OBJECTIVES:Evaluate associations between serum copper (Cu), rubidium (Rb), selenium (Se), strontium (Sr), and zinc (Zn) and psychophysical health in adults from Italy's Sarno River Basin within the 2025 PREVES-STOP program. METHODS:Adults aged 30-65 completed validated questionnaires plus clinical evaluation and blood sampling. Elements were quantified by collision/reaction-cell inductively coupled plasma mass spectrometry (ICP-MS). Associations were evaluated using Spearman and partial Spearman correlations. RESULTS:Significant associations included Zn and Rb associated with lower odds (odds ratio, OR) of severe fatigue - Recognizing and Estimating Signs of Tiredness (REST): Zn OR=0.38, 95 % confidence interval (CI) 0.21-0.68, q=0.02; Rb OR=0.33, 95 % CI 0.15-0.71, q=0.03 - while Sr was associated with higher well-being - the World Health Organization-5 Well-Being Index (WHO-5) OR=1.36, 95 % CI 1.12-1.65, q=0.02. CONCLUSIONS:Findings support broader trace-element panels to inform psychophysical and cardiometabolic risk beyond classical toxic metals, complementing prior PREVES-STOP evidence on lead (Pb) and cadmium (Cd). Further investigation is warranted.

Background: Next-generation sequencing (NGS)-detected ERBB2 amplification occurs in a subset of urothelial carcinomas, but its role as a treatment-selection marker for trastuzumab deruxtecan (T-DXd) remains uncertain. Methods: We retrospectively reviewed four patients with metastatic urothelial carcinoma treated with T-DXd in routine practice from 2024. Treatment selection was based on NGS-detected ERBB2 amplification because HER2 immunohistochemistry and in situ hybridization were unavailable. Results: Four men aged 65–76 years received T-DXd: one in the second line and three in the fourth or fifth line. The best radiological responses, abstracted from contemporaneous radiology reports and oncology medical records, were complete response in one patient, partial response in one, and stable disease in two. Three patients had previously received enfortumab vedotin. Documented adverse events included fatigue, anemia, diarrhea, rash, and leukopenia. No interstitial lung disease or pneumonitis was documented in the available records. Conclusions: These observations are descriptive and hypothesis-generating. They do not establish the efficacy or safety of T-DXd or validate ERBB2 amplification as a predictive biomarker, but they support prospective evaluation of genomic ERBB2 amplification when standard HER2 testing is unavailable.

Evidence on modifiable post-diagnosis factors influencing outcomes after intravesical Bacillus Calmette–Guérin (BCG) therapy for high-risk non-muscle-invasive bladder cancer (NMIBC) is limited. In this exploratory, feasibility-focused prospective multicenter cohort (March 2023–November 2024), BCG-naïve patients completed repeated interviewer-administered 24 h dietary recalls; prespecified food groups, selected foods, and nutrients were screened for associations with 1-year intravesical recurrence using Firth’s penalized logistic regression adjusted a priori for age, sex, and total energy intake, with false discovery rate control within each exposure family. Forty-six patients were enrolled; 41 had evaluable recurrence status, including 8 recurrences (19.5%). Participants were predominantly overweight (mean body mass index (BMI) 28.4 kg/m2) and had low adherence to a Mediterranean dietary pattern (median Mediterranean Adequacy Index 2.25). No dietary exposure met the within-family false discovery rate threshold; the smallest q-value was 0.361. Nominal inverse associations were observed for leafy green vegetables (OR per 1 SD 0.385; 95% CI 0.101–0.972) and for energy-adjusted zinc (OR 0.280; 95% CI 0.069–0.802) and magnesium intakes (OR 0.260; 95% CI 0.045–0.872), but these did not remain significant after FDR adjustment. These exploratory signals warrant replication in larger, biomarker-informed cohorts incorporating dietary biomarkers and immune profiling during BCG. Given the limited sample size and low number of recurrence events, these findings are strictly hypothesis-generating and should not be interpreted as evidence of definitive protective or risk dietary factors.

Background: Fatigue is a prevalent and complex condition with significant impacts on well-being. Existing fatigue assessments often lack comprehensiveness or practicality for general population studies. Methods: This study validated the REST Questionnaire, a novel fatigue assessment tool, in a sample of 268 adults. Psychometric properties, including internal consistency and construct validity, were evaluated. REST scores were correlated with WHO-5 well-being, BMI, self-rated health, and chronic conditions. Exploratory factor analysis identified underlying dimensions of fatigue. Results: The REST Questionnaire demonstrated excellent internal consistency (Cronbach’s alpha = 0.918) and construct validity. Higher fatigue scores were associated with lower well-being, female gender, and the presence of certain chronic conditions (cancer, kidney stones, gastric ulcers). Two distinct fatigue dimensions, “physical fatigue and functional impacts” and “emotional and social consequences”, were identified. Conclusions: The REST Questionnaire is a reliable and valid tool for assessing fatigue in the general population. Its multidimensional framework and sensitivity to comorbidities offer valuable insights for research and public health applications, with the potential to inform targeted interventions aimed at improving well-being.

This editorial explores the intricate landscape of supplement use in oncology, highlighting the growing interest and challenges surrounding their integration into cancer care. It discusses the disparity in regulatory oversight between supplements and pharmaceutical drugs, the blurred lines in their classification, and the ethical complexities in patient-doctor communication. The importance of transparency, shared decision-making, and realistic expectations is emphasized. While acknowledging the value of traditional research models, the editorial advocates for innovative approaches like retrospective studies, biomarker analysis, and personalized medicine to advance our understanding of supplement efficacy and safety. By integrating these diverse perspectives, we can unlock the full potential of supplements in oncology, ensuring that they are used effectively and responsibly to enhance patient outcomes.

Background: The Mediterranean lifestyle is widely recognized for its role in reducing the risk of chronic diseases, including cardiovascular diseases, type 2 diabetes, and cancer. The PREVESMED questionnaire was developed to evaluate adherence to this lifestyle, integrating dietary and non-dietary behaviors. Unlike existing tools, PREVESMED incorporates underexplored elements such as eating pace, herbal tea consumption, and physical activity, providing a multidimensional approach to lifestyle assessment. Methods: The validation of PREVESMED was carried out as part of a planned interim analysis using data collected from participants in the PREVES-ENERGY survey, a cross-sectional study targeting 1,000 adults aged 18 years and above. To assess the reliability of the PREVESMED scale, internal consistency was evaluated using Cronbach’s alpha, ensuring an acceptable level of reliability. To investigate the relationships between lifestyle factors, individual questionnaire items, and adherence to Mediterranean lifestyle according to the PREVESMED scale, a correlation analysis was performed. Additionally, to identify significant predictors of better adherence, a multivariable linear regression model was utilized, highlighting key factors influencing adherence. Finally, an exploratory factor analysis (EFA) was conducted to reveal the underlying structure of the PREVESMED scale, identifying key dimensions and their contributions to the total variance. Results: The cohort analyzed for the preliminary validation of the PREVESMED questionnaire consisted of 268 participants, in line with the protocol’s planned sample size. Internal consistency analysis demonstrated acceptable reliability (Cronbach’s alpha = 0.628). In the correlation analysis, the strongest associations with the total PREVESMED score emerged for physical activity, extra virgin olive oil use, and fruit/vegetable consumption, whereas daily alcohol intake showed the weakest correlation. The multivariable linear regression highlighted higher education, lower BMI, nonsmoking status, higher WHO-5 scores, and older age as significant predictors of better adherence. Exploratory factor analysis identified five factors explaining 59.32% of the total variance. Conclusion: Our findings suggest that the PREVESMED questionnaire is a promising, multidimensional tool for evaluating adherence to a Mediterranean lifestyle, demonstrating acceptable reliability and significant associations with key health indicators. Further refinement and extended validation – encompassing test-retest reliability, weighted scoring, and biomarker correlations – will strengthen its applicability across diverse populations.

