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Objective: Metastatic Leydig cell tumors (LCT) are rare, difficult-to-treat malignancies without known underlying molecular-genetic events. An index case of metastatic LCT showed an LDLR-TERT gene fusion upon routine genetic profiling for detection of therapeutic targets, which was then followed by an investigation into a cohort of additional LCTs., Patients and Methods: Twenty-nine LCT (27 male and 2 female patients) were profiled using next-generation sequencing and immunohistochemistry., Results: TERT gene fusions were detected only in testicular metastatic LCTs, in 3 of 7 successfully analyzed cases (RMST:TERT, LDLR:TERT, and B4GALT5:TERT). TOP1 and CCND3 amplifications were identified in the case with a B4GALT5:TERT fusion. A TP53 mutation was detected in 1 metastatic tumor without a TERT fusion. Five primary (4 testicular and 1 ovarian) LCTs showed multiple gene amplifications, without a consistent pattern. A single metastatic ovarian LCT showed BAP1 mutation and copy number amplifications affecting the NPM1, PCM1, and SS18 genes. At the protein level, 4 of 7 metastatic and 6 of 10 primary testicular LCTs overexpressed Topo1. Androgen receptor was overexpressed in 10 of 13 primary testicular tumors and 2 of 5 metastatic testicular LCTs (without detectable ARv7 messenger RNA or ARv7 protein). Only 1 metastatic testicular LCT exhibited a high tumor mutational burden; all tested cases were microsatellite instability stable and did not express programmed cell death ligand 1., Conclusions: Our study for the first time identified TERT gene fusions as a main genetic alteration and a potential therapeutic target in metastatic LCTs. Topo1 and androgen receptor may guide decisions on chemotherapy and/or hormone therapy for selected individual patients., (Copyright © 2021. Published by Elsevier Inc.)

Background: Hypofractionated post-prostatectomy radiotherapy is emerging practice, however with no randomized evidence so far to support it's use. Additionally, patients with persistent PSA after prostatectomy may have aggressive disease and respond less well on standard salvage treatment. Herein we report outcomes for conventionally fractionated (CFR) and hypofractionated radiotherapy (HFR) in patients with persistent postprostatectomy PSA who received salvage radiotherapy to prostate bed., Methods: Single institution retrospective chart review was performed after Institutional Review Board approval. Between May 2012 and December 2016, 147 patients received salvage postprostatectomy radiotherapy. PSA failure-free and metastasis-free survival were calculated using Kaplan-Meier method. Cox regression analysis was performed to test association of fractionation regimen and other clinical factors with treatment outcomes. Early and late toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0., Results: Sixty-nine patients who had persistent PSA (≥ 0.1 ng/mL) after prostatectomy were identified. Median follow-up was 67 months (95% CI 58-106 months, range, 8-106 months). Thirty-six patients (52.2%) received CFR, 66 Gy in 33 fractions, 2 Gy per fraction, and 33 patients (47.8%) received HFR, 52.5 Gy in 20 fractions, 2.63 Gy per fraction. Forty-seven (68%) patients received androgen deprivation therapy (ADT). 5-year PSA failure- and metastasis-free survival rate was 56.9% and 76.9%, respectively. Thirty patients (43%) experienced biochemical failure after salvage radiotherapy and 16 patients (23%) experienced metastatic relapse. Nine patients (13%) developed metastatic castration-resistant disease and died of advanced prostate cancer. Median PSA failure-free survival was 72 months (95% CI; 41-72 months), while median metastasis-free survival was not reached. Patients in HFR group were more likely to experience shorter PSA failure-free survival when compared to CFR group (HR 2.2; 95% CI 1.0-4.6, p = 0.04). On univariate analysis, factors significantly associated with PSA failure-free survival were radiotherapy schedule (CFR vs HFR, HR 2.2, 95% CI 1.0-4.6, p = 0.04), first postoperative PSA (HR 1.02, 95% CI 1.0-1.04, p = 0.03), and concomitant ADT (HR 3.3, 95% CI 1.2-8.6, p = 0.02). On multivariate analysis, factors significantly associated with PSA failure-free survival were radiotherapy schedule (HR 3.04, 95% CI 1.37-6.74, p = 0.006) and concomitant ADT (HR 4.41, 95% CI 1.6-12.12, p = 0.004). On univariate analysis, factors significantly associated with metastasis-free survival were the first postoperative PSA (HR 1.07, 95% CI 1.03-1.12, p = 0.002), seminal vesicle involvement (HR 3.48, 95% CI 1.26-9.6,p = 0.02), extracapsular extension (HR 7.02, 95% CI 1.96-25.07, p = 0.003), and surgical margin status (HR 2.86, 95% CI 1.03-7.97, p = 0.04). The first postoperative PSA (HR 1.04, 95% CI 1.00-1.08, p = 0.02) and extracapsular extension (HR 4.24, 95% CI 1.08-16.55, p = 0.04) remained significantly associated with metastasis-free survival on multivariate analysis. Three patients in CFR arm (8%) experienced late genitourinary grade 3 toxicity., Conclusions: In our experience, commonly used hypofractionated radiotherapy regimen was associated with lower biochemical control compared to standard fractionation in patients with persistent PSA receiving salvage radiotherapy. Reason for this might be lower biological dose in HFR compared to CFR group. However, this observation is limited due to baseline imbalances in ADT use, ADT duration and Grade Group distribution between two radiotherapy cohorts. In patients with persistent PSA post-prostatectomy, the first postoperative PSA is an independent risk factor for treatment failure. Additional studies are needed to corroborate our observations.

