F Roller

Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial

BACKGROUND Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas. METHODS We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335. FINDINGS 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p<0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p<0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0.0001), and stomatitis (16 [6%] vs 47 [19%]; p<0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024). INTERPRETATION In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects. FUNDING Roche Pharma AG, Ribosepharm/Mundipharma GmbH.

T1, T2 Mapping and Extracellular Volume Fraction (ECV): Application, Value and Further Perspectives in Myocardial Inflammation and Cardiomyopathies.

UNLABELLED Cardiac magnetic resonance imaging (CMRI) is a versatile diagnostic tool. One of its main advantages is the possibility of tissue characterization. T1-weighted images for scar and T2-weighted images for edema visualization are key methods for tissue characterization. Otherwise these sequences are strongly limited for the detection of diffuse myocardial pathologies. Recently, rapid technical innovations have generated new techniques. T1, T2 mapping and evaluation of the extracellular volume fraction (ECV) allow quantification of diffuse myocardial pathologies and showed great potential in the visualization of fibrosis, edema, amyloid, iron overload and lipid. In the future these techniques might enable the detection of early cardiac involvement, even act as a prognosticator. Moreover, therapy monitoring and follow-up might be possible due to versatile parameter quantification with these new techniques. KEY POINTS CMR allows for tissue characterization via T1- and T2-weighted sequences. In cases of diffuse, global myocardial pathologies, correct image interpretation with traditional CMR sequences might be difficult. T1, T2 mapping and ECV can quantify diffuse, global myocardial pathologies. Alterations of myocardial T1 and T2 relaxation times occur in various myocardial diseases (e.g. acute myocarditis). In the future mapping might act as a prognosticator or therapy monitoring tool.

N-terminal pro–B-type natriuretic peptide for monitoring after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

BACKGROUND Balloon pulmonary angioplasty (BPA) is an emerging interventional treatment option for chronic thromboembolic pulmonary hypertension (CTEPH). The non-invasive monitoring of CTEPH patients is a clinical challenge. In this study we examined changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients undergoing BPA for inoperable CTEPH and related them to peri-procedural success. METHODS In this study we analyzed a total of 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between March 2014 and March 2017. Serum samples for NT-proBNP measurement were collected before every BPA and at 6-MFU. RESULTS The 51 patients underwent 265 interventions involving angioplasty of a total of 410 vessels. The 6-month survival rate was 96.1%. The baseline (BL) mean pulmonary artery pressure (PAP) was 39.5 ± 12.1 mm Hg, pulmonary vascular resistance (PVR) was 515.8 ± 219.2 dynes/s/cm5 and the median NT-proBNP level was 820 (153 to 1,871.5) ng/liter. At BL, World Health Organization functional class (FC) was ≥III in 96.1% of the patients, whereas, at 6-MFU, 11.8% were in WHO FC ≥III. At 6-MFU, mean PAP (32.6 ± 12.6 mm Hg; p < 0.001), PVR (396.9 ± 182.6 dynes/s/cm5; p < 0.001) and NT-proBNP (159.3 [84.4 to 464.3] ng/liter; p < 0.001) levels were reduced. The decrease in NT-proBNP levels correlated with the decrease in mean PAP (rrs = 0.43, p = 0.002) and PVR (rrs = 0.50, p = 0.001). A reduction in the NT-proBNP level of 46% indicated a decrease in mean PAP of ≥25% (area under the curve [AUC] = 0.71) and a reduction of 61% indicated a decrease in PVR of ≥35% (AUC 0.77). CONCLUSIONS Our results demonstrate that NT-proBNP levels decrease after BPA, providing valuable evidence of procedural success. NT-proBNP measurement allows identification of patients who are BPA non-responders and may thus be a valuable adjunct in therapy monitoring.

Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic disease

Symptomatic patients with residual pulmonary perfusion defects or vascular lesions but no pulmonary hypertension at rest are diagnosed with chronic thromboembolic disease (CTED). Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), but data regarding the safety and efficacy of BPA in patients with CTED are lacking. We report a prospective series of ten consecutive patients with CTED who underwent 35 BPA interventions (median of four per patient) at two German institutions. All patients underwent a comprehensive diagnostic workup at baseline and 24 weeks after their last intervention. BPA was safe, with one pulmonary vascular injury and subsequent self-limiting pulmonary bleeding as the only complication (2.9% of the interventions, 10% of the patients). After the procedures, World Health Organization functional class, 6-min walking distance, pulmonary vascular resistance, and pulmonary arterial compliance improved, and NT-proBNP concentrations declined in 9/10 patients. BPA may be a new treatment option for carefully selected patients with CTED. A larger, prospective, international registry is required to confirm these results.

