The Effect of Reproductive Factors on Breast Cancer Presentation in Women Who Are BRCA Mutation Carrier.

PURPOSE: Germline mutations in the BRCA1 and BRCA2 genes confer increased risks for breast cancers. However, the clinical presentation of breast cancer among women who are carriers of the BRCA1 or BRCA2 (BRCA1/2 carriers) mutations is heterogenous. We aimed to identify the effects of the reproductive histories of women with the BRCA1/2 mutations on the clinical presentation of breast cancer. METHODS: We retrospectively analyzed clinical data on women with proven BRCA1 and BRCA2 mutations who were recruited to the Korean Hereditary Breast Cancer study, from 2007 to 2014. RESULTS: Among the 736 women who were BRCA1/2 mutation carriers, a total of 483 women had breast cancers. Breast cancer diagnosis occurred at significantly younger ages in women who experienced menarche at ≤14 years of age, compared to those who experienced menarche at >14 years of age (37.38±7.60 and 43.30±10.11, respectively, p<0.001). Additionally, the number of full-term pregnancies was significantly associated with the age of diagnosis, especially in women with the BRCA2 mutation. The prevalence of advanced stages (stage II or III vs. stage I) of disease in parous women was higher than in nulliparous women (68.5% vs. 55.2%, p=0.043). This association was more pronounced in women with the BRCA2 mutation (hazard ratio, 2.67; p=0.014). CONCLUSION: Our results suggest that reproductive factors, such as the age of onset of menarche and the presence of parity, are associated with the clinical presentation patterns of breast cancer in BRCA1/2 mutation carriers.

Suggestion of BRCA1 c.5339T>C (p.L1780P) variant confer from 'unknown significance' to 'Likely pathogenic' based on clinical evidence in Korea.

PURPOSE: We describe a rationale for the re-classification of the BRCA1 c.5539T>C (L1780P) variant using a clinical evidence. METHODS: A retrospective review was conducted to identify all patients with breast or ovarian cancer and the L1780P variant between 2002 and 2015 at a single institution. RESULTS: We identified the BRCA1/2 genetic mutation test results of 1223 breast cancer patients and 174 patients with ovarian cancer. Of the 160 BRCA 1/2 variant unknown significance, 16 (10.0%) patients were identified as having the L1780P variant. Among them, 10 had breast cancer, 4 had ovarian cancer, and 2 had both breast and ovarian cancer. Thirteen (81.3%) patients with this variant had family histories of breast or ovarian cancer. Two (16.7%) also had comorbid ovarian cancer. Two patients with this variant showed that co-segregation of the disease in multiple family members and family histories of breast and ovarian cancer. This variant was found to be either absent or at extremely low frequency in general population databases. CONCLUSION: The L1780P variant might confer to "Likely pathogenic" according to a clinical evidence and the ACMG standards and guidelines. A nation-wide or global survey and a functional analysis are needed to confirm the pathogenicity of the L1780P variant.

Reliability and validity of the Korean version of Pediatric Voice Handicap Index: in school age children.