INTRODUCTION:The burden of androgen deprivation therapy (ADT) is only partially captured by legacy prostate cancer questionnaires, which devote few items to hormonal sequelae. Patient-Reported Evaluation of the Effects of Hormone Therapy (PREVES-HOR) is a 29-item, distress-anchored instrument developed to quantify ADT-specific physical, emotional, cognitive, sexual, and body image morbidity from a patient-centered, subjective perspective. We report the prespecified phase 1 psychometric evaluation. METHODS:Italian-speaking men receiving ADT were consecutively enrolled. Participants completed PREVES-HOR plus external comparators for fatigue (REST), mood (HEAL-BDLC), sleep (PEACE), and well-being (WHO-5). Internal consistency was estimated with Cronbach's α and McDonald's ω; convergent validity with Spearman correlations; dimensionality with exploratory factor analysis (polychoric matrix, principal axis factoring, oblimin rotation, parallel analysis). RESULTS:One hundred and forty-five patients were analyzed. PREVES-HOR showed excellent reliability (α = 0.95; McDonald's ω = 0.97; domain α/ω 0.80-0.95). Six factors - physical fatigue and pain, emotional well-being, mental clarity, quality of life, relationships and stress, sexual health and body image - accounted for 79% of variance, with a dominant general distress factor (∼50%). All but four items had communalities ≥0.40 and cross-loadings <0.30. Total PREVES-HOR correlated strongly with fatigue (REST ρ = 0.69) and depression/anxiety (HEAL-BDLC ρ = 0.78) and inversely with well-being (WHO-5 ρ = -0.49) and sleep quality (PEACE ρ = -0.37), confirming convergent but nonredundant validity. CONCLUSION:Phase 1 findings support PREVES-HOR's content validity, internal coherence, and ability to detect clinically meaningful distress overlooked by broader instruments such as EPIC or FACT-P. Its forced-choice format eliminated missing data but will be reconsidered, along with responsiveness, test-retest stability, and cross-cultural adaptation, in the ongoing 1,000 patient phase 2/3 program. Pending confirmation, PREVES-HOR, may become a complementary tool for individualizing supportive care and evaluating ADT-modifying interventions.

Background and Objectives: Environmental pollution in regions like the Sarno River Basin in southern Italy significantly affects physical and psychological health. This study aimed to validate three novel psychometric tools—REST, HEAL-BDLC, and PEACE—for assessing fatigue, mood disturbances, and sleep quality in environmentally exposed populations. While correlations with heavy metal exposure will be addressed in a separate manuscript, this study focuses solely on psychometric validation. Materials and Methods: The PREVES-STOP Initiative recruited 88 participants aged 30–65 years from the Sarno River Basin. Participants completed psychometric questionnaires tailored to measure fatigue (REST), symptoms of depression and anxiety (HEAL-BDLC), and sleep quality (PEACE). Internal consistency, construct validity, and reliability were analyzed using Cronbach’s alpha, correlation analyses, and principal component analysis (PCA). A subgroup received a nutraceutical intervention for us to explore their responsiveness to change over a two-week period. Results: REST (α = 0.969), HEAL-BDLC (α = 0.962), and PEACE (α = 0.736) demonstrated strong reliability. PCA confirmed the unidimensional structure of REST and the two-component structure of HEAL-BDLC (depression and anxiety dimensions) and PEACE (insomnia and sleep quality). Correlations with established measures, such as the WHO Well-Being Index, supported construct validity. Among the intervention participants, significant improvements were observed in fatigue (−12.5 REST median score), mood (−13.0 HEAL-BDLC median score), sleep (+1.5 PEACE median score), and overall well-being (+4.0 WHO-5 median score). Conclusions: REST, HEAL-BDLC, and PEACE are reliable and valid instruments for assessing nuanced health outcomes in environmentally exposed populations. They hold potential for guiding public health interventions and evaluating environmental remediation impacts. These findings lay the groundwork for future studies linking psychometric outcomes with heavy metal exposure.

Bladder cancer is considered a global health concern characterized by significant morbidity and mortality rates. The complex relationship between diet and bladder cancer is examined, with a specific focus on the role of diet in risk, outcomes, and treatment efficacy. Attention is drawn to the burgeoning field of immunotherapy in bladder cancer treatment, and the possible influence of diet on its outcomes is explored. While evidence remains limited, prior studies in other cancer types have suggested a potential connection between diet and immunotherapy response. To address this knowledge gap, the ongoing BLOSSOM study is presented, which aims to investigate the link between dietary factors, lifestyle, and the effectiveness of immunotherapy in patients with non-muscle-invasive bladder cancer. Ongoing efforts to decipher the intricate relationship between diet and bladder cancer care are highlighted, emphasizing the quest to unravel the dietary puzzle for the improvement of bladder cancer management.

Background: Cabozantinib use in everyday clinical practice for advanced or metastatic renal cell carcinoma (RCC) is relatively recent, and real-world data on treatment persistence, adherence and sequencing are still limited. Methods: We conducted an analysis based on an integrated administrative database, covering around 6.9 million health-assisted Italian individuals, to explore the use of cabozantinib for RCC. Patients with at least one prescription for cabozantinib during 2017-2020 were searched. These were characterized during all available period (i.e. from 2010 onwards) before the index date and were observed after inclusion. Results: A total of 113 patients treated with cabozantinib in second or subsequent line were included, and their demographic, clinical and treatment characteristics were described. About half of these RCC patients were aged >65 years (47.8%). Sixty patients (53.1%) were highly adherent to cabozantinib therapy, and the median cabozantinib treatment duration of use was 8.7 months (95% confidence interval: 5.8-11.1). During the first year of follow-up, the average total cost per patient was €32,508. Conclusions: We described second or subsequent line cabozantinib treatment for RCC in a real-world setting and the economic burden of disease in Italy, taking advantage of large, integrated administrative databases.

Instant messaging applications, such as WhatsApp® and Telegram®, have transformed global communication, offering unique business models and minimal user expenses. Unlike traditional SMS, these apps facilitate unlimited, multimedia-rich communication globally, driven by widespread smartphone adoption. This shift not only broadens communication horizons but also enhances privacy compared to conventional voice calls. In healthcare, instant messaging, particularly unidirectional communication, proves impactful, evidenced by trials like TEXT ME and Healthy Text. These studies highlight text messages' efficacy in cardiovascular disease prevention and cancer prevention, demonstrating improved patient outcomes and behavioral changes. Bidirectional communication through instant messaging holds promise in cancer care, facilitating patient-doctor interactions, adverse event management, and medication compliance. Studies on pharmacist-run tele-oncology services and WeChat-based doctor-patient communication showcase positive impacts on chemotherapy monitoring, patient adherence, and overall survival rates. Despite these advantages, challenges arise from the use of widely available apps like WhatsApp and WeChat, including a lack of structure, constant message influx, and potential physician burnout. Innovative solutions, exemplified by the Esperto in chat® platform, introduce structured approaches to doctor-patient communication, addressing financial considerations, scheduling, and maintaining work-life balance for healthcare professionals. In conclusion, while instant messaging revolutionizes healthcare communication, challenges necessitate innovative solutions. Striking a balance between accessibility and safeguarding healthcare professionals' well-being is crucial as the digital transformation of healthcare continues.

Background: Oxidative stress has emerged as a key contributor to numerous NCDs (non-communicable diseases), including cardiovascular diseases, cancer, and diabetes. This study aims to explore the potential of targeted interventions to mitigate oxidative stress as part of a primary prevention strategy. Methods: The study included 32 healthy participants (11 men, 21 women) aged 45-65 who completed both the initial and follow-up assessments of the Healthy Days Initiative, a community-based wellness program organized by the non-profit Associazione O.R.A. ETS. Through blood analysis, vital sign assessment, lifestyle questionnaires, and individualized recommendations, participants received guidance on improving their health and reducing disease risk. The initiative also offered the opportunity for participants to consume a flavonoid supplement containing quercitrin, rutin, and hesperidin, with the goal of reducing oxidative stress. Participants who opted for supplementation were instructed to take 1-2 tablets daily for two weeks. Data collected included demographic information, anthropometric measurements, vital signs, dietary and lifestyle habits, medical history, WHO-5 Well-Being Index scores, and blood parameters. Results: Significant reductions were observed in glucose levels (from 82 to 74.5 mg/dL), reactive oxygen metabolites (d-ROMs) (from 394.5 to 365.5 U.CARR), and systolic blood pressure (from 133 to 122 mmHg) after the two-week flavonoid intervention. Most participants (26/31) reported no side effects, and the majority (30/31) expressed a willingness to continue using a product combination of quercitrin, rutin, and hesperidin or a similar product long-term. Conclusions: While limited in scope and duration, the PREVES-FLAVON study contributes valuable insights to the growing body of evidence suggesting that flavonoid supplementation may play a significant role in reducing risk factors associated with NCDs in primary prevention settings. By targeting novel risk factors such as oxidative stress, this intervention holds promise for mitigating the global burden of NCDs and promoting healthy aging.

