Protective effect of bevacizumab on chemotherapy-related acute exacerbation of interstitial lung disease in patients with advanced non-squamous non-small cell lung cancer.

BACKGROUND: Acute exacerbation of interstitial lung disease (AE-ILD) is the most serious complication in lung cancer patients with pre-existing ILD receiving chemotherapy. The role of vascular endothelial growth factor (VEGF) in pathogenesis of AE-ILD is conflicting. The influence of bevacizumab (Bev), a monoclonal antibody against VEGF, on lung cancer patients with pre-existing ILD remains unclear. We examined the effect of Bev on reducing AE-ILD risk in non-squamous non-small cell lung cancer (NSCLC) patients receiving chemotherapy. METHODS: We analysed incidence of AE-ILD and outcomes of 48 patients with advanced non-squamous NSCLC with ILD who received first-line chemotherapy with (Bev group, n = 17) and without (non-Bev group, n = 31) Bev between July 2011 and July 2016. Gray's test, which was competing risk analysis during the study period, was performed for both groups. RESULTS: The most common regimen used for first-line chemotherapy was the combination of carboplatin plus pemetrexed (PEM) in both groups. The incidences of chemotherapy-related AE-ILD 120 days after first-line chemotherapy initiation were significantly lower in the Bev than in the non-Bev groups (0% vs. 22.6%, p = 0.037, Gray's test). However, there were no differences in development of progressive disease of lung cancer and other events as the competing risk factors of AE-ILD between the two groups. Only patients receiving PEM-containing regimens also showed a significant difference in the incidence of AE-ILD between the two groups (p = 0.044). The overall-cumulative incidence of AE-ILD during the first-line and subsequent chemotherapy was 29.2% (14 of the 48). The median progression-free survival was significantly longer in the Bev than in the non-Bev groups (8.0 vs. 4.3 months, p = 0.026). CONCLUSIONS: The addition of Bev to chemotherapy regimens may reduce the risk of chemotherapy-related AE-ILD in patients with lung cancer.

Down-regulated Th17 cells in a patient with familial Mediterranean fever associated with amyloid A amyloidosis in the treatment of canakinumab.

Autoinflammatory diseases are innate immune-mediated inflammatory disorders, unlike autoimmune diseases, which are characterised by abnormalities in adoptive immunity, although autoimmune and autoinflammatory diseases have certain similar clinical features. Familial Mediterranean fever (FMF), the most common monogenic autoinflammatory disease, is associated with mutations in the MEFV gene that encodes pyrin, which results in inflammasome activation and uncontrolled production of interleukin (IL)-1ß. Regular use of colchicine, the primary drug for FMF treatment, prevents febrile attacks and reduces the long-term risk of subsequent complications of amyloid A (AA) amyloidosis. However, a minority of FMF patients develop colchicine resistance, and anti-IL-1ß treatment with canakinumab, which is a genetically modified human IgG subclass type 1 (IgG1) monoclonal antibody specific for human IL-1ß, was beneficial in inhibiting inflammation in such patients. Here, we present a patient with FMF associated with AA amyloidosis, who was treated with canakinumab and demonstrated down-regulated Th17 cells and activated Th17 cells (from 21.4% to 12.8%, and from 1.45% to 0.83%, respectively) in peripheral blood, as shown by immunophenotyping via multicolour flow cytometry and by disease activity and improved laboratory inflammatory surrogate markers-C-reactive protein (CRP) and serum AA protein (SAA). CRP had values within normal limits, but SAA did not (Spearman's rank correlation coefficient; ρ = 0.133). We report that SAA and IL-1ß may differentiate Th17 cells from CD4+-naïve T cells, and we discuss interactions between autoinflammation and autoimmunity as a model based on this case, through modes of action with IL-1ß and SAA. This report is the first demonstrating that an IL-1ß antagonist may reduce Th17 cells in FMF as a therapeutic option.

[Methotrexate-related lymphomatoid granulomatosis in a patient with rheumatoid arthritis].

A 76-year-old man who was taking prednisolone and methotrexate for rheumatoid arthritis presented with gastric ulcers. Chest X-ray images showed multiple pulmonary nodules. Transbronchial lung biopsy specimens showed lymphocytic infiltrates but no malignant cells. The radiographic findings gradually ameliorated over a month, but then deteriorated 5 months later. We performed video-assisted thoracoscopic biopsy of the left lung, and the biopsy specimens showed lymphocytic infiltration with necrosis, in which the atypical lymphocytes were positive for Epstein-Barr virus-encoded small RNAs in situ hybridization (EBER-ISH). A diagnosis of lymphomatoid granulomatosis was determined. One year before this diagnosis, the patient was found to have an inflammatory liver tumor that had disappeared spontaneously within a month. A new pathological review of the liver and stomach lesions demonstrated EBER-ISH-positive lymphocytes, and therefore we assumed that they were pathological features of lymphomatoid granulomatosis. The chest radiographic findings improved gradually after the discontinuation of methotrexate. We therefore suggest that methotrexate treatment may be associated with the development of lymphomatoid granulomatosis in patients with rheumatoid arthritis. Lymphoproliferative disorders, including lymphomatoid granulomatosis, should be considered in patients with rheumatoid arthritis who are receiving methotrexate.

