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Estradiol (E2) increases not only the cell growth but also the cancer stem cell (CSC) proportion in estrogen receptor (ER)-positive breast cancer cells. It has been suggested that the non-canonical hedgehog (Hh) pathway activated by E2 plays an important role in the regulation of CSC proportion in ER-positive breast cancer cells. We studied anti-CSC activity of a non-canonical Hh inhibitor GANT61 in ER-positive breast cancer cells. Effects of GANT61 on the cell growth, cell cycle progression, apoptosis and CSC proportion were investigated in four ER-positive breast cancer cell lines. CSC proportion was measured using either the mammosphere assay or CD44/CD24 assay. Expression levels of pivotal molecules in the Hh pathway were measured. Combined effects of GANT61 with antiestrogens on the anti-cell growth and anti-CSC activities were investigated. E2 significantly increased the cell growth and CSC proportion in all ER-positive cell lines. E2 increased the expression levels of glioma-associated oncogene (GLI) 1 and/or GLI2. GANT61 decreased the cell growth in association with a G1-S cell cycle retardation and increased apoptosis. GANT61 decreased the E2-induced CSC proportion measured by the mammosphere assay in all cell lines. Antiestrogens also decreased the E2-induced cell growth and CSC proportion. Combined treatments of GANT61 with antiestrogens additively enhanced anti-cell growth and/or anti-CSC activities in some ER-positive cell lines. In conclusion, the non-canonical Hh inhibitor GANT61 inhibited not only the cell growth but also the CSC proportion increased by E2 in ER-positive breast cancer cells. GANT61 enhanced anti-cell growth and/or anti-CSC activities of antiestrogens in ER-positive cell lines., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: To investigate whether high b value diffusion-weighted imaging (DWI) contributes to the improvement of diagnostic ability of extracapsular extension (ECE) in prostate cancer (PC)., Materials and Methods: Forty-three patients with PC underwent multiparametric MRI including DWI (b values: 0, 2000 s/mm 2 ) at 3-T. Two radiologists assessed the presence of ECE and the diagnostic certainty degree using conventional diagnostic method by consensus. Tumor apparent diffusion coefficient (ADC, ×10 -3 mm 2 /s) was also measured. Independent predictors of ECE were identified among PSA, tumor ADC, Gleason score, and conventional MRI. ECE in patients with low diagnostic certainty by conventional MRI was further reevaluated using ADC cutoff value, and the results were combined with those of patients with high diagnostic certainty by conventional MRI (MRI + ADC method)., Results: Tumor ADC was an independent predictor of ECE, and the ADC cutoff value was 0.72. The sensitivity, specificity, and accuracy of conventional MRI and MRI + ADC method in the diagnosis of ECE were 44, 92, and 72%, and 78, 96, and 88%, respectively. Among MRI findings leading to the judgement of low diagnostic certainty, broad tumor contact was most common (72% of the patients)., Conclusions: The addition of ADC obtained with high b value DWI at 3-T to conventional MRI improved the diagnostic ability of ECE.

Aims: While cancer immunity is involved in tumour progression from the very early stage, no detailed study has been reported on the relationship between 'early-stage' breast cancer and tumour-infiltrating lymphocytes (TILs). We focused on microinvasive carcinoma to investigate the relationship between histological tumour factors and immunity in 'early' breast cancer., Methods: Of 2593 resected breast carcinomas, 46 microinvasive carcinomas (1.8%) were included. The relationships between tumour characteristics (invasive form, grade, comedo, subtype) and immunological characteristics (TIL, healing) were examined. The invasive form was divided into 'cluster-like' (ie, invasive foci consisted of a small number of cancer cells) and 'non-cluster-like' (ie, nested and classifiable into particular histological type)., Results: Among all cases, 34.8% were grade 1. ER+HER2-, ER+HER2+, ER-HER2+ and ER-HER2- accounted for 58.7%, 8.7%, 28.3% and 4.3%, respectively. Compared with ER+HER2-, ER-HER2+ cases had a significantly stronger association with grade 3 (92.3% vs 0%), comedo (100% vs 55.6%), high TIL (100% vs 29.3%), high CD8+ TIL (92.3% vs 33.3%) and healing (76.9% vs 14.8%) (p<0.001). Compared with 'non-cluster-like', 'cluster-like' carcinoma showed significantly higher rates of HER2 positivity (69.2% vs 24.2%), high TIL (92.3% vs 42.4%) and high CD8+ TIL (76.9% vs 39.4%) (p<0.01)., Conclusions: Our study revealed that microinvasive carcinoma has two progressive pathways; 'low-grade luminal pathway' and 'high-grade HER2 pathway'. HER2-positive cases showed the following unique characteristics: 'high-grade; comedo, high TIL and CD8+ TIL; healing; cluster-like invasion'. These results suggest that the cluster-like invasion might occur because of tumour immunity that leads to disruption of the duct and formation of microinvasive carcinoma in HER2-positive cases., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Purpose: To examine the value of preoperative multiparametric magnetic resonance imaging (MRI) as a predictor of surgical margin (SM) status in patients with prostate cancer (PC)., Materials and Methods: The Institutional Review Board approved this retrospective study; the requirement for informed consent was waived. Fifty-six male patients with histologically proven PC underwent preoperative 3T multiparametric MRI including high b value (0, 2000 s/mm(2) ) diffusion-weighted imaging. In each patient, clinical data, such as biopsy Gleason score and D'Amico clinical risk score, and multiparametric MRI findings, such as tumor location, tumor size, tumor extension in the apical or proximal region, tumor apparent diffusion coefficient (ADC), and the presence or absence of MRI findings of extracapsular extension (ECE) were evaluated. Statistical evaluations included the Fisher's exact test, χ(2) test, Mann-Whitney U-test, and logistic regression analysis., Results: On histopathological evaluation, 15 patients (27%) were SM-positive (SMP group), and 41 (73%) were SM-negative (SMN group). The tumor ADC was significantly lower in the SMP group than in the SMN group (P = 0.001). The frequency of tumor extension in the apex or base and suspected ECE on MRI were significantly higher in the SMP group than in the SMN group (P = 0.037 and 0.011, respectively). On multivariate analysis, tumor ADC was the only predictor of SM status in PC (P = 0.003)., Conclusion: PC with positive SM was characterized by tumor extension in the apical and proximal regions, lower tumor ADC, and tumors with positive MRI findings of ECE, compared to tumors with negative SM. J. Magn. Reson. Imaging 2016;44:584-593., (© 2016 International Society for Magnetic Resonance in Medicine.)

