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Biomedical subjects

G J Morgan

Publications and source records attributed to G J Morgan.

At least 19 recordsLinked to original sources
PubMed2005

Evolving treatment strategies for myeloma.

In this article, we will discuss how treatment strategies for myeloma have evolved and outline the challenges now faced following the introduction of a number of novel active agents. In particular, we will focus on how achieving a maximum response and maintaining such responses is becoming a key therapeutic strategy and how novel agents can be used to achieve this in the context of current strategies such as autologous transplantation.

Angiogenesis Inhibitors↗
PubMed2004

Serum free light chains for monitoring multiple myeloma.

Monoclonal immunoglobulin free light chains (FLC) are found in the serum and urine of patients with a number of B-cell proliferative disorders, including multiple myeloma. Automated immunoassays, which can measure FLC in serum, are useful for the diagnosis and monitoring of light chain (AL) amyloidosis, Bence Jones myeloma and non-secretory myeloma patients. We report the results of a study investigating the utility of serum FLC measurements in myeloma patients producing monoclonal intact immunoglobulin proteins. FLC concentrations were measured in presentation sera from 493 multiple myeloma patients with monoclonal, intact immunoglobulin proteins. Serial samples were assayed from 17 of these patients and the FLC measurements were compared with other disease markers. Serum FLC concentrations were abnormal in 96% of patients at presentation. FLC concentrations fell more rapidly in response to treatment than intact immunoglobulin G (IgG) and showed greater concordance with serum beta2 microglobulin concentrations and bone marrow plasma cell assessments. It was concluded that serum FLC assays could be used to follow the disease course in nearly all multiple myeloma patients. In addition, because of their short serum half-life, changes in serum FLC concentrations provide a rapid indication of the response to treatment.

Biomarkers↗
PubMed2004

Proteomics and the haematologist.

Understanding haematological malignancies at the protein level is important as the development of targeted treatments must be based on knowledge regarding the molecular pathogenesis of the tumour, inherited genetic variation and the mode of action of drugs. 'Proteomics' describes the analysis of the entire proteome of a cell or tissue and incorporates multiple technologies including Western blotting, two-dimensional gel electrophoresis, mass spectrometry, and ProteinChip-based technology. Although there are a limited number of studies to date in haematology those performed highlight the potential future impact of these technologies in the discovery of novel markers, proteins associated with drug resistance and the identification of tumour biomarkers which may facilitate the development of a rapid diagnostic test easily applicable in the clinical setting. Rapid large-scale analysis of the proteome in normal pathways and disease offers the opportunity of identification of potential diagnostic/prognostic markers and proteins associated with the malignant phenotype. This review discusses the current situation regarding the use of these technologies and the potential opportunities their future use may offer in the field of haematology.

Biomarkers, Tumor↗
PubMed2004

Minor salivary gland carcinoma involving the oral cavity or oropharynx.

BACKGROUND: Minor salivary gland carcinomas are uncommon but most often occur in the oral cavity, particularly the hard palate. Dental examination may provide an opportunity for early detection. METHODS: Patients referred to the multidisciplinary head and neck clinic at Westmead Hospital between 1980-2002 with a diagnosis of minor salivary gland carcinoma of the oral cavity or oropharynx were retrospectively identified. Data were collected on histology, treatment, outcome and the referring practitioner. RESULTS: A total of 30 patients diagnosed with a malignant minor salivary gland carcinoma were identified. Many patients, 16/30 (53 per cent), were referred by dentists. There were 15 males and 15 females with a mean age of 62 years (range, 22-86 yrs). Most (73 per cent) presented with early stage disease (stage 1/11). Adenoid cystic carcinoma was the most common histological subtype (40 per cent) followed by mucoepidermoid carcinoma (30 per cent) and polymorphous low-grade adenocarcinoma (20 per cent). All but two patients underwent surgery with 12/30 (40 per cent) also receiving adjuvant radiotherapy usually in the setting of an incomplete/close margin. One patient developed local recurrence and one developed widespread metastatic disease. At last follow-up 83 per cent of patients were alive and disease free. CONCLUSIONS: Early diagnosis and treatment of minor salivary gland carcinoma is likely to lead to a better outcome. In our study dentists were responsible for half of all referrals to our multidisciplinary head and neck clinic. Awareness of this uncommon entity is important for dental practitioners.

Adenocarcinoma↗
PubMed2003

The development of targeted chemotherapy for CNS lymphoma-a pilot study of the IDARAM regimen.

