Publications by authors named "Andrew Will"

36 Publications

The Evoked Compound Action Potential as a Predictor for Perception in Chronic Pain Patients: Tools for Automatic Spinal Cord Stimulator Programming and Control.

Front Neurosci 2021 12;15:673998. Epub 2021 Jul 12.

Medtronic PLC, Minneapolis, MN, United States.

Objectives: Spinal cord stimulation (SCS) is a drug free treatment for chronic pain. Recent technological advances have enabled sensing of the evoked compound action potential (ECAP), a biopotential that represents neural activity elicited from SCS. The amplitudes of many SCS paradigms - both sub- and supra-threshold - are programmed relative to the patient's perception of SCS. The objective of this study, then, is to elucidate relationships between the ECAP and perception thresholds across posture and SCS pulse width. These relationships may be used for the automatic control and perceptually referenced programming of SCS systems.

Methods: ECAPs were acquired from 14 subjects across a range of postures and pulse widths with swept amplitude stimulation. Perception (PT) and discomfort (DT) thresholds were recorded. A stimulation artifact reduction scheme was employed, and growth curves were constructed from the sweeps. An estimate of the ECAP threshold (ET), was calculated from the growth curves using a novel approach. Relationships between ET, PT, and DT were assessed.

Results: ETs were estimated from 112 separate growth curves. For the postures and pulse widths assessed, the ET tightly correlated with both PT ( = 0.93; < 0.0001) and DT ( = 0.93; < 0.0001). The median accuracy of ET as a predictor for PT across both posture and pulse width was 0.5 dB. Intra-subject, ECAP amplitudes at DT varied up to threefold across posture.

Conclusion: We provide evidence that the ET varies across both different positions and varying pulse widths and suggest that this variance may be the result of postural dependence of the recording electrode-tissue spacing. ET-informed SCS holds promise as a tool for SCS parameter configuration and may offer more accuracy over alternative approaches for neural and perceptual control in closed loop SCS systems.
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http://dx.doi.org/10.3389/fnins.2021.673998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320888PMC
July 2021

A Clinical Feasibility Study of Spinal Evoked Compound Action Potential Estimation Methods.

Neuromodulation 2021 Jul 22. Epub 2021 Jul 22.

Medtronic plc, Minneapolis, MN, USA.

Objectives: Spinal cord stimulation (SCS) is a treatment for chronic neuropathic pain. Recently, SCS has been enhanced further with evoked compound action potential (ECAP) sensing. Characteristics of the ECAP, if appropriately isolated from concurrent stimulation artifact (SA), may be used to control, and aid in the programming of, SCS systems. Here, we characterize the sensitivity of the ECAP growth curve slope (S) to both neural response (|S |) and SA contamination (|S |) for four spinal ECAP estimation methods with a novel performance measure (|S /S |).

Materials And Methods: We collected a library of 112 ECAP and associated artifact recordings with swept stimulation amplitudes from 14 human subjects. We processed the signals to reduce SA from these recordings by applying one of three schemes: a simple high pass (HP) filter, subtracting an artifact model (AM) consisting of decaying exponential and linear components, or applying a template correlation method consisting of a triangularly weighted sinusoid. We compared these against each other and to P2-N1, a standard method of measuring ECAP amplitude. We then fit the ECAP estimates from each method with a function representing the growth curve; we then calculated the S and S parameters following the fit.

Results: Any SA reduction scheme selected may result in under- or overestimation of neural activation, or misclassification of SA as ECAP. In these experiments, the ratio of neural signal preservation to SA misclassification (|S /S |) on the ECAP estimate was superior (p < 0.05) with the HP and AM schemes relative to the others.