Prostate cancer and its treatment, particularly androgen deprivation therapy (ADT), can profoundly impact patients’ quality of life. The aim of the prospective observational study reported here was to evaluate the effects of ADT on various aspects of quality of life in men with prostate cancer at a community-based hospital in Southern Italy. Eligible men initiating hormonal therapy were recruited between December 2021 and December 2023. Data were collected at baseline (T0) and after 3 months (T1) and 6 months (T2) of ADT using standardized questionnaires (European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30, EORTC QLQ-PR25) and semi-structured interviews. Of the 52 participants, 43 completed all three assessments. The EORTC QLQ-C30 showed a statistically significant worsening in physical functioning (mean score decrease from 83.8 at T0 to 76.7 at T2; p < 0.001), increased fatigue (from 23.7 to 35.2; p < 0.001), and insomnia (from 23.7 to 31.8; p = 0.048) following ADT initiation. The QLQ-PR25 revealed a significant decline in sexual functioning (from 59 to 26.9; p < 0.001) and sexual activity (from 27.3 to 12; p = 0.001). Interviews revealed a significant rise in the number of patients reporting depressed mood. Interviews also highlighted a worsening in body image perception and sexuality, increased feelings of dependence, and challenges in the social and relational spheres. ADT significantly impacts various aspects of quality of life in men with prostate cancer, particularly physical functioning, fatigue, sexual function, body image, and emotional well-being. These results underscore the critical importance of a comprehensive, patient-centered approach that addresses both the physical and psychosocial aspects of care.

This retrospective study investigates the efficacy of cemiplimab, a monoclonal antibody targeting the PD-1 receptor, in treating squamous cell carcinoma (SCC) of the skin. The study analyzes data from 50 patients with SCC, focusing on various clinical parameters, including patient demographics, tumor characteristics, treatment history, disease status at the beginning of therapy, and survival outcomes. Of the patients who received at least one cycle of cemiplimab, 42

Anti-VEGF (vascular endothelial growth factor) agents were associated with increased risk of several cardiovascular events, while one meta-analysis did not show any significantly increased risk of cardiotoxicity associated with the use of immune checkpoint inhibitors (ICIs). This meta-analysis of randomized-controlled trials (RCTs) was designed to compare cardiovascular toxicity of anti-VEGF agents plus ICI vs anti-VEGF agents without ICIs. A systematic search of the literature was conducted to include all full papers reporting about phase II and III randomized controlled trials (RCTs) conducted in patients with solid malignancies randomized to an anti-VEGF agent plus an ICI vs. an anti-VEGF agent without an ICI. Overall incidences of cardiovascular events were compared between these two treatment groups estimating the corresponding odds ratios. This analysis suggests that ICIs may increase the risk of cardiovascular toxicities associated with anti-VEGF therapies. Further research, including real world studies, is warranted.

INTRODUCTION:Several programmed death ligand-1 (PD1/L1) immune checkpoint inhibitors (ICIs) are approved in urothelial carcinoma (UC). PATIENTS AND METHODS:To address the need for predictors of the efficacy of ICIs in metastatic urothelial carcinoma (mUC), randomized controlled trials of PD1/L1 inhibitors alone or in combination with chemotherapy in this patient population were systematically reviewed, and differences in ICI-associated survival outcomes according to available baseline variables were quantitatively assessed. RESULTS:The quantitative analysis included 6524 patients with mUC. No visceral metastatic site (HR 0.67; 95% CI, 0.76-0.90) and high PDL-1 expression (HR 0.74; 95% CI, 0.640.87) were significantly associated with a reduced risk of death. CONCLUSION:Treatment with an ICI-containing regimen was associated with a reduced risk of death in mUC patients, which was associated with PDL-1 expression and metastatic site. Further research is warranted.

