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Objective Oral lichen planus (OLP) displays various and complicated clinical presentations which often make their differential diagnosis challenging, and thus helpful clinical practice guidelines for the diagnosis and treatment of OLP have been long awaited. Methods The Japanese OLP Working Group (OLP-WG) has collected and analyzed a total of 393 OLP cases provided by 48 institutions nationwide from 2009 to 2011 toward the establishment of valuable clinical practice guidelines for OLP. Collected samples were classified according to their original diagnoses into three groups: bilateral reticular (Group 1); bilateral atrophic/erosive (Group 2); and unilateral (Group 3) buccal lesions. Ten OLP-WG members used intraoral pictures to categorize the cases into Andreasen’s six types, and then examined the biopsy specimens to make pathological and comprehensive diagnoses. Results When Andreasen’s reticular, plaque, and papular types were sorted into white (W) type, and when atrophic, erosive, and bullous types were sorted into red (R) type, they formed six clusters based on the number of the members’ judgments: W1 (W dominant), W/R (W-R competing), R1 (R dominant), UD (undeterminable dominant), W2 (boundary), and R2 (boundary). Both in the bilateral and unilateral lesion groups, proportions of cases which were comprehensively diagnosed as OLP were significantly higher in cluster W1 than those in cluster R1 (p Conclusions These results indicated that the simple W or R classification would be a better substitute for Andreasen’s in the clinical categorization of OLP.

A 69-year-old man, who had been receiving prednisolone for 11 months for treatment of interstitial pneumonia, was diagnosed with acute myeloid leukemia. During induction therapy, he developed severe pneumonia. Although meropenem and micafungin were started, he died of circulatory failure owing to massive gastrointestinal bleeding. Autopsy specimens obtained from the stomach revealed fungal hyphae, which had invaded diffusely into submucosal vessels and caused the massive gastric bleeding. The same hyphae were also observed in both lungs. A diagnosis of disseminated zygomycosis was confirmed by its characteristic histopathological findings. Because zygomycetes are spontaneously resistant to the newer antifungal agents, such as voriconazole or micafungin, it seems likely that the prevalence of zygomycosis as a breakthrough infection may increase in the future. Zygomycosis is a rare, but life-threatening, deep fungal infection that appears in immunologically or metabolically compromised hosts. Its manifestations are clinically similar to those of invasive aspergillosis. In addition to the well-established epidemiology of zygomycosis, this case suggests the following new characteristics. (1) Although the gastrointestinal manifestation of zygomycosis is relatively rare, it is observed more frequently than invasive aspergillosis. (2) Gastrointestinal zygomycosis occasionally leads to the development of necrotic ulcers and may induce hemorrhagic shock.(3) We should be cautious of an occurrence of breakthrough zygomycosis when we use echinocandins for patients with known risk factors, especially steroid use and neutropenia. (4) For patients who are receiving broad-spectrum antibiotics and echinocandins, who are negative for culture studies and aspergillus antigen, and who present with unresolved fever, it is important to make a prompt clinical diagnosis of zygomycosis.

A 67-year-old woman with systemic lupus erythematosus (SLE) was admitted to our hospital because of lupus nephritis. Methylprednisolone minipulse therapy dramatically reduced her proteinuria; however; she then complained of general fatigue with low-grade fever. Radiological and culture studies revealed no infectious focus, but she was treated with meropenem and micafungin, considering her immunosuppressive state. Cytomegalovirus antigenemia was later determined and ganciclovir was added. She became afebrile, but complained of nausea and headache, and disorientation, without meningeal signs. Because a brain computed tomography (CT) scan showed no abnormality, we initially suspected some kind of drug interaction. Despite the discontinuation of all drugs, however, she still suffered from disturbance of consciousness. A lumbar puncture revealed yeast cells stained by India ink. A diagnosis of cryptococcal meningitis was confirmed. Though fluconazole and meropenem were administered, the patient died. Autopsy findings revealed disseminated cryptococcosis concomitant with pulmonary aspergillosis. Micafungin is a recently approved echinocandin-class antifungal agent that is now widely used in Japan because of its minimal toxicity and broadspectrum activity. However, such echinocandins have limited activity against a number of fungi. Indeed, breakthrough trichosporonosis is becoming a significant problem in patients with hematological malignancies who are receiving echinocandins. To the best of our knowledge, breakthrough cryptococcosis, as seen in our patient, has not been reported previously in patients who were receiving micafungin as an empiric antifungal therapy. This case highlights that cryptococcosis should be kept in mind as a possible breakthrough infection during the administration of echinocandins, especially in patients with cellular immunodeficiency.

