metastasis could be a parameter able to stratified prognosis among patients with mRCC among different risk groups defined by the International Metastatic Renal Cell Database Consortium (IMDC) model. The site of initial metastasis was defined as the primary tissue or organ in which metastasis was diagnosed in the course of the medical history of the disease. Patients and Methods A total of 134 patients treated between January 2010 and December 2018 in our institution were retrospectively evaluated. The primary outcome was overall survival (OS) defined as the time from initiation of first-line therapy to death from any cause. Of note, 26 (19.4%) patients received immune-checkpoint inhibitors. Univariable analysis was performed through the log-rank test to estimate the effect of number of metastatic sites and site of initial metastasis on OS. Subsequently, a Cox regression proportional hazards model was employed in multivariable analysis. Results Of the 12 variables analyzed, 4 were statistically associated to worse OS in univariable analysis (number of metastases and liver, bone, or central nervous system metastases). Multivariate analysis confirmed that bone (hazard ratio [HR], 1.92; 95% confidence interval [CI], 1.17-3.13), liver (HR, 2.65; 95% CI, 1.59-4.42), and central nervous system (HR, 3.3; 95% CI, 1.62-6.74) initial metastases were independent parameters related to worse OS. The presence of 1 or more of the selected sites recognized specific populations of patients associated to worse prognosis in both good (P = .003) and intermediate (P = .047) risk groups. Conclusion The site of initial metastasis defines specific populations of patients associated with worse prognosis in the good and intermediate IMDC groups.

Background: With hormonal agents quickly expanding as novel therapeutic options in nonmetastatic castration-resistant prostate cancer (nmCRPC), the toxicity profile of enzalutamide, apalutamide, an...

In the past few years several hormonal agents have been tested in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) leading to an impressive improvement in terms of metastases-free survival (MFS). We performed a meta-analysis aimed to: (1) estimate the pooled effect of new hormonal compounds in terms of MFS, overall survival (OS) in overall and specific subpopulations; and (2) estimate the effect of high-grade toxicities of these drugs. We identified 881 studies published between January 1, 2010 and February 16, 2018 on PubMed/Medline, Cochrane Library, and Scopus. Three randomized placebo controlled clinical trials were selected (PROSPER, SPARTAN, and ARAMIS). Because of the absence of individual data, all of the analyses performed were made on aggregated data provided in selected studies. We used the inverse variance technique for the meta-analysis of the hazard ratios collected for MFS and OS analysis. Fixed and randomized models were used. Relative risk and 95% confidence intervals and risk difference were estimated considering the number of Grade 3 adverse events in treatment and control arms. Administration of new hormonal compounds in nmCRPC patients led to a significant benefit in MFS in the overall population and in all subgroups analyzed. These agents might also improve OS but longer follow-up is needed to confirm this hypothesis. Indeed results of OS analysis should be carefully evaluated because none of the studies selected provided mature OS data. Administration of these agents resulted in a significant increased risk of treatment-related death, high cardiovascular toxicity, hypertension, fractures, and falls. Administration of new hormonal compounds prolongs the time of metastases occurrence and might prolong also survival in patients with nmCRPC. Treatment-related toxicity is an important issue because these agents increase the risk of death, cardiovascular toxicity, hypertension, fractures, and risk of falls.

CONTEXT: 9p loss appears a reliable and promising marker able to differentiate specific categories of patients with renal cell carcinoma associated with a worse prognosis. OBJECTIVE: The aim was to systematically evaluate relative risk of death, cancer-specific survival (CSS) and disease-free survival (DFS) among patients harboring 9p loss. EVIDENCE SYNTHESIS: We found a total of 92 potentially relevant articles focused on the detection of 9p loss in patients with renal cell carcinoma and clinical outcomes of this population. Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were employed to carry out this work. Fourteen studies resulted to be eligible for this analysis; 11 of these reported data on 5-year overall survival, six on CSS and four on DFS. An increased risk of death has been observed in patients harboring 9p loss (pooled relative risk of 3.965; 95% confidence interval [CI] 2.647-5.940, p