OBJECTIVE: The aim of this study was to assess the reliability and validity of the Pediatric Voice Handicap Index (pVHI) for cross-cultural adaptation of the Korean version with school age children. METHODS: The questionnaire was translated into Korean and was completed by 101 Korean parents who have children with or without disordered voice. The Korean version-pVHI scores were obtained with 60 parents of normal children and 41 parents who have children with voice problems. Content validity was verified by five experienced speech-language pathologists with clinical specialization in voice disorders. Internal consistency was calculated through Cronbach's α coefficient and test-retest reliability of the Korean version-pVHI score was determined using Pearson product-moment correlation coefficients. Mann-Whitney U test was used to compare GRBAS with the Korean version-pVHI scores between normal and dysphonia group. The relationship between the parent-reported the Korean version-pVHI total scores and perceptual ratings of voice quality from experts was investigated using Spearman correlation coefficients. RESULTS: The results showed that the Korean version-pVHI provided a high internal consistency (α=0.92) and test-retest reliability of its subscales: total (T) 0.97, functional (F) 0.90, physical (P) 0.95, emotional (E) 0.92. The Korean version-pVHI mean scores in normal group were 1.28 (T), 0.62 (F), 0.35 (P) and 0.32 (E), respectively whereas those of the Korean version-pVHI in children group with dysphonia were 23.13 (T), 8.90 (F), 9.54 (P) and 4.93 (E). Significant differences in the Korean version-pVHI (T, F, P, E) and perceptual evaluation (grade, rough, breathy) between normal and dysphonia group were revealed (P<0.05). Moreover, relatively moderate-to-high correlation between the Korean version-pVHI parameters (T) and perceptual measures (G) was exhibited in children with dysphonia. CONCLUSIONS: The subjective Korean version-pVHI can be applicable and useful supplementary tool for evaluating parents' perception of their children's voice dysfunction, identifying multifactors on daily life affecting their children's voice and measuring treatment efficacy before and after therapeutic intervention.

Clinical and histologic response to methylprednisolone pulse therapy in glomerulonephritis.

We retrospectively analyzed the data of the first and second renal biopsies to investigate the adverse effects as well as the clinical and histologic responses of methylprednisolone pulse therapy in patients with chronic glomerulonephritis. At the time of the second renal biopsy, the activity index had decreased significantly and the chronicity index was well preserved. The activity index and interstitial fibrosis were improved in the complete and partial remission groups, but not in the nonresponse group. These findings indicate that methylprednisolone pulse therapy is effective in patients with chronic glomerulonephritis and has an acceptably low risk of side effects.

Necrotizing fasciitis in a neonate - the role of keratinocyte allografts.

The authors report the case of a 9-day-old female infant with necrotizing fasciitis of the lower back due to methicillin-resistant Staphylococcus aureus (MRSA) to emphasize the role of keratinocyte allografts. Keratinocyte allografts were found helpful in this case to manage an extensive skin defect.

Remission of refractory minimal change nephrotic syndrome after basiliximab therapy.

Minimal change nephrotic syndrome has been proposed to be a disorder of T cell dysfunction. It is hypothesized that a circulating factor(s) from activated T cells might alter glomerular permeability to protein. Some studies have provided evidence that up-regulation of interleukin-2 may be involved, not only in the pathophysiology of minimal change nephrotic syndrome, but also in steroid resistance. Basiliximab, an anti-interleukin-2 receptor antibody, is indicated for the prophylaxis of acute organ rejection in adults and children with kidney transplants. Clinical trials have shown that basiliximab is effective and well tolerated. We describe here a pediatric patient who continuously had massive proteinuria and hypoalbuminemia for 5 years, despite pulse therapy with methylprednisolone and cyclophosphamide and prolonged oral treatment with cyclosporine and mizoribine. He had experienced several disease- and treatment-associated complications, such as bacterial infections, indirect inguinal hernias, and cataracts. After he had been given a single dose of basiliximab, he achieved complete remission of proteinuria and then discontinued all immunosuppressant treatment.

The accuracy of preoperative core biopsy in determining histologic grade, hormone receptors, and human epidermal growth factor receptor 2 status in invasive breast cancer.

BACKGROUND: Proper determination of histologic type and biomarkers in a core biopsy specimen is important before preoperative systemic therapy. The purpose of this study was to determine the accuracy of preoperative core biopsy through comparative analysis of histologic grade (HG), hormone receptors, and human epidermal growth factor receptor 2 (HER-2) status in both the core biopsy and surgical specimens. METHODS: We identified 104 patients with invasive ductal cancer who underwent core biopsy and definitive surgery in our institution. The histologic type, HG, estrogen receptor (ER), progesterone receptor (PR), and HER-2 status were determined in both the core biopsy and surgical specimens by one pathologist. RESULTS: The mean age of the 104 patients was 50 +/- 9.9 years and the mean number of core biopsies was 5.1 +/- .9. The concordance rates for histologic type, HG, ER, PR, and HER-2 status were 100%, 80.8%, 99%, 97.1%, and 86.5%, respectively. CONCLUSIONS: Core biopsy can predict histologic type, HG, ER, PR and HER-2 status preoperatively in breast cancer when used properly.

Activated Akt signaling pathway in invasive ductal carcinoma of the breast: correlation with HER2 overexpression.

Akt/PKB is a serine/threonine kinase that plays a crucial role in cell survival and apoptosis. Aberrant activation of pAkt is associated with various malignant human cancers, including breast carcinoma. In vitro studies show that pAkt activation is mediated by estrogen and acts as a downstream effector of HER2 with implications in breast cancer progression and drug resistance. We investigated the incidence of Akt activation in invasive ductal carcinoma and its correlation with other clinicopathological variables. Using tissue microarray technology, immunohistochemical expression of phosphorylated Akt (pAkt) at Ser-473 was evaluated in 127 cases of invasive ductal carcinomas, together with hormone receptors, HER2, p53, Ki-67 and other clinicopathological variables. Both nuclear and cytoplasmic expression was noted for pAkt, with 46 cases (36.2%) showing high cytoplasmic pAkt expression and 37 cases (29.1%) showing high nuclear pAkt expression. There was a significant association between both high cytoplasmic and nuclear pAkt expression with HER2 overexpression (both p<0.0001). There was also a positive correlation between high nuclear pAkt expression with both estrogen receptor and progesterone receptor status (p=0.042 and p=0.015, respectively). High cytoplasmic pAkt expression was associated with high Ki-67 expression (p=0.052), however, there was no association between pAkt and p53 expression. In the present study, activation of the Akt pathway shows strong association with HER2 overexpression, which is consistent with many in vitro studies. Our study also showed a positive correlation between pAkt and hormone receptors, which suggested the possible mechanism of endocrine resistance in ER-positive breast cancer. These results also suggest the prognostic value of pAkt and its importance in the prediction of therapeutic response in invasive ductal carcinoma of the breast.

Resistance to Fas-mediated apoptosis is restored by cycloheximide through the downregulation of cellular FLIPL in NK/T-cell lymphoma.

Extranodal NK/T-cell lymphoma (NKTL), nasal type, is a highly aggressive neoplasm and is strongly associated with Epstein-Barr virus (EBV). In this study, we demonstrate that EBV-positive NKTL cell lines, namely, Hank-1, NK-YS, and NK-L, are resistant to Fas-mediated apoptosis induced by anti-Fas antibodies despite high levels of Fas surface expression and no mutation in the Fas gene. Fas stimulation of Hank-1 and NK-YS cells showed little processing of caspase 8, caspase 3, or bid, although the proximal signaling molecules of the death-inducing signaling complex, namely, Fas, Fas-associated protein with a death domain, caspase 8, and bid were present in these cells. Consistent with previous reports on the hypermethylation of death associated protein (DAP) kinase in NKTLs, the promoter of DAP kinase was methylated and its mRNA not detected in Hank-1 cells. However, the restoration of DAP kinase expression by 5-aza-2'-deoxycytidine did not sensitize Hank-1 to Fas-mediated apoptosis, indicating that DAP kinase deficiency does not contribute to resistance to Fas-mediated apoptosis. Since etoposide-induced apoptosis involved caspase 3 activation in Hank-1 and NK-YS cells, the caspase 3-dependent apoptotic machinery appears to be intact. Interestingly, cotreatment of Hank-1 with cycloheximide, a protein synthesis inhibitor, markedly sensitized cells to Fas-mediated apoptosis along with caspase 8 activation and c-FLIP(L) (cellular FLICE inhibitory protein long form) downregulation. Moreover, immunohistochemistry on paraffin-embedded tissue revealed c-FLIP expression in 39% (14 of 36) of NKTL patients. Taken together, these findings indicate that c-FLIP(L)-mediated resistance to Fas contributes to the development and progression of NKTLs. This study also suggests that agents capable of downregulating c-FLIP(L) could be used to treat NKTL.