[A case of bronchial glomus tumor].

A 67-year-old man was admitted to our hospital because of a cough and hemoptysis. Chest CT and bronchoscopy demonstrated a polypoid tumor in the truncus intermedius. The pathological diagnosis of the biopsy specimens was glomus tumor, which is an extremely rare tumor of the respiratory tract. We performed a successful bronchoscopic removal of the tumor using a high-frequency-wave snare and microwave coagulation. After one year of follow-up, there was no recurrence. To the best of our knowledge, this is only the 24th report of a tracheobronchial glomus tumor.

Amyloid A amyloidosis in a patient with Caplan's syndrome, with special reference to genetic predisposition.

Secondary amyloid A (AA) amyloidosis, which is a disorder of protein conformation and metabolism, is an important serious complication of inflammatory diseases, especially rheumatoid arthritis (RA). AA amyloidosis develops when AA fibrils, which are derived from the acute-phase reactant, serum amyloid AA (SAA) protein, in the circulation, are deposited in organs and cause systemic organ dysfunction. Caplan's syndrome, or rheumatoid pneumoconiosis, is a rare type of lung disease in which individuals suffering from RA develop lung nodules that are associated with occupational exposure to silica and coal dust. Confirmation of diagnosing as Caplan's syndrome requires the patient's occupational history, imaging studies, and serology. A 72-year-old male, working as a tunnel construction worker for 38 years, with RA who had both chronic cardiac and renal dysfunction was referred to our hospital. He received a diagnosis of pneumoconiosis about 20 years ago, after which he was also diagnosed with RA. So far we performed medical English literature searches on the combination of Caplan's syndrome with AA amyloidosis; there were no articles in relation to such association. Although RA is one of the most common underlying diseases that occur with AA amyloidosis, our report here is the first description of a case of Caplan's syndrome associated with AA amyloidosis. In this report, we provide details about this rare disease occurring with AA amyloidosis and discuss on the possible pathogenesis of AA amyloidosis from a genetic point of aetiological view.

Prognostic impact of pre-existing interstitial lung disease in non-HIV patients with Pneumocystis pneumonia.

BACKGROUND: The increasing incidence of life-threatening Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients is a global concern. Yet, no reports have examined the prognostic significance of pre-existing interstitial lung disease (ILD) in non-HIV PCP. METHODS: We retrospectively reviewed the medical records of non-HIV PCP patients with (ILD group) or without (non-ILD group) pre-existing ILD. The clinical features and outcomes of the ILD group were compared with those of the non-ILD group. Cox regression models were constructed to identify prognostic factors. RESULTS: 74 patients were enrolled in this study. The 90-day mortality was significantly higher in the ILD group than in the non-ILD group (62.5% versus 19.0%, p<0.001). In the ILD group, patients with a higher percentage of bronchoalveolar lavage fluid neutrophils had worse outcomes compared to those having a lower percentage (p=0.026). Multivariate analyses revealed that pre-existing ILD (p=0.002) and low levels of serum albumin (p=0.009) were independent risk factors for 90-day mortality. Serum levels of ß-d-glucan were significantly reduced after treatment of PCP in both groups, whereas levels of Krebs von den Lungen-6 (KL-6) significantly increased in the ILD group. In the ILD group, the 90-day mortality of patients with increasing KL-6 levels after treatment was significantly higher than those with decreasing levels (78.9% versus 0%, p=0.019). CONCLUSION: In non-HIV PCP patients, pre-existing ILD is associated with a poorer prognosis. Prophylaxis for PCP is needed in patients with pre-existing ILD under immunosuppression.

[Individualized inhalation instruction using check sheets by a pharmacist in community pharmacy improves inhalation techniques in asthmatic patients].

