A multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma.

BACKGROUND: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear. METHODS: We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP 'group 1'; R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX 'group 2'; dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX 'group 3'. RESULTS: Overall, 217 patients were identified (49, 125 and 43 in groups 1-3, respectively). With median follow-up of 3.4 (range 0.2-18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1-3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5-33.1%), 6.9% (3.5-13.4%) and 2.3% (0.4-15.4%) in groups 1-3, respectively (P=0.009). CONCLUSIONS: The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.

Limited role for surveillance PET-CT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy.

BACKGROUND: The usefulness of positron emission tomography with computed tomography (PET-CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied. METHODS: We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET-CT after achieving complete metabolic response (CMR) following primary therapy. RESULTS: Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8-133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI) <3 was 56% compared with 80% in patients with IPI ≥3. Including indeterminate scans, PET-CT retained high sensitivity 95% and specificity 97% for relapse. CONCLUSION: Positron emission tomography with computed tomography is not useful in patients for the majority of patients with diffuse large B-cell lymphoma in CMR after primary therapy, with the possible exception of patients with baseline IPI ≥3 in the 18 months following completion of primary therapy. This issue could be addressed by a prospective clinical trial.

The frequency, manifestations, and duration of prolonged cytopenias after first-line fludarabine combination chemotherapy.

BACKGROUND: Fludarabine-based chemoimmunotherapy has well-recognised efficacy and short-term toxicity in the treatment of lymphoid malignancies. However, the presence and significance of prolonged cytopenias after completion of treatment have not been thoroughly quantified. METHODS: Sixty-one patients receiving initial therapy with fludarabine-based regimens were categorised according to the presence of post-treatment cytopenias (haemoglobin <110-130 g/l depending on sex and age, neutrophils <2.0 x 10(9)/l, or platelets <140 x 10(9)/l) lasting >3 months. RESULTS: Persistent cytopenias unrelated to persistent disease were found in 43% of patients. Cytopenias were associated with clinically important rates of infection and transfusion requirement (P = 0.03) and predicted for worse overall survival (61% versus 96% at 60 months, P = 0.05). Increasing age predicted for persistent cytopenias (P = 0.02), but the presence of pretreatment cytopenias and delivered dose intensity were not predictive. The median times to resolution of anaemia, neutropenia, and thrombocytopenia were 7, 9, and 10 months, respectively. CONCLUSIONS: Cytopenias often persist >3 months after first-line fludarabine combination therapy and can lead to important clinical sequelae. Although cytopenias generally resolve over time, treating physicians should be aware of these factors when considering fludarabine combination chemotherapy and when documenting treatment response status in chronic lymphocytic leukaemia.

"Reversible" myelodysplastic syndrome or ineffectual clonal haematopoiesis? - add(6p) myeloid neoplasm with a spontaneous cytogenetic remission.

Cytotoxic chemotherapy has inherent mutagenic potential and alters the bone marrow microenvironment after therapy. In some cases, this potentiates expansion of an aberrant clone and may lead to a therapy-related myeloid neoplasm if the clone overcomes selective pressure. We present the case of a 43-year-old woman diagnosed with an indolent, therapy-related myeloid neoplasm with an isolated chromosome 6p abnormality following treatment for de novo Acute Myeloid Leukaemia (AML), who manifest a sustained spontaneous cytogenetic remission two years later, possibly due to an ineffectual or non-dominant founding clone. This case reminds us to be mindful of the possibility that clonal haematopoiesis may not always equate to clinically relevant disease, even in the setting of an abnormal clonal karyotype.

The effects of high shear blending on alpha-lactose monohydrate.

alpha-Lactose monohydrate is an important pharmaceutical excipient used extensively in dry powder inhaler (DPI) formulations. The ways in which a high shear blending process affect this material have been investigated and important process parameters have been identified. Total energy input (kJ/kg), blade design and the conditions in which lactose was stored prior to blending were found to have the most significant effect on the apparent particle size distribution of the processed material, which may subsequently affect the performance of DPI formulations. The power conditions used during blending, equipment temperature and humidity of the headspace above the powder were found to be less important in this respect. Additionally, it was found that high energy blending could induce changes in the water sorption characteristics of the material, although the formation of amorphous material could not be confirmed.