Future Science OAVol. 8, No. 1 EditorialOpen AccessCOVID-19 and prostate cancer: a complex scenario with multiple facetsFelice Crocetto, Luciana Buonerba, Luca Scafuri, Vincenzo Caputo, Biagio Barone, Antonella Sciarra, Antonio Verde, Armando Calogero, Carlo Buonerba & Giuseppe Di LorenzoFelice CrocettoDepartment of Neurosciences, Human Reproduction & Odontostomatology, University of Naples Federico II, Naples, 80131, Italy, Luciana BuonerbaOncology Unit, Hospital 'Andrea Tortora', ASL Salerno, Pagani, Italy, Luca ScafuriOncology Unit, Hospital 'Andrea Tortora', ASL Salerno, Pagani, ItalyAssociazione O.R.A., Somma Vesuviana, Naples, Italy, Vincenzo CaputoDepartment of Neurosciences, Human Reproduction & Odontostomatology, University of Naples Federico II, Naples, 80131, Italy, Biagio BaroneDepartment of Neurosciences, Human Reproduction & Odontostomatology, University of Naples Federico II, Naples, 80131, Italy, Antonella SciarraDepartment of Experimental Medicine, University of Campania 'Luigi Vanvitelli', Naples, NA, Italy, Antonio VerdeAssociazione O.R.A., Somma Vesuviana, Naples, Italy, Armando CalogeroDepartment of Advanced Biomedical Sciences, University of Naples Federico II, Naples, 80131, Italy, Carlo Buonerba*Author for correspondence: E-mail Address: carbuone@hotmail.comOncology Unit, Hospital 'Andrea Tortora', ASL Salerno, Pagani, ItalyAssociazione O.R.A., Somma Vesuviana, Naples, Italy & Giuseppe Di LorenzoOncology Unit, Hospital 'Andrea Tortora', ASL Salerno, Pagani, ItalyAssociazione O.R.A., Somma Vesuviana, Naples, ItalyDepartment of Medicine & Health Science, University of Molise, Campobasso, ItalyPublished Online:23 Nov 2021https://doi.org/10.2144/fsoa-2021-0113AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit Keywords: COVID-19prostate cancerSARS-CoV-2COVID-19, the infectious disease caused by SARS-CoV-2, has claimed the lives of over 4.5 million people worldwide as of 18 September 2021 [1]. Besides having a multitude of social, economic and sanitary consequences [2–4], which have aggravated pre-existing threats to public health, such as those related to pollution [5], the global pandemic has profoundly affected several aspects of cancer care, including doctor–patient relationships, [6], access to therapy and physicians' therapeutic choices [7]. This has ultimately negatively influenced cancer-specific mortality [8]. Conversely, COVID-19 is associated with higher mortality rates in cancer versus non-cancer patients [9].In the particular case of prostate cancer, the second most frequently diagnosed cancer in men, the COVID-19 pandemic has had a negative impact both on early diagnosis by reducing participation to screening programs [10] and on time from diagnosis to surgery/radiotherapy [11], which may translate in a worse prostate-cancer-specific mortality in the next years [12]. In spite of the hurdles associated with diagnosis of prostate cancer [13], population-based prostate-specific antigen (PSA) screening has proven to reduce prostate-cancer-specific mortality, although over 1000 men have to be screened to prevent a single death from prostate cancer [14]. A retrospective study conducted at the University Hospitals of Verona was designed to identify all test requests for total PSA and vitamin D for outpatients from 10 December 2016 to 10 December 2020 and compare the weekly requests for these tests between 25 February and 9 December 2020, to those sent during the same period of the past 4 years (2016–2019). Of note, the weekly rate of test requests was consistent across the years, but a sharp decline was recorded during the lockdown period (between 10 March and 17 May 2020), with median decrease of 76% for vitamin D and 62% for total PSA, respectively [10]. Another retrospective observational study conducted in 2020 at a high-volume center was designed to assess the impact of COVID-19 on time to surgery of patients on the urology surgical waiting list. In the overall cohort of 350 patients (including 20 patients with prostate cancer), the mean time of 97.33 days on the waiting list was reported, which was significantly longer compared with that reported in 2019 [11]. In a population-based study exploring patterns of radiotherapy use, mean weekly radiotherapy courses decreased by 19.9% in April, 6.2% in May and 11.6% in June 2020 compared with corresponding months in 2019, with the largest reduction reported for prostate cancer (77.0% in April) [15]. The delayed diagnosis caused by the COVID-19 pandemic has been estimated to result in a 17.2% increase in prostate cancer deaths in the years 2022–24 using a novel modeling approach [12]. While a meta-analysis of six retrospective studies including a total of 50,220 patients suggested that androgen deprivation therapy may not be associated with an increased risk of being infected with SARS-CoV-2 [16], the number of previous systemic lines of treatment may influence prognosis. In a retrospective multicenter study including 34 patients with metastatic castration-resistant prostate cancer who were observed at the time of COVID-19 diagnosis, 17 patients (50.0%) had recovered, 13 patients (38.2%) had died and four (11.7%) were still positive for SARS-CoV-2, after a median follow-up time of 21 days. Importantly, the multivariate analysis of this retrospective cohort showed that the number of previously administered antineoplastic treatments for metastatic castration-resistant prostate cancer was significantly associated with COVID-19 mortality. Although one COVID-19 case was reported in a patient receiving the hormonal treatment enzalutamide [17] with no apparent enzalutamide-related detrimental effects on COVID-19 prognosis, there are no data suggesting that patients on novel oral androgen-receptor targeting agents (such as enzalutamide or abiraterone [18]) may be safer compared with chemotherapy agents such as cabazitaxel [19] in the case of SARS-CoV-2 infection. The lack of clinically significant bone marrow toxicity and their oral route of administration have made androgen-receptor axis targeting agents a more attractive therapeutic option compared with intravenous taxanes during the COVID-19 pandemic. Finally, it must be considered how COVID-19 can affect accuracy of imaging techniques. In a retrospective multicenter study including nine men with COVID-19 who underwent 68Ga-PSMA-11-PET/CT for prostate cancer [20], all of them showed different grades of abnormal 68Ga-PSMA-11 uptake in the lungs, but only a single patient actually had lung metastasis. This finding highlights the potential confounding effect of COVID-19 on prostate cancer staging using nuclear medicine techniques.Overall, the findings discussed here show how COVID-19 has deeply affected all aspects of prostate cancer care, including early diagnosis, treatment and staging, with negative consequences that are not fully predictable and understandable at the present time. On the other hand, it is foreseen that SARS-CoV-2 will continue to circulate despite mass vaccination programs, so a continued effort to analyze its effects on prostate cancer care is mandatory. Physicians treating prostate cancer should consider preferring oral compared with intravenous agents and performing remote visits, if feasible. Also, they should be aware that COVID-19 may affect accuracy of some imaging techniques such as PSMA (prostate specific membrane antigen) PET. On the other hand, research should focus on the potential interaction of COVID-19 with available treatments against prostate cancer, which remains largely ignored. As an example, patients with localized prostate cancer recovering from COVID-19 may represent a clinically significant population requiring a specific treatment algorithm regarding the use of surgery versus radiotherapy. Also, patients with metastatic prostate cancer with a history of symptomatic COVID-19 might suffer from more severe adverse events associated with chemotherapy. Observational prospective and retrospective studies designed to assess the impact of COVID-19 on treatment efficacy and toxicity remain a compelling need regardless of the success of vaccination campaigns in SARS-CoV-2 eradication in the complex scenario caused by this vicious and unprecedented pandemic.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Ethical conduct of researchC Buonerba is a member of the Future Science OA Editorial Board. They were not involved in any editorial decisions related to the publication of this article, and all author details were blinded to the article's peer reviewers as per the journal's double-blind peer review policy.Open accessThis work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/References1. World Health Organization (2021). https://covid19.who.int/Google Scholar2. Napolitano L, Barone B, Crocetto F, Capece M, La Rocca R. The COVID-19 pandemic: is it a wolf consuming fertility? Int. J. Fertil. Steril. 14, 159–160 (2020).CAS, Google Scholar3. Fernández-Méndez C, Pathan S. Environmental stocks, CEO health risk and COVID-19. Res. Int. Bus. Finance 59, 101509 (2022).Crossref, Google Scholar4. Bojanowska A, Kaczmarek ŁD, Koscielniak M, Urbańska B. Changes in values and well-being amidst the COVID-19 pandemic in Poland. PLoS ONE 16, e0255491 (2021).Crossref, CAS, Google Scholar5. Di Lorenzo G, Federico P, De Placido S, Buonerba C Increased risk of bladder cancer in critical areas at high pressure of pollution of the Campania region in Italy: a systematic review. Crit Rev Oncol Hematol. 96, 534–541 (2015).Crossref, Google Scholar6. Esposito C, Masieri L, Castagnetti M, Crocetto F, Escolino M .Letter to the editor: robot-assisted and minimally invasive pediatric surgery and urology during the COVID-19 pandemic: a short literature review. J. laparoendosc. Adv. Surg. Tech. A 30, 915–918 (2020).Crossref, Google Scholar7. Pratapa SK, Acharya S, Mamidipalli SS, Andhale A. Caring for cancer patients during corona pandemic-(COVID-19)-a narrative review. South Asian J. Cancer 10, 19–22 (2021).Crossref, Google Scholar8. Maringe C, Spicer J, Morris M et al. The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: a national, population-based, modelling study. Lancet Oncol. 21, 1023–1034 (2020).Crossref, CAS, Google Scholar9. Bertuzzi AF, Ciccarelli M, Marrari A,et alImpact of active cancer on COVID-19 survival: a matched-analysis on 557 consecutive patients at an academic hospital in Lombardy, Italy. Br. J. Cancer 125, 358 -366 (2021).Crossref, CAS, Google Scholar10. Ferrari A, Sanchis-Gomar F, Mattiuzzi C, Henry BM, Lippi G. Is COVID-19 impacting prostate cancer screening? A survey of prostate-specific antigen test requests during a local outbreak. EJIFCC 32, 69–77 (2021).CAS, Google Scholar11. García-Rojo E, Manfredi C, Santos-Pérez-de-la-Blanca R et al. Impact of COVID-19 outbreak on urology surgical waiting lists and waiting lists prioritization strategies in the post-COVID-19 era. Actas Urol. Esp. 45, 207–214 (2021).Google Scholar12. Ward ZJ, Walbaum M, Walbaum B et al. Estimating the impact of the COVID-19 pandemic on diagnosis and survival of five cancers in Chile from 2020 to 2030: a simulation-based analysis. Lancet Oncol. doi:10.1016/S1470-2045(21)00426-5 (2021) (Epub ahead of print).Crossref, Google Scholar13. De Luca L, Crocetto F, Barone B et al. Granulomatous prostatitis mimicking prostate cancer in a patient with psoriatic arthritis: a case report. Future Sci. OA 6(7), FSO591 (2020).Link, Google Scholar14. Schröder FH, Hugosson J, Roobol MJ et al. Prostate-cancer mortality at 11 years of follow-up. N. Engl. J. Med. 366, 981–990 (2012).Crossref, Google Scholar15. Spencer K, Jones CM, Girdler R et al. The impact of the COVID-19 pandemic on radiotherapy services in England, UK: a population-based study. Lancet Oncol. 22, 309–320 (2021).Crossref, CAS, Google Scholar16. Sari Motlagh R, Abufaraj M, Karakiewicz PI et al. Association between SARS-CoV-2 infection and disease severity among prostate cancer patients on androgen deprivation therapy: a systematic review and meta-analysis. World J. Urol. (2021) (Epub ahead of print).Google Scholar17. Di Lorenzo G, Buonerba L, Ingenito C et al. Clinical characteristics of metastatic prostate cancer patients infected with COVID-19 in South Italy. Oncology doi:10.1159/000509434 (2020) (Epub ahead of print).Google Scholar18. Ferro M, Lucarelli G, Crocetto F et al. First-line systemic therapy for metastatic castration-sensitive prostate cancer: an updated systematic review with novel findings. Crit. Rev. Oncol. Hematol. 157, 103198 (2021).Crossref, Google Scholar19. Buonerba C, Pond GR, Sonpavde G et al. Potential value of Gleason score in predicting the benefit of cabazitaxel in metastatic castration-resistant prostate cancer. Future Oncol. 9, 889–897 (2013).Crossref, CAS, Google Scholar20. Farolfi A, Telo S, Castellucci P et al. Lung uptake detected by (68)Ga-PSMA-11 PET/CT in prostate cancer patients with SARS-CoV-2: a case series. Am. J. Nucl. Med. Mol. Imaging 11, 300–306 (2021).Google ScholarFiguresReferencesRelatedDetailsCited ByContinuous care needs in patients with cancer receiving chemotherapy during the recent omicron wave of COVID-19 in Shanghai: A qualitative study4 January 2023 | Frontiers in Psychology, Vol. 13Modified Prostate Health Index Density Significantly Improves Clinically Significant Prostate Cancer (csPCa) Detection7 April 2022 | Frontiers in Oncology, Vol. 12 Vol. 8, No. 1 Follow us on social media for the latest updates Metrics History Received 18 September 2021 Accepted 14 October 2021 Published online 23 November 2021 Published in print January 2022 Information© 2021 Carlo BuonerbaKeywordsCOVID-19prostate cancerSARS-CoV-2Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Ethical conduct of researchC Buonerba is a member of the Future Science OA Editorial Board. They were not involved in any editorial decisions related to the publication of this article, and all author details were blinded to the article's peer reviewers as per the journal's double-blind peer review policy.Open accessThis work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/PDF download

