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Introduction: Microscopic polyangiitis (MPA) with interstitial lung disease (ILD) has a significant impact on morbidity and mortality. This study evaluated the clinical characteristics, treatment responses, and prognostic factors of patients with ANCA-associated vasculitis with ILD (AAV-ILD) and pulmonary limited vasculitis (PLV)., Patients and Methods: A retrospective chart review of ILD patients positive for MPO-ANCA was conducted from 2008 to 2021. Patients were classified into AAV-ILD or PLV groups. Data included laboratory test results, pulmonary function tests, and high-resolution computed tomography (HRCT) images. Statistical analyses were used to assess group differences and survival outcomes., Results: Of 114 patients, 80 were diagnosed with PLV and 34 with AAV-ILD. The AAV-ILD group had higher corticosteroid treatment rates, higher serum creatinine levels, and better survival than the PLV group. The PLV group had higher KL-6 levels, lower %VC and % FVC in pulmonary function tests. Survival in the PLV group was significantly worse than that in the AAV-ILD group, and survival of patients with an alternative diagnosis on HRCT was better than that of patients with a UIP pattern. Cox regression analysis identified a diagnosis of MPA and HRCT classification as significant prognostic factors., Conclusions: Patients with AAV-ILD had a better prognosis than those with PLV. HRCT patterns, particularly an alternative diagnosis on HRCT, were associated significantly with a favourable prognosis. The efficacy of corticosteroid treatment in PLV patients was limited. These findings highlight the importance of early and accurate diagnosis, as well as careful consideration of treatment strategies, for patients with in MPO-ANCA-positive ILD., Competing Interests: Conflict of interest Y. Miyazaki received a research grant from Nippon Boehringer Ingelheim Co., Ltd; Y. Miyazaki received lecture fees from Nippon Boehringer Ingelheim Co., Ltd; The remaining authors have no conflict of interst., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: The diagnosis of fibrotic hypersensitivity pneumonitis (fHP) from other interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), is often difficult. This study aimed to examine computed tomography (CT) findings that were useful for differentiating between fHP and IPF and to develop and validate a radiological diagnostic model., Methods: In this study, 246 patients (fHP, n = 104; IPF, n = 142) from two institutions were included and randomly divided into the test (n = 164) and validation (n = 82) groups (at a 2:1 ratio). Three radiologists evaluated CT findings, such as pulmonary fibrosis, small airway disease, and predominant distribution, and compared them between fHP and IPF using binomial logistic regression and multivariate analysis. A prognostic model was developed from the test group and validated with the validation group., Results: Ground-glass opacity (GGO) with traction bronchiectasis (TB), honeycombing, hypoattenuation area, three-density pattern, diffuse craniocaudal distribution, peribronchovascular opacities in the upper lung, and random distribution were more common in fHP than in IPF. In multivariate analysis, GGO with TB, peribronchovascular opacities in the upper lung, and random distribution were significant features. The area under the curve of the fHP diagnostic model with the three aforementioned CT features was 0.733 (95% confidence interval [CI], 0.655-0.811, p < 0.001) in the test group and 0.630 (95% CI, 0.504-0.755, p < 0.047) in the validation group., Conclusion: GGO with TB, peribronchovascular opacities in the upper lung, and random distribution were important CT features for differentiating fHP from IPF., Competing Interests: Declaration of competing interest KK received lectures fees from Boehringer Ingelheim. YK received lectures fees from Boehringer Ingelheim. YM received grants from Boehringer Ingelheim, and lectures fees from Boehringer Ingelheim and AstraZeneca. TJ received lectures fees from Bohlinger Ingelheim, AstraZeneca, and Kyorin Inc. The other authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Exposure assessment is integral to the diagnosis of hypersensitivity pneumonitis (HP). Although the clinical relevance of exposed antigens is essential for the assessment, many of the previous guidelines or reports have only evaluated simple exposure histories or immunological tests. To overcome this problem, the Exposure Assessment Form (EAF) was developed as an assessment tool for classifying the exposure grade from G0 to G4. The EAF was modified from the description in the Japanese clinical practice guide 2022 for HP published by the Japanese Respiratory Society., Methods: One hundred and seventy-two consecutive patients with interstitial lung disease who underwent multidisciplinary discussion (MDD) at our hospital were retrospectively examined. We assessed whether the use of the EAF improved the diagnostic performance of the international guideline of HP. We also evaluated whether the exposure grade affected the prognosis of HP., Results: Even when a HP diagnosis was made with a confidence of 70% or higher according to the international guideline, less than half of these cases resulted in a final diagnosis of HP when the exposure grades were lower than G3. When the result of the EAF was integrated into the exposure definition of the international guideline, the specificity of the diagnostic performance improved, while sensitivity was maintained. Furthermore, HP patients with an exposure grade of G3 or higher showed a tendency to take a longer time to initiate medication., Conclusions: This is the first study to evaluate the clinical relevance of possible antigens using the EAF. Assessing the exposure grade prevents overdiagnosis and improves the diagnostic performance of the international guideline., (© 2024. The Author(s).)

Since ancient times, Piper longum Linn. fruits have been recognized for exhibiting various effects, including the diaphoretic effects linked to enhanced blood flow. Piperine and piperlongumine coexist in Piper longum Linn. fruits, although the cardiovascular effects of both compounds remain elusive. We investigated their action of piperine and piperlongumine in porcine coronary arteries, comparing them to the Ca 2+ channel antagonist diltiazem. Piperlongumine, unlike piperine or diltiazem, concentration-dependently inhibited basal contractile tone in endothelium-denuded coronary arteries. All three compounds inhibit tonic contractions induced by high potassium chloride (KCl) concentrations. The order of relaxation potency indexed by the half-maximal effective concentration (EC 50 ) were as follows: diltiazem > piperlongumine > piperine. These effects were not different between endothelium-intact and -denuded preparations. In endothelial-denuded preparations, pretreatment with these compounds not only inhibited KCl-induced tonic contractions attenuated calcium chloride (CaCl 2 )-induced ones in a Ca 2+ -free medium. Histamine-induced phasic contractions in a Ca 2+ -free medium containing intracellular Ca 2+ chelator was completely suppressed by selective inositol trisphosphate receptor antagonist and piperlongumine, whereas piperine or diltiazem do not have the same effect. These findings suggest that piperine and piperlongumine similar to diltiazem cause vasorelaxation by inhibiting both KCl- and CaCl 2 -induced contractions in coronary arteries, possibly through the inhibition of voltage-dependent Ca 2+ channels. Piperlongumine inhibits histamine-induced contractions in a Ca 2+ -free medium, which is associated with the intracellular Ca 2+ signaling pathway, suggesting that the relaxant effect of piperlongumine differs from that of piperine.

Background: Serum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) are candidate diagnostic and activity markers for fibrotic hypersensitivity pneumonitis (HP), although their correlation with prognosis remains unclear. We aimed to evaluate the prognostic usefulness of serum KL-6 and SP-D in patients with fibrotic HP., Methods: This was a retrospective medical record review of 185 patients with fibrotic HP at a single center from 2005 to 2019. The baseline and minimum serum KL-6 and SP-D levels over two years were recorded. The contribution of KL-6 and SP-D levels to the incidence of progressive fibrosing interstitial lung disease (PF-ILD) and mortality were evaluated using multivariate analysis., Results: The respective baseline and minimum levels were 1441 and 808 U/ml for KL-6 and 254 and 132 ng/mL for SP-D. A high minimum SP-D level was significantly associated with a high incidence of PF-ILD by logistic regression, independent of baseline forced vital capacity and honeycombing. Similarly, a high minimum SP-D level was significantly associated with high mortality by Cox proportional hazard model analysis. The stratified minimum SP-D levels of <100, 100-200, and >200 revealed significantly distinct groups in the entire cohort, with PF-ILD incidence rates of 28%, 48%, and 74% and median survival times of 120, 74, and 45 months, respectively., Conclusions: High minimum SP-D levels over two years were correlated with an unfavorable prognosis in our cohort. Patient with consistently high SP-D levels during the clinical course may have a poor prognosis and be a candidate for early treatment intensification., Competing Interests: Conflict of Interest Yasunari Miyazaki received lecture fees from Nippon Boehringer Ingelheim and AstraZeneca. Tsukasa Okamoto received donations from Nippon Boehringer Ingelheim Co., Ltd., and Chugai Pharmaceutical Co., Ltd. The other authors declare that they have no competing interests., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

A 52-year-old woman presented with repeating episodes of pneumonia which spontaneously resolved after hospitalization. Hypersensitivity pneumonitis was suspected, but the causative antigen was not determined whether the parakeets she kept or the humidifier she owned was causative exposure. To identify which exposure is culprit, individual provocation test to a responsible environment was sequentially conducted. First, a home-returning provocation test to the parakeet was negative. Contrarily, the humidifier provocation test to her own humidifier was positive for symptoms, radiological changes, and inflammatory responses in blood test. Finally, she was diagnosed as having humidifier lung. When several antigens are suspected to be the causative agents for hypersensitivity pneumonitis, a step-by-step provocation tests is useful., Competing Interests: The authors state that they have no conflict of interest., (© 2022 The Authors. Published by Elsevier Ltd.)

