Lung Cancer and Interstitial Lung Diseases.

Lung cancer continues to be one of the leading causes of cancer-related death worldwide. There is evidence of a complex interplay between lung cancer and interstitial lung disease (ILD), affecting disease progression, management strategies, and patient outcomes. Both conditions develop as the result of common risk factors such as smoking, environmental exposures, and genetic predispositions. The presence of ILD poses diagnostic and therapeutic challenges in lung cancer management, including difficulties in interpreting radiological findings and increased susceptibility to treatment-related toxicities, such as acute exacerbation of ILD after surgery and pneumonitis after radiation therapy and immunotherapy. Moreover, due to the lack of large, phase III randomized controlled trials, the evidence-based therapeutic options for patients with ILDs and lung cancer remain limited. Antifibrotic treatment may help prevent pulmonary toxicity due to lung cancer treatment, but its effect is still unclear. Emerging diagnostic modalities and biomarkers and optimizing personalized treatment strategies are essential to improve outcomes in this patient population.

Clinical Utility of Pepsin and Bile Acid in Tracheal Secretions for Accurate Diagnosis of Aspiration in ICU Patients.

BACKGROUND: Aspiration of stomach content or saliva in critical conditions-e.g., shock, intoxication, or resuscitation-can lead to acute lung injury. While various biomarkers in bronchoalveolar lavage fluids have been studied for diagnosing aspiration, none have been conclusively established as early indicators of lung damage. This study aims to evaluate the diagnostic value of pepsin, bile acid, and other biomarkers for detecting aspiration in an intensive care unit (ICU). MATERIALS AND METHODS: In this study, 50 ICU patients were enrolled and underwent intubation before admission. The evaluation of aspiration was based on clinical suspicion or documented instances of observed events. Tracheal secretion (TS) samples were collected within 6 h after intubation using sterile suction catheters. Additional parameters, including IL-6, pepsin, and bile acid, were determined for analysis. Pepsin levels were measured with an ELISA kit, while bile acid, uric acid, glucose, IL-6, and pH value in the tracheal secretion were analyzed using standardized lab methods. RESULTS: The 50 patients admitted to the ICU with various diagnoses. The median survival time for the entire cohort was 52 days, and there was no significant difference in survival between patients with aspiration pneumonia (AP) and those with other diagnoses (p = 0.69). Among the AP group, the average survival time was 50.51 days (±8.1 SD; 95% CI 34.63-66.39), while patients with other diagnoses had a mean survival time of 32.86 days (±5.1 SD; 95% CI 22.9-42.81); the survival group comparison did not yield statistically significant results. The presence of pepsin or bile acid in TS patients did not significantly impact survival or the diagnosis of aspiration. The p-values for the correlations between pepsin and bile acid with the aspiration diagnosis were p = 0.53 and p > 0.99, respectively; thus, pepsin and bile acid measurements did not significantly affect survival outcomes or enhance the accuracy of diagnosing aspiration pneumonia. CONCLUSIONS: The early and accurate diagnosis of aspiration is crucial for optimal patient care. However, based on this study, pepsin concentration alone may not reliably indicate aspiration, and bile acid levels also show limited association with the diagnosis. Further validation studies are needed to assess the clinical usefulness and reliability of gastric biomarkers in diagnosing aspiration-related conditions. Such future studies would provide valuable insights for improving aspiration diagnosis and enhancing patient care.

Relevance of Cor Pulmonale in COPD With and Without Pulmonary Hypertension: A Retrospective Cohort Study.

BACKGROUND: The relevance of cor pulmonale in COPD and pulmonary hypertension due to COPD (PH-COPD) is incompletely understood. We aimed to investigate the relationship of right ventricular-pulmonary arterial (RV-PA) uncoupling with disease severity in COPD, and the relationship of RV-PA uncoupling and use of targeted PH therapies with mortality in PH-COPD. METHODS: We retrospectively analyzed 231 patients with COPD without PH and 274 patients with PH-COPD. COPD was classified according to GOLD stages and the modified Medical Research Council dyspnoea scale. PH was categorized as mild-to-moderate or severe. RV-PA uncoupling was assessed as the echocardiographic tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio. RESULTS: Of the cohort with COPD without PH, 21, 58, 54 and 92 were classified as GOLD I, II, III and IV, respectively. Patients in advanced GOLD stages and those with severe dyspnoea showed significantly decreased TAPSE/PASP.Of the PH-COPD cohort, 144 had mild-to-moderate PH and 130 had severe PH. During follow-up, 126 patients died. In univariate Cox regression, TAPSE/PASP and 6-min walk distance (6MWD; 10 m increments) predicted survival [hazard ratios (95% CI): 0.12 (0.03-0.57) and 0.95 (0.93-0.97), respectively]; notably, PH severity and simplified European Society of Cardiology/European Respiratory Society risk stratification did not. Among patients in the lowest or intermediate tertiles of TAPSE/PASP and 6MWD, those with targeted PH therapy had higher survival than those without (53 vs. 17% at 3 years). CONCLUSION: Cor pulmonale (decreased TAPSE/PASP and 6MWD) is associated with disease severity in COPD and predicts outcome in PH-COPD.

Evaluation of Regional Pulmonary Ventilation in Spontaneously Breathing Patients with Idiopathic Pulmonary Fibrosis (IPF) Employing Electrical Impedance Tomography (EIT): A Pilot Study from the European IPF Registry (eurIPFreg).

OBJECTIVES: In idiopathic pulmonary fibrosis (IPF), alterations in the pulmonary surfactant system result in an increased alveolar surface tension and favor repetitive alveolar collapse. This study aimed to assess the usefulness of electrical impedance tomography (EIT) in characterization of regional ventilation in IPF. MATERIALS AND METHODS: We investigated 17 patients with IPF and 15 healthy controls from the University of Giessen and Marburg Lung Center (UGMLC), Germany, for differences in the following EIT parameters: distribution of ventilation (TID), global inhomogeneity index (GI), regional impedance differences through the delta of end-expiratory lung impedance (dEELI), differences in surface of ventilated area (SURF), as well as center of ventilation (CG) and intratidal gas distribution (ITV). These parameters were assessed under spontaneous breathing and following a predefined escalation protocol of the positive end-expiratory pressure (PEEP), applied through a face mask by an intensive care respirator (EVITA, Draeger, Germany). RESULTS: Individual slopes of dEELI over the PEEP increment protocol were found to be highly significantly increased in both groups (p < 0.001) but were not found to be significantly different between groups. Similarly, dTID slopes were increasing in response to PEEP, but this did not reach statistical significance within or between groups. Individual breathing patterns were very heterogeneous. There were no relevant differences of SURF, GI or CGVD over the PEEP escalation range. A correlation of dEELI to FVC, BMI, age, or weight did not forward significant results. CONCLUSIONS: In this study, we did see a significant increase in dEELI and a non-significant increase in dTID in IPF patients as well as in healthy controls in response to an increase of PEEP under spontaneous breathing. We propose the combined measurements of EIT and lung function to assess regional lung ventilation in spontaneously breathing subjects.

Assessing the Effectiveness of Pirfenidone in Idiopathic Pulmonary Fibrosis: Long-Term, Real-World Data from European IPF Registry (eurIPFreg).

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic pulmonary disease with rising incidence. In this study the effectiveness of pirfenidone, as measured by longitudinal change in individual slope of forced vital capacity (FVC) prior to and after initiating pirfenidone treatment, was evaluated in IPF patients recruited into the European registry for idiopathic pulmonary fibrosis (eurIPFreg). Secondary variables were the evaluation of the change in individual slope of diffusion capacity of the lungs for carbon monoxide (DLco), the Borg dyspnea scale, and six-minute walking distance (6MWD), as well as survival analyses. RESULTS: Data of 122 eurIPFreg patients, who had at least two pulmonary function tests (PFTs) prior to or under treatment with pirfenidone, were analyzed by calculating slope-changes. The global analysis revealed an average slope change of +1.48 ± 0.28 (% per annum (p.a)) after start of treatment (p < 0.001), reflecting a reduction in annual FVC decline of approx. 50% under pirfenidone; it also showed a reduction in DLco, and increase in 6MWD (both p < 0.0001), as well as a flattening of the Borg dyspnea scale (p = 0.02). The median survival under treatment was 4.82 years. Patients with a more restrictive disease (FVC < 80% pred.), with a rapid progression (FVC decline >10% pred. p.a.), previous smokers and patients > 60 years of age seemed to profit more from pirfenidone treatment. CONCLUSIONS: We report the effectiveness of pirfenidone in a European "real world" IPF cohort with outcome data extending up to 9 years. Global analyses demonstrated a positive effect of pirfenidone on the decline of the lung function over time. Survival was dependent on Gender-Age-Physiology (GAP) score and age prior to therapy.

Clinical and Functional Characteristics of Patients with Unclassifiable Interstitial Lung Disease (uILD): Long-Term Follow-Up Data from European IPF Registry (eurIPFreg).

(1) Aim of the study: In spite of extensive research, up to 20% of interstitial lung diseases (ILD) patients cannot be safely classified. We analyzed clinical features, progression factors, and outcomes of unclassifiable ILD (uILD). (2) Methods: A total of 140 uILD subjects from the University of Giessen and Marburg Lung Center (UGMLC) were recruited between 11/2009 and 01/2019 into the European Registry for idiopathic pulmonary fibrosis (eurIPFreg) and followed until 01/2020. The diagnosis of uILD was applied only when a conclusive diagnosis could not be reached with certainty. (3) Results: In 46.4% of the patients, the uILD diagnosis was due to conflicting clinical, radiological, and pathological data. By applying the diagnostic criteria of usual interstitial pneumonia (UIP) based on computed tomography (CT), published by the Fleischner Society, 22.2% of the patients displayed a typical UIP pattern. We also showed that forced vital capacity (FVC) at baseline (p = 0.008), annual FVC decline ≥10% (p < 0.0001), smoking (p = 0.033), and a diffusing capacity of the lung for carbon monoxide (DLco) ≤55% of predicted value at baseline (p < 0.0001) were significantly associated with progressive disease. (4) Conclusions: The most important prognostic factors in uILD are baseline level and decline in lung function and smoking. The use of Fleischner diagnostic criteria allows further differentiation and accurate diagnosis.

Recognition of breathprints of lung cancer and chronic obstructive pulmonary disease using the Aeonose® electronic nose.

OBJECTIVES: There is a high unmet need in a non-invasive screening of lung cancer (LC). We conducted this single-center trial to evaluate the effectiveness of the electronic nose Aeonose ® in LC recognition. MATERIALS AND METHODS: Exhaled volatile organic compound (VOC) signatures were collected by Aeonose ® in 42 incident and 78 prevalent LC patients, of them 29 LC patients in complete remission (LC CR), 33 healthy controls (HC) and 23 COPD patients. By dichotomous comparison of VOC's between incident LC and HC, a discriminating algorithm was established and also applied to LC CR and COPD subjects. Area under Curve (AUC), sensitivity, specificity and Matthews's correlation coefficient (MC) were used to interpret the data. RESULTS: The established algorithm of Aeonose ® signature allowed safe separation of LC and HC, showing an AUC of 0.92, sensitivity of 0.84 and a specificity of 0.97. When tested in a blinded fashion, the device recognized 19 out of 29 LC CR patients (=65.5%) as LC-positive, of which only five developed recurrent LC later on (after 18.6 months [Formula: see text]; mean value [Formula: see text]). Unfortunately, the algorithm also recognized 11 of 24 COPD patients as being LC positive (with only one of the 24 COPD patients developing LC 56 months after the measurement). CONCLUSION: The Aeonose ® revealed some potential in distinguishing LC from HC, however, with low specificity when applying the algorithm in a blinded fashion to other disease cohorts. We conclude that relevant VOC signals originating from comorbidities in LC such as COPD may have erroneously led to the separation between LC and controls. CLINICAL TRIAL REGISTRATION: (NCT02951416).

Exploring the Ability of Electronic Nose Technology to Recognize Interstitial Lung Diseases (ILD) by Non-Invasive Breath Screening of Exhaled Volatile Compounds (VOC): A Pilot Study from the European IPF Registry (eurIPFreg) and Biobank.

BACKGROUND: There is an increasing interest in employing electronic nose technology in the diagnosis and monitoring of lung diseases. Interstitial lung diseases (ILD) are challenging in regard to setting an accurate diagnosis in a timely manner. Thus, there is a high unmet need in non-invasive diagnostic tests. This single-center explorative study aimed to evaluate the usefulness of electronic nose (Aeonose®) in the diagnosis of ILDs. METHODS: Exhaled volatile organic compound (VOC) signatures were obtained by Aeonose® in 174 ILD patients, 23 patients with chronic obstructive pulmonary disease (COPD), and 33 healthy controls (HC). RESULTS: By dichotomous comparison of VOC's between ILD, COPD, and HC, a discriminating algorithm was established. In addition, direct analyses between the ILD subgroups, e.g., cryptogenic organizing pneumonia (COP, n = 28), idiopathic pulmonary fibrosis (IPF, n = 51), and connective tissue disease-associated ILD (CTD-ILD, n = 25) were performed. Area under the Curve (AUC) and Matthews's correlation coefficient (MCC) were used to interpret the data. In direct comparison of the different ILD subgroups to HC, the algorithms developed on the basis of the Aeonose® signatures allowed safe separation between IPF vs. HC (AUC of 0.95, MCC of 0.73), COP vs. HC (AUC 0.89, MCC 0.67), and CTD-ILD vs. HC (AUC 0.90, MCC 0.69). Additionally, to a case-control study design, the breath patterns of ILD subgroups were compared to each other. Following this approach, the sensitivity and specificity showed a relevant drop, which results in a poorer performance of the algorithm to separate the different ILD subgroups (IPF vs. COP with MCC 0.49, IPF vs. CTD-ILD with MCC 0.55, and COP vs. CT-ILD with MCC 0.40). CONCLUSIONS: The Aeonose® showed some potential in separating ILD subgroups from HC. Unfortunately, when applying the algorithm to distinguish ILD subgroups from each other, the device showed low specificity. We suggest that artificial intelligence or principle compound analysis-based studies of a much broader data set of patients with ILDs may be much better suited to train these devices.

Clinical characteristics of patients with familial idiopathic pulmonary fibrosis (f-IPF).

BACKGROUND: The aim of this study was to analyze the relative frequency, clinical characteristics, disease onset and progression in f-IPF vs. sporadic IPF (s-IPF). METHODS: Familial IPF index patients and their family members were recruited into the European IPF registry/biobank (eurIPFreg) at the Universities of Giessen and Marburg (UGMLC). Initially, we employed wide range criteria of f-IPF (e.g. relatives who presumably died of some kind of parenchymal lung disease). After narrowing down the search to occurrence of idiopathic interstitial pneumonia (IIP) in at least one first grade relative, 28 index patients were finally identified, prospectively interviewed and examined. Their family members were phenotyped with establishment of pedigree charts. RESULTS: Within the 28 IPF families, overall 79 patients with f-IPF were identified. In the same observation period, 286 f-IIP and s-IIP patients were recruited into the eurIPFreg at our UGMLC sites, corresponding to a familial versus s-IPF of 9.8%. The both groups showed no difference in demographics (61 vs. 79% males), smoking history, and exposure to any environmental triggers known to cause lung fibrosis. The f-IPF group differed by an earlier age at the onset of the disease (55.4 vs. 63.2 years; p < 0.001). On average, the f-IPF patients presented a significantly milder extent of functional impairment at the time point of inclusion vs. the s-IPF group (FVC 75% pred. vs. FVC 62% pred., p = 0.011). In contrast, the decline in FVC was found to be faster in the f-IPF vs. the s-IPF group (4.94% decline in 6 months in f-IPF vs. 2.48% in s-IPF, p = 0.12). The average age of death in f-IPF group was 67 years vs. 71.8 years in s-IPF group (p = 0.059). The f-IIP group displayed diverse inheritance patterns, mostly autosomal-dominant with variable penetrance. In the f-IPF, the younger generations showed a tendency for earlier manifestation of IPF vs. the older generation (58 vs. 66 years, p = 0.013). CONCLUSIONS: The 28 f-IPF index patients presented an earlier onset and more aggressive natural course of the disease. The disease seems to affect consecutive generations at a younger age. TRIAL REGISTRATION: Nr. NCT02951416 http://www.www.clinicaltrials.gov.

