Antineutrophil cytoplasmic antibodies and their relationship with disease activity and presence of staphylococcal superantigens in nasal swabs in patients having granulomatosis with polyangiitis: results of a study involving 115 patients from a single center.

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCAs) are considered a risk factor for granulomatosis with polyangiitis (GPA) exacerbation, especially when staphylococcal superantigens (SAgs) are present in nasal swabs. Their role in monitoring disease activity remains controversial. This study determined the relationship of ANCAs with disease activity and presence of SAgs in GPA patients. METHODS: Among a total of 115 GPA patients hospitalized in the period 2009-2016, we investigated the presence of SAgs and ANCA concentration. Blood samples and nasal swabs were taken at each visit (referred further to as episodes). Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). RESULTS: We analyzed 362 episodes. ANCAs were detected in 215 (59.4%), while SAgs were detected in 126 (34.8%) episodes. We found a significant correlation between the presence of ANCAs and disease activity (p = 0.0032), as well as between their level and GPA severity (r = 0.25363, p = 0.000001). We also determined that an ANCA values ≥ 138 Ru/ml were an indicator of active disease with high specificity and low sensitivity (84.4% and 37.3%, respectively). The relationship between ANCA presence and the presence of SAgs was not confirmed; however, when SAgs were analyzed based on the different types, ANCA levels were found to be significantly higher in the group with SAg type B (p = 0.031). CONCLUSIONS: There was no detectable evidence for the association between ANCA level and the presence of SAgs. Although monitoring ANCA levels as a marker of disease activity may be clinically relevant, GPA management cannot proceed on the basis of ANCA levels alone. Key Points • ANCA concentration usually correlates with GPA activity, although in half of patients, ANCAs persist despite effective treatment and clinical remission. • ANCA values of 138 Ru/ml seem to be an indicator of active disease with high specificity, but low sensitivity. • Although there is a relevance for ANCA monitoring as a marker of disease activity, GPA management cannot be based on ANCA levels alone. • The suspected clinical correlation between ANCA formation and SAg presence in nasal swabs is not obvious and requires further investigations.

Pneumothorax in Patients with Pulmonary Langerhans Cell Histiocytosis.

INTRODUCTION: Pneumothorax often develops in pulmonary Langerhans cell histiocytosis (PLCH), but some patients take a long time to be correctly diagnosed. OBJECTIVES: This study assessed the frequency of pneumothorax in PLCH and analysed the role of chest computed tomography (CT) in the prompt diagnosis. PATIENTS AND MATERIAL: Of the 90 patients with PLCH seen from 2000 to 2015, 29 (32%) had pneumothorax as the initial finding. In this group, 18 (62%) patients were diagnosed within 1 month, whereas the diagnosis was delayed for 4-120 months in 11 (38%) patients. RESULTS: Patients who had pneumothorax as the initial sign of PLCH tended to be younger (mean age 27.7 ± 7.92 vs. 39.9 ± 13.21 years; P = 0.0001), male (69% vs. 43%; P = 0.028), smoked less (mean pack/years 8.4 ± 6.85 vs. 19 ± 17.16; P = 0.003), and had a significantly lower mean FVC (77.96 ± 19.62 vs. 89.47 ± 21.86% pred.; P = 0.015) and FEV1 (68.6 ± 19.93 vs. 79.4 ± 21.48% pred.; P = 0.03 than patients who had no pneumothorax. Recurrent pneumothorax was diagnosed more frequently in the group with a delayed diagnosis (82% vs. 39%; P = 0.02). CT was performed in all of the patients who were diagnosed promptly, but in none of the patients with a delayed diagnosis. CONCLUSIONS: Patients who had pneumothorax as the initial sign of PLCH were younger, more frequently men, and had greater respiratory impairment than those who had no pneumothorax. CT in patients with pneumothorax led to a correct diagnosis of this disease.

Cryptogenic Organizing Pneumonia: IL-1ß, IL-6, IL-8, and TGF- ß1 Serum Concentrations and Response to Clarithromycin Treatment.

