Association of an Increased Abnormal Mitochondria Ratio in Cardiomyocytes with a Prolonged Oxygen Uptake Time Constant during Cardiopulmonary Exercise Testing of Patients with Non-ischemic Cardiomyopathy.

Objective The cardiac function, blood distribution, and oxygen extraction in the muscles as well as the pulmonary function determine the oxygen uptake (VO2) kinetics at the onset of exercise. This factor is called the VO2 time constant, and its prolongation is associated with an unfavorable prognosis for heart failure (HF). The mitochondrial function of skeletal muscle is known to reflect exercise tolerance. Morphological changes and dysfunction in cardiac mitochondria are closely related to HF severity and its prognosis. Although mitochondria play an important role in generating energy in cardiomyocytes, the relationship between cardiac mitochondria and the VO2 time constant has not been elucidated. Methods We calculated the ratio of abnormal cardiac mitochondria in human myocardial biopsy samples using an electron microscope and measured the VO2 time constant during cardiopulmonary exercise testing. The VO2 time constant was normalized by the fat-free mass index (FFMI). Patients Fifteen patients with non-ischemic cardiomyopathy (NICM) were included. Patients were divided into two groups according to their median VO2 time constant/FFMI value. Results Patients with a low VO2 time constant/FFMI value had a lower abnormal mitochondria ratio than those with a high VO2 time constant/FFMI value. A multiple linear regression analysis revealed that the ratio of abnormal cardiac mitochondria was independently associated with a high VO2 time constant/FFMI. Conclusion An increased abnormal cardiac mitochondria ratio might be associated with a high VO2 time constant/FFMI value in patients with NICM.

Clinicopathological features of gastric adenocarcinoma of the fundic gland (chief cell predominant type) by retrospective and prospective analyses of endoscopic findings.

BACKGROUND AND AIM: Gastric adenocarcinoma of the fundic gland type (chief cell predominant type) (GA-FG-CCP) is a variant of gastric adenocarcinoma with chief cell differentiation. GA-FG-CCP is rare and not well understood. The present study aimed to investigate the clinicopathological features of GA-FG-CCP using retrospective and prospective analyses of endoscopic findings. METHODS: A total of 20 patients including nine cases treated with endoscopic submucosal dissection (ESD) were diagnosed with GA-FG-CCP. Morphological changes were analyzed by retrospectively retracing past endoscopic records and following up after definitive diagnoses, including the status of Helicobacter pylori (H. pylori) infection. RESULTS: GA-FG-CCP were small and whitish lesions accompanied by atypical vascular growth and their macroscopic types were classified as 0-IIa (60%), 0-IIb (25%), and 0-IIc (15%), respectively. The lesions were found in the non-atrophic gastric mucosa of the upper (70%) or middle portion (30%), although gastric mucosal atrophy associated with current or past H. pylori infection was identified in 75% of cases. In the nine cases treated with ESD, submucosal invasion was identified in 80% of the resected lesions, but no lymphovenous infiltration was detected. Ki-67 labeling index of GA-FG-CCP was low at 3.2% and visible morphological changes were rarely detected during long-term endoscopic observation for 58.9 ± 13.1 months. CONCLUSIONS: These data indicate that GA-FG-CCP, even when submucosal invasion occurs easily, might be of low-grade malignancy as long as it is the chief cell predominant type without other epithelial abnormalities. In addition, GA-FG-CCP might develop despite H. pylori infection or gastric mucosal atrophy.

Clinical significance of white gastric crypt openings observed via magnifying endoscopy.