Management of metastatic renal cell carcinoma has drastically changed in the last few years, witnessing the advent of more and more target therapies and, recently, of immune-checkpoint inhibitors. On the other hand, the adjuvant setting still lacks a clear beneficial treatment. Medical treatment still remains a compelling challenge. A large number of clinical trials is ongoing with the aim to identify new therapeutic approaches to expand the options in our repertoire. Several strategies are under investigation in renal cell carcinoma (RCC). These include new targeted agents and combinations of target therapy and immunotherapy. Programmed death receptor-1 (PD-1), programmed death receptor ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are just part of the intricate network that regulates our immune response to cancer cells. Co-stimulators, such as glucocorticoid-induced TNFR-related protein (GITR) and tumor necrosis factor receptor superfamily, member 4 (OX40), and co-repressors, example.g. T cell immunoglobulin and mucin domain 3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3), also take part. As knowledge of the functioning of the immune system grows, so do these pathways to target with new drugs. This review is an overview of the current state of the clinical research, providing a report of ongoing Phase I, II and III clinical trials for localized and metastatic RCC, including novel target therapies, novel immunotherapy agents and new combinations strategies.

Although tyrosine kinase inhibitors (TKIs) are widely used in the metastatic setting, they have shown more limited effectiveness in the adjuvant setting. Despite multiple clinical trials, there has been no improvement in overall survival (OS) with the use of these agents as adjuvant therapy, and conflicting data on disease-free survival (DFS). We carried out a meta-analysis of available phase III randomized clinical trials on adjuvant TKIs in clear-cell renal cell carcinoma (RCC). Primary end points of our study were the effect of adjuvant TKIs on OS and DFS in the overall population. Furthermore, we investigated if use of adjuvant TKIs resulted in improved DFS among patients with different risk of tumor relapse. Higher-risk patients were patients with 1 or more of the following features: positive nodes (N+), T4 tumors and T3 tumors, with higher Fuhrman grades (3-4). We adopted Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to carry out our study. In the overall population, the pooled hazard ratio (HR) of OS and DFS was 0.89 (95% confidence interval [CI], 0.76-1.04) and 0.84 (95% CI, 0.76-0.93), respectively. In the low- and high-risk populations, the pooled DFS HR was 0.98 (95% CI, 0.82-1.17) and 0.85 (95% CI, 0.75-0.97), respectively. Adjuvant use of TKIs do not appear to provide a statistically significant OS benefit. However, a benefit in DFS has been observed in overall and high-risk populations, suggesting that better selection of patients might be important for the evaluation of adjuvant therapies in RCC.

Treatment response is usually assessed by the response evaluation criteria in solid tumors (RECIST). These criteria may not be adequate to evaluate the response to immunotherapy, considering the peculiar patterns of response reported with this therapy. With the advent of immunotherapy these criteria have been modified to include the evaluation of the peculiar responses seen with this type of therapy (iRECIST criteria), including pseudoprogressions and hyperprogressions. Tumor growth rate (TGR) is a dynamic evaluation that takes into account the kinetics of response to treatment and may help catch the real efficacy of an immunotherapy approach. We performed a retrospective monocentric study to explore the impact of TGR change after nivolumab administration as the second or later line of treatment in patients with metastatic renal cell carcinoma (RCC). We evaluated 27 patients, divided into three categories: Disease control (DC) if there was no PD, lower velocity PD (LvPD) if disease progressed but the TGR at second assessment (TGR2) was lower than the TGR at first assessment (TGR1), higher velocity PD (HvPD) if TGR2 was higher than TGR1. The median OS for the DC group was 11.0 months (95% CI 5.0–17.0) (reference) vs. (not reached) NR (95% CI NR-NR) for LvPD (HR 0.27, 95% CI 0.06–1.30, p 0.102) vs. NR (95% CI NR–NR) for HvPD (HR 0.23, 95% CI 0.06–0.88, p 0.032). There was no difference between LvPD and DC (HR 1.21, 95% CI 0.20–7.28, p 0.838). In patients with metastatic RCC, the second or later line of nivolumab treatment may lead to a deceleration in TGR resulting in an improved survival outcome similar to that observed in patients experiencing tumor regression. In this subgroup, especially in the presence of a clinical benefit, continuing the treatment beyond progression can be recommended.

