Molecular characterization of a bladder pleomorphic rhabdomyosarcoma in an adult patient

Pleomorphic rhabdomyosarcoma (PRMS) is a rare but highly aggressive soft tissue tumor, accounting for 3% of soft tissue sarcomas. PRMS is the most frequent subtype of RMS in adulthood and it is mainly located in the large muscles of the extremities, particularly the lower limbs and the trunk, more rarely in other locations especially in the bladder. At our knowledge, only six cases of adult pleomorphic rhabdomyosarcoma of the bladder have been reported in the literature. In this study, we report a case of PRMS of bladder with a very poor prognosis. In fact, the patient died a month after surgery. The tumor was characterized by poorly differentiated, medium-sized sometimes rhabdoid cells, mixed with large-sized and pleomorphic elements with evident anisonucleosis, and with large areas of necrosis. We used an extensive immunohistochemical panel to exclude other tumors much more frequently reported at this site. The positivity for myogenic markers such as actin, desmin, myogenin and MyoD1 allowed the correct diagnosis. Furthermore, since preliminary studies highlighted a series of specific molecular alterations in PMRS cell lines, we analyzed a panel of specific mutations and gene rearrangements by RT-PCR and FISH methods. We showed a copy gains of CCND1 and MALT genes in our samples, suggesting an accurate molecular characterization of PRMS to establish a better management of patients and new therapeutic opportunities

Bladder‐sparing, combined‐modality approach for muscle‐invasive bladder cancer

AbstractBACKGROUND.The authors evaluated their long‐term experience with combined‐modality, conservative treatment in patients with muscle‐invasive bladder cancer.METHODS.In total, 121 patients with T2, T3, or T4 bladder cancer (mean age, 63 years; ratio of men to women, 3:1) underwent induction by transurethral resection (TUR) of the tumor and received 2 cycles of neoadjuvant chemotherapy followed by radiotherapy (RT) (n = 43 patients) or radiochemotherapy (RCT) (n = 78 patients). Six weeks after RT or RCT, responses were evaluated by restaging TUR. Patients who achieved a complete response (CR) were observed at regular intervals. In patients who had persistent or recurrent invasive tumor, further treatment was recommended.RESULTS.Local response evaluation by restaging TUR was possible in 119 patients, and 102 of those patients (85.7%) achieved a CR. After a median follow‐up of 66 months (range, 6–182 months), no local or distant disease recurrences were observed in 67 of 102 complete responders (65.7%), 17 of 102 complete responders (16.7%) experienced superficial local disease recurrence, and 18 of 102 complete responders (17.6%) had a muscle‐invasive relapse. The 5‐year tumor‐specific, overall, and bladder‐intact survival rates were 73.5%, 67.7%, and 51.2%, respectively. Treatment modality, tumor classification, and resection status after initial TUR had an impact on survival rates (P = .04, P = .02, and P = .02, respectively).CONCLUSIONS.The current results indicated that conservative combined treatment is a reasonable alternative to radical cystectomy in selected patients with muscle‐invasive bladder cancer. Cancer 2008. © 2007 American Cancer Society

New Cross-Talk Layer between Ultraconserved Non-Coding RNAs, MicroRNAs and Polycomb Protein YY1 in Bladder Cancer

MicroRNAs (miRNAs) are highly conserved elements in mammals, and exert key regulatory functions. Growing evidence shows that miRNAs can interact with another class of non-coding RNAs, so-called transcribed ultraconserved regions (T-UCRs), which take part in transcriptional, post-transcriptional and epigenetic regulation processes. We report here the interaction of miRNAs and T-UCRs as a network modulating the availability of these non-coding RNAs in bladder cancer cells. In our cell system, antagomiR-596 increased the expression of T-UCR 201+. Moreover, T-UCR 8+ silencing increased miR-596 expression, which in turn reduced total T-UCR 283+, showing that the perturbation of one element in this network changes the expression of other interactors. In addition, we identify the polycomb protein Yin Yang 1 (YY1) as mediator of binding between miR-596 and T-UCR 8+. These new findings describe for the first time a network between T-UCRs, miRNAs and YY1 protein, highlighting the existence of an additional layer of gene expression regulation

Prognostic accuracy of Prostate Health Index and urinary Prostate Cancer Antigen 3 in predicting pathologic features after radical prostatectomy

Objective: To compare the prognostic accuracy of Prostate Health Index (PHI) and Prostate Cancer Antigen 3 in predicting pathologic features in a cohort of patients who underwent radical prostatectomy (RP) for prostate cancer (PCa). Methods and materials: We evaluated 156 patients with biopsy-proven, clinically localized PCa who underwent RP between January 2013 and December 2013 at 2 tertiary care institutions. Blood and urinary specimens were collected before initial prostate biopsy for [-2] pro-prostate-specific antigen (PSA), its derivates, and PCA3 measurements. Univariate and multivariate logistic regression analyses were carried out to determine the variables that were potentially predictive of tumor volume >0.5. ml, pathologic Gleason sum 657, pathologically confirmed significant PCa, extracapsular extension, and seminal vesicles invasions. Results: On multivariate analyses and after bootstrapping with 1,000 resampled data, the inclusion of PHI significantly increased the accuracy of a baseline multivariate model, which included patient age, total PSA, free PSA, rate of positive cores, clinical stage, prostate volume, body mass index, and biopsy Gleason score (GS), in predicting the study outcomes. Particularly, to predict tumor volume>0.5, the addition of PHI to the baseline model significantly increased predictive accuracy by 7.9% (area under the receiver operating characteristics curve [AUC] = 89.3 vs. 97.2, P>0.05), whereas PCA3 did not lead to a significant increase.Although both PHI and PCA3 significantly improved predictive accuracy to predict extracapsular extension compared with the baseline model, achieving independent predictor status (all P's<0.01), only PHI led to a significant improvement in the prediction of seminal vesicles invasions (AUC = 92.2, P<0.05 with a gain of 3.6%).In the subset of patients with GS 646, PHI significantly improved predictive accuracy by 7.6% compared with the baseline model (AUC = 89.7 vs. 97.3) to predict pathologically confirmed significant PCa and by 5.9% compared with the baseline model (AUC = 83.1 vs. 89.0) to predict pathologic GS 657. For these outcomes, PCA3 did not add incremental predictive value. Conclusions: In a cohort of patients who underwent RP, PHI is significantly better than PCA3 in the ability to predict the presence of both more aggressive and extended PCa

Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer

With the intent to identify biomarkers in renal cell carcinoma (RCC) the functional status of T-regulatory cells (Tregs) was investigated in primary RCC. Tregs were isolated from tumoral-(TT), peritumoral tissue-(PT) and peripheral blood-(PB) of 42 primary RCC patients and function evaluated through effector T cells (Teff) proliferation, cytokines release and demethylation of Treg Specific Region (TSDR). The highest value of Tregs was detected in TT with the uppermost amount of effector-Tregs-(CD4+CD25hiFOXP3hiCD45RA-). PB-RCC Tregs efficiently suppress Teff proliferation compared to healthy donor (HD)-Tregs and, at the intrapatient evaluation, TT-derived Tregs were the most suppressive. Higher demethylation TSDR was detected in TT- and PB-RCC Tregs vs HD-Tregs (P <0,001). CXCR4 is highly expressed on Tregs, thus we wished to modulate Tregs function through CXCR4 inhibition. CXCR4 antagonism, elicited by a new peptidic antagonist, Peptide-R29, efficiently reversed Tregs suppression of Teff proliferation. Thus Tregs functional evaluation precisely reflects Tregs status and may be a reliable biomarker of tumoral immune response. In addition, treatment with CXCR4 antagonist, impairing Tregs function, could improve the anticancer immune response, in combination with conventional therapy and/or immunotherapy such as checkpoints inhibitors

Qualitative assessment of contrast-enhanced ultrasound in differentiating clear cell renal cell carcinoma and oncocytoma

Background: We aimed to assess whether clear cell renal cell carcinoma (ccRCC) can be differentiated from renal oncocytoma (RO) on a contrast-enhanced ultrasound (CEUS). Methods: Between January 2021 and October 2022, we retrospectively queried and analyzed our prospectively maintained dataset. Renal mass features were scrutinized with conventional ultrasound imaging (CUS) and CEUS. All lesions were confirmed by histopathologic diagnoses after nephron-sparing surgery (NSS). A multivariable analysis was performed to identify the potential predictors of ccRCC. The area under the curve (AUC) was depicted in order to assess the diagnostic accuracy of the multivariable model. Results: A total of 126 renal masses, including 103 (81.7%) ccRCC and 23 (18.3%) RO, matched our inclusion criteria. Among these two groups, we found significant differences in terms of enhancement (homogeneous vs. heterogeneous) (p &lt; 0.001), wash-in (fast vs. synchronous/slow) (p = 0.004), wash-out (fast vs. synchronous/slow) (p = 0.001), and rim-like enhancement (p &lt; 0.001). On the multivariate logistic regression, heterogeneous enhancement (OR: 19.37; p = &lt;0.001) and rim-like enhancement (OR: 3.73; p = 0.049) were independent predictors of ccRCC. Finally, these two variables had an AUC of 82.5% and 75.3%, respectively. Conclusions: Diagnostic imaging for presurgical planning is crucial in the choice of either conservative or radical management. CEUS, with its unique features, revealed its usefulness in differentiating ccRCC from RO

Mouse Models in Prostate Cancer Translational Research: From Xenograft to PDX

Despite the advancement of clinical and preclinical research on PCa, which resulted in the last five years in a decrement of disease incidence by 3-4%, it remains the most frequent cancer in men and the second for mortality rate. Based on this evidence we present a brief dissertation on numerous preclinical models, comparing their advantages and disadvantages; among this we report the PDX mouse models that show greater fidelity to the disease, in terms of histopathologic features of implanted tumor, gene and miRNA expression, and metastatic pattern, well describing all tumor progression stages; this characteristic encourages the translation of preclinical results. These models become particularly useful in meeting the need of new treatments identification that eradicate PCa bone metastases growing, clarifying pathway of angiogenesis, identifying castration-resistant stem-like cells, and studying the antiandrogen therapies. Also of considerable interest are the studies of 3D cell cultures derived from PDX, which have the ability to maintain PDX cell viability with continued native androgen receptor expression, also showing a differential sensitivity to drugs. 3D PDX PCa may represent a diagnostic platform for the rapid assessment of drugs and push personalized medicine. Today the development of preclinical models in vitro and in vivo is necessary in order to obtain increasingly reliable answers before reaching phase III of the drug discovery

Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis

Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR-binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR-596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for early diagnosis and prognosis as well as for development of new RNA-based cancer therapies

Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review

Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) "unique" in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell "fate". Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy