Predicting treatment outcomes and responder subsets in scleroderma‐related interstitial lung disease

Objective

To identify baseline characteristics of patients with scleroderma‐related interstitial lung disease (SSc‐ILD) that could serve as predictors of the most favorable response to 12‐month treatment with oral cyclophosphamide (CYC).

Methods

Regression analyses were retrospectively applied to the Scleroderma Lung Study data in order to identify baseline characteristics that correlated with the absolute change in forced vital capacity (FVC) (% predicted values) and the placebo‐adjusted change in % predicted FVC over time (the CYC treatment effect).

Results

Completion of the CYC arm of the Scleroderma Lung Study was associated with a placebo‐adjusted improvement in the % predicted FVC of 2.11% at 12 months, which increased to 4.16% when patients were followed up for another 6 months (P = 0.014). Multivariate regression analyses identified the maximal severity of reticular infiltrates (assessed as maximum fibrosis scores) on high‐resolution computed tomography (HRCT) at baseline, the modified Rodnan skin thickness score (MRSS) at baseline, and the Mahler baseline dyspnea index as independent correlates of treatment response. When patients were stratified on the basis of whether 50% or more of any lung zone was involved by reticular infiltrates on HRCT and/or whether patients exhibited an MRSS of at least 23, a subgroup of patients emerged in whom there was an average CYC treatment effect of 9.81% at 18 months (P < 0.001). Conversely, there was no treatment effect (a −0.58% difference) in patients with less severe HRCT findings and a lower MRSS at baseline.

Conclusion

A retrospective analysis of the Scleroderma Lung Study data identified the severity of reticular infiltrates on baseline HRCT and the baseline MRSS as patient features that might be predictive of responsiveness to CYC therapy.

     

Clinical outcomes of advanced non-small cell lung cancer patients screened for epidermal growth factor receptor gene mutations

Purpose  

To evaluate the relationship between the epidermal growth factor receptor (EGFR) mutation status and the effectiveness of gefitinib monotherapy or chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).     

Second-line epidermal growth factor receptor inhibitors followed by third-line pemetrexed or the reverse sequence: a retrospective analysis of 83 Chinese patients with advanced lung adenocarcinoma

Background  

The optimal treatment sequence of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) and pemetrexed in previously treated advanced lung adenocarcinoma patients is currently unknown.     

Transbronchial Cryobiopsy in Immunocompromised Patients with Pulmonary Infiltrates: A Pilot Study

Background

In immunocompromised patients with pulmonary infiltrates, transbronchial lung biopsies (TBB) obtained by forceps has been shown to increase the diagnostic yield over simple bronchoalveolar lavage. Cryo-TBB is a novel modality for obtaining lung biopsies. We aimed to evaluate for the first time the efficacy and safety of cryo-TBB in immunocompromised patients.

Methods

Fifteen immunocompromised patients with pulmonary infiltrates underwent cryo-TBB. During the procedure two to three biopsy samples were taken. Procedure characteristics, complications, and the diagnostic yield were retrospectively evaluated.

Results

Most patients (n = 11) were immunocompromised due to hematological malignancies. The remaining four patients were receiving chronic immunosuppressive treatment due to previous solid-organ transplantation (n = 2) or collagen-vascular disease (n = 2). No major complications occurred in the cryo-TBB group. The mean surface area of the specimen taken by cryo-TBB was 9 mm². The increase in surface area and quality of biopsy samples translated to a high percentage of alveolated tissue (70 %) that enabled a clear histological detection of the following diagnoses: noncaseating granulomatous inflammation (n = 2), acute interstitial pneumonitis consistent with drug reaction (n = 5), nonspecific interstitial pneumonia fibrotic variant (n = 1), diffuse alveolar damage (n = 3), organizing pneumonia (n = 3), and pulmonary cryptococcal pneumonia (n = 1). Diagnostic information obtained by cryo-TBB led to change in the management of 12 patients (80 %).

Conclusion

Cryo-TBB in immunocompromised patients with pulmonary infiltrates provides clinically important diagnostic data with a low complication rate. These advantages should be further compared with traditional forceps TBB in a prospective randomized trial.     

