Jiro Kumagai

Improvement in Atrophic Gastritis and Intestinal Metaplasia in Patients in Whom Helicobacter pylori Was Eradicated

Few long-term studies of chronic gastritis associated with Helicobacter pylori have been published. Kuipers (1) and Valle (2) and their colleagues showed that in about one third of infected patients, nonatrophic gastritis progressed to glandular atrophy and intestinal metaplasia before final follow-up (mean duration of follow-up, 11.5 years and 32 years, respectively). Two studies of 10 patients (3) and 35 patients (4) infected with H. pylori found long-term improvement in intestinal metaplasia after H. pylori eradication. However, in one study of more than 100 patients with H. pylori infection, glandular atrophy and intestinal metaplasia did not improve during long-term follow-up (5). We evaluated histologic changes 12 to 15 months after attempted eradication of H. pylori to explore whether glandular atrophy and intestinal metaplasia improve after eradication. Methods Patients We enrolled all consecutive patients with dyspepsia and H. pylori infection who were seen at our gastroenterology clinic in Tokyo, Japan, for diagnostic upper gastrointestinal endoscopy. The proportions of patients who were self-referred, were referred from within our hospital, and were referred from other hospitals were roughly equal. Patients with possible allergy to penicillin, amoxicillin, or proton-pump inhibitors and those with previous gastrectomy were excluded. Written informed consent was obtained from participants in accordance with the Declaration of Helsinki and its later revision. The protocol was approved by the institutional review board of Tokyo Medical and Dental University, Tokyo, Japan. Study Design At entry, patients underwent upper gastrointestinal endoscopy; gastric mucosa was histologically evaluated by performing biopsy. Helicobacter pylori status was assessed by using bacteriologic culture, histologic results, the rapid urease test, and the urea breath test. Eligible patients were treated for 1 week with a proton-pump inhibitor (omeprazole or lansoprazole), amoxicillin, and clarithromycin with or without a mucoprotective agent (ecabet sodium, rebamipide, or sofalcone). At 1 to 3 months (short-term follow-up) and at 12 to 15 months (long-term follow-up) after eradication therapy, patients again underwent upper gastrointestinal endoscopy and gastric biopsy specimens were examined histopathologically. H. pylori Assessment At each endoscopy, three biopsy specimens each were taken from the greater curvature of the antrum and the greater curvature of the corpus of the stomach. One sample from each site was cultured, one was used for the rapid urease test, and one was used for histologic examination. Cultures on modified Skirrow agar with 10% horse blood were incubated for 5 to 7 days at 37 C in a microaerobic atmosphere. We identified H. pylori by observing colony structure and performing biochemical tests for urease, catalase, and oxidase activities. Biopsy specimens for histologic examination were stained with Giemsa stain or hematoxylineosin. After an overnight fast, a [13C]urea breath test was done with 100 mg of [13C]urea per 100 mL of distilled H2O. The results were considered negative if the ratio of 13CO2 to 12CO2 in 15 minutes increased by less than 5 parts per million. The presence of H. pylori was investigated at each endoscopic examination. The bacterium was considered to be present if results of at least two of four tests (bacteriologic culture, histologic results, rapid urease test, and urea breath test) were positive. Helicobacter pylori was considered eradicated if results were negative for all four tests at both short-term and long-term follow-up. No patient had only one positive test result. Gastritis Scores The endoscopists were blinded to the results of treatment. For each patient, two pathologists who were blinded to the results of treatment made independent histologic diagnoses by examining one biopsy specimen each from the antrum and corpus. The pathologists disagreed on the diagnosis in 99 of the 978 specimens examined (49 specimens from the antrum and 50 specimens from the corpus; the final diagnoses were chronic inflammation in 24 specimens, neutrophil activity in 39, glandular atrophy in 27, and metaplasia in 9). Consensus was reached by re-examination and discussion. Severity of chronic inflammation, neutrophil activity, glandular atrophy, and intestinal metaplasia was graded from 0 (normal) to 3 (markedly abnormal) according to the visual analogue scales of the updated Sydney System (6). Specimens stained with Giemsa were evaluated for H. pylori by another investigator. Statistical Analysis We divided patients into two groups on the basis of the success or failure of H. pylori eradication. We examined background factors and histologic findings at baseline to identify pretreatment differences between the two groups. We used the unpaired t-test for age, the chi-square test for sex ratios in the two groups, both the