Exhalative Breath Markers Do Not Offer for Diagnosis of Interstitial Lung Diseases: Data from the European IPF Registry (eurIPFreg) and Biobank.

Background: New biomarkers are urgently needed to facilitate diagnosis in Interstitial Lung Diseases (ILD), thus reducing the need for invasive procedures, and to enable tailoring and monitoring of medical treatment. Methods: In this study we investigated if patients with idiopathic pulmonary fibrosis (IPF; n = 21), non-IPF ILDs (n = 57) and other lung diseases (chronic obstructive pulmonary disease (COPD) n = 24, lung cancer (LC) n = 16) as well as healthy subjects (n = 20) show relevant differences in exhaled NO (FeNO; Niox MINO), or in eicosanoid (PGE2, 8-isoprostane; enzyme-linked immunosorbent assay (ELISA)) levels as measured in exhaled breath condensates (EBC) and bronchoalveolar lavage fluids (BALF). Results: There was no significant difference in FeNO values between IPF, non-IPF ILDs and healthy subjects, although some individual patients showed highly elevated FeNO. On the basis of the FeNO signal, it was neither possible to differentiate between the kind of disease nor to detect exacerbations. In addition, there was no correlation between FeNO values and lung function. The investigation of the eicosanoids in EBCs was challenging (PGE2) or unreliable (8-isoprostane), but worked out well in BALF. A significant increase of free 8-isoprostane was observed in BALF, but not in EBCs, of patients with IPF, hypersensitivity pneumonitis (HP) and sarcoidosis, possibly indicating severity of oxidative stress. Conclusions: FeNO-measurements are not of diagnostic benefit in different ILDs including IPF. The same holds true for PGE2 and 8-isoprostane in EBC by ELISA.

Perceived distress, personality characteristics, coping strategies and psychosocial impairments in a national German multicenter cohort of patients with Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: This study examined differences in personality, psychological distress, and stress coping in inflammatory bowel disease (IBD) depending on type of disease and disease activity. We compared patients suffering from Crohn's disease (CD) and ulcerative colitis (UC) with controls. While the literature is replete with distinctive features of the pathogenesis of IBD, the specific differences in psychological impairments are not well studied. METHODS: In this German national multicenter study, participants were recruited from 32 centers. Two hundred ninety-seven questionnaires were included, delivering vast information on disease status and psychological well-being based on validated instruments with a total of 285 variables. RESULTS: CD patients were more affected by psychological impairments than patients suffering from UC or controls. Importantly, patients with active CD scored higher in neuroticism (p < 0.01), psychological distress (p < 0.001) and maladaptive stress coping (escape, p = 0.03; rumination, p < 0.03), but less need for social support (p = 0.001) than controls. In contrast, patients suffering from active UC showed psychological distress (p < 0.04) and maladaptive coping (avoidance, p < 0.03; escape, p = 0.01). Patients in remission seemed to be less affected. In particular, patients with UC in remission were not inflicted by psychological impairments. The group of CD patients in remission however, showed insecurity (p < 0.01) and paranoid ideation (p = 0.04). CONCLUSIONS: We identified specific aspects of psychological impairment in IBD depending on disease and disease activity. Our results underscore the need for psychological support and treatment particularly in active CD.

