[Alveolar echinococcosis (fox tapeworm)-a surprising diagnosis in a patient with epididymal tumor]. / Echinococcosis alveolaris (Fuchsbandwurmerkrankung) ­ eine überraschende Diagnose bei Nebenhodentumor.

Alveolar ecchinococcosis, caused by the fox tapeworm (echinococcosus multilocularis), is in principle a lethal illness. We report on a 31-year-old man presenting with an unclear epididymal tumor, in whom further examinations revealed multiple and extended partially cystic, partially solid intra-abdominal tumors. Diagnosis was achieved histologically by percutaneous biopsy of a spleen lesion and serologically. As a surgical resection of the lesions was not feasible, therapy with albendazol was initiated.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.

This corrects the article DOI: 10.1038/leu.2017.9.

Long-term survival of sorafenib-treated FLT3-ITD-positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation.

BACKGROUND: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. METHODS: We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD-positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. FINDINGS: With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. INTERPRETATION: Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD-positive AML relapsing after allo-SCT.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.

It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86+pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86+pDC (n=12). This suggested that low CD86+pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86+pDC per 105 lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86+pDC (hazard ratio (HR) 3.4, 95%-CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86+pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86+pDC counts significantly correlated with leukemia-specific CD8+ T-cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86+pDC counts have a higher risk of relapse after TKI discontinuation.

Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey.

Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

NFATc1 as a therapeutic target in FLT3-ITD-positive AML.

Internal tandem duplications (ITD) in the Fms-related tyrosine kinase 3 receptor (FLT3) are associated with a dismal prognosis in acute myeloid leukemia (AML). FLT3 inhibitors such as sorafenib may improve outcome, but only few patients display long-term responses, prompting the search for underlying resistance mechanisms and therapeutic strategies to overcome them. Here we identified that the nuclear factor of activated T cells, NFATc1, is frequently overexpressed in FLT3-ITD-positive (FLT3-ITD+) AML. NFATc1 knockdown using inducible short hairpin RNA or pharmacological NFAT inhibition with cyclosporine A (CsA) or VIVIT significantly augmented sorafenib-induced apoptosis of FLT3-ITD+ cells. CsA also potently overcame sorafenib resistance in FLT3-ITD+ cell lines and primary AML. Vice versa, de novo expression of a constitutively nuclear NFATc1-mutant mediated instant and robust sorafenib resistance in vitro. Intriguingly, FLT3-ITD+ AML patients (n=26) who received CsA as part of their rescue chemotherapy displayed a superior outcome when compared with wild-type FLT3 (FLT3-WT) AML patients. Our data unveil NFATc1 as a novel mediator of sorafenib resistance in FLT3-ITD+ AML. CsA counteracts sorafenib resistance and may improve treatment outcome in AML by means of inhibiting NFAT.

Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.

A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses.

Preliminary evidence suggests that the multikinase inhibitor sorafenib has clinical activity in FLT3-ITD-positive (FLT3-ITD) acute myeloid leukemia (AML). However, the quality and sustainability of achievable remissions and clinical variables that influence the outcome of sorafenib monotherapy are largely undefined. To address these questions, we evaluated sorafenib monotherapy in 65 FLT3-ITD AML patients treated at 23 centers. All but two patients had relapsed or were chemotherapy-refractory after a median of three prior chemotherapy cycles. Twenty-nine patients (45%) had undergone prior allogeneic stem cell transplantation (allo-SCT). The documented best responses were: hematological remission in 24 patients (37%), bone marrow remission in 5 patients (8%), complete remission (with and without normalization of peripheral blood counts) in 15 patients (23%) and molecular remission with undetectable FLT3-ITD mRNA in 10 patients (15%), respectively. Seventeen of the patients without prior allo-SCT (47%) developed sorafenib resistance after a median treatment duration of 136 days (range, 56-270 days). In contrast, allo-SCT patients developed sorafenib resistance less frequently (38%) and significantly later (197 days, range 38-225 days; P=0.03). Sustained remissions were seen exclusively in the allo-SCT cohort. Thus, sorafenib monotherapy has significant activity in FLT3-ITD AML and may synergize with allogeneic immune effects to induce durable remissions.

Performance of cardiac output measurement derived from arterial pressure waveform analysis in patients requiring high-dose vasopressor therapy.

