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.

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).

Prophylactic strategies to meet infectious complications in fludarabine-treated CLL.

Fludarabine has emerged as salvage therapy in chlorambucil-resistant CLL. However, encouraging response rates have been compromised by a high incidence of serious infectious complications. Prophylactic measures to reduce the frequency of infections are needed, but up to now, there are no established standards for supportive therapy in fludarabine-treated CLL. Clinicians have observed an increasing frequency of life-threatening opportunistic infections but only some of these may be explained by fludarabine-induced impairment of cell-mediated immunity. Neutrocytopenia commonly found during initial fludarabine treatment may not have been addressed sufficiently as risk factor for infections. Thus, G-CSF supplementation may improve the rate of infectious complications by reducing the duration of fludarabine-induced neutrocytopenia. The changing spectrum of infectious complications should stimulate additional trials on the value of IVIG replacement in fludarabine-treated CLL patients and on the role of low-dose co-trimoxazole in patients at high risk of Pneumocystis carinii infections.

Levels of circulating endothelial adhesion molecules (sE-selectin and sVCAM-1) in adult patients with acute leukemia.

The spread of leukemia extends from mobilization of leukemic blast cells from the bone marrow to extramedullary tissue infiltration. Migration of leukemic blasts resembles that of neutrophils and may be regulated by activated endothelial cells via endothelial adhesion molecules such as E-selectin, VCAM-1 and ICAM-1. Plasma levels of soluble adhesion molecules may therefore indicate interaction between leukemic blasts and endothelium, and may be related to leukemic cell mass or subtype of leukemia. In this study, plasma levels of soluble E-selectin, VCAM-1 and ICAM-1 were analyzed in 40 untreated patients with acute leukemia (35 ANLL, five ALL). Plasma concentrations of all three receptors were significantly elevated when compared to healthy controls (P = 0.006, P = 0.0001, and P = 0.0001, respectively) but demonstrated high interindividual variations among leukemic patients. sE-selectin but not sVCAM-1 and sICAM-1 levels correlated with peripheral leukocyte and blast cell counts. Increased levels of either sE-selctin or sVCAM-1 were present in 32 out 40 leukemic patients (80%). FAB subgroups differed in levels of sVCAM-1. The highest levels were measured in acute myelomonocytic and lymphoblastic leukemia, ie in leukemia subtypes with a high incidence of extramedullary blast cell infiltration.

Increases of sICAM-1 during neutropenic pneumonia in leukemic patients.

Aggressive chemotherapy of leukemia increases the risk of severe infections during treatment-induced myelosuppression. However, the assessment of an infectious origin of neutropenic fever is often difficult. Leukocyte adhesion molecules such as E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are involved in early inflammatory response. We studied plasma concentrations of their soluble isoforms during 48 treatment courses with myeloablative chemotherapy in 32 leukemic patients. There were 35 febrile episodes during neutropenia. Pneumonia was clinically and microbiologically documented in 15 cases, six had proven infections but normal chest radiograph, and 14 were classified as fever of unknown origin. Longitudinal studies revealed a sustained increase of sICAM-1 plasma levels associated with pneumonia. Increase of sICAM-1 plasma levels distinguished patients with pneumonia from those with fever not related to pneumonia (positive predictive value 0.87, negative predictive value 0.94). Plasma levels of sICAM-1 were elevated in both, fungal and non-fungal pneumonia. Increases of sICAM-1 paralleled first radiographic evidence of pulmonary infiltrations in most cases. In contrast, no elevation of sVCAM-1 or sE-selectin was documented during febrile events prior to recovery of leukocyte counts.

Idarubicin, melphalan and cyclophosphamide: an intensified high-dose regimen for the treatment of myeloma patients.

Following conventional chemotherapy, eight myeloma patients presenting with advanced tumor stages were treated with an intensified high-dose regimen and autologous peripheral blood stem cell transplantation. High-dose chemotherapy consisted of idarubicin 20 mg/m2 on days -13, -12 and -11, melphalan 100 mg/m2 on days -5 and -4 and cyclophosphamide 60 mg/kg (plus mesna 60 mg/kg) on days -3 and -2 (IMC). Seven patients achieved a complete remission or a very good partial remission (reduction of M-component > or =90%). There were no toxic deaths. Severe mucositis and fever of unknown origin were seen in all patients. Reversible supraventricular tachycardias without clinical signs of cardiac failure occurred in five patients. One patient developed a persistent deterioration of cardiac function. We surmise that high-dose chemotherapy with IMC is very effective and well tolerated in myeloma patients.