chi-square test and the Fisher exact test for comorbid conditions, and the Wilcoxon rank-sum test for histologic findings. For the antrum and corpus, we performed the Wilcoxon signed-rank test to compare histologic findings at baseline with those at follow-up (1 to 3 months and 12 to 15 months after treatment). To evaluate differences in changes in the histologic findings during follow-up, we performed mixed-effects ordinal logistic regression by using the computer program MIXOR (7). This method prevents problems caused by regression to the mean. We used SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina), to perform all other analyses. A P value less than 0.05 was considered statistically significant. Results We studied 207 consecutive patients with H. pylori infection and dyspepsia. Patients underwent endoscopy before treatment and at least once after treatment, at 1 to 3 months. In addition, 163 patients agreed to undergo another endoscopy at 12 to 15 months after treatment (mean, 14 months). Thirty-three patients declined to undergo a second follow-up examination, and 11 patients were untraceable because they had moved out of the area. Helicobacter pylori was eradicated without serious side effects in 115 of the 163 patients who had long-term follow-up. The 115 patients in whom H. pylori was eradicated were similar to the 48 who remained infected in terms of mean (SD) age (54 12 years vs. 59 10 years), sex distribution (84 men and 31 women vs. 30 men and 18 women), and diagnosis (47 and 18 patients with chronic gastritis, 30 and 15 with duodenal ulcers, 25 and 15 with gastric ulcer, and 13 and 0 with gastroduodenal ulcers). The Table shows histologic findings for the gastric mucosa before treatment and again at the two follow-up points. The two groups did not differ significantly in histologic findings before treatment. In patients with successful eradication, scores for chronic inflammation and neutrophil activity at both sites were lower at both follow-up points than before treatment, and scores for glandular atrophy in the corpus and intestinal metaplasia in the antrum were lower at 12 to 15 months than before treatment. Glandular atrophy in the corpus improved in 34 (89%) of the 38 patients with atrophy before treatment, and intestinal metaplasia in the antrum improved in 28 (61%) of the 46 patients with metaplasia before treatment. Table. Histologic Results before Treatment To Eradicate Helicobacter pylori and at Short- and Long-Term Follow-up In patients with unsuccessful eradication of H. pylori, no significant histologic changes were observed at follow-up, except for progression of chronic inflammation. Mixed-effects ordinal logistic regression showed statistically significant differences between groups in changes at follow-up for chronic inflammation and neutrophil activity at both sites and for intestinal metaplasia in the antrum (Table, Figure). Individual histologic changes were as follows (some percentages do not total 100 because of rounding). Among patients with successful eradication of H. pylori, glandular atrophy in the antrum decreased in 29% and 27% at short- and long-term follow-up, respectively, was unchanged in 40% and 30%, and increased in 31% and 43%; in the corpus, glandular atrophy decreased in 24% and 30%, was unchanged in 70% and 64%, and increased in 6% and 6%. Intestinal metaplasia in the antrum decreased in 16% and 25% of patients of these patients, was unchanged in 78% and 71%, and increased in 5% and 4%; intestinal metaplasia in the corpus decreased in 3% and 4%, was unchanged in 88% and 91%, and increased in 10% and 5%. Among patients without eradication of H. pylori, glandular atrophy in the antrum decreased in 23% and 38%, at short- and long-term follow-up, respectively, was unchanged in 44% and 29%, and increased in 33% and 33%; glandular atrophy in the corpus decreased in 25% and 19%, was unchanged in 46% and 65%, and increased in 29% and 17%. Intestinal metaplasia in the antrum decreased in 0% and 0%, was unchanged in 98% and 96%, and increased in 2% and 4%; intestinal metaplasia in the corpus decreased in 12% and 8%, was unchanged in 81% and 83%, and increased in 6% and 8%. Figure. Predicted curves obtained by mixed-effects ordinal logistic regression models for histologic changes in the gastric mucosa in patients in whom Helicobacter pylori infection was or was not successfully eradicated . H. pylori H. pylori P Discussion Tucci and colleagues (8) reported that atrophic gastritis of the corpus of the stomach had regressed by 12 months after discontinuation of treatment in 10 of 20 patients with fundic atrophic gastritis in whom H. pylori was successfully eradicated. In contrast, Witteman and colleagues (10) found no changes at 57 weeks in glandular atrophy of the antrum and corpus of patients in whom the bacterium was eradicated. In a prospective study with a mean follow-up of 1 year (range, 6 to 18 months), van der Hulst and colleagues (5) found that the degree of atrophy did not change; however, their grading of a