Development and Suggestion of a Cardiac CTA Scoring System for the Prediction of Revascularization Success in Chronic Total Occlusions (CTO) of the Coronary Arteries

OBJECTIVE Analyzing occluded segments with computed tomography angiography (CTA) prior to percutaneous coronary intervention (PCI) increased revascularization success in chronic total occlusions (CTO). The aim of our study was to develop a scoring system for the prediction of PCI success in CTO. MATERIALS AND METHODS 41 consecutive CTO patients (30 male; 63.1 years +/- 8.3 standard deviation) underwent CTA prior to PCI. All CTOs were categorized by two radiologists in consensus regarding the presence of special features and without knowledge of PCI outcome. All outcome criteria were evaluated. Afterwards one point was assigned for each unequally distributed outcome criteria per CTO and all points were added up to a single score. RESULTS Severe calcifications (failure group 68.8 % vs. success group 28.0 %; p < 0.02) and intraluminal calcifications (68.8 %; 40.0 %), tortuosity (25.0 %; 0 %; p < 0.02), linear intrathrombus enhancement (37.5 %; 60.0 %) and distal vessel disease (68.8 %; 44.0 %) were unequally distributed. By adopting a threshold of 4 points or higher (maximum 5 points), the results were: sensitivity 31.3 %, specificity 100 %, negative predictive value (NPV) 69.4 % and positive predictive value (PPV) 100 %. The PCI complication rate was 9.8 % and the mean contrast media amount was 234.4 ml. CONCLUSION With the suggested scoring system, based on five CTA criteria, PCI failure could be predicted with high PPV and specificity in our group of patients, but the NPV and sensitivity are low. However, 5 unsuccessful PCIs (13.2 %) could have been avoided and none would have been wrongly omitted. Regarding the complication rate during PCI and the high amounts of contrast media needed, a prediction system appears to be desirable and should be the object of large-scale trials. KEY POINTS Single predictors of revascularization success in CTO have been identified. Success rates are improved by analyzing CTA data sets prior to revascularization approaches. Prediction of revascularization success via a scoring system based on five CTA criteria seems promising. Patient selection for the right treatment options might be improved in the future due to application of the scoring system. Also risks, complications, contrast media amounts and radiation doses might be reduced.

Dynamics of high-sensitivity cardiac troponin T during therapy with balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

Aims Balloon pulmonary angioplasty (BPA) is an interventional treatment modality for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Therapy monitoring, based on non-invasive biomarkers, is a clinical challenge. This post-hoc study aimed to assess dynamics of high-sensitivity cardiac troponin T (hs-cTnT) as a marker for myocardial damage and its relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels as a marker for cardiac wall stress. Methods and results This study included 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between 3/2014 and 3/2017. Biomarker measurement was performed consecutively prior to each BPA and at 6-MFU. In total, the 51 patients underwent an average of 5 BPA procedures. The 6-month survival rate was 96.1%. The baseline (BL) meanPAP (39.5±12.1mmHg) and PVR (515.8±219.2dyn×sec×cm-5) decreased significantly within the 6-MFU (meanPAP: 32.6±12.6mmHg, P<0.001; PVR: 396.9±182.6dyn×sec×cm-5, P<0.001). At BL, the median hs-cTnT level was 11 (IQR 6–16) ng/L and the median NT-proBNP level was 820 (IQR 153–1872) ng/L. The levels of both biomarkers decreased steadily after every BPA, showing the first significant difference after the first procedure. Within the 6-MFU, hs-cTnT levels (7 [IQR 5–12] ng/L; P<0.001) and NT-proBNP levels (159 [IQR 84–464] ng/l; P<0.001) continued to decrease. The hs-cTnT levels correlated with the PVR (rrs = 0.42; p = 0.005), the meanPAP (rrs = 0.32; p = 0.029) and the NT-proBNP (rrs = 0.51; p<0.001) levels at BL. Conclusion Non-invasive biomarker measurement provides valuable evidence for the decreasing impairment of myocardial function and structure during BPA therapy. Changes in hs-cTNT levels are suggestive for a reduction in ongoing myocardial damage.

Correlation of native T1 mapping with right ventricular function and pulmonary haemodynamics in patients with chronic thromboembolic pulmonary hypertension before and after balloon pulmonary angioplasty

ObjectivesThe aim of this study was to assess native T1 mapping in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) before and 6 months after balloon pulmonary angioplasty (BPA) and compare the results with right heart function and pulmonary haemodynamics.MethodsMagnetic resonance imaging at 1.5 T and right heart catheterisation were performed in 21 consecutive inoperable CTEPH patients before and 6 months after BPA. T1 values were measured within the septal myocardium, the upper and lower right ventricular insertion points, and the lateral wall at the basal short-axis section. In addition, the area-adjusted septal native T1 time (AA-T1) was calculated and compared with right ventricular function (RVEF), mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR).ResultsThe mean AA-T1 value decreased significantly after BPA (1,045.8 ± 44.3 ms to 1,012.5 ± 50.4 ms; p < 0.001). Before BPA, native T1 values showed a moderate negative correlation with RVEF (r = -0.61; p = 0.0036) and moderate positive correlations with mPAP (r = 0.59; p < 0.01) and PVR (r = 0.53; p < 0.05); after BPA correlation trends were present (r = -0.21, r = 0.30 and r = 0.35, respectively).ConclusionsNative T1 values in patients with inoperable CTEPH were significantly lower after BPA and showed significant correlations with RVEF and pulmonary haemodynamics before BPA. Native T1 mapping seems to be indicative of reverse myocardial tissue remodelling after BPA and might therefore have good potential for pre-procedural patient selection, non-invasive therapy monitoring and establishing a prognosis.Key Points• BPA is a promising treatment option for patients with inoperable CTEPH• Native septal T1 values significantly decrease after BPA and show good correlations with right ventricular function and haemodynamics before BPA• Prognosis and non-invasive therapy monitoring might be supported in the future by native T1 mapping

