Search

OBJECTIVE: An increased cardiovascular mortality and morbidity has been widely reported in patients with atrial fibrillation (AF). In this study, a subanalysis of the AntiThrombotic Agents Atrial Fibrillation (ATA‐AF) is performed with the aim to evaluate estimated glomerular filtration rate (eGFR) as an independent prognostic marker of cardiovascular mortality and morbidity in patients with AF. METHODS AND RESULTS: The ATA‐AF study enrolled 7148 patients with AF, in 360 Italian centers. The eGFR was calculated from data reported in patient notes or hospital database. This post‐hoc analysis included 1097 AF patients with eGFR data available and 1‐year clinical follow‐up. The endpoint was assessed as cardiovascular mortality and/or hospital admission for cardiovascular causes at follow‐up. Patients were also divided in two groups according to the eGFR (

Patients with locally advanced penile squamous-cell carcinoma have a poor prognosis. No difference in survival was noted when using chemotherapy before or after surgery. Uncertainties persist regarding the optimal management of these patients, and new treatments are urgently required, particularly for patients at highest risk, with bilateral and/or pelvic lymph node involvement. 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.

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.

Simple Summary Active surveillance (AS) has evolved as an alternative to radical treatment for potentially indolent prostate cancer. However, current selection criteria for entering AS are suboptimal, and a significant percentage of patients discontinue AS because of disease reclassification. Hence, there is an unmet need for novel biomarkers for the accurate identification of high-risk PCa and the unequivocal classification of indolent disease. Circulating biomarkers, including microRNAs identified through liquid biopsies, represent a valuable approach to improve on currently available clinicopathological risk-stratification tools. In an attempt to identify specific microRNA signatures as potential circulating biomarkers, the authors performed an unprecedented analysis of the global microRNA profile in plasma samples from AS patients and identified and validated a three-microRNA signature able to predict patient reclassification. The addition of the three-microRNA signature was able to improve the performance of currently available clinicopathological variables, thus showing potential for the refinement of AS patients’ selection. Abstract Active surveillance (AS) has evolved as a strategy alternative to radical treatments for very low risk and low-risk prostate cancer (PCa). However, current criteria for selecting AS patients are still suboptimal. Here, we performed an unprecedented analysis of the circulating miRNome to investigate whether specific miRNAs associated with disease reclassification can provide risk refinement to standard clinicopathological features for improving patient selection. The global miRNA expression profiles were assessed in plasma samples prospectively collected at baseline from 386 patients on AS included in three independent mono-institutional cohorts (training, testing and validation sets). A three-miRNA signature (miR-511-5p, miR-598-3p and miR-199a-5p) was found to predict reclassification in all patient cohorts (training set: AUC 0.74, 95% CI 0.60–0.87, testing set: AUC 0.65, 95% CI 0.51–0.80, validation set: AUC 0.68, 95% CI 0.56–0.80). Importantly, the addition of the three-miRNA signature improved the performance of the clinical model including clinicopathological variables only (AUC 0.70, 95% CI 0.61–0.78 vs. 0.76, 95% CI 0.68–0.84). Overall, we trained, tested and validated a three-miRNA signature which, combined with selected clinicopathological variables, may represent a promising biomarker to improve on currently available clinicopathological risk stratification tools for a better selection of truly indolent PCa patients suitable for AS.

Age-related macular degeneration (AMD) is a common disease with a multifactorial aetiology, still lacking effective and curative therapies. Among the early events triggering AMD is the deterioration of the retinal pigment epithelium (RPE), whose fundamental functions assure good health of the retina. RPE is physiologically exposed to high levels of oxidative stress during its lifespan; thus, the integrity and well-functioning of its antioxidant systems are crucial to maintain RPE homeostasis. Among these defensive systems, the Nrf2-pathway plays a primary role. Literature evidence suggests that, in aged and especially in AMD RPE, there is an imbalance between the increased pro-oxidant stress, and the impaired endogenous detoxifying systems, finally reverberating on RPE functions and survival. In this in vitro study on wild type (WT) and Nrf2-silenced (siNrf2) ARPE-19 cells exposed to various AMD-related noxae (H2O2, 4-HNE, MG132 + Bafilomycin), we show that the Nrf2-pathway activation is a physiological protective stress response, leading downstream to an up-regulation of the Nrf2-targets HO1 and p62, and that a Nrf2 impairment predisposes the cells to a higher vulnerability to stress. In search of new pharmacologically active compounds potentially useful for AMD, four nature-inspired hybrids (NIH) were individually characterized as Nrf2 activators, and their pharmacological activity was investigated in ARPE-19 cells. The Nrf2 activator dimethyl-fumarate (DMF; 10 μM) was used as a positive control. Three out of the four tested NIH (5 μM) display both direct and indirect antioxidant properties, in addition to cytoprotective effects in ARPE-19 cells under pro-oxidant stimuli. The observed pro-survival effects require the presence of Nrf2, with the exception of the lead compound NIH1, able to exert a still significant, albeit lower, protection even in siNrf2 cells, supporting the concept of the existence of both Nrf2-dependent and independent pathways mediating pro-survival effects. In conclusion, by using some pharmacological tools as well as a reference compound, we dissected the role of the Nrf2-pathway in ARPE-19 stress response, suggesting that the Nrf2 induction represents an efficient defensive strategy to prevent the stress-induced damage.