High Expression of HER3 Is Associated with a Decreased Survival in Gastric Cancer

Background: The role of human epidermal growth factor receptor (HER) 3 and HER4 has been elucidated in gastric cancer. HER1 and HER2 overexpression are regarded as prognostic factors and targets of treatment. The dimerization of the HER family receptors activates downstream signal pathways and promotes tumor progression. This study investigated the positive correlation between HER1 and HER4 expression and the prognosis of patients with gastric cancers. Experimental Design: Tumor samples were obtained from gastric adenocarcinomas of 134 patients who underwent a gastrectomy from 1999 to 2002. The expression of each HER was analyzed in the tumor by immunohistochemical staining. Parametric correlations were done between HER expression and the clinicopathologic findings. A multivariate analysis was done with the overall survival. Results: HER3 expression was significantly associated with parameters involved with tumor progression, including the depth of tumor invasion (T1 versus T2-T4; P = 0.000), involved lymph nodes (P = 0.000), distant metastasis (P = 0.008), tumor stage (P = 0.000), and recurrent disease (P = 0.000). HER1 was also significantly associated with those factors excluding distant metastasis. A significant relationship was observed between the expression of HER1 and HER3 (P = 0.000). HER3 overexpression was associated with a significantly worse survival (P = 0.0000) and was an independent prognostic factor in the multivariate analysis (hazard ratio, 2.382; 95% confidence interval, 1.009-5.625; P = 0.048). Conclusions: HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer. It may become a new prognostic factor and a target of treatment.

Disappearance of Hyperplastic Polyps in the Stomach after Eradication of Helicobacter pylori: A Randomized, Controlled Trial

