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MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate growth and differentiation. miRNAs are frequently located at cancer-specific fragile sites in the human genome, such as chromosome 7q. The nuclear oncogene SKI is up-regulated in acute myeloid leukemia (AML) with -7/del7q. Here we asked whether loss of miRNAs on chromosome 7q may explain this up-regulation. miR-29a expression was found to be down-regulated in AML with -7/del7q. Forced expression of miR-29a down-regulated Ski and its target gene, Nr-CAM, whereas miR-29a inhibition induced Ski expression. Luciferase assays validated a functional binding site for miR-29a in the 3' untranslated region of SKI. Finally, in samples of AML patients, we observed an inverse correlation of Ski and miR-29a expression, respectively. In conclusion, up-regulation of Ski in AML with -7/del7q is caused by loss of miR-29a. miR-29a may therefore function as an important tumor suppressor in AML by restraining expression of the SKI oncogene. [ABSTRACT FROM AUTHOR]

Novel treatment schedules of induction therapy for acute lympoblastic leukaemia (ALL) use combinations of immunosuppressive and cytotoxic drugs that are associated with neutropenia and acquisition of invasive fungal infections. It has been described that posaconazole, a triazole antifungal drug, is active against a variety of Candida and Aspergillus species in vitro. Moreover, large clinical trials using posaconazole in severely immunosuppressed patients provided data on efficacy against Aspergillus in vivo. As patients with ALL are also affected by difficult-to-treat Aspergillus infections, we conducted a pilot study to prove the safety of posaconazole in patients undergoing intensified induction phase treatment. We report on eight patients receiving prophylactic (200 mg t.i.d.) dose of posaconazole and demonstrate good tolerability of the drug. The most obvious side effect was liver toxicity as defined by abnormal serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase and bilirubin levels (

Abstract: Introduction: PKC412 has proven activity in the treatment of acute myelogenous leukemia (AML). The drug is extensively metabolized, and recently it was shown that its metabolites have differing efficacies against malignant cells. Therefore, we established a new isocratic HPLC method, which sensitively detects PKC412 and five of its metabolites. Method: Quantification was performed using N-phenyl-1-naphtylamine as an internal standard. We could demonstrate linearity in a range from 10 to 10,000 ng/ml PKC412 with an intra-day variability of less than 7.5% and an inter-day-variability of less than 11%. Results: The assay was used to monitor plasma samples from patients with AML treated within a clinical trial. Here we could demonstrate the ability of the assay to detect five metabolites of PKC412 and describe the application of the assay for drug monitoring in clinical situations. Conclusion: The assay described here will enable a discriminative analysis of PKC412 and its metabolites in human plasma samples. First clinical application of the assay suggests different rates of metabolism of the individual metabolites of PKC412 with e.g. accumulation of CGP52421 epimer 2 even after cessation of therapy. Since it is assumed that different metabolites of PKC412 have a very individual mode of actions, determination of PKC412 and its metabolites within clinical studies of the drug will be important. [Copyright &y& Elsevier]

Investigates the association of acute myeloid leukemia with mdr1 gene expression and mutations in Ras proto-oncogenes. Influence of Ras on mdr1 activity; Detection of Ras mutation in human cancer; Importance of cell cycle for mdr1 expression.

Long‐term data of chronic lymphocytic leukemia (CLL) patients with favorable risk who were treated with fludarabine, cyclophosphamide, and rituximab (FCR) within clinical trials show good efficacy. We here report long‐term data collected within the GCLLSG registry. Altogether, 417 CLL patients who received first‐line treatment with FCR were analyzed, of which 293 (70.3%) were treated outside of clinical trials. The median observation time from first‐line was 95.8 (interquartile range 58.7–126.8) months. Focusing on data of 194 (46.5%) patients who received FCR first‐line treatment after 2013 (start of data collection within GCLLSG registry), responses were documented in 85% of the patients, non‐responses in 15%, and for 3.6% the assessment was missing. Median event‐free survival (EFS, time until disease progression, subsequent treatment, or death) was 60.2 months with a 5‐year EFS‐rate of 50.6%. Patients with higher‐risk disease, characterized by unmutated IGHV (N = 78), had a median EFS of 45.4 months with a 5‐year EFS rate of 36.3%, while the median EFS was 77.5 months with a 5‐year EFS rate of 60.3% in patients with mutated IGHV (N = 40). Median overall survival was not reached with a 5‐year survival rate of 92.7%. In summary, first‐line FCR was associated with long EFS, especially in patients exhibiting a mutated IGHV status. [ABSTRACT FROM AUTHOR]

Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661 ; substudy active and recruiting). Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0–23·4) in the imetelstat group and 17·5 months (12·1–22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9–49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1–26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3–4 treatment-emergent adverse events. The most common treatment-emergent grade 3–4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter. [ABSTRACT FROM AUTHOR]

The approved dose of bosutinib in chronic phase CML is 400 mg QD in first-line and 500 mg QD in later-line treatment. However, given that gastrointestinal (GI) toxicity typically occurs early after treatment initiation, physicians often tend to start therapy with lower doses although this has never been tested systematically in prospective trials in the Western world. The Bosutinib Dose Optimization (BODO) Study, a multicenter phase II study, investigated the tolerability and efficacy of a step-in dosing concept of bosutinib (starting at 300 mg QD) in chronic phase CML patients in 2nd or 3rd line who were intolerant and/or refractory to previous TKI treatment. Of 57 patients included until premature closure of the study due to slow recruitment, 34 (60%) reached the targeted dose level of 500 mg QD following the 2-weekly step-in dosing regimen. While the dosing-in concept failed to reduce GI toxicity (grade II–IV, primary study endpoint) to < 40% (overall rate of 60%; 95% CI: 45–74%), bosutinib treatment (mean dosage: 403 mg/day) showed remarkable efficacy with a cumulative major molecular remission (MMR) rate of 79% (95% CI: 66 to 88%) at month 24. Of thirty patients refractory to previous therapy and not in MMR at baseline, 19 (64%) achieved an MMR during treatment. GI toxicity did not significantly impact on patient-reported outcomes (PRO) and led to treatment discontinuation in only one patient. Overall, the results of our trial support the efficacy and safety of bosutinib after failure of second-generation TKI pre-treatment. Trial registration: NCT02577926. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to investigate the clinical impact of reactivation of human herpes virus-6 (HHV-6) and HHV-7 infections in stem cell transplantation recipients, and to examine a possible increase in virulence of the two roseoloviruses when a reactivation of CMV (HHV-5) simultaneously occurs. For this purpose, quantitative real-time PCR systems were developed to assess the viral load of CMV, HHV-6, or HHV-7 in the plasma of haematopoetic stem cell recipients. One hundred and ninety-eight plasma samples from 37 patients who underwent allogeneic stem cell transplantation were tested for CMV, HHV-6, and HHV-7 by a 5′-exonuclease (TaqMan) quantitative real-time PCR. The CMV load obtained by the real-time PCR assay was compared retrospectively with results generated previously with a commercially available test (COBAS AMPLICOR™ CMV MONITOR Test, Roche). The results suggest that CMV and HHV-6 may be associated with post-transplantation end-organ disease, while HHV-7 reactivation had no impact on the patients included in this study. No evidence for a potential interaction of the roseoloviruses and CMV infections was found. [Copyright &y& Elsevier]

Abstract: Objectives:: Macrophage migration inhibitory factor 1α (MIF), a cytokine with immunoregulatory functions has been suggested to be involved in atherosclerotic plaque development. However, little is known about MIF-inducing conditions in the atherosclerotic process and the association of MIF with plaque instability. Methods and results:: Forty-two carotid endatherectomy samples from 36 patients and 4 aortic samples from young accident victims (as healthy controls) were analyzed for MIF staining. MIF expressing tissues in the atherosclerotic plaques are mainly mononuclear cells (MNCs), but also endothelial cells of intimal microvessels (MVECs). The magnitude and the intensity of their MIF expression was associated with the progression of plaques from early lesions (Stary I–III) to complicated plaque stages (Stary IV–VIII). In highly inflammatory and neovascularized regions of the plaques the colocalization of MIF expressing MNCs with CD40-L+ and angiotensin II (Ang II)-producing MNCs could be established. This finding supports the notion that CD40-L fusion protein and Ang II are able to induce MIF production in the monocytic cell line THP-1. Furthermore hypoxia (≤1% O2) as a further proinflammatory and especially proangiogenetic factor was able to stimulate MIF secretion by THP-1, human monocytes and HUVECs. Hyperglycemia and insulin remained without effect. Conclusion:: MIF is expressed in advanced atherosclerotic lesions in close correlation with signs of instability, such as mononuclear cell inflammation and neointimal microvessel formation. Furthermore, the colocalization of MIF with Ang II-producing MNCs and CD40-L+ cells in these plaques and the finding that proathero- and -angiogenic mediators such as CD40-L, Ang II and hypoxia are able to stimulate MIF expression in vitro suggest an important role of MIF in the modulation of atherosclerotic plaque stability. [Copyright &y& Elsevier]

