Diabetes as a prognostic factor in HER-2 positive breast cancer patients treated with targeted therapy.

PURPOSE: Recent studies revealed that metabolic stress influences the outcomes of breast cancer treatment. We sought to evaluate the prognostic effect of type 2 diabetes and find the molecular mechanism of relapses in postoperative HER-2+ breast cancer patients treated with HER-2 targeted therapy. MATERIALS AND METHODS: We evaluated 190 HER-2+ breast cancer patients (pT1-4N0-2M0) who were treated with surgical resection and trastuzumab (HER-2 targeted therapy) between 2006 and 2015. Survival outcomes and failure patterns were compared between such patients with (n = 12) and without (n = 178) type 2 diabetes. RESULTS: The median follow-up period was 42.4 months (range 12.0-124.7 months). Twenty-one patients (11.1%) showed relapse (including nine patients with locoregional failure), and three patients (1.6%) died as a result of cancer relapse. One-third of the patients with diabetes experienced relapse (4/12, 33.3%). The 3-year disease-free survival (DFS) and overall survival (OS) rates were 90.7% and 98.6%, respectively. Diabetic patients showed shorter DFS compared with non-diabetic patients (p = 0.006, 74.1% vs. 91.9%). OS was also shorter in diabetic patients compared with non-diabetic patients (p = 0.017, 91.7% vs. 99.1%). Of our interest, the levels of HER-3 and its ligand neuregulin-1 were significantly increased in the tumor specimen in HER-2+ breast cancer patients suffering with type 2 diabetes than that in the euglycemic control group. CONCLUSIONS: Type 2 diabetes was associated with detrimental effects on survival in postoperative HER-2+ breast cancer patients who were treated with trastuzumab. The poor prognostic effect of diabetes in HER-2+ breast cancer patients could be associated with the high levels of HER-3 and neuregulin 1, thus it should be considered and evaluated more.

Differences in Clinical Outcomes between Luminal A and B Type Breast Cancers according to the St. Gallen Consensus 2013.

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-positive luminal B type comprises estrogen receptor (ER)-positive and HER2-positive cancers, and HER2-negative luminal B type comprises ER-positive cancers showing a Ki-67 labeling index ≥14% or progesterone receptor (PR) expression of <20% according to the St. Gallen consensus 2013. The current study aimed to classify intrinsic subtypes according to the St. Gallen consensus 2013 and determine the differences in clinicopathological parameters and survival outcomes among the molecular types, especially among the luminal types. METHODS: Assessment of molecular types was performed for 267 invasive ductal carcinomas. The differences in clinicopathological parameters, disease-free survival (DFS), and overall survival (OS) among the molecular types were analyzed. RESULTS: The luminal B type was the most prevalent, at 44.9%, followed by the luminal A, triple-negative (including basal-like type), and HER2 type, at 21.7%, 18.7%, and 14.6%, respectively. There were statistically significant differences in size (p=0.003), nodal status (p=0.046), histologic grade (p<0.001), p53 (p<0.001) and cyclooxygenase 2 (COX-2) positivity (p=0.002), recurrence (p=0.001) and death rates (p=0.036), DFS (p=0.002), and OS (p=0.039) among the molecular types. Significant differences in size (p=0.009), nodal metastasis (p=0.019), histologic grade (p<0.001), p53 positivity (p=0.001), and PR expression (p<0.001) were noted between the luminal A and B types. Among the luminal B type cancers, the distributions of ER and PR scores showed significant differences (p=0.003, p=0.003). p53 positivity in the luminal B type cancers was related to shortened DFS (p=0.034). In luminal type cancers, COX-2 positivity was related to longer DFS (p=0.026). CONCLUSION: Different management guidelines should be considered for the luminal A and luminal B breast cancer types. Positive p53 expression in luminal B type cancers and negative COX-2 expression in luminal type cancers seem to be related to poor clinical outcome.

Prognostic impact of circumferential resection margin in rectal cancer treated with preoperative chemoradiotherapy.