OC-05 - D-Dimer, fibrinogen and TEG-MA predict thromboembolism in non-small cell lung cancer - interim results from a prospective cohort study.

INTRODUCTION: Cancer associated thromboembolism (TE) is common however the risk is heterogeneous and dynamic. AIM: To assess the TE risk profile of patients with Non-Small Cell Lung Cancer (NSCLC), though treatment phases, and generate a risk-stratified decision algorithm for appropriate thromboprophylaxis. MATERIALS AND METHODS: Single centre, prospective observational study, profiling NSCLC patients using clinical-, tumour- and treatment-related risk factors, in conjunction with an extensive thrombogenic biomarker panel, during treatment (surgery, chemotherapy, targeted therapy and/ or radiotherapy) and disease phases. Biomarkers include: FBC, APTT, PT, D-dimer, fibrinogen, FVIIIc, TM, TAT, vWF, prothrombin fragments 1+ 2, fibrin monomers, TEG, microparticles, OHP. Cancer management is per clinician discretion and/or concurrent interventional study protocol. Biomarkers are assessed at baseline; weeks 1, 4 and 12 after commencing cancer treatment; 3 monthly until 12 months. RESULTS: The interim cohort for analysis included 68 patients, 43 (63%) males, median age 67 years (range 43-67) and with median follow-up 5 months (range 0.2-11). Importantly, 21 patients (15% of patients screened) were ineligible for this study, having presented with TE at diagnosis of NSCLC, while a further 15 patients (15% of study cohort) developed TE while on study. Median time to TE on study was 2.4 months (range 0.1-7). Patients who developed TE demonstrated a biomarker profile indicative of a hypercoagulable state. Khorana score did not adequately stratify or predict TE in this cohort (PPV 20%, NPV 80%), with more than half of patients classified as low or intermediate risk (score 1 (44%), 2 (29%). However, D-dimer ≥1.44mg/L+Fibrinogen ≥4g/L+TEG-MA ≥69mm, as a single measurement at baseline, predicted TE (OR 4.2, p=0.005) and at 4-weeks after commencing cancer treatment (OR 6.7, p=0.005). Predictive power increased further, when considering longitudinal measurements from baseline to 12-weeks after commencing cancer treatment, with OR 14.0 (p<0.001) and PPV 40%, NPV 95%. Inclusion of other Khorana parameters in this model, did not improve predictive performance. CONCLUSIONS: Interim study results reveal a high TE risk among patients with NSCLC. Simple, routine, algorithmic thrombogenic biomarkers demonstrate the capacity to stratify risk and predict TE. Ongoing analyses with the planned larger cohort, expanded biomarker panel and longer follow-up, with longitudinal assessments, are likely to provide greater insight and enhance predicative power. The results will contribute to the development of a simple clinical and biomarker risk stratification tool, to facilitate real-time and dynamic decision-making for appropriate thromboprophylaxis strategies.

A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study.

In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow-cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10(-5)). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high-throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10(-4)) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10(-6)). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL.

The effect of the amount of binder liquid on the granulation mechanisms and structure of microcrystalline cellulose granules prepared by high shear granulation.

