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Information about the conference entitled "Leukemia and lymphoma development—the role of inflammation, autoimmunity and infections" that was held in May 2008 in Stockholm, Sweden. The conference aims to create an opportunity to gather preclinical, clinical and epidemiological experts from various research fields to discuss the risk factors and the possible mechanisms behind leukemia and lymphoma development. It also focuses on lymphoid malignancies such as Hodgkin lymphoma.

Gene panel sequencing has become a common diagnostic tool for detecting somatically acquired mutations in myeloid neoplasms. However, many panels have restricted content, provide insufficient sensitivity levels, or lack clinically validated workflows. We here describe the development and validation of the Genomic Medicine Sweden myeloid gene panel (GMS-MGP), a capture-based 191 gene panel including mandatory genes in contemporary guidelines as well as emerging candidates. The GMS-MGP displayed uniform coverage across all targets, including recognized difficult GC-rich areas. The validation of 117 previously described somatic variants showed a 100% concordance with a limit-of-detection of a 0.5% variant allele frequency (VAF), achieved by utilizing error correction and filtering against a panel-of-normals. A national interlaboratory comparison investigating 56 somatic variants demonstrated highly concordant results in both detection rate and reported VAFs. In addition, prospective analysis of 323 patients analyzed with the GMS-MGP as part of standard-of-care identified clinically significant genes as well as recurrent mutations in less well-studied genes. In conclusion, the GMS-MGP workflow supports sensitive detection of all clinically relevant genes, facilitates novel findings, and is, based on the capture-based design, easy to update once new guidelines become available. The GMS-MGP provides an important step toward nationally harmonized precision diagnostics of myeloid malignancies., (© 2024 The Author(s). Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Aims and Background: Whole-genome sequencing (WGS) is increasingly applied in clinical practice and expected to replace standard-of-care (SoC) genetic diagnostics in hematological malignancies. This study aims to assess and compare the fully burdened cost ('micro-costing') per patient for Swedish laboratories using WGS and SoC, respectively, in pediatric and adult patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)., Methods: The resource use and cost details associated with SoC, e.g. chromosome banding analysis, fluorescent in situ hybridization, and targeted sequencing analysis, were collected via activity-based costing methods from four diagnostic laboratories. For WGS, corresponding data was collected from two of the centers. A simulation-based scenario model was developed for analyzing the WGS cost based on different annual sample throughput to evaluate economy of scale., Results: The average SoC total cost per patient was €2,465 for pediatric AML and €2,201 for pediatric ALL, while in adults, the corresponding cost was €2,458 for AML and €1,207 for ALL. The average WGS cost (90x tumor/30x normal; sequenced on the Illumina NovaSeq 6000 platform) was estimated to €3,472 based on an annual throughput of 2,500 analyses, however, with an annual volume of 7,500 analyses the average cost would decrease by 23% to €2,671., Conclusion: In summary, WGS is currently more costly than SoC, however the cost can be reduced by utilizing laboratories with higher throughput and by the expected decline in cost of reagents. Our data provides guidance to decision-makers for the resource allocation needed when implementing WGS in diagnostics of hematological malignancies.