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.

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

Background In head and neck cancer, the presence of extranodal extension (ENE) in lymph nodes (LNs) has been shown prospectively to require adding chemotherapy to postoperative radiation therapy (RT). Limited data exist regarding ENE in LNs from primary penile cancer (PeCa). Objective To determine the association of RT and ENE in PeCa. Design, setting, and participants We retrospectively analyzed the outcomes of 93 patients with pT1–4 N3 M0 (American Joint Committee on Cancer 7th edition) squamous cell carcinoma of the penis across four international centers. Intervention If the inguinal nodal specimen had ENE or two or more positive inguinal LNs, RT was delivered to an ipsilateral inguinal field. An ipsilateral pelvic field was added for positive pelvic LNs on dissection. The delivered dose was usually 50 Gy in 25 daily fractions. Outcome measurements and statistical analysis Clinical and demographic characteristics of relapse-free (RFS), disease-specific (DSS), and overall (OS) survival were compared by ENE status and receipt of adjuvant RT. Results and limitations Seventy-two percent of patients had inguinal ENE, and 49% had pelvic ENE. On multivariable analysis (MVA) of ENE-negative patients, an OS benefit was noted with postoperative chemotherapy (p = 0.038) and inguinopelvic RT (p = 0.037). RFS suffered with worsening grade of the lesion (moderately: p = 0.027; poorly: p = 0.038), but was improved with groin (p = 0.016) and inguinopelvic (p = 0.006) RT. On MVA of patients with ENE, inguinopelvic RT was associated with better DSS (p = 0.041). Grade impacted DSS (moderately: p = 0.043; poorly: p = 0.033), and poorly differentiated lesions impacted RFS (p = 0.013). Conclusions Inguinopelvic RT may benefit regional control in PeCa patients with positive pelvic LNs, but this appears to be limited to those without ENE. Patient summary For patients with penile cancer and positive pelvic lymph nodes, postoperative radiation therapy was found to decrease the likelihood of disease recurrence in the groin or pelvis only if extranodal extension was absent.

To improve the prognostic allocation of patients with penile squamous-cell carcinoma (PSCC) receiving regional lymph node dissection (LND).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.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 (P0.001), the pathologically involved/total removed LN ratio (P0.001), pN stage (overall P0.001), 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.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.

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.

Autoimmune diseases are a family of more than 80 chronic, and often disabling, illnesses that develop when underlying defects in the immune system lead the body to attack its own organs, tissues, and cells. Diagnosis of autoimmune pathologies is based on research and identification of antinuclear antibodies (ANA) through indirect immunofluorescence (IIF) method and is performed by analyzing patterns and fluorescence intensity. We propose here a method to automatically classify the centromere pattern based on the grouping of centromeres on the cells through a clustering K-means algorithm. The described method was tested on a public database (MIVIA). The results of the test showed an Accuracy equal to (92.0 ± 1.0)%. Comparing our results with the results obtained on the MIVIA database it is possible to note that our method has a performance comparable with the three best values obtained. Indeed, the method here proposed allows an automatic segmentation and counting of the cells in the images, while the participants to the contest received the training set with the original images of the cells already segmented by specialists.

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.

