Primary diffuse large B-cell lymphoma of bone

This thesis describes a study on primary diffuse large B cell lymphoma of bone with large patient numbers in chapter 2. The tumor presents mostly in the long bones. The clinical outcome is usually favorable. We found a trend towards worse survival for the immunoblastic tumor subtype. In chapter three, We studied the MRI characteristics of 29 bone lymphoma patients. The majority of the patients displayed a combination of definite cortical abnormalities and extension to the soft tissue, but up to 31% of the patients showed MRI features that looked radiologically non-aggressive or even benign. In chapter four, we determined the prognostic significance of BCL-6, CD10, MUM1, BCL-2, p53, CD30 and CD44. Applying the Hans__ algorithm, we concluded that 19 out of a cohort of 36 cases displayed a germinal center-like phenotype. No significant influence on survival was found. In chapter five, we investigated genomic alterations in nine cases. We found several recurrent genomic aberrations, but none had statistically significant prognostic influence. The most frequent finding was five cases with gain of 1q (five out of nine cases) and 2p16.1 amplification (four out of nine cases). In chapter six we investigated 50 cases for involvement of aberrant NF-_B activation by performing immunohistochemical stainings. In a minority (19%) of cases, we found substantial nuclear staining of p50. The nuclear expression of p50 was not preferentially detected in non-germinal center or germinal center type cases, or related to an inferior prognosis.Roche, Celgene, Novartis oncology, Medisch centrum haaglandenUBL - phd migration 201

A case of angioimmunoblastic T-cell non-Hodgkin lymphoma with a neocentric inv dup(1)

Neocentromeres are rare epigenetic phenomena in which functional centromeres are formed onto novel chromosomal locations without any a-satellite DNA. To date, constitutional human neocentromeres have been reported in at least 90 cases. In cancer, however, the knowledge is much more limited. Acquired neocentromeres have been described in a particular class of lipomatous tumors (atypical lipomas and well-differentiated liposarcomas; ALP-WDLPS), three cases of acute myeloid leukemia (AML), one case of non-Hodgkin lymphoma (NHL), and one case of lung carcinoma. Here, we report on a 66-year-old male with angioimmunoblastic T-cell NHL. Cytogenetic analysis of his bone marrow showed multiple aberrations, including the presence of a supernumerary chromosome. Using the fluorescence in situ hybridization technique, the supernumerary chromosome was demonstrated to be entirely composed of material derived from chromosome I. It represented an inverted duplication of the segments between 1q21 and 1qter with a neocentromere in band 1q31. To our knowledge, this is the second reported case of NHL (both T-cell) with the presence of a neocentromere. The occurrence of neocentromeres in tumor cells, however, may be underestimated because of technical limitations during the routine diagnostic chromosomal analysis. The prognostic impact is therefore currently unknown. (C) 2010 Elsevier Inc. All rights reserved.Hereditary cancer genetic

Array-based comparative genomic hybridisation analysis reveals recurrent chromosomal alterations in primary diffuse large B cell lymphoma of bone

Aims Primary non-Hodgkin's lymphoma of bone (PLB) is a rare subtype of primary extranodal diffuse large B cell lymphoma. PLB has morphological homogeneity and a relatively favourable clinical behaviour. Recent studies report that array-based comparative genomic hybridisation (array-CGH) analysis can be used to classify lymphomas into clinically and biologically relevant phenotypes and possibly reveal differences in oncogenic mechanisms. Here the authors performed the first array-CGH study to detect illness related genomic alterations in nine, clinically well-staged primary lymphoma of bone cases. Methods Nine frozen samples from primary lymphoma of bone patients were immunophenotyped and subsequently investigated using a well-established array-CGH platform. The array-CGH results were confirmed by fluorescence in situ hybridisation. Clinical data and follow-up were obtained for all nine patients. Results Of the nine patients, eight reached complete remission, and one had progressive disease and died of primary lymphoma of bone. Frequent aberrations were: loss of 14q32 (n=7), trisomy 7 (n=6), gain of the long arm of chromosome 1 (n=5) and amplification of 2p16.1 (n=4). No statistically significant correlation between genetic abnormalities and clinical outcome was found. Conclusions The authors found several recurrent genomic aberrations, including five cases with gain of 1q and four cases with 2p16.1 amplification. These findings are associated with a germinal centre-like phenotype and favourable treatment outcome, and differ from chromosomal aberrations found in other extranodal lymphomas. These findings further substantiate the notion that primary lymphoma of bone should be considered as a distinct entity not only on clinic-pathological grounds but also on the genomic level as well.Molecular tumour pathology - and tumour genetic

Quality of life in long-term survivors of acute pulmonary embolism.

