Kazuhide Kumagai

Gastric and Intestinal Phenotypic Marker Expression in Gastric Carcinomas and Its Prognostic Significance: Immunohistochemical Analysis of 136 Lesions

Objective: It is well known that both gastric and intestinal phenotypic cell markers are expressed in gastric carcinomas, irrespective of their histologic type. However, the clinicopathologic significance of these expressions has not yet been clarified. Methods: We analyzed the correlations among gastric and intestinal phenotypic marker expression patterns of the tumor, clinicopathologic findings and the patient’s outcome in 136 advanced gastric carcinomas. Results: Phenotypic marker expression was immunohistochemically evaluated using the monoclonal antibodies 45M1 (anti-human gastric mucin; HGM), CLH5 (anti-MUC6), Ccp58 (anti-MUC2) and 56C6 (anti-CD10). All tumors were classified as gastric (G), gastric and intestinal mixed (GI), intestinal (I) or unclassified (UC) phenotype. Of the 136 gastric carcinomas, 50 (36.8%), 56 (41.2%), 21 (15.4%) and 9 (6.6%) were classified as G, GI, I and UC phenotype, respectively. The G-phenotype tumors were associated with a higher rate of undifferentiated-type and infiltrative histology as compared with the I-phenotype tumors (p < 0.05 and p < 0.001, respectively). Furthermore, both univariate and multivariate analysis of survival revealed the G-phenotype tumor to be associated with a significantly poorer outcome than the I-phenotype tumor (p < 0.05). Conclusion: Our present results indicate that the gastric and intestinal phenotypic marker expression pattern of tumors, determined by the combination of HGM, MUC6, MUC2 and CD10 expression, is prognostically useful for patients with gastric carcinoma.

Peritoneal metastasis in gastric cancer with particular reference to lymphatic advancement; Extranodal invasion is a significant risk factor for peritoneal metastasis

We investigated the relationship between peritoneal metastasis and lymphatic involvement in gastric cancer by examining resected specimens.

Questionnaire survey regarding the current status and controversial issues concerning reconstruction after gastrectomy in Japan

The Japanese Society for the Study of Postoperative Morbidity after Gastrectomy conducted a nationwide questionnaire survey to clarify the current status of reconstruction after gastrectomy. One hundred and forty-five institutions (66%) responded to the survey. The questionnaire dealt with the reconstruction after a distal gastrectomy, pylorus-preserving gastrectomy (PPG), total gastrectomy, and proximal gastrectomy. The most common method of reconstruction after distal gastrectomy was Billroth I in 112 institutions (74%), and Roux-en-Y (RY) in 30 (21%). Seventy-seven institutions (53%) responded to the PPG questions. The lengths of the antral cuff were widely distributed among the institutions. Segmental gastrectomy was performed by 23 institutions for limited cases. The most common method of reconstruction after total gastrectomy was RY in 138 institutions (95%). Reconstruction with a pouch after total gastrectomy was done in 26 institutions (18%). The most common reconstructions after proximal gastrectomy were esophagogastrostomy in 69 institutions (48%), jejunal interposition in 41 (28%), double tract in 19 (13%) and pouch reconstruction in 6 (7%). Although most Japanese surgeons are concerned about the revised methods of reconstruction and quality of life after gastrectomy, surgeons have not yet reached a full consensus on these issues.