Value of Cardiac T1-Mapping and ECV Quantification in Duchenne Muscular Dystrophy (DMD): Case Report, Typical Imaging Findings and Review of the Literature

Duchenne muscular dystrophy (DMD) is a X-linked recessive disorder affecting approximately 1 of 5000 males. It is the most common inherited muscular dystrophy. Key feature of the disease is a mutation in the gene for dystrophin. Absence, mutation or lack of dystrophin causes cell membrane rupture with consecutive release of creatine kinase. This results in myasthenia and muscular atrophy. Cardiac involvement with progressive global ventricular cardiac dysfunction and dilation can be present. Autopsy studies showed that cardiac pathologies in DMD contain myocyte hypertrophy but also atrophy, fibrosis and fatty and connective tissue conversions. It is also known that cardiac involvement in DMD is on its way long before symptoms develop. Cardiac disease is the leading cause of death in DMD patients in the second or third decade of life. Late gadolinium enhancement (LGE) showed promising results in detecting cardiac DMD and in prediction of adverse disease outcome. Silva et al. showed that LGE was present in 7 of 10 DMD patients and identified the lateral wall as the most commonly affected region (Silva et al. Am Coll Cardiol 2007; 49(18): 1874 – 1879), and Florian et al. showed that the transmurality of LGE predicts occurrence of adverse cardiac events (Florian et al. J Cardiovasc Magn Reson 2014; 16: 81). However, LGE imaging underlies several limitations in displaying global myocardial pathologies due to the lack of regional differences in signal intensity. It could also be shown that LGE was more likely to be detected in myocardial segments with at least 15 % collagen fiber components, whereas areas with less advanced fibrosis could not be visualized by LGE (Kim et al. J Am Coll Cardiol 2003; 41: 1568– 1572). Parametric imaging techniques, like T1mapping and extracellular volume fraction quantification (ECV), aim to overcome these problems and exhibited great potential in the early detection of different cardiac diseases. In fact, a recent study demonstrated pathologic native T1 and ECV values in DMD patients with normal heart function and absence of LGE (Soslow et al. J Cardiovasc Magn Reson 2016; 18: 5). Our case report impressively demonstrates typical imaging findings in a young male DMD patient.

Dedifferentiated Liposarcoma of the Anterior Mediastinum: A Rare Case

Liposarcoma accounts for approximately 14% of all malignant soft-tissue tumors, regardless of anatomical location (Kransdorf MJ et al. Imaging of soft tissue tumors. Philadelphia: Lippincott Williams & Wilkins, 2014). Primary mediastinal liposarcomas are rare. Liposarcoma is classified into four histologic subtypes: Myxoid/round cell, pleomorphic, atypical lipomatous tumor/ well-differentiated liposarcoma and dedifferentiated liposarcoma. Dedifferentiated liposarcoma occurs most commonly in the retroperitoneum and in the soft tissues of the extremities. Like atypical lipomatous tumor/well-differentiated liposarcoma, it is characterized by amplification of MDM2 and CDK4 genes on chromosome 12 (Crago AM et al. Curr Opin Oncol 2011; 23: 373– 378). Possible symptoms of mediastinal liposarcoma are dyspnea, wheezing, chest pain, cough, superior vena cava syndrome, and weight loss (Macchiarini P et al. Lancet Oncol 2004; 5: 107–118).

Seltener Fall der bildgebenden Dokumentation eines rapide wachsenden primären kardialen Lymphoms

Das primäre Herzlymphom ist ein sehr seltener kardialer Tumor. Der Anteil an allen Herztumoren beträgt in etwa nur 2%. Eine sekundäre Infiltration des Herzens oder des Perikards durch ein diffuses systemisches Lymphom wird dagegen in etwa 20% der Fälle beschrieben (Chinen K et al. Ann Hematol 2005; 84: 498–505). Zur Diagnosesicherung erfolgt in den meisten Fällen eine Biopsie mit Gewebsentnahme. Moderne Bildgebungstechniken wie die Magnetresonanztomografie ermöglichen uns eine Lokalisationsbestimmung sowie eine genaue Charakterisierung des Wachstumsmusters, des Infiltrationsverhaltens und des Kontrastmittelaufnahmeverhaltens der Raumforderung. Hierdurch wird in einigen Fällen eine Diagnosestellung mit einem damit verbundenen früheren Therapiebeginn möglich. Wir präsentieren einen Fall eines primären kardialen großzelligen B-Zell-Lymphoms bei einem 56-jährigen männlichen Patienten.