Seminoma is the most common testicular cancer. Pituitary tumor-transforming gene 1 (PTTG1) is a securin showing oncogenic activity in several tumors. We previously demonstrated that nuclear PTTG1 promotes seminoma tumor invasion through its transcriptional activity on matrix metalloproteinase 2 (MMP-2) and E-cadherin (CDH1). We wondered if specific interactors could affect its subcellular distribution. To this aim, we investigated the PTTG1 interactome in seminoma cell lines showing different PTTG1 nuclear levels correlated with invasive properties. A proteomic approach upon PTTG1 immunoprecipitation uncovered new specific securin interactors. Western blot, confocal microscopy, cytoplasmic/nuclear fractionation, sphere-forming assay, and Atlas database interrogation were performed to validate the proteomic results and to investigate the interplay between PTTG1 and newly uncovered partners. We observed that spectrin beta-chain (SPTBN1) and PTTG1 were cofactors, with SPTBN1 anchoring the securin in the cytoplasm. SPTBN1 downregulation determined PTTG1 nuclear translocation, promoting its invasive capability. Moreover, a PTTG1 deletion mutant lacking SPTBN1 binding was strongly localized in the nucleus. The Atlas database revealed that seminomas that contained higher nuclear PTTG1 levels showed significantly lower SPTBN1 levels in comparison to non-seminomas. In human seminoma specimens, we found a strong PTTG1/SPTBN1 colocalization that decreases in areas with nuclear PTTG1 distribution. Overall, these results suggest that SPTBN1, along with PTTG1, is a potential prognostic factor useful in the clinical management of seminoma.
Partial nephrectomy (PN) is the gold standard treatment for localized renal masses. Robot-assisted PN (RAPN) has overcome laparoscopy’s technical limitations, greatly expanding the indications of minimally invasive PN, which is dominated by renal artery clamping in almost all published series. We compared off-clamp RAPN (OFFC-RAPN) with the open approach (OFFC-OPN) using propensity score (PS) matching. A favourable pentafecta outcome was defined as a combination of no positive surgical margins (PSM), no complications of Clavien−Dindo (CD) grade ≥ 3, post-operative eGFR loss <10%, length of hospital stay (LOS) ≤ 5 days and estimated blood loss (EBL) < 200 mL. A total of 340 consecutive patients were included. The PS-matched cohort included 142 patients: 71 matched pairs well-balanced for all covariates. The OFFC-RAPN group showed significantly shorter operative time (149.8 vs. 173.9 min, p = 0.003), lower EBL (182.1 vs. 329.3 mL, p = 0.001), and shorter LOS (5.8 vs. 6.9 days, p = 0.02), with a higher proportion of patients with LOS ≤ 5 days (57.7% vs. 23.9%, p < 0.001). No significant differences were found for PSM rate (2.8% vs. 8.4%, p = 0.27), CD > 2 complication rate (4.2% vs. 2.8%, p = 1.00) and mean ± SD eGFR change (−0.06 ± 0.3 vs. −0.8 ± 0.3, p = 0.5). Pentafecta was achieved in 56.3% and 21.1% in the OFFC-RAPN and OFFC-OPN series, respectively (p < 0.0001). On multivariable analysis, surgical approach and BMI proved to be independent predictors of achieving pentafecta. After adjusting for potential treatment selection bias, OFFC-RAPN outperformed OFFC-OPN for important peri-operative outcomes, without compromising oncological and functional safety.
