Downregulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date no molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed using biopsies on 27 unresected MPM patients with distinct clinical outcome: 15 patients had short survival (OS<12 months) and 12 patients had long survival (OS>36 months). Three prognostic miRNAs (mir-99a, let-7c, and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High-risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high-risk score was independently associated with shorter OS (HR=3.14; 95% CI, 1.18-8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM.

Renal Leiomyosarcoma. A Report of Two Cases.

BACKGROUND: Leiomyosarcoma represents a rather uncommon malignancy, and reports of cases characterized by a renal genesis are particularly rare. CASES: We describe 2 cases of leiomyosarcoma of the kidney, in a 63-year-old woman and in a 53-year-old man, respectively. Both tumors share a common immunohistochemical profile with a strong positivity for smooth muscle actin, a focal positivity for desmin, and negativity for cytokeratins and other markers. CONCLUSION: We provide a comparison between our findings and the data available in the literature, and we note an interesting relatively long survival in our patients (10 months for the first case and 20 months for the second case).

HOXA7, 9, and 10 are methylation targets associated with aggressive behavior in meningiomas.

Meningioma is one of the most common intracranial tumors and is graded according to the World Health Organization (WHO) classification system. Although these tumors are often surgically curable, a malignant behavior also may occur in meningiomas with benign histologic profiles (WHO I). Thus, it is mandatory to identify biomolecular parameters useful to improve the classification of these tumors. HOXA genes belong to the HOX gene family that encodes homeodomain-containing transcription factors known to be key regulators of embryonic development, involved in cell growth and differentiation and in the development of the central nervous system. Moreover, altered HOXA gene methylation and expression have prognostic value in many tumors. The purpose of this study was to determine whether the level of HOXA3, 7, 9, and 10 methylation in meningioma could be a biomarker linked to the pathologic characteristics of the tumor. We found that methylation levels of HOXA7, 9, and 10 in 131 meningioma samples were significantly higher in WHO II/III tumors compared with WHO I tumors. Moreover, in newly diagnosed WHO I meningiomas, HOXA7, 9, and 10 methylation was significantly lower than in WHO I samples derived from recurring tumors, and multiple meningiomas presented significantly higher HOXA 10 methylation with respect to solitary meningiomas. This study demonstrates that HOXA7, 9, and 10 are methylation targets in meningioma, associated with histopathology and clinical aggressiveness parameters. Our findings suggest the possibility of detecting the malignancy potential of meningioma by assessing the HOXA methylation level and identifying patients at higher risk who could benefit from closer follow-up or postoperative adjuvant treatments.

Quantitative methylation analysis of HOXA3, 7, 9, and 10 genes in glioma: association with tumor WHO grade and clinical outcome.

PURPOSE: The purpose of this study was to determine whether specific HOXA epigenetic signatures could differentiate glioma with distinct biological, pathological, and clinical characteristics. METHODS: We evaluated HOXA3, 7, 9, and 10 methylation in 63 glioma samples by MassARRAY and pyrosequencing. RESULTS: We demonstrated the direct statistical correlation between the level of methylation of all HOXA genes examined and WHO grading. Moreover, in glioblastoma patients, higher level of HOXA9 and HOXA10 methylation significantly correlated with increased survival probability (HOXA9-HR: 0.36, P = 0.007; HOXA10-HR: 0.46, P = 0.045; combined HOXA9 and 10-HR 0.28, P = 0.004). CONCLUSIONS: This study identifies HOXA3, 7, 9, and 10 as methylation targets mainly in high-grade glioma and hypermethylation of the HOXA9 and 10 as prognostic factor in glioblastoma patients. Our data indicate that these epigenetic changes may be biomarkers of clinically different subgroups of glioma patients that could eventually benefit from personalized therapeutic strategies.

SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity.

Glioblastoma, the most aggressive cerebral tumor, is invariably lethal. Glioblastoma cells express several genes typical of normal neural stem cells. One of them, SOX2, is a master gene involved in sustaining self-renewal of several stem cells, in particular neural stem cells. To investigate its role in the aberrant growth of glioblastoma, we silenced SOX2 in freshly derived glioblastoma tumor-initiating cells (TICs). Our results indicate that SOX2 silenced glioblastoma TICs, despite the many mutations they have accumulated, stop proliferating and lose tumorigenicity in immunodeficient mice. SOX2 is then also fundamental for maintenance of the self-renewal capacity of neural stem cells when they have acquired cancer properties. SOX2, or its immediate downstream effectors, would then be an ideal target for glioblastoma therapy.

Interferon therapy does not prevent hepatocellular carcinoma in HCV compensated cirrhosis.

BACKGROUND/AIMS: Recent experiences suggest that interferon may significantly decrease the incidence of hepatocellular carcinoma. We conducted a randomized study with interferon versus no therapy in hepatitis C virus Child A cirrhosis with abnormal alanine aminotransferase and HCV-RNA positive serum with the aim to investigate the incidence of hepatocellular carcinoma, worsening of cirrhosis's stage and death or orthotopic liver transplantation. METHODOLOGY: A cohort of 122 patients prospectively followed was analyzed retrospectively to assess the effect of interferon therapy (mean follow-up: 96 +/- 18.3 months). We only chose patients with hepatitis C virus infection who had undergone blood transfusion before 1980. Hepatitis C virus serotype was determined by hepatitis C virus serotyping 1-6 assay (Murex Biothec Limited Temple Hill, Dartford, Kent, UK). HCV-RNA level was determined by bDNA, Chiron Corporation Emeryville, CA. Diagnosis of hepatocellular carcinoma was made on the basis of the appearance of local lesions at periodic ultrasound examination of the liver and confirmed with spiral computed tomography. Fine needle biopsy under sonographic guidance was effected. Fifty-nine patients (mean age: 55.3 +/- 7) received interferon (3MU three times a week for 12 months), 8 stopped therapy for side effects, 71 did not receive interferon (mean age: 56.8 +/- 8). Baseline characteristics were similar. RESULTS: It emerges how interferon does not reduce the risk of hepatocellular carcinoma in compensated cirrhosis. In interferon treated patients an improvement in relation with worsening and death/orthotopic liver transplantation has been noted. CONCLUSIONS: The use of the interferon seems to be scarcely useful when structural alterations of the cirrhotic kind show up, as cirrhosis represents by itself a risk factor for hepatocellular carcinoma. Nevertheless, in relation to the worsening of cirrhosis's stage the interferon therapy can be useful in compensated cirrhosis.