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Background: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC). Patients and methods: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival. Results: A total of 675 patients were included; BMI was >25 kg/m2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m2 versus those with BMI ≤25 kg/m2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P=.044). In the BMI ≤25 kg/m2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002). Conclusion: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups.

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.

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.

Background Drug-drug interactions are a major concern in oncology and may potentially affect the outcome of patients with cancer. Objective In this study, we aimed to determine whether the concomitant use of statins, metformin, or proton pump inhibitors affects survival in patients with metastatic renal cell carcinoma treated with first-line combination therapies. Methods Medical records of patients with documented metastatic renal cell carcinoma between January 2016 and November 2021 were reviewed at 17 participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. Patients were assessed for overall survival, progression-free survival, and overall clinical benefit. Univariate and multivariate analyses were conducted to explore the association of variables of interest with overall survival and progression-free survival. Results A total of 304 patients receiving dual immunotherapy (51%) or immunotherapy/vascular endothelial growth factor-tyrosine kinase inhibitor (49%) combinations were eligible for inclusion in this retrospective study. Statin use was a significant prognostic factor for longer overall survival in a univariate analysis (hazard ratio 0.48, 95% confidence interval 0.26-0.87; p = 0.016) and a multivariate analysis (hazard ratio 0.48, 95% confidence interval 0.31-0.74; p < 0.001) and was significantly associated with an overall clinical benefit (83% in statin users vs 71% in non-users; p = 0.045). Otherwise, the use of metformin or proton pump inhibitors did not affect the outcome of these patients. Conclusions Our study suggests a prognostic impact of statin use in patients receiving first-line immuno-oncology combinations. The mechanism of this interaction warrants further elucidation.

Background: Statins are widely used in an ageing population, including subjects with solid malignancies. However, no conclusive evidence is currently available on their potential influence on patients' outcome. We aimed to assess whether statin exposure affects the survival of patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab.Patients and methods: Medical records of patients with documented mRCC treated with second- or third-line nivolumab were reviewed at ten institutions from Italy, Spain and the USA. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit. Univariate and multivariate analyses were used to explore the association of variables of interest with survival.Results: A total of 219 patients with mRCC receiving nivolumab between January 2016 and September 2021 were eligible for inclusion in this study; 59 (27%) were statin users. The median OS (34.4 versus 18.6 months, p = 0.017) and PFS (11.7 versus 4.6 months, p = 0.013) resulted apparently longer in statin users. Stratified by age, longer median OS and PFS were associated with statin exposure in both patients aged >= 70 y (median OS: 21.4 versus 10.1 months, p = 0.047; median PFS: 16.4 versus 4.6 months, p = 0.022) and

Prostate cancer represents the most frequent tumor in men, accounting for the 21% of all diagnosed tumors, with 191,930 new cases and 33,330 deaths estimated in 2020. Advanced prostate cancer represents a heterogeneous disease, ranging from hormone naive or hormone sensitive to castration resistant. The therapeutic armamentarium for this disease has been implemented in the last years by novel hormonal therapies and chemotherapies. However, the percentage of patients who achieve complete responses still results negligible. On this scenario, the design of clinical trials investigating new therapeutic approaches represent a dramatic medical need. Predicting cancer incidence may be fundamental to design specific clinical trials, to optimize the allocation of economic resources, and to plan future cancer control programs. ERG, SPOP and DDR genes alterations can act as therapeutic targets in prostate cancer patients and can be tested to identify a gene-selected patient population to enrol in specific trials. According to our predictions, ERG gene fusions will be the most predominant molecular subtype, accounting for 69,050 new cases in 2030. Mutation in SPOP gene will be diagnosed in 16,512 tumors, corresponding to the number of cases associated with alterations in DDR genes (including 7,956 BRCA2 mutated tumors). In this article, we analyzed and discussed the future molecular and clinical profiles of prostate cancer in the United States, aimed to describe a series of distinct subpopulations and to quantify potential clinical trial candidates in the next years.

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.

