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Background: International disease management guidelines recommend the regular assessment of depression and anxiety in heart failure patients. Currently there is little data on the effect of screening for depression and anxiety on the quality of life and the prognosis of heart failure (HF). We will investigate the association between the recognition of current depression/anxiety by the general practitioner (GP) and the quality of life and the patients' prognosis.
Methods/Design: In this multicenter, prospective, observational study 3,950 patients with HF are recruited by general practices in Germany. The patients fill out questionnaires at baseline and 12-month follow-up. At baseline the GPs are interviewed regarding the somatic and psychological comorbidities of their patients. During the follow-up assessment, data on hospitalization and mortality are provided by the general practice. Based on baseline data, the patients are allocated into three observation groups: HF patients with depression and/or anxiety recognized by their GP (P+/+), those with depression and/or anxiety not recognized (P+/-) and patients without depression and/or anxiety (P-/-). We will perform multivariate regression models to investigate the influence of the recognition of depression and/or anxiety on quality of life at 12 month follow-up, as well as its influences on the prognosis (hospital admission, mortality).
Discussion: We will display the frequency of GP-acknowledged depression and anxiety and the frequency of installed therapeutic strategies. We will also describe the frequency of depression and anxiety missed by the GP and the resulting treatment gap. Effects of correctly acknowledged and missed depression/anxiety on outcome, also in comparison to the outcome of subjects without depression/anxiety will be addressed. In case results suggest a treatment gap of depression/anxiety in patients with HF, the results of this study will provide methodological advice for the efficient planning of further interventional research.
Das menschliche MHS2 Gen ist eine sehr gut charakterisierte Komponente des Mismatch-Reparatur-Systems (MMR) und häufig mit der HNPCC Erkrankung assoziiert. Der Mechanismus über den MSH2 an der Karzinomentwicklung beteiligt ist, sind Defekte in der DNA-Reparatur. Es konnte gezeigt werden, dass Mutationen in den kodierenden Regionen dieses Gens direkt in die Mikrosatelliteninstabilität involviert sind. Generell ist MSH2 ein Teil des postreplikativen Reparatursystems der Zellen, und schützt so vor der Akkumulation von Mutationen. Dadurch wird die genetische Stabilität und Integrität gewährleistet. Ein anderer Teil der zellulären Krebsabwehr ist das p53 Tumorsuppressorgen. Ein möglicher DNA Schaden, der in der Lage ist, p53 zu aktivieren, ist UV-Licht. Eine weitere gut charakterisierte Komponente der zellulären UV Reaktion ist der Transkriptionsfaktor c-Jun. Ziel der Arbeit war es die Regulation und Signalfunktion von MSH2 näher zu charakterisieren. Dazu wurde der Promotor des Gens in ein Luziferase Promotorgenkonstrukt kloniert. Dieses Konstrukt wurde in menschliche Keratinozyten transfiziert, die nachfolgend mit UV bestrahlt wurden. Es konnte eine zeit- und dosisabhängige Hochregulation von MSH2 gezeigt werden. Diese Transkriptionserhöhung wurde von p53 initiiert, denn durch eine gezielte Mutation der p53-Bindungsstelle im MSH2 Promotor war dieser Effekt vollkommen aufgehoben. Interessanterweise war dieser Effekt von einem zusätzlichen Faktor abhängig, ohne den keine Hochregulation erkennbar war. Verantwortlich hierfür war der Transkriptionsfaktor c-Jun. Dadurch konnte eine funktionelle Interaktion von p53 und c-Jun in der transkriptionellen Aktivierung von hMSH2 gezeigt werden. Dieser zeit- und dosisabhängige Effekt war sowohl auf RNA als auch auf Proteinebene nachvollziehbar. Der größte Anstieg war bei 50 J/m2 zu verzeichnen, wohin gegen bei Verwendung von 75 J/m2 die Transkriptmenge geringer wurde, um bei 100 J/m2 erneut anzusteigen. Um diesen erneuten Anstieg des Proteins näher zu beschreiben wurden bei den stark bestrahlten Zellen TUNEL-Untersuchungen durchgeführt. Hierbei zeigte sich eine positive Korrelation zwischen der Menge an MSH2 Protein und an TUNEL-positiven apoptotischen Zellen. Um weiter zu zeigen, dass der zweite Anstieg des Proteins nicht mit einer Reparaturfunktion verbunden ist, wurde ein biochemisch basierter Test durchgeführt, welcher die Reparaturkapazität semiquantitativ beschreibt. Dabei konnte klar gezeigt werden, dass die mit 100 J/m2 bestrahlten Zellen keine Reparaturfunktion mehr erfüllen. FACS-Analysen und Zellfärbungen gegen Annexin V und mit Propidiumiodid bestätigten die stattfindende Apoptose in den Zellen. Eine weitere Komponente des MMR-Systems ist MSH6. MSH6 bildet mit MSH2 ein Dimer, welches den Fehler in der DNA erkennt und das weitere Reparaturprogramm einleitet. Die Expression dieses Proteins konnte nur bis zu einer Dosis von 50-75 J/m2 UV nachgewiesen werden. Im Gegensatz zu MSH2 war MSH6 nicht in 100 J/m2 bestrahlten Keratinozyten detektierbar. Um über die Lokalisation dieser Proteine mehr zu erfahren wurden Immunfärbungen gegen MSH2 durchgeführt. Es zeigte sich eine Translokation des Proteins vom Kern in das Zytoplasma in Korrelation zum zunehmenden DNA-Schaden durch höhere Dosen an UV-Licht. Dies stellt eine mögliche Verbindung zwischen dem Mismatch-Reparatursystem und apoptotischen Signalwegen dar.
