CD19(+)CD21(low) B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS), pathognomonic for chronic graft-versus-host disease (cGVHD) of the lung, is a progressive and often fatal complication after allogeneic hematopoietic cell transplantation (HCT). Biomarkers for the prediction and diagnosis of BOS are urgently needed to improve patients' prognosis. We prospectively evaluated B-cell subpopulations and B-cell activating factor (BAFF) in 136 patients (46 BOS, 41 no cGVHD, 49 cutaneous cGVHD) to define novel biomarkers for early diagnosis of National Institutes of Health-defined BOS diagnosed a median of 11 mo after HCT. Patients with newly diagnosed BOS had significantly higher percentages of CD19(+)CD21(low) B cells (25.5 versus 6.6%, P < .0001), BAFF (7.3 versus 3.5 ng/mL, P = .02), and BAFF/CD19(+) ratio (0.18 versus 0.02 ng/10(3) CD19(+) B cells, P 5 .007) compared with patients without cGVHD. The area under the receiver operating curve for CD19(+)CD21(low) B cells was 0.97 (95% confidence interval, 0.94-0.99) and a cutoff point >9% was optimal for diagnosing BOS in patients with first drop of pulmonary function tests with a sensitivity of 96% and a negative predictive value of 94%. Thus, elevated levels of CD19(+)CD21(low) B cells are a potential novel biomarker for HCT patients at risk for developing BOS at an early stage and could allow improvement of patient outcome.

Incidence of lung cancer in patients with systemic sclerosis treated with extracorporeal photopheresis.

BACKGROUND: Extracorporeal photopheresis (ECP) improves skin sclerosis in systemic sclerosis (SSc) patients. SSc is associated with an increased risk of lung cancer. As ECP is supposed to exert immunomodulatory effects, a possible impact of ECP on the incidence of lung cancer in SSc patients was evaluated. METHODS: Seventy-one SSc patients treated with ECP at the Photopheresis Unit of the Department of Dermatology at the Medical University of Vienna between 1991 and 2013 were analyzed retrospectively. RESULTS: We calculated a standardized incidence ratio (SIR) for lung cancer in ECP-treated SSc patients of 2.34 [95% confidence interval (CI) 1.63-2.49]. This is in accordance with recent meta-analyses demonstrating a significantly enhanced risk of lung carcinoma in SSc patients. Comparison of the lung cancer risks of these patients with our ECP-treated patients revealed that ECP has no influence. Each patient with lung carcinoma had previously been diagnosed with lung involvement of the non-specific interstitial pneumonitis (NSIP) type. CONCLUSION: We confirm that SSc patients are at significantly increased risk for lung cancer. However, ECP does not influence this risk. NSIP may be a risk factor for lung cancer in SSc patients.

PMA-zeolite can modulate inflammation associated markers in irritable bowel disease - an explorative randomized, double blinded, controlled pilot trial.

OBJECTIVES: Preclinical and clinical data suggest, that the microporous mineral with large inner surface and ion exchanger capability PMA-(Panaceo-micro-activation)-zeolite can bind irritating and inflammation associated chime-constituents. We hypothesised whether or not it can ameliorate subclinical inflammation, and investigated the potential in the management of patients with Irritable Bowel syndrome (IBS). METHODS: The trial design was prospective, randomized, controlled, double-blinded, pilot study with 41 patients. They received orally 3 g of the medicinal product PMA-zeolite or microcrystalline cellulose (control) twice a day. At baseline and after three months the symptom load, blood and stool parameters, like high sensitivity C-reactive protein (hsCRP), zonulin, α1-antitrypsin, interleukin IL-10, and changes in the gut microbiome were determined by means of ANOVA, ANCOVA and non parametric statistical analyses. RESULTS: The IBS-associated symptom scores decreased significantly in both groups (p=0,001) indicating a strong placebo effect. In the verum but not in the placebo group various inflammation related laboratory parameters decreased. The gross statistical comparison revealed a reduction of α1-antitrypsin significant (p=0,037), a lowered inflammation marker hsCRP, paralleled specific microbiome changes (Lactobacillus, Bifidobacteria, and Firmicutes). CONCLUSIONS: The decrease of blood hsCRP and decreased stool α1-antitrypsin suggest that PMA-zeolite possibly can lower inflammation in the gut of IBS patients. The corresponding increase of the immune modulating species Bifidobacteria and Lactobacillus and the reduction of Firmicutes also point at an inflammation ameliorating effect and a possible mucous layer strengthening effect. The protocol of this explorative pilot study is feasible for a sufficiently powered trial on inflammation amelioration in IBS patients.