The treatment of castration-sensitive prostate cancer (CSPC) has been revolutionized by the advent of apalutamide and enzalutamide in this setting; however, a direct comparison between these agents is still missing. In the current paper, we performed both Number Needed to Treat (NNT) and Number Needed to Harm (NNH) analyses aimed to compare clinical outcomes in CSPC patients treated with apalutamide or enzalutamide; data from 3323 CSPC patients enrolled in the ARCHES, ENZAMET and TITAN phase III studies were included. According to our results, apalutamide showed better results in terms of overall survival (OS) and safety in patients with CSPC, while better outcomes were observed with enzalutamide in the low-volume subgroup.

Background Breast cancer (BC) is the second most common type of cancer worldwide. Among targeted therapies for Hormone Receptor-positive (HR+) and Human Epidermal growth factor Receptor 2-negative (HER2−) BC, the Cyclin-Dependent Kinases (CDK4/6) are targeted by inhibitors such as Ribociclib (Rib); however, resistance to CDK4/6 inhibitors frequently develops. The aim of this work is to assess in vitro activity of Rib and Everolimus (Eve) in HR+HER2− MCF-7 and HR−HER2−BT-549 BC cell lines. Methods HR+HER2− MCF-7 and HR−HER2− BT-549 BC cell lines were treated with increasing concentration of Rib and Eve (up to 80 μg/mL) for 48–72 h. Subsequently, HR+HER2− MCF-7 cells were silenced for Retinoblastoma (Rb) gene, and thus, the effect of Rib in sequential or concurrent schedule with Eve for the treatment of both Rb wild type or Rb knock-down MCF-7 in vitro was evaluated. Cell viability of HR+HER2− MCF-7cells treated with sequential and concurrent dosing schedule was analyzed by MTT assay. Moreover, cell cycle phases, cell death and senescence were evaluated by cytofluorimetric analysis after treatment with Rib or Eve alone or in combination. Results The sequential treatment didn’t produce a significant increase of cytotoxicity, compared to Rib alone. Instead, the cotreatment synergized to increase the cytotoxicity compared to Rib alone. The cotreatment reduced the percentage of cells in S and G2/M phases and induced apoptosis. Rib triggered senescence and Eve completely reversed this effect in Rb wild type BC cells. Rib also showed Rb-independent effects as shown by results in Rb knock-down MCF-7. Conclusion Overall, the Rib/Eve concurrent therapy augmented the in vitro cytotoxic effect, compared to Rib/Eve sequential therapy or single treatments.

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.

Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICI) are lacking.We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in advanced cancer patients. IrAEs were categorized into “early” (≤12 months) and “late” (>12 months).From September 2013 to October 2019, 436 consecutive patients were evaluated. 223 experienced any grade early-irAEs (51.1%), while 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, while 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced G3/G4 irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95%CI: 2.8-4.2), while the median time to onset of late-irAEs was 16.6 months (95%CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (HR = 0.63 [95%CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95%CI: 0.37-1.56], p = 0.452). Also the time-adjusted cumulative risk of death according to both early-irAEs (HR = 0.79 [95%CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95%CI: 0.49-1.74], p = 0.811) did not show statistically significant differences.Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs, and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs.

Introduction: The route to precision medicine in Renal Cell Carcinoma (RCC) is still full of challenges for worldwide uro-oncologists. This is mainly related to the high complexity of the genomic l...

