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Background: Antibody-dependent-mediated cytotoxicity (ADCC) is one of the modes of action for trastuzumab. Recent data have suggested that fragment C γ receptor (FcγR) polymorphisms have an effect on ADCC. This prospective phase II trial aimed to evaluate whether these polymorphisms are associated with clinical efficacies in patients who received trastuzumab.Patients and methods: Patients in a neoadjuvant (N) setting received Adriamycin and cyclophosphamide followed by weekly paclitaxel/trastuzumab. Patients in a metastatic (M) setting received single trastuzumab until progression. In total, 384 distinct single nucleotide polymorphisms of different FcγR, HER2, and fucosyltransferase loci were assessed.Results: Fifteen operable and 35 metastatic HER2-positive breast cancer patients were enrolled in each of the N and M settings, respectively. The FcγR2A-131 H/H genotype was significantly correlated with the pathologically documented response (pathological response) (P = 0.015) and the objective response (P = 0.043). The FcγR3A-158 V/V genotype was not correlated with the pathological response, but exhibited a tendency to be correlated with the objective response. Patients with the FcγR2A-131 H/H genotype had significantly longer progression-free survival in the M setting (P = 0.034).Conclusion: The FcγR2A-131 H/H polymorphism predicted the pathological response to trastuzumab-based neoadjuvant chemotherapy in early-stage breast cancer, and the objective response to trastuzumab in metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Summary: A 26-month-old thoroughbred colt with a 4-month history of continuous diarrhoea and weight loss was subject to necropsy examination. The small intestinal mucosa was thickened and this change particularly affected the terminal ileum. Microscopical examination revealed multifocal epithelial hyperplasia, with multifocal granulomas and marked lymphocytic infiltration of the lamina propria. Numerous gram-negative argyrophilic curved bacilli were observed within the cytoplasm of affected enterocytes. Macrophages and epithelioid cells forming the granulomas had abundant, lightly eosinophilic, foamy cytoplasm, with occasional large, clear vacuoles containing gram-positive coccobacilli. Immunohistochemical studies suggested that the argyrophilic bacilli were Lawsonia intracellularis and the gram-positive coccobacilli were Rhodococcus equi. L. intracellularis-specific DNA fragments were amplified from the affected ileocaecal mucosa by polymerase chain reaction. Virulent R. equi (VapA positive) was isolated in pure culture from the liver and mesenteric lymph nodes. These results suggested that the two intracytoplasmic organisms had induced multifocal proliferative and granulomatous enteritis accompanied by severe and extensive lymphocytic infiltration. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to examine the changes in temporomandibular joint (TMJ) morphology and clinical symptoms after intraoral vertical ramus osteotomy (IVRO) with and without a Le Fort I osteotomy. Of 50 Japanese patients with mandibular prognathism with mandibular and bimaxillary asymmetry, 25 underwent IVRO and 25 underwent IVRO in combination with a Le Fort I osteotomy. The TMJ symptoms and joint morphology, including disc tissue, were assessed preoperatively and postoperatively by magnetic resonance imaging and axial cephalogram. Improvement was seen in just 50% of joints with anterior disc displacement (ADD) that received IVRO and 52% of those that received IVRO with Le Fort I osteotomy. Fewer or no TMJ symptoms were reported postoperatively in 97% of the joints that received IVRO and 90% that received IVRO with Le Fort I osteotomy. Postoperatively, there were significant condylar position changes and horizontal changes in the condylar long axis on both sides in the two groups. There were no significant differences between improved ADD and unimproved ADD in condylar position change and the angle of the condylar long axis, although distinctive postoperative condylar sag was seen. These results suggest that IVRO with or without Le Fort I osteotomy can improve ADD and TMJ symptoms along with condylar position and angle, but it is difficult to predict the amount of improvement in ADD. [Copyright &y& Elsevier]

Objective: To describe the clinical course and outcome of 10 patients with Kawasaki disease (KD) treated with a calcineurin inhibitor after failing to respond to multiple therapies.Study Design: Demographic and clinical data were prospectively collected using standardized case report forms. T-cell phenotypes were determined by flow cytometry, and KD risk alleles in ITPKC (rs28493229), CASP3 (rs72689236), and FCGR2A (rs1801274) were genotyped.Results: Intravenous followed by oral therapy with cyclosporine (CSA) or oral tacrolimus was well tolerated and resulted in defervescence and resolution of inflammation in all 10 patients. There were no serious adverse events, and a standardized treatment protocol was developed based on our experiences with this patient population. Analysis of T-cell phenotype by flow cytometry in 2 subjects showed a decrease in circulating activated CD8(+) and CD4(+) T effector memory cells after treatment with CSA. However, suppression of regulatory T-cells was not seen, suggesting targeting of specific, proinflammatory T-cell compartments by CSA.Conclusion: Treatment of refractory KD with a calcineurin inhibitor appears to be a safe and effective approach that achieves rapid control of inflammation associated with clinical improvement. [ABSTRACT FROM AUTHOR]