Cryptogenic organizing pneumonia (COP) is a distinct clinicopathological entity with unknown etiology. Inflammatory cytokines play a role in the development of the disease. The present study was performed to assess the correlation between concentrations of IL-1ß, IL-6, IL-8, and TGF-ß1 in the serum with response to clarithromycin (CAM) treatment in patients with COP. A total of 39 patients with COP were enrolled in to this study. An oral dose of 500 mg CAM was administered to all of the patients twice daily for 3 months. A complete response was noticed in 31 (80 %) of patients, and 8 (20 %) patients failed to respond to treatment. The concentration of cytokines were assessed by ELISAs before and after treatment. CAM treatment was associated with decreases in serum IL-6 (3.8 pg/mL [IQR 0.9-11.8] vs. 1.1 pg/mL [IQR 0.2-3.1]; p = 0.004), IL-8 (13.6 pg/mL [IQR 9.8-17.5] vs. 8.1 pg/mL [IQR 6.2-13.2]; p = 0.004), and TGF-ß1 (37.1 ng/mL [IQR 31.7-46.2] vs. 25.7 ng/mL [IQR 22-41.7];p = 0.0001), which was particularly notable in the responders. We conclude that IL-6, IL-8, and TGF-ß1 may play a role in the pathogenesis of COP, as their decreased concentrations were associated with a positive response to CAM treatment.

Pulmonary Function Abnormalities in Regard to Age at the Time of Diagnosis of Hypersensitivity Pneumonitis.

Hypersensitivity pneumonitis (HP) is a complex syndrome caused by exaggerated immune response to inhalation of a variety of organic particles in susceptible individuals. In this study we assessed the relationship between age at the time of diagnosis and the degree of functional and radiological changes in HP. The diagnosis of HP was made on the basis of a combination of clinical symptoms, medical history, serological tests, radiologic evidence of diffuse lung disease, and absence of other identifiable causes of lung disease. We reviewed the records of 111 patients (68 women) diagnosed with HP over a period of 18 years (1995-2013). The patients were stratified into 3 age-groups: <30, 30-49, and ≥50 years old. The commonest cause of HP was avian antigens (56.8 %). Dyspnea was present in 97.3 % of patients, weight loss in 54.7 % of patients, and respiratory insufficiency in 24.3 % of patients. Lung fibrosis in chest computed tomography was found in 35.1 % of patients. Lung function was impaired more seriously in the youngest age-group, with lung diffusing capacity for carbon monoxide (DLCO) <40 % in 69.2 % of these patients. Restrictive pattern was present in 92.3 % of patients in this group, as compared with the 41.0 % in the whole cohort. In this group, desaturation in the six minute walk test also was most notable, amounting to a median of 11 %. In conclusion, diagnosis of HP at young age is predictive of a more severe clinical course of disease, with lung fibrosis and higher disturbances in pulmonary function.

Influence of delays in diagnosis and treatment on survival in small cell lung cancer patients.

The purpose of this study was to evaluate the influence on survival of delays in the diagnosis and treatment in an unselected population of small cell lung (SCLC) patients. Demographic and disease data of 3,479 SCLC patients were registered in the National Tuberculosis and Lung Diseases Research Institute in Warsaw, Poland during 1995-1998. In 50 % of patients, treatment started within 78 days from the appearance of first symptom(s). The median delay was 30 days (mean 47 days) and the median referral delay to a specialist was 19 days (mean 36 days). Half of SCLC patients were diagnosed during 34 days (mean 55 days). The mean time elapse from the diagnosis to the onset of therapy was 30 days (median 6 days). The multivariate analysis revealed that male gender-HR (hazard ratio = 1.2), ECOG Performance Status of 2 (HR = 1.5) and 3 + 4 (HR = 2.4), and clinical stage III (HR = 1.3) and IV (HR = 1.9) of the disease were independent negative predictors of survival. The patients treated with surgery and combined modality treatment had a better prognosis than those treated with chemoradiotherapy (HR = 1.6), chemotherapy (HR = 2.5), symptomatically (HR = 4.0), or those who refused therapy (HR = 3.9). The delay in the diagnosis and treatment had no effect on survival. Interestingly, patients who were diagnosed faster (below 42 days) actually had a worse prognosis than those diagnosed later. We conclude that a prolonged workup of SCLC patients and an extended time for treatment onset have a positive influence on survival, which may likely have to do with the determination of disease stage and more targeted treatment.

