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Tall cell carcinoma with reversed polarity (TCCRP) is a rare histologic type of low-grade breast cancer, consisting of tall columnar cells with reversed nuclear polarity and characterized by frequent IDH2 mutations. We herein report 3 cases of TCCRP with sequencing analyses of the IDH2 gene and immunohistochemical examination using monoclonal antibodies (11C8B1) against IDH2 R172. IDH2 R172 mutations were detected in all 3 resected tumors (R172S in 2 tumors and R172T in 1 tumor), and the presence of these mutations was confirmed by IDH2 R172 immunohistochemistry. Tumor cells of TCCRP showed strong and diffuse staining for the antibody against IDH2 R172. In 1 case, tumor tissue from 2 core needle biopsy samples collected on different days were also immunohistochemically positive for IDH2 R172. These results indicate that IDH2 R172 immunohistochemistry is suitable for the detection of TCCRP in both resection and biopsy samples. In addition, a literature review revealed that R172S and R172T account for 76% of IDH2 mutations in TCCRP, suggesting that 11C8B1, which reacts with R172S and R172T, was likely most sensitive for IDH2 -mutated TCCRP among many available antibodies for IDH2 R172. Furthermore, the combination of 2 or more antibodies against IDH2 R172 could be more effective for detecting TCCRP mutation. However, it is important to note that IDH2 R172 immunohistochemistry is not absolute, because IDH2 wild type is found in a small proportion (10%) of cases, and a few cases of IDH2 -mutated TCCRP may harbor rare subtypes of R172 that are not covered by available antibodies.

Background We examined the vascularity of mammary Paget disease histologically to confirm the increased blood flow observed previously by clinical imaging. The relationships among blood vessel density (BVD), histopathological parameters of blood flow in the nipple, and the expression of angiogenic factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) were examined. Methods We calculated the average CD34-positive BVD and podoplanin (D2–40)-positive lymphatic vessel density (LVD) and the proportion of proliferating of endothelial cells in 14 Paget disease, 3 dermatitis biopsy, and 14 age-matched control cases. As a parameter related to blood flow in the nipple, the total CD34-positive blood vessel lumen area relative to the entire nipple area was measured in each Paget disease and control case using an automated image analysis system. Immunohistochemical expression of bFGF and VEGFA in Paget cells was also examined. Results The average BVD and LVD were significantly higher in the Paget disease cases than in the dermatitis (p = 0.003) and control (p p = 0.003). The average BVD was correlated with the average LVD (r = 0.734, p r = 0.692, p p = 0.003) and control (p r = 0.818, p r = 0.503, p = 0.006). Conclusion These results provide direct histopathological evidence of a marked increase in nipple blood flow in Paget disease detected by clinical imaging. bFGF is considered to play a pivotal role in angiogenesis in mammary Paget disease.

Mikulicz’s disease, an immunoglobulin G4-related disease (IgG4-RD) occurs frequently in the head and neck region but rarely in the larynx. We report a case of IgG4-RD with pseudotumor formation in the larynx. A 50-year-old man presented at our facility for a complete physical examination and diagnostic testing of a left arytenoid tumor. On examination, a large supraglottic mass was noted with signs of dyspnea. Movement disorder of the vocal fold was absent. The patient underwent surgery with general anesthesia to improve respiratory symptoms and a resected specimen was submitted for diagnosis. The pathology findings revealed lymph follicle formation, interstitial follicular fibrosis, angiogenesis, and inflammatory cell infiltration with plasmacytosis. Immunohistologic staining at high magnification revealed one hundred or more IgG4-positive plasma cells and fifty percent IgG4/IgG. In addition, obliterative phlebitis was observed. Medical history was positive for retroperitoneal fibrosis with serum IgG4 levels below the diagnostic criteria of IgG4-RD, but histological characteristics of IgG4-RD were met. The diagnosis of IgG4-RD was established, oral treatment with prednisolone (0.6 mg/kg/day) was initiated, and the tumor reduced in size. IgG4-RD may cause irreversible functional impairment. Early diagnosis and treatment are important in reducing the risk of permanent impairment of vocal fold mobility.

Background: Currently, treatment for older breast cancer patients is largely based on data derived from trials enrolling younger patients; thus, the standard of care for older breast cancer patients remains controversial. Aim: To investigate the clinicopathological characteristics, treatments, and prognosis in older stage II and III breast cancer patients using data from the Japanese Breast Cancer Registry (JBCR). Methods: We reviewed data from the JBCR, a nationwide registry of newly diagnosed and operated primary breast cancer patients in Japan. To clarify those characteristics, we compared clinicopathological characteristics, treatments, and prognosis among three groups: older group, patients aged ≥75 years; young-old group, patients aged 65–74 years; post-menopause group, patients aged 55–64 years. Results: In total, we reviewed 56,093 cases of stage II/III breast cancer diagnosed between 2004 and 2011 (older: n=12,727; young-old: n=17,860; post-menopause: n=25,506). The estrogen receptor (ER) positivity rate was higher (older vs. young-old vs. post-menopause: 73.3% vs. 72.0% vs. 68.0%) and HER2 positivity rate was lower in the older group than in the other two groups (12.9% vs. 16.8% vs. 23.6%) (p The following table shows the rate of administration of adjuvant systemic therapy according to the ER and HER2 status. Age (years)≥7565–7455–64p-valueER+Chemotherapy10.042.562.9 Nearly half of the older patients (48.3%) who received chemotherapy received either cyclophosphamide-methotrexate-fluorouracil or oral fluorouracil. As for hormone therapy, tamoxifen was used more frequently in the older group than in the young-old and post-menopause groups (16.5% vs. 8.6% vs. 7.2%). The following table shows the results of the 5-year overall survival (OS) and breast cancer-specific survival (BCSS) analyses: Conclusions: Chemotherapy was less common in older patients, especially patients with HER2+ or triple negative breast cancer, resulting in worse BCSS. As older patients tend to have several comorbidities, comprehensive geriatric assessment might be helpful in determining systemic therapies for older patients. Age (years)≥7565–7455–64p-valueER+OS/BCSS (%)84.1/94.592.5/96.093.2/94.9 Citation Format: Akimitsu Yamada, Masataka Sawaki, Hiraku Kumamaru, Hiroaki Miyata, Kanako Nakayama, Chikako Shimizu, Mika Miyashita, Naoko Honma, Itaru Endo, Naruto Taira, Shigehira Saji. Systemic therapy for and prognosis of older stage II and III breast cancer patients: Evaluation of data from the Japanese breast cancer registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-06.

