Relationship between the type of hormone replacement therapy and incidence of breast cancer in Korea.

OBJECTIVE: This study aimed to investigate the relationship between hormone replacement therapy (HRT) types and breast cancer (BC) incidence in postmenopausal women in Korea. METHODS: The nested case-control study used data from the National Health Insurance Service database. Among the women aged ≥50 years who menopaused between 2004 and 2007, BC incidence up to 2017 was analyzed in 36,446 women using or having used HRT for >1 year and in 36,446 women who did not use any HRT for more than 1 year. HRT types and duration were classified into three categories. RESULTS: BC risk (BCR) decreased with tibolone use for all ages. With HRT initiation in women aged ≥50 years, BCR was lower with tibolone and estrogen-progestogen therapy. HRT for <3 years showed lower BCR with tibolone, while higher BCR was observed with estrogen-only therapy. BCR was lower in women of all ages on HRT for >5 years than in the control group. CONCLUSIONS: For women in their 50s, tibolone use lowers BCR; for all ages, the use of any HRT for >5 years showed lower BCR in Korea. These divergent results from western countries could be associated with the specific characteristics of BC in Korea.

Impact of QuickFISH in addition to antimicrobial stewardship on vancomycin use and resource utilization in cancer patients with coagulase-negative staphylococcal blood cultures.

OBJECTIVE: To evaluate the impact of rapidly identifying coagulase-negative staphylococci (CoNS) from positive blood cultures combined with an established antimicrobial stewardship (AS) programme at a tertiary cancer centre. METHODS: We compared cancer patients ≥18 years old who between 01/1/13 and 12/31/13 had one or more positive CoNS blood culture(s) identified by Staphylococcus QuickFISH® (a peptide nucleic acid fluorescence in situ hybridization assay) with cancer patients ≥18 years old who had CoNS identified by standard microbiological techniques between 01/01/11 and 12/31/11 (baseline). Positive blood culture results were reported to the clinician by microbiology staff; restricted antibiotics (e.g., vancomycin) required approval by the AS team. RESULTS: There were 196 baseline and 103 QuickFISH patients. Faster median time to organism identification (33 (IQR 27-46) versus 49 (IQR 39-63) hours, p < 0.001), more vancomycin avoidance (51/103 (50%) versus 60/196 (31%), p 0.002), shorter median antibiotic duration (1 (IQR 0-3) versus 2 (IQR 0-6) days, p 0.019), fewer central venous catheter (CVC) removals (14/78 (18%) versus 57/160 (36%), p 0.004), and reduced vancomycin level monitoring (16/52 (31%) versus 71/136 (52%), p 0.009) were observed in the QuickFISH group. QuickFISH implementation was predictive of a lower likelihood of antibiotic therapy prescription (OR 0.35, 95%CI 0.20-0.62, p < 0.001). Prior transplant (RR 1.47, 95%CI 1.13-1.92, p 0.004), neutropenia (RR 1.47, 95%CI 1.09-1.99, p 0.012), multiple positive blood cultures (RR 4.23, 95%CI 3.23-5.54, p < 0.001), and CVC (RR 1.60, 95%CI 1.02-2.53, p 0.043) were independent factors for antibiotic duration. CONCLUSIONS: QuickFISH implementation plus AS support leads to greater avoidance of vancomycin therapy and improved resource utilization in cancer patients with CoNS blood cultures.

The effect of prolonged breast-feeding on the development of postmenopausal osteoporosis in population with insufficient calcium intake and vitamin D level.