PURPOSE: We have developed and evaluated a CNS-targeted chemotherapy regimen based on the pharmacokinetic properties of the individual drugs in the combination. PATIENTS AND METHODS: In a twin-track study, 16 patients with secondary CNS lymphoma (SCNSL) and 8 with primary CNS lymphoma (PCNSL) were treated with IDARAM which comprised idarubicin 10 mg/m(2) i.v., days 1 and 2; dexamethasone 100 mg, 12-h infusion, days 1, 2 and 3; cytosine arabinoside (ARA-C) 1.0 g/m(2), 1-h infusion, days 1 and 2; methotrexate 2.0 g/m(2), 6-h infusion, day 3 (with folinic acid rescue); and cytosine arabinoside 70 mg plus methotrexate 12 mg, intrathecally, days 1 and 8. Two cycles were delivered at 3-weekly intervals. After response assessment, patients received adjuvant cranial radiotherapy (40 Gy over 20 fractions). RESULTS: The series comprised 24 patients, 11 male and 13 female. Their median age was 53 years (range 21 to 73 years). Grade 4 neutropenia and thrombocytopenia occurred in the majority of patients treated. Of the eight PCNSL patients, seven achieved complete remission (CR). Four remained in CR at the time of this report with a median duration of follow-up of 25 months (range 11 to 42 months). Of the 16 SCNSL patients, 12 achieved CR. Seven patients remained in CR at the time of this report with a median duration of follow-up of 24 months (range 18 to 57 months). CONCLUSION: This study suggests that IDARAM is an effective regimen in both PCNSL and SCNSL and is suitable for further development and evaluation.

Adult↗
PubMed2003

Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin.

Autoimmune associated bone disease and intestinal inflammation are closely linked with deregulation and hyperactivation of autoreactive CD4 T cells. How these T cells are activated and mediate disease is not clear. Here we show that in the Interleukin 2-deficient mouse model of autoimmunity spontaneous osteopenia and colitis are caused by increased production of the ligand for receptor activator of NFkappaB (RANKL). RANKL acting via its receptor, receptor activator of NFkappaB (RANK), increases bone turnover and promotes intestinal dendritic cell (DC) survival in vivo. Modulation of RANKL-RANK interactions with exogenous recombinant osteoprotegerin (Fc-OPG) reverses skeletal abnormalities and reduces colitis by decreasing colonic DC numbers. This study identifies a common causal link between bone disease and intestinal inflammation and establishes the importance of DC in mediating colonic inflammation in vivo.

Adjuvants, Immunologic↗
PubMed2003

Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936.

In a European BIOMED-2 collaborative study, multiplex PCR assays have successfully been developed and standardized for the detection of clonally rearranged immunoglobulin (Ig) and T-cell receptor (TCR) genes and the chromosome aberrations t(11;14) and t(14;18). This has resulted in 107 different primers in only 18 multiplex PCR tubes: three VH-JH, two DH-JH, two Ig kappa (IGK), one Ig lambda (IGL), three TCR beta (TCRB), two TCR gamma (TCRG), one TCR delta (TCRD), three BCL1-Ig heavy chain (IGH), and one BCL2-IGH. The PCR products of Ig/TCR genes can be analyzed for clonality assessment by heteroduplex analysis or GeneScanning. The detection rate of clonal rearrangements using the BIOMED-2 primer sets is unprecedentedly high. This is mainly based on the complementarity of the various BIOMED-2 tubes. In particular, combined application of IGH (VH-JH and DH-JH) and IGK tubes can detect virtually all clonal B-cell proliferations, even in B-cell malignancies with high levels of somatic mutations. The contribution of IGL gene rearrangements seems limited. Combined usage of the TCRB and TCRG tubes detects virtually all clonal T-cell populations, whereas the TCRD tube has added value in case of TCRgammadelta(+) T-cell proliferations. The BIOMED-2 multiplex tubes can now be used for diagnostic clonality studies as well as for the identification of PCR targets suitable for the detection of minimal residual disease.

Chromosome Aberrations↗
PubMed2003

The use of genetic microarray analysis to classify and predict prognosis in haematological malignancies.

The introduction of microarrays offers the opportunity to examine the expression of many thousands of genes in a single experiment. Investigations in leukaemia and lymphoma have led to the identification of a number of subgroups, with a defined gene expression pattern, not previously identified by morphology, cytogenetics or molecular techniques. In many cases these expression patterns can be linked to the tumour cells normal developmental counterpart, and represent distinct disease subgroups with different clinical presentations and outcomes. The technology has also identified genes that may be important in tumour cell biology including key genes in cell proliferation, adhesion, apoptosis, and the development of drug resistance. These early studies demonstrate that genetic microarrays will be useful in classifying haematological malignancies, predicting response to treatment, predicting prognosis, and identifying novel targets for therapy.

Computational Biology↗
PubMed2003

Tongue cancer: do patients younger than 40 do worse?