A large number of studies have suggested an inhibitory role of estrogens against colorectal cancer (CRC), but persistent controversy exists. CRC characteristics are affected by sex, age, and tumor locus, suggesting the need for a systematic study considering these factors. The purpose of this study was to verify the difference in the pathobiological role of estrogens in CRC according to patient/tumor backgrounds.Surgical specimens from 116 postmenopausal women (≥ 70 years/o, n = 74; 70 years/o, n = 42) were studied. Estrogen receptor-β (ER-β), the main ER in the colorectal epithelium, was immunohistochemically examined. The concentrations of estradiol (E2) and estrone (E1) were examined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). These factors were compared according to the tissue type (cancerous or non-cancerous), patients' age, tumor backgrounds (locus, histology, pathological stage, status of mismatch repair protein = MMR), and clinical outcome.ER-β-positivity, higher E2 concentration, deficient-MMR, and medullary/mucinous histology (Med/Muc) were closely related to right-sided tumors in women who were aged ≥ 70 years /o (R-Ca ≥ 70) and also closely related to each other. ER-β reduction compared with non-cancerous counterparts was observed only in left-sided tumors of patients 70 years /o (L-Ca 70), non-Med/Muc, or proficient-MMR tumors.The present results suggest that estrogens do not suppress, but rather promote, R-Ca ≥ 70, Med/Muc, or deficient-MMR tumors, whereas estrogens suppress L-Ca 70, non-Med/Muc, or proficient-MMR tumors, confirming the difference in pathobiological role of estrogens in postmenopausal colon cancer according to the patients' age and tumor background. This may at least partly explain the controversy regarding the association between estrogens and CRC.

Purpose Patients with breast cancer may develop cognitive impairment as a result of hormone therapy and aging. This study aimed to describe older patients’ experience of cognitive impairment related to hormone therapy for breast cancer. Methods A qualitative and descriptive design was used. Semi-structured interviews were conducted for 11 patients to ask about their experience in daily life related to their cognitive impairment. Study participants were evaluated by cancer-specific geriatric assessment. Inductive content analysis was conducted using interview records. Results Three themes emerged from the patients’ narrative data: recognizing of cognitive impairments, impacts on mental health, and coping with cognitive impairments. Recognizing of cognitive function consisted of two categories: perception of cognitive changes and acknowledging their cognitive function status through interacting with others. Impacts on mental health consisted of six categories: decreased motivation for social activities, upset by perception of cognitive decline, concerns about impacts of cognitive impairment on treatment of breast cancer, concerns about care burden of their family, concerns about progressing of cognitive impairments, and feeling secure that their cognitive impairment is not unusual. Coping with cognitive impairments consisted of two categories: coping with problems related to cognitive impairment and trying to maintain and improve cognitive function. Conclusion Medical professionals should perform a comprehensive evaluation of older patients receiving hormone therapy for breast cancer.

Although numerous recent studies have reported the development of sarcoidosis in patients treated with tumor necrosis factor alpha (TNF-α) inhibitors, it is unclear whether the pathogenesis of drug-induced sarcoidosis is identical to that of spontaneous sarcoidosis. We herein present the case of a patient who developed sarcoidosis 6 months after the introduction of etanercept as treatment for rheumatoid arthritis. Typical clinical symptoms with noncaseating epithelioid granulomas detected in a mediastinal lymph node specimen were consistent with the diagnosis of sarcoidosis. Immunohistochemistry revealed Propionibacterium acnes in the noncaseating granulomas. The present findings suggest that Propionibacterium acnes is a cause of sarcoidosis, even when the disease is induced by TNF-α inhibitors.

Aim: The purpose of this study is to evaluate the prevalence of the immunohistochemical subtypes of breast cancer among Lao women by using immunohistochemistry (according to the St. Gallen 2017 guidelines) and to study their correlation to clinicopathological features in order to help guide better treatment plans for patients. Materials and methods: Formalin-fixed and paraffin embedded tissue blocks of 76 cases of primary invasive breast cancer were retrieved from the University of Health Sciences, Vientiane, Lao PDR, from 2013 to 2016. Patients’ information and previous histological reports were reviewed. Immunohistochemistry was done using antibodies against estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2/neu) and Ki-67 (MIB-1). Results: The mean age of the patients was 49 years, and the major histologic type was invasive ductal carcinoma, NOS (90.7%). The proportion of each subtype was hormone receptor-positive and HER2-negative, 44.7%; hormone receptor-positive and HER2-positive, 3.9%; hormone receptor-negative and HER2-positive, 13.2%; and triple-negative, 38.2%. ER was positive in 40.8% of the cases, while PR was positive in 47.4%. More than half of the cases were poorly differentiated cancer (65.8%), followed by moderately differentiated (34.2%). Tumors presented with pT2 (60.5%), followed by pT3 (25.0%) and pT4 (7.9%). Conclusion: Breast cancer among Lao women is characterized by a large percentage of the triple-negative subtype that is less susceptible to hormonal treatments. The empirical treatment with tamoxifen should be reconsidered since it would be less effective to these patients. More importantly, basic pathology services should be the first requirement in Lao PDR in order to provide adequate care.

This study aimed at investigating the real-world prognostic impact of systemic treatment in older patients with stage II/III breast cancer (BC)., This retrospective cohort study included patients with stage II/III primary BC, aged ≥55 years, and registered in the Japanese Breast Cancer Registry from 2004 to 2011. The clinicopathological characteristics, treatments, and prognosis of patients aged ≥75 years (older) were compared to those of younger patients., In total, 56,093 patients (12,727, ≥75 years; 17,860, 65-74 years; 25,506, 55-64 years) were enrolled. In the older group, 9.2% with a luminal (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), 32.9% with a triple-negative (TN, HR-/HER2-), and 27.4% with a HER2-positive (any-HR/HER2+) receptor were administered chemotherapy. In those with luminal cancer, the 5-year breast cancer-specific survival (BCSS) was approximately 95% in all age groups. Meanwhile, among those with TN and HER2-positive BC, the older group had a poorer BCSS. The 5-year overall survival (OS) was also poorer in the older group across all subtypes. Among older patients matched using clinicopathological factors, chemotherapy use was associated with improved OS in the luminal and HER2-positive subtypes., Chemotherapy use was lower among older patients with stage II/III breast cancer. Those with TN and HER2-positive BC had a lower BCSS than their younger counterparts. Chemotherapy may be beneficial in improving the OS in older patients with luminal and HER2-positive BCs. Treatment for older patients should be individualized, based on tumor-related factors, quality of life, and the patient's health status.

