[A case of anti-titin antibody positive nivolumab-related necrotizing myopathy with myasthenia gravis].

A 53-year-old man suffering from squamous cell lung cancer presented with bilateral ptosis and bulbar palsy a month after initial treatment with the immune checkpoint inhibitor nivolumab. The symptoms showed worsening from midday, suggesting myasthenia gravis (MG), although anti-AChR antibody was negative. Although no muscle weakness was detected, the CK level was elevated to 5,255 IU/l, and MRI of the thigh revealed inflammation of the bilateral rectus femoris muscle. A muscle biopsy showed signs of necrotizing myopathy with expression of sarcolemmal HLA class I and accumulation of macrophages, CD4, CD8, and CD20-positive lymphocytes. Positivity for anti-titin antibody, one of the anti-striated muscle antibodies, was evident. The patient was diagnosed as having nivolumab-related necrotizing myopathy with myasthenia gravis, an immune-related adverse event (irAE). Treatment with prednisolone rapidly ameliorated the symptoms, and the serum CK level normalized. There have been several reports of nivolumab-related myositis with MG. On the basis of the muscle pathology and antibody data, we were able to clarify that necrotizing myopathy was related to the pathogenesis of this case.

[Two cases of IgG4-related disease with pleural effusion].

We describe 2 cases of IgG4-related disease with pleural effusion in elderly men. Both patients had elevated serum IgG4 levels, and the characteristics of their pleural effusion were similar. Patient 1 had pericardial effusion and retroperitoneal fibrosis, and a biopsy specimen from the pericardium showed infiltration of abundant IgG4-positive plasma cells with fibrosis. Because his pleurisy, pericarditis and retroperitoneal fibrosis responded to steroid therapy, we diagnosed pleurisy associated with IgG4-related disease. Patient 2 had been treated with steroids because of IgG4-related sialadenitis and interstitial pneumonitis, but pleural effusion developed. Although histopathological examination of the pleura showed infiltration of abundant IgG4-positive plasma cells with fibrosis, Mycobacterium tuberculosis was cultured from the pleural effusion, and histologic examination also showed epithelioid granuloma. Chemotherapy for tuberculosis was effective for the pleurisy, and we diagnosed tuberculous pleurisy as a complication of IgG4-related disease. In cases of IgG4-related disease associated with pleural effusion, the clinical course should be considered together with the serum IgG4 levels and pleural histology.

TTF-1 is useful for primary site determination in duodenal metastasis.

We report here on a case of duodenal metastasis from primary lung adenocarcinoma. A 69-year old man was diagnosed with primary lung adenocarcinoma. Four courses of combined chemotherapy with carboplatin and paclitaxel associated with irradiation of 60 Gy shrunk the lung tumor. However, soon after,the para-aortic lymph node became swollen. Esophagogastroduodenoscopy revealed three duodenal tumors. Differential diagnosis between malignant lymphoma and metastatic duodenal cancer was endoscopically difficult. The histology of biopsied specimens was poorly differentiated adenocarcinoma. Immunohistochemical analysis revealed a positive reaction for thyroid transcription factor-1 (TTF-1). Thus, we concluded that these were metastatic duodenal tumors from lung adenocarcinoma. Two courses of gemcitabine led to a complete remission in this duodenal metastasis and para-aortic lymph node swelling with only scarring remaining in computed tomography. He is now on the continuous generalized chemotherapy. In conclusion, duodenal metastasis from primary lung adenocarcinoma is rare and hard to diagnose. In such an instance, TTF-1 immunostaining is crucial to obtain the correct diagnosis.

[Interstitial pneumonia associated with stiff-person syndrome].

A 68-year-old man who was given a diagnosis of interstitial pneumonia. Chest computerized tomography (CT) revealed subpleural honeycomb formations and traction bronchiectasis. Three months after the diagnosis of interstitial pneumonia, he noticed neurological symptoms, such as facial spasms, dysphagia, muscle rigidity and muscle cramp, and repeatedly received clonazepam. He was diagnosed with stiff-person syndrome on electromyography when he was hospitalized due to aspiration pneumonia. He has needed continuous rehabilitation due to the progression of neurological symptoms despite the partial efficacy of anti-epilepsy agents. We report a case of interstitial pneumonia with stiff-person syndrome.

Effects of IS-741, a synthetic anti-inflammatory agent, on bleomycin-induced lung injury in mice.

Bleomycin (BLM)-induced lung injury consists of excessive inflammatory cell infiltration and fibrosis. IS-741 has been reported to be an anti-inflammatory drug through an inhibitory action on cell adhesion. In this study we investigated whether IS-741 could inhibit the progression of pulmonary fibrosis through inflammatory cell infiltration. Lung injury was induced in female C57BL/6 mice by intratracheal instillation of BLM. IS-741 was administered daily intraperitoneally. The hydroxyproline content and fluid content in the lung on Day 28 were significantly lower in the IS-741-treated mice. The histological degree of lung injury or fibrosis was reduced in IS-741-treated mice. Administration of IS-741 caused significant reduction in the absolute number of total cells, monocyte chemoattractant protein (MCP)-1, and cysteinyl leukotriene (cysLTs) levels in bronchoalveolar lavage fluid on Day 7. Furthermore, the hydroxyproline content was significantly lower in IS-741-treated mice even though IS-741 was started on Day 14 after BLM instillation. Treatment with IS-741 had an inhibitory effect on BLM-induced lung injury and fibrosis via the repression of MCP-1 or cysLTs in this murine experimental model.