International audience; Antinuclear antibodies (ANAs) are significant biomarkers in the diagnosis of autoimmune diseases in humans, done by mean of Indirect ImmunoFluorescence (IIF) method, and performed by analyzing patterns and fluorescence intensity. This paper introduces the AIDA Project (autoimmunity: diagnosis assisted by computer) developed in the framework of an Italy-Tunisia cross-border cooperation and its preliminary results. A database of interpreted IIF images is being collected through the exchange of images and double reporting and a Gold Standard database, containing around 1000 double reported images, has been settled. The Gold Standard database is used for optimization of a CAD(Computer Aided Detection) solution and for the assessment of its added value, in order to be applied along with an Immunologist as a second Reader in detection of autoantibodies. This CAD system is able to identify on IIF images the fluorescence intensity and the fluorescence pattern. Preliminary results show that CAD, used as second Reader, appeared to perform better than Junior Immunologists and hence may significantly improve their efficacy; compared with two Junior Immunologists, the CAD system showed higher Intensity Accuracy (85,5% versus 66,0% and 66,0%), higher Patterns Accuracy (79,3% versus 48,0% and 66,2%), and higher Mean Class Accuracy (79,4% versus 56,7% and 64.2%).

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.

BACKGROUND: Outcomes of radiotherapy (RT) compared with chemotherapy (CT) remain poorly defined for clinical stage (CS) IIA and IIB seminoma. We aimed to evaluate the current role of the two treatment modalities in this setting of testicular seminoma. PATIENTS AND METHODS: A systematic review and meta-analysis (MA) was carried out to identify all evaluable studies. Search was limited to studies published after 1990 and included the Medline, Embase databases, and abstracts from ASCO (GU), ESMO, AUA, and ASTRO meetings up to April 2014. Sensitivity analyses were applied including the following: CSIIA and CSIIB, paraortic + iliac RT only in both stages, RT dose (≥30 versus

MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) chemotherapy (classic or dose-dense) is one of the current choices of therapy for locally advanced and metastatic urothelial cancer. The poor safety profile and not significantly greater efficacy as compared with cisplatin/gemcitabine are major issues. The authors analyzed the outcomes of a series of modified MVAC schedules in these patients, all treated at their center over a 26-year period. A fairly good tolerability, coupled with efficacy seemingly equal to that of the original MVAC, was obtained. Background: The classic MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) regimen was the first recognized option for untreated patients with locally advanced or metastatic urothelial cancer (UC). Modifying MVAC by reducing side effects may have the potential to improve efficacy. Patients and Methods: Changes to classic MVAC were provided at the authors' institution: (1) deletion of day 22 and administration of 25 mg/m(2) cisplatin on days 2 to 5 (modified [m] MVAC); (2) deletion of day 22 only (simplified [s] MVAC1); and (3) deletion of days 15 and 22 in a 3-week schedule (sMVAC2). A total of 4 to 6 cycles were provided. Multivariate analysis was undertaken for recognized clinical variables. Results: For the period from September 1986 to May 2012, 157 patients were identified (25 with mMVAC, 72 with sMVAC1, and 60 with sMVAC2). Overall, 43.9% had a Memorial Sloan-Kettering Cancer Center score of 1 or 2, with differences across series (P = .002). Altogether, 65.8% attained a complete (19.1%) or partial response (46.7%), and 24.3% a stable disease, with no difference across regimens. After a median follow-up of 87 months (interquartile range, 37-161), median progression-free survival was 10.2 months (95% CI, 8.4-10.8), and median overall survival (OS) was 19.5 months (95% CI, 16.3-24.1). Responses were mainly seen in nodal metastases or soft tissue relapse (odds ratio, 2.48; 95% CI, 1.12-5.54). Only visceral (hazard ratio [HR], 2.42; 95% CI, 1.37-4.30) and nodal metastases/local relapse (HR, 1.70; 95% CI, 1.07-2.69) were independently associated with OS. Grade 3 or 4 toxicities were similar across regimens and were 36% neutropenia, 14% thrombocytopenia, 12% anemia, 10% mucositis, and 4% renal toxicity. Two treatment-related deaths occurred. Conclusion: Simplifying MVAC may result in improved efficacy and reduced toxicity. The combined results of the original and modified MVAC regimens encourage a reappraisal of the frontline management of advanced UC.

