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PURPOSE: We evaluated the oncologic efficacy of early inguinal lymph-node dissection, observation or dynamic sentinel node biopsy followed by delayed or selective inguinal lymph-node dissection in cN0 patients with penile squamous cell carcinoma. MATERIALS AND METHODS: Between 1980 and 2017 (inclusive), 296 evaluable consecutive cN0 penile squamous cell carcinoma patients underwent early inguinal lymph-node dissection (16), observation (114) or dynamic sentinel node biopsy (166). Median followup was 50 months. Tumor stage, grade, lympho-vascular invasion and age were considered. Kaplan-Meier plots illustrated 5-year inguinal relapse-free and cancer specific survival rates. Multivariable Cox regression models tested the treatment effect. Analyses were repeated after inverse probability of treatment weighting adjustment. RESULTS: The 5-year inguinal relapse-free survival and cancer specific survival rates following early, observation and dynamic sentinel node biopsy inguinal lymph-node dissection were 100%, 87%, 89%, and 84%, 81%, 85%, respectively. The 5-year crude inguinal relapse-free survival and cancer specific survival rates were 90% and 93% in low-risk patients undergoing observation. Clavien grade 3 complications were 0.6 vs 12.5% in the dynamic sentinel node biopsy and early inguinal lymph-node dissection group, respectively. After inverse probability after treatment weighting adjustment, 5-year inguinal relapse and cancer specific survival were 90% vs 73% and 90% vs 77% following dynamic sentinel node biopsy and observation, respectively. At multivariable Cox regression model, patients undergoing dynamic sentinel node biopsy had significantly lower inguinal relapse (HR 0.4, 95% CI 0.2-0.85, p 0.02) and cancer specific mortality (HR 0.29, 95% CI 0.11-0.77; p=0.01) compared to those under observation. The low number of patients undergoing early inguinal lymph-node dissection made a reliable comparison with this group impractical. CONCLUSIONS: Selective inguinal lymph-node dissection following dynamic sentinel node biopsy significantly improved inguinal relapse and cancer specific mortality when compared with observation, providing evidence of efficacy of dynamic sentinel node biopsy in clinical stage N0 squamous cell carcinoma of the penis.

Renal tumor biopsy was provided in patients candidate to radical nephrectomy for a renal mass ≥4 cm, to evaluate treatment deviation.Between 2008 and 2017, 102 patients with a solid renal mass ≥4 cm with no distant metastases underwent preliminary renal tumor biopsy. We investigated the proportion of patients who proceeded with radical nephrectomy, variables predicting non-renal cell carcinoma (RCC) and concordance between biopsy findings and definitive pathology.Median tumor size was 70 mm (IQR 55-110). Clinical stage was cT1b in 41, cT2 in 33, cT3 in 25 and cT4 in three patients. A median of three (IQR 2-3) renal tumor biopsies were taken with 16/18 Gauge needles in 97% of cases. Clavien grade I complications occurred in five cases. Malignant tumors were documented in 84 patients: 78 RCCs and six non-RCCs. Fifteen biopsies documented oncocytoma and three were non-diagnostic. Grade was reported in 50 RCCs: 42 (84%) were low and eight (16%) high grade. Eighty-three patients proceeded with radical nephrectomy; six non-RCC malignant tumors underwent combined and/or intensified treatment; 13 of 15 patients with oncocytoma did not undergo radical nephrectomy (eight underwent observation). Definitive pathology confirmed diagnosis in all cases. Grade concordance was 84%, considering two tiers (high vs low grade). No preoperative clinical variable predicted definitive pathology.Renal tumor biopsy is a safe procedure that leads to radical nephrectomy in most tumors ≥4 cm. Nonetheless, 20% of patients exhibited non-RCC histology. Renal tumor biopsy should be considered in this setting.