We conducted a risk-adapted upfront docetaxel (DOC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Here, we reported an interim analysis of the study. The study enrolled 68 patients with newly diagnosed mHSPC between 2016 and 2018. According to the presence of visceral metastasis, an EOD score ≥ 3, or prostate-specific antigen (PSA) level at 3 months of ≥ 1 ng/mL, patients were divided into low- and high-risk groups. Patients were treated with androgen deprivation therapy (ADT) with or without bicalutamide; those in the high-risk group received upfront treatment involving six cycles of DOC (70 mg/m2). Short-term treatment effect, adverse events, and quality of life (QOL) were evaluated. Fifty (73.5%) were classified in the high-risk group, and 46 (67%) received upfront ADT + DOC. In the ADT + DOC group, 43.5% (20/46) patients achieved a PSA level ≤ 0.2 ng/mL. PSA nadir and time to PSA nadir were 0.291 ng/mL and 288 days, respectively. In the ADT + DOC group, 76.1% (35/42) patients had adverse events (AEs) of grade ≥ 3. During a median follow-up of 18.5 months, 36.4% (8/22) patients in the ADT group and 43.5% (20/46) in the ADT + DOC group had CRPC. Two QOL scores including the physical status and appetite loss at 6 months significantly worsened in the ADT + DOC group but was resolved by 12 months. Upfront DOC achieved high PSA responses without long-term QOL deterioration. However, the short-term outcomes were limited. Longer follow-up is needed to determine the survival advantage.

Background and Aims Vascular endothelial growth factor‐directed therapies play a significant role in patients with metastatic renal cell carcinoma (mRCC). Biomarkers for predicting treatment efficacy and resistance are required to develop personalized medicine. We evaluated multiple serum cytokine levels in patients with mRCC treated with axitinib to explore predictive biomarkers. Methods From September 2012 to October 2015, serum samples were collected from 44 patients with mRCC before treatment and 4 weeks after axitinib initiation. Bio‐Plex Pro Human Cancer Biomarker Panels 1 and 2 were used to measure levels of 34 serum biomarkers related to angiogenesis and cell proliferation. Results Patients with partial response or stable disease had significantly decreased serum plasminogen activator inhibitor‐1 (PAI‐1) level from pre‐treatment to 4 weeks after axitinib initiation compared with those with progressive disease (P = .022). The median progression‐free survival (PFS) and median overall survival (OS) in patients with increased serum PAI‐1 level from pre‐treatment to 4 weeks after axitinib initiation were significantly shorter than those with decreased serum PAI‐1 level (P = .027 and P = .026, respectively). Increased serum PAI‐1 level from pre‐treatment to 4 weeks after axitinib initiation was an independent prognostic marker for shorter PFS and OS in multivariate analyses (P = .015 and P = .032, respectively). The immunohistochemical staining intensity of PAI‐1 in tumor specimens was significantly associated with Fuhrman grade and presence of distant metastasis (P = .026 and P = .010, respectively). Conclusions The initial change in serum PAI‐1 level in the early stage of axitinib treatment could be a useful prognostic biomarker in patients with mRCC.

Triple-negative breast cancer (TNBC) lacks an effective treatment target and is usually treated with chemotherapy. Treatment of older patients with TNBC, however, should be decided carefully because of the side effects of chemotherapy in this population. Some forms of TNBC are associated with a favorable prognosis and do not require chemotherapy. To optimize the treatment of older patients with TNBC, it is important to know the clinicopathological characteristics and a prognostic marker. In this study, classic clinicopathological factors, immunohistochemical characteristics (androgen receptor [AR], cytokeratin 5/6 [CK5/6], epidermal growth factor receptor), tumor-infiltrating lymphocytes (TILs), and the clinical outcome based on the status of each biomarker were compared among a consecutive series of female patients with TNBC aged ≥75 years (n = 75) and among those aged 55–64 years matched for the pathological stage (n = 47) who underwent surgery without neoadjuvant therapy. TNBC with special histology (particularly apocrine carcinoma, pleomorphic invasive lobular carcinoma, and metaplastic carcinoma) was more frequent in the older group than in the younger group (35/75, 57% versus 11/47, 23%, P = 0.010). The AR positivity rate was higher in older patients than in younger patients, whereas TILs and CK5/6 exhibited the opposite results. In multivariate analyses, AR positivity was an independent predictor of a favorable outcome in older patients (lower recurrence rate), whereas the high level of TILs was favorable in younger patients (lower recurrence and mortality rates). AR positivity or apocrine morphology was frequent and predicts a favorable clinical outcome in older patients with TNBC, suggesting the importance of AR examination in this population.

Patients with breast cancer may develop cognitive impairment as a result of hormone therapy and aging. This study aimed to describe older patients' experience of cognitive impairment related to hormone therapy for breast cancer.A qualitative and descriptive design was used. Semi-structured interviews were conducted with 11 patients asking about their experience in daily life related to their cognitive impairment. Study participants were evaluated by cancer-specific geriatric assessment. Inductive content analysis was conducted using the interview records.Three themes emerged from the patients' narrative data: recognizing of cognitive impairments, impacts on mental health, and coping with cognitive impairments. Recognizing of cognitive function consisted of two categories: perception of cognitive changes and acknowledging their cognitive function status through interacting with others. Impacts on mental health consisted of six categories: decreased motivation for social activities, upset by perception of cognitive decline, concerns about impacts of cognitive impairment on treatment of breast cancer, concerns about the care burden of their family, concerns about progression of cognitive impairments, and feeling secure that their cognitive impairment is not unusual. Coping with cognitive impairments consisted of two categories: coping with problems related to cognitive impairment and trying to maintain and improve cognitive function.Oncology nurses should assess cognitive function and complete a comprehensive evaluation of older patients receiving hormone therapy for breast cancer. An evaluation of cognitive function would enable a tailored approach to education and support to enhance coping ability in the longer term.

Minimal data are available to support the clinical management of older breast cancer patients. Consequently, the standard of care remains unclear. Our aim was to clarify the clinicopathological characteristics, practical treatments, and prognosis of older Japanese breast cancer patients and discuss clinical issues. We reviewed 132,240 cases, diagnosed between 2004 and 2011, from the Japanese Breast Cancer Registry. Focusing on older patients, we compared data among three age groups: 75 years and over (n = 27,385), 65–74 years (n = 43,839), and 55–64 years (n = 61,016). Data revealed the proportions of mucinous and apocrine carcinoma were higher in older patients, and they more frequently had clinical stage II and III cancer. Their ER-positive rates were higher, in contrast to the lower HER2-positive, breast-conserving surgery (BCS), post-BCS irradiation, and adjuvant chemotherapy rates. Almost half of the older patients who underwent chemotherapy received CMF or oral 5FU, during hormone therapy, Tamoxifen was administered more frequently. The overall survival rate decreased with age, but the breast cancer-specific survival (BCSS) at 5 years remained similar. The rate of other cause of death in the oldest group was about a half, and more than double that in those aged 55–64 years. We showed clinical data of older breast cancer patients in Japan. Their disease was more advanced at the time of diagnosis, post-BCS irradiation and primary systemic chemotherapy were omitted more frequently, and overall, BCSS was similar among age categories, although the rate of other causes of death was higher.

