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Background and Objective: Combinations of VEGFR-TKIs plus ICI against PD1/PD-L1 are the standard first-line therapy for patients with mRCC, irrespective of the prognostic class. This study aims to investigate the feasibility and safety of withdrawing the VEGFR-TKI but continuing the anti- PD1/PD-L1 in patients who achieve response to their combination., Methods: This was a single-arm phase 2 trial in patients with treatment naïve mRCC with prior nephrectomy, without symptomatic/bulky disease and no liver metastases. Enrolled patients received axitinib+avelumab, after 36 weeks of therapy those who achieved tumor response interrupted axitinib and continued avelumab maintenance until disease progression. The primary endpoint was the rate of patients without progression eight weeks after the axitinib interruption. Secondary endpoints were the median value for progression free (mPFS) and overall survival (mOS) and the safety in the overall population., Key Findings and Limitations: 79 patients were enrolled and 75 evaluated for efficacy. A total of 29 (38%) patients had axitinib withdrawn, as per the study design, with 72% of them having no progression after eight weeks and thus achieving the primary endpoint. The mPFS of the overall population was 24 months while the mOS was not reached. The ORR was 76% (12% CR, 64% PR), with 19% of patients having stable disease. In the patients who discontinued axitinib, the incidence of AEs of any grade was 59% and 3% for grade 3 or 4. This study was limited by the lack of the comparative arm., Conclusions and Clinical Implications: The TIDE-A study demonstrates that the withdrawal of VEGFR-TKI with ICI maintenance is feasible for selected mRCC patients with evidence of response to the VEGFR-TKI+ICI combination employed in first-line therapy. Axitinib interruption with avelumab maintenance led to decreased side effects and should be further investigated as a new strategy to delay tumor progression., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The standard of care for advanced or metastatic urothelial carcinoma (mUC) was historically identified with platinum-based chemotherapy. Thanks to the advances in biological and genetic knowledge and technologies, new therapeutic agents have emerged in this setting recently: the immune checkpoint inhibitors and the fibroblast growth factor receptor inhibitors as the target therapy for patients harboring alterations in the fibroblast growth factor receptor (FGFR) pathway. However, chasing a tumor's tendency to recur and progress, a new class of agents has more recently entered the scene, with promising results. Antibody-drug conjugates (ADCs) are in fact the latest addition, with enfortumab vedotin being the first to receive accelerated approval by the U.S. Food and Drug Administration in December 2019, followed by sacituzumab govitecan. Many other ADCs are still under investigation. ADCs undoubtedly represent the new frontier, with the potential of transforming the management of mUC treatment in the future. Therefore, we reviewed the landscape of mUC treatment options, giving an insight into the molecular basis and mechanisms, and evaluating new therapeutic strategies in the perspective of more and more personalized treatments.

