Papers by Christer Sundström
Journal of Experimental Medicine, 2013
DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversi... more DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis.
European Journal of Haematology, 2009
An unusual case of IgE-producing non-Hodgkin lymphoma (NHL) is presented. The patient's h... more An unusual case of IgE-producing non-Hodgkin lymphoma (NHL) is presented. The patient's history included a 6-year period of increasing IgE level before a low grade NHL was diagnosed. The patient developed lymph node, skin, bone marrow and lung infiltrations. With a cytostatic combination therapy a temporary improvement was achieved, but the patient died from progressive disease after 2 yr. The morphological appearance of the tumour varied between that of LP immunocytoma and a centrocytic lymphoma. Immunophenotype studies showed intracytoplasmic IgE lambda in tumour cells and B-cell surface phenotype (BB-1 pos; OKT 10 pos; PCA weakly pos and SIgE lambda).
Upsala Journal of Medical Sciences, 1973
In an infant who died when less than one hour old, with clear morphological signs of cytomegalovi... more In an infant who died when less than one hour old, with clear morphological signs of cytomegalovirus infection in the liver, kidneys, lungs and pancreas, cell degeneration and necrosis were observed in the islets of Langerhans, with CMV cells and insulitis. Electronmicroscopically all three types of islet cells showed signs of involvement, but this was most distinct in the cells. No symptoms of diabetes had been observed.
Inflammation, 1990
The origin of myeloperoxidase (MPO) in bronchoalveolar lavage (BAL)
International Journal of Cancer, 1983
Different types of human cells which normally grow as monolayers or suspension cultures were test... more Different types of human cells which normally grow as monolayers or suspension cultures were tested for their capacity to form and grow as spheroids. Sixteen out of the 27 tested tumour cell lines formed spheroids. Nearly all of these spheroids also grew. With only two exceptions the doubling times were longer when the tumour cells grew as spheroids than when they grew in conventional mass culture. Eleven out of 13 tested human non-tumour cells formed small spheroids but of these only the spheroids of lymphoid origin could grow. These lymphoid cells grew faster when aggregated to spheroids than when in singlecell suspension culture. None of the other non-tumour cells, which normally grew as monolayers, could grow as spheroids. The normally monolayer-cultured tumour cells formed symmetrical spheroids with smooth surfaces while the normally suspension-cultured cells formed irregular spheroids with rough surfaces. All large spheroids had a necrotic centre surrounded by a shell of viable cells.
International Journal of Cancer, 1994
The semi-automated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement ... more The semi-automated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) by viable cells, was employed for cytotoxic drug sensitivity testing of tumor cells from patients with hematological or solid tumors. In total, 390 samples from 20 diagnoses were tested with up to I 2 standard cytotoxic drugs. The technical success rate for different tumor types ranged from 67 to 95%.
Acta Oncologica
Twenty-two patients with relapsed or progressive B-cell lymphomas (BCL) were analysed for alterat... more Twenty-two patients with relapsed or progressive B-cell lymphomas (BCL) were analysed for alterations in the rearrangement status in the immunoglobulin heavy (IgH) chain gene in samples obtained on different occasions during the course of the disease. The analysis was performed using Southern blot hybridization of the IgH gene and polymerase chain reaction (PCR) amplification of the VH gene families combined with single-strand conformation polymorphism (SSCP) analysis. Using Southern blot analysis, we found that all 22 lymphomas displayed clonal IgH rearrangements, and changes during tumour progression occurred in 8 cases. These alterations were mainly observed in cases with follicular or transformed lymphomas. More than one malignant (sub)clone, indicated by more than two rearranged bands, was detected in one case at diagnosis and in three cases at relapse. Outgrowth of subclones with divergent rearrangement patterns in different compartments was also observed in 2 out of 8 cases. PCR-SSCP analysis indicated that all 15 cases studied displayed clonal rearrangements and in 6 cases altered rearrangement patterns were detected in later samples. Southern blotting and PCR-SCCP analysis gave equivalent results. No association was found between time to relapse or survival time and alterations in rearrangement pattern. The present study illustrates that the neoplastic cell clones in BCL often display alterations in their IgH locus, but the significance of this feature remains to be clarified.