Abnormal pulmonary arterial pressure limits exercise capacity in patients with COPD.

OBJECTIVE: Pulmonary hypertension (PH) is common in patients with chronic obstructive pulmonary disease (COPD). Mean pulmonary artery pressure (mPAP) is often only slightly elevated at rest but is increased by exercise. The purpose of this study was to determine whether abnormal pulmonary artery pressure impairs exercise capacity in patients with COPD. PATIENTS AND METHODS: 42 patients with moderate-to-very-severe COPD (28 men, 14 women) underwent symptom-limited incremental cardiopulmonary exercise testing and also right-heart catheterization at rest. Abnormal pulmonary artery pressure was defined as mPAP>20 mmHg at rest. RESULTS: Resting mPAP was elevated in 32 patients (PH, mPAP=26.8+/-5.9 mmHg) and normal in 10 non-hypertensive (NPH) patients (NPH, mPAP=16.8+/-2 mmHg). There were no significant differences in lung function between the PH and NPH groups. Maximum oxygen uptake during exercise (VO2max) was significantly lower in PH (785+/-244 ml/min) than in NPH (1052+/-207 ml/min, P=0.004). Dead-space ventilation (Vd/Vt) was greater in PH (P=0.05) with higher VE/VCO2 (ratio of minute ventilation to carbon dioxide output=47.3+/-10 vs 38.6+/-3.5, P=0.025) and significantly higher arterial-end-tidal pCO2 difference [p(a-ET)CO2]. Pulmonary vascular resistance measured at rest correlated significantly with VO2max, VE/VCO2 and p(a-ET)CO2. CONCLUSIONS: In patients with COPD, abnormal pulmonary artery pressure impairs gas exchange, decreases maximum oxygen uptake during exercise and impairs exercise capacity.

Vasoactive intestinal peptide gene alterations in patients with idiopathic pulmonary arterial hypertension.

Pulmonary arterial hypertension is a progressive disease, characterised by increased proliferation of pulmonary artery smooth muscle cells, vasoconstriction and remodelling of the vascular wall leading to right heart failure and death. The idiopathic form is rare (idiopathic arterial primary hypertension (IPAH); formerly PPH, MIM# 178600). Our group correlated a deficiency in vasoactive intestinal peptide (VIP; MIM# 192320) levels in serum and lung tissue with the pathogenesis of IPAH. The aim of this study was to investigate the relevance of genetic alterations in VIP to the development of IPAH. We screened 10 patients (age 4-66 years) for alterations in the coding, the noncoding regions and the enhancer region of the VIP gene by direct sequencing. In eight of 10 patients, we found alterations compared to the wild-type sequence. We detected nine alterations. In the noncoding regions, eight alterations were in the introns 1, 2, 3 and 4 (g.448G>A g.501C>T g.764T>C g.2267A>T g.2390C>T g.3144T>C g.3912A>G g.4857A>G). In the coding regions, a single alteration in the 3' untranslated region in exon 7 (g.8129T>C) was observed in five patients. It appeared in 46% of the control group. The frequency of this alteration in the coding region of the VIP gene could therefore not be correlated with the appearance of IPAH. Apart from the importance of VIP signalling, genetic and/or environmental modifiers might therefore contribute to the development and perpetuation of the disease.

Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension.