To support laparoscopic post-chemotherapy retroperitoneal lymph-node dissection (L-PC-RPLND) as a potential new standard, we report on a large dataset of patients systematically undergoing L-PC-RPLND.Patients with unilateral residual mass (≥1 cm), normalized markers, limited encasement (30%) of gross retroperitoneal vessels underwent unilateral L-PC-RPLND with no adjuvant chemotherapy. Surgical performances, histology, hospital stay, complications within 30 days and follow-up visits were recorded. Multivariable linear and logistic regression models were used.Between February 2011 and January 2021, 151 consecutive patients underwent L-PC-RPLND. Median size of the residual mass was 25 mm (interquartile range [IQR] 20-35 mm). Overall median operative time was 208 min (IQR 177-241) and was 51 min longer (p-value0.001) for right L-PC-RPLNDs. Eleven procedures were converted to open surgery. Median number of removed and positive nodes was 11 (IQR 8-16) and 1 (IQR 1-2), respectively. Mean hospital stay was 2 days (IQR 2-3). Nine complications (6%) occurred: two were Clavien-Dindo grade III. Definitive pathology revealed post-pubertal teratoma in 65.6%, fibro-necrotic tissue in 23.8%, teratoma with malignant somatic component in 6.6% and viable tumour in 4.0% patients. In multivariable linear regression models, fibro-necrotic tissue (32 min, CI 8.5-55.5; p 0.01) and residual volume (1.05 min, CI 0.24-1.85; p 0.01) achieved independent predictor status for longer operative time. All patients, but one, are alive and disease-free after a median follow-up of 22 months (IQR 10, 48).L-PC-RPLND, when adequately planned, is safe and effective for most patients with low to medium volume residual masses.

Introduction: Patients with stage II germ-cell tumours (GCT) usually undergo radiotherapy (seminoma only) or chemotherapy. Both strategies display a recognised risk of long-term side effects. We evaluated retroperitoneal lymph node dissection (RPLND) as exclusive treatment in stage II GCT. Methods: Between 2008 and 2019 included, 66 selected stage II GCT patients underwent primary open (O-) or laparoscopic (L-)RPLND. Type of procedure and extent of dissection, operative time, node rescue, hospital stay, complications (according to Clavien-Dindo), administration of chemotherapy, relapse and site of relapse were evaluated. Results: Five patients had pure testicular seminoma. Nineteen (28.8%) had raised markers prior to RPLND; 48 (72.7%), 16 (24.2%) and two (3.0%) were stage IIA, IIB and IIC, respectively. O-RPLND and unilateral L-RPLND were 36 and 30 respectively. Six stage II A patients (12.5%) had negative nodes. Four patients underwent immediate adjuvant chemotherapy. One patient was lost at follow-up. After a median follow-up of 29 months, 48 (77.4%) of the 62 patients undergoing RPLND alone remained recurrence-free; one patient had an in-field recurrence following a bilateral dissection. According to procedure, number of rescued nodes (O-RPLND: 25. IQR 21-31; L-RPLND: 20, IQR 15-26; p: 0.001), hospital stay (L-RPLND: 3 days, IQR 3-4; O-RPLND: 6 days, IQR 5-8; p: .001) and grade ≥2 complications (L-RPLND 7%, O-RPLND 22%; p: 0.1) were the only significant differences. Conclusion: Primary RPLND is safe in stage II GCT, including seminoma, and may warrant a cure rate greater than 70%. When feasible, L-RPLND may be as effective as O-RPLND with better tolerability.

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.

The administration of adjuvant chemotherapy for patients with penile squamous cell carcinoma (PSCC) with high-risk features is controversial. In 21 patients who had received adjuvant taxane, cisplatin, and 5-fluorouracil, the expression of p53 in the tumor-positive lymph nodes was the only factor that showed a trend toward poorer survival endpoints. If confirmed, these findings could help in selecting the best candidates for adjuvant chemotherapy. 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. (C) 2016 Elsevier Inc. All rights reserved.