Background: Tyrosine-kinase inhibitors (TKIs) still represent a first-line option for selected patients with metastatic Renal Cell Carcinoma (mRCC). We aimed to compare the real-world efficacy of nivolumab or cabozantinib as second-line therapy in specific mRCC subpopulations. Patients and Methods: We retrospectively collected data from 11 centers from Italy, Spain and US. Overall Survival (OS) and Progression-Free Survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses. Results: We collected data from 343 patients with mRCC, 123 (36%) treated with cabozantinib and 220 (64%) with nivolumab. The median OS resulted longer, but not statistically significant, with nivolumab in patients aged >70 years (21.4 vs. 15.4 months, P = .746), treated with first-line pazopanib (26.8 vs. 11.6 months, P = .450), or with good (47.0 vs. 15.5 months, P = .285) or intermediate-risk criteria (14.4 vs. 11.0 months, P = .357), while it was longer, but even not statistically significant, for cabozantinib in patients who received previous sunitinib (25.7 vs. 21.7 months, P = .638) or with bone metastases (28.4 vs. 24.4 months, P = .871). The median PFS was significantly longer with cabozantinib in patients with clear cell histology (7.8 vs. 5.4 months, P = .026) and in patients with good risk features (12.3 vs. 5.7 months, P = .022). Conclusions: Nivolumab and cabozantinib resulted active in mRCC patients, showing distinct results when stratified into clinico-pathological features.

Statins are commonly prescribed to reduce plasma cholesterol levels and risk of cardiovascular events and mortality. Statin exposure may have cancer-preventive properties in some solid tumors, including Renal Cell Carcinoma (RCC). Emerging evidences show that statins can inhibit RCC cell growth by inducing cell cycle arrest and apoptosis in a dose- and time-dependent manner. In addition, statins inhibit the phosphorylation of AKT, mammalian target of rapamycin (mTOR), and ERK leading to reduced motility of RCC cells. Interestingly, the potential impact of concomitant statin intake has been recently evaluated in RCC patients treated by targeted therapy or immunotherapy. In this review, we illustrate the most recent data on the preclinical activity of statins in Renal Cell Carcinoma models and discuss the impact of their use on the prevention and survival of patients affected by this tumor.

Treatment-related neurotoxicity is a common side effect in cancer patients. However, few data are available regarding the risk of several neurotoxicities in patients treated with immune checkpoint inhibitors. The MOUSEION-02 study is an up-to-date meta-analysis aimed at assessing the risk of peripheral neuropathy, peripheral sensory neuropathy, and headache in cancer patients receiving immunotherapy and immuno-oncology combinations. Patients receiving immunotherapy (as monotherapy or in combination with other anticancer agents) showed lower risk of all-grade peripheral neuropathy (RR, 0.50; 95% CI, 0.35���0.70) and all-grade peripheral sensory neuropathy (RR, 0.49; 95% CI, 0.30���0.79). Similarly, in patients treated with immune checkpoint inhibitor monotherapy, we observed lower risk of all-grade peripheral neuropathy (RR, 0.05; 95% CI, 0.03���0.10) and all-grade peripheral sensory neuropathy (RR, 0.11; 95% CI, 0.05���0.23). No differences were observed in terms of all-grade headache. Although the results of this meta-analysis should be interpreted with caution due to several issues, our study draws attention to immunotherapy-related neurotoxicity with the aim of maximizing clinical outcomes of cancer patients experiencing these not uncommon, and yet poorly studied, adverse events.

The primary endpoint of MOUSEION-01 was to assess overall survival (OS) in male and female patients receiving immune checkpoint inhibitors versus control treatments, calculating the pooled OS Hazard Ratio (HR) and 95 % Confidence Interval (CI) in both groups. 37 randomized phase III studies and 22646 patients (16382 men and 6264 women) were included. In patients treated with immunotherapy (as monotherapy or in combination with other agents), the pooled OS HR was 0.78 (0.75-0.82) and 0.77 (95 % CI, 0.72-0.83) in male and female subjects, respectively. The pooled HR for OS in male patients treated with single-agent immunotherapy versus control was 0.77 (95 % CI, 0.70-0.85), while this benefit was smaller in female patients (HR, 0.81; 95 % CI, 0.73-0.9). Our findings highlight that high-quality trials accounting for potential confounders are needed before being able to suggest a real effect of the patient's gender on immune checkpoint inhibitors efficacy in different settings.