Fatal hyperleukocytic syndrome in a patient with chronic myelomonocytic leukemia.

A 53-year-old male patient was admitted to our hospital with painful splenomegaly. He was diagnosed as having chronic myelomonocytic leukemia (CMML) with leukocytosis, monocytosis, increased lysozyme concentrations in serum und urine, and lack of the Philadelphia chromosome. The clinical course of the disease was characterized by rapidly rising leukocyte counts, cutaneous infiltrates, respiratory insufficiency and neurological symptoms. Excessive hyperleukocytosis with a significant increase in monocytic cells led to microcirculatory obstruction, vascular endothelial damage and organ malfunction. This complication could not be prevented by low-dose chemotherapy with cytosine arabinoside. The patient finally died from pulmonary and cerebral hyperleukocytic syndrome.

Cutaneous bacillary angiomatosis in a patient with chronic lymphocytic leukemia.

BACKGROUND: Bacillary angiomatosis is a recently described vascular disorder that is associated with infection by Bartonella henselae (formerly known as Rochalimaea henselae) and Bartonella quintana (formerly known as Rochalimaea quintana); this disorder usually occurs in patients with human immunodeficiency virus infection. We report a case of cutaneous bacillary angiomatosis that occurred in a patient with chronic lymphocytic leukemia. OBSERVATIONS: A 55-year-old man with chronic lymphocytic B-cell leukemia, Rai stage IV, presented with multiple angiomatous papules that clinically resembled pyogenic granulomas. Histopathologic examination revealed circumscribed lobules of small vessels with plump endothelial cells, numerous neutrophils, and abundant nuclear dust; these features were diagnostic for bacillary angiomatosis. The diagnosis was confirmed by the Grocott-Gomori methenamine-silver nitrate stain that revealed argyrophilic bacteria and by ultrastructural demonstration of bacillary structures with trilaminar walls. Treatment with clarithromycin led to complete resolution of the lesions within 4 weeks. CONCLUSIONS: This case emphasizes that (1) bacillary angiomatosis must be considered in the differential diagnosis of vascular lesions in immunocompromised patients without human immunodeficiency virus infection, (2) Grocott-Gomori methenamine-silver nitrate stain is a simple and satisfactory alternative to the Warthin-Starry stain for the demonstration of bacilli in this condition, and (3) clarithromycin is an effective oral antibiotic for the treatment of this disease.

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.

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.

Fibrinolytic mechanisms in tumor growth and spreading.

The high prevalence of hypercoagulative states in cancer patients has been known for more than a century. Venous thrombosis in gastric cancer was described by Trousseau in 1865 [55]. In 1878, Billroth observed intravascular thrombus formation in association with metastasis [4]. Thrombohemorrhagic complications regularly occur in patients with disseminated malignancy and are related to an increase in fibrinogen and fibrin turnover. During the past decade, clinicians have witnessed considerable advances in the understanding of fibrinolysis. Initially centered on the role as part of a dynamic, hemostatic balance, research began to unravel the pathophysiological contribution of fibrinolysis to tumor progression. The mechanisms of tumor invasion and metastasis formation in cancer are of critical importance, since metastasis is the major cause of treatment failure and death. It has been suggested that cell-associated proteolytic enzymes contribute to tumor aggressiveness [11, 22, 23]. Fibrinolytic mechanisms are involved in a number of physiological processes in which tissue degradation and remodeling occurs. These include disruption of the ovarian follicle during ovulation and blastocyst implantation. These events in part resemble the invasive growth of cancer [37, 47]. Inspired by this hypothesis, the role of fibrinolytic processes in tumor invasion is under intensive study.

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.

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.

Relation of platelet abnormalities to thrombosis and hemorrhage in chronic myeloproliferative disorders.

The chronic myeloproliferative disorders (MPD), predominantly polycythemia vera and essential thrombocythemia, are characterized by a high incidence of thromboembolic and, to a lesser degree, hemorrhagic complications. The disease process in chronic MPD affects a pluripotent progenitor cell and results in trilineage hematopoietic proliferation. Clonal involvement of megakaryocytopoiesis is regarded as the main origin of thromboembolism in MPD and results in abnormal platelet production. These platelets show increased size heterogeneity and ultrastructural abnormalities, and their function in vitro is in many ways impaired with a high degree of individual variability. Elevated levels of platelet-specific proteins, increased thromboxane generation, and expression of activation-dependent epitopes on the platelet surface are common on chronic MPD, and may reflect an inappropriate state of platelet activation. Although a variety of platelet receptor deficiencies and some defects of intracellular signaling pathways have been identified, the different platelet defects in MPD could not be traced back to an underlying general pathogenetic mechanism. On progression of chronic MPD to more advanced stages of the disease, the number of platelet abnormalities tend to increase. Cytoreductive drugs may partly improve platelet dysfunction, and platelet inhibitory agents reduce symptoms of platelet activation. However, neither of these therapeutic principles is able to normalize platelet function in MPD. As an alternative to conventional treatment, specific suppression of clonal megakaryocyte growth and recovery of polyclonal hematopoiesis may be achieved by biologic agents such as interferon alpha. Such treatment strategies may prevent thromboembolic complications together with hematologic symptoms and progression of the disease and should be further evaluated in prospective studies.