Association of gastric and intestinal phenotypic marker expression of gastric carcinomas with tumor thymidylate synthase expression and response to postoperative chemotherapy with 5-fluorouracil

PurposeIt is well known that both gastric and intestinal phenotypic markers are expressed in gastric carcinomas, irrespective of their histological type. In the present study, the associations among phenotypic marker expression of gastric carcinomas, tumor thymidylate synthase (TS) expression, and the chemotherapeutic response to 5-fluorouracil (5-FU) were examined.MethodsThe gastric and intestinal phenotypic marker expression of the tumor was determined by the combination of the expression of human gastric mucin (HGM), MUC6, MUC2, and CD10, and was evaluated in comparison with tumor TS expression in 137 advanced gastric carcinomas in 137 patients (75 with postoperative chemotherapy with 5-FU and 62 without postoperative chemotherapy). Tumors were classified into the gastric- (G-), gastric and intestinal mixed- (GI-), intestinal- (I-), or unclassified- (UC-) phenotype according to the immunopositivity of HGM, MUC6, MUC2, and CD10 stainings. The associations among the gastric and intestinal phenotypic marker expression of the tumor, tumor TS expression, effect of postoperative chemotherapy with 5-FU, and the patient’s prognosis were examined.ResultsOf the 137 gastric carcinomas, 48 (35.0%), 58 (42.3%), 23 (16.8%), and 8 (5.8%)were classified as the G-, GI-, I- and UC-phenotype, respectively. The high TS expression of more than 25% tumor cell positivity was found in 25 (52.1%) of the 48 G-phenotype tumors, 39 (67.2%) of the 58 GI-phenotype tumors, 18 (78.3%) of the 23 I-phenotype tumors, and 4 (50.0%) of the 8 UC-phenotype tumors. The I-phenotype tumors were significantly correlated with the higher rate of the high TS expression as compared with the G-phenotype tumors (P<0.05). Among 48 patients with the G-phenotype tumor, the 5-year survival rate in patients with and without postoperative chemotherapy was 39.7 and 27.8%, respectively. The patients with postoperative chemotherapy had a significantly better prognosis than those without postoperative chemotherapy (P<0.05). Conversely, there were no significant correlations between the presence of postoperative chemotherapy and the patient’s prognosis among patients with GI-, I-, and UC-phenotype tumors.ConclusionsThese results indicate that postoperative chemotherapy with 5-FU could be effective for patients with the G-phenotype tumor, since the incidence of intratumoral expression of TS, the target enzyme of 5-FU, is significantly low in G-phenotype tumors.

Gastrointestinal cancer metastasis and lymphatic advancement

The role of angiogenesis in the growth of solid tumors is well established, but the role of lymphatic vessels and the relationship between lymphangiogenesis and tumor spread are less clear. Recently, the molecular pathway that signals lymphangiogenesis and specific markers for lymphatic endothelium have been discovered; however, the lymphatic pathway of cancer metastasis is only partly clarified. Several investigators from the mid 20th century indicated the existence of lymphatico-venous communications, and some observed the retrograde filling of lymph flow and lymphatico-venous communication in obstructive lymphopathy. In the 1960s Burn reported the importance of lymphovenous communication in his clinical and animal experimental data. Thus, the role of potential peripheral lymphatico-venous communication must be considered in the mechanism of cancer metastasis. We observed the lymphatico-venous (portal) communication, as well as lymph retention and reflux, in a rat model of mesenteric lymph vessel obstruction. Based on the phenomenon of lymphatico-venous communication and lymph flow reflux by lymphatic obstruction, we speculate that tumor cell obstruction in the lymph system will lead to the establishment of liver and/or peritoneal metastasis. Clinically, we observed extranodal cancer invasion in a model of lymphatic obstruction, and noted a strong relationship between extranodal invasion and liver or peritoneal metastasis. Thus, the existence of peritoneal and liver metastasis via a lymphatic pathway should be considered.

The usefulness of postoperative continuous epidural morphine in abdominal surgery.

The influence of continuous epidural morphine on the recovery course of intestinal activity, urinary function, and ambulation after surgery was studied in 40 patients who underwent either gastrectomy for gastric cancer or cholecystectomy for cholelithiasis. Compared with a control group of patients whose postoperative pain was managed by pentazocine or hydroxyzine as before, the length of time before passing flatus or faeces was significantly shortened in the morphine groups (P<0.05). Following gastrectomy, the urinary catheter was able to be removed significantly earlier in the morphine group (P<0.05) although there was no statistical difference between both cholecystectomy groups. The morphine group experienced no difficulty with postoperative ambulation and exercise, although the difference in time before ambulation between the two groups was not considered significant. The results of this study led us to conclude that the postoperative continuous epidural infusion of morphine would be more beneficial following major abdominal surgery than the conventionally used methods of administering postoperative analgesia.