Background: Fibrotic hypersensitivity pneumonitis (HP) is a chronic interstitial lung disease caused by allergic responses to repeated exposures to a causative antigen. Therapeutic evidence of the use of corticosteroids to treat fibrotic HP remains lacking, although corticosteroids are recognized as a major treatment option. The purpose of this study was to evaluate the efficacy of corticosteroid treatment in patients with fibrotic HP in a propensity score-matched cohort., Methods: A retrospective review of the medical records from 2005 to 2019 in a single center was conducted, and 144 patients with fibrotic HP were identified. Semiquantitative scores for lung abnormalities on HRCT were evaluated. Patients who received (PDN group) and did not receive (non-PDN group) corticosteroid treatment were matched using a propensity score method. Survival rates, serial changes in pulmonary function and annual changes in HRCT scores were compared in the matched cohort., Results: In the matched analysis, 30 individuals in the PDN group were matched with 30 individuals in the non-PDN group, the majority of whom had ILD without extensive fibrosis. The survival rate was significantly better in the PDN group (P = 0.032 for the stratified Cox proportional hazards model; HR, 0.250). The absolute changes in FVC at 6, 12, and 24 months from baseline were significantly better in the PDN group. Fewer patients in the PDN group experienced annual deterioration, as reflected in the HRCT score, due to ground-glass attenuation, consolidation, reticulation, traction bronchiectasis and honeycombing., Conclusion: We demonstrated that corticosteroids improved survival and slowed fibrotic progression in a matched cohort, the majority of whom had ILD without extensive fibrosis. Fibrotic HP with less severe fibrosis may benefit from corticosteroid treatment. We propose that the early initiation of corticosteroids should be considered for fibrotic HP when worsening fibrosis is observed., (© 2021. The Author(s).)

Hypersensitivity pneumonitis (HP) typically presents with interstitial inflammation and granulomas induced by an aberrant immune response to inhaled Ags in sensitized individuals. Although IL-17A is involved in the development of HP, the cellular sources of IL-17A and the mechanisms by which IL-17A contributes to granuloma formation remain unclear. Recent studies report that γδ T cells produce IL-17A and exhibit memory properties in various diseases. Therefore, we focused on IL-17A-secreting memory γδ T cells in the sensitization phase and aimed to elucidate the mechanisms by which IL-17A contributes to granuloma formation in HP. We induced a mouse model of HP using pigeon dropping extract (PDE) in wild-type and IL-17A knockout (IL-17A -/- ) mice. IL-17A -/- mice exhibited reduced granulomatous areas, attenuated aggregation of CD11b + alveolar macrophages, and reduced levels of CCL2, CCL4, and CCL5 in the bronchoalveolar lavage fluid. Among IL-17A + cells, more γδ T cells than CD4 + cells were detected after intranasal PDE administration. Interestingly, the expansion of IL-17A-secreting Vγ4 + or Vγ1 - Vγ4 - cells of convalescent mice was enhanced in response to the sensitizing Ag. Additionally, coculture of macrophages with PDE and Vγ4 + cells purified from PDE-exposed convalescent mice produced significantly more IL-17A than coculture with Vγ4 + cells from naive mice. Our findings demonstrate that in the sensitization phase of HP, IL-17A-secreting memory γδ T cells play a pivotal role. Furthermore, we characterized the IL-17A/CCL2, CCL4, CCL5/CD11b + alveolar macrophage axis, which underlies granuloma formation in HP. These findings may lead to new clinical examinations or therapeutic targets for HP., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Pulmonary enteric adenocarcinoma is a unique pulmonary adenocarcinoma subtype and has histopathological findings that are similar to those of colorectal adenocarcinoma. A man in his 50s visited our hospital because of discomfort in his right lower leg for the last 9 months. Imaging studies revealed a mass in his right soleus muscle, and needle biopsy was performed. Histological findings revealed adenocarcinoma, and immunohistochemical staining showed that the tumor cells were positive for CK20 and CDX-2. The tumor was first suspected to be metastasis of gastrointestinal malignant tumors. FDG-PET/CT showed increased FDG uptake in the right soleus muscle mass and presented with increased FDG uptake in a right upper lobe mass and right mediastinum lymphadenopathy. There were no findings in other organs. Scraping cytology of a transbronchial biopsy indicated adenocarcinoma. Upper and lower gastrointestinal endoscopy showed no findings of malignancy. He was finally diagnosed with pulmonary enteric adenocarcinoma(cT3N2M1b, Stage ⅣA). Treatment with cisplatin(CDDP), pemetrexed( PEM), and bevacizumab(BEV) was initiated. After 4 courses of the regimen, the tumor was partially reduced, and the patient showed stable disease(SD).

