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.

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

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.

Primary lymphoma of bone: extranodal lymphoma with favourable survival independent of germinal centre, post-germinal centre or indeterminate phenotype.

AIMS: To determine prognostic significance of immunohistochemical markers and investigate possible germinal centre (GC) derivation in primary lymphoma of bone (PLB). METHODS: Immunohistochemical expression of BCL-6, CD10, BCL-2, p53, CD30, CD44 and MUM-1 was studied in 36 patients with PLB. All cases were clinically staged and cases of secondary bone involvement of primary nodal lymphomas were excluded, prior to immunostaining. Clinical charts were reviewed for clinical symptoms and therapy given; survival post-biopsy was calculated. RESULTS: All patients presented with pain and a palpable mass. The majority showed centroblastic-multilobated morphology; half of the cases (19/36) had a GC phenotype (CD10+BCL-6+ or CD10-BCL-6+MUM-1-), whereas 8/36 cases had a non-GC phenotype (CD10-BCL-6- or CD10-BCL-6+MUM-1+). Nine cases were of indeterminate phenotype (CD10-BCL-6+; MUM-1 not available). Eight of 22 evaluated patient samples showed immunoreactivity for MUM-1. Most patients (31/36) received combination therapy in the form of polychemotherapy and radiotherapy. The five-year overall survival was 75%. No significant difference in survival was found between the three different tumour phenotypes, or for the tested antigens individually. Age at presentation and stage of disease had a significant influence on five-year overall survival. Survival rates were 90% for the patients <60 years of age and 40% for those > or =60 years. Survival rates were 90% for stage I and 41% for stage IV. CONCLUSION: This study illustrates the homogeneity of PLB. The majority of cases are of the GC phenotype which has a favourable prognosis.

[A patient with an extremely severe immunohaemolytic anemia due to diclofenac]. / Een patiënt met zeer ernstige immuunhemolytische anemie veroorzaakt door diclofenac.

A 77-year-old male was diagnosed with immunohaemolytic anaemia. He presented with fever, jaundice and oliguric renal insufficiency. He had been taking diclofenac for three days. Additional examinations and tests revealed a Coombs-positive haemolytic anaemia and thrombopenia. The micro-card gel-agglutination test demonstrated antibodies against diclofenac metabolites. After discontinuation of diclofenac and short-term treatment with prednisone and haemodialysis for two days, the patient made an almost full recovery. Haemolytic anaemia caused by diclofenac is rare. It can be caused by autoantibodies against erythrocytes and complement-fixing antibodies that bind to erythrocytes only in the presence of diclofenac or its metabolites. A timely diagnosis-supported by the appropriate laboratory tests--is of critical importance in this rare but extremely serious complication of the use of diclofenac. The treatment consists of withdrawal of diclofenac and supportive measures, possibly in combination with immunosuppressants.

Primary non-Hodgkin's lymphoma of bone: a clinicopathological investigation of 60 cases.

A retrospective analysis of patients presenting with primary lymphoma of bone (PLB) was performed to determine clinical factors affecting prognosis in relation to histological subtype and treatment outcome. Data from 106 patients, presenting with a PLB between 1943 and 1996, were retrieved from the files of the Netherlands Committee on Bone Tumours and Leiden University Medical Centre. The lymphomas were reclassified according to the REAL and updated Kiel classification. The clinical presentation, survival and prognostic factors were investigated. Sixty patients had sufficient clinical information and adequate follow-up to be included in the study. All 33 PLB that could be immunophenotyped were of B cell origin. According to the REAL classification, most PLB were large (B) cell lymphomas (92%) and according to the Kiel classification 45% of the tumours were centroblastic multilobated. PLB presented most often in the long bones (48%), with Ann Arbor stage I (46%), II (16%), IV (16%) and unknown (20%). Stage IV disease was exclusively caused by the presence of multiple bone lesions. Notwithstanding the heterogeneous treatment, the 5-year overall survival was 61%; 46% of patients were progression free at 5 years. Patients at presentation older than 60 had a worse overall survival (76% vs 37%, P = 0.0002) and a worse progression-free period (58% vs 28%, P = 0.0073). Patients with the immunoblastic subtype had a worse survival than the centroblastic mono/polymorphic subtype or the centroblastic multilobated subtype (P = 0.015). Primary lymphoma of bone represents an uncommon bone tumour with a relatively homogeneous morphology and clinical behaviour. Compared to other aggressive lymphomas, PLB have a favourable prognosis.

Correlation of volumetric magnetization transfer imaging with clinical data in MS.

We examined the relations between quantitative volumetric estimates of cerebral lesion load based on magnetization transfer imaging (MTI), clinical data, and measures of neuropsychological function in 44 patients with clinically diagnosed MS. In this population we assessed the correlation between several volumetric MTI measures, measures of neurologic function (Kurtzke Expanded Disability Status Scale and Ambulation Index), and disease duration using Spearman's correlation coefficient. Patients were classified on the basis of neuropsychological test performance as severely impaired, moderately impaired, and normal. We assessed differences between these groups with respect to MTI results using the Kruskal-Wallis test. MTI measures corrected for brain volume were found to correlate with disease duration (p < 0.01) and showed suggestive correlations with measures of neurologic impairment (p < 0.05). Individual neuropsychological tests correlated with MTI measures corrected and not corrected for brain volume (p < 0.001). An MTI measure not corrected for brain volume differed (p < 0.05) between severely impaired, moderately impaired, and normal patients. These preliminary results suggest that volumetric MTI analysis provides new measures that reflect more accurately the global lesion load in the brain of MS patients, and they may serve as a method to study the natural course of the disease and as an outcome measure to evaluate the effect of drugs.

Global volumetric estimation of disease burden in multiple sclerosis based on magnetization transfer imaging.

We report a semiautomated postprocessing method based on magnetization transfer MR imaging that can quantify the extent of global disease in patients with multiple sclerosis. The technique combines segmentation and quantitative analysis of imaging data reflecting the structural integrity of white matter. Applications of this technique may include assessment of disease progress and of the efficacy of experimental therapeutic intervention. The height of the histogram peak corresponding to white matter was found to be lowered in patients with multiple sclerosis and the overall distribution of magnetization transfer ratios was shifted to lower values.