BACKGROUND: Arterial pressure waveform analysis of cardiac output (APCO) without external calibration (FloTrac/Vigileo™) is critically dependent upon computation of vascular tone that has necessitated several refinements of the underlying software algorithms. We hypothesized that changes in vascular tone induced by high-dose vasopressor therapy affect the accuracy of APCO measurements independently of the FloTrac software version. METHODS: In this prospective observational study, we assessed the validity of uncalibrated APCO measurements compared with transpulmonary thermodilution cardiac output (TPCO) measurements in 24 patients undergoing vasopressor therapy for the treatment of cerebral vasospasm after subarachnoid haemorrhage. RESULTS: Patients received vasoactive support with [mean (sd)] 0.53 (0.46) µg kg(-1) min(-1) norepinephrine resulting in mean arterial pressure of 104 (14) mm Hg and mean systemic vascular resistance of 943 (248) dyn s(-1) cm(-5). Cardiac output (CO) data pairs (158) were obtained simultaneously by APCO and TPCO measurements. TPCO ranged from 5.2 to 14.3 litre min(-1), and APCO from 4.1 to 13.7 litre min(-1). Bias and limits of agreement were 0.9 and 2.5 litre min(-1), resulting in an overall percentage error of 29.6% for 68 data pairs analysed with the second-generation FloTrac(®) software and 27.9% for 90 data pairs analysed with the third-generation software. Precision of the reference technique was 2.6%, while APCO measurements yielded a precision of 29.5% and 27.9% for the second- and the third-generation software, respectively. For both software versions, bias (TPCO-APCO) correlated inversely with systemic vascular resistance. CONCLUSIONS: In neurosurgical patients requiring high-dose vasopressor support, precision of uncalibrated CO measurements depended on systemic vascular resistance. Introduction of the third software algorithm did not improve the insufficient precision (>20%) for APCO measurements observed with the second software version.

[Sorafenib in relapsed and refractory FLT3-ITD positive acute myeloid leukemia: a novel treatment option]. / Sorafenib bei rezidivierter und therapierefraktärer FLT3-ITD-positiver akuter myeloischer Leukämie: eine neue Behandlungsoption.

BACKGROUND: The therapeutic options for relapsed or refractory FLT3-ITD positive AML are limited, particularly in case of a prior allogenic stem cell transplantation (SCT) or poor performance status. The clinical value of a targeted intervention using the FLT3-ITD-specific inhibitor sorafenib in this situation is largely unknown. PATIENTS AND METHODS: Between 2007 and 2010 eight patients (4 men, 4 women; age 40-75 years) with relapsed or refractory FLT3-ITD positive acute myeloid leukemia (AML) before (n=4) and after allogenic SCT (n=5) were treated off-label with sorafenib. RESULTS: All patients showed rapid hematological responses. There were three complete molecular remissions when sorafenib was given after allogenic SCT. Two of them are ongoing for 12 and 15 months, respectively. Long-term remissions after prior allogenic SCT were associated with the re-establishment of a chronic graft versus host reaction. Side effects could be controlled by dose reduction. CONCLUSION: Sorafenib is apparently an effective treatment alternative for patients with relapsed or refractory FLT3-ITD positive AML. In the context of a prior allogenic SCT it may have curative potential via inducing a synergism between targeted inhibition of FLT3-ITD and anti-leukemic immunity.

["Malignant" ARDS]. / "Malignes" ARDS.

Acute respiratory failure and the "acute respiratory distress syndrome" (ARDS) are frequent medical conditions in critically ill patients. Various causes can potentially result in the development of ARDS. Two cases are presented, in which malignant diseases were identified as causes of the respiratory failure. The first patient was diagnosed with an acute myeloic leukemia M5 (FAB). In the second patient, lung histology revealed an adenocarcinoma of the lung. These case reports show that in addition to the classical causes of ARDS, specific disease entities can mimic this form of respiratory failure. Beside solid cancers and lymphomas, acute and progressive forms of inflammatory, parenchymal lung diseases (such as acute interstitial pneumonitis, acute eosinophilic pneumonia, diffuse alveolar hemorrhagia, and acute hypersensitivity pneumonitis) can manifest with this picture. As a consequence, the diagnostic workup of respiratory failure of unknown cause should include these entities.

Inhaled iloprost to control pulmonary artery hypertension in patients undergoing mitral valve surgery: a prospective, randomized-controlled trial.

BACKGROUND: Pulmonary hypertension (PHT) is common in patients undergoing mitral valve surgery and is an independent risk factor for the development of acute right ventricular (RV) failure. Inhaled iloprost was shown to improve RV function and decrease RV afterload in patients with primary PHT. However, no randomized-controlled trials on the intraoperative use of iloprost in cardiac surgical patients are available. We therefore compared the effects of inhaled iloprost vs. intravenous standard therapy in cardiac surgical patients with chronic PHT. METHODS: Twenty patients with chronic PHT undergoing mitral valve repair were randomized to receive inhaled iloprost (25 microg) or intravenous nitroglycerine. Iloprost was administered during weaning from cardiopulmonary bypass (CPB). Systemic and pulmonary haemodynamics were assessed with pulmonary artery catheterization and transoesophageal echocardiography. Milrinone and/or inhaled nitric oxide were available as rescue medication in case of failure to wean from CPB. RESULTS: Inhaled iloprost selectively decreased the pulmonary vascular resistance index after weaning from CPB (208 +/- 108 vs. 422 +/- 62 dyn.s/cm(5)/m(2), P<0.05), increased the RV-ejection fraction (29 +/- 3% vs. 22 +/- 5%, P<0.05), improved the stroke volume index (27 +/- 7 vs. 18 +/- 6 ml/m(2), P<0.05) and reduced the transpulmonary gradient (10 +/- 4 vs. 16 +/- 3 mmHg, P<0.05). In all patients receiving inhaled iloprost, weaning from CPB was successful during the first attempt. In contrast, three patients in the control group required re-institution of CPB and had to be weaned from CPB using rescue medication. CONCLUSIONS: In patients with pre-existing PHT undergoing mitral valve surgery, inhaled iloprost is superior to intravenous nitrogylycerine by acting as a selective pulmonary vasodilator, reducing RV afterload and moderately improving RV-pump performance.

