CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age

Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) proteins P-glycoprotein, encoded by the MDR1/ABCB1 gene, multidrug resistant-related protein (MRP/ABCC1), the lung resistance-related protein (LRP), or major vault protein (MVP), and the breast cancer resistance protein (BCRP/ABCG2). The clinical value of MDR1, MRP1, LRP/MVP, and BCRP messenger RNA (mRNA) expression was prospectively studied in 154 newly diagnosed AML patients ≥60 years who were treated in a multicenter, randomized phase 3 trial. Expression of MDR1 and BCRP showed a negative whereas MRP1 and LRP showed a positive correlation with high white blood cell count (respectively, p < 0.05, p < 0.001, p < 0.001 and p < 0.001). Higher BCRP mRNA was associated with secondary AML (p < 0.05). MDR1 and BCRP mRNA were highly significantly associated (p < 0.001), as were MRP1 and LRP mRNA (p < 0.001) expression. Univariate regression analyses revealed that CD34 expression, increasing MDR1 mRNA as well as MDR1/BCRP coexpression, were associated with a lower complete response (CR) rate and with worse event-free survival and overall survival. When adjusted for other prognostic actors, only CD34-related MDR1/BCRP coexpression remained significantly associated with a lower CR rate (p = 0.03), thereby identifying a clinically resistant subgroup of elderly AML patients

Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics

In December 2016, a panel of experts in microbiology, nutrition and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics to review the definition and scope of prebiotics. Consistent with the original embodiment of prebiotics, but aware of the latest scientific and clinical developments, the panel updated the definition of a prebiotic: a substrate that is selectively utilized by host microorganisms conferring a health benefit. This definition expands the concept of prebiotics to possibly include non-carbohydrate substances, applications to body sites other than the gastrointestinal tract, and diverse categories other than food. The requirement for selective microbiota-mediated mechanisms was retained. Beneficial health effects must be documented for a substance to be considered a prebiotic. The consensus definition applies also to prebiotics for use by animals, in which microbiota-focused strategies to maintain health and prevent disease is as relevant as for humans. Ultimately, the goal of this Consensus Statement is to engender appropriate use of the term ‘prebiotic’ by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category. To this end, we have reviewed several aspects of prebiotic science including its development, health benefits and legislation

Hodgkin’s lymphoma: Belgina hematology Society guidelines in diagnosis, treatment and follow-up

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Dose-response relationship in cyclophosphamide-treated B-cell lymphoma xenografts monitored with [F-18]FDG PET

Although [(18)F]FDG PET can measure therapy response sooner and more accurately than morphological imaging techniques, there is still some debate as to whether [(18)F]FDG uptake really reflects changes in the viable cell fraction. In this study changes in [(18)F]FDG uptake were investigated in a lymphoma model at several time-points after treatment and with different doses of chemotherapy. Data were analysed in terms of several parameters.SCID mice were subcutaneously inoculated with 5x10(6) Daudi cells in the right thigh. One group was not treated (control group). The other groups received cyclophosphamide 75 mg/kg (low-dose group), 125 mg/kg (medium-dose group) and 175 mg/kg (high-dose group) on day 0. Sequential [(18)F]FDG small-animal PET (microPET) scans were performed on days 0, 2, 6, 9, 13 and 16 after treatment. The mean and maximum standardized uptake value (SUV(mean) and SUV(max)), metabolic tumour volume (Vol(metab)) and total lesion glycolysis (TLG) were calculated.A significant decrease in [(18)F]FDG uptake was observed on day 2 in the medium-dose and high-dose groups and on day 6 in the low-dose group, all preceding morphological changes. SUV(mean) and SUV(max) formed a plateau from day 6 to day 9, corresponding to the known influx of inflammatory cells. No obvious plateau was observed with TLG which was found to be the most sensitive parameter clearly differentiating the low-dose group from the medium- and high-dose groups early after therapy.[(18)F]FDG uptake was able to reflect the dose-response relationship for cyclophosphamide. TLG was the best parameter for dose-related response assessment in this tumour model

The need for improved neutropenia risk assessment in DLBCL patients receiving R-CHOP-21: findings from clinical practice

Febrile neutropenia (FN) risk-assessment and granulocyte-colony stimulating factor (G-CSF) prophylaxis use in clinical practice was evaluated in patients with diffuse large B-cell lymphoma receiving R-CHOP-21. More G-CSF primary prophylaxis was used in patients assessed as high FN risk, but R-CHOP-21 was associated with substantial myelotoxicity in both high- and low-risk groups. In a multivariate analysis, older age, poor performance status, lower baseline hemoglobin, and lack of G-CSF prophylaxis were significantly associated with occurrence of FN in any cycle. Results highlight the need for improved FN risk-assessment and thorough guideline adherence to further reduce FN and better support chemotherapy delivery

Rituximab in auto-immune haemolytic anaemia and immune thrombocytopenic purpura: A Belgian retrospective multicentric study