Background: Immune-checkpoint inhibitors (ICIs) have significantly improved metastatic renal cell carcinoma (mRCC) prognosis, although their efficacy in patients with bone metastases (BMs) remains poorly understood. We investigated the prognostic role of natremia in pretreated RCC patients with BMs receiving immunotherapy., Materials and Methods: This retrospective multicenter study included RCC patients with BMs receiving nivolumab as second-line therapy or beyond. Inclusion criteria involved baseline sodium levels (pre-ICI) and sodium levels after 4 weeks of nivolumab initiation (post-ICI). The population was divided into two groups based on the median value, and response rates, progression-free survival (PFS), and overall survival (OS) were assessed., Results: Among 120 eligible patients, those with pre-treatment sodium levels ≥140 mEq/L showed longer OS (18.7 vs. 12.0 months, p=0.04). Pre-treatment sodium levels ≥140 mEq/L were associated with better OS compared to levels <140 mE/L (18.7 vs. 12.0, p=0.04). Post-treatment sodium levels ≥140 mEq/L were associated with improved PFS (9.6 vs . 3.2 months) and OS (25.1 vs. 8.8 months) (p=0.05 and p<0.01, respectively). Patients with consistent sodium levels ≥140 mEq/L at both time points exhibited the best outcomes compared to those with lower values (PFS 11.5 vs. 3.3 months and OS 42.2 vs. 9.0 months, respectively, p<0.01). Disease control rate was significantly higher in the latter group (p<0.01). Multivariate analysis confirmed the prognostic significance of sodium levels., Conclusion: Elevated sodium levels (≥140 mEq/L) pre- and post-ICI treatment correlate with better survival outcomes in mRCC patients with BMs. This finding suggests sodium level assessment as a potential prognostic factor in these patients and warrants further investigation, particularly in combination immunotherapy settings., Competing Interests: GB: Speaker bureau: Astellas, Astrazeneca, Amgen. Patents: n. 4 patents with ST Microelectronics. Travel, Accommodations for scientific conferences: Merck, Janssen. UG: services as advisory/board member of Astellas, Bayer, BMS, IPSEN, Janssen, Merck, Pfizer, Sanofi, received research grant/funding to the institution from AstraZeneca, Roche, Sanofi and travel/accommodations/expenses from BMS BMS, IPSEN, Janssen, Pfizer. LC: has received honoraria for advisory boards, speaker engagements and scientific consultancy for educational purposes from AstraZeneca, EISAI, MSD, Ipsen, BMS, A.A.A.; past MSD employee in Medical Affairs. MS: honoraria as consultant or advisory role from Janssen; grant for participation at scientific events: Astellas Pharma, Sanofi, Roche Novartis, Ipsen, Janssen, Bristol Myers Squibb, Pfizer; research funding: Roche, Merck, Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Catalano, Rebuzzi, Maruzzo, De Giorgi, Buti, Galli, Fornarini, Zucali, Claps, Chiellino, Zampiva, Pipitone, Ricotta, Sorarù, Mollica, Tudini, Fratino, Prati, Caffo, Atzori, Morelli, Prati, Nolè, Vignani, Cavo, Di Napoli, Malgeri, Naglieri, Signori, Banna, Rescigno, Cerbone, Antonuzzo and Roviello.)

Background: Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment., Materials and Methods: A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses., Results: A total of 571 patients with a median age of 61 years (range 17-85) were included in the analysis. With a median follow-up of 22.1 (1.0-89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders., Conclusion: This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy., (© 2024. The Author(s).)

Endometrial cancer (EC) incidence and mortality rates have been increasing, particularly among young females. Although more than 90% of ECs are sporadic, 5-10% are hereditary, a majority of which occurs within Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC) or Lynch syndrome. The traditional histopathological classification differentiates EC between two main groups: type I (or endometrioid) and type II (including all other histopathological subtypes). However, this classification lacks reproducibility and does not account for the emerging molecular heterogeneity. In 2013, The Cancer Genome Atlas (TCGA) project proposed EC molecular classification defining four groups with different prognostic and predictive values and the current international guidelines are progressively establishing EC risk stratification and treatment based on both histopathological and molecular criteria. Our manuscript aims to summarize the current state of EC molecular characterizations, including germline alterations at the basis of hereditary EC predisposition, to discuss their clinical utility as prognostic and predictive markers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of BRCA1 or BRCA2 pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript.

Background & Aims: Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours., Methods: Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure., Results: In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96)., Conclusions: Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes., Impact and Implications: Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Ovarian cancer is metastatic at presentation in about 62% of cases, but brain metastases are rare, reported in 3.3-4% of patients. Brain metastasis seems to be more frequent in advanced stages at diagnosis and in patients with BRCA1/2 mutation., Case Presentation: We present a case of a 47-year-old Caucasian woman, BRCA wild type, with an ovarian cancer that started with single cerebellar metastasis., Conclusion: Brain metastases in ovarian cancer are rare and complex for diagnosis and management. This case focuses both on diagnosis and treatment, emphasizing the importance of a multimodal approach in a multidisciplinary team., (© 2023. The Author(s).)