Kaposi’s sarcoma (KS) is a rare tumor of vascular origin. It is quite common in HIV patients. It is rarely located on the glans penis, especially in HIV-negative patients (just some tens in the literature). Owing to the rarity of the disease, both the real impact on survival and the most suitable therapy are not known.However, in this 3-patient case series, carbon dioxide laser therapy was effective both for local control and survival. In fact, two late relapses but no disease-related death were recorded. Probably, KS in HIV-negative patients is a slowly progressive disease, not so aggressive as in HIV-positive patients. Laser therapy is easy, fast, and cheap, and may treat the disease radically.If these data are confirmed by further studies, in the foreseeable future, laser therapy may become the gold standard for treating HIV-negative patients affected by penile KS.

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 (1cm 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 27mm (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.

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 N2-3 or M1 (TNM 2009), and no prior chemotherapy administration. The primary endpoint was the objective response-rate (ORR, according to RECIST v1.1). 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 follow-up duration was 19.8 months (IQR: 6.3-25.7); 12-month progression-free survival was 26.2% (95%CI: 13.2-51.9); 12-month overall survival (OS) was 54.9% (95%CI: 36.4-82.8). The median OS of locally-advanced patients was 20 months (IQR: 11.1-not reached). The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in 3 patients (10.7%). Tissue samples from 25 patients were analyzed. Only two patients had HR-HPV-positive tumor. EGFR amplification was found in 4 patients (equally responders and non responders) and it was confirmed in all post-dacomitinib samples. TERT mutations (60%) were found in responders only, PI3K/mTOR pathway gene mutations in 42.9% responders versus 8.3% non responders. Conclusion Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combination chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signaling in relation to dacomitinib activity deserve further studies. This article is protected by copyright. All rights reserved.

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 400 mg 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.

Aims and Background To evaluate postoperative pain (PoP) and quality of life (QoL) in patients undergoing open (O-) or laparoscopic (L-) retroperitoneal lymph node dissection (RPLND) for clinical stage I (CS I) and normal markers CS IIA nonseminomatous germ cell tumors. Methods Since March 2010, a prospective nonrandomized trial evaluated dynamic and rest (R) numeric pain scale (NPS) following patient-controlled analgesia and baseline (T0), 3-month (T3), and 6-month (T6) QoL status assessed by Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire and the Italian-validated Functional Assessment of Chronic Illness Therapy (FACT-T-SG) at T6. Secondary endpoints included length of hospital stay (LHS), interval to recovery (ItR), complications, and oncologic outcomes. Results In March 2012, 69 (64 CS I) patients were enrolled. Five patients only chose O-RPLND. The PoP and complete QoL data are available in 41 and 56 patients, respectively. The R-NPS significantly improved in days 1-2 vs day 0 (pConclusions Almost all patients chose L-RPLND, which is associated with a rapid improvement of postoperative pain; QoL scores improved up to 6 months. The L-RPLND may be considered as an alternative only when performed in highly experienced centers.

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.

Primary epithelioid angiosarcoma of the adrenal gland is extremely rare. Only 37 cases have been reported in the scientific literature.Here we describe the case of a 55-year-old woman affected by metastatic angiosarcoma in the right adrenal gland, who died few days after the histological diagnosis made by fine-needle aspiration (FNA). This is the second case of primary epithelioid angiosarcoma diagnosed by FNA among scientific articles published in English in PubMed. Microscopically, the tumor showed a predominant epithelioid differentiation, thus making the diagnostic process more difficult than usual. Immunohistochemical examination revealed positive reactivity for cytokeratin, CD31, and CD34. The literature shows that epithelioid adrenal angiosarcoma has poor clinical outcome, especially when metastatic at presentation.

