Mark A Catherwood

University of Porto, Oporto, Porto, Portugal

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Publications (36)152.72 Total impact

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    ABSTRACT: Utility of p53 as a prognostic assay has been elusive. We describe a novel, reproducible scoring system and assess the relationship between differential p53 IHC expression patterns, TP53 mutation status and patient outcomes for breast cancer. Tissue microarrays were used to study p53 IHC expression patterns: expression was defined as extreme positive (EP), extreme negative (EN) and intermediate patterns as non-extreme (NE). Overall survival was used to define patient outcome. A representative subgroup (n=30) displaying the various p53 immunophenotypes was analysed for TP53 hotspot mutation status (exons 4-9). Extreme expression of any type occurred in 176/288 (61%) cases. EP p53 compared to NE p53 was significantly associated (p = 0.039) with poor OS. In addition, EN p53 compared to NE p53 was associated (p = 0.059) with poor OS. Combining cases displaying either EP/EN expression better predicted OS than either pattern alone (p = 0.028). This combination immunophenotype was significant in univariate but not multivariate analysis. In subgroup analysis six substitution exon mutations were detected, all corresponding to extreme IHC phenotypes. Five missense mutations corresponded to EP staining while the nonsense mutation corresponded to EN staining. None were detected in the NE group. Patients with extreme p53 IHC expression have a worse OS compared to those with NE expression. Accounting for EN as well as EP p53 improves its prognostic impact. Extreme expression positively correlates with nodal stage and histological grade and negatively with hormone receptor status. Extreme expression may relate to specific mutational status. This article is protected by copyright. All rights reserved.
    Histopathology 02/2014; · 2.86 Impact Factor
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    ABSTRACT: Molecular medicine is transforming modern clinical practice, from diagnostics to therapeutics. Discoveries in research are being incorporated into the clinical setting with increasing rapidity. This transformation is also deeply changing the way we practise pathology. The great advances in cell and molecular biology which have accelerated our understanding of the pathogenesis of solid tumours have been embraced with variable degrees of enthusiasm by diverse medical professional specialties. While histopathologists have not been prompt to adopt molecular diagnostics to date, the need to incorporate molecular pathology into the training of future histopathologists is imperative. Our goal is to create, within an existing 5-year histopathology training curriculum, the structure for formal substantial teaching of molecular diagnostics. This specialist training has two main goals: (1) to equip future practising histopathologists with basic knowledge of molecular diagnostics and (2) to create the option for those interested in a subspecialty experience in tissue molecular diagnostics to pursue this training. It is our belief that this training will help to maintain in future the role of the pathologist at the centre of patient care as the integrator of clinical, morphological and molecular information.
    Journal of clinical pathology 02/2014; · 2.43 Impact Factor
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    ABSTRACT: Next Generation Sequencing (NGS) has the potential of becoming an important tool in clinical diagnosis and therapeutic decision-making in oncology owing to its enhanced sensitivity in DNA mutation detection, fast-turnaround of samples in comparison to current gold standard methods and the potential to sequence a large number of cancer-driving genes at the one time. We aim to test the diagnostic accuracy of current NGS technology in the analysis of mutations that represent current standard-of-care, and its reliability to generate concomitant information on other key genes in human oncogenesis. Thirteen clinical samples (8 lung adenocarcinomas, 3 colon carcinomas and 2 malignant melanomas) already genotyped for EGFR, KRAS and BRAF mutations by current standard-of-care methods (Sanger Sequencing and q-PCR), were analysed for detection of mutations in the same three genes using two NGS platforms and an additional 43 genes with one of these platforms. The results were analysed using closed platform-specific proprietary bioinformatics software as well as open third party applications. Our results indicate that the existing format of the NGS technology performed well in detecting the clinically relevant mutations stated above but may not be reliable for a broader unsupervised analysis of the wider genome in its current design. Our study represents a diagnostically lead validation of the major strengths and weaknesses of this technology before consideration for diagnostic use.