[A case of non-small cell lung carcinoma dying of acute respiratory failure due to aerogenous metastasis].

A 63-year-old man was admitted to our hospital, because of exacerbation of backache and erythema. At the time of admission the chest X-ray film showed infiltrative shadows in the left middle and lower lung fields. Our investigation revealed primary mucinous type bronchioloalveolar carcinoma in the left lung (cT4N2M1 Stage IV). Radiotherapy (C7-Th2, L3-L5. Total 30 Gy/10 fr) was administered to relieve his pain. After radiotherapy, he developed respiratory failure, fever, and infiltrative shadow in his chest X-ray. Antibiotic therapy improved his symptoms, laboratory findings and radiological abnormal findings. We suspected complication with nosocomial infection. However the ground-glass appearance appeared in the right lung a few days later. Although antibiotics and steroids were administered, he died of respiratory failure in 6 days. Necropsy findings revealed bronchioloalveolar carcinoma in the right lung suggesting aerogenous metastasis. Considering these facts together, we diagnosed non-small cell lung carcinoma dying of acute respiratory failure due to aerogenous metastasis.

[Case of central neurosarcoidosis with panhypopituitalism].

A 63-year-old man was admitted because of dizziness, polydipsia, polyuria, and diminished libido. His brain MRI showed swelling of the pituitary gland. Because of panhypopituitarism suggested by hormonal examination, hydrocortisone, desmopressin and levothyroxine sodium were started as hormone replacement therapy. He was given a clinical diagnosis of central neurosarcoidosis with panhypopituitarism because of the presence of an abnormal lung shadow, positive gallium scintigram in bilateral hilar lymph nodes, negative tuberculin skin test, lymphocytosis and a high CD4/8 ratio in bronchoalveolar lavage fluid. After prednisolone therapy, his lung shadow and pituitary swelling reduced significantly. Anti-diuretic hormones and anterior pituitary hormones tended to increase, and his urine volume also decreased. This case suggested that endocrinological abnormalities in central neurosarcoidosis might be improved by prednisolone therapy even if the initiation of treatment is delayed.

Isolation and immunophenotyping of mononuclear cells from human lung tissue.

OBJECTIVE: To quantitatively isolate and immunologically phenotype mononuclear cells contained in human lung tissue. METHODS: Normal appearing lung tissue as far distal to the resected lesion as possible was obtained from lung cancer patients. Lung tissue was thoroughly washed and cut into small pieces and digested with collagenase. Peripheral blood mononuclear cells (PBMNC) were prepared from controls using Ficoll gradient. Isolated cells and PBMNC were analyzed by flow cytometry. We immunohistochemically stained snap-frozen lung tissue with anti-CD3, CD4, CD8, CD20, and CD161 antibodies. PARTICIPANTS: Nineteen patients with lung cancer who underwent lobectomy were enrolled. Twelve healthy volunteers also participated as controls for flow cytometric analysis of PBMNC. RESULTS: In forward scatter vs side scatter, 92.1+/-7.8% of isolated cells in the lymphoid population expressed leukocyte common antigen, CD45. The frequency of CD45-positive cells in the lymphoid population from lung tissue was as high as that from PBMNC (p=0.118). CD45-positive cells were successfully further extended by anti-CD3, CD4, CD8, CD19, and CD161 antibodies. Monocyte-macrophages bearing CD68 were also detected. CD68-positive alveolar macrophages disappeared from alveolar spaces after thorough washing by immunohistochemical staining. Mononuclear cells in the interstitium were positively stained by anti-CD3, CD4, CD8, CD20, and CD161 monoclonal antibodies. CONCLUSIONS: We could isolate interstitial cells and analyze cell surface markers via flow cytometry from fresh lung specimens by collagenase digestion without further purification. Immunohistochemistry confirmed the presence of the cells detected by flow cytometry in the lung interstitium.

[An autopsy case of Aspergillus pneumonia after inhalation of a great deal of dust in a mushroom factory].

A man in his forties with alcoholic liver injury was referred to our hospital because of progressive dyspnea and diffuse infiltrative shadows in both lung fields. Two weeks before admission he had carried a lot of rotten Enoki mushrooms in his factory, and then inhaled a great deal of airborne dust. Serological examination showed extremely elevated beta-D-glucan and positive Aspergillus antigen. Culture of dust collected from the floor of the factory proved to be positive for Aspergillus fumigatus. Aspergillus pneumonia was diagnosed and treatment with anti-fungal drugs was started. In spite of intensive treatment he died of respiratory failure. The autopsy disclosed multiple abscess formation containing hyphae of Aspergillus fumigatus and granulomatous reaction with multinuclear giant cells. However, there was no Aspergillus invasion in other organs. This was a rare case of invasive pulmonary aspergillosis that developed after inhalation of organic dust in a non-immunocompromised host.