A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1 (TM5614) in mild to moderate COVID-19.

An inhibitor of plasminogen activator inhibitor (PAI)-1, TM5614, inhibited thrombosis, inflammation, and fibrosis in several experimental mouse models. To evaluate the efficacy and safety of TM5614 in human COVID-19 pneumonia, phase IIa and IIb trials were conducted. In an open-label, single-arm trial, 26 Japanese COVID-19 patients with mild to moderate pneumonia were treated with 120-180 mg of TM5614 daily, and all were discharged without any notable side effects. Then, a randomized, double-blind, placebo-controlled trial was conducted in Japanese COVID-19 patients with mild to moderate pneumonia. The number of study participants was set to be 50 in each arm. Even after extension of the enrollment period, the number of study participants did not reach the initially intended sample size, and 75 patients were enrolled in the study. The total oxygenation scale from Day 1 to Day 14 as the primary endpoint was 1.5 in the TM5614 group vs 4.0 in the placebo group (p = 0.22), and the number of days of oxygen administration required as the secondary endpoint was 2.0 days in the TM5614 group vs 3.5 days in the placebo group (p = 0.34). Further studies will be necessary to verify the efficacy of PAI-1 inhibition for the treatment of COVID-19 pneumonia.Clinical trial registration: Two studies were conducted: a prospective, multicenter, open-label phase II study at https://jrct.niph.go.jp (jRCT2021200018) (First registration date 18/08/2020) and a prospective, multicenter, randomized, double-blind, placebo-controlled, phase II study at https://jrct.niph.go.jp (jRCT2021210006) (First registration date 28/05/2021).

PD-L1-negative Non-small-cell Lung Cancer Treated with Nivolumab Plus Ipilimumab during Maintenance Hemodialysis Results in Rapid Initial Progression Followed by a Long-lasting Response.

Nivolumab plus ipilimumab is one of the first-line treatments for advanced non-small-cell lung cancer (NSCLC), but the safety and efficacy in patients on hemodialysis (HD) is unclear. We herein report a patient with NSCLC on HD in whom nivolumab and ipilimumab were initiated. We observed general deterioration and enlarged lesions, followed by a long-term response. The patient developed secondary hypoadrenocorticism, an immune-related adverse event that was easily controlled. Nivolumab plus ipilimumab can be used safely for patients with NSCLC on HD. Long-term effectiveness can be observed after initial progression, so we should carefully assess the response.

Effectiveness of bronchial thermoplasty in patients with asthma exhibiting overweight/obesity and low quality of life.

Bronchial thermoplasty (BT) is effective in some severe asthma patients; however, the specific asthma phenotypes that produce a good response to BT are not fully understood. Clinical data were retrospectively reviewed in severe asthma patients who underwent BT at a single institution in Japan. At the follow-up assessment, the Asthma Quality of Life Questionnaire (AQLQ) scores (P = 0.003), maintenance oral corticosteroid doses (P = 0.027), and exacerbation frequency (P = 0.017) were significantly improved, while prebronchodilator-forced expiratory volume in 1 second (% predicted) did not significantly change (P = 0.19). When we grouped the patients into 2 groups according to their body mass index levels, the AQLQ scores were more improved in patients with overweight/obesity than those with normal weight (P = 0.01). This study showed that patients with non-controlled severe asthma exhibiting overweight/obesity and low quality of life had potential benefits from BT.

[EFFECTIVENESS OF ADD-ON SUBLINGUAL IMMUNOTHERAPY FOR THE TREATMENT OF JAPANESE CEDAR POLLINOSIS-ASSOCIATED ALLERGIC ASTHMA IS IT POSSIBLE TO REDUCE THE DOSE OF INHALED CORTICOSTEROID BY ADDING SUBLINGUAL IMMUNOTHERAPY?]

BACKGROUND: This study investigated the effect of adjuvant sublingual immunotherapy (SLIT) on inhaled corticosteroid (ICS) dose in patients with pollinosis-associated asthma. METHODS: We retrospectively evaluated patients with cedar pollinosis-associated asthma who initiated pharmacotherapy with or without adjuvant SLIT therapy from December 2014 to December 2016 and who continued treatment for 3 years. Changes in ICS dose (fluticasone propionate or its equivalent), antihistamine use, leukotriene antagonist use and intranasal corticosteroid (INCS) use over the 3-year period were compared. RESULTS: The study included 36 and 35 patients in the add-on SLIT and standard treatment groups, respectively. At 3 years, the add-on SLIT group showed a significant decline in ICS dose (p = 0.024). Although leukotriene antagonist use and INCS use did not differ between the two groups, the percentage of patients using antihistamines at 3 years was significantly lower in the add-on SLIT group than in the standard treatment group (p = 0.009); one in three patients on adjuvant SLIT therapy was able to discontinue ICS treatment. Patients who discontinued ICS treatment were younger (44.6±13.3 years vs. 55.0±14.1 years, p = 0.042), had a higher FEV1% predicted (109.9±14.4 vs. 94.8±18.6, p = 0.02), and were on a lower treatment step (2.1±0.7 vs. 3.0±0.8, p = 0.002) than those who did not. CONCLUSION: The addition of SLIT to standard pharmacotherapy resulted in a significant reduction in ICS dose at 3 years.