Fluorine-18 fluorodeoxyglucose positron emission tomography is increasingly used by many centers for staging and response assessment of metastatic transitional cell carcinoma. We prospectively evaluated 31 patients undergoing metabolic restaging after only 2 cycles of first-line chemotherapy (PET2). Early metabolic response was associated with patient outcome. The aim was to provide a proof of principle for a risk-adapted approach based on PET2 that may guide new trial design for early-recognized unresponsive patients. Background: The prognostic impact of early metabolic response by fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) after 2 cycles of first-line chemotherapy is still unrecognized in metastatic transitional cell carcinoma (TCC). Patients and Methods: Patients with metastatic TCC receiving the modified combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), according to institutional protocol, underwent computed tomography (CT) and FDG-PET imaging at baseline, a restaging with PET imaging after 2 cycles only (PET2), and a CT (+/- FDG-PET) scan at the end of treatment and during follow-up. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method; univariate (UVA) and multivariate (MVA) Cox models were fitted. Prespecified variables were the presence of visceral metastases, nodal or soft tissue disease, and early PET response. Results: In the period from May 2010 to October 2012, 31 patients with Eastern Cooperative Oncology Group performance status 0 received the modified MVAC regimen every 3 weeks. In all, 6 patients (19.3%) had a complete response (CR) and 17 (54.8%) a partial metabolic response (PR), 4 had stable disease (SD), and 4 progressed. PET2 responders had a median PFS of 8 months (95 % CI, 7-11 mo) compared with 3 months (95 % CI, 2-5 mo) of patients without response (P = .024). They also had a significant benefit in 8-month PFS (P < .001 via Klein test) and 15-month OS (P = .016). PET2 response was significant for PFS in both UVA and MVA Cox models (P = .027 and P = .023, respectively). Conclusion: PET response after 2 cycles of first-line chemotherapy, compared with detection by early CT, was associated with longer PFS and OS in advanced TCC and warrants further investigation in the field. (C) 2014 Elsevier Inc. All rights reserved.

Purpose: We determined predictors of pelvic lymph node metastases in patients with penile cancer. Materials and Methods: We retrieved a total of 188 node positive inguinal groins from 142 patients treated for penile cancer. Logistic regression models were fitted to test for predictors of pelvic lymph node metastases. The minimum p value method was used to determine the most significant cutoff values of each predictor. Results: Pelvic lymph node metastases were observed in 45 cases (31.7%). The 5-year cancer specific survival rate was 71.0% vs 33.2% in patients with inguinal vs pelvic lymph node metastases. The most significant cutoff values were 3 inguinal lymph node metastases and a metastasis diameter of 30 mm. According to univariable logistic regression models the number of inguinal metastases (OR 1.92, p

Objective To evaluate the association between lymph node ratio (LNR) and cancer-specific survival (CSS) in a population of patients with penile cancer and lymph node metastases (LNM). Patients and Methods We evaluated 81 patients with pathologically determined LNM who were surgically treated at our institution between 2000 and 2012. We considered LNR both as a continuously coded and as a categorically coded variable. The minimum-P-value approach was used to determine the most significant LNR threshold. The Kaplan–Meier method was used to determine CSS rates, and univariable and multivariable Cox regression models were fitted to test the predictors of CSS. Results The median (interquartile range [IQR]) numbers of positive and removed lymph nodes were 2 (1–4) and 22 (13–30), respectively. The median (IQR) LNR was 10.3 (6.3–16.6)% and the most significant LNR threshold was 22%. The median (IQR) follow-up was 26 (16–62) months. Overall, the 5-year CSS rate was 50.5%. After stratification according to LNR, 5-year CSS rates were 65.2% vs 9.6% in patients with LNR < 22% vs LNR ≥ 22%, respectively (P < 0.001). In multivariable Cox regression models, after adjusting for several established prognostic factors, LNR was as independent predictor of CSS (P≤0.012). Finally, LNR significantly improved the accuracy of multivariable Cox regression models by 4.9–10.5%. Conclusions Although further investigations are needed to evaluate the relationship between tumour burden and treatment intensity, LNR may represent a powerful predictor of CSS in patients with penile cancer and pathologically determined LNM.