UNLABELLED: Breast-feeding affects bone metabolism and calcium homeostasis, and prolonged breast-feeding may influence the development of postmenopausal osteoporosis, particularly in highly susceptible populations. The study determined that breast-feeding may be a risk factor for postmenopausal osteoporosis, especially in people with low calcium intakes and vitamin D deficiencies. INTRODUCTION: The purpose of this study was to determine whether breast-feeding is a risk factor in the development of postmenopausal osteoporosis, especially in highly susceptible population. METHODS: The study was performed using data from the 2010 to 2011 Korea National Health and Nutrition Examination Survey, and it included 1231 postmenopausal women who were aged between 45 and 70 years. Osteoporosis was defined using the World Health Organization's T-score criteria, namely, a T-score of ≤-2.5 at the femoral neck or the lumbar spine. The patients' ages, body mass indexes, daily calcium intakes, serum vitamin D levels, exercise levels, smoking histories, and reproductive factors relating to menarche, menopause, delivery, breast-feeding, hormone treatment, and oral contraceptive use were evaluated. Comparisons between the osteoporosis and non-osteoporosis groups were undertaken using Student's t test and the chi-square test, and logistic regression models were built. RESULTS: A significant increase in the risk of osteoporosis was apparent in postmenopausal women with prolonged breast-feeding histories (≥24 months) (model 1: odds ratio [OR] = 2.489; 95 % confidence interval [CI] = 1.111 to 5.578, p = 0.027; model 2: OR = 2.503; 95 % CI = 1.118 to 5.602, p = 0.026; model 3: OR = 2.825; 95 % CI = 1.056 to 7.56, p = 0.039), particularly in those with inadequate serum vitamin D levels and calcium intakes (<800 mg/day). CONCLUSIONS: Breast-feeding seems to increase the risk of postmenopausal osteoporosis; however, its impact may not be definitive in women with sufficient vitamin D levels and calcium intakes. Therefore, sufficient calcium intakes and adequate vitamin D levels may be important to prevent osteoporosis in postmenopausal women that is derived from breast-feeding.

Legionella jordanis in hematopoietic SCT patients radiographically mimicking invasive mold infection.

Opportunistic pulmonary infections are a major cause of post-transplant morbidity and mortality. Among these infections, Aspergillus is a common cause of fatal pneumonia. Owing to the precarious clinical condition of many patients who acquire invasive mold infections, clinicians often treat them on the basis of radiographic findings, such as the halo sign. However, in patients who do not respond to treatment or who have uncommon presentations, bronchoscopy or lung biopsy looking for other pathogens should be considered. This study describes two cases in which the radiographic halo signs characteristic of Aspergillus were in fact due to Legionella jordanis, a pathogen that has been culture proven only in two patients previously (both of whom had underlying lung pathology) and diagnosed by serologic evidence in several other patients. In immunocompromised patients, Legionella can present as a cavitary lesion. Thus, presumptive treatment for this organism should be considered in post-transplant patients who do not have a classic presentation for invasive fungal infection and/or who fail to respond to conventional treatment. These cases illustrate the importance of obtaining tissue cultures to differentiate among the wide variety of pathogens present in this patient population.

TXNIP potentiates Redd1-induced mTOR suppression through stabilization of Redd1.

The mammalian target of rapamycin (mTOR) is a highly conserved serine-threonine kinase activated in response to growth factors and nutrients. Because of frequent dysregulation of the mTOR signaling pathway in diverse human cancers, this kinase is a key therapeutic target. Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex. In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein. Redd1 and TXNIP expression was induced by a synthetic glucose analog, 2-deoxyglucose (2-DG). Moreover, Redd1 expression in response to 2-DG was regulated by activating transcription factor 4 (ATF4). Overexpression of TXNIP was associated with reduced mTOR activity mediated by an increase in Redd1 level, whereas knockdown of TXNIP using small interfering RNA resulted in recovery of mTOR activity via downregulation of Redd1 during treatment with 2-DG. Interestingly, Redd1 was additionally stabilized via interactions with N-terminal-truncated TXNIP, leading to suppression of mTOR activity. Our results collectively demonstrate that TXNIP stabilizes Redd1 protein induced by ATF4 in response to 2-DG, resulting in potentiation of mTOR suppression. To the best of our knowledge, this is the first study to identify TXNIP as a novel member of the mTOR upstream that acts as a negative regulator in response to stress signals.

Hepatic safety of voriconazole after allogeneic hematopoietic stem cell transplantation.

