Modulation of Genes and MicroRNAs in the Neurospheres of Glioblastoma Cell Lines U343 and T98G Induced by Ionizing Radiation and Temozolomide Therapy.

INTRODUCTION: Glioblastoma is the most prevalent primary malignant neoplasm of the central nervous system. It has increased its incidence, while the overall survival remains over 14 months. PURPOSE: The purpose is to evaluate the expression of the genes EGFR, PTEN, MGMT, and IDH1/2, and microRNAs miR-181b, miR-145, miR-149, and miR-128a in adhered cells (AC) and neurospheres (NS) from cell lines (T98G and U343) submitted to temozolomide (TMZ) and ionizing radiation (IR). METHODS: T98G and U343 were treated with TMZ, IR, and TMZ+IR. The analysis of gene expression and miRNAs was performed using real-time PCR. RESULTS: This study demonstrated: a) an improvement in the expression of IDH1 after IR and TMZ + IR in the NS (T98G); b) an increase in the expression of MGMT in NS (T98G) in IR groups and TMZ + IR. The expression of miRNAs results as a) AC (U343) expressed more miR-181b after TMZ, IR, and TMZ + IR; and miR-128a improved after TMZ, IR, and TMZ + IR; b) NS (T98G) after TMZ + IR expressed: miR-181b; miR-149; miR-145 and miR-128a; c) NS (U343) after IR huge expressed miR-149 and miR-145. CONCLUSION: IR was an independent and determining radioresistance factor in NS. However, we observed no complementarity action of oncomiRs regulation.

Novel histone deacetylase inhibitors for the treatment of pediatric brain tumors.

Pediatric brain tumors (BT) represent a broad group of malignancies that affect children, displaying different degrees of aggressiveness and prognosis. Current studies demonstrate a crosslink between genetic and epigenetic changes within these tumors. Histone modifications are key elements in the pathogenesis of cancer in general and in brain tumors in particular. It is well documented that at least two classes of enzymes control acetylation of histones: histone acetyltransferases (HATs) and histone deacetylase (HDACs). Transformed HAT or HDAC action was identified in a number of human tumors. It has been hypothesized that HDACs regulate gene expression by deacetylating important genes for cell maintenance. Several HDACs inhibitors have been characterized in the last years and have been shown to promote growth blockage, differentiation and apoptosis in various types of tumors, including glioblastomas, medulloblastomas, neuroblastomas, melanomas, and leukemias. Some of these inhibitors are currently under clinical investigation for different cancer treatments. This review summarizes important mechanisms of histone modifications and discusses recent discoveries with impact on the pre-clinical and clinical field of pediatric brain tumor treatment.

Prognostic factors for late urinary toxicity grade 2-3 after conformal radiation therapy on patients with prostate cancer.

OBJECTIVE: Identify prognostic factors associated to late urinary toxicity in patients with prostate cancer submitted to radical conformal radiotherapy (3DCRT). MATERIALS AND METHODS: From July 1997 to January 2002, 285 patients with localized prostate cancer were consecutively treated with 3DCRT and retrospectively analyzed. Thirty seven (13%) patients were submitted to transurethral prostate resection previously to 3DCRT. The median dose delivered to the prostate was 7920 cGy (7020-8460). Patient and treatment characteristics were analyzed and correlated to late urinary toxicity grade 2-3, especially whether certain radiation doses applied to certain bladder volumes, when visualized through computerized tomography (CT) planning, correlated with the observed actuarial incidences of late urinary complications, using bladder volume as a continuous variable. RESULTS: On a median follow-up of 53.6 months (3.6-95.3), the 5-year actuarial free from late urinary toxicity grade 2-3 survival was 91.1%. Seven and fifteen patients presented late urinary toxicity grades 2 and 3, respectively. Prior transurethral resection of prostate and radiation dose over 70 Gy on 30% of initial bladder volume were independent prognostic factors for late urinary toxicity grade 2-3. CONCLUSIONS: This study suggests that restricting radiation doses to 70 Gy or less on 30% of bladder volume, visualized through CT planning, may reduce late urinary complications. It furthermore suggests that patients with prior transurethral resection of prostate may indicate a group of patients with a greater risk for late urinary toxicity grade 2-3 after 3DCRT.

Salvage conformal radiotherapy for biochemical recurrent prostate cancer after radical prostatectomy.