BACKGROUND: The circumferential resection margin (CRM) is a strong prognostic factor in rectal cancer. The purpose of this study was to investigate the relationship between CRM distance and recurrence in patients with locally advanced rectal cancer who received preoperative chemoradiotherapy (CRT). METHODS: We analyzed data for 561 patients who underwent preoperative CRT and curative surgery for locally advanced rectal cancer between August 2001 and December 2008. CRM was divided into four groups: group 1, CRM > 2 mm; group 2, 1.1-2.0 mm; group 3, 0.1-1.0 mm; and group 4, 0 mm. We assessed the associations of CRM with local recurrence and disease-free survival. RESULTS: Groups 1, 2, 3, and 4 comprised 487, 36, 20, and 18 patients, respectively. The local recurrence rate was highest and the disease-free survival rate was lowest in group 4, followed by groups 3, 2, and 1. Survival was similar between groups 2 and 1. Local recurrence rates were lower in groups 3, 2, and 1 than in group 4 [hazard ratio (HR) 0.28, 95 % confidence interval (CI) 0.09-0.91, P = 0.035; HR 0.11, 95 % CI 0.03-0.46, P = 0.002; HR 0.18, 95 % CI 0.08-0.42, P < 0.0001, respectively]. Disease-free survival rates were higher in groups 3, 2, and 1 than in group 4 (HR 0.32, 95 % CI 0.13-0.75, P = 0.009; HR 0.24, 95 % CI 0.10-0.54, P = 0.001; HR 0.26, 95 % CI 0.14-0.48, P < 0.0001, respectively). CONCLUSIONS: After preoperative CRT, CRM distance provides useful information for risk stratification in the recurrence of rectal cancer.

Overestimation of nuclear matrix protein 22 in concentrated urine.

OBJECTIVE: To confirm the hypothesis that nuclear matrix protein 22 (NMP22) is overestimated in concentrated urine, we compared the NMP22 values measured at different dietary states. METHODS: We retrospectively reviewed 531 healthy subjects who had had abnormal urinary NMP22 values ≥ 10 U/mL at the first test and underwent a second NMP22 test within 2 weeks. The first NMP22 test was performed after overnight fasting, and the second was performed with no dietary restrictions. We compared the NMP22 values between the 2 measurements and investigated the relationship between the NMP22 value and urine specific gravity. RESULTS: At the second test, 504 subjects (94.9%) had a normal NMP22 value of <10 U/mL and only 27 subjects (5.1%) persistently had an abnormal NMP22 value of ≥ 10 U/mL. Both NMP22 and urine specific gravity at the first test were significantly higher than at the second test (P <.0001). Subjects with an abnormal NMP22 value tended to have a more concentrated urine with a greater urine specific gravity than did the subjects with a normal NMP22 value. This difference was significant in the subgroup undergoing bowel preparation for colonoscopy (P <.001). CONCLUSION: NMP22 will be overestimated in concentrated urine after overnight fasting. When interpreting the NMP22 value, we should consider the overestimation of NMP22 in concentrated urine.

Practice guidelines for the early detection of cervical cancer in Korea: Korean Society of Gynecologic Oncology and the Korean Society for Cytopathology 2012 edition.

The consensus guideline development committee of Korean Society of Gynecologic Oncology was reconvened in March 2012. The committee consisted of 36 experts representing 12 university hospitals and professional organizations. The objective of this committee was to develop standardized guidelines for cervical cancer screening tests for Korean women and to distribute these guidelines to every clinician, eventually improving the quality of medical care. Since the establishment of the consensus guideline development committee, evidence-based guidelines have either been developed de novo considering specific Korean situations or by adaptation of preexisting consensus guidelines from other countries. Recommendations for cervical cancer screening tests, management of atypical squamous and glandular cells, and management of low-grade and high-grade squamous intraepithelial lesions were developed. Additionally, recommendations for human papillomavirus DNA testing and recommendations for adolescent and pregnant women with abnormal cervical screening test results were also included.

Genetic variations of α -methylacyl-CoA racemase are associated with sporadic prostate cancer risk in ethnically homogenous Koreans.