The clinical use of staging bone scan in patients with breast carcinoma: reevaluation by the 2003 American Joint Committee on Cancer staging system.

BACKGROUND: Using the new 2003 American Joint Committee on Cancer (AJCC) staging system, the authors evaluated the usefulness of the staging bone scan in patients with primary breast carcinoma. METHODS: The authors examined 1939 patients with primary breast carcinoma for staging bone scan who were treated at a single institution. Pathologic stage was assigned retrospectively according to the 1988 and the 2003 AJCC staging systems. RESULTS: Bone metastasis rates were 0.7% (4 of 586) for patients with Stage I disease, 0.7% (5 of 699) for patients with Stage IIA disease, 2.1% (10 of 479) for patients with Stage IIB disease, 4.5% (7 of 154) for patients with Stage IIIA disease, and 10.5% (2 of 19) for patients with Stage IIIB disease according to the 1988 AJCC staging system. The authors found a significant difference in the bone metastasis rate between patients with Stages IIA and IIB disease in the 1988 staging system (P = 0.039). Reevaluating the patients by the 2003 system resulted in significant upstaging, especially for patients with Stage II/III disease. According to the 2003 staging system, bone metastasis rates were 0.7% (4 of 586) for patients with Stage I disease, 0.6% (4 of 648) for patients with Stage IIA disease, 0.6% (2 of 310) for patients with Stage IIB disease, 4.0% (9 of 225) for patients with Stage IIIA disease, 16.7% (2 of 12) for patients with Stage IIIB disease, and 4.4% (7 of 158) for patients with Stage IIIC disease. It was noteworthy that there was a significant difference between Stages IIB and IIIA in the 2003 staging system (P = 0.010). CONCLUSIONS: Stage reclassification using the new AJCC staging system resulted in upstaging of high-risk patients, as well as a significant decrease in the bone metastasis rate in patients with Stage IIB breast carcinoma. Considering the cost-effectiveness of staging bone scan, the data suggested that it was of little value for patients with Stage I and II breast carcinoma, but was highly recommended for patients with worse than Stage III disease by the new 2003 staging system.

Genistein-induced apoptosis via Akt signaling pathway in anaplastic large-cell lymphoma.

More than half of anaplastic large-cell lymphoma (ALCL) are associated with chromosomal translocation t(2;5)(p23;q35) that leads to the expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncoprotein. NPM-ALK activates the antiapoptotic phosphatidylinositol-3 kinase/Akt (PI3K/Akt) signaling pathway, which plays a critical role in cell survival and apoptosis. Inhibition of the PI3K/Akt pathway has been considered as a therapeutic target for cancer where PI3K/Akt activation is a causative factor. Genistein, a natural isoflavonoid found in soy products, has been shown to inhibit cell growth and induce apoptosis in a wide variety of cell lines. Here, we demonstrated that treatment of two t(2;5) ALCL cell lines, SUDHL-1 and Karpas299, with genistein induced apoptosis in a time- and dose-dependent manner. Concurrently, these cells exhibited a decrease in Akt protein levels and subsequent downregulation of Akt activity (Akt phosphorylation). Furthermore, genistein treatment induced mitochondrial membrane potential change, caspase-3 activation and PARP cleavage. From these results, we conclude that inhibition of the Akt signaling pathway and induction of apoptosis by genistein could be used as a new treatment modality for the prevention and/or treatment of t(2;5) ALCL and other hematopoietic malignancies.

Transcriptional regulation of TNF family receptors and Bcl-2 family by chemotherapeutic agents in murine CT26 cells.