The structure of granules changes during the high shear granulation process. The purpose of this research was to investigate the effect of the amount of binder liquid on the structure of the granules and the structural changes which occur during the granulation process, using microcrystalline cellulose (MCC) and water as the model system. The structure is the result of the granulation mechanism; therefore, conclusions can be drawn about the latter by studying the former. X-ray microtomography and scanning electron microscopy (SEM) were applied in order to visualise the densification process of granules, which were first freeze dried in order to preserve their structure. Variations in their porosity were quantified by applying image analysis to the tomography results. In order to link the granule mechanical properties to their structural differences, a micromanipulation technique was used to measure granule resistance to deformation. MCC granules granulated with 100% (w/w) water showed increased densification with time, as expected; detailed examination showed that densification is more pronounced in the core of the granule; whereas the outer part remained more porous. Increased densification reduces deformability, so that granules become more resistant to breakage. The lower deformability of the densified granules in the final stages of granulation might result in establishment of equilibrium between attrition and growth, without substantial gross breakage. On the other hand, when more water was used (125%, w/w), densification was hardly observed; the porosity of the granule core was still high even after prolonged granulation times. This may be explained by the fact that higher water content increases the ease of deformation of granules. This increased deformability led to significant granule breakage even during the final phases of the granulation process. Therefore, for these granules a final equilibrium between breakage and coalescence might be established. This also explains why more granules produced with 125% granulation liquid were composed of fragments of irregular shape. Our results establish the link between the granulation behaviour of MCC in the latter stages and the material structure of these granules, which is determined by their liquid content. The process conditions (amount of liquid) to be chosen depend largely on the final purpose for which the granular material is produced.

Fast-track rapid warfarin reversal for elective surgery: extending the efficacy profile to high-risk patients with cancer.

Periprocedural management of patients on long-term warfarin therapy remains a common and important clinical issue, with little high-quality data to guide this complex process. The current accepted practice is cessation of warfarin five days preoperatively, but this is not without risk and can be complicated, particularly if bridging is required. An alternative method utilising low-dose intravenous vitamin K the day before surgery has been shown previously to be efficacious, safe and convenient in an elective surgical population receiving chronic warfarin therapy. The efficacy and utility of this 'fast-track' warfarin reversal protocol in surgical patients with cancer, who were at high risk of both thromboembolism and bleeding was investigated in a prospective, single-arm study at a dedicated cancer centre. Seventy-one patients underwent 82 episodes of fast-track warfarin reversal (3 mg intravenous vitamin K 18 to 24 hours before surgery). No patient suffered an adverse reaction to intravenous vitamin K, all but one achieved an International Normalized Ratio =1.5 on the day of surgery, and no surgery was deferred. Assays of vitamin K-dependent factor levels pre- and post-vitamin K demonstrated restoration of functional activity to within an acceptable range for surgical haemostasis. While this alternative method requires further validation in a larger prospective randomised study, we have now extended our use of fast-track warfarin reversal using vitamin K to patients with cancer, on the basis of our experience of its safety, convenience, reliability and efficacy.

Identification of the high-risk asthmatic patient. Experience with 39 patients undergoing ventilation for status asthmaticus.

Thirty-nine asthmatic patients required mechanical ventilation (IPPV) for status asthamticus over a seven and a half year period. We reviewed their clinical records with particular emphasis on the events leading to intermittent positive pressure ventilation (IPPV) and the long-term courses of those patients who survived IPPV. Long delays by patients before seeking medical attention, incomplete assessment of acute attacks, underuse of corticosteroids prior to admission and overuse of sedation were important factors often influencing the necessity for IPPV. Four patients died during IPPV. Of the 35 who survived, 32 were regularly followed in our Respiratory Clinic. Nine patients subsequently died, eight undoubtedly from asthma. Serial measurements of forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were retrospectively analyzed to determine patterns of asthma. Of the 23 patients still alive, 14 have well controlled asthma, five have a pattern of persistent airflow obstruction, two have markedly labile asthma, and two have gradually deteriorating airflow obstruction. By contrast, seven patients who died sufficiently long after IPPV to enable categorization of their patterns showed either markedly labile asthma or gradually deteriorating airflow obstruction. None had relatively constant ventilatory function at either normal or suboptimal levels. We suggest that patterns of asthma are useful guides in detecting patients at high-risk. Patterns characterized by markedly labile asthma or gradually deteriorating airflow obstruction appear to be associated with an increased risk of sudden death from asthma.

Metastatic endotracheal tumor from ovarian carcinoma.

This report describes a patient with acute airways obstruction and respiratory failure secondary to a large endotracheal metastasis from a primary ovarian carcinoma first detected seven years previously. Associated airflow obstruction due to mucus impaction contributed significantly to the development of respiratory failure. The tumor responded to radiotherapy, and radiologic evidence for tracheal obstruction was no longer present five months after irradiation.