Angiotensin converting enzyme (ACE) inhibitors significantly improve survival in patients with atherosclerosis. Although ACE inhibitors reduce local angiotensin II (AngII) formation, serine proteases form AngII to an enormous amount independently from ACE. Therefore, our study concentrates on the effect of the ACE-inhibitor ramiprilat on chemokine release, AngII receptor (ATR) expression, and NF-κB activity in monocytes stimulated with AngII.AngII-induced upregulation of IL-8 and MCP-1 protein and RNA in monocytes was inhibited by the AT1R-blocker losartan, but not by the AT2R-blocker PD 123.319. Ramiprilat dose-dependently suppressed AngII-induced upregulation of IL-8 and MCP-1. The suppressive effect of ramiprilat on AngII-induced chemokine production and release was in part caused by downregulation of NF-κB, but more by a selective and highly significant reduced expression of AT1 receptors as shown in monocytes and endothelial cells.In our study we demonstrated for the first time that ramiprilat reduced expression of AT1R in monocytes and endothelial cells. In addition, ramiprilat downregulated NF-κB activity and thereby reduced the AngII-induced release of IL-8 and MCP-1 in monocytes. This antiinflammatory effect, at least in part, may contribute to the clinical benefit of the ACE inhibitor in the treatment of coronary artery disease. [Copyright &y& Elsevier]

Purpose: The German Maintenance Study (GERMAIN) was designed to evaluate the impact of lenalidomide maintenance after induction therapy with bortezomib, melphalan and prednisolone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (MM) patients. Methods: Due to poor accrual and high dropout rate, only 85 patients (planned 286) entered the trial and 40 (planned 200) were randomized to lenalidomide maintenance (n = 19) vs. observation (n = 21). Results: The primary endpoint, improved progression-free survival, was not met (p = 0.3572). After a median follow-up of 12.9 months, median progression-free survival in the lenalidomide arm was 14.4 months and 11.4 months with placebo. The hazard ratio 0.621 (95% confidence interval: [0.224, 1.725]) was about the same as expected (0.625). However, with only 40 patients randomized, the actual power to detect a difference was 11%. Of patients receiving at least one dose of induction, 54% were frail according to a modified International Myeloma Working Group frailty score. Discontinuations were high during induction (47%), and affected mainly frail patients (54%). Despite a higher rate of adverse events in the lenalidomide arm (p = 0.0061), only 2 patients discontinued lenalidomide due to toxicity. Conclusion: A frailty assessment with appropriate dose modification for induction therapy should be mandatory for all elderly non-transplant-eligible myeloma patients. [ABSTRACT FROM AUTHOR]

• Peripheral blood immune parameters predict efficacy of chemoimmunotherapy in HNSCC. • Various differences of immune parameters before and after treatment allowed the best prediction. • Cells of the innate immune system are prominent predictors. • Polymorphonuclear cells, monocytes, and plasmacytoid dendritic cells serve as best predictors. Individual prediction of treatment response is crucial for personalized treatment in multimodal approaches against head-and-neck squamous cell carcinoma (HNSCC). So far, no reliable predictive parameters for treatment schemes containing immunotherapy have been identified. This study aims to predict treatment response to induction chemo-immunotherapy based on the peripheral blood immune status in patients with locally advanced HNSCC. The peripheral blood immune phenotype was assessed in whole blood samples in patients treated in the phase II CheckRad-CD8 trial as part of the pre-planned translational research program. Blood samples were analyzed by multicolor flow cytometry before (T1) and after (T2) induction chemo-immunotherapy with cisplatin/docetaxel/durvalumab/tremelimumab. Machine Learning techniques were used to predict pathological complete response (pCR) after induction therapy. The tested classifier methods (LDA, SVM, LR, RF, DT, and XGBoost) allowed a distinct prediction of pCR. Highest accuracy was achieved with a low number of features represented as principal components. Immune parameters obtained from the absolute difference (lT2-T1l) allowed the best prediction of pCR. In general, less than 30 parameters and at most 10 principal components were needed for highly accurate predictions. Across several datasets, cells of the innate immune system such as polymorphonuclear cells, monocytes, and plasmacytoid dendritic cells are most prominent. Our analyses imply that alterations of the innate immune cell distribution in the peripheral blood following induction chemo-immuno-therapy is highly predictive for pCR in HNSCC. [ABSTRACT FROM AUTHOR]

