To investigate what heterogeneity exists in breast cancer, 228 consecutive patients with operable invasive duetal carcinoma (IDC), not otherwise specified, were categorized on the basis of the horizontal progression model of carcinogenesis. Using the reversed Black's nuclear grade (RBNG) in the IDC component and the association of ductal carcinoma in situ (DCIS), the patients were classified into pure IDC (IDC de novo or ab initio) as Group I, non-high grade (RBNG 1 and 2) IDC with DCIS as Group II, and high grade (RBNG 3) IDC with DCIS as Group III. The Groups classified in the present study appeared as a prognostic factor independent of known prognostic and predictive factors in multivariate test. Group I had the worst prognosis among the three groups and was the most non-responsive to tamoxifen. After performing stratifying analyses by group, it was found that metastasis-free survival was statistically associated with the status of hormone receptors estrogen receptor and progesterone receptor and tamoxifen therapy only in Group II. In addition, the status of c-erbB-2 expression had prognostic significance only within the Group III. Our results may be used to frame an alternative hypothetical model for breast cancer evolution and will lead us to reconsider the tailoring of the comprehensive therapeutic modality used at the present time.
Treatment Outcome ; Time Factors ; Receptors, Progesterone/metabolism ; Receptors, Estrogen/metabolism ; Prognosis ; Neoplasm Metastasis ; Middle Aged ; Humans ; Female ; Disease-Free Survival ; *Classification ; Cell Nucleus/metabolism ; Carcinoma, Ductal, Breast/*classification/*diagnosis/pathology ; Breast Neoplasms/*classification/*diagnosis/pathology ; Aged ; Adult

PURPOSE: Breast Cancer is an inter-tumoral and intra-tumoral heterogeneous disease. It remains unclear whether this heterogeneity results from different target cells or from different subsets of genetic abnormalities, otherwise from both. We postulated that in addition to genetic cloning, a variety of cells that exist during the defined developmental stages of the human mammary gland could give rise to the heterogeneity of breast cancer. To verify this postulation, we have analyzed pure ductal carcinoma in situ (DCIS) for the expression of the biomarkers that represent the mammary stem cell, the early progenitor cells, and the glandular and myoepithelial cells of the mammary gland. METHODS: We investigated the relationship between the immnuohistochemical expression of the mammary development-associated biomarkers {cytokeratin-18 (CK18), cytokeratin-6 (CK6), alpha-smooth muscle actin (SMA), Wnt-1, Notch 3} and some other factors {the menopausal status, the estrogen receptor (ER) status, the progesterone receptor (PR) status, c-erbB-2, and the number of tumor foci} in 26 cases of DCIS. RESULTS: All 26 cases included in this study showed the positive expressions of CK18 and SMA. The expression of all the markers was not correlated with the menopausal status. The positive expression of CK6 had a statistically significant relationship with a negative estrogen receptor (p=0.014), positive c-erbB-2 (p=0.048), high nuclear grade (p=0.001), and single focus of DCIS (p=0.017). The expression of Wnt-1 and Notch 3 did not have significant correlation with any factors. However, the positive expression of Wnt-1 showed a tendency of a negative ER (p=0.061) and the positive expression of Notch 3 also showed a tendency of a negative ER (p=0.086) and a high nuclear grade (p=0.086). CONCLUSION: The CK6 positive tumor is thought to originate from the more primitive cells compared to the CK6 negative tumor. Unifocality of the CK positive tumor might result from the arrest of differentiation of the original cell after disease affection. DCISs could be categorized into the CK6 positive and negative groups.
Actins ; Biomarkers ; Breast Neoplasms ; Carcinoma, Ductal* ; Carcinoma, Intraductal, Noninfiltrating* ; Clone Cells ; Cloning, Organism ; Estrogens ; Keratin-6 ; Mammary Glands, Human* ; Population Characteristics ; Receptors, Progesterone ; Stem Cells*

