Invariant chain expression in gastric cancer.

Invariant chain (Ii) is a chaperone molecule that inhibits the binding of endogenous antigens to HLA class II. The tumor cell with overexpressed Ii chain is thought to escape attacking cytotoxic lymphocytes by suppressing the host immune. However, the relationship between Ii expression by the tumor and clinicopathological factors in gastric cancer remains unclear. We studied 126 patients with gastric cancer who had undergone curative gastrectomy at Kagoshima University Hospital between 1988 and 1997. In order to detect Ii and HLA-DR expression by tumor cells, immunohistochemical staining with anti-CD74 and anti-HLA-DR antibodies were performed by avidin-biotin peroxidase complex method. The 126 patients studied were divided into two groups based on Ii expression. Ii and HLA-DR were expressed both on the surface and in the cytoplasm of tumor cells and tumor infiltrating lymphocytes. A total of 48 patients were identified as Ii positive, while the remaining 78 patients were Ii negative. Ii expression negatively correlated with the depth of invasion of the tumor as well as the patients' clinical stage. Ii expression was negatively correlated with HLA-DR expression. Patients with Ii negative expression had significantly better surgical outcomes than those with Ii positive expression (P<0.05). Ii expression in gastric cancer affected surgical outcome and Ii expression was negatively correlated with depth of invasion and HLA-DR expression. Ii expression in gastric cancer may be a prognostic factor related to suppressive effects on host immune responses to tumor cells.

Clinical importance of preoperative carcinoembryonic antigen and carbohydrate antigen 19-9 levels in gastric cancer.

Although serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are commonly measured before surgery for gastric carcinoma, this clinical significance is not fully understood. We evaluated a total of 549 patients with gastric cancer who underwent gastrectomy. Levels of CEA and CA19-9 were measured preoperatively in all patients. We retrospectively analyzed correlations between CEA or CA19-9 and clinicopathologic features, and estimated the prognostic utility of the tumor markers by analyzing clinicopathologic characteristics of the carcinoma as a function of seropositivity or negativity of the antigens in combination or by raising the levels. The positivity rates of CEA (> or =5 ng/mL) and CA19-9 (> or =37 U/mL) were 19.5% and 18%, respectively. Serum CEA and CA19-9 positivity significantly correlated with depth of invasion, hepatic metastasis, and curativity. Forty-nine patients positive for both CEA and CA19-9 had significantly higher frequencies of lymph node metastasis, deeper invasion by the tumor, lower rates of curative resection (p < 0.01), and higher rates of hepatic metastasis (p < 0.05) than 377 patients with normal levels of CEA and CA19-9. Surgical outcomes of patients who were CEA- and CA19-9-positive were poorer than those of patients with normal CEA and CA19-9 levels (p < 0.01). Significant correlation was found between serum CEA and CA19-9 level (p < 0.001, r = 0.24). Doubling the threshold level of serum positivity to 10 ng/mL (CEA) and 74 U/mL (CA19-9) improved the prognostic value of these factors. However, multivariate analysis using Cox's hazards model revealed that only CEA positivity using the doubled threshold value (10 ng/mL) (p = 0.04, hazard ratio = 1.7), nodal involvement (p = 0.01, hazard ratio = 1.9), and depth of invasion (p = 0.02 hazard ratio = 1.5) significantly predicted prognosis. Carcinoembryonic antigen positivity using the doubled threshold level (10 ng/mL) was an important prognostic factor in patients with gastric cancer.

Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer.