BACKGROUND: Many types of inhaled medications are used for the treatment of asthma; however, inadequate inhalation techniques and poor adherence cause exacerbations of asthma symptoms. It is necessary to therefore provide adequate instruction to acquire correct inhalation techniques. This study aimed to evaluate the usefulness of individualized inhalation instruction in asthmatic outpatients by a community pharmacist for an improvement of the inhalation techniques and asthma control. METHODS: Twenty-eight asthmatic outpatients who have developed asthma over a long period and received prescriptions from Kumamoto Chuo Hospital from April to August 2008 were instructed by a pharmacist on inhalation techniques at Shimokawa Hamasen Pharmacy. Individual instruction by the pharmacist consisted of a skill-check with inhalers, followed by the use of a checklist of inhalation technique, a self-evaluation checklist, and visual information for the patients. Outcomes were evaluated based on changes in inhalation technique mastery between their first visit and the subsequent visit. Nineteen of the 28 patients who completed the Asthma Control Test (ACT) were also evaluated for asthma control according to changes in their ACT scores. RESULTS: Twenty patients showed inadequate inhalation techniques. The individualized instruction resulted in significant improvement in the inhalation techniques. Moreover, there were significant improvement in the ACT scores (from 19.1 to 21.4) of 19 patients who received the individualized instruction. CONCLUSION: The individualized instruction to the asthmatic outpatients enables them to improve the inhalation techniques to mend their asthmatic symptoms. We suggest that coordination with hospital and community pharmacy improves therapeutic outcomes in inhaled medication for the asthmatic outpatients.

[A case of lymphomatoid granulomatosis].

An 83-year-old man was found to have multiple pulmonary nodules and ground-glass opacities after a left upper lobectomy for non-small-cell lung cancer. After bronchoalveolar lavage and transbronchial lung biopsy, he was put on a regimen of steroids for a tentative diagnosis of organizing pneumonia. Over the course of 3 months, the radiographic findings improved; however, they progressively deteriorated during the steroid tapering period and new skin lesions also appeared. Skin biopsy specimens showed lymphohistiocytic infiltration in which the atypical lymphocytes were positive for EBV encoding small RNAs by in situ hybridization; we therefore diagnosed lymphomatoid granulomatosis. The pulmonary and cutaneous lesions responded to steroid and cyclophosphamide therapy, but the patient died unexpectedly due to a rapid onset of massive pulmonary thromboembolism.

Three-rods test as drivers' license vision test from the viewpoint of reproducibility, eye deviation, and functional visual acuity.

BACKGROUND: Three-rods test is required as depth perception vision test to obtain motor vehicle license to drive taxies, buses, and trucks in Japan. Functional visual acuity is measured automatically by successive visual target presentation in a fixed period of time. This study examined three-rods test from the viewpoint of reproducibility, eye deviation, and functional visual acuity to assess the feasibility for drivers' license vision test. METHODS: At three-rods test, a central rod was moved at the speed of 50 mm/sec forward and backward automatically against two fixed rods on both sides inside an illuminated box. An examinee at the distance of 2.5 m observed the rods inside the box from a small window and pushed a button to stop the central rod in alignment with the fixed rods. Erred distance of the central rod from the fixed rods as a mean of 4 measurements was used. At functional visual acuity test, an examinee moved a joystick to the same direction as Landolt-C opening as a visual target which was sequentially presented every 2 seconds for 30 times in 1 minute. RESULTS: The mean erred distance of three-rods test was reproducible between two tests done on separate occasions (n = 44, ρ = 0.679, P < 0.0001, Spearman rank correlation). Exophoria induced by wearing 4-prism-diopter base-out prism did not significantly influence the mean erred distance while vertical diplopia induced by wearing 4-prism-diopter base-up prism disrupted the measurement (n = 9). The mean erred distance of three-rods test was better correlated with functional visual acuity tested with both eyes open than with conventional visual acuity with both eyes open (n = 17, ρ = 0.2 versus ρ = 0.179). CONCLUSION: In the context of the small sample size in the present study, the three-rods test was reproducible, and testable in the presence of phoria, but not testable in diplopia, indicating the feasibility as a depth perception vision test.

[Case of drug-induced lung injury due to Rebamipide].

A 76-year-old man was admitted because of chest discomfort and diffuse pulmonary interstitial shadows. The diagnosis of drug-induced lung injury due to Rebamipide was made based on the transbronchial lung biopsy specimen and Drug Lymphocyte Stimulating Test (DLST) for Rebamipide (Mucosta). Corticosteroid therapy was effective.

Successful treatment of primary pulmonary angiosarcoma.

Angiosarcoma in the lung is an uncommon disorder and is usually attributable to metastasis from a primary site. Primary pulmonary angiosarcoma is extremely rare, and the prognosis of affected individuals is dismal, with most patients dying within months of presentation. Indeed, there have been no reported instances of successful treatment of this condition. We now report the case of a patient with primary pulmonary angiosarcoma who responded to a combination of radiotherapy and immunotherapy with recombinant interleukin-2. The patient remains well without signs of recurrence 1 year after initial presentation. This combination therapy may be a promising strategy to prolong the survival of patients with primary pulmonary angiosarcoma.