BACKGROUND: To assess if the variants of (R)-alpha-methyl-CoA racemase (AMACR) gene would be associated with the risk of sporadic prostate cancer in ethnically homogenous Koreans. MATERIALS AND METHODS: We enrolled 194 patients with prostate cancer and 169 healthy controls. A total of 17 single nucleotide polymorphisms of the AMACR gene were selected. The distribution of each genotype and haplotype was analyzed and their association with the incidence of prostate cancer was evaluated. Further, we detected AMACR expression in tumor with immunohistochemistry and analyzed its association with genotype regarding prostate cancer risk. RESULTS: AG or GG genotype of rs2278008 (E277K) tended to lower prostate cancer risk. The minor G allele was found to be a significant allele that decreased the risk of prostate cancer (adjusted OR, 0.57; 95% CI, 0.35-0.93, P value = 0.025). In patients expression AMACR, AG or GG genotype was also significant genotype in terms of prostate cancer risk (adjusted OR, 0.47; 95% CI, 0.26-0.87, P value = 0.017). Further, [GGCGG] haplotype consisted of five coding SNPs of rs2278008, rs34677, rs2287939, rs10941112, and rs3195676 which decreased the risk of prostate cancer (P value = 0.047). CONCLUSIONS: Genetic variations of AMACR are associated with the risk of sporadic prostate cancer that underwent radical prostatectomy in Koreans.

The prognostic impact of microRNA sequence polymorphisms on the recurrence of patients with completely resected non-small cell lung cancer.

OBJECTIVES: MicroRNAs (miRNAs) are widely known for their function as regulators of gene expression via translational repression. Polymorphisms in miRNAs have been shown to affect the regulatory capacity of miRNAs by influencing miRNA processing and/or miRNA-mRNA interactions. The purpose of this study was to investigate the association between 7 single nucleotide polymorphisms (SNPs) commonly found in precursor miRNA (pre-miRNA) and primary miRNA (pri-miRNA) sequences and the recurrence of disease in patients who underwent a complete resection of non-small cell lung cancer (NSCLC). METHODS: Five SNPs found in pre-miRNAs (rs11614913/miR-196a2, rs2910164/miR-146a, rs6505162/miR-423, rs2289030/miR-492, and rs895819/miR-27a) and 2 SNPs found in pri-miRNAs (rs7372209/miR-26a-1 and rs213210/miR-219-1) were genotyped in 388 patients with NSCLC. RESULTS: Among 388 patients, variants of the rs2910164 SNP were significantly associated with recurrence-free survival (RFS) (P = .016, log-rank test). When the results were subdivided by the tumor stage, variants of the rs2910164 and rs11614913 SNPs positively correlated with a better RFS (adjusted hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.28-0.80; adjusted HR, 0.60; 95% CI, 0.38-0.94, respectively) in patients with stage II and stage III disease. Moreover, RFS significantly improved in patients with higher numbers of variant alleles in the rs2910164 and rs11614913 SNPs. CONCLUSIONS: Our findings suggest that polymorphisms in the rs2910164 of miR-146a and the rs11614913 of miR-196a2 are associated with prognosis in patients with completely resected NSCLC.

Association of common variations of 8q24 with the risk of prostate cancer in Koreans and a review of the Asian population.

