Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial.

BACKGROUND: Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia. METHODS: This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m2 on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617. FINDINGS: Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n=294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n=4, standard of care plus rituximab n=5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (<1%) was intersex, and 143 (59%) of 244 participants had high-risk cytogenetics. In the standard-of-care plus rituximab group, median age was 46 years (IQR 23-65), 159 (55%) of 294 participants were male, 130 (45%) were female, and 140 (60%) of 235 participants had high-risk cytogenetics. After a median follow-up of 53·7 months (IQR 40·3-70·4), 3-year event-free survival was 43·7% (95% CI 37·8-49·5) for standard of care versus 51·4% (45·4-57·1) for standard of care plus rituximab (hazard ratio [HR] 0·85 [95% CI 0·69-1·06]; p=0·14). The most common adverse events were infections and cytopenias, with no difference between the groups in the rates of adverse events. There were 11 (4%) fatal (grade 5) events in induction phases 1 and 2 in the standard-of-care group and 13 (5%) events in the standard-of-care plus rituximab group). 3-year non-relapse mortality was 23·7% (95% CI 19·0-29·4) in the standard-of-care group versus 20·6% (16·2-25·9) in the standard-of-care plus rituximab group (HR 0·88 [95% CI 0·62-1·26]; p=0·49). INTERPRETATION: Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient. FUNDING: Cancer Research UK and Blood Cancer UK.

Risk management in dialectical behavior therapy: Treating life-threatening behaviors as problems to be solved.

Dialectical behavior therapy (DBT) is an empirically supported behavioral treatment for individuals with borderline personality disorder who frequently exhibit life-threatening behavior, such as suicide attempts, nonsuicidal self-injury urges and actions, and suicidal ideation. We provide an overview of the theoretical framework by which DBT conceptualizes these life-threatening behaviors and the principles by which safety planning measures are implemented and maintained throughout treatment. The importance of orienting clients to treatment and obtaining their commitment to decrease life-threatening behavior is reviewed. Relevant strategies associated with risk management and assessment, such as the diary card, chain analysis, solution analysis, phone coaching, and consultation team, are described. The overview concludes with a case example to illustrate the application of these techniques with a DBT client with a long-standing history of engaging in life-threatening behaviors. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

How Will You Feel on Valentine's Day? Affective Forecasting and Recall Biases as a Function of Anxiety, Depression, and Borderline Personality Disorder Features.

Introduction: The prediction of affective experiences, also known as affective forecasting, is an integral component of individuals' decision-making processes. Yet, research consistently demonstrates that affective forecasts (AF) and recollections (AR) are generally inaccurate. Recent research has demonstrated distinct patterns of AF/R bias related to psychopathology. The present study examined the relationship between AF/R and features of Borderline Personality Disorder (BPD), anxiety, and depression using Valentine's Day as the target event. Methods: Undergraduate students (N=263; 33% white; 63% female; Mage=19.08) predicted their affective states a week before, and then reported their actual affective states on Valentine's Day and the two days after, and recalled Valentine's Day affect two days later. Results: Results indicate that higher BPD symptomatology predicted a significant overestimation of negative affect (B=.17, p=.02), even after controlling for anxiety and depression. Additionally, individuals' levels of depressive, anxious, and BPD symptomatology were significant predictors of AF of positive affect when entered into regression analyses separately, however when entered together, only depressive symptoms remained significant. Specifically, higher depressive symptoms predicted a significant underestimation of positive affect (B=-.21, p=.01). Discussion: Results were in line with prior research indicating that unique patterns of AF biases are associated with symptoms of psychopathology. However, results failed to support prior research linking AR biases to symptoms of psychopathology. Implications for future studies of affective biases and psychopathology more generally are discussed.

Language measurement in childhood epilepsy: A review.

The psychosocial well-being of children and adolescents with epilepsy is affected by comorbid language deficits. Little is known about the focus of current research in language and epilepsy. A systematic review of research was conducted to identify gaps in knowledge regarding language and epilepsy. In total, 83 published articles were eligible for inclusion. More studies included samples presenting with focal seizures (k = 39) compared to generalized seizures (k = 10), few included measures of morphology (k = 4). Most studies (k = 66) included samples of participants across a wide age range. Our review indicated t-hat future research should include a greater focus on participants with more diversity in epilepsy etiology (e.g., symptomatic epilepsy), and seizure type (e.g., generalized seizures), assessment of additional areas of language (e.g., morphology), increased focus on early childhood, focused examination of specific developmental stages, and greater use of comparison groups with an alternate epilepsy diagnosis.

