Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma.

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions.

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.

Pulmonary Nocardiosis With Endobronchial Involvement Caused by Nocardiaaraoensis.

We report a rare case of pulmonary nocardiosis with endobronchial involvement caused by Nocardia araoensis. A 79-year-old man with a history of asthma and a previous right upper lobectomy for lung cancer and organizing pneumonia presented with cough and dyspnea. He presented with right bronchial stenosis associated with various mucosal lesions, including ulcerative and exophytic lesions. N araoensis was detected in sputum samples collected via bronchoscopy. The mucosal lesions improved after a 2-week course of meropenem. After a further 6 months of oral sulfamethoxazole-trimethoprim treatment, the mucosal lesions completely disappeared. Based on bronchoscopic and pathophysiologic findings, the patient was diagnosed with pulmonary nocardiosis with endobronchial involvement. Nocardiosis should be considered in the differential diagnosis of endobronchial mucosal lesions.

[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.

CD8 and CD103 are highly expressed in asthmatic bronchial intraepithelial lymphocytes.

BACKGROUND: Although characteristics of intraepithelial lymphocytes (IELs) in mucosal immunity have been well defined in the intestine, bronchial IELs have been little investigated. Recently, we showed that bronchial IELs have a distinct function that partly resembles that of intestinal IELs; however, surface antigen expression of bronchial IELs and the relationship of that expression to airway disease have not been studied. METHODS: We analyzed phenotypic profiles of human bronchial IELs and lamina propria lymphocytes (LPLs) by double-staining immunohistochemistry using full-thickness bronchial specimens (10 nonasthmatic controls and 7 asthmatics) from lung resections. RESULTS: In controls, the percentage of CD4+ cells was lower, and the percentage of CD8+ cells was higher in IELs compared to LPLs (CD4: median 50.0% in IELs vs. 65.9% in LPLs, p = 0.01; CD8: 50.9% in IELs vs. 34.4% in LPLs, p = 0.007). The percentage of cells positive for CD103 (αE-integrin) was higher in IELs than that in LPLs (median 60.1% in IELs vs. 16.9% in LPLs; p < 0.001). In IELs from asthmatics, these characteristics were particularly significant (CD4: median 26.2%, p = 0.008; CD8: 79.8%, p = 0.007; CD103: 76.2%, p = 0.019; all compared with IELs from nonasthmatics). CONCLUSIONS: These results suggest that human bronchial IELs have roles distinct from subsets of other lymphocytes, and that CD8+ cells and CD103+ cells have potentially important functions in the bronchial epithelium.

[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.

Severe pulmonary alveolar proteinosis with respiratory failure treated by intrapulmonary percussive ventilation.

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by abnormal accumulation of surfactant in the alveoli. Whole lung lavage (WLL) is the standard treatment for severe autoimmune PAP (aPAP); however, it is highly invasive. Intrapulmonary percussive ventilation (IPV) is a non-invasive technique that delivers small bursts of high-flow respiratory gas into the lung and mobilizes secretions. As IPV is beneficial for chronic respiratory diseases such as cystic fibrosis and bronchiectasis to reduce sputum, it was hypothesized that IPV will ameliorate aPAP by mobilizing and removing accumulated surfactant and foamy macrophages. Here, we report the case of a 52-year-old female with severe aPAP and progressive respiratory failure. She received intermittent IPV therapy for six months and thereby showed improvement in assessments of chest computed tomography (CT), lung function, and oxygenation. We suggest that IPV should be used as an alternative therapy for patients with aPAP and respiratory failure.

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.

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.

Improvement of arterial stiffness by the antioxidant and anti-inflammatory effects of short-term statin therapy in patients with hypercholesterolemia.

The preventive effect of statins on coronary events is not only associated with the cholesterol-lowering effect of these drugs, but also various direct effects on the vascular wall, which include improvement of endothelial function, antioxidant activity, and anti-inflammatory activity. We investigated whether short-term statin therapy could improve arterial stiffness and assessed its mechanism of action in patients with hypercholesterolemia. We assessed arterial stiffness in 10 patients (mean age: 62.9 +/- 9.0 years) with hypercholesterolemia (total cholesterol > or =220 mg/dl). The patients were treated with cerivastatin (0.15 mg/day) for 4 weeks. Before and after 4 weeks of treatment, we determined arterial stiffness from brachial-ankle pulse wave velocity and the ankle-brachial blood pressure index (ABI) using a FORM apparatus (Colin, Komaki, Japan). We also measured the blood levels of high-sensitivity C-reactive protein (hsCRP) and malondialdehyde low-density lipoprotein (MDA-LDL) as markers of inflammation and oxidation, respectively. After statin therapy, both the right and left abPWV were significantly decreased from 1544.6 +/- 157.1 to 1349.0 +/- 223.9 cm/s and from 1592.1 +/- 164.8 to 1424.8 +/- 245.2 cm/s, respectively (P < 0.05). However, the ABI was unchanged after 4 weeks of cerivastatin therapy. MDA-LDL decreased significantly (from 161.2 +/- 42.4 to 119.4 +/- 33.5 U/l, P < 0.05) and hsCRP also decreased. Total cholesterol and LDL-cholesterol decreased, while triglycerides and high-density lipoprotein-cholesterol were unchanged. Blood pressure was not significantly altered from the baseline value by statin therapy. These results suggest that the preventive effect of statins on coronary events is partly associated with the various actions of these drugs on the vascular wall, and that statins are not only cholesterol-lowering agents but also antiatherosclerotic agents.

T cells of atopic asthmatics preferentially infiltrate into human bronchial xenografts in SCID mice.

T cells play an important role in the pathogenesis of bronchial asthma. However, it is not completely known how circulating lymphocytes infiltrate into the airways of asthmatic patients. Because SCID mice are unable to reject xenogenic transplants, many xenotransplant models using various human tissues have been developed. Therefore, to examine the interaction between bronchi and T lymphocytes of asthma, it may be possible to use the human bronchial xenograft and PBMC xenograft in SCID mice. We transplanted human bronchi into the subcutaneum of SCID mice and i.p. injected PBMCs that were obtained from patients with atopic asthma, atopic dermatitis and rheumatoid arthritis, and normal subjects (asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice). There was no difference in the percentage of CD3-, CD4-, CD8-, CD25-, CD45RO-, CD103-, and cutaneous lymphocyte Ag-positive cells in PBMCs among the patients with asthma, dermatitis, rheumatoid arthritis, and normal subjects, and CD3-positive cells in peripheral blood of asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice. The number of CD3-, CD4-, and CD8-positive cells in the xenografts of asthmatic huPBMC-SCID mice was higher than those of dermatitis, rheumatic, and normal huPBMC-SCID mice. IL-4 mRNA and IL-5 mRNA were significantly higher in the xenografts of asthmatic huPBMC-SCID mice than those in the xenografts of normal huPBMC-SCID mice, but there were no significant differences in the expressions of IL-2 mRNA or IFN-gamma mRNA between them. These findings suggest that T cells, especially Th2-type T cells, of asthmatics preferentially infiltrate into the human bronchi.