A 73-year-old woman was admitted to our hospital for treatment of vomiting. Four months previously, she had been diagnosed with lung adenocarcinoma (cT3N3M1a stage IVA) and started receiving afatinib as first-line treatment. On admission, the primary tumor had shrunk, but abdominal computed tomography revealed a new retroperitoneal lesion causing duodenal obstruction and hydronephrosis. She underwent gastrojejunostomy, and a biopsy of the peritoneum revealed adenocarcinoma. She was treated with second-line chemotherapy but developed cerebral infarction and died 104 days after admission. An autopsy revealed marked fibrosis with scattered tumor cells in the retroperitoneum. The underlying mechanism of the metastasis is discussed.

Simple Summary Triple-negative breast cancer (TNBC) lacks all of three treatment targets (estrogen receptor-α, ER-α; progesterone receptor, PgR; and human epidermal growth factor receptor 2, HER2) and is usually associated with a poor clinical outcome; however, several sex steroid receptors, such as androgen receptor (AR), ER-β, and G-protein-coupled estrogen receptor, are frequently expressed and their biological and clinical importance has been suggested. Despite the structural similarity between sex steroid hormones (androgens and estrogens) or receptors (AR and ER-β), similar signaling mechanisms of these hormones, and the coexistence of these hormones and their receptors in TNBC in a clinical setting, most studies or reviews focused on only one of these receptors, and rarely reviewed them in a comprehensive way. In this review, the carcinogenic or pathobiological role of sex steroid hormones in TNBC is considered, focusing on common and differing features of hormone actions. Abstract Triple-negative breast cancer (TNBC) lacks an effective treatment target and is usually associated with a poor clinical outcome; however, hormone unresponsiveness, which is the most important biological characteristic of TNBC, only means the lack of nuclear estrogenic signaling through the classical estrogen receptor (ER), ER-α. Several sex steroid receptors other than ER-α: androgen receptor (AR), second ER, ER-β, and non-nuclear receptors represented by G-protein-coupled estrogen receptor (GPER), are frequently expressed in TNBC and their biological and clinical importance has been suggested by a large number of studies. Despite the structural similarity between each sex steroid hormone (androgens and estrogens) or each receptor (AR and ER-β), and similarity in the signaling mechanisms of these hormones, most studies or reviews focused on one of these receptors, and rarely reviewed them in a comprehensive way. Considering the coexistence of these hormones and their receptors in TNBC in a clinical setting, a comprehensive viewpoint would be important to correctly understand the association between the carcinogenic mechanism or pathobiology of TNBC and sex steroid hormones. In this review, the carcinogenic or pathobiological role of sex steroid hormones in TNBC is considered, focusing on the common and divergent features of the action of these hormones.

Cavernous hemangioma is a rare, non-functional, benign adrenal tumor. Adrenal cavernous hemangioma is often diagnosed after surgery with a histologic examination. A 70-year-old man complaining of appetite loss was admitted to our hospital. An incidental large left adrenal mass was found by computed tomography (CT). There were no clinical signs of adrenogenital syndrome, Cushing's syndrome or primary aldosteronism. Total resection was carried out. The pathological diagnosis was cavernous hemangioma. The differentiation of adrenal tumor is necessary in cases of large tumors, and resection is desirable given the risks of hemorrhaging and rupture.

To clarify the clinicopathological features of colorectal cancer in older people, systematic studies considering age, sex, and the tumor locus is needed. We focused on colon cancer in postmenopausal women (

We report a case of idiopathic penile pyoderma gangrenosum that was successfully treated with corticosteroid treatment without penectomy. A 67-year-o1d man with induration and tenderness of the penile shaft visited a local hospital. A penile abscess was suspected on magnetic resonance imaging, and needle biopsy did not reveal malignancy. After the tension of the penile shaft had worsened, he was referred to our hospital where surgical drainage and re-biopsy were performed. Microbiological cultures revealed no growth, and pathological examination revealed no evidence of malignancy. Despite drainage, the abscess recurred on postoperative day 18. With a working diagnosis of penile pyoderma gangrenosum, we initiated prednisolone 30 mg once daily followed by taper and performed a second surgical drainage, leaving the wound open to heal by secondary intention. Wound discharge declined gradually, and no recurrence of abscess has yet been observed. Pyoderma gangrenosum is clinically diagnosed when subcutaneous chronic inflammatory findings are present without concurrent bacterial infection. Corpus cavernosum abscess presenting as the initial symptom of pyoderma gangrenosum is rare. Most cases of recurrent corpus cavernosum abscess eventually result in total penectomy. In this case, we successfully avoided penectomy by suspecting pyoderma gangrenous and initiating prednisolone treatment appropriately.

Although numerous recent studies have reported the development of sarcoidosis in patients treated with tumor necrosis factor alpha (TNF-α) inhibitors, it is unclear whether the pathogenesis of drug-induced sarcoidosis is identical to that of spontaneous sarcoidosis. We herein present the case of a patient who developed sarcoidosis 6 months after the introduction of etanercept as treatment for rheumatoid arthritis. Typical clinical symptoms with noncaseating epithelioid granulomas detected in a mediastinal lymph node specimen were consistent with the diagnosis of sarcoidosis. Immunohistochemistry revealed Propionibacterium acnes in the noncaseating granulomas. The present findings suggest that Propionibacterium acnes is a cause of sarcoidosis, even when the disease is induced by TNF-α inhibitors.

The aim of the study was to investigate the clinicopathological features of pancreatic cancer at different stages using autopsy results.We retrospectively evaluated 8399 consecutive cases of autopsy performed between 1972 and 2013 at our geriatric hospital.Macroscopic pancreatic lesions were detected in 6.13% of the cases. Primary and secondary pancreatic tumors were observed in 2.88% and 2.10% of the cases, respectively. Most primary tumors were invasive ductal adenocarcinomas (193 cases [2.31%]; mean patient age, 78.09 years) with a peak incidence at 50 to 59 years. Occult invasive ductal adenocarcinoma was discovered incidentally in 15 cases, with distant metastasis present in 26.67% of those. Microscopically, occult and advanced tumors exhibited similar characteristics such as hyalinized fibrous stroma, necrosis, invasion into vessels, peripancreatic fat tissues, and extrapancreatic nerve plexus. Mucin 1 and 2 immunohistochemical expression levels were also similar. Occult cancer incidence increased with age. Patients aged 85 years or older had shorter survival, a small tumor size, and a low incidence of lymph node metastasis. Approximately 8% of pancreatic invasive ductal adenocarcinomas progressed asymptomatically and were discovered incidentally at autopsy.Pancreatic cancers in elderly patients tend to progress asymptomatically, but once symptoms develop, they are more often fatal than those in younger patients.