Bronchial hyperreactivity in sarcoidosis patients: correlation with airflow limitation indices.

UNLABELLED: Bronchial hyperreactivity (BHR) in sarcoidosis has been reported in 5 to 83% of patients, but the relationship between BHR and airway functional status being unclear. The aim of the study was to assess the prevalence and degree of BHR in a group of pulmonary sarcoidosis patients and how BHR does relate to the functional status of airways. MATERIAL AND METHODS: 56 consecutive sarcoidosis outpatients (26 f, 30 m) were included. There were 14 (25%) patients in stage I, 32 (57.1%) patients in stage II and 10 (17.9%) patients in stage III. In all patients the standard evaluation included a history, physical examination, chest radiogram, serum ACE activity and lung function assessment were done. The provocation challenge test with doubling concentrations of histamine was performed in all patients using the standardized protocol recommended by the ERS. RESULTS: 4 patients (7%) were restrictive, airway obstruction was detected in 7 (12.5%) cases. Up to 32% of patients had maximal expiratory flows at low lung volumes below the lower limit of normal (LLN). The histamine challenge test results: in 9 cases (16%) the fall in FEV1 was < 20% of the baseline; mean PC20H (n = 47) was 5.7 +/- 5.9 mg/mL, range: 0.56-26.7 mg/mL. The challenge test was regarded as positive (PC20H < or = 8 mg/mL) in 71.4% of the group. BHR expressed as ln(PC20H) correlated weakly but significantly with FEV1, FEV1%VC, MMEF and PEF. CONCLUSION: BHR occurs frequently in sarcoidosis patients and should be considered especially in patients with airflow limitation.

Neoadjuvant therapy affects tumor growth markers in early stage non-small-cell lung cancer.

INTRODUCTION: While adjuvant therapy of early-stage non-small-cell lung cancer (NSCLC) is widely accepted, literature data concerning neoadjuvant treatment provide contradictory results with both improved and unaffected survival rates. Also, data concerning potential effects of neo-adjuvant therapy on cellular level are scarce. OBJECTIVE: The aim of present study was to analyze the effect of chemotherapy followed by surgical resection on several key biological markers of tumor growth (TGF-beta, VEGF), apoptosis (sAPO-1/Fas/CD95) and invasiveness (TIMP-1) assessed in the sera of NSCLC early-stage patients (IB-IIIA). - MATERIAL AND METHODS: Measurements were performed by ELISA method in blood serum from 24 NSCLC patients (I-IIIA) collected prior therapy, one day before surgery and 3 days after. RESULTS: TGF-beta serum concentrations were significantly lower after both chemotherapy (P<0.05) and surgery (P<0.01) in comparison to the baseline. VEGF levels decreased following NEO therapy with subsequent significant up-regulation after surgery (P<0.001). Interestingly, post-surgery serum VEGF strongly correlated with TGF-beta concentration (r = 0.52, P = 0.014). No significant differences were observed for serum sAPO-1/CD95/FAS as well as TIMP-1 concentrations at any of three evaluated time-points. CONCLUSION: Neoadjuvant treatment of early-stage NSCLC affects mostly mechanisms responsible for tumor growth and vascularization. Its effect on cancer cells apoptotic activity needs further evaluation.

Interferon gamma production in the course of Mycobacterium tuberculosis infection.

