Multiple myeloma is characterized by the malignant proliferation of clonal plasma cells producing monoclonal paraproteins, leading to multi-organ damage. On the other hand monoclonal B-cell lymphocytosis (MBCL) is characterized by the malignant proliferation of clonal B-lymphocytes, with potential to develop into chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). CLL/SLL can result in visceromegaly, anemia, thrombocytopenia, fevers, night sweats and unintentional weight loss. Literature review demonstrates these two malignant clonal bone marrow disorders are most frequently seen independently in patients; however, we report one rare diagnostic challenge where both clonal disorders were identified in a single patient concurrently. A 64-year-old man initially presented with worsening back pain. Thoracic spine x-ray revealed a T11 compression fracture, confirmed by magnetic resonance imaging. Complete blood count revealed a white blood cell count of 7.3 K/uL with 54% lymphocyte predominance and peripheral smear demonstrated a population of small lymphocytes with round nuclei and an atypical chromatin pattern suggestive of CLL/MBCL. Flow cytometry revealed a monoclonal B-cell CD5 positive, CD23 positive, CD10 negative population with an absolute count of 1.6 K/uL. Due to the instability and pain associated with the spinal fracture, patient had kyphoplasty performed and intraoperative bone biopsies were taken from both T11 and T12 vertebrae. Interestingly each bone biopsy revealed involvement by both a kappa-light chain restricted plasma cell neoplasm, ranging from 15% to 30% cellularity, as well as a CD5-positive B-cell lymphocyte population. It suggested two concurrent but pathologically distinct pathologies including plasma cell myeloma and a separate B-cell lymphoproliferative disorder with immunophenotypic features suggestive of CLL/MBCL. Bone marrow biopsy was performed for definitive evaluation and confirmed multiple myeloma with 15-20% kappa-restricted plasma cells identified, and also confirmed concurrent MBCL with CD5 and CD23-positive, kappa-restricted B-cells identified on bone marrow flow cytometry. Adding an additional layer of complexity, bone marrow molecular genetics revealed presence of a MYD88 mutation, raising concern for possible lymphoplasmacytic lymphoma (LPL). However, secondary pathologic review ruled out LPL, as the immunophenotypic pattern of the clonal B-cells was not consistent with that of LPL, and although the MYD88 mutation is predominantly seen in LPL, it has also been seen in a small percentage of CLL/SLL cases and exceedingly rarely described in MM as well. Serum protein electrophoresis with immunofixation, serum quantitative immunoglobulins and serum quantitative free light chain assay revealed findings consistent with IgG kappa multiple myeloma and systemic CT imaging was negative for any lymphadenopathy, confirming MBCL. Patient was started on first-line multiple myeloma systemic therapy for transplant eligible patients and has demonstrated an excellent response to treatment thus far. This patient case serves to demonstrate the importance of maintaining a broad differential when approaching hematological problems; It also underlines the necessity for a complete diagnostic evaluation to identify rare clinical conundrums such as with our patient, allowing for proper and timely treatment. While we use “Occam’s razor” to explain multiple problems with a single unifying diagnosis the rare possibility of divergent diagnosis is to be always entertained.

Thalidomid ist eine in der Therapie des fortgeschrittenen refraktären oder rezidivierten multiplen Myeloms (MM) wirksame Substanz, obwohl dosislimitierende Toxizitäten (DLT) ihren Einsatz beschränken können. In der vorliegenden Phase-I-Studie mit 28 Patienten mit rezidiviertem oder refraktärem MM nach konventioneller Chemotherapie oder Hochdosis (HD)-Chemotherapie mit Stammzelltransplantation (SCT) konnte gezeigt werden, dass eine Kombination von niedrig dosiertem Thalidomid mit Bendamustin und Prednisolon (BPT) die Wirksamkeit beibehält oder erhöht und gleichzeitig keine DLT auftritt. Die BPT-Therapie umfasste eine Dosis von Bendamustin (60mg/m2) Tag 1, 8 und 15 und Prednisolon (100mg) Tag 1, 8, 15 und 22, und eine eskalierende tägliche Dosis Thalidomid (50, 100, 200mg). Die Behandlungszyklen wurden alle 28 Tage bis zum Auftreten des maximalen Ansprechens, DLT oder Fortschreiten der Erkrankung wiederholt. 24 Patienten sprachen nach mindestens zwei Zyklen auf die Therapie an (vier komplette, sechs sehr gute partielle und 14 partielle Remissionen). Das mediane progressionsfreie Überleben und Gesamtüberleben für alle Patienten betrug 11 und 19 Monate. Nur leichte oder mittelschwere nicht-hämatologische Nebenwirkungen wurden beobachtet und kein Patient entwickelte dosislimitierende Hämatotoxizitäten. Die BPT-Therapie weist bei Patienten mit rezidiviertem oder refraktärem MM eine gute Verträglichkeit mit einem Ansprechen von über 80% auf. Die maximal tolerierte Dosis von Thalidomid wurde in dieser Studie nicht erreicht.

