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.

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.

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.

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.

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.

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.

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.

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.