Background: A subset of patients with metastatic renal cell carcinoma (mRCC), deemed as primary refractory, shows progressive disease as the best response to first-line therapy even when treated with novel immune-based combos. Objective: We aimed to assess the outcome of patients treated with second-line cabozantinib for mRCC primary refractory to first-line therapy defined as Response Evaluation Criteria in Solid Tumors (RECIST) progression in the computed tomography scan as the best response to the upfront treatment. Design, setting, and participants: We retrospectively collected data from 11 worldwide centers. Outcome measurements and statistical analysis: Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses. Results and limitations: We collected data from 108 patients with mRCC primary refractory to pembrolizumab plus axitinib (17%), nivolumab plus ipilimumab (36%), or tyrosine kinase inhibitors (TKIs; 31% sunitinib and 16% pazopanib). The median OS with cabozantinib was 9.11 mo, and it was 8.84 and 9.11 mo in patients primary refractory to immunocombinations and TKIs, respectively (p = 0.952). A significant difference was found between patients primary refractory to pembrolizumab plus axitinib (OS not reached) and those primary refractory to nivolumab plus ipilimumab (median OS 8.12 mo, p = 0.024). The median PFS with cabozantinib was 7.30 mo, without significant differences between patients primary refractory to immunocombinations and those primary refractory to TKIs (6.90 vs 7.59 mo, p = 0.435) or between patients primary refractory to pembrolizumab plus axitinib and those primary refractory to nivolumab plus ipilimumab (7.92 and 6.02, p = 0.509). Investigator-assessed overall response rates were 21% and 12% in patients primary refractory to first-line immunocombinations and TKIs, respectively, with a clinical benefit of 48% in the overall population. Conclusions: Our data show that cabozantinib is active in primary refractory mRCC patients regardless of which treatment is received as first-line therapy. Systemic options and prognosis of primary refractory patients with mRCC, particularly those treated with novel immune-based combos, are among the major challenges that we need to face in this field. Patient summary: Patients primary refractory to first-line therapy are characterized by a poor prognosis. Herein, we aimed to assess the outcome of patients treated with second-line cabozantinib for metastatic renal cell carcinoma (mRCC) primary refractory to first-line therapy. Our results suggest that cabozantinib is active in primary refractory mRCC patients.

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.

One of the most attractive cancer-related genes under investigation is BAP1. Reasons of this growing interest are related to the wide spectrum of pathways directly or indirectly modulated by this gene and shared by several solid tumors. Programmed cell-death, cell metabolisms, immune cells development, ferroptosis and defects in DNA damage response are only some of the multitude of processes depending on BAP1. Loss of this gene seems to occur in different times of tumor history. Moreover, times of BAP1 loss strongly diverge among primary tumors suggesting the presence of several and different triggering factors. Regardless of when it happens, BAP1 loss usually results in prognosis worsening and in the acquisition of more aggressive clinical features by cancer cells.

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.

Introduction Signal transducer and activator of transcription 3 (STAT3) is involved in cancer initiation and resistance to chemo-radiation therapies and targeted agents. The role of STAT3 in inflammation and immunity together with its involvement in a variety of diseases including genitourinary, gastrointestinal, lung, ovarian and brain tumors makes STAT3 an ideal candidate for therapeutic strategies. Areas covered The authors provided an overview on STAT3 inhibitors and examined the most recent results obtained by these agents in cancer patients. The authors discussed the results published since 2015 and the ongoing clinical trials on anti-STAT3 agents in cancer patients. The authors also provide our opinion on the future perspectives of this therapeutic approach in this context. The manuscript includes information from trial databases and scientific literature. Expert opinion Future challenges include the development of non-peptide small-molecule inhibitors of STAT3 designed to directly inhibit STAT3 activity. In addition, inhibitors of STAT3/STAT3 nuclear translocation or DNA binding activity are also emerging as novel promising therapeutic approaches A better comprehension of the role of STAT3 in modulating immune response together with advances in understanding the mechanisms of STAT3-induced chemo and/or radio-resistance will also help the design of combined strategies in cancer patients.

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.