(Purpose) It has recently been suggested that a slow delivery rate of shockwaves by extracorporeal shock wave lithotripsy (SWL) improved treatment outcomes for urinary stones. We retrospectively analyzed the treatment outcomes of different shockwave delivery rates at 120 and 60 shockwaves per minute. (Patients and method) A total of 88 patients were treated at a fast delivery rate of 120 shockwaves per minute between July 2010 and April 2012, and 139 patients were treated at a slow delivery rate of 60 shockwaves per minute between May 2012 and May 2014 (n=227) using a Sonolith® Praktis lithotripter. The treatment outcome of stone-free rate (SFR) after one SWL session was assessed at four weeks. (Result) SWL at 60 shockwaves per minute resulted in a significantly higher SFR compared with SWL at 120 shockwaves per minute (39.8% and 59.0%, respectively, p=0.0047), particularly for upper ureter (U1) stones (53.1% and 72.0%, respectively, p=0.028). Multivariate analysis showed that younger age, stone sizes of 10 mm or less, U1 stones, and slow delivery rate were significant predictors of a stone-free outcome. There were fewer adverse events after the delivery rate of 60 shockwaves per minute (p=0.058). (Conclusion) Our study suggests that SWL at 60 shockwaves per minute should be recommended to successfully treat urinary stones using the Sonolith® Praktis lithotripter.

To clarify the profile of adverse events from endocrine therapies in older patients. We surveyed 15 subjective symptoms including hot flashes, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, lethargy, forgetfulness, depressive state, irritated state, genital bleeding, leukorrhea increase, vaginal dryness, bone fracture, and weight gain by a questionnaire among 2044 patients over 55 years old (total number of answered sheets, 8875) and compared the results according to age (56–69 years old vs. ≥ 70 years old) and type of therapy (aromatase inhibitors (AIs) vs. selective estrogen receptor modulators (SERMs)). Among patients 56–69 years old, 6093 and 314 responses were from patients treated with AIs (1477 patients) and SERMs (123 patients), respectively, and 2292 and 176 responses were from those ≥ 70 years old treated with AIs (581 patients) and SERMs (51 patients), respectively. In patients ≥ 70 years old, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, and lethargy were significantly more frequent/severe with AIs than with SERMs. In those aged 56–69, knuckle stiffness and vaginal dryness were significantly more frequent with AIs than with SERMs, but the opposite occurred for hot flashes, leukorrhea increase, genital bleeding, and weight gain. Among patients ≥ 70 years old, many symptoms were significantly more frequent/severe with AIs than with SERMs, compared with those aged 56–69, which suggests a difference in the profile of adverse events according to the type of endocrine therapy and the patient’s age. It is important to consider the benefits and risks of each treatment to optimize endocrine therapy for older patients.

Purpose Paget disease of the breast is a rare cancer that originates from the nipple–areolar complex. It is often overlooked and misdiagnosed as benign chronic eczema of the nipple. We aimed to retrospectively verify whether blood flow analysis using Doppler sonography was useful for detecting the presence of Paget disease. Methods In this retrospective study, 12 patients with pathologically proven unilateral nipple eczematous lesions (seven with Paget disease and five with simple dermatitis) were included. Nipple blood flow signal was observed using Doppler sonography, and the detected blood flow signals were quantified using digitally recorded images. Quantified blood flow ratio and pathologically examined capillary density were evaluated between affected and unaffected nipples. Findings of mammography, grayscale sonography, and contrast-enhanced magnetic resonance imaging (CE-MRI) were reviewed. Results In patients with Paget disease, Doppler effects in the affected nipple were more clearly visible than those in the unaffected nipple. These effects were sufficiently visible to identify Paget disease. No obvious effects were observed in the affected and unaffected nipples of simple dermatitis. The quantified blood flow ratio and pathologically examined capillary density were significantly higher for the Paget lesion than those for the non-Paget lesion. The sensitivity of CE-MRI and Doppler sonography was markedly correlated, revealing blood flow changes in the nipple lesions of Paget disease. Conclusion Doppler sonography visualized the proliferation of blood vessels in Paget lesions. The visualization of increased nipple blood flow using Doppler sonography is a simple and low-cost method that provides useful data for identifying Paget disease during routine medical care.

As estrogens play an important role in maintaining physiological function in various organs, the estrogen decrease after menopause is thought to cause various diseases frequently observed in postmenopausal or elderly women. With the aging of society and a decrease in infectious or vascular diseases, neoplasms have now become the most frequent cause of death in Japan. Cancers of the colorectum, breast, and lung have been rapidly increasing both in incidence and death, especially among postmenopausal women. Interestingly, all three of these cancers are associated with estrogens. In premenopausal women, ovarian estrogens plays major roles in the female reproductive organs through the classic estrogen receptor, ER-α. In postmenopausal women, however, estrogens produced/activated by peripherally localized estrogen-metabolizing enzymes such as aromatase, which converts androgen into estrogens, are thought to play physiologically and pathobiologically important roles in various organs through second ER, namely ER-β, distributing systemically. In this article, the association of estrogens with these cancers in postmenopausal or elderly women are reviewed, especially focusing on the role of ER-β and peripheral estrogen metabolism. The possibility of prevention or treatment of these diseases through estrogenic control is also discussed.

Objective Squamous cell carcinoma (SCC) is a rare histological type of breast cancer. The cytological diagnosis of non-keratinising, poorly differentiated SCC is often difficult, and distinguishing it from invasive ductal carcinoma or apocrine carcinoma (AC) is especially challenging. We aimed to define the diagnostic cytological features of poorly differentiated SCC of the breast. Methods We studied the cytological findings of poorly differentiated SCC (n=10) and compared them to those of IDC (n=15) and AC (n=14). The following six cytological features were evaluated: streaming arrangement, nucleolar enlargement, dense nuclei, cannibalism, atypical keratinocytes and necrotic background. Results SCC exhibited significantly higher frequencies of streaming arrangement (70% vs 6.7%, P=.002), nucleolar enlargement (80% vs 27%, P=.02), and necrotic background (80% vs 36%, P=.002) than invasive ductal carcinoma. The detection of two or three of these features yielded a higher sensitivity (80%) and specificity (93%) for the diagnosis of SCC. Streaming arrangement (70% vs 0%, P