A low but invariable proportion of patients with advanced germ cell tumors still fail to be cured by first-line chemotherapy, and the number of life years lost is one of the highest among solid tumors. For patients with chemoresistant disease, the readministration of cisplatin, combined with paclitaxel and gemcitabine (TPG), was tolerable and provided long-term remissions in otherwise incurable patients. Background: Rescue of patients who fail to be cured after 2 or 3 chemotherapy combinations (including high-dose chemotherapy [HDCT]) or whose disease is refractory to cisplatin is still an unmet need. We assessed the efficacy of a triple-combination chemotherapy in the salvage setting, beyond second-line regimens. Patients and Methods: We retrospectively reviewed institutional data on consecutive patients who received paclitaxel 80 mg/m(2) intravenously (IV), cisplatin 50 mg/m(2) IV, and gemcitabine 800 mg/m(2) IV on days 1 and 8 every 3 weeks for a maximum of 8 administrations, followed by surgery. Response, survival (progression-free survival [PFS] and overall survival [OS]), and safety/toxicity outcomes were the end points. The Kaplan-Meier method was used for survival estimates, and multiple Cox regression models were used to analyze the prognostic factors. Results: Seventy-five patients were treated from April 1999 to July 2011. Eight complete responses (CR, 10.7%), 29 partial responses with normal markers (PRm(-), 38.7%), and 13 cases of incomplete response/stable disease were recorded, for a major response rate (CR + PRm(-)) of 49%. Thirty-three patients (44%) underwent surgery, which was radical in 14 cases (42.4%). Two-year PFS was 14.8% (95% confidence interval [CI], 8.5%-25.8%), whereas 2-year OS was 29.5% (95% CI, 20.3%-42.7%). Five-year OS in disease-free patients (no evidence of disease) was 60.3% (95% CI, 42.2%-86.2%), and median OS between patients with and without evidence of disease was significantly different (71 [interquartile range {IQR}, 14-116] vs. 12.5 [IQR, 8-19] months with a 6-month landmark analysis; P=.0019). Conclusion: TPG is an effective combination, and best results were achieved if a radical clearance of residual disease could be accomplished. A randomized comparison with dose-intensified regimens is advisable. (C) 2014 Elsevier Inc. All rights reserved.

Background: Since 1985, we introduced a modified combination of etoposide, ifosfamide, and cisplatin (PEI) as second-line therapy of adult male germ cell tumors with the aim to reduce toxic effect while maintaining efficacy over the original regimen. Patients and Methods: Patients received four cycles of ifosfamide at 2.5 g/m 2 on days 1–2, etoposide, and cisplatin at 100 and 33 mg/m 2 , respectively, on days 3–5 every 21 days, followed by surgery. Results were stratified according to the International Germ Cell Consensus Classification Group-2 (IGCCCG-2). Results: From February 1985 to January 2012, 189 patients were treated. 72.6% were IGCCCG-2 intermediate-to-very high risk. Thirty-five patients (18.5%) had a complete response, 67 (35.4%) a marker normalization (PRm�). Median follow-up was 122.1 months (inter-quartile range [IQR]: 71.4–232.0). Two-year progression-free and 5-year overall survival were 34.3% [95% confidence interval (CI) 28.1% to 41.9%] and 42.1% (95% CI 35.3% to 50.2%), respectively. Survival estimates compared favorably with those obtained by conventional dose chemotherapy (CDCT) regimens in each prognostic category. 70.4% of grade 3–4 neutropenia (25.5% febrile neutropenia), 48.1% thrombocytopenia, 21.2% anemia, 3.2% neurotoxic effect, and no severe renal toxic effect were recorded. Conclusion: Dose-modified Italian PEI should be considered as an appropriate benchmark for CDCT in the first salvage

Purpose: We reviewed the slides of patients with clinical stage I nonseminomatous germ cell testicular tumors who underwent retroperitoneal lymph node dissection to evaluate the concordance between original and reviewed vascular invasion status, and other histological correlates. Materials and Methods: Between 2002 and 2007 at our institution 202 consecutive patients underwent retroperitoneal lymph node dissection. We requested the slides of 183 patients who underwent orchiectomy elsewhere. The risk of nodal metastasis was considered high in those with vascular invasion and/or greater than 90% embryonal carcinoma, and low in those with no vascular invasion and embryonal carcinoma less than 90%. Using Cohen's kappa we assessed the concordance index between original and reviewed parameters (vascular invasion and risk category). Using the chi-square test we also evaluated the association between nodal status at retroperitoneal lymph node dissection and original vs reviewed parameters. Results: The original report did not contain vascular invasion information on 98 of 183 cases (53.4%). A total of 164 patients were evaluable since we had no slides for 19. Vascular invasion absence and presence were confirmed in 27 (73.0%) and 30 (78.9%) of 37 patients, respectively (Cohen's kappa = 0.16). Low and high risk status was confirmed in 20 of 28 patients (71.4%) and in 47 of 64 (50.6%), respectively (Cohen's kappa = 0.22). Reviewed vascular invasion and risk category were significantly associated with nodal status at retroperitoneal lymph node dissection (chi-square test p = 0.03 and 0.01, respectively), although the original parameters were not. Conclusions: In half of the patients no information was available on vascular invasion in the original reports. Concordance between original and reviewed reports was generally poor. Reviewed parameters better predicted nodal status at retroperitoneal lymph node dissection. These findings may have important implications in clinical practice.