Efficacy of thalidomide therapy for extramedullary relapse of myeloma following allogeneic transplantation.

Treatment options for patients with myeloma who relapse after allogeneic stem cell transplantation are limited. Thalidomide, an antineoplastic agent, has been shown to be effective in multiple myeloma through proposed mechanisms that may include angiogenesis inhibition. Herein we report successful thalidomide treatment of four patients who relapsed following allogeneic transplantation, three of whom had predominantly extramedullary relapse. Thalidomide was well tolerated in all patients; in two patients interferon-alpha was subsequently added to thalidomide as maintenance therapy without worsening graft-versus-host disease. We suggest that extramedullary myeloma is particularly sensitive to thalidomide, speculating that growth biology may in part be dependent on angiogenesis.

A case of clinical indolent natural killer cell lineage large granular lymphocytic leukemia in a patient with rheumatoid arthritis.

We report a case of natural killer (NK) cell leukemia with unusual biological features in a 65-year-old woman with a 20-year history of rheumatoid arthritis. She presented with neutropenia, thrombocytopenia, splenomegaly and bone marrow infiltration. Immunophenotyping (CD2+ CD3- CD4- CD5- CD8- CD16+ CD56-) confirmed NK cell leukemia. Her neutropenia and thrombocytopenia resolved following splenectomy and she has remained well with stable disease for 12 months on oral low-dose methotrexate. In contrast to all previous reports, in this instance the phenotype of large granular lymphocytic (LGL) leukemia occurring in the context of rheumatoid arthritis was NK-cell rather than T-cell. Furthermore, the clinical course was indolent, whereas, all prior literature reports have described a very aggressive clinical course for this disorder with a median survival of just 3.5 months. This case illustrates previously unrecognized heterogeneity in the natural history of this disorder.

Fatal disseminated infection by Scedosporium prolificans during induction therapy for acute leukemia: a case report and literature review.

We report a case of fatal disseminated fungal infection by Scedosporium prolificans which occurred in a patient with acute leukemia during induction chemotherapy. Rapid clinical deterioration despite high-dose empirical amphotericin B highlights both the pathogenicity of this fungus in immunocompromised hosts and its resistance to standard antifungal therapy.

The role of familiarity in item recognition, associative recognition, and plurality recognition on self-paced and speeded tests.

Four experiments compare the effect of familiarity on item, associative, and plurality recognition on self-paced and speeded tests. The familiarity of test items was enhanced by presenting a prime that matched the subsequent test item. On item and plurality recognition tests, participants were more likely to respond "old" to primed than to unprimed test items. In associative recognition, priming increased the proportion of old responses on a speeded test, but not on a self-paced test. This suggests that familiarity plays a larger role in item and plurality recognition than in associative recognition on self-paced tests. On speeded tests, priming has a similar effect on item, associative, and plurality recognition. Results suggest that item and associative recognition rely differentially on familiarity and recollection. They are also consistent with recent evidence suggesting that different processes underlie plurality and associative recognition.

On the generality of the revelation effect.

Seven experiments demonstrate the robustness of the revelation effect, which is the tendency to call recognition test items old if they are distorted when they initially appear and if they are revealed before the recognition judgment. With anagrams as the distortion, a revelation effect was found in within- and between-subjects designs, in a frequency-judgment task, in a list-discrimination task, when new items were used as targets, when the study list and the test were presented in different modalities, and when the word that was revealed did not match the word that was recognized. These results challenge accounts that attribute the revelation effect either to an increase in the familiarity of the revealed test word or to a positive response bias.

The revelation that the revelation effect is not due to revelation.

The revelation effect is the tendency to call an item on a recognition test "old" if it is preceded by a different task interpolated between study and test. Seven experiments explored the generality of the revelation effect across a number of interpolated tasks. A revelation effect emerged when a variety of tasks preceded recognition test items; the effect was found for test items that followed a memory-span task, a synonym-generation task, and a letter-counting task. The compatibility between the test stimuli and the stimuli that composed the interpolated task was found to be a critical factor. With words as stimuli on a recognition test, a revelation effect was found when the stimuli in the interpolated task were words and letters. However, when numbers were the stimuli in the interpolated task, no revelation effect was found.