We analyzed the clinical and pathological features of renal cell carcinoma (RCC) patients treated with cabozantinib stratified by body mass index (BMI). We retrospectively collected data from 16 worldwide centers involved in the treatment of RCC. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan&ndash, Meier curves. Cox proportional models were used at univariate and multivariate analyses. We collected data from 224 patients with advanced RCC receiving cabozantinib as second- (113, 5%) or third-line (111, 5%) therapy. The median PFS was significantly higher in patients with BMI &ge, 25 (9.9 vs. 7.6 months, p &lt, 0.001). The median OS was higher in the BMI &ge, 25 subgroup (30.7 vs. 11.0 months, p = 0.003). As third-line therapy, both median PFS (9.2 months vs. 3.9 months, p = 0.029) and OS (39.4 months vs. 11.5 months, p = 0.039) were longer in patients with BMI &ge, 25. BMI was a significant predictor for both PFS and OS at multivariate analysis. We showed that a BMI &ge, 25 correlates with longer survival in patients receiving cabozantinib. BMI can be easily assessed and should be included in current prognostic criteria for advanced RCC.

Background The Androgen Receptor Splice Variant 7 (AR-V7) has been associated with poor clinical outcomes in patients with castration-resistant prostate cancer (CRPC). Herein, we performed a meta-analysis aimed at systematically exploring the association between metastatic sites and AR-V7 expression in CRPC patients across prospective clinical trials. Methods We retrieved all the relevant prospective clinical trials 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 metastatic sites (lymph node metastases, any site metastases, visceral metastases, and bone metastases) in AR-V7 positive and AR-V7 negative CRPC patients. Odds Ratios (ORs) and 95 % confidence intervals (CI) were calculated. Results Overall, 14 eligible prospective studies involving a total of 1944 CRPC patients (AR-V7 positive: 467; AR-V7 negative: 1477) were included in the analysis. According to our results, no differences between AR-V7 positive and AR-V7 negative CRPC patients were observed in terms of lymph node (OR 1.01; 95 % CI 0.49–2.09) and visceral metastases (OR 1.23; 95 % CI 0.89–1.71). Conversely, AR-V7 positive CRPC patients presented higher rate of any site metastases (OR 2.22; 95 % CI 1.58–3.12) and bone metastases (OR 2.03; 95 % CI 1.42–2.9) compared to AR-V7 negative subjects. Conclusions The results of this meta-analysis, the first in literature to be specifically focused on this topic so far, suggest that AR-V7 positivity may be associated with any site metastases and bone metastases; conversely, no association has been highlighted between AR-V7 expression and lymph node or visceral metastases. Although this meta-analysis should be interpreted with caution due to some limitations, our findings confirm that AR-V7 status could designate a unique and peculiar subtype of PC. Further studies aimed at improving and standardizing AR-V7 detection in clinical trials on CRPC patients are warranted.

Aims: To capture the complex relationships between risk factors and cancer incidences in the US and predict future cancer burden. Materials & methods: Two artificial neural network (ANN) algorithms were adopted: a multilayer feed-forward network (MLFFNN) and a nonlinear autoregressive network with eXogenous inputs (NARX). Data on the incidence of the four most common tumors (breast, colorectal, lung and prostate) from 1992 to 2016 (available from National Cancer Institute online datasets) were used for training and validation, and data until 2050 were predicted. Results: The rapid decreasing trend of prostate cancer incidence started in 2010 will continue until 2018–2019; it will then slow down and reach a plateau after 2050, with several differences among ethnicities. The incidence of breast cancer will reach a plateau in 2030, whereas colorectal cancer incidence will reach a minimum value of 35 per 100,000 in 2030. As for lung cancer, the incidence will decrease from 50 per 100,000 (2017) to 31 per 100,000 in 2030 and 26 per 100,000 in 2050. Conclusion: This up-to-date prediction of cancer burden in the US could be a crucial resource for planning and evaluation of cancer-control programs.

