Publications by authors named "Roberto Salvioni"

92 Publications

Radiotherapy after testis-sparing surgery for seminoma in monorchid patients: safety and efficacy.

Tumori 2021 Feb 15:300891621992428. Epub 2021 Feb 15.

Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Purpose: To evaluate local control and longitudinal endocrine data in monorchid patients treated with testicular-sparing surgery and adjuvant radiotherapy (RT) for seminomatous germ-cell tumors.

Methods: We searched our database established in 2009 for patients with seminoma who received testis irradiation following partial orchiectomy up to 2018. Eleven patients were identified. All had associated germ cell neoplasia in situ (GCNIS) in surrounding parenchyma. Analysis focused on local control and testosterone levels preservation after RT. We considered age, baseline (pre-RT) testosterone and luteinizing hormone (LH) levels, residual testicular volume, tumor size, and testosterone and LH levels trend over time in order to identify any association with endocrine impairment leading to hormonal replacement need.

Results: After a median follow-up of 21 months, no local or distant relapses were observed and hormonal function was maintained in 54.5% of patients (6/11). No significant interactions were observed for the investigated covariates. Notably, we observed an association between higher baseline testosterone levels and a decreased risk of exogenous androgen replacement (hazard ratio [HR] 0.409, 95% confidence interval [CI] 0.161-1.039, = 0.060), whereas tumor size was associated with an increased risk of exogenous androgen replacement (HR 1.847, 95% CI 0.940-3.627, = 0.075).

Conclusions: Radiotherapy after testicular sparing surgery is effective in preventing local disease relapse in presence of GCNIS in the medium term. This strategy allows a preservation of adequate endocrine function in about half of patients. More patients and longer follow-up are needed to confirm these findings.
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http://dx.doi.org/10.1177/0300891621992428DOI Listing
February 2021

Supporting Patients With Untreated Prostate Cancer on Active Surveillance: What Causes an Increase in Anxiety During the First 10 Months?

Front Psychol 2020 19;11:576459. Epub 2020 Nov 19.

Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: The psychological burden possibly deriving from not immediately undergoing radical treatment for prostate cancer (PCa) could be a potential disadvantage of active surveillance (AS), especially in the eve of some relevant clinical exams [i.e., re-biopsy, prostate-specific antigen (PSA) test, and medical examination]. Even if it is known from the literature that the majority of PCa men in AS do not report heightened anxiety, there is a minority of patients who show clinically significant levels of anxiety after diagnosis. The present study aimed to investigate if demographic, clinical, and psychological variables at the entrance in AS (T0) were associated with the risk of developing clinically significant PCa-related anxiety 2 months before the first re-biopsy (T1) and to offer psychological support to improve quality of life (QoL).

Materials And Methods: A total of 236 patients participated in the PCa Research International: AS (PRIAS) protocol and in PRIAS-QoL study. Demographic/clinical features, health-related QoL domains, coping with cancer, PCa-related anxiety [Memorial Anxiety Scale for PCa (MAX-PC)], personality traits, and decision-making-related factors were assessed at T0. MAX-PC was also administered at T1. PCa-related anxiety at T1 was considered to be of clinical significance if the MAX-PC score was ≥1.5. Multivariable logistic regression coupled to bootstrap was used to detect factors associated with high levels of anxiety.

Results: The median age was 64.4 years. Fifty-six patients (24%) reported MAX-PC total score above the cutoff. Three factors were associated with a high level of PCa anxiety at T1: anxious preoccupation [odds ratio (OR) = 4.36], extraversion (OR = 1.9), and prostate-related symptoms (median OR = 0.46). Physical well-being was associated with a low PCa anxiety subscale (median OR = 0.15); neuroticism and functional well-being were associated with PSA anxiety (median OR = 7.05 and 0.73, respectively). Neuroticism and helplessness/hopelessness were associated with fear of progression (median OR = 18.1 and 5.8, respectively).

Conclusion: Only a partial portion of the sample experienced significant levels of anxiety after 10 months. Psychological assessment should be routinely conducted to detect risk factors (i.e., anxious preoccupation, extraversion) for increased anxiety, offering tailored psychological interventions aimed at promoting interpersonal awareness and emotional well-being.
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http://dx.doi.org/10.3389/fpsyg.2020.576459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753742PMC
November 2020

Association Between Human Papillomavirus Infection and Outcome of Perioperative Nodal Radiotherapy for Penile Carcinoma.

Eur Urol Oncol 2020 Nov 13. Epub 2020 Nov 13.

San Raffaele Hospital and Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address:

Background: Data on the impact of human papillomavirus (HPV) infection status and outcomes for perioperative treatments for patients with lymph node-involved penile squamous-cell carcinoma (PSCC) are lacking.

Objective: To analyze the benefit from perioperative radiotherapy (RT) for PSCC according to HPV infection status.

Design, Setting, And Participants: In an international multicenter database of 1254 patients with PSCC who received inguinal lymph node dissection (ILND), 507 had suitable clinical information.

Intervention: ILND, with or without chemotherapy or RT for involved lymph nodes.

Outcome Measurements And Statistical Analysis: Kaplan-Meier and restricted mean survival time (RMST) analyses for overall survival (OS) were performed for all patients and after propensity score-matching (PSM; n = 136), for which patient age, histology, type of penile surgical procedure, pathological tumor and nodal stage, ILND laterality, pelvic LND, and perioperative treatment were taken into account when assessing differences between HPV and HPV- patients. Finally, we looked at genomic alterations in PSCC using data from the Foundation Medicine database (n = 199) to characterize HPV PSCC.

Results And Limitations: Patients with HPV PSCC (n = 86; 17%) had lower clinical N stage (p < 0.001) and inguinal lymph node metastasis density (p < 0.001). Perioperative RT was delivered in 49 patients (9.7%), with the vast majority receiving adjuvant RT (n = 40). HPV patients had similar median OS (p = 0.1) but longer RMST than HPV- patients at different time points. Nevertheless, HPV patients treated with perioperative RT exhibited longer median OS (p = 0.015) and longer RMST compared to HPV- patients. In the PSM cohorts, HPV status remained significantly associated with longer OS after RT. The HPV- PSCC group had a higher frequency of TP53 mutations compared to HPV PSCC (75% vs 15%; p < 0.001). The results are limited by the retrospective nature of the data.