Voriconazole is increasingly used in allogeneic hematopoietic stem cell transplantation (HSCT) for prophylaxis and treatment of fungal infections. Hepatic dysfunction is common in patients undergoing HSCT and may have an impact on the clinical decision to institute voriconazole. We conducted a retrospective review of all adult and pediatric HSCT recipients who received >2 consecutive doses of voriconazole between January 2005 and February 2008. Clinical hepatotoxicity was defined as the subjective attribution of liver enzyme elevation (even a mild one) to hepatotoxicity because of voriconazole by the treating physician and leading to discontinuation of voriconazole. Biochemical hepatotoxicity was defined as an elevation in one or more liver enzymes to >3 times the upper limit of normal or >3 times the baseline value if abnormal at baseline. Liver enzymes assessed included aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin. Simple and multiple logistic regressions were used to define the risks for hepatic dysfunction. The Wilcoxon signed-rank test was used to assess the differences in liver function test values before, during, and after the use of voriconazole. Sixty-eight of 200 patients (34%) developed hepatotoxicity while on voriconazole. The median duration of voriconazole therapy was 72 days (range, 1-804 days). Biochemical hepatotoxicity occurred in 51 patients (75%); clinical hepatotoxicity, in 17 patients (25%). Thirty-five (51%) of the patients with hepatotoxicity required discontinuation of therapy. In simple logistic regression, acute graft-versus-host disease (GVHD) was a risk factor for hepatotoxicity, and receipt of a T-cell depleted allograft was protective. In multiple logistic regression, acute GVHD (P = .002) remained significant. There were no cases of liver failure or death attributed to voriconazole. In this cohort of patients undergoing allogeneic HSCT, the rate of hepatotoxicity while on voriconazole was 34%. In general, the hepatic dysfunction was mild and reversible. Voriconazole therapy with monitoring appears to be reasonably safe for use in HSCT recipients at high risk for invasive fungal infections.

Upregulation of the NNP-1 (novel nuclear protein-1, D21S2056E) gene in keloid tissue determined by cDNA microarray and in situ hybridization.

BACKGROUND: A keloid results from excessive collagen deposition, the cause of which remains elusive. A thorough understanding of the pathophysiology of keloid tissue can help determine the most appropriate treatment strategy. OBJECTIVES: To assess the differences in gene expression between keloids and adjacent normal skin in order to define the genes involved in keloid formation. METHODS: Three Korean patients with keloids underwent excision of the keloid and adjacent normal skin, which was used as the control. We investigated expression patterns of genes in the keloids and the normal skin using cDNA microarray and in situ hybridization techniques. RESULTS: Nine genes in the keloid tissue were consistently upregulated over the 2.0 ratio compared with the normal control from the cDNA microarray composed of 3063 clones: collagen type I alpha1 (NM_000088), DNA segment on chromosome 21 (unique) 2056 expressed sequence (D21S2056E, NNP-1, NM_003683), suppressor of Ty 5 homologue (NM_003169), phosphoglycerate dehydrogenase (NM_032692), adenosine triphosphate synthase beta (NM_001686), serine (or cysteine) proteinase inhibitor, clade H (heat shock protein 47, NM_001235), LIV-1 protein, oestrogen regulated (LIV-1, NM_012319), interleukin-11 receptor alpha (IL11RA, NM_004512) and carbonyl reductase 3 (CBR3, NM_001236). From the in situ hybridization study, the staining signals in the keloid tissue hybridized with anti sense probes of NNP-1 mRNA were stronger than signals in normal controls. Further, endothelial epithelium, but not the epidermis, expressed the signal equally in both keloid and normal control tissue. CONCLUSIONS: We identified nine upregulated genes in keloid tissue using cDNA microarray. Of the nine, the NNP-1 gene was confirmed by topological information using the in situ hybridization technique. We conclude that these nine genes, especially NNP-1, probably contribute either directly or indirectly to keloid formation.

Murine keratocytes function as antigen-presenting cells.

