Role of molecular analysis in the adjuvant treatment of gastrointestinal stromal tumours: It is time to define it

Sendur et al pointed out the attention on the importance of mutational analysis for adjuvant treatment of gastrointestinal stromal tumor (GIST) in an article published in World Journal of Gastroenterology . In particular, they suggested that the optimal dose and duration of adjuvant therapy could be defined by the mutational status of the primary disease. This comment would underline the importance of centralised laboratories, given the increasingly important role of molecular analysis in the work-flow of all GIST, and the need of retrospective analyses for subgroups population stratified for the mutational status from the available studies in the adjuvant setting, in order to define the role of mutational analysis in choosing the optimal dose and duration of adjuvant therapy.

Nilotinib-mediated mucosal healing in a rat model of colitis

AIM:To investigate the effects of nilotinib in a rat model of trinitrobenzene sulfonic acid(TNBS)-induced colitis.METHODS:Twenty-one Wistar albino female rats obtained from Dokuz Eylul University Department of Laboratory Animal Science were categorized into a control(n=7),TNBS(n=7)and nilotinib group(n=7).Saline was administered orally for 14 d to the control and the TNBS group.The TNBS group received rectal TNBS on the first day while saline was administered to the control group.The nilotinib group received 20mg/kg nilotinib for 14 d in 2 divided doses,starting the same day as TNBS administration.For 14 d,the rats were fed a standard diet,and their weights were recorded daily.After sacrifice,colon tissue samples from each group were scored for macroscopic and microscopic pathology.Apoptotic indices were determined by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling method.Platelet-derived growth factor receptor(PDGFR)alpha and beta levels were assessed through immunohistochemistry staining scores and compared among the groups.Tissue and serum tumor necrosis factor(TNF)alpha levels were determined by enzyme-linked immunosorbent assay.RESULTS:Between days 1 and 14,the nilotinib group rats lost significantly less weight than the TNBS group rats(-0.7 g vs-14.0 g,P=0.047).The difference in weight between the control and nilotinib groups was also statistically significant(+8.3 gvs-0.7 g,P=0.031).From day 7 to day 14,the weight differences of the control group vs the TNBS group,the TNBS group vs the nilotinib group,and the control group vs the nilotinib group were all statistically significant(+8.0 g vs-11.1 g,P=0.007;-11.1 g vs+2.9 g,P=0.015;+8.0g vs+2.9 g,P=0.042,respectively).Macroscopic and microscopic scores were significantly lower in the nilotinib group than in the TNBS group(0.00±0.00 vs 1.43±0.65,P=0.009;2.86±0.55 vs 7.71±1.48,P=0.030,respectively).However,these scores were similar between the nilotinib and control groups.While no significant difference for the nilotinib vs control groups could be determined for PDGFR alpha and beta scores,PDGFR alpha and beta scores were lower in the nilotinib group than in the TNBS group.Furthermore,the TNF alpha levels in the serum,tissue and apoptosis scores were similar between the nilotinib and TNBS groups.CONCLUSION:Nilotinib prevents weight loss,facilitates mucosal healing by improving the pathological scores without introducing variation into the apoptotic scores or TNF alpha levels.

Immunohistochemical and molecular genetic analyses of multiple sporadic gastrointestinal stromal tumors

A 77-year-old Japanese male patient was admitted to our hospital complaining of general fatigue and melena. A gastroduodenal endoscopic examination revealed no def initive localized lesions. However, both a large amount of cruor and blood ? ow from the small intestine into the ascending colon was observed during the colonoscopic examination. At least three tumors, believed to originate from the small intestine, were detected by abdominal computed tomography. Based on these f indings, multiple and hemorrhagic small intestinal tumors were diagnosed and surgical treatment of the tumors planned. During the celiotomy, twelve tumors were found in the small intestine. Intestinal wedge or partial resection was applied. All excised specimens demonstrated morphology of a submucosal tumor and the largest tumor had a delle with coagulation on the mucosal face. In the histological f indings, hematoxylin and eosin staining showed spindlecell morphology. The immunohistochemical examination revealed that the tumor cells were diffusely positive for KIT and CD34. The myenteric plexus layer of the small intestine was focal-positive for KIT and showed no intestinal cells of Cajal hyperplasia. The tumor sequencing results revealed an identical missense mutation in codon 642 of c-kit exon 13 leading to the replacement of lysine by glutamic acid and a silent germ-line mutation in exon 12 of the PDGFRA gene concerning whole blood, normal mucosa and tumors. We concluded that the current subject was categorized as having multiple sporadic-type gastrointestinal stromal tumor with identical mutational types. Although the patient did not receive any adjuvant chemotherapy, there has been no sign of recurrence over the 3 years since the surgery.

Involvement of p38 mitogen-activated protein kinase in the regulation of platelet-derived growth factor -induced cell migration

The aim of this study was to investigate the role of p38 mitogen-activated protein kinase(MAPK)in cell migration induced by platelet-derived growth factor(PDGF).Western blot was performed to detect the phosphorylation of p38 in NIH3T3 cells treated with PDGF.A Transwell cell migration system was used to determine the effects of PDGF treatment on the migration of NIH3T3 cells and the influence of p38 deficiency on this process in a p38 gene knockout(p38^(−/−))mouse embryonic fibroblast cell line.On the stimulation of PDGF,the migration of NIH3T3 cells was significantly increased(P<0.001)compared to the control and p38 MAP kinase was simultaneously phosphorylated.Furthermore,the PDGF-induced cell migration was significantly blocked in p38 gene knockout(p38^(−/−))mouse embryonic fibroblasts(MEFs)(P<0.001)as compared with the wild type cells(p38+/+).p38 MAPK plays an important role in the regulation of cell migration induced by PDGF.