Conclusions: This work represents the first comprehensive assessment of spinal ECAP estimation schemes. Understanding the clinically relevant sensitivities of these schemes is increasingly important, particularly with closed-loop SCS systems using ECAP as a feedback control variable where misclassification of artifact as neural signal may lead to suboptimal therapy adjustments.
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http://dx.doi.org/10.1111/ner.13510DOI Listing
July 2021

High penetrance of myeloid neoplasia with diverse clinical and cytogenetic features in three siblings with a familial GATA2 deficiency.

Cancer Genet 2021 Aug 23;256-257:77-80. Epub 2021 Apr 23.

Manchester Academic Health Science Centre; Department of Paediatric Haematology and Oncology, Royal Manchester Children's Hospital, Manchester NHS Foundation Trust Manchester, UK; Stem Cell and Leukaemia Proteomics Laboratory, Faculty of Medical and Human Sciences, Division of Cancer Studies, University of Manchester, UK; Department of Paediatric and Adolescent Oncology, The Christie NHS Foundation Trust, Manchester, UK. Electronic address:

Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.
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http://dx.doi.org/10.1016/j.cancergen.2021.04.002DOI Listing
August 2021

How we treat the platelet glycoprotein defects; Glanzmann thrombasthenia and Bernard Soulier syndrome in children and adults.

Br J Haematol 2018 09 17;182(5):621-632. Epub 2018 Aug 17.

Department of Paediatric Haematology, Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

The inherited platelet glycoprotein deficiencies, Glanzmann thrombasthenia (GT) and Bernard Soulier syndrome (BSS) are rare but important long-term bleeding disorders. Once diagnosed, affected patients should be referred to a specialist centre for bleeding disorders for general advice and ongoing management. Patients do not require prophylactic treatment and so the management of GT and BSS focuses around prophylactic treatment prior to high risk procedures and treatment in response to non-surgical bleeding events and, in women, the management of menorrhagia and pregnancy. There is no consistent approach to the treatment or prevention of bleeding complications. Management must be tailored for each individual and the approach may not be the same for different events, even for the same patient, depending on the type of accident or invasive procedure, the extent of bleeding and the presence or not of platelet refractoriness.
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http://dx.doi.org/10.1111/bjh.15409DOI Listing
September 2018

Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging.

Br J Radiol 2015 15;88(1056):20150088. Epub 2015 Sep 15.

3 Children's Brain Tumour Research Network, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.

Objective: Fanconi anaemia (FA) is an inherited disease associated with congenital and developmental abnormalities resulting from the disruption of a multigenic DNA damage response pathway. This study aimed to define the MRI appearances of the brain in patients with FA in correlation with their genetic and clinical features.

Methods: A review of the brain MRI in 20 patients with FA was performed. Pituitary size and frequencies of the radiological findings of individuals with FA and age-matched controls were determined.

Results: Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males). In five cases (25%, p = 0.02), the pituitary morphology was also abnormal. Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy-Walker variant (n = 2) and cerebellar atrophy (n = 2). Six patients (30%, p = 0.01) had morphological structural variation of the corpus callosum (CC).

Conclusion: The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development. MRI brain imaging is important for endocrine assessment and pre-transplant evaluation and can make an important contribution to clinical decision-making.

Advances In Knowledge: The incidence of brain structural abnormalities in FA is higher than previously reported, with abnormalities of the posterior fossa, CC and pituitary being common. There is an association with gender and reduction in pituitary size which does not strongly correlate with biochemically evident endocrine abnormality.
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http://dx.doi.org/10.1259/bjr.20150088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984929PMC
March 2016

Evolving concepts in tumour lysis syndrome management - response to Ayed et al.

Br J Haematol 2016 05 27;173(3):486-7. Epub 2015 Jul 27.

Department of Haematology, Derriford Hospital, Plymouth, Devon, UK.

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http://dx.doi.org/10.1111/bjh.13616DOI Listing
May 2016

Neonatal haemostasis and the management of neonatal thrombosis.

Authors:
Andrew Will

Br J Haematol 2015 May 19;169(3):324-32. Epub 2015 Jan 19.

Department of Paediatric Haematology, Royal Manchester Children's Hospital, Manchester, UK.

Two detailed reviews of the management of neonatal thrombosis were published in 2012; one was an up-dated version of guidance first issued in 2004 and the other was a comprehensive review. Both of these publications gave very similar advice regarding the practical aspects of the indications, dosage and management of antithrombotic therapy. The authors stated that the evidence supporting most of their recommendations for anti-thrombotic therapy in neonates remained weak and so the therapy for a neonate with a thrombosis has to be based on an individualized assessment of estimated risk versus potential benefit. The aim of this present review is to give the treating physician an outline of the unique physiology of neonatal coagulation and how this affects the monitoring, dosing and even the choice of therapeutic strategy for the management of thrombosis in the neonate.
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http://dx.doi.org/10.1111/bjh.13301DOI Listing
May 2015

An assessment of risk posed by a Campylobacter-positive puppy living in an Australian residential aged-care facility.

Western Pac Surveill Response J 2014 11;5(3):1-6. Epub 2014 Aug 11.

Department of Microbiology and Infectious Diseases, Canberra Hospital and Health Services, Canberra, Australia .

Introduction: In April and June 2012, two outbreaks of Campylobacter gastroenteritis were investigated in an Australian aged-care facility (ACF); a Campylobacter-positive puppy was identified as a potential source of infection.

Methods: An expert panel was convened to assess transmission risk from the puppy to elderly residents and to guide further public health action. Criteria considered as part of the panel's assessment included the puppy's infectivity, the bacterium's transmissibility, puppy-resident contact, infection control and cleaning practices and animal management at the facility. A literature review was used to assist the panel, with a final risk being determined using a likelihood and consequence matrix.

Results: The panel determined that the setting and low infective dose made transmission likely despite varying degrees of contact between the puppy and cases. While infection control practices were generally appropriate, the facility's animal policy did not adequately address potential zoonotic risk.

Conclusion: In summary, puppies should not be considered as companion animals in ACFs due to high rates of Campylobacter carriage and the underlying susceptibility of the elderly. Infection control and animal policies in ACFs should reflect an awareness of zoonotic disease potential.
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http://dx.doi.org/10.5365/WPSAR.2014.5.2.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197190PMC
September 2015

Newborn bloodspot results: predictive value of screen positive test for thalassaemia major.

J Med Screen 2013 Dec 25;20(4):183-7. Epub 2013 Nov 25.

NHS Sickle Cell and Thalassaemia Screening Programme, King's College School of Medicine, 6th Floor, Capital House, 42 Weston Street, SE1 3QD, London.

Aim: There are limited published data on the performance of the percentage of haemoglobin A (Hb A) as a screening test for beta thalassaemia major in the newborn period. This paper aims to analyse data derived from a national newborn bloodspot screening programme for sickle cell disease on the performance of haemoglobin A (Hb A) as a screening test for beta thalassaemia major in the newborn period.

Methods: Newborn bloodspot sickle cell screening data from 2,288,008 babies were analysed. Data reported to the NHS Sickle Cell and Thalassaemia Screening Programme in England for the period 2005 to 2012 were also reviewed to identify any missed cases (4,599,849 babies).

Results: Within the cohort of 2,288,008 births, 170 babies were identified as screen positive for beta thalassaemia major using a cut-point of 1.5% HbA. There were 51 identified through look-back methods and 119 prospectively identified from 4 screening laboratories. Among 119 babies with prospective data, 7 were lost to follow up and 15 were false positive results. Using a cut-off value of 1.5% Hb A as a percentage of the total haemoglobin as a screening test for beta thalassaemia major in the newborn provides an estimated sensitivity of 99% (from the look back arm of the study) with a positive predictive value of 87% (from the prospective arm of the study). Excluding infants born before 32 weeks gestation, the positive predictive value rose to 95%.

