Efficacy of tacrolimus as maintenance therapy after cyclophosphamide for treating antineutrophil cytoplasmic antibody-associated vasculitis

Azathioprine (AZA), methotrexate, or rituximab is used for the maintenance therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Although the efficacy of tacrolimus (TAC) in various autoimmune diseases has been demonstrated, there have been few reports on the efficacy of TAC in AAV. We investigated the efficacy of TAC as maintenance therapy for AAV and compared its efficacy with that of AZA.We retrospectively analyzed the medical records of 81 patients with AAV who received cyclophosphamide as induction therapy and AZA or TAC as maintenance therapy. All-cause death, relapse, and progression to end-stage renal disease (ESRD) were analyzed.Among 81 patients with AAV, 69 patients received AZA alone, 6 patients received TAC alone, and 6 patients received TAC after AZA for maintenance therapy. Overall, 11 patients (13.6%) died, 30 patients (37.0%) experienced relapse, and 16 patients (19.8%) progressed to ESRD during a median of 33.8 months. No significant differences were observed in cumulative patients’, relapse-free, and ESRD-free survival rates between patients administered AZA alone and TAC alone. There were no significant differences in the cumulative patients’ and relapse-free survival rate between patients who received AZA alone and TAC after AZA. However, the cumulative ESRD-free survival rate was lower in patients who received TAC after AZA than in those who received AZA alone (P = .027).Patients who received TAC as maintenance therapy showed a higher incidence of ESRD than those who received AZA; however, this might be attributed to the lack of efficacy of AZA rather than the low ESRD prevention effect of TAC.     

Comorbidities,age and period of diagnosis influence treatment and outcomes in early breast cancer

Survival for breast cancer (BC) is lower in eastern than northern/central Europe, and in older than younger women. We analysed how comorbidities at diagnosis affected whether selected standard treatments (STs) were given, across Europe and over time, also assessing consequences for survival/relapse. We analysed 7581 stage I/IIA cases diagnosed in 9 European countries in 2009–2013, and 4 STs: surgery; breast-conserving surgery plus radiotherapy (BCS + RT); reconstruction after mastectomy; and prompt treatment (≤6 weeks after diagnosis). Covariate-adjusted models estimated odds of receiving STs and risks of death/relapse, according to comorbidities. Pearson's R assessed correlations between odds and risks. The z-test assessed the significance of time-trends. Most women received surgery: 72% BCS; 24% mastectomy. Mastectomied patients were older with more comorbidities than BCS patients (p < 0.001). Women given breast reconstruction (25% of mastectomies) were younger with fewer comorbidities than those without reconstruction (p < 0.001). Women treated promptly (45%) were younger than those treated later (p = 0.001), and more often without comorbidities (p < 0.001). Receiving surgery/BCS + RT correlated strongly (R = −0.9), but prompt treatment weakly (R = −0.01/−0.02), with reduced death/relapse risks. The proportion receiving BCS + RT increased significantly (p < 0.001) with time in most countries. This appears to be the first analysis of the influence of comorbidities on receiving STs, and of consequences for outcomes. Increase in BCS + RT with time is encouraging. Although women without comorbidities usually received STs, elderly patients often received non-standard less prompt treatments, irrespective of comorbidities, with increased risk of mortality/relapse. All women, particularly the elderly, should receive ST wherever possible to maximise the benefits of modern evidence-based treatments.     

Pinus densiflora bark extract ameliorates 2,4‐dinitrochlorobenzene‐induced atopic dermatitis in NC/Nga mice by regulating Th1/Th2 balance and skin barrier function

Korean red pine (Pinus densiflora) bark has been traditionally used in Korea and other parts of East Asia to relieve inflammatory diseases. Although many studies using P. densiflora bark have been reported, its effect on atopic dermatitis (AD) has not been elucidated. Thus, we investigated whether the P. densiflora bark extract (PBE) has potential to attenuate AD symptoms and elucidated the molecular mechanism. Oral administration of PBE to mice with 2,4‐dinitrochlorobenzene (DNCB)‐induced AD lessened dermatitis scores and scratching behavior and significantly reduced measures of epidermal thickness, infiltration of mast cells and eosinophils, levels of immunoglobulin E (IgE), and IgG₁/IgG_2a ratio in serum. PBE not only inhibited IL‐4, IL‐5, and IL‐13 but also increased IFN‐γ in splenic production. Furthermore, PBE significantly suppressed mRNA expression of thymic stromal lymphopoietin and further downregulated the mRNA expression of Th2 and Th17 cytokines such as IL‐4, IL‐13, IL‐17, IL‐31, and TNF‐α. In addition, the protein expressions of filaggrin, involucrin, and loricrin in lesional skin were recovered by PBE. These results suggest that PBE attenuates DNCB‐induced AD via regulating Th1/Th2 balance and skin barrier function.     