We developed a phantom using a hollow-fiber hemodialyzer to evaluate the quantitative reliability of cerebral computed tomography (CT) perfusion. Our phantom consisted of a hollow-fiber hemodialyzer and a syringe-shaped X-ray device made up of resin. The phantom can give theoretical true values for cerebral blood volume, cerebral blood flow, and mean transit time. We compared the values measured in the phantom with predicted theoretical values. The purpose of the current report is to describe the theory and experimental technique used to obtain an absolute value in a phantom.

Favipiravir, a viral RNA-dependent RNA polymerase inhibitor, has recently been approved in Japan for influenza pandemic preparedness. Here, we conducted a cell-based screening system to evaluate the susceptibility of influenza viruses to favipiravir. In this assay, the antiviral activity of favipiravir is determined by inhibition of virus-induced cytopathic effect, which can be measured by using a colorimetric cell proliferation assay. To demonstrate the robustness of the assay, we compared the favipiravir susceptibilities of neuraminidase (NA) inhibitor-resistant influenza A(H1N1)pdm09, A(H3N2), A(H7N9) and B viruses and their sensitive counterparts. No significant differences in the favipiravir susceptibilities were found between NA inhibitor-resistant and sensitive viruses. We, then, examined the antiviral susceptibility of 57 pairs of influenza viruses isolated from patients pre- and post-administration of favipiravir in phase 3 clinical trials. We found that there were no viruses with statistically significant reduced susceptibility to favipiravir or NA inhibitors, although two of 20 paired A(H1N1)pdm09, one of 17 paired A(H3N2) and one of 20 paired B viruses possessed amino acid substitutions in the RNA-dependent RNA polymerase subunits, PB1, PB2 and PA, after favipiravir administration. This is the first report on the antiviral susceptibility of influenza viruses isolated from patients after favipiravir treatment., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: We have recently reported that a new regimen of short-term oral immunotherapy (OIT) with the Cry j1-galactomannan conjugate for Japanese cedar pollinosis (JCP) is effective to the improvement in the symptoms and medication use during the pollen season and relatively safe. The effect of OIT on quality of life (QOL) of JCP patients has not been assessed. Therefore, we evaluated for the first time the effect of OIT on QOL during the Japanese cedar/cypress pollen season., Methods: A prospective, randomized, open-label trial was conducted over a period of 4 months. Participants were randomly divided into two groups. The OIT and control groups comprised 23 and 24 subjects, respectively. The build-up phase was initiated 1 month before the expected pollen season. The maintenance phase was continued for 51 days during the peak of the cedar pollen season. The QOL score in the Japan Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) No. 1 and visual analog scale (VAS) throughout the pollen season were evaluated., Results: Participants receiving OIT showed significant improvements in the total QOL score and VAS throughout the pollen season compared with the control group. In addition, the mean total QOL score and VAS correlated in both groups during the pollen season., Conclusion: The new regimen of short-term OIT using the Cry j1-galactomannan conjugate results in meaningful improvements in QOL of JCP patients. Our findings suggest that short-term OIT using allergen-galactomannan conjugates, as well as sublingual and subcutaneous immunotherapy, improves QOL of patients with pollinosis. The study was registered in UMIN-CTR (UMIN000013408) as the name of "a prospective, randomized, open study of oral Cry j1-galactomannan conjugate immunotherapy for Japanese cedar pollen allergy"., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Short-term oral immunotherapy (OIT) using the Cry j1-galactomannan conjugate for Japanese cedar pollinosis may be effective and relatively safe. However, a treatment regimen has not been established. In the present study, we examined a new OIT regimen with a build-up phase and extended the maintenance phase of OIT to the peak period of the pollen season to enhance the therapeutic effect and safety of OIT., Methods: A prospective, randomized, open-label trial was conducted over a period of 4 months. Participants were randomly divided into two groups. The OIT group comprised 23 subjects. The build-up phase was initiated 1 month before the expected pollen season. The maintenance phase was continued for 51 days during the peak pollen season. The control group comprised 24 subjects. The symptoms and medication score, levels of allergen-specific serum antibodies throughout the pollen season, and adverse effects with OIT were evaluated., Results: Participants receiving OIT showed significant improvements in total symptom scores, medication score, and total symptom-medication scores throughout the pollen season compared with the control group. The levels of allergen-specific serum IgG4 were significantly increased in the OIT group but not in the control group throughout the cedar pollen season. Importantly, no severe adverse effects were observed with OIT., Conclusions: The new regimen of short-term OIT using the Cry j1-galactomannan conjugate for Japanese cedar pollinosis is effective, relatively safe and induces immune tolerance. Thus, OIT using allergen-galactomannan conjugates may provide a rapid, effective, and thus convenient immunotherapy for pollinosis instead of SLIT or SCIT., (Copyright © 2014 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Objective: Among many immunotherapeutic approaches, oral immunotherapy (OIT) is thought to be an effective route for desensitization against a variety of allergens. However, there is little evidence that OIT is effective for airway allergic diseases such as pollen allergy. Thus, in the present study, we assessed the safety, efficacy and immune response of OIT using the Cry j1-galactomannan conjugate for Japanese cedar pollen allergy., Methods: An open trial was conducted over a period of 4 months. The OIT group comprised of 23 subjects. Treatment was initiated 1 month before the estimated pollen season and continued for 1 month. The control group (the pharmacological treatment group without OIT) comprised of 11 subjects. The symptoms and medication score, levels of allergen-specific serum antibodies, cellular components of lymphocytes and cytokine production from peripheral blood mononuclear cells (PBMCs) were evaluated throughout the pollen season., Results: The participants receiving OIT treatment showed significant improvements in total symptom scores and symptom-medication scores during the pollen season compared with the control group. The levels of allergen-specific serum IgG4 and IL-10 production in PBMCs were significantly increased in the OIT group compared with that in the control group. Importantly, no severe adverse effects were observed in the participants receiving OIT treatment., Conclusion: Short-term OIT using the Cry j1-galactomannan conjugate is effective, relatively safe and induces tolerant immune responses such as increased allergen-specific serum IgG4 and IL-10 production in PBMCs. These results suggest that OIT using allergen-galactomannan conjugates may provide a rapid, effective, and safe immunotherapy regimen for cedar pollen allergy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Subject and Methods: From April 2011 to March 2013, 20 patients with cancer pain that was not controlled by non-opioid analgesics were treated with a short-acting opioid for cancer pain management.The primary carcinoma sites were the stomach( n=5), colo-rectum(n=5), lungs(n=3), urinary bladder(n=2), breast(n=2), pancreas(n=2), and liver(n=1). The analgesic effects and adverse events were evaluated, and a shift to fentanyl patches was made for patients whose cancer pain was relieved.After the shift, the efficiency and safety were validated., Results: All 6 patients with a numeric rating scale (NRS)less than 5 at the time of opioid induction had a good analgesic effect, and in only 1 patient, grade 2 constipation and grade 3 anorexia was observed.Of the 14 patients who had an NRS of 6 or greater, 11 had a good analgesic effect.However, 3 patients experienced no effect, and their survival periods after opioid induction were very short.In the 11 patients with good pain control, only 3 patients exhibited grade 2 adverse events.Nine patients out of 17 with a good analgesic effect caused by short-acting opioids were shifted to fentanyl patches, and 8 patients were under good analgesic control for 2 weeks or more., Conclusion: Opioid induction using rapid release drugs was effective and safe.However, these drugs should be clinically considered at an early stage.Furthermore, in patients where a shift to a fentanyl patch was possible, good long-term pain control was achieved.

Six influenza A(H1N1)pdm09 viruses were detected in Sapporo, Japan, between November and December 2013. All six viruses possessed an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir. No epidemiological link among the six cases could be identified; none of them had received neuraminidase inhibitors before specimen collection. The haemagglutinin and neuraminidase genes of the six viruses were closely related to one another, suggesting clonal spread of a single resistant virus.

Reconstruction of a tracheal defect is a challenge because it often requires invasive surgery associated with relatively high morbidity. We recently invented a less-invasive method using a modified infrahyoid myocutaneous (IHMC) flap for the reconstruction of a tracheal defect in an 83-year-old male. A tracheal defect, the right half of the cricoid cartilage plus the right three quarters of the I-IV tracheal cartilage (about 3 × 4 cm), was reconstructed with a modified IHMC flap composed of the sternohyoid and platysma muscles and a skin pedicle. Considering the age of patient, we avoided rigid reconstruction and used a soft silicone tracheal opening retainer (Koken Co., Ltd., Tokyo, Japan) as an anterior wall dilator after surgery and waited for the scarring of the flap until it become rigid enough. The postoperative course was uneventful and the trachea was reconstructed safely. Tracheal reconstruction with an IHMC flap is a useful and less-invasive alternative compared to end-to-end anastomosis or reconstruction with a forearm flap, which is currently used as a mainstay., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)