Conclusion: A haemoglobin A value of less than 1.5% is a reliable screening test for beta thalassaemia major in the newborn period.
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http://dx.doi.org/10.1177/0969141313514217DOI Listing
December 2013

Heterozygote FANCD2 mutations associated with childhood T Cell ALL and testicular seminoma.

Fam Cancer 2012 Dec;11(4):661-5

Department of Clinical Genetics and Human Genetics, University Medical Centre, Free University of Amsterdam, Amsterdam, The Netherlands.

Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities characterised by cellular cross linker hypersensitivity. FA is caused by mutations in any of so far 15 identified FANC genes, which encode proteins that interact in a common DNA damage response (DDR) pathway. Individuals with FA have a high risk of developing acute myeloid leukaemia (AML) and squamous cell carcinoma. An increased cancer risk has been firmly established for carriers of mutations in FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, RAD51C/FANCO and link the FA pathway to inherited breast and ovarian cancer. We describe a pedigree with FANCD2 mutations c.458T > C (p.Leu153Ser) and c.2715 + 1G > A (p.Glu906LeufsX4) with mild phenotype FA in the index case, T cell ALL in the Leu153Ser heterozygous brother and testicular seminoma in the p.Glu906LeufsX4 heterozygous father. Both FANCD2 alleles were present in the T Cell ALL and the seminoma. This links specific FANCD2 mutations to T cell ALL and seminoma without evidence of allelic loss in the tumour tissue.
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http://dx.doi.org/10.1007/s10689-012-9553-3DOI Listing
December 2012

Jordan's anomaly in a case of Chanarin-Dorfman syndrome.

Br J Haematol 2011 Nov 21;155(4):412. Epub 2011 Jun 21.

Department of Clinical Haematology, Royal Manchester Children's Hospital, Manchester, UK.

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http://dx.doi.org/10.1111/j.1365-2141.2011.08780.xDOI Listing
November 2011

The clinical management of tumour lysis syndrome in haematological malignancies.

Br J Haematol 2011 Jul 9;154(1):3-13. Epub 2011 May 9.

Department of Paediatric Haematology, Royal Manchester Children's Hospital, Manchester, UK.

Tumour lysis syndrome (TLS) is caused by the disintegration of malignant cells, usually following the instigation of chemotherapy, although it may already be established at the time of initial presentation in a minority of cases. As a direct consequence of malignant cell breakdown, intracellular ions, proteins, nucleic acids and their metabolites are released into the plasma causing the characteristic metabolic abnormalities of TLS; hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia. In many cases the release of large amounts intracellular contents is so abrupt that the normal homeostatic mechanisms are rapidly overwhelmed and without prompt, effective management, the clinical effects of TLS soon become apparent.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08697.xDOI Listing
July 2011

Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency.

Am J Hum Genet 2011 Feb;88(2):216-25

Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester, Manchester, UK.

Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease.
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http://dx.doi.org/10.1016/j.ajhg.2011.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035707PMC
February 2011

Growth, final height and endocrine sequelae in a UK population of patients with Hurler syndrome (MPS1H).

J Inherit Metab Dis 2011 Apr 21;34(2):489-97. Epub 2011 Jan 21.

Royal Manchester Children's Hospital, Manchester, UK.

Objective: Hurler Syndrome, (MPSIH) is an inborn error of glycosaminoglycan metabolism. Haematopoietic stem cell transplantation (HSCT) has transformed the prognosis for these children. Prior to transplant patients receive chemotherapy or chemo-radiotherapy. Regular screening for the development of endocrine sequelae is therefore essential. We present for the first time data on final adult height and endocrine complications in children with MPSIH post HSCT.

Design: Retrospective case note study and a prospective programme of growth and endocrine assessment.

Patients: 22 patients were included, mean age at last assessment 12.2 (Range 6.3-21.6) years. Mean age at HSCT was 1.3 (SD 0.6) years. Conditioning included mostly busulphan and cyclophosphamide, with 5 patients receiving total body irradiation prior to second transplant.