Ciliopathies are a group of multi-organ diseases caused by the disruption of the primary cilium. This event leads to a variety of kidney disorders, including nephronophthisis, renal cystic dysplasia, and renal cell carcinoma (RCC). Primary cilium contributes to the regulation of the cell cycle and protein homeostasis, that is, the balance between protein synthesis and degradation by acting on the ubiquitin-proteasome system, autophagy, and mTOR signaling. Many proteins are involved in renal ciliopathies. In particular, fibrocystin (PKHD1) is involved in autosomal recessive polycystic kidney disease (ARPKD), while polycystin-1 (PKD1) and polycystin-2 (PKD2) are implicated in autosomal dominant polycystic kidney disease (ADPKD). Moreover, primary cilia are associated with essential signaling pathways, such as Hedgehog, Wnt, and Platelet-Derived Growth Factor (PDGF). In this review, we focused on the ciliopathies associated with kidney diseases, exploring genes and signaling pathways associated with primary cilium and the potential role of cilia as therapeutic targets in renal disorders.

The interplay between microbiota and nervous system has been associated with a variety of diseases, including stress, anxiety, depression and cognition. The growing body of evidences on the essential role of gut microbiota in modulating acute and chronic pain has opened a new frontier for pain management. Gut microbiota is involved in the development of visceral, inflammatory and neuropathic pain. Bacterial alterations due to chronic opioid administration have been directly related to the development of drug tolerance, which can be potentially restored by the use of probiotics and antibiotics. In this review we describe the mechanisms underlying the brain/gut axis and the relationship between gut microbiota, immunity and pain.

Background: We hypothesized that non-small cell lung cancer (NSCLC) patients with a tumor positive for single nucleotide polymorphisms (SNPs) of the Excision Repair Cross Complementation Group 1 (ERCC-1) gene could be more genetically instable and consequently more responsive to a programmed cell death-1 (PD-1) blockade. Methods: We evaluated the T19007C and C8092A ERCC-1 SNPs by pyrosequencing assay, on tumor specimens from two independent cohorts of patients who relapsed after one or more prior systemic treatments for advanced NSCLC and who received nivolumab (3 mg/kg intravenously every 2 weeks) as part of the Italian Expanded Access Program. We aimed to assess the outcome of enrolled subjects according to the ERCC-1 SNPs status, to evaluate the role of these polymorphisms as putative biomarkers associated with a response/clinical benefit to anti-PD-1 therapies. Results: Of the 45 patients included in the final analysis, 21 (47%) and 16 (36%) were positive for the T19007C and C8092A polymorphic genotype (PG), respectively. In univariate analyses, overall survival (OS) and progression free survival (PFS) were shorter in patients with the T19007C PG, but neither difference achieved statistical significance (P = 0.131 and P = 0.717, respectively). The presence of the C8092A PG was associated with a longer OS and PFS, although statistical significance was only reached for PFS (P = 0.112 and P = 0.025, respectively). These results were confirmed by multivariate analyses. The response rate was only significantly higher in patients with the C8092A PG vs. wild type ERCC-1 (62 vs. 7%, P < 0.001). Conclusions: Results from this hypothesis generating pilot study, provided suggestive evidence that a subgroup of NSCLC patients could benefit differently from nivolumab according to the C8092A ERCC-1 SNP status. However, these data warrant further investigation., SCOPUS: ar.j, info:eu-repo/semantics/published

Background and Objectives: Several systemic treatments are available for metastatic hormone sensitive prostate cancer (mHSPC) including docetaxel (D), abiraterone and prednisone (A + P) and new anti-androgens (NA). In our study we performed a systematic review and meta-analysis assessing efficacy outcomes (survival and radiological-free survival), safety and survival on specific subgroups of patients. Methods: Outcomes of interest were: (i) Risk of death, biochemical and radiological progression among all patients. (ii) Risk of death according to different pathological/clinical features. (iii) Evaluation of the relative risk (RR) and risk difference of serious toxicity defined as adverse events (AEs) with grade ≥ 3 specific AEs. Hazard ratios (HRs) and RR were measures adopted for endpoints 1–3. Results: Overall, eight randomized trials were included in meta-analysis for a total of 9987 patients. Administration of D, A + P and NA resulted in improved overall survival (OS) and radiological progression-free survival (rPFS). Survival benefit was not confirmed in patients receiving NA and previously exposed to docetaxel (HR 0.948, 95% CI 0.671–1.338). Patients with visceral metastases and high lactate dehydrogenase (LDH) did not benefit from NA treatment, while it seems that patients with low Gleason score do not benefit from A + P. NA showed the more favorable safety profile. Conclusion: NA may not provide survival benefit when adopted subsequently or in concomitant to D. Specific subgroups of patients may benefit more from A + P, D or NA. Safety profiles significantly differ among agents evaluated.