Intratumoral natural killer cells (NKC) and dendritic cells (DC) may affect the clinical features of various gastrointestinal cancers. However, the relationship between intratumoral NKC and DC remains unclear. We examined 169 patients with gastric cancer who underwent gastrectomy at Kagoshima University Hospital. Immunohistochemical staining of CD57 and S-100-protein was performed to evaluate NKC and DC infiltration, respectively. A total of 25 areas containing pericancerous tissue were selected for determining the number of NKC and DC under high power microscopy (x400). Patients were classified into two groups according to NKC and DC population. Intratumoral lymphocytic infiltration was also calculated in 15 areas with a high power (x400) objective. The degree of NKC and DC infiltration was gradually decreased according to the progression of nodal involvement. Patients with many NKC infiltration had a lower positivity of lymph node metastasis and lymphatic invasion than patients with little NKC infiltration. DC infiltration was also negatively correlated with depth of invasion, lymph node metastasis and curativity. DC infiltration was positively correlated with lymphocytic infiltration (P=0.01. r=0.6). The 5-year survival rates of patients with many NKC infiltration and patients with DC many infiltration were 75 and 78%, respectively, both of which were significantly better than that of patients with little NKC and DC infiltration (P<0.05). NKC may be activated without DC or intratumoral lymphocytes. Intratumoral NKC may act as an independent immunologic effector against tumor cells, unlike DC.

Intranodal antitumor immunocyte infiltration in node-negative gastric cancers.

The status and role of immunocytes and dendritic cells in regional lymph nodes in patients with gastric cancer are examined in this study. Forty-nine patients with gastric cancer who underwent curative resection were enrolled in the present study. These patients had no lymph node metastases according to a histological examination. The infiltration of natural killer (NK) cells, dendritic cells, and MIB-1-positive immunocytes was investigated. Based on the Japanese Classification of Gastric Carcinoma, regional lymph nodes were divided into three compartments: (a) compartment 1 (lymph node station numbers 1-6); (b) compartment 2 (lymph node station numbers 7-12); and (c) compartment 3 (lymph node station numbers 14 and 16). Dendritic cells and MIB-1-positive immunocytes infiltrated compartment 1 lymph nodes in increased numbers compared with the lymph nodes of compartments 2 or 3 (P < 0.05). Conversely, intranodal NK cell infiltration did not differ significantly among the three compartments. The incidence of intranodal dendritic and MIB-1-positive cell infiltration in patients with submucosal gastric cancer was significantly higher than in patients with tumors that invaded beyond the muscularis propria. The decreased expression of these immunological markers correlated well with recurrent disease, regardless of tumor depth. The immunocyte level is higher in lymph nodes near the primary tumor (compartment 1) than in those that are distant from the tumor (compartments 2 and 3). This pertains to all three markers, i.e., NK, dendritic, and MIB-1-positive cells. Unlike dendritic and MIB-1-positive cells, intratumoral infiltration of NK cells did not correlate well with either lymph node compartment or the depth of tumor invasion. The degree of NK cell infiltration may be directly associated with antitumor effects, especially in compartment 1. A decrease in all three markers is associated with tumor recurrence.

Prognostic value of intratumoral natural killer cells in gastric carcinoma.

BACKGROUND: Natural killer (NK) cells are a group of effector cells that act nonspecifically against tumor cells. The correlation between intratumoral NK cell infiltration and clinicopathologic features remains unclear. METHODS: The authors selected 146 patients with gastric carcinoma who underwent gastrectomy at Kagoshima University Hospital between 1985-1995. Immunohistochemical staining with the CD57 antibody was performed for the evaluation of NK cell infiltration. A total of 25 areas containing CD57 positive cells were selected and the number of NK cells were counted (magnification, x200). The patients were divided into 2 groups: patients with a high level of NK infiltration (n = 39) (>25 NK cells/25 high-power fields [HPF]) and patients with a low level of NK infiltration (n = 107) (<25 NK cells/25 HPF). Intratumoral lymphocytic infiltration also was counted in 25 areas at a magnification of x200. Patients were classified into a high infiltrating lymphocyte (IL) group (n = 69) (>150 cells/HPF) and a low IL group (n = 77) (<150 cells/HPF). The Kaplan-Meier curve was used to analyze surgical outcome. Multivariate analyses were performed to evaluate prognostic factors. RESULTS: Patients with a high level of NK infiltration had a higher rate of early gastric carcinoma, fewer metastases to the lymph nodes (P < 0.01), and less lymphatic invasion (P < 0.05) than patients with a low level of NK infiltration. NK cell infiltration also was found to correlate with depth of invasion, clinical stage, and venous invasion. There was no correlation between NK cells and lymphocytic infiltration (P = 0.07; correlation coefficient = 0.15). The 5-year survival rate of patients with a high rate of NK infiltration was 78%, which was significantly better than that of patients with a low level of NK infiltration (P < 0.01). Multivariate analysis did not show NK cell infiltration to be a significant prognostic factor. Combination analysis of the number of NK cells and lymphocytic infiltration was shown to be an independent prognostic factor (P = 0.02; hazard ratio = 1.32). CONCLUSIONS: Patients with a high level of NK infiltration were found to have a better prognosis than those with a low level of NK infiltration. Combination analysis with lymphocytic infiltration may provide useful information regarding the immunologic condition of patients with gastric carcinoma.