Conclusions: Perioperative RT was more effective in the HPV PSCC subgroup. Reasons for the enhanced radiosensitivity may be related to the lack of TP53 mutations.

Patient Summary: We analyzed data from a large multicenter database for patients with penile cancer who had received inguinal lymph node dissection, with or without chemotherapy or radiotherapy. We found that for tumors positive for human papillomavirus (HPV), use of radiotherapy resulted in prolonged survival compared to HPV-negative tumors. On the basis of these results we are inspired to design studies on the use of radiotherapy in HPV-selected patients.
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http://dx.doi.org/10.1016/j.euo.2020.10.011DOI Listing
November 2020

A risk calculator predicting recurrence in lymph node metastatic penile cancer.

BJU Int 2020 11 7;126(5):577-585. Epub 2020 Aug 7.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Objectives: To develop and externally validate a risk calculator for prediction of any cancer recurrence in patients with penile squamous cell carcinoma (pSCC) and inguinal lymph node metastases (ILNM), as to date no validated prognostic tool is available for patients with pSCC and ILNM.

Patients And Methods: The development cohort included 234 patients from seven referral centres. The external validation cohort included 273 patients from two additional referral centres. Cox regression identified predictors of any recurrence, which were used to develop a risk calculator. The risk-calculator grouped the development and the validation cohorts according to the individual risk of any recurrence at 24 months (24m-R). Adjuvant treatment effects were tested on overall survival (OS) according to the derived tertiles, within the development and validation cohorts.

Results: Positive surgical margins, pN , and ILNM ratio were associated with higher recurrence rate. The 2-year OS rates were lower for patients with high (>37%) and intermediate (19-37%) compared to low (<19%) 24m-R risk of recurrence, for both the development (43% and 58% vs 83%, P < 0.001) and validation cohort (44% and 50% vs 85%, P < 0.001). Results were confirmed in the subgroup of patients who did not receive adjuvant treatment (P < 0.001), but not in patients who did receive adjuvant treatments in both the development and validation cohorts (P > 0.1).

Conclusion: Adjuvant treatment planning is crucial in patients with pSCC with ILNM, where only weak evidence is available. The current tool proved to successfully stratify patients according to their individual risk, potentially allowing better tailoring of adjuvant treatments.
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http://dx.doi.org/10.1111/bju.15177DOI Listing
November 2020

Response of a comprehensive cancer center to the COVID-19 pandemic: the experience of the Fondazione IRCCS-Istituto Nazionale dei Tumori di Milano.

Tumori 2020 May 4:300891620923790. Epub 2020 May 4.

Scientific Director, Fondazione IRCCS Istituto Tumori di Milano, Milan, Italy.

Background: The rapid spread of coronavirus disease (COVID-19) is affecting many countries. While healthcare systems need to cope with the need to treat a large number of people with different degrees of respiratory failure, actions to preserve aliquots of the healthcare system to guarantee treatment to patients are mandatory.

Methods: In order to protect the Fondazione IRCCS-Istituto Nazionale dei Tumori di Milano from the spread of COVID-19, a number of to-hospital and within-hospital filters were applied. Among others, a triage process to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity in patients with cancer was developed consisting of high-resolution low-dose computed tomography (CT) scan followed by reverse transcription polymerase chain reaction (RT-PCR) detection of SARS-CoV-2 in nose-throat swabs whenever CT was suggestive of lung infection. To serve symptomatic patients who were already admitted to the hospital or in need of hospitalization while waiting for RT-PCR laboratory confirmation of infection, a COVID-19 surveillance zone was set up.

Results: A total of 301 patients were screened between March 6 and April 3, 2020. Of these, 47 were hospitalized, 53 needed a differential diagnosis to continue with their cancer treatment, and 201 were about to undergo surgery. RT-PCR was positive in 13 of 40 hospitalized patients (32%), 14 of 52 day hospital patients (27%), and 6 of 201 surgical patients (3%).

Conclusion: Applying filters to protect our comprehensive cancer center from COVID-19 spread contributed to guaranteeing cancer care during the COVID-19 crisis in Milan. A surveillance area and surgical triage allowed us to protect the hospital from as many as 33 patients infected with SARS-CoV-2.
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http://dx.doi.org/10.1177/0300891620923790DOI Listing
May 2020

Identifying an optimal lymph node yield for penile squamous cell carcinoma: prognostic impact of surgical dissection.

BJU Int 2020 01 26;125(1):82-88. Epub 2019 Aug 26.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Objective: To evaluate the prognostic impact of lymph node yield (LNY) on survival outcomes for penile squamous cell carcinoma (SCC).

Patients And Methods: In all, 532 patients who underwent inguinal LN dissection (ILND) across tertiary referral centres from Europe, China, Brazil and North America were retrospectively evaluated. From this cohort, 198 patients received pelvic LND (PLND).We identified threshold values for ILND and PLND using receiver operating characteristic curves. We tested prognostic value of LNY for recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) using the Kaplan-Meir method and Cox proportional hazard regression models.

Results: The median (interquartile [IQR]) age was 59 (49-68) years and the median (IQR) follow-up after ILND was 28 (12-68.2) months. Overall, 85% of the patients had bilateral dissections. The median (IQR) number of inguinal LNs removed was 15 (10-22). Of those receiving PLND, The median (IQR) number of LNs was 13 (8-19). A LNY of ≥15 was used for dichotomisation of ILND patients, and a LNY of ≥9 was used in the PLND cohort. Patients with a LNY ≥15 had significantly better 5-year OS vs patients with a LNY <15 (70.1% vs 58.7%). On multivariable analyses, a LNY ≥15 was a predictor of OS (hazard ratio [HR] 0.68, P = 0.029). For cN0 patients, a LNY ≥15 was an independent predictor of RFS (HR 0.52, P = 0.043) and OS (HR 0.53, P = 0.021). In the PLND cohort, a LNY ≥9 was a predictor of RFS (HR 0.53, P = 0.032).

Conclusions: Using one of the largest LND datasets to date, we found LNY to be a significant predictor of outcomes after lymphatic staging for penile SCC. Prospective validation is warranted.
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http://dx.doi.org/10.1111/bju.14883DOI Listing
January 2020

Nomogram-based prediction of overall survival after regional lymph node dissection and the role of perioperative chemotherapy in penile squamous cell carcinoma: A retrospective multicenter study.

Urol Oncol 2019 08 1;37(8):531.e7-531.e15. Epub 2019 May 1.

