Ethnic Difference in the Pharmacodynamics-efficacy Relationship of Dipeptidyl Peptidase-4 Inhibitors Between Japanese and non-Japanese Patients: A Systematic Review.

A systematic review of the differences in the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors between Japanese and non-Japanese subjects was conducted. We searched for randomized controlled trials in patients with type 2 diabetes mellitus (T2DM) that studied the intervention of a DPP-4 inhibitor once-daily vs. placebo, as monotherapy or as add-on therapy. Data regarding placebo-corrected HbA1c reduction and trough DPP-4 inhibition rate after ≥12 weeks' treatment were extracted. In the 12 eligible studies, linear regression analysis revealed that the hemoglobin A1c (HbA1c) reduction at each DPP-4 inhibition level was larger in studies involving Japanese patients than in studies involving non-Japanese patients, with statistical significance between the two groups (P < 0.0001). Sensitivity analysis excluding studies of add-on therapies supported the robustness of the result. Our study indicated that DPP-4 inhibitors show greater efficacy in Japanese patients than in non-Japanese patients, which may be an important consideration in the global development strategy of new diabetic medications.

Immunohistochemical investigation of lymphatic vessel formation control in mouse tooth development: lymphatic vessel-forming factors and receptors in tooth development in mice.

The presence of lymphatic vessels in dental pulp has recently been controversial, and no conclusion has been reached. In this study, we investigated the control of lymphangiogenesis with dental pulp development in the mouse mandibular molar using VEGF-C, VEGF-D, and VEGFR-3 as indices of lymphatic vessel-controlling factors. In addition, to distinguish blood and lymphatic vascular epithelial cells, we performed immunohistochemical analysis using von Willebrand factor (vWF) and statistical analysis. In dental papilla in the bell-stage non-calcified period, mesenchymal cells positive for VEGF-C, VEGF-D, and VEGFR-3 increased and lumen-forming endothelial cells were noted, but vWF was negative, suggesting that these were actively forming lymphatic vessels. Positive undifferentiated mesenchymal cells, an increase in endothelial cells in dental pulp, and lumen expansion were noted early after birth. Positivity was also detected in the odontoblast layer and sheath of Hertwig after birth, suggesting that these factors also play important roles in odontoblast differentiation and maturation and periodontal ligament and tooth root formation. We embryologically clarified lymphatic vessel formation in dental pulp and a process of lymphatic vessel formation from blood vessels, suggesting involvement of the surrounding tissue, odontoblasts, and sheath of Hertwig in vessel formation.

Chronic tonsillitis and IgA nephropathy. Clinical study of patients with and without tonsillectomy.

To determine whether tonsillectomy is a significantly effective treatment in the clinical course of IgA nephropathy, we did a comparative study on 50 patients with IgA nephropathy and chronic tonsillitis. We divided the patients into two groups: 35 patients with and 15 without tonsillectomy (control group). With or without tonsillectomy, renal function became progressively worse during the follow-up period in most patients with a serum creatinine level of > 1.4 mg/dl at the time of renal biopsy. In patients with a serum creatinine level of < or = 1.4 mg/dl, renal function remained normal in all subjects with tonsillectomy, but worsened in 3 patients out of 13 without tonsillectomy. Improvement in proteinuria/hematuria was found more frequently in the tonsillectomized group than in the controls. Furthermore, the serum IgA level was significantly reduced after tonsillectomy, especially in patients showing improvement. From these results we conclude that tonsillectomy was effective for patients with IgA nephropathy complicated by tonsillitis when the operation was performed before deterioration of renal function.

Signet-ring cell carcinoma of the stomach. A quantitative analysis on its submucosal invasion using a computer image analyzer.

As has been indicated, signet-ring cell carcinoma often shows a three-layered pattern of mucus-containing cells in the mucosa, reproducing an organized differentiation in the normal mucosa. In 110 lesions of early stage signet-ring cell carcinoma of the stomach, the proportion between the area with the three-layered pattern and the non-layered area without such layered pattern was measured using a computer image analyzer. As the result, a positive correlation could be demonstrated between the extent of the non-layered area and the tumor size expressed in the largest diameter (r = 0.2777, P < 0.01). The incidence of submucosal invasion significantly increased when the non-layered area exceeded 50% of the total area of signet-ring cell carcinoma. The sites of submucosal invasion were almost always limited to within the non-layered area bearing another positive correlation between the area of submucosal invasion and that of non-layered intramucosal pattern (r = 0.4427, P < 0.01). Thus, it is indicated that the incidence of submucosal invasion in early signet-ring cell carcinoma was significantly related to a dissolution of the three-layered pattern of carcinoma within the mucosa. In addition, the presence or absence of fibrous and lymphoid stromal reactions to the carcinoma was evaluated in relation to the incidence of submucosal invasion.