Objective Recent years have registered the advent of novel treatment options for metastatic renal cell carcinoma (mRCC), including combination therapies with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). Immuno-TKI combinations have been suggested to improve clinical outcomes but may also result in increased toxicity, including gastrointestinal (GI) adverse events. Methods Herein, we performed a meta-analysis aimed at comparing the risk of certain GI toxicities in mRCC patients treated with immuno-TKI combinations versus sunitinib monotherapy. Overall, four phase III trials (KEYNOTE-426, JAVELIN Renal 101, CheckMate 9ER, CLEAR) involving 3059 mRCC patients were available. Results The meta-analysis suggested an increased risk of all-grade diarrhea, grade 3-4 diarrhea and grade 3-4 decreased appetite in patients treated with immuno-TKI combinations. Conversely, an apparently higher risk of all-grade nausea was observed in the sunitinib group. Conclusion The meta-analysis suggested that immuno-TKI combinations are associated with higher risk of GI toxicities compared with sunitinib. Beyond the efficacy of immuno-TKI combinations in mRCC patients, careful consideration should be given to treatment-related adverse events, including GI toxicities. Early recognition and treatment are critical to maximize recovery.

Introduction: Substantial paradigm shifts have been recently registered in metastatic renal cell carcinoma (mRCC), with combination therapies including immunotherapy showing unprecedented results. We performed number needed to treat (NNT) and number needed to harm (NNH) analyses to evaluate these approaches in mRCC.Areas covered: Clinical data of mRCC patients enrolled in four phase III trials were collected. The rates at 6, 12, 18, and 24 months for overall survival (OS), duration of response (DoR), and progression-free survival (PFS) were considered. At 6 months, the number of patients that should be treated to prevent one death with sunitinib was 20 for both pembrolizumab-lenvatinib or axitinib, 14 for nivolumab-cabozantinib, and 50 for nivolumab-ipilimumab. NNT was 100 (at 6 months) or >100 (at 12 and 18 months) for nivolumab-ipilimumab. The combinations reported peculiar and not superimposable safety profiles at the NNH analysis.Expert opinion: Although our results should be interpreted with caution, the analysis provides useful insight into the increasingly compelling interpretation of clinical trials. Immune combinations present clinically meaningful differences in terms of efficacy, with some treatments reporting different results at the NNT and the NNH analyses.

Simple Summary Prostatic diseases are important worldwide, being the prostate cancer (PC) the most common tumor in men. Among the factors associated with PC development, the preneoplastic lesions are well-recognized. Preneoplastic lesions are cellular morphological alterations, induced by different factors and present a potential to progression for PC. In this scenario, dogs are considered spontaneous models. Dogs naturally develops prostatic hyperplasia, preneoplastic lesions and PC. Among the preneoplastic lesions, the proliferative inflammatory atrophy (PIA) develops spontaneously in dogs. PIA is an epithelial lesion induced by prostatic chronic inflammation, leading to a proliferative atrophy of the prostate gland. Thus, this study aimed to perform a full PIA morphological, phenotypical and molecular characterization in dogs. After reviewing the archives of the veterinary pathology service, it was identified 171 dogs containing PIA in the prostate gland, and among the PC cases (N = 84), it was identified PIA lesions surrounding 60.7% of PC cases. Besides that, we identified loss of genes related to the maintenance of prostatic tissue and can predispose to malignant transformation. Moreover, mutations in androgen receptor gene were identified, demonstration alteration in DNA in PIA. Overall, these results support the hypothesis that PIA can be considered a preneoplastic lesion in canine prostate. Abstract Proliferative inflammatory atrophy (PIA) is an atrophic lesion of the prostate gland that occurs in men and dogs and is associated with a chronic inflammatory infiltrate. In this study, we retrospectively reviewed canine prostatic samples from intact dogs, identifying 50 normal prostates, 140 cases of prostatic hyperplasia, 171 cases of PIA, 84 with prostate cancer (PC), 14 with prostatic intraepithelial neoplasia (PIN) and 10 with bacterial prostatitis. PIA samples were then selected and classified according to the human classification. The presence of PIA lesions surrounding neoplastic areas was then evaluated to establish a morphological transition from normal to preneoplastic and neoplastic tissue. In addition, the expression of PTEN, P53, MDM2 and nuclear androgen receptor (AR) were analyzed in 20 normal samples and 20 PIA lesions by immunohistochemistry and qPCR. All PIA lesions showed variable degrees of mononuclear cell infiltration around the glands and simple atrophy was the most common histopathological feature. PIA was identified between normal glands and PC in 51 (61%) out of the 84 PC samples. PIA lesions were diffusely positive for molecular weight cytokeratin (HMWC). Decreased PTEN and AR gene and protein expression was found in PIA compared to normal samples. Overall, our results strongly suggest that PIA is a frequent lesion associated with PC. Additionally, this finding corroborates the hypothesis that in dogs, as is the case in humans, PIA is a pre neoplastic lesion that has the potential to progress into PC, indicating an alternative mechanism of prostate cancer development in dogs.