We evaluated the associations between tumor-infiltrating lymphocytes (TIL) including CD8-positive [+] lymphocytes in ductal carcinoma in situ (DCIS) and histopathologic factors, particularly spontaneous "healing" and immunohistochemical (IHC)-based subtypes, to clarify the effects of host immune response to cancer cells proliferation during early carcinogenesis for the breast cancer. This cohort enrolled 82 DCIS patients. We examined the relationships between clinicopathologic factors including age, DCIS architecture, Van Nuys classification, grade, comedo necrosis, apocrine features, TIL, CD8(+) lymphocytes, healing, estrogen receptor and HER2 positivity, and IHC-based subtypes [luminal, luminal-HER2, HER2-positive, triple negative (TN)]. The results were analyzed by univariate and multivariate analyses. High numbers of TIL (high-TIL) and healing were seen in 30.5% and 39.0% of the cohort, respectively. The distributions of luminal, luminal-HER2, HER2 and TN subtypes were 73.2%, 9.8%, 13.4%, and 3.6%, respectively. High Van Nuys grading, high-grade, comedo necrosis, apocrine features, high-TIL, high CD8(+) lymphocytes and healing were significantly associated with HER2-positive (luminal-HER2, HER2), and TN subtypes. High-TIL was significantly associated with high-grade, comedo necrosis, apocrine features, healing, high CD8(+) lymphocytes and HER2 and TN subtypes. Healing was significantly correlated with high CD8(+) lymphocytes, high-grade, comedo necrosis, apocrine features, and HER2-positive and TN subtypes. Logistic regression analysis revealed a strong association between healing and TIL (odds ratio: 11.72, P = 0.024). High CD8(+) lymphocytes was also significantly associated with healing (odds ratio: 9.26, P = 0.009). The results of this study suggested that the spontaneous healing phenomenon might be induced by CD8(+) high-TIL associated with high-grade, comedo necrosis, apocrine features and HER2-positive DCIS., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Eribulin mesylate (eribulin), a non-taxane microtubule dynamic inhibitor, has been widely used in the treatment of patients with advanced or metastatic breast cancer. The combined antitumor and anticancer stem cell (CSC) activities of eribulin with endocrine therapeutic agents have not yet been examined in breast cancer cells. We herein investigated the combined effects of eribulin and antiestrogens., Methods: A panel of eight breast cancer cell lines, including five estrogen receptor (ER)-positive and three ER-negative cell lines, was used. These cells were treated with eribulin and/or the antiestrogen, 4-hydroxytamoxifen or fulvestrant. Their growth inhibitory activities and effects on cell cycle progression, apoptosis, and the CSC population were investigated. CSCs were detected using the CD44/CD24/EpCAM, Aldefluor, and mammosphere assays., Results: The 50% growth inhibitory concentrations of eribulin were 0.38-2.64 nM for the eight cell lines tested. Eribulin exhibited significant antitumor activity under estrogen-supplemented conditions in ER-positive breast cancer cells. The combined antitumor activity of eribulin with an antiestrogen was evaluated using the combination index. The combination index was 0.43-1.46 for ER-positive cell lines. The additive antitumor effect of eribulin with 4-OHT was only significant in MCF-7 cells. Eribulin induced the accumulation of G2/M and apoptosis, while antiestrogens induced the retardation of G1-S cell cycle and apoptosis, respectively. Estrogen markedly increased the proportion of CSCs, whereas antiestrogens inhibited increases in ER-positive cell lines. Moreover, eribulin decreased the proportion of CSCs in either ER-positive or ER-negative cell lines. The combined treatment of eribulin with an antiestrogen did not additively decrease the proportion of CSCs in ER-positive cell lines., Discussion: The results of the present study demonstrated that eribulin had potent antitumor effects on estrogen-stimulated ER-positive breast cancer cells and the combined treatment of eribulin with an antiestrogen resulted in a weakly additive antitumor effect. We herein suggested for the first time that eribulin exhibited anti-CSC effects on either ER-positive or ER-negative breast cancer cells.

Breast cancers contain variable histologies as well as biology. Gene expression profiling and cluster analyses have been performed since the beginning of the 21st century. The use of intrinsic subtype classification has replaced histological classification of breast carcinomas, as it frequently yields the same results. For examples, around 80% of triple negative (estrogen receptor-, progesterone receptor-, and HER2-negative) cancers are of the basal-like subtype. In daily practice, adjuvant therapy is selected based on histological features, but the results of ordinal cluster analyses and histological intrinsic subtypes are not always the same for individual cases. With advanced genetic analysis, new concepts have been elucidated, ie, the molecular identification of claudin-low breast cancer. Proposals of a new classification system and a new therapeutic approach are expected in the future.

Purpose: To determine the clinical, histopathologic and imaging features of pancreatic adenocarcinomas without secondary signs on dynamic CT., Materials and Methods: Seventy patients (mean age 70 years) with histologically proven pancreatic adenocarcinoma underwent preoperative contrast material-enhanced multiphasic multidetector CT before pancreatic resection. In each patient, clinical data including carbohydrate antigen 19-9, frequency of isoattenuating tumours, and presence of secondary signs and histopathologic findings such as tumour location, tumour stage, and microscopic infiltrative growth grade were evaluated., Results: Ten tumours (14%) were without secondary signs, and 60 (86%) were with secondary signs. Tumours without and with secondary signs were located in the uncinate process in 5 (50%) and 3 (5%), head in 3 (30%) and 29 (48%), body in 2 (20%) and 22 (37%), and tail in 0 (0%) and 6 (10%), respectively (p = .001). The frequency of isoattenuating pancreatic adenocarcinomas without secondary signs was significantly higher than those with secondary signs (p = 0.034). The tumour stage of pancreatic adenocarcinomas without secondary signs was earlier than that in tumours with secondary signs (p = 0.041)., Conclusions: Pancreatic adenocarcinomas without secondary signs is characterized by the presence of uncinate and isoattenuating tumours and earlier tumour stage compared to tumours with secondary signs., Key Points: Frequency of pancreatic adenocarcinomas without secondary signs on multiphasic CT is 14 . Pancreatic adenocarcinomas without secondary signs are common in the uncinate process. Pancreatic adenocarcinomas without secondary signs are common in isoattenuating tumours. Pancreatic adenocarcinomas without secondary signs are characterized by earlier-stage tumours.

Twelve high schools in Japan (of which six are in Fukushima Prefecture), four in France, eight in Poland and two in Belarus cooperated in the measurement and comparison of individual external doses in 2014. In total 216 high-school students and teachers participated in the study. Each participant wore an electronic personal dosimeter 'D-shuttle' for two weeks, and kept a journal of his/her whereabouts and activities. The distributions of annual external doses estimated for each region overlap with each other, demonstrating that the personal external individual doses in locations where residence is currently allowed in Fukushima Prefecture and in Belarus are well within the range of estimated annual doses due to the terrestrial background radiation level of other regions/countries.

Background: 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., Patients and Methods: 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., Results: 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 of <13.25 % and in those with a Ki67 labeling index of >13.25 % (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., Conclusion: 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.

Dermatofibrosarcoma protuberans (DFSP) in children is often clinically misdiagnosed as hemangioma or vascular malformation. Ultrasonography and color Doppler imaging are useful noninvasive tools for the diagnosis of skin tumors and may help distinguish DFSP from other vascular skin lesions in children.