Pathology and prognosis of gastric carcinoma. Findings in 10,000 patients who underwent primary gastrectomy.

BACKGROUND: Despite recent advances in diagnosis and treatment, gastric carcinoma remains a major cause of death in the world. METHODS: The clinicopathologic profile of 10,000 consecutive patients who underwent primary gastrectomy during 1962-1989 were reviewed and prognostic factors influencing survival in those with gastric carcinoma were analyzed in 7031 patients. RESULTS: Incidence of gastrectomy for carcinoma has increased steadily and the rate of early carcinoma exceeded that of advanced carcinoma in the recent period of 1985-1989. Five-year and 10-year survival rates were 46.1% and 35.2% in 3868 patients with advanced carcinoma, and 88.8% and 77.3% in 3163 patients with early carcinoma, respectively. In patients with advanced carcinoma, significantly poorer survival rates were noticed for patients older than 70 years of age, those who underwent total gastrectomy, tumors involving the entire stomach or greater than 10 cm in diameter, a macroscopic diffusely infiltrative pattern, adenosquamous histologic type, positive surgical resection margins, or lymph node metastasis. None of the above poor prognostic features were identified in patients with early gastric carcinoma group except for those older than 70 years of age. Although lymph node metastases were present in 10% of early gastric carcinomas, this feature did not impart a poor prognosis. Patients with advanced carcinoma grossly resembling an early carcinoma had an intermediate prognosis, suggesting the existence of a developmentally midstage lesion between early and advanced carcinoma. CONCLUSIONS: The study illustrates that the most important role for clinicians treating with gastric carcinoma should be early detection and aggressive surgery for resectable tumors, followed by detailed pathologic examination.

Tetrasomy 8 in acute myelomonocytic leukemia developing after a gastric cancer operation.

A 70 year-old-Japanese man underwent gastrectomy for early gastric cancer with preoperative hypocellular marrow. Three weeks later, acute myelomonocytic leukemia developed with tetrasomy for chromosome 8 (48,XY,+8,+8). The patient died of leukemia on the 33rd postoperative day. Whether or not the operation triggered the leukemia remains unknown.

Depressed adenoma of the stomach, revisited. Histologic, histochemical, and immunohistochemical profiles.

For 52 patients with depressed adenomas of the stomach, histopathologic studies were done on 56 tumors and for 43 of them, histochemical and immunohistochemical features were examined. In addition, nondepressed adenomas (n = 57) and the depressed type of early gastric adenocarcinomas of the well-differentiated variety (n = 44) were studied as the controls. Depressed adenomas in the majority (73%) involved the entire thickness of the mucous membrane of the stomach with tubules of atypical epithelium, presenting a severe grade in many of the cases (41%). Paneth's cells were found in cases of a depressed adenoma, in significantly higher percentages (61%) than in those with a nondepressed adenoma (P less than 0.01). The frequency of cases with argyrophil cells was also higher in depressed adenoma (63%) than in nondepressed adenoma (36%) or in cases of early gastric carcinoma (32%). Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were noticed in tumor cells, immunohistochemically in 28% of the cases with depressed adenoma, the frequency being intermediate between cases of a benign nondepressed adenoma (6% for both CEA and CA 19-9) and cases of early gastric carcinoma (71% for CEA and 66% for CA 19-9). No difference was noticed in lectin reactivity and mucin content between depressed and nondepressed adenomas, whereas tumor cells in the early depressed carcinoma had a higher lectin reactivity and less mucin content than those seen in the adenomas. It would thus appear that depressed adenoma is a benign neoplastic lesion; however, the malignant potential of this lesion is somewhat higher than the nondepressed counterpart, as indicated by the immunoreactivity to tumor markers and follow-up results reported by colleagues previously.

S-100 protein-positive dendritic cells in colorectal adenocarcinomas. Distribution and relation to the clinical prognosis.