Psychometric properties and minimal important differences of SF-36 in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare disease with a median survival of 3-5 years after diagnosis with limited treatment options. The aim of this study is to assess the psychometric characteristics of the Short Form 36 Health Status Questionnaire (SF-36) in IPF and to provide disease specific minimally important differences (MID). METHODS: Data source was the European IPF Registry (eurIPFreg). The psychometric properties of the SF-36 version 2 were evaluated based on objective clinical measures as well as subjective perception. We analysed acceptance, feasibility, discrimination ability, construct and criterion validity, responsiveness and test-retest-reliability. MIDs were estimated via distribution and anchor-based approaches. RESULTS: The study population included 258 individuals (73.3% male; mean age 67.3 years, SD 10.7). Of them 75.2% (194 individuals) had no missing item. The distribution of several items was skewed, although floor effect was acceptable. Physical component score (PCS) correlated significantly and moderately with several anchors, whereas the correlations of mental component score (MCS) and anchors were only small. The tests showed mainly significant lower HRQL in individuals with long-term oxygen therapy. Analyses in stable individuals did not show significant changes of HRQL except for one dimension and anchor. Individuals with relevant changes of the health status based on the anchors had significant changes in all SF-36 dimensions and summary scales except for the dimension PAIN. PCS and MCS had mean MIDs of five and six, respectively. Mean MIDs of the dimensions ranged from seven to 21. CONCLUSION: It seems that the SF-36 is a valid instrument to measure HRQL in IPF and so can be used in RCTs or individual monitoring of disease. Nevertheless, the additional evaluation of longitudinal aspects and MIDs can be recommended to further analyse these factors. Our findings have a great potential impact on the evaluation of IPF patients. TRIAL REGISTRATION: The eurIPFreg and eurIPFbank are listed in https://clinicaltrials.gov ( NCT02951416 ).

Lung CT Densitometry in Idiopathic Pulmonary Fibrosis for the Prediction of Natural Course, Severity, and Mortality.

BACKGROUND: In this study, we retrospectively assessed the relationships among physiologic measurements, survival, and quantitative high-resolution CT (HRCT) scanning indexes in patients with idiopathic pulmonary fibrosis (IPF). METHODS: Seventy patients (48 male; mean [SD] age, 66.4 [9.0] years) with IPF were enrolled in the study. After segmentation of the lungs in thin-section CT scanning with the patient in the supine position at full inspiration, we assessed following parameters: mean lung attenuation (MLA), skewness, kurtosis, peak attenuation, total lung area, inflexion point with slope, and area right of the inflexion point (AROIP). Additionally, FVC, FEV1, total lung capacity, diffusing capacity or transfer factor of the lung for carbon monoxide (Dlco), and 6-min walk distance were analyzed. Univariate and multivariate analysis were used for the prediction of physiologic outcomes by HRCT scanning indexes and then were correlated to survival in a proportional hazards analysis. RESULTS: The strongest correlation was observed between MLA and FEV1, with an r of -0.63. MLA, peak attenuation, slope, attenuation, and AROIP correlated negatively with all physiologic measurements. AROIP was the best predictor of Dlco. Analysis for prediction of mortality showed that AROIP, kurtosis, and FVC were related significantly to survival. Multivariate regression revealed a significant impact of only AROIP (among age, sex, MLA, skewness, kurtosis, FVC, and Dlco) on survival. CONCLUSIONS: These data indicate that HRCT scanning indexes are correlated to physiologic measurements. The newly defined parameter, AROIP, is of additive value for prediction of outcome. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02951416; URL: www.clinicaltrials.gov.

The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research. METHODS: The registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management. RESULTS: This paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001). CONCLUSIONS: Our data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time. TRIAL REGISTRATION: The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov( NCT02951416 ).

IL-9 and its receptor are predominantly involved in the pathogenesis of UC.