Background: Individuals with metastatic bone disease (MBD) and multiple myeloma (MM) are commonly excluded from exercise oncology research due to safety concerns regarding potential skeletal complications including the incidence of pain, impaired mobility, pathological fracture, and spinal cord compression. However, over the past decade research has demonstrated that exercise is not only safe for this population but may offer other therapeutic benefits. To our knowledge, the specific perspectives and needs of individuals with MBD related to physical activity and exercise have not yet been explored. The objective of this study was to identify the attitudes towards and needs related to physical activity and exercise among individuals with MBD and MM. Methods: A phenomenological qualitative study utilizing a pragmatic approach to thematic analysis within a patient-oriented research framework was utilized. Semi-structured interview questions and various questionnaires were utilized to gather this descriptive information. Thematic analysis was completed using the 7-stage Framework Method, including transcription, familiarization, coding, analytical framework, and interpreting the data. Results: Of the 20 volunteer participants (90% male), four were living with MM (20%), and 16 had MBD diagnosed within 2-66 months of the study. Half of the participants did not report feeling any bone pain, with none experiencing severe bone pain, and eight (40%) experienced pain specifically with movement. Most participants engaged in a variety of physical activities and at various intensities, although 25% were found to be sedentary/insufficiently active. Five major themes emerged from the interviews including “meaning of physical activity”, “cancer care ‘exercise is medicine’ support (or lack thereof)”, “motivators to engage in physical activity”, “barriers causing a reduction in physical activity post diagnosis”, and “physical activity program preferences”. These themes encompassed a total of 32 categories and 44 subcategories, creating the overall thematic framework. Discussion: Individuals with MBD and MM do engage in regular physical activity, although differences in the frequency and intensity of exercise exist. Exercise has a recognized and valued role in their lives and health, including bone health. These patients are genuinely interested in some form of exercise program as part of their cancer care. Movement or activity modifications may be required for some based on bony lesions and fracture prevention. Differences may also be related to comorbidities, preferences, and/or abilities. While there is no “one size fits all” approach to oncology-based exercise prescription and implementation among this population, the findings of this study demonstrate that there is a strong patient-identified need to support those living with MBD and MM to engage in regular exercise in order to obtain its physical and psychological benefits. / Graduate / 2023-03-03

Neisseria meningitidis infection in humans usually manifests as meningitis and septicemia with skin manifestations. Infections of the respiratory tract with N meningitidis have been documented in the past, but often this organism is not routinely considered in the differential diagnosis of pneumonia. The pathogenic role of N meningitidis in lower respiratory tract infections may be underestimated because its isolation is difficult, particularly when oropharyngeal flora are present. We profile 2 elderly patients with primary meningococcal pneumonia to show the importance of Gram stain and culture in early diagnosis. These modalities helped guide treatment and prophylactic measures.

Chest pain is an extremely common presenting symptom that is usually related to a cardiac cause. This case illustrates an unusual presentation of multiple myeloma as a cause of atypical chest pain. This case presentation shows the importance of having a broad differential diagnosis while evaluating patients with atypical chest pain. It also illustrates the potential role of Tc-99m sestamibi imaging as a diagnostic modality in patients with multiple myeloma.

Indiana University-Purdue University Indianapolis (IUPUI) / Multiple myeloma (MM) is the most frequent cancer to involve the skeleton, with over 80% of myeloma patients developing lytic bone disease (MMBD). Importantly, MM-associated bone lesions rarely heal even when patients are in complete remission. Bone marrow stromal cells (BMSCs) isolated from MM patients have a distinct genetic profile and an impaired osteoblast (OB) differentiation capacity when compared to BMSCs from healthy donors. Utilizing an in vivo model of MMBD and patient samples, we showed that BMSCs from tumor-bearing bones failed to differentiate into OBs weeks after removal of MM cells. Both Runx2 and Osterix, the master transcription factors for OB differentiation, remained suppressed in these BMSCs. However, the molecular mechanisms for MM-induced long-term OB suppression are poorly understood. We characterized both Runx2 and Osterix promoters in murine pre-osteoblast MC4 cells by chromatin immunoprecipitation (ChIP). The transcriptional start sites (TSSs) of Runx2 and Osterix in untreated MC4 cells were co-occupied by transcriptionally active histone 3 lysine 4 tri-methylation (H3K4me3) and transcriptionally repressive histone 3 lysine 27 tri-methylation (H3K27me3), termed the “bivalent domain”. These bivalent domains became transcriptionally silent with increasing H3K27me3 levels when MC4 cells were co-cultured with MM cells or treated with TNF-α, an inflammatory cytokine increased in MM bone marrow microenvironment. The increasing H3K27me3 levels induced by MM cells or TNF-α were associated with the downregulation of the H3K27 demethylase JMJD3 in MC4 cells and murine BMSCs. Knockdown of JMJD3 in MC4 cells was sufficient to inhibit OB differentiation. Further, ectopic overexpression of JMJD3 in MC4 cells partially rescued the suppression of osteoblast differentiation induced by TNFa. We also found that pre-incubation of MC4 cells with the NF-kB inhibitor quinazoline (QNZ) before TNF-a treatment prevented the downregulation of JMJD3. In agreement with our in vitro findings, BMSCs from MM patients had persistently decreased JMJD3 expression compared to healthy BMSCs. Our findings together demonstrate that decreased JMJD3 expression in BMSCs contributes to the long-term OB suppression in MMBD by remodeling histone landscapes at the Runx2 and Osterix TSSs. Thus, developing strategies to restore JMJD3 expression in BMSCs should increase bone formation and possibly decrease tumor burden in MM.