Background: The best management for patients with clinical stage I (CS1) nonseminomatous germ cell tumours (NSGCT) is still under debate. Objective: We evaluated the long-term oncologic outcome of retroperitoneal lymph node dissection (RPLND) in patients with CS1 NSGCTs and reevaluated the traditional predictors of recurrence in a set of patients not undergoing adjuvant treatment. Design, setting, and participants: Between 1985 and 1995, 322 consecutive CS1 NSGCT patients underwent primary RPLND not followed by adjuvant chemotherapy in a single referral centre. Patients were followed until relapse for a median time of 17 yr. Measurements: We estimated the crude cumulative incidence of any recurrence. Categories pN and pT, vascular invasion (VI), percentage of embryonal carcinoma, and presence of teratoma were evaluated as 2-yr recurrence predictors of event in a binary logistic model. Results and limitations: Fifty patients had a recurrence (46 in 2 yr). The 10-yr recurrence incidence was 15.2%. Significant predictors of recurrence at multivariable analysis were pN+, pT > 1, and the presence of VI. However, the discriminative ability of the model was modest (Harrell C = 0.74); only 9% and 3% of patients had a predicted recurrence probability > 30% and > 50%, respectively. Conclusions: RPLND alone could prevent recurrence in 85% of patients and minimise late relapses to 1.2%. Most patients could avoid the immediate and late toxicity of chemotherapy. Prognostic parameters combined into the multivariable model appeared of limited use in identifying a subset of patients at high risk of recurrence. (C) 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.

We conducted an analysis of immunohistochemical expression of multiple biomarkers in patients with metastatic (M) urothelial carcinoma (UC), including their prognostic effect in the setting of first-line chemotherapy. Expression of vascular endothelial growth factor receptor (VEGFR)-3 and platelet-derived growth factor receptor (PDGFR)-alpha were associated with a divergent prognostic meaning. Present data do not support the use of immunohistochemistry (IHC) to select patients for clinical trials and highlight the hurdles of targeting angiogenesis in this field. Background: Knowledge of the expression of molecular drivers and potentially druggable targets might enhance prognostic classification of M UC. Materials and Methods: We analyzed archival tissue from patients with UC who underwent first-line chemotherapy for locally advanced (LA) and M disease between the years 2000 and 2013. The following biomarkers were evaluated using IHC: excision repair cross complementation (ERCC) group 1 (ERCC1), epidermal growth factor receptor (EGFR), HER2, VEGFR-3, PDGFR alpha, p53, and p63. Expression of ERCC1, EGFR, and HER2 was dichotomized as positive (2+, 3+) or negative (