Future Science OAVol. 7, No. 7 EditorialOpen AccessImmune checkpoint inhibitors in penile cancerCarlo Buonerba, Luca Scafuri, Ferdinando Costabile, Bruno D'Ambrosio, Simona Gatani, Pasquale Verolino, Rossella Di Trolio, Vincenzo Cosimato, Antonio Verde & Giuseppe Di LorenzoCarlo Buonerba*Author for correspondence: E-mail Address: carlo.buonerba@unina.itCentro di Referenza Nazionale per l'Analisi e Studio di Correlazione tra Ambiente, Animale e Uomo, Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici 80055, Italy, Luca ScafuriCentro di Referenza Nazionale per l'Analisi e Studio di Correlazione tra Ambiente, Animale e Uomo, Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici 80055, ItalyOncology Unit, Hospital 'Andrea Tortora', ASL Salerno, Pagani, Italy, Ferdinando CostabileCentro di Referenza Nazionale per l'Analisi e Studio di Correlazione tra Ambiente, Animale e Uomo, Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici 80055, ItalyOncology Unit, Hospital 'Andrea Tortora', ASL Salerno, Pagani, Italy, Bruno D'AmbrosioOncology Unit, Hospital 'Andrea Tortora', ASL Salerno, Pagani, Italy, Simona GataniOncology Unit, Hospital 'Andrea Tortora', ASL Salerno, Pagani, Italy, Pasquale VerolinoMultidisciplinary Department of Medical-Surgical & Dental Specialties, Plastic Surgery Unit, University of Campania Luigi Vanvitelli, Naples, Italy, Rossella Di TrolioUnit of Melanoma, Cancer Immunotherapy & Development Therapeutics, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples, Italy, Vincenzo CosimatoDivision of Laboratory Medicine, Civil Hospital 'Maria SS. Addolorata', ASL Salerno, Eboli, Italy, Antonio VerdeCentro di Referenza Nazionale per l'Analisi e Studio di Correlazione tra Ambiente, Animale e Uomo, Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici 80055, Italy & Giuseppe Di LorenzoOncology Unit, Hospital 'Andrea Tortora', ASL Salerno, Pagani, ItalyPublished Online:21 May 2021https://doi.org/10.2144/fsoa-2021-0044AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: immune checkpoint inhibitorsimmunotherapypenile cancerPenile cancer (PCa) is a rare yet deadly disease, with an incidence rate varying in the range of 1–10 cases per 100,000 men across countries worldwide and a 5-year survival rate ranging from 90% in stage I patients to a dismal 5% in stage IV patients [1]. With 300 men dying annually of advanced/recurrent PCa in the USA alone [2], effective systemic therapeutic options remain a highly unmet need, and only a few currently available chemotherapy agents are recommended on the basis of noncomparative prospective [3,4] or retrospective [5] studies. The EGFR may represent a valuable druggable target, based on the frequent expression of EGFR in PCa [6–8] and preliminary evidence of efficacy obtained with anti-EGFR agents [9], although more supporting prospective data are needed for approval and its widespread use in clinical practice.The advent of immune check-point inhibitors (ICI), mainly directed at programmed death-1 (PD-1), programmed death ligand-1 (PDL-1) or cytotoxic t-lymphocyte antigen 4 (CTLA-4), has truly revolutionized therapy of solid malignancies and may also expand the limited treatment landscape of advanced PCa. In fact, PD-L1 expression, a known marker predictive of efficacy of anti-PD-1/PDL-1 inhibitors across different solid tumors [10], was reported in 51% of cases in a surgical cohort of 35 men with PCa undergoing penectomy, and in 69% of those with node-positive disease [11]. In another retrospective analysis of 53 archival PCa specimens, 40% of cases were positive for PDL-1, with 38% of node-positive tumors showing PD-L1 expression [12]. As a result of the biological rationale and the compelling need for additional systemic options, a few ICIs have been explored in patients with advanced PCa, with promising results. Chahoud [13] and others originally reported on two cases who received anti-PD-1 agent pembrolizumab after chemotherapy, radiation and surgery: one man with a high tumor mutation burden achieved a complete response maintained for >38 months and another man achieved a partial response, maintained for >18 months. Conversely, a report of a Phase II trial conducted in various rare malignancies showed that pembrolizumab was not capable of providing any benefits in two patients with microsatellite-stable PCa, while a durable response was obtained in a single man with a microsatellite instability high tumor [14]. Combination of anti-CTLA-4 agent ipilimumab and anti-PD-1 agent nivolumab administered at standard doses was associated with a prominent response in a patient refractory to paclitaxel, ifosfamide and cisplatin who was selected for treatment with ICIs on the grounds of the results of extensive molecular analysis showing high PDL-1 expression, microsatellite instability and tumor mutational burden, as well as alterations in DNA mismatch repair genes [15]. Conversely, in a single-arm, multicohort, Phase II trial, assessing nivolumab and ipilimumab in patients with advanced rare genitourinary cancers not selected on the grounds of any molecular biomarker, only two of five patients evaluable for radiological response showed stable disease [16]. Finally, anti-PD-1 agent cemiplimab tested in patients with advanced squamous cell carcinoma of the skin was associated with a partial response in a single patient with metastatic PCa included in the trial [17], and a complete response was reported in a separate case report of an HIV+ patient receiving cemiplimab [18].Overall, the scanty data reported suggest that some, albeit unsatisfactory progress has been made over the past 5 years in the field of immunotherapy of PCa [19]. One unexplored, yet potentially effective strategy is the use of combination therapy based on ICIs plus chemotherapy or biological agents. One meta-analysis including quantitative data from 5388 patients with different solid tumors showed that ICI plus chemotherapy was associated with a significantly higher tumor response rate (relative risk: 2.51; 95% CI: 1.82–3.47), decreased chances of progression (hazard ratio [HR]: 0.62; 95% CI: 0.53–0.74), and death (HR: 0.69; 95% CI: 0.61–0.78), compared with single agent ICI or chemotherapy [20]. Considering that anti-PD-1 agents such as pembrolizumab have been successfully combined with cisplatin and fluorouracil [21], combination of cisplatin + 5-fluoruracil, which has proven to be active as a first-line therapy of advanced PCa [5], with pembrolizumab appears to be an appealing experimental therapeutic option. Conversely, in patients who are unfit for chemotherapy, but are candidates for anti-EGFR therapy on the basis of molecular data, combination of an anti-PD-1 agent like nivolumab and an anti-EGFR agent like cetuximab has proven to be well tolerated [22] and may also represent a promising therapeutic option. Finally, with the hurdles associated with the rarity of the disease, which makes it difficult for pharmaceutical companies to obtain regulatory approval, patient selection for ICIs based on known predictive markers, including microsatellite instability, tumor mutational burden, PDL-1 expression, will be mandatory before treatment with an ICI, especially as these biomarkers become more widely available in clinical practice. The rarity of this disease, as in the case of other rare tumors, makes it more difficult to draw an exact line between an experimental and a nonexperimental setting even in common clinical practice. An international effort made by independent scientists, governmental institutions and pharmaceutical companies is compelling in order to increase funding to support research against such a deadly and neglected disease; provide access to nonapproved, high-cost novel agents based on a sound scientific rationale; and increase data sharing among clinicians and researchers through the use of web-based public repositories, specifically designed to collect data on rare diseases. These goals can be better achieved if both patients and clinicians are aware that PCa, as a rare disease, must be treated at referral centers with proven expertise.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/References1. Sonpavde G, Pagliaro LC, Buonerba C, Dorff TB, Lee RJ, Di Lorenzo G. Penile cancer: current therapy and future directions. Ann. Oncol. 24(5), 1179–1189 (2013).Crossref, CAS, Google Scholar2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 70(1), 7–30 (2020).Crossref, Google Scholar3. Di Lorenzo G, Federico P, Buonerba C et al. Paclitaxel in pretreated metastatic penile cancer: final results of a Phase II study. Eur. Urol. 60(6), 1280–1284 (2011).Crossref, Google Scholar4. Pagliaro LC, Williams DL, Daliani D et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a Phase II study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 28(24), 3851–3857 (2010).Crossref, CAS, Google Scholar5. Di Lorenzo G, Buonerba C, Federico P et al. Cisplatin and 5-fluorouracil in inoperable, stage IV squamous cell carcinoma of the penis. BJU Int. 110(11 B), E661–E666 (2012).Google Scholar6. Di Lorenzo G, Buonerba C, Gaudioso G et al. EGFR mutational status in penile cancer. Expert Opin. Ther. Targets 17(5), 501–505 (2013).Crossref, Google Scholar7. Di Lorenzo G, Perdonà S, Buonerba C et al. Cytosolic phosphorylated EGFR is predictive of recurrence in early stage penile cancer patients: a retropective study. J. Transl. Med. 11(1), (2013).Google Scholar8. Di Lorenzo G, Buonerba C, Ferro M et al. The epidermal growth factor receptors as biological targets in penile cancer. Expert Opin. Biol. Ther. 5(4), 473–476 (2015).Google Scholar9. Buonerba C, Di Lorenzo G, Pond G et al. Prognostic and predictive factors in patients with advanced penile cancer receiving salvage (2nd or later line) systemic treatment: a retrospective, multi-center study. Front. Pharmacol. 7(DEC), (2016).Google Scholar10. Sun L, Zhang L, Yu J et al. Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis. Sci. Rep. 10(1), 2083 (2020).Crossref, CAS, Google Scholar11. De Bacco MW, Carvalhal GF, MacGregor B et al. PD-L1 and p16 expression in penile squamous cell carcinoma from an endemic region. Clin. Genitourin. Cancer. 18(3), e254–e259 (2020).Crossref, Google Scholar12. Cocks M, Taheri D, Ball MW et al. Immune-checkpoint status in penile squamous cell carcinoma: a North American cohort. Hum. Pathol. 59, 55–61 (2017).Crossref, CAS, Google Scholar13. Chahoud J, Skelton WP 4th, Spiess PE et al. Case report: two cases of chemotherapy refractory metastatic penile squamous cell carcinoma with extreme durable response to pembrolizumab. Front. Oncol. 10, 615298 (2020).Crossref, Google Scholar14. Hahn AW, Chahoud J, Campbell MT et al. Pembrolizumab for advanced penile cancer: a case series from a Phase II basket trial. Invest. New Drugs (2021).Crossref, Google Scholar15. Baweja A, Mar N. Metastatic penile squamous cell carcinoma with dramatic response to combined checkpoint blockade with ipilimumab and nivolumab. J. Oncol. Pharm. Pract. 27(1), 212–215 (2021).Crossref, Google Scholar16. McGregor BA, Campbell MT, Xie W et al. Results of a multicenter, Phase II study of nivolumab and ipilimumab for patients with advanced rare genitourinary malignancies. Cancer 127(6), 840–849 (2021).Crossref, CAS, Google Scholar17. Migden MR, Rischin D, Schmults CD et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N. Engl. J. Med. 379(4), 341–351 (2018).Crossref, CAS, Google Scholar18. Proietti I, Skroza N, Filippi L et al. Pembrolizumab for advanced penile cancer: a case series from a Phase II basket trial. Dermatol. Ther. e14744 (2021).Google Scholar19. Buonerba C, Pagliuca M, Vitrone FM et al. Immunotherapy for penile cancer. Future Sci. OA3 (3), FSO195 (2017).Link, Google Scholar20. Nie R-C, Zhao C-B, Xia X-W et al. The efficacy and safety of PD-1/PD-L1 inhibitors in combination with conventional therapies for advanced solid tumors: a meta-analysis. Biomed Res. Int. 2020, 5059079 (2020).Crossref, Google Scholar21. Shitara K, Van Cutsem E, Bang Y-J et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric Cancer: The KEYNOTE-062 Phase III randomized clinical trial. JAMA Oncol. 6(10), 1571–1580 (2020).Crossref, Google Scholar22. Chung CH, Bonomi MR, Steuer CE et al. Concurrent cetuximab (CTX) and nivolumab (NIVO) in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): results of Phase II study. J. Clin. Oncol. 38(Suppl. 15), 6515 (2020).Crossref, Google ScholarFiguresReferencesRelatedDetails Vol. 7, No. 7 Follow us on social media for the latest updates Metrics Downloaded 572 times History Received 1 April 2021 Accepted 14 April 2021 Published online 21 May 2021 Published in print August 2021 Information© 2021 Carlo BuonerbaKeywordsimmune checkpoint inhibitorsimmunotherapypenile cancerFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/PDF download