Primary pulmonary hypertension is a fatal disease causing progressive right heart failure within 3 years after diagnosis. We describe a new concept for treatment of the disease using vasoactive intestinal peptide, a neuropeptide primarily functioning as a neurotransmitter that acts as a potent systemic and pulmonary vasodilator. Our rationale is based on the finding of a deficiency of the peptide in serum and lung tissue of patients with primary pulmonary hypertension, as evidenced by radioimmunoassay and immunohistochemistry. The relevance of this finding is underlined by an upregulation of corresponding receptor sites as shown by Northern blot analysis, Western blot analysis, and immunological techniques. Consequently, the substitution with the hormone results in substantial improvement of hemodynamic and prognostic parameters of the disease without side effects. It decreased the mean pulmonary artery pressure in our eight study patients, increased cardiac output, and mixed venous oxygen saturation. Our data provide enough proof for further investigation of vasoactive intestinal peptide and its role in primary pulmonary hypertension.

Involvement of endothelial NO in the dilator effect of VIP on rat isolated pulmonary artery.

The endothelium and its interaction with smooth muscle play a central role in the local control of the pulmonary vasculature, and endothelial dysfunction is thought to contribute to pulmonary hypertension and chronic obstructive pulmonary disease. Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide, relaxes the rat pulmonary artery, but there is controversy as to whether or not this action of VIP depends on the endothelium. The aim of this study, therefore, was to investigate the role of the endothelium and nitric oxide (NO), the major endothelium-derived relaxing factor, in the dilator action of VIP on the rat isolated pulmonary artery. Pulmonary artery preparations pre-contracted by the alpha(1)-adrenoceptor agonist L-phenylephrine were relaxed by VIP (0.003-1 microM) and acetylcholine (0.003-10 microM) in a concentration-dependent manner. Mechanical removal of the endothelium reduced the maximal response to VIP by about 50% and practically abolished the response to acetylcholine. Inhibition of NO synthesis by N(omega)-nitro-L-arginine methyl ester (0.5 mM) had a similar effect, abolishing the vasorelaxation caused by acetylcholine and attenuating the vasorelaxation caused by VIP by about 50%. From these data it is concluded that the relaxant action of VIP on the rat isolated pulmonary artery depends in part on the presence of the endothelium and that this part is mediated by endothelial NO.

Does MALT lymphoma of the lung require immediate treatment? An analysis of 11 untreated cases with long-term follow-up.

BACKGROUND: Mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) of the lung is a relatively rare disease. As little is known about the natural clinical course if left untreated, all patients undergoing a watch-and-wait policy at our institution were investigated. PATIENTS AND METHODS: A retrospective analysis identified a total of 11 patients with MALT lymphoma of the lung who did not undergo treatment following initial diagnosis. All patients had undergone extensive staging and were closely observed with restaging every three months. Histological assessment included immunhistochemistry for demonstration of the immunphenotype CD20+/CD5-/ CD10-/cyclinD1-/CD23-. Genetic aberrations were assessed, using RT-PCR for t(11;18) (q21;21) and fluorescence in situ hybridisation for the evaluation of t(14;18)(q32;q21), t(1;14) (p22;q32), trisomies 3 and 18. RESULTS: Five patients had MALT lymphoma restricted to the lung, while the remaining six had additional extrapulmonary sites detected during staging. The median time of observation without therapy was 28.1 months (inter-quartile range: 5 to 60 months); within this time, all 11 patients showed at least stable disease. Six of these 11 patients, however, had spontaneous regressions and wax-and-wane phenomena of the pulmonary lesions, but not of extrapulmonary manifestations. Three of these patients had evidence of t(11;18)(q21;q21), while the remaining three had no evidence of genetic aberrations. One patient was referred for treatment after progression in the lung, while two patients experienced progression outside the lung. Currently, all patients are alive, with 8 patients still only being watched. CONCLUSION: Our findings suggest that MALT lymphoma of the lung is a very indolent disease with the potential for spontaneous regression. In view of this, patients diagnosed with pulmonary MALT lymphoma might not require immediate treatment in the absence of symptoms and a watch-and-wait policy could be adopted.

