Georgia Levidou

Gastrointestinal stromal tumor

BackgroundGISTs are a subset of mesenchymal tumors and represent the most common mesenchymal neoplasms of GI tract. However, GIST is a recently recognized tumor entity and the literature on these stromal tumors has rapidly expanded.MethodsAn extensive review of the literature was carried out in both online medical journals and through Athens University Medical library. An extensive literature search for papers published up to 2009 was performed, using as key words, GIST, Cajals cells, treatment, Imatinib, KIT, review of each study were conducted, and data were abstracted.ResultsGIST has recently been suggested that is originated from the multipotential mesenchymal stem cells. It is estimated that the incidence of GIST is approximately 10-20 per million people, per year.ConclusionThe clinical presentation of GIST is variable but the most usual symptoms include the presence of a mass or bleeding. Surgical resection of the local disease is the mainstay therapy. However, therapeutic agents, such as Imatinib have now been approved for the treatment of advanced GISTs and others, such as everolimus, rapamycin, heat shock protein 90 and IGF are in trial stage demonstrate promising results for the management of GISTs.

The efficacy and safety of gonadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study.

OBJECTIVE The objective of the study was to evaluate the long-term effect of GnRH analog (GnRHa) treatment on final height (FH), body mass index (BMI), body composition, bone mineral density (BMD), and ovarian function. SUBJECTS/METHODS Ninety-two females, evaluated in adulthood, were categorized as follows: group A, 47 girls with idiopathic central precocious puberty (33 GnRHa treated and 14 nontreated); group B, 24 girls with isolated GH deficiency (15 GnRHa and GH treated and nine GH treated); group C, 21 girls with idiopathic short stature (seven GnRHa and GH treated, seven GnRHa treated, and seven nontreated). RESULTS FH, BMD, and percent fat mass of GnRHa-treated patients in all three groups were comparable with those of the respective nontreated subjects. BMI values of GnRHa-treated and nontreated subjects in groups A and C were comparable, whereas in group B, a higher BMI was found in subjects treated only with GH. Nontreated patients with ICPP had greater maximal ovarian volumes, higher LH and LH to FSH ratio, and more severe hirsutism than GnRHa-treated ones. Menstrual cycle characteristics were not different between treated and nontreated subjects. The prevalence of polycystic ovary syndrome in treated and untreated girls with ICPP was comparable, whereas in the entire cohort, it was 11.1% in GnRHa treated and 32.1% in the untreated (P = 0.02). CONCLUSIONS Girls treated in childhood with GnRHa have normal BMI, BMD, body composition, and ovarian function in early adulthood. FH is not increased in girls with ICPP in whom GnRHa was initiated at about 8 yr. There is no evidence that GnRHa treatment predisposes to polycystic ovary syndrome or menstrual irregularities.

A comprehensive immunohistochemical and molecular approach to the PI3K/AKT/mTOR (phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene/mammalian target of rapamycin) pathway in bladder urothelial carcinoma.

Whats known on the subject? and What does the study add?

High incidence of MGMT and RARbeta promoter methylation in primary glioblastomas: association with histopathological characteristics, inflammatory mediators and clinical outcome.

Glioblastomas, the most frequent primary brain tumors in adults, are characterized by a highly aggressive, inflammatory and angiogenic phenotype. Methylation of CpG islands in cancer-related genes may serve as an epigenetic biomarker for glioblastoma diagnosis and prognosis. The aim of this study was to analyze the methylation status of four critical tumor-associated genes (MGMT, RARβ, RASSF1A, CDH13), and investigate possible links with inflammatory (interleukin (IL)-6, IL-8) and angiogenic mediators (vascular endothelial growth factor (VEGF), cyclooxygenase (COX)-2) and clinical outcome in 23 glioma samples (6 grade II astrocytomas, 17 grade IV glioblastomas). RARβ and MGMT genes were more frequently methylated in 70.58% and 58.8% of glioblastomas, respectively. RASSF1A and CDH13 displayed a similar methylation frequency (23.52%) in glioblastomas. No gene methylation was observed in grade II astrocytomas. Tumor grade correlated positively with MGMT and RARβ methylation (P = 0.005 and P = 0.019, respectively) and the extent of necrosis (P= 0.001 and P= 0.003). Interestingly, the marker of chronic inflammation, IL-6, was positively associated with methylation of MGMT (P = 0.004), RARβ (P = 0.002), and RASSF1A (P = 0.0081) as well as the total number of methylated genes (P < 0.0001), indicating the important role of IL-6 in maintaining promoter methylation of these genes. VEGF expression correlated positively with MGMT and RARβ methylation although these relationships were of marginal significance (P= 0.0679 and P = 0.0757). Kaplan-Meier univariate survival analysis indicated an unfavorable survival period in patients with MGMT methylation compared with those without methylation (P= 0.0474). Our study highlights the implication of MGMT and RARβ methylation in the aggressive phenotype of primary glioblastomas. The association of MGMT methylation with clinical outcome indicates its potential prognostic value.

