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

Leung Sau Ching. / Thesis submitted in: October 2003. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 142-165). / Abstracts in English and Chinese. / Acknowledgments --- p.ii / Abstract (English Version) --- p.iii / Abstract (Chinese Version) --- p.vi / Table of Contents --- p.viii / List of Tables --- p.xii / List of Figures --- p.xiii / List of Abbreviations --- p.xv / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Multiple Myeloma (MM) --- p.1 / Chapter 1.1.1 --- Epidemiology --- p.3 / Chapter 1.1.2 --- Clinical and Pathologic Features of MM --- p.3 / Chapter 1.1.3 --- Diagnosis and Staging --- p.4 / Chapter 1.1.4 --- Prognosis --- p.6 / Chapter 1.1.5 --- Treatment --- p.7 / Chapter 1.2 --- Molecular Abnormalities of MM --- p.8 / Chapter 1.2.1 --- Genetic Alterations: Chromosomal Aberrations --- p.8 / Chapter 1.2.2 --- Genetic Alterations: Ras Mutations --- p.11 / Chapter CHAPTER 2 --- LITERATURE REVIEW --- p.12 / Chapter 2.1 --- Epigenetic Alterations: DNA Methylation --- p.12 / Chapter 2.1.1 --- Characteristics of CpG Island --- p.14 / Chapter 2.1.2 --- Mechanism of Methylation-Related Gene Silencing --- p.14 / Chapter 2.1.3 --- DNA Methylation Is Important for Normal Cellular Functions --- p.17 / Chapter 2.1.4 --- DNA Methylation Changes in Cancer Cells --- p.17 / Chapter 2.1.5 --- Global DNA Hypomethylation --- p.18 / Chapter 2.1.6 --- Regional DNA Hypermethylation --- p.20 / Chapter 2.1.6.1 --- De Novo Methylation --- p.21 / Chapter 2.1.6.2 --- DNA Hypermethylation Acts as a Third Pathway to Loss of Function in Carcinogenesis --- p.21 / Chapter 2.1.6.3 --- DNA Hypermethylation Contributes to Tumorigenesis --- p.25 / Chapter 2.1.6.4 --- Methodologies in the Study of DNA Hypermethylation --- p.26 / Chapter 2.1.6.5 --- Single Gene Hypermethylation --- p.28 / Chapter 2.1.6.6 --- Multiple Gene Hypermethylation --- p.30 / Chapter 2.1.6.7 --- Potential Clinical Applications of DNA Hypermethylation --- p.36 / Chapter 2.1.6.7.1 --- Tumor Cells Detection by 5'CpG Island Hypermethylation --- p.37 / Chapter 2.1.6.7.2 --- Prognostic and Predictive Significances of DNA Hypermethylation --- p.39 / Chapter 2.1.6.7.3 --- Therapeutic Intervention of CpG island Hypermethylation --- p.40 / Chapter 2.2 --- DNA Hypermethylation in MM and MGUS --- p.43 / Chapter 2.3 --- Six-Genes Panel for the Hypermethylation Study --- p.45 / Chapter 2.3.1 --- Apoptotic Pathway: DAP-kinase --- p.45 / Chapter 2.3.2 --- Retinoid Signaling Pathway: RARβ --- p.50 / Chapter 2.3.3 --- Angiogenic Pathway: THBS-1 --- p.52 / Chapter 2.3.4 --- Cell cycle Regulatory Pathway: pl6 and p15 --- p.57 / Chapter 2.3.5 --- Ras Signaling Pathway: RASSF1A --- p.62 / Chapter CHAPTER 3 --- BACKGROUND OF STUDY --- p.67 / Chapter 3.1 --- Rationale --- p.67 / Chapter 3.2 --- Hypothesis --- p.69 / Chapter 3.3 --- The Objectives of Study --- p.70 / Chapter CHAPTER 4 --- MATERIALS AND METHODS --- p.71 / Chapter 4.1 --- Culture of Human Multiple Myeloma (MM)-derived Cell Lines --- p.71 / Chapter 4.2 --- Demethylation Treatment --- p.72 / Chapter 4.3 --- Patient and Control Samples --- p.72 / Chapter 4.4 --- DNA Extraction --- p.73 / Chapter 4.5 --- MS-PCR --- p.73 / Chapter 4.6 --- Plasma Cell Isolation --- p.77 / Chapter 4.7 --- RNA Extraction and RT-PCR --- p.78 / Chapter 4.8 --- Statistics --- p.82 / Chapter CHAPTER 5 --- RESULTS --- p.84 / Chapter 5.1 --- Patient Characteristics --- p.84 / Chapter 5.2 --- Single Gene Hypermethylation --- p.87 / Chapter 5.2.1 --- Normal PB Did Not Show Methylation --- p.87 / Chapter 5.2.2 --- DNA Hypermethylation in Human MM-derived Cell Lines --- p.87 / Chapter 5.2.3 --- DNA Hypermethylation in Primary MM --- p.89 / Chapter 5.3 --- Demethylation Treatment --- p.93 / Chapter 5.4 --- Concurrent Hypermethylation --- p.96 / Chapter 5.5 --- Statistical Analyses of Primary MM --- p.101 / Chapter 5.5.1 --- Statistical Analyses Between Single Gene Hypermethylation and Clinical Parameters (Categorical) --- p.101 / Chapter 5.5.2 --- Statistical Analyses Between Single Gene Hypermethylation and Clinical Parameters (Non-Categorical) --- p.101 / Chapter 5.5.3 --- Survival Analyses of Single Gene Hypermethylation --- p.105 / Chapter 5.5.4 --- Correlation Analyses of Concurrent Hypermethylation --- p.107 / Chapter 5.5.5 --- Correlation Analyses Between Concurrent Hypermethylation and Clinical Parameters --- p.107 / Chapter CHAPTER 6 --- DISCUSSION --- p.110 / Chapter 6.1 --- Involvement of Cellular Pathways by Hypermethylation --- p.111 / Chapter 6.1.1 --- Apoptotic Pathway: DAP-kinase and RARβ --- p.111 / Chapter 6.1.2 --- "Cell Cycle Regulatory Pathway: p16, p15 and RASSF1A" --- p.113 / Chapter 6.1.3 --- Angiogenic Pathway: THBS-1 --- p.117 / Chapter 6.2 --- Hypermethylation-Associated Gene Silencing --- p.119 / Chapter 6.3 --- Hypermethylation in Cell Lines and Primary MM --- p.120 / Chapter 6.4 --- Concurrent Hypermethylation --- p.122 / Chapter 6.4.1 --- DNA Hypermethylation is Common in MM --- p.122 / Chapter 6.4.2 --- Extent of Hypermethylation --- p.123 / Chapter 6.4.3 --- Involvement of Cellular Pathways by DNA Hypermethylation --- p.124 / Chapter 6.4.4 --- Concurrent p16 and DAP-kinase Hypermethylation --- p.126 / Chapter 6.5 --- Clinical Applications of DNA Hypermethylation --- p.129 / Chapter 6.5.1 --- Methylation As Tumor Markers for MM --- p.129 / Chapter 6.5.2 --- Prognostic Implications of DNA Hypermethylation in MM --- p.130 / Chapter 6.5.3 --- Correlations Between DNA Hypermethylation and Clinical Parameters --- p.131 / Chapter 6.6 --- MS-PCR --- p.136 / Chapter CHAPTER 7 --- CONCLUSION --- p.137 / Chapter CHAPTER 8 --- FURTHER STUDIES --- p.140 / References --- p.142