Estrogens play a physiologically important role in the brain, but controversies exist regarding the association between Alzheimer’s disease (AD) and estrogens. Estrogen-related factors were comprehensively examined in frontal lobe tissues from autopsied AD patients, and compared with controls. Concentrations of estrogens, expression of estrogen receptors (ERs), and estrogen-metabolizing enzymes (EMEs) which are important for determining the peripheral estrogen concentrations, were examined using liquid chromatography tandem mass spectrometry, immunohistochemistry, and quantitative real-time PCR, respectively. Body mass index (BMI), known to correlate with the serum estrogen concentrations, was also taken into consideration. There were no significant differences in estrogen concentrations or each EME level between the two groups in both the cortex and white matter, whereas glial nuclear ER-β expression was significantly lower in white matter from the AD group than the control group (Allred score, 3.2 ± 0.3 and 6.5 ± 0.3, respectively. P

The aim of this study was to extensively analyze the signaling pathway molecules in breast cancer and to explore candidate biomarkers for clinicopathological relevance. We assessed the expression of key factors in cell signaling, namely p-AKT, cyclin D1, P27, p-p70S6 K, p-4EBP1, and p-MAPK/ERK, within 338 invasive breast cancer patients. These factors were immunohistochemically examined in tumor tissues and assessed by staining score. Staining scores were analyzed by a clustering method to devise a new classification based on pathway activity. We investigated the relationships among staining scores, the clustering classification, and patient characteristics. The proportion of patients displaying high expression levels were as fol lows: p-AKT, 75 %; cyclin D1, 12 %; P27, 53 %; p-p70S6 K, 37 %; p-4EBP1, 19 %; and p-MAPK/ERK, 3 %. Patients were classified into two groups on the basis of staining scores. Group 1 (39 %) included more positive cases for p-4EBP1, p-MAPK/ERK, and p-p70S6 K and fewer positive cases for P27 and cyclin D1 than Group 2 (61 %). The clustering classification was significantly related to subgrouping by hormone receptor and HER2 (P

A lack of consistent methods to evaluate Ki67 expression is problematic in terms of accurately predicting prognosis in breast cancer. Accordingly, this study aimed to identify the causes of discrepancies in Ki67 labeling index measurements by different observers under different conditions using breast cancer samples.This Japanese study group compared and assessed immunohistochemical (IHC) analysis of the Ki67 labeling index when measured by different pathologists. Six pathologists (pathologists A-F) in Japan participated in this ring study. One hundred and ten surgical cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative invasive breast cancer treated in 2007 were identified from the breast cancer database of Tokai University Hospital and were included in this study.For all 6 pathologists, the Ki67 labeling index were significantly different between grade 3 and grade 1 cases and between grade 3 and grade 2 cases, whereas the index tended to be different between grade 1 and grade 2 cases. Further, the Ki67 labeling indexes measured by the 6 pathologists were strongly correlated (ρ: 0.73-0.88). The IHC scores recorded by pathologist A were in moderate to good agreement with those recorded by the others in patients with a Ki67 labeling index of13.25 % and in those with a Ki67 labeling index of13.25 % (κ = 0.429-0.660). The Ki67 low and high concordance rates between pathologist A and the others were 0.452-0.778 and 0.862-0.979, respectively. The most pertinent reason for discrepancy in scores seemed to be the selection of the area for counting and the quality of nuclear staining.The Ki67 labeling index measured by 6 pathologists without method standardization was in fair to good agreement. We plan to undertake a second ring study, pending recommendations by the international Ki67 panel.

Background Aim: To clarify the clinicopathological characters and treatments and prognosis in elderly breast cancer patients using the Japanese Breast Cancer Registry (JBCR) system. Methods We reviewed data from JBCR, which is the nation-wide registry of newly diagnosed and operated primary breast cancer patients in Japan. To clarify its characteristics, we compared elderly patients aged 75 and over (elderly) with aged from 65 to 74 (young-old; y-o) and that from 55 to 64 (post-menopausal; p-m), respectively. Results In total 132,240 cases diagnosed between 2004 and 2011 were reviewed (elderly; n = 27,385, y-o; n = 43,839, p-m; n = 61,016). In histology, the proportion of mucinous carcinoma and apocrine carcinoma were higher in elderly (6.1%, 1.8%, y-o; 3.5%, 1.7%, p-m; 1.8%, 1.3%, respectively). Patients with clinical stage II and III were more frequent in elderly (45.1%, y-o; 39.0%, p-m; 39.8%). ER -positive rate was higher (76.8%, y-o; 76.3%, p-m; 72.7%) and HER2-positive rate was lower in elderly (10.5%, y-o; 12.8%, p-m; 18.6%, p Table . 238P Age ≧75 65-74 55-64 Distant disease-free survival (%) 93.1 94.3 93.1 Overall survival (%) 84.3 93.7 94.4 Breast cancer-specific survival (BCSS) (%) 94.2 96.7 95.9 Other disease death (%) 48.0 35.8 20.6 Conclusions Elderly patients suffered from more advanced disease at the time of diagnosis. Irradiation after BCS and primary systemic chemotherapy was more frequently omitted in the elderly patients. Overall, BCSS was similar among ages, but the rate of other causes of death was higher in elderly patients. Legal entity responsible for the study The authors. Funding Japanese Breast Cancer Society. Disclosure All authors have declared no conflicts of interest.

We previously reported 2 osteoporosis-susceptibility genes--formiminotransferase N-terminal sub-domain containing gene (FONG) and thrombospondin, type 1, domain-containing 7A (THSD7A)--in which we identified two common single-nucleotide polymorphisms, rs7605378 (FONG) and rs12673692 (THSD7A). The former was associated with a predisposition to osteoporosis and the latter with bone mineral density. To further elucidate the importance of these polymorphisms in the pathogenesis of osteoporosis, we examined their association with the incidence of vertebral fracture. DNA extracted from the renal cortex of 2427 consecutive Japanese autopsies (1331 men, mean age: 79 years; 1096 women, mean age: 82 years) were examined in this study. The presence or absence of vertebral fracture during each subject's lifetime was determined by a thorough examination of the clinical records, as well as autopsy reports. After adjustments for sex and age at autopsy, logistic regression analysis revealed that homozygotes for the risk alleles of rs7605378 (A-allele) or rs12673629 (A-allele) possess an increased risk of vertebral fracture. The subjects simultaneously homozygous for both the risk alleles of rs7605378 (AA genotype) and rs12673629 (AA genotype) showed significantly higher risk of vertebral fracture (odds ratio 2.401, 95% confidence interval 1.305-4.416, P = 0.0048) than those who had at least one non-risk allele of either rs7605378 (AC/CC genotypes) or rs12673629 (AG/GG genotypes). The results suggest that Japanese subjects homozygous for the risk alleles of rs7605378 and rs12673629 have a higher risk of vertebral fracture.