Lysyl oxidase interacts with AGE signalling to modulate collagen synthesis in polycystic ovarian tissue

Connective tissue components – collagen types I, III and IV – surrounding the ovarian follicles undergo drastic changes during ovulation. Abnormal collagen synthesis and increased volume and density of ovarian stroma characterize the polycystic ovary syndrome (PCOS). During the ovulatory process, collagen synthesis is regulated by prolyl hydroxylase and lysyl oxidase (LOX) activity in ovarian follicles. LOX catalyzes collagen and elastin cross‐linking and plays essential role in coordinating the control of ovarian extracellular matrix (ECM) during follicular development. We have recently shown accumulation of advanced glycation end products (AGEs), molecules that stimulate ECM production and abnormal collagen cross‐linking, in ovarian tissue. However, the possible link between LOX and AGEs‐induced signalling in collagen production and stroma formation in ovarian tissue from PCOS remains elusive. The present study investigates the hypothesis of AGE signalling pathway interaction with LOX gene activity in polycystic ovarian (PCO) tissue. We show an increased distribution and co‐localization of LOX, collagen type IV and AGE molecules in the PCO tissue compared to control, as well as augmented expression of AGE signalling mediators/effectors, phospho(p)‐ERK, phospho(p)‐c‐Jun and nuclear factor κB (NF‐κB) in pathological tissue. Moreover, we demonstrate binding of AGE‐induced transcription factors, NF‐κB and activator protein‐1 (AP‐1) on LOX promoter, indicating a possible involvement of AGEs in LOX gene regulation, which may account for the documented increase in LOX mRNA and protein levels compared to control. These findings suggest that deposition of excess collagen in PCO tissue that induces cystogenesis may, in part, be due to AGE‐mediated stimulation of LOX activity.

Clinical significance of nuclear factor (NF)-κB levels in urothelial carcinoma of the urinary bladder

Nuclear factor (NF)-κB has been reported to be constitutively activated in various human neoplasms. However, its clinical significance in bladder urothelial carcinoma (UC) remains an unresolved issue. We conducted this study trying to elucidate the role of NFκB in bladder UC and its potential prognostic significance, by quantifying immunohistochemically the levels of p65/RelA expression in paraffin-embedded tissue from 116 patients. Some of the cases had previously been stained for cellular FLICE-like inhibitory protein (c-FLIP) and bcl-2. Seventy-four cases displayed concurrent cytoplasmic and nuclear immunoreactivity, whereas 18 only nuclear immunoexpression and 21 only cytoplasmic immunoexpression, and the remaining three cases were negative for p65/RelA. Nuclear p65/RelA expression was positively associated with tumour grade and T-category (p = 0.0001 in both cases). In addition, cytoplasmic p65/RelA expression was lower in advanced T-category (p = 0.0030). Moreover, p65/RelA nuclear expression was positively correlated with c-FLIP (p = 0.0109) and bcl-2 (p = 0.0452). p65/RelA nuclear expression adversely affected survival in both univariate and multivariate analysis in superficial (Ta–T1; p = 0.0010 and p = 0.0008) as well as in muscle-invasive carcinomas (T2–T4; p = 0.0004 and p = 0.0003). Our results demonstrate that NF-κB nuclear expression is correlated with histologic grade and T category in bladder UC. Moreover, NF-κB nuclear expression emerges as an independent prognosticator of adverse significance, conveying information beyond that obtained by standard clinicopathological prognosticators.