Pembrolizumab-associated bronchiolitis in an elderly lung cancer patient required the treatment with an inhaled corticosteroid, erythromycin and bronchodilators.

Immune checkpoint inhibitors (ICIs) have been used to treat lung cancer. Several types of ICI-related interstitial lung diseases have been reported, including organizing pneumonia, non-specific interstitial pneumonia, and diffuse alveolar damage. However, pembrolizumab-associated bronchiolitis requiring treatment for persistent cough has not yet been reported. Here, we describe a patient who developed dry cough while being treated with pembrolizumab for lung adenocarcinoma. Radiography and lung biopsy findings indicated bronchiolitis. His cough improved after the discontinuation of pembrolizumab and treatment with erythromycin, an inhaled corticosteroid, a long-acting muscarinic antagonist, and a long-acting ß2 agonist.

Interstitial Lung Disease as an Initial Manifestation of Giant Cell Arteritis.

Interstitial lung disease (ILD) has rarely been reported as a manifestation of giant cell arteritis (GCA). We herein report a unique case of GCA in a 76-year-old woman who presented with ILD as an initial manifestation of GCA. Ten years before admission, she had been diagnosed with granulomatous ILD of unknown etiology. Corticosteroid therapy induced remission. One year after the cessation of corticosteroid therapy, she was admitted with a persistent fever. After admission, she developed left oculomotor paralysis. Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) proved extremely useful in establishing the diagnosis. Our case promotes awareness of GCA as a possible diagnosis for granulomatous ILD with unknown etiology.

Successful Treatment with Alectinib for Choroidal Metastasis in Anaplastic Lymphoma Kinase Rearranged Non-small Cell Lung Cancer.

Choroidal metastasis is rare in cancer patients and it may cause visual disturbances that reduce their quality of life. In non-small cell lung cancer (NSCLC), targeted therapy against actionable driver mutations has gradually replaced radiotherapy as the treatment of choice for choroidal metastasis. Recently, there have been several case reports of choroidal metastasis in patients with anaplastic lymphoma kinase (ALK)-rearranged NSCLC. We herein report the case of a 40-year-old Japanese woman diagnosed with choroidal metastasis of an ALK-rearranged NSCLC who received alectinib as the first-line chemotherapy. Alectinib may be the best treatment for choroidal metastasis in patients harboring an ALK translocation because of its favorable side effect profile involving visual disturbances.

Varicella Reinfection with Unilateral Varicella Pneumonia.

Varicella zoster virus (VZV) infection does not always provide lifelong immunity. A reinfection with VZV occurs more commonly than previously thought. Varicella infection spreads through the blood-stream, causing pneumonia. Varicella pneumonia results in bilateral pulmonary nodular infiltrations. We herein report a case of varicella reinfection with unilateral varicella pneumonia in which a reduced pulmonary blood flow due to radiation damage was considered to be the cause of unilateral pneumonia. In patients with an asymmetric pulmonary blood flow, careful interpretation of unilateral infiltration is therefore considered to be important with making a differential diagnosis.

Pulmonary Sarcoidosis Presenting with Miliary Opacities.

Lung lesions often appear in patients with sarcoidosis; however, miliary opacities are rare. We herein report the case of a 40-year-old woman with pulmonary sarcoidosis who presented with dyspnea on exertion. Subsequent computed tomography showed miliary opacities, and the presence of granulomas was confirmed by a transbronchial lung biopsy. Glucocorticoid therapy was initiated and the symptoms and miliary opacities rapidly improved. Although miliary sarcoidosis is uncommon, physicians should consider sarcoidosis in addition to tuberculosis, malignancy, and pneumoconiosis when presented with miliary opacities.

Hard metal lung disease diagnosed on a transbronchial lung biopsy following recurrent contact dermatitis.

