Shunji Kohnoe

Clinical significance of occult micrometastasis in lymph nodes from patients with early gastric cancer who died of recurrence

BACKGROUND Even after curative resection of an early gastric cancer, some patients die of a recurrence. It is our view that patients with early gastric cancer who died of their disease had occult micrometastases in perigastric lymph nodes at the time of the original diagnosis. In an attempt to identify these micrometastases, lymph nodes dissected from early gastric cancer lesions were stained after operation with monoclonal antibody against cytokeratin, an essential constituent of the cytoskeleton of epithelial cells. METHODS The 420 dissected lymph nodes from 34 patients with node-negative early gastric cancer who died of a recurrence were examined for the presence of tumor cells. We used immunocytochemical techniques and an antiserum to epithelial membrane antigen. The monoclonal antibody CAM 5.2 recognizes cytokeratin polypeptides (human cytokeratin numbers 8 and 18) commonly present in epithelial cells. Clinicopathologic characteristics and prognosis were determined for patients with cytokeratin-positive cells in the lymph nodes. RESULTS. Of 420 lymph nodes, 15 (3.6%) nodes and 23.5% (8 of 34) of the patients presented with cytokeratin-positive cells at the time of primary operation. The presence of cytokeratin positivity was not related to various clinicopathologic factors. The histologic stage of eight cytokeratin-positive cases was upstaged by the group of cytokeratin-positive lymph nodes from stage I to three of stage II, four of stage III, and one of stage IV, hematogenous recurrences were common, and the prognosis was poorer. CONCLUSIONS Immunohistochemical techniques aid in identifying micrometastatic disease in lymph nodes missed in routine hematoxylin-eosin staining. Cytokeratin staining of the dissected lymph nodes is recommended to precisely determine tumor stage and prognosis for patients with early gastric cancer.

Role of Transforming Growth Factor-β1 in Invasion and Metastasis in Gastric Carcinoma

PURPOSE Transforming growth factor-beta1 (TGF-beta1) is a major modulator of cellular proliferation and extracellular matrix formation. We determined the role of TGF-beta1 in invasion and metastasis in gastric cancer. MATERIALS AND METHODS We detected TGF-beta1 expression in primary and lymph node metastatic lesions of gastric cancer, using an antibody and in situ hybridization. The plasma TGF-beta1 levels in the peripheral vein and in the tumor drainage vein were assayed. RESULTS In the cytoplasm of cancer cells, TGF- beta1 was immunostained in 35.9% (78 of 217) of primary gastric carcinomas, and this expression was confirmed by in situ hybridization. Of 59 gastric carcinomas with a TGF-beta1-negative primary tumor, metastatic lymph nodes were positive for TGF-beta1 staining in 32 cases (54.2%). Positive staining of TGF-beta1 in gastric cancer tissues was closely related to serosal invasion, infiltrative growth, and lymph node metastasis. Multivariate analysis showed that the expression of TGF-beta1 was an independent risk factor for serosal invasion and infiltrative growth of the tumor. The plasma level of TGF-beta1 did not differ between TGF-beta1-negative and -positive groups. There were also no differences in plasma TGF-beta1 levels among each tumor stage, between the peripheral and the tumor drainage veins, and between preoperative and postoperative testings. CONCLUSION Transforming growth factor-beta1 is closely related to the invasion and metastasis of gastric cancer, and production of TGF-beta1 in the tumor does not contribute to the total amount of TGF-beta1 in the blood circulation. We interpret our observations to mean that in a tumor microenvironment, TGF-beta1 alters the biologic behavior of the tumor.