Moffitt Cancer Center and Research Institute, Tampa, FL.

Objectives: To improve the prognostic allocation of patients with penile squamous-cell carcinoma (PSCC) receiving regional lymph node dissection (LND).

Patients And Methods: An international, multicenter, retrospective study was performed on patients with PSCC who received regional LND, with or without perioperative therapy, from 1980 to 2017. We first used a random forest (RF) method with missing data imputation. Additionally, data were modeled using Cox proportional hazard regression, and a Cox model was also fit including prespecified variables. Based on the latter model, a nomogram for estimating 12-month and 24-month overall survival (OS) was developed.

Results: There were 743 patients who received LND at 7 referral centers from Europe, the USA, Brazil, and China. Of these patients, 689 were analyzed: 86 (12.5%) received neoadjuvant chemotherapy (NAC); 171 (24.8%) received adjuvant chemotherapy (AC), and 74 (10.7%) received adjuvant radiotherapy. The variables significantly associated with OS were age (P < 0.001), the pathologically involved/total removed LN ratio (P < 0.001), pN stage (overall P < 0.001), and NAC (P = 0.013). NAC and AC were ineffective in N1-2 patients (clinical and pathological, respectively), whereas they provided OS improvements in N3 patients. Finally, we developed a nomogram predicting 12- and 24-month OS based on prespecified variables (c-index: 0.75). The study is limited by its retrospective nature.

Conclusions: We propose a tool that can be offered as an aid to physicians to enhance decision-making, clinical research, and patient counseling whenever LND is needed for PSCC. Administration of NAC and AC should be restricted to clinical and pathological N3 patients, respectively.
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http://dx.doi.org/10.1016/j.urolonc.2019.04.003DOI Listing
August 2019

Recommendations for surveillance and follow-up of men with testicular germ cell tumors: a multidisciplinary consensus conference by the Italian Germ cell cancer Group and the Associazione Italiana di Oncologia Medica.

Crit Rev Oncol Hematol 2019 May 20;137:154-164. Epub 2019 Mar 20.

IGG Italian Germ cell cancer Group, Italy; AIOM - Associazione Italiana di Oncologia Medica, Italy.

Background: No compelling evidence is available about surveillance and follow-up of patients with testicular germ cell tumour (TGCT).

Methods: In the light of the best clinical evidence, the Italian Germ cell cancer Group (IGG) and the Associazione Italiana di Oncologia Medica (AIOM) set up a multidisciplinary national consensus conference, involving 42 leading experts and 3 TGCT survivors. A minimum of 50% of votes was required in order to achieve a consensus recommendation on 29 questions.

Results: Recommendations have been summarized in three tables, divided by stage I seminoma, stage I nonseminoma and the advanced disease, which may be useful for clinicians to appropriately choose the clinical investigation and its timing during the surveillance and follow-up of TGCT patients based on an accurate estimation of their risk of disease relapse.

Conclusions: The IGG-AIOM consensus recommendations may help clinicians to choose appropriate clinical investigations for the surveillance and follow-up of TGCT patients.
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http://dx.doi.org/10.1016/j.critrevonc.2019.03.006DOI Listing
May 2019

Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study.

J Clin Oncol 2018 12 20;36(34):3353-3360. Epub 2018 Oct 20.

Andrea Necchi, Andrea Anichini, Daniele Raggi, Simona Massa, Maurizio Colecchia, Patrizia Giannatempo, Roberta Mortarini, Elena Farè, Francesco Monopoli, Antonella Messina, Roberto Salvioni, and Luigi Mariani, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori; Alberto Briganti, Roberta Lucianò, Marco Bianchi, Renzo Colombo, Andrea Gallina, Andrea Salonia, and Francesco Montorsi, Vita Salute San Raffaele University and Urological Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milan, Italy; Siraj M. Ali, Russell Madison, Jeffrey S. Ross, and Jon H. Chung, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Upstate Medical University, Syracuse, NY.

Purpose: To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used.

Patients And Methods: In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0). Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay), genomic sequencing (FoundationONE assay), and an immune gene expression assay.

Results: Fifty patients were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%). As a secondary end point, downstaging to pT<2 was achieved in 27 patients (54%; 95% CI, 39.3% to 68.2%). In 54.3% of patients with PD-L1 CPS ≥ 10% (n = 35), RC indicated pT0, whereas RC indicated pT0 in only 13.3% of those with CPS < 10% (n = 15). A significant nonlinear association between tumor mutation burden (TMB) and pT0 was observed, with a cutoff at 15 mutations/Mb. Expression of several genes in pretherapy lesions was significantly different between pT0 and non-pT0 cohorts. Significant post-therapy changes in the TMB and evidence of adaptive mechanisms of immune resistance were observed in residual tumors.

Conclusion: Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with MIBC. This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of MIBC when limited to patients with PD-L1-positive or high-TMB tumors.
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http://dx.doi.org/10.1200/JCO.18.01148DOI Listing
December 2018

TARIBO trial: targeted therapy with or without nephrectomy in metastatic renal cell carcinoma: liquid biopsy for biomarkers discovery.

Tumori 2018 Oct 9;104(5):401-405. Epub 2018 May 9.

1 Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan - Italy.

Purpose:: Two randomized trials in the cytokine era showed that cytoreductive nephrectomy (CN) had a role in metastatic renal cell carcinoma (mRCC), increasing life expectancy. The survival benefit of tyrosine kinase inhibitors (TKIs), including first-line sunitinib and pazopanib, in mRCC has been demonstrated, but the majority of patients enrolled in the pivotal phase III studies had undergone nephrectomy. Therefore it is unknown if similar survival benefit with targeted agents could be achieved without CN. We hypothesize that in these patients CN could increase overall survival (OS) in comparison to targeted therapy without CN. We also will investigate mechanisms of primary and secondary resistance to TKIs in patients with mRCC and identify prognostic or predictive biomarkers.

Methods:: This is a randomized, open-label, controlled, multicenter phase 3 study comparing sunitinib or pazopanib vs CN followed by sunitinib or pazopanib as first-line therapy for patients with mRCC who have not received surgery and prior systemic treatment for metastatic disease. We will identify 270 patients eligible for randomization. The planned treatment duration per patient will be until progressive disease is observed. Secondary endpoints are the evaluation of progression-free survival (PFS) and response rate and the assessment of the safety profile. Exploratory objectives include the evaluation of circulating tumor cells and circulating tumor DNA and correlation with response/resistance to treatment.