Strategy of gastric cancer in patients 85 years old and older.

BACKGROUND/AIMS: There is little information about the clinical and pathological features of patients with gastric cancer aged 85 years old and older. METHODOLOGY: We analyzed data of 197 gastric cancer patients aged 75 years and older. The patients were dividing into three age groups and we retrospectively studied 25 gastric cancer patients aged 85 years old and older and compared their clinical courses with those of 94 patients in their late 70s and 78 patients in their early 80s. RESULTS: The patients aged 85 years and older had a significantly higher rate of symptoms on admission such as gastric outlet obstruction and progressive anemia (64%), than did the other two age groups (p<0.05). Twenty-five percent of the oldest age group did not have surgery, and none had a D2 lymph node dissection. Perioperative complications were more frequent in the oldest group than in the youngest group (p<0.05). Survival in the oldest patients was not affected by surgical resection. CONCLUSIONS: These results indicate curative gastric surgery has a less positive impact in patients aged 85 years and older than younger patients. Treatment for gastric cancer in patients 85 years old and older should emphasize the palliation of symptoms but not curative resection.

Carcinomatous lymphatic invasion in early gastric cancer invading into the submucosa.

BACKGROUND: Lymphatic invasion is a risk factor for lymph node metastases in patients with gastric cancer. No studies have been reported, however, on the correlation between lymphatic invasion and lymph node metastasis in early gastric cancer invading into the submucosa. METHODS: We performed a retrospective analysis of lymphatic invasion in 170 patients with early gastric cancer invading into the submucosa. RESULTS: Lymphatic invasion was found in 76 patients. Lymphatic invasion correlated significantly with the presence of lymph node metastasis and vascular invasion (P < .05) and with the degree of cancerous submucosal involvement (P < .05). The presence of lymph node metastasis also correlated with the grade of submucosal invasion and lymphatic invasion. The 5-year survival of patients with lymphatic invasion was poorer than that of patients without lymphatic invasion (P < .05). Node-negative patients had similar survival, regardless of the presence of lymphatic invasion. All patients with severe lymphatic invasion had sm3 invasion and lymph node metastases. CONCLUSION: Although lymphatic invasion is the first stage of lymph node metastasis, lymphatic invasion in itself does not have clinical importance except for severe invasion in early gastric cancer. It is possible to predict lymph node metastases from the combined evaluation of degree of lymphatic invasion and submucosal involvement of the tumor in patients with early gastric cancer invading into the submucosa.

Clinical features and surgery for acquired progressive esotropia associated with severe myopia.

PURPOSE: The purpose of this study was to evaluate the clinical and physiological findings and to determine the most appropriate surgical procedure for acquired progressive esotropia with severe myopia. METHODS: Thirty-eight cases of acquired progressive esotropia with severe myopia were examined to evaluate their clinical and physiological findings. All cases were divided into four groups according to the limitation of their abduction. The eyeball in group IV is fixed in an extremely adducting position. Thirty-one cases underwent strabismus surgery; medial rectus muscle recession and lateral rectus muscle resection in 23 cases, transposition of superior and inferior rectus muscles (modified Jensen procedure included) in eight cases. RESULTS: The medial rectus muscle recession with the lateral rectus muscle resection procedure was effective in the early stage of acquired progressive esotropia patients. Transposition procedure was effective in the severe abducting limited patients. CONCLUSIONS: As the recession & resection procedure is easier than the transposition procedure, we recommend performing surgery in the earlier stage of the abducting disorder before the eyeball is fixed in an extremely adducting position.