Extracorporeal IgE Immunoadsorption in Allergic Asthma: Safety and Efficacy.

BACKGROUND: Prevention of IgE-binding to cellular IgE-receptors by anti-IgE (Omalizumab) is clinically effective in allergic asthma, but limited by IgE threshold-levels. To overcome this limitation, we developed a single-use IgE immunoadsorber column (IgEnio). IgEnio is based on a recombinant, IgE-specific antibody fragment and can be used for the specific extracorporeal desorption of IgE. OBJECTIVE: To study safety and efficacy of IgEnio regarding the selective depletion of IgE in a randomized, open-label, controlled pilot trial in patients with allergic asthma and to investigate if IgEnio can bind IgE-Omalizumab immune complexes. METHODS: Fifteen subjects were enrolled and randomly assigned to the treatment group (n=10) or to the control group (n=5). Immunoadsorption was done by veno-venous approach, processing the twofold calculated plasma volume during each treatment. A minimum average IgE-depletion of 50% after the last cycle in the intention-to-treat population was defined as primary endpoint. Safety of the treatment was studied as secondary endpoint. In addition, possible changes in allergen-specific sensitivity were investigated, as well as clinical effects by peak flow measurement and symptom-recording. The depletion of IgE-Omalizumab immune complexes was studied in vitro. The study was registered at clinicaltrials.gov (NCT02096237) and conducted from December 2013 to July 2014. RESULTS: IgE immunoadsorption with IgEnio selectively depleted 86.2% (±5.1% SD) of IgE until the end of the last cycle (p<0.0001). Removal of pollen allergen-specific IgE was associated with a reduction of allergen-specific basophil-sensitivity and prevented increases of allergen-specific skin-sensitivity and clinical symptoms during pollen seasons. IgEnio also depleted IgE-Omalizumab immune complexes in vitro. The therapy under investigation was safe and well-tolerated. During a total of 81 aphereses, 2 severe adverse events (SAE) were recorded, one of which, an episode of acute dyspnea, possibly was related to the treatment and resolved after administration of antihistamines and corticosteroids. CONCLUSIONS: This pilot study indicates that IgE immunoadsorption with IgEnio may be used to treat patients with pollen-induced allergic asthma. Furthermore, the treatment could render allergic patients with highly elevated IgE-levels eligible for the administration of Omalizumab and facilitate the desorption of IgE-Omalizumab complexes. This study was funded by Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.

The vasoactive intestinal peptide receptor turnover in pulmonary arteries indicates an important role for VIP in the rat lung circulation.

Vasoactive intestinal peptide (VIP) is a potent vasorelaxing peptide that plays a role in lung physiology and possibly in pulmonary hypertension. We investigated the turnover of the VIP receptors on rat pulmonary arteries ex vivo. There was evidence for a fast receptor turnover in pulmonary arteries, which underlines the important role of VIP for the regulation of pulmonary circulation and pulmonary pathology.

The calcium channel blocker amlodipine exerts its anti-proliferative action via p21(Waf1/Cip1) gene activation.

Proliferation of vascular smooth muscle cells (VSMC) contributes to the progression of atherosclerotic plaques. Calcium channel blockers have been shown to reduce VSMC proliferation, but the underlying molecular mechanism remains unclear. p21(Waf1/Cip1) is a potent inhibitor of cell cycle progression. Here, we demonstrate that amlodipine (10(-6) to 10(-8) M) activates de novo synthesis of p21(Waf1/Cip1) in vitro. We show that amlodipine-dependent activation of p21(Waf1/Cip1) involves the action of the glucocorticoid receptor (GR) and C/EBP-alpha. The underlying pathway apparently involves the action of mitogen-activated protein kinase or protein kinase C, but not of extracellular signal-related kinase or changes of intracellular calcium. Amlodipine-induced p21(Waf1/Cip1) promoter activity and expression were abrogated by C/EBP-alpha antisense oligonucleotide or by the GR antagonist RU486. Amlodipine-dependent inhibition of cell proliferation was partially reversed by RU486 at 10(-8) M (58%+/-29%), antisense oligonucleotides targeting C/EBP-alpha (91%+/-26%), or antisense mRNAs targeting p21(Waf1/Cip1) (96%+/-32%, n=6); scrambled antisense oligonucleotides or those directed against C/EBP-beta were ineffective. The data suggest that the anti-proliferative action of amlodipine is achieved by induction of the p21 (Waf1/Cip1) gene, which may explain beneficial covert effects of this widely used cardiovascular therapeutic drug beyond a more limited role as a vascular relaxant.

Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension.

OBJECTIVES: To evaluate the effect of long-term oral therapy with sildenafil in patients with pulmonary arterial hypertension receiving long-term IV epoprostenol. DESIGN: Open, uncontrolled trial. SETTING: University hospital. PATIENTS: Two patients with primary pulmonary hypertension and one patient with pulmonary arterial hypertension after surgical closure of an atrial septal defect. All patients were receiving continuous epoprostenol for 1.7 to 7.1 years; two patients also received inhaled iloprost for 1.8 years and 3.8 years, respectively. INTERVENTIONS: Addition of oral sildenafil, up to 200 mg/d, divided in four to six single doses, and hemodynamic measurements and the 6-min walking distance (6MWD) before and after 5 months of treatment with sildenafil. RESULTS: One patient was treated with sildenafil, 200 mg/d; two patients received 75 mg/d due to nausea and headache. Long-term treatment with sildenafil in the three patients reduced mean pulmonary artery pressure by 14%, 41%, and 22%, respectively; in two patients, pulmonary vascular resistance was decreased by 52% and 55%. The 6MWD increased by 34%, 6%, and 29%, respectively. No significant systemic hypotension or decrease of arterial oxygen saturation was seen. CONCLUSION: Sildenafil therapy may be of benefit in patients with pulmonary arterial hypertension receiving long-term infusion of epoprostenol.

The interaction of endothelin-1 and TGF-ß1 mediates vascular cell remodeling.

BACKGROUND: Pulmonary arterial hypertension is characterized by increased thickness of pulmonary vessel walls due to both increased proliferation of pulmonary arterial smooth muscle cell (PASMC) and deposition of extracellular matrix. In patients suffering from pulmonary arterial hypertension, endothelin-1 (ET-1) synthesis is up-regulated and may increase PASMC activity and vessel wall remodeling through transforming growth factor beta-1 (TGF-ß1) and connective tissue growth factor. OBJECTIVE: To assess the signaling pathway leading to ET-1 induced proliferation and extracellular matrix deposition by human PASMC. METHODS: PASMC were serum starved for 24 hours before stimulation with either ET-1 and/or TGF-ß1. ET-1 was inhibited by Bosentan, ERK1/2 mitogen activated protein kinase (MAPK) was inhibited by U0126 and p38 MAPK was inhibited by SB203580. RESULTS: ET-1 increased PASMC proliferation when combined with serum. This effect involved the mitogen activated protein kinases (MAPK) ERK1/2 MAPK and was abrogated by Bosentan which caused a G1- arrest through activation of p27((Kip)). Regarding the contribution of extracellular matrix deposition in vessel wall remodeling, TGF-ß1 increased the deposition of collagen type-I and fibronectin, which was further increased when ET-1 was added mainly through ERK1/2 MAPK. In contrast, collagen type-IV was not affected by ET-1. Bosentan dose-dependently reduced the stimulatory effect of ET-1 on collagen type-I and fibronectin, but had no effect on TGF-ß1. CONCLUSION AND CLINICAL RELEVANCE: ET-1 alone does not induce PASMC proliferation and extracellular matrix deposition. However, ET-1 significantly up-regulates serum induced proliferation and TGF-ß1 induced extracellular matrix deposition, specifically of collagen type-I and fibronectin. The synergistic effects of ET-1 on serum and TGF-ß1 involve ERK1/2 MAPK and may thus present a novel mode of action in the pathogenesis of pulmonary arterial hypertension.

Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: a single-center experience.

BACKGROUND: Bronchiolitis obliterans (BO) is a detrimental late pulmonary complication after allogeneic hematopoietic stem cell transplantation (HCT) associated with chronic graft-versus-host disease (cGvHD). When systemic immunosuppressive treatment fails to improve, severe BO patients should be considered for lung transplantation (LuTX). We present seven patients undergoing LuTX for severe refractory BO after HCT. METHODS: Seven patients with hematologic malignancies developed severe cGvHD with lung involvement presenting as BO after allogeneic HCT. Evaluation for LuTX was initiated after failure of a median of 4 immunosuppressive regimens. RESULTS: Between 1996 and 2012, seven patients with severe refractory BO were evaluated for LuTX. The median time from HCT to diagnosis of chronic lung GvHD was 8.2 months (range, 3.7-16.6). At a median time of 18.1 months (range, 6-120) after diagnosis of BO, six patients received a bilateral sequential LuTX, and one patient received a single LuTX. Six postoperative courses were uneventful; the patient with single LuTX died from septic multiorgan failure. Three LuTX recipients had a mild acute rejection after one to three months after LuTX, and one patient experienced fatal chronic rejection and hemolytic uremic syndrome. At present, three (43%) LuTX recipients remain alive at a median observation time of 26 months (range, 1 month-16 years) after LuTX. The median overall survival from LuTX was 24 months (95% CI, 0.5-78); the median overall survival time after allogeneic HCT is 98 months (95% CI, 46-198). CONCLUSION: This case series illustrates that LuTX is a possible therapeutic option for selected patients with severe treatment-refractory BO.

Strength training increases maximum working capacity in patients with COPD--randomized clinical trial comparing three training modalities.

BACKGROUND AND OBJECTIVE: Skeletal muscle dysfunction contributes to exercise limitation in patients with chronic obstructive pulmonary disease (COPD). Strength training increases muscle strength and muscle mass, but there is an ongoing debate on the additional effect concerning the exercise capacity. The purpose of this study was to compare the effects of three different exercise modalities in patients with COPD including endurance training (ET), progressive strength training (ST) and the combination of strength training and endurance training (CT). DESIGN: A prospective randomized trial. METHODS: Thirty-six patients with COPD were randomly allocated either to ET, ST, or CT. Muscle strength, cardiopulmonary exercise testing, lung function testing and quality of life were assessed before and after a 12-week training period. RESULTS: Exercise capacity (Wmax) increased significantly in all three training groups with increase of peak oxygen uptake (VO2peak) in all three groups, reaching statistical significance in the ET group and the CT group. Muscle strength (leg press, bench press, bench pull) improved in all three training groups, with a higher improvement in the ST (+39.3%, +20.9%, +20.3%) and the CT group (+43.3%, +18.1%, +21.6%) compared to the ET group (+20.4%, +6.4%, +12.1%). CONCLUSIONS: Progressive strength training alone increases not only muscle strength and quality of life, but also exercise capacity in patients with COPD, which may have implications in prescription of training modality. CLINICALTRIALS.GOV IDENTIFIER: NCT01091623.

Vasoactive intestinal peptide (VIP) receptor expression in monocyte-derived macrophages from COPD patients.

