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1.  mTOR pathway: A current, up-to-date mini-review (Review) 
Oncology Letters  2014;8(6):2367-2370.
Mammalian target of rapamycin (mTOR) is a protein serine/threonine kinase that was initially identified as the cellular target of rapamycin. This kinase regulates cell growth, proliferation, motility and survival, as well as the gene transcription and protein synthesis that are activated in response to hormones, growth factors and nutrients. Results from preclinical studies have indicated that factors antagonizing the mTOR pathway exert an antitumor effect on lung cancer. Furthermore, primary clinical trials of mTOR inhibitors have demonstrated that the inhibitors may be effective against lung carcinoma. The present study explores the association between mTOR and lung carcinogenesis and describes the clinical trials of mTOR inhibitors.
PMCID: PMC4214394  PMID: 25360163
mTOR; lung cancer; targeted therapy
2.  Inhaled tyrosine kinase inhibitors for pulmonary hypertension: a possible future treatment 
Pulmonary hypertension is a disease with severe consequences for the human body. There are several diseases and situations that induce pulmonary hypertension and are usually underdiagnosed. Treatments include conventional medical therapies and oral, inhaled, intravenous, and subcutaneous options. Depending on its severity, heart or lung transplant may also be an option. A possible novel treatment could be tyrosine kinase inhibitors. We conducted experiments with three jet nebulizers and three ultrasound nebulizers with erlotinib, gefitinib, and imatinib. Different residual cup designs and residual cup loadings were used in order to identify the best combination to produce droplets of less than 5 μm in mass median aerodynamic diameter. We found that gefitinib could not be transformed into a powder, so conversion to an aerosol form was not possible. Our experiments indicated that imatinib is superior to erlotinib with regard to small droplet size formation using both inhaled technologies (1.37 μm <2.23 μm and 1.92 μm <3.11 μm, jet and ultrasound, respectively) and, at jet devices (1.37 μm <1.92 μm). Cup designs C and G contribute best to small droplet creation uniquely supporting and equally well the activity of both drugs. The disadvantage of the large droplets formed for erlotinib was offset when combined with residual cup C (1.37 μm instead of 2.23 μm). At a 2 mL dose, the facemask and cone mouthpieces performed best and evenly; the facemask and low dose were the best choice (2.08 μm and 2.12 μm, respectively). Erlotinib and imatinib can be administered as an aerosols, and further in vivo experimentation is necessary to investigate the positive effects of these drugs in the treatment of pulmonary hypertension.
PMCID: PMC4199972  PMID: 25336919
erlotinib; gefitinib; imatinib; jet nebulizers; ultrasound nebulizers
3.  KRAS, NRAS and BRAF mutations in Greek and Romanian patients with colorectal cancer: a cohort study 
BMJ Open  2014;4(5):e004652.
Treatment decision-making in colorectal cancer is often guided by tumour tissue molecular analysis. The aim of this study was the development and validation of a high-resolution melting (HRM) method for the detection of KRAS, NRAS and BRAF mutations in Greek and Romanian patients with colorectal cancer and determination of the frequency of these mutations in the respective populations.
Diagnostic molecular laboratory located in Athens, Greece.
2425 patients with colorectal cancer participated in the study.
Primary and secondary outcome measures
2071 patients with colorectal cancer (1699 of Greek and 372 of Romanian origin) were analysed for KRAS exon 2 mutations. In addition, 354 tumours from consecutive patients (196 Greek and 161 Romanian) were subjected to full KRAS (exons 2, 3 and 4), NRAS (exons 2, 3 and 4) and BRAF (exon 15) analysis. KRAS, NRAS and BRAF mutation detection was performed by a newly designed HRM analysis protocol, followed by Sanger sequencing.
KRAS exon 2 mutations (codons 12/13) were detected in 702 of the 1699 Greek patients with colorectal carcinoma analysed (41.3%) and in 39.2% (146/372) of the Romanian patients. Among the 354 patients who were subjected to full KRAS, NRAS and BRAF analysis, 40.96% had KRAS exon 2 mutations (codons 12/13). Among the KRAS exon 2 wild-type patients 15.31% harboured additional RAS mutations and 12.44% BRAF mutations. The newly designed HRM method used showed a higher sensitivity compared with the sequencing method.