Objectives: To retrospectively analyze the efficacy and safety results of the combination of methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMACO) regimen for patients with human chorionic gonadotropin (HCG)-producing germ cell tumors and who had failed multiple courses of chemotherapy. Methods: Patients who had failed at least 2 regimens received methotrexate 100 mg/m(2), followed by methotrexate 200 mg/m(2) over 12 hours day 1, etoposide 100 mg/m(2) and dactinomycin 0.5 mg days 1 and 2, folinic acid 25 mg orally every 6 hours days 2 and 3, alternating with cyclophosphamide 600 mg/m(2) plus vincristine 1 mg/m(2) day 8, every 21 days. Treatment was continued until marker normalization and for additional 2 cycles. Response rate, progression-free (PFS), and overall survival (OS) were the efficacy endpoints. Cox regression analyses examined the prognostic impact of candidate factors on PFS and OS. Results: From February 92 to May 13, 41 patients were treated in third. line (n=20, 49%) or beyond (n=21, 51%). Seventeen (41%) had received high-dose chemotherapy. Thirty-one patients (75.6%) had a response with marker reduction, including 4 complete (9.8%) and 5 (12.2%) partial responses with HCG normalization. Median PFS was 3 months (95% confidence interval [CI], 2-4) and median OS was 8 months (95% CI, 6-10). Most frequent grade 3-4 toxicity was hematologic (20 patients, 48.8%). One toxic death (cerebral hemorrhage) occurred. On multivariable analysis, the line of treatment (greater than third vs. third) was the only significant predictor of both PFS (hazard ratio: 2.50, 95% CI, 1.20-5.24, P=0.015) and OS (hazard ratio: 3.17, 95% CI: 1.46-6.89, P=0.004). Conclusions: EMACO is an attractive regimen with acceptable toxicity and could be considered an option for HCG-expressing germ cell tumors whenever multiple relapses occur.

Purpose: CD30 is expressed by untreated embryonal carcinoma, supporting the rationale for a targeted approach. However, the reported chemotherapy induced switching off of CD30 noted on immunohistochemistry may affect its therapeutic potential for disease relapse. We evaluated persistent CD30 expression and its prognostic meaning in cases of post-chemotherapy residual disease. Materials and Methods: Paraffin blocks of surgical samples that yielded nonteratomatous viable cells after 1 or more cisplatin based chemotherapy treatments were retrieved and reassessed by 2 pathologists blinded to the study purpose. Multivariable analysis was done for prespecified factors. Results: A total of 49 cases of pure embryonal carcinoma or mixed germ cell tumor from August 1991 to August 2012 had full clinical data and suitable tissue available for analysis. Of the 35 cases (71.4%, 95% CI 56.7-83.4) with preserved CD30 positivity 14 (40.0%) showed residual disease after a median of 1 regimen (IQR 1-2). Five-year overall survival in CD30 positive and negative cases was 37.0% (95% CI 22.1-61.8) and 50.1% (95% CI 27.9-90.0, p 0.078), while after first line treatment it was 23.2% (95% CI 8.6-62.5) and 47.6% (95% CI 18.8-100, p - 0.025), respectively. On multivariable analysis CD30 positivity was a significant prognostic factor for progression-free survival (HR 2.32, 95% CI 1.04-5.19) and overall survival (HR 2.77, 95% CI 1.05-7.29). Conclusions: CD30 was retained even after an intensive pretreatment load, confirming that it is a reliable treatment target. Its expression was associated with a significantly poorer prognosis in multiple relapse/ chemoresistant cases and it was an independent prognostic factor for survival.

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.