Prediction of epidermal growth factor receptor mutations in the plasma/pleural effusion to efficacy of gefitinib treatment in advanced non-small cell lung cancer

Purpose  

Recently, mutations in the epidermal growth factor receptor (EGFR) gene were reported to correlate with EGFR tyrosine kinase inhibitor response in advanced non-small cell lung cancer (NSCLC). In this study, we attempted to detect EGFR mutations in plasma and pleural effusion samples and to make clear its correlations with gefitinib response and survival in NSCLC patients.     

The different efficacy of gefitinib or erlotinib according to epidermal growth factor receptor exon 19 and exon 21 mutations in Korean non-small cell lung cancer patients

Background  

Epidermal growth factor receptor (EGFR) mutations are associated with sensitivity to gefitinib or erlotinib in non-small cell lung cancer (NSCLC). We investigated the relationships between the two most common types of somatic EGFR mutations, exon 19 deletions and L858R mutations, and clinical outcomes of Korean NSCLC patients after treatment with gefitinib or erlotinib.     

Validation of the clinical utility of sGaw as a response variable in methacholine challenge testing

Background and Objective

Airway hyperresponsiveness (AHR) is commonly assessed by a methacholine challenge test (MCT), during which a provocative concentration causing a 20% reduction in forced expiratory volume in 1 second (FEV₁) (PC₂₀) < 8 mg/ml is considered a positive response. However, a fall in specific airway conductance (sGaw) may also have clinical significance. The purpose of this study was to assess whether AHR determined by a provocative concentration causing a 40% reduction in sGaw (PC₄₀) < 8 mg/ml corresponds to a clinical diagnosis of asthma.

Methods

We analysed the changes in spirometry, lung volumes and sGaw during MCT in 211 randomly selected patients being evaluated for AHR to support a clinical diagnosis of asthma.

Results

The mean (SD) age of the group was 53 (15) years, with 141 women (67%). Overall lung function was normal, with FEV₁ = 92 (15) % predicted, total lung capacity = 97 (13) % predicted and sGaw = 0.19 (0.15–0.23) L/s/cm H₂O/L, (median, 25–75 IQR). There were many more patients who responded by PC₄₀ only (n = 120) than who responded by PC₂₀ (n = 52). There was no significant difference in asthma diagnosis between the PC₂₀ (98%) and PC₄₀ (93%) groups, and we estimate 34% of patients with a diagnosis of asthma would have been classified as having no AHR if only the FEV₁ criterion was used.

Conclusion

Changes in sGaw during MCT indicate clinically significant AHR in support of a clinical diagnosis of asthma among patients being evaluated for asthma.     

Anatomic localization of immature and mature dendritic cell subsets in dermatomyositis and polymyositis: Interaction with chemokines and Th1 cytokine–producing cells

Objective

To clarify the involvement of dendritic cells (DCs), chemokines, and proinflammatory Th1 cytokines in the pathogenesis of the chronic muscle diseases dermatomyositis (DM) and polymyositis (PM).

Methods

We characterized by immunohistochemistry the DC subsets and their interaction with cells producing chemokines and the Th1 cytokines interleukin‐17 (IL‐17) and interferon‐γ (IFNγ). Immature and mature DCs were defined by the expression of CD1a and DC‐LAMP/CD83, respectively.

Results

Immature DCs were mainly detected in lymphocytic infiltrates in DM and PM muscle tissue samples. Mature DCs were detected in perivascular infiltrates and surrounded muscle fibers. IL‐17–positive and IFNγ‐positive cells were also observed in perivascular infiltrates in both cases. We then focused on the expression of the CCL20/CCR6 chemokine/receptor complex, which controls immature DC migration, and on the expression of the CCL19/CCR7 and CCL21/CCR7 chemokine/receptor complexes, which control mature DC migration. CCL20 and CCR6 colocalized in lymphocytic infiltrates in DM and PM samples. CCL21 was rarely observed in DM samples and never observed in PM samples. CCL19‐ and CCR7‐expressing cells were absent in both tissues.

Conclusion

The close association between CCL20/CCR6 and immature DCs suggests the contribution of CCL20 to CCR6+ immature DC homing. Detection of mature DCs in DM and PM muscle tissue samples despite the lack of CCL19 and CCR7 is evidence for a local maturation of DCs in inflammatory muscle tissue without lymphoid organ organization.