    PLoS ONE 01/2013; 8(7):e69604. · 3.53 Impact Factor
  • M A Catherwood, F Schmitt, M Salto-Tellez
    Cytopathology 10/2012; 23(5):283-5. · 1.71 Impact Factor
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    ABSTRACT: Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) can compromise the successful treatment of many malignancies including plasma cell myeloma (PCM). However, methods do not yet exist that can accurately determine P-gp activity in PCM patient samples. In this study, we have utilized new advances in flow cytometric methods to determine the activity of P-gp in PCM tumor cells. Furthermore, we have used several PCR-based approaches to perform a pilot study determining the functional impact of ABCB1 SNPs in patients with PCM. No associations were seen between P-gp activity or expression and subgroups of PCM. Similarly, no association was seen between P-gp expression and SNPs within ABCB1 although a nonsignificant reduction in activity was demonstrated for rs1045642 (P = 0.121). We have described a new method for the determination of P-gp and MRP activity suitable for use in clinical studies and have optimized this method to include a gating strategy, allowing routine use on PCM bone marrow aspirate samples. This is the first patient study to consider the full impact of SNPs within ABCB1 all the way from the genome to the proteome in PCM. The methods described here could also be utilized for future studies of "stem cell like" side populations in PCM that are considered to be drug resistant. Furthermore, minor amendments to these methods will facilitate studies of P-gp, MRP, and BCRP activity in other haematological malignancies.
    Cytometry Part B Clinical Cytometry 03/2012; 82(4):229-37. · 2.23 Impact Factor
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    British Journal of Haematology 07/2011; 156(1):133-6. · 4.94 Impact Factor
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    ABSTRACT: Multi-drug resistance (MDR) leads to impaired treatment efficacy in all forms of malignancy. The main forms of MDR are thought to be mediated by the substrate transporting actions of certain adenosine triphosphate binding cassette (ABC) transport proteins. The genes ABCB1, ABCB4, ABCC1, ABCG2 and LRP1 have been identified as the most prominent contributors to clinically significant MDR. To date, no study has investigated the expression of these genes in plasma cell myeloma (PCM), or attempted to relate their expression to the incidence of relapse and/or stage at presentation. Here, we show that ABCB4 may be a prominent mediator of tumour cell MDR within PCM. Additionally, there are three SNPs (rs1045642, rs2032582 and rs1128503) within the most widely studied of these genes, ABCB1, which have been suggested to have a potential impact on OS in PCM and which may form a haplotype in ABCB1. rs1045642 in ABCB1 appears to be the only SNP affecting OS within the PCM patients studied, with minimal linkage disequilibrium demonstrated between it and rs2032582 and rs1128503.
    Leukemia research 06/2011; 35(11):1457-63. · 2.36 Impact Factor
  • Stephen Drain, Mark A Catherwood, H Denis Alexander
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    ABSTRACT: Multidrug resistance (MDR) is a phenomenon in malignancy whereby tumor cells generate mechanisms to resist cytotoxic treatments. Several such mechanisms have been identified. However, to date the most significant research on MDR has involved the adenosine triphosphate binding cassette (ABC) transporter proteins, including P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP). These proteins have natural functions involving substrate transport in normal cells but are detrimental to treatment when expressed in the membrane of tumor cells. It remains unclear whether ABC mediated MDR functions primarily through protein up-regulation or via a relevant signaling mechanism, or is simply due to selective pressure on an already resistant tumor cell subpopulation. Here we present an overview of MDR in the chronic lymphoproliferative disorders (CLPDs), in particular that attributed to the ABC transporter protein family.
    Leukemia & lymphoma 10/2010; 51(10):1793-804. · 2.61 Impact Factor
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    ABSTRACT: Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC(50) of 0.55 micromol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV(H) genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15-induced apoptosis. Pharmacologic inhibition of c-jun NH(2)-terminal kinase inhibited PBOX-15-induced apoptosis in mutated IgV(H) and ZAP-70(-) CLL cells but not in unmutated IgV(H) and ZAP-70(+) cells. PBOX-15 exhibited selective cytotoxicity in CLL cells compared with normal hematopoietic cells. Our data suggest that PBOX-15 represents a novel class of agents that are toxic toward both high-risk and low-risk CLL cells. The need for novel treatments is acute in CLL, especially for the subgroup of patients with poor clinical outcome and drug-resistant disease. This study identifies a novel agent with significant clinical potential.