We addressed the use of perioperative chemotherapy in nodal metastates from penile cancer. Forty-seven N2 to 3M0 patients received perioperative taxane, cisplatin and 5-fluorouracil (T-PF) and 38.3% are disease-free at 22 months. Neoadjuvant T-PF allowed 12 (43%) clinical responsesand4 (14%) complete pathologic remissions among 28 patients, and the 2-year disease-free survival (DFS) was 7.1%. The 2-year DFS was 36.8% after adjuvant T-PF. T-PF is active and is associated with long-term survival after surgery. Chemotherapy must be offered with caution in patients with resectable nodal metastases. Background: The role of chemotherapy in nodal metastases from penile squamous cell carcinoma is not defined. We evaluated the efficacy of a combination of T-PF(a taxane, cisplatin, and 5-fluorouracil) in neoadjuvant and adjuvant settings. Patients and Methods: Since June of 2004, T-PF was administered to stage N2 to 3 patients. With time, neoadjuvant chemotherapy administration prevailed with respect to use in the adjuvant setting. Primary end points were progression-free (PFS) and overall (OS) survival. Secondary objectives were tolerability and activity in the neoadjuvant setting. Nonparametric tests, Kaplan-Meier, and regression analyses were performed. Results: As of October of 2012, 47 consecutive N2 to 3 M0 patients had undergone neoadjuvant (n = 28) or adjuvant (n = 19) T-PF: 18 patients (38.3%) remain disease-free after a median follow-up of 22 months (interquartile range, 17-42 months). The 2-year disease- free survivals were 36.8% (95% confidence interval [CI], 15.2-58.5) versus 7.1% ( 95% CI, 0-16.7) after adjuvant and neoadjuvant therapy, respectively. N3 metastases were associated with a poorer PFS, and bilateral metastases and mutated p53 were associated with a poorer OS. After neoadjuvant treatment, 43% clinical responses and 14% complete pathologic remissions were recorded, but responses were not associated with survival. Neutropenia (25.5%) was the most frequent Grade >= 2 toxicity. Conclusion: The T-PF regimen is well tolerated and compares with other regimens in terms of activity and efficacy in the neoadjuvant setting, and very long survivals have been recorded after adjuvant administration. The role of perioperative treatment in these patients remains controversial. Some caution in administering preemptive treatment in patients with resectable disease is needed. (C) 2015 Elsevier Inc. All rights reserved.

Surgery in germ cell tumors of the testis (TGT) may result in andrological disorders, both after orchiectomy and after retroperitoneal lymphadenectomy (RPLND). Bilateral orchiectomy suppresses both testicular functions: exocrine and endocrine. In selected cases with bilateral TGT (metachronous/synchronous), or in the case of TGT in monorchid patients, partial orchiectomy (enucleation of the tumor) can preserve both functions with a low risk of relapse in residual testicular parenchyma, in the absence of intraepithelial neoplasia (TIN). In cases of TIN and normal testosterone levels (80%), the fertility is maintained in 50% of patients. In these cases the use of radiotherapy on the residual testicular parenchyma can prevent the future development of invasive cancer, though compromising the hormonal function. The RPLND (open or laparoscopic) can produce major side effects, such as retrograde ejaculation. Knowledge of the adrenergic fiber retroperitoneal neuroanatomy enables to implement a "nerve sparing" surgery with an almost total reduction of this serious side effect, but that option is only available in few centers of excellence. Semen cryopreservation has become a common practice performed before any treatment that might impact on the andrological function of patients.

The treatment of tumors of the testis represents an ideal model of care for cancer. Many different, intersecting strategies are available for managing germ-cell cancers, particularly in the early-stage disease. Which is ‘right’ remains a matter of debate, and requires balancing efficacy against late effects, bearing in mind the complexity of treatment strategies and the available expertise. The cornerstone of this model of success is linked to the quality and appropriateness of care. The current therapeutic strategy is very complex (Fig. 1). High-tech surgery, medical oncology and radiotherapy are involved at various levels of diagnostic techniques of the latest generation. The choice of therapy, alone or integrated, is often influenced by prognostic factors. In this article we will examine the important points and sometimes the subject of controversy in both diagnosis and treatment of these early-stage tumors (Clinical Stage I: disease confined to the testis; Clinical Stage IIA: retroperitoneal lymph nodes