AIM: To evaluate the relationship between Helicobacter pylori (H. pylori)-induced gastritis and white gastric mucosal crypt openings (COs) in the gastric corpus. METHODS: A total of 175 consecutive patients (including 69 patients with gastric cancer) were enrolled in this study. We used magnifying endoscopy (ME) to observe the mucosa microsurface of the lesser and greater curvature of the gastric corpus (350 areas in all). We focused on areas with a round pit microstructure (primarily observed in non-atrophied areas) and evaluated the white openings of these gastric pits. We classified the whiteness of the COs as the "white-edged dark spot" type (consisting of a dark spot bordered by white); the "white" type (pure white with no dark spot); and the "dense white pit (DWP)" type (dense white, resembling a snowball). Gastritis was also histologically evaluated according to the updated Sydney System. RESULTS: We detected round COs using ME in 246 of the 350 areas examined. The histological examination showed significantly more mononuclear cells and neutrophil infiltration in the "white" and "DWP" types than the "white-edged dark spot" type (P < 0.001). Furthermore, significantly high-grade inflammation and evidence of active H. pylori-induced gastritis was observed in the "DWP" type (P < 0.001). Significant differences were observed in the whiteness of COs between H. pylori-positive (n = 139) and negative (n = 36) patients (P < 0.001). The sensitivity and specificity of the "white" and "DWP" types for predicting H. pylori infection were 78.5% and 81.7%, respectively. Of the patients with gastric cancer, 22.5% (18/80) had "white-edged dark spots", 51.3% (41/80) had "white" COs, and 26.3% (21/80) had "DWP"-type COs. "DWPs" were frequently observed among patients with undifferentiated gastric cancer [45.7% (16/35)]. CONCLUSION: CO whiteness detected via ME was associated with histological evidence of gastritis and helps to predict the severity of inflammation and H. pylori-induced activity.

Prognostic and diagnostic significance of tumor budding associated with ß-catenin expression in submucosal invasive colorectal carcinoma.

Endoscopic resection has become a major curative treatment for early colorectal carcinoma without lymph node metastasis. However, lymph node metastasis, a poor prognostic factor in colorectal carcinoma, occurs in about 10% of the patients with submucosal invasive colorectal carcinoma. Therefore, it is important to identify a high-risk factor for lymph node metastasis in submucosal invasive colorectal carcinoma. This study was designed to identify the relationship between tumor budding with ß-catenin expression and lymph node metastasis in submucosal invasive colorectal carcinoma. We investigated the immunohistochemistry of tumor budding in the 142 patients who underwent surgical resection for submucosal invasive colorectal carcinomas between 1984 and 1999 and the expression pattern of ß-catenin in budding tumor cells. Accordingly, all the patients were followed up for at least 10 years or until death. Among the 142 patients, lymph node metastasis was detected in 14 patients (9.9%). Univariate analysis showed that tumor budding with ≥ 5 tumor cells or cell clusters with expression of ß-catenin in the nucleus was significantly associated with lymph node metastasis (P = 0.005). In contrast, tumor budding detected by hematoxylin and eosin staining was not associated with lymph node metastasis. Multivariate logistic regression analysis showed that tumor budding with ≥ 5 tumor cells or cell clusters with expression of ß-catenin in the nucleus was a significant risk factor for lymph node metastasis (odds ratio, 7.124; 95% confidence interval, 1.407-36.062). Thus, tumor budding associated with ß-catenin expression is a risk factor for lymph node metastasis in submucosal invasive colorectal carcinoma.

Topographic differences in gastric micromucosal patterns observed by magnifying endoscopy with narrow band imaging.

BACKGROUND AND AIM: The distributions and grades of Helicobacter pylori induced gastritis are known to vary among H. pylori-associated diseases. The aim of this study was to investigate the differences in distributions of gastric micromucosal structures observed by magnifying narrow band imaging (NBI) endoscopy among patients with different H. pylori-associated diseases. METHODS: Ninety-five patients with active duodenal ulcers (n = 24) and diffuse-type (n = 24) and intestinal-type (n = 47) early gastric cancers were enrolled. The magnified NBI findings were evaluated at the lesser and greater curvatures in the upper gastric corpus and were classified according to the modified A-B classification system. Biopsy specimens were also evaluated. RESULTS: In a total of 190 areas observed with magnifying NBI, histological grading (inflammation, activity, atrophy and intestinal metaplasia) showed significant differences among the classified micromucosal patterns (P < 0.001). Types B-1 and B-2, with mild atrophic changes and few areas of intestinal metaplasia, were seen mostly in the duodenal ulcers group. Types B-3 and A-1, with moderate atrophic changes, were seen in the diffuse-type early gastric cancers at the lesser curvature. Types A-1 and A-2, with severe atrophic change and a high frequency of intestinal metaplasia, were seen in the intestinal-type early gastric cancers at the lesser curvature. The prevalence of micromucosal structures differed significantly among the three groups both at the lesser and greater curvatures (P < 0.001). CONCLUSIONS: Magnifying NBI endoscopy clearly revealed detailed micromorphological differences corresponding to the histology and endoscopic findings among patients with different H. pylori-associated diseases.

[A case of gastrointestinal stromal tumor of the stomach arising from the muscularis mucosae].