Acute Immune Signatures and Their Legacies in Severe Acute Respiratory Syndrome Coronavirus-2 Infected Cancer Patients.

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19+ non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care.

Language in childhood epilepsy: A systematic review and meta-analysis.

The abnormal brain activity associated with childhood epilepsy can have an impact on the developmental trajectory of cognitive processes, like language, in this population. However, there is variation in how researchers study language ability in children with epilepsy and the findings that are reported (no differences vs. a significant difference). The current systematic review and meta-analysis uses data from 13 available studies to consider the magnitude of language differences in children with epilepsy compared to their typically developing peers. Seizure classification, age of onset, component of language measured, and instrument used to measure language were all considered as potential moderators of differences in language skill. The results indicate a significant large effect size for language deficits in children with epilepsy compared to their peers. Seizure classification partially, but not fully, accounts for the variability in effect size. In addition, effect sizes differ relative to component of language measured; effect sizes were greatest in magnitude for semantic language and verbal fluency, and minimal for syntax, but only when including all studies of children with epilepsy, regardless of seizure classification. These findings differ when considering language component in children with generalized or focal seizures only. The data reported here also indicate distinct differences in effect size depending on type of instrument used to measure one aspect of language, verbal fluency.

Changes in Emotions Over the Course of Dialectical Behavior Therapy and the Moderating Role of Depression, Anxiety, and Posttraumatic Stress Disorder.

Evidence-based borderline personality disorder (BPD) treatments such as dialectical behavior therapy (DBT) emphasize the acquisition and use of strategies to down regulate negative emotion. However, little research examines whether specific emotions change during DBT. Further, it is unclear if BPD-relevant comorbidities that involve heightened emotion-namely, depression, anxiety disorders, and posttraumatic stress disorder (PTSD)-moderate these outcomes. This study investigated which specific emotions (hostility/anger, fear, shame/guilt, and sadness) decrease during DBT, and whether comorbid depression, anxiety disorders, and PTSD moderate these outcomes. Individuals with BPD (N = 101) completed 6 months of standard DBT and provided measurements of specific emotions at every session and at pre-, mid-, and posttreatment. Generalized estimating equations revealed moderate effect-sized reductions in anger at major assessment time points. Anxiety disorders and PTSD moderated the effect of time on fear, shame, and guilt. PTSD also moderated the effect of time on sadness. For all moderating effects, individuals with the comorbidity exhibited greater reductions than those without. These findings corroborate that DBT reduces several specific emotions, and comorbid PTSD and anxiety disorders may facilitate this effect for fear, shame/guilt, and sadness (clinical trial registration number = NCT03123198).

Type 1 Interferon Responses Underlie Tumor-Selective Replication of Oncolytic Measles Virus.

The mechanism of tumor-selective replication of oncolytic measles virus (MV) is poorly understood. Using a stepwise model of cellular transformation, in which oncogenic hits were additively expressed in human bone marrow-derived mesenchymal stromal cells, we show that MV-induced oncolysis increased progressively with transformation. The type 1 interferon (IFN) response to MV infection was significantly reduced and delayed, in accordance with the level of transformation. Consistently, we observed delayed and reduced signal transducer and activator of transcription (STAT1) phosphorylation in the fully transformed cells. Pre-treatment with IFNß restored resistance to MV-mediated oncolysis. Gene expression profiling to identify the genetic correlates of susceptibility to MV oncolysis revealed a dampened basal level of immune-related genes in the fully transformed cells compared to their normal counterparts. IFN-induced transmembrane protein 1 (IFITM1) was the foremost basally downregulated immune gene. Stable IFITM1 overexpression in MV-susceptible cells resulted in a 50% increase in cell viability and a significant reduction in viral replication at 24 h after MV infection. Overall, our data indicate that the basal reduction in functions of the type 1 IFN pathway is a major contributor to the oncolytic selectivity of MV. In particular, we have identified IFITM1 as a restriction factor for oncolytic MV, acting at early stages of infection.

Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress.

We investigated and modeled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukemia (ALL). We used gene expression profiling, cytokine/chemokine quantification, flow cytometry, and a variety of imaging techniques to show that MSCs, directly isolated from the primary bone marrow specimens of patients with ALL, frequently adopted an activated, cancer-associated fibroblast phenotype. Normal, primary human MSCs and the MSC cell line HS27a both were activated de novo, when exposed to the reactive oxygen species (ROS)-inducing chemotherapy agents cytarabine (AraC) and daunorubicin (DNR), a phenomenon blocked by the antioxidant N-acetyl cysteine. Chemotherapy-activated HS27a cells were functionally evaluated in a coculture model with ALL targets. Activated MSCs prevented therapy-induced apoptosis and death in ALL targets, via mitochondrial transfer through tunneling nanotubes (TNTs). Reduction of mitochondrial transfer by selective mitochondrial depletion or interference with TNT formation by microtubule inhibitors, such as vincristine (VCR), prevented the "rescue" function of activated MSCs. Corticosteroids, also a mainstay of ALL therapy, prevented the activation of MSCs. We also demonstrated that AraC (but not VCR) induced activation of MSCs, mitochondrial transfer, and mitochondrial mass increase in a murine NSG model of disseminated SEM cell-derived ALL, wherein CD19+ cells closely associated with nestin+ MSCs after AraC, but not in the other conditions. Our data propose a readily clinically exploitable mechanism for improving treatment of ALL, in which traditional ROS-inducing chemotherapies are often ineffective at eradicating residual disease, despite efficiently killing the bulk population.

Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia.

CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent in vitro and in vivo activity is induced by NI-1701 to kill cancer cells across a plethora of B-cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the coengagement of CD47/CD19 on B cells inducing potent antibody-dependent cellular phagocytosis of the targeted cells. NI-1701-induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were coadministered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B-cell malignancies refractory/resistant to anti-CD20-targeted therapy. Mol Cancer Ther; 17(8); 1739-51. ©2018 AACR.

Social context as a risk factor for psychopathology in children with epilepsy.

Epilepsy is the number one neurological disorder in children in western society. Childhood epilepsy is highly comorbid with psychopathology. Although neurological and biological factors may partially explain the increased risk of psychopathology in children with epilepsy, social contextual factors are also important to understanding development of psychopathology in children with epilepsy. The current paper examines the development of children with epilepsy utilizing Bronfenbrenner's micro-, meso-, exo-, and macrosystem social contexts. Negative interpersonal interactions within the microsystems and the ripple effect of social context at the other levels may contribute to increased risk for psychopathology.

How does uncertainty shape patient experience in advanced illness? A secondary analysis of qualitative data.

BACKGROUND: Uncertainty is common in advanced illness but is infrequently studied in this context. If poorly addressed, uncertainty can lead to adverse patient outcomes. AIM: We aimed to understand patient experiences of uncertainty in advanced illness and develop a typology of patients' responses and preferences to inform practice. DESIGN: Secondary analysis of qualitative interview transcripts. Studies were assessed for inclusion and interviews were sampled using maximum-variation sampling. Analysis used a thematic approach with 10% of coding cross-checked to enhance reliability. SETTING/PARTICIPANTS: Qualitative interviews from six studies including patients with heart failure, chronic obstructive pulmonary disease, renal disease, cancer and liver failure. RESULTS: A total of 30 transcripts were analysed. Median age was 75 (range, 43-95), 12 patients were women. The impact of uncertainty was frequently discussed: the main related themes were engagement with illness, information needs, patient priorities and the period of time that patients mainly focused their attention on (temporal focus). A typology of patient responses to uncertainty was developed from these themes. CONCLUSION: Uncertainty influences patient experience in advanced illness through affecting patients' information needs, preferences and future priorities for care. Our typology aids understanding of how patients with advanced illness respond to uncertainty. Assessment of these three factors may be a useful starting point to guide clinical assessment and shared decision making.

Measles to the Rescue: A Review of Oncolytic Measles Virus.