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE • To investigate the optimal management and prognostic factors of patients with malignant transformation (MT) in germ-cell tumour (GCT) by re-evaluating Institutional series. PATIENTS AND METHODS • Patients with an MT within GCT have been identified from the institutional database and all slides have been reviewed by the referral pathologist. RESULTS • From June 1982 to October 2009, 48 patients and 13 somatic histologies have been identified. Twelve patients presented with stage I, 12 with stage II and 24 with stage III disease. All stage I patients are alive and disease-free after a median follow up of 88 months (interquartile range 38–103). • Of the 36 metastatic cases, 11 underwent GCT-oriented chemotherapy plus surgery and seven of them are currently disease-free. Three patients underwent MT-chemotherapy, one relapsed and is still under treatment. Overall, 17 patients relapsed (35%) and three of them have been rescued by GCT-chemotherapy. Five-year overall survival was 100% for stage I, 80% (95% CI 40–94) for stage II and 44% (95% CI 19–67) for stage III patients. Stage III disease at MT, incomplete surgical removal and primitive neuroectodermal tumours plus adenocarcinoma histologies were significant adverse prognostic factors for survival. CONCLUSIONS • New insights emerged into the impact of histology and chemotherapy on MT. The development of an adenocarcinoma component as well as the possible efficacy of a GCT-tailored chemotherapy in a multimodal strategy are addressed for the first time, while disease extent at transformation and extent of radical surgery are confirmed as significant prognosticators. • An international web database for registration of all cases of MT worldwide is presented.

564 Background: Despite the overall high cure-rate for patients (pts) with CSI seminoma (sem) regardless of the intervention used, huge discrepancy exists in the number of CT scans that are proposed to pts during FUP period, mainly during active surveillance (AS). The impact of such discrepancy in diagnosing pts with a high-risk relapse was assessed in published literature with a meta-analysis (MA). Methods: We searched for arms of studies of AS or active treatment (AT, adjuvant chemotherapy and radiotherapy) in pts with CSI sem. Meta-analytic techniques were used to pool and compare study level data of AS and AT groups and to study the impact of the number of CT scans (as a continuous variable) during FUP upon the % of pts with CSIII or with IGCCCG intermediate (int) prognosis sem at relapse. Results: 22 studies were analyzed (33 arms, n = 11025 pts). 39.6% had a high-risk sem, 38.8% (n = 4274) underwent AS vs 61.2% (n = 6751) AT. The number of CT scans ≤2y ranged 4-8, and 0-7 for AS and AT groups. Overall, 922 pts experienced a relapse (651 in AS and 271 in AT arms), 73.9%

90 Background: Prostate biopsy findings at diagnosis and follow-up are essential criteria in Active Surveillance (AS). In a previous work (Nicolai Eur Urol Suppl 2013) upgrading (UPG) and upsizing (UPS) at 1-yr rebiopsy resulted to be independent outcomes with different predictors. Aim of the present work is to validate these models on an independent population and to evaluate the probability of not-developing UPG, thus the chance of continuing AS Methods: Pts enrolled in 2011-2017 were considered for validation, while 318 AS pts enrolled in 2005-2011 were considered for model development. UPG model included: age (risk), PSA density (risk), prostate volume (>60 cc, protective); UPS model: age (protective), % core length containing cancer (>5%, risk), number of positive cores (>1, risk) Performance on the independent population was evaluated through AUC and calibration. Logistic model for not-developing UPG at 1 yr was fitted using all available AS pts Results: 433 pts were included in the validation set. UPG and UPS were registered in 43 and 29 pts, respectively; 38 pts had UPG+UPS. Predictors for UPG and UPS were mainly confirmed in the validation cohort (Table), with Odds Ratios (OR) very similar to the development model. Discrimination was confirmed (AUCs) and calibration was excellent (slope~1, R2>0.90). Probability of not-developing UPG (evaluated on 751 pts) was associated to age, prostate volume and PSA density (Table). Conclusions: UPG and UPS in AS pts should be considered as independent events and their management implying different strategies. Specifically, age, volume and PSA density play a key role in the chance to continue AS, i.e. in not developing UPG. A nomogram estimating the likelihood of continuing AS has been developed and will be presented. [Table: see text]