In this article, the authors examined 11 biomarkers, including PIK3CA and AKT1mutation, with regard to event-free survival (EFS) and overall survival (OS) of 75 TNBC patients with lymph-node metastases who had received adjuvant chemotherapy. In a result, they found a correlation between HER4 and pAKT expression, and found that both factors were associated with longer EFS. Furthermore, pERK expression was also related to longer EFS and OS of patients.Background Triple-negative breast cancer (TNBC) patients are a poor prognostic subgroup, and currently, there is no biomarker for targeted therapy. Patients and methods Tissue samples were obtained from 75 TNBC patients with lymph-node metastases who had received adjuvant chemotherapy. We examined 11 biomarkers, including PIK3CA and AKT1mutation, with regard to event-free survival (EFS) and overall survival (OS) of patients. Results In the tumor tissues, phospho-AKT (pAKT) expression was significantly related to HER4 expression. Expression of each of these biomarkers was significantly related to longer EFS (P = 0.024 and 0.03, respectively). pERK expression was also a good prognostic factor regarding EFS and OS in TNBC (P = 0.002 and 0.006, respectively). We also identified a correlation between epidermal growth factor receptor positivity and insulin-like growth factor receptor type 1 positivity (P = 0.001). pERK and T-stage (1–3 versus >3) were independent good prognostic factors by multivariate analysis. Conclusions We determined that tumors expressing pAKT or pERK are a good prognostic subtype in node-positive TNBC. Different targeted therapies may be necessary for TNBC that involves activation of PI3K/AKT or MAPK pathways. [ABSTRACT FROM AUTHOR]

Background: This study aimed to examine the quality in oncology registration trials for new drug application (NDA) or supplemental new drug application (sNDA) as extensions of the indications for use in Japan based on Good Clinical Practice (GCP) audit findings.Materials and methods: We collected audit reports of on-site GCP inspections for registration trials in 383 NDAs or sNDAs that were reviewed by the Pharmaceuticals and Medical Devices Agency between the fiscal years 2004 and 2009.Results: Among the 40 audits for oncology drug applications, the frequencies at which one or more deficiencies ascribed to institution, investigator, sponsor, and institutional review board were found to be 15 (37.5%), 13 (32.5%), 21 (52.5%), and 10 (25.0%), respectively. The exclusion of patients from the review objective due to serious violations of GCP in 40 audits for oncology drug applications was observed in 2 (5.0%) cases, whereas that in the remaining 343 audits for other drug applications was observed in 40 (11.7%) cases.Conclusion: The overall compliance of GCP in oncology registration trials was moderately better than that in registration trials for other diseases, although there was no statistically significant difference between them. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to develop a prediction model of progressive disease (PD) in breast cancer patients without measurable disease in first-line chemotherapy.Methods: We developed a model to predict PD using carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 15-3 in metastatic breast cancer patients who were enrolled in a phase III trial. The model was determined using the area under the receiver operating characteristic curve (AUC) calculated by the bootstrap method as internal validation. We verified the model for those who received first-line chemotherapy in a clinical setting as external validation. We categorized patients without measurable disease into PD and non-PD groups and compared the time to progression (TTP).Results: The model consisted of percent changes in CEA and CA 15-3 levels from second to third chemotherapy course and baseline abnormality of them. The AUC after external validation was 0.90. Patients without measurable disease were categorized into PD (N = 10) and non-PD groups (N = 53) by the model. The difference in TTP between the two groups was statistically significant (hazard ratio, 0.437; P = 0.021).Conclusion: The model may be useful to determine PD in metastatic breast cancer patients without measurable disease. [ABSTRACT FROM PUBLISHER]

Aim: To clarify the clinicopathological characters and treatments and prognosis in elderly breast cancer patients using the Japanese Breast Cancer Registry (JBCR) system. 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. 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 < 0.001). As for surgery, the rate of breast conserving surgery (BCS) was lower in elderly (46.4%, y-o; 55.0%, p-m; 59.6%), and the rate of no surgery for axilla was higher in elderly (18.4%, y-o; 5.9%, p-m; 4.8%, p < 0.001). Irradiation after BCS was performed only in 41.3% of elderly patients, whereas y-o and p-m were 75.9%, 83.0%, respectively. Adjuvant chemotherapy was performed only in 10.8% of elderly patients, y-o and p-m were 31.8%, 46.2%, respectively. Half of elderly patients (49.8%) who underwent chemotherapy were given CMF or oral 5FU. As for hormone therapy, Tamoxifen was used more frequently in elderly (18.1%, y-o; 10.6%, p-m; 9.7%). The 5 years-survival analysis is shown in Table. Table 238P Table 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 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. The authors. Japanese Breast Cancer Society. All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]