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Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 1999. / Härtill 7 uppsatser.

Background: Burkitt lymphoma (BL) is a rare, highly aggressive B-cell malignancy treated most successfully with brief-duration, high-intensity chemotherapeutic regimens. The benefit of the addition of rituximab to these regimens remains uncertain. We sought to examine the effectiveness of chemotherapy with and without rituximab in patients with BL. Methods: This study is a retrospective cohort study of all adult patients with BL diagnosed and treated with modern, dose-intense chemotherapeutic regimens from 1998–2008 at two tertiary care institutions. All cases were confirmed by application of WHO 2008 criteria by hematopathologists. Medical records were reviewed for patient-, disease-, and treatment- related factors as well as treatment response and survival. Factors associated with survival were analyzed using Cox proportional hazards modeling. Results: A total of 35 patients were analyzed: 18 patients received rituximab with chemotherapy (R-chemo) and 17 received chemotherapy (chemo) alone. The median age was 42 (range 20–74 years); 57% were male; 71% had Ann Arbor Stage IV disease; 33% had central nervous system involvement; 78% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. R-chemo was associated with significantly longer overall survival (OS) than chemo alone (5-year OS 70% and 29%, respectively, p = 0.040). On multivariate regression analysis, poor performance status and central nervous system involvement were associated with poorer survival. The addition of rituximab to chemotherapy was associated with improved OS in patients with Burkitt lymphoma. Poor performance status and central nervous system involvement were prognostically significant on multivariate analysis.

Murine plasmacytoma models human cancers that involve deregulation of MYC. Overexpression and duplication of the immature colon carcinoma transcript 1 gene, Ict1, along with MYC deregulation may contribute to the aggressive mechanism for disease development in fast-onset mouse plasmacytomas. This study looks at Ict1 and c-MYC overexpression in mouse PreBmycER cells that serve as a cell culture model for MYC-dependent plasmacytomagenesis. An Ict1 inducible vector was transfected into the mouse PreBmycER cell line that contains inducible c-MYC. This allowed us to examine the effect of overexpression of ICT1 and c-MYC proteins simultaneously or each separately, on selected hallmark cancer cell traits such as increased proliferation, evasion of apoptosis and increased genomic instability. An increase in the number of cells in the S-phase was observed by 15 % and up to 20 % at 24 and 36 hours respectively, and cell doubling time shortened by almost 2 hours at 24 hours during peak ICT1 and c-MYC overexpression. Although, no noticeable change in apoptosis levels, or large scale genomic alterations were detected up to 96 hours post-ICT1 and c-MYC peak-overexpression, genomic instability was observed when MYC protein was overexpressed with or without ICT1 protein overexpression. Extrachromosomal elements increased in number and size during conditional MYC deregulation, and most of these elements (25 %) classified as Chromosome 11. These findings support Ict1 as a candidate gene that is selected for by MYC-deregulation during plasmacytomagenesis, and show promise that the experimental model of induced MYC and ICT1 overexpression in mouse PreB cells, deserves further investigation, specifically with in vivo studies. / October 2016

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Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references (leaves [85]-98).

Burkitt lymphoma is a highly aggressive B cell non-Hodgkin lymphoma characterized by the translocation t(8,14) and deregulation of the MYC gene on chromosome 8. The endemic (African) form presents classically as an expanding mass in the jaw. The nonendemic (European/North American) form often presents with an abdominal mass. We present an interesting case of Burkitt’s Lymphoma with atypical features. A thirty-five-year-old lady with no significant medical history presented to the hospital with a three week complaint of vaginal bleeding and lower abdominal pain/cramps associated with night sweats and chills. She underwent gynecologic workup with an ultrasound revealing endometrial thickening followed by a hysteroscopic Dilatation and Curettage procedure. Laboratory workup revealed direct hyperbilirubinemia and elevated liver enzymes. MRCP showed gallbladder wall thickening but no biliary obstruction. A diagnosis of acalculous cholecystitis was considered and she underwent a laproscopic cholecystectomy and liver biopsy. Her initial complete blood count revealed mild leukocytosis. Follow up lab work revealed worsening leukocytosis and a hematology consultation was sought. A peak WBC of 81,000 with peripheral blood blasts as high as 31% was noted. Peripheral smear exam revealed moderate sized immature wbc precursors/blasts with high nuclear-cytoplasmic ratio. Further hematological work up including bone marrow aspirate and biopsy was expedited. Pathology resulted positive for Burkitt's lymphoma/leukemia, positive molecular studies, t(8,14), involving bone marrow, gallbladder, liver and endometrium. Patient was emergently treated with dexamethasone and nitrogen mustard as elevated bilirubin levels precluded standard treatment. She was started on Rituxan as this neoplasm is a CD 20+ B cell malignancy but could not tolerate it. HyperCVAD multi-agent chemotherapy was subsequently initiated along with intrathecal chemotherapy (cytarabine and methotrexate). CSF cytology remained negative for lymphoma. Patient’s clinical condition has improved after 2 cycles of chemotherapy and she is currently receiving on going therapy. Burkitt’s lymphoma is one of the most aggressive neoplasms with a tumor doubling time of a few days. The usual presentation is with constitutional symptoms and adenopathy or a mass lesion, and sometimes may manifest solely in the peripheral circulation as an L3 variant of acute lymphoblastic leukemia. Hepatic parenchymal involvement is rare, but reported. Gallbladder involvement with endoluminal deposits is even rarer. Simultaneous hepatic, gallbladder, uterine, nodal and leukemic involvement at presentation is unique. Treatment is primarily with systemic chemotherapy and multi agent regimens effective in acute lymphoblastic leukemia and/or aggressive lymphomas have been used successfully in this condition with a complete response rate of 80%-90% with a long-term survival rate of approximately 60%. Therapy is fraught with risks of fatal tumor lysis syndrome, pancytopenia, infection/sepsis, and bleeding. Potential progression/relapse in the CNS with the CSF serving as a sanctuary site has been well documented necessitating prophylactic intra thecal chemotherapy administration as in our patient. Aggressive biology of this disease required urgent treatment, as delay in institution of combination chemotherapy could result in poor outcome. This case highlights the need to maintain an open mind while evaluating apparently routine symptoms and the importance of rapid diagnosis and treatment of a hematologic-oncologic emergency.

Background: We characterized B-cell non-Hodgkin lymphoma (NHL) cases over ten years at a tertiary children's hospital to contribute to the body of knowledge on pediatric lymphoma in developing countries with a high human immunodeficiency virus (HIV) burden. Methods: A retrospective cohort study using clinical and laboratory records of children newly diagnosed with B-cell NHL from January 2005 to December 2014. Results: Seventy-five children ≤ 15 years were included. The majority had Burkitt lymphoma (n = 61). Twenty-five percent (n = 19) were HIV positive and 16% (n = 12) had concurrent active tuberculosis. Bulky disease was present in 65.7% (n = 46) and 30.1% (n = 22) were classified as Lymphomes Malins B (LMB) risk group C. The five year survival estimates for HIV-negative and HIV-positive children were similar in our cohort: 81% vs. 79% for eventfree survival and 85% vs. 83.9% for overall survival. Of three children with Burkitt lymphoma, HIV and LMB group C, two died within one year. Conclusions: Irrespective of HIV status, the survival of children in our B-cell NHL cohort compares favorably with cure rates in developed nations, although advanced disease remains associated with a poor prognosis. Characterization of childhood NHL cases contributes to accurate risk stratification and tailored treatment.

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