Results: Height SDS decreased over time. Final height (FH) was attained in seven patients with male FH SDS -4.3 (Range -3.8, -5.1) and female FH SDS -3.4 (Range -2.9, -5.6). Eight of 13 patients tested had evidence of high growth hormone (GH) levels, while one had GH deficiency. Adrenal and thyroid function was normal in all. 11 patients were pubertal or post pubertal. Two females had pubertal failure requiring intervention. All male patients had spontaneous, complete puberty; however three patients have reduced testicular volumes. Five out of 13 patients tested had an abnormal oral glucose tolerance test.

Conclusion: Growth is impaired, primarily related to skeletal dysplasia, but also associated with GH resistance. Pubertal development may be compromised and abnormalities of glucose metabolism are common. We recommend a structured endocrine surveillance programme for these patients.
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http://dx.doi.org/10.1007/s10545-010-9262-8DOI Listing
April 2011

A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3.

Blood 2009 Jul 16;114(5):1091-8. Epub 2009 Apr 16.

University Department of Haematology, Manchester Royal Infirmary, Manchester, M13 9WL, United Kingdom.

Direct sequencing of VWF genomic DNA in 21 patients with type 3 von Willebrand disease (VWD) failed to reveal a causative homozygous or compound heterozygous VWF genotype in 5 cases. Subsequent analysis of VWF mRNA led to the discovery of a deletion (c.221-977_532 + 7059del [p.Asp75_Gly178del]) of VWF in 7 of 12 white type 3 VWD patients from 6 unrelated families. This deletion of VWF exons 4 and 5 was absent in 9 patients of Asian origin. We developed a genomic DNA-based assay for the deletion, which also revealed its presence in 2 of 34 type 1 VWD families, segregating with VWD in an autosomal dominant fashion. The deletion was associated with a specific VWF haplotype, indicating a possible founder origin. Expression studies indicated markedly decreased secretion and defective multimerization of the mutant VWF protein. Further studies have found the mutation in additional type 1 VWD patients and in a family expressing both type 3 and type 1 VWD. The c.221-977_532 + 7059del mutation represents a previously unreported cause of both types 1 and 3 VWD. Screening for this mutation in other type 1 and type 3 VWD patient populations is required to elucidate further its overall contribution to VWD arising from quantitative deficiencies of VWF.
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http://dx.doi.org/10.1182/blood-2008-08-173278DOI Listing
July 2009

Amplification and translocation of 3q26 with overexpression of EVI1 in Fanconi anemia-derived childhood acute myeloid leukemia with biallelic FANCD1/BRCA2 disruption.

Genes Chromosomes Cancer 2007 Apr;46(4):359-72

Academic Unit of Paediatric Oncology, Christie Hospital Trust, University of anchester, Manchester, UK.

Fanconi anemia (FA) is an inherited disease with congenital abnormalities and an extreme risk of acute myeloid leukemia (AML). Genetic events occurring during malignant transformation in FA and the biology of FA-associated AML are poorly understood, but are often preceded by the development of chromosomal aberrations involving 3q26-29 in bone marrow of FA patients. We report here the molecular cytogenetic characterization of FA-derived AML cell lines SB1685CB and SB1690CB by conventional and array comparative genomic hybridization, fluorescence in situ hybridization, and SKY. We identified gains of a 3.7 MB chromosomal region on 3q26.2-26.31, which preceded transformation to overt leukemia. This region harbors the oncogenic transcription factor EVI1. A third FA-derived cell line, FA-AML1, carried a translocation with ectopic localization of 3q26 including EVI1. Rearrangements of 3q, which are rare in childhood AML, commonly result in overexpression of EVI1, which determines specific gene expression patterns and confers poor prognosis. We detected overexpression of EVI1 in all three FA-derived AML. Our results suggest a link between the FA defect, chromosomal aberrations involving 3q and overexpression of EVI1. We hypothesize that constitutional or acquired FA defects might be a common factor for the development of 3q abnormalities in AML. In addition, cryptic imbalances as detected here might account for overexpression of EVI1 in AML without overt 3q26 rearrangements.
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http://dx.doi.org/10.1002/gcc.20417DOI Listing
April 2007

Spectrum and significance of variants and mutations in the Fanconi anaemia group G gene in children with sporadic acute myeloid leukaemia.