A 63-year-old man employed in a hard metal manufacturing company for 40 years presented with a chronic dry cough and exertional dyspnea 20 years after the onset of recurrent exanthemas. A chest radiograph revealed bilateral reticular shadows in the upper lung field. Pathological specimens in which tungsten was detected were obtained via a transbronchial lung biopsy. Patch tests were positive for cobalt and other metals. The patient was diagnosed with hard metal lung disease (HMLD) concurrent with contact dermatitis and treated with corticosteroids. This case suggests that allergies to metal may play a role in the onset of HMLD.

Anaplastic large cell lymphoma mimicking fibrosing mediastinitis.

Fibrosing mediastinitis is rare. One type of this disease is idiopathic fibrosing mediastinitis. It is necessary to rule out malignancy in order to accurately diagnose fibrosing mediastinitis. We herein report a case of anaplastic large cell lymphoma diagnosed three months after a preliminary diagnosis of fibrosing mediastinitis. Glucocorticoid therapy was not successful in controlling disease progression. Immediately after initiating chemotherapy for lymphoma, the patient's symptoms improved dramatically and the mediastinal lesion decreased in size. Although few similar cases have been reported, hidden malignancy may present as fibrosing mediastinitis. Therefore, physicians should consider the probability of malignancy in patients with fibrosing mediastinitis because treatments may vary accordingly.

[A clinical study of pulmonary Mycobacterium abscessus infection].

Pulmonary Mycobacterium abscessus infection is resistant to many antibiotics and is difficult to treat. We retrospectively analyzed the clinical characteristics of pulmonary infection due to M. abscessus. Eleven cases diagnosed as having pulmonary M. abscessus infection at Osaka Red Cross Hospital from January. 2008, to June, 2012 were enrolled in this study. The average age of the 11 cases was 63 years (all were females). Nine cases showed underlying diseases, comprising 5 cases with Mycobacterium avium complex lung infection, 3 with old pulmonary tuberculosis, and 3 with bronchiectasis. The radiological examination revealed that 10 cases showed the small nodular type, 7 showed the bronchiectatic type, 4 showed a cavity lesion and 4 showed infiltrative shadows. A microbiological definite diagnosis was made from sputum in 10 cases and bronchial lavage fluid in one. As treatment for M. abscessus pulmonary infection, combined multi-drug chemotherapy was carried out in 7 of the 11 cases. No patients were successfully treated with antibiotics alone, whereas 4 patients had no exacerbation of radiological findings without any treatment. One patient received antibiotics including clarithromycin, amikacin and levofloxacin for 2 to 12 months following surgical excision and her sputum cultures have been maintained as negative over the long-term. During the study, none of the 11 patients were known to have died. In this study, we found that M. abscessus pulmonary infection is more common among females, and is found frequently in patients with M. avium complex lung infection. We also found that the clinical course of M. abscessus pulmonary infection was different among patients. We think this is because M. abscessus was shown to comprise three closely related species. M. abscessus is extremely difficult to eradicate, and surgical resection of localized disease or the main lesion or cavity may be significantly effective in preventing the progression of disease.

[A case of nocardiosis with associated endobronchial excavated lesions].

A case of nocardiosis with associated endobronchial excavated lesions is reported. A 79-year-old woman was diagnosed as having dermatomyositis in March, 2010. She was started on prednisolone (50mg/day) and was then switched to betamethasone due to lower limb edema and tapered to a dose of 2.5mg/day. A periodic chest X-ray examination in July, 2010, incidentally revealed nodular densities and associated cavities in the upper right lung field. On thoracoabdominal computed tomography (CT), bilateral pulmonary nodular shadows with various-sized cavities and multiple, new, intrahepatic, low-density regions were also identified. On bronchoscopy, a white, excavated lesion resembling an ulcerous lesion was observed in the left upper lobe bronchus, and a small exophytic lesion was observed in the right B6 bronchus. Nocardia asteroides complex was isolated from cultures of bronchial lavage fluid and sputum. The patient was treated with 4 weeks of intravenous imipenem (1.5g/day), followed by oral minocycline therapy (200mg/day) for 6 months, after which lesion resolution was confirmed on CT and treatment was discontinued. No recurrence has been reported in the roughly 18 months of follow-up to date. Nocardiosis results from infection with bacteria of the zoonotic, aerobic, Actinomyces genus and presents with disseminated lesions. Reported cases of human infection are increasing due to greater numbers of immunocompromised patients and improved diagnostic techniques. However, nocardiosis involving endobronchial lesions is extremely rare, and, to the best of our knowledge, the present case is the first report of endobronchial excavated lesions caused by nocardiosis.