The HRM method developed was shown to be a reliable method for KRAS, NRAS and BRAF mutation detection. Furthermore, no difference in the mutation frequency of KRAS, NRAS and BRAF was observed between Greek and Romanian patients with colorectal cancer.
PMCID: PMC4039802  PMID: 24859998
Molecular Biology
4.  Safety and Efficacy of Suicide Gene Therapy with Adenosine Deaminase 5-Fluorocytosine Silmutaneously in in Vitro Cultures of Melanoma and Retinal Cell Lines 
Journal of Cancer  2014;5(5):368-381.
Local treatment as a treatment modality is gaining increased general acceptance over time. Novel drugs and methodologies of local administration are being investigated in an effort to achieve disease local control. Suicide gene therapy is a method that has been investigated as a local treatment with simultaneously distant disease control. In our current experiment we purchased HTB-70 (melanoma cell line, derived from metastatic axillary node) and CRL-2302 (human retinal epithelium) were from ATCC LGC Standards and Ancotil®, 2.5 g/250 ml (1 g/00ml) (5-Flucytosine) MEDA; Pharmaceuticals Ltd. UK. Adenosine Cytosine Deaminase (Ad.CD) was also used in order to convert the pro-drug 5-Flucytosine to the active 5-Fluoracil. Three different concentrations of 5-Flucytosine (5-FC) were administered (0.2ml, 0.8ml and 1.2ml). At indicated time-points (4h, 8h and 24h) cell viability and apoptosis were measured. Our concept was to investigate whether suicide gene therapy with Ad. CD-5-FC could be used with safety and efficiency as a future local treatment for melanoma located in the eye cavity. Indeed, our results indicated that in every 5-FC administration had mild cytotoxicity for the retinal cells, while increased apoptosis was observed for the melanoma cell line.
PMCID: PMC4007525  PMID: 24799955
suicide gene therapy; 5-fluorocytosine; melanoma; retinal.
5.  Prognostic significance of different immunohistochemical S100A2 protein expression patterns in patients with operable nonsmall cell lung carcinoma 
OncoTargets and therapy  2012;5:363-373.
S100 proteins are involved in carcinogenesis, metastasis, and survival. S100A2 is a member of the S100 family, and its expression and precise role in patients with non-small cell lung carcinoma (NSCLC) has been debated. Therefore, we examined the immunohistochemical expression patterns of S100A2 in NSCLC in relation to clinicopathological parameters, important molecular biomarkers, and patient outcome. Microarray data for 74 paraffin-embedded specimens from patients with NSCLC were immunostained for S100A2 and p53 proteins. Immunohistochemical staining patterns of S100A2 in the NSCLC tissue samples examined were either nuclear (nS100A2), cytoplasmic (cS100A2), or both. A significant association between nS100A2 positivity and better disease-free interval was observed (hazards ratio 0.47; 95% confidence interval 0.23–0.99; P = 0.047). Similarly, cS100A2 negativity was marginally associated with shorter overall survival (P = 0.07). Patients without lymphatic infiltration and an earlier disease stage had significantly better overall survival and disease-free interval. The S100A2 expression pattern in operable NSCLC varies widely, and this differential expression (nuclear, cytoplasmic or both) seems to correlate with prognosis. Intensity of expression was highest in the early and advanced stages, and equally distributed in the middle stages. This observation may be indicative of a dual role for this protein both during earlier and advanced disease stages, and may also explain the differential immunoexpression of S100A2. Analysis of the disease-free interval showed that nS100A2-negative and p53-positive expression was associated with a statistically significant (P = 0.003) shorter disease-free interval in comparison with nS100A2-positive and p53-negative expression (12 versus 30 months, respectively). Further studies are required to establish whether S100A2 protein may have a substantial role as a prognostic or predictive indicator in this unfavorable group of patients.
PMCID: PMC3507318  PMID: 23189031
S100A2; expression; lung cancer; thoracic surgery
6.  γ-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer 
OncoTargets and therapy  2012;5:309-314.
Phosphorylation of the H2AX histone is an early indicator of DNA double-strand breaks and of the resulting DNA damage response. In the present study, we assessed the expression and prognostic significance of γ-H2AX in a cohort of 96 patients with operable non-small cell lung carcinoma.
