Randomized phase-III study of low-dose cytarabine and etoposide + /- all-trans retinoic acid in older unfit patients with NPM1-mutated acute myeloid leukemia.

The aim of this randomized clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with non-intensive chemotherapy in older unfit patients (> 60 years) with newly diagnosed NPM1-mutated acute myeloid leukemia. Patients were randomized (1:1) to low-dose chemotherapy with or without open-label ATRA 45 mg/m2, days 8-28; the dose of ATRA was reduced to 45 mg/m2, days 8-10 and 15 mg/m2, days 11-28 after 75 patients due to toxicity. Up to 6 cycles of cytarabine 20 mg/day s.c., bid, days 1-7 and etoposide 100 mg/day, p.o. or i.v., days 1-3 with (ATRA) or without ATRA (CONTROL) were intended. The primary endpoint was overall survival (OS). Between May 2011 and September 2016, 144 patients (median age, 77 years; range, 64-92 years) were randomized (72, CONTROL; 72, ATRA). Baseline characteristics were balanced between the two study arms. The median number of treatment cycles was 2 in ATRA and 2.5 in CONTROL. OS was significantly shorter in the ATRA compared to the CONTROL arm (p = 0.023; median OS: 5 months versus 9.2 months, 2-years OS rate: 7% versus 10%, respectively). Rates of CR/CRi were not different between treatment arms; infections were more common in ATRA beyond treatment cycle one. The addition of ATRA to low-dose cytarabine plus etoposide in an older, unfit patient population was not beneficial, but rather led to an inferior outcome.The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2010-023409-37, first posted 14/12/2010).

A comprehensive analysis of the cellular and EBV-specific microRNAome in primary CNS PTLD identifies different patterns among EBV-associated tumors.

Primary central nervous system (pCNS) posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation characterized by poor outcome. In contrast to systemic PTLD, Epstein-Barr virus (EBV)-association of pCNS PTLD is almost universal, yet viral and cellular data are limited. To identify differences in the pattern of EBV-association of pCNS and systemic PTLD, we analyzed the expression of latent and lytic EBV transcripts and the viral and cellular microRNAome in nine pCNS (eight EBV-associated) and in 16 systemic PTLD samples (eight EBV-associated). Notably although 15/16 EBV-associated samples exhibited a viral type III latency pattern, lytic transcripts were also strongly expressed. Members of the ebv-miR-BHRF1 and ebv-miR-BART clusters were expressed in virtually all EBV-associated PTLD samples. There were 28 cellular microRNAs differentially expressed between systemic and pCNS PTLD. pCNS PTLD expressed lower hsa-miR-199a-5p/3p and hsa-miR-143/145 (implicated in nuclear factor kappa beta and c-myc signaling) as compared to systemic PTLD. Unsupervised nonhierarchical clustering of the viral and cellular microRNAome distinguished non-EBV-associated from EBV-associated samples and identified a separate group of EBV-associated pCNS PTLD that displayed reduced levels of B cell lymphoma associated oncomiRs such as hsa-miR-155, -21, -221 and the hsa-miR-17-92 cluster. EBV has a major impact on viral and cellular microRNA expression in EBV-associated pCNS PTLD.

[Fever, atrial fibrillation, and angina pectoris in a 58-year-old man]. / Fieber, Vorhofflimmern und Angina pectoris bei einem 58-jährigen Patienten.

Primary cardiac lymphoma (PCL) respresents a very rare type of cardiac tumour. This report illustrates a case of PCL in an immunocompetent 58-year-old man presenting with atrial fibrillation and febrile syndrome. Comprehensive imaging [computer tomography (CT), cardiac magnetic resonance imaging (cMRI), 3-dimensional transesophageal echocardiography (3D-TEE)] identified a large right atrial tumour, leading to pericardial effusion. Isolated cardiac involvement was confirmed by positron emission tomography (PET)-CT. A diffuse large B-cell lymphoma (DLBCL) was diagnosed based on the results of a TEE-guided biopsy. A normalized PET scan (PETAL study) indicated complete remission following R-CHOP 14 immunochemotherapy. Thus, an interdisciplinary and multimodal approach avoided unnecessary cardiac surgery.

Dalteparin for prevention of catheter-related complications in cancer patients with central venous catheters: final results of a double-blind, placebo-controlled phase III trial.