BACKGROUND: Debate continues as to whether being young confers a worse prognosis for patients with squamous cell carcinoma of the tongue. Recent papers have provided conflicting views in this debate. In this study we aimed to investigate if young age at the time of diagnosis of squamous cell carcinoma of the tongue confers a worse prognosis. METHODS: Eligible patients were identified through the computer database of the Department of Radiation Oncology, Westmead Hospital, Sydney. All eligible patients were treated with radical intent. Using age 40 as a cut off multivariate and survival analysis was undertaken to compare age groups. RESULTS: Median age at diagnosis was 60 years (range, 19-86 years) in 84 males (65 per cent) and 45 females (35 per cent). Median follow-up time was 43 months (range, 2.3-203 months). Fifteen patients (12 per cent) were aged <40 years. On univariate analysis stage and age were significant determinants of disease-specific survival. There was no difference in overall survival between the young (<40 years) and middle-aged groups (40-60 years). However, the young and the middle aged were both more likely to survive than the older age group (>60 years). On multivariate analysis age remained a significant factor for determining disease-specific survival, with the older age group 2.9 times more likely to die than the younger groups. CONCLUSION: Young age (<40 years) did not portend to worse survival in comparison to older tongue cancer patients.

Adult↗
PubMed2002

Age-specific incidence rates for cytogenetically-defined subtypes of acute myeloid leukaemia.

It is generally considered that most cancers arise following the accumulation of several genetic events and that as a consequence its incidence increases with age. We report a cytogenetic subgroup of acute myeloid leukaemia whose incidence is independent of age. This observation indicates that acute myeloid leukaemia can develop via multiple pathways, and underlines the importance of cytogenetics in understanding this disease.

Acute Disease↗
PubMed2002

Smoking and the risk of acute myeloid leukaemia in cytogenetic subgroups.

Cytogenetically-defined subgroups of acute myeloid leukaemia have distinct biologies, clinical features and outcomes. Evidence from therapy-related leukaemia suggests that chromosomal abnormalities are also markers of exposure. Our results suggest that the smoking-associated risk for acute myeloid leukaemia is restricted to the t(8;21)(q22;q22) subgroup. This supports the hypothesis that distinct cytogenetic subgroups of acute myeloid leukaemia have separate aetiologies.

Chromosome Aberrations↗
PubMed2002

Isotype class switching and the pathogenesis of multiple myeloma.

Translocations at the immunoglobulin heavy chain locus (14q32) are now considered the commonest karyotypic change in multiple myeloma. These translocations are thought to be intimately involved in the pathogenesis of this disease. The heavy chain locus is strongly transcriptionally active in B and plasma cells and transfer of a potential oncogene to 14q32 would result in its dysregulation. Molecular characterization suggests that the majority of these breakpoints cluster in switch regions within the heavy chain locus. Switch regions are normally involved in the regulated process of isotype switching so that in myeloma the rearrangements are believed to be a result of so-called illegitimate (aberrant) switch recombination and are likely to be an early event in myeloma development. A legitimate switch recombination event occurs between two switch regions producing a hybrid switch; this is necessary for class switching to proceed on a productive allele. In this review we describe the process of isotype switching and how illegitimate class switching may be related to the pathogenesis of multiple myeloma.

Humans↗
PubMed2002

Myeloma aetiology and epidemiology.

Recently there have been substantial improvements in our understanding of the biology of myeloma. These findings have important implications for aetiological studies aimed at defining the causative factors for myeloma. Myeloma is closely related to monoclonal gammopathy of unknown significance (MGUS), which is now recognized to be very common in the older population. The epidemiology of these conditions is presented and discussed in the context of the genetic factors governing both the risk of developing MGUS or of transformation to myeloma. Biological studies support a role for aberrant class switch recombination early in the natural history of myeloma suggesting that factors in the environment may interact with this mechanism to increase myeloma risk. Case-control and cohort studies have identified several known and suspected environmental exposures. These exposures include high doses of ionizing radiation, and occupational exposure in the farming and petrochemical industries. The data supporting these associations are presented and discussed in the context of the molecular mechanisms underlying these exposures. In particular DNA damage occurring as a consequence could readily interact with the class switch recombination process to increase the risk of chromosomal translocations, oncogene deregulation and malignant transformation. A further hypothesis, which has been extensively investigated, is the role of chronic immune/antigenic stimulation and the risk of myeloma. This concept is difficult to explain in the context of our current immunological concepts. The data supporting the association and how molecular epidemiological studies using genetic variants in cytokine genes are allowing us to revisit this concept are discussed in detail.

Animals↗
PubMed2002

Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination.

