USP44 Promoter Methylation in Plasma Cell-Free DNA in Prostate Cancer.

Liquid biopsy provides real-time monitoring of tumor evolution and response to therapy through analysis of circulating tumor cells (CTCs) and plasma-circulating tumor DNA (ctDNA). USP44 is a critical gene which plays an important role in cell proliferation; however, its accurate role in other cellular networks is under research. USP44 promoter methylation has been so far reported in colorectal neoplasia and metastatic breast cancer. In this study, we examined for the first time USP44 promoter methylation in plasma cell-free DNA (cfDNA) of patients with prostate cancer (early stage n = 32, metastatic n = 39) and 10 healthy donors (HD). USP44 promoter methylation was detected in plasma cell-free DNA by a newly developed highly specific and sensitive real-time MSP method. Our findings indicate that USP44 promoter is methylated in plasma cell-free DNA of metastatic prostate cancer patients and that detection of USP44 promoter methylation is significantly associated with overall survival (OS) (p = 0.008). We report for the first time that detection of USP44 promoter methylation in plasma cell free DNA provides significant prognostic information in metastatic prostate cancer.

Multiparametric Magnetic Resonance Imaging of the Prostate for Tumour Detection and Local Staging: Imaging in 1.5T and Histopathologic Correlation.

PURPOSE: The study sought to prospectively evaluate which technique among T2-weighted images, dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), diffusion-weighted (DW) MRI, or a combination of the 2, is best suited for prostate cancer detection and local staging. METHODS: Twenty-seven consecutive patients with biopsy-proven adenocarcinoma of the prostate underwent MRI on a 1.5T scanner with a surface phased-array coil prior radical prostatectomy. Combined anatomical and functional imaging was performed with the use of T2-weighted sequences, DCE MRI, and DW MRI. We compared the imaging results with whole mount histopathology. RESULTS: For the multiparametric approach, significantly higher sensitivity values, that is, 53% (95% confidence interval [CI]: 41.0-64.1) were obtained as compared with each modality alone or any combination of the 3 modalities (P < .05). The specificity for this multiparametric approach, being 90.3% (95% CI: 86.3-93.3) was not significantly higher (P < .05) as compared with the values of the combination of T2+DCE MRI, DW+DCE MRI, or DCE MRI alone. Among the 3 techniques, DCE had the best performance for tumour detection in both the peripheral and the transition zone. High negative predictive value rates (>86%) were obtained for both tumour detection and local staging. CONCLUSIONS: The combination of T2-weighted sequences, DCE MRI, and DW MRI yields higher diagnostic performance for tumour detection and local staging than can any of these techniques alone or even any combination of them.

Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Tasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit. PATIENTS AND METHODS: Men with chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point. RESULTS: In all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) between March 2011 and December 2012 at 241 sites in 37 countries. Baseline characteristics were balanced between groups: median age, 71 years; Karnofsky performance status ≥ 90%, 77.3%; and visceral metastases, 21.1%. Estimated median rPFS by central review was 7.0 months (95% CI, 5.8 to 8.2 months) with tasquinimod and 4.4 months (95% CI, 3.5 to 5.5 months) with placebo (HR, 0.64; 95% CI, 0.54 to 0.75; P < .001). Median OS was 21.3 months (95% CI, 19.5 to 23.0 months) with tasquinimod and 24.0 months (95% CI, 21.4 to 26.9 months) with placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). Grade ≥ 3 adverse events were more frequent with tasquinimod (42.8% v 33.6%), the most common being anemia, fatigue, and cancer pain. CONCLUSION: In chemotherapy-naïve men with mCRPC, tasquinimod significantly improved rPFS compared with placebo. However, no OS benefit was observed.

A pilot study in prostate cancer patients treated with the AE37 Ii-key-HER-2/neu polypeptide vaccine suggests that HLA-A*24 and HLA-DRB1*11 alleles may be prognostic and predictive biomarkers for clinical benefit.