Ninety-six paraffin-embedded specimens of non-small cell lung cancer patients were examined. All patients underwent radical thoracic surgery of primary tumor (lobectomy or pneumonectomy) and regional lymph node dissection. γ-H2AX expression was assessed by standard immunohistochemistry. Follow-up was available for all patients; mean duration of follow-up was 27.50 ± 14.07 months (range 0.2–57 months, median 24 months).
Sixty-three patients (65.2%) died during the follow-up period. The mean survival time was 32.2 ± 1.9 months (95% confidence interval [CI]: 28.5–35.8 months; median 30.0 months); 1-, 2- and 3-year survival rates were 86.5% ± 3.5%, 57.3% ± 5.1%, and 37.1% ± 5.4%, respectively. Low γ-H2AX expression was associated with a significantly better survival as compared with those having high γ-H2AX expression (35.3 months for low γ-H2AX expression versus 23.2 months for high γ-H2AX expression, P = 0.009; hazard ratio [HR] 1.95, 95% CI: 1.15–3.30). Further investigation with multivariate Cox proportional hazards regression analysis revealed that high expression of γ-H2AX remained an independent prognostic factor of shorter overall survival (HR 2.15, 95% CI: 1.22–3.79, P = 0.026). A combined p53/γ-H2AX analysis was performed, and we found that the p53 low/γ-H2AX low phenotype was associated with significantly better survival compared with all other phenotypes.
Our study is the first to demonstrate that expression of γ-H2AX detected by immunohistochemistry may represent an independent prognostic indicator of overall survival in patients with non-small cell lung cancer. Further studies are needed to confirm our results.
PMCID: PMC3501397  PMID: 23180966
H2AX; DNA damage response; non-small cell lung cancer; p53; prognosis
7.  Reversible Posterior Leukoencephalopathy Syndrome Induced by Pazopanib 
BMC Cancer  2012;12:489.
The reversible posterior leukoencephalopathy syndrome is a clinical/radiological syndrome characterized by headache, seizures, impaired vision, acute hypertension, and typical magnetic resonance imaging findings. There are several reports in the literature that depict its occurrence in cancer patients. The list of common anticancer and supportive care drugs that predispose to reversible posterior leukoencephalopathy syndrome is expanding and includes not only a large number of chemotherapeutic agents but also an increased number of new targeted drugs, particularly angiogenesis inhibitors such as bevacizumab,sorefenib and sunitinib. Pazopanib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit which after a positive phase III randomized clinical trial in patients with advanced renal cell cancer received FDA approval for the treatment of advanced renal cell carcinoma. Until now no cases of reversible posterior leukoencephalopathy syndrome induced by pazopanib have been reported.
Case report
We present the case of a 40 years old female patient with heavily pre-treated metastatic renal cell carcinoma who received pazopanib as salvage treatment. After 21 days of pazopanib therapy the patient referred to the emergency department with epileptic seizure, impaired vision at both eyes and headache. MRI of the brain revealed subcortical oedema at the occipital and parietal lobes bilaterally. She was treated with anticonvulsants, i.v. administration of mannitol and antihypertensives and she recovered completely from her symptoms and was discharged on the tenth hospital day. A brain MRI performed 3 weeks after showed that the subcortical oedema had been subsided.
In conclusion this is the first case of pazopanib induced reversible posterior leukoencephalopathy syndrome. Although usually reversible, this syndrome is a serious and potentially life threatening adverse effect, if untreated, that should be considered by physicians treating metastatic renal cell carcinoma patients with pazopanib.
PMCID: PMC3487903  PMID: 23088634
Reversible posterior leukoencephalopathy syndrome; Pazopanib; Renal cell carcinoma
8.  Preliminary Results of Hyperthermic Intraperitoneal Intraoperative Chemotherapy as an Adjuvant in Resectable Pancreatic Cancer 
Background and Aims. 5-year survival in patients with pancreatic cancer is poor. Surgical resection is the only potentially curative resection. The results of adjuvant treatment either with chemotherapy or with radiotherapy have been contradictory and the incidence of local-regional recurrence remains high. If local-regional recurrence is controlled survival may be expected to increase. Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) may be used in order to control local-regional recurrences. The purpose of the study is to identify the effect of HIPEC in patients with pancreatic cancer undergoing potentially resection. Patients and Methods. From 2007–2011, 21 patients, mean age 69.4 ± 9.5 (50–86) years, underwent tumor resection, and HIPEC with gemcitabine. The hospital mortality and morbidity rate was 9.5% and 33.3%, respectively. 5-year and median survival was 23% and 11 months, respectively. The recurrence rate was 50% but no patient developed local-regional recurrence. No patient was recorded with gemcitabine-induced toxicity. Conclusions. This clinical study of 21 patients is the first to combine an R0 pancreas cancer resection with HIPEC. Increased morbidity and mortality from intraoperative gemcitabine was not apparent. Patients with pancreatic cancer undergoing potentially curative resection in combination with HIPEC may be offered a survival benefit. Data suggested that local-regional recurrences may be greatly reduced. Further studies with greater number of patients are required to confirm these findings.
