Pre-Existing Interstitial Lung Abnormalities Are Independent Risk Factors for Interstitial Lung Disease during Durvalumab Treatment after Chemoradiotherapy in Patients with Locally Advanced Non-Small-Cell Lung Cancer.

Introduction/Background: Chemoradiotherapy (CRT) followed by durvalumab, an immune checkpoint inhibitor, is the standard treatment for locally advanced non-small-cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a life-threatening toxicity caused by these treatments; however, risk factors for the ILD have not yet been established. Interstitial lung abnormalities (ILAs) are computed tomography (CT) findings which manifest as minor interstitial shadows. We aimed to investigate whether ILAs could be risk factors for grade-two or higher ILD during durvalumab therapy. Patients and Methods: Patients with NSCLC who received durvalumab after CRT from July 2018 to June 2021 were retrospectively enrolled. We obtained patient characteristics, laboratory data, radiotherapeutic parameters, and chest CT findings before durvalumab therapy. Results: A total of 148 patients were enrolled. The prevalence of ILAs before durvalumab treatment was 37.8%. Among 148 patients, 63.5% developed ILD during durvalumab therapy. The proportion of patients with grade-two or higher ILD was 33.8%. The univariate logistic regression analysis revealed that older age, high dose-volume histogram parameters, and the presence of ILAs were significant risk factors for grade-two or higher ILD. The multivariate analysis showed that ILAs were independent risk factors for grade-two or higher ILD (odds ratio, 3.70; 95% confidence interval, 1.69−7.72; p < 0.001). Conclusions: We showed that pre-existing ILAs are risk factors for ILD during durvalumab treatment after CRT. We should pay attention to the development of grade-two or higher ILD during durvalumab treatment in patients with ILAs.

Association between work-related changes caused by the COVID-19 pandemic and severe psychological distress among Japanese workers.

This study aimed to evaluate the association between work-related changes caused by COVID-19 and psychological distress among Japanese workers. The cross-sectional study was conducted from August 25 to September 30, 2020. The participants were 15,454 employees who were registered as panelists with an online survey company. The Kessler psychological distress scale with a 13-point cutoff was used to measure psychological distress. Multiple logistic regression was performed. Of the respondents, 8.9% were evaluated as having severe psychological distress. Among five examined work-related changes, being laid off and changing jobs (adjusted odds ratio [aOR] = 5.43; 95% confidence interval [CI]: 4.18-7.05), experiencing temporary workplace closure (aOR = 1.94; 95% CI: 1.67-2.25), being forced to visit the workplace for paperwork (aOR = 1.84; 95% CI: 1.58-2.15), and starting telework from home (aOR = 1.18; 95% CI: 1.01-1.37) were associated with increased psychological distress; no significant association was found for participation in work-related online meetings. The impact on psychological distress was greater among men, especially for being laid off and changing jobs because of COVID-19. It is important to assess and reduce negative mental health effects among workers experiencing work-related changes caused by the COVID-19 pandemic, taking gender differences into account.

Selexipag for the treatment of chronic thromboembolic pulmonary hypertension.

BACKGROUND: Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remain limited. Selexipag, an oral selective IP prostacyclin receptor agonist approved for pulmonary arterial hypertension, is a potential treatment option for CTEPH. METHODS: In this multicentre, randomised, double-blind, placebo-controlled study, 78 Japanese patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and/or balloon pulmonary angioplasty were randomly assigned to receive placebo or selexipag. The primary end-point was the change in pulmonary vascular resistance (PVR) from baseline to week 20. Secondary end-points were changes in other haemodynamic parameters: 6-min walk distance (6MWD), Borg dyspnoea scale score, World Health Organization (WHO) functional class, EuroQol five-dimension five-level tool and N-terminal pro-brain natriuretic peptide. RESULTS: The change in PVR was -98.2±111.3 dyn·s·cm-5 and -4.6±163.6 dyn·s·cm-5 in the selexipag and placebo groups, respectively (mean difference -93.5 dyn·s·cm-5; 95% CI -156.8 to -30.3; p=0.006). The changes in cardiac index (p<0.001) and Borg dyspnoea scale score (p=0.036) were also significantly improved over placebo. 6MWD and WHO functional class were not significantly improved. The common adverse events in the selexipag group corresponded to those generally observed following administration of a prostacyclin analogue. CONCLUSION: Selexipag significantly improved PVR and other haemodynamic variables in patients with CTEPH, although exercise capacity remained unchanged. Further large-scale investigation is necessary to prove the role of selexipag in CTEPH.