There is no clear indication for postchemotherapy surgery in patients with metastatic urothelial cancer (UC). We analyzed the contribution of postchemotherapy lymphadenectomy on survival in patients treated at our center. Twenty-eight patients were identified and results compared with those of a nonsurgically treated cohort. Surgery and response to chemotherapy were prognostic for progression-free (PFS) and overall survival (OS). If confirmed, results might have implications in daily practice and clinical trials. Background: The contribution of postchemotherapy pelvic (PLND) or retroperitoneal lymphadenectomy (RPLND) on survival in patients with advanced and metastatic UC is still unclear. Patients and Methods: Between September 1986 and May 2012, 157 patients with locally advanced or metastatic UC received first-line chemotherapy consisting of mMVAC (modified methotrexate, vinblastine, doxorubicin, and cisplatin), according to our policy. Patients with subdiaphragmatic nodal disease and/or local recurrence only and who experienced at least stable disease (SD) were selected. Fifty-nine patients were identified, 28 of whom underwent surgery, 31 started consolidation chemotherapy with or without radiotherapy or observation. The prognostic effect of candidate factors on survival was evaluated using Cox proportional hazard regression models. Results: A total of 14 PLND and 14 RPLND patients were identified after they had achieved a complete response (CR; n = 7) or a partial response (PR) and SD (n = 21). Median follow-up was 88 months (interquartile range, 24-211 months). Median PFS was 18 (95% confidence interval [CI], 11-not estimated) and 11 (95% CI, 5-19) months, respectively, in favor of the surgical cohort and curves were statistically different (log-rank test, P = .009). In multivariate analysis, postchemotherapy surgery was significantly prognostic for PFS and OS and response to chemotherapy (PR and SD vs. CR) was prognostic for PFS and trended to significance for OS. A model including these 2 factors showed bootstrap-corrected Harrel C statistics for PFS and OS of 0.65 and 0.68, respectively. Conclusion: In well selected patients with UC like those who achieved a clinical benefit with chemotherapy and had nodal metastatic disease, there was a survival advantage in removal of disease residuals.

Primary mediastinal nonseminomatous germ cell tumors comprise a heterogeneous series of neoplasms characterized by limited chemosensitivity and a poor prognosis. We analyzed a large series of patients from our tertiary cancer center, including pre- and postsurgical variables, with the aim to provide a prognostic model that might be suitable for clinical use. The variables identified in the prognostic model were surgical removal of residuals after first-line chemotherapy, histological response, and the presence of lung metastases. Their joint analysis defined distinct overall survival (OS) curves. Background: Primary mediastinal germ cell tumors (PMGCTs) poorly benefit from chemotherapy and half of patients die because of disease progression. Enhancing the risk stratification might result in tailoring a more personalized treatment strategy from the time of diagnosis. Patients and Methods: Between the years 1985 and 2012, 86 patients with PMGCT were treated at our center. Cox proportional hazards regression analysis was conducted in the population of nonseminomas to examine the prognostic effect of candidate factors on progression-free and OS. OS curves were compared using the Kaplan-Meier method and the log-rank test. Results: Mean age was 29.8 years (range, 15-63 years). Twenty-five patients (29.1%) had lung and 8 (9.3%) liver, bone, or brain metastases. Twelve patients (13.9%) received upfront high-dose chemotherapy and 45 patients (52.3%) underwent surgery after chemotherapy. Cox analyses included 61 evaluable primary mediastinal nonseminomatous germ cell tumors (PMNSGCTs). The final model of factors indicating a poor prognosis included the combination of surgery and histological response (overall P = .011) and lung metastases (hazard ratio, 3.03; 95% confidence interval, 1.12-8.15; P = .028). The model showed a bootstrap-corrected Harrel c-statistic for OS of 0.66. A risk stratification model based on the combination of these factors and accounting for a 50% 5-year survival cutoff identified 2 groups (poor prognosis, n = 33 vs. good prognosis, n = 28) with distinct OS curves (P < .001). Preoperative serum tumor marker level was not associated with the final histology (P = .853, chi(2) test). Results were limited by small numbers. Conclusion: Patients with PMNSGCT included 2 subpopulations with distinct prognosis, and therapeutic improvements are needed for patients with poor-risk features.

We evaluated the changes in regional coronary hemodynamics induced by diltiazem, 0.25 mg/kg intravenously, in nine patients with 75% to 90% diameter stenosis of the left anterior descending coronary artery (LAD) (group 1) and in 10 patients with 100% occlusion of the LAD and collaterals to the distal LAD (group 2). Although diltiazem induced similar changes in systemic hemodynamics in the two groups, a decrease in anterior coronary vascular resistance (ACVR) and an increase in great cardiac vein flow (GCVF) were observed after administration of diltiazem in all patients in group 1 but in only 6 of 10 patients in group 2 (subgroup 2B). ACVR increased and GCVF decreased after administration of diltiazem in 4 of 10 patients in group 2 (subgroup 2A). Clinico-angiographic characteristics, origin of collaterals, and diltiazem-induced changes in systemic hemodynamics were similar in subgroups 2A and 2B. Thus diltiazem increases coronary flow distal to a stenotic coronary artery but can decrease regional coronary flow and increase regional coronary resistance in a minority of patients with an occluded coronary artery supplied by collaterals, probably through a steal mechanism.