M. Mansour Ceesay

A comprehensive diagnostic approach using galactomannan, targeted β-d-glucan, baseline computerized tomography and biopsy yields a significant burden of invasive fungal disease in at risk haematology patients

Invasive fungal disease (IFD) is difficult to diagnose. We investigated the incidence of IFD and risk factors using the revised European Organization for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG) definitions. Patients (N = 203) undergoing intensive therapy with expected neutropenia ≥10 d were recruited prospectively and followed for a median (range) of 556 (12–730) d. Baseline chest computerized tomography (CT) was performed pre‐therapy. Twice‐weekly surveillance with galactomannan (GM) was combined with targeted β‐d‐glucan (BDG) testing on patients with possible IFD or who were GM‐positive. Tissue diagnosis was obtained whenever possible. The cumulative incidence of proven/probable IFD among the 202 evaluable cases after 2 years follow‐up was 21%, including 14 proven and 30 probable IFDs. Using either GM or BDG as the sole biomarker (plus host and clinical evidence) the apparent overall incidence of proven/probable IFD was 11% and 16%, respectively. Combined GM/BDG detected all biopsy‐proven mould IFD. Baseline CT abnormalities were found in 76/202 (38%) patients. Baseline CT abnormalities and Karnofsky score <90, monocytopenia >10 d and bacteraemia were independent risk factors associated with greater than twofold increased IFD risk. This combined diagnostic approach identified a high incidence of IFD and important risk factors in this cohort.

Phase II study on combination therapy with CHOP-Zenapax for HTLV-I associated adult T-cell leukaemia/lymphoma (ATLL)

Adult T-cell leukaemia lymphoma (ATLL) is an aggressive T-cell malignancy caused by the human T-lymphotropic virus type-1 (HTLV-1) and is associated with a very poor prognosis. Combination chemotherapy has had little impact on the long term survival of these patients. ATLL cells are characterised by the expression of CD25 (IL-2Rα), which is not expressed in normal resting T-cells. Daclizumab (Zenapax(®)) is a humanised murine anti-CD25 monoclonal antibody, which contains 10% murine CDR sequences. In this prospective trial 15 patients with aggressive ATLL were treated with CHOP-Zenapax (CHOP-Z) to determine the tolerability and feasibility of this novel regimen as well as evaluate its efficacy. Eleven patients had acute ATLL and four had the lymphoma subtype. The main presenting features were elevated LDH (100%), lymphocytosis (73%), lymphadenopathy (67%), skin lesions (40%), hypercalcaemia (53%), and hepato-splenomegaly (27%). Ten (67%) patients received the six scheduled cycles. Complete response (CR) lasting for two months or more was seen in 5 (33%), partial response in 3 (20%), minor response in 1 (7%), and no response in 6 (40%) patients. The median overall survival was 10 months (95% CI: 0.05-20.88) but this was significantly longer among responders (18 months) compared to non responders (3 months) (P = 0.019). For patients who achieved CR the disease free survival (DFS) was 15 months while the event-free survival (EFS) was 5 months. In conclusion CHOP-Z is safe and in those who achieve a complete response it was associated with prolonged overall survival.

Rituximab and thalidomide combination therapy for Castleman disease

Arachchillage, DRJ, Dalley, CD, Reilly, JT, Wilson, G, Collins, N & Snowden, JA (2010) Long-term dual donor derived haematopoietic reconstitution following double unrelated cord blood transplantation – single unit dominance is not always the case. British Journal of Haematology, 149, 298–299. Ballen, KK, Spitzer, TR, Yeap, BY, McAfee, S, Dey, BR, Attar, E, Haspel, R, Kao, G, Liney, D, Alyea, E, Lee, S, Cutler, C, Ho, V, Soiffer, R & Antin, JH (2007) Double unrelated reduced-intensity umbilical cord blood transplantation in adults. Biology of Blood and Marrow Transplanatation, 13, 82–89. Chan, KW, Grimley, MS, Taylor, C & Wall, DA (2008) Early identification and management of graft failure after unrelated cord blood transplantation. Bone Marrow Transplantation, 42, 35 –41. Dvorak, CC, Gilman, AL, Horn, B & Cowan, MJ (2009) Primary graft failure after umbilical cord blood transplant rescued by parental haplocompatible stem cell transplantation. Journal of Pediatric Hematology/Oncology, 31, 300–303. Ferrara, JL (1993) Cytokine dysregulation as a mechanism of graft versus host disease. Current Opinion in Immunology, 5, 794–799. Lauglin, MJ, Barker, J, Bambach, B, Koc, ON, Rizzieri, DA, Wagner, JE, Gerson, SL, Lazarus, HM, Cairo, M, Stevens, CE, Rubinstein, P & Kurtzberg, J (2001) Haematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. New England Journal of Medicine, 344, 1815–1822. Narimatsu, H, Kami, M, Miyakoshi, S, Murashige, N, Yuji, K, Hamaki, T, Masuoka, K, Kusumi, E, Kishi, Y, Matsumura, T, Wake, A, Morinaga, S, Kanda, Y & Taniquchi, S (2006) Graft failure following reduced-intensity cord blood transplantation for adult patients. British Journal of Haematology, 132, 36–41. Rodrigues, CA, Sanz, G, Brunstein, CG, Sanz, J, Wagner, JE, Renaud, M, de Lima, M, Cairo, MS, Furst, S, Rio, B, Dalley, C, Carreras, E, Harousseau, JL, Mohty, M, Taveira, D, Dreger, P, Sureda, A, Gluckman, E & Rocha, V (2009) Analysis of risk factors for outcomes after unrelated cord blood transplantation in adults with lymphoid malignancies: a study by the Eurocord-Netcord and lymphoma working party of the European group for blood and marrow transplantation. Journal of Clinical Oncology, 27, 256–263. Erratum in: Journal of Clinical Oncology, 27, 1923. Weiss, L & Slavin, S (1999) Prevention and treatment of graft-verus-host disease by down–regulation of anti-host reactivity with veto cells of host origin. Bone Marrow Transplantation, 23, 1139–1143.