Acta Radiologica
To evaluate the role of CT with and without clinical information as compared to CT-guided bone bi... more To evaluate the role of CT with and without clinical information as compared to CT-guided bone biopsy in the assessment of suspected bone metastases. The study comprised 51 consecutive patients with suspected bone metastases who had undergone CT-guided bone biopsies with an eccentric drill system. CT of the targets, clinical information, and histopathology were scored separately as malignant, uncertain or benign. The results of CT alone and CT in combination with clinical information were compared to the results of histopathology. Histopathology diagnosed 45/51 lesions (88%), 23 as malignant and 22 as benign. CT correctly depicted 17 of these 23 malignant lesions. The remaining 6 malignant lesions were CT-scored as uncertain (n = 5) or benign (n = 1). CT correctly depicted only 3 of the 22 benign lesions. The remaining 19 benign lesions were CT-scored as malignant (n = 2) or uncertain (n = 17). When uncertain CT scores were combined with clinical scores, the true-positive and true-negative results for malignancy increased from 44% to 82%. In most cases, CT in combination with clinical information gives enough information about the nature-malignant or benign-of a skeletal lesion. In uncertain cases, diagnostic accuracy can be improved by means of CT-guided bone biopsy.
Apmis
A series of 55 biopsies from different types of malignant lymphomas were characterized in short-t... more A series of 55 biopsies from different types of malignant lymphomas were characterized in short-term culture experiments and during prolonged growth in vitro. The majority of the lymphocytic lymphomas and half of the histiocytic lymphomas expressed surface immunoglobulin, either in monoclonal or polyclonal form, indicating B-lymphocyte derivation. No lysozyme production was noted in either type of lymphoma, giving further support to the notion that histiocytic lymphomas are not truly histiocytic. Production of β-microglobulin was higher in histiocytic than in lymphocytic lymphoma and Hodgkin's disease but did not significantly differ from the production observed in non-neoplastic lymph node disorders. Incorporation of 3H-thymidine varied greatly within each category of lymphoma;the highest mean labelling index was noted in histiocytic lymphoma, possibly reflecting the generally more malignant course in such cases. Epstein-Barr virus-associated nuclear antigen was observed in one...
Skeletal Radiology, 1979
ABSTRACT A case of Majewski Syndrome is described with roentgen and pathoanatomic examination inc... more ABSTRACT A case of Majewski Syndrome is described with roentgen and pathoanatomic examination including proximal and distal epiphyses. Dysplastic involvement of all the embryonic tissue layers is demonstrated. The microscopic involvement of the bone appears to be similar to that described in the Ellis-Van Creveld syndrome, but is generally more pronounced. An autosomal recessive inheritance is assumed for this syndrome. Differentiation from other types of short-rib polydactyly syndromes is discussed.
Leukemia & Lymphoma, 2002
Patients with relapsing Hodgkin&a... more Patients with relapsing Hodgkin's lymphoma (HL) have a rather poor prognosis and mechanisms that lead to resistance to therapy are poorly understood. Our aims were to investigate the immunohistochemical staining patterns of Rb (retinoblastoma protein) and the p53 tumour suppressor protein in HL at initial presentation and at relapse in order to elucidate a possible role in disease progression and resistance to therapy. Further to evaluate the presence and prognostic importance of Epstein-Barr virus (EBV) and anaplastic lymphoma kinase (ALK). Eighty-one cases of relapsing HL were reexamined histopathologically and immunostained for the expression of p53, Rb, ALK and CD30. EBV was detected with LMP-1 stainings and in situ hybridisation for EBER. Clinical data were extracted from the Swedish National Health Care Programme for HL. Median follow-up time was six years (range 0-12) from the date of relapse. The majority of cases were positive for p53 and Rb both at presentation and at relapse, though to a different extent. Both an increase and a decrease in the proportion of stained tumour cells were observed. None of our cases was ALK-positive and 44% were EBV-positive. No specific staining pattern was directly correlated to survival. In 12 patients a switch in HL subtype from diagnosis to relapse was observed and the five-year Hodgkin-specific survival (HLS) was statistically significantly inferior, 37 vs 81% (p = 0.002), in those patients. We found a significant relation between the expression of p53 and EBV at diagnosis and relapse, indicating a clonal relationship. We were unable to find any specific staining pattern of p53 or Rb, affecting survival.