BACKGROUND: Cancer patients receiving chemotherapy experience thromboembolic complications associated with the use of long-term indwelling central venous catheters (CVCs). This prospective, double-blind, placebo-controlled, multicenter study evaluated whether prophylactic treatment with a low molecular weight heparin could prevent clinically relevant catheter-related thrombosis. PATIENTS AND METHODS: Patients with cancer undergoing chemotherapy for at least 12 weeks (n=439) were randomly assigned, in a 2:1 ratio, to receive either dalteparin (5000 IU) or placebo, by subcutaneous injection, once daily for 16 weeks. Patients underwent upper extremity evaluation with either venography or ultrasound at the time of a suspected catheter-related complication (CRC) or upon completion of study medication. The primary end point, as determined by a blinded adjudication committee, was the occurrence of a CRC, defined as the first occurrence of any one of the following: clinically relevant catheter-related thrombosis that was symptomatic or that required anticoagulant or fibrinolytic therapy; catheter-related clinically relevant pulmonary embolism; or catheter obstruction requiring catheter removal. RESULTS: There was no significant difference in the frequency of CRCs between the dalteparin arm (3.7%) and the placebo arm (3.4%; P=0.88), corresponding to a relative risk of 1.0883 (95% confidence interval 0.37-3.19). No difference in the time to CRC was observed between the two arms (P=0.83). There was no significant difference between the dalteparin and placebo groups in terms of major bleeding (1 versus 0) or overall safety. CONCLUSIONS: Dalteparin prophylaxis did not reduce the frequency of thromboembolic complications after CVC implantation in cancer patients. Dalteparin was demonstrated to be safe over 16 weeks of treatment in these patients.

[Occlusion of central venous port catheters after simultaneous 24 h infusions of 5-FU and calcium-folinic acid in patients with gastrointestinal cancer]. / Hohe Verschlussrate von zentralen Venenkathetersystemen durch Calcit-Präzipitate unter 24 h-Mischinfusion aus 5-Fluorouracil und Calciumfolinat bei Patienten mit gastrointestinalen Tumoren.

Folinic acid-modulated 5-FU regimens are standard elements in several chemotherapy combinations like FOLFIRI, FOLFOX or AIO-regimen in the palliative treatment of patients with gastrointestinal cancer. When the simultaneous mixed infusion of 5-FU and calcium-folinic acid (Leucovorin) was authorized by the BfArM in 2002, we introduced this application regimen in the treatment of our cancer patients. 19 patients (AIO-regimen [5], FOLFIRI [12] and FOLFOX [2]) received a simultaneously mixed infusion of calcium-folinic acid and 5-FU over 24 hours with a total of 110 applications. 5-FU doses varied between 2000 and 2600 mg/m2, calcium-folinic acid was given with 500 mg/m2, infusion rate was 10 ml/hour using a 24 h pump. Central venous catheters employed included single Barth-Port in 18 cases, 1 patient had a Viggon-Port. In 3 out of the 19 patients catheter occlusion was noticed after 8-10 weekly applications of the mixed infusion. Heparine and subsequently urokinase were not successful in reversing the obstruction. All three catheters had to be explanted. Catheter tips in all cases showed a yellow cristalline precipitation. The crystallographic analysis exhibited calcium carbonate (CaCO3) in its polymorphic form (calcite). Thus, we confirmed calcite formation causing catheter occlusion as a frequent complication during a continuous 24 h-infusion of mixed high dose 5-FU and calcium-folinic acid. This reaction could not be avoided by increasing infusion volume and the application flow rate. As a result of our findings, recommending using calcium-folinic acid mixed with 5-FU has been withdrawn in the meantime.

5-Fluorouracil induces arterial vasocontractions.

BACKGROUND: From 2% to 10% of cancer patients treated with 5-fluorouracil (5-FU) will develop symptomatic cardiotoxicity. Nevertheless, the underlying pathophysiology is mostly unknown. PATIENTS AND METHODS: We investigated the influence of intravenous chemotherapy (CTX) on the diameter of the brachial artery using high resolution ultrasound in patients with malignant tumors, mostly gastrointestinal cancer. Cytostatic drugs included 30 cases with 5-FU and 30 cases with non-5-FU CTX (cis/carboplatin, anthracycline and cyclophosphamide). In addition, plasma levels of big endothelin were assessed prior to and after CTX. RESULTS: Fifteen of 30 patients (50%) showed a contraction of the brachial artery after the end of 5-FU application (median 11%, range 4.3-18.5), whereas no single contraction was noticed in 30 patients following non-5-FU-based CTX. Vessel tonus generally normalized within 30 min after stopping 5-FU. Five patients positive for 5-FU associated vessel contraction were repeatedly exposed to 5-FU. Vessel contractions reoccurred in 86% (18/21) of these administrations. When patients with 5-FU bolus application were pre-treated with glyceroltrinitrate no contraction of the brachial artery was detected in five out of five occasions. There was a trend towards increased big endothelin plasma levels after 5-FU application (median 1.52 versus 1.99 fmol/ml; P = 0.07), whereas big endothelin levels remained unchanged after non-5-FU CTX (1.83 versus 1.83 fmol/ml; P = 0.99). CONCLUSIONS: Application of 5-FU is commonly accompanied by arterial vessel contractions, which is likely to represent the first step in 5-FU-induced cardiotoxicity. 5-FU-associated vessel contractions were highly reproducible on re-exposure and were in the case of bolus application completely preventable by glyceroltrinitrate.