Treatment rationale and design of the PROLONG study: safety and efficacy of pembrolizumab as first-line therapy for elderly patients with non-small cell lung cancer.

BACKGROUND: Pembrolizumab is recommended as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and a Programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, the safety and efficacy were not investigated among patients who were ≥75 years old. METHODS: This open-label single-arm phase II study is designed to evaluate pembrolizumab as first-line therapy for patients who are ≥75 years old with advanced NSCLC and a PD-L1 TPS of ≥50% without driver mutations. The primary endpoint is progression-free survival, and the secondary endpoints are overall survival, objective response rate, safety, and quality of life. Recruitment started in October 2017 and is expected to continue for approximately 3 years. CONCLUSIONS: Given the currently poor prognosis of elderly patients with advanced NSCLC, we hope that the findings of this study will facilitate more effective treatment in this setting.

Appendicitis complicated by appendiceal metastasis via peritoneal dissemination from lung cancer.

Peritoneal disseminations from lung cancer are difficult to detect during the patient's clinical course. Therefore, complications of this condition are unclear. We report a case in which peritoneal dissemination from lung cancer complicated appendicitis. A 74-year-old man with lung cancer who was receiving maintenance therapy presented at our hospital because of abdominal pain. It was the seventh day after the 14th cycle of maintenance therapy with bevacizumab. He was diagnosed with acute appendicitis. The resected appendix showed acute appendicitis complicated by appendiceal metastasis from lung cancer. Adenocarcinoma was observed predominantly in the serous membrane from the neck to the tail of the appendix. The distribution of the adenocarcinoma was diffuse. Peritoneal dissemination was considered the route of metastasis. He was admitted to the palliative care unit 10 months after appendectomy. Appendiceal metastasis via peritoneal dissemination from lung cancer complicated appendicitis in our patient who had been receiving bevacizumab.

Establishment of reference costs for occupational health services and implementation of cost management in Japanese manufacturing companies.

OBJECTIVES: We developed a standardized cost estimation method for occupational health (OH) services. The purpose of this study was to set reference OH services costs and to conduct OH services cost management assessments in two workplaces by comparing actual OH services costs with the reference costs. METHODS: Data were obtained from retrospective analyses of OH services costs regarding 15 OH activities over a 1-year period in three manufacturing workplaces. We set the reference OH services costs in one of the three locations and compared OH services costs of each of the two other workplaces with the reference costs. RESULTS: The total reference OH services cost was 176,654 Japanese yen (JPY) per employee. The personnel cost for OH staff to conduct OH services was JPY 47,993, and the personnel cost for non-OH staff was JPY 38,699. The personnel cost for receipt of OH services-opportunity cost-was JPY 19,747, expense was JPY 25,512, depreciation expense was 34,849, and outsourcing cost was JPY 9,854. We compared actual OH services costs from two workplaces (the total OH services costs were JPY 182,151 and JPY 238,023) with the reference costs according to OH activity. The actual costs were different from the reference costs, especially in the case of personnel cost for non-OH staff, expense, and depreciation expense. CONCLUSIONS: Using our cost estimation tool, it is helpful to compare actual OH services cost data with reference cost data. The outcomes help employers make informed decisions regarding investment in OH services.

Life-threatening pulmonary lymphedema secondary to thoracic duct ligation.

We herein report an extremely rare adult case presenting with life-threatening pulmonary lymphedema secondary to generalized lymphedema. A 47-year-old woman with generalized lymphedema from her feet to below her chest, had undergone surgical ligation of the thoracic duct and bilateral pleurodesis for the treatment of intractable idiopathic chylothorax three years earlier. Chest computed tomography demonstrated bilateral ground-glass opacities, air-space consolidation and interlobular septal wall thickening, presenting as a crazy-paving appearance predominantly on the gravity side. Bronchoalveolar lavage revealed marked lymphocytosis. She was treated with long-term oxygen therapy with noninvasive positive-pressure ventilation, followed by lymphovenous anastomoses of the lower extremities.

[ACTH therapy for two cases of epileptic spasms without hypsarrhythmia].