     

Performance of whole-blood interferon-gamma release assay in patients admitted to the emergency department with pulmonary infiltrates

Background  

This study was conducted to evaluate the performance of a whole-blood interferon-gamma release assay in inpatients who were admitted to the emergency department (ED) with pulmonary infiltrates who required a differential diagnosis with pulmonary tuberculosis (TB).     

N-methyl-d-aspartate receptor antibody encephalitis: a treatable disorder involving B-lymphocytes. A report of two patients

Introduction

N-methyl-D-aspartate receptor antibody (anti-NMDA-r AB) encephalitis has been recently identified. We report two cases illustrating the clinical features, response to immunomodulatory treatment and involvement of B-lymphocytes that characterizes this disorder.

Case reports

These patients illustrated the classic clinical features of anti-NMDA-r AB encephalitis including occurrence in young female, presence of severe neurological and psychiatric manifestations with confusion, seizures, mutism, hypovigilence and involuntary movements, and inflammatory cerebrospinal fluid. Both patients improved after immunotherapy. In case 1, the encephalitis was associated with an ovarian teratoma containing neuronal elements. In case 2, there was no tumor identified. A brain biopsy showed prominent perivascular B-cells infiltrates with some T-cells distributed in the brain parenchyma.

Conclusion

Anti-NMDA-r AB encephalitis is certainly not rare and needs to be promptly recognized and treated. An associated neoplasia is inconstant and the pathophysiology involves humoral immunity.     

Respiratory muscle metabolic activity on PET/CT correlates with obstructive ventilatory defect severity and prognosis in patients undergoing lung cancer surgery

Background and Objective

Respiratory muscle activity is increased in patients with chronic respiratory disease. ¹⁸F-FDG-PET/CT can assess respiratory muscle activity. We hypothesized that respiratory muscles metabolism was correlated to lung function impairment and was associated to prognosis in patients undergoing lung cancer surgery based on the research question whether respiratory muscle metabolism quantitatively correlates with the severity of lung function impairment in patients? Does respiratory muscle hypermetabolism have prognostic value?

Methods

Patients undergoing ¹⁸F-FDG-PET/CT and pulmonary function tests prior to lung cancer surgery were identified. Maximum Standardized Uptake Value (SUVm) were measured in each respiratory muscle group (sternocleidomastoid, scalene, intercostal, diaphragm), normalized against deltoid SUVm. Respiratory muscle hypermetabolism was defined as SUVm >90th centile in any respiratory muscle group. Clinical outcomes were collected from a prospective cohort.

Results

One hundred fifty-six patients were included, mostly male [110 (71%)], 53 (34%) with previous diagnosis of COPD. Respiratory muscle SUVm were: scalene: 1.84 [1.51–2.25], sternocleidomastoid 1.64 [1.34–1.95], intercostal 1.01 [0.84–1.16], diaphragm 1.79 [1.41–2.27]. Tracer uptake was inversely correlated to FEV1 for the scalene (r = −0.29, p < 0.001) and SCM (r = −0.17, p = 0.03) respiratory muscle groups and positively correlated to TLC for the scalene (r = 0.17, p = 0.04). Respiratory muscle hypermetabolism was found in 45 patients (28.8%), who had a lower VO₂ max (15.4 [14.2–17.5] vs. 17.2 mL/kg/min [15.2–21.1], p = 0.07) and poorer overall survival when adjusting to FEV1% (p < 0.01).

Conclusion

Our findings show respiratory muscle hypermetabolism is associated with lung function impairment and has prognostic significance. ¹⁸F-FDG/PET-CT should be considered as a tool for assessing respiratory muscle activity and to identify high-risk patients.     

A C118T polymorphism of <Emphasis Type="Italic">ERCC1</Emphasis> and response to cisplatin chemotherapy in patients with late-stage non-small cell lung cancer

Purpose  

To investigate the association between a single-nucleotide polymorphism (SNP) of ERCC1, Asn118Asn (C → T), and the response of patients with late-stage non-small cell lung cancer (NSCLC) (n = 142) to cisplatin-based chemotherapy.     

