Naoko Honma

Telomere lengths are characteristic in each human individual.

BACKGROUND A great deal of attention has been focused on telomeres in relation to cellular aging, immortality, and cancer. However, there is no simple link between telomeres and tissue turnover. We recently proposed a hypothesis that telomere shortening with aging and telomere lengths in different organs are characteristic for human individuals. METHODS To test this, telomere lengths were measured using DNA from cerebral cortex, myocardium, liver, renal cortex and spleen tissues obtained from human subjects ranging in age from neonates to centenarians. RESULTS Regression analyses demonstrated telomere reduction rates of 29-60 base pair (bp) per year in the liver, renal cortex and spleen, but no such decrease in the cerebral cortex and myocardium. Significant correlation was found between tissues within individuals, such as cerebral cortex versus (vs) myocardium, cerebral cortex vs liver, cerebral cortex vs renal cortex, myocardium vs liver, myocardium vs renal cortex, and liver vs renal cortex. In most cases, the longest telomeres were observed in the myocardium and the shortest in the liver or renal cortex. CONCLUSIONS Telomere lengths did not show clear correlation with tissue renewal times in vivo, but rather were characteristic for individuals.

Age-related mitochondrial DNA deletion in human heart: Its relationship with cardiovascular diseases

Background and aims: Accumulation of damage to mitochondrial DNA (mtDNA) occurs in myocardial tissue with advancing age. However, despite higher incidence of cardiac diseases in the elderly, little attempt has been made to detect deletions of mtDNA in the myocardial tissue of aged individuals. The aim of the present study was to clarify the relationship between aging, mtDNA deletion and cardiovascular (CV) diseases. Methods: We examined 163 autopsy cases, aged 60 years or older, using two different kinds of polymerase chain reaction (PCR): highly sensitive PCR to detect a common 4977- bp deletion and long- PCR for multiple deletions, which could be detected in case that deleted mtDNA accounted for more than several percents in total mtDNA. Results: The common 4977- bp deletion was detected in 156 cases (95.7%), showing no significant difference among these age groups and no relation to CV diseases. By long- PCR, multiple deletions in cardiac mtDNA were found in 33 (20.2%) of 163 cases. The proportion of the mtDNA deletion in the nineties (46.2%) was significantly higher than those in the younger (15.3%, p<0.05). Female predominance was significantly found in the group with the mtDNA deletion (p<0.05). Multiple deletions of mtDNA were not significantly related to ischemic change, valvular diseases, left ventricular hypertrophy, congestive heart failure, coronary sclerosis, or heart weight except for right ventricular hypertrophy. Conclusions: These findings suggest that there is a close relationship between aging and deletion of mtDNA, and that the ratio of deleted mtDNA to total mtDNA increases with advancing age. Age-related deletion of mtDNA may have little influence on CV diseases except for right ventricular hypertrophy.

Clinical Importance of Estrogen Receptor-β Evaluation in Breast Cancer Patients Treated With Adjuvant Tamoxifen Therapy

PURPOSE The clinicopathologic importance of a second estrogen receptor (ER), ER-beta, in breast cancers has been intensely studied; however, there is still no real consensus regarding the clinical utility of an ER-beta assay, probably because of the lack of standardized methodology, the presence of several ER-beta isotypes (ER-beta1-5, and so on), and, more importantly, the lack of convincing data on whether the ER-beta status provides clinically useful information over what is already provided by the traditional ER-alpha/progesterone receptor (PR) assay. A large and systematic study is needed to address these important issues. PATIENTS AND METHODS Archival materials of 442 invasive breast cancers from women treated with adjuvant tamoxifen monotherapy and with a long follow-up period (median, 11.1 years) were subjected to immunohistochemical study using three commercially available anti-ER-beta antibodies that detect ER-beta1-3 (ER-betaN), ER-beta1, and ER-betacx (ER-beta2). RESULTS Positive staining for ER-betaN or ER-beta1 was associated with significantly better survival. By contrast, ER-betacx status did not influence survival. In multivariate analysis, ER-beta1 status emerged as an independent predictor of recurrence and mortality. ER-beta1 status was significantly associated with survival in postmenopausal, but not premenopausal, women. Importantly, ER-beta1 positivity was associated with significantly better survival in patients with ER-alpha-negative/PR-negative or ER-alpha-negative/PR-negative/human epidermal growth factor receptor 2-negative (triple-negative) tumors, which are widely believed to be hormone unresponsive, have poor prognosis, and require chemotherapy. CONCLUSION Immunohistochemical examination of ER-beta1 in addition to ER-alpha and PR is clinically important in patients with breast cancer treated with tamoxifen monotherapy. Further studies are needed to confirm our findings.