Results:: The study is enrolling patients.

Conclusions:: The use of CN in addition to targeted therapy in patients with renal cell carcinoma with synchronous metastases could lead to a significant improvement in OS and PFS.
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http://dx.doi.org/10.5301/tj.5000699DOI Listing
October 2018

Association of Androgen Receptor Expression on Tumor Cells and PD-L1 Expression in Muscle-Invasive and Metastatic Urothelial Carcinoma: Insights for Clinical Research.

Clin Genitourin Cancer 2018 04 7;16(2):e403-e410. Epub 2017 Oct 7.

Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Limited information is available regarding the use of androgen receptor (AR) immunohistochemical expression in muscle-invasive or metastatic urothelial carcinoma. We aimed to evaluate the frequency of AR expression by tumor cells (TC), its prognostic role, and its relationship with programmed cell-death ligand 1 (PD-L1) expression in these patients.

Patients And Methods: From September 2015 to January 2017, we collected tissue from patients who received platinum-based chemotherapy at our center. Immunohistochemistry for AR was performed (1% cutoff of TC). PD-L1 coexpression, by TC or immune cells (1% cutoff), was also analyzed. Molecular analysis of AR gene was performed by sequencing of exons 5 to 8 and by fluorescence in-situ hybridization analysis. Cox models for overall survival (OS), adjusted for stage, visceral metastases, and platinum type, were fitted.

Results: A total of 110 patients had tumor samples stained. Overall, 48 (43.6%) had AR-expressing TC: 19 (17.3%) had 1%-5% expression, 15 (13.6%) 5%-25% expression, and 14 (12.7%) > 25% expression. Among the latter, 7 had molecularly evaluated tumor tissue: no AR gene mutations or amplifications were found, but polysomy of Xq chromosome was seen. PD-L1 expression by TC and immunohistochemistry concordantly decreased with increasing levels of AR expression by TC. In Cox analyses, AR expression was not associated with OS, both on univariable (P = .477) and multivariable (P = .505) analyses.

Conclusion: AR is frequently expressed in patients with muscle-invasive and advanced urothelial carcinoma, and it does not seem to be prognostic for OS. The AR pathway is worthy of clinical studies to assess its synergistic action with anti-PD-L1 therapy.
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http://dx.doi.org/10.1016/j.clgc.2017.09.016DOI Listing
April 2018

Laparoscopic Retroperitoneal Lymph Node Dissection for Clinical Stage I Nonseminomatous Germ Cell Tumors of the Testis: Safety and Efficacy Analyses at a High Volume Center.

J Urol 2018 03 28;199(3):741-747. Epub 2017 Sep 28.

Testis Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Purpose: The prognosis of stage I nonseminomatous germ cell tumor of the testis is favorable. Early and late side effects of treatment may affect quality of life and survival. We determined the tolerability, safety and efficacy of laparoscopic retroperitoneal lymph node dissection in patients with stage I nonseminomatous germ cell tumor of the testis at a high volume center.

Materials And Methods: Unilateral laparoscopic retroperitoneal lymph node dissection was prospectively recorded in 225 patients from 2000 to 2014. Since 2007, patients have been treated at a multidisciplinary clinic and were proposed surgery as an alternative to surveillance or adjuvant chemotherapy. The indication for adjuvant chemotherapy changed during the study period. Descriptive statistics and regression analyses were used to evaluate the domains of safety and oncologic outcomes.

Results: A total of 221 patients were evaluable. Median operative time was 200 minutes. Conversion to open surgery was done in 20 cases (9%). A median of 14 nodes (IQR 11-20) was retrieved. Grade greater than 2 complications in 8 cases (3.6%) increased as the number of retrieved nodes increased. Antegrade ejaculation was maintained in 98.6% of patients. Nodal metastases were found in 29 patients (13%), of whom 7 underwent adjuvant chemotherapy. There were 14 recurrences (6.3%), including 8 of 192 (4.2%) associated with no nodal metastases and 6 of 22 (27.3%) associated with nodal metastases in patients not undergoing adjuvant chemotherapy. At regression analyses lymph node ratio was the only significant factor predictive of recurrence and of the administration of any chemotherapy (each p <0.001). Operative time, the number of retrieved nodes and conversions improved with time.

Conclusions: In the context of a high volume center laparoscopic retroperitoneal lymph node dissection was safe and its oncologic efficacy was comparable to that of open surgery. Select patients with stage I nonseminomatous germ cell tumor could be offered laparoscopic retroperitoneal lymph node dissection as an alternative to other options.
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http://dx.doi.org/10.1016/j.juro.2017.09.088DOI Listing
March 2018

First-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma: results of an open-label, single-arm, single-centre, phase 2 study.

BJU Int 2018 03 4;121(3):348-356. Epub 2017 Oct 4.

Urology Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Objective: To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan-epidermal growth factor receptor (HER) inhibitor.

Patients And Methods: In a phase 2 study (NCT01728233), patients received dacomitinib 45 mg/day, orally, continuously. Inclusion criteria were SCC histology, clinical stage N or M (Tumour-Node-Metastasis classification system 2009), and no prior chemotherapy administration. The primary endpoint was the objective response rate (ORR, according to the Response Evaluation Criteria in Solid Tumors, version 1.1). Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% were set.

Results: From June 2013 to October 2016, 28 patients were treated. Eight (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) clinically involved bilateral lymph nodes. One complete and eight partial responses were obtained (ORR 32.1%, 80% credibility interval 21.0-43.0%). The median (interquartile range [IQR]) follow-up duration was 19.8 (6.3-25.7) months; 12-month progression-free survival was 26.2% (95% confidence interval [CI] 13.2-51.9); 12-month overall survival (OS) was 54.9% (95% CI 36.4-82.8). The median (IQR) OS of locally advanced patients was 20 (11.1-not reached) months. The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in three patients (10.7%). Tissue samples from 25 patients were analysed. Only two patients had high-risk human papillomavirus-positive tumours. Epidermal growth factor receptor (EGFR) amplification was found in four patients (equally responders and non-responders) and it was confirmed in all post-dacomitinib samples. Telomerase reverse transcriptase (TERT) mutations were found in responders only (60%), and phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway gene mutations were found in 42.9% of responders vs 8.3% of non-responders.

