Thesis(M Med (Haematology)) -- University of Limpopo, 2011. / BACKGROUND: Multiple myeloma (MM) is a rare age-related disorder with increasing incidence with advancing age. It is a B-cell malignancy characterised by monoclonal expression and accumulation of abnormal plasma cells in the bone marrow. It comprises about 1 % of all malignant tumours worldwide and 10% of haemopoietic neoplasms. MM accounted for 0.43% of newly diagnosed malignancies in South Africa in 1999 and Visser et al (2009), found the incidence to be 0.00054%. Mwambakana in 2000 at Ga-Rankuwa Hospital, now known as Dr George Mukhari Hospital (DGMH), found MM to be the commonest haematological malignancy. No clear risk factors have been identified in this disease. The natural history of MM is one of progressive bone destruction, refractory cytopenias and end-organ damage. The diagnosis and staging of MM is based on different criteria and systems. OBJECTIVES: To establish a profile of patients diagnosed with MM at DGMH from 1 January 2004 to 31 December 2009. METHODS: We conducted a descriptive retrospective review of medical records of patients diagnosed and treated for MM at DGMH from 2004-2009. RESULTS: Thirty-four patients' records were found. MM was found to be present in these patients as early as the third decade, more females than males were diagnosed and females were surviving longer than their male counterparts. Clinical features were not significantly different from those previously reported. The WHO 2001 diagnostic criteria created by Durie & Salmon and the International Staging System were used more frequently and most patients presented at an advanced stage of the disease.

Thesis (M.Res.(Med.))--University of Hong Kong, 2007.

Thesis (doctoral)--København, 1965. / Includes bibliographical references.

Thesis (PhD)--University of South Australia, 2002.

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

published_or_final_version / Medicine / Master / Master of Research in Medicine

published_or_final_version / Pathology / Master / Master of Medical Sciences

No description available.

Eine ernstzunehmende Nebenwirkung der anti-resorptiven Therapie (AR-Therapie) beim Multiplem Myelom ist die Medikamenten-assoziierten Kiefernekrose. Für die vorliegende Arbeit wurden 50 Patienten mit Medikamenten-assoziierter Kiefernekrose (MRONJ-Gruppe) einer gleich großen Kontrollgruppe ohne Medikamenten- assoziierter Kiefernekrose (KTRL-Gruppe) gegenübergestellt. In der MRONJ-Gruppe dauerte die AR-Therapie signifikant länger als in der KTRL-Gruppe (p < 0,001). Die MRONJ-Patienten erhielten die AR-Therapie im Schnitt knapp 4 Jahre, die KTRL- Patienten 2,5 Jahre. Zudem wurde den MRONJ-Patienten die AR-Therapie signifikant häufiger im 4-wöchentlichen Intervall verabreicht als den KTRL-Patienten (n = 49 vs. n = 36, p = 0,003). Das mediane Gesamtüberleben der MRONJ-Gruppe lag signifikant über dem Gesamtüberleben der KTRL-Gruppe (126 vs. 86 Monate, p = 0,013). Das mediane Gesamtüberleben des gesamten Patientenkollektivs lag bei 111 Monaten. Zudem korrelierte das Gesamtüberleben aller Patienten dieser Arbeit signifikant mit der kumulativen Zoledronatdosis (p < 0,001, r = 0,557). Die Stadieneinteilung und die CRAB-Kriterien zeigten bei Erstdiagnose keine signifikanten Unterschiede zwischen den Gruppen. Die Gründe für das längere Gesamtüberleben der MRONJ-Gruppe können auf die Unterschiede in der AR-Therapie zurückgeführt werden. Es bestand ein signifikanter Unterschied in der Therapiedauer, dem verabreichten Intervall und der kumulativen Zoledronatdosis zwischen den beiden Gruppen. Die Sinnhaftigkeit der Fortführung der AR-Therapie muss regelmäßig evaluiert werden und eine engmaschige Untersuchung des stomatognathen Systems ist von höchster Relevanz, um ein längeres Überleben bei guter Lebensqualität zu ermöglichen. / A serious side effect of anti-resorptive therapy (AR therapy) in multiple myeloma is medication-related osteonecrosis of the jaw. In this study, 50 patients with medication- related osteonecrosis of the jaw (MRONJ group) were compared to an equally sized control group without medication-related osteonecrosis of the jaw (KTRL group). In the MRONJ group, AR therapy lasted significantly longer than in the KTRL group (p < 0.001). MRONJ patients received AR therapy for an average of nearly 4 years, whereas KTRL patients received AR therapy for 2.5 years. In addition, the MRONJ patients were significantly more likely to receive AR therapy at a 4 week interval than the KTRL patients were (n = 49 vs. n = 36, p = 0.003). The median overall survival of the MRONJ group was significantly higher than the overall survival of the KTRL group (126 vs. 86 months, p = 0.013). The median overall survival of the entire patient population was 111 months. In addition, overall survival of all patients in this work correlated significantly with cumulative zoledronate dose (p < 0.001, r = 0.557). Classification into different stages and CRAB criteria showed no significant differences between groups at initial diagnosis. The reasons for the longer overall survival of the MRONJ group may be attributed to the differences in AR therapy. There was a significant difference in the duration of therapy, intervals administered, and cumulative zoledronate dose between the two groups. The usefulness of continuing AR therapy must be evaluated regularly, and close examination of the stomatognathic system is of paramount relevance to facilitate prolonged survival with good quality of life.