Carcinomatous infiltration into the submucosa as a predictor of lymph node involvement in early gastric cancer.

The clinicopathologic features of 114 patients with resectable early gastric cancer (EGC) invading the submucosa were examined retrospectively with respect to lymph node involvement and the possibility of performing a minimally invasive operation. Patients were divided into node-positive (n = 25) and node-negative (n = 81) groups. Among several pathologic factors, the diameter of the tumor and lymphatic involvement were significantly correlated with nodal involvement. Within the submucosal layer the depth of invasion and the horizontal cancerous expansion also correlated with lymph node disease (p < 0.05). The size of the tumor did not correlate with the length of submucosal infiltration (r = 0.12, p = 0.1). Patients with both slight invasion into the submucosa and less than 5 mm of horizontal expansion were often negative for lymph node involvement and thus may benefit from local surgery as an alternative to gastrectomy.

Prognostic value of HLA-DR expression and dendritic cell infiltration in gastric cancer.

We attempted to correlate the expression of human leukocyte antigen DR (HLA-DR) and tumor infiltration by S-100-protein-positive dendritic cells with clinicopathologic features in 165 patients with gastric cancer. The expression of HLA-DR was correlated with the histologic type. Infiltration of dendritic cells correlated negatively with distant lymph node metastases, clinical stage, and peritoneal invasion. There was no correlation between the expression of HLA-DR and infiltration by dendritic cells. In patients with resectable gastric cancer, the grade of infiltrating dendritic cells may be a suitable predictor of prognosis.

Results of surgery for paralytic esotropia due to abducens palsy.

The surgical effects of three methods, transposition of the vertical rectus muscles, Jensen's procedure, and resection (advancement) of the lateral rectus muscle, were compared among 109 cases of paralytic esotropia due to abducens palsy. These procedures were combined with recession of the medial rectus muscle in about half the cases. Of the 109 cases, 22 were followed up for 4 years or longer. Results were similar, provided that the following protocols for surgery were adhered to: in cases of complete paralysis, transposition of the vertical rectus muscles was done, and in cases of incomplete paralysis, resection (advancement) of the lateral rectus muscle was performed. With both procedures, results were improved if recession of the medial rectus muscle was carried out at the same time.

Long-term results of surgery for superior oblique palsy.

The results one month after surgery in 159 cases of superior oblique palsy were compared according to the method of surgery with the results 4 years or longer after surgery. There were 141 cases of congenital palsy and 18 cases of acquired palsy, for a total of 159 cases. Our study showed that surgery on the oblique muscle provided long-lasting effects, while recession of the superior rectus muscle or recession of the contralateral inferior rectus muscle could cause late overcorrection. When performing surgery on the rectus muscle, careful attention must be paid to suturing the muscle.

Results of surgery for paralytic exotropia due to oculomotor palsy.

In 138 cases of paralytic exotropia due to oculomotor palsy, transposition of the superior oblique muscle and resection of the medial rectus muscle were carried out. Surgery was performed with or without recession of the lateral rectus muscle. The long-term prognosis for 4 years or more was observed in 35 cases. We found that the same results could be obtained by selecting transposition of the superior oblique muscle in cases of complete palsy and resection of the medical rectus muscle in cases of incomplete palsy. There was no benefit in combining resection of the medial rectus muscle when performing the transposition of the superior oblique muscle. Regardless of which method was used, a combination with recession of the lateral rectus muscle greatly improved the effectiveness of the procedure.