Although the malignant potential of hyperplastic gastric polyps was originally denied, a low risk for carcinomatous conversion (1.5% to 3%) is now recognized [1, 2]. Patients with gastric polyps may present with bleeding of the upper gastrointestinal tract, abdominal pain, or gastric outlet obstruction [3]. Therefore, most endoscopists agree that large gastric polyps or polyps associated with complications should be removed endoscopically or surgically [4]. In a previous investigation of the relation of Helicobacter pylori infection to various gastric polyps [5], we found that H. pylori infection was closely associated with hyperplastic polyps and that H. pylori was present in 100% of hyperplastic polyps. This relation is supported by two case reports [6, 7] indicating that clearance and eradication of H. pylori led to the disappearance of hyperplastic polyps. We also reported that 15 polyps (8 to 26 mm in diameter) in a patient with hyperplastic polyps had disappeared by 12 months after eradication of H. pylori [8]. However, these observations were made in only a few patients. We conducted a randomized, controlled trial to see whether hyperplastic polyps would disappear after eradication of H. pylori. Methods Patients We enrolled 35 patients (19 men and 16 women; age range, 29 to 75 years) with H. pylori infection and hyperplastic polyps of the stomach diagnosed by endoscopic biopsy. These patients were randomly assigned to one of two groups and sequentially numbered. In the treatment group (n = 17), patients received a proton-pump inhibitor (omeprazole or lansoprazole), amoxicillin, and either clarithromycin or ecabet sodium; in the control group [n = 18], patients had endoscopic examination but did not receive treatment. Our criteria for hyperplastic gastric polyps were 1) hyperplasia of the foveolar epithelium on histologic examination and 2) infiltration of inflammatory cells into the stroma in biopsy specimens [9]. Polyps were diagnosed by two blinded pathologists. Two patients who had hyperplastic polyps 2 mm or less in diameter and 1 patient who did not have H. pylori infection were excluded. Written, informed consent was obtained from each study participant in accordance with the Declaration of Helsinki (1964) and revisions thereof. The protocol was planned according to the guidelines of the H. pylori eradication trial approved by the committee of the Japanese Society of Gastroenterology. If polyps progressed and were accompanied by malignant transformation, the study was stopped and the polyps were removed endoscopically. After our study was completed, treatment for controls and for patients in whom the first attempt at eradication had failed was proposed in the form of endoscopic removal of polyps or eradication of H. pylori. Data entry and data analyses were done by code so that treatment assignments remained concealed. Compliance with treatment was assessed by pill count. Endoscopy and Assessment of Eradication of Helicobacter pylori Patients in the treatment group underwent endoscopy 1 to 3, 7 to 9, and 12 to 15 months after the end of treatment. On each occasion, biopsy specimens were taken from the same areas (three from the antrum and three from the body, exclusive of polyps) for culture, rapid urease testing, and histologic examination. Controls underwent endoscopy 12 to 15 months after enrollment. The H. pylori cultures were done by using a modified Skirrow agar with 10% horse blood and were incubated for 5 to 7 days at 37C in a microaerobic atmosphere. We identified H. pylori by colony morphology and biochemical tests, such as urease, catalase, and oxidase activity tests. Rapid urease testing was done with the CLO test (Delta West Pty. Ltd., Bentley, Australia), and the result was considered positive if the color changed after 24 hours. Biopsy specimens for histologic examination were immediately placed in 10% neutral buffered formalin, embedded in paraffin wax, stained with hematoxylin and eosin and with Giemsa, and evaluated for the presence of H. pylori. After patients had fasted overnight, the 13C-urea breath test was done by using 100 mg of urea per 100 mL of 13C-urea solution. The test result was considered negative if the excess delta 13CO2/sup 12 CO2 after 15 minutes was less than 5 parts per million. The presence of H. pylori was determined at each endoscopic examination and was defined by positive results on at least two of four tests: culture, urease testing, histologic examination, and urea breath testing. Eradication of H. pylori was confirmed by negative results on all four tests 1 to 3 months after the end of treatment and at each endoscopic examination. Endoscopists were blinded to treatment assignments. The size and number of polyps were measured at each endoscopic examination by using biopsy forceps (FB-25K, Olympus, Tokyo, Japan) placed near the polyp (open size, 6 mm in diameter; closed size, 2 mm in diameter), and the endoscopic film data on the disappearance and regression of polyps were reviewed independently by two blinded endoscopists. Histologic Examination, Gastrin Levels, and Titer of IgG to Helicobacter pylori Histologic diagnosis of the biopsied mucosa of the antrum and body was made by two blinded pathologists. The severity of activity, inflammation, atrophy, and metaplasia was graded on a scale from 1 to 4 and expressed by using the histologic index according to the updated Sydney System [10]: 1 = normal, 2 = mild, 3 = moderate, and 4 = marked. The serum gastrin level for each patient in both study groups was measured under fasting conditions before the start of treatment and 1, 3, and 12 months after the end of treatment by using radioimmunoassay (GASTRIN-RIA KIT II, Dinabot Co. Ltd., Tokyo, Japan [normal range, 37 to 172 pg/mL]). The titer of IgG to H. pylori was measured by using an enzyme immunoassay kit (HEL-pTEST II, AMRAD Operations Pty. Ltd., Victoria, Australia [range indicating negativity, <30 U/mL]) in serum specimens obtained before treatment and 1, 3, and 12 months after the end of treatment. Laboratory analyses were done by code so that treatment assignments remained concealed. Statistical Analysis Pretreatment clinical and laboratory data were analyzed by using the unpaired t-test (for age), the Wilcoxon rank-sum test (for number and size of polyps, histologic findings, serum gastrin levels, and titer of IgG to H. pylori), and the Fisher exact test (for sex, coexisting disease, and distribution of polyps). Post-treatment data were analyzed by using the Fisher exact test (for rates of disappearance, regression of polyps, and eradication of H. pylori) and the Wilcoxon rank-sum test (for histologic and laboratory data). P values less than 0.05 were considered statistically significant. All statistical analyses were done by using STATVIEW software (version 4.02, Japanese edition, Nankodo, Inc., Tokyo, Japan). Results The treatment and control groups were similar with respect to number of patients; age; sex; coexisting disease; number, size, and distribution of polyps; histologic findings; serum gastrin levels; and titers of IgG to H. pylori (Table 1). All patients in both groups completed the entire study protocol and had coexisting chronic atrophic gastritis. Table 1. Baseline Characteristics of the Treatment and Control Groups* During the follow-up period in the control group, no hyperplastic polyps regressed or disappeared (Table 2). Polyps enlarged or increased in number in 3 of the 18 patients. However, no polyps in the control group were accompanied by malignant transformation. Table 2. Results of Analyses of the Treatment and Control Groups In the treatment group (Table 2), H. pylori was successfully eradicated without serious side effects in 15 of 17 patients (88% [95% CI, 64% to 98%]), and polyps disappeared in 12 of 17 patients (71% [CI, 44% to 89%]). In 12 of the 15 patients (80% [CI, 52% to 95%]) in whom eradication was successful, disappearance of the polyps and histologic confirmation of a reduction of the inflammatory cell infiltration in the gastric mucosa were seen. The polyps had disappeared in these 12 patients by 3 to 15 months (average, 7.1 1.2 months) after the end of treatment. Smaller polyps tended to disappear within a few months. However, in the 2 patients in whom H. pylori was not eradicated, no polyps showed regression at 12 to 15 months after the end of treatment and no diminution of the inflammatory cell infiltration in the gastric mucosa was seen. The rates of disappearance of polyps in the treatment group were significantly higher than those in the control group (P < 0.001). In patients who received eradication therapy, a significant decrease was seen in serum gastrin levels and titers of IgG to H. pylori compared with those in patients who did not receive eradication therapy (P < 0.001 for serum gastrin levels; P < 0.002 for titers of IgG to H. pylori) (Table 2). Discussion In our study, the disappearance of hyperplastic polyps with histologic confirmation of a reduction in the inflammatory cell infiltration in the gastric mucosa was seen in 12 of the 15 patients (80%) in whom eradication of H. pylori was successful. The polyps had disappeared in the 12 patients by 3 to 15 months (average, 7.1 1.2 months) after the end of treatment. However, none of the polyps in any of the controls or in either of the patients in whom H. pylori was not eradicated showed regression. These results strongly suggest that eradication of H. pylori leads to regression and disappearance of hyperplastic gastric polyps. The patients in both study groups had high serum gastrin levels (251 pg/mL in the treatment group and 299 pg/mL in the control group) at baseline. Bonilla and associates [11] also reported that patients with hyperplastic polyps had high serum gastrin levels. Because gastrin has a trophic effect on the enterochromaffin-like cells of the gastric mucosa [12] and colonic mucosa [13], an elevated plasma gastrin level is of intere

