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Purpose The proliferation marker Ki67 has prognostic and predictive values in breast cancer, and the cutoff of the Ki67 label index (LI) is a key index for chemotherapy. However, poor interobserver consistency in Ki67 assessment has limited the clinical use of Ki67, especially in luminal cancers. Here, we reported a modified Ki67 assessment method, size-set semiautomatic counting (SSSAC) and investigated its interobserver reproducibility. Methods One hundred invasive breast cancer tissues were set immunostained for Ki67 in one laboratory, scanned as digital slides, and sent to 41 pathologists at the laboratories of 16 hospitals for Ki67 LI assessment using size-set semiautomatic counting (SSSAC), size-set visual assessment (SSVA) and size-set digital image analysis (SSDIA) with a specific image viewing software (Aperio Image Scope, Leica, Germany). The intraclass correlation coefficient (ICC) and Bland-Altman plot were used to evaluate interobserver reproducibility. The Wilcoxon signed-rank test was used to analyze the difference in the Ki67 values assessed by SSSAC and SSDIA. Results SSSAC demonstrated better interobserver reproducibility (ICC = 0.942) than SSVA (ICC = 0.802). The interobserver reproducibility was better in Ki67 homogeneously stained slides and centralized hot-spot slides than in scattered hot-spot slides. The Ki67 value assessed with SSSAC was obviously higher than that assessed with SSDIA (negative ranks (SSDIA SSSAC): N = 17, sum of ranks = 478.50; Z = −6.837; P, Highlights • A modified method for Ki67 LI assessment based on digital image, size-set semiautomatic counting (SSSAC). • Investigated the interobserver reproducibility of SSSAC for Ki67 LI assessment of 100 cases in 41 pathologists of 16 hospitals. • SSSAC has better interobserver reproducibility than current visual assessment and was more accurate than DIA in Ki67 assessment. • SSSAC is a better choice for Ki67 LI assessment.

Background Extra nodal NK/T cell lymphoma (ENKTL) is rarely occurred in the gallbladder, and it is generally difficult to diagnose before surgery. Here we present a case of primary ENKTL of gallbladder. Case presentation A 61-year-old female with pain in the right upper abdomen, and Murphy's sign was positive. Ultrasonography showed that a submucosal tumor-like lesion in the neck of the gallbladder, and the gallbladder wall thickness was 0.6cm; there were several high-signal stone shadows. Microscopic examination revealed coagulative necrosis in the lamina propria of the mucosa, the tumor cells were grown diffusely infiltrating, which with medium to large size and inconspicuous or small nucleoli. Immunohistochemistry showed that the tumor cells were positively expressed CD3, CD2, CD56, CD43, TIA-1, Perforin, Granzyme-B, and EBER-ISH (-). Based on these findings, the pathological diagnosis was ENKTL of the gallbladder. The patient received CHOP chemotherapy regimens, who has been free of recurrence for 8 months after the surgery. Conclusion In the early stage, histological diagnosis of ENKTL is difficult, and the patient may not have obvious symptoms, for patients with the gallbladder wall thickens and has protrusions, ENKTL should be regarded as one of the differential diagnosis.