INTRODUCTION: Cathepsin D (CD) is a lysosomal protease that can be used as an important prognostic cytosolic factor for breast cancer. Its over-expression in breast cancer cells and in the host stromal cells in the tumor has been proposed as being a poor prognostic indicator. However, its prognostic value is still being debated. Therefore, CD expression needs to be examined in more relevant subsets of tissue in order to refine its prognostic significance and the clinical applications. METHODS: Regardless of the lymph node status, 110 T1 invasive ductal carcinomas of the breast were immunohistochemically evaluated for the CD expression using rabbit anti-cathepsin D monoclonal antibody. This study separately assessed the expression of CD in the invasive component (IDC), in the in situ component (DCIS), and in the juxtatumoral stromal cells (JTSC). The CD expression level in these three kinds of tissues were correlated with the nuclear grade, ER, PR, c-erb-B2, p53, the N stage, the T stage, and the 5 year metastasis-free survival. RESULTS: Positive CD expression in the JTSC was associated with the T stage (p = 0.001) and the N stage (p = 0.029), whereas positive CD expression in the DCIS and IDC was not. In addition, strong CD expression in the JTSC correlated with the nuclear grade of the invasive component (p = 0.024). In all three components, no statistically significant correlation was found between the biomarker (ER, PR, cerb-B2, p53) and the CD expression. On univariate analysis, positive expression in the JTSC was correlated with a poor 5 year- metastasis free survival (p = 0.007), but the positive expression in the IDC and DCIS was not. CONCLUSION: CD expression of the JTSC could represent the N stage, the T stage, and the nuclear grade of T1 IDC. Whether or not it would have an independent influence on the prognosis of T1 IDC, CD expression in the JTSC is probably an indicator of the tumor virulence. CD expression in the JTSC will provide an important clue for the development of new CD targeted therapies, and it will serve as an important criterion for selecting the appropriate candidates for these future targeted therapies.
Breast ; Breast Neoplasms ; Carcinoma, Ductal* ; Carcinoma, Intraductal, Noninfiltrating ; Cathepsin D* ; Cathepsins* ; Cytosol ; Lymph Nodes ; Neoplasm Metastasis ; Prognosis ; Stromal Cells* ; Virulence

BACKGROUND/AIMS: Loss of transforming growth factor beta1 (TGF-beta1) exhibits a similar pathology to that seen in a subset of individuals infected with Helicobacter pylori, including propagated gastric inflammation, oxidative stress, and autoimmune features. We thus hypothesized that gastric mucosal TGF-beta1 levels could be used to determine the outcome after H. pylori infection. METHODS: Northern blot for the TGF-beta1 transcript, staining of TGF-beta1 expression, luciferase reporter assay, and enzyme-linked immunosorbent assay for TGF-beta1 levels were performed at different times after H. pylori infection. RESULTS: The TGF-beta1 level was markedly lower in patients with H. pylori-induced gastritis than in patients with a similar degree of gastritis induced by nonsteroidal anti-inflammatory drugs. There was a significant negative correlation between the severity of inflammation and gastric mucosal TGF-beta1 levels. SNU-16 cells showing intact TGF-beta signaling exhibited a marked decrease in TGF-beta1 expression, whereas SNU-638 cells defective in TGF-beta signaling exhibited no such decrease after H. pylori infection. The decreased expressions of TGF-beta1 in SNU-16 cells recovered to normal after 24 hr of H. pylori infection, but lasted very spatial times, suggesting that attenuated expression of TGF-beta1 is a host defense mechanism to avoid attachment of H. pylori. CONCLUSIONS: H. pylori infection was associated with depressed gastric mucosal TGF-beta1 for up to 24 hr, but this apparent strategy for rescuing cells from H. pylori attachment exacerbated the gastric inflammation.
Blotting, Northern ; Enzyme-Linked Immunosorbent Assay ; Gastritis ; Helicobacter pylori ; Humans ; Inflammation ; Luciferases ; Oxidative Stress ; Transforming Growth Factor beta ; Transforming Growth Factor beta1 ; Ulcer

BACKGROUND/AIMS: Functional dyspepsia (FD) is one of the most common gastrointestinal disorders, and FD imposes social and economic burden worldwide. The aim of this study is to identify the prevalence and risk factors of FD in health check-up population in tertiary centers in Korea. METHODS: A nationwide multicenter prospective study was performed at 9 tertiary healthcare centers in Korea between September 2016 and June 2017. A total of 2525 subjects were investigated based on endoscopic findings and questionnaires with the Rome III criteria, and Helicobacter pylori serology (IgG). RESULTS: A total of 1714 subjects without organic disease were enrolled. The mean (± SD) age was 51.5 (± 12.7) years, and 917 patients (53.5%) were female. The proportion of H. pylori seropositivity was 51.0% (874/1714). The prevalence of FD was 10.3% (176/1714), and the subtypes of postprandial distress syndrome alone, epigastric pain syndrome alone, and postprandial distress syndrome-epigastric pain syndrome overlap were 4.8%, 3.0%, and 2.5%, respectively. Multivariate analysis showed that female gender (OR, 1.58; 95% CI, 1.14–2.21) and education below college level (OR, 1.45; 95% CI, 1.01–2.07) were related to FD. Multivariate analysis based on age 60 showed female gender as a significant (OR, 2.90; 95% CI, 1.06–7.94) factor in the group ≥60 years. CONCLUSIONS: The prevalence of FD was 10.3% in the health check-up population in Korea. Female sex and education below college level were risk factors for FD. Female sex is a risk factor for FD in old age, underscoring the need for close attention in this age group.
Dyspepsia ; Education ; Female ; Helicobacter pylori ; Humans ; Korea ; Multivariate Analysis ; Prevalence ; Prospective Studies ; Risk Factors ; Tertiary Healthcare

