Reactive oxygen species activation of MAPK pathway results in VEGF upregulation as an undesired irradiation response.

BACKGROUND: Radioresistance limits the effectiveness of radiotherapy in head and neck squamous cell carcinoma. We previously demonstrated post-radiogenic mitogen-activated protein kinase (MAPK) pathway activation and vascular endothelial growth factor (VEGF) release resulting in reduced tumor cell response. Here, we examined the association of this mechanism with the induction of reactive oxygen species (ROS) under irradiation (IR). METHODS: Intracellular ROS after IR were measured. We modeled radiation-induced ROS by exposure of two SCC lines to H2 O2 and evaluated the impact of irradiation and ROS on ERK phosphorylation by Western blot, immunohistochemistry, and ELISA. RESULTS: We found elevated pERK levels after treatment with IR and H2 O2 , which could be distinctly suppressed by U0126. Immunohistochemistry and ELISA revealed increased intracellular VEGF levels after H2 O2 application. CONCLUSIONS: Our data show that irradiation-induced ROS activate the MAPK pathway and release of VEGF. As VEGF is known to be released after cellular distress resulting in cytoprotection, the described mechanism is potentially of importance for therapy success.

The incidence of adenoidal regrowth after adenoidectomy and its effect on persistent nasal symptoms.

Objective of the study is to evaluate the effectiveness of adenoidectomy for children, to asses the rates of adenoidal regrowth and find out if the regrowth of adenoidal tissue affects persistent nasal symptoms post-surgery. A prospective study was carried out in the period of 2005-2007. The inclusion criteria for patients in the study were hypertrophic adenoid tissue and moderate or severe persistent nasal obstruction. One hundred and fifty children had undergone an adenoidectomy using consistent technique and visual control. Medium-term follow-up results were conducted 12-24 months (the mean follow-up period was 17.1 months) post-surgery, performing transnasal fibroscopy and completing the questionnaire. A total of 104 (69.3%) out of 150 patients polled. Children's parents answered the questions that were used for the subjective assessment of symptoms and to ascertain the history of the patient's nasal obstruction and upper respiratory tract infection prior to surgery. The age range was from 3 to 15, of which, 68 (65.3%) of them had undergone a transnasal fibroscopy. There was a significant reduction in symptoms that were displayed by children prior to the operation: there were 5.8% patients with nasal obstruction after the surgery, while incidences of upper airway infections dropped from 79.8 to 7.7% after surgery (P < 0.001). Eighty-six (82.7%) parents considered their child's well-being as "having improved" and they were "satisfied" with the results. Transnasal fibroscopy examinations identified some regrowth of adenoidal tissue in 13 cases (19.1%), with only 3 cases demonstrating adenoidal regrowth to grade 1. Adenoidal regrowth was correlative with the age of the patients (P = 0.048) and to numerous postoperative treatment with antibiotics (P = 0.032). Adenoids rarely regrow after surgery and where there were traces of adenoidal tissue, it did not manifest clinically. Nasal obstruction after the adenoidectomy is rhinogenic origin, not the cause of enlarged adenoids. Adenoidal regrowth more often occurs in children younger than five years old and in those patients who were treated postoperatively with antibiotics on numerous occasions.

Increased radioresistance via G12S K-Ras by compensatory upregulation of MAPK and PI3K pathways in epithelial cancer.

BACKGROUND: Irradiation-induced signaling via the 2 pathways, Raf-MEK-ERK and PI3K-Akt, is known to be closely associated with a limited response to radiotherapy. In the present study we analyzed the relevance of constitutively active K-Ras for postradiogenic pathway stimulation and the option of coordinated inhibition to overcome these rescue mechanisms. METHODS: We used 2 epithelial tumor cell lines as a model system, one of them harboring a G12S K-Ras mutation. Cells were irradiated and the effect of combined treatment with ionizing radiation and inhibitors on the expression of pERK and pAkt was determined by Western blotting. Additionally, clonogenic assays were performed to functionally analyze survival of the cell lines. RESULTS: Compared with the nonmutated cells we observed the G12S cell line showing a clearly reduced response to inhibitor treatment under irradiation. In the case of pharmacologic inhibition of 1 of the pathways a compensatory upregulation of the second cascade leading to increased clonogenic survival seems feasible. However, there was a good functional response of this cell line to double inhibition with both compounds represented by minimized colony forming ability. The activation of ERK and Akt after irradiation was confirmed in xenotransplants showing elevated postradiogenic protein levels. CONCLUSION: With our data we confirmed our hypothesis of postradiogenic constitutive activation of the 2 pathways both required for Ras-mediated radioresistance in epithelial cells. If this effect should prove itself as a general mechanism in Ras-mutated tumors, application of specific inhibitors to block both cascades in parallel could contribute to enhance radiosensitivity in these types of cancer.

Results of treatment of extrahepatic cholangiocarcinoma at Kaunas University of Medicine Hospital.

Adenocarcinoma of the extrahepatic bile ducts is considered to be a rare cause of obstructive jaundice. Prognosis is poor and only radical surgery can prolong the life of such patients. The aim of study was to evaluate the outcome of treatment of patients having extrahepatic carcinoma of the bile ducts. Patients underwent treatment at Kaunas University of Medicine Hospital. A retrospective study was performed of 57 patients suffering from cancer of extrahepatic bile ducts in 1996-2001. Diagnosis was established by ultrasonography, endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography and computed tomography. Sixteen patients (25%) received symptomatic treatment. Thirty-three patients (61%), receiving palliative therapy, underwent a biliodigestive bypass (n=14), an intraoperative biliary stenting (n=10), an endoscopic biliary drainage (n=6), or percutaneous transhepatic biliary drainage (n=3). Eight patients (14%) underwent radical resections of bile ducts: five patients had resections of bile ducts with D2 lymphonodectomy, two patients had bile duct resections in combination with pancreatoduodenal resection and one patient had resection of the bile ducts in combination with right hepatectomy. Histological examinations of the resected specimens revealed a curative effect in seven out of eight cases. There were no deaths in the group of radically treated patients. In the group of patients receiving palliative therapy 8 patients died: four patients died because of cardiovascular complications, two patients died of hepatorenal syndromes, one patient died because of multiorgan failure and one died of peritonitis. Five patients died in the group receiving symptomatic treatment. Assessing remote results of treatment, median survival time of patients who underwent resection was 89 days. Survival results of patients who had curative resections were much better (ranging from 277 to 1084 days). Median survival time of patients, receiving palliative treatment, was 65 days and 29 days of group, receiving symptomatic treatment. Recent progress made in surgical techniques and in perioperative management of extrahepatic cholangiocarcinomas as well as modern diagnostic achievements has greatly contributed to the outcomes of radical surgery. The main aim of the treatment is to perform resection of the bile ducts cancer.