[Surgical and botulinum toxin treatment in two cases of abnormal retinal correspondence-exotropia with congenital homonymous hemianopsia].

We report 2 unusual cases of congenital occipital hemianopsia associated with abnormal retinal correspondence (ARC)-exotropia. Two Japanese males, 25 and 28 years of age, visited our hospital for surgical correction of manifest exotropia with dissociated vertical deviation and overaction of the superior oblique muscle. Visual field examination demonstrated homonymous hemianopsia with approximately 5 to 10 degrees of macular sparing. Visually evoked potential examination showed small amplitude similar to dissociated vertical deviation patients in all half-field stimulation. Electrooculogram examination demonstrated defective pursuit to the ipsilateral side. Some investigators have speculated that progressive exotropia compensates for homonymous hemianopsia and is a rare contraindication for strabismus surgery. To confirm the deterioration of motor and visual functions before surgery in these patients, we tried injections of botulinum A type toxin into the lateral rectus muscle ipsilateral to the hemianopsia. Contrary to the hypothesis, our patients had no change in their binocular visual fields and visual function. Finally, we performed recession of the lateral rectus muscle, so that both patients were satisfied with their ocular alignment, with no marked change of visual behavior.

[Computed tomography findings in convergent strabismus fixus].

X-ray computed tomography (CT) of the eyeball and orbit revealed the cause of eye movement disorder in convergent strabismus fixus. The findings suggest that the disease can be diagnosed and treated at an early stage. Twelve cases of progressive esotropia with high myopia and 20 cases with normal visual acuity served as subjects in this study. The CT slice was parallel to the German horizontal plane, and the lens and medial and lateral rectus muscles were scanned. The average axial length of the affected eyes was significantly longer than in normal eyes. In progressive esotropia, the characteristic CT findings are an elongated eyeball, mechanical contact between the eyeball and lateral wall of the orbit, and a downward displacement of the lateral rectus muscle. Thus, it is reasonable to conclude that eye movement disorder in convergent strabismus fixus results from weakness of the lateral rectus muscle which has been displaced downward due to compression of the eyeball against the orbital wall.

[Botulinum toxin type A (BOTOX) for treatment of blepharospasm: an open label, dose-response study].

The clinical effect of Botulinum Toxin Type A (BOTOX) were studied in patients with blepharospasm. Clinical symptoms were evaluated with Jankovic's rating scale, widely used for blepharospasm. To see dose response, eyelid muscle force of the patients was measured with a device recently developed for measurement of eyelid muscle force. The results showed significant improvement (p = 0.0000) on Jankovic's rating scale in all patient groups after effective dose injections of 0.5, 1.25, and 2.5 U/site. Particularly the number of patients with marked improvement (decrease of six points or more in total score on Jankovic's rating scale) increased with higher dose injections. The eyelid muscle force also decreased by 33.2 +/- 28.1%, 41.7 +/- 25.1%, and 69.6 +/- 5.0% in patients groups after effective dose injections of 0.5, 1.25, and 2.5 U/site, respectively. The decrease of the eyelid muscle force showed significant dose response (p = 0.0254). Mean duration of effect was 12.9 weeks in patients after effective dose injections of 1.25 U/site, which was significantly longer (p = 0.0205) than that of 9.6 weeks in patients after effective dose injections of 0.5 U/site. No severe adverse effects were observed. We concluded that BOTOX injections of 1.25 U/site or more are a safe and effective treatment of blepharospasm.

[Quantitative analysis of electromyogram interference pattern in extraocular muscle].