714 Background: Intermediate IMDC group is the largest and most heterogeneous group of mRCC. Current first-line (1L) therapy options for these patients (pts) are based on either an anti-angiogenic agent (VEGFR-TKI) combined with immunotherapy (IO), or a combo of IO (ipilimumab+nivolumab [I/N]). No biomarkers (BM) for selecting the most effective regimen have been identified so far. Methods: Immunohistochemical expression of PBRM1, PD-L1, CD31, and CD4/CD8 ratio was evaluated on histological samples of intermediate-risk mRCC pts treated with VEGFR-TKI monotherapy, and then in pts receiving a VEGFR-TKI-based therapy or the immune doublet I/N. PBRM1 positivity score was based on the percentage of positive cells and on the intensity of nuclear expression; PD-L1 positivity was defined as CPS≥10; CD31 high-density had moderate to strong nuclear staining; and the CD4/CD8 ratio cut-off for positivity was >0.2. Cox model was used to assess the correlation between BM and outcomes; PFS and OS were estimated by Kaplan-Meier method. Results: After screening of tumor tissues from 150 pts, a total of 111 were included in the final analysis (Table). In pts treated with VEGFR-TKI monotherapy, a significant correlation with PFS was observed with loss of PBRM1 expression (HR 0.58, p=0.035), PD-L1 negativity (HR 0.44, p=0.048), and high CD4/CD8 ratio (HR 0.62, p=0.073). CD31 density did not significantly correlate with PFS. A profile potentially predictive of angiogenesis (AP+) was defined based on the PBRM1 loss, PD-L1 negative, and high CD4/CD8. In pts treated with VEGFR-TKI monotherapy, tumors with the AP+ (43% of all cases) had a significantly longer median PFS (mPFS 23.8 vs. 11.8 months, p=0.003) and mOS (41.5 vs. 26.9 months, p=0.024) compared to the others. The AP+ retained its significant correlation with PFS (mPFS 23.8 vs. 11.1 months, p<0.001) and OS (41.5 vs. 24.9, p=0.006) in pts receiving VEGFR-TKI-based therapies. The rate of AP+ tumors was 55.6% and 32.7% in pts with one or two IMDC risk factors, respectively (p=0.022). In the small cohort of pts treated with I/N, no differences were observed in PFS (p=0.64) and OS (p=0.75) between AP+ and AP-negative. Conclusions: The AP+ signature (loss of PBRM1, PD-L1 negative, and CD4/CD8 high ratio) was associated with improved clinical outcomes in mRCC pts at IMDC intermediate prognosis treated with VEGFR-TKI-based therapy; this correlation was significant regardless from the addition of IO to VEGFR-TKI monotherapy. Prospective validation of this signature is required for guiding the selection of the most appropriate 1L therapy. [Table: see text]
Introduction: Prostate cancer (PCa) is one of the most common adult malignancies worldwide, and a major leading cause of cancer-related death in men in Western societies. In the last years, the prognosis of advanced PCa patients has been impressively improved thanks to the development of different therapeutic agents, including taxanes (docetaxel and cabazitaxel), second-generation anti-hormonal agents (abiraterone and enzalutamide), and the radiopharmaceutical Radium-223. However, great efforts are still needed to properly select the most appropriate treatment for each single patient.Areas covered: Several prognostic or predictive biomarkers have been studied, none of which has an established validated role in daily clinical practice. This paper analyzed the major biomarkers (including PSA, androgen receptor (AR) splice variants, βIII-tubulin, ALP, circulating tumor cells, and DNA repair genes) with a potential prognostic and/or predictive role in advanced PCa patients.Expert commentary: Surrogate biomarkers - measurable, reproducible, closely associated with tumor behavior and linked to relevant clinical outcomes - are urgently needed to improve PCa patient management.