Verbal-overshadowing effect: evidence for a general shift in processing.

Two experiments investigate the nature of the verbal-overshadowing effect-the finding that recognition performance for certain stimuli is impaired if it is described verbally (Schooler & Engstler-Schooler, 1990). Impairment on a face-recognition task was found, although participants produced not a verbal description of the target but, instead, a description of another object (a car) presented in the study phase. These results support the idea that the verbal-overshadowing effect reflects a general shift in the processes involved in face recognition rather than a specific impairment for the described stimulus. Results also support the notion that the impairing effect of verbalization is unique to certain types of stimuli; verbalization impaired recognition of a face but not of a car.

Plerixafor plus pegfilgrastim is a safe, effective mobilization regimen for poor or adequate mobilizers of hematopoietic stem and progenitor cells: a phase I clinical trial.

The safety, kinetics and efficacy of plerixafor+pegfilgrastim for hematopoietic stem and progenitor cell (HSPC) mobilization are poorly understood. We treated 12 study patients (SP; lymphoma n=10 or myeloma n=2) with pegfilgrastim (6 mg SC stat D1) and plerixafor (0.24 mg/kg SC nocte from D3). Six SP were 'predicted poor-mobilizers' and six were 'predicted adequate-mobilizers'. Peripheral blood (PB) CD34(+) monitoring commenced on D3. Apheresis commenced on D4. Comparison was with 22 historical controls (HC; lymphoma n=18, myeloma n=4; poor mobilizers n=4), mobilized with pegfilgrastim alone. Eight (67%) SP had PB CD34(+) count ⩽5 × 10(6)/L D3 post pegfilgrastim; all SP surpassed this threshold the morning after plerixafor. In SP, PBCD34(+) counts peaked D4 6/12 (50%), remaining ⩾5 × 10(6)/L for 4 days in 8/12 (67%). All SP successfully yielded target cell numbers (⩾2 × 10(6)/kg) within four aphereses. After maximum four aphereses, median total CD34+ yield was higher in SP than HC; 8.0 (range 2.4-12.9) vs 4.8 (0.4-14.0) × 10(6)/kg (P=0.04). Seven of twelve (58%) SP achieved target yield after one apheresis. Flow cytometry revealed no tumor cells in PB or apheresis product of SP. Plerixafor+pegfilgrastim was well tolerated with bone pain (n=2), diarrhoea (n=2) and facial paraesthesiae (n=3). Plerixafor+pegfilgrastim is a simple, safe and effective HSPC mobilization regimen in myeloma and lymphoma, in both poor and good mobilizers, and is superior to pegfilgrastim alone.

Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy.

Fludarabine combination chemotherapy achieves high response rates in chronic lymphocytic leukemia (CLL) and indolent lymphoma. The aim of this study was to investigate the incidence and characteristics of treatment-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) after treatment with fludarabine in combination for lymphoproliferative disorders and identify risk factors for its development. In all, 176 patients treated with fludarabine combination were followed for a median of 41 months (range 6-125 months). In all, 19 cases of t-MDS/AML have been identified for an overall rate of 10.8%. Median overall survival post-t-MDS/AML diagnosis was 11 months. Patients developing t-MDS/AML included 11/54 with follicular lymphoma (FL) (crude rate 20.4%), 5/82 with CLL (6.1%) and 3/24 with Waldenstrom macroglobulinemia or marginal zone lymphoma (12.5%). Most patients had other cytotoxic treatments (median 4, range 0-7) but three with FL had fludarabine combination as their only line of treatment. Of the eleven patients (6.3%) who received mitoxantrone with their first fludarabine combination, four (36.4%) developed t-MDS/AML (P=0.007). There was a trend toward prior cytotoxic therapy increasing the risk for t-MDS/AML (P=0.067). Fludarabine combination chemotherapy is associated with a moderate risk of t-MDS/AML particularly when combined with mitoxantrone. This complication should be considered when evaluating the potential benefit of this treatment in lymphoproliferative disorders.