Recently, several types of immunotherapies have been shown to induce encouraging clinical results, though in a restricted number of patients. Consequently, there is a need to identify immune biomarkers to select patients who will benefit from such therapies. Such predictive biomarkers may be also used as surrogates for overall survival (OS). We have recently found correlations between immunologic parameters and clinical outcome in prostate cancer patients who had been vaccinated with a HER-2/neu hybrid polypeptide vaccine (AE37) and received one booster 6 months post-primary vaccinations. Herein, we aimed to expand these retrospective analyses by studying the predictive impact of HLA-A*24 and HLA-DRB1*11 alleles, which are expressed at high frequencies among responders in our vaccinated patients, for clinical and immunological responses to AE37 vaccination. Our data show an increased OS of patients expressing the HLA-DRB1*11 or HLA-A*24 alleles, or both. Vaccine-induced immunological responses, measured as interferon γ (IFN-γ) responses in vitro or delayed-type hypersensitivity reactions in vivo, were also higher in these patients and inversely correlated with suppressor elements. Preexisting (i.e., before vaccinations with AE37) levels of vaccine-specific IFN-γ immunity and plasma TGF-ß, among the HLA-A*24 and/or HLA-DRB1*11 positive patients, were strong indicators for immunological responses to AE37 treatment. These data suggest that HLA-DRB1*11 and HLA-A*24 are likely to be predictive factors for immunological and clinical responses to vaccination with AE37, though prospective validation in larger cohorts is needed.

The Role of Virtual Cystoscopy, after Multidetector Computed Tomography Imaging Reconstruction without the Use of Contrast Medium, in the Diagnosis and Evaluations of Bladder Tumors: Preliminary Study.

Introduction. Although conventional cystoscopy is considered to be the gold standard for diagnosis and follow-up of bladder tumors, it remains an invasive and costly procedure. With the advent of the multidetector CT (MDCT) scanners supported by specialized software virtual cystoscopy (VC) is possible. We assess the role of VC in diagnosing and evaluating bladder lesions. Materials and Methods. Between September 2010 and October 2011, 25 consecutive patients with cystoscopically confirmed bladder tumor underwent VC. The radiologists involved in this prospective study were blinded to the exact findings. After draining any residual urine with a catheter, the bladder was retrogradely insufflated with 200-600 cc of air. No intravenous or intravesical contrast was used. MDCT scan was performed in supine and prone positions and three-dimensional reconstruction of the urinary bladder was performed. Results. The examination was well tolerated by all patients with no complications. In total, 43 lesions were detected both with conventional cystoscopy and VC. Tumor size measured by CT ranged from 3 to 80 mm in diameter. The pathological report revealed noninvasive transitional cell carcinomas in all cases. Conclusion. VC has promising results in detecting exophytic bladder lesions. In the future it could be part of the diagnostic algorithm for bladder tumors.

Hexaminolevulinate-induced fluorescence versus white light during transurethral resection of noninvasive bladder tumor: does it reduce recurrences?

OBJECTIVE: To evaluate the effect of hexaminolevulinate (HAL)-induced fluorescence during resection of noninvasive bladder cancer on tumor recurrence compared with resection under white light. METHODS: Between 2008 and 2010, 102 consecutive patients with suspected bladder cancer were randomized to undergo transurethral resection with either conventional white light or combination of white light and HAL-induced fluorescence. Difference in tumor recurrence rate and recurrence-free survival between the 2 groups was evaluated. Subgroup analysis on recurrence-free survival was performed for different tumor parameters. RESULTS: Cystoscopy at 3 months revealed tumor recurrence in 6 of 45 (13.3%) patients of the white light group compared with only 1 of 41 patients of the HAL group (2.4%) (P < .001). The recurrence-free rates in white light patients at 12 and 18 months were 56.3% and 50.6%, respectively, compared with 91% and 82.5% in HAL patients (P = .0006). In subgroup analyses, recurrence-free survival was similar between the 2 groups when solitary tumors were treated (P = .3525). However, the HAL group had a favorable recurrence-free survival compared with the white light group when multifocal tumors (P < .001), primary tumors (P = .0237), recurrent tumors (P = .0189), nonaggressive (papillary urothelial neoplasm of low malignant potential and low grade) tumors (P = .0204), or aggressive (high grade and carcinoma in situ) tumors (P = .0134) were treated. CONCLUSION: HAL significantly aids resection of non-muscle-invasive bladder cancer with the result of reduction in tumor recurrence rates.

Results from a phase I clinical study of the novel Ii-Key/HER-2/neu(776-790) hybrid peptide vaccine in patients with prostate cancer.