BACKGROUND: We reported a positive correlation between body mass index (BMI) and clinical response to neo-adjuvant hormonal therapy (NAH) with steroidal aromatase inhibitor, exemestane, in post-menopausal breast cancer patients (Takada M et al. Breast 2012). Here, we examined the relationship between serum concentrations of sex steroids and BMI, and explored their predictive value for clinical response. PATIENTS AND METHODS: Among the 116 post-menopausal patients enrolled in the JFMC 34–0601 clinical trial of 24 weeks (wks) of NAH with exemestane, serums from 60 patients at pre-treatment, at 4wks and end of the treatment (24wks) were subjected to this study. Estradiol (E2), estrone (E1), dehydroepiandrosterone (DHEA), androstenedione (A-dione), 5-androstene-3β, 17β-diol (Aenediol), 5α-androstane-3β, 17β-diol (Aanediol) were measured using LC-MS/MS analysis and E1- sulfate (E1S) was by RIA. RESULTS: There were no significant correlations between pre-treatment concentrations of sex steroids and BMI, except for moderate correlation of E2 and BMI (p = 0.004). In multivariate analysis, E1 was an independent predictive factor for objective response [odds 6.0, 95% confidence interval (CI) 1.5 — 34.6, p = 0.011], as well as BMI. All of the estrogens decreased to under-detection levels (0.5 for E1 and E2, 5 pg/assay for E1S) at 4 wks of treatment, and maintained through to the end of treatment in almost all patients independently of clinical response. The geometric mean percentage changes in androgens after NAH were: DHEA −0.2% (95%CI −15.3% — +17.6%) for patients without progressive disease (non-PD) and +44.8% (95%CI +22.1% — +71.8%) for patients with progressive disease (PD); A-dione −2.3% (95%CI −17.3% — +15.4%) for non-PD and +45.6% (95%CI +28.3% — +65.3%) for PD; Aenediol −11.5% (95%CI −20.6% — −1.4%) for non-PD and +24.9% (95%CI +1.9% — +53.0%) for PD; Aanediol +21.3% (95%CI −5.5% — +55.8%) for non-PD and +56.3% (95%CI +5.3% — +132.0%) for PD, respectively. The changes in the concentrations of both DHEA and A-dione in patients with PD were statistically significant (p = 0.008 and p = 0.002, respectively). In all of the PD patients, the serum concentrations of DHEA and A-dione were increased after NAH. CONCLUSION: Pretreatment serum concentration of E1 was an independent predictive factor for clinical response to NAH with exemestane. Measurement of dynamics of the serum androgen concentrations might be helpful for monitoring treatment response, and mechanism of increase of androgens has a value for further investigation. Our results should be validated using a larger dataset. (UMIN ID; C000000345) Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-18.

Cortical synaptic strengths vary substantially from synapse to synapse and exhibit a skewed distribution with a small fraction of synapses generating extremely large depolarizations. Using multiple whole-cell recordings from rat hippocampal CA3 pyramidal cells, we found that the amplitude of unitary excitatory postsynaptic conductances approximates a lognormal distribution and that in the presence of synaptic background noise, the strongest fraction of synapses could trigger action potentials in postsynaptic neurons even with single presynaptic action potentials, a phenomenon termed interpyramid spike transmission (IpST). The IpST probability reached 80%, depending on the network state. To examine how IpST impacts network dynamics, we simulated a recurrent neural network embedded with a few potent synapses. This network, unlike many classical neural networks, exhibited distinctive behaviors resembling cortical network activity in vivo. These behaviors included the following: 1) infrequent ongoing activity, 2) firing rates of individual neurons approximating a lognormal distribution, 3) asynchronous spikes among neurons, 4) net balance between excitation and inhibition, 5) network activity patterns that was robust against external perturbation, 6) responsiveness even to a single spike of a single excitatory neuron, and 7) precise firing sequences. Thus, IpST captures a surprising number of recent experimental findings in vivo. We propose that an unequally biased distribution with a few select strong synapses helps stabilize sparse neuronal activity, thereby reducing the total spiking cost, enhancing the circuit responsiveness, and ensuring reliable information transfer.

Background: The pathogenesis of breast cancer in very elderly women is of interest, because estrogen levels are likely to be extremely low during the development of the disease. Estrogens have opposing effects on the pathogenesis of breast cancer and osteoporosis. In an effort to understand the significance of estrogens in the pathogenesis of breast cancer in this group, we examined the association between breast cancer and osteoporosis in women at least 85 years old, taking body mass index (BMI) and hormone receptors status into consideration. Methods:Clinical records of consecutive elderly women (≥ 85 y/o) who underwent breast cancer surgery at Tokyo Metropolitan Geriatric Hospital (BC) and control women of the same age group (Cont) were reviewed; osteoporosis and BMI status in both groups were recorded and compared. The status of estrogen receptor (ER) and progesterone receptor (PR) of breast cancers was examined immunohistochemically and compared between BC with and without osteoporosis (BC-OP and BC-nonOP, respectively). Results:Frequency of osteoporosis was significantly lower among BC than Cont. There was no difference in BMI measured after 85 y/o between BC and Cont; however, percentage of women, whose BMI measured when they were in their sixties or seventies was ≥ 20% higher than BMI measured when they were 85 y/o or older, was significantly higher among BC than Cont (31% and 2%, respectively. P = 0.0001). ER positivity of breast cancer did not differ between BC-OP and BC-nonOP, whereas PR positivity was significantly higher among BC-nonOP than BC-OP (P = 0.0359). Discussion: The inverse relationship between the incidence of breast cancer and osteoporosis suggests an important role for estrogens in the pathogenesis of breast cancer in the very elderly women. Our finding that one third of BC had ≥ 20% higher BMI when they were in their sixties or seventies suggests they may also had elevated serum estrogens during these earlier years, because increased BMI has been reported to be associated with increased serum estrogens in postmenopausal women. Expression of PR is regulated by estrogen-ER signaling, and PR positivity is considered to reflect the effectiveness of estrogen-ER pathway. Significant difference of PR positivity between BC-nonOP and BC-OP suggests the more importance of estrogens in BC-nonOP than BC-OP. Conclusion:Estrogens seem to play an important role in the pathogenesis of breast cancers in very elderly women, especially without osteoporosis. With increasing aging population in developed countries, those findings may have implications for breast cancer prevention in this age group. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-17-04.