Various chemotherapeutic agents have been shown to sensitize cancer cells to members of the tumor necrosis factor (TNF) family. However, it is unclear whether sensitization by chemotherapeutic agents involves the transcriptional regulation of apoptosis-related genes. In this study, we investigated mRNA regulation of TNF family receptors and Bcl-2 family members after treating the murine colon cancer cell line, CT26, with various apoptosis inducers. We found that treatment with cycloheximide, a protein synthesis inhibitor, remarkably increased CD40 mRNA levels by semi-quantitative RT-PCR. Other protein synthesis inhibitors, such as anisomycin and emetine, also enhanced CD40 mRNA expression, which was significantly blocked by a NF-kappaB antagonist and a p38 MAP kinase antagonist. After treatment with cycloheximide, and further cultivation in fresh medium, CD40 protein levels were found to increase by flow cytometry. Additionally, we found that cycloheximide treatment appeared to downregulate the Bcl-xL mRNA level but not the Bax mRNA level by RNase protection assay. Because the upregulation of CD40 mRNA and the downregulation of Bcl-xL correlated with CT26 cell death, our results suggest that chemotherapeutic agents, including cycloheximide, may exert their synergistic effects on the TNF family treatment of cancer cells by regulating the mRNA levels of apoptosis-related genes.

Comparative analysis of NK/T-cell lymphoma and peripheral T-cell lymphoma in Korea: Clinicopathological correlations and analysis of EBV strain type and 30-bp deletion variant LMP1.

Natural killer/T-cell lymphoma (NKTL) and peripheral T-cell lymphomas (PTCL) are prevalent in the Asian population and exhibit a high association with the Epstein-Barr virus (EBV). Moreover, differentiation of these two groups is often difficult and problematic. We investigated 35 cases of NKTL (22 nasal cases and 13 extranasal cases) and 30 cases of PTCL in terms of their clinical features, immunohistology, EBV positivity, EBV strain-type polymorphism and latent membrane protein 1 (LMP1) deletion variant distribution. Eighteen cases (82%) of nasal NKTL and seven (54%) of extranasal NKTL showed EBV positivity by EBV in situ hybridization. Fifteen cases (50%) of PTCL revealed EBV positivity. EBV strain type A was predominant in NKTL (18:5), and EBV strain types A and B were distributed evenly in PTCL (6:6). EBV-positive patients had significantly shorter survival than EBV-negative patients (P < 0.05), and EBV positivity correlated with advanced clinical stage (P < 0.05). Patients harboring type A EBV showed slightly poorer prognoses than those having type B, though it was not obviously statistically different (P = 0.07). The LMP1 deletion variant was prevalent in both NKTL (three wild-type LMP1, 15 deletion variants) and PTCL (three wild-type LMP1, eight deletion variants, two coexistent forms) patients, but did not have prognostic impact. Our results indicate that EBV acts as a negative prognostic factor in NKTL and PTCL, and that the intrinsic properties of a specific viral strain might influence the clinical behavior of these diseases.

Identification of angiogenesis in primary breast carcinoma according to the image analysis.

Tumor angiogenesis may be an independent prognostic factor for breast cancer survival. However, we can get the angiogenic property of the breast cancer only after the removal of breast tissue. To get this information before surgical resection of the tumor, we evaluated 29 breast carcinoma patients with Tc-99m MIBI scintimammography and power Doppler ultrasound (US) with a microbubble contrast agent preoperatively and compare their results with intratumoral microvessel density (IMD) and reverse transcriptase-polymerase chain reaction (RT-PCR) of VEGF mRNA. IMD was well correlated with VEGF121 (r = 0.220, P = 0.024) and VEGF165 (r = 0.419, P = 0.046) mRNA level of the tumor. Power Doppler US grading of the tumor is well correlated with IMD (r = 0.552, P = 0.033). However, early uptake and washout index calculated from Tc-99m MIBI scintimammography showed no correlation with IMD or VEGF mRNA level, while washout index was inversely correlated with power Doppler US grading (r = -0.945, P = 0.001). In conclusion, the preoperative evaluation of breast cancer with power Doppler US with a microbubble contrast agent could predict tumor angiogenesis. Tc-99m MIBI scintimammography needs further study to use it as an image analysis for angiogenesis.