Vasoactive intestinal peptide (VIP) is one of the most abundant molecules found in the respiratory tract. Due to its anti-inflammatory and bronchodilatatory properties, it has been proposed as a novel treatment for chronic obstructive pulmonary disease (COPD). The actions of VIP are mediated via three different G-protein-coupled receptors (VPAC1, VPAC2 and PAC1) which are expressed in the respiratory tract and on immunocompetent cells including macrophages. Alveolar macrophages (AM) are key players in the pathogenesis of COPD and contribute to the severity and progression of the disease. While VPAC1 has been reported to be elevated in subepithelial cells in smokers with chronic bronchitis, little is known about VPAC expression of AM in COPD patients. AM from COPD patients show a strong VPAC1 expression which exceeds VPAC2. A similar receptor expression pattern was also observed in lipopolysaccharide (LPS)-activated monocyte-derived macrophages (MDM) from healthy volunteers and COPD patients. VIP has been shown to down-regulate interleukin 8 (IL-8) secretion significantly in MDM after LPS stimulation. The response to VIP was similar in MDM from COPD patients and healthy volunteers. Our results indicate that VPAC1 up-regulation in macrophages is a common mechanism in response to acute and chronic pro-inflammatory stimuli. Although VPAC1 up-regulation is dominant, both receptor subtypes are necessary for optimal anti-inflammatory signaling. The high VPAC1 expression in AM may reflect the chronic pro-inflammatory environment found in the lung of COPD patients. Treatment with VIP may help to decrease the chronic inflammation in the lung of COPD patients.

Antibiotic treatment is not effective in patients infected with Helicobacter pylori suffering from extragastric MALT lymphoma.

PURPOSE: Apart from anecdotal reports implicating Helicobacter pylori (HP) in the development of extragastric mucosa associated lymphoid tissue (MALT) lymphoma, no large scale prospective studies have been performed on this topic. PATIENTS AND METHODS: A total of 77 patients with extragastric MALT lymphoma were prospectively studied. The presence or absence of HP was tested by histology, urease breath test, and serology. Patients were also tested for hepatitis A, B, and C and autoimmune conditions along with assessment of MALT lymphoma-specific genetic changes. RESULTS: Evidence for infection with HP was present in 35 of 77 patients (45%), and three of 75 patients tested (4%) were positive for hepatitis C and one for hepatitis B. All patients with HP-infection underwent eradication, 16 before initiation of further therapy. Apart from one patient with lymphoma involving parotid and colon, who achieved regression of the colonic lesions, none of these 16 patients showed regression of the lymphoma after a median follow-up of 14 months (range, 8 to 48+ months) before initiation of definitive treatment. No correlation between HP-status, localization, stage, autoimmune diseases, and genetic findings was seen. CONCLUSION: In our series, HP-eradication was ineffective for treatment of extragastric MALT lymphomas. This finding, along with an infection rate of 45%-as could also be expected in the general Austrian population-suggests that HP does not play a role in the development of these lymphomas. Antibiotic treatment targeting HP should, therefore, be discouraged in patients with extragastric MALT lymphomas.

The influence of VIP and epoprostenol on platelet CD62P expression and primary haemostasis in vitro.

Human vasoactive intestinal peptide (VIP) and epoprostenol (prostacyclin) have vasodilatative effects in the pulmonary circulation. Both VIP and epoprostenol are successfully used to treat pulmonary hypertension in humans and experimental animal models. The positive effects of epoprostenol on the course of this disease are achieved through vasodilatation and inhibitory effects on platelet activity. Since VIP also binds specifically to platelets, we compared the in vitro effects of VIP and epoprostenol on platelet P-Selectin (CD62P) expression and primary haemostasis. Anti-aggregative effects of VIP (10(-6) mol and 10(-8) mol) and epoprostenol (50, 5 and 0.5 ng/ml) on platelets were determined by agonist-induced CD62P expression and in vitro bleeding time (PFA-100 trade mark system). Blood from healthy individuals was either incubated with epoprostenol, VIP or saline control and was analysed by whole blood flow cytometry and the PFA-100 trade mark. Prior to flow cytometric analysis, the platelets were stimulated with either arachidonic acid (AA) or adenosine diphosphate (ADP). Whole blood flow cytometry analysis showed that epoprostenol inhibited dose-dependently agonist-induced CD62P expression, whereas VIP did not inhibit CD62P expression. PFA analysis revealed substantial closure time prolongation by epoprostenol and again no effects of VIP. These results indicate that VIP, in contrast to epoprostenol, has no effect on platelet CD62P expression and primary haemostasis.