No description available.

Multiple myeloma is an aggressive plasma cell cancer that consistently acquires multi-drug resistance and relapses despite initial treatment successes. Patients may go through greater than 10-lines of therapy, highlighting the need for more effective treatment options. Immunotherapies are the latest evolution in targeted cancer treatments, and thus far have displayed impressive results in several hematological cancers, including multiple myeloma. T cells possess robust anti-tumor functions which can be harnessed and refined for the treatment of cancers. Genetic engineering of T cells to express a chimeric antigen receptor (CAR) confers antigen-specific tumor-targeting, and adoptive transfer of patient-derived CAR-engineered T (CAR T) cells has been efficacious in relapsed/refractory multiple myeloma. Despite the high efficacy, CAR T cell therapy for myeloma is associated with serious adverse events, which limits dose levels and patient eligibility. We have developed a novel synthetic antigen receptor platform, called the T cell antigen coupler (TAC) receptor, which has shown comparatively higher efficacy with a reduced pro-inflammatory profile compared with CAR T cells in pre-clinical models. The TAC receptor was purpose-built to co-opt the natural T cell activation machinery and lacks the costimulatory signaling typically incorporated in CAR designs. This thesis investigates strategies to augment TAC T cell function against for multiple myeloma through the evaluation of ancillary pharmacological and protein stimuli that would complement the anti-tumor functions of TAC T cells without modifying the TAC receptor design. In chapter 2, I investigated a strategy combining TAC T cells with the SMAC mimetic LCL161 to provide transient costimulatory effects. While LCL161 boosted TAC T cells survival and proliferation, the drug also enhanced susceptibility of TAC T cells to apoptosis and offered no advantage to the TAC T cells when challenged with myeloma. In chapter 3, I engineered TAC T cells to secrete IL-27 in an attempt to modulate the myeloma microenvironment and support T cell cytolytic function. IL-27 did not enhance the anti-tumor activity of TAC T cells but forced expression of IL-27 led to a reduction in the production of pro-inflammatory cytokines without altering cytotoxicity. In appendix I, I describe the process of optimizing CRISPR/Cas9 editing of primary TAC T cells. This methodology was required for much of the work in chapter 2. Ph.D. Thesis – Arya Afsahi McMaster University – Biochemistry and Biomedical Sciences v In appendix II, I describe an assessment of mRNA-engineering as a method to produce TAC T cells. This approach proved to be therapeutically futile and was not pursued beyond the work described herein. The work presented here highlights methods of combining TAC T cells with a clinically relevant SMAC mimetic, or the cytokine IL-27, and provides insights into the biological mechanisms that are affected by these approaches. / Thesis / Doctor of Philosophy (PhD)

Multiple myeloma, or myeloma, is a bone marrow cancer which characterizes by uncontrolled proliferation of mutant plasma cells. It is a disease that claims many lives every year, mostly due to the absence of curative treatment. Finding a suitable treatment is therefor of great importance. One way to study different diseases is to use a gene editing method for knockdown or knockout of specific genes. The main aim of this project was to design guide RNAs, to be able to use CRISPR/Cas9 for knockout of the two genes BMPR1A and BMPR2 in different myeloma cell lines (KJON, INA-6 and IH-1). This, to be able to study the expression and function of these genes. Further aim of the project was to investigate potential SMAD activation by treatment with different bone morphogenetic proteins (BMPs). However, due to limited time this could not be carried through. Six guide RNAs were designed and ligated into pLentiCRISPRv2. Plasmid amplification was done by transformation of Escherichia coli. To check the quality of the plasmids, PCR, gel electrophoresis and Sanger sequencing was performed. The results from the gel electrophoresis showed that nine of the twelve samples for BMPR1A and seven of the thirteen samples for BMPR2, that were tested, were positive. The results from the Sanger sequencing confirmed that all guides that were tested (BMPR1A 3.2.3, BMPR1A 4.2.2, BMPR2 1.1.4 and BMPR2 2.1.2), were properly ligated into the plasmids. The main aim of the project was successfully accomplished, but additional work is needed for any further conclusions.

No description available.