Conclusion: Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combined chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signalling in relation to dacomitinib activity deserve further studies.
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http://dx.doi.org/10.1111/bju.14013DOI Listing
March 2018

Neoadjuvant sorafenib, gemcitabine, and cisplatin administration preceding cystectomy in patients with muscle-invasive urothelial bladder carcinoma: An open-label, single-arm, single-center, phase 2 study.

Urol Oncol 2018 01 12;36(1):8.e1-8.e8. Epub 2017 Sep 12.

Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Background: Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676).

Patients And Methods: After transurethral resection of the bladder, T2-T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400mg q12h daily, continuously, was added to standard GC chemotherapy. In a Simon's 2-stage design, the primary endpoint was the pathologic complete response (pT0), assuming H0: ≤0.20 and H1: ≥0.40, with a type I and type II error of 5% and 10%, respectively.

Results: From April 2011 to June 2016, 46 patients were enrolled. Pathologic T0 response was obtained in 20 patients (43.5%, 95% CI: 28.9-58.9); pT ≤ 1 in 25 (54.3%, 95% CI: 39.0-69.1). After a median follow-up of 35 months, the median progression-free survival was not reached (NR, interquartile range: 23.6-NR), nor was median overall survival (interquartile range: 30.3-NR). Hematologic and extrahematologic grade 3 to 4 adverse events occurred in 45.6% and 26.1% of patients, respectively. In 29 samples from responders (pT ≤ 1) and nonresponders, different distribution of missense mutations involved DNA-repair genes, RAS-RAF pathway genes, chromatin-remodeling genes, and HER-family genes. ERCC1 immunohistochemical expression was associated with pT ≤ 1 response (P = 0.047). The absence of a comparator arm prevented us to quantify sorafenib contribution.

Conclusions: SGC combination was active in MIUBC, and the identified molecular features included alterations that may help personalize treatment in MIUBC with new more potent targeted agents, combined with chemotherapy.
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http://dx.doi.org/10.1016/j.urolonc.2017.08.020DOI Listing
January 2018

Eleven-year management of prostate cancer patients on active surveillance: what have we learned?

Tumori 2017 09 14;103(5):464-474. Epub 2017 Jun 14.

Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.

Purpose: To evaluate the outcomes of active surveillance (AS) on patients with low-risk prostate cancer (PCa) and to identify predictors of disease reclassification.

Methods: In 2005, we defined an institutional AS protocol (Sorveglianza Attiva Istituto Nazionale Tumori [SAINT]), and we joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study in 2007. Eligibility criteria included clinical stage ≤T2a, initial prostate-specific antigen (PSA) <10 ng/mL, and Gleason Pattern Score (GPS) ≤3 + 3 (both protocols); ≤25% positive cores with a maximum core length containing cancer ≤50% (SAINT); and ≤2 positive cores and PSA density <0.2 ng/mL/cm3 (PRIAS). Switching to active treatment was advised for a worsening of GPS, increased positive cores, or PSA doubling time <3 years. Active treatment-free survival (ATFS) was assessed using the Kaplan-Meier method. Factors associated with ATFS were evaluated with a multivariate Cox proportional hazards model.

Results: A total of 818 patients were included: 200 in SAINT, 530 in PRIAS, and 88 in personalized AS monitoring. Active treatment-free survival was 50% after a median follow-up of 60 months. A total of 404/818 patients (49.4%) discontinued AS: 274 for biopsy-related reclassification, 121/404 (30%) for off-protocol reasons, 9/404 (2.2%) because of anxiety. Biopsy reclassification was associated with PSA density (hazard ratio [HR] 1.8), maximum percentage of core involvement (HR 1.5), positive cores at diagnostic biopsy (HR 1.6), older age (HR 1.5), and prostate volume (HR 0.6) (all p<0.01). Patients from SAINT were significantly more likely to discontinue AS than were the patients from PRIAS (HR 1.65, p<0.0001).

Conclusions: Five years after diagnosis, 50% of patients with early PCa were spared from active treatment. Wide inclusion criteria are associated with lower ATFS. However, at preliminary analysis, this does not seem to affect the probability of unfavorable pathology.
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http://dx.doi.org/10.5301/tj.5000649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379800PMC
September 2017

Italian cultural adaptation of the Memorial Anxiety for Prostate Cancer scale for the population of men on active surveillance.

Tumori 2018 Jun 9;104(3):172-178. Epub 2018 May 9.

1 Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.

Purpose: The Memorial Anxiety Scale for Prostate Cancer (MAX-PC) is a self-report questionnaire that was developed in English to assess prostate cancer (PCa)-related anxiety. The aim of this study was to perform a cultural adaptation for the tool to be used in a population of Italian men on active surveillance (AS).

Methods: A total of 222 patients with localized PCa who were recruited for the Prostate Cancer Research International: Active Surveillance (PRIAS) protocol completed the MAX-PC. Psychometric analysis was performed to assess reliability indexes. A Spearman rank correlation was used to test the association between MAX-PC scales and other questionnaires and was used for longitudinal analysis.

Results: Cronbach coefficients and item to total correlation demonstrated good internal consistency. Some items related to the repetition of the PSA test showed a large floor effect and thus were poorly effective in measuring anxiety for PSA testing in patients on AS. Confirmatory factor analysis partly failed to reproduce the structure of the original version. A modified version of MAX-PC, excluding the items with a large floor effect, was thus considered for AS patients. Factor analysis on this version demonstrated considerable consistency with the presence of 3 subscales: anxiety related to PCa, anxiety related to PSA testing, and anxiety related to the fear of tumor progression. Longitudinal analysis showed an acceptable validity over time. The MAX-PC was correlated with the anxious preoccupation subscale of the Mini-Mental Adjustment to Cancer scale.

Conclusions: A slightly modified version of the MAX-PC was developed for use in Italian men on AS. This instrument appears to be a valid and reliable tool that measures anxiety in men with PCa who are enrolled in AS programs.
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http://dx.doi.org/10.5301/tj.5000646DOI Listing
June 2018

Clinical Outcomes of Perioperative Chemotherapy in Patients With Locally Advanced Penile Squamous-Cell Carcinoma: Results of a Multicenter Analysis.

Clin Genitourin Cancer 2017 10 27;15(5):548-555.e3. Epub 2017 Feb 27.

UAB Comprehensive Cancer Center, Birmingham, AL.