Background: Adjuvant trastuzumab has been routinely used in HER2-positive operable breast cancer patients. Prognostic factors remain to be well characterized in these patients and might correlate with primary and/or acquired resistance to trastuzumab., Patients and Methods: The study subjects were 78 HER2-positive operable breast cancer patients treated with adjuvant chemotherapy followed by 1-year trastuzumab between 2005 and 2010 in our institute. All breast tumors showed a HercepTest score of 3+ or that of 2+ and positive fluorescence in situ hybridization. Expression levels of HER1, phosphorylated HER2 (pY1248), HER3, HER4, and p53 were assessed by immunohistochemistry. Prognostic factors were investigated with univariate and multivariate analyses using the Kaplan-Meier/log-rank test and Cox proportional hazards model, respectively., Results: The median age and follow-up period of the patients were 54 years and 39 months, respectively. The mean tumor size was 2.1 cm and the node-positive rate was 42 %. Eight patients had recurrent diseases but no patient died of cancer. Univariate analysis revealed that pHER2 positivity was only a significantly worse prognostic factor for relapse-free survival (RFS) (P = 0.049). A HercepTest score of 2+ and high expression level of p53 showed a trend. Multivariate analysis revealed three biological markers: pHER2 positivity [hazard ratio (HR) = 11.6, 95 % confidence interval (CI) 1.3-111.1, P = 0.031], p53 positivity (HR = 6.4, 95 % CI 1.0-40.0, P = 0.047) and a HercepTest score of 2+ (HR = 8.6, 95 % CI 1.6-45.2, P = 0.011) to be worse prognostic factors for RFS. Notably, three out of five patients with breast tumors expressing HER2 at a score of 2+ and pHER2 had recurrent diseases. Interestingly, the expression level of pHER2 significantly correlated with the expression levels of HER2 and HER3 in HER2-positive breast tumors., Conclusions: This retrospective cohort study suggests that a lower expression level of HER2 and high expression levels of pHER2 and p53 may indicate a worse prognosis in HER2-positive breast cancer patients treated with trastuzumab and chemotherapy. Further studies are needed to evaluate pHER2 expression in HER2-positive breast cancer as a prognostic and/or predictive marker.

Uterine carcinosarcoma is a highly aggressive gynecological neoplasm that responds poorly to conventional chemotherapy and radiotherapy. Recent studies have shown high angiogenic activities of this tumor, hence anti-angiogenic approaches are expected to provide new treatment strategies for this tumor. In previous work, azaspirene was isolated from Neosartorya sp. fungi, and in vitro anti-angiogenic activities were shown. In the present study, the anti-angiogenic effects of azaspirene analogs, synthetic molecules with a shorter ethyl group replacing a hexadienyl side-chain of the natural compound, were assessed in vitro using human umbilical vein endothelial cells (HUVECs) co-cultured with FU-MMT-3 human uterine carcinosarcoma cells. The anti-tumor and anti-angiogenic effects of these analogs were also evaluated in vivo using FU-MMT-3 xenografted tumors in nude mice. The azaspirene analogs inhibited the tube formation of HUVECs induced by FU-MMT-3 cells in vitro and significantly suppressed tumor growth in vivo compared to the untreated group (control). A significant reduction of the microvessel density in tumors was observed, in comparison to the control. No apparent toxicity, including body loss, was observed in any mice treated in this study. These azaspirene analogs may be effective against uterine carcinosarcoma, possibly acting via potent anti-angiogenic effects., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aims: To assess the outcome of breast papillary lesions diagnosed by ultrasound-guided core needle biopsy (CB) or vacuum-assisted 'mammotome' biopsy (MT), the accuracy of these diagnoses, and whether it is justified not to undertake surgical excision of non-malignant papillary lesions so diagnosed., Methods and Results: Among 3219 (MT, 2195; CB, 1024) breast biopsies spanning 5 years, 185 (5.7%) papillary lesions [MT, 162 (88%); CB, 23 (12%)] were identified. Of these, 142 cases (77%; MT/CB, 125/17) were benign, 24 (13%, 23/1) were atypical, and 19 (10%; 14/5) were malignant. Of the 142 benign cases, 114 had imaging follow-up (FU) (FU period 2-81 months); 17 of 114 cases were excised, and four were malignant (3.5%) (FU period 4-57 months). Of the 24 atypical cases (23 had FU), 19 were excised: six were benign (32%) and 13 malignant (68%). The remaining four cases were considered to be non-malignant (FU period 7-54 months)., Conclusions: Benign papillary lesions diagnosed by MT or CB might not require immediate excision, but should receive imaging FU for at least 5 years. Excision should be performed in cases showing changes in imaging features, as the possibilities of carcinoma coexisting with papilloma or carcinoma developing from papilloma cannot be excluded, as illustrated by the 4% upgrade rate at excision in this study., (© 2014 John Wiley & Sons Ltd.)

Most mammals have two major olfactory subsystems: the main olfactory system (MOS) and vomeronasal system (VNS). It is now widely accepted that the range of pheromones that control social behaviors are processed by both the VNS and the MOS. However, the functional contributions of each subsystem in social behavior remain unclear. To genetically dissociate the MOS and VNS functions, we established two conditional knockout mouse lines that led to either loss-of-function in the entire MOS or in the dorsal MOS. Mice with whole-MOS loss-of-function displayed severe defects in active sniffing and poor survival through the neonatal period. In contrast, when loss-of-function was confined to the dorsal MOB, sniffing behavior, pheromone recognition, and VNS activity were maintained. However, defects in a wide spectrum of social behaviors were observed: attraction to female urine and the accompanying ultrasonic vocalizations, chemoinvestigatory preference, aggression, maternal behaviors, and risk-assessment behaviors in response to an alarm pheromone. Functional dissociation of pheromone detection and pheromonal induction of behaviors showed the anterior olfactory nucleus (AON)-regulated social behaviors downstream from the MOS. Lesion analysis and neural activation mapping showed pheromonal activation in multiple amygdaloid and hypothalamic nuclei, important regions for the expression of social behavior, was dependent on MOS and AON functions. Identification of the MOS-AON-mediated pheromone pathway may provide insights into pheromone signaling in animals that do not possess a functional VNS, including humans.

The number of breast cancer patients among Japanese women has been increasing, and one in fourteen women may develop breast cancer during their lifetime. Most cases of breast cancer occur in the terminal duct-lobular units, but their pathological features are quite heterogeneous. Thus, it is necessary to examine them pathologically, to establish appropriate adjuvant therapy for individual patients. In addition to determining the histological type, tumor size, tumor grade, lymphovascular invasion, node metastases, and surgical margin status (for breast-conserving surgery), we should clarify the biomarker status. Analyses of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor 2 (HER2) are routinely performed currently, but strict quality control is strongly recommended, including pre-analytical issues. In addition, the Ki-67 labeling index has been employed as a marker to determine the indication for adjuvant chemotherapy for hormone receptor (ER/PgR)-positive, HER2-negative invasive carcinoma patients. The significance of PgR may alter, too. The threshold for the therapeutic indication may alter with the progress of pharmacology. The evidence-based data and expert consensus (i.e., St. Gallen international meeting consensus) may influence our daily practice. In this issue, we introduce the newest histological classifications (by the WHO and the Japanese Society of Breast Cancer) and the Japanese Breast Cancer Treatment Guideline. Several issues to be included in the pathology reports are examined, and the current status as well as future perspectives of biomarker analysis will be discussed.