Importance: Low sodium levels have been associated with negative outcomes among patients with metastatic renal cell carcinoma (mRCC) receiving therapies other than immune checkpoint inhibitors (ICIs)., Objective: To investigate the role of natremia in patients with mRCC receiving nivolumab as a second-line or subsequent therapy., Design, Setting, and Participants: In this retrospective cohort study, the clinical and biochemical data of patients with mRCC receiving nivolumab were collected from October 2015 to November 2019 as part of a multicenter Italian study. Data analysis was performed from February to March 2023., Exposure: Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks and, since May 2018, at a fixed dose of 240 mg every 2 weeks or 480 mg every 4 weeks. Patients were divided into 2 groups according to their median serum sodium value (<140 or ≥140 mEq/L)., Main Outcomes and Measures: The primary outcomes were the associations of pre-ICI and post-ICI sodium levels with overall survival (OS), progression-free survival (PFS), objective response rate, and disease control rate (DCR). The Kaplan-Meier method was used to estimate PFS and OS, and differences between groups were compared using the log-rank test., Results: A total of 401 patients with mRCC receiving nivolumab as second-line therapy were evaluated, and 355 eligible patients (median [range] age, 76 [44-84] years; 258 male patients [72.7%]) were included in the final cohort. Among patients with pre-ICI sodium greater than or equal to 140 mEq/L compared with those with sodium less than 140 mEq/L, the median PFS was 9.3 months (95% CI, 6.5-11.5 months) vs 7.4 months (95% CI, 4.6-10.1 months; P = .90), and the median OS was 29.2 months (95% CI, 21.8-35.9 months) vs 20.0 months (95% CI, 14.1-26.8 months; P = .03). Patients with post-ICI sodium values greater than or equal to 140 mEq/L had longer PFS (11.1 months [95% CI, 8.5-1.5 months] vs 5.1 months [95% CI, 4.1-7.5 months]; P = .01) and OS (32.9 months [95% CI, 25.1-42.6 months] vs 17.1 months [95% CI, 12.6-24.5 months]; P = .006) compared with patients with sodium values less than 140 mEq/L. Patients with both pre-ICI and post-ICI sodium values greater than or equal to 140 mEq/L exhibited a significant improvement in clinical outcomes compared with those with a value less than 140 mEq/L (PFS, 11.5 months [95% CI, 8.8-16.4 months] vs 5.8 months [95% CI, 4.4-8.3 months]; P = .008); OS, 37.6 months [95% CI, 29.0-49.9 months] vs 19.4 months [95% CI, 14.1-24.5 months]; P = .01). Moreover, sodium levels greater than or equal to 140 mEq/L were associated with significantly better DCR than lower sodium levels., Conclusions and Relevance: In this retrospective cohort study of patients with mRCC receiving nivolumab, sodium values greater than or equal to 140 mEq/L, both before and/or after ICI, were associated with better OS and PFS, as well as a higher DCR, compared with levels less than 140 mEq/L. These findings suggest that sodium levels may be associated with survival outcomes in patients with mRCC and may have potential use as variables to consider in patients' risk scores.

De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities for de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have modified the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road toward personalized treatment for de novo mHSPC is still long, considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that did not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as a predictive biomarker requires further validation, and it remains to be ascertained how the genomic variants detected in mHSPC, which are regarded as predictive in the castration-resistant disease, can be exploited in the mHSPC setting.

The neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammatory index (SII) have been reported as prognosticators in non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and melanoma. This analysis of the INVIDIa-2 study on influenza vaccination in patients with cancer treated with immune checkpoint inhibitors (ICIs) assessed NLR and SII on overall survival (OS) by literature-reported (LR), receiver operating characteristic curve (ROC)-derived (ROC) cutoffs or as continuous variable (CV). NLR and SII with ROC cutoffs of <3.4 (p < 0.001) and <831 (p < 0.001) were independent factors for OS in multivariate analysis. SII with LR, ROC, or CV significantly predicted OS in NSCLC (p = 0.002, p = 0.003, p = 0.003), RCC (p = 0.034, p = 0.014, p = 0.014), and melanoma (p = 0.038, p = 0.022, p = 0.019). NLR with LR and ROC cutoffs predicted OS in first line (p < 0.001 for both) and second line or beyond (p = 0.006 for both); likewise SII (p < 0.001; p = 0.002 and p < 0.001). NLR and SII are prognosticators in NSCLC, RCC, and melanoma treated with ICIs., Competing Interests: The Federation of Italian Cooperative Oncology Groups (FICOG) received funding for the present study from Roche S.p.A. and Seqirus, and outside the present research from AstraZeneca, Bristol-Myers Squibb (BMS), and Sanofi. G.L.B. received fees for speaker bureau from AstraZeneca and Astellas Pharma. M.B. received funding for the present study from Roche S.p.A. and Seqirus (through FICOG as Institution, no personal fees). She also received, outside the current work, research funding from Pfizer and Novartis (through Institutions); honoraria as a speaker at scientific events (personal fees) by BMS, MSD, IPSEN, Novartis, AstraZeneca, Pierre Fabre, and Pfizer; as a consultant for advisory role (personal fees) from IPSEN, Novartis, Sanofi, Pierre-Fabre, and Merck; and personal fees for copyright transfer from Sciclone Pharmaceuticals, Pierre-Fabre, MSD, IPSEN, Pfizer, and Sanofi. S.B. received honoraria as a speaker at scientific events and in advisory role by BMS, Pfizer; MSD, Ipsen, Roche S.p.A., Eli-Lilly, AstraZeneca, and Novartis; he also received research funding from Novartis. A.C. received speaker fees and grant consultancies by AstraZeneca, MSD, IQVIA, OncoC4, and EISAI. U.D.G. has served as a consultant for Astellas, Bayer, BMS, Ipsen, Janssen, Novartis, Pfizer, Sanofi, and Pharmamar; he received research funding from AstraZeneca, Roche, and Sanofi; and received travel funds from BMS, Ipsen, Janssen, Pfizer, and Roche during the conduct of the study. P.E. received honoraria for advisory role from MSD, BMS, and Astellas. F.G. received honoraria for advisory role from Eli Lilly, Roche, Boehringer Ingelheim, AstraZeneca, Pierre Fabre, BMS, MSD, Novartis, Merck, Otsuka, Novartis, Takeda, and Bayer; seminar/talks to industry from Eli Lilly, Roche, Boehringer Ingelheim, AstraZeneca, Pierre Fabre, AMGEN, Celgene, BMS, and MSD; and research funding from AstraZeneca, BMS, and MSD. M.D.M. reports personal fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; has been local principal investigator for trials sponsored by Beigene, Exelixis, Merck Sharp & Dohme, and Pfizer; and received research grant, institutional and financial support, and drug supply for the Meet-URO12 trial from Tesaro GlaxoSmithKline. D.G. received honoraria from Amgen for speaker bureau. M.M. received honoraria for advisory role from MSD and travel and accommodation expenses from Janssen, Roche, and Pfizer. C.P. received honraria for advisory role, speaker bureau, and travel and accommodation expenses from Amgen, Astellas, AstraZeneca, Bayer, Bristol Meyer Squibb, Celgene, Clovis Oncology, Eisai, Ipsen, Janssen, Incyte, Merck-Serono, Merck Sharp & Dohme, Novartis, Roche, Sandoz, Sanofi, and Servier. P.R. received honoraria for advisory role from AstraZeneca, Janssen, Gilead, BMS, and MSD Italy. M.R. received honoraria for advisory role or speaker bureau from Pfizer, Novartis, MSD, AstraZeneca, Bristol-Myers Squibb (BMS), and Merck. V.S. participated, with personal fees, in advisory boards and speaker’s bureaus for Roche S.p.A. S.C. declared his role in an international board for Eli Lilly international. M.S. received honoraria for advisory role from Janssen and grants for participation at scientific events from BMS, Ipsen, Janssen, Astella, Sanofi, Pfizer, and Novartis. E.V. received honoraria for advisory role from MSD, AstraZeneca, Ipsen, and Janssen. P.A.Z. acts in a consultant or advisory role for Sanofi, BMS, Pfizer, MSD, Astellas, Janssen, Ipsen, and Novartis, all outside the scope of work. A.A. undertook consulting or advisory roles from BMS, AstraZeneca, Boehringer Ingelheim, Roche, MSD, Pfizer, Eli Lilly, and Astellas and participated in speaker’s bureaus from Eli Lilly and AstraZeneca. All other authors declare no competing interests., (© 2023 The Authors.)