Background: The prognosis of patients with locally advanced penile squamous-cell carcinoma is primarily related to the extent of lymph node metastases. Surgery alone yields suboptimal results, and there is a paucity of data on these patients' outcomes.

Patients And Methods: This retrospective study evaluated patients who received neoadjuvant or adjuvant chemotherapy from 1990 onward at 12 centers. Cox models were used to investigate prognostic factors for relapse-free survival and overall survival (OS).

Results: Among the 201 included patients, 39 (19.4%) had disease of T3-4 and N0 clinical stage; the remaining patients had clinical lymph node involvement (cN+). Ninety-four patients received neoadjuvant chemotherapy (group 1), 78 received adjuvant chemotherapy (group 2), and 21 received both (group 3). Eight patients for whom the timing of perioperative chemotherapy administration was unavailable were included in the Cox analyses. Forty-three patients (21.4%) received chemoradiation. Multivariate analysis for OS (n = 172) revealed bilateral disease (P = .035) as a negative prognostic factor, while pelvic cN+ tended to be nonsignificantly associated with decreased OS (P = .076). One-year relapse-free survival was 35.6%, 60.6%, and 45.1% in the 3 groups, respectively. One-year OS was 61.3%, 82.2%, and 75%, respectively. No significant differences were seen on univariable analyses for OS between the groups (P = .45). Platinum type of chemotherapy and chemoradiation were not significantly associated with any outcome analyzed.

Conclusion: Benchmark survival estimates for patients receiving perioperative chemotherapy for locally advanced penile squamous-cell carcinoma have been provided, with no substantial differences observed between neoadjuvant and adjuvant administration. This analysis may result in improved patient information, although prospective studies are warranted.
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http://dx.doi.org/10.1016/j.clgc.2017.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854657PMC
October 2017

Treatment of Carcinoma In Situ of the Glans Penis With Topical Imiquimod Followed by Carbon Dioxide Laser Excision.

Clin Genitourin Cancer 2017 06 18;15(3):e483-e487. Epub 2017 Jan 18.

Department of Urology, IRCCS Fondazione, Istituto Nazionale dei Tumori, Milan, Italy.

Background: Different approaches have been described in published studies for carcinoma in situ (CIS) of the glans penis (erythroplasia of Queyrat), including topical chemotherapy or immunotherapy and laser or surgical excision. We evaluated the efficacy of topical imiquimod (IQ) followed by carbon dioxide laser ablation of the lesion.

Patients And Methods: From 2010 to 2015, 10 patients affected by CIS of the glans were treated by IQ, followed by carbon dioxide laser ablation. For every patient, we performed histologic examination before and after IQ. Local toxicity and adverse effects were recorded.

Results: After treatment, histologic examination showed no residual tumor in 6 patients (complete response [CR]), stable disease in 2 patients, and progressive disease in 2 patients. Those with a CR had human papillomavirus-related lesions, and they had no experienced relapses after a mean follow-up of 26 months. The 2 patients with progressive disease underwent total penectomy. All patients were alive at the last follow-up examination. All patients experienced a mild local toxicity (burning erythema) but no major adverse effects.

Conclusion: Local treatment with IQ for glans CIS is effective mainly for human papillomavirus-related lesions. The present study is the first to record the histologic examination findings before and after IQ treatment. The small number of patients, owing to the rarity of this disease, was the main limitation of the present study. IQ must be used carefully, and a close follow-up protocol is mandatory because of the lack of long-term efficacy data.
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http://dx.doi.org/10.1016/j.clgc.2017.01.009DOI Listing
June 2017

Surgery of locally advanced and metastatic kidney cancer after tyrosine kinase inhibitors therapy: single institute experience.

Tumori 2018 Oct 8;104(5):388-393. Epub 2018 May 8.

1 Department of Urology, Fondazione IRCCS Istituto dei Tumori, Milan - Italy.

Purpose:: Renal cell carcinoma (RCC) is the most common tumor of the kidney. Considering the TNM classification of 2009, locally advanced and metastatic diseases are included in the groups stage III and IV. The surgical treatment of these tumors could be divided into 3 categories: (1) curative (nephrectomy and/or metastasectomy), (2) cytoreductive, and (3) palliative. Targeted agents showed impressive antitumor efficacy and prolongation of progression-free survival. The integration between target therapy and surgery in patients with locally advanced or metastatic RCC has sometimes facilitated surgery. We aimed to evaluate patients' response to tyrosine kinase inhibitor (TKI) therapy and the feasibility of surgery after that and to observe complications related to surgery.

Methods:: From February 2007 to September 2014 in the Istituto Tumori of Milan, IRCCS, we selected patients with locally advanced or metastatic diseases, treated with target therapy before surgery (which comprised nephrectomy or partial nephrectomy, cytoreductive surgery, and metastasectomy) and cryoablation.

Results:: We selected 33 patients who underwent surgery after TKI therapy. As for response to TKIs, 20 patients (60%) had stable disease, 9 patients (28%) had a partial response, and 4 patients (12%) had progressive disease. A total of 17 patients (51%) presented complications directly or indirectly related to surgery and most of those were classified as grade II Clavien-Dindo score.

Conclusions:: The association between TKI and surgery seems to have no contraindications. Our dataset provides an example of how surgery after TKI is possible in locally advanced metastatic tumor and does not have an excessive rate of postoperative complications.
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http://dx.doi.org/10.5301/tj.5000596DOI Listing
October 2018

Lifestyle interventions to improve the quality of life of men with prostate cancer: A systematic review of randomized controlled trials.

Crit Rev Oncol Hematol 2016 Dec 20;108:13-22. Epub 2016 Oct 20.

Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.

Improving quality of life is a key issue for patients with prostate cancer (PCa). Lifestyle interventions could positively impact the quality of life of patients. However, there is no clear-cut understanding of the role of diet, exercise and risky behaviour reduction in improving the quality of life of men with PCa. The aim of this review was to systematically summarize randomized controlled trials on lifestyle in PCa patients with quality of life as main outcome. 17 trials were included. Most of them referred to exercise interventions (71%) and involved men undergoing androgen deprivation therapy (47%). Exercise studies yielded the greater amount of positive results on quality of life outcomes (67%), followed by dietary interventions (50%) and combined lifestyle interventions (33%). In particular, supervised exercise programs with resistance training sessions were the ones producing greater convincing evidence for benefits on quality of life. Further studies with high methodological quality providing adequate information to develop evidence-based, personalized lifestyle interventions that can effectively ameliorate PCa-related quality of life are needed.
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http://dx.doi.org/10.1016/j.critrevonc.2016.10.007DOI Listing
December 2016

"What if…": decisional regret in patients who discontinued active surveillance.

