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Journal: British journal of haematology


Interactions between the Bruton tyrosine kinase (BTK) inhibitor PCI-32765 and the proteasome inhibitor (bortezomib) were examined in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells, including those highly resistant to bortezomib. Co-administration of PCI-32765/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre- or activated B-cell-like-DLBCL cells and in MCL cells. These events were accompanied by marked AKT and nuclear factor (NF)-κB (NFKB1) inactivation, down-regulation of Mcl-1 (MCL1), Bcl-xL (BCL2L1), and XIAP, and enhanced DNA damage (e.g., γH2A.X formation) and endoplasmic reticulum (ER) stress. Similar interactions were observed in highly bortezomib-resistant DLBCL and MCL cells, and in primary DLBCL cells. In contrast, PCI-32765/bortezomib regimens displayed minimal toxicity toward normal CD34(+) bone marrow cells. Transfection of DLBCL cells with a constitutively active AKT construct attenuated AKT inactivation and significantly diminished cell death, whereas expression of an NF-κB “super-repressor” (IκBα(ser34/36) ) increased both PCI-32765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant-negative eIF2α construct were resistant to this regimen. Finally, combined exposure to PCI-32765 and bortezomib resulted in more pronounced and sustained reactive oxygen species (ROS) generation, and ROS scavengers significantly diminished lethality. Given promising early clinical results for PCI-32765 in DLBCL and MCL, a strategy combining BTK/proteasome inhibitor warrants attention in these malignancies.

Concepts: DNA, Cancer, Adenosine triphosphate, Mitochondrion, Bone marrow, Endoplasmic reticulum, Reactive oxygen species, Mantle cell lymphoma


Delta storage pool deficiency (δ-SPD) is a rare heterogeneous group of platelet disorders characterized by a reduction in the number or content of dense granules. δ-SPD causes a mild to moderate bleeding diathesis characterized mainly by mucocutaneous bleeding. Currently, no specific treatment is available and the therapeutic approach is based on prevention of excessive bleeding. However, during the last few years, important insights into the pathophysiology of δ-SPD have been achieved using mouse models and dense granule deficiency-associated congenital diseases, such as Hermansky-Pudlak syndrome and Chediak-Higashi syndrome. It thus appears that δ-SPD represents a genetically heterogeneous group of intracellular vesicle biogenesis and/or trafficking disorders. This review summarizes recent data regarding the molecular mechanisms together with clinical features of the different types of δ-SPD. Although the molecular basis of isolated inherited δ-SPD remains currently unknown, next-generation sequencing strategies should enable researchers to identify the causative genes. Identification of those genes should contribute to our understanding of the pathophysiology, represent useful tools for genetic diagnosis, and eventually lead to new specific therapeutic approaches.

Concepts: DNA, Gene, Genetics, Cell, Molecular biology, Organelles, Platelet alpha-granule, Dense granule


Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by severely disturbed immune homeostasis. It can affect all age groups. Diagnostic evaluation of the patient with suspected HLH has to address three main questions: (i) does the patient have HLH? There is no simple diagnostic test, but a number of clinical and laboratory criteria define this clinical syndrome. (ii) Can a trigger be identified? A variety of infections, malignant or autoimmune diseases can contribute to the disturbed immune homeostasis with important consequences for treatment. (iii) Does the patient suffer from a genetic disease predisposing to HLH? Recent advances in the understanding of the genetic and pathophysiological basis of HLH have enabled a better and more rapid answer to this question, which is relevant for prognosis and the decision to perform haematopoietic stem cell transplantation. This review summarizes the current diagnostic approach to the patient with HLH.

Concepts: Genetics, Cancer, Disease, Genetic disorder, Medical terms, Hematology, Genetic disorders, Hemophagocytic lymphohistiocytosis


A number of single nucleotide polymorphisms (SNP) have been linked to higher risk of venous thromboembolism (VTE). We investigated the VTE risk associated with SNPs in the GP6 (rs1613662), SERPINC1 (rs2227589), F11 (rs2036914 and rs2289252), FGG (rs2066865), and F12 (rs1801020) genes. In F11, the CC genotype for rs2036914 and the CT and TT genotypes for rs2289252 were associated with a significantly higher VTE risk. A trend toward a thrombogenic effect was observed for the risk alleles of the GP6 and FGG SNPs. Risk estimates were unaffected by adjustments for blood type and F5 rs6025 (Factor V Leiden) mutation.

Concepts: DNA, Gene, Genetics, Allele, Evolution, Blood, Hematology, Factor V Leiden


Positron Emission Tomography (PET) is a functional imaging technique that, combined with computerized tomography (PET-CT), is increasingly used in lymphoma. Most subtypes accumulate fluorodeoxyglucose (FDG) and the increased sensitivity of PET-CT, especially for extranodal disease, compared to CT, makes PET-CT an attractive staging tool. The availability of a staging PET-CT scan also improves the accuracy of subsequent response assessment. ‘Interim’ PET-CT can be used to assess early response and end-of-treatment PET-CT assesses remission. Clinical trials are currently seeking to establish whether the predictive value of PET-CT can be successfully used to guide individual treatment to reduce toxicity and/or to improve outcomes. Standardized methods for performing and reporting PET have been developed in the context of trials. The role of PET in transplantation selection is currently evolving, as it appears to be more accurate and prognostic than CT. The role of FDG PET-CT throughout the management course in patients with lymphoma is explored in this review, with areas discussed that may limit the use of PET-CT imaging which clinicians should be familiar with to inform practice.