The last three decades have witnessed a revolution in the therapeutic scenario of metastatic renal cell carcinoma (mRCC), due to the advent of novel agents including tyrosine kinase inhibitors, immune checkpoint inhibitors and the combination of both treatments. These strategies have reported unprecedented response rates, thus improving the clinical outcomes of mRCC patients, and current international guidelines support the use of immune-based combinations as first-line treatment in patients with metastatic disease. However, more data are awaited to help clinicians in the decision-making process. Herein, we provide an overview of recently published results regarding immune-based combinations as first-line treatment in mRCC patients, critically discussing available data that could help in suggesting determinants of treatment in this setting.Lay abstract In the recent years, the treatment of metastatic renal cell carcinoma drastically changed with the introduction of immunotherapy, a type of therapy that stimulates the immune response against tumor cells. Combination treatments with two different immunotherapy agents or an immune checkpoint inhibitor and an anti-angiogenic agent (a drug that blocks vascularization of the tumor) are associated with prolonged responses and increased patients’ survival. We performed an overview of the recent studies of first-line treatment for metastatic renal cell carcinoma, critically analyzing important issues to consider when choosing a specific treatment.

Despite several clinical trials have assessed different agents in the adjuvant setting, renal cell carcinoma (RCC) still remains a disease orphan of an effective adjuvant treatment. In fact, systemic therapies targeting angiogenesis that have been observed to be effective in metastatic setting failed to show an improvement in terms of clinical outcomes when used ad adjuvant treatments. In this study, we performed a meta-analysis of 5 randomized clinical trials to assess the impact of tyrosine kinase inhibitors (TKIs) targeting angiogenesis after surgery: ASSURE, S-TRAC, PROTECT, ATLAS, SORCE. Among the 6,531 patients assessed, we confirmed the lack of efficacy of adjuvant treatments in terms of disease-free survival (DFS) (pooled-HR 0.93, 95% CI, 0.84-1.02, P=0.16) and overall survival (OS) (pooled-HR 0.98, 95% CI, 0.88-1.09, P=0.54). To the best of our knowledge, we still ignore why some treatments active in the metastatic setting do not show similar efficacy as adjuvant treatment. Exploring possible reasons of this apparently conflicting results is important as it may offer new insights that should be evaluated in next generation adjuvant trials. Immune checkpoint inhibitors (ICIs) have reported significant results-as monotherapy or in combinations with other anticancer agents-in metastatic setting, and the results of trials evaluating these agents in the adjuvant setting are awaited.