Over the last decades, rapid technological and scientific advances have led to a merge of molecular sciences and clinical medicine, resulting in a better understanding of disease mechanisms and the development of novel therapies that exploit specific molecular lesions or profiles driving disease. Precision oncology is here used as an example, illustrating the potential of precision/personalized medicine that also holds great promise in other medical fields. Real-world implementation can only be achieved by dedicated healthcare connected centers which amass and build up interdisciplinary expertise reflecting the complexity of precision medicine. Networks of such centers are ideally suited for a nation-wide outreach offering access to precision medicine to patients independent of their place of residence. Two of these multicentric initiatives, Genomic Medicine Sweden (GMS) and the Centers for Personalized Medicine (ZPM) initiative in Germany have teamed up to present and share their views on core concepts, potentials, challenges, and future developments in precision medicine. Together with other initiatives worldwide, GMS and ZPM aim at providing a robust and sustainable framework, covering all components from technology development to clinical trials, ethical and legal aspects as well as involvement of all relevant stakeholders, including patients and policymakers in the field., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Considering treatment changes and an improved prognosis of non-Hodgkin lymphoma (NHL) over time, knowledge regarding long-term health outcomes, including late effects of treatment, has become increasingly important. We report on time trends of second primary malignancies (SPMs) in Swedish NHL patients, encompassing the years before as well as after the introduction of anti-CD20 antibody therapy. We identified NHL patients in the Swedish Cancer Register 1993 to 2014 and matched comparators from the Swedish Total Population Register. The matched cohort was followed through 2017. By linking to the Swedish Lymphoma Register, subcohort analyses by NHL subtype were performed. Flexible parametric survival models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of SPM among patients and comparators. Among 32 100 NHL patients, 3619 solid tumors and 217 myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) cases were observed, corresponding to a 40% higher rate of solid tumors (HRsolid tumors = 1.4; 95% CI, 1.4-1.5) and a 5-fold higher rate of MDS/AML (HRMDS/AML = 5.2; 95% CI, 4.4-6.2) than for comparators. Overall, the observed excess risks for solid tumors or MDS/AML remained stable over the study period, except for follicular lymphoma, where the excess rate of MDS/AML attenuated with time (P for trend = .012). We conclude that NHL survivors have an increased risk of both solid tumors and hematologic malignancies, in particular MDS/AML. Stable excess risks over time indicate that contemporary treatment standards are not associated with modified SPM risk. Encouragingly, decreasing rates of MDS/AML were noted among patients with follicular lymphoma, possibly due to the increasing use of nonchemotherapy-based treatments., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The Genomic Medicine Sweden (GMS) initiative aims to strengthen precision medicine across the country. This will be accomplished through the implementation of large-scale sequencing techniques in Swedish healthcare. With a patient-centered view, initial efforts will focus on rare diseases, cancer, pharmacogenomics, and infectious diseases, and subsequently extend to complex diseases. GMS is being implemented as a broad collaborative project involving healthcare, universities with medical faculty, SciLifeLab, industry and patient organizations. To deliver top tier diagnostics, regional genomic medicine centers (GMC) are currently under establishment together with a national informatics infrastructure for data sharing. GMS will also offer a unique resource for research that could pave the way for the development of novel drugs, and enhance collaboration with industry. In summary, GMS provides Sweden with an opportunity to take an international forefront position in the field of precision medicine.