Is there a set of histologic changes that are invariably reflux associated

Many histologic changes have been described in the esophageal squamous mucosa in patients with gastroesophageal reflux disease (GERD), including dilated intercellular spaces, balloon cells, intrapapillary vessel dilation, elongated papillae, basal cell hyperplasia, acanthosis, intraepithelial eosinophils, Langerhans cells, and p53 protein overexpression. To define a set of histologic changes that are invariably reflux associated, we examined the histologic changes in esophageal specimens from normal controls, patients with GERD, patients without GERD but with a suspicion of other pathology, and patients with esophageal carcinoma. We also examined biopsy specimens from sites with differing endoscopic features, including cloudy white and reddened mucosa. A definitive set of reflux-associated histologic changes could not be defined from the small number of biopsy specimens examined in the present study. Histologic changes indicative of GERD are likely to be found somewhere in the esophagus in all patients with GERD, but these changes are nonspecific. A set of histologic changes that are invariably reflux associated may exist, but these changes are nonspecific. To develop a set of characteristic reflux-associated features, endoscopists may perform targeted biopsies from several sites with various endoscopic features and at different stages of disease.

Expression of GCDFP-15 and AR decreases in larger or node-positive apocrine carcinomas of the breast

Aims : Apocrine carcinoma of the breast is typically, though not always, positive for gross cystic disease fluid protein‐15 (GCDFP‐15). In order to clarify the clinical significance of GCDFP‐15 in apocrine carcinomas, GCDFP‐15 expression was examined in apocrine carcinomas of different stages and compared with clinicopathological factors. Apocrine lesions reportedly exhibit an unusual immunohistochemical status, expressing androgen receptors (AR) instead of oestrogen receptors (ER), progesterone receptors (PR), or bcl‐2. Their expression was also examined.

Telomere shortening with aging in the human pancreas

We have conducted systematic studies to measure telomere length in human tissues of all types. Progressive telomere shortening with aging was studied in specimens of normal pancreas obtained at autopsy from 69 subjects aged 0 to 100 yr, and age-related shortening of telomere length at a rate of 36 base pairs (bp) per year was detected. Mean telomere length (+/-SD) was 13.9+/-1.4 kilobase pairs (kbp) in 16 neonates, as opposed to 8.4 kbp in 2 centenarians. Mean telomere length (+/-SD) in four age groups, 0-24, 25-49, 50-74, and 75-100 yr, was 13.5+/-1.5, 12.3+/-0.7, 11.3+/-2.5, and 10.7+/-1.8, respectively.

Pathologic characteristics of gastric cancer in the elderly: a retrospective study of 994 surgical patients

BackgroundThe clinicopathologic features of gastric carcinoma in elderly people have been reported previously. The present study examined the patterns and distribution of gastric carcinomas in the elderly, especially in patients aged 85 and older.MethodsA retrospective study of 994 consecutive Japanese patients aged 65 years or older was performed. In this group, a total of 1147 lesions were analyzed. Pathological findings in the very old group (older than 85 years; n = 126) were compared with those in younger groups (65–74 years [young-old group]; n = 356) and (75–84 years [middle-old group]; n = 512).ResultsWhile the male-to-female ratio significantly decreased with advancing age, the relative odds of gastric cancer in men were higher than those in women in all age groups. In the very old group, cancer of the lower third of the stomach tended to increase with advancing age, and accounted for 43.7% of cases. In the population overall, differentiated-type adenocarcinoma accounted for 89.6% in the early cancers and 50.3% in the advanced cancers. The proportion of cases involving differentiated-type carcinoma significantly increased with advancing age in early cancer and female advanced cancer cases, whereas no significant change was found in male advanced-cancer patients. In the very old group, lymph node metastasis was found in 5.4% of early cancers and 72.7% in advanced cancers. Multiple cancers significantly increased with advancing age (P < 0.05; 10.7% in the younger-old group, 12.7% in the middle-old group, and 19.0% in the very old group).ConclusionThese results indicate that, in the very old group, gastric cancers showed a distal shift with predominantly differentiated-type carcinoma in the early stages and increased undifferentiated-type carcinomas in advanced stages. These results suggest increased histologic diversity with tumor growth. These findings have important implications for the screening and diagnosis of gastric cancer in the elderly.