Colorectal cancer screening with odour material by canine scent detection

Objective Early detection and early treatment are of vital importance to the successful treatment of various cancers. The development of a novel screening method that is as economical and non-invasive as the faecal occult blood test (FOBT) for early detection of colorectal cancer (CRC) is needed. A study was undertaken using canine scent detection to determine whether odour material can become an effective tool in CRC screening. Design Exhaled breath and watery stool samples were obtained from patients with CRC and from healthy controls prior to colonoscopy. Each test group consisted of one sample from a patient with CRC and four control samples from volunteers without cancer. These five samples were randomly and separately placed into five boxes. A Labrador retriever specially trained in scent detection of cancer and a handler cooperated in the tests. The dog first smelled a standard breath sample from a patient with CRC, then smelled each sample station and sat down in front of the station in which a cancer scent was detected. Results 33 and 37 groups of breath and watery stool samples, respectively, were tested. Among patients with CRC and controls, the sensitivity of canine scent detection of breath samples compared with conventional diagnosis by colonoscopy was 0.91 and the specificity was 0.99. The sensitivity of canine scent detection of stool samples was 0.97 and the specificity was 0.99. The accuracy of canine scent detection was high even for early cancer. Canine scent detection was not confounded by current smoking, benign colorectal disease or inflammatory disease. Conclusions This study shows that a specific cancer scent does indeed exist and that cancer-specific chemical compounds may be circulating throughout the body. These odour materials may become effective tools in CRC screening. In the future, studies designed to identify cancer-specific volatile organic compounds will be important for the development of new methods for early detection of CRC.

Signet ring cell carcinoma of the stomach

Between 1965 and 1985, 51 of 1500 patients (3.4%) with gastric cancer who had gastric resection had signet ring cell gastric cancer. Patients with this form of cancer tended to be younger and female; the tumors were smaller and involved the stomach body, serosal invasion was less prominent, and lymph node metastases were less likely to be present. Early mucosal and submucosal cancer was present in 54.9% of the patients with the signet ring cell and in 24.6% with other types of gastric cancer. In 15.7% of patients with signet ring cell cancer, a noncurative resection was performed. The 5‐year survival rate was 74.5% for patients with signet ring cell cancer and 52.4% for those with other types of gastric cancer (P < 0.01). In patients with signet ring cell gastric cancer, the lesion is less extensive; thus, these patients probably can expect a longer survival time.

Risk Factors Associated with Surgical Site Infection in Upper and Lower Gastrointestinal Surgery

PurposeTo assess the risk factors of surgical site infection (SSI) in gastrointestinal surgery.MethodsSurgical site infection surveillance was conducted in 27 hospitals.ResultsThe incidence of SSI in the 941 patients studied was 15.5%. The factors associated with SSI were body mass index (BMI), comorbidity, emergency procedures, wound classification, blood loss, the suture material used for intra-abdominal ligation, the method of subcutaneous incision, the frequency of glove changes, and the absence of subcutaneous sutures. In lower alimentary tract procedures, additional factors influencing the incidence of SSI were sex, smoking status, operating time, the suture material used for abdominal wound closure and seromuscular sutures, and the combined resection procedures. According to a multiple logistic regression analysis, the independent risk factors for SSI were as follows: the type of operation, blood loss, wound classification, emergency procedures, the frequency of glove changes, the use of subcutaneous sutures, combined resection procedures, and the material used for seromuscular suturing.ConclusionStrict asepsis and minimal blood loss were associated with a lower incidence of SSI following gastrointestinal surgery. The use of absorbable suture material may be involved in reducing the risk of SSI.

Infiltration of dendritic cells in relation to tumor invasion and lymph node metastasis in human gastric cancer

The infiltration of dendritic cells determined in 210 patients with gastric carcinoma was investigated from the standpoint of tumor invasion, lymph node metastasis, and prognosis. Dendritic cell infiltration was graded as “slight” and “marked.” The 39% frequency in the marked infiltration group at the mucosal stage did not change in proportion to invasion into the deeper layers. The 5‐year survival rate was 60.4% in patients with marked infiltration and 38.8% in those with slight infiltration, which was statistically different (P < 0.01). The difference in survival rates was only statistically significant in those with cancer emerging from the serosa (P < 0.001). There was a similar incidence of lymph node metastasis between the marked and slight infiltration groups in each grade of tumor invasion. However, marked infiltration of dendritic cells prevented widespread nodal involvement beyond the primary node in cases of advanced carcinoma (P < 0.05). These findings indicate that infiltrating dendritic cells do not prevent the spread of tumor invasion but do prevent nodal involvement; therefore, for patients with a gastric cancer emerging from the serosa, the prognosis will be good.