Physiological Age as an Outcome Predictor for Abdominal Surgery in Elderly Patients

It would seem that a large discrepancy exists between the “chronological” age and “apparent” age of elderly patients, and we often observe that the latter reflects the results of surgical procedures very well. In the present study, we reviewed 258 patients aged 70 years or older who underwent elective abdominal operations under general anesthesia, to evaluate an outcome predictor representing their “physiological” age. A total of 24 preoperative variables were compared between patients who left the hospital in a satisfactory condition, being survivors, and those who died in hospital despite the operative procedure performed, being nonsurvivors. In the group of patients aged between 70 and 79 years, there was no significant difference between the survivor and nonsurvivor groups for any of the variables examined; however, in the group of patients aged over 80 years old, the oldest of whom was 93 years, there were significant differences in the total lymphocyte count (TLC) and the performance status (PS), as well as in age, between the survivor and nonsurvivor groups. Utilizing the three variables of age, PS, and TLC, a computer-generated discriminant function analysis yielded an equation which discriminated survival with 97% accuracy, and mortality with 83% accuracy. These findings indicate that the PS and TLC scores added to the chronological age should be considered when deciding whether a surgical procedure is appropriate for an elderly patient.

Intractable Ascites following Surgery for Gastric Carcinoma

Over the past 11 years, I have experienced a few patients with intractable ascites after extended radical surgery for gastric carcinomas, which accounted for 1.0% (4 of 394) of all gastric carcinomas resected in our institute. These 4 patients underwent total or subtotal gastrectomy with extended lymphadenectomy, including the lymph nodes of the hepatoduodenal ligament. Histopathologic examination of an intraoperative liver biopsy specimen revealed chronic hepatitis or liver cirrhosis. The characteristics of the ascites led me to conclude that the ascites comprised liver lymphatic fluid. Surgeons must recognize that intractable ascites due to leakage of liver lymphatic fluid after gastrectomy with extended lymphadenectomy is likely to occur in patients with chronic hepatitis or liver cirrhosis.

The significance of preoperative chemotherapy for early gastric carcinoma

In order to achieve a complete prognosis for early gastric carcinoma, a greater effort must be made to improve its present treatment, considering the small percentage of patients who still die from recurrence despite the prompt initiation of surgery. Over the past 9 years, 26 patients with early gastric carcinoma have undergone surgical resection after receiving preoperative chemotherapy in the form of oral 5-FU or 5′-DFUR in our institute. The effectiveness of preoperative chemotherapy was evaluated by histopathological examination of the resected stomachs. Of a total of 24 patients with depressed type gastric cancer, 19 were histologically found to have a cancerless area within the cancerous lesion, 8 of whom were classified as being over Grade 1b. Gross changes were observed in 13 of these 24 patients. The frequency of multiple early gastric cancer occurring in patients who had not received chemotherapy was 11.6%, whereas in those who had received chemotherapy it was 3.8%. The findings of this study thus indicate that preoperative chemotherapy is useful for reducing minute cancer foci and microscopic metastatic lesions.

A case of Crohn's disease limited to the appendix, showing a portentous ultrasonographic finding

A case of Crohns disease limited to the appendix is reported. A preoperative ultrasonic study of the lower right abdomen revealed an interesting appearance that we named the “milky way sign.” Microscopic findings in the resected specimen confirmed that the sign represented adipose tissue of the mesoappendix that had become involved by transmural inflammation. This seems to be highly suggestive of Crohns disease.