Br J Haematol 2006 May;133(3):284-92

Department of Paediatric Haematology and Oncology, Central Manchester and Manchester Children's University Hospital and Christie Hospital NHS Trusts, Manchester, UK.

Childhood acute myeloid leukaemia (AML) is uncommon. Children with Fanconi anaemia (FA), however, have a very high risk of developing AML. FA is a rare inherited disease caused by mutations in at least 12 genes, of which Fanconi anaemia group G gene (FANCG) is one of the commonest. To address to what extent FANCG variants contribute to sporadic childhood AML, we determined the spectrum of FANCG sequence variants in 107 children diagnosed with sporadic AML, using polymerase chain reaction (PCR), fluorescent single-strand conformational polymorphism (SSCP) and sequencing methodologies. The significance of variants was determined by frequency analysis and assessment of evolutionary conservation. Seven children (6.5%) carried variants in FANCG. Two of these carried two variants, including the known IVS2 + 1G>A mutation with the novel missense mutation S588F, and R513Q with the intronic deletion IVS12-38 (-28)_del11, implying that these patients might have been undiagnosed FA patients. R513Q, which affects a semi-conserved amino acid, was carried in two additional children with AML. Although not significant, the frequency of R513Q was higher in children with AML than unselected cord bloods. While FANCG mutation carrier status does not predispose to sporadic AML, the identification of unrecognised FA patients implies that FA presenting with primary AML in childhood is more common than suspected.
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http://dx.doi.org/10.1111/j.1365-2141.2006.05985.xDOI Listing
May 2006

Diagnosis of acute graft-versus-host disease.

Transplantation 2006 Feb;81(4):505-6

Department of Haematology, Royal Manchester Children's Hospital, Manchester, UK.

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http://dx.doi.org/10.1097/01.tp.0000200312.29965.35DOI Listing
February 2006

The impact of monitoring Epstein-Barr virus PCR in paediatric bone marrow transplant patients: can it successfully predict outcome and guide intervention?

Pediatr Blood Cancer 2006 Aug;47(2):200-5

Department of Haematology and Bone Marrow Transplantation, Manchester Royal Infirmary, Pendlebury, Manchester, UK.

Background: Epstein-Barr virus (EBV) associated lymphoproliferative disease is a complication of haemopoietic stem cell transplantation (HSCT). In certain groups (unrelated and mismatched donor transplants, T-cell depleted) the risk may be as high as 25% with significant morbidity and mortality. Strategies to predict the impending development of this disorder and allow early intervention have therefore assumed importance. We routinely screen the peripheral blood of all recipients of allogeneic HSCT to detect EBV DNA by quantitative polymerase chain reaction (PCR) technology and report here how this correlates with clinical disease and management.

Procedure: Data on 28 successive patients who underwent HSCT at our institution were reviewed. The relationship between EBV reactivation demonstrated by quantitative PCR and development of post transplant lymphoproliferative disease (PTLD) was determined.

Results: EBV reactivation occurred in 68% of patients, however only 7% developed clinical PTLD. Patients with high level reactivation (n = 9) had more frequent episodes of reactivation and all patients who progressed to overt PTLD were found in this group. In contrast none of those patients with low level reactivation (n = 10) or persistently negative results (n = 9) showed any signs of clinical disease. Anti-CD20 monoclonal antibody (Rituximab) therapy was instigated in both cases of proven PTLD and three cases of high level reactivation with successful outcomes. Response to treatment was associated with a prompt decline in viral copy number.