Background: In the phase III AVAGAST trial, the addition of bevacizumab to chemotherapy improved progression-free survival (PFS) but not overall survival (OS) in patients with advanced gastric cancer. We studied the role of Angiopoietin-2 (Ang-2), a key driver of tumour angiogenesis, metastasis and resistance to antiangiogenic treatment, as a biomarker.
Methods: Previously untreated, advanced gastric cancer patients were randomly assigned to receive bevacizumab (n = 387) or placebo (n = 387) in combination with chemotherapy. Plasma collected at baseline and at progression was analysed by ELISA. The role of Ang-2 as a prognostic and a predictive biomarker of bevacizumab efficacy was studied using a Cox proportional hazards model. Logistic regression analysis was applied for correlations with metastasis. Results: Median baseline plasma Ang-2 levels were lower in Asian (2143 pg ml\(^-\)\(^1\)) vs non-Asian patients (3193 pg ml\(^-\)\(^1\)), P<0.0001. Baseline plasma Ang-2 was identified as an independent prognostic marker for OS but did not predict bevacizumab efficacy alone or in combination with baseline VEGF. Baseline plasma Ang-2 correlated with the frequency of liver metastasis (LM) at any time: Odds ratio per 1000 pg ml\(^-\)\(^1\) increase: 1.19; 95% CI 1.10-1.29; P<0.0001 (non-Asians) and 1.37; 95% CI 1.13-1.64; P = 0.0010 (Asians).
Conclusions: Baseline plasma Ang-2 is a novel prognostic biomarker for OS in advanced gastric cancer strongly associated with LM. Differences in Ang-2 mediated vascular response may, in part, account for outcome differences between Asian and non-Asian patients; however, data have to be further validated. Ang-2 is a promising drug target in gastric cancer.
Aims
Treating patients with acute decompensated heart failure (ADHF) presenting with volume overload is a common task. However, optimal guidance of decongesting therapy and treatment targets are not well defined. The inferior vena cava (IVC) diameter and its collapsibility can be used to estimate right atrial pressure, which is a measure of right‐sided haemodynamic congestion. The CAVA‐ADHF‐DZHK10 trial is designed to test the hypothesis that ultrasound assessment of the IVC in addition to clinical assessment improves decongestion as compared with clinical assessment alone.
Methods and results
CAVA‐ADHF‐DZHK10 is a randomized, controlled, patient‐blinded, multicentre, parallel‐group trial randomly assigning 388 patients with ADHF to either decongesting therapy guided by ultrasound assessment of the IVC in addition to clinical assessment or clinical assessment alone. IVC ultrasound will be performed daily between baseline and hospital discharge in all patients. However, ultrasound results will only be reported to treating physicians in the intervention group. Treatment target is relief of congestion‐related signs and symptoms in both groups with the additional goal to reduce the IVC diameter ≤21 mm and increase IVC collapsibility >50% in the intervention group. The primary endpoint is change in N‐terminal pro‐brain natriuretic peptide from baseline to hospital discharge. Secondary endpoints evaluate feasibility, efficacy of decongestion on other scales, and the impact of the intervention on clinical endpoints.
Conclusions
CAVA‐ADHF‐DZHK10 will investigate whether IVC ultrasound supplementing clinical assessment improves decongestion in patients admitted for ADHF.
Background
Depression is a common comorbidity in patients with chronic heart failure (HF) and linked to a wider range of symptoms which, in turn, are linked to a decreased health-related quality of life (HRQOL). Treatment of depression might improve HRQOL but detecting depression is difficult due to the symptom overlap between HF and depression. Therefore, clinical guidelines recommend to routinely screen for depression in HF patients. No studies have so far investigated the treatment after getting aware of a depressive symptomatology and its correlation with HRQOL in primary care HF patients. Therefore, we examined the factors linked to depression treatment and those linked to HRQOL in HF patients. We hypothesized that GPs’ awareness of depressive symptomatology was associated with depression treatment and HRQOL in HF patients.
Methods
For this observational study, HF patients were recruited in primary care practices and filled out a questionnaire including PHQ-9 and HADS. A total of 574 patients screened positive for depressive symptomatology. Their GPs were interviewed by phone regarding the patients’ comorbidities and potential depression treatment. Descriptive and regression analysis were performed.
Results
GPs reported various types of depression treatments (including dialogue/counselling by the GP him/herself in 31.8% of the patients). The reported rates differed considerably between GP-reported initiated treatment and patient-reported utilised treatment regarding psychotherapy (16.4% vs. 9.5%) and pharmacotherapy (61.2% vs. 30.3%). The GPs' awareness of depressive symptomatology was significantly associated with the likelihood of receiving pharmacotherapy (OR 2.8; p < 0.001) but not psychotherapy. The patient’s HRQOL was not significantly associated with the GPs' awareness of depression.
Conclusion
GPs should be aware of the gap between GP-initiated and patient-utilised depression treatments in patients with chronic HF, which might lead to an undersupply of depression treatment. It remains to be investigated why GPs’ awareness of depressive symptomatology is not linked to patients’ HRQOL. We hypothesize that GPs are aware of cases with reduced HRQOL (which improves under depression treatment) and unaware of cases whose depression do not significantly impair HRQOL, resulting in comparable levels of HRQOL in both groups. This hypothesis needs to be further investigated.