Non-Secretory Multiple Myeloma (NSMM) is characterized by typical morphological and pathological multiple myeloma (MM) characteristics and the absence of an M-protein on immunofixation electrophoresis with estimated prevalence of 3%. Among the NSMM cases there is a subset in which no cytoplasmic Immunoglobulin synthesis is detected, and this entity is called ‘’Non-Producing’’ Multiple Myeloma (NPMM). Plasma cell leukemia (PCL) is an aggressive form of MM characterized by high levels of abnormal plasma cells circulating in the peripheral blood. We present a rare case of non-producing variant of PCL. 75-year-old male was admitted due to anemia and thrombocytopenia. His CBC revealed hemoglobin of 9.0 g/dl and platelets were 9 k/ul. CMP showed creatinine of 1.34 mg/dl, total protein of 6 g/dl, albumin 3.6 g/dl and corrected calcium was normal. LDH was 204 IU/L. Peripheral smear review showed 8% circulating atypical plasmacytoid cells, normochromic normocytic anemia and thrombocytopenia. SPEP showed no monoclonal protein. IgA was normal. IgG, IgM were low 315 mg/dl and 20 mg/dl respectively. Serum beta-2 microglobulin was high (5.5, 1.1 – 2.4 mg/dl). Serum free kappa light chain was low (0.15, 0.33-1.94 mg/dl), lambda light chain and ratio was normal. Skeletal survey showed possible lytic lesions in right femur neck and subtrochanteric left femur. Bone marrow biopsy showed plasma cell myeloma involving 90-95% of bone marrow cellularity. The plasma cells show morphologic heterogeneity with prominent immature, plasmablastic and pleomorphic morphology. Flow cytometry shows a dominant abnormal CD45-dim population with expression of CD38, CD138, CD56 and CD117 (partial). The abnormal cells are negative for cytoplasmic kappa and lambda immunoglobulin light chains and negative for myeloid and lymphoid markers (by flow cytometry and immunohistochemical stains). Complex chromosomal analysis. Plasma cell FISH studies was positive for t(11;14). Based on suggested revised diagnostic criteria for PCL from outcomes of patients at mayo clinic, our patient was diagnosed with plasma cell leukemia. Given aggressive biology of this disease, he was started on VD-PACE chemotherapy. Bone marrow biopsy after cycle 1 chemotherapy showed no morphologic, immunophenotypic or flow cytometric features of a plasma cell neoplasm. Given excellent treatment response and discussion with transplant center subsequent cycle 2 was changed to Velcade, Revlimid and low-dose dexamethasone. He is scheduled for stem cell transplant later this month. Primary plasma cell leukemia (pPCL) is the most aggressive form of the plasma cell dyscrasias. The outcome of pPCL has improved with the introduction of autologous stem cell transplantation and combination approaches with novel agents, including bortezomib and immunomodulatory drugs, such as lenalidomide. This case highlights the challenges in diagnosis of non-producer primary plasma cell leukemia.

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

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Multiple myeloma is a bone marrow malignancy characterized by the presence of monoclonal plasma cells. In 50-75% of myeloma patients, chromosome translocations at the IgH locus are observed, which result in overexpression of oncogenes from the translocated chromosome due to linkage with the IgH enhancers. IgH enhancer activity is mediated by the B cell-specific transcription factors Bob1 and Oct2. We hypothesized that inhibiting the IgH enhancer, through inhibition of Bob1 and Oct2, is a potential therapeutic strategy for translocation-positive myeloma. The expression and prognostic value of Bob1 and Oct2 in myeloma patient samples were assayed. High Bob1 expression was associated with increased survival, whereas high Oct2 expression was associated with reduced survival. In a t(4;14) myeloma cell line, Bob1 inhibition led to decreased expression of the translocated oncogene, FGFR3; however, this did not lead to decreased proliferation or increased apoptosis. To fully understand the roles of Bob1 and Oct2 in myeloma, further research is required. / Experimental Oncology