UNLABELLED: What's known on the subject? and What does the study add? The association between subjects with the genetic variation of 8q24 and the risk of development of prostate cancer in Korean men was found. As a result of haplotype analysis, [AGC] and [CTA] carriers showed a significant association with prostate cancer risk. This is clinically meaningful as an initial study on genetic susceptibility to prostate cancer in Korean men and the first report of 8q24 haplotypes in an Asian population. OBJECTIVE: To determine the association between genetic variation of 8q24 with prostate cancer risk in Korean men. PATIENTS AND METHODS: With a hospital-based case-control study design, we enrolled 194 patients with prostate cancer and 169 healthy controls from visitors for cancer screening. DNA samples were obtained from peripheral blood for the analysis of single nucleotide polymorphisms (SNPs). Three SNPs of 8q24, including rs16901979, rs6983267, and rs1447295, were genotyped on cases and controls. RESULTS: The subjects with the rs1447295 CA or AA genotype had a higher risk of prostate cancer than the CC genotype. The A allele at SNP rs1447295 was associated with the incidence of prostate cancer. The rs16901979 CA genotype carriers had a higher risk of prostate cancer than the CC genotype. Individuals with the [AGC] and [CTA] haplotypes had a significantly increased risk of prostate cancer compared with the [CTC] haplotype ([AGC] with adjusted odds ratio [OR] 1.79; 95% confidence interval [CI] 1.09-2.96; P = 0.022; [CTA] with adjusted OR 5.17; 95% CI 2.40-11.15; P < 0.001). CONCLUSIONS: The genetic variation of 8q24 is associated with the risk of prostate cancer in Korean men. Individuals with the [AGC] and [CTA] haplotypes had a significant association with prostate cancer risk.

Diagnostic difficulties in fine needle aspiration of benign salivary glandular lesions.

BACKGROUND: The diagnostic accuracy of fine needle aspiration cytology (FNAC) of salivary lesions is relatively high, but cytologic interpretation might be confusing if the sample is lacking typical cytologic features. METHODS: There were 77 cases of benign salivary lesions, consisting of pleomorphic adenoma (PA) in 61 cases, Warthin's tumor (WT) in 12 cases, and other benign lesions in 4 cases. The causes of the discrepancies between the FNAC and the histologic diagnoses were evaluated. RESULTS: Major discrepancies were noted in 4 of the 61 PA cases, and in 1 of 12 WT cases. The causes of the major discrepancies were a mislabeled site in 1 PA and 1 WT case, and an interpretation error in 3 PA cases. Minor discrepancies were more common in the WT cases (7 of 12 cases) than in the PA cases (11 of 61 cases). The causes of the minor discrepancies were a mislabeled site in 1 PA and 1 WT case, an inadequate sample in 7 PA and 2 WT cases, a lack of typical cytomorphology in 2 PA and 2 WT cases, and an interpretation error in 1 PA and 2 WT cases. CONCLUSIONS: To increase the diagnostic accuracy in the benign salivary lesions, recognition of both characteristic and less typical cytomorphology is needed.

Haplotype analysis of prostate stem cell antigen and association with prostate cancer risk.

PURPOSE: Prostate stem cell antigen has become a promising target as a potential biomarker for prostate cancer, but to our knowledge there are no reports of a genetic variation of the PSCA gene associated with prostate cancer risk. We determined the potential association between specific variations of the PSCA gene and prostate cancer in Korean men. MATERIALS AND METHODS: In this hospital based, case-control study 194 patients newly diagnosed with histologically confirmed prostate cancer were enrolled. Visitors for cancer screening served as healthy controls. We genotyped 12 PSCA gene single nucleotide polymorphisms in 194 cases and 169 healthy controls. RESULTS: Men with the rs1045531 AA genotype were at higher risk for prostate cancer than those with the CC genotype. Individuals with the CCCAGGTACGG haplotype were at significantly increased risk for prostate cancer. When considering clinical factors, rs3736001, which is a nonsynonymous cDNA single nucleotide polymorphism (Glu39Lys), showed an association with prostate specific antigen 10 ng/ml or greater and prostate cancer risk. CONCLUSIONS: Men with the rs1045531 AA genotype of PSCA were at higher risk for prostate cancer. On haplotype analysis CCCAGGTACGG and CGA haplotype carriers showed a significant association with prostate cancer risk. To our knowledge this is the first report of PSCA genetic variation associated with prostate cancer risk.

Paclitaxel and cisplatin chemotherapy for metastatic urothelial carcinoma after failure of two courses of platinum-based regimens.