PURPOSE: Of the hypothetical models of the carcinogenesis of breast cancer, the horizontal progression is most acceptable at the present time. According to the hypothesis, there are genetically different pathways among pure invasive ductal carcinoma (IDC), non-high grade IDC with ductal carcinoma in situ (DCIS), and high grade IDC with DCIS. The purpose of this study is to determine if there is any heterogeneity in biological behavior among these three categories. METHODS: With reversed Black nuclear grade (RBNG) in IDC component and the association of DCIS, we divided 184 breast cancer patients, who had underwent curative operations, into three groups. The patients with pure IDC were included in Group 1, non-high grade (RBNG 1 and 2) IDC with DCIS in Group 2, and high grade (RBNG 3) IDC with DCIS in Group 3. And we retrospectively analyzed and compared three groups with mean age, menopausal status, T stage, N stage, the expression rate of ER, PR, p53, and c-erbB-2, and cumulative metastasis-free survival. RESULTS: The percentage of the postmenopausal patients was significantly smaller in Group 3 (14.0%, P=0.025) than Group 1 and 2 (36.1% and 30.6%). There were significantly higher expression rates of ER and PR in Group 2 with 78.3% and 68.3%, respectively (P=0.000 and P=0.030). The 5-year metastasis- free survival rate were 70.4% in Group 1, 85.2% in Group 3, and 87.5% in Group 2. The Log Rank test in Kaplan-Meier cumulative survival curve showed the statistically significant differences among three groups (P= 0.041). CONCLUSION: We can say that there would be clinical heterogeneity among three groups classified by histopathologic findings. To apply this classification to the multi-disciplinary therapeutic modality of breast cancer, further study using a new biologic marker, which is associated with invasiveness and metastagenicity and can discrminate the three categories of breast cancers in any kind of specimen biopised preoperatively, is needed.
Biomarkers ; Breast ; Breast Neoplasms ; Carcinogenesis ; Carcinoma, Ductal* ; Carcinoma, Intraductal, Noninfiltrating ; Classification* ; Humans ; Population Characteristics ; Retrospective Studies ; Survival Rate

BACKGROUND/AIMS: Orientia -tsutsugamushi infection is an acute febrile disease due to the accidental transmission through human skin of forest dwelling vector Leptotrombidium larva. The authors observed liver dysfunctions in patients diagnosed with tsutsugamushi disease (Scrub typhus) in the past 3 years and report the data in the hope of bringing attention to this disease in the differential diagnosis of autumn-season hepatitis, especially of non-A, non-B and non-C hepatitis. METHODS: Medical records of 22 patients diagnosed with tsutsugamushi disease by the hemagglutinin method between October 2000 and November 2002 were reviewed. RESULTS: Female gender was dominant in the ratio of 3.4:1. Mean age was 56.4 +/- 2.6. Admission was between 23rd September and 15th November with the peak between mid October and early November. Fever, being the most common symptom, was observed in 21 cases, myalgia in 13, arthralgia in 12, chills in 6, and skin rash in 6. An incubation period of 7-9 days was most common (10 cases), 13-15 days (4), 10-12 days (3), within 3 days (3), and 4-6 days (2). Average ALT, AST and GGTP were increased to 93.2 +/- 17.3 IU/L (18 +/- 345 IU/L), 92.5 +/- 11.7 IU/L (34-255 IU/L) and 132.2 +/- 14.5 IU/L (19-251 IU/L), respectively, but total bilirubin was normal. All the patients improved with doxycycline therapy. CONCLUSIONS: Since it usually shows liver dysfunction, it is important to take Orientia tsutsugamushi into consideration in differential diagnosis of autumn-season, febrile hepatic disease.
Adult ; Aged ; Diagnosis, Differential ; *Disease Outbreaks ; Hepatitis/*diagnosis/microbiology ; Humans ; Korea/epidemiology ; Male ; Middle Aged ; Scrub Typhus/complications/*diagnosis/epidemiology