A 75-year-old man, in whom upper gastrointestinal endoscopy revealed a submucosal tumor in the greater curvature of the gastric angle, was hospitalized for further investigations. Since the tumor was shown to be located in the submucosal layer by endoscopic ultrasonography, we performed endoscopic mucosal resection. Pathological studies of the resected specimen revealed a gastrointestinal stromal tumor of the stomach. It was also formed that the tumor was connected not to muscularis propria, but to the muscularis mucosae. There has been no previous report about a case of gastrointestinal stromal tumor of the stomach arising from the muscularis mucosae in Japan.

Lipocalin-type prostaglandin D synthase as a melanocyte marker regulated by MITF.

Microphthalmia-associated transcription factor (MITF) is responsible for differentiation of melanocytes. A recessive MITF mutant, black-eyed white Mitf(mi-bw) mouse, is characterized by white coat color and deafness, due to the lack of melanocytes in the skin and inner ears. By cDNA microarray analysis, we have identified lipocalin-type prostaglandin D synthase (L-PGDS), whose mRNA is undetectable in the homozygous Mitf(mi-bw) skin. Immunohistochemical analysis of wild-type mice identified the specific expression of L-PGDS in follicular melanocytes. L-PGDS mRNA is expressed in B16 mouse melanoma cells, but undetectable in human melanoma cell lines. RNA interference analysis against MITF suggests that L-PGDS expression is dependent on MITF in B16 melanoma cells. Furthermore, we have provided evidence that MITF is involved in the melanocyte lineage-specific transcription of the mouse L-PGDS gene. Thus, L-PGDS represents a newly identified melanocyte marker. MITF may modulate the production of prostaglandin D(2) by activating the L-PGDS gene in melanocytes.

[A case of gastric cancer with metastasis to cervical lymph nodes and pulmonary lymphangitis carcinomatosa responding to neoadjuvant chemotherapy with TS-1 and CDDP].

The patient was a 61-year-old man who had gastric cancer with metastasis to cervical lymph nodes and pulmonary lymphangitis carcinomatosa. He received daily oral administration of 120 mg of TS-1 (day 1-21) and systemic administration of 100 mg of CDDP (day 8) as one treatment course. As the metastatic lesions had disappeared after chemotherapy, he underwent total gastrectomy. Histopathological examination of resected regional lymph nodes revealed marked fibrosis and a small amount of scattered cancer cells. Although much peritoneal dissemination was observed macroscopically, histopathological examination of these tumors revealed only fibrosis with no cancer cells. These findings supported the effect of this neoadjuvant chemotherapy. He died of recurrence of the carcinoma 203 days after surgery, without any sign of recurrence of metastasis to cervical lymph nodes or pulmonary lymphangitis carcinomatosa.

Three-dimensional reconstruction and fractal geometric analysis of serrated adenoma.

Serrated adenoma (SA) is a relatively newly defined entity of colorectal neoplasm first characterized by Longacre and Fenoglio-Preiser in 1990. This lesion is characterized by a complicated serrated edge of crypts. In this study, we performed three-dimensional (3-D) reconstruction, including 3-D distribution patterns of Ki-67-positive cells and fractal dimension of SA, in order to evaluate the nature of the complicated architecture, including its possible morphogenesis. We studied nine colonoscopic polypectomy specimens including three SAs, three tubular adenomas (TAs), and three hyperplastic polyps (HPs). Sixty serial tissue sections per case were stained alternately with hematoxylin and eosin (H&E) and Ki-67 immunostain. Each serial image was then digitized for 3-D computer analysis and the distribution pattern of Ki-67-positive cells was evaluated. Ki-67-immunostained sections were also subjected to 2-D quantitative morphometric study. In addition, the fractal dimensions of images from H&E-stained sections were examined using a box-counting method. Results of the 3-D reconstruction study demonstrated that glandular budding and branching were more frequent in SA than in TA or HP. These findings were confirmed quantitatively by the results of fractal geometric analysis of these polyps (fractal dimension:1.34 +/- 0.08 for SA, 1.23 +/- 0.07 for TA, and 1.28 +/- 0.12 for HP). Ki-67-positive cells in HP were localized mainly in the bottom of crypts and those in TA were diffusely distributed, while Ki-67-positive cells in SA were mainly aggregated in the depressed sites of serrated epithelia. These findings were also confirmed quantitatively using 2-D morphometry. These distribution patterns of the proliferative zone of SA are considered to contribute to the formation of the characteristic serrated epithelia and the complicated morphological appearance of SA.