Peptidoglycan recognition proteins (PGRPs), a novel family of pattern recognition molecules involved in innate immunity conserved from insects to mammals, recognize bacterial cell wall peptidoglycan (PGN) and have been suggested to act as anti-bacterial factors. In humans, four kinds of PGRPs (PGRP-L, -Iα, -Iβ and -S) have been cloned and all four of them bind PGN. Chemically synthesized pathogen-associated molecular patterns (PAMPs) in bacterial cell surface components (synthetic lipopeptide [TLR2 agonist], synthetic lipid A [TLR4 agonist], synthetic iE-DAP [NOD1 agonist], and muramyldipeptide [MDP, NOD2 agonist]) markedly upregulated the mRNA expressions of the four PGRPs and cell surface expressions of PGRP-Iα and -Iβ, but did not induce either mRNA expression or the secretion of inflammatory cytokines in oral epithelial cells. Suppression of the expressions of TLR2, TLR4, NOD1 and NOD2 by RNA interference specifically inhibited the upregulation of PGRP mRNA expression induced by lipopeptide, lipid A, iE-DAP and MDP, respectively. In addition, these PAMPs definitely activated nuclear factor (NF)-κB in the epithelial cells, and suppression of NF-κB activation clearly prevented the induction of PGRP mRNA expression induced by these PAMPs in the cells. These findings suggested that bacterial PAMPs induced the expression of PGRPs, but not proinflammatory cytokines. Although the function of human PGRPs has not been clarified so far, in contrast to insect PGRPs, human PGRPs might be also involved in host defence against bacterial invasion without accompanying inflammatory responses. Further studies are required to elucidate the function of human PGRPs.

To investigate the role of human gingival fibroblasts (HGF) in periodontitis, we examined the expression of interleukin-2 receptor (IL-2R) and IL-15R subunits in HGF from normal and inflamed regions and the role of endogenous IL-15 in IL-2-mediated signaling. Normal HGF expressed IL-2Rβ and common γ-chain (γc) but not IL-2Rα or IL-15Rα, whereas inflamed HGF expressed IL-2Rα, IL-15Rα, IL-2Rβ and γc. Exogenous IL-2 and IL-15 induced production of monocyte chemoattractant protein-1 (MCP-1) but not IL-8 in normal HGF, and induced the production of both chemokines in inflamed HGF. Both HGF constitutively transcribed 48aa-IL-15 isoform, and the isoform existed as a membrane-bound form. Pretreatment with anti-IL-15 neutralizing mAb completely inhibited the production of MCP-1 induced by IL-2 and IL-15 and IL-2-induced phosphorylation of Janus tyrosine kinase 1 and 3 in HGF. The pretreatment and RNA interference targeted to IL-15 mRNA resulted in total inhibition of the IL-2Rβ and γc expression at mRNA and protein levels. Furthermore, inhibition of nuclear factor (NF)-κB abrogated the expression of IL-2Rβ and γc, and IL-2-induced-nuclear translocation of NF-κB was completely inhibited by the RNA interference in HGF. These results suggest that endogenous membrane-bound IL-15 sustains recruitment of IL-2Rβ and γc through activation of NF-κB in HGF.