Laparoscopic enucleation of a nonfunctioning neuroendocrine tumor of the pancreas

Laparoscopic approaches are increasingly used in pancreatic surgery. In the treatment of neuroendocrine tumors (NETs) of the pancreas, enucleation is one of the recommended surgery. Although many clinical experiences have reported the safety and efficacy of laparoscopic enucleation of functioning NETs, such as insulinomas, few reports have explored such treatment for non-functioning NETs. Here, we present a case of 70-year old female patient who underwent successful laparoscopic enucleation of a nonfunctioning NET located in the body of the pancreas.     

Identification of hepatitis C virus genotype 6 in Korean patients by analysis of 5' untranslated region using a matrix assisted laser desorption/ionization time of flight-based assay, restriction fragment mass polymorphism

Previous surveys of the prevalence of hepatitis C virus (HCV) in Korea have identified types 1 and 2, but little has been said of other genotypes and viral subtypes. In this study, HCV genotypes in Korea were investigated using Restriction Fragment Mass Polymorphism (RFMP) assay, a sensitive and specific method for genotyping based on MALDI-TOF mass spectrometry. A total of 1,043 independent serum samples from HCV-infected patients were analyzed. Of interest, 15 subjects (1.4%) were determined to contain HCV genotype 6 and 46 subjects (4.4%) contained mixed genotypes with the most prevalent genotypes being HCV 1b and 2a/c (45.0% and 35.4%, respectively). The 15 subjects with HCV genotype 6 comprised eight cases of subtype 6c, including one case of mixed infection with 1b, three cases of HCV 6a, and six cases of unassigned subtypes. Sequencing corroborated the identity of genotype 6 from 13 subjects, while the line probe assay (LiPA) mis-identified them as genotype 1b. The majority (7/9) of the genotype 6 patients enrolled for interferon/ribavirin therapy, achieved a sustained virologic response. The ability of the RFMP assay to differentiate various HCV genotypes should enable better analysis of the relationship between HCV genotype and disease prognosis.     

Gene expression of <Emphasis Type="Italic">Clonorchis sinensis</Emphasis> metacercaria induced by gamma irradiation

Gamma-rays are a form of ionizing radiation and produce serious cellular damage to nuclei and organelles. Gamma irradiation induces the expressions of genes involved in DNA repair. Clonorchis sinensis resides in and provokes pathophysiologic changes in the bile ducts of mammals. The C. sinensis metacercariae are unsusceptible or resistant to gamma irradiation with LD₅₀ of 16.5 Gy. Using the annealing control primer-based polymerase chain reaction (PCR) method, 19 genes were found to be up-regulated in C. sinensis metacercariae exposed to gamma rays. Contigs of up-regulated genes (URGs) were retrieved in a C. sinensis expressed sequence tag pool and extended by DNA-walking. Of the 13 URGs annotated putatively as functional genes, five URGs were associated with energy metabolism, six with protein processing, and the other two with DNA repair protein RAD23 and inhibitor of apoptosis protein. Four URGs were confirmed up-regulated by gamma irradiation by quantitative real-time PCR. One unknown gene, which was up-regulated to the greatest extent, might contribute to early recovery from gamma-irradiation-induced damage. The up-regulations of genes encoding DNA repair, protein processing, and energy metabolism proteins suggests that increases in gene products orchestrate DNA lesion repair and recover cellular functions in gamma-irradiated C. sinensis metacercariae.     

Poly I:C-induced anti-herpes simplex virus type 1 activity in inflammatory macrophages is mediated by induction of interferon-beta.

We examined the mechanism by which Polyriboinosinic:Polyribocytidylic acid (Poly I:C) augments resistance of thioglycolate-elicited inflammatory macrophages to infection with herpes simplex virus type 1 (HSV-1). We show that Poly I:C-induced antiviral activity is completely abrogated by antibodies to interferon-beta (IFN-beta) whereas antibodies to other interferons or to other cytokines have no effect. Furthermore, treatment of inflammatory macrophages with exogenous IFN renders them resistant to HSV-1, whereas treatment with other cytokines does not. In addition, we demonstrate that supernatants from macrophages treated with Poly I:C contain IFN-beta but not IFN-alpha. Taken together these data indicate that the antiviral effects of Poly I:C in inflammatory macrophages are mediated solely by IFN-beta, which acts in an autocrine manner to induce resistance to HSV-1.