Oncolytic virotherapeutic agents are likely to become serious contenders in cancer treatment. The vaccine strain of measles virus is an agent with an impressive range of oncolytic activity in pre-clinical trials with increasing evidence of safety and efficacy in early clinical trials. This paramyxovirus vaccine has a proven safety record and is amenable to careful genetic modification in the laboratory. Overexpression of the measles virus (MV) receptor CD46 in many tumour cells may direct the virus to preferentially enter transformed cells and there is increasing awareness of the importance of nectin-4 and signaling lymphocytic activation molecule (SLAM) in oncolysis. Successful attempts to retarget MV by inserting genes for tumour-specific ligands to antigens such as carcinoembryonic antigen (CEA), CD20, CD38, and by engineering the virus to express synthetic microRNA targeting sequences, and "blinding" the virus to the natural viral receptors are exciting measures to increase viral specificity and enhance the oncolytic effect. Sodium iodine symporter (NIS) can also be expressed by MV, which enables in vivo tracking of MV infection. Radiovirotherapy using MV-NIS, chemo-virotherapy to convert prodrugs to their toxic metabolites, and immune-virotherapy including incorporating antibodies against immune checkpoint inhibitors can also increase the oncolytic potential. Anti-viral host immune responses are a recognized barrier to the success of MV, and approaches such as transporting MV to the tumour sites by carrier cells, are showing promise. MV Clinical trials are producing encouraging preliminary results in ovarian cancer, myeloma and cutaneous non-Hodgkin lymphoma, and the outcome of currently open trials in glioblastoma multiforme, mesothelioma and squamous cell carcinoma are eagerly anticipated.

Discovering the hidden benefits of cognitive interviewing in two languages: The first phase of a validation study of the Integrated Palliative care Outcome Scale.

BACKGROUND: The Integrated Palliative care Outcome Scale is a newly developed advancement of the Palliative care Outcome Scale. It assesses patient-reported symptoms and other concerns. Cognitive interviewing is recommended for questionnaire refinement but not adopted widely in palliative care research. AIM: To explore German- and English-speaking patients' views on the Integrated Palliative care Outcome Scale with a focus on comprehensibility and acceptability, and subsequently refine the questionnaire. METHODS: Bi-national (United Kingdom/Germany) cognitive interview study using 'think aloud' and verbal probing techniques. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis and pre-defined categories. Results from both countries were collated and discussed. The Integrated Palliative care Outcome Scale was then refined by consensus. SETTING/PARTICIPANTS: Purposely sampled patients from four palliative care teams in palliative care units, general hospital wards and in the community. RESULTS: A total of 15 German and 10 UK interviews were conducted. Overall, comprehension and acceptability of the Integrated Palliative care Outcome Scale were good. Identified difficulties comprised the following: (1) comprehension problems with specific terms (e.g. 'mouth problems') and length of answer options; (2) judgement difficulties, for example, due to the 3-day recall for questions; and (3) layout problems. Combining the results from both countries (e.g. regarding 'felt good about yourself') and discussing them from both languages' perspectives resulted in wider consideration of the items' meaning, enabling more detailed refinement. CONCLUSION: Cognitive interviewing proved valuable to increase face and content validity of the questionnaire. The concurrent approach in two languages - to our knowledge the first such approach in palliative care - benefited the refinement. Psychometric validation of the refined Integrated Palliative care Outcome Scale is now underway.

The Role of Neutrophils in Measles Virus-mediated Oncolysis Differs Between B-cell Malignancies and Is Not Always Enhanced by GCSF.

The mechanism by which oncolytic measles virus (MV) kills cancer cells remains obscure. We previously showed that neutrophils are involved in MV-mediated tumor regressions and become activated, upon MV infection. In the present study, we attempted to enhance the neutrophil response toward MV-infected tumor targets by generating an oncolytic MV-expressing human granulocyte colony-stimulating factor (MVhGCSF). Evaluating the effects in two different models of B-cell malignancy, we showed that depletion of neutrophils abrogated the MV therapeutic effect in an in vivo Raji-but not Nalm-6 tumor model. Next, we compared MVhGCSF with the unmodified backbone virus MVNSe. MVhGCSF enhanced the oncolytic capacity of MV in the Raji model in vivo, whereas in the Nalm-6 model, the opposite was unexpectedly the case. This finding was recapitulated by exogenously administered hGCSF. MVhGCSF replicated within an MV-infectable CD46 transgenic mouse model with detectable serum levels of hGCSF but no toxicity. Our data suggest that a "one-size-fits-all" model of immune response to viral oncolysis is not appropriate, and each tumor target will need full characterization for the potential of both direct and indirect, innate immune responses to generate benefit.