Measurement of posaconazole, itraconazole, and hydroxyitraconazole in plasma/serum by high-performance liquid chromatography with fluorescence detection.

Background: Itraconazole and posaconazole are used in the prevention and treatment of invasive fungal infections. However, the oral bioavailability of both compounds varies widely, and dose–serum concentration relationships are poorly defined for these analytes. The aim of this work was to develop and validate a simple assay that could be implemented in most laboratories for the purpose of therapeutic drug monitoring. Methods: Calibrators (n = 7) and internal quality control solutions (n = 3) were prepared in pooled human serum. Sample (100 μL), internal standard solution (25 μL), Tris solution (2 mol/L; pH 10.6), and extraction solvent (methyl tert-butyl ether, 600 μL) were vortex mixed and centrifuged. The solvent layer was removed and evaporated to dryness and the residue reconstituted in water:methanol (1 + 3, 50 μL). A portion (5 μL) of the reconstituted extract was analyzed using a 3-μm Gemini C6 phenyl column with fluorescence detection (excitation 260 nm, emission 350 nm). The method was used to measure itraconazole and hydroxyitraconazole, or posaconazole, in serum samples taken 1–2 hours before the next dose, from patients forming part of a study into management and diagnostic strategies for invasive aspergillosis. Results: Response was linear over the calibration ranges. Accuracy and imprecision were 92–111.4% and 3.2–13.4% (relative standard deviation), respectively. No interferences were noted. There was a good agreement with nominal values of each analyte in an external quality assessment scheme. In patients prescribed either 400 mg/d of itraconazole (n = 46) or 600–800 mg/d of posaconazole (n = 28) only 24% and 7% of samples, respectively, had serum itraconazole or posaconazole concentrations above the target threshold suggested in published guidelines. Conclusions: A simple, sensitive high-performance liquid chromatographic method has been developed for the analysis of itraconazole, hydroxyitraconazole, and posaconazole in serum/plasma. Few of the samples measured from patients participating in the clinical study attained concentrations of the drug/metabolite in serum that have been recommended for effective antifungal therapy.

Composite biomarker panel for prediction of severity and diagnosis of acute GVHD with T-cell-depleted allogeneic stem cell transplants—single centre pilot study

Aims Acute graft-versus-host disease (aGVHD) is a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the clinical utility of a composite biomarker panel to help identify individuals at risk of developing aGVHD, and to help predict and differentiate between severity of aGVHD following T-cell-depleted allogeneic HSCT. Methods We retrospectively analysed our cohort of biopsy confirmed patients with aGVHD, who underwent T-cell-depleted HSCT and matched them with negative controls without any evidence of aGVHD. Post-transplant serum samples on days 0 and 7 and at onset of aGVHD were analysed for elafin, regenerating islet-derived 3-α, soluble tumour necrosis factor receptor-1, soluble interleukin-2 receptor-α and hepatocyte growth factor. Biomarker data were combined as composite panels A–F (table 2) using logistic regression analysis. Receiver operating characteristic analysis was performed to study sensitivity and specificity of the composite panels. Results Our composite biomarker panels significantly differentiated between aGVHD and no GVHD patients at time of onset (panel E) and reliably predicted severity of GVHD grades at days 0 and 7 post-transplant (panels B and D). The area under the curve for the composite panel at time of onset was 0.65 with specificity, sensitivity, positive and negative predictive values of 100%, 55.6%, 100% and 78.9%, respectively (p=0.03). Conclusions This pilot data support the usefulness of these composite biomarker panels in the prediction of severity and diagnosis of aGVHD in patients undergoing T-cell-depleted reduced intensity allogeneic HSCT.

Pre‐symptomatic (Baseline) computed tomography predicts invasive pulmonary aspergillosis in high‐risk adult haemato‐oncology patients

Additional Supporting Information may be found in the online version of this article: Table SI. Whole exome sequencing results on 3 follicular lymphoma patients (FL01, FL02 and FL03) with available paired samples (pre and post ibrutinib); only COSMIC mutations are reported to improve mutation calling specificity in the unpaired-normal setting. Table SII. Summary of the number of mutations annotated in COSMIC in patients sequenced by whole exome sequencing. Table SIII. Sequencing results using targeted next-generation sequencing in 2 patients (FL04, FL05: paired samples, pre and post ibrutinib available for FL04; 1 post ibrutinib sample FL05). Data S1. Mutation sequencing methodology.

Erdheim-Chester disease presenting as bradycardia in an elderly man

![Figure][1] An 80-year-old man was noted to be bradycardic while being transferred to the United Kingdom following neck of femur fracture abroad. He had a 3-month history of weight loss, pruritus, and bone pain. Echocardiogram and cardiac magnetic resonance imaging showed a concentric right