Objectives Approximately one-third of the metastatic germ cell tumors (GCT) in patients are classified as intermediate-risk metastatic GCT, and available guidelines recommend the same treatment of poor-risk cases. Yet the prognosis of these patients is heterogeneous, and consequently refining the intensity of treatment is warranted. We aimed to address the heterogeneity of this category by providing a proof of principle for reclassification attempt. Patients and methods Data on consecutive patients with intermediate-risk metastatic GCT and who received treatment at Fondazione INT Milano in the time frame between February 1980 and March 2014 were collected. Cox regression analyses were done, evaluating potential prognostic factors for overall survival (OS, primary end point) to first-line therapy. Each factor was evaluated in a multivariable model. Recursive partitioning was performed to define prognostic risk groups. Results A total of 224 patients were suitable for the present analysis. Median age was 26 years (interquartile range: 22–31), 11 patients (4.9%) had a retroperitoneal primary tumor, 6 yielded seminomatous histology, 85 (37.9%) had lung metastases, and 58 (25.9%) had bulky (i.e.,≥10 cm) retroperitoneal lymph nodes. Patients received cisplatin, bleomycin, and etoposide (PEB, n = 199) or vinblastine (PVB, n = 23); however, 2 patients received other treatments. Median follow-up was 135 months (interquartile range: 81–223). Globally, 5-year progression-free survival and OS rates were 72.8% (95% CI: 67.1–79.0) and 86.2% (81.7–91.0), respectively. In the multivariable model for OS, elevated alfa fetoprotein (AFP) level was the only significant prognostic factor (hazard ratio = 1.48, 95% CI: 1.12–1.96). The 2 separate prognostic groups with differential OS outcomes were identified based on the cutoff level of 6,200 IU/ml. The 10-year OS rate was 55.6% (95% CI: 36.6–84.3), and it was 86.7% (95% CI: 82.0–91.7) for those with AFP levels more than (n = 19, 8.5%) and less than (n = 205, 91.5%) the cutoff, respectively. Conclusions A small fraction of patients with highly elevated AFP levels have an OS approximating the poor prognostic category, whereas most of them are close to good-risk cases. This might have implications to select outlier patients for clinical trials and molecular characterization.

In this retrospective study, patients with poor-prognosis germ cell tumors (GCT) treated from a single referral center demonstrated high survival estimates that were stable through the years. Indeed, the major clinical implication is that using the available prognostic classification of metastatic GCT cannot allow the recognition of patients with a true chemoresistant disease. Moreover, the prognostic effect of treating patients with disseminated disease in referral centers should be further assessed. Background: Survival estimates with first-line treatment for patients with metastatic poor prognosis germ cell tumors (GCT) are still suboptimal in the literature. We conducted a retrospective study to evaluate the outcome of patients referred to our tertiary cancer center. Patients and Methods: A retrospective analysis was conducted on patients who received at least first-line chemotherapy at our center. Distribution of clinical characteristics was evaluated in the periods < 1997, 1997 to 2001, 2001 to 2006, and 2007 to 2013. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Univariable and multivariable Cox models with prespecified clinical variables were undertaken for PFS and OS. All tests and confidence intervals were 2-sided and set at a P = .05 level of significance. Results: Between 1982 and 2013, 168 patients were identified. The median age was 27 years (inter-quartile range [IQR], 22-34). The presence of liver, bone, or brain metastases trended to greater incidence from 1997 onward (27.5% < 1997 to 55.6% in 2007-2013; chi(2) P = .054). Median follow-up was 102 (IQR, 63-166) months. Global 5-year PFS was 48.5% (95% confidence interval [CI], 41.5-56.8) and OS was 63.2% (95% CI, 56.0-71.2). In multivariable analysis, treatment period was not significantly associated with either PFS (overall P = .229) or OS (overall P = .216). Conclusion: In this single-center series of consecutive poor prognosis GCT we could observe greater PFS and OS than the historical estimates. This observation was independent from the period of treatment. Based on the present results, studies focused on improving the outcome in the sole poor-risk cohort should be discouraged. Results were biased by their retrospective quality.