We present two patients with epileptic spasms without hypsarrhythmia (ESWoH) who were successfully treated with ACTH. One patient was an 18-month-old boy who had normal development for the first 16 months of his life. Thereafter, he experienced sudden flexion of the axial muscles, resulting in head nodings, or epileptic spasms (ES). EEG tracings showed generalized polyspikes that appeared frequently during sleep without associated hypsarrhythmia. We were thus able to diagnose him with ESWoH and treated him with ACTH, which resolved his seizures. Another patient was a 7-year-old boy. At 18 months of age, the patient began to sufferdil from sudden ES. Anti-epileptic drugs were administered individually and in combination but were proved ineffective. Like the first case, this child's EEG tracing showed generalized polyspikes during sleep without associated hypsarrhythmia. We diagnosed him with ESWoH and treated him with ACTH. His ES disappeared soon after the initiation of treatment. These two cases demonstrate the difficulty of treating ESWoH only with standard anti-epileptic drugs, we emphasize the importance of early treatment with ACTH.

Asymptomatic primary tuberculous pleurisy with intense 18-fluorodeoxyglucose uptake mimicking malignant mesothelioma.

BACKGROUND: The pathogenesis of primary tuberculous pleurisy is a delayed-type hypersensitivity immunogenic reaction to a few mycobacterial antigens entering the pleural space rather than direct tissue destruction by mycobacterial proliferation. Although it has been shown that pulmonary tuberculosis induces 18-fluorodeoxyglucose (FDG) uptake in active lesions, little is known about the application of FDG positron emission/computed tomography (FDG PET/CT) to the management of primary tuberculous pleurisy. CASE PRESENTATION: We report a case of asymptomatic primary tuberculous pleurisy presenting with diffuse nodular pleural thickening without distinct pleural effusion and parenchymal lung lesions mimicking malignant mesothelioma. An initial FDG PET/CT scan demonstrated multiple lesions of intense FDG uptake in the right pleura and thoracoscopic biopsy of pleural tissue revealed caseous granulomatous inflammation. The patient received antituberculous therapy for 6 months, with clearly decreased positive signals on a repeated FDG PET/CT scan. CONCLUSION: FDG PET/CT imaging may be useful for evaluating disease activity in tuberculous pleurisy patients with an unknown time of onset.

Association of airway inflammation with asthma control level evaluated by the asthma control test.

BACKGROUND: The association between airway inflammation and asthma control level is not clear at present. OBJECTIVE: This study aimed to explore the association by using induced sputum and asthma control status as determined by the Asthma Control Test (ACT). We also evaluated the association between the scores for each ACT question item and eosinophilic or neutrophilic airway inflammation. METHODS: The ACT and sputum induction were performed at the same time. Associations between total scores or scores for each question item and sputum eosinophil or neutrophil counts were examined. The study was approved by an Institutional Review Board. RESULTS: Of the 101 patients with chronic asthma enrolled, data from 98 (controlled n = 66, uncontrolled n = 32) were analyzed [60.0 years (43.0-68.0) M:F = 34:64]. Current control status determined by the ACT was not significantly associated with eosinophilic or neutrophilic inflammation. Among the ACT items, only nocturnal symptoms were associated with sputum eosinophils: patients with a positive answer to the question had significantly higher eosinophil counts than patients with a negative answer [5.4 (2.2-17.6) versus 2.1 (0.7-7.3), respectively, p = 0.08]. Furthermore, significant correlation was found between eosinophil counts and the scores for nocturnal symptoms (rs = -0.218 p = 0.031). On the other hand, patients with rescue use of a short-acting b2-agonist (SABA) had significantly higher sputum neutrophil counts than non-SABA users [73.4 (52.8-83.4) versus 61.0 (36.3-74.8), respectively, p = 0.031]. The other ACT items were not significantly associated with sputum neutrophils. The neutrophil count correlated significantly with the frequency of rescue SABA use (rs = -0.218 p = 0.031). CONCLUSIONS: Asthma control level evaluated by the ACT was not associated with airway eosinophilic or neutrophilic inflammation. However, the frequency of nocturnal symptoms was associated with sputum eosinophilia, and the frequency of rescue SABA use was associated with sputum neutrophilia.

[Effective cyclophosphamide pulse therapy for an young infant with severe dermatomyositis].