    Cancer Research 10/2009; 69(21):8366-75. · 9.28 Impact Factor
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    ABSTRACT: This report describes a case of aleukaemic myeloid sarcoma of the small intestine in a 50-year-old woman presenting with small bowel obstruction. Fluorescence in situ hybridisation analysis of interphase nuclei revealed a split CBFbeta signal, consistent with an underlying inversion of chromosome 16, inv(16)(p13q22). The resultant type A CBFbeta/MYH11 transcript was detected by reverse transcriptase PCR. Immunohistochemistry with the AH107 antibody to the CBFbeta-SMMHC chimeric protein showed strong nuclear staining of the tumour cell nuclei. This represents the first use of this antibody in the diagnosis of this subtype of myeloid sarcoma in the small intestine.
    Journal of clinical pathology 09/2009; 62(8):757-9. · 2.43 Impact Factor
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    ABSTRACT: Multi-drug resistance (MDR) may compromise the successful management of haematological malignancies, impairing the effectiveness of chemotherapy. The P-glycoprotein (P-gp) drug efflux pump, encoded by the gene ABCB1 (MDR1), is the most widely studied component in MDR. A single nucleotide polymorphism (SNP) has been identified within ABCB1, rs1045642 (C3435T), which may alter P-gp substrate specificity and have an impact on the effectiveness of treatment, and hence overall survival (OS). We estimated the frequency of this SNP in the Northern Irish population and investigated its impact on the OS of patients with plasma cell myeloma (PCM). There was no significant difference in the frequency of rs1045642 between the PCM cohort and an age- and gender-matched control population. Findings within the PCM cohort suggest that rs1045642 genotype influences OS (p = 2 x 10(-2)). If confirmed in larger studies, these results suggest that genotyping rs1045642 may be a useful predictor of outcome in PCM and could indicate modified treatment modalities in certain individuals.
    Leukemia & lymphoma 05/2009; 50(4):566-70. · 2.61 Impact Factor
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    ABSTRACT: Biased IgHV gene usage in chronic lymphocytic leukemia (CLL) is well documented and suggests antigen involvement in leukemogenesis. IgHV1-69 is one of the most frequently rearranged IgHV genes in CLL and the majority of IgHV1-69 cases lack somatic hypermutation and display poor prognosis. However, its independent prognostic impact remains uncertain given reports showing a low proportion of mutated IgHV1-69 cases and stereotyped IgHV1-69 subsets with divergent clinical outcome. We assessed the frequency and clinical significance of IgHV1-69 gene usage in a cohort of 330 CLL patients. Functional IgHV1-69 gene rearrangements were detected in 32 cases (9.7%), 31 of which were characterised further. Seven (22.6%) were found to have undergone somatic hypermutation. This subgroup had shorter and more diverse complementarity determining region 3 (CDR3) sequences compared with unmutated IgHV1-69 cases. In addition, mutated IgHV1-69 gene status was associated with lower cell surface CD38 expression and less progressive disease as monitored by Binet staging, lymphocyte doubling time and requirement of chemotherapeutic intervention. To conclude, we present data confirming that IgHV1-69 gene rearrangements in CLL are not exclusively associated with unmutated IgHV status. In addition, we show that a somatically hypermutated subgroup may demonstrate more indolent characteristics despite the general association of IgHV1-69 gene usage with aggressive disease.