Concepts: Lung cancer, Medical imaging, Positron emission tomography, Neuroimaging, Positron, Radiology, Fludeoxyglucose, Fluorine-18


Patients with aggressive non-Hodgkin lymphoma (NHL) who relapse after autologous stem cell transplantation (ASCT) have a poor prognosis. Additional therapy is often poorly tolerated, and new treatment modalities are needed. This efficacy and safety study was a retrospective analysis of two phase II trials (NHL-002 and NHL-003) that studied single-agent lenalidomide in patients with relapsed/refractory aggressive NHL with prior (n = 87) compared with no prior ASCT (n = 179). The overall response rate in the ASCT group was 39% [14% complete response (CR)], including 29% in patients with diffuse large B-cell lymphoma, 63% in mantle cell lymphoma, and 60% in transformed lymphoma. The timing of transplant relative to receiving lenalidomide had no effect on outcomes. Median progression-free survival for the ASCT group was 3·7 months (16·9 months for patients in CR; 7·3 months for partial responders) at a median 12·5-month follow-up. Median response duration was 7·9 months. Regardless of prior ASCT, lenalidomide monotherapy was efficacious in heavily pretreated patients with aggressive, relapsed/refractory NHL, with a safety profile that was consistent with prior studies of single-agent lenalidomide.

Concepts: Effectiveness, Types of cancer, Lymphoma, Organ transplant, Mantle cell lymphoma, T-cell lymphoma


The association between angiodysplasia and von Willebrand disease (VWD) has been known for more than 40 years. Bleeding in the gastrointestinal tract associated with angiodysplasia worsens the clinical course of this inherited haemorrhagic disorder and management may become difficult and challenging. Angiodysplasia associated with acquired defects or dysfunctions of von Willebrand factor (VWF) has also been reported in a variety of conditions such as monoclonal gammopathies, Heyde syndrome and in carriers of ventricular assist devices. The most recent advances concerning the mechanistic, clinical and therapeutic aspects of VWD-associated angiodysplasia are summarized in this review, together with the limitations of our knowledge that warrant further research in the frame of international cooperation.

Concepts: Platelet, Von Willebrand factor, Von Willebrand disease, Aortic valve stenosis, Heyde's syndrome


This systematic review and meta-analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty-nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66-0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51-0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91-1·16; P = 0·63). Higher-dose DNR, compared to lower-dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60-0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75-0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high-dose DNR (90 mg/m(2) daily × 3 or 50 mg/m(2) daily × 5) and IDA (12 mg/m(2) daily × 3) can achieve 5-year survival rates of between 40 and 50 percent.

Concepts: Epidemiology, Medical statistics, Randomized controlled trial, Leukemia, Acute myeloid leukemia, Anthracycline, Daunorubicin, Idarubicin


Elevated foetal haemoglobin (HbF) levels are protective against some manifestations of sickle cell anaemia but the impact on retinopathy is unknown. We report on 123 children with HbSS, 10·6% of whom developed retinopathy. Independent of hydroxycarbamide, children with a HbF <15% had 7·1-fold (95% confidence interval, 1·5-33·6) higher odds of developing retinopathy. In children treated with hydroxycarbamide, those with retinopathy had lower HbF levels compared to children without retinopathy (9% vs. 16%; P = 0·005). We report a protective benefit of elevated HbF regarding retinopathy, and our data suggests induction of HbF with hydroxycarbamide may prevent retinopathy in children.

Concepts: Hemoglobin, Fetus, Red blood cell, Interval finite element, Sickle-cell disease, Blood proteins, Fetal hemoglobin, Sickle


There is a lack of contemporary prospective data examining the adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) and Stanford V (SV; doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone) regimens in older Hodgkin lymphoma (HL) patients. Forty-four advanced-stage, older HL patients (aged ≥60 years) were treated on the randomized study, E2496. Toxicities were mostly similar between chemotherapy regimens, although 24% of older patients developed bleomycin lung toxicity (BLT), which occurred mainly with ABVD (91%). Further, the BLT-related mortality rate was 18%. The overall treatment-related mortality for older HL patients was 9% vs. 0·3% for patients aged <60 years (P < 0·001). Among older patients, there were no survival differences between ABVD and SV. According to age, outcomes were significantly inferior for older versus younger patients (5-year failure-free survival: 48% vs. 74%, respectively, P = 0·002; 5-year overall survival: 58% and 90%, respectively, P < 0·0001), although time-to-progression (TTP) was not significantly different (5-year TTP: 68% vs. 78%, respectively, P = 0·37). Furthermore, considering progression and death without progression as competing risks, the risk of progression was not different between older and younger HL patients (5 years: 30% and 23%, respectively, P = 0·30); however, the incidence of death without progression was significantly increased for older HL patients (22% vs. 9%, respectively, P < 0·0001). Altogether, the marked HL age-dependent survival differences appeared attributable primarily to non-HL events.

Concepts: Chemotherapy, Hodgkin's lymphoma, Chemotherapy regimens, Vincristine, Doxorubicin, ABVD, Antineoplastic drugs, Stanford V