[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.

[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.

Retinoic acid in the treatment of acute promyelocytic leukemia: inefficacy of the 13-cis isomer and induction of complete remission by the all-trans isomer complicated by thromboembolic events.

The clinical course of three patients with acute promyelocytic leukemia receiving all-trans retinoic acid (ATRA) as a single agent is reported. The first two patients were in first and second relapse of their leukemia that had occurred despite maintenance treatment with 13-cis retinoic acid after chemotherapy-induced complete remission (CR). A switch to ATRA was followed by achievement of a CR in two patients. The third patient received ATRA as first-line therapy. Two patients experienced thromboembolic complications during the phase of ATRA-induced leukocytosis. One of them died of pulmonary embolism on day 16 of treatment. The two responding patients who did not receive consolidation chemotherapy relapsed after 6 and 9 months, respectively. Increase of the ATRA dose failed to induce a new remission.

Specific pattern of circulating endothelial adhesion molecules in HIV-associated Kaposi's sarcoma.

BACKGROUND: Circulating endothelial adhesion molecules have been found to be increased in states of immune activation, but little is known about their significance in the assessment of endothelial neoplasms. One of the most common tumors supposed to be derived from endothelial origin is HIV-associated Kaposi's sarcoma (KS). METHODS: Plasma concentrations of sCD54 (= intercellular adhesion molecule-1), sCD106 (= vascular cell adhesion molecule-1), and sCD62E (= E-selectin) were quantified by sandwich ELISA in 54 AIDS patients who were either free of active opportunistic disorders (n = 15, AIDS controls), or suffering from acute infections (n = 16), or exhibiting KS (n = 23), and in 18 age- and sex-matched healthy HIV-negative controls. RESULTS: Both sCD54 and sCD106 plasma levels were consistently increased in all AIDS patients irrespective of concurrent opportunistic disorders (p < 0.005), while sCD62E levels were not altered in AIDS patients without KS (p > 0.05). In KS patients, sCD62E concentrations were decreased both compared to healthy (p = 0.0007) and to AIDS controls (p = 0.04), and stimulated sCD54 levels were less elevated than those of AIDS controls (p = 0.02). Plasma concentrations of all three adhesion molecules did not correlate to KS tumor stage. CONCLUSION: There appears to be a specific pattern of circulating endothelial adhesion molecules in AIDS patients with associated KS. Although the present findings do not support a role for their determination as tumor markers, they might be involved in KS tumor pathogenesis.

Neutrophilic dermal infiltrates in granulocytopenic patients with acute leukemia.

Acute febrile neutrophilic dermatosis (AFND, Sweet's syndrome) is clinically characterized by fever, neutrophilic leukocytosis, and tender dermal plaques. Histological examination typically reveals infiltration of the dermis by neutrophils. In three patients (2 female, 1 male, 54-59 years) with acute leukemia (2 myelogenous, 1 lymphoblastic) dermal plaques developed during febrile episodes in chemotherapy-induced pancytopenia. The clinical appearance was compatible with AFND. The diagnosis was substantiated by skin biopsies which showed dense neutrophilic dermal infiltrates without leukemic cells. Leukocytoclastic vasculitis was considered as differential diagnosis. Plasma levels of soluble adhesion molecules ICAM-1, VCAM-1, and E-selectin regulating leukocyte transendothelial migration were in the normal range. Systemic glucocorticoids were avoided because of the high risk of infection during prolonged bone marrow aplasia. The lesions were treated with topical steroids and resolved without scarring within 1-5 weeks. AFND has been reported in association with acute leukemia at normal or elevated white blood cell counts. Although implausible from a pathophysiological point of view, similar neutrophilic dermal infiltrates were found in three patients during chemotherapy-induced pancytopenia with white blood cell counts distinctly below 1 x 10(9)/l.