Objectives: To investigate concordance in survival time among first-degree relatives with lymphoid malignancies., Methods: By linkage of national Swedish registers, we identified 66 430 patients diagnosed with a lymphoid malignancy 1958-2016 with information on first-degree relationships and follow-up until 2017. Among these, we identified pairs of first-degree relatives with any (N = 3326) or a similar (N = 690) lymphoid malignancy subtype. We defined survival in the first-degree relative as good, expected, or poor based on tertiles of deviance residuals from a multivariable Cox regression model. Next, we used Cox regression to estimate hazard ratios (HR) of death with 95% confidence intervals (CI) among patients, using the survival of their first-degree relative as exposure and adjusting for confounders., Results: There was no concordance in survival among first-degree relatives with any lymphoid malignancy (HR good  = 1.00 (reference), HR Expected  = 1.02, 95% CI: 0.89-1.17, HR Poor  = 1.12, 95% CI: 0.98-1.27, P trend  = .08). Among first-degree relatives with indolent lymphoma, including chronic lymphocytic leukemia, those with a first-degree relative to an expected or poor survival had worse outcome compared to those with a first-degree relative with good survival (HR Expected  = 1.44, 95% CI: 0.82-2.53, HR Poor  = 1.79, 95% CI: 1.07-3.00, P trend  = .03)., Conclusion: Our results support a role of inherited factors in the outcome of indolent lymphoma, including chronic lymphocytic leukemia., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Bendamustine + rituximab (BR) is the current first-line standard-of-care for chronic lymphocytic leukaemia (CLL) in fit patients aged 66-70 years, whereas chlorambucil + CD20 antibody is recommended in older patients with co-morbidities. This retrospective real-world study investigated whether risk-adapted BR was safe and effective in elderly patients. All 141 CLL patients in the Stockholm region (diagnosed from 2007 to 2016, identified from regional registries) who had received BR as first (n = 84) or later line (n = 57) were analysed. Median age was 72 years, 49% had Binet stage C, 40% had Cumulative Illness Rating Scale (CIRS) score ≥ 6, 20% Eastern Cooperative Oncology Group (ECOG) score 2. None had del(17p). Only 15% of patients aged ≥80 years received full-dose bendamustine and 65% of them postponed rituximab until cycle 2. Corresponding numbers in patients 73-79 years were 21% and 36% and in <73 years, 63% and 33%. Overall response rate was 83% (first line) and 67% (later line) (P < 0·022) equally distributed between age subsets. ECOG, immunoglobulin heavy chain variable region (IGHV) mutational status and cytogenetics, but not treatment line and age, were significant factors on progression-free survival (PFS) in multivariate analysis. Infections and neutropenia/thrombocytopenia (≥grade 3) were similar across age subgroups. In summary, BR was well tolerated even in patients ≥80 years, with similar efficacy and safety as in less old patients, provided that carefully adapted dosing was applied., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome., (© 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

This study explored the informational needs of individuals attending genetic counseling for hereditary cancer, using a free-choice and a forced choice method. Prior to the consultation the informational needs of 334 counselees from Sweden and Norway were assessed by the QUOTE-gene (ca) questionnaire and by a study specific forced choice method, using Q-methodology. Questionnaire responses indicated that counselees' major concerns pertained to the need to be taken seriously, to be provided with sufficient risk estimation and medical/genetic information and to be involved in the decision making process. Furthermore, prior to counseling, counselees noted that the counselors' consideration and skillfulness were also extremely important. Analysis of the Q-sorting results revealed that counselees' needs could be assigned to one of five groups: the "need for facts; caring communication and medical information; information and support in communicating the genetic information to others; practical care and practical/medical information". Particularly noteworthy, counselees with varying backgrounds characteristics prioritized different needs. Cancer genetic counselees probably have different needs due to their medical and demographic background when attending genetic counseling. Addressing counselees' specific concerns more sufficiently and thereby increasing the overall effectiveness of the counseling session requires increased insight into individual needs, by for instance, utilizing screening methods such as QUOTE-gene (ca) prior to the counseling session.

Advances in next-generation RNA-sequencing have revealed the complexity of transcriptomes by allowing both coding and noncoding(nc)RNAs to be analyzed. However, limited data exist regarding the whole transcriptional landscape of chronic lymphocytic leukemia(CLL). In this pilot-study, we evaluated RNA-sequencing in CLL by comparing two subsets which carry almost identical or "stereotyped" B-cell receptors with distinct clinical outcome, that is the poor-prognostic subset #1 (n 5 4) and the more favorable-prognostic subset #4(n 5 4). Our analysis revealed that 156 genes (e.g. LPL, WNT9A) and 76 ncRNAs, (e.g. SNORD48, SNORD115) were differentially expressed between the subsets. This technology also enabled us to identify numerous subset-specific splice variants (n 5 406), which were predominantly expressed in subset #1, including a splice-isoform of MSI2 with a novel start exon. A further important application of RNA-sequencing was for mutation detection and revealed 16–30 missense mutations per sample; notably many of these changes were found in genes with a strong potential for involvement in CLL pathogenesis, e.g., ATM and NOTCH2.This study not only demonstrates the effectiveness of RNA-sequencing for identifying mutations, quantifying gene expression and detecting splicing events, but also highlights the potential such global approaches have to significantly advance our understanding of the molecular mechanisms behind CLL development.

