STAT6 gain-of-function variant exacerbates multiple allergic symptoms.

BACKGROUND: Allergic diseases were long considered to be complex multifactorial disorders. However, recent findings indicate that severe allergic inflammation can be caused by monogenic immune defects. OBJECTIVES: We sought to clarify the molecular pathogenesis of a patient with early-onset multiple allergic diseases, a high serum IgE level, hypereosinophilia, treatment-resistant severe atopic dermatitis with increased dermal collagen fiber deposition, and eosinophilic gastrointestinal disorder with numerous polypoid nodules. METHODS: A missense variant in STAT6 was identified, and its function was examined using peripheral blood, transfected HEK293 cells, lymphoblastoid cell lines, and knock-in mice with the corresponding mutation. RESULTS: Whole-exome sequencing identified a de novo heterozygous missense variant in signal transducer and activator of transcription 6 (STAT6) (p.Asp419Asn). Luciferase reporter assay revealed that the transcriptional activity of this STAT6 mutant was upregulated even without IL-4 stimulation. Phosphorylation of STAT6 was not observed in either the patient's TH2 cells or lymphoblastoid cell lines without stimulation, whereas it was induced more strongly in both by IL-4 stimulation compared with healthy controls. STAT6 protein was present in the nuclear fraction of the lymphoblastoid cell lines of the patient even in the absence of IL-4 stimulation. The patient's gastric mucosa showed upregulation of STAT6-, fibrosis-, and germinal center formation-related molecules. Some of the knock-in mice with the corresponding mutation spontaneously developed dermatitis with skin thickening and eosinophil infiltration. Moreover, serum IgE levels and mRNA expression of type 2 cytokines were increased in the knock-in mice-with or without development of spontaneous dermatitis-compared with the wild-type mice. CONCLUSIONS: A novel STAT6 gain-of-function variant is a potential cause of primary atopic disorders.

Laundry detergents and surfactants-induced eosinophilic airway inflammation by increasing IL-33 expression and activating ILC2s.

INTRODUCTION: Epidemiological studies demonstrated that cleaning work and frequent use of cleaning products are risk factors for asthma. Laundry detergents have been reported to have epithelial barrier-opening effects. However, whether laundry detergents directly induce airway inflammation and its mechanisms in vivo remain to be elucidated. METHODS: Two commercial laundry detergents and two commonly used surfactants for cleaning and cosmetics (sodium lauryl sulfate and sodium dodecyl benzene sulfonate) were intranasally administered to mice. Lungs were analyzed using flow cytometry, histology, ELISA, and quantitative PCR. Human bronchial epithelial cells were stimulated with laundry detergents and analyzed using quantitative PCR and western blotting. Involvement of oxidative stress was assessed using an antioxidant. Dust samples from homes were analyzed to determine their detergent content by measuring their critical micelle concentration (CMC). RESULTS: The administered laundry detergents and surfactants-induced eosinophilic airway inflammation accompanied by increased IL-33 expression and activation of group 2 innate lymphoid cells (ILC2s). Detergent-induced eosinophilic airway inflammation was significantly attenuated in Rag2-/- Il2rg-/- , Il33-/- mice, and also in wild-type mice treated with NAC. Detergent-induced IL-33 expression in airways was attenuated by NAC treatment, both in vivo and in vitro. CMCs were found in all of the tested dust extracts, and they differed significantly among the homes. CONCLUSION: The laundry detergents and surfactants-induced eosinophilic airway inflammation in vivo through epithelial cell and ILC2 activation. They induced IL-33 expression in airway epithelial cells through oxidative stress. Furthermore, detergent residues were present in house dust and are presumably inhaled into the airway in daily life.

Evaluation of a Novel Immunochromatographic Assay Using Monoclonal Antibodies against the Matrix Protein of Human Metapneumovirus.

BACKGROUND: The aim of this study was to determine the sensitivity and specificity of a novel immunochromatographic (IC) assay (APD1806) using monoclonal antibodies against the matrix (M) protein of human metapneumovirus (hMPV) for detection of hMPV from nasopharyngeal swab samples based on the results of real-time RT-PCR. METHODS: Nasopharyngeal swab samples taken from 189 patients aged 0 - 5 years who were suspected of having respiratory tract infections associated with hMPV were used in this study. The samples were tested both by the IC assay and by real-time RT-PCR for detection of hMPV. RESULTS: The sensitivity and specificity of the IC assay for detection of hMPV were 88.8% (95/107) and 92.7% (76/82), respectively. CONCLUSIONS: The IC assay using monoclonal antibodies against the M protein of hMPV is an accurate and fast assay that is suitable as a diagnostic tool for hMPV infection. The optimal timing of the IC assay is 12 hours or more after the onset of fever due to hMPV infection.