by Nellie Yuk Fei Chung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 111-120). / Abstract also in Chinese. / Abstract --- p.i / List of Abbreviations --- p.iii / Acknowledgements --- p.iv / Publication of this study --- p.vi / Table of Contents --- p.vii / Chapter Chapter1: --- Introduction --- p.1 / Chapter 1.1 --- Multiple Myeloma --- p.2 / Chapter 1.2 --- The Problem --- p.2 / Chapter Chapter2: --- Literature Review --- p.5 / Chapter 2.1 --- Molecular Genetics of Multiple Myeloma --- p.6 / Chapter 2.1.1 --- Cytogenetics --- p.6 / Chapter 2.2 --- Alterations of Proto-Oncogenes --- p.9 / Chapter 2.2.1 --- c-myc --- p.9 / Chapter 2.2.2 --- Ras --- p.10 / Chapter 2.2.3 --- Bcl-2 and Related Protein --- p.10 / Chapter 2.3 --- Alteration of Tumor-Suppressor genes --- p.11 / Chapter 2.3.1 --- p53 Gene Mutations --- p.11 / Chapter 2.3.2 --- Retinoblastoma (Rb) Gene --- p.11 / Chapter 2.3.3 --- p16 and p15 Genes --- p.13 / Chapter Chapter3: --- DNA Methylation and Cancers --- p.14 / Chapter 3.1 --- Role of DNA Methylation --- p.15 / Chapter 3.2 --- CpG Islands --- p.15 / Chapter 3.3 --- Abnormalities of DNA Methylation in Neoplasia --- p.16 / Chapter 3.3.1 --- DNA Hypomethylation in Cancer --- p.16 / Chapter 3.3.2 --- DNA Methyltransferase Activity in Cancer --- p.17 / Chapter 3.4 --- Regional DNA Hypermethylation in Cancer --- p.17 / Chapter 3.4.1 --- p16 and p15 Genes in Solid Tumors --- p.18 / Chapter 3.4.2 --- The p16 and p15 Genes in Leukemia and other Hematopoietic Malignancies --- p.19 / Chapter 3.4.3 --- Retinoblastoma Gene --- p.20 / Chapter 3.5 --- Mechanism Underlying the DNA Methylation Changes --- p.21 / Chapter Chapter4: --- Background of Study --- p.23 / Chapter 4.1 --- Background of Study --- p.24 / Chapter 4.2 --- Project Objectives --- p.27 / Chapter Chapter5: --- Materials and Methods --- p.29 / Chapter 5.1 --- Patients Samples --- p.30 / Chapter 5.2 --- Normal Controls --- p.30 / Chapter 5.3 --- Storage of the Samples --- p.32 / Chapter 5.4 --- Materials --- p.32 / Chapter 5.4.1 --- Chemicals --- p.32 / Chapter 5.4.2 --- Primers --- p.33 / Chapter 5.4.3 --- Enzymes --- p.35 / Chapter 5.5 --- Methods --- p.35 / Chapter 5.5.1 --- Cloning of p16 and p15 Exon 1 Probes for Southern Analysis --- p.35 / Chapter 5.5.1.1 --- PCR Amplification of p16 and p15 exon1 Probes from Normal Blood DNA --- p.35 / Chapter 5.5.1.2 --- Recovery and Purification of p16 and p15 Exon 1 DNA Fragment --- p.36 / Chapter 5.5.1.3 --- Ligation --- p.37 / Chapter 5.5.1.4 --- Transformation --- p.37 / Chapter 5.5.1.5 --- Plating --- p.38 / Chapter 5.5.1.6 --- Screening of Recombinant Plasmid --- p.38 / Chapter 5.5.1.7 --- Confirmation of Cloned DNA by Sequencing --- p.42 / Chapter 5.5.2 --- DNA Extraction and Purification --- p.45 / Chapter 5.5.2.1 --- DNA Extraction from Bone Marrow Aspirate and Peripheral Blood --- p.45 / Chapter 5.5.2.2 --- Isolation of Plasmid DNA from Transformant Cutures --- p.46 / Chapter 5.5.2.3 --- Qualification and Quantification of DNA --- p.49 / Chapter 5.5.3 --- Detection of Hypermethylation by Southern Analysis --- p.50 / Chapter 5.5.3.1 --- Restriction Enzyme Digestion --- p.50 / Chapter 5.5.3.2 --- Agarose Gel Electrophoresis --- p.51 / Chapter 5.5.3.3 --- Southern Transfer --- p.51 / Chapter 5.5.3.4 --- Membrane Fixation --- p.51 / Chapter 5.5.3.5 --- Recovery and Purification of p16 and p15 Exon 1 Probes from Plasmid --- p.52 / Chapter 5.5.3.6 --- Probe Labeling --- p.54 / Chapter 5.5.3.7 --- Purification of Radioactive labeled DNA --- p.54 / Chapter 5.5.3.8 --- Southern Hybridization --- p.55 / Chapter 5.5.3.9 --- Post Hybridization --- p.55 / Chapter 5.5.3.10 --- Autoradiography --- p.56 / Chapter 5.5.4 --- Polymerase Chain Reaction-Single Strand Conformational Polymorphism Analysis (PCR-SSCP) --- p.56 / Chapter 5.5.4.1 --- 5'- end Radioactive Labeling of Primer --- p.56 / Chapter 5.5.4.2 --- Amplification of Target Sequence by PCR --- p.57 / Chapter 5.5.4.3 --- Non-denaturing Polyacrylamide Gel Electrophresis --- p.57 / Chapter 5.5.4.4 --- Direct DNA Sequence of PCR Products --- p.58 / Chapter 5.5.5 --- Prevention of Overall Contamination in PCR --- p.60 / Chapter 5.5.6 --- "Sensitivity, Specificity Controls" --- p.62 / Chapter Chapter6: --- Results --- p.64 / Chapter 6.1 --- Patient Characteristics --- p.65 / Chapter 6.1.1 --- General Patient Characteristics --- p.65 / Chapter 6.1.2 --- Clinical and Laboratory Features --- p.65 / Chapter 6.2 --- Southern Blot Analysis of p16/p15 and Rb --- p.79 / Chapter 6.2.1 --- Absence of Deletions or hypermethylationin Normal Controls --- p.79 / Chapter 6.2.2 --- Absence of Homozygous Deletions or Mutationsin p16/15 and Rb among all MM Patients --- p.79 / Chapter 6.2.3 --- Hypermethylation of p16 --- p.89 / Chapter 6.2.4 --- Hypermethylation of p15 --- p.92 / Chapter 6.3 --- Hypermethylation of p16/p15 and Clinico-pathologic Correlation --- p.94 / Chapter Chapter7: --- Discussion --- p.97 / Chapter 7.1 --- "Absence of Homozygous Deletions, Gene Rearrangements and Mutations in p16/p15 and Rb" --- p.98 / Chapter 7.2 --- Hypermethylation of p16/p15-An Alternative Way for Gene Inactivation --- p.100 / Chapter 7.2.1 --- Methylation of p15 Gene --- p.101 / Chapter 7.2.2 --- Methylation of 5'-CpG Island of p16/p15 and Lack of Gene Expression --- p.102 / Chapter 7.2.3 --- Comparison of Methylation Status of Primary Samples and Cell Lines in MM --- p.103 / Chapter 7.2.4 --- Progressive Gene Inactivation by Random Methylation Errors --- p.104 / Chapter 7.2.5 --- The Lack of Correlation of Tumor Contents Revealed by the Southern Analysis and Morphologic Assessment --- p.105 / Chapter 7.3 --- Knudson's Two-hit Model of Tumorigenesis --- p.106 / Chapter 7.4 --- Inverse Relationship of p16 and Rb --- p.107 / Chapter 7.5 --- Implications of Our Findings --- p.109 / Chapter 7.6 --- Future Studies --- p.109 / References --- p.111