Objective: The objective of our study was to investigate tumor conspicuity and the discrimination potential for tumor aggressiveness on diffusion-weighted magnetic resonance imaging (DW-MRI) with high b value at 3-T., Materials and Methods: The institutional review board approved this study and waived the requirement for informed consent. A total of 50 patients with prostate cancer (69 cancer foci; 48 in the PZ, 20 in the TZ, and one in whole prostate) who underwent multiparametric prostate MRI including DW-MRI (b values: 0, 1000 s/mm2 and 0, 2000 s/mm2) on a 3-T system were included. Lesion conspicuity score (LCS) using visual assessment (1 = invisible for surrounding normal site; 2 = slightly high intensity; 3 = moderately high; and 4 = very high) and tumor-normal signal intensity ratio (TNR) were assessed, and apparent diffusion coefficient (ADC, ×10-3 mm2/s) of the tumor regions and normal regions were measured., Results: Mean LCS and TNR at 0, 2000 s/mm2 was significantly higher than those at 0, 1000 s/mm2 (p<0.001 for both). In addition, ADC at both 0, 1000 and 0, 2000 s/mm2 was found to distinguish intermediate or high risk cancer with Gleason score ≥7 from low risk cancer with Gleason score ≤6 (p<0.001 for both). Furthermore, ADC of tumor regions correlated with Gleason score at both 0, 1000 s/mm2 (ρ = -0.602; p<0.001) and 0, 2000 s/mm2 (ρ = -0.645; p<0.001)., Conclusions: For tumor conspicuity and characterization of prostate cancer on DW-MRI of 3-T MRI, b = 0, 2000 s/mm2 is more useful than b = 0, 1000 s/mm2.

Purpose: Whether postoperative chemotherapy should be added to endocrine therapy or not is an important issue in patients with hormone receptor-positive and human epidermal growth factor receptor (HER)2-negative breast cancer. To identify patients who should be treated with additional chemotherapy, prognostic factors were investigated in breast cancer patients postoperatively treated with endocrine therapy alone., Patients and Methods: Tumor samples and clinicopathological data were collected from patients who underwent curative surgery and were postoperatively treated with endocrine therapy alone between 1999 and 2003 in three different institutes. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and HER2 in primary tumors were centrally retested. Patients with ER-negative and/or HER2-positive tumors and/or with unknown nodal status were excluded from the study subjects. Immunohistochemical analysis of Ki67, HER1, insulin-like growth factor-1 receptor, and aldehyde dehydrogenase-1 was also performed. Prognostic factors were investigated by univariate and multivariate analyses., Results: A total of 261 patients were the subjects of this study. The median age was 59 years old, the mean tumor size was 1.9 cm, the node-positive rate was 20 %, and 65 % received tamoxifen alone. Distant metastases were observed in 11 patients at a median follow-up of 98 months, and four patients had died of breast cancer at a median follow-up of 99 months. Univariate analysis showed that marked lymphovascular invasion (LVI), PgR negativity, high Ki67 labeling index (LI), and high nuclear grade were significantly worse prognostic factors for distant metastasis. Multivariate analysis revealed that marked LVI [hazard ratio (HR) 21.8] and PgR negativity (HR 10.3) were independently worse prognostic factors for distant metastasis, respectively. Multivariate analysis also revealed that marked LVI (HR 287.3), PgR negativity (HR 25.1), and high Ki67 LI (HR 19.6) were independently worse prognostic factors for breast cancer-specific death, respectively., Conclusions: The results of this multi-institute cohort study indicated that endocrine therapy alone could not prevent distant metastasis in breast cancer patients with PgR-negative tumors and/or with tumors showing marked LVI or high cell proliferation. These patients may need postoperative adjuvant chemotherapy in addition to endocrine therapy.

Experimental studies have demonstrated the involvement of angiogenesis-related factors in the progression of chronic kidney disease (CKD). There have so far been no reports investigating the distribution and clinical roles of Vasohibin-1 (VASH-1), a negative feedback regulator of angiogenesis, in CKD. We recruited 54 Japanese CKD patients and 6 patients who had normal renal tissues excised due to localized renal cell carcinoma. We evaluated the correlations between the renal expression level of VASH-1 and the clinical/histological parameters. VASH-1 was observed in renal endothelial/mesangial cells, crescentic lesions and interstitial inflammatory cells. Significant positive correlations were observed between 1) crescent formation and the number of VASH-1+ cells in the glomerulus (r＝0.48, p＝0.001) or cortex (r＝0.64, p＜0.0001), 2) interstitial cell infiltration and the number of VASH-1+ cells in the cortex (r＝0.34, p＝0.02), 3) the glomerular VEGFR-2+ area and the number of VASH-1+ cells in the glomerulus (r＝0.44, p＝0.01) or medulla (r＝0.63, p＝0.01). These results suggest that the renal levels of VASH-1 may be affected by local inflammation, crescentic lesions and VEGFR-2.

Background: Although the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitor olaparib is known to have potent antitumor activity in BRCA-related breast cancer cells, a limited number of preclinical and clinical studies have shown antitumor activity of olaparib in non-BRCA-related breast cancer. We investigated antitumor activity of olaparib in breast cancer cell lines derived from patients with nonfamilial sporadic breast cancer., Methods: Effects of olaparib alone or in combination with five different chemotherapeutic agents on cell growth, cell cycle progression, apoptosis, and proportion of cancer stem cells using the mammosphere assay and CD44/CD24/ESA cell surface marker assay were investigated in a panel of six sporadic breast cancer cell lines. Extracellular-signal-regulated kinase (ERK) phosphorylation was also investigated to elucidate action mechanisms of olaparib., Results: Olaparib inhibited the growth of two estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell lines and two ER-negative and HER2-negative breast cancer cell lines (50% growth inhibitory concentrations 1.3-3.0 μM) associated with G2/M accumulation and induction of apoptosis. In contrast, two HER2-positive cell lines were resistant to olaparib. Interestingly, olaparib significantly decreased the proportion of putative cancer stem cells in either sensitive or resistant cell lines. In addition, olaparib increased expression of p-ERK. Combined treatments of olaparib with a mitogen-activated protein kinase kinase (MEK) inhibitor U0126 completely suppressed expression of p-ERK. These treatments also inhibited the G2/M accumulation and apoptosis induction by olaparib. Among five chemotherapeutic agents commonly used for breast cancer treatment, only an irinotecan metabolite SN38 showed additive antitumor activity with olaparib. Importantly, the combined treatment enhanced the increase in G2/M accumulation and apoptosis induction as well as a decrease in the proportion of cancer stem cells., Conclusions: This study has indicated for the first time that the PARP inhibitor olaparib has substantial antitumor and anticancer stem cell activity in breast cancer cell lines of nonfamilial origin. Upregulation of p-ERK might explain, at least in part, antitumor and anticancer stem cell activity of olaparib. Combined treatment of olaparib with irinotecan might be effective in treatment of non-BRCA-related breast cancer.

In situ zymography has been used to assess gelatinolytic activity, which is mainly due to matrix metalloproteinases (MMPs) in cancer tissues. MMPs play an important role in cancer invasion and metastasis. Film in situ zymography (FIZ) enables the in situ evaluation of gelatinolytic activity with high reproducibility. In this article, we report a study of FIZ, in a case of breast cancer with an invasive carcinoma component showing clear gelatinolytic activity, and in a non-invasive carcinoma component showing little gelatinolytic activity. Immunohistochemistry on FIZ was also performed. The simultaneous detection of gelatinolytic activity and immunohistochemical reaction was established in a single film. Immunohistochemistry on FIZ may have good potential for the investigation of cancer microenvironment.