Unlabelled: The IGHV3-21 gene has been shown to be overrepresented in Scandinavian patients with chronic lymphocytic leukemia (CLL). By investigating a population-based cohort of 337 Swedish patients with CLL, a lower (6.5%)IGHV3-21 frequency was determined relative to our previous hospital-based studies (10.1%-12.7%), yet this frequency remained higher compared to other Western CLL cohorts (2.6%-4.1%). Furthermore, we confirmed the poor outcome for patients with IGHV3-21 to be independent of mutational and stereotypy status., Background: Scandinavian patients with CLL have shown an overrepresentation of the poor-prognostic IGHV3-21 gene. Furthermore, approximately 50% of patients with IGHV3-21 carry stereotyped B-cell receptors, which implicate antigen selection in leukemogenesis. These patients have also been reported to have shorter time to progression than patients with nonstereotyped IGHV3-21., Materials and Methods: To investigate the IGHV3-21 frequency and the clinical impact of IGHV3-21 stereotypy, 337 newly diagnosed Swedish CLL patients from a population-based cohort were analyzed., Results: Interestingly, the IGHV3-21 frequency was indeed lower (6.5%) in this indolent patient cohort than in our previous hospital-based cohort studies (10.1%-12.7%). Hence, a selection bias of more-aggressive cases rendered a higher proportion of IGHV3-21 cases in our original studies. Nevertheless, the Swedish IGHV3-21 frequency still remained higher when compared with other larger European or American studies (2.6%-4.1%). Finally, we confirmed the poor outcome for IGHV3-21 patients to be independent of mutational status and found stereotypy to have no impact on survival or time to treatment., Conclusion: The Swedish geographic bias in IGHV3-21 gene frequency was validated albeit at a lower frequency than previously reported. Moreover, no prognostic value could be attributed to IGHV3-21 stereotype status., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Benefits and risks of corticosteroid treatment in rheumatoid arthritis (RA) are debated. Patients with RA are at increased risk of malignant lymphomas. In a large case-control study of risk factors for lymphoma in RA, it was recently reported that steroid treatment was associated with decreased lymphoma risk., Objective: To further assess the nature of the association between steroid treatment in RA and the risk of lymphoma., Methods: In a cohort of 74 651 patients with RA, 378 patients with lymphoma and 378 matched RA controls were identified, and information on inflammatory activity and different aspects of steroid treatment (duration, therapeutic strategy and mode of administration) abstracted from their medical records. Lymphomas were reclassified (WHO classification) and examined for Epstein-Barr virus. Relative risks were assessed as adjusted odds ratios (ORs) through conditional logistic regression., Results: A total duration of oral steroid treatment of <2 years was not associated with lymphoma risk (OR=0.87; 95% CI 0.51 to 1.5), whereas total treatment >2 years was associated with a lower lymphoma risk (OR=0.43; 95% CI 0.26 to 0.72). RA duration at the initiation of oral steroids did not affect lymphoma risk. Intra-articular steroids were associated with a reduced lymphoma risk, but only when used as swift flare treatment (OR=0.22; 95% CI 0.13 to 0.37). Analyses by lymphoma subtype showed a reduced risk of diffuse large B-cell lymphoma (crude OR=0.59; 95% CI 0.37 to 0.94)., Conclusion: In this RA population, use of steroids was associated with reduced lymphoma risk. Whether this association is a generic effect of steroids or specific to the studied population remains unknown.

Minimal residual disease (MRD) detection during the early treatment phase has become an important stratification parameter in many childhood acute lymphoblastic leukaemia (ALL) treatment protocols. Here, we aimed to address the applicability of rearranged antigen-receptor genes as potential MRD markers using real-time quantitative polymerase chain reaction (RQ-PCR) in a Swedish population-based cohort. From 334 childhood ALL cases diagnosed during 2002-2006, we analysed 279 