Tumori 2016 Dec 22;102(6):562-568. Epub 2016 Sep 22.

 Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.

Purpose: To investigate the presence of regret in patients about having followed an active surveillance (AS) protocol. The secondary aim was to identify variables that influence regret.

Methods: From February 2006 to May 2014, 204 patients discontinued the AS protocols and were invited to enter the study. Sociodemographic variables were collected at AS enrollment, together with health-related quality of life (Functional Assessment of Cancer Therapy-Prostate version [FACT-P]) and coping (Mini-Mental Adjustment to Cancer). Patients were asked to complete a Treatment Regret Scale as well as the FACT-P questionnaire. Clinical data were gathered, as well as time of stay within the AS protocol, reason for discontinuing AS, kind of post-AS treatment, and time elapsed since AS discontinuation. Questionnaires were completed by 105 patients (51.5% of those who had been invited to enter the study).

Results: Most of the patients had a low or null degree of regret on the Treatment Regret Scale from 0 to 100 (82/105 patients [78.1%] obtained a score <30, and about 30% of the sample had a score equal to zero). Only 5 patients (4.7%) scored 60 or more, indicating some degree of regret. None of the statistical tests between regret scores and a number of analyzed variables reached significance.

Conclusions: These results show that the degree of regret about following an AS protocol and after its discontinuation because of entering active treatment was very low. The regret after AS was not related to sociodemographic or clinical factors.
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http://dx.doi.org/10.5301/tj.5000564DOI Listing
December 2016

Effect of Bleomycin Administration on the Development of Pulmonary Toxicity in Patients With Metastatic Germ Cell Tumors Receiving First-Line Chemotherapy: A Meta-Analysis of Randomized Studies.

Clin Genitourin Cancer 2017 04 8;15(2):213-220.e5. Epub 2016 Sep 8.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Background: Limited information is available about the effect of bleomycin administration on the development of pulmonary toxicity in metastatic germ cell tumors (GCT).

Patients And Methods: A literature search was conducted to identify randomized trials of first-line chemotherapy for GCT. We conducted univariate and multivariate analyses using random effects models to evaluate the predictive role of bleomycin administration in the development of all Grade and Grade 3 to 4 (G3-4) pulmonary toxicity. The results were adjusted for length of follow-up, prognostic risk group, year of treatment, presence of lung metastases, and primary mediastinal GCT.

Results: Fifty-three study arms of 25 phase II and III trials encompassing 6498 patients were selected: 40 that used bleomycin (n = 5093) and 13 that did not (n = 1405). The pooled probability of all-Grade pulmonary toxicity in the bleomycin and nonbleomycin arms was 11.7% (95% confidence interval [CI], 8.4%-16.0%) and 1.7% (95% CI, 0.7%-4.2%), respectively. Univariate analysis indicated that bleomycin administration was associated with the incidence of all-Grade (odds ratio [OR], 7.57; 95% CI, 2.84-20.18; Wald test P < .001) and G3-4 pulmonary toxicity (OR, 5.19; 95% CI, 1.57-17.16; P = .007). Multivariate analysis showed a significant association of bleomycin administration with the incidence of all-Grade pulmonary toxicity (OR, 4.14; 95% CI, 1.36-12.59; P = .012) and a trend toward significance for G3-4 toxicity (OR, 2.24; 95% CI, 0.91-5.51; P = .080).

Conclusion: We quantified the bleomycin-associated effect on the development of pulmonary toxicity in patients with GCT who received first-line chemotherapy. This information might be useful for planning clinical trials aimed at reducing chemotherapy as well as to inform patients in the clinic.
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http://dx.doi.org/10.1016/j.clgc.2016.08.021DOI Listing
April 2017

A Suggested Prognostic Reclassification of Intermediate and Poor-Risk Nonseminomatous Germ Cell Tumors.

Clin Genitourin Cancer 2017 04 8;15(2):306-312.e3. Epub 2016 Aug 8.

Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.

Background: The International Germ Cell Cancer Collaborative Group (IGCCCG) classification has been used since 1997 to allocate metastatic germ cell tumors (GCTs), but its applicability needs an update. We aimed to revisit the outcomes of intermediate and poor risk nonseminomatous GCTs (NSGCTs).

Patients And Methods: Individual patient-level data from the databases of 2 institutions were collected. Outcomes of consecutive patients who received first-line chemotherapy from 1990 to 2014 were used. The Kaplan-Meier method was used to estimate relapse-free (RFS) and overall survival (OS). Cox regression analyses were used to evaluate potential prognostic factors of RFS and OS univariably. Forward stepwise selection was used to construct a multivariable model. A risk factor (RF) model was then constructed and compared with IGCCCG classification using the concordance statistics (CS).

Results: A total of 647 patients were identified. Four RFs for OS in the multivariable model were identified: primary mediastinal NSGCT (P < .001), brain metastases (P < .001), lung metastases (P = .016), and age at the time of diagnosis (P = .003). CS were improved on the basis of the number of RF (0, 1, 2, and 3 or 4) compared with IGCCCG (RFS: 0.63 vs. 0.58; OS: 0.65 vs. 0.59). For intermediate risk, there were no differences between 3 (n = 25) and 4 cycles of cisplatin, etoposide, and bleomycin (BEP; n = 159) or BEP × 3 + etoposide and cisplatin (EP) × 1 (n = 31) for RFS (P = .35) and OS (P = .061).

Conclusion: An improved risk stratification was obtained for intermediate and poor risk GCTs. Our reclassification system might provide an aid for a reclassification attempt of all GCT patients. Our prognostic model might be offered to clinicians to improve their ability to assess patient prognosis, enhance stratification, and inform patients.
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http://dx.doi.org/10.1016/j.clgc.2016.07.022DOI Listing
April 2017

Laparoscopic Postchemotherapy Retroperitoneal Lymph-Node Dissection Can Be a Standard Option in Defined Nonseminomatous Germ Cell Tumor Patients.