Breast carcinoma in women over the age of 85: distinct histological pattern and androgen, oestrogen, and progesterone receptor status

Aims:  The pathogenesis of breast carcinoma in very elderly women is of interest, because oestrogen levels are likely to be extremely low during the development of the disease. In an effort to understand the pathogenesis of breast carcinoma in these women, this study was undertaken to compare the histological patterns and hormone receptor status of breast carcinomas arising in very elderly and younger women.

Molecular characterization of apocrine carcinoma of the breast: validation of an apocrine protein signature in a well-defined cohort.

Invasive apocrine carcinomas (IACs), as defined by morphological features, correspond to 0.3–4% of all invasive ductal carcinomas (IDC), and despite the fact that they are histologically distinct from other breast lesions there are currently no standard molecular criteria available for their diagnosis and no unequivocal information as to their prognosis. In an effort to address these concerns we have been using protein expression profiling technologies in combination with mass spectrometry and immunohistochemistry (IHC) to discover specific biomarkers that could allow us to molecularly characterize these lesions as well as to dissect some of the steps in the processes underlying breast apocrine metaplasia and development of precancerous apocrine lesions. Establishing these apocrine‐specific markers as best practice for the routine pathology evaluation of breast cancer, however, will require their validation in large cohorts of patients. Towards this goal we have composed a panel of antibodies against components of an apocrine protein signature that includes probes against the apocrine‐specific markers 15‐prostaglandin dehydrogenase (15‐PGDH), and acyl‐CoA synthetase medium‐chain family member 1 (ACSM1), in addition to a set of categorizing markers that are consistently expressed (AR, CD24) or not expressed (ERα, PgR, Bcl‐2, and GATA‐3) by apocrine metaplasia in benign breast lesions and apocrine sweat glands. This panel was used to analyze a well‐defined cohort consisting of 14 apocrine ductal carcinoma in situ (ADCIS), and 33 IACs diagnosed at the Cancer Institute Hospital, Tokyo between 1997 and 2001. Samples were originally classified on the basis of cellular morphology with all cases having more than 90% of the tumour cells exhibiting cytological features typical of apocrine cells. Using the expression of 15‐PGDH and/or ACSM1 as the main criterion, but taking into account the expression of other markers, we were able to identify unambiguously 13 out of 14 ADCIS (92.9%) and 20 out of 33 (60.6%) IAC samples, respectively, as being of apocrine origin. Our results demonstrate that IACs correspond to a distinct, even if heterogeneous, molecular subgroup of breast carcinomas that can be readily identified in an unbiased way using a combination of markers that recapitulate the phenotype of apocrine sweat glands (15‐PGDH+, ACSM1+, AR+, CD24+, ERα−, PgR−, Bcl‐2−, and GATA‐3−). These results pave the way for addressing issues such as prognosis of IACs, patient stratification for targeted therapeutics, as well as research strategies for identifying novel therapeutic targets for developing new cancer therapies.

Oncocytic Adenocarcinoma of the Stomach: Parietal Cell Carcinoma

We report 10 cases of an unusual type of gastric adenocarcinoma that occurred in elderly patients 58–81 years of age. Histologically, the tumors were well to moderately differentiated tubular adenocarcinomas with very eosinophilic, finely granular cytoplasm. Immunohistochemical stains for antimitochondrial antibody were strongly positive. Ultrastructurally, the tumor cells had numerous mitochondria in their cytoplasm and occasional intracytoplasmic lumina with associated long microvilli. These histologic and ultrastructural features are similar to those of parietal cells in normal gastric fundic mucosa, but immunohistochemical staining of the tumors using four different antiparietal cell antibodies (anti-H+-K+-adenosine triphosphatase antibodies) was negative in all cases. Therefore, we think that these tumors were not parietal cell carcinomas but could be termed oncocytic adenocarcinomas, or adenocarcinomas with oncocytic differentiation. Previously reported cases of parietal cell carcinoma have been said to have a favorable prognosis, but it will be necessary to study a larger number of cases to determine the prognosis of oncocytic adenocarcinoma.