Prostate cancer (PCa) is the most commonly diagnosed neoplasm among men. Since it often resembles benign prostate hyperplasia (BPH), biomarkers with a higher differential value than PSA are required. Epigenetic biomarkers in liquid biopsies, especially miRNA, could address this challenge. The absolute expression of miR-375-3p, miR-182-5p, miR-21-5p, and miR-148a-3p were quantified in blood plasma and seminal plasma of 65 PCa and 58 BPH patients by digital droplet PCR. The sensitivity and specificity of these microRNAs were determined using ROC curve analysis. The higher expression of miR-182-5p and miR-375-3p in the blood plasma of PCa patients was statistically significant as compared to BPH ( p = 0.0363 and 0.0226, respectively). Their combination achieved a specificity of 90.2% for predicting positive or negative biopsy results, while PSA cut-off of 4 µg/L performed with only 1.7% specificity. In seminal plasma, miR-375-3p, miR-182-5p, and miR-21-5p showed a statistically significantly higher expression in PCa patients with PSA >10 µg/L compared to ones with PSA ≤10 µg/L. MiR-182-5p and miR-375-3p in blood plasma show higher performance than PSA in discriminating PCa from BPH. Seminal plasma requires further investigation as it represents an obvious source for PCa biomarker identification.

Tuberculous trochanteric bursitis (TTB) is an extremely rare form of extrapulmonary tuberculosis. Due to a low clinical suspicion and poor collaboration among medical professionals, the diagnosis of TTB can be often delayed. In this report, we describe a case of neglected TTB in an adolescent girl that initially presented with right thigh swelling and fluctuance. The patient underwent repeated unsuccessful surgical treatment; however, dull pain and periodic wound drainage remained for eight years. Complete excision of fistula and trochanteric bursa and one year of oral antituberculous drug therapy led to complete recovery. This case report highlights tuberculosis as a diagnostic challenge, when rare localizations are affected. In addition, this report addresses several diagnostic pitfalls and reviews the literature regarding TTB in adolescent patients. Orthopedic surgeons need to consider TTB, when swelling, fluctuance or repeated wound drainage are present on the thigh.

Testicular germ cell tumors (TGCTs) are ever more affecting the young male population. Germ cell neoplasia in situ (GCNIS) is the origin of TGCTs, namely, seminomas (SE) and a heterogeneous group of nonseminomas (NS) comprising embryonal carcinoma, teratoma, yolk sac tumor, and choriocarcinoma. Response to the treatment and prognosis, especially of NS, depend on precise diagnosis with a necessity for discovery of new biomarkers. We aimed to perform comprehensive in silico analysis at the DNA, RNA, and protein levels of six prospective ( HOXA9 , MGMT , CFC1 , PRSS21 , RASSF1A , and MAGEC2 ) and six known TGCT biomarkers ( OCT4 , SOX17 , SOX2 , SALL4 , NANOG , and KIT ) and assess its congruence with histopathological analysis in all forms of TGCTs. Cancer Hallmarks Analytics Tool, the Search Tool for the Retrieval of Interacting Genes/Proteins database, and UALCAN, an interactive web resource for analyzing cancer OMICS data, were used. In 108 TGCT and 48 tumor-free testicular samples, the immunoreactivity score (IRS) was calculated. SE showed higher frequency in DNA alteration, while DNA methylation was significantly higher for all prospective biomarkers in NS. In GCNIS, we assessed the clinical positivity of RASSF1 and PRSS21 in 52% and 62% of samples, respectively, in contrast to low or nil positivity in healthy seminiferous tubules, TGTCs as a group, SE, NS, or all NS components. Although present in approximately 80% of healthy seminiferous tubules (HT) and GCNIS, HOXA9 was diagnostically positive in 64% of TGCTs, while it was positive in 82% of NS versus 29% of SE. Results at the DNA, mRNA, and protein levels on putative and already known biomarkers were included in the suggested panels that may prove to be important for better diagnostics of various forms of TGCTs., Competing Interests: The authors report no conflict of interest., (Copyright © 2020 Dora Raos et al.)