PMCID: PMC3368190  PMID: 22693491
9.  Cytoreductive Surgery Combined with Hyperthermic Intraperitoneal Intraoperative Chemotherapy in the Treatment of Advanced Epithelial Ovarian Cancer 
Journal of Oncology  2012;2012:358341.
Background/Aims. Intraperitoneal intraoperative hyperthermic chemotherapy (HIPEC) has been used in the treatment of ovarian cancer. The purpose of the study is to determine the efficacy of HIPEC after cytoreductive surgery in advanced ovarian cancer. Patients/Methods. From 2006 to 2010 patients with advanced ovarian cancer were enrolled in a prospective nonrandomized study to undergo cytoreductive surgery combined with HIPEC. Clinical and histopathological variables were correlated to hospital mortality, morbidity, survival, and recurrences. Results. The mean age of 43 women was 59.9 ± 13.8 (16–82) years. The hospital mortality and morbidity rate were 4.7% and 51.2%, respectively. Complete cytoreduction was possible in 69.8%. The overall 5-year survival rate was 54%. The prognostic indicators of survival were the extent of prior surgery (P = 0.048) and the extent of peritoneal dissemination (P = 0.011). The recurrence rate was 30.2%. Conclusions. Maximal cytoreductive surgery combined with HIPEC is a well-tolerated, feasible, and promising method of treatment in advanced ovarian cancer.
PMCID: PMC3306908  PMID: 22481924
10.  Synchronous Carcinoma of the Ampulla of Vater and Colon Cancer 
Case Reports in Gastroenterology  2011;5(2):301-307.
Carcinoma of the papilla of Vater is a relatively rare tumor and its coexistence with other primary sporadic cancers is very exceptional. Here we report the case of a 76-year-old man who presented with painless obstructive jaundice, pathologically elevated liver function tests and increased serum levels of carbohydrate antigen 19-9 and carcinoembryonic antigen. Endoscopic retrograde cholangiography revealed a large polypoid mass in the ampulla of Vater. A large tumor in the ascending colon was also incidentally detected by abdominal computed tomography. Endoscopic biopsies from both lesions showed adenocarcinomas. Metastases to the liver and to the hepatoduodenal ligament and hepatic artery lymph nodes were found during surgery. Right colectomy and a biliary bypass were performed. Histological analysis showed an ampullary adenocarcinoma with metastases to regional lymph nodes and the liver and a colonic adenocarcinoma with local invasion into the pericolic fat. Treatment with gemcitabine plus cisplatin was suggested postoperatively. The association of sporadic ampullary and colonic adenocarcinomas and the mutually increased risk of developing either a synchronous or a metachronous tumor following each other should be considered in patients with primary ampullary or colorectal cancer during the preoperative evaluation and postoperative follow-up of these patients.
PMCID: PMC3124321  PMID: 21712944
Ampullary carcinoma; Colorectal carcinoma; Papilla of Vater carcinoma; Second primary cancer; Synchronous cancer
11.  Synchronous Breast and Rectal Cancers in a Man 
Case Reports in Oncology  2011;4(2):281-286.
Breast cancer in men is relatively rare and its coexistence with other primary non-breast cancers exceptional. Here, we report the case of a 50-year-old man who presented with symptoms of rectal adenocarcinoma and in whom a synchronous, asymptomatic cancer of the left breast was found incidentally at physical examination.
PMCID: PMC3124462  PMID: 21734883
Colorectal carcinoma; Male breast cancer; Second primary cancer; Synchronous cancer

Results 1-11 (11)