Induction of prolonged infiltration of T lymphocytes and transient T lymphocyte–dependent collagen deposition in mouse lungs following adenoviral gene transfer of CCL18

Objective

Levels of CCL18 are elevated in patients with scleroderma lung disease and other fibrotic pulmonary diseases associated with T lymphocyte involvement. We sought to determine whether CCL18 alone can induce pulmonary T lymphocytic infiltration and fibrosis in mouse lungs.

Methods

An adenovirus vector was constructed and used for CCL18 delivery to mouse lungs in vivo. Immunohistochemical, flow cytometric, and enzyme‐linked immunosorbent assay analyses were used to assess the resulting changes.

Results

Overexpression of CCL18 led to massive perivascular and peribronchial infiltration of T lymphocytes. Although the expression of CCL18 peaked on day 7, the infiltration persisted up to day 64 after infection. The infiltrates were negative for proliferating cell nuclear antigen and TUNEL, suggesting the role of cell trafficking, rather than proliferation and apoptosis, in the infiltration dynamics. Patchy destruction of the alveolar architecture and collagen accumulation in association with the infiltrates were also noticed. These changes were infiltration‐dependent, rather than CCL18‐dependent, since treatment with antilymphocyte serum completely abrogated the CCL18‐induced changes. The infiltrates consisted almost exclusively of T lymphocytes that were minimally activated, with a minimal increase in the expression of CD69 and no changes in the expression of CD25, Fas, FasL, or CD40L. There was no increase in total pulmonary levels of profibrotic cytokines transforming growth factor β1 (TGFβ1) or interleukin‐13, although active TGFβ1 was present locally in association with the infiltrates and areas of distorted alveolar architecture. Prestimulation of primary T lymphocytes with CCL18 in vitro caused an up‐regulation of TGFβ1 and collagen production in T lymphocyte/fibroblast cocultures.

Conclusion

CCL18 promotes selective, long‐term pulmonary infiltration of T lymphocytes and infiltration‐dependent accumulation of collagen through a TGFβ1‐dependent mechanism.

     

The Diagnostic Yield,Safety, and Impact of Flexible Bronchoscopy in Non-HIV Immunocompromised Critically Ill Patients in the Intensive Care Unit

Background

Flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) have major roles in the evaluation of parenchymal lung diseases in immunocompromised patients. Given the limited evidence, lack of standardized practice, and variable perception of procedural safety, uncertainty still exists on what constitutes the best approach in critically ill patients with immunocompromised state who present with pulmonary infiltrates in the era of prophylactic antimicrobials and the presence of new diagnostic tests.

Objective

To evaluate the diagnostic yield, safety and impact of FB and BAL on management decisions in immunocompromised critically ill patients admitted to the intensive care unit (ICU).

Methods

A prospective, observational study of 106 non-HIV immunocompromised patients admitted to the intensive care unit with pulmonary infiltrates who underwent FB with BAL.

Results

FB and BAL established the diagnosis in 38 (33%) of cases, and had a positive impact on management in 44 (38.3%) of cases. Escalation of ventilator support was not required in 94 (81.7%) of cases, while 18 (15.7%) required invasive and 3 (2.6%) required non-invasive positive pressure ventilation after the procedure. Three patients (2.6%) died within 24 h of bronchoscopy, and 46 patients (40%) died in ICU. Significant hypoxemia developed in 5% of cases.

Conclusion

FB can be safely performed in immunocompromised critically ill patients in the ICU. The yield can be improved when FB is done prior to initiation of empiric antimicrobials, within 24 h of admission to the ICU, and in patients with focal disease.

     

H1N1 (2009) influenza A infection in transplant recipient patients: a comparative study versus non-transplanted patients

Objective

To compare H1N1 (2009) influenza A infection characteristics between transplant recipient patients and non-transplanted patients. To assess the evolution of transplanted patients up to 6 months following infection.

Methods

Patients diagnosed with confirmed influenza A infection from three Parisian transplant centers between September 1st, 2009 and February 15th, 2010. Clinical symptoms, biological, and radiological findings, and management were analysed and retrospectively compared between transplanted (T) and non-transplanted patients (NT). The evolution was assessed by a follow-up questionnaire, CT results 1 to 3 months after influenza infection and FEV1 variation.