OBJECTIVE: Several pathogenic roles attributed over the past two decades to either T helper (Th)1 or Th2 cells are increasingly becoming associated with interleukin (IL)-17 and most recently IL-9 signalling. However, the implication of IL-9 in IBD has not been addressed so far. DESIGN: We investigated the expression of IL-9 and IL-9R by using peripheral blood, biopsies and surgical samples. We addressed the functional role of IL-9 signalling by analysis of downstream effector proteins. Using Caco-2 cell monolayers we followed the effect of IL-9 on wound healing. RESULTS: IL-9 mRNA expression was significantly increased in inflamed samples from patients with UC as compared with controls. CD3(+) T cells were major IL-9-expressing cells and some polymorphonuclear leucocytes (PMN) also expressed IL-9. IL-9 was co-localised with the key Th9 transcription factors interferon regulatory factor 4 and PU.1. Systemically, IL-9 was abundantly produced by activated peripheral blood lymphocytes, whereas its receptor was overexpressed on gut resident and circulating PMN. IL-9 stimulation of the latter induced IL-8 production in a dose-dependent manner and rendered PMN resistant to apoptosis suggesting a functional role for IL-9R signalling in the propagation of gut inflammation. Furthermore, IL-9R was overexpressed on gut epithelial cells and IL-9 induced STAT5 activation in these cells. Moreover, IL-9 inhibited the growth of Caco-2 epithelial cell monolayers in wound healing experiments. CONCLUSIONS: Our results provide evidence that IL-9 is predominantly involved in the pathogenesis of UC suggesting that targeting IL-9 might become a therapeutic option for patients with UC.

Long term follow up of through-the-scope balloon dilation as compared to strictureplasty and bowel resection of intestinal strictures in crohn's disease.

BACKGROUND & AIMS: Ileo-colonic strictures are common complication of Crohn's disease (CD), and may result in repeated endoscopic or surgical therapy with a risk of further complications, such as perforation or short bowel syndrome. Strictures develop as a consequence of tissue remodelling and fibrosis due to chronic inflammation. This study compares the outcome of CD patients undergoing primarily endoscopic treatment with those undergoing surgery at an university hospital. METHODS: In this study we retrospectively included 88 CD patients with intestinal strictures (37 males, 51 females, mean age 40 years, range 19-65 years) of both our medical and our surgical department, who underwent either surgical or endoscopic therapy between January 2002 and January 2006 with prospective, controlled follow-up, extended till January 2010 (mean follow-up period: 5 years; range 4-8 years). The primary end-point was operation- and symptom-free time. Patients were primarily divided into four groups: only surgical therapy, only endoscopic therapy, endoscopy with subsequent surgery, and initial surgical therapy followed by endoscopic dilations. RESULTS: 53% of all patients remained surgery-free with mean follow-up of 49 months; a single endoscopic dilation was sufficient enough in 9 patients to achieve a surgery-free time of 51 months, other patients required up to 5 dilations. The average interval between first and second dilation was 6.5 months, between second and third 10.5 months. In the group of patients with only endoscopic therapy, surgery- and symptom-free time was shorter, as compared to the group of only surgical therapy. We found that stenoses in the surgical group with an average length of 6.5 cm were as expected longer, as compared to the endoscopic group (3 cm, ranging from 2-4 cm). The surgery-free time was 49 months (42-71 months, P = 0.723) with a symptom-free time of 12 months (4.5-46 months, P = 0.921). In the group of only surgically treated patients, 68.4% of the patients had only one stenosis, 18.4% had 2-3 stenoses and 13.2% more than 3 stenoses. In all patients the surgery- and symptoms- free time was 69 months (57-83 months, P = 0.850 and 0.908). The other two groups showed similar results. We found no significant effect of characteristic of stenosis (length, inflammation, the number of stenoses), injection of prednisolone, disease activity at the time of dilation and medication at the time of dilation on the long-term outcome. Importantly, the success of symptom free time correlated with the diameter of the balloon. CONCLUSIONS: Endoscopic dilation should be considered as a first-line therapy for short, accessible, fibrotic strictures. Careful patient selection and proper diagnostic imaging pre-procedure are essential requirements for safe and successful treatment. The balloon diameter seems to correlate positively with the long term outcome of dilation. However, at ever shorter intervals between endoscopic interventions, surgery should be discussed as an option for further treatment.

