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Abstract: We report an increased incidence of infectious deaths during maintenance treatment of the ninth protocol for acute lymphoblastic leukaemia of the Dutch Childhood Oncology Group (DCOG-ALL-9). The main difference in maintenance treatment between DCOG-ALL-9 and the DCOG-ALL-7 and DCOG-ALL-8 protocols is the interruption of methotrexate and 6-mercaptopurine by vincristine (2mg/m2 weekly) and dexamethasone (6mg/m2 daily) for 14 days every 7 weeks in the DCOG-ALL-9 protocol. The 1107 children treated with the DCOG-ALL-7, DCOG-ALL-8 or DCOG-ALL-9 protocol were included and screened for infectious death during maintenance treatment (July 1988–July 2002). Seven of the 510 children died of severe infections during the maintenance phase of DCOG-ALL-9, compared to none of the 597 patients during the DCOG-ALL-7 and DCOG-ALL-8 protocols (1.37% versus 0.0%; p =0.013). Results from the current study suggest that repeated, prolonged exposure to dexamethasone results in an increase of lethal infections from 0% to 1.37%. In the dosing-schedule used, the advantage of dexamethasone may not outweigh the higher risk of infectious death. [Copyright &y& Elsevier]

Multidrug resistance, cross-resistance to structurally and functionally unrelated drugs, is an important cause of treatment failure in acute leukemia. Multidrug resistance can result from the overexpression of ATP-dependent efflux pumps, such as P-glycoprotein and members of the multidrug resistance associated protein (MRP) family. Recently a novel transporter has been identified, which is called breast cancer resistance protein (BCRP), ABCG2 or mitoxantrone resistance protein. BCRP confers resistance to chemotherapeutic agents, such as mitoxantrone, doxorubicin and daunorubicin. This review describes BCRP detection techniques and the normal physiology of BCRP. The role of BCRP in the physiology of hematopoietic stem cells is addressed as well as the involvement of BCRP in multidrug resistance in acute leukemia. In AML and ALL, several studies showed that BCRP is expressed and functionally active at low, but variable levels. However, further studies are warranted to investigate its effect on clinical outcome, and explore whether patients could benefit from the combination of BCRP inhibitors and chemotherapy. [ABSTRACT FROM AUTHOR]

There is a distinct difference in prognosis between childhood versus adult acute lymphoblastic leukaemia (ALL). To define whether multidrug resistance (MDR) genes might contribute to this distinction, the expression and functional activity of P-glycoprotein (P-gp) and MDR associated proteins (MRP) were determined with RT-PCR (MDR-1, MRP1, MRP2, MRP3) and flow cytometry (P-gp and MRP). Patient samples were obtained from 36 children and 35 adults with de novo ALL. Of these patients, 38 showed a T-lineage and 33 showed a B-lineage immunophenotype. In the samples, large variability in P-gp activity (0.8-4.9) and MRP activity (1.1-13.9) was observed. Most T-ALL patients with high P-gp activity were adults (89%). The mRNA expression of MDR-1 correlated weakly with P-gp activity. In contrast, MRP activity did not correlate with the mRNA expression of MRP1, MRP2 and MRP3. In T-ALL, a worse overall survival and event-free survival was observed with increasing P-gp activity. P-gp activity had no prognostic impact in B-lineage ALL. In addition, high MRP activity did not influence treatment outcome in either T- or B-lineage ALL. Multivariate Cox regression analysis, showed P-gp activity to be the only unfavourable prognostic factor for overall survival in T-ALL. In conclusions this study demonstrates the prognostic relevance of P-gp activity in T-ALL. Since the majority of the patients with high P-gp activity were adults, P-gp might contribute to the poor prognosis of adult T-ALL. [ABSTRACT FROM AUTHOR]

Background In this national multicentre study, we examined the safety of reducing antibiotics in selected paediatric cancer patients with febrile neutropenia. Methods Patients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk and received antibiotic therapy. Remaining patients were allocated to low- or medium risk, depending on their interleukin-8 level. Low-risk patients did not receive any antibiotics and were discharged from the hospital after having been afebrile for 12 h. Medium-risk patients were re-evaluated after 72 h of antibiotic treatment and, in selected patients, antibiotics were stopped. Results Two hundred thirty-three febrile neutropenic episodes in 141 paediatric cancer patients were included in the study. Sixty-four episodes were classified high risk (28%), 122 medium risk (52%), and 47 (20%) low risk. In the medium-risk group, antibiotics were stopped after 72 h in 50 in 122 episodes (41%). Median duration of antibiotic treatment and hospital admission was significantly lower in low- and medium-risk episodes with early discharge. No failures were observed in the medium-risk group with early discharge. In the low-risk group, six failures were observed (12.8%), due to coagulase-negative staphylococci -positive blood cultures and recurrent fever. Conclusion We showed that it is safe to shorten antibiotic treatment to 72 h in selected medium-risk patients with febrile neutropenia, regardless of the neutrophil count. The safety of withholding antibiotics in selected low-risk paediatric cancer patients with febrile neutropenia requires further investigation, using more suitable definitions for safety. Reduction in hospital admissions allows children with cancer more time at home and consequently improves their quality of life. [ABSTRACT FROM AUTHOR]