Quantitative analysis of electromyogram (EMG) interference pattern was performed for objective evaluation. EMGs of 261 horizontal rectus muscles had been recorded in our laboratory during the past 18 years, and they were divided according to the clinical diagnosis into four categories: 56 records due to complete neuropathy, 67 due to incomplete neuropathy, 19 due to myopathy, and 119 normal. The turns and amplitude analysis program was used for EMG analysis. A turn was one wave of the interference pattern, for which we used an amplitude of more than 15 microV. Turns meant the number of turn waves per second. Turns/second and mean amplitude/turn (A/T) were plotted against each other on an X-Y diagram, and a statistical evaluation of data was done. Complete neuropathy recordings that had lower turns and lower A/T were separated from the other three categories. Incomplete neuropathy and myopathy occurred on the lower A/T area. There was a significant difference (p < 0.05) between each pair of comparisons from all four categories except for turns evaluated between myopathy and normal. Quantitative analysis proved useful for the objective evaluation of the EMG interference pattern, particularly between cases of complete and incomplete neuropathy.

[Preoperative prediction of the amount of surgical correction by using Botulinum A type toxin for the treatment of paralytic esotropia].

The aim of this study was to obtain the correct choice of initial surgical procedure and to predict the amount of surgical correction by using the maximum reduction rate of eye position after Botulinum A-type toxin injection for the treatment of acquired neurogenic paralytic strabismus. The subjects were 30 with sixth nerve palsy and 33 with non-paralytic esotopia with no previous surgery. The results were that if the maximum reduction rate of eye position after the first injection of 1.25 U was less than 68%, the modified Jensen procedure with recession of medial rectus muscle was necessary to achieve 100% recovery. However, if it was more than 100%, then recession-resection of the horizontal rectus muscles alone produced successful ocular alignment. Based on our data of 100 cases of sixth nerve palsy that showed spontaneous recovery, we conclude that surgical treatment should be planned, if the maximum percentage reduction of preoperative eye position after Botulinum A-type toxin treatment is under 68% (reflecting the inability of the medial rectus muscle to contract and the lengthening of the lateral rectus muscle), and if the patient has no spontaneous improvement at all within 12 weeks after onset.

Botulinum toxin type A purified neurotoxin complex for the treatment of blepharospasm: a dose-response study measuring eyelid force.

The clinical efficacy of botulinum toxin type A was studied in patients with blepharospasm. Clinical symptoms were evaluated using the Jankovic rating scale. To measure dose response, we used a recently developed device to measure eyelid muscle force. The results showed significant improvement (P = 0.0000) in the Jankovic rating scale scores in all dose groups. The number of patients with marked improvement (6-point decrease or more in the total Jankovic rating scale score) increased with higher dose injections. After injections of 0.50, 1.25, or 2.50 U/site, 6 sites/eye, the eyelid muscle force decreased by 33.2 +/- 28.1%, 41.7 +/- 25.1%, or 69.6 +/- 5.0%, respectively. The decrease of eyelid muscle force showed a significant dose response (P = 0.0254). The mean duration of effect was 12.9 weeks in patients after dose injections of 1.25 U/site, which was significantly longer (P = 0.0205) than the 9.6 weeks in patients after dose injections of 0.50 U/site. No severe adverse effects were observed. We concluded that injections of botulinum toxin type A at an initial dose of 1.25 U/site are a safe and effective treatment for blepharospasm.

Quantitative analysis of electromyogram interference pattern in extraocular muscle.

Turns and amplitude analysis of the electromyogram (EMG) interference pattern has been applied to the extraocular muscles for the first time in the literature, to the best of our knowledge. EMGs of 261 horizontal rectus muscles recorded during the past 18 years were retrospectively examined and divided into four categories according to the clinical diagnosis: 56 complete palsy due to neuropathy, 67 incomplete palsy due to neuropathy, 19 myopathy, and 119 normal. The number of turns per second and mean amplitude between a pair of successive turns were automatically calculated by computer. Significant differences (P < 0.05) were encountered in all data among the four clinical categories except for the number of turns between myopathy and normal. The number of turns was plotted against the amplitude in each muscle on an X-Y diagram. The data of completely paretic muscle showed less number of turns and smaller amplitude and were clearly distinguishable from the data of the other three categories on the X-Y diagram. The interference pattern of incomplete palsy and myopathy had smaller amplitude than that of normal muscle. However, most of the data overlapped on the X-Y diagram particularly between data of incomplete neuropathy and myopathy.