Interferon regulatory factor 4 modulates epigenetic silencing and cancer-critical pathways in melanoma cells.

Interferon regulatory factor 4 (IRF4) was initially identified as a key controller in lymphocyte differentiation and function, and subsequently as a dependency factor and therapy target in lymphocyte-derived cancers. In melanocytes, IRF4 takes part in pigmentation. Although genetic studies have implicated IRF4 in melanoma, how IRF4 functions in melanoma cells has remained largely elusive. Here, we confirmed prevalent IRF4 expression in melanoma and showed that high expression is linked to dependency in cells and mortality in patients. Analysis of genes activated by IRF4 uncovered, as a novel target category, epigenetic silencing factors involved in DNA methylation (DNMT1, DNMT3B, UHRF1) and histone H3K27 methylation (EZH2). Consequently, we show that IRF4 controls the expression of tumour suppressor genes known to be silenced by these epigenetic modifications, for instance cyclin-dependent kinase inhibitors CDKN1A and CDKN1B, the PI3-AKT pathway regulator PTEN, and primary cilium components. Furthermore, IRF4 modulates activity of key downstream oncogenic pathways, such as WNT/ß-catenin and AKT, impacting cell proliferation and survival. Accordingly, IRF4 modifies the effectiveness of pertinent epigenetic drugs on melanoma cells, a finding that encourages further studies towards therapeutic targeting of IRF4 in melanoma.

Predictive factors for the development of brain metastases in patients with malignant melanoma: a study by the Anatolian society of medical oncology.

BACKGROUND: The development of brain metastases (BMs) was associated with poor prognosis in melanoma patients. Patients with BMs have a median survival of <6 months. Melanoma is the third most common tumor to metastasize to the brain with a reported incidence of 10-40 %. Our aim was to identify factors predicting development of BMs and survival. PATIENTS AND METHODS: We performed a retrospective analysis of 470 melanoma patients between 2000 and 2012. The logistic regression analyses were used to identify the clinicopathological features of primary melanoma that are predictive of BMs development and survival after a diagnosis of brain metastases. RESULTS: There were 52 patients (11.1 %) who developed melanoma BMs during the study period. The analysis of post-BMs with Kaplan-Meier curves has resulted in a median survival rate of 4.1 months (range 2.9-5.1 months). On logistic regression analysis site of the primary tumor on the head and neck (p = 0.002), primary tumor thickness (Breslow >4 mm) (p = 0.008), ulceration (p = 0.007), and pathologically N2 and N3 diseases (p = 0.001) were found to be significantly associated with the development of BMs. In univariate analysis, tumor thickness and performance status had a significant influence on post-BMs survival. In multivariate analysis, these clinicopathologic factors were not remained as significant predictive factors. CONCLUSIONS: Our results revealed the importance of primary tumor characteristics associated with the development of BMs. Ulceration, primary tumor thickness, anatomic site, and pathologic ≥N2 disease were found to be significant predictors of BMs development.

Nocardial tubo-ovarian abscess in a pregnant woman: a rare case report.

Nocardiosis is a rare disease associated with significant morbidity and mortality in immunocompromised patients. We report on a 32-year-old pregnant woman with nocardiosis, which may be the third reported case in which no risk factor for the infection (other than the pregnancy itself) could be found. Pregnancy was complicated by the formation of a tubo-ovarian nocardia abscess, resulting in abortion. Lapartomy with trimethopprim-sulfamethoxazole led to complete cure of the patient at the end of the fifth month. This case emphasizes the difficulty in the diagnosis and treatment of a nocardial infection during pregnancy.

The relation of increased uterine artery blood flow resistance and impaired trophoblast invasion in pre-eclamptic pregnancies.

OBJECTIVE: To assess the association between histopathologically confirmed vascular abnormalities developed during pre-eclampsia and abnormal arterial blood flows recorded during Doppler sonographies. MATERIALS AND METHODS: From pregnant women who attended our clinic between 01/03/2002 and 01/07/2002, a detailed medical history was obtained and routine biochemical blood tests, fetal ultrasonography and UA Doppler scans were performed. In addition, from pre-eclamptic and normal pregnant women who underwent cesarean sections, placental bed biopsies were taken. Thirty two pre-eclamptic [12 mild, 20 severe cases according to American College of Obstetricians and Gynecologists (ACOG) criteria] cases and as a control group 20 normal pregnancies were included in the study. In our study trophoblast invasion into decidual spiral arteries was observed in 75% of mild (9/12), and 55% of severe (11/20) pre-eclampsias. In the control group all the cases demonstrated trophoblast invasion in decidual spiral arteries. Trophoblast invasion in myometrial spiral arteries was noted in 50% (6/12) of mild and 25% (5/20) of severe pre-eclamptic pregnancies. It was seen in 16 cases out of 20 (80%) pregnancies. In the control group, decidual spiral artery invasion manifests significant differences (P<0.01) among groups studied. Invasion in decidual spiral arteries was seen in all normal pregnancies of the control group. There is not any significant difference between mild and severely pre-eclamptic groups (P>0.05). CONCLUSION: Doppler ultrasonography is not only a non-invasive method for evaluating fetal status in pre-eclamptic pregnancies, but it also correlates with partial trophoblastic invasion in spiral arteries, which contributes to the pathophysiologic mechanisms involved in pre-eclampsia.