Background Three or four cycles of cisplatin-based chemotherapy is the standard neoadjuvant treatment prior to cystectomy in patients with muscle-invasive bladder cancer. Although NCCN guidelines recommend 4 cycles of cisplatin-gemcitabine, three cycles are also commonly administered in clinical practice. In this multicenter retrospective study, we assessed a large and homogenous cohort of patients with urothelial bladder cancer (UBC) treated with three or four cycles of neoadjuvant cisplatin-gemcitabine followed by radical cystectomy, in order to explore whether three vs. four cycles were associated with different outcomes. Methods Patients with histologically confirmed muscle-invasive UBC included in this retrospective study had to be treated with either 3 (cohort A) or 4 (cohort B) cycles of cisplatin-gemcitabine as neoadjuvant therapy before undergoing radical cystectomy with lymphadenectomy. Outcomes including pathologic downstaging to non-muscle invasive disease, pathologic complete response (defined as absence of disease -ypT0), overall- and cancer-specific- survival as well as time to recurrence were compared between cohorts A vs. B. Results A total of 219 patients treated at 14 different high-volume Institutions were included in this retrospective study. Patients who received 3 (cohort A) vs. 4 (cohort B) cycles of neoadjuvant cisplatin-gemcitabine were 160 (73,1%) vs. 59 (26,9%).At univariate analysis, the number of neoadjuvant cycles was not associated with either pathologic complete response, pathologic downstaging, time to recurrence, cancer specific, and overall survival. Of note, patients in cohort B vs. A showed a worse non-cancer specific overall survival at univariate analysis (HR= 2.53; 95 CI= 1.05 - 6.10; p=0.046), although this finding was not confirmed at multivariate analysis. Conclusions Our findings suggest that 3 cycles of cisplatin-gemcitabine may be equally effective, with less long-term toxicity, compared to 4 cycles in the neoadjuvant setting.