OBJECTIVE: Assess the results of salvage conformal radiotherapy in patients with biochemical failure after radical prostatectomy and identify prognostic factors for biochemical recurrence and toxicity of the treatment. MATERIALS AND METHODS: From June 1998 to November 2001, 35 patients were submitted to conformal radiotherapy for PSA > or = 0.2 ng/mL in progression after radical prostatectomy and were retrospectively analyzed. The mean dose of radiation in prostatic bed was of 77.4 Gy (68-81). Variables related to the treatment and to tumor were assessed to identify prognostic factors for biochemical recurrence after salvage radiotherapy. RESULTS: The median follow-up was of 55 months (17-83). The actuarial survival rates free of biochemical recurrence and free of metastasis at a distance of 5 years were 79.7% e 84.7%, respectively. The actuarial global survival rate in 5 years was 96.1%. The actuarial survival rate free of biochemical recurrence in 5 years was 83.3% with PSA pre-radiotherapy < or = 1, 100% when > 1 and < or = 2, and 57.1% when > 2 (p = 0.023). Dose > 70 Gy in 30% of the bladder volume implied in more acute urinary toxicity (p = 0.035). The mean time for the development of late urinary toxicity was 21 months (12-51). Dose > 55 Gy in 50%bladder volume implied in more late urinary toxicity (p = 0.018). A patient presented late rectal toxicity of 2nd grade. CONCLUSIONS: Conformal radiotherapy showed to be effective for the control of biochemical recurrence after radical prostatectomy. Patients with pre-therapy PSA < or = 2 ng/mL have more biochemical control.

Prognostic factors for late urinary toxicity grade 2-3 after conformal radiation therapy on patients with prostate cancer

OBJECTIVE: Identify prognostic factors associated to late urinary toxicity in patients with prostate cancer submitted to radical conformal radiotherapy (3DCRT) MATERIALS AND METHODS: From July 1997 to January 2002, 285 patients with localized prostate cancer were consecutively treated with 3DCRT and retrospectively analyzed. Thirty seven (13 percent) patients were submitted to transurethral prostate resection previously to 3DCRT. The median dose delivered to the prostate was 7920 cGy (7020-8460). Patient and treatment characteristics were analyzed and correlated to late urinary toxicity grade 2-3, especially whether certain radiation doses applied to certain bladder volumes, when visualized through computerized tomography (CT) planning, correlated with the observed actuarial incidences of late urinary complications, using bladder volume as a continuous variable RESULTS: On a median follow-up of 53.6 months (3.6-95.3), the 5-year actuarial free from late urinary toxicity grade 2-3 survival was 91.1 percent. Seven and fifteen patients presented late urinary toxicity grades 2 and 3, respectively. Prior transurethral resection of prostate and radiation dose over 70 Gy on 30 percent of initial bladder volume were independent prognostic factors for late urinary toxicity grade 2-3 CONCLUSIONS: This study suggests that restricting radiation doses to 70 Gy or less on 30 percent of bladder volume, visualized through CT planning, may reduce late urinary complications. It furthermore suggests that patients with prior transurethral resection of prostate may indicate a group of patients with a greater risk for late urinary toxicity grade 2-3 after 3DCRT.

Salvage conformal radiotherapy for biochemical recurrent prostate cancer after radical prostatectomy

OBJECTIVE: Assess the results of salvage conformal radiotherapy in patients with biochemical failure after radical prostatectomy and identify prognostic factors for biochemical recurrence and toxicity of the treatment. MATERIALS AND METHODS: From June 1998 to November 2001, 35 patients were submitted to conformal radiotherapy for PSA > 0.2 ng/mL in progression after radical prostatectomy and were retrospectively analyzed. The mean dose of radiation in prostatic bed was of 77.4 Gy (68-81). Variables related to the treatment and to tumor were assessed to identify prognostic factors for biochemical recurrence after salvage radiotherapy. RESULTS: The median follow-up was of 55 months (17-83). The actuarial survival rates free of biochemical recurrence and free of metastasis at a distance of 5 years were 79.7 percent e 84.7 percent, respectively. The actuarial global survival rate in 5 years was 96.1 percent.The actuarial survival rate free of biochemical recurrence in 5 years was 83.3 percent with PSA pre-radiotherapy < 1, 100 percent when > 1 and < 2, and 57.1 percent when > 2 (p = 0.023). Dose > 70 Gy in 30 percent of the bladder volume implied in more acute urinary toxicity (p = 0.035). The mean time for the development of late urinary toxicity was 21 months (12-51). Dose > 55 Gy in 50 percent bladder volume implied in more late urinary toxicity (p = 0.018). A patient presented late rectal toxicity of 2nd grade. CONCLUSIONS: Conformal radiotherapy showed to be effective for the control of biochemical recurrence after radical prostatectomy. Patients with pre-therapy PSA < 2 ng/mL have more biochemical control.