Estrogens play an important role in the pathobiology of breast cancer. In postmenopausal women, peripheral synthesis of estrogens from adrenal/ovarian androgens, dehydroepiandrosterone (DHEA) or androstenedione (Adione), by estrogen-metabolizing enzymes is important. Besides estrone (E1) and estradiol (E2), androgen metabolites, such as androstene-3β, 17β-diol (Aenediol) or 5α-androstane-3β, 17β-diol (Aanediol), are known to have estrogenic functions, although they have been studied much less in breast cancer. To precisely elucidate steroid metabolism in breast cancer patients and to identify the pathobiological role of estrogenic androgen metabolites, concentrations of DHEA, Adione, Aenediol, Aanediol, E1, and E2 in pairs of serum and tumor tissue from patients with primary breast cancer were measured by liquid chromatography-tandem mass spectrometry. Cell proliferation assays using Aenediol were performed for four breast cancer cell lines. Serous E2 concentration was extremely low in postmenopausal women; however, a marked increase in tumor tissue was observed in hormone receptor-positive cases. E1 concentration, in contrast, was sustained at a higher level, even in postmenopausal serum, and did not increase in tumor tissue irrespective of the hormone receptor status. Dehydroepiandrosterone was most abundant in all samples, and exhibited a similar pattern as Adione and Aenediol. 5α-Androstane-3β, 17β-diol was undetectable in most samples. Androstene-3β, 17β-diol proliferated estrogen receptor-apositive breast cancer cells in the absence of E2. The intratumoral increase of E2, but not E1, in hormone receptor-positive postmenopausal breast cancer tissue, as well as the proliferative role of Aenediol, was elucidated.

目的 : 乳腺乳頭状病変の細胞学的判定において, 良悪性鑑別に重要とされている所見が高齢者病変でも有用か否かを明らかにすることを目的とした.方法 : 65 歳以上の高齢者に発生し, 穿刺吸引細胞診と組織学的診断が得られた乳管内乳頭腫 (intraductal papilloma : 以下 IDP) 3 例と乳管腺腫 (ductal adenoma : 以下 DA) 2 例を対象とした. これらと乳頭状病変のみられた悪性 8 例とを臨床細胞学的に比較検討した.成績 : 高齢者良性乳頭状病変は 5 例中 3 例が画像診断を含め臨床的に悪性ないし悪性疑いと判定された. 細胞学的には良性病変全例で間質成分を含め多量の細胞が採取された. 筋上皮細胞・アポクリン化生細胞は良性病変でそれぞれ 3 例, 4 例にみられたが, 悪性病変では認められなかった.結論 : 乳頭状病変の細胞学的良悪性鑑別点は年齢を問わず同じであるが, 高齢者例では臨床的に悪性と判定されることが多いので細胞学的判定には十分注意を払う必要がある.

The occurrence of malignant neoplasms increases with advancing age. Although aging and carcinogenesis are basically different processes, they share phenomena such as the accumulation of DNA damage and abnormal proteins. Recent advances in molecular biology have shown an accumulation of genetic and epigenetic changes in both aging and carcinogenesis, as well as the alteration of metabolism, immunosenescence and shortened telomeres. DNA methylation is a representative epigenetic phenomenon and is frequently involved in controlling gene functions during development and tumorigenesis. We herein focused on methylation of genes in the development of gastrointestinal carcinomas in the elderly. The proportion of gastric and colorectal carcinomas with hypermethylation of the hMLH1 promoter increases with age, reaching 25–30% of all carcinomas of the stomach and large intestine in elderly patients. These tumors have clinicopathological and molecular characteristics such as loss of hMLH1 expression, microsatellite instability, poorly differentiated histology, peritumoral inflammatory cell infiltration, low incidence of lymph node metastasis and favorable prognosis. However, methylation-related carcinogenesis accounts for up to approximately one-third of tumors, and other mechanisms; for example chromosomal instability as a result of telomere dysfunction, are responsible for the development of most carcinomas in the elderly. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S207–S212.

Purpose The clinicopathologic importance of a second estrogen receptor (ER), ER-β, in breast cancers has been intensely studied; however, there is still no real consensus regarding the clinical utility of an ER-β assay, probably because of the lack of standardized methodology, the presence of several ER-β isotypes (ER-β1-5, and so on), and, more importantly, the lack of convincing data on whether the ER-β status provides clinically useful information over what is already provided by the traditional ER-α/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-β antibodies that detect ER-β1-3 (ER-βN), ER-β1, and ER-βcx (ER-β2). Results Positive staining for ER-βN or ER-β1 was associated with significantly better survival. By contrast, ER-βcx status did not influence survival. In multivariate analysis, ER-β1 status emerged as an independent predictor of recurrence and mortality. ER-β1 status was significantly associated with survival in postmenopausal, but not premenopausal, women. Importantly, ER-β1 positivity was associated with significantly better survival in patients with ER-α–negative/PR-negative or ER-α–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-β1 in addition to ER-α and PR is clinically important in patients with breast cancer treated with tamoxifen monotherapy. Further studies are needed to confirm our findings.

Background Bcl-2 plays an anti-apoptotic role, resulting in poor clinical outcome or resistance to therapy in most tumor types expressing Bcl-2. In breast cancer, however, Bcl-2 expression has been reported to be a favorable prognostic factor. The positive correlation of Bcl-2 with estrogen receptor (ER)/progesterone receptor (PR) status, and endocrine therapy frequently given for hormone receptor-positive tumors, may obscure the independent pathobiological role of Bcl-2. We constructed a large systematic study to determine whether Bcl-2 has an independent role in breast cancer. Methods Bcl-2 expression was immunohistochemically evaluated and compared with other clinicopathological factors, including clinical outcome, in 1081 breast cancer cases with long follow-up, separately analyzing 634 cases without any adjuvant therapy and 447 cases with tamoxifen monotherapy. The χ2-test for independence using a contingency table, the Kaplan-Meier method with the log-rank test, and a Cox proportional hazards model were used for the comparison of clinicopathological factors, assessment of clinical outcome, and multivariate analyses, respectively. Results In both patient groups, Bcl-2 expression strongly correlated with positive ER/PR status, low grade, negative human epidermal growth factor receptor 2 (HER2) status, and small tumor size, as previously reported. Bcl-2 expression did not independently predict clinical outcome in patients with ER-positive and/or PR-positive tumors or in those who received tamoxifen treatment; however, it was an independent unfavorable prognostic factor in patients with ER-negative/PR-negative or triple-negative (ER-negative/PR-negative/HER2-negative) tumors who received no adjuvant therapy. The latter was even more evident in postmenopausal women: those with hormone receptor-negative or triple-negative tumors lacking Bcl-2 expression showed a favorable outcome. Conclusion Bcl-2 expression is an independent poor prognostic factor in patients with hormone receptor-negative or triple-negative breast cancers, especially in the absence of adjuvant therapy, suggesting that the anti-apoptotic effect of Bcl-2 is clearly exhibited under such conditions. The prognostic value of Bcl-2 was more evident in postmenopausal women. The present findings also highlight Bcl-2 as a potential therapeutic target in breast cancers lacking conventional therapeutic targets such as triple-negative tumors. The favorable prognosis previously associated with Bcl-2-positive breast cancer probably reflects the indirect effect of frequently coexpressed hormone receptors and adjuvant endocrine therapy.