    Leukemia & lymphoma 05/2008; 49(4):763-8. · 2.61 Impact Factor
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    P C Winter, M F McMullin, M A Catherwood
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2008; · 10.16 Impact Factor
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    P C Winter, M F McMullin, M A Catherwood
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2008; 22(8):1629-31; discussion 1631-3. · 10.16 Impact Factor
  • L Venkatraman, M Catherwood, G Benson, M Drake
    Histopathology 01/2008; 51(6):866-8. · 2.86 Impact Factor
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    ABSTRACT: PCR detects clonal rearrangements of the Ig gene in lymphoproliferative disorders. False negativity occurs in germinal centre/post-germinal centre lymphomas (GC/PGCLs) as they display a high rate of somatic hypermutation (SHM), which causes primer mismatching when detecting Ig rearrangements by PCR. To investigate the degree of SHM in a group of GC/PGCLs and assess the rate of false negativity when using BIOMED-2 PCR when compared with previously published strategies. DNA was isolated from snap-frozen tissue from 49 patients with GC/PGCL (23 diffuse large B cell lymphomas (DLBCLs), 26 follicular lymphomas (FLs)) and PCR-amplified for complete (VDJH), incomplete (DJH) and Ig kappa/lambda rearrangements using the BIOMED-2 protocols, and compared with previously published methods using consensus primers. Germinal centre phenotype was defined by immunohistochemistry based on CD10, Bcl-6 and MUM-1. Clonality detection by amplifying Ig rearrangements using BIOMED-2 family-specific primers was considerably higher than that found using consensus primers (74% DLBCL and 96% FL vs 69% DLBCL and 73% FL). Addition of BIOMED-2 DJH rearrangements increased detection of clonality by 22% in DLBCL. SHM was present in VDJH rearrangements from all patients with DLBCL (median (range) 5.7% (2.5-13.5)) and FL (median (range) 5.3% (2.3-11.9)) with a clonal rearrangement. Use of BIOMED-2 primers has significantly reduced the false negative rate associated with GC/PGCL when compared with consensus primers, and the inclusion of DJH rearrangements represents a potential complementary target for clonality assessment, as SHM is thought not to occur in these types of rearrangements.
    Journal of Clinical Pathology 06/2007; 60(5):524-8. · 2.44 Impact Factor
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    ABSTRACT: Routine interphase fluorescence in situ hybridization (FISH) analysis of chronic lymphocytic leukemia (CLL) with LSI IGH/CCND1 assay, applied to differentiate CLL from leukemic mantle cell lymphoma, identified a subset of cases (42/174) with translocation-like IGH signal pattern. To unravel the underlying 14q32/IGH aberrations, 14 of these cases were subjected to cytogenetic, detailed FISH, and V(H) mutation analyses. FISH identified cryptic losses of various portions of the IGHV region in all 14 cases. Fine mapping of these V(H) deletions revealed a strict correlation between their distal border and localization of the used VH gene, suggesting that they are not oncogenic but reflect physiological events accompanying somatic V-D-J assembly. This hypothesis was further supported by FISH analysis of 20 CLL and hairy cell leukemia cases with the known V(H) usage showing a constant loss of sequences proximal to the used gene, identification of V(H) deletions in normal B cells, and their exclusive demonstration in B cell malignancies, but not of T cell and myeloid linage. Given that these cryptic physiological VH losses in B cells may seriously complicate analysis of B cell leukemia/lymphoma and lead to false conclusions, FISH users should take them into consideration when interpreting IGH aberrations in these malignancies.
    Journal of Molecular Diagnostics 03/2007; 9(1):47-54. · 3.95 Impact Factor
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    ABSTRACT: This study determined IgV(H) gene usage in 228 chronic lymphocytic leukaemia patients to investigate associations between gene usage and other biological or clinical characteristics. V(H)3-48 [N=8] and V(H)3-53 [N=4] gene rearrangements showed biased lambda light chain restriction and were predominantly found in female patients with short lymphocyte doubling time but without adverse prognosis cytogenetics. Overuse of V(L)3-21(Vlambda2-14) gene and highly homologous LCDR3 sequences were found in V(H)3-48 patients. V(H)3-21 gene usage [N=18, 7.9%] was associated with poor prognosis, overuse of V(L)3-21(Vlambda2-14) gene and highly homologous heavy- and light-chain CDR3 sequences, but was not associated with poor prognosis chromosomal aberrations.