Background In recent years, HER2 amplification has been evaluated as a potential prognostic biomarker and therapeutic target in urothelial carcinoma (UC). In this retrospective study, we aimed at exploring the prognostic role of HER2 amplification in UC, measured by chromogenic in situ hybridization (CISH). Methods We retrospectively evaluated the presence of HER2 amplification by using CISH in 31 UC patients followed at a single institution between 2018 and 2020. The primary objective was to assess the frequency of HER2 amplification and to compare clinical outcomes of HER2-amplified patients with non-amplified UCs. Results HER2 amplification was identified in 4 out of 31 patients (12.9 %). After a median follow-up of 28.1 months (95 % Confidence Intervals [CI] 11.2–45.1), median overall survival (OS) in the whole population was 10.9 months (95 % CI 3.5–22.1). Despite not reaching statistical significance, median OS was shorter in HER2-amplified patients (6.8 months, 95 % CI 3.9–9.7) compared to HER2-negative UCs (15.4 months, 95 % CI 7.5–23.3) (p = 0.45). Conclusions Although limited by the small sample size, the results of our study suggest that HER2 amplifications by CISH could represent a prognostic factor for shorter survival in UC patients.

Simple Summary Over the disease course of metastatic prostate cancer, approximately the 90% of patients develops bone metastases, with bone involvement frequently leading to various skeletal complications including pathological fractures, spinal cord compression, and pain. Notably enough, the peculiar inclination of prostate cancer cells to seed the bone is considered an important cause of morbidity for prostate cancer patients. Recent years have witnessed the advent of several novel treatments for prostate cancer, and therapeutic paradigms are rapidly shifting. In this review, we aim at giving an overview of current knowledge on the relationship between prostate cancer and bone, especially focusing on the use of bone-targeted agents in this setting. Abstract Bone health represents a major issue in castration-resistant prostate cancer (CRPC) patients with bone metastases; in fact, the frequently prolonged use of hormonal agents causes important modifications in physiological bone turnover and most of these men will develop skeletal-related events (SREs), including spinal cord compression, pathologic fractures and need for surgery or radiation to bone, which are estimated to occur in almost half of this patient population. In the last decade, several novel therapeutic options have entered into clinical practice of bone metastatic CRPC, with recent approval of enzalutamide and abiraterone acetate, cabazitaxel chemotherapy and radium-223, on the basis of survival benefit suggested by landmark Phase III trials assessing these agents in this setting. Conversely, although bone-targeted agents (BTAs)—such as the bisphosphonate zoledronic acid and the receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor denosumab—are approved for the prevention of SREs, these compounds have not shown benefit in terms of overall survival. However, emerging evidence has suggested that the combination of BTAs and abiraterone acetate, enzalutamide and the radiopharmaceutical radium-223 could result in improved clinical outcomes and prolonged survival in bone metastatic CRPC. In this review, we will provide an overview on bone tropism of prostate cancer and on the role of BTAs in metastatic hormone-sensitive and castration-resistant prostate cancer.

Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP–ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called “antibody–drug conjugates” (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells’ surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.

Background: Recent years have witnessed the advent of novel treatment options for metastatic renal cell carcinoma (mRCC), including combination therapies with immune checkpoint inhibitors. Herein, we conducted an up-to-date and comprehensive meta-analysis including recently published data of phase III clinical trials evaluating immune-based combinations in mRCC. Methods: We retrieved all the relevant trials published from 15th June 2008 to 24th February 2021, evaluating immune-based combinations in treatment-naïve mRCC through PubMed/MEDLINE, Cochrane library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Outcomes of interest included overall survival (OS), progression-free survival (PFS), complete response (CR) rate, and overall response rate (ORR). Hazard ratios (HRs) and their 95% confidence intervals (CIs) for OS and PFS, and odds ratios (ORs) and 95% CIs for CR rate and ORR, were extracted. Results: Overall, 6 phase III studies involving 5175 treatment-naïve mRCC patients were available for the meta-analysis (immune-based combinations, n = 2576; sunitinib, n = 2597). According to our results, the use of immune-based combinations decreased the risk of death by 26% (HR 0.74, 95% CI 0.67–0.81, P < 0.001); similarly, a PFS benefit was observed (HR 0.68, 95% CI 0.54–0.85, P = 0.001). In addition, immune-based combinations showed better CR rate and ORR, with ORs of 3.04 (95% CI 2.31–3.99, P = 0.001) and 2.53 (95% CI 1.77–3.62, P < 0.03), respectively. Conclusions: The results of our meta-analysis confirm the clinical benefit provided by immunotherapy combinations, with CR rate more than tripled in mRCCs receiving immune-based combinations. Further studies in real-world setting are warranted to validate the findings of our meta-analysis, the most updated to systematically evaluate immune-based combinations in mRCC.