We herein report a 3 year-old boy, who showed proximal muscle weakness and pain at the age of one and a-half years. When he visited our hospital at the age of 1 year and 11 months, he could hardly move by himself. He also had difficulty in swallowing and suffered from multiple dermal ulcers. His blood test showed slightly elevated muscle enzyme activity, and magnetic resonance imaging suggested severe inflammation of the muscles. Radiological examination proved hypoperistalsis of the esophagus. With additional skin and muscle biopsies, we diagnosed him with juvenile dermatomyositis (JDM). Methyl-prednisolone pulse therapy was not effective enough, thus oral methotrexate, cyclosporine A and monthly cyclophosphamide pulse therapy were added. After the fourth cyclophosphamide pulse therapy, his muscular strength was restored, and the ulcers healed dramatically. Due to scarcity of severe cases, neither standardized classification nor grading system for severity in JDM has ever been established, which perplexes physicians in finding the best therapeutic strategy. Further investigation, experience and efforts are necessary to standardize an evaluating system and therapeutic strategy against JDM.

[The ketogenic diet as an effective treatment for Ohtahara syndrome].

We here report on a male infant with Ohtahara syndrome. Tonic spasms in series appeared in an one-month-old baby, with his EEG showing a typical suppression burst pattern. We attempted these therapies in the following order; high-dose pyridoxal phosphate; anti-epileptic drugs; sodium valproate, phenobarbital, clonazepam and clobazam in various doses and combination; ACTH; TRH; and gamma-globulin. These did not, however, prove effective enough. Then we tried the ketogenic diet and brought his seizures under control. Therefore, we recommend that doctors who treat Ohtahara syndrome consider using the ketogenic diet earlier in the treatment regimen if the patient does not seem to be responding to conventional drug therapies.

[A case of tumor microembolism diagnosed by perfusion scan and transbronchial lung biopsy].

A 70-year-old woman with breast cancer treated with hormonal therapy had progressive shortness of breath for one month. Chest radiograph and computed tomography showed mild interstitial changes, but could not account for her respiratory failure. Lymphangitic carcinomatosis, drug-induced pneumonitis, idiopathic interstitial pneumonitis, opportunistic infection, and pulmonary edema were considered in the differential diagnosis of the CT findings. A perfusion scan revealed numerous small subsegmental perfusion defects in both lung fields. Bronchoalveolar lavage fluid (BALF) contained some cancer cells, suggesting lymphangitic carcinomatosis. Transbronchial biopsy (TBLB) specimen showed tumor emboli in small pulmonary arteries. Immunohistochemical findings of TBLB specimen were consistent with breast cancer cells. A diagnosis of tumor microembolism caused by breast cancer metastasis was made. Antemortem diagnosis of tumor microembolism is very difficult. Here, we report a case of tumor microembolism diagnosed by perfusion scan and TBLB.

Blood levels of catecholamine metabolites and brain-derived neurotrophic factor in a case of Sydenham's chorea.

We report a case of Sydenham's chorea with neuropsychiatric symptoms who was successfully treated with low-dose risperidone. We also longitudinally investigated serum BDNF levels and plasma levels of catecholamine metabolite in the patient. Serum BDNF levels were increased and plasma levels of HVA and MHPG were decreased according to the recovery from the active phase of the disease. These results suggest that dysfunctions of catecholaminergic neurons and neurotrophic factors might exist in Sydenham's chorea, and the decreasing catecholamine activities in response to risperidone might be associated with the improvement of the disease.

Anti-inflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease.