[A case of polaprezinc-induced pneumonitis].

A 77-year-old man referred to our hospital three months ago presented with dyspnea on effort and chest radiograph abnormalities. Chest computed tomography showed consolidation and irregular thickening of the peribronchovascular interstitium. Bronchoalveolar lavage fluids showed increases in the percentage of lymphocytes and a decrease of the CD4/8 ratio. Transbronchial lung biopsy specimens showed signs of organizing pneumonia. The patient had been given polaprezinc for the treatment of hypogeusia six months before. A lymphocyte-stimulating test for polaprezinc was positive, and so our diagnosis was polaprezinc-induced pneumonitis.

Fibroproliferative changes on high-resolution CT in the acute respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational cohort study.

OBJECTIVES: To examine whether the extent of fibroproliferative changes on high-resolution CT (HRCT) scan influences prognosis, ventilator dependency and the associated outcomes in patients with early acute respiratory distress syndrome (ARDS). DESIGN: A prospective observational cohort study. SETTING: Intensive care unit in a teaching hospital. PARTICIPANTS: 85 patients with ARDS who met American-European Consensus Conference Criteria and eligible criteria. INTERVENTIONS: HRCT scans were performed and prospectively evaluated by two independent observers on the day of diagnosis and graded into six findings according to the extent of fibroproliferation. An overall HRCT score was obtained by previously published method. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was 60-day mortality. Secondary outcomes included the number of ventilator-free days, organ failure-free days, the incidence of barotraumas and the occurrence of ventilator-associated pneumonia. RESULTS: Higher HRCT scores were associated with statistically significant decreases in organ failure-free days as well as ventilator-free days. Multivariate Cox proportional hazards model showed that the HRCT score remained an independent risk factor for mortality (HR 1.20; 95% CI 1.06 to 1.36; p=0.005). Multivariate analysis also revealed that the CT score had predictive value for ventilator weaning within 28 days (OR 0.63; 95% CI 0.48 to 0.82; p=0.0006) as well as for an incidence of barotraumas (OR 1.61; 95% CI 1.08 to 2.38; p=0.018) and for an occurrence of ventilator-associated pneumonia (OR 1.46; 95% CI 1.13 to 1.89; p=0.004). A HRCT score <210 enabled prediction of 60-day survival with 71% sensitivity and 72% specificity and of ventilator-weaning within 28 days with 75% sensitivity and 76% specificity. CONCLUSIONS: Pulmonary fibroproliferation assessed by HRCT in patients with early ARDS predicts increased mortality with an increased susceptibility to multiple organ failure, including ventilator dependency and its associated outcomes.

Prediction of prognosis for acute respiratory distress syndrome with thin-section CT: validation in 44 cases.

PURPOSE: To retrospectively evaluate whether the thin-section computed tomographic (CT) appearance has prognostic value for prediction of mortality, number of ventilator-free days (ie, days without mechanical ventilation), and 28-day risk of barotrauma in patients with a clinically early stage of acute respiratory distress syndrome (ARDS) from diverse causes. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Two independent observers who were blinded to patient outcomes retrospectively evaluated the thin-section CT scans obtained within 7 days after clinical ARDS onset in 26 survivors and 18 nonsurvivors. Of 44 patients, there were 37 men and seven women (mean age +/- standard deviation, 61.8 years +/- 15.6). CT findings were graded on a scale of 1-6 that corresponded with consecutive pathologic phases: score of 1, normal attenuation; score of 2, ground-glass attenuation; score of 3, consolidation; score of 4, ground-glass attenuation associated with traction bronchiolectasis or bronchiectasis; score of 5, consolidation associated with traction bronchiolectasis or bronchiectasis; and score of 6, honeycombing. An overall CT score was obtained by adding the six averaged scores (three zones in each lung). Multivariate regression analysis was used to assess the independent predictive value of the CT score. RESULTS: The area of increased attenuation associated with traction bronchiolectasis or bronchiectasis (P = .002), as well as the overall CT score (P = .002), was smaller in survivors than in nonsurvivors. Results of multivariate regression analysis revealed that CT score was independently associated with mortality (P = .006). A CT score of less than 230 enabled prediction of survival with 73% sensitivity and 75% specificity and was associated with both a greater number of ventilator-free days (P = .018) and a lower incidence of barotrauma (P = .013) within 28 days after ARDS onset. CONCLUSION: Extensive thin-section CT abnormalities indicative of fibroproliferative changes were independently predictive of poor prognosis in patients with a clinically early stage of ARDS.