Keratocytes express MHC class I molecules constitutively, and keratocytes stimulated with IFN-gamma express MHC class II molecules. Unstimulated keratocytes constitutively express B7-1 and ICAM-1, as well as low levels of CD40 and 4-1BBL. These findings indicate that keratocytes may deliver both antigen-specific and costimulatory signals to CD4(+) and CD8(+) T cells. To demonstrate that keratocytes expressing B7-1 provide a costimulatory signal to T cells, CD4(+) or CD8(+) mouse T cells were incubated with anti-CD3 mAb and irradiated keratocytes. Enhanced proliferation of both CD4(+) and CD8(+) T cells occurred, and could be inhibited by anti-B7-1 mAb, indicating T cell costimulatory activity by B7-1 on the keratocytes. To demonstrate that keratocytes can deliver an antigen-specific signal, CD4(+) and CD8(+) T cells from herpes-infected mice were incubated with HSV-1-infected, irradiated keratocytes. The resulting T cell proliferation and production of Th1 cytokines (IL-2, IFN-gamma) indicated T cell activation by antigens presented by the infected keratocytes. These results show that keratocytes in the corneal stroma of the mouse can function as antigen-presenting cells and, thus, may play a role in immune-mediated stromal inflammation such as herpetic stromal keratitis.

Lichenoid sarcoidosis in a 3-year-old girl.

We report a case of lichenoid sarcoidosis in a 3-year-old girl. She had numerous discrete skin-colored or erythematous, infiltrated follicular papules on the buttocks and extremities since 2 months of age. Histopathologic examination showed follicular plugging and an upper dermal granulomatous infiltrate of epithelioid cells closely surrounding the follicular ducts. No acid-fast bacilli were seen in the sections examined. Chest radiograph and high-resolution computed tomography (CT) showed no hilar lymphadenopathy or pulmonary parenchymal changes. An angiotensin-converting enzyme level was elevated. The Mantoux reaction was negative and results of ophthalmologic examinations were normal. Treatment was started with triamcinolone 0.2 mg/kg and prednicarbate ointment. Some lesions healed completely and others showed residual pitting.

Cytomegalovirus ventriculoencephalitis in a bone marrow transplant recipient receiving antiviral maintenance: clinical and molecular evidence of drug resistance.

We describe a case of CMV ventriculoencephalitis in a severely immunocompromised bone marrow transplant recipient who was receiving combination therapy with ganciclovir and foscarnet for treatment of viremia and retinitis. Analysis of sequential viral isolates recovered from the patient's cerebrospinal fluid suggested that disease developed because of the presence of viral resistance and, possibly, low tissue penetration of antiviral agents.

4-1BB: still in the midst of darkness.

4-1BB is a member of the tumor necrosis factor receptor superfamily. The receptor functions mainly as a costimulatory molecule in T lymphocytes. In addition, several lines of evidence have shown that interactions between 4-1BB and its ligand are involved in the antigen presentation process and the generation of cytotoxic T cells. Recent studies, however, have demonstrated that 4-1BB plays more diverse roles: Signals through 4-1BB are important for long-term survival of CD8+ T cells and the induction of helper T cell anergy. Clinically, there is great interest in 4-1BB, because T-cell activation induced by anti-4-1BB monoclonal antibodies is highly efficient in the eradication of established tumor cells in mice. Now, since mice deficient in 4-1BB or the 4-1BB ligand are available, subtle roles played by 4-1BB may be revealed in the near future.

Kasabach-Merritt syndrome: identification of platelet trapping in a tufted angioma by immunohistochemistry technique using monoclonal antibody to CD61.

Kasabach-Merritt syndrome (KMS) consists of large and rapidly growing vascular tumors associated with thrombocytopenia, generalized petechiae, and bleeding. The cause of the thrombocytopenia is thought to be related to the trapping of platelets by the abnormal endothelium of the tumor. We report an infant with KMS that developed in association with a large tufted angioma. In this case we directly demonstrated platelet trapping in the vascular lumen of the tumor by an immunohistochemical technique using a monoclonal antibody against CD61, a marker of platelets and megakaryocytes.