OBJECTIVES: We investigated the outcomes of paclitaxel and cisplatin chemotherapy as an optional regimen for patients with metastatic urothelial carcinoma after failure of two consecutive platinum-based regimens. METHODS: We retrospectively analyzed the data of 21 patients who had evidence of disease progression after two consecutive platinum-based regimens, gemcitabine and cisplatin (GC course), and methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC course) as first-line and second-line treatments. As third-line chemotherapy, patients received paclitaxel (175 mg/m(2)) and cisplatin (70 mg/m(2)) every 3 weeks until disease progression. RESULTS: Complete remission occurred in one patient (4.8%), partial remission occurred in three patients (14.3%) and stable disease occurred in five patients (23.8%). The overall response rate was 19.0% and the overall disease control rate, including stable disease, was 42.9%. The median progression-free survival (PFS) was 3 months (95% CI 3.0-5.0). The median overall survival was 9 months (95% CI 7.0-15.0). Grade 3 to 4 neutropenia appeared in 85.7% of patients. No life-threatening complications were observed. CONCLUSIONS: Paclitaxel and cisplatin chemotherapy could be an optional regimen for patients with metastatic urothelial carcinoma after the failure of two consecutive standard platinum-based regimens.

Transcriptional targeting of gene expression in breast cancer by the promoters of protein regulator of cytokinesis 1 and ribonuclease reductase 2.

For cancer gene therapy, cancer-specific over- expression of a therapeutic gene is required to reduce side effects derived from expression of the gene in normal cells. To develop such an expression vector, we searched for genes over-expressed and/or specifically expressed in cancer cells using bioinformatics and have selected genes coding for protein regulator of cytokinesis 1 (PRC1) and ribonuclease reductase 2 (RRM2) as candidates. Their cancer-specific expressions were confirmed in both breast cancer cell lines and patient tissues. We compared each promoter's cancer-specific activity in the breast normal and cancer cell lines using the luciferase gene as a reporter and confirmed cancer-specific expression of both PRC1 and RRM2 promoters. To test activities of these promoters in viral vectors, the promoters were also cloned into an adeno-associated viral (AAV) vector containing green fluorescence protein (GFP) as the reporter. The GFP expression levels by these promoters were various depending on cell lines tested and, in MDA-MB-231 cells, GFP activities derived from the PRC1 and RRM2 promoters were as strong as that from the cytomegalovirus (CMV) promoter. Our result showed that a vector containing the PRC1 or RRM2 promoter could be used for breast cancer specific overexpression in gene therapy.

Multi-resolution wavelet-transformed image analysis of histological sections of breast carcinomas.

Multi-resolution images of histological sections of breast cancer tissue were analyzed using texture features of Haar- and Daubechies transform wavelets. Tissue samples analyzed were from ductal regions of the breast and included benign ductal hyperplasia, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (CA). To assess the correlation between computerized image analysis and visual analysis by a pathologist, we created a two-step classification system based on feature extraction and classification. In the feature extraction step, we extracted texture features from wavelet-transformed images at 10x magnification. In the classification step, we applied two types of classifiers to the extracted features, namely a statistics-based multivariate (discriminant) analysis and a neural network. Using features from second-level Haar transform wavelet images in combination with discriminant analysis, we obtained classification accuracies of 96.67 and 87.78% for the training and testing set (90 images each), respectively. We conclude that the best classifier of carcinomas in histological sections of breast tissue are the texture features from the second-level Haar transform wavelet images used in a discriminant function.

Mixed tumor of the vagina: a case report.

We report a case of mixed tumor arising in the lower vaginal wall. The patient was a 20-yr-old nullipararous woman. The tumor was relatively well-defined with expansile margin, and showed solid sheets or fascicles of stromal-type spindle cells and ovoid epithelial cells with sparsely scattered nests of mature squamous epithelium and glands lined by mucinous epithelium. Cellular atypia was not conspicuous, however, mitosis was counted upto 6 per 10 high power fields. We examined this tumor immunohistochemically and ultrastructurally and reviewed the articles to identify the histogenesis. Positive reaction for vimenin and cytokeratin of stromaltype spindle cells and presence of desmosome-like structures and tonofilaments on electron microscopic examination suggested the epithelial origin of the stromaltype spindle cells.