International Journal of Cancer, 1997
The occurrence of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) appearing in the same i... more The occurrence of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) appearing in the same individual indicates a closer relationship between the 2 diseases than previously believed. The purpose of our study was to analyze cases of HD and NHL in a defined population clinically, histopathologically and immunohistochemically to look for similarities indicating a common cellular origin. Between 1974 and 1994, 77 individuals were identified from the Swedish Cancer Registry and the National Health Care Programme for HD as potentially having both diagnoses. Thirty-two patients who had both HD and NHL were available for histo-pathological re-examination and immunohistochemical staining with CD30, CD15, LMP, p53, CD45 (LCA), CD3, CD45R0 (UCHL-1), L26, MB2 and CD45R (4KB5). The most common relation was HD preceding a high-grade malignant NHL (16 of 32 patients), unexpectedly often of T-cell phenotype (7 of 16 patients). The next common association was NHL of B-CLL type followed by HD (7 of 32 patients). At clinical presentation, the first lymphoma did not differ from lymphomas not associated with a second lymphoma, whereas the second one often appeared with a disseminated and aggressive clinical form. There was a significant correlation between the expression of p53 and LMP in first and second lymphomas. CD3 antibody was frequently expressed both in HD and NHL, whereas positivity for B-cell-related antibodies, CD30, CD15 and CD45R0, was less frequent and generally lower than previously described. The occurrence of HD and NHL in an individual is unusual. Tumour biological features common to both HD and NHL may indicate a similar cellular origin, regardless of the time interval between the diagnoses, and may contribute to the understanding of the pathogenesis of lymphoma. Int.
International Archives of Occupational and Environmental Health, 2005
Objectives: To evaluate the use of cellular and cordless telephones as the risk factor for non-Ho... more Objectives: To evaluate the use of cellular and cordless telephones as the risk factor for non-Hodgkin's lymphoma (NHL). Methods: Male and female subjects aged 18-74 years living in Sweden were included during a period from 1 December 1999 to 30 April 2002. Controls were selected from the national population registry. Exposure to different agents was assessed by questionnaire. Results: In total, 910 (91%) cases and 1016 (92%) controls participated. NHL of the B-cell type was not associated with the use of cellular or cordless telephones.
Diagnostic Molecular Pathology, 1997
Four different detection systems were compared for evaluation of polymerase chain reaction (PCR) ... more Four different detection systems were compared for evaluation of polymerase chain reaction (PCR) amplified immunoglobulin heavy-chain gene rearrangements in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) of B-cell lineage. In 63.0% of the fragments detected by ethidium bromide stained agarose gel electrophoresis (Agarose-EtBr) the sensitivity was insufficient to separate the specific clonal population from the background of normal B cells. Using polyacrylamide gel electrophoresis (PAGE), PAGE combined with single-strand conformation polymorphism (PAGE-SSCP) and PhastGel-SSCP (Phast-SSCP) analysis with silver staining, the resolution was improved and the majority of the inconclusive amplicons were elucidated. However, Phast-SSCP displayed a slightly higher detection level compared to PAGE and PAGE-SSCP. According to our findings PAGE-SSCP and Phast-SSCP were superior to agarose-EtBr and PAGE in detecting new emerging clones and clonal evolution.
Clinical Lymphoma and Myeloma, 2008
Arachidonic acid metabolites have been suggested to play an important role in carcinogenesis. We ... more Arachidonic acid metabolites have been suggested to play an important role in carcinogenesis. We have recently reported that the cysteinyl leukotriene receptor 1 (CysLT1) and 15-lipoxygenase-1 (15-LO-1) are expressed by the malignant Hodgkin Reed-Sternberg cells of Hodgkin lymphoma and certain Hodgkin lymphoma cell lines, and that these cells convert arachidonic acid to the novel proinflammatory eoxins. The expression of the CysLT1 receptor and 15-LO-1 was investigated in a broad range of non-Hodgkin lymphomas (NHLs) by immunohistochemistry. The functionality of the CysLT1 receptor in primary mediastinal B-cell lymphoma (PMBCL) cell lines was studied by calcium mobilization assays. Primary mediastinal B-cell lymphoma was the only NHL entity showing tumor cells positive for the CysLT1 receptor (9 of 10 tumors), and the PMBCL cell line Med-B1 expressed functional CysLT1 receptors, responding with a robust calcium signal upon cysteinyl leukotriene challenge. Furthermore, the tumor cells in 1 of 4 T-cell-derived anaplastic large-cell lymphomas, in contrast to all other studied NHLs, strongly expressed 15-LO-1. Among the NHL entities included in this study, the CysLT1 receptor was exclusively expressed by the tumor cells of PMBCL. Thus, this further corroborates the pathologic overlap between PMBCL and classical Hodgkin lymphoma.