Lichen planus is a chronic inflammatory disease of the skin and oral mucosa in which the cell-mediated cytotoxicity is regarded as a major mechanism of pathogenesis. To understand its pathophysiology further, the present study examined the in situ expression of chemokines and chemokine receptors in oral lichen planus. Immunohistochemical analysis of 15 cases has consistently revealed that infiltrating CD4+ and CD8+ T cells in the submucosa predominantly expressed CCR5 and CXCR3. Furthermore, infiltrating T cells, particularly CD8+ T cells, were positive for RANTES/CCL5 and IP-10/CXCL10, the ligands of CCR5 and CXCR3, respectively. By immunoelectron microscopy, these chemokines were localized in the cytolytic granules of CD8+ T cells. Lesional keratinocytes also overexpressed the ligands of CXCR3, namely, MIG/CXCL9, CXCL10, and I-TAC/CXCL11. Our data suggest that the chemokines signaling via CCR5 and CXCR3, which are known to be selectively expressed by type 1 T cells, are predominantly involved in T-cell infiltration of oral lichen planus. Furthermore, the presence of CCL5 and CXCL10 in the cytolytic granules of tissue-infiltrating CD8+ T cells expressing CCR5 and CXCR3 reveals a potential self-recruiting mechanism involving activated effector cytotoxic T cells.

Introduction: The double therapy of trastuzumab and pertuzumab (TP) will come into widespread use, because of the beneficial effects on HER2 positive breast cancer. However, we don't have enough information about the safety of TP in Japanese patients. In our hospital, triple therapy of eribulin and TP for previously treated HER2 positive breast cancer is ongoing (UMIN000012018). In this study, we assessed the safety of TP, including the data of participants in the triple therapy trial. Patients and methods: We assessed the safety of 8 patients who were administered TP in our hospital. Adverse events (AEs) were graded according to CTCAE v4.0. Results: Five patients were administered TP with eribulin, three patients were administered TP without cytotoxic agents. The most common AEs were diarrhea (4 patients), leukopenia (3 patients), neutropenia (3 patients), hypokalemia (3 patients), infusion reaction (3 patients), lymphopenia (2 patients), stomatitis (2 patients), skin disorders (2 patients). Hematologic toxicity, diarrhea, hypokalemia, stomatitis were frequently observed in patients who were administered TP with eribulin. Grade 3 AEs were neutropenia (2 patients), leukopenia (1 patient), lymphopenia (1 patient), pathological fracture (1 patient) and middle otitis (1patient). Grade 4/5 AEs were not observed. Conclusions: The TP therapy would be tolerable for Japanese patients. We will report updated results at the meeting.

Aim: Head and neck cancer (HNC) patients have a high incidence of primary esophageal tumor. Moreover, second primary esophageal tumor (SPET) also had a negative impact on survival of HNC patients and previous studies reported that 3-year survival rate of HNC patients with SPET was 0-15%. Therefore, the establishment of optimal management for HNC patients with SPET is crucial. Recent advances in endoscopy such as magnifying endoscopy enabling early detection of esophageal tumor and the novel treatment may lead to improve survival for HNC patients with SPET. Methods: A total of 226 HNC patients who underwent magnifying esophagogastroduodenoscopy at our institute from October 2005 to September 2012 were retrospectively examined in this study. We investigated the incidence of SPET, the difference in the therapeutic outcome between HNC patients with and without SPET and the prognostic value of the presence of SPET in HNC patients. Results: Out of 226 HNC patients, 34 patients (15%) had SPET during their clinical course. The median age was 71 years (range 51 to 88) and 33 patients were male. All patients had squamous cell esophageal carcinoma. The majority of patients (79%) had SPET with stage 0 (26%) or 1(53%) disease. Out of 34 patients with SPET, 10 patients (29%) underwent endoscopic resection for SPET and 10 patients (29%) underwent simultaneous chemoradiation therapy with cisplatin plus continuous infusional 5-fluorouracil for HNC and SPET. The median over survival was 23.9 months in HNC patients with SPET, as compared with 27.0 months in HNC patients without SPET. The 3-years survival rates in HNC patients with SPET and in HNC patients without SPET were 50.9% and 72.0 %, respectively. Multivariate analysis identified the clinical stage of HNC (p = 0.01, hazard ratio 2.36) and the presence of SPET (p = 0.03, hazard ratio 1.9) as significant and independent determinants of overall survival. Conclusions: Our study suggested that although survival of HNC patients with SPET might be considerably improved due to early detection and treatment of SPET, the presence of SPET still remained an independent negative prognostic factor for HNC patients. Disclosure: All authors have declared no conflicts of interest.