It is not clear why some individuals with unknown predisposition develop tuberculosis, while others remain healthy in spite of heavy exposure. Interferon gamma (IFNgamma) is considered to be the key cytokine responsible for resistance to M. tuberculosis infection, as confirmed by increased susceptibility to mycobacterial infections in rare inherited defects in IL-12-IFNgamma axis. The aim of this study was to assess the IFNgamma production by peripheral blood lymphocytes from immunocompetent tuberculosis (TB) patients. The study group included 51 TB patients. In all cases, TB was confirmed by culture. Twenty healthy TB contacts were considered as control group. Commercially available ELISA-based assays were used to measure IFNgamma in the supernatant of whole blood cell cultures after stimulation with PWM (Phytolacca Americana), PHA (phytohemagglutynin), and PPD (purified protein derivative). No difference in IFNgamma secretion between the patients and control group was found when blood cells were stimulated by PWM or PHA. PPD-induced IFNgamma formation was higher in TB patients than in controls. The secretion of IFNgamma after non-specific stimulation varied in different clinical and radiological presentation of tuberculosis and it was lower in most advanced and extensive forms of the disease. It is unclear whether the difference in formation and release of IFNgamma is a primary or secondary phenomenon in the course of the disease.

Neuroendocrine phenotype of non-small cell lung carcinoma: immunohistological evaluation and biochemical study.

AIMS AND METHODS: The prevalence and distribution of neuroendocrine differentiation in non-small cell lung cancer (NSCLC) was estimated by assays for synaptophysin (SYN), chromogranin A (CgA), Leu7 and neuron-specific enolase (NSE). Serum NSE and CgA were determined in parallel to find the values of these markers for distinguishing neuroendocrine differentiation in NSCLC. Fifty-eight resected NSCLC specimens and 34 sera of NSCLC patients entered the study. Neuroendocrine differentiation was graded according to the percentage of neuroendocrine tumor cells as NE0--0%, NE1-NE4--1%->76%. Serum NSE <12.5 ng/mL and serum CgA <46 U/L were taken as cutoff levels. RESULTS: 63.8% (37/58) of NSCLC were scored as NE1-NE4 according to the SYN, CgA and Leu7 levels; 34.5% as NE1; 29.3% as NE2-NE4. 56.8% of tumors were positive for SYN, 34.4% for CgA, 22.4% for Leu7, and 79.3% for NSE. A significant relationship was found between tumor SYN and tumor CgA expression, and between tumor SYN expression and tumor stage. Adenocarcinomas showed a significantly higher rate of neuroendocrine differentiation than squamous cell carcinomas. All normal serum CgA levels corresponded to a lack of CgA expression in the tumors. The increased serum NSE levels presented by 26% of NSCLC patients (mainly <16 ng/mL) did not correlate with tumor NSE expression. CONCLUSIONS: The prevalence of neuroendocrine differentiation in NSCLC varies and depends on the immunohistochemical criteria used; this warrants standardization of the immunohistochemical criteria for neuroendocrine differentiation in NSCLC. NSE expression in the tumor and a mild increase in serum NSE are poor markers for distinguishing neuroendocrine differentiation in NSCLC.

Expression of vascular endothelial growth factor and basic fibroblast growth factor receptors in lung cancer.

OBJECTIVE: To determine the expression of two angiogenic factors, vascular endothelial growth factor (VEGF) and fibroblast growth factor receptors (FGFR), in non-small cell lung carcinoma (NSCLC) in relation to tumor stage (TN0, TN1, TN2) and in association with the expression of p53 protein, a potential suppressor of tumor angiogenesis. STUDY DESIGN: The immunohistochemical (IHC) expression of VEGF and FGFR was examined in paraffin sections of 56 NSCLC in relation to the presence of lymph node metastases and p53 expression. Nodal status of NSCLC determined: 27 tumors, N0; 16, N1; and 13, N2 stage. Semiquantitative analysis with a score corresponding to IHC staining intensity and percentage of positive cells was used. Statistical analysis was performed with the chi 2 test. RESULTS: A significant association was noted between VEGF and FGFR expression in NSCLC. No relation was found between VEGF, FGFR expression and lymph node metastasis or p53 expression. CONCLUSION: We assume that VEGF and FGFR act in a synergistic manner in NSCLC and that their expression is not related to lymph node metastases. Angiogenesis is a very complex phenomenon and heterogeneous within tumors. Also, it is affected by microenviromental factors.