Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma

This study estimated the risk of second primary malignancies after Hodgkin's lymphoma (HL) in relation to family history of cancer, age at diagnosis and latency, among 6946 patients treated for HL in Sweden in 1965–1995 identified through the Swedish Cancer Register (SCR). First-degree relatives (FDRs) to the HL patients and their malignancies were then ascertained together with their malignancies through the Multi-Generation Registry and SCR. The HL patient cohort was stratified on the number of FDRs with cancer, and standardised incidence ratios (SIRs) of developing SM were analysed. In the HL cohort, 781 SM were observed 1 year or longer after HL diagnosis. The risk for developing SM increased with the number of FDRs with cancer, SIRs being 2.26, 3.01, and 3.45 with 0, 1, or ⩾2 FDRs with cancer, respectively. Hodgkin's lymphoma long-term survivors treated at a young age with a family history of cancer carry an increased risk for developing SM and may represent a subgroup where standardised screening for the most common cancer sites could be offered in a stringent surveillance programme

Comparison of germinal center markers CD10, BCL6 and human germinal center-associated lymphoma (HGAL) in follicular lymphomas

<p>Abstract</p> <p>Background</p> <p>Recently, human germinal center-associated lymphoma (HGAL) gene protein has been proposed as an adjunctive follicular marker to CD10 and BCL6.</p> <p>Methods</p> <p>Our aim was to evaluate immunoreactivity for HGAL in 82 cases of follicular lymphomas (FLs) - 67 nodal, 5 cutaneous and 10 transformed - which were all analysed histologically, by immunohistochemistry and PCR.</p> <p>Results</p> <p>Immunostaining for HGAL was more frequently positive (97.6%) than that for BCL6 (92.7%) and CD10 (90.2%) in FLs; the cases negative for bcl6 and/or for CD10 were all positive for HGAL, whereas the two cases negative for HGAL were positive with BCL6; no difference in HGAL immunostaining was found among different malignant subtypes or grades.</p> <p>Conclusions</p> <p>Therefore, HGAL can be used in the immunostaining of FLs as the most sensitive germinal center (GC)-marker; when applied alone, it would half the immunostaining costs, reserving the use of the other two markers only to HGAL-negative cases.</p

How I treat splenomegaly in myelofibrosis

Symptomatic splenomegaly, a frequent manifestation of myelofibrosis (MF), represents a therapeutic challenge. It is frequently accompanied by constitutional symptoms and by anemia or other cytopenias, which make treatment difficult, as the latter are often worsened by most current therapies. Cytoreductive treatment, usually hydroxyurea, is the first-line therapy, being effective in around 40% of the patients, although the effect is often short lived. The immunomodulatory drugs, such as thalidomide or lenalidomide, rarely show a substantial activity in reducing the splenomegaly. Splenectomy can be considered in patients refractory to drug treatment, but the procedure involves substantial morbidity as well as a certain mortality risk and, therefore, patient selection is important. For patients not eligible for splenectomy, transient relief of the symptoms can be obtained with local radiotherapy that, in turn, can induce severe and long-lasting cytopenias. Allogeneic hemopoietic stem cell transplantation is the only treatment with the potential for curing MF but, due to its associated morbidity and mortality, is usually restricted to a minority of patients with poor risk features. A new class of drugs, the JAK2 inhibitors, although also palliative, are promising in the splenomegaly of MF and will probably change the therapeutic algorithm of this disease

Molecular genetics of lymphoid malignancies

A b s t r a c t MOLECULAR GENETICS OF LYMPHOID MALIGNANCIES Mats Merup, MD Department of Medicine, Karolinska Institute at Huddinge Hospital, 141 86 Huddinge and Radiumhemmet, Karolinska Hospital, 171 76 Stockholm, Sweden. Advances in molecular genetics during the last decade has made it possible to identify genetic lesions in malignant cells that are specific for disease entities with a common clinical presentation and prognosis. In chronic lymphocytic leukemia (CLL) deletions in 13ql4 are the most frequently occurring abnormalities and deletions cluster around marker D13S319 suggesting that a tumor suppressor gene is located in this region. Southern blot identifies deletions of D13S319 in more than 40% of CLL patients. Interphase FISH is equally efficient in detecting deletions and it also reveals that different subclones can occur with variable numbers of alleles in the D13S319 region. Trisomy 12 is the most common cytogenetic abnormality in CLL, but it is still unknown how this abnormality contributes to disease development or progression. In a detailed FISH analysis of a case with a chromosome 12 abnormality we found amplification of the 12ql3-15 region. The MDM2 gene was found to be most frequently amplified, suggesting that genes in this region can provide a growth advantage for CLL cells. Deletions of the long arm of chromosome 6 are frequently found in lymphoid malignancies. PCR analysis of loss of heterozygosity (LOH) revealed that deletions of 6q occur in 36% of acute lymphoblastic leukemia (ALL) cases, showing that this abnormality is more frequent than has been previously recognized. A minimal deleted region of 4 cM around marker D6S283 has been identified and our results suggest that this is the location of a tumor suppressor gene relevant for ALL. Our results also indicate that there is at least one more region on 6q that is commonly deleted in NHL that might contain a gene of interest for the development of high grade lymphomas. In B-CLL patients, deletions of 6q are found particularly in a subgroupt of patients with abberant, non-productive rearrangements of the genes for the B chain of the T-cell receptor. Abberrant TcR B gene rearrangement is a rare event in B-CLL occuring in 6% of patients. The reason for the connection between TcR B gene rearrangement and deletion of 6q is not clear. The BCL-2 protein, which can contribute to disease development and acquisition of resistance to drug therapy, is overexpressed in several different lymphoid malignancies including CLL. However, translocation of the BCL-2 gene seems to be a rare event occuring in 9% of the CLL cases. These results suggest that BCL-2 overexpression in CLL in most cases is caused by mechanism other than gene translocation. Cytogenetic studies suggest the presence of a candidate gene relevant for development of hairy cell leukemia (HCL) at chromosome 5ql3.3. We have defined a YAC clone spanning the breakpoint and two cosmid clones on either side of the breakpoint. Using the cosmids for interphase FISH analysis in HCL patients we detect breakpoints in subclones of the malignant cells. The defined region is closely connected to a recently reported breakpoint region found in AML and MDS, suggesting that the candidate gene in HCL may be identical to a gene that is deleted in myeloid malignancies. ISBN 91-628-2450-

X-bunden trombocytopeni med talassemi i två svenska familjer : Överväg hereditära orsaker till trombocytopeni och benmärgsfibros

[X-linked thrombocytopenia with thalassemia in two families in Sweden. Consider hereditary causes of thrombocytopenia and bone marrow fibrosis] (Engelsk titel)</p

The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with no known single predisposing genetic factor shown in all cases. Recently, a single nucleotide polymorphism (SNP) T393C in the GNAS1 gene has been reported to have a clinical impact on CLL progression and overall survival. In order to further investigate the T393C SNP in CLL, we have genotyped 279 CLL cases and correlated the genotypes to clinical outcome and other known prognostic factors such as the immunoglobulin heavy chain variable (IGHV) gene mutation status and CD38 expression. In the present study, no difference in overall survival or time to treatment was observed in the CLL patients with the different genotypes in contrast to the previous report. Furthermore, no correlation was observed with the T393C genotypes and IGHV mutational status, Binet stage or CD38 in this cohort. In summary, our data does not support the use of the T393C GNAS SNP as a clinical prognostic factor in CLL