Dendritic cells (DC) in 121 colorectal adenocarcinomas were investigated immunohistochemically, using anti-S-100 protein antibody. S-100(+)DC were recognized among the malignant cells and/or around the tumor and differed in distribution either from lysozyme-positive macrophages or from neuron-specific enolase-positive neural tissue. Patients with many S-100(+)DC (more than 30 cells per 10 high-power fields) in the tumor survived longer than did those with few such cells (less than 30 cells), most often with no metastases (P less than 0.001). The grade of S-100(+)DC infiltration was related to both density of lymphocytic infiltration in the primary tumor and the degree of paracortical hyperplasia in the regional lymph nodes (P less than 0.05). Dendritic cells, therefore, as antigen-presenting cells, conceivably mediate cell immunity in a tumor with lymphoid infiltration and in the regional lymph nodes. The number of S-100(+) DC in the primary colorectal carcinomas represents one aspect of such a series of antitumor immunoreaction, in vivo.

Prognostic value of immunohistochemically identified CEA, SC, AFP, and S-100 protein-positive cells in gastric carcinoma.

Gastric tissues from 85 patients with advanced carcinoma were studied immunohistochemically for localization of carcinoembryonic antigen (CEA), secretory component (SC) and alpha-fetoprotein (AFP), and for S-100 protein-positive cells. Our objective was to determine if these factors could serve as prognostic indicators. Forty patients died of recurrence or metastases within 2 years (Group I), and the remaining 45 survived 10 years or longer (Group II) after resection. CEA-positive cells were present in 93% and 89% of Groups I and II, respectively. In case of staining for CEA, positive results were seen not only in the malignant cells but also in the stroma in 35% of Group I but none in Group II. The immunohistochemical status of SC was not essentially different between Groups I and II; the positive staining was recognized in 50% and in 57%, respectively. Gastric carcinomas rarely reacted to AFP. S-100 protein-positive cells, which play an important role in local immunity, were often present in Group II (47%) but rarely in Group I (10%). Thus, in addition to the various prognostic factors available to the surgical pathologist, the presence of CEA and the appearance of S-100 protein-positive cells in tumor tissue will aid in predicting the prognosis of patients with advanced gastric carcinoma.

Early gastric carcinoma with multiple endocrine cell micronests.

We report a case of early gastric carcinoma associated with multiple endocrine cell micronests detected in a 64-year-old Japanese man. The micronests were present in the deeper layer of the lamina propria mucosae, an area occupied by early gastric carcinoma involving the mucous membrane of the anterior wall of the gastric body. Histologic and immunohistochemical studies suggested that the micronests were produced by budding of the neoplastic argyrophil cells scattered within the malignant tubules of the carcinoma and may therefore represent another phenotype of this well-differentiated adenocarcinoma.

[Experimental pneumoconiosis induced by cemented tungsten and sequential concentrations of cobalt and tungsten in the lungs of the rat (author's transl)].

Experimental pneumoconiosis was induced by intratracheal injection of dusts of presintered cemented tungsten carbide, G2 (WC : Co=98 : 2) and TX20 (WC : Co : TiC : TaC=64 : 16 : 6 : 14) into the lungs of rats in order to document the pathological changes in lung tissues associated with environmental cobalt and tungsten. The following results were obtained. 1) Six months after the administration of G2 and TX20 dusts, marked fibrotic foci were noted and tungsten was detected in the lung tissues of all of the experimental animals. 2) Twelve months after the administration of both dusts, both the fibrotic changes and the tungsten levels were reduced in both test groups, but the reduction was more notable in the G2 group. The cases with fibrotic changes were relatively concomitant with the cases in which tungsten was detected. 3) On examination of tissue levels of cobalt derived from the dust, the cobalt levels in the lungs and bone tissues were less influenced by the dust of the G2 group at any point of investigation, whereas only the pulmonary cobalt levels at six months after the administration of the TX20 group showed a remarkable influence from the dust cobalt (p less than 0.01). 4) In the cases where tungsten was detected six months after the administration of both groups and twelve months after the administration of the TX20 group, pulmonary cobalt levels had not reached the value that should have been gained by the addition of expected values (dust cobalt levels calculated from the tungsten levels) to the control values. 5) The above results indicate that both G2 and TX20 dusts induced marked fibrotic changes in rat pulmonary tissues. However, these changes were reversible to some extent. In addition, a portion of the dust cobalt was dissolved in the body fluid and disappeared from the pulmonary fields.