The DNA double stranded break (DSB) repair mechanism, non-homologous end joining (NHEJ) represents an essential step in antigen receptor gene rearrangement mechanisms, processes believed to be intimately involved in the aetiology of lymphoproliferative disease. We investigated the potential impact that previously undescribed polymorphisms identified within NHEJ DNA ligase IV (LIG4) have upon predisposition to several lymphoproliferative disorders, including leukaemia, lymphoma, and multiple myeloma. Two LIG4 polymorphisms were examined, both C>T transitions, which result in the amino acid substitutions A3V and T9I. Inheritance of the LIG4 A3V CT genotype was found to be significantly associated with a two-fold reduction in risk of developing multiple myeloma (OR 0.49, 95% CI 0.27 to 0.89). Similarly, inheritance of the LIG4 T9I CT and the T9I TT genotypes were found to associate with a 1.5-fold reduction (OR 0.77, 95% CI 0.51 to 1.17) and a four-fold reduction (OR 0.22, 95% CI 0.07 to 0.70) in risk of developing multiple myeloma respectively, suggesting a gene dosage effect for this polymorphism. The LIG4 A3V and T9I variant alleles are in linkage disequilibrium (D'=0.95, p<0.0001), and the protective effect associated with these polymorphisms was found to be the result of inheritance of the A3V-T9I CT and A3V-T9I TT haplotypes. These data suggest that genetic variants of NHEJ LIG4 may modulate predisposition to multiple myeloma, a tumour characterised by aberrant immunoglobulin (Ig) class switch recombination.

Base Sequence↗
PubMed2001

Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia.

Glutathione S-transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1. Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11-2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39-5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43-13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50-2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.

Chromosome Aberrations↗
PubMed2001

Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma.

The antiangiogenic activity of thalidomide (Thal), coupled with an increase in bone marrow angiogenesis in multiple myeloma (MM), provided the rationale for the use of Thal in MM. Previously, the direct anti-MM activity of Thal and its analogues (immunomodulatory drugs, IMiDs) on MM cells was demonstrated, suggesting multiple mechanisms of action. In this study, the potential immunomodulatory effects of Thal/IMiDs in MM were examined. It was demonstrated that Thal/IMiDs do not induce T-cell proliferation alone but act as costimulators to trigger proliferation of anti-CD3-stimulated T cells from patients with MM, accompanied by an increase in interferon-gamma and IL-2 secretion. However, an increase in autologous T-cell killing of patient MM cells could not be demonstrated. A role for natural killer (NK)- and LAK-cell-mediated killing is suggested because IL-2-primed peripheral blood mononuclear cells (PBMCs) treated with Thal/IMiDs demonstrated significantly increased lysis of MM cell lines. Cold target inhibition assays suggested NK- rather than LAK-cell-mediated killing. Furthermore, this killing was not major histocompatibility complex-class restricted, and the depletion of CD56(+) cells blocked the drug-induced MM cell lysis. It was significant that increased killing of patient MM cells by autologous PBMCs treated with Thal/IMiDs was also observed. Although the in vivo relevance of NK-cell-mediated MM cell killing is unknown, phenotypic analysis performed in MM patients receiving Thal therapy demonstrated an increase in CD3(-)CD56(+) cells in patients responding to therapy. Thus in vitro and in vivo data support the hypothesis that Thal may mediate its anti-MM effect, at least in part, by modulating NK cell number and function.

Adjuvants, Immunologic↗
PubMed2001

Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy.

Previous studies have suggested that the level of residual disease at the end of therapy predicts outcome in chronic lymphocytic leukemia (CLL). However, available methods for detecting CLL cells are either insensitive or not routinely applicable. A flow cytometric assay was developed that can differentiate CLL cells from normal B cells on the basis of their CD19/CD5/CD20/CD79b expression. The assay is rapid and can detect one CLL cell in 10(4) to 10(5) leukocytes in all patients. We have compared this assay to conventional assessment in 104 patients treated with CAMPATH-1H and/or autologous transplant. During CAMPATH-1H therapy, circulating CLL cells were rapidly depleted in responding patients, but remained detectable in nonresponders. Patients with more than 0.01 x 10(9)/L circulating CLL cells always had significant (> 5%) marrow disease, and blood monitoring could be used to time marrow assessments. In 25 out of 104 patients achieving complete remission by National Cancer Institute (NCI) criteria, the detection of residual bone marrow disease at more than 0.05% of leukocytes in 6 out of 25 patients predicted significantly poorer event-free (P =.0001) and overall survival (P =.007). CLL cells are detectable at a median of 15.8 months (range, 5.5-41.8) posttreatment in 9 out of 18 evaluable patients with less than 0.05% CLL cells at end of treatment. All patients with detectable disease have progressively increasing disease levels on follow-up. The use of sensitive techniques, such as the flow assay described here, allow accurate quantitation of disease levels and provide an accurate method for guiding therapy and predicting outcome. These results suggest that the eradication of detectable disease may lead to improved survival and should be tested in future studies.

Adult↗