Expression of BMP-7 in human gastric cancer and its clinical significance.

BACKGROUND: Bone morphogenetic protein-7 (BMP-7) is a signalling molecule belonging to the transforming growth factor--superfamily. Recent studies have demonstrated the clinical impact of BMP-7 expression in various human cancers. However, there have been few reports detailing this in gastric cancer. METHODS: We immunohistochemically investigated the expression of BMP-7 in 233 gastric cancer patients to disclose the clinicopathological features of BMP-7-positive gastric cancer. RESULTS: Immunohistochemically, in human gastric cancer, BMP-7 expression was identified in cellular membranes but also in the cytoplasm of cancer cells. Bone morphogenetic protein-7-positive expression was found in 129 of 233 patients (55%). Bone morphogenetic protein-7 expression was correlated with tumour size, nodal involvement, lymphatic invasion, venous invasion and histology (P<0.05). Bone morphogenetic protein-7 expression was significantly correlated with patient postoperative outcome, especially in the undifferentiated group. Multivariate analysis revealed BMP-7 expression as one of the independent prognostic factors next to the depth of invasion and nodal involvement (P<0.01). CONCLUSIONS: From the data collected, it would be appropriate to conclude on the possible regulation of gastric cancer progression by autocrine or paracrine BMP-7 loops. We can use BMP-7 expression as one of the strong predictors of risk of tumour recurrence in gastric cancer.

Functional RET G691S polymorphism in cutaneous malignant melanoma.

RET proto-oncogene encodes a receptor tyrosine kinase whose ligand is glial cell line-derived neurotrophic factor (GDNF), and its polymorphism at G691S juxtamembrane region (RETp) is a germline polymorphism. Cutaneous melanomas, particularly the desmoplastic subtype, are highly neurotropic; thus we sought to determine the frequency of RETp in cutaneous melanoma and its functional responsiveness to GDNF. RETp was assessed in 71 non-desmoplastic cutaneous melanomas (non-DMs) and 70 desmoplastic melanomas (DMs). Melanoma cell lines with RETp, RET wild type (RETwt), BRAF V600E mutation (BRAFmt) or BRAF wild type (BRAFwt) were assessed for functional activity. RETp frequency was significantly higher in DMs (61%) than in non-DMs (31%, P<0.001). BRAFmt was detected in only 11% of DMs. GDNF stimulation significantly amplified cell proliferation, migration and invasion in RETp, but not in RETwt melanoma cells. GDNF stimulation of RETp cell lines enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt of the RET-RAS-RAF-ERK and RET-phosphatidylinositol 3-kinase (PI3K)-Akt pathways, respectively. GDNF response of RETp cells in signal transduction and other functional studies were not affected by BRAFmt. The study demonstrates that RETp is frequently found in cutaneous melanoma, particularly desmoplastic subtypes, and responds to GDNF inducing events favorable for tumor progression.

Lymphatic invasion using D2-40 monoclonal antibody and its relationship to lymph node micrometastasis in pN0 gastric cancer.

The monoclonal antibody D2-40 is a specific lymphatic endothelial markers and D2-40 staining have been applicable to evaluate lymphatic invasion in various malignant neoplasms. In the present study, we investigated lymph node micrometastasis determined by immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR) in all dissected lymph nodes obtained from 80 patients with node-negative gastric cancer, and analysed the relationship between micrometastasis and clinicopathological findings including lymphatic invasion of the resected primary tumour using D2-40 immunohistochemical staining. The incidence of micrometastasis determined by IHC and RT-PCR was 11.3% (nine out of 80) and 31.3% (25 out of 80), respectively. Although haematoxylin-eosin (HE) staining revealed lymphatic invasion in 11.3% (nine out of 80) of patients, D2-40 staining uncovered new invasion in 23.8% (19 out of 80) of patients. In the diagnosis of HE and D2-40 staining, the incidence of micrometastasis was significantly higher in patients with lymphatic invasion than in those without lymphatic invasion (P=0.0150 and P<0.0001, respectively). Micrometastasis correlated more closely with D2-40 than with HE staining. We demonstrated a high incidence of micrometastasis and lymphatic invasion and a correlation between them even in pN0 gastric cancer. When planning less invasive treatment, the presence of such occult cancer cells should be considered.

Detection of sentinel nodes and micrometastases using radioisotope navigation and immunohistochemistry in patients with gastric cancer.

BACKGROUND: Patients with early gastric cancer may be treated by minimally invasive surgery. This study investigated the value of sentinel node (SN) navigation surgery, including detection of micrometastases, in patients with clinical (c) T1 and T2 gastric cancer. METHODS: The day before surgery (99m)Tc-radiolabelled tin colloid was injected submucosally near the tumour. After resecting the stomach, radioisotope uptake in all dissected lymph nodes was measured during and after surgery. Micrometastasis was detected immunohistochemically using an anticytokeratin antibody. RESULTS: SNs were identified in 99 of 104 patients. The rate of identification of SNs in patients with cT1 and cT2 tumours, excluding three technical failures, was 99 and 95 per cent respectively. Lymph node metastases and/or micrometastases were found in 28 patients (15 cT1 and 13 cT2). In the 15 patients with cT1 tumours, at least one SN contained metastasis and/or micrometastasis. For cT1 tumours, the sensitivity and accuracy of detecting SNs were both 100 per cent. Six patients with cT2 tumours had false-negative results. CONCLUSION: SN navigation surgery appears to be clinically useful only for cT1 tumours. Based on SN results, the extent of lymphadenectomy may be reduced in patients with early gastric cancer.