RAS mutations are frequently found among acute myeloid leukemia patients (AML), generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We have previously shown that treatment of AML patients with high-dose cytarabine is preferentially beneficial for those harboring oncogenic RAS. On the basis of a murine AML cell culture model, we ascribed this effect to a RAS-driven, p53-dependent induction of differentiation. Hence, in this study we sought to confirm the correlation between RAS status and differentiation of primary blasts obtained from AML patients. The gene expression signature of AML blasts with oncogenic NRAS indeed corresponded to a more mature profile compared to blasts with wildtype RAS, as demonstrated by gene set enrichment analysis (GSEA) and real-time PCR analysis of myeloid ecotropic viral integration site 1 homolog (MEIS1) in a unique cohort of AML patients. In addition, in vitro cell culture experiments with established cell lines and a second set of primary AML cells showed that oncogenic NRAS mutations predisposed cells to cytarabine (AraC) driven differentiation. Taken together, our findings show that AML with inv(16) and NRAS mutation have a differentiation gene signature, supporting the notion that NRAS mutation may predispose leukemic cells to AraC induced differentiation. We therefore suggest that promotion of differentiation pathways by specific genetic alterations could explain the superior treatment outcome after therapy in some AML patient subgroups. Whether a differentiation gene expression status may generally predict for a superior treatment outcome in AML needs to be addressed in future studies. [ABSTRACT FROM AUTHOR]

The article discusses a study comparing the benefit of the type 2 glycoengineered antibody obinutuzumab (GA101) with that of rituximab, each combined with chlorambucil, in treating patients with chronic lymphocytic leukemia (CLL). Topics addressed include the creatinine clearance of study patients having a median age of 73 years and increased response rates and longer progression-free survival among those receiving combination treatment compared with chlorambucil monotherapy.

Abstract: The composition of the hematopoietic stem cell (HSC) niche within the bone marrow is highly dynamic, tightly regulated, and of importance for various HSC properties. Integrins are important molecules within this niche that influence those properties through the interactions of HSCs and mesenchymal stem cells (MSCs). Here we investigated the function of miR-134 in integrin regulation in MSCs. In MSCs, miR-134 post-transcriptionally regulated β1 integrin expression. This negative regulation of β1 integrin was mediated by the binding of miR-134 to its 3′ untranslated region, which contains two conserved binding sites for miR-134. The miR-134-mediated silencing of β1 integrin in MSCs was shown by atomic force microscopy to decrease the adhesion of 32D cells to MSCs transfected with miR-134. Furthermore, the adhesion of MSCs to fibronectin was reduced after transfection with miR-134. MSCs from patients with myelodysplastic syndrome (MDS) revealed highly significant miR-134 overexpression compared with MSCs from healthy bone marrow donors. MSCs from MDS patients showed lower β1 integrin protein, but not lower mRNA, expression, suggesting post-transcriptional regulation. The present study demonstrates miR-134-mediated negative regulation of β1 integrin that influences cell adhesion to and of MSCs. These results further contribute to our understanding of the complexity of MDS. [Copyright &y& Elsevier]

Abstract: In immunocompromised patients, the diagnosis of infections with herpesviruses and adenoviruses relies mainly on PCR amplification of viral genomic DNA from clinical samples. In the case of co-infections with two or more viruses, single amplification of viral DNA from clinical samples has proven to be time-consuming and expensive, hampering the efficient diagnosis and therapy of viral co-infections. In this study, a diagnostic DNA-microarray allowing simultaneous detection of herpes simplex virus types 1 and 2 (HSV 1/2), varicella zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus-6 types A and B (HHV-6 A/B), and adenovirus in clinical samples was developed and validated. The assay displays a high analytical sensitivity (10genomeequivalents(GE)/reaction) and specificity, being cost-effective and time-saving. Because the DNA-microarray uses the same analytical conditions as real-time quantitative PCR, it can be used as a screening device for multiple viral infections, followed by selective viral load measurement depending on the clinical context. Those features make the DNA-microarray an attractive device for the management of viral infections in immunocompromised patients. [Copyright &y& Elsevier]