Abstract: Background: Rhabdomyosarcoma (RMS) is an aggressive soft tissue tumour mainly affecting children and adolescents. Since survival of high-risk patients remains poor, new treatment options are awaited. The aim of this study is to investigate anaplastic lymphoma kinase (ALK) and insulin-like growth factor-1 receptor (IGF-1R) as potential therapeutic targets in RMS. Patients and methods: One-hundred-and-twelve primary tumours (embryonal RMS (eRMS)86; alveolar RMS (aRMS)26) were collected. Expression of IGF-1R, ALK and downstream pathway proteins was evaluated by immunohistochemistry. The effect of ALK inhibitor NVP-TAE684 (Novartis), IGF-1R antibody R1507 (Roche) and combined treatment was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays in cell lines (aRMS Rh30, Rh41; eRMS Rh18, RD). Results: IGF-1R and ALK expression was observed in 72% and 92% of aRMS and 61% and 39% of eRMS, respectively. Co-expression was observed in 68% of aRMS and 32% of eRMS. Nuclear IGF-1R expression was an adverse prognostic factor in eRMS (5-year survival 46.9±18.7% versus 84.4±5.9%, p =0.006). In vitro, R1507 showed diminished viability predominantly in Rh41. NVP-TAE684 showed diminished viability in Rh41 and Rh30, and to a lesser extent in Rh18 and RD. Simultaneous treatment revealed synergistic activity against Rh41 and Rh30. Conclusion: Co-expression of IGF-1R and ALK is detected in eRMS and particularly in aRMS. As combined inhibition reveals synergistic cytotoxic effects, this combination seems promising and needs further investigation. [Copyright &y& Elsevier]

Increased levels of circulating VEGF-A have been demonstrated in patients with non-Hodgkin lymphoma (NHL) and are associated with progressive disease and poor clinical outcome. We investigated the role of VEGF-A in lymphoma tumour growth on a molecular level in order to identify the mechanism of VEGF-A-promoted tumour growth and to identify the potential targets for therapy. We used a model in which Daudi (human Burkitt lymphoma) tumour cells were transduced with VEGF-A165 or an empty vector (negative control) and subcutaneously injected in NOD/SCID mice. The weight of tumours overexpressing VEGF-A was increased 4-fold compared to that of control tumours (p <0.0001), whereas no in vitro growth advantage was demonstrated upon VEGF-A overexpression. VEGF-A-tumours were associated with increased microvessel densities (p =0.004) and increased tumour cell proliferation (Ki67; p <0.001) compared to control tumours. VEGF-A-tumours were characterised by upregulation of phosphorylated STAT-4 and STAT-6 and downregulation of phospho-p27KIP1, a crucial cell cycle inhibitor (p <0.05). This was accompanied by increased levels of phosphorylated receptor tyrosine kinases, including EGFR (ErbB-2 and ErbB-4, p <0.05), an upstream regulator of STAT proteins. We demonstrated that various mouse-derived cytokines produced by mouse-derived tumour stromal cells are upregulated in VEGF-A-tumours compared to control tumours (p <0.05). These results indicate an important role for the tumour microenvironment in paracrine promotion of lymphoma tumour growth in response to tumour-derived VEGF-A. In conclusion, lymphoma-derived VEGF-A promoted lymphoma tumour growth in a paracrine loop by activation of tumour stromal cells. Our study reveals VEGF-A and STAT proteins as potential additional targets in the treatment of lymphoma. [Copyright &y& Elsevier]

Abstract: Children with cancer treated with chemotherapy are susceptible to bacterial infections and serious infectious complications. However, fever and neutropenia can also result from other causes, for which no antibiotic treatment is needed. In the past decades attempts have been made to stratify the heterogeneous group of pediatric cancer patients with fever and neutropenia into high- and low-risk groups for bacterial infections or infectious complications. Strategies for risk assessment have resulted in treatment regimens with early discharge or even no hospital admission at all, and/or treatment with oral or no antibiotics. We will provide a historical overview of the changing approach to low-risk fever and neutropenia, and we will also try to identify clear and objective parameters for risk assessment strategies and illustrate their relationship to innate immunity. In the future, new insights into genetic susceptibility on neutropenic fever might be of use in children with cancer with fever and neutropenia. [Copyright &y& Elsevier]

Abstract: Research has provided evidence that tumor growth depends on the interaction of tumor cells with stromal cells, as already suggested in 1889 by Paget. Experimental and clinical studies have revealed that tumor stromal cells can be derived from bone marrow (BM)-derived progenitor cells, such as mesenchymal stem cells (MSCs), which can be mobilized into the circulation and incorporate into tumor micro-environments. Many observations indicate that, in the tumor micro-environment, MSCs have several tumor growth promoting functions, including expression of growth factors, promotion of tumor vessel formation and creation of tumor stem cell niches. This review will discuss the currently known tumor growth promoting BM-derived cells and focus on the role of MSCs in modulating tumor micro-environments. In addition, we will discuss the potential of inhibiting BM-derived cells and their utilization as cellular vehicles for selective delivery of cancer therapeutics as additional strategies in the treatment of cancer. [Copyright &y& Elsevier]

Cancer patients treated with chemotherapy are susceptible to bacterial infections. Therefore, all neutropenic cancer patients with fever receive standard therapy consisting of broad-spectrum antibiotics and hospitalization. However, febrile neutropenia in cancer patients is often due to other causes than bacterial infections. Therefore, standard therapy should be re-evaluated and new treatment strategies for patients with variable risk for bacterial infection should be considered. This paper reviews the changing spectrum of microorganisms and resistance of microorganisms to antibiotics in infection during neutropenia and discusses new strategies for the selection of patients with low-risk for bacterial infection using clinical and biochemical parameters such as acute phase proteins and cytokines. These low-risk patients may be treated with alternative therapies such as oral antibiotics, early discharge from the hospital or outpatient treatment. [Copyright &y& Elsevier]