Expression of nuclear factor κB in human gastric carcinoma: relationship with IκBa and prognostic significance

Nuclear factor (NF)-κB is a transcription factor constitutively activated in various neoplasms, including gastric carcinoma. However, its clinical significance in the latter remains an unresolved issue, as published information is limited and controversial. Furthermore, no data is available about the interaction of NFκB with its inhibitory protein IκBa in gastric carcinoma cases. In this study, the expression of NFκB1/p50 and pIκBa protein was evaluated immunohistochemically in paraffin-embedded tissues from 93 patients. The effect of NFκB1/p50 and pIκBa on clinical outcome was assessed. Positive immunostaining was detected for nuclear NFκB1/p50, cytoplasmic NFκB1/p50 and pIκBa in 91, 68 and 85.7% of cases, respectively. A positive correlation emerged between nuclear NFκB1/p50 and pIκBa (p < 0.0001) and a negative one between cytoplasmic NFκB1/p50 and pIκBa (p = 0.0033). Nuclear NFκB1/p50 was associated with stage (p = 0.0388), the depth of invasion (p = 0.0382), World Health Organization (WHO; p = 0.0326) and Lauren’s histological classification (p = 0.0046). NFκB1/p50 nuclear expression adversely affected survival in both univariate and multivariate analysis (p < 0.0001 and p = 0.02, respectively). Our results suggest that NFκB1/p50 nuclear expression and therefore activation is regulated by its interaction with IκBa and that the former may serve as a useful independent molecular marker for stratifying patients with gastric carcinoma in terms of prognosis.

Phosphorylated 4E-binding protein 1 (p-4E-BP1): a novel prognostic marker in human astrocytomas.

Korkolopoulou P, Levidou G, El‐Habr E A, Piperi C, Adamopoulos C, Samaras V, Boviatsis E, Thymara I, Trigka E‐A, Sakellariou S, Kavantzas N, Patsouris E & Saetta A A 
(2012) Histopathology 61, 293–305

Association of aberrant DNA methylation with clinicopathological features in breast cancer

Aberrant DNA methylation is responsible for the epigenetic silencing of genes associated with tumourigenesis and progression of cancer. In this study, we assessed the methylation status of eight genes in 49 snap-frozen primary breast tumours. Epigenetic alterations of 8 genes were analysed with methylation-specific polymerase chain reaction (MS-PCR) (DCR1, DAPK1, RASSF1A and DCR2) or methylation-sensitive high-resolution melting analysis (MS-HRM) (APC, MGMT, GSTP1 and PTEN). MS-HRM performance was validated by bisulfite pyrosequencing regarding the methylation levels of MGMT. Promoter methylation was observed in APC 54.34%, 40.4% DCR1, 37.5% DAPK1, 33.3% RASSF1A, 22.44% MGMT, 16.6% GSTP1, 6% PTEN and 0% DCR2 promoters, respectively. Interestingly, 37 out of 49 cases (75.5%) displayed aberrant promoter methylation in at least one gene. An association of MGMT promoter methylation with age and tumour grade was recorded. Moreover, a correlation with advanced T-category was elicited for GSTP1, RASSF1 and DAPK1 promoter methylation. Finally, concurrent methylation of several genes showed a marginal statistical relationship with N-category. We conclude that APC, DCR1, DAPK1 and RASSF1A promoter methylation represents a common event in breast cancer tumourigenesis. Our results suggest that GSTP1, RASSF1, DAPK1 and MGMT may be implicated in the acquisition of a more aggressive phenotype in breast cancer.

pERK activation in esophageal carcinomas: Clinicopathological associations

MAPK (mitogen-activated protein kinase) pathway is considered a control regulator in various malignant tumors but its role in esophageal carcinomas remains elusive. In our study, we examined the possible prognostic significance of MAPK pathway in human esophageal cancer. We searched for mutations in exons 18-21 of EGFR gene, codons 12 and 13 of K-RAS gene and exon 15 of B-RAF gene by high resolution melting analysis (HRMA) and pyrosequencing in 44 esophageal carcinomas. Immunohistochemistry was performed in 29 cases in order to evaluate expression levels of pERK (extracellular-signal regulated kinase). In one laser microdissected squamous cell carcinoma, a somatic K-RAS mutation at codon 12 was detected, whereas none of the cases displayed mutations in EGFR and B-RAF genes. Elevated nuclear as well as cytoplasmic pERK expression (100% and 62% of cases respectively) was observed independently of EGFR and B-RAF mutational status. Increasing pERK nuclear and cytoplasmic expression as well as the intensity of nuclear staining was found to be significantly correlated with tumor grade in univariate and multivariate statistical analysis. Our findings depict the presence of activated ERK despite the low frequency of upstream alterations, implicating ERK activation in the acquisition of a more aggressive phenotype in esophageal cancer.