Purpose The NOEY2 gene mutations and protein expression in human breast cancers, adjacent breast tissues and breast benign lesions were analysed to explore the potential correlation between the mutation spectrum and breast cancer development and progression. Experimental design The promoter, exon and intron regions of NOEY2 gene were amplified by polymerase chain reaction (PCR) with DNA extracted from 50 human breast cancer and corresponding adjacent breast tissues as well as 50 breast benign lesions, respectively. The PCR products were then sequenced and analysed. The effect of mutations on the expression of NOEY2 protein by immunohistochemistry were proven as well. Results Twenty-one of 50 (42%) breast cancer mutations were identified in promoter (11 cases) and exon 2 (seven cases on untranslation region and three on coding region) and 17 of 50 (34%) adjacent breast tissues (all were atypical hyperplasia lesions) occurred mutations, including six promoter mutations and 11 exon 2 changes (10 cases on untranslation region and one on coding region). Interestingly, the mutations were identified in both breast cancers and the corresponding adjacent breast tissues collected from the same patient in seven of them. No mutation was identified in all benign breast tissues. Immunohistochemical analysis showed that two of 17 mutational adjacent breast tissue samples were NOEY2 immunoreaction negative, and in all 21 mutations of breast cancers five cases were of loss of NOEY2 expression. All mutations with immunoreaction negative factor were located at promoter and/or exon 2 coding region. NOEY2 gene mutations were not correlated with patient ages, histological types, tumour sizes, histological grades, clinical stages, axillary lymph node metastases or with the condition of hormone receptor (ER, PR) expression and HER2 amplification. Conclusions The mutations of human NOEY2 were identified in human breast cancers and the corresponding adjacent breast tissues. The hot mutation spots were its promoter and exon 2 regions, and those occurring at the exon2 coding region and part of the promoter may alter the expression of NOEY2. The presence of NOEY2 mutations in human breast cancer and early-stage lesions indicates that NOEY2 mutations may be partly associated with breast tumourigenesis.

Previous investigations indicated that glucagon-like peptide-1 (GLP-1) played important roles in bone turnover via GLP-1 receptors (GLP1Rs) in postmenopausal state. Furthermore, polymorphisms in GLP1R gene were suggested to affect the function of GLP1Rs and be associated with many diseases. However, the relationships between GLP1R polymorphisms and osteoporosis susceptibility and bone strength remain unexplored. To address this issue, a total of 458 Chinese Han postmenopausal women were included in this study. The bone mineral density (BMD) in the lumbar spine (L 2 -L 4) and femoral neck was measured by dual-energy X-ray absorptiometry (DEXA). A missense mutation (rs1042044) in GLP1R was genotyped using allele specific TaqMan probes. Our data showed that genetic variants of rs1042044 were significantly associated with osteoporosis (P = 0.003) and that the C allele of rs1042044 was a protective factor against osteoporosis compared to the A allele with gene dosage-dependent manner (OR, 0.579; 95% CI, 0.366 to 0.916 for AC genotype and OR, 0.404; 95% CI, 0.238 to 0.688 for CC genotype). These findings indicate that polymorphisms in GLP1R gene may affect BMD and development of osteoporosis in Chinese Han postmenopausal women, which provide novel insight into the mechanisms of osteoporosis development and target for personal prevention and treatment of osteoporosis. Key words : Glucagon-like peptide-1 receptor, single nucleotide polymorphism, osteoporosis, bone mineral density.

We previously found that genetic polymorphisms in gene coding for histamine H4 receptors were related to the risk and malignant degree of breast cancer. The roles of polymorphisms in other histamine-related genes, such as histidine decarboxylase (HDC), histamine N-methyltransferase (HNMT) and histamine H3 receptor (HRH3), remain unexplored. The aim of this study is to analyze the clinical associations of polymorphisms in HDC, HNMT and HRH3 with breast cancer. Two hundred and one unrelated Chinese Han breast cancer patients and 205 ethnicity-matched health controls were recruited for case-control investigation. Genomic DNA from the participants was extracted and 5 single nucleotide polymorphisms (SNPs) in HDC, HNMT and HRH3 were genotyped. We found that polymorphisms of HNMT and HRH3 were irrelevant with breast cancer in the present study. However, the T allele of rs7164386 in HDC significantly decreased the risk of breast cancer (adjusted odds ratios [ORs], 0.387; 95% confidence intervals [CIs], 0.208–0.720; P = 0.003). Furthermore, for HDC haplotypes, the CG haplotype of rs7164386-rs7182203 was more frequent among breast cancer patients (adjusted OR, 1.828; 95% CI, 1.218–2.744; P = 0.004) while the TG haplotype was more frequent among health controls (adjusted OR, 0.351; 95% CI, 0.182–0.678; P = 0.002). These findings indicated that polymorphisms of HDC gene were significantly associated with breast cancer in Chinese Han population and may be novel diagnostic or therapeutic targets for breast cancer. Further studies with larger participants worldwide are still needed for conclusion validation.