Results

Seventy patients were included. Thirteen patients had an allograft (lung: eight, kidney: four, stem cells: one): (1) hospitalization: 100% (13 out of 13) in group T, 54% (31 out of 57) in group NT (P = 0.0013); (2) pneumonia: 62% (eight out of 13) in group T, 26% (eight out of 57) in group NT (P = 0.004); (3) mortality rate among hospitalized patients: 7.7% (one out of 13) in the group T, 9.7% (three out of 57) in group NT (P = NS); (4) chest CT scan abnormalities remained in four lung transplanted patients; (5) a minimum 10% decrease in FEV1 was detected in four lung transplant recipients.

Conclusion

Our results suggest that H1N1(2009) influenza A infection in transplant recipient patients compared to non-transplanted patients: (1) more often leads to hospitalization; (2) is more frequently associated with pneumonia; (3) is responsible for a persistent graft functional impairment in lung transplant recipients; (4) has a low mortality rate similar to admitted non-transplanted patients.     

Dose effect of cigarette smoking on frequency and spectrum of epidermal growth factor receptor gene mutations in Korean patients with non-small cell lung cancer

Purpose  

This study aimed to determine the dose effect of smoking on the mutational frequency and spectrum of epidermal growth factor receptor (EGFR) gene in Korean non-small cell lung cancer (NSCLC).     

Exacerbations in Idiopathic Pulmonary Fibrosis Triggered by Pulmonary and Nonpulmonary Surgery: A Case Series and Comprehensive Review of the Literature

Background

Acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are well recognized in the progression of this uniformly fatal disease. Surgical lung biopsy and lung resection may initiate these acute events leading to a rapid deterioration and permanent decline in lung function. Our aim is to discuss the role of pulmonary and nonpulmonary surgery as a precipitating factor and to review the literature on the nature, course, and outcomes of acute exacerbations in the context of surgical interventions.

Methods

This study consisted of a retrospective case series of patients at the Johns Hopkins Hospital who experienced acute exacerbation following a surgical procedure. Patients included in the case series suffered from aggravation of dyspnea within 1?month after surgical intervention, with new infiltrates on imaging. There was no other more likely cause after diagnostic evaluation. A comprehensive review of the current literature pertaining to AEs of IPF in the context of a surgical intervention was performed.

Results

In a series of four patients from Johns Hopkins Hospital with AE in IPF, two of three patients who underwent video-assisted thoracoscopic surgery (VATS) lung biopsy had a fatal outcome. The fourth patient survived an AE after a total knee replacement but had a fatal outcome after a subsequent coronary artery bypass graft surgery. We found no report in the literature of AE in an IPF patient who underwent nonpulmonary surgery.

Conclusions

Acute exacerbations of IPF can occur postoperatively after both pulmonary and nonpulmonary surgery and are associated with a high mortality rate. As a next step, a prospective multicenter clinical study of patients with IPF undergoing both pulmonary and nonpulmonary surgeries would allow the identification of perioperative risk factors in the development of AE of IPF.     

The role of leptin receptor gene polymorphisms in determining the susceptibility and prognosis of NSCLC in Chinese patients

Aim  

Although the role of genetic polymorphisms of leptin receptor (LEPR) gene in several cancers has been documented, the association between polymorphisms of LEPR gene and lung cancer remains unknown.     

Expression and clinical significance of leptin,the functional receptor of leptin (OB-Rb) and HER-2 in non-small-cell lung cancer: a retrospective analysis

Background  

The human epidermal growth factor receptor 2 (HER-2) and leptin/OB-R system have been reported to be intertwined in several cancer types. However, limited research has been conducted with regard to this interaction in lung cancers. In this study, we investigated the relationship between the expression levels of these proteins and the development, progression and prognosis of non-small-cell lung cancer (NSCLC).     

Blood and alveolar lymphocyte subsets in pulmonary cytomegalovirus infection after lung transplantation

Background  

Cytomegalovirus (CMV) pneumonitis has been shown to be associated with lymphocytic alveolitis after lung transplantation. In the present study, we investigated a series of bronchoalveolar (BAL) and blood samples, collected in the absence of rejection or acute infectious episodes. in order -1: to evaluate intra-alveolar cell population changes concomitant with CMV replication and -2: to reappraise the value of cell population analysis in the management of patients after lung transplantation.