PURPOSE: We analyzed the histopathologic findings of the patients with ultrasongraphic Breast Imaging Reporting and Data System (BI-RADS) Category 4a breast lesions to determine which patient can be excluded from any invasive, diagnostic procedure in the future. METHODS: Of the 180 cases of BI-RADS Category 4a breast lesions that were diagnosed with ultrasonography during a 6 month-period, 132 cases were pathologically confirmed and these were analyzed retrospectively. Four benign cases that did not undergo any further procedure after fine needle biopsy and 6 malignant cases (4.5%) were excluded from this study. RESULTS: Of the 122 cases, 77 cases (63.1%) showed homogeneous benign finding, and 45 cases (36.9%) showed heterogeneous finding that was made up of two or more different pathologic lesions. Fibroadenoma (55.8%) was the most frequent pathologic finding in the cases with homogeneous finding, followed by fibrocystic change (14.3%), and fibrosis (7.8%). The cases with heterogeneous finding presented fibrocystic change (55.5%), microcalcification (48.8%), ductal hyperplasia (42.2%), and fibroadenoma (31.1%) in the order of frequency. CONCLUSION: Lesion with heterogeneous histopathologic nature was the most frequent finding defined as category 4a in breast ultrasonography, followed by fibrodenoma, fibrocystic change, microcalcification, and ductal hyperplasia. Refining more specific ultrasonographic findings of these lesions would guarantee that radiologists exclude more benign lesions from category 4a.
Biopsy, Fine-Needle ; Breast ; Fibroadenoma ; Fibrosis ; Humans ; Hyperplasia ; Information Systems ; Retrospective Studies ; Ultrasonography, Mammary

PURPOSE: The purpose of the current study is to evaluate the clinical and radiographic outcomes of primary total hip arthroplasty (THA) using a single titanium tapered stem with alumina bearing, which was performed through a modified direct lateral approach. MATERIALS AND METHODS: One hundred twenty consecutive primary THAs were performed in 102 patients, and retrospectively reviewed. There were 53 men and 49 women of mean age 54 years, and all patients were followed for a minimum follow-up period of 5 years (range, 5-8.1 years). Clinical outcomes assessment consisted of calculation of the Harris hip score (HHS), and evaluation of the presence of thigh pain or limp. Sequential radiographs were evaluated for implant migration, osteolysis, reactive line, cortical hypertrophy, or evidence of component loosening. RESULTS: At the final follow-up, the mean preoperative HHS of 46 points improved to 94 points; and activity-related thigh pain occurred in two hips, and mild limps in four hips. There was no evidence of implant migration, osteolysis, or component loosening. Audible squeaking was present in two hips, without pain and radiographic abnormality. Dislocation occurred in three hips. CONCLUSION: The minimum 5-year results of titanium tapered stem with alumina bearing in cementless primary THA, using a modified direct lateral approach, were encouraging.
Aldosterone ; Aluminum Oxide ; Arthroplasty ; Arthroplasty, Replacement, Hip ; Dislocations ; Female ; Follow-Up Studies ; Hip ; Humans ; Hypertrophy ; Male ; Osteolysis ; Outcome Assessment (Health Care) ; Prostheses and Implants ; Retrospective Studies ; Tacrine ; Thigh ; Titanium ; Ursidae

BACKGROUND/AIMS: Chronic gastritis is a common finding during endoscopy and it is very important to describe it correctly. This study was designed to evaluate the distribution of endoscopic gastritis and the differences according to age, sex or area. MATERIALS AND METHODS: A clinical analysis was conducted on 25,536 subjects who had undergone an upper endoscopy for routine health check-up. Endoscopic gastritis was classified into four types, superficial gastritis, erosive gastritis, atrophic gastritis and intestinal metaplasia. The distribution of the four types of gastritis was evaluated according to sex, age and area. RESULTS: 51.6% of the patients had experienced at least one of the symptoms (epigastric pain or discomfort, soarness, dyspepsia, abdominal pain) on at least a few occasions during the previous year. The incidence of normal gastric finding was 3,593 (14.1%). 21,943 (85.9%) subjects have at least more than one of endoscopic gastritis. The number of cases with superficial gastritis was 7,983 (31.3%), erosive gastritis 6,054 (23.7%), atrophic gastritis 6,918 (27.1%), and intestinal metaplasia 1,181 (7.1%). Erosive gastritis, atrophic gastritis and intestinal metaplasia were more frequent in men than women (P<0.001) and in the older age group (> or =60 years) than younger age group (P<0.001). CONCLUSIONS: The prevalence of endoscopic gastritis was very common, 85.9%. In addition, erosive gastritis, atrophic gastritis and intestinal metaplasia were more frequent in men and in the older age group, which is similar to gastric cancer or peptic ulcer. Cautious regular endoscopic follow-up might be necessary regardless of gastrointestinal symptoms in Korea.
Dyspepsia ; Endoscopy ; Female ; Gastritis ; Gastritis, Atrophic ; Helicobacter pylori ; Humans ; Incidence ; Korea ; Male ; Metaplasia ; Peptic Ulcer ; Prevalence ; Stomach Neoplasms