Socioeconomic indicators of health inequalities and female mortality: a nested cohort study within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: Evidence is mounting that area-level socioeconomic indicators are important tools for predicting health outcomes. However, few studies have examined these alongside individual-level education. This nested cohort study within the control arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) assesses the association of mutually adjusted individual (education) and area-level (Index of Multiple Deprivation-IMD 2007) socioeconomic status indicators and all-cause female mortality. METHODS: Participants resident in England who had completed both baseline (Wave 1) and follow up (Wave 2) questionnaires were included. Follow-up was through the Health and Social Care Information Centre with deaths censored on 31st December 2012. IMD, education and a range of covariates were explored. Cox regression models adjusted for all covariates were used. Sensitivity analysis using imputation was performed (1) including those with missing data and (2) on the entire cohort who had completed the baseline questionnaire. RESULTS: Of the 54,539 women resident in England who completed both Wave 1 and Wave 2 questionnaires, 4,510 had missing data. The remaining 50,029 women were included in the primary analysis. Area-level IMD was positively associated with all-cause mortality for the most deprived group compared to the least deprived (HR=1.42, CI=1.14-1.78) after adjusting for all potential confounders. Sensitivity analyses showed similar results with stronger associations in the entire cohort (HR=1.90, CI=1.68-2.16). The less educated an individual, the higher the mortality risk (test for trend p=<0.001). However, the crude effect on mortality of having no formal education compared to college/university education disappeared when adjusted for IMD rank (HR=1.08, CI=0.93-1.26). CONCLUSION: Women living in more deprived areas continue to have higher mortality even in this less deprived cohort and after adjustment for a range of potential confounders. TRIAL REGISTRATION: This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978.

HIV status does not impair the outcome of patients diagnosed with diffuse large B-cell lymphoma treated with R-CHOP in the cART era.

OBJECTIVE: To compare the outcome of patients diagnosed with HIV infection and diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP in the cART era with that of a HIV-negative control group. METHODS: From 2003 to 2011, 305 patients (97 HIV-positive) were diagnosed with DLBCL and treated with R-CHOP. Clinical features were compared using chi-square or Fisher's exact test. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed using the Cox regression proportional hazards model. RESULTS: HIV-positive patients had more B symptoms and extranodal sites of disease at diagnosis, but the proportion of patients with high-intermediate/high-risk disease according to the international prognostic index (IPI) was similar between groups. Response rate was 73%, both for patients with and without HIV infection. After a median follow-up of 48 months, 30 patients relapsed after achieving a complete remission, including four HIV-positive patients. Ninety-six patients have died (19 HIV-positive), 73 of them due to DLBCL. Three patients (one HIV-positive) died due to treatment toxicity. Patients with HIV infection had a significantly longer disease-free survival (DFS) (5-year: 94 vs. 77%; P = 0.03) and overall survival (OS) (78 and 64% for HIV-positive and HIV-negative patients, respectively; P = 0.03). These results were confirmed on multivariate analysis when controlled for other potential prognostic confounders. CONCLUSION: HIV-positive patients diagnosed with DLBCL in the cART era have an excellent outcome when treated with standard immunochemotherapy. Therefore, the choice of chemotherapy in patients with lymphoma should not be influenced by HIV status.

Pitfalls in obtaining and interpreting bone marrow aspirates: to err is human.

Pitfalls relating to bone marrow aspirates and their interpretation start even before the aspirate is obtained. There can be failure to perform an aspiration that is clinically indicated or, conversely, an aspiration may be done that is not actually necessary. Once an aspirate is obtained it may be unhelpful because it is a blood tap or very dilute, or because of the sampling error that is intrinsic to the procedure. Even if an adequate aspirate is obtained, it may be misinterpreted. Megaloblastic marrows and children's marrows with increased haematogones or marked reactive changes are particularly prone to misinterpretation. A constant awareness of potential pitfalls and an assessment of the aspirate in the appropriate clinical context will help to reduce errors.