Future Science OAVol. 7, No. 4 EditorialOpen AccessUrologic malignancies: advances in the analysis and interpretation of clinical findingsFelice Crocetto, Carlo Buonerba, Vincenzo Caputo, Matteo Ferro, Francesco Persico, Francesco Trama, Ester Iliano, Sebastiano Rapisarda, Maida Bada, Gaetano Facchini, Antonio Verde, Sabino De Placido & Biagio BaroneFelice Crocetto *Author for correspondence: E-mail Address: felice.crocetto@gmail.comhttps://orcid.org/0000-0002-4315-7660Department of Neurosciences, Human Reproduction & Odontostomatology, University of Naples Federico II, Naples 80131, Italy, Carlo BuonerbaDepartment of Oncology & Hematology, Regional Reference Center for Rare Tumors, AOU Federico II of Naples, Naples 80131, Italy, Vincenzo CaputoDepartment of Neurosciences, Human Reproduction & Odontostomatology, University of Naples Federico II, Naples 80131, Italy, Matteo FerroDivision of Urology, European Institute of Oncology-IRCCS, Milan 20122, ItalyCentro di Referenza Nazionale per l'Analisi e Studio di Correlazione tra Ambiente, Animale e Uomo, Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici, Naples 80055, Italy, Francesco PersicoDepartment of Urology, Humanitas Clinical & Research Center-IRCCS, Rozzano, Milan 20089, Italy, Francesco TramaAndrology & Urogynecological Clinic, Santa Maria Terni Hospital, University of Perugia, Terni 05100, Italy, Ester IlianoAndrology & Urogynecological Clinic, Santa Maria Terni Hospital, University of Perugia, Terni 05100, Italy, Sebastiano RapisardaDepartment of Urology, Ospedale Pederzoli, Peschiera del Garda, Verona 37019, Italy, Maida BadaDepartment of Urology, San Bassiano Hospital, Bassano del Grappa, Vicenza 36061, Italy, Gaetano FacchiniUOC of Medical Oncology, ASL NA 2 Nord, "S M delle Grazie" Hospital, Pozzuoli, Naples 80078, Italy, Antonio VerdeDepartment of Clinical Medicine & Surgery, University Federico II of Naples, Naples 80131, Italy, Sabino De PlacidoDepartment of Clinical Medicine & Surgery, University Federico II of Naples, Naples 80131, Italy & Biagio Barone https://orcid.org/0000-0003-4884-132XDepartment of Neurosciences, Human Reproduction & Odontostomatology, University of Naples Federico II, Naples 80131, ItalyPublished Online:4 Feb 2021https://doi.org/10.2144/fsoa-2020-0210AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: biomarkersimmunotherapyurologic malignanciesThe most commonly occurring urologic malignancies include prostate, bladder and kidney cancer. While prostate cancer is diagnosed in males, bladder and kidney cancer are more commonly reported in males versus females. In male US citizens, prostate, bladder and kidney cancer account for 191,930, 62,100 and 45,520 cases, respectively, of the approximately 893,660 new cancer cases expected in 2020. In the US women, of 912,930 new cancer cases estimated to be diagnosed in 2020, bladder and kidney cancer account for 19,300 and 28,230 cases, respectively. Interestingly, 5-year survival rates in localized disease are >60% in prostate and kidney cancer but remain unsatisfactory in bladder cancer (≈30%), while also remaining disappointing in patients with distant metastasis (≈5% in prostate and bladder cancer, ≈15% in kidney cancer); this underlines the compelling need for more effective systemic therapeutic options [1].In prostate cancer, over the past decade, advances in systemic therapy have not been mostly accomplished by introducing novel agents [2], but rather by developing novel indications for approved treatments [3]. Large, randomized Phase III trials have demonstrated that men with metastatic, castration-sensitive prostate cancer can benefit from both docetaxel and novel hormonal agents, including androgen-receptor-axis-target agents (ARAT) such as enzalutamide, abiraterone and apalutamide [4]. A recently conducted network meta-analysis showed that while men with castration-sensitive prostate cancer treated with either docetaxel or an ARAT agent as first-line therapy reported an overall hazard ratio (HR) for death of 0.69 (95% CI: 0.61–0.78), those treated with an ARAT agent versus docetaxel showed a HR for death favoring the ARAT group of 0.78 (95% CI: 0.67–0.91) [4]. Conversely, sequential or concomitant use of docetaxel plus an ARAT agent in the castration-sensitive setting is not expected to provide any additional benefit compared with the use of an ARAT agent alone [5]. Significant progresses have been made with the results obtained with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which was capable of prolonging survival in selected men with mutations in BRCA1, BRCA2 or ATM genes [6]. In the cohort of the PROFOUND trial including 245 men with at least one alteration in BRCA1, BRCA2 or ATM, olaparib compared with physician's choice of enzalutamide or abiraterone was associated with a significantly longer survival, with a HR for death of 0.69; 95% CI: 0.50–0.97; p = 0.02 (median overall survival [OS], 19.1 months with olaparib and 14.7 months with control therapy). Although these results represent a breakthrough in prostate cancer, it must be noted that only a minority of patients with advanced prostate cancer harbor these mutations, and additional research is needed to explore whether olaparib-based combination therapy may be effective in unselected men.In bladder cancer, the advent of immunotherapy based on antiprogrammed death 1(PD-1)/programmed death ligand-1 (PDL-1) inhibitors has provided a survival advantage in patients with advanced cancer who have a poor prognosis. In the JAVELIN Bladder 100 trial, patients with advanced urothelial cancer were randomized to best supportive care with or without the anti-PDL-1 agent avelumab after completing the primary platinum-based systemic treatment. In the study cohort consisting of 700 patients, 1-year OS rate was 71.3 in the avelumab group and 58.4% in the control group, with a HR for death of 0.69 (95% CI: 0.56–0.86; p = 0.001) [7]. These results are consistent with those obtained in the randomized Phase III trial KEYNOTE 045, in which 542 patients with recurrent advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy were randomized to anti PD-1 agent pembrolizumab at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with vinflunine, paclitaxel or docetaxel. In the overall cohort, median OS was 10.3 versus 7.4 months in the pembrolizumab versus chemotherapy group (HR for death: 0.73; 95% CI: 0.59–0.91; p = 0.002). Although survival results seem to be slightly more favorable in the JAVELIN trial, additional studies are required to establish the optimal approach to deliver anti PD-1/PDL-1 therapy (at the end of first-line platinum chemotherapy versus at progression after first-line platinum chemotherapy).In kidney cancer, significant progress has been made with the results obtained with anti PD-1/PDL-1 agents in the first-line setting. Avelumab, pembrolizumab, nivolumab and atezolizumab have been successfully combined with both anti-VEGF (avelumab + axitinib, pembrolizumab+ axitinib, atezolizumab + bevacizumab) and anti-CTLA-4 agents (nivolumab + ipilimumab) [8]. Importantly, pembrolizumab + axitinib in unselected patients and ipilimumab + nivolumab in patients at intermediate/poor prognosis are recommended by European Society of Medical Oncology guidelines (ESMO) [9]. Importantly, the results from the Phase III CheckMate 9ER study assessing nivolumab plus cabozantinib versus sunitinib in the first-line treatment setting of advanced clear cell renal cell carcinoma (RCC) were recently presented at the ESMO 2020 Virtual Congress [10]. In this trial, 651 patients were randomized in a 1:1 ratio to receive a 240 mg flat dose of iv. nivolumab every 2 weeks plus oral cabozantinib at 40 mg once daily or oral sunitinib at 50 mg for 4 weeks in 6-week cycles. Of note, with median follow-up of 18.1 months, a median progression-free survival of 16.6 versus 8.3 months (HR: 0.51; 95% CI: 0.41–0.64; p < 0.0001) was achieved, with a HR of 0.60 (98.89% CI: 0.40–0.89; p = 0.0010. These results led ESMO guidelines to include combination of cabozantinib + nivolumab among the