Background: Vasohibin-1 (VASH1) is an endothelium-produced angiogenesis inhibitor. Renal cell carcinoma is highly vascularised, but the significance of endogenous VASH1 in renal cell carcinoma has not been defined., Aims: To identify VASH1 expression and its possible relationship with various clinicopathological factors and prognosis in renal cell carcinoma., Methods: A retrospective analysis of 122 tumours obtained from 118 consecutive patients with renal cell carcinoma was performed. The expression patterns of VASH1, CD31, vascular endothelial growth factor (VEGF) and VEGF receptor type 2 (VEGFR2) were examined immunohistochemically and their relationships with clinicopathological factors were analysed., Results: Microvessel density, VASH1 and VEGFR2 expression were significantly higher in clear cell carcinoma than in other subtypes. The VEGF expression pattern differed significantly between clear cell carcinoma and other histological subtypes. VASH1, pT factor and TNM stage were significantly associated with disease-free survival (p=0.030, p = 0.0012 and p = 0.0018, respectively). Cox models of multivariable disease-free survival analyses indicated that VASH1 and stage are independent prognostic factors (p=0.019 and p = 0.024)., Conclusions: VASH1 expression may be useful for estimating the prognosis of renal cell carcinoma. Further studies of the role of VASH1 in renal cell carcinoma involving larger sample sizes are warranted.

Neoadjuvant chemotherapy or preoperative systemic therapy is increasingly considered for patients with operable breast cancer. Patients with breast cancer were examined for pathologic factors predictive of response to neoadjuvant chemotherapy, using an anthracycline-based regimen. For clinical histomorphology and biomarkers, factors were compared among 16 pathologically complete responses and 52 nonpathologically complete responses, using univariate analysis and multivariate regression analysis of principal components, using preneoadjuvant chemotherapy needle biopsy samples as follows: degree of tumor-infiltrating lymphocytes, histologic grade, biology-based tumor type (hormone receptors and HER2 [human epidermal growth factor receptor type 2]), age, clinical TNM stage, and TNM staging. In univariate analysis, high tumor-infiltrating lymphocyte, high histologic grade, and hormone receptors(-)/HER2(+) were significantly associated with pathologically complete responses (93.7%, P < .0001; 81.3%, P = .0206; 43.7%, P = .014, respectively). In multivariate principal component regression analysis, high tumor-infiltrating lymphocytes were the best independent predictor for pathologically complete responses (odds ratio, 4.7; confidence interval, 2.2-10.06; P < .0001). Among tumor-infiltrating lymphocytes and biology-based tumor types, patients with high tumor-infiltrating lymphocytes had pathologically complete responses more than nonpathologically complete responses, especially in the hormone receptors(-)/HER2(+) group. Among high tumor-infiltrating lymphocyte cases, T lymphocytes showed more predominant tendency than B lymphocytes in the pathologically complete responses cases, compared with nonpathologically complete responses cases. These findings indicate that high tumor-infiltrating lymphocytes are important predictors of pathologically complete responses to neoadjuvant chemotherapy, especially in the hormone receptors(-)/HER2(+) group., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We report a rare case of growing teratoma syndrome(GTS). The patient was a 37-year-old man diagnosed as having a mixed germ cell tumor of the right testis. After resection of the right testis, the patient developed multiple lung metastases and chemotherapy was administered. However, in spite of the normalization of the serum AFP level, the lung metastases continued to increase in size. The lung metastases were successfully resected and pathological examination revealed the diagnosis of a mature teratoma. GTS is defined as an enlarging tumor mass during or after chemotherapy in the case of germ cell tumors, with normalization of the serum AFP. Total surgical resection of the mass yielded a good result. Recognition of this syndrome is important for successful treatment.

Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor and VASH2 is its homolog. Our previous analysis revealed that VASH1 is expressed in endothelial cells to terminate angiogenesis, whereas VASH2 is expressed in infiltrating mononuclear cells mobilized from bone marrow to promote angiogenesis in a mouse model of hypoxia-induced subcutaneous angiogenesis. To test the possible involvement of VASH2 in the tumor, we examined human ovarian cancer cells for the presence of VASH2. Immunohistochemical analysis revealed that VASH2 protein was preferentially detected in cancer cells of serous ovarian adenocarcinoma. We then used SKOV-3 and DISS, two representative human serous adenocarcinoma cell lines, and examined the role of VASH2 in the tumor. The knockdown of VASH2 showed little effect on the proliferation of cancer cells in vitro but notably inhibited tumor growth, peritoneal dissemination, and tumor angiogenesis in a murine xenograft model. Next, we stably transfected the human VASH2 gene into two types of murine tumor cells, EL-4 and MLTC-1, in which endogenous VASH2 was absent. When either EL-4 or MLTC-1 cells were inoculated into VASH2 (-/-) mice, the VASH2 transfectants formed bigger tumors when compared with the controls, and the tumor microvessel density was significantly increased. VASH2 stimulated the migration of endothelial cells, and its increased expression in cancer cells is related to the decrease of mir-200b. These results indicate that VASH2 expressed in serous ovarian carcinoma cells promoted tumor growth and peritoneal dissemination by promoting angiogenesis.

Photochemical planar-to-planar chirality transfer was effected by using (R)-[10]paracyclophane-12-carboxylates as a planar-chiral sensitizer and (Z)-cyclooctene and (Z,Z)-1,5-cyclooctadiene as prochiral substrates to give a planar-chiral (E)- and (E,Z)-isomer in up to 44% and 87% enantiomeric excess, respectively, the latter of which being the highest ever reported for a sensitized photochirogenic reaction.

Introduction: The significance and handling of microscopic invasion of non-small cell lung cancer (NSCLC) into hilar peribronchovascular soft tissue (SHEATH+) have not been defined in the TNM classification by AJCC/UICC; nevertheless, SHEATH+ may be equivalent to spread into the mediastinum. Also, assessment of the margin of peribronchial resection is challenging because of the technical difficulty of inking, and intraoperative and postoperative artifacts., Methods: Records of 592 consecutive Asian patients with primary NSCLC (excluding adenocarcinoma in situ) who had, without any preoperative therapy, undergone lobectomy, sleeve lobectomy and pneumonectomy were examined. SHEATH+, simply defined as invasion of hilar peribronchovascular soft tissue, without categorizing any invasive patterns, and its significance were statistically analyzed., Results: Forty-four SHEATH+ cases demonstrated significantly advanced TNM stages, and were statistically associated with central occurrence, pN1-3, and vascular invasion, as assessed by logistic regression analysis. No statistically significant differences were observed between TNM stage-adjusted frequency of recurrence and recurrence-free intervals. Kaplan-Meier's estimates of the rate of overall and recurrence-free survival after surgery showed no statistically significant differences between SHEATH+ and SHEATH-. Cox's multivariate analysis suggested SHEATH was not a statistically independent prognostic factor under the TNM classification by AJCC/UICC (7th edition)., Conclusions: SHEATH+ in NSCLC was simply associated with central occurrence and advanced TNM stages. To the best of our knowledge, this is the first report on the significance of SHEATH+ in NSCLC., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Total synthesis of the proposed structure 2 for phomopsin B was achieved by using an intramolecular olefin metathesis as a key step. The spectral data, however, did not match with those of the natural product reported. Re-examination of the reported NMR data led to the structural revision of phomopsin B to known dothiorelone A 18. The R configuration of dothiorelone A was determined by total synthesis through a cross-metathesis with a chiral olefin 19.