British Journal of Haematology, 2002
Evaluating the potential benefit of the new anthracycline, idarubicin (Ida), in lymphoma, 58 tumo... more Evaluating the potential benefit of the new anthracycline, idarubicin (Ida), in lymphoma, 58 tumour samples from patients suffering from low-grade non-Hodgkin's lymphoma (L-NHL), were analysed in vitro for their sensitivity to 0AE5 lg/ml Ida. This was compared with the sensitivity to other anthracyclines (0AE5 lg/ml), using the fluorometric microculture cytotoxicity assay. A total of 132 samples from patients with acute leukaemia and a cell-line panel representing different resistance mechanisms was included for comparison. The median cell survival of L-NHL cells did not differ after exposing the cells to Ida or daunorubicin (Dnr), whereas epirubicin, doxorubicin (Dox) and mitoxantrone (Mitox) were significantly less cytotoxic than Ida (P < 0AE001). The median cell survival in L-NHL cells did not differ from that of acute leukaemia cells after exposure to 0AE5 lg/ml Ida, Dnr, Dox and Mitox. Cells from previously treated patients with L-NHL had a higher median survival than cells from untreated patients after exposure to all drugs, except for Ida. In samples from previously untreated patients, Spearman rank correlations were high (Rho ¼ 0AE81-0AE90) between cell survival after exposure to Ida and the other anthracyclines. The same pattern was observed in the cell-line panel (Rho ¼ 0AE78-0AE91) (P < 0AE05). In contrast, low correlations (Rho ¼ 0AE24-0AE42) were observed among samples from previously treated patients. Our results indicate a potential benefit of Ida in previously drug-treated patients with L-NHL.
Annals of Oncology, 1994
Alteration of morphological appearance as well as of clinical behaviour is common in relapsing no... more Alteration of morphological appearance as well as of clinical behaviour is common in relapsing non-Hodgkin&#39;s lymphomas. The aim of this study was to investigate the stability of the genes encoding the immunoglobulin heavy-chain and the T-cell receptor during the course of the disease in relapsing non-Hodgkin&#39;s lymphomas. Nineteen patients with relapsed or progressive non-Hodgkin&#39;s lymphomas were analysed with respect to alterations of the restriction fragment length polymorphism (RFLP) pattern for Ig heavy chain (IgH) using probes for the C mu and J regions and for T-cell receptor (T-beta, T-gamma chain) genes. DNA was extracted from tumour material taken at different occasions during the course of the disease. All 19 cases showed clonal rearrangements of the IgH locus, and 2 cases showed simultaneous rearrangement of the genes coding for the T-cell receptors. Three or more rearranged bands, indicating more than one malignant clone, were detected in 1 case at the time of the diagnosis and in 5/19 (26%) cases in DNA from samples taken at relapse, all 6 cases showing discordant or transformed morphology. Altogether, in 11 out of 19 cases (58%), changes of the IgH rearrangement pattern could be visualized by RFLP. In all these cases except one, the new RFLP pattern included at least one rearranged band from the pattern of the first taken sample. In one case a clonal T-gamma receptor gene rearrangement was detected in a diagnostic sample but not in a sample taken at relapse. In 4 out of 6 cases with transformed lymphomas, clonal changes were observed at time of transformation. Evolution of clones with different RFLP patterns in different compartments were observed in 1 out of 6 studied cases. The present study illustrates that non-Hodgkin&#39;s lymphomas are unstable in their IgH genome. The observations of clonal evolution, multiclonality, and different clones in different compartments offer an explanation to the troublesome situation when treating relapsed lymphomas.
Acta Radiologica, 1995
Twenty-eight consecutive CT (n = 23) or ultrasonographically (n = 5) guided biopsy procedures wer... more Twenty-eight consecutive CT (n = 23) or ultrasonographically (n = 5) guided biopsy procedures were performed on musculoskeletal lytic lesions covered (n = 13) or not covered (n = 15) with intact bone. Specimens were obtained by means of Biopty techniques (n = 27), i.e. Biopty and Monopty instruments, through different cannulas with normal or shortened needle-throws. Four out of 5 bone penetrations were successful with an Ostycut needle, and all 8 bone penetrations by a coaxial bone biopsy system with an eccentric drill. The eccentric drill makes a hole in the cortical bone larger than the diameter of the outer cannula of this system, making it easy to anchor the cannula and then coaxially insert a Biopty-Gun needle for example. The overall histopathological diagnostic accuracy of the Biopty techniques was 25/27 (92.6%).