Evaluation of a Novel Immunochromatographic Assay for Detection of Human Adenoviruses from Throat Swab Samples Compared with Real-time PCR.

BACKGROUND: The aim of this study was to determine the sensitivity and specificity of a novel immunochromatographic assay (ICA) kit, ALSONIC® Adeno (Alfresa Pharma Co., Osaka, Japan), for the detection of human adenovirus (HAdV) from throat swab samples based on the results of real-time PCR. The incubation time required for the novel assay kit (5 minutes) is shorter than that required for other ICA kits that are available in Japan. METHODS: Throat swab samples were taken from 151 patients aged 6 months to 15 years who were suspected of having respiratory tract infections caused by HAdV. RESULTS: The sensitivity and specificity of the ICA for detection of HAdV were 92.2% (83/90) and 95.1% (58/61), respectively, and the assay showed positive and negative predictive values of 96.5% (83/86) and 89.2% (58/65), respectively. CONCLUSIONS: ALSONIC® Adeno is suitable as a diagnostic tool in the acute phase of HAdV infection.

Clinical effectiveness of four neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) for children with influenza A and B in the 2014-2015 to 2016-2017 influenza seasons in Japan.

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012).

[Endovascular repair for coarctation of the aorta in an adult].

A 27-year-old woman with Turner's syndrome who underwent successful endovascular treatment for coarctation of the aorta is presented. She was admitted to our hospital complaining of upper extremity hypertension. Computed tomography revealed discrete stenosis of the proximal descending aorta and developed collateral circulation. After endovascular repair with a balloon expandable stent, her transcoarctation gradient fell from 44 mmHg preoperatively to less than 10 mmHg. She was discharged with no complications on the 7th postoperative day. Coarctation of the aorta in an adult patient could be safely and effectively managed by endovascular treatment.

Short- and long-term efficacy of bronchial artery embolization using a gelatin sponge for the treatment of cryptogenic hemoptysis.

Bronchial artery embolization (BAE) is the first choice treatment for hemoptysis. With advances in endovascular treatment, various embolic materials have become available. However, the optimal embolic material for the treatment of cryptogenic hemoptysis has not been determined. This study aimed to investigate the short-and long-term efficacy of BAE using a gelatin sponge in the treatment of patients with cryptogenic hemoptysis. The clinical characteristics, angiographic findings, and short- and long-term outcomes of BAE were retrospectively analyzed in 22 consecutive patients who underwent BAE for control of cryptogenic hemoptysis between January 2010 and September 2018. Selective angiography and super-selective BAE were successfully performed for all patients. A gelatin sponge was used in all patients. Further, polyvinyl alcohol was mixed with the gelatin sponge in 11 patients (50%). Angiography showed that the bronchial artery was responsible for hemoptysis in all patients, along with the intercostal artery in one patient (4.5%) and the inferior phrenic artery in one patient (4.5%). Immediate hemostasis was achieved in all patients. The recurrence-free rate was 100% for 1 month, 94.1% for 3 months, 94.1% for 12 months, and 87.4% for 24 months. Of two patients with recurrent hemoptysis, one underwent bronchoscopic hemoptysis and the other received intravenous hemostatic agents. No patient underwent BAE for recurrence. No severe complications occurred. In conclusion, BAE using a gelatin sponge has short- and long-term hemostatic efficacy for treating cryptogenic hemoptysis without any severe complications. A gelatin sponge is a suitable embolic material for patients with cryptogenic hemoptysis.

P1 gene of Mycoplasma pneumoniae isolated from 2016 to 2019 and relationship between genotyping and macrolide resistance in Hokkaido, Japan.

We characterized 515 Mycoplasma pneumoniae specimens in Hokkaido. In 2013 and 2014, the p1 gene type 1 strain, mostly macrolide-resistant, was dominant and the prevalence of macrolide resistance was over 50 %. After 2017, the p1 gene type 2 lineage, mostly macrolide-sensitive, increased and the prevalence of macrolide resistance became 31.0 % in 2017, 5.3 % in 2018 and 16.3 % in 2019.

A case of diffuse pulmonary lymphangiomatosis with a venous anomaly presenting with acute respiratory failure and hemoptysis.