S100A1 is a calcium-binding protein and a member of the S100 family. Recently, S100A1 immunohistochemistry may be an available marker in the differential diagnosis between renal oncocytoma and chromophobe renal cell carcinoma (RCC). However, there are no reports on S100A1 expression in oncocytic papillary RCC that has been recently identified. In this article, we immunohistochemically examined the expression of S100A1 protein in 18 renal tumors including 4 renal oncocytoma, 10 chromophobe RCCs, and 4 oncocytic papillary RCCs. All the cases of renal oncocytoma and oncocytic papillary RCC showed a positive reaction for S100A1 with cytoplasmic pattern. In chromophobe RCC, 3 of 4 tumors with typical variant and 4 of 6 tumors in eosinophilic variant were completely negative for S100A1. Finally, S100A1 immunohistochemistry may be useful in distinguishing renal oncocytoma from chromophobe RCC, but it may be of no use in the differential diagnosis between renal oncocytoma and oncocytic papillary RCC.

The objective of this study was to introduce the clinical and cytological aspects of myospherulosis. A total of 5,174 consecutive breast fine needle aspiration (FNA) cytology cases were reviewed, among which 23 cases of myospherulosis of the breast were found, all in female patients. The main findings of myospherulosis, best seen with the Papanicolaou stain, consisted in the observation of spherules that were homogeneously smooth or contained one or more internal dense bodies. Routine Papanicolaou-stained slides with or without Romanowsky staining were analyzed. Immunocytochemistry was conducted for carbonic anhydrase 1 (CA1), glycophorin C, KP1, and PGM1. The patients' ages ranged from 41 to 79 years (mean age: 56 years). Of the 23 patients, 21 had a previous history of breast surgery. Cytologically malignant or suspicious diagnoses were made in four of the 23 cases. The size of parent bodies varied from 18.2 to 151 μm (mean, 52 μm). The size of spherules ranged from 2.1 to 16.4 μm (mean, 6.6 μm). Immunocytochemistry showed that the myospherules reacted with anti-CA1 and anti-glycophorin C antibodies. Most breast myospheruloses occur in patients with a history of breast surgery. Immunocytochemistry for CA1 and glycophorin C can enhance the diagnosis of myospherulosis., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Recent studies have suggested that the Src inhibitor dasatinib preferentially inhibits the growth of breast cancer cells of the basal-like subtype. To clarify this finding and further investigate combined antitumor effects of dasatinib with cytotoxic agents, a panel of breast cancer cell lines of various subtypes was treated with dasatinib and/or chemotherapeutic agents., Methods: Seven human breast cancer cell lines were treated with dasatinib and/or seven chemotherapeutic agents. Effects of the treatments on c-Src activation, cell growth, cell cycle, apoptosis and the proportion of aldehyde dehydrogenase (ALDH) 1-positive cells were examined., Results: The 50%-growth inhibitory concentrations (IC50s) of dasatinib were much lower in two basal B cell lines than those in the other cell lines. The IC50s of chemotherapeutic agents were not substantially different among the cell lines. Dasatinib enhanced antitumor activity of etoposide in the basal B cell lines. Dasatinib induced a G1-S blockade with a slight apoptosis, and a combined treatment of dasatinib with etoposide also induced a G1-S blockade in the basal B cell lines. Dasatinib decreased the expression levels of phosphorylated Src in all cell lines. Interestingly, dasatinib significantly decreased the proportion of ALDH1-positive cells in the basal B cell lines but not in the other cell lines., Conclusions: The present study indicates that dasatinib preferentially inhibits the growth of breast cancer cells of the basal B subtype associated with a significant loss of putative cancer stem cell population. A combined use of dasatinib with etoposide additively inhibits their growth. Further studies targeting breast cancers of the basal B subtype using dasatinib with cytotoxic agents are warranted.

Since the concept of gene profile-based intrinsic subtypes was proposed, various studies on pathological characteristics have been performed. Particularly, triplenegative (TN) breast cancer, which is negative for all hormone receptors [estrogen receptor (ER) and/or progesterone receptor (PgR) and human epidermal growth factor 2 (HER2)], has been attracting attention because effects of endocrine and targeting therapies cannot be anticipated and thus selecting a treatment method is difficult. TN cancer accounts for about 10%-15% of all invasive breast cancer cases in Japanese, which is significantly lower than the incidence reported in the United States. Cytokeratin (CK) 5/6 or epidermal growth factor receptor (EGFR) is positive in 80%, being classified as basal-like carcinoma, but it should be understood that TN breast cancer and basal-like carcinoma are not necessarily the same. Criteria for positivity judgment of ER, PgR, and HER2 were established to select treatment in cases positive for each marker, and greater importance is attached to strict accuracy control. Inversely, the level of negative findings to judge TN varies among the judgment criteria. In any case, the prognosis of TN breast cancer is poor. Pathologically, TN breast cancer shows certain morphological characteristics, such as high grade and a pushing margin, and abnormalities of BRCA1 and p53 are frequently noted. At present, as no effective therapeutic strategy has been established for TN breast cancer, further clarification of the molecular biological characteristics of such cancers is needed. In addition, the incidence of TN-type ductal carcinoma in situ (DCIS) is low, suggesting that TN does not remain preinvasive DCIS for a prolonged period and that it transforms to invasive cancer in an early stage. Because mammary gland basal cells have characters of progenitor or stem cells that differentiate into both luminal epithelium and myoepithelial cells, these cells may be utilized for the differential diagnosis of the benignity or malignancy of intraductal lesions in routine pathological practice. As proliferation markers, such as Ki-67, and multiple gene arrays for gene signature are also utilized to select adjuvant therapy, analysis may progress further in the future.

Metastasis of one neoplasm to another is also known as metastasis of "tumor to tumor", "cancer to cancer", "tumor in tumor", and "one to another". We describe the case of a 75-year-old woman with the metastasis of signet-ring cell carcinoma of the stomach to clear cell renal cell carcinoma. Six years earlier, the patient had undergone gastrectomy for early gastric cancer. She complained of lumbago, and a mass was found in her left kidney. Examination of a partial nephrectomy revealed clear cell renal cell carcinoma containing signet-ring cells. Morphological and immunohistochemical findings of the signet-ring cells found in kidney cancer and gastric cancer were identical. Subsequent examinations revealed the patient had multiple bone metastases. The diagnosis of carcinoma metastasizing to renal cell carcinoma can be challenging; therefore, additional clinical information and immunohistochemical panel studies are requisite.