Incidence of Benign Pathologic Lesions at Partial Nephrectomy for Presumed RCC Renal Masses: Japanese Dual-Center Experience with 176 Consecutive Patients

OBJECTIVES To determine the incidence of benign pathologic findings at elective partial nephrectomy for renal masses thought to be renal cell carcinoma (RCC) on preoperative imaging in Japanese patients. METHODS From 1993 to 2007, 176 patients (46 women and 130 men) underwent elective partial nephrectomy for presumed RCC masses in 2 Japanese centers. The mean size of the resected lesions was 2.3 cm (range 0.3-5.8). Overall, 97 and 79 patients had a renal mass of < or = 2 cm and > 2 cm, respectively. Of the 176 patients, 100%, 89%, and 32% had preoperatively undergone computed tomography, ultrasonography, and magnetic resonance imaging, respectively. RESULTS Of the 176 masses resected, the pathologic examination revealed benign findings in 19 (11%), angiomyolipoma in 10 (5.7%), oncocytoma in 5 (2.8%), complicated cysts in 2 (1.1%), and a solitary fibrous tumor and scar of the kidney 1 each (0.6%). Of the 46 women, 12 (26.1%) had benign lesions compared with 7 of the 130 men (5.3%; P = .0003). Of the 10 angiomyolipomas diagnosed, 8 were diagnosed in women (P = .0004). Tumor size was not associated with benign histologic findings. The incidence of benign lesions was equivalent (10% and 12%) between the 2 centers. CONCLUSIONS The present incidence (11%) of benign lesions in presumed RCC masses at surgery in Japanese patients was lower than the incidence of 20%-30% previously reported from Western countries, probably because of the low incidence of oncocytomas in Japanese patients. Women had almost 5 times the likelihood of having a benign lesion compared with men, because of the high incidence of angiomyolipomas in women.