The advent of immunotherapy has revolutionized the treatment landscape of several hematological and solid tumors [...]

The immune system has a fundamental role in controlling the development and progression of tumors, including those originating in the bladder, kidney and prostate. However, malignant cells and cell...

Non-clear cell renal cell carcinomas are a miscellaneous group of tumors that include different histological subtypes, each one characterized by peculiarity in terms of genetic alteration, clinical behavior, prognosis, and treatment response. Because of their low incidence and poor enrollment in clinical trials, alongside their heterogeneity, additional efforts are required to better unveil the pathogenetic mechanisms and, consequently, to improve the treatment algorithm. Nowadays, tyrosine kinase inhibitors, mTOR and MET inhibitors, and even cisplatin-based chemotherapy and immunotherapy are potential weapons that are still under evaluation in this setting. Various biomarkers have been evaluated for detecting progression and monitoring renal cell carcinoma, but more studies are necessary to improve this field. In this review, we provide an overview on the molecular characteristics of this group of tumors and the recently published trials, giving an insight into what might become the future therapeutic standard in this complex world of non-clear cell kidney cancers.

Aim: Immune checkpoint inhibitor (ICI)-based combinations have become the new standard of primary systemic treatment for metastatic renal cell carcinoma patients. We performed a meta-analysis aimed at evaluating ICIs plus tyrosine kinase inhibitors (TKIs) combinations across International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups. Materials & methods: All the relevant randomized clinical trials were retrieved through Cochrane library, PubMed/Med and EMBASE; three Phase III randomized clinical trials were included. Results: ICI–TKI combinations significantly decreased the risk of death in IMDC poor- and intermediate-risk patients. Conversely, a nonstatistically significant benefit was observed in favorable-risk patients. Conclusion: Our results suggest that IMDC poor-risk patients benefit most from ICI–TKI combinations, while a proportion of metastatic renal cell carcinoma patients could respond to targeted agent monotherapy.

The occurrence of kidney oncocytic lesions with an admixed papillary component is not unusual in routine pathology practice. These neoplasms with dual morphology are classically recognized as collision tumors with variable malignant potential. Using immunohistochemistry, we investigated fluorescent in situ hybridization and next generation sequencing of the genetic and phenotypic profiles in the two components of 11 kidney tumors with colliding oncocytic and papillary features. The oncocytic component was CD117 positive, CK7 negative, and AMACR negative, the papillary component was CK7 positive, AMACR positive, and CD117 negative in all cases. Fluorescence in situ hybridization (FISH) results were inconsistent. Next generation sequencing (NGS) analysis demonstrated that the mutations identified in the two tumor components were identical and displayed an allelic frequency of approximately 50%, strongly suspicious for genetic polymorphisms. The two oncocytic and papillary tumor counterparts shared the same genetic profile and did not harbor pathogenic mutations. Clinical confirmation of the biological benign features of these tumors is required. The term collision tumor is not suitable for these neoplasms, and we propose the term oncopapillary tumor for this histological entity.