Limitations of arterial pulse pressure variation and left ventricular stroke volume variation in estimating cardiac pre-load during open heart surgery.

BACKGROUND: In addition to their well-known ability to predict fluid responsiveness, functional pre-load parameters, such as the left ventricular stroke volume variation (SVV) and pulse pressure variation (PPV), have been proposed to allow real-time monitoring of cardiac pre-load. SVV and PPV result from complex heart-lung interactions during mechanical ventilation. It was hypothesized that, under open-chest conditions, when cyclic changes in pleural pressures during positive-pressure ventilation are less pronounced, functional pre-load indicators may be deceptive in the estimation of ventricular pre-load. METHODS: Forty-five patients undergoing coronary artery bypass grafting participated in this prospective, observational study. PPV and SVV were assessed by pulse contour analysis. The thermodilution technique was used to measure the stroke volume index and global and right ventricular end-diastolic volume index. Trans-oesophageal echocardiography was used to determine the left ventricular end-diastolic area index. All parameters were assessed before and after sternotomy, and, in addition, after weaning from cardiopulmonary bypass before and after chest closure (pericardium left open). Patients were ventilated with constant tidal volumes (8 +/- 2 ml/kg) throughout the study period using pressure control. RESULTS: SVV and PPV decreased after sternotomy and increased after chest closure. However, these changes could not be related to concomitant changes in the ventricular pre-load. The stroke volume index was correlated with SVV and PPV in closed-chest conditions only, whereas volumetric indices reflected cardiac pre-load in both closed- and open-chest conditions. SVV and PPV were correlated with left and right ventricular pre-load in closed-chest-closed-pericardium conditions only (with the best correlation found for the right ventricular end-diastolic volume index). CONCLUSIONS: SVV and PPV may be misleading when estimating cardiac pre-load during open heart surgery.

Prediction of fluid responsiveness in patients during cardiac surgery.

BACKGROUND: Left ventricular stroke volume variation (SVV) has been shown to be a predictor of fluid responsiveness in various subsets of patients. However, the accuracy and reliability of SVV are unproven in patients ventilated with low tidal volumes. METHODS: Fourteen patients were studied immediately after coronary artery bypass grafting (CABG). All patients were mechanically ventilated in pressure-controlled mode [tidal volume 7.5 (1.2) ml kg(-1)]. In addition to standard haemodynamic monitoring, SVV was assessed by arterial pulse contour analysis. Left ventricular end-diastolic area index (LVEDAI) was determined by transoesophageal echocardiography. A transpulmonary thermodilution technique was used for measurement of cardiac index (CI), stroke volume index (SVI) and intrathoracic blood volume index (ITBI). All variables were assessed before and after a volume shift induced by tilting the patients from the anti-Trendelenburg (30 degrees head up) to the Trendelenburg position (30 degrees head down). RESULTS: After the change in the Trendelenburg position, SVV decreased significantly, while CI, SVI, ITBI, LVEDAI, central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP) increased significantly. Changes in SVI were significantly correlated to changes in SVV (r=0.70; P<0.0001) and to changes in LVEDAI, ITBI, CVP and PAOP. Only prechallenge values of SVV were predictive of changes in SVI after change from the anti-Trendelenburg to the Trendelenburg position. CONCLUSIONS: In patients after CABG surgery who were ventilated with low tidal volumes, SVV enabled prediction of fluid responsiveness and assessment of the haemodynamic effects of volume loading.

Expression of the p14ARF tumor suppressor predicts survival in acute myeloid leukemia.

Cell cycle aberrations are associated with therapy outcome in many types of cancer. We analyzed mRNA expression levels of 18 cell cycle-related genes in bone marrow samples from 78 acute myeloid leukemia (AML) patients and six controls using high-throughput quantitative RT-PCR. Samples of AML patients contained significantly increased mRNA expression levels of the mdm2 and c-myc oncogenes. Also, the average expression levels of p14ARF and p16INK4A were higher in patient samples compared to controls. Leukemic blasts and control bone marrow samples did not differ significantly in the expression levels of proliferation-associated genes such as cyclin A2 and pcna. When single genes were analyzed for prognostic significance in Kaplan-Meier and Cox regression analyses, a low p14ARF level emerged as a strong and independent predictor for poor survival (P=0.04 and 0.029). Subsequently, p14ARF mRNA levels were analyzed in a second, independent patient population (n=57). Again, low p14ARF levels were associated with a worse outcome. Finally, immunohistochemistry analysis of AML tissue arrays confirmed the widespread expression of c-myc and p14ARF in AML on the protein level. Taken together, the expression of the p53 regulators mdm2 and p14ARF are altered in AML, and low p14ARF levels indicate a poor prognosis.