Introduction: Knowledge of the complex biology of prostate cancer is constantly growing, opening the field up to new therapeutic advances. The selection of patients on the basis of prognostic and predictive biomarkers is a challenging and emerging clinical need, not yet completely fulfilled. In this scenario, liquid biopsy offers a noninvasive and attractive approach to give important information about tumor biology and eventual resistance to treatments.Areas covered: The aim of this review of the literature is to evaluate the current knowledge and the promising value of liquid biopsy in prostate cancer. Circulating tumor cells and circulating tumor DNA identified by liquid biopsies are currently under evaluation to guide therapeutic decisions in prostate cancer management, even though practical applications of these approaches are still very limited. We examined the current areas of interest in which circulating tumor cells and circulating tumor DNA are being investigated, such as their prognostic and predictive role in response to chemotherapy or androgen receptor signaling inhibition, especially in the castration-resistant setting.Expert opinion: As the body of knowledge on liquid biopsy rapidly grows, we need to identify which can be the real applications of this technique in clinical practice and to overcome the problems that are limiting its routinely use.

Background:This prospective, multicentre, observational INVIDIa-2 study is investigating the clinical efficacy of influenza vaccination in advanced-cancer patients receiving immune-checkpoint inhibitors (ICIs), enrolled in 82 Italian centres, from October 2019 to January 2020. The primary endpoint was the incidence of influenza-like illness (ILI) until 30 April 2020. All the ILI episodes, laboratory tests, complications, hospitalizations and pneumonitis were recorded. Therefore, the study prospectively recorded all the COVID-19 ILI events.Patients and methods:Patients were included in this non-prespecified COVID-19 analysis, if alive on 31 January 2020, when the Italian government declared the national emergency. The prevalence of confirmed COVID-19 cases was detected as ILI episode with laboratory confirmation of SARS-CoV-2. Cases with clinical-radiological diagnosis of COVID-19 (COVID-like ILIs), were also reported.Results:Out of 1257 enrolled patients, 955 matched the inclusion criteria for this unplanned analysis. From 31 January to 30 April 2020, 66 patients had ILI: 9 of 955 cases were confirmed COVID-19 ILIs, with prevalence of 0.9% [95% confidence interval (CI): 0.3–2.4], a hospitalization rate of 100% and a mortality rate of 77.8%. Including 5 COVID-like ILIs, the overall COVID-19 prevalence was 1.5% (95% CI: 0.5–3.1), with 100% hospitalization and 64% mortality. The presence of elderly, males and comorbidities was significantly higher among patients vaccinated against influenza versus unvaccinated ( p = 0.009, p Conclusion:COVID-19 has a meaningful clinical impact on the cancer-patient population receiving ICIs, with high prevalence, hospitalization and an alarming mortality rate among symptomatic cases. Influenza vaccination does not protect from SARS-CoV-2 infection.

The management of patients with metastatic RCC (mRCC) has been completely changed in the last decade by the introduction of novel molecularly targeted approaches. Although partial or radical nephrectomy still remains the standard approach for patients with localized RCC, systemic therapies are recommended in patients with mRCC. Till 2005, cytokine therapies represented the gold standard but were associated with a poor toxicity profile and a low response rate. Successively, the growing knowledge of the key role of angiogenesis in the development and progression of mRCC has led to the development of several targeted agents, which have increased the life expectancy of these patients. In this chapter, we describe the main agents currently used into daily clinical practice and the results of the clinical studies that have led to their approval in patients with mRCC.