Abstract: The expression of the fusion protein BCR/ABL is a hallmark of chronic myeloid leukemia. BCR/ABL is a constitutively active tyrosine kinase influencing cell proliferation, apoptosis, and differentiation. To what extent and by which mechanism BCR/ABL affects the adhesion of leukemic cells to bone marrow stromal cells (BMSC) is controversial. To characterize adhesion of BCR/ABL-transformed 32D cells (32D-BCR/ABL) to the BMSC line M2-10B4, we used washing assays and single-cell force spectroscopy (SCFS). Compared to control 32D cells (32D-V), 32D-BCR/ABL developed threefold higher adhesion forces. This enhanced cell adhesion could be reduced to control levels after specifically inhibiting the activity of the tyrosine kinase BCR/ABL using imatinib mesylate (IM). SCFS showed that the adhesion forces of 32D-BCR/ABL were strongest to fibronectin and collagen type I, suggesting that β1-integrin has a major role in mediating the adhesion of leukemic cells to BMSC. Indeed, the β1-integrin blocking antibody Ha2/5 abrogated the attachment of 32D-V and 32D-BCR/ABL cells to BMSC. Although 32D-BCR/ABL cells show significantly increased β1-integrin expression, no significant difference of β1-integrin mRNA levels could be detected, indicating a post-transcriptional regulation of β1-comprising integrin heterodimers by BCR/ABL. The data presented here argue that the interaction of β1-integrin and extracellular matrix components is functionally important in leukemic cells expressing high-levels of BCR/ABL, and could provide a rationale for the development of optimized targeted therapies. [Copyright &y& Elsevier]

MicroRNAs (miRNAs) play an important role in cellular differentiation and cancer pathogenesis. This study analysed the expression of 154 human miRNAs in acute myeloid leukaemia (AML) and control samples using a stem-loop real-time reverse transcription polymerase chain reaction approach. Global patterns of miRNA expression in AML, normal bone marrow (NBM) and CD34+ progenitor cells allowed correct class predictions similar to whole genome microarray expression analyses that were performed at the same time. At single miRNA species level, MIRN23B was repressed in AML specimens compared to NBM and purified CD34+ haematopoietic progenitor cells. In contrast, the MIRN221/MIRN222 cluster and MIRN34A were expressed at significantly higher levels in AML blasts. Patients with high MIRN221/MIRN222 expression showed low levels of KIT RNA and protein expression but the correlation between kit protein and KIT mRNA was significantly stronger than the correlation of either one with MIRN221/MIRN222. A global analysis between miRNA expression levels and mRNA expression of predicted target genes revealed only weak associations in the majority of miRNA species. Nonetheless, the presence of two or more miRNA binding sites within the mRNA was usually associated with a decrease in mRNA levels. Taken together, these findings provide evidence that specific miRNA expression patterns exist in AML. [ABSTRACT FROM AUTHOR]

AMD3100, a competitive antagonist of CXCR-4, disrupts the binding of its ligand, stromal cell-derived factor-1 (SDF-1), and facilitates stem cell mobilisation in patients with haematological malignancies. This study investigated the differential kinetics of CXCR-4 and adhesion molecule expression and their impact on stem cell yield during mobilisation with granulocyte-colony stimulating factor (G-CSF) (days 1-4) followed by AMD3100 in 10 patients with multiple myeloma. A four-colour flow cytometry-based determination of CXCR-4, VLA-4, L-selectin, PECAM, LFA-1 and CD44 expression on CD34+ cells and measurement of SDF-1 concentration were performed at different time points. After G-CSF alone, CXCR-4 expression on patients' blood and marrow CD34+ cells was significantly lower than in the healthy controls (p < 0.001), but allowed no prediction of stem cell yield. Except in the single poorly mobilising patient, AMD3100 led to a further significant decrease of CXCR4 (p = 0.001), which inversely correlated with the CD34+ counts in the blood (p = 0.005). SDF-1 level in patients' marrow was positively correlated with CXCR-4 expression on CD34+ cells (p = 0.011). It is interesting to note that the expression of adhesion molecules remained unaffected by AMD3100 administration. Further studies will define the possible prognostic role of AMD3100 mediated changes in CXCR-4 expression for the prediction of stem cell yield attainable with this new mobilisation regimen. [ABSTRACT FROM AUTHOR]