Introduction: Since 2016, the progressive use of immune checkpoint inhibitors (ICIs) starting from second-line treatment has led to an improvement in overall survival in locally advanced and metastatic urothelial cancer (UC). Clinical trials are underway testing the role of ICIs since the first stages of the disease, alone or in combination with standard therapies., Areas Covered: This review summarizes the current updated evidence regarding the role of ICIs in the different stages of UC, the ongoing clinical trials exploring the potential benefit of immunotherapy alone or in combination with standard-of-care therapies, as well as the promising association of ICIs with antibody-drug conjugates (ADCs)., Expert Opinion: In the first-line setting, ICIs alone in platinum-unfit patients have shown unconvincing results; the ongoing EV-302 trial will probably suggest enfortumab vedotin plus pembrolizumab as a new effective option. The optimal duration of maintenance immunotherapy is still to be determined, finding a balance with the risk-benefit profile. The clinical benefit of ICIs as second-line treatment is limited to a subset of patients that cannot be definitively established yet. In the next 5 years, a lot of new ADCs will likely emerge for the treatment of UC.

Renal cell carcinoma (RCC) is the second most common cancer of the urinary system. The current therapeutic strategies are based on partial or total nephrectomy and/or targeted therapies based on immune checkpoint inhibitors to which patients are often refractory. Preventive and screening strategies do not exist and the few available biomarkers for RCC are characterized by a lack of sensitivity, outlining the need for novel noninvasive and sensitive biomarkers for early diagnosis and better disease monitoring. Blood liquid biopsy (LB) is a non- or minimally invasive procedure for a more representative view of tumor heterogeneity than a tissue biopsy, potentially allowing the real-time monitoring of cancer evolution. Growing interest is focused on the extracellular vesicles (EVs) secreted by either healthy or tumoral cells and recovered in a variety of biological matrices, blood included. EVs are involved in cell-to-cell crosstalk transferring their mRNAs, microRNAs (miRNAs), and protein content. In particular, transferred miRNAs may regulate tumorigenesis and proliferation also impacting resistance to apoptosis, thus representing potential useful biomarkers. Here, we present the latest efforts in the identification of circulating miRNAs in blood samples, focusing on the potential use of EV-derived miRNAs as RCC diagnostic and prognostic markers.

Clinically relevant bone metastases are a major cause of morbidity and mortality for prostate cancer patients. Distinct phenotypes are described: osteoblastic, the more common osteolytic and mixed. A molecular classification has been also proposed. Bone metastases start with the tropism of cancer cells to the bone through different multi-step tumor-host interactions, as described by the "metastatic cascade" model. Understanding these mechanisms, although far from being fully elucidated, could offer several potential targets for prevention and therapy. Moreover, the prognosis of patients is markedly influenced by skeletal-related events. They can be correlated not only with bone metastases, but also with "bad" bone health. There is a close correlation between osteoporosis-a skeletal disorder with decreased bone mass and qualitative alterations-and prostate cancer, in particular when treated with androgen deprivation therapy, a milestone in its treatment. Systemic treatments for prostate cancer, especially with the newest options, have improved the survival and quality of life of patients with respect to skeletal-related events; however, all patients should be evaluated for "bone health" and osteoporotic risk, both in the presence and in the absence of bone metastases. Treatment with bone-targeted therapies should be evaluated even in the absence of bone metastases, as described in special guidelines and according to a multidisciplinary evaluation.