J Endourol 2016 10;30(10):1112-1119

2 Urology Unit, Fondazione IRCCS Istituto Nazionale Tumori , Milan, Italy .

Background: Residual retroperitoneal masses in NSGCT need postchemotherapy retroperitoneal lymph-node dissection (PC-RPLND). Open (O) PC-RPLND is a standardized procedure, but morbidity is not negligible and mostly attributable to laparotomy. Laparoscopic (L) PC-RPLND may improve tolerability profile. We evaluated viability, toxicity, and short to medium-term oncologic outcome of L-PC-RPLND following well-defined selection criteria.

Patients And Methods: Since February 2011, consecutive patients with a unilateral residual mass (≥1 cm or growing), normalized markers, and limited encasement of inferior vena cava and/or aorta were candidate to unilateral L-PC-RPLND. Surgical performances, histology, hospital stay, complications within 30 days, and survival were recorded. Patients were regularly followed up. Adjuvant chemotherapy was not provided.

Results: Sixty-seven patients (stage IIA = 14; IIB = 41; IIC = 7; III = 5), representing 29% of all those candidate to PC-RPLND in this time frame, underwent L-PC-RPLND up to August 2015. Median size of the mass was 27 mm (interquartile range [IQR] 15-31). Median operative time was 234 minutes (IQR 184-250). Three procedures were converted to open surgery. Mean hospital stay was 3 days (IQR 2-4). Out of three (4.5%), one grade III (lymphocele requiring drainage) complication occurred. Sixty-six (98.5%) patients maintained antegrade ejaculation. Histology revealed teratoma in 76%, fibronecrotic tissue in 21%, and viable cancer in 3% patients. All patients are alive and event free after a median follow-up of 21 months (IQR 10-30).

Conclusions: In a referral center, L-PC-RPLND is a transferable option for a proportion of patients with a residual mass. Tolerability is acceptable, and current oncologic outcome is consistent with a safe oncologic profile.
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http://dx.doi.org/10.1089/end.2016.0458DOI Listing
October 2016

Immunotherapy advances in uro-genital malignancies.

Crit Rev Oncol Hematol 2016 Sep 17;105:52-64. Epub 2016 Jun 17.

Department of Medical Oncology, Fondazione IRCSS Istituto Nazionale Tumori, Milan, Italy. Electronic address:

Immunotherapy for the treatment of cancer has made significant progresses over the last 20 years. Multiple efforts have been attempted to restore immune-mediated tumor elimination, leading to the development of several targeted immunotherapies. Data from recent clinical trials suggest that these agents might improve the prognosis of patients with advanced genito-urinary (GU) malignancies. Nivolumab has been the first immune checkpoint-inhibitor approved for pre-treated patients with metastatic renal cell carcinoma. Pembrolizumab and atezolizumab have shown promising results in both phase I and II trials in urothelial carcinoma. Brentuximab vedotin has demonstrated early signals of clinical activity and immunomodulatory effects in highly pre-treated patients with testicular germ cell tumors. In this review, we have summarized the major clinical achievements of immunotherapy in GU cancers, focusing on immune checkpoint blockade as well as the new immunomodulatory monoclonal antibodies (mAbs) under clinical evaluation for these malignancies.
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http://dx.doi.org/10.1016/j.critrevonc.2016.06.012DOI Listing
September 2016

Prognostic Factors of Adjuvant Taxane, Cisplatin, and 5-Fluorouracil Chemotherapy for Patients With Penile Squamous Cell Carcinoma After Regional Lymphadenectomy.

Clin Genitourin Cancer 2016 12 10;14(6):518-523. Epub 2016 Mar 10.

Urology Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Little is known about the outcomes and prognostic factors of adjuvant chemotherapy for locally advanced penile squamous cell carcinoma after regional lymphadenectomy (LAD).

Patients And Methods: We retrospectively reviewed the data from 21 patients who had received taxane, cisplatin, and 5-fluorouracil (TPF, every 3 weeks) in the adjuvant setting at our center. Univariable and multivariable Cox regression analyses were undertaken for disease-free (DFS) and overall survival (OS) of TPF.

Results: The patients had received TPF from July 2004 to July 2012 after inguinal (n = 6) or inguinal plus pelvic LAD (n = 15), and the median follow-up was 52 months. Thirteen (61.9%) had pelvic and 5 (23.8%) bilateral inguinal nodal metastases. The median time from LAD to the start of TPF was 5.4 weeks (interquartile range [IQR], 4.1-7.3 weeks). Metastatic tumor tissue from 11 of 19 evaluable patients (57.9%) showed positive immunohistochemistry staining for p53. Univariably, only the expression of p53 showed a trend toward poorer DFS (hazard ratio [HR], 4.14; 95% confidence interval [CI], 0.87-19.68; P = .074) and OS (HR, 4.54; 95% CI, 0.95-21.56; P = .056). The same results were obtained multivariably for DFS (HR, 3.76; 95% CI, 0.78-17.96; P = .096) and OS (HR, 4.29; 95% CI, 0.89-20.57; P = .067). The median DFS was 8.9 months (IQR, 5.9-22.7 months) for p53-expressing patients versus not estimable for non-p53-expressing patients (P = .051) and the median OS was 17.2 months (IQR, 12.8-22.7 months) and not estimable, respectively (P = .037).

Conclusion: In patients who had received adjuvant TPF for node-positive penile squamous cell carcinoma, p53 IHC expression seemed to be associated with a poorer outcome, and further study is warranted in larger data sets to confirm these findings. This information might be useful to improve the prognostic allocation.
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http://dx.doi.org/10.1016/j.clgc.2016.03.005DOI Listing
December 2016

An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer.

Invest New Drugs 2016 Apr 12;34(2):236-42. Epub 2016 Feb 12.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy.

Background: Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A.

Methods: A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H0 ≤ 5%, H1 ≥ 20%, α = 10% and β = 20%). Eligibility included failure of at least one platinum-based regimen.

Results: From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4%) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4%) had an ECOG-performance status 1-2. Two partial responses (PR, ORR: 9.1%), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7-10.3), 6-month progression-free survival (PFS) was 13.6% (95%CI: 4.8-39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1%, 95%CI: 41.7-83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3-4 adverse events (AE) were: 40.9% mucositis, 36.4% fatigue, 18.2% neutropenia (13.6% febrile neutropenia). There were 2 treatment-related deaths.

Conclusions: The study did not meet the primary EP, yet sustained disease control was obtained in about 14% of patients. The incidence of AE and the issue of patient selection are two major concerns.
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http://dx.doi.org/10.1007/s10637-016-0328-9DOI Listing
April 2016