recommended first-line therapies for advanced clear cell RCC [9].The wealth of effective treatments, which are approved on an 'average' efficacy, underlines the compelling need for additional predictors of efficacy and also toxicity to incorporate in the therapeutic algorithm. In fact, trials show how there is a substantial proportion of patients with urological malignancies who do not benefit at all from the novel treatments discussed. Such a need can be satisfied by three different research tools, which include: prospective and retrospective, nontranslational clinical studies; prospective and retrospective, biomarker-based observational clinical studies; meta-analysis of randomized-controlled trials assessing the influence of baseline clinical variables and biomarkers on treatment efficacy.In prostate cancer, our work group conducted two observational studies in patients treated with the taxane agent cabazitaxel after failure of docetaxel and showed that a higher Gleason score was associated with improved efficacy of cabazitaxel [11] and that baseline neutrophil count of less than 4570/mm was associated with increased risk of severe neutropenia [12]. Also, meta-analysis of published trials on the use of ARAT agents in the metastatic castration-sensitive setting showed that a high tumor volume according to the CHAARTED criteria and presence of visceral metastasis were associated with decreased progression-free survival outcomes [5].In patients with kidney cancer, a recently published meta-analysis showed that therapy with anti PD-1/PDL-1 agents was associated with a significantly greater overall and complete response rate in PD-L1 positive versus negative patients (odds ratio (OR): 1.84; 95% CI: 1.48–2.28; OR: 3.11; 95% CI: 2.04–4.75) [8]. Another recently published meta-analysis conducted by our work group assessed data from 3814 RCC patients receiving anti PD-1/PDL-1 based combination therapy in the intention-to-treat cohort, of whom 512 showed sarcomatoid features. In the sarcomatoid RCC subgroup versus the ITT population, pooled estimates of the HR for progression or death were 0.57 (95% CI: 0.45–0.74) versus 0.79 (95% CI: 0.70–0.89), respectively, with a statistically significant interaction favoring patients with sarcomatoid RCC. Furthermore, patients with versus without sarcomatoid features reported a higher increase in complete response rate +0.10 (95% CI: 0.04–0.16) versus +0.04 (95% CI: 0.00–0.07), with a statistically significant difference of +0.06 (95% CI: 0.02–0.10; p = 0.007) [13].Finally, in bladder cancer the role of PD-L1 expression in predicting the benefit from anti PD-1/PDL-1 agents is unclear [14], although molecular subtypes of bladder cancers may provide significant prognostic and predictive information [15].In conclusion, significant progress has expanded the therapeutic scenario over the last year in urologic malignancies. The need for effective biomarkers necessary to tailor treatment can be satisfied by appropriately designed clinical studies and meta-analysis. In this regard, harmonization of baseline variables (e.g., cutoff values for PDL-1 expression) is also essential to pool data from different randomized-controlled trials.Financial & competing interests disclosureC Buonerba is a member of the Editorial Board of Future Science OA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/References1. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J. Clin. 70, 7–30 (2020).Crossref, Google Scholar2. Rescigno P, Buonerba C, Bellmunt J et al. New perspectives in the therapy of castration resistant prostate cancer. Curr Drug Targets 13, 1676–1686 (2012).Crossref, Google Scholar3. Pagliuca M, Buonerba C, Fizazi K et al. The evolving systemic treatment landscape for patients with advanced prostate cancer. Drugs 79, 381–400 (2019).Crossref, CAS, Google Scholar4. Ferro M, Lucarelli G, Crocetto F et al. First-line systemic therapy for metastatic castration-sensitive prostate cancer: an updated systematic review with novel findings. Crit. Rev. Oncol. Hematol. 103198. doi:https://doi.org/doi:10.1016/j.critrevonc.2020.103198 (2020) (Epub ahead of print).Google Scholar5. Buonerba C, Ferro M, Dolce P et al. Predictors of efficacy of androgen-receptor-axis-targeted therapies in patients with metastatic castration-sensitive prostate cancer: a systematic review and meta-analysis. Crit. Rev. Oncol. Hematol . 151, 102992 (2020).Crossref, Google Scholar6. Hussain M, Mateo J, Fizazi K et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N. Engl. J. Med. doi:10.1056/NEJMoa2022485 (2020) (Epub ahead of print).Crossref, Google Scholar7. Powles T, Park SH, Voog E et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N. Engl. J. Med. 383, 1218–1230 (2020).Crossref, CAS, Google Scholar8. Mori K, Abufaraj M, Mostafaei H et al. The predictive value of programmed death ligand 1 in patients with metastatic renal cell carcinoma treated with immune-checkpoint inhibitors: a systematic review and meta-analysis. Eur. Urol. doi:10.1016/j.eururo.2020.10.006 (2020) (Epub ahead of print).Crossref, Google Scholar9. Curigliano G, Lamarre J. Recent eUpdate on cabozantinib and nivolumab for first-line clear cell renal cancer to the ESMO clinical practice guidelines on renal cell carcinoma. Ann.Oncol. doi:10.1016/j.annonc.2020.11.016 (2020) (Epub ahead of print).Google Scholar10. Choueiri TK, Powles T, Burotto M et al. 696O_PR nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann. Oncol. 31, S1159 (2020).Crossref, Google Scholar11. Buonerba C, Pond GR, Sonpavde G et al. Potential value of Gleason score in predicting the benefit of cabazitaxel in metastatic castration-resistant prostate cancer. Future Oncol. 9, 889–897 (2013).Crossref, CAS, Google Scholar12. Di Lorenzo G, D'Aniello C, Buonerba C et al. Peg-filgrastim and cabazitaxel in prostate cancer patients. Anticancer Drugs 24, 84–89 (2012).Google Scholar13. Buonerba C, Dolce P, Iaccarino S et al. Outcomes associated with first-line anti-PD-1/PD-L1 agents vssunitinib in patients with sarcomatoid renal cell carcinoma: a systematic review and meta-analysis. Cancers (Basel). 12, doi:10.3390/cancers12020408 (2020) (Epub ahead of print).Crossref, Google Scholar14. Liu H, Ye T, Yang X et al. Predictive and prognostic role of PD-L1 in urothelial carcinoma patients with anti-PD-1/PD-L1 therapy: a systematic review and meta-analysis. Dis. Markers 8375348–8375348 doi:10.1155/2020/8375348. (2020) (Epub ahead of print).Google Scholar15. Weinstein JN, Akbani R, Broom BM et al. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014).Crossref, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByCytoreductive prostatectomy improves survival outcomes in patients with oligometastases: a systematic meta-analysis9 August 2022 | World Journal of Surgical Oncology, Vol. 20, No. 1Awareness of testicular cancer among adult Polish men and their tendency for prophylactic self-examination: conclusions from Movember 2020 event12 September 2022 | BMC Urology, Vol. 22, No. 1Radiomic Machine Learning and External Validation Based on 3.0 T mpMRI for Prediction of Intraductal Carcinoma of Prostate With Different Proportion28 June 2022 | Frontiers in Oncology, Vol. 12Enhanced Recovery After Surgery Protocol Optimizes Results and Cost of Laparoscopic Radical Nephrectomy4 April 2022 | Frontiers in Oncology, Vol. 12Circular RNAs and Drug Resistance in Genitourinary Cancers: A Literature Review9 February 2022 | Cancers, Vol. 14, No. 4Commentary: Increased CDC6 Expression Associates With Poor Prognosis in Patients With Clear Cell Renal Cell Carcinoma5 October 2021 | Frontiers in Oncology, Vol. 11 Vol. 7, No. 4 Follow us on social media for the latest updates Metrics History Received 16 December 2020 Accepted 21 December 2020 Published online 4 February 2021 Published in print April 2021 Information© 2021 Felice CrocettoKeywordsbiomarkersimmunotherapyurologic malignanciesFinancial & competing interests disclosureC Buonerba is a member of the Editorial Board of Future Science OA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/PDF download