CD10 is a cell surface neutral endopeptidase that is not consistently expressed in the stromal cells of the normal breast. Expression of CD10 is sometimes observed in the stromal cells of invasive ductal carcinoma, but its clinical significance has never been studied. Immunohistochemical examination of CD10 was performed in 123 cases of breast cancer. The median follow-up period of all patients was 8.0 years, and univariate and multivariate analyses were performed to evaluate the prognostic significance of stromal CD10 expression. There was no staining in the stromal cells of 13 non-invasive ductal carcinomas or normal breast tissue. Of 110 invasive ductal carcinomas, 20 cases (18%) in which more than 10% of the stromal cells stained positive throughout the cancer tissue were judged "positive". The frequency of positive stromal staining was significantly higher in the cases with axillary lymph-node metastasis ( P=0.038), but there were no correlations between stromal CD10 expression and age, tumor size, histologic grade, or clinical stage. The patients whose tumors contained CD10-positive stromal cells had a shorter metastasis-free interval ( P=0.0008). Univariate analysis demonstrated that patients with lymph-node metastasis also had a significantly shorter metastasis-free interval (metastasis vs no metastasis; P=0.0318). In the multivariate analysis, only CD10 remained a significant predictor for time to recurrence ( P=0.0059), and CD10 was the single significant prognostic factor for overall survival in the univariate analysis ( P=0.0021). These results suggest that stromal expression of CD10 in breast cancer is an important novel prognostic factor.

ObjectiveGout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only.MethodsA GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls.ResultsFive gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10−8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10−12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10−23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10−9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case–control ORs for two distinct types of gout (r=0.96 [p=4.8×10−4] for urate clearance and r=0.96 [p=5.0×10−4] for urinary urate excretion).ConclusionsOur findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

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Insulin-derived amyloidosis caused poor glycemic control and increased insulin dose requirements because of impairments in insulin absorption.

Bacterial infections, including surgical site infections (SSI), are a common and serious complication of diabetes. Staphylococcus aureus, which is eliminated mainly by neutrophils, is a major cause of SSI in diabetic patients. However, the precise mechanisms by which diabetes predisposes to staphylococcal infection are not fully elucidated. The effect of insulin on this infection is also not well understood. We therefore investigated the effect of insulin treatment on SSI and neutrophil function in diabetic mice. S. aureus was inoculated into the abdominal muscle in diabetic db/db and high-fat-diet (HFD)-fed mice with or without insulin treatment. Although the diabetic db/db mice developed SSI, insulin treatment ameliorated the infection. db/db mice had neutrophil dysfunction, such as decreased phagocytosis, superoxide production, and killing activity of S. aureus; however, insulin treatment restored these functions. Ex vivo treatment (coincubation) of neutrophils with insulin and euglycemic control by phlorizin suggest that insulin may directly activate neutrophil phagocytic and bactericidal activity independently of its euglycemic effect. However, insulin may indirectly restore superoxide production by neutrophils through its euglycemic effect. HFD-fed mice with mild hyperglycemia also developed more severe SSI by S. aureus than control mice and had impaired neutrophil phagocytic and bactericidal activity, which was improved by insulin treatment. Unlike db/db mice, in HFD mice, superoxide production was increased in neutrophils and subsequently suppressed by insulin treatment. Glycemic control by insulin also normalized the neutrophil superoxide-producing capability in HFD mice. Thus, insulin may restore neutrophil phagocytosis and bactericidal activity, thereby ameliorating SSI.T he number of patients with diabetes mellitus has increased greatly worldwide (8,48). It is well known that diabetic patients are more prone to bacterial infections, including surgical site infections (SSI), than healthy individuals. Although many clinical reports have demonstrated that glycemic control reduces the risk of infections, the precise mechanisms by which diabetes predisposes to infections are not well understood (2, 21, 38). Control of bacterial infections has become more important for diabetic patients than in the past, because of the increase in diabetic patients and their susceptibility to infections. Foot infections following skin ulceration are also common causes of hospitalization for diabetic patients (6). These infectious complications seriously impair prognoses for diabetic patients (44).Gram-positive bacteria cause more than half of cases of diabetesrelated wound infections. Especially, Staphylococcus aureus is a major pathogen in these infections (44). Methicillin-resistant S. aureus (MRSA) also has become prevalent among both nosocomial and community-acquired infections in diabetic patients (44). Neutrophils play crucial roles in eliminating bacteria, including S. aureus, from hosts (22). Therefore, neutrophil ...

The prognostic value of TNM7 is better than that of TNM6; however, improvement over TNM5 is insignificant. By considering all regional NDs as LNM irrespective of their morphology, TNM classification can be simplified and its prognostic value improved.

Breast carcinoma with a high histologic grade is highly invasive and metastatic. One reason for its irregular morphology is the formation of excessive protrusions due to assemblages of branched actin filament networks. In mammalian cells, the actin-related protein 2 and 3 (Arp2/3) complex initiates actin assembly to form lamellipodial protrusions by binding to the Wiskott-Aldrich syndrome (WASP)/WASP family verprolinehomologous protein2 (WAVE2), a member of the WASP protein family. In this study, the localization Arp2 and WAVE2 in breast carcinoma was investigated to clarify whether coexpression of the two proteins is associated with histologic grade or patient outcome. Immunohistochemical staining of Arp2 and WAVE2 was performed on mirror specimens of 197 breast carcinomas, and the association between coexpression of the two proteins and clinicopathologic factors was examined. Kaplan-Meier disease-free survival and overall survival curves were analyzed to determine the prognostic significance of Arp2 and WAVE2 coexpression in breast carcinoma. Coexpression of Arp2 and WAVE2 was detected in 64 (36%) of 179 invasive ductal carcinomas and in 2 (11%) of 18 ductal carcinomas in situ, but was not detected in any adjacent non-cancerous tissue. The proportion of cancer cells expressing both Arp2 and WAVE2 was significantly higher in cases with high histologic grade (Po0.0001), and cases with lymph node metastasis (P ¼ 0.0150). The patients whose cancer cells showed such coexpression had shorter disease-free (P ¼ 0.0002) and overall survival (P ¼ 0.0122) than patients whose cancer cells expressed only one or none of Arp2 and WAVE2. Multivariate Cox regression analysis revealed that coexpression of Arp2 and WAVE2 is an independent factor for both tumor recurrence (P ¼ 0.0308) and death (P ¼ 0.0455). These results indicate that coexpression of Arp2 and WAVE2 is a significant prognostic factor that is closely associated with aggressive morphology of invasive ductal carcinoma of the breast.

These results do not support the TNM system in which S-ND is treated differently from I-ND in tumor staging; LNM and ND should be considered together in the same category. The presence of ND (v/pni+) has a considerable adverse prognostic effect.