Development and External Validation of a New Outcome Prediction Model for Patients With Clear Cell Renal Cell Carcinoma Treated With Nephrectomy Based on Preoperative Serum C-Reactive Protein and TNM Classification: The TNM-C Score

PURPOSE C-reactive protein has been shown to be a prognostic factor for renal cell carcinoma. We developed a new prediction model including C-reactive protein in patients with clear cell renal cell carcinoma. MATERIALS AND METHODS This study is based on 2 cohorts of Japanese patients with clear cell renal cell carcinoma, including 249 for evaluating prognostic factors and developing the prediction model, and 290 for external validation. Analyzed factors included TNM classification, tumor size, Fuhrman nuclear grade, tumor necrosis and preoperative serum C-reactive protein (cutoff 0.5 mg/dl). We developed a scoring model based on multivariate analysis to predict cancer specific survival. Predictive ability of the model was evaluated using the concordance index. RESULTS Multivariate analysis showed that pT stage, lymph node involvement, distant metastasis, tumor necrosis and C-reactive protein were independent predictors of cancer specific survival. A new scoring model was developed, consisting of C-reactive protein and the TNM classification. The 5-year cancer specific survival rate in patients with a score of 0, 1 and 2, 3 and 4, and 5 or more was 99%, 89%, 69% and 18%, respectively. Cancer specific survival rates were clearly discriminated by the stratification according to the scoring model (p <0.001). The concordance index of the new model was 0.820, which was externally validated as a concordance index of 0.865. CONCLUSIONS In patients with clear cell renal cell carcinoma a new simple scoring model based on serum C-reactive protein and the TNM classification is a useful and easy to use tool for predicting outcome.

The impact of preoperative serum C‐reactive protein on the prognosis of patients with upper urinary tract urothelial carcinoma treated surgically

To assess the impact of preoperative C‐reactive protein (CRP) levels on the prognosis in patients with upper urinary tract (UUT) urothelial carcinoma (UC) primarily treated surgically, as it is increasingly recognized that a systemic inflammatory response is associated with the prognosis for patients with various malignancies.

Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.

Absence of either gastric or intestinal phenotype in microscopic differentiated gastric carcinomas

Differentiated gastric carcinoma (DGC) corresponds roughly to the intestinal type of gastric carcinoma described by Laurén. It has been suggested that DGCs arise from intestinalized gastric mucosa, but recent findings regarding their mucin expression do not support this hypothesis. To evaluate the histogenetic relationship between DGCs and intestinal metaplasia, lesions that are as small as possible should be examined. Twenty‐five DGCs, ranging in their greatest dimension from 0.4 to 2.7 mm, were collected and divided into two groups by size. Group A consisted of 13 lesions less than 1.4 mm across, and group B of 12 lesions 1.4 mm or more. The presence of mucin and a brush border was assessed by immunostaining with antibodies against human gastric mucin, pyloric‐gland‐type mucin, Muc‐2 glycoprotein, and CD10 antigen, and the lesions were classified as having the gastric phenotype (G‐type), intestinal phenotype (I‐type), mixed gastric and intestinal phenotype (M‐type), or null phenotype (N‐type). Thirteen (52%) of the 25 lesions were N‐type, 5 (20%) lesions were G‐type, 5 (20%) were I‐type, and 2 (8%) were M‐type. Group A had a larger proportion of N‐type lesions than B (10/13, or 77%, vs. 3/12, or 25%; p = 0.027, chi‐square test for proportions). Group B had a larger proportion of G‐type lesions than A (5/12, or 42%, vs. 0/13, or 0%; p = 0.033). The phenotypes of the carcinomas and their surrounding mucosa were unrelated. Therefore, DGCs may arise from gastric mucosa affected by intestinal metaplasia or not, without having either the gastric or intestinal phenotype. Copyright