Background: Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era., Methods: We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups., Results: Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32-0.60, p < 0.001) with a longer median overall survival (OS) (35.9 months vs 12.1 months), 1-year OS of 71.6% vs 50.5% and 2-years OS of 56.5% vs 22.0% compared to those who did not. No significant interaction between nephrectomy and the overall five Meet-URO score risk groups was observed (p = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 (p = 0.038) and associated with a longer OS for the first three prognostic groups (p < 0.001), but not for groups 4 and 5 (p = 0.54)., Conclusions: Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score., (© 2022. The Author(s).)

This is a retrospective analysis on the safety and activity of compassionate Ipilimumab and Nivolumab (IPI-NIVO) administered to patients with metastatic Renal Cell Carcinoma (mRCC) with intermediate or poor International Metastatic RCC Database Consortium (IMDC) score as a first-line regimen. IPI was infused at 1 mg/kg in combination with Nivolumab 3 mg/kg every three weeks for four doses, followed by maintenance Nivolumab (240 or 480 mg flat dose every two or four weeks, respectively) until disease progression or unacceptable toxicity. A total of 324 patients started IPI-NIVO at 86 Italian centers. Median age was 62 years, 68.2% IMDC intermediate risk. Primary tumor had been removed in 65.1% of patients. Two hundred and twenty patients (67.9%) completed the four IPI-NIVO doses. Investigator-assessed overall response rate was 37.6% (2.8% complete). Twelve-month survival rate was 66.8%, median progression-free survival was 8.3 months. Grade 3 or 4 treatment-related adverse events occurred in 67 patients (26.9%). IMDC intermediate risk, nephrectomy, BMI ≥ 25 kg/m2, and steroid use for toxicities correlated with improved survival, while age < 70 years did not. IPI-NIVO combination is a feasible and effective regimen for the first-line treatment of intermediate-poor IMDC risk mRCC patients in routine clinical practice.

Introduction: Xp11.2 translocation is a rare subtype of renal cell carcinoma (RCC), identified as a single entity only from 2004 by World Health Organization (WHO). These tumors involve pediatric age group and rarely patients over 40 years old. Children show indolent disease; adult population has invasive tumor at diagnosis with rapid progression., Case Report: We describe a case report of a young woman affected by metastatic clear cell renal carcinoma with Xp11.2 translocation. She achieved a longer stable disease (SD) to first line treatment with atezolizumab plus bevacizumab, obtaining a progression free survival (PFS) of 21 months. After she received cabozantinib, sunitinib and then sorafenib., Conclusions: The patient had an overall survival (OS) of 51 months, which is much higher than that reported in literature data. Unfortunately, the biology of Xp11.2 translocation RCC and its therapeutic management are still unclear.

