Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

BACKGROUND: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. METHODS: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. RESULTS: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. CONCLUSIONS: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.

No evidence to support the impact of migration background on treatment response rates and cancer survival: a retrospective matched-pair analysis in Germany.

BACKGROUND: Immigration has taken the central stage in world politics, especially in the developed countries like Germany, where the continuous flow of immigrants has been well documented since 1960s. Strikingly, emerging data suggest that migrant patients have a poorer response to the treatment and lower survival rates in their new host country, raising concerns about health disparities. Herein, we present our investigation on the treatment response rate and cancer survival in German patients with and without an immigrant background that were treated at our comprehensive cancer center in Germany. METHODS: Initially, we considered 8162 cancer patients treated at the Center for Integrated Oncology (CIO), University Hospital Bonn, Germany (April 2002-December 2015) for matched-pair analysis. Subsequently, the German patients with a migration background and those from the native German population were manually identified and catalogued using a highly specific name-based algorithm. The clinical parameters such as demographic characteristics, tumor characteristics, defined staging criteria, and primary therapy were further adjusted. Using these stringent criteria, a total of 422 patients (n = 211, Germans with migration background; n = 211, native German population) were screened to compare for the treatment response and survival rates (i.e., 5-year overall survival, progression-free survival, and time to progression). RESULTS: Compared to the cohort with migration background, the cohort without migration background was slightly older (54.9 vs. 57.9 years) while having the same sex distribution (54.5% vs. 55.0% female) and longer follow-up time (36.9 vs. 42.6 months). We did not find significant differences in cancer survival (5-year overall survival, P = 0.771) and the response rates (Overall Remission Rate; McNemar's test, P = 0.346) between both collectives. CONCLUSION: Contrary to prior reports, we found no significant differences in cancer survival between German patients with immigrant background and native German patients. Nevertheless, the advanced treatment protocols implemented at our comprehensive cancer center may possibly account for the low variance in outcome. To conduct similar studies with a broader perspective, we propose that certain risk factors (country-of-origin-specific infections, dietary habits, epigenetics for chronic diseases etc.) should be considered, specially in the future studies that will recruit new arrivals from the 2015 German refugee crisis.

A matched-pair analysis on survival and response rates between German and non-German cancer patients treated at a Comprehensive Cancer Center.

BACKGROUND: Research shows disparities in cancer outcomes by ethnicity or socio-economic status. Therefore, it is the aim of our study to perform a matched-pair analysis which compares the outcome of German and non-German (in the following described as 'foreign') cancer patients being treated at the Center for Integrated Oncology (CIO) Köln Bonn at the University Hospital of Bonn between January 2010 and June 2016. METHODS: During this time, 6314 well-documented patients received a diagnosis of cancer. Out of these patients, 219 patients with foreign nationality could be matched to German patients based on diagnostic and demographic criteria and were included in the study. All of these 438 patients were well characterized concerning survival data (Overall survival, Progression-free survival and Time to progression) and response to treatment. RESULTS: No significant differences regarding the patients' survival and response rates were seen when all German and foreign patients were compared. A subgroup analysis of German and foreign patients with head and neck cancer revealed a significantly longer progression-free survival for the German patients. Differences in response to treatment could not be found in this subgroup analysis. CONCLUSIONS: In summary, no major differences in survival and response rates of German and foreign cancer patients were revealed in this study. Nevertheless, the differences in progression-free survival, which could be found in the subgroup analysis of patients with head and neck cancer, should lead to further research, especially evaluating the role of infectious diseases like human papillomavirus (HPV) and Epstein-Barr virus (EBV) on carcinogenesis and disease progression.

Hypoxia-induced endothelial dysfunction in apolipoprotein E-deficient mice; effects of infliximab and L-glutathione.

OBJECTIVE: Obstructive sleep apnoea (OSA) has been implicated as a risk factor for atherosclerosis. The aim of our study was to examine the effects of chronic intermittent hypoxia in apoE-/- mice serving as model of OSA on endothelial dysfunction and oxidative stress and to evaluate the reversibility of hypoxia-induced changes under anti-inflammatory infliximab and anti-oxidative l-glutathione. METHODS: ApoE-/- mice were divided into 4 groups (n = 9 each): 1. intermittent hypoxia 8 h/day for 6 weeks, 2. intermittent hypoxia + injections of infliximab, 3. intermittent hypoxia + injections of l-glutathione, 4. normoxia = control. RESULTS: Endothelial function was impaired under hypoxia compared to control. Application of infliximab and l-glutathione improved it to a level of control. The percentage of endothelial microparticles increased under hypoxia compared to other groups. Levels of NADPH oxidase 2-derived reactive oxygen species were approximately 9 times higher in the hypoxia group. The number of sca-1/flk-1+ endothelial progenitor cells was higher in bone marrow and lower in blood under hypoxia vs. other groups. Stromal cell derived factor-1alpha- and matrix metalloproteinase-9-dependent release of these cells from bone marrow was attenuated under hypoxia. The number of DilacLDL+/lectin + early outgrowth progenitor cells and that of colony forming units from these cells were higher under hypoxia. Atherosclerotic plaques in the aorta were more frequent under hypoxia and control in comparison with both drug groups. CONCLUSION: Intermittent hypoxia contributes to endothelial dysfunction by the local increase in reactive oxygen species and reduction of the peripheral repair capacity. Infliximab and l-glutathione prevent hypoxia-induced vascular and extravascular changes.