Background In the late 1990s, the use of high-dose chemotherapy (HDCT) and stem-cell rescue held promise for patients with advanced and poor prognosis germ-cell tumors (GCT). We started a randomized phase II trial to assess the efficacy of sequential HDCT compared with cisplatin, etoposide, and bleomycin (PEB). Patients and methods Patients were randomly assigned to receive four cycles of PEB every 3 weeks or two cycles of PEB followed by a high-dose sequence (HDS) comprising HD-cyclophosphamide (7.0 g/m2), 2 courses of cisplatin and HD-etoposide (2.4 g/m2) with stem-cell support, and a single course of HD-carboplatin [area under the curve (AUC) 27 mg/ml × min] with autologous stem-cell transplant. Postchemotherapy surgery was planned on responding residual disease in both arms. The primary end point was progression-free survival (PFS). The study was designed to detect a 30% improvement of 5-year PFS (from 40% to 70%), with 80% power and two-sided α at 5%. Results From December 1996 to March 2007, 85 patients were randomized: 43 in PEB and 42 in HDS arm. Median follow-up was 114.2 months [interquartile range (IQR): 87.7–165.8]. Complete or partial response with normal markers (PRm-) were obtained in 28 (65.1%) and 29 (69.1%) patients, respectively. Five-year PFS was 55.8% [95% confidence interval (CI) 42.8–72.8] and 54.8% (95% CI 41.6%–72.1%) in PEB and HDS arm, respectively (log-rank test P = 0.726). Five-year overall survival was 62.8% (95% CI 49.9–79.0) and 59.3% (95% CI 46.1–76.3). One toxic death (PEB arm) was recorded. Conclusions The study failed to meet the primary end point. Furthermore, survival estimates of conventional-dose chemotherapy higher than expected should be accounted for and will likely limit further improvements in the first-line setting. ClinicalTrials.gov NCT02161692.

OBJECTIVE To assess the clinical outcome of testicular sex cord stromal tumors (TSCST) according to management and stage. PATIENTS AND METHODS Clinical and pathologic features, stage, and treatment of patients with TSCST were retrieved from our database. The Kaplan-Meier method estimated the relapse-free survival and cancer-specific survival. RESULTS We identified 67 patients between December 1982 and January 2013: 55 patients (82.1%) had a Leydig cell tumor and 11 patients (16.4%) had a Sertoli cell tumor. Four patients (5.9%) presented with gynecomastia. Forty-eight patients (71.6%) had no pathologic risk factor, and patients 3 had >= 3 risk factors. Testis-sparing surgery was performed in 31 patients (46.3%) and orchiectomy in 36 patients (53.7%). The median tumor diameter was 0.7 cm (interquartile range, 0.6-1.3) and 1.5 cm (interquartile range, 0.9-2.6) in the 2 groups, respectively (P,.007 at Mann-Whitney rank-sum test). The 5-year relapse-free survival was 89.4% (95% confidence interval, 75.9%-95.5%) and cancer-specific survival was 90.3% (95% confidence interval, 72.7%-96.7%), respectively. Metastases were documented in 8 patients (11.9%), 5 relapsing after a median follow-up of 37.4 months. All 3 patients with >= 3 risk factors had metastatic disease. Four of 5 patients with retroperitoneal metastases only were cured by retroperitoneal lymph node dissection (3 patients at presentation and 1 during follow-up); 4 patients undergoing chemotherapy progressed and ultimately died of disease. CONCLUSION Most of the patients with TSCST had a favorable prognosis. Testis-sparing surgery may be feasible and effective in case of small tumors. Few patients had metastatic spread, but only those with nodal metastases may benefit from an early retroperitoneal lymph node dissection. Risk factors associate with disease behavior, but indications to prophylactic intervention remain controversial. (C) 2015 Elsevier Inc.