Contains fulltext : 89526.pdf (publisher's version ) (Closed access)BACKGROUND: To our knowledge, studies evaluating the quality of life (QoL) in patients with a history of acute pulmonary embolism (PE) are not available, even though QoL is a key outcome component of medical care and a predictor of disease-specific prognosis. METHODS: As part of a large follow-up study, the Short Form 36 (SF-36) was presented to consecutive patients who had survived one or more episodes of acute PE. The results of all nine subscales of the SF-36 were compared with sex- and age-adjusted Dutch population norms. Single and multivariate analyses were performed to identify independent determinants of the QoL in our study population. RESULTS: The SF-36 was completed by 392 patients. Except for the health change subscale, patients had substantially lower QoL than population norms on all eight remaining subscales. After multivariate analysis, the time interval between the last thromboembolic episode and study inclusion was inversely related to QoL, and significant determinants of poor QoL were prior PE, age, obesity, active malignancy, and cardiopulmonary comorbid conditions. Regression models that included all identified significant determinants proved to be quite modest predictors for QoL in the individual patient. Awareness of illness, coping mechanisms, and self-management behavior might be additional important indicators of QoL in our study population but require further investigation. CONCLUSION: We identified several PE- and non-PE-related determinants of QoL in patients with a history of acute PE, which is impaired compared with sex- and age-adjusted population norms. QoL after acute PE should be studied more extensively and added as a standard measure to outcome studies.1 december 201

Patient outcomes after acute pulmonary embolism. A pooled survival analysis of different adverse events.

Contains fulltext : 89853.pdf (publisher's version ) (Closed access)RATIONALE: There is a lack of information on the long-term prognosis of patients with acute pulmonary embolism (PE). OBJECTIVES: To assess the long-term risk for adverse events after PE. METHODS: Consecutive patients diagnosed with PE between January 2001 and July 2007, and patients in whom PE was ruled out from a previous study were followed until July 2008 for the occurrence of adverse clinical events: mortality, symptomatic recurrent venous thromboembolism, cancer, arterial cardiovascular events and chronic thromboembolic pulmonary hypertension. Hazard ratios (HR) for all endpoints and a combined endpoint were calculated and adjusted for potential confounders. MEASUREMENTS AND MAIN RESULTS: Three hundred eight patients with unprovoked, 558 with provoked, and 334 without PE were studied with a median follow-up period of 3.3 years. Patients with unprovoked PE had a lower overall risk for mortality than patients with provoked PE (HR, 0.59; 95% confidence interval [CI], 0.43-0.82), but a higher risk for nonmalignancy-related mortality (HR, 1.8; 95% CI, 1.3-2.5), recurrent venous thromboembolism (HR, 2.1; 95% CI, 1.3-3.1), cancer (HR, 4.4; 95% CI, 2.0-10), cardiovascular events (HR, 2.6; 95% CI, 1.5-3.8) and chronic thromboembolic pulmonary hypertension (1.5 vs. 0%). The risk for the combined endpoint did not differ between both groups (HR, 0.98; 95% CI, 0.82-1.1). Patients without PE had similar risks for malignancy and cardiovascular events than patients with provoked PE, but lower risks for the remaining outcomes. The fraction of both patients with provoked and unprovoked PE without events after 1 year was only 70% and decreased to fewer than 60% after 2 years and fewer than 50% after 4 years, whereas this latter was 84% for the control patients. CONCLUSIONS: The clinical course of acute PE is complicated by high rates of serious adverse events, which occur in half of the patients within 4 years

Prevalence and potential determinants of exertional dyspnea after acute pulmonary embolism.

Contains fulltext : 89635.pdf (publisher's version ) (Closed access)BACKGROUND: The exact prevalence and etiology of exertional dyspnea in the clinical course of acute pulmonary embolism (PE) have not yet been established. METHODS: A large cohort of consecutive patients diagnosed with acute PE was subjected to a dyspnea questionnaire and invited for cardiopulmonary work-up including the 6-min walk test, spirometry and echocardiography. The prevalence, severity, determinants and underlying diseases of exertional dyspnea were evaluated. RESULTS: Of the registered 877 patients, 259 (30%) had died and 11 (1.3%) were excluded for geographical reasons. From the remaining 607 patients, 217 reported exertional dyspnea (36%; 95% CI 32-40%) 3.6 +/- 1.7 years after the PE. In 76% this dyspnea had developed or worsened after the acute PE. 421 patients completed the cardiopulmonary work-up. Cardiopulmonary comorbidity (OR 12; 95% CI 6.5-20), advanced age (OR 1.02 per year; 95% CI 1.01-1.03), higher BMI (OR 1.06 per kg/m(2); 95% CI 1.01-1.1) and a smoking history (OR 1.6; 95% CI 1.02-2.6) were identified as independent predictors of exertional dyspnea. A pre-defined dyspnea explaining diagnosis could be established in all patients with exertional dyspnea. In only 4 patients, this diagnosis was directly correlated to the acute PE. Increased severity of dyspnea was associated with decreased exercise performance (p < 0.001) and a higher number of dyspnea-related diagnoses (p < 0.001). CONCLUSION: Exertional dyspnea is a frequent symptom in the long term clinical course of acute PE. More severe dyspnea results in decreased exercise capacity and increased burden of cardiopulmonary comorbidity. This dyspnea is likely to be unrelated to the past thromboembolic event in the vast majority of patients.1 november 201