The purpose of the present study was to develop a new method of chemoembolization to improve the therapeutic effectiveness and safety profile of cancer treatment. A chemoembolization approach was designed for human solid tumors using resorbable calcium-phosphate ceramic microspheres loaded with an agent anti-angiogenic to tumor vasculature in vivo. The human uterine sarcoma cell line FU-MMT-3 was used in this study because this tumor is aggressive and also exhibits a poor response to radiotherapy or any chemotherapy currently used. The calcium-phosphate ceramic microspheres loaded with TNP-470, an anti-angiogenic agent, were injected into FU-MMT-3 xenografts in nude mice three times per week for 8 weeks. The treatment using TNP-470-loaded microspheres suppressed tumor growth, compared to treatment with TNP-470 alone, microspheres alone, and the control. The mean tumor weight after treatment using TNP-470-loaded microspheres was significantly lower than that after treatment with microspheres alone. These ceramic microspheres were remarkably embolized in tumor microvessels as well as in the feeding arteries and a significant reduction of intratumoral vascularity was also demonstrated following treatment with TNP-470-loaded microspheres. Severe loss of body weight was not observed in any mice treated with the TNP-470-loaded microspheres, compared to treatment with TNP-470 alone. These results suggest that targeting tumor vasculature in human uterine sarcoma using calcium-phosphate microspheres might be more effective and safer than the treatment that employs anti-angiogenic agent alone. This new chemoembolization method incorporating an anti-angiogenic agent may contribute to the effective treatment of locally advanced or recurrent solid tumors.

A 33-year-old woman presented with rare brain metastases from undifferentiated high-grade sarcoma manifesting as headache and vomiting. Magnetic resonance (MR) imaging demonstrated multiple tumors in the brain, subcutaneous soft tissue, and mediastinum. The patient underwent surgery, followed by chemotherapy and radiotherapy. The histological diagnosis was undifferentiated high-grade sarcoma. Radiotherapy was effective, but the brain tumors recurred 6 months later. The patient underwent high-dose methotrexate therapy, but showed no response. Promoter hypermethylation in the O(6)-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) genes was detected and MGMT protein expression was negative in the recurrent tumor, so temozolomide (TMZ) salvage chemotherapy was given, and follow-up MR imaging showed tumor reduction. This case suggests that TMZ may be effective for brain metastasis of undifferentiated sarcoma without MGMT protein expression.

Nodal staging is a crucial factor in choosing the treatment option for non-small cell lung cancer (NSCLC). However, so far as we know, a computer-based histomorphometric analysis of lymph nodes in NSCLC has never been developed. We studied 299 surgically resected lymph nodes from 108 patients with NSCLC. Microscopic digital images were analyzed with Scion Image software. Seventy lymph nodes had at least one metastatic focus. The metastasis occupancy area per node ranged from 0.01 to 209.58 mm(2) (mean, 29.58 +/- 5.87 mm(2)). The metastasis occupancy ratio ranged from 0.01% to 100% (mean, 48.70% +/- 42.10%). The short-axis diameter of malignant lymph nodes was significantly longer than that of benign lymph nodes (P = 0.0002). The average metastasis occupancy area in the regional lymph nodes of NSCLC is quite small. Various inflammatory conditions can result in a false-positive diagnosis when these techniques are used. Studies that combine analysis of primary tumor size and serum carcinoembryonic antigen (CEA) levels with imaging methods should be considered. Finally, the use of mediastinoscopy or video-assisted thoracoscopic surgery is encouraged in determining the exact nodal status in NSCLC.

Immunohistochemistry may be helpful in the diagnosis of various breast lesions. It can be used to assist in distinguishing benign and malignant conditions, or to clarify the histological subtype of invasive carcinomas. There are several markers relatively frequently utilised. Myoepithelial markers (p63, alpha-SMA, smooth muscle myosin heavy chain, and others) are useful to highlight myoepithelial cells. They are employed to verify myoepithelial cell lining in intraductal papillary lesions, or to recognise peripheral myoepithelial cells for non-invasive carcinoma, although their staining results are not always excellent. High molecular weight cytokeratins (CK5/6, CK14, 34betaE12) typically show a mosaic-like pattern of expression in benign papillary/hyperplastic lesions, and are mostly negative in ductal in situ carcinoma, but some exceptions exist. Neuroendocrine differentiation (confirmed by anti-chromogranin A or synaptophysin) suggests malignancy in solid and papillary intraductal epithelial proliferations. The significance of immunohistochemical evaluation of apocrine lesions is still controversial. Negative E-cadherin staining is used for making confirmative diagnosis of lobular carcinoma, with a specificity and sensitivity of approximately 90%. Cytokeratins, especially the antibody 34betaE12, are of value to differentiate spindle cell carcinoma from phyllodes tumour. There are some other useful markers for characterising certain histological subtypes. Nevertheless, for accurate diagnosis, it is essential to correlate the immmunohistochemical staining results with the histological findings.

Immunohistochemistry (IHC) is routinely performed during pathology practice for various breast lesions. Hormone receptor and HER2 analysis for primary breast carcinoma and cytokeratin staining for sentinel lymph nodes analysis are widely conducted. In addition to those markers, there are several situations in which certain IHC staining is valuable as an ancillary tool. This manuscript will present three useful examples of IHC for making differential diagnosis between benign and malignant lesions. Case 1 is an intraductal papilloma with solid epithelial proliferation, for which diagnosis was resolved by myoepithelial markers and high-molecular-weight cytokeratins (HMWCKs). Case 2 is a noninvasive ductal carcinoma with solid and papillary morphology. Many cases with such morphology mimic benign papillomas, but expression of neuroendocrine markers may lead to the correct diagnosis. Case 3 is a benign complex sclerosing lesion, with recognition of a pseudoinvasive process by myoepithelial markers. Although IHC results were excellent in these cases, they are effective only for limited situations. It is important to use IHC with caution, and re-evaluation of histological findings on hematoxylin and eosin stain and clinicopathological correlation of each case is essential.

Objectives: To investigate the effect of the presence of histologic inflammation in needle biopsy specimens on the detection of prostate cancer (PCa) in men with a high serum prostate-specific antigen (PSA) level., Methods: This study included 143 consecutive patients with serum a PSA level of 10-50 ng/mL who had undergone initial needle biopsies of the prostate. We defined moderate or severe inflammation in the biopsy specimens, according to De Marzo et al., as the presence of histologic inflammation., Results: Of the 143 patients, 86 and 57 were diagnosed with PCa (PCa group) or benign prostatic disease (BPD group), respectively. The prostate volume and transition zone volume in the PCa group were significantly smaller than those in the BPD group, and the serum PSA level, PSA density (PSAD), and PSAD in the transition zone were significantly greater than those in the BPD group. A significant difference was found in the incidence of histologic inflammation between the PCa (40.7%) and BPD (73.7%) groups. Among the factors examined, the PSAD and the presence of histologic inflammation appeared to be independently associated with the detection of PCa. Furthermore, the combined consideration of these 2 independent factors could differentiate PCa from BPD in the biopsy specimens with a sensitivity, specificity, positive predictive value, and negative predictive value of 87.2%, 63.2%, 78.1%, and 76.6%, respectively., Conclusions: It seems possible to avoid unnecessary repeat biopsy using the PSAD and the presence of histologic inflammation in biopsy specimens in patients with continuously elevated serum PSA levels after the initial biopsy.