Lymphatic invasion and potential for tumor growth and metastasis in patients with gastric cancer

BACKGROUND Lymph node metastasis is a risk factor for the occurrence of peritoneal dissemination and liver metastasis in patients with gastric cancer. METHODS We analyzed data on 324 patients with serosally invasive gastric cancer with respect to the relation between lymphatic invasion and potential for tumor growth and metastasis. All these patients were curatively treated in the Department of Surgery II, Kyushu University. RESULTS Lymphatic invasion was evident in 214 patients, in whom vascular invasion was more frequent and the rate of lymph node metastasis was higher compared with patients with no lymphatic invasion. There was no difference in tumor size. The type of recurrence varied, and the prognosis was poor in patients with lymphatic invasion. The DNA ploidy pattern was higher, and the levels of proliferating cell nuclear antigen labeling and argyrophilic nucleolar organizer regions count were significantly higher in tumor tissues with lymphatic invasion than in those without invasion. CONCLUSIONS Gastric cancers with characteristics of lymphatic invasion have higher proliferating activities, and metastases to distant organs are likely.

Clinical implications of serum anti-p53 antibodies for patients with gastric carcinoma

Mutations of p53 can lead to the production of anti‐p53 antibodies in sera of cancer patients. Before this study, the value of preoperative serum anti‐p53 antibodies in determining the prognoses of patients with gastric carcinoma had yet to be determined.

Biological mechanism and clinical effect of protein-bound polysaccharide K (KRESTIN®): Review of development and future perspectives

The mechanism of action of protein-bound polysaccharide K (PSK; KRESTIN®) involves the following actions: (1) recovery from immunosuppression induced by humoral factors such as transforming growth factor (TGF)-β or as a result of surgery and chemotherapy; (2) activation of antitumor immune responses including maturation of dendritic cells, correction of Th1/Th2 imbalance, and promotion of interleukin-15 production by monocytes; and (3) enhancement of the antitumor effect of chemotherapy by induction of apoptosis and inhibition of metastasis through direct actions on tumor cells. The clinical effectiveness of PSK has been demonstrated for various cancers. In patients with gastric or colorectal cancer, combined use of PSK with postoperative adjuvant chemotherapy prolongs survival, and this effect has been confirmed in multiple meta-analyses. For small-cell lung carcinoma, PSK in conjunction with chemotherapy prolongs the remission period. In addition, PSK has been shown to be effective against various other cancers, reduce the adverse effects of chemotherapy, and improve quality of life. Future studies should examine the effects of PSK under different host immune conditions and tumor properties, elucidate the mechanism of action exhibited in each situation, and identify biomarkers.

Suppressed MKP-1 Is an Independent Predictor of Outcome in Patients with Hepatocellular Carcinoma

Objective: An increase in the activity of mitogen-activated protein kinases (MAPKs) has been correlated with a more malignant phenotype in several tumor models in vivo. This study was designed to clarify the expression of MKP-1 in surgically resected hepatocellular carcinoma (HCC). Methods: We reviewed the cases of 77 patients who had undergone initial liver resection for HCC without preoperative treatment. Immunohistochemical analysis of MKP-1 was performed on paraffin-embedded tissues. The correlation between MKP-1 expression and clinical outcome was investigated. Results: Tumor cells were immunohistochemically stained for MKP-1 expression, and the same levels as in normal hepatocytes were detected in 66 (85%) of 77 HCC patients, being decreased in 11 (15%) HCCs. Decreased MKP-1 expression significantly correlated with serum α-fetoprotein levels and tumor size (p < 0.05). The disease-free survival rates in MKP-1-negative and -positive patients were 0 and 31.0% at 5 years, respectively (p < 0.01). The survival rates after a surgical resection in MKP-1-negative and -positive patients were 18.2 and 65.5% at 5 years, respectively (p < 0.01). Conclusions: The MKP-1 expression in HCC was an independent prognostic factor for outcome in HCC patients. In the future, it will be useful to explore whether the phosphatase expression might account for the response to HCC treatments targeting at MAPK activation.