    Leukemia Research 03/2007; 31(2):231-4. · 2.76 Impact Factor
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    ABSTRACT: Fine-needle aspiration cytology (FNAC) is used as a screening test to evaluate lymphadenopathy. The combined use of genetic analysis and flow cytometry for immunophenotyping has increased the accuracy of diagnosis and correct categorisation of lymphomas on cytological preparations. To show the utility of immunocytochemistry and polymerase chain reaction (PCR) in the evaluation of cytological preparations of lymph nodes. Fine needle aspirates were obtained from 33 patients (initial presentation, n = 27; recurrence, n = 6). Routine examination was undertaken using immunocytochemistry and DNA PCR to detect clonality and specific translocations. The cytodiagnosis and subclassification of lymphoma was correlated with histological diagnosis in the available follow-up biopsies. 14 patients had a cytological diagnosis of non-Hodgkin's lymphoma (NHL), 4 had suspected NHL, 2 had atypical lymphoid proliferation and 13 had reactive hyperplasia. A World Health Organization (WHO) subtype was suggested in 8 patients. Incorporating the results of immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements enabled diagnosis of lymphoma in 17 patients, including 5 of the 6 patients suspected to have NHL or an atypical lymphoid proliferation. Identification of the translocations t (14;18) and t (2;5) helped WHO categorisation in 3 of the patients. The cytological findings were confirmed in 12 out of the 13 patients for whom histological follow-up was available. Seven of the 18 lymphoma patients were managed without a subsequent biopsy. We made one false-positive diagnosis of B-cell NHL on cytology. The use of immunocytochemistry and PCR is valuable in the definitive diagnosis and subtyping of malignant lymphomas on cytological preparations. The use of these techniques may avoid lymph node biopsies in some cases and allow definitive treatment based on aspirate findings alone.
    Journal of Clinical Pathology 12/2006; 59(11):1160-5. · 2.44 Impact Factor
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    ABSTRACT: Two P-glycoprotein (P-gp) genes, MDR-1 (ABCB1) and MDR-3 (ABCB4), have been identified in humans. This study was designed to investigate whether associations exist between expression of MDR-1 and MDR-3 P-gp and other markers of poor prognosis and/or prior exposure to therapeutic agents in chronic lymphocytic leukemia (CLL). IgVH mutational status, gene usage, CD38 positivity, FISH analysis and clinical information were available on all patients. Twenty-one of 101 patients tested showed MDR-3 P-gp positivity. Associations with markers of poor prognosis or prior chemotherapy did not reach statistical significance, but MDR-3 P-gp positive patients had significantly shorter survivals than MDR-3 P-gp negative patients. MDR-1 P-gp expression (18/25) showed a strong association with unmutated IgVH genes and adverse prognosis cytogenetics (p = 0.015, p = 0.014, respectively), but was independent of prior exposure to chemotherapeutic agents. These results suggest a role for MDR-1 and MDR-3 in chemoresistant disease. This study highlights the value of determining MDR phenotype in CLL patients prior to treatment, to allow the design of novel drug regimens containing agents that reverse MDR function.
    Leukemia and Lymphoma 12/2006; 47(11):2308-13. · 2.61 Impact Factor

Publication Stats

544 Citations
152.72 Total Impact Points

Institutions

  • 2012
    • University of Porto
      • Institute of Molecular Pathology and Immunology (IPATIMUP)
      Oporto, Porto, Portugal
    • Belfast Health and Social Care Trust
      Béal Feirste, N Ireland, United Kingdom
  • 2011
    • University of Ulster
      Aontroim, N Ireland, United Kingdom
  • 2003–2011
    • Belfast Healthy Cities
      Béal Feirste, N Ireland, United Kingdom
  • 2007
    • KU Leuven
      • Department of Human Genetics
      Leuven, VLG, Belgium
  • 2002
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
  • 1998–2002
    • Queen's University Belfast
      Béal Feirste, N Ireland, United Kingdom