Seminomas are the most frequent kind of testicular germ cell tumors (TGCTs), accounting for 50% of tumor diagnosis in young men, whereas non-seminomas account for 40% and mixed forms for 10% of cases. It is currently supposed that TGCTs evolve from a pre-invasive stage of carcinoma in situ (CIS). Octamer-binding transcription factor 4 (OCT4) is essential for self-renewal of stem cells. It is considered as a major regulator of cell pluripotency. Prior studies have shown that seminoma expresses OCT4. Transcription factor Krüppel-like factor 4 (KLF4) has moreover associated with embryonic stem cell maintenance. Finally, we previously demonstrated the expression of PTTG1 in CIS and seminomas. In this pilot study, we compared the combined expression of PTTG1 with KLF4 and OCT4 in seminoma, in order to validate our hypotesis that PTTG1 marks a specific population of stem cells in neoplastic tissue, strictly related with tumor. Formalin-fixed and paraffin-embedded testicular tissues by 5 patients who underwent an orchidectomy for seminoma have been collected and immunofluorescence analysis was performed using antibody rabbit monoclonal PTTG-1 and mouse monoclonal OCT4 or mouse monoclonal KLF4 antibody. In seminoma we observed that tumor cells strongly express OCT-4 in all seminomas and in the intratubular areas of seminoma. Expression of KLF-4 was observed in many tumor cells. PTTG1 marks some specific OCT4- and KLF4-positive tumor cells, mainly localized at the periphery of the neoplasm. In the intertubular infiltration areas nests of cells expressing both OCT4/KLF4 and PTTG1 have been observed. This is the first identification of a cell population in seminoma characterized for being OCT4, KLF4, and PTTG1 positive cells in seminoma, associated with cancer invasiveness. Further investigation is needed to elucidate if a functional abrogation of PTTG1 might be used in order to offer new therapeutic approaches in the clinical workout of seminoma.
We report a case of giant spermatic cord liposarcoma (SCL) in an 81-year-old patient, presenting with a huge scrotal mass that reached up to the knee joint. SCL is a rare tumor, and about 200 cases have been reported in the literature so far. Although 20% of liposarcomas arise in the retroperitoneum, only 0.1% present as incidental inguinal hernias. The occasional presence of myxoid stroma in well-differentiated liposarcomas can lead to confusion with myxoid sarcoma subtypes. Correct diagnosis is critical and reflects remarkable differences in behavior and therapeutic choices.
Angiogenesis is essential for the growth of solid tumors. We have observed previously that the vascular endothelial cells of astrocytic brain tumors express human telomerase reverse transcriptase (hTERT) mRNA, suggesting a role for telomerase in the angiogenesis of these neoplasms. Here, we used an in vitro model to demonstrate that the telomerase machinery might be trans-activated in primary endothelial cells by glioblastoma tumor cells. We found that glioblastoma cells in vitro do induce hTERT mRNA and hTERT protein expression, as well as telomerase enzyme activity in the endothelial cells, and that this phenomenon is mediated by diffusible factor(s). These results provide strong evidence of the involvement of telomerase in tumor angiogenesis and will stimulate research on antitelomerase drugs for treatment of malignant brain gliomas.
Aims Bladder EpiCheck is one of several urinary tests studied to identify bladder tumours and analyses 15 methylation biomarkers determining bladder cancer presence on the basis of methylation profile. Methods 374 patients diagnosed with high-grade non-muscle invasive bladder cancer were treated and followed for 1 year with voided urine cytology and white-light cystoscopy and biopsies according to European Association of Urology Guidelines. 268 cases were diagnosed with high-grade papillary carcinoma, while 106 cases were carcinoma in situ. Bladder EpiCheck test was performed together with cytology in all cases. Results Comparing cytological categories of negative for high-grade urothelial carcinoma (NHGUC) and atypical urothelial cells (AUCs), we found that an EpiScore <60 correlates with NHGUC (p=0.0003, Fisher’s exact test), while comparing AUC and suspicious for high-grade urothelial carcinoma (SHGUC) or SHGUC and high-grade urothelial carcinoma (HGUC) categories, an EpiScore ≥60 correlates with SHGUC and HGUC, respectively (p=0.0031 and p=0.0027, Fisher’s exact test). In each TPS category, we found that sensitivity, specificity, Positive Predicitve Value (PPV) and Negative Predictive Value (NPV) of the Bladder EpiCheck test in HGUC category were higher than those observed in SHGUC group (sensitivity=98%, specificity=100%, NPV=85.7%, PPV=100% vs sensitivity=86.6%, specificity=52.3%, NPV=84.6%, PPV=56.5%). Conclusions Analysing methylation study results, we demonstrated that different TPS cytological categories also carry a distinct molecular signature. Moreover, our results confirm that cytological categories SHGUC and HGUC are different entities also from a molecular point of view and should continue to represent distinct groups in TPS.