Background: Immunotherapy has brought clinical benefits to patients with metastatic renal cell cancer (mRCC). Most patients tolerate immunotherapy but serious immune-related adverse events (irAEs) have been reported. Some studies indicate a correlation between irAEs and clinical response in other cancer types (eg, lung cancer and melanoma). For patients with mRCC, the impact of irAE on clinical outcome is unknown., Patients and Methods: A retrospective review of 167 patients with mRCC treated with nivolumab as standard of care between March 2017 and January 2018 in 16 Italian centers was performed. irAEs were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0., Results: Any grade and grade 3/4 irAEs occurred in 46% and 8.9% of patients, respectively. The median time to appearance of irAEs was 10 weeks; 38.8% of patients required steroid treatment. The most common irAEs were cutaneous (33.7%) and gastrointestinal (23.3%). The median overall survival and progression-free survival were 20.13 and 7.86 months, respectively. Patients with irAEs showed a greater overall survival (hazard ratio, 0.38; 95% confidence interval [CI], 0.23-0.63) and progression-free survival (hazard ratio, 0.44; 95% CI, 0.29-0.66) benefit as well as better overall response rate (27.3% vs. 13.7%; odds ratio, 2.36; 95% CI, 1.03-5.44) and disease control rate (68.8% vs. 48%; odds ratio, 2.4; 95% CI, 1.23-4.67) if compared with those without irAEs. No correlation was found between steroid use and clinical outcomes., Conclusions: Our analysis revealed that the appearance of irAEs was associated with better outcomes in patients treated with nivolumab. This data may be limited by sample size and the retrospective nature of the study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The identification of BRCA mutations plays a crucial role in the management of hereditary cancer prevention and treatment. Nonetheless, BRCA-testing in pancreatic cancer (PC) patients is not universally introduced in clinical practice. A retrospective analysis was conducted, firstly, to evaluate the rate of BRCA-positive families among those presenting a family history of PC besides breast and/or ovarian cancer. Secondly, the relationship between BRCA pathogenic variants and PC risk was evaluated. Finally, the characteristics of PC developed in BRCA families were described. Among 5143 family trees reporting breast and/or ovarian cancer cases, 392 showed a family history of PC. A total of 35 families (24.5% selected by the Modena Criteria and 21.3% by the NCCN Criteria) were positive to BRCA testing. Among the BRCA1 mutations, 36.8% were found within a region defined by c.3239⁻c.3917, whilst 43.7% of BRCA2 mutations were located within c.7180⁻c.8248. This study confirmed that an increase in the rate of positive tests in families with PC when associated to breast and/or ovarian tumors. Moreover, this analysis indicated two possible Pancreatic Cancer Cluster Regions that should be verified in future research. Finally, PC in families with breast and/or ovarian cancer history, particularly in BRCA families, were diagnosed at younger age and showed better one-year overall survival., Competing Interests: The authors have declared no conflict of interest.

Triple-negative breast cancer (TNBC) remains the poorest-prognosis breast cancer (BC) subtype. Gene expression profiling has identified at least six different triple-negative subtypes with different biology and sensitivity to therapies. The heterogeneous nature of TN tumors may justify the difficulty in treating this BC subtype. Several targeted agents have been investigated in clinical trials without demonstrating a clear survival benefit. Therefore, systemic chemotherapy remains the cornerstone of current clinical practice. Improving the knowledge of tumor biology is mandatory for patient management. In stages II and III, neoadjuvant systemic treatment is an effective option of care. The achievement of a pathological complete response represents an optimal surrogate for survival outcome as well as a test for tumor drug sensitivity. In this review, we provide a brief description of the main predictive biomarkers for tumor response to systemic treatment. Moreover, we review the treatment strategies investigated for TNBCs in neoadjuvant settings focusing on experimental drugs such as immunotherapy and poly [ADP-ribose] polymerase inhibitors that hold promise in the treatment of this aggressive disease. Therefore, the management of TNBC represents an urgent, current, unmet need in daily clinical practice. A key recommendation is to design biology-driven clinical trials wherein TNBC patients may be treated on the basis of tumor molecular profile., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Introduction: Pancreatic ductal adenocarcinoma cancer (PDAC) is the fourth leading cause of cancer death worldwide. Recently, two chemotherapy regimens have proven to improve median overall survival in comparison with gemcitabine. Based on better understanding of tumor molecular biology and of the role of tumor microenvironment, monoclonal antibodies (mAbs) could be an interesting and new type of targeted treatment of PDAC. Areas covered: Preclinical and clinical trials have evaluated the efficacy of several mAbs in pancreatic cancer treatment. This review will underline the most important targeted pathways by mAbs involved in this disease, including EGFR, HER-2, IGF-1 R, VEGF/VEGFR, NOTCH, WNT and immune checkpoints. Expert opinion: Despite the promising results of preclinical and phase I trials, the addition of mAbs to standard chemotherapy or in association with other target agents seems not to confirm these results in the following phase II and III trials in pancreatic cancer patients. However, an improved patient selection before treatment based on molecular characteristics in association with reliable predictive biomarkers can identified more efficacious treatment approaches, minimizing toxicity profile of these drugs.