BACKGROUND: The airway inflammation of chronic obstructive pulmonary disease (COPD) demonstrates a poor response to the anti-inflammatory actions of corticosteroids. However, long-acting beta(2)-agonists and low-dose theophylline are reported to have a possible anti-inflammatory effect in COPD. The aim of this study was to compare the effects of treatment between theophylline and the tulobuterol patch (transdermal patch preparation designed to yield sustained beta(2)-agonistic effects for 24h) on airway inflammation in addition to quality of life (QOL) and pulmonary function in mild-to-moderate COPD. METHODS: The study subjects consisted of 26 patients with COPD who were treated with theophylline or tulobuterol for 8 weeks with a wash-out period of 4 weeks in a randomized open-label crossover study. We prospectively investigated the differential cell counts and levels of inflammatory markers in induced sputum before and after treatment with theophylline and tulobuterol. We also examined pulmonary function and quality of life (QOL) as assessed by St. George's Respiratory Questionnaire. RESULTS: In the induced sputum, the total inflammatory cell count and number of neutrophils were significantly reduced by treatment with low-dose theophylline. Neither of these parameters was significantly changed by treatment with tulobuterol. Pulmonary function measurements such as FEV(1), FEV(1) % pred, FVC, PEF, MEF(50), and MEF(25) were significantly improved by the treatment with low-dose theophylline but not tulobuterol. The total QOL scores, levels of interleukin 8 and myeloperoxidase in the supernatants of induced sputum, and serum levels of hypersensitive C-reactive protein were not significantly changed by either of the treatments. CONCLUSION: These results suggest that treatment with low-dose theophylline but not the tulobuterol patch may have anti-inflammatory effects and improve pulmonary function in mild-to-moderate COPD.

[A 16-year-old boy with meningoencephalitis with auto-antibody against glutamate receptor].

We herein report a 16-year-old boy who presented with fever and generalized convulsion. His symptoms progressively worsened, and electroencephalography (EEG) showed status with bi-frontal focus. One month after the initial presentation, examination of the cerebrospinal fluid showed pleocytosis, an increase in the IgG index and a positive oligoclonal IgG band. Brain MRI suggested slightly high signal intensity in the cerebral gray matter on FLAIR images. We considered that the patient had autoimmune meningoencephalitis, and therefore treated him with methyl-predonisolone pulse therapy, which substantially improved both his clinical condition and EEG findings. Before the therapy, the IgM and IgG auto-antibodies against glutamate receptor (GluR) epsilon 2 and delta 2 were positive, however they became negative after the therapy. In conclusion, some cases of meningoencephalitis with auto-antibodies against GluR may show an electrical status, mild brain MRI findings, and a good response to methylprednisolone pulse therapy. These clinical features were quite different from those observed for cases of Rasmussen's encephalitis.

Infantile neuronal ceroid lipofuscinosis: the first reported case in Japan diagnosed by palmitoyl-protein thioesterase enzyme activity deficiency.

We herein report on a Japanese boy with infantile neuronal ceroid lipofuscinosis (INCL). He was born of incest to a girl and her maternal uncle. His development was normal at 12 months, and began to display regression at 14 months. He lost his social smile and tracking eye movement at 16 months, and could not stand and developed severe hypotonic tetraplegia at 19 months. Myoclonic movement was observed in his trunk, eye and extremities. His height, body weight and head circumstance had been normal. Both MRI and CT scans of his head showed severe cerebral, cerebellar and brainstem atrophy. The electroretinogram showed a decrease in amplitude. Enzyme studies revealed a deficiency of palmitoyl-protein thioesterase activity in his lymphocytes at 0.98 nmol/h/mg protein (control: 90.99+/-34.23). This is the first case of INCL in Japan diagnosed by enzyme activity deficiency.

[A boy with nystagmus, refractory dystonia and apneic attack due to alternating hemiplegia of childhood].

We herein report the findings of a 2-year-6-month-old boy, who had been experiencing monocular pendular nystagmus, strabismus, and episodic eye deviation nystagmus, intractable dystonia and apneic attack which all began when he was 2 days of age. He underwent a complete blood count test, blood chemistry test, analysis of amino acids in the blood and urine, analysis of pyruvate/lactate in blood and cerebrospinal fluid, head computed tomography and magnetic resonance imaging and no abnormal results were identified. His attacks were resistant to multiple antiepileptic and dopaminergic drugs. He showed transient left and/or right hemiplegia after nystagmus, dystonia and/or apneic attacks at 8-months of age with retardation in intelligence. We diagnosed him to have alternating hemiplegia of childhood (AHC). We were unsure how to deal with his attacks after he was discharged from the hospital, however, resuscitation with the ambu bag by his mother at home and the intravenous infusion of diazepam or thiamylal at the hospital together was proven to be an effective method for treating his severe apneic attacks. The effect of diazepam and amantadine on these attacks was transient, however, the administration of flunarizine with amantadine resulted in an improvement in his attacks. We therefore consider the administration of flunarizine to be essential for the effective treatment of AHC in this case.