Conclusions: Our results indicate that EBV reactivation is a common occurrence in the paediatric allogeneic transplant setting and that only a proportion of patients will progress to PTLD. Frequent monitoring may help to predict those at highest risk and guide intervention.
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http://dx.doi.org/10.1002/pbc.20604DOI Listing
August 2006

A cross-linker-sensitive myeloid leukemia cell line from a 2-year-old boy with severe Fanconi anemia and biallelic FANCD1/BRCA2 mutations.

Genes Chromosomes Cancer 2005 Apr;42(4):404-15

Cancer-Immunogenetics Laboratory, University of Manchester, St. Mary's Hospital, Hathersage Road, Manchester M13 0JH, United Kingdom.

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital and developmental abnormalities, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), and strong predisposition to acute myeloid leukemia (AML). In this article, we describe clinical and molecular findings in a boy with a severe FA phenotype who developed AML by the age of 2. Although he lacked a strong family history of cancer, he was subsequently shown to carry biallelic mutations in the FANCD1/BRCA2 gene. These included an IVS7 splice-site mutation, which is strongly associated with early AML in homozygous or compound heterozygous carrier status in FA-D1 patients. Myeloid leukemia cells from this patient have been maintained in culture for more than 1 year and have been designated as the SB1690CB cell line. Growth of SB1690CB is dependent on granulocyte macrophage colony stimulating factor or interleukin-3. This cell line has retained its MMC sensitivity and has undergone further spontaneous changes in the spectrum of cytogenetic aberrations compared with the primary leukemia. This is the second AML cell line derived from an FA-D1 patient and the first proof that malignant clones arising in FA patients can retain inherited MMC sensitivity. As FA-derived malignancies are normally not very responsive to treatment, this implies there are important mechanisms of acquiring correction of the cellular FA phenotype that would explain the poor chemoresponsiveness observed in FA-associated malignancies and might also play a role in the initiation and progression of cancer in the general population.
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http://dx.doi.org/10.1002/gcc.20153DOI Listing
April 2005

Bone mineral density in childhood survivors of acute lymphoblastic leukemia treated without cranial irradiation.

J Clin Endocrinol Metab 2005 Feb 23;90(2):689-94. Epub 2004 Nov 23.

Department of Hematology and Oncology, Royal Manchester Children's Hospital, Manchester, UK.

Adult survivors of childhood acute lymphoblastic leukemia (ALL) whose treatment included cranial irradiation (XRT) have reduced bone mineral density (BMD). Fifty-three survivors of ALL (aged 6-17 yr; 22 males and 31 females), who had completed their treatment without XRT, at least 1 yr previously, and 187 (5-19 yr; 86 males and 101 females) healthy controls were examined with dual energy x-ray absorptiometry of the total body and L1-L4 vertebrae and peripheral quantitative computer tomography at the distal and midradial sites. The total body and lumbar spine BMDs did not differ between the ALL survivors and controls. Distal radial trabecular BMD (difference, -0.080 mg/cm(3); 95% confidence interval, -0.139 to -0.020; P = 0.009), but not total BMD (difference, -0.006 mg/cm(3); confidence interval, -0.051 to 0.039; P = 0.80), was lower in ALL survivors compared with controls. At the midradial site, both endosteal (11% larger; P = 0.0001) and periosteal (4% larger; P = 0.001) circumferences were greater, and cortical thickness was thinner by 6% (P = 0.006) in the ALL subjects, leading to an increase in the axial moment of inertia in the ALL subjects (difference, 13%; P = 0.008). In conclusion, BMD, except at the radius, is normal in childhood survivors of ALL treated without XRT. At the midradial site, we speculate that ALL or its treatment resulted in endosteal bone loss and cortical bone thinning, but the axial moment of inertia and, hence, strength was maintained as a result of bone gain at the periosteal surface.
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http://dx.doi.org/10.1210/jc.2004-1476DOI Listing
February 2005
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