Leukemia Research, 2011
The p16(INK4a) tumor suppressor gene can be inactivated by a variety of events including promoter... more The p16(INK4a) tumor suppressor gene can be inactivated by a variety of events including promoter hypermethylation. In diffuse large B-cell lymphoma (DLBCL), p16(INK4a) methylation has been associated with advanced disease stage and higher IPI. The prognostic impact of p16(INK4a) methylation in DLBCL remains unclear; however, it has been suggested to correlate with inferior outcome. To further investigate the clinical impact of p16(INK4a) methylation in DLBCL, promoter methylation of this gene was assessed quantitatively by pyrosequencing. Forty-two of 113 (37%) DLBCL patients with methylation level above 5% were categorized as methylated and subsequently divided into low, intermediate and high methylation categories. Overall, no association was shown between the extent of p16(INK4a) methylation and patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; clinical characteristics, except disease stage (P=0.049). Moreover, we could not reveal any impact of p16(INK4a) methylation on lymphoma-specific survival. Although &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;25% of p16(INK4a) methylation correlated with a better progression-free survival (P=0.048) in patients &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;65 years old, the significance of this finding, if any, needs to be further investigated. In conclusion, our finding questions the role of p16(INK4a) promoter methylation as a negative prognostic factor in DLBCL.
Annals of the Rheumatic Diseases, 2013
ABSTRACT Background Lymphoma risk in RA remains a concern, in particular the long-term risks with... more ABSTRACT Background Lymphoma risk in RA remains a concern, in particular the long-term risks with biological therapies. Objectives To extend assessments of relative risks, and of distribution of subtypes, of malignant lymphomas in patients with RA starting biological therapies Methods Data from the Swedish Biologics Register (ARTIS) were cross-linked with nation-wide population-based registers: the Patient Register, the Cancer Register, and the Total Population Register. Incidences of a first malignant lymphoma in patients starting a first anti-TNF therapy 1998 through 2010 (n=10,998) within a nation-wide cohort of patients with RA (n=42,230, censored at first start of anti-TNF therapy), and in a matched general population referent cohort (n=170,649) were compared using Cox’ regression (hazard ratios (HR)), taking age, sex, calendar time, selected co-morbidities, and family history of lymphoma into account. Patients were considered at risk since start of first anti-TNF therapy. HRs were assessed overall and per age and accumulated time of active anti-TNF therapy. Following histopathological review, the distribution of lymphoma subtypes was compared to previously reported distributions of biologics-naive RA-lymphomas 1964-1995 from our group (1) and to the distribution in general lymphoma patients ( National Swedish Lymphoma Register 2000-2006). Results Whereas both anti-TNF treated (45 lymphomas/56,493 person-years) and anti-TNF naive RA patients (185 lymphomas/197,056 person-years) were at increased risk compared to the general population (407 lymphomas/873,326 person-years), HR=2.2 (95% CI 1.6-2.9) and HR=1.9 (95%CI 1.6-2.3), respectively, the incidence of lymphoma following start of anti-TNF therapy was not higher than in anti-TNF naive RA, HR=1.1 (95%CI 0.8-1.6, Table). There was no obvious trend in HRs with accumulated time on active anti-TNF therapy, nor any appreciable difference in HRs across attained age during follow-up. The overall distribution of B-cell, T-cell and Hodgkin lymphoma was similar among anti-TNF treated RA, anti-TNF naive RA, and the general population lymphoma patients. Diffuse large B-cell lymphoma was numerically more frequent in anti-TNF treated RA (34%) than in general lymphoma patients (24%), but was lower than in biologics-naive RA from the pre-biologic era (48%). Of all anti-TNF treated lymphomas, 75 % had been treated with only one biologic. Conclusions In this study, the already increased lymphoma risk in patients with RA does not seem to increase further following anti-TNF therapy, at least not following up to 5-10 years of active treatment, nor did we find any treatment-related excess risk in younger or older adults. The distribution of lymphoma subtypes was not markedly different from that in general lymphoma patients. References Baecklund et al, Arthritis Rheum, 2006 Disclosure of Interest None Declared
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Papers by Christer Sundström