Dierickx D, Verhoef G, Van Hoof A, Mineur P, Roest A, Triffet A, Kentos A, Pierre P, Boulet D, Bries G, Lê P-Q, Janssens A, Delannoy A (University Hospital Gasthuisberg, Leuven; Algemeen Ziekenhuis St. Jan, Brugge; Grand Hôpital de Charleroi, Gilly; ZNA Stuyvenberg, Antwerpen; Centre Hospitalier Universitaire, Charleroi; ULB Hôpital Erasme, Brussels; Cliniques du Sud-Luxembourg, Arlon; CHR Saint Joseph, Mons; Virga Jesseziekenhuis, Hasselt; Children's University Hospital Reine Fabiola, Brussels; and Hôpital de Jolimont, Haine-Saint-Paul and Cliniques Universitaires St Luc, Brussels; Belgium). Rituximab in auto-immune haemolytic anaemia and immune thrombocytopenic purpura:a Belgian retrospective multicentric study. J Intern Med 2009;Objectives. For better characterizing the effect of anti-CD20 therapy, we analysed the use of rituximab in Belgian patients experiencing auto-immune haemolytic anaemia (AIHA) and immune thrombocytopenic purpura (ITP). Design. We performed a retrospective multicentric analysis of patients with AIHA and ITP treated with rituximab in Belgium. Setting. Haematological departments were invited to fill in a questionnaire about patient and disease characteristics. Subjects. All patients with AIHA and ITP, both primary and secondary to other diseases, who received one or more courses of rituximab during their disease course were included. Sixty-eight courses of rituximab in 53 patients with AIHA and 43 courses in 40 patients with ITP were analyzed. Intervention. Response rates, duration of response and factors predictive for response were assessed. Results. All patients were given rituximab after failing at least one previous line of treatment, including splenectomy in 19% and 72.5% of AIHA-patients and ITP-patients respectively. Overall response rates were 79.2% in AIHA and 70% in ITP, with a median follow-up since first rituximab administration of 15 months (range 0.5-62) in AIHA and 11 months (range 0-74) in ITP. Progression free survival at 1 and 2 years were 72% and 56% in AIHA and 70% and 44% in ITP. In this retrospective analysis we were not able to identify pretreatment characteristics predictive for response to rituximab. Nine patients with AIHA and three patients with ITP were given one or more additional courses of rituximab. Most of these patients, who had responded to a previous course, experienced a new response comparable to the previous one, both in terms of quality and of duration of response. Finally, the outcome of patients who failed to respond to rituximab therapy was poor both in terms of response to subsequent therapy and in terms of survival. Conclusions. This study confirms that rituximab induces responses in a majority of previously treated patients with AIHA and ITP. Response duration generally exceeds 1 year. Retreatment with rituximab in responding patients is most often successful. The outcome of patients who fail on rituximab is poor. We were not able to identify pretreatment patient characteristics predicting for response. © 2009 Blackwell Publishing Ltd.SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

Non-invasive detection of genomic imbalances in Hodgkin/Reed-Sternberg cells in early and advanced stage Hodgkin's lymphoma by sequencing of circulating cell-free DNA: a technical proof-of-principle study

Background Hodgkin's lymphoma is one of the most common lymphoid neoplasms in young adults, but the low abundance of neoplastic Hodgkin/Reed-Sternberg cells in the tumour hampers the elucidation of its pathogenesis, biology, and diversity. After an incidental observation that genomic aberrations known to occur in Hodgkin's lymphoma were detectable in circulating cell-free DNA, this study was undertaken to investigate whether circulating cell-free DNA can be informative about genomic imbalances in Hodgkin's lymphoma. Methods We applied massive parallel sequencing to circulating cell-free DNA in a prospective study of patients with biopsy proven nodular sclerosis Hodgkin's lymphoma. Genomic imbalances in Hodgkin/Reed-Sternberg cells were investigated by fluorescence in-situ hybridisation (FISH) on tumour specimens. Findings By non-invasive prenatal testing, we observed several genomic imbalances in circulating cell-free DNA of a pregnant woman, who was subsequently diagnosed with early-stage nodular sclerosis Hodgkin's lymphoma stage IIA during gestation. FISH on tumour tissue confirmed corresponding genomic imbalances in Hodgkin/Reed-Sternberg cells. We prospectively studied circulating cell-free DNA of nine nodular sclerosis Hodgkin's lymphoma cases: eight at first diagnosis and one at first relapse. Seven patients had stage IIA disease and two had stage IVB disease. In eight, genomic imbalances were detected, including, among others, gain of chromosomes 2p and 9p, known to occur in Hodgkin's lymphoma. These gains and losses in circulating cell-free DNA were extensively validated by FISH on Hodgkin/Reed-Sternberg cells in biopsy samples. Initiation of chemotherapy induced normalisation of circulating cell-free DNA profiles within 2-6 weeks. The cell cycle indicator Ki67 and cleaved caspase-3 were detected in Hodgkin/Reed-Sternberg cells by immunohistochemistry, suggesting high turnover of Hodgkin/Reed-Sternberg cells. Interpretation In early and advanced stage nodular sclerosis Hodgkin's lymphoma, genomic imbalances in Hodgkin/Reed-Sternberg cells can be identified by massive parallel sequencing of circulating cell-free DNA at diagnosis. The rapid normalisation of circulating cell-free DNA profiles on therapy initiation suggests a potential role for circulating cell-free DNA profiling in early response monitoring. This finding creates several new possibilities for exploring the diversity of Hodgkin's lymphoma, and has potential implications for the future clinical development of biomarkers and precision therapy for this malignanc

Waldenström’s macroglobulinaemia: Belgian Hematology Society guidelines

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