Diagnosis of invasive fungal infections in hematology and oncology--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

Invasive fungal infections are a primary cause of morbidity and mortality in patients with hematological malignancies. Establishing a definite diagnosis of invasive fungal infection in febrile neutropenic patients is particularly challenging and time-consuming, but a delay of antifungal treatment leads to higher mortality. This situation has lead to the strategy of initiation "empirical" antifungal therapy prior to the detection of fungi. Meanwhile, improvements in diagnostic procedures are achieved, especially with imaging techniques and non-culture based methods which include antigen-based assays, metabolite detection and molecular detection of fungal DNA from body fluid samples using conserved or specific genome sequences. The AGIHO presents recommendations for the diagnosis of invasive fungal infections with risk-adapted screening concepts for the neutropenic and febrile episodes of patients with hemato-oncological disorders.

[Antimicrobial therapy of febrile neutropenia--current developments]. / Antimikrobielle Therapie febriler Neutropenien--aktuelle Entwicklungen.

Standard management of febrile neutropenia requires prompt administration of empirical, broad-spectrum, parenteral antibiotic therapy, since febrile neutropenia is associated with a significant risk of infectious complications and mortality. Although in-patient treatment is effective in up to 90%, hospitalization leads to excessive resource utilization. Over the last ten years chemotherapy for solid tumors has shifted out of the hospital setting into the ambit of community-based oncologists, and outpatient treatment with complex multidrug protocols has become more and more common. With the increase in the numbers of outpatients undergoing multidrug chemotherapy there has been a corresponding rise in the severity and duration of neutropenia and in the increase of febrile complications. Risk-assessment models have been developed that differentiate febrile patients with neutropenia according to their risk for infectious complications and/or mortality. Patients with neutropenia of short duration (< 7 days) and fever are at relatively low risk for complications if they have no concurrent comorbidities, and in these circumstances outpatient antibiotic treatment is an alternative to costly hospitalization. Drugs whose antimicrobial coverage and pharmacokinetics render them particularly suitable for outpatient treatment of febrile neutropenia include intravenous and oral quinolones and, for once-daily dosing, intravenous glycopeptides, ceftriaxone and intravenous aminoglycosides. Response rates of 60%-95% have been achieved with such regimens in clinical trials, with hospital admission avoided in 75%-95% of cases.

[Thromboembolism complications in tumor diseases: pathophysiology, risk factors and preventive approaches]. / Thromboembolische Komplikationen bei Tumorerkrankungen: Pathophysiologie, Risikofaktoren und Prophylaxestrategien.

Thromboembolic complications are among the most common causes of death in cancer patients and result in considerable reduction in quality of life in patients affected. Besides immobilization therapeutical interventions such as surgery, chemotherapy and insertion of an indwelling central venous line have been identified as additional risk factors for thromboembolism. While postoperative prophylaxis is recommended, anticoagulation in presence of other risk factors, especially concerning cost-benefit ratio, is still a matter of debate. Evaluation of genetic risk factors for thromboembolism may add in the near future to the decision-making process to provide cancer patients with antithrombotic prophylaxis. With the introduction of low molecular weight heparin to clinical practice clinicians now face an alternative option to oral anticoagulants for long-term therapy and prophylaxis. Suggestive evidence that low molecular weight heparin reduce mortality of cancer patients independent of cardiovascular causes have stimulated intensive clinical efforts to reinvestigate anticoagulation in cancer patients.

Serum and plasma parameters in clinical evaluation of neutropenic fever.