Background/aim: Peritumoral clefting is one of the main histologic features of basal cell carcinoma of the skin (BCC). The aim of the study was to analyze the expression of MMP-2 and MMP-9 both in cells of basal cell carcinoma and in the adjacent stroma and to correlate the findings of immunohistochemical analysis with the presence of peritumoral clefting., Patients and Methods: The study was made on archival material comprising 48 cases of BCC. These were scanned for the presence of peritumoral clefts. The results of immunohistochemical staining for MMP-2 and MMP-9 were determined semiquantitatively using immunohistochemical staining index (ISI)., Results: Peritumoral retractions were found in 40 BCC cases. Positive immunohistochemical reaction for MMP-2 in tumor cells was found in 47 cases and in all cases in the adjacent stroma. Positive immunostaining for MMP-9 in BCC tumor cells was observed in 37 cases and in all cases in the adjacent stroma. There was no statistically significant association between peritumoral retractions and expression of MMPs. A statistically significant correlation was found in the expression of both MMP-2 and MMP-9 between the tumor and the stroma., Conclusion: Tumor cells elaborate MMP-2 and -9, but they also produce some other factors that may induce production of MMPs in adjacent stromal cells. The role of MMPs in the development of peritumoral clefts could not be confirmed., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The aim of this prospective clinical study was to determine the detection rate of prostate cancers by multiparametric magnetic resonance and transrectal ultrasound (mpMRI-TRUS) cognitive fusion biopsies in patients with a previously negative TRUS-guided biopsy. Between 1 October 2016 and 1 July 2017, in 101 consecutive patients with elevated antigen (PSA) and/or positive digital rectal examination and after a negative first TRUS biopsy, a second, repeated prostate biopsy was performed. In 24 patients, cognitive fusion mpMRI-TRUS biopsy of the prostate with 8-10 system cores and 1-3 target biopsies was performed, in line with the European Association of Urology guidelines. In 77 patients, only a classic, repeated TRUS guided biopsy was performed. In patients with mpMRI, the detection rate according to PIRADS-v2 reporting system was: PIRADS 1, n = 0; PIRADS 2, n = 0; PIRADS 3, n = 0; PIRADS 4, n = 6/8 (75%); and PIRADS 5, n = 2/3 (67%). In the group of patients with MR-TRUS cognitive fusion biopsy, the prostate cancer detection rate was 8/24 (33%), while in the control group the detection rate was 12/77 (16%), which was statistically significant (t test, p = 0.037, CI 95% is 0.01 to 0.37). Patients with PIRADS ≤ 3 (54%) could have avoided the biopsy.

Background: Gender difference in survival of patients with gastric cancer is not well investigated. The aim of this study was to analyze the gender-related distribution of estrogen receptor alpha (ERα) and androgen receptor (AR) in the epithelium and stroma of intestinal-type gastric cancer., Materials and Methods: Immunohistochemical analysis was performed in 60 patients (42% females)., Results: In gastric cancer patients, frequency of ERα-positive cells was lower in epithelium than in healthy individuals, but not significantly. In stroma and epithelium, AR-positive cells were absent from samples of women with T1 and T2 stage disease, while in men, their frequency was significantly increased in stroma of those with T3 and T4 stages and was significantly higher compared to women. AR-positive cells in stroma were fibroblasts, myofibroblasts and mast cells., Conclusion: To our knowledge, this study is the first to show gender differences in the distribution and frequency of AR-positive cells in neoplastic stroma of gastric cancer., (Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Only few reports validated contemporary Epstein criteria for insignificant prostate cancer, and only one being from Europe. Patients with insignificant prostate cancer should be offered active surveillance and spared radical treatment. In our study we tested Epstein biopsy criteria for predicting unfavorable final pathology and biochemical relapse in low risk prostate cancer patients, who were eligible for active surveillance but where treated with radical prostatectomy. Between January 2003 and January 2008, 586 patients were subjected to radical prostatectomy in our institution. Among them, 106 where eligible for active surveillance according to Epstein biopsy criteria for insignificant prostate cancer. We analyzed the presence of adverse pathological findings in the final pathohistological specimen after radical prostatectomy which excludes low risk disease. Adverse pathohistological findings were noted in 41 (38.6%) patients, who could have been offered active surveillance. During the follow up of 48 (12-72) months, biochemical relapse was noted in 6 (5.6%) patients. Although active surveillance is becoming more popular because of the long natural course of prostate cancer and fear of overtreatment of patients with indolent course of disease, both doctors and patients must be aware of potentially significant disease in this group and limitations of current preoperative criteria defining low risk patients.