Various radiation-induced tumors, including meningioma, glioma, and sarcoma, have been reported; however, metachronous intracranial double tumors induced by radiation therapy are extremely rare. A 1-year-old boy had undergone tumor removal and craniospinal radiation therapy (30 Gy) for cerebellar medulloblastoma. At 24 years old, parasagittal meningioma developed in the left parietal region and was totally removed. Six years later, an infiltrative tumor was newly found in the right fronto-temporal white matter. The patient underwent stereotactic biopsy, and the tumor was found to be an anaplastic astrocytoma. Chromosomal analysis by fluorescence in situ hybridization (FISH) revealed loss of heterozygosity (LOH) of 1p. As the patient had previously had craniospinal irradiation, no additional radiation therapy was delivered. He underwent chemotherapy with temozolomide and the disease is now stable. Since both secondary tumors were located within the area of previous radiation and the patient did not have any genetic disease predisposing him to tumors, radiation therapy was considered to be responsible for their tumorigenesis. To our knowledge, this case is the fourth case of radiation-induced double CNS tumors arising after radiotherapy to be described in the literature. Whenever radiation is administered to children or young adults, careful serial screening studies are needed.

Aim: Oncological outcomes including surgical margin status and biological progression-free survival (bPFS) were analyzed in patients who underwent laparoscopic prostatectomy (LRP) only., Methods: A total of 136 patients who underwent LRP only without lymph node metastasis or perioperative supportive therapy between April 2000 and October 2005 were analyzed. All patients received > or =6 months postoperative follow-up. Biological progression was defined as elevation of prostate-specific antigen by >0.2 ng/mL., Results: The positive margin (ew+) rate was 36.8% and the 3-year bPFS was 72.6% for all patients. Positive margin rates in pT2a-b, pT2c, pT3a and pT3b were 10.0%, 27.5%, 77.3% and 53.8%, respectively. Three-year bPFS rates in pT2, pT3a and pT3b were 91.8%, 66.8% and 44.9%, respectively. Although the positive margin rate at posterior and anterior sites decreased as more patients were recruited, no significant improvements were observed at apex and base sites. Three-year bPFS rates in pT2 ew-, pT2 ew+, pT3 ew- and pT3 ew+ were 95.8%, 85.7%, 81% and 48.5%, respectively, indicating that positive margins exert a greater impact in pT3 disease than in pT2 disease., Conclusions: Although 3-year bPFS results were almost identical to previous reports of LRP and retropubic radical prostatectomy, the positive margin rate in pT3a disease was particularly high, probably due to immature surgical skill. Although positive margins at posterior and anterior sites decreased with the leaning curve, improvements are needed to reduce positive margin rates at the apex. Positive margins exert greater impact in pT3 disease than in pT2 disease.

Bone marrow (BM) histology of 102 myelodysplastic syndromes (MDS) patients was analyzed retrospectively. All the cases were reclassified according to the World Health Organization (WHO) classification. Karyotype study was conducted for all except one. Fifteen of the MDS cases were hypoplastic. The cellularity in bone marrow histology is sometimes ineffective in the differential diagnosis of MDS and aplastic anemia (AA). Nonetheless, a marked decrease in the number of megakaryocytes (average, 0.3/mm(2); range, 0-2/mm(2)) even in the hyperplastic foci of the marrow of AA was the most important histological feature differentiating AA from MDS, whereas the number of megakaryocytes increased in most MDS cases (44/mm(2); range, 1-240/mm(2)) and also in hypoplastic MDS (14/mm(2); range, 8-26/mm(2)). Hyperplastic marrow had a significantly high frequency of progress to acute myeloid leukemia (AML) and hypoplastic MDS had a lower rate of progress to AML. Severe myelofibrosis had a significantly poor prognosis. An increase in CD34-positive cells in MDS indicated a high rate of progress to AML. As for the patients with refractory cytopenia with multilineage dysplasia (RCMD; the new category under the WHO classification), the increased number of megakaryocytes was correlated with poor prognosis.

A 30-year-old man presented with a supratentorial malignant glioma manifesting as isolated progressive left oculomotor nerve paresis. Computed tomography and magnetic resonance imaging showed an intra-axial tumor in the left temporal lobe, extending to the basal and prepontine cisterns, and compressing the brainstem. The tumor was removed subtotally. The histological diagnosis was anaplastic astrocytoma. Malignant glioma with exophytic growth in the temporal lobe should be considered in the differential diagnosis of isolated oculomotor nerve paresis.

Background: It was previously reported that a functional human (h) Rad9 protein accumulated in the nuclei of non-small cell lung carcinoma (NSCLC) cells. Those experiments, however, did not examine whether the hRad9 gene was mutated in those cells. The sequence of the HRAD9 gene in NSCLC cells was investigated., Methods: The sequence of the HRAD9 was examined in tumor and peripheral normal lung tissues obtained from 50 lung adenocarcinoma patients during surgery. The expression of its mRNA using reverse transcription polymerase chain reaction (RT-PCR) was also examined., Results: No sequence alterations were detected in the HRAD9 gene, which was found to be normally transcribed in surgically resected lung carcinoma cells. However, in eight (16.0%) cases a single nucleotide polymorphism (SNP) was observed at the second position of codon 239 (His/Arg heterozygous variant) of the gene. This frequency was significantly higher than that found in the normal population., Conclusions: Whereas the capacity to produce a functional hRad9 protein was intact in lung adenocarcinoma cells, a nonsynonymous SNP of HRAD9 was detected that might be associated with the development of lung adenocarcinoma.

Background: The management of conjunctival malignant melanoma remains controversial. Interferon-beta (IFN-beta) is a well-known antineoplastic agent against cutaneous malignant melanoma., Case: A 44-year-old man was referred to Kobe University, Hospital for treatment of pigmented lesions in the corneal limbus of his right eye, first recognized in 2000 and growing gradually., Findings: There were two pigmentary neoplastic lesions in the conjunctiva of his right eye, one at 9 o'clock in the limbus and the other at the inferior bulbar conjunctiva close to the fornix. Primary acquired melanosis (PAM) extended widely over the bulbar conjunctiva and the corneal surface. These findings led to the clinical diagnosis of conjunctival malignant melanoma. Systemic work-up did not detect any other neoplastic lesion., Course: The melanotic lesions were resected and histopathologically malignant melanoma was diagnosed. Microscopically, the tumor cells were present at the surgical margin. Melanoma recurred a half-year later at 3 o'clock in the limbus of the right eye. IFN-beta (3 million units/) was injected subconjunctivally 22 times. Side effects observed were as follows: corneal epithelial erosion, increase of the corneal thickness, lid swelling, conjunctival congestion, subconjunctival hemorrhage, and liver dysfunction. These findings were transient. Melanotic lesions, including PAM, diminished 6 months after the end of treatment., Conclusion: This therapeutic trial of local therapy using the subconjunctival administration of IFN-beta demonstrated excellent efficacy for the treatment of conjunctival malignant melanoma. Local and systemic side effects were seen, though transient, suggesting the necessity of long-term follow-up study.