Clinicians are searching for a marker which may add to exclusion or diagnosis of relevant infection underlying neutropenic fever. The rise of such a parameter should ideally precede the date of significant microbiologic findings or justify additional intensive search for a focus of infection even in patients without pyrexia. However, the literature concerning the significance of CRP, proinflammatory cytokines and soluble adhesion molecules in the clinical evaluation of neutropenic fever is surprisingly small. In the case of procalcitonin, available data look very preliminary. Furthermore, in case of CRP, it appears that the widespread view that its determination may add substantially to the clinical evaluation of neutropenic fever is not well founded by most clinical trials listed here. Most of the studies available demonstrate several limitations such as poor design and small size of the study population. Additionally, studies were heterogeneous with respect to patients recruited (children and adults, patients with leukemia and patients with solid tumors) and compared different categories of febrile episodes. None of the investigators analyzed cost-effectiveness or impact of serial measurements of these parameters on patients' outcome. To our knowledge no single multicenter trial has been published addressing this issue. Although the group of proinflammatory cytokines and known acute-phase reactants will surely grow, more data on relevance of the available parameters in the diagnosis of neutropenic fever are needed.

Transdermal fentanyl during high-dose chemotherapy and autologous stem cell support.

We report on our experience in the use of transdermal fentanyl in management of acute pain due to mucositis WHO-grade IV during high-dose chemotherapy (HDC) and autologous stem cell support (APBSCT). Between 8/96 and 12/98 74 patients received HDC and PBSCT for progressive disease or relapse of non-Hodgkin's lymphoma (n=32), multiple myeloma (n=37), Hodgkin's lymphoma (n=5). All patients suffered from mucositis WHO-grade IV with a need for continuous pain management. Instead of pethidine i.v. fentanyl TTS was used. Sufficient analgesia was achieved mostly with a dose of 50 microg/h. There was no need of supplementary analgesia. Relevant fentanyl-associated side effects were not seen. Patient compliance and acceptance were excellent. The results suggest that transdermal fentanyl is reliable in pain management of chemotherapy-associated mucositis grade IV.

Evaluation of neutropenic fever: value of serum and plasma parameters in clinical practice.

Treatment-related mortality due to infectious complications following potentially curable aggressive chemotherapy remains a major clinical problem. However, the diagnosis of neutropenic infections is difficult. Although it is common practice to institute empirical broad-spectrum antibiotics in neutropenic fever, liberal use of antibiotics may contribute to increasing resistance and superinfection such as systemic mycosis. Clinicians are searching for a highly specific and sensitive marker indicating early infection. Serum concentrations of several acute-phase proteins (C-reactive protein, serum amyloid A), proinflammatory cytokines (TNFalpha, IL-1, IFNgamma, IL-6, IL-8), soluble adhesion molecules (soluble E-selectin, vascular cell adhesion molecule 1, intercellular adhesion molecule 1) and more recently procalcitonin have been investigated as to whether these may contribute to identifying infections as the cause of neutropenic fever. Unfortunately, at present, based on the small and inconsistent amount of data available from the literature one is tempted to conclude that the predictive values of all these parameters are too low to influence the clinically based initial treatment decisions in patients with neutropenic fever.

[Role of aggressive treatment strategies for myelodysplastic syndromes]. / Stellenwert aggressiver Behandlungsstrategien im Therapiekonzept myelodysplastischer Syndrome.

Myelodysplastic syndromes (MDS) constitute a heterogenous group of acquired bone marrow disorders characterized by ineffective hematopoiesis, cellular dysfunction and an increased risk of transformation into acute myeloid leukemia (AML). The percentage of medullary blast cells and the karyotype at diagnosis are the most important predictors of survival. Patients with more than 10% blast cells or an unfavourable karyotype (chromosome 7 abnormalities or complex aberrations) usually survive less than 12 months. This review article focuses on the roles of intensive AML-type chemotherapy, autologous stem cell transplantation and allogeneic bone marrow transplantation in the management of patients with advanced MDS. Recent studies suggest that, with appropriate selection of patients, intensive chemotherapy produces high rates of complete remission. Chances of entering remission are particularly high in patients with a good Karnofsky score, bone marrow blast count < 30% and normal karyotype. When compared with acute myeloid leukemia, results of autologous bone marrow transplantation in MDS are disappointing. A major disadvantage of this approach is the delayed recovery of hematopoiesis. Autologous peripheral blood progenitor cell transplantation overcomes this difficulty and is currently explored as consolidation therapy after successful remission induction with polychemotherapy in an intergroup study of the EORTC and EBMT. Allogeneic bone marrow transplantation remains the treatment of choice for younger MDS patients, offering a good chance of cure if the transplantation is performed at an early stage of disease or if the patient receives the transplant in complete remission after conventional chemotherapy.