PURPOSE: Active immunotherapy is emerging as a potential therapeutic approach for prostate cancer. We conducted the first phase I trial of an Ii-Key/HER-2/neu(776-790) hybrid peptide vaccine (AE37) with recombinant granulocyte macrophage colony-stimulating factor as adjuvant in patients with HER-2/neu(+) prostate cancer. The primary end points of the study were to evaluate toxicity and monitor patients' immune responses to the vaccine. EXPERIMENTAL DESIGN: Thirty-two HER-2/neu(+), castrate-sensitive, and castrate-resistant prostate cancer patients were enrolled. Of these, 29 patients completed all six vaccination cycles with AE37. Immunologic responses in the total patient population were monitored by delayed-type hypersensitivity and IFN-gamma ELISPOT and intracellular staining. Regulatory T-cell (Treg) frequency and plasma HER-2/neu and transforming growth factor-beta levels were also determined. Immunologic responses were also analyzed among groups of patients with different clinical characteristics. Local/systemic toxicities were monitored throughout the study. RESULTS: Toxicities beyond grade 2 were not observed. Seventy-five percent of patients developed augmented immunity to the AE37 vaccine and 65% to the unmodified AE36 peptide as detected in the IFN-gamma-based ELISPOT assay. Intracellular IFN-gamma analyses revealed that AE37 elicited both CD4(+) and CD8(+) T-cell responses. Eighty percent of the patients developed a positive delayed-type hypersensitivity reaction to AE36. Additionally, significant decreases could be detected in circulating Treg frequencies, plasma HER-2/neu, and serum transforming growth factor-beta levels. Patients with less extensive disease developed better immunologic responses on vaccination. CONCLUSION: AE37 vaccine is safe and can induce HER-2/neu-specific cellular immune responses in patients with castrate-sensitive and castrate-resistant prostate cancer, thus emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of prostate cancer.

Two cycles of etoposide/cisplatin cured all patients with stage I testicular seminoma: risk-adapted protocol of the Hellenic Cooperative Oncology Group.

OBJECTIVES: Adjuvant carboplatin is used as adjuvant therapy in Stage I testicular seminoma. Although cure is the rule, relapses still occur, especially in high-risk populations. We report the results of a risk-adapted strategy by the Hellenic Cooperative Oncology Group. METHODS: From 1996 to 2003, 64 patients with Stage I seminoma and one of two risk factors (maximal tumor diameter greater than 4 cm and/or age younger than 34 years) were prospectively included in a protocol of adjuvant chemotherapy. Treatment consisted of two 3-week courses of etoposide 120 mg/m2 and cisplatin 40 mg/m2 for three consecutive days with granulocyte colony-stimulating factor support. RESULTS: Of the 64 patients, 43 (67%) were younger than 34 years and 55 (86%) had a tumor diameter greater than 4 cm. Neutropenia and nausea and vomiting were the most frequent grade 3 or 4 toxicities (16.5% and 9.5%, respectively), apart from alopecia. After a median follow-up of 60 months (range 7 to 118), no disease relapses have occurred. A metachronous testicular carcinoma has been reported. One patient died of causes unrelated to his disease. CONCLUSIONS: The results of our study have shown that two cycles of etoposide and cisplatin is an effective and safe form of adjuvant therapy for Stage I testicular seminoma. Risk factors can be used to identify patients who could benefit from etoposide and cisplatin treatment.

Clinical usage of the squamous cell carcinoma antigen in patients with penile cancer.

BACKGROUND: We present our initial experience with the use of the squamous cell carcinoma (SCC) antigen (SCCAg) in 16 men with penile SCC (SCC group), in four men with condyloma acuminatum (benign group), and in 32 blood donors (control group). METHODS: The SCCAg levels were measured at presentation and every 6 months (upper limit was 2 ng/mL). The mean follow-up time was 4 years. RESULTS: All non-SCC patients had normal SSCAg serum levels in contrast with the SCC patients. The presence of nodal and/or distant metastases resulted in statistically significant higher SCCAg levels, both at presentation and during the follow-up. In patients undergoing lymph node dissection with elevated SCCAg levels prior to the procedure, there was a statistically significant decrease of the SCCAg levels after the operation. CONCLUSION: The SCCAg level could be a serum marker that holds promise for clinical use in penile SCC. Sequential monitoring of SCCAg level might indicate developing of nodal and/or distant metastases and could be useful in following the response to treatment.