Multi drug resistance (MDR) is a major obstacle for cancer therapy. The three major candidates accounting for the development of MDR in acute myeloid leukaemia (AML) are multi drug resistance gene (MDR1), multi drug resistance-related protein gene (MRP1) and lung resistance protein gene(LRP). So far, the differential impact of resistance gene expression on treatment outcome in AML is not clear. Therefore, we examinedMDR1,MRP1andLRPgene expression at diagnosis in 331 adult AML patients in the context of other known prognostic factors, such as age, disease status, cytogenetics and FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication mutational status. Median observation time was longer than 5 years [64·1 months (40·0–87·6)].MDR1expression proved to be an independent prognostic factor for outcome of induction therapy (P < 0·001) and overall survival (P = 0·02), whereasMRP1expression was an independent predictor for disease-free survival (P = 0·01) in the multivariate analysis. This prognostic impact of both resistance genes was also found in patients with intermediate risk cytogenetics.LRPexpression, however, had no impact on treatment outcome in AML. Our study shows that resistance gene expression should be considered together with age, cytogenetics and FLT3 mutational status for risk-adapted treatment strategies in AML in the future. [ABSTRACT FROM AUTHOR]

Background. Clinical trials evaluating idarubicin (IDA) in acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma (NHL) have provided some evidence for an increased myelotoxicity of IDA compared to other anthracyclines. IDA is known to be less sensitive towards multidrug resistance mediated by P-glycoprotein (P-gp). This phenotype is a major impediment to successful antineoplastic treatment, but P-gp is also expressed on hematopoietic stem cells (HSC). Methods. We investigated the pharmacokinetics of IDA and etoposide (ETO) in seven previously untreated patients with aggressive NHL. The patients received a CHOP-derived protocol (CIVEP) in which doxorubicin (DOX) was substituted by IDA 11–16 mg/m2 and ETO 3×100 mg/m2 was added. Furthermore, we evaluated in vitro the impact of P-gp expression on the cytotoxicity of DOX and IDA in cells from three parental chemosensitive leukemia and lymphoma cell lines (HL60, U937, CCRF) and their resistant sublines, as well as in CD34-positive HSC. Results. The peak plasma levels (Cmax), terminal elimination half-life (t1/2) and area under the concentration curve (AUC) both for IDA and for ETO did not differ from published data. In cell line models the numbers of viable cells in a P-gp-expressing resistant CCRF-VCR100 subline were significantly more reduced by IDA (P<0.001), but there was no difference in the cytotoxicities of IDA and DOX in chemosensitive CCRF cells and in the (non-P-gp-expressing) resistant U937 and HL60 sublines. Cytotoxicity against HSC was more pronounced after incubation with IDA than after treatment with DOX (P=0.014), even when a tenfold higher concentration of DOX than of IDA was used. The addition of cyclosporin A increased the cytotoxic effect of DOX but not that of IDA in HSC. Conclusions. The pharmacokinetics of IDA and its main metabolite idarubicinol in CHOP-derived protocols were not different from data obtained with other combinations or monotherapy. The increased myelotoxicity of IDA may be a consequence of P-gp expression in CD34-positive HSC. [ABSTRACT FROM AUTHOR]