Flat adenomas and flat adenocarcinomas of the colorectal mucosa in Japanese and Swedish patients

PURPOSE: In recent years, flat adenomas of the colorectal mucosa have been intensively investigated by Japanese pathologists. Results of that work indicate that flat adenomas may antedate the development of colorectal carcinomas. Because of differences in the Histologic definition of flat adenomas with severe dysplasia and with intramucosal carcinoma within the group, one single observer having both Western and Asian training in pathology reviewed the material. METHODS: A total of 287 flat colorectal lesions were reviewed: 109 from the Karolinska Hospital, Stockholm, 137 from the Tokyo Medical and Dental University (TMDU) (which included 50 cases from the Nagoya City University), and 41 from the Cancer Institute (CI), Tokyo. Lesions were histologically classified following strict Histologic criteria. Thus, flat adenomas were divided into those having lowgrade dysplasia (LGD; having dysplastic cells in the deeper half of the epithelium), high-grade dysplasia (HGD; dysplastic cells were found even in the superficial half of the epithelium), intramucosal carcinoma (dysplastic glands displayed molding with buddings and often a cribriform pattern), and adenocarcinoma (breaking through the muscularis mucosa, with neoplastic cells in the submucosal layer or deeper). RESULTS: Whereas in Stockholm only 14.7 percent of lesions had HGD, as much as 56.9 percent and 56.1 percent, respectively, had HGD at the two Tokyo Hospitals. Intramucosal carcinomas were not found in the Stockholm material but occurred in 2.2 percent of lesions seen at TMDU and in 4.9 percent of those seen at the CI. Notably, only 2.7 percent of the specimens at Karolinska Hospital had invasive adenocarcinoma, but it was seen in as many as 4.4 percent at TMDU and 21.9 percent at the CI. CONCLUSIONS: This study indicates that there were Histologic differences between flat neoplasias of the colorectal mucosa harvested in Stockholm and Tokyo. In Japan, lesions were obviously more advanced (in terms of HGD) and more aggressive (in terms of intramucosal and submucosal invasion). The cause for the differences found in those two disparate geographic regions remains poorly understood. The results, however, may help us understand some of the unclear points and discussions appearing in the literature on this subject.

External Validation of the Mayo Clinic Cancer Specific Survival Score in a Japanese Series of Clear Cell Renal Cell Carcinoma

PURPOSE We validated the Mayo Clinic SSIGN (stage, size, grade and necrosis) score in an independent Japanese sample of patients. MATERIALS AND METHODS Between 1985 and 2006, 406 consecutive Japanese patients underwent nephrectomy for clear cell renal cell carcinoma. The prognostic value of pathological features for disease specific survival was evaluated using the Cox proportional hazards regression model. The predictive ability of the SSIGN score was evaluated using the concordance index. RESULTS Median followup in the 406 patients was 56 months. Of the patients 100 died of renal cell carcinoma and the 5-year cancer specific survival rate was 78.4%. All features comprising the SSIGN score were significantly associated with death from renal cell carcinoma on univariate analysis. Primary tumor classification, regional lymph node involvement, distant metastasis and Fuhrman nuclear grade were significantly associated with death from renal cell carcinoma in a multivariate setting. The median SSIGN score in the 406 patients was 3 (range 0 to 15). The concordance index of the SSIGN score was 0.814. The 5-year cancer specific survival rate in patients with a score of 0 to 2, 3 or 4, 5 or 6, 7 to 9 and 10 or more was 96.8%, 92.5%, 78.8%, 57.7% and 18.1%, respectively. The survival rate in the latter 3 groups was higher than reported rates in American and European patients. CONCLUSIONS The Mayo Clinic SSIGN score can be applicable to Japanese patients with renal cell carcinoma with a high degree of prognostic accuracy. Future studies are needed to determine whether Japanese patients with moderate and high SSIGN scores survive longer than their American and European counterparts.