Renal cell carcinoma (RCC) scenario has radically changed with the advent of immunotherapy; in this setting, the identification of predictive and prognostic factors represents an urgent clinical need to evaluate which patients are the best candidate for an immunotherapy approach. The aim of our study was to analyze the association between nivolumab in pretreated patients with metastatic RCC and clinicopathological features, metastatic sites, and clinical outcomes. A total of 37 patients treated between January 2017 and April 2020 in our institution were retrospectively evaluated. All patients received nivolumab as second- or later-line of therapy after progression on previous tyrosine kinase inhibitors. The primary outcomes were overall survival (OS) from immunotherapy start and OS from first-line start. Univariate analysis was performed through the log-rank test and a Cox regression proportional hazards model was employed in multivariable analysis. Of the 12 variables analyzed, 4 were significantly associated with prognoses at multivariate analysis. Cox proportional hazard ratio models confirmed that International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) risk group, liver metastases at diagnosis, and central nervous system (CNS) metastases at diagnosis were associated with worse OS with an estimated hazard ratio of 4.76 [95% confidence interval (CI), 2.05-19.8] for liver metastases and 2.27 (95% CI, 1.13-28.9) for CNS metastases. Pancreatic metastases at diagnosis were correlated to a better prognosis with an estimated hazard ratio of 0.15 (95% CI, 0.02-0.38). IMDC risk group, liver metastases at diagnosis, and CNS metastases at diagnosis may identify a population of patients treated with immunotherapy in second- or later-line associated with worse prognosis.

Renal cell carcinoma is a malignant tumor that arises in the kidney parenchyma. For many years, sunitinib has represented the mainstay of medical treatment for metastatic renal cell carcinoma. Herein, we present the case of a 66-year-old woman with metastatic clear cell renal carcinoma undergoing treatment with sunitinib for two years that developed encephalic leukocytoclastic vasculitis, probably due to a paraneoplastic syndrome.

Aims: Quality of life (QoL) assessment is frequently not included among the end points of clinical trials (CTs) on renal cell carcinoma. Herein we aimed to describe the assessment and reporting of QoL in Phase II and Phase III CTs published between 2010 and 2020. Methods: A total of 25 CTs were included; 76% of trials included were conducted in metastatic renal cell carcinoma patients, while 20% of studies evaluated adjuvant systemic treatments. Results: In 13/25 publications, QoL was not listed among the end points, with secondary publications dedicated to QoL present in a minority of cases. Conclusions: QoL was not included among the end points of a large percentage of CTs. Implementing the inclusion of QoL represents an urgent need.

Background: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. Methods: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. Results: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS – mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. Conclusion: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.

Made available in DSpace on 2022-04-29T08:37:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Background: Urothelial carcinoma (UC), also known as transitional cell carcinoma, is the most common malignant tumor of the canine urinary bladder and represents a model for studying human bladder cancer. However, the existing literature has limited data on the clinicopathological characteristics of these tumors and their prognostic value. Aim: The aim of this study was to evaluate such factors, correlating them with follow-up, in a group of 32 dogs with bladder UC. Methods: Clinical data of these cases, submitted to São Paulo State University and VetPat Private Laboratory (São Paulo/Brazil), were recorded between January 2000 and November 2019. For each case, formalin-fixed and paraffinembedded sections were stained with hematoxylin and eosin and histologically evaluated. Survival analysis was carried out, and the prognostic value of the presence of lymphatic invasion and the treatment used was determined. Results: Dogs with neoplastic lymphatic vessel invasion had a lower overall survival compared to those without lymphatic invasion, and dogs that received vinblastine in addition to surgery had higher global survival when compared to animals that received carboplatin in addition to surgery. Conclusion: The results obtained show the importance of further studies regarding the prognostic value of the two factors demonstrated as potential survival predictors, especially the lymphatic vessel invasion. Department of Veterinary Surgery and Animal Reproduction School of Veterinary Medicine and Animal Science Sao Paulo State University—UNESP Laboratorio di Istologia Sede Territoriale di Milano Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia-Romagna (IZSLER) Department of Veterinary Medicine University of Milan VetPat Laboratory Department of Veterinary Clinic School of Veterinary Medicine and Animal Science Sao Paulo State University— UNESP Institute of Health Sciences Paulista University—UNIP Department of Veterinary Surgery and Animal Reproduction School of Veterinary Medicine and Animal Science Sao Paulo State University—UNESP Department of Veterinary Clinic School of Veterinary Medicine and Animal Science Sao Paulo State University— UNESP