Simple Summary: The study compares the effects on complete remission rate (CR) of a single dose of durvalumab/tremelimumab immediately after a single-cycle platinum and docetaxel as part of induction therapy for a controlled trial in head and neck cancer with chemotherapy alone from a historical collective. The CR rate was 60.3% after induction chemoimmunotherapy (ICIT; induction chemotherapy plus double immune checkpoint blockade) compared with 40.3% after induction chemotherapy (IC) alone. Patients with HPV-positive oropharyngeal cancer may benefit the most from additive double checkpoint inhibition, which is presumably due to the higher amount of infiltrating immune cells. Patients older than 60 years without HPV-positive oropharyngeal cancer are unlikely to benefit. To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m2 d1-3 and docetaxel 75 mg/m2 d1 combined with durvalumab 1500 mg fixed dose d5 and tremelimumab 75 mg fixed dose d5 (ICIT) within the CheckRad-CD8 trial were compared with a retrospective cohort receiving the same chemotherapy (IC) without immunotherapy. The endpoint of this analysis was the complete response rate (CR). A total of 53 patients were treated with ICIT and 104 patients with IC only. CR rates were 60.3% for ICIT and 40.3% for IC (p = 0.018). In the total population (n = 157), the most important predictor to achieve a CR was treatment type (OR: 2.21 for ICIT vs. IC; p = 0.038, multivariate analysis). The most diverse effects in CR rates between ICIT and IC were observed in younger (age ≤ 60) patients with HPV-positive OPSCCs (82% vs. 33%, p = 0.176), while there was no difference in older patients without HPV-positive OPSCCs (53% vs. 48%). The analysis provides initial evidence that ICIT could result in higher CR rates than IC. Young patients with HPV-positive OPSCCs may have the greatest benefit from additional immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

We report a stem cell transplant recipient who developed human herpesvirus 6 encephalitis. Human herpesvirus 6 load indicated massive intrathecal viral replication. Administration of cidofovir followed by foscarnet was associated with total clearance of human herpesvirus 6 infection. Cidofovir and foscarnet combination therapy may be beneficial for reducing mortality of (neutropenic) stem cell transplant recipients with human herpesvirus 6 encephalitis. [ABSTRACT FROM AUTHOR]

Abstract: Although new approaches have dramatically improved, the treatment of acute promyelocytic leukemia (APL) involvement of the central nervous system (CNS) confers a bad prognosis in the disease. Here, we report a patient who was diagnosed with relapsed APL preferentially involving the CNS. Treatment with arsenic trioxide led to impressive morphological changes in CNS cellularity consistent with the induction of a differentiation syndrome. Since arsenic trioxide could be identified in the CNS, we provide evidence that the drug can cross the blood-brain barrier and can be used for treatment of extramedullary APL. [Copyright &y& Elsevier]

Acute myeloid leukaemia (AML) carrying t(8;21) has an overall favourable prognosis. However, relapse occurs and the impact of multidrug resistance gene (MDR1) expression on recurring disease in this group of patients is not known. We determined quantifiable MDR1 expression in the bone marrow of 28 AML patients with t(8;21) by a validated real-time polymerase chain reaction assay. Using MDR1 expression, white blood cell count and CD56 expression at diagnosis we observed complete concordance of predicted and observed relapses. A calculated logit out of these three variables was a strong independent prognostic factor for overall (P = 0007) and disease-free survival (P = 0.002). [ABSTRACT FROM AUTHOR]

Objective: The study investigated differential microRNA (miRNA) expression patterns in acute myeloid leukemia (AML) patients with intermediate-risk (IR) characteristics. After characterization and validation of miR-10a, which was specifically upregulated in nucleophosmin 1 (NPM1) mutant AML samples, functional consequences of miR-10a overexpression were further delineated in vitro. Materials and Methods: Microarray analysis of miRNAs in bone marrow samples from AML (IR) patients with NPM1 mutations and healthy donors was performed to detect differential expression patterns. After validation of miRNA expression specific for NPM1 mutation in AML patients by quantitative reverse transcription polymerase chain reaction, a functional target gene search was conducted using complementary DNA microarray data from samples transfected with miR-10a. Potential target gene validation was done using transient transfection of K562 cells followed by Western blotting and luciferase reporter assay. Results: In comparison with wild-type samples, NPM1 mutant AML samples were shown to markedly overexpress miR-10a. Subsequent in vitro miR-10a overexpression induced differential gene expression as determined by microarray analysis. Here the murine double minute 4 (MDM4) gene turned out as a candidate gene for miR-10a. Validation of MDM4 in leukemic cells revealed a robust negative relationship between miR-10a overexpression and MDM4 downregulation. Furthermore, we determined an inverse association between miR-10a and MDM4 expression in AML (IR) samples with respect to their NPM1 mutational status. Conclusions: miR-10a expression is highly characteristic for AML (IR) patients with NPM1 mutations and may influence its biological properties in AML by interfering with the p53 machinery partly regulated by MDM4. [Copyright &y& Elsevier]