Normalized autofluorescence imaging diagnostics in upper GI tract: a new method to improve specificity in neoplasia detection.

BACKGROUND & AIMS: This study was performed to improve the autofluorescence imaging (AFI) in the upper GI tract by applying a new method of normalized autofluorescence (NAFI) obtained via tri-modal imaging. OBJECTIVE: NAFI may provide lower false positive rate to achieve ultimately better specificity at acceptable sensitivity. PATIENTS AND METHODS: This is a prospective, controlled single-centre study. 18 patients with suspected esophagus or stomach cancer undergoing esophagogastroduodenoscopy (EGD) were enrolled between February and May 2010. After endoscopy each patient was assigned into one of two groups: (1) non-cancer, including inflammation; (2) cancer group. EGDs were performed using video white light endoscopy, followed by AFI/NAFI. The targeted biopsy samples were taken from the abnormal areas as well as from adjacent mucosa. NAFI was compared versus AFI for cancer diagnostics in terms of specificity and sensitivity. RESULTS: NAFI detected all neoplastic lesions. WLE or NBI detected no additional neoplasia. The AFI displayed mucosal inflammation and carcinomas of esophagus and stomach as dark red color, the normal mucosa background was displayed as light green. The NAFI didn't differentiate inflamed tissue from normal in majority of cases, but in tumorous mucosa, the cancer areas were detected precisely. AFI shows 100% sensitivity but 50% specificity which correlates with previous literature data. On the other hand, NAFI demonstrated lower sensitivity (88%) but higher specificity compared to AFI (69%). CONCLUSIONS: Measuring the NAFI instead of the AFI was found improving the specificity of cancer diagnosis. Use of fiber-optic endoscopes to analyze AFI and possible endoscopic and histological sampling error are the main potential limitations of this method.

Characterization of lymphoid follicles with red ring signs as first manifestation of early Crohn's disease by conventional histopathology and confocal laser endomicroscopy.

BACKGROUND AND AIMS: Clinical observations suggest that the lymphoid follicles (LFs) may play a crucial role in the pathogenesis of inflammatory bowel disease (IBD), especially in Crohn's disease (CD) as the site of initial mucosal inflammation. The aim of this study was to compare the morphology of LFs in CD, ulcerative colitis (UC) and control patients using confocal laser endomicroscopy (CLE) in correlation to histological and immunohistochemical findings of biopsies. METHODS: 79 patients with IBD (46 with CD, 32 with UC and 1 patient with indeterminate colitis) and 67 controls patients were enrolled prospectively in this study. Median age was 32.5 years (range 19-65) and 37.4 years (range 20-65 years) respectively. To analyze the LFs, standardized images from the terminal ileum and the colon were taken using white-light video endoscopes. Additionally, CLE was performed to analyze subsurface structure of LFs. Targeted biopsies of LFs were analyzed using haematoxylin and eosin stain and immunohistochemistry. RESULTS: LFs were seen in all parts of the lower GI tract, but mostly in the terminal ileum and cecum. Endoscopy in 15 out of 17 patients with the first manifestation of CD showed LFs surrounded by red ring (so-called red ring sign, RRS). Histologically, LFs with RRS showed hypervascularization at the base of the LFs associated with numerous CD15-positive granulocytes. Similar features were not seen in LFs without RRS and in the control group. In some LFs with RRS early aphthous ulcers were seen. Using CLE, RRS showed abolished normal crypt architecture, crypt distortion, increased cellular infiltrate within the lamina propria, and dilated vessels. CONCLUSION: LFs with RRS probably represent an early sign of aphthous ulcers in early CD and, thus, may be considered as early markers of first manifestation and flares in CD.