Diffuse pulmonary lymphangiomatosis (DPL) is a rare lymphatic disease that can cause diverse respiratory symptoms. A 22-year-old man, whose chest CT had shown an abnormality for years, presented with acute respiratory failure due to the abrupt onset of hemoptysis. The diagnosis of DPL was confirmed by surgical lung biopsy and lymphangiography. Histopathological investigation showed dilated vascular and lymphatic vessels. DPL can cause acute and life-threatening symptoms during its chronic clinical course. A coexisting anomaly in the venous system may be present in DPL patients with hemoptysis.

Cost-effectiveness of bronchial thermoplasty for severe asthmatic patients in Japan.

Bronchial thermoplasty (BT) is an interventional endoscopic treatment for severe bronchial asthma. Some studies have shown the clinical efficacy of this intervention, but its cost-effectiveness is unclear. The aim of this study was to evaluate the cost-effectiveness of BT. We collected data from the medical records of 16 Japanese patients who were treated with BT between February 2015 and April 2017, and compared asthma-related medical expenses between the year preceding and the year following BT. Four patients were Global Initiative for Asthma (GINA) treatment step 4, and 12 were step 5. In 8 patients who had a successful response to BT, the annual asthma-related medical expenses decreased because of a reduction in hospitalization and emergency outpatient visits due to asthma attacks, and termination of the use of biologics. Most patients in the non-responder group had increased asthma-related medical costs postoperatively. The main reason for the increase in medical costs was the add-on treatment of biologics. BT was cost-effective in the responder group. If its effects continue for more than 10 years, BT will be a cost-effective treatment. Medical costs will be reduced if those who respond to BT can be identified prior to commencement of treatment.

In-transit recurrence of Merkel cell carcinoma associated with Bowen's disease: The first reported case successfully treated by avelumab.

A 65-year-old Japanese man presented with a dome-shaped nodule, the base of which was contiguous with a dull brown plaque, on the left leg. After local excision of the cutaneous lesion and left inguinal lymph node dissection, several dermal and subcutaneous nodules developed successively on the left lower extremity. Hematoxylin-eosin staining of the primary cutaneous lesion demonstrated uniform neoplastic cells arranged in a trabecular pattern extending from the dermis to subcutis. Mitotic figures were abundant. Although the overlying epidermis was substantially intact, the Merkel cells had invaded the epidermis, resulting in Pautrier-like microabscesses. The hyperplastic epidermis adjacent to the nodule consisted of abnormally growing atypical keratinocytes. The enlarged left inguinal lymph node and successive secondary nodules contained Merkel cells similar to those in the primary nodule. Immunohistochemically, most tumor cells were positive for CAM5.2, synaptophysin, chromogranin A, CD56 and vimentin. The tumor cells in the left inguinal lymph node were positive for CAM5.2, synaptophysin and cytokeratin 20 but negative for CM2B4, and less than 1% of the cells expressed programmed cell death ligand 1. The patient was treated with avelumab, which showed significant efficacy against the in-transit recurrence. Two months later, all nodules had disappeared completely. We describe a case of in-transit recurrence of Merkel cell carcinoma that was associated histologically with Bowen's disease and was successfully treated with avelumab. Although accumulation of additional cases is needed, avelumab therapy may be a useful treatment for in-transit recurrence of Merkel cell carcinoma.

Bronchial Thermoplasty for Severe Asthma with Mucus Hypersecretion.

Bronchial thermoplasty (BT), which delivers thermal radiofrequency to the bronchial wall, is an effective therapy for patients with severe persistent uncontrolled asthma. We herein report the case of a 47-year-old man who underwent BT for uncontrolled severe asthma. After BT, his asthma control, asthma-related quality of life, and pulmonary function improved. Furthermore, a histologic examination of transbronchial biopsy specimens revealed a decrease in goblet cell hyperplasia and the smooth muscle mass as well as in the subepithelial basement membrane thickness. BT can be effective for patients with severe uncontrolled asthma and mucus hypersecretion.

Refractory Chylothorax and Lymphedema Caused by Advanced Gastric Cancer.

Chylothorax is the accumulation of lipid pleural effusion. Few reports have described chylothorax caused by gastric cancer. A 45-year-old woman presented with progressive lymphedema and bilateral chylothorax. Although repetitive thoracentesis was performed to relieve her dyspnea, swelling of her axillary lymph nodes became significant. Positron emission tomography/computed tomography demonstrated the accumulation of 18F-fluorodeoxyglucose in these nodes, and a lymph node biopsy showed signet ring cell carcinoma. The primary site was a 0-IIc type lesion in the gastric body that was only detected by upper gastrointestinal endoscopy. The patient was diagnosed with advanced gastric cancer 3.5 months after presentation for chylothorax.

Can the Number of Radiofrequency Activations Predict Serious Adverse Events after Bronchial Thermoplasty? A Retrospective Case-Control Study.

INTRODUCTION: Bronchial thermoplasty (BT) is a bronchoscopic procedure that involves the delivery of thermal radiofrequency energy to the bronchial wall for treating severe asthma. It has been suggested that too many radiofrequency activations could induce serious adverse events (SAEs) at an early stage. We aimed to examine the number of radiofrequency activations at each session and early lung function changes from baseline to determine whether these are related to SAEs. METHODS: We retrospectively investigated 13 consecutive patients who underwent three sessions each of BT for severe asthma from February 2015 to January 2016. Lung function tests were performed on the day before and after each BT procedure. Since we compared the number of activations and lung function changes from baseline after each session, a total of 39 sessions were reviewed. The relationship between the number of radiofrequency activations and each lung function change from baseline was also examined by linear regression analysis. RESULTS: A total of 10 SAEs (4 of pneumonia, 3 of atelectasis, 2 of bronchial asthma exacerbation and 1 of hemoptysis) were observed following the 39 BT sessions. When we compared sessions with and without SAEs, there were no differences in the number of activations (mean ± SD, 71.5 ± 28.6 times in sessions with SAEs; 66.5 ± 25.1 times in sessions without SAEs; p = 0.772) and lung function changes (mean changes in FVC/%FVC/FEV1/%FEV1/%PEF from baseline; - 0.49 l/- 14.2%/- 0.36 l/- 11.7%/- 9.6% in sessions with SAEs; - 0.43 l/- 13.3%/- 0.34 l/- 12.1%/- 9.4% in sessions without SAEs; p > 0.05 for all the above). Increase in the number of activations correlated with decreased FEV1 (R2 = 0.17, p = 0.0088) and %FEV1 (R2 = 0.11, p = 0.0357). CONCLUSIONS: Increase in the number of radiofrequency activations during BT is related to a decrease in FEV1 and %FEV1 from baseline. The number of radiofrequency activations, however, is not associated with SAEs after BT.

Indeterminate dendritic cell neoplasm accompanied by eosinophilic pneumonia successfully treated by systemic steroid therapy: Report of the first case with muscular and parotid involvement and review of published work.

A 34-year-old Japanese man presented with an indolent nodule on the right flank. Computed tomography of the chest and abdomen demonstrated a large nodule measuring 55 mm × 50 mm in the abdominal oblique muscle layer of the right flank, and several small nodules were seen in the muscle layer throughout the body and subcutaneous tissue of the lower abdomen. 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography revealed nodular lesions in the bilateral parotid glands, bilateral cervical lymph nodes and lower lobe of the right lung. Intermittently, ground-glass shadows developed in the bilateral lungs. Histologically, sheet-like nodules in the abdominal oblique muscle layer and parotid gland were composed of large polygonal cells with convoluted nuclei and ample eosinophilic cytoplasm. Several lymphocytes and considerable eosinophils were intermingled. Lung biopsy demonstrated an inflammatory infiltrate of lymphocytes and considerable eosinophils in the alveoli. Immunohistochemically, polygonal cells were positive for S100 protein and CD1a, but negative for langerin and BRAFV600E . Some cells were positive for CD68. Electron microscopy demonstrated histiocytic cells with phagosomes and interdigitating processes. However, no Birbeck granules were observed. Eosinophilia was seen in the peripheral blood. Multifocal nodules and ground-glass shadows gradually diminished following systemic administration of oral prednisolone. We describe a case of indeterminate dendritic cell neoplasm with multifocal involvement of the muscle, subcutis, lymph node and parotid gland accompanied by chronic eosinophilic pneumonia that was successfully treated by systemic steroid therapy. Neither muscular nor parotid indeterminate dendritic cell neoplasms accompanied by eosinophilic pneumonia have been previously reported.

Clinically simplified screening methods to evaluate maximum standard uptake value from F-18-FDG-PET/CT in patients with non-small-cell lung cancer.

Maximum standard uptake value (SUVmax) of F-18-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) is reportedly useful for evaluating regional lymph nodes (RLNs) of non-small-cell lung cancer (NSCLC) to predict malignancy. However, it is difficult for clinicians to measure SUVmax (mSUVmax) as calculated by a workstation.We assessed the utility of simplified SUVmax (sSUVmax) in screening RLNs for pathologic malignancy. The highest color was visually defined in the region of interest. The resulting color can be quantified using the color bar, and interpreted as sSUVmax. Patients in respiratory medicine and surgery who underwent both contrast-enhanced CT and FDG-PET/CT within 3 months before radical lobectomy were evaluated retrospectively. The correlation was examined by regression analysis and receiver operating characteristic (ROC) curve analyses.Participants comprised 69 patients with NSCLC treated between May 2009 and April 2016. Medical group comprised 22 patients from respiratory medicine. The prediction model could be written as a linear relationship (mSUVmax = 1.019 × sSUVmax; R = 0.930). A total of 316 RLNs resected by surgery in total cohort were pathologically determined. From ROC curves, area under curve for sSUVmax was 0.72 (95% confidence interval, 0.61-0.83; P < .0002). The cutoff sSUVmax was 2.42 (sensitivity, 52%; specificity, 88%; accuracy, 85%).The sSUVmax allows quantification of colors from FDG-PET/CT and shows a close correlation to mSUVmax. This value may have potential in screening for RLNs, and thoracic clinicians can readily determine the value. These findings may facilitate better planning of therapeutic strategy in the real world.

Pseudovascular squamous cell carcinoma: A review of the published work and reassessment of prognosis.

A 90-year-old Japanese woman presented with a dome-shaped, dark-red, ulcerated nodule measuring 23 mm × 19 mm × 9 mm on the right side of the nasal root. Histologically, anastomosing cord-like arrays of atypical polygonal keratinocytes exhibiting internal pseudolumina containing detached cells and erythrocytes were observed. Although acantholytic and cohesive areas overlapped, cancer pearls were not detected. The lower epidermis partially demonstrated scattered dyskeratotic and acantholytic keratinocytes with loss of polarity, continuous with an underlying tumor mass. The tumor cells were positive for a variety of cytokeratins, p40 and vimentin. The Ki-67 proliferation index was 50-60%. Both CD31 and CD34 were expressed in reactive blood vessels of the tumor. A local excision margined by 1 mm was performed, followed by X rays and electron beam irradiation. Neither lymph node nor distant metastasis has appeared over the 14 months since the excision. We performed a review of the published work and identified 24 previously reported patients with pseudovascular squamous cell carcinoma of the skin, oral mucosa and vulva to reassess the prognosis of this tumor. In 12 of these patients (50%), sites other than the head and neck were involved. Eight (33%) tumor-associated deaths occurred. It is believed that pseudovascular squamous cell carcinoma has a tendency to develop at morbid skin and mucous membranes sites in organs other than the face and neck and to possess an aggressive clinical behavior.

Two cases of infundibular squamous cell carcinoma on the nose with aggressive clinical behavior: Case report and review of the published work.

Case 1 was a 75-year-old Japanese man who presented with a poorly demarcated, dark-red nodule with a destructive defect in the center, measuring 3 cm × 2 cm on the right wing of his nose. The histological diagnosis was a common form of infundibular squamous cell carcinoma. Atypical neoplastic cells radiated from the wall of a follicular infundibulum. The majority of neoplastic cells were positive for AE1/AE3 and 34ßE12. Cytokeratin 17 expression was seen in the suprabasal cells of the deeply situated neoplastic components. Case 2 was a 73-year-old Japanese man who presented with a poorly demarcated, dark-red nodule with an irregularly shaped ulcer in the center, measuring 3 cm × 2 cm on the left wing of his nose. The histological diagnosis was a crater form of infundibular squamous cell carcinoma. Atypical neoplastic cells radiated from the broad base of the central keratin-filled crater, continuous with two infundibular canals. In both cases, some of the more deeply situated aggregations were composed of neoplastic keratinocytes with eosinophilic glassy or pale cytoplasm. In addition, no atypical keratinocytes could be seen in the interfollicular epidermis. In case 1, a hematogenous metastasis to the vocal cord and the forehead occurred in addition to a lymph node metastasis. In case 2, a local recurrence occurred with an intralymphatic dissemination. We describe two cases of infundibular squamous cell carcinoma on the nose with aggressive clinical behavior, one of which was accompanied by a hematogenous metastasis while another revealed a local recurrence.