Oncologic Outcome and Morbidity in the Elderly Rectal Cancer Patients After Preoperative Chemoradiotherapy and Total Mesorectal Excision: A Multi-institutional and Case-matched Control Study.

OBJECTIVE: To determine the toxicity and oncologic outcome of neoadjuvant chemoradiotherapy (CRT) followed by curative total mesorectal excision (TME) in the elderly (≥70 yrs) and younger (<70 yrs) rectal cancer patients. BACKGROUND: Sufficient data for elderly rectal cancer patients who received definitive trimodality have not been accumulated yet. PATIENTS AND METHODS: A total of 1232 rectal cancer patients who received neoadjuvant CRT and TME were enrolled in this study. After propensity-score matching, 310 younger patients and 310 elderly patients were matched with 1:1 manner. Treatment response, toxicity, surgical outcome, recurrence, and survival were assessed and compared between the 2 groups of patients. RESULTS: The median age was 58 years for the younger patient group and 74 years for the elderly group. Pathologic complete response rates were not significantly different between the 2 groups (younger and elderly: 17.1% vs 14.8%, P = 0.443). The 5-year recurrence-free survival (younger and elderly: 67.7% vs 65.5%, P = 0.483) and overall survival (younger and elderly: 82.9% vs. 79.5%, P = 0.271) rates were not significantly different between the 2 groups either. Adjuvant chemotherapy after surgery was less frequently delivered to the elderly than that to younger patients (83.9% vs 69.0%). Grade 3 or higher acute hematologic toxicity was observed more frequently in the elderly than that in the younger group (9.0% vs 16.1%, P = 0.008). Late complication rate was higher in the elderly group compared with that in the younger group without statistical significance (2.6% vs 4.5%, P = 0.193). CONCLUSIONS: Although acute hematologic toxicity was observed more frequently in the elderly patients than that in the younger patients, elderly rectal cancer patients with good performance status who received preoperative CRT and TME showed favorable tumor response and recurrence-free survival similar to younger patients.

High glucose-induced apoptosis in bovine retinal pericytes is associated with transforming growth factor beta and betaIG-H3: betaIG-H3 induces apoptosis in retinal pericytes by releasing Arg-Gly-Asp peptides.

BACKGROUND: Transforming growth factor beta (TGF-beta) plays an important role in diabetic retinopathy. betaIG-H3 is a downstream target molecule of TGF-beta that may participate in the pathogenesis of diabetic retinopathy and in particular in the loss of pericytes during early pathological changes. METHODS: We observed bovine retinal pericytes apoptosis and the increased expression of TGF-beta and betaIG-H3 induced by high concentrations of glucose in the cell culture media. An anti-TGF-beta antibody was used to block glucose-induced retinal pericytes apoptosis. Retinal pericytes were also transfected with cDNA encodings either wild-type or mutant betaIG-H3 lacking Arg-Gly-Asp (RGD) sequences in order to validate the effects of betaIG-H3 and RGD signalling on retinal pericytes apoptosis. RESULTS: A cell death-detecting enzyme-linked immunosorbent assay revealed that 25 mM glucose significantly increased cell death compared with 5.5 mM glucose after 5 or 7 days of exposure (P < 0.01). High glucose significantly increased the TGF-beta levels as compared with 5.5 mM glucose after 5 days, and betaIG-H3 levels after 3, 5 and 7 days of exposure (P < 0.01). TGF-beta increased cell death and betaIG-H3 levels in a dose-dependent manner, with a maximal effect observed at 1 ng/mL. An anti-TGF-beta antibody nearly completely blocked high glucose-induced cell death. Wild-type betaIG-H3-transfected cells showed a significant increase in cell death as compared with mutant betaIG-H3-transfected (Mycb-c) cells, untransfected or mock-transfected cells. CONCLUSION: These results suggest that hyperglycaemia-induced expression of TGF-beta and betaIG-H3 contributes to accelerated retinal pericytes apoptosis. betaIG-H3 induces pericytes apoptosis through its RGD motif, which may constitute an important pathogenic mechanism leading to pericytes loss in diabetic retinopathy.

Intracellular fatty acid metabolism in skeletal muscle and insulin resistance.

Triglyceride accumulation in skeletal muscle is increased in subjects with insulin resistance. Increased intracellular lipolysis from stored triglyceride may induce insulin resistance in skeletal muscle by activating the glucose-fatty acid cycle. However, inconsistent with this hypothesis, intracellular lipolysis from skeletal muscle is decreased in high fat-fed, insulin resistant rats. Therefore, it is suggested that an increase in triglyceride accumulation is the result of decreased mitochondrial fatty acid oxidation in the cells. As evidence, fenofibrate (a PPARalpha activator), rosiglitazone (a PPARgamma activator) and alpha-lipoic acid completely prevented the development of diabetes in obese diabetes-prone rats. All three drugs increased fatty acid oxidation and decreased triglyceride accumulation in skeletal muscle. Administration of ALA activated AMPK and increased fatty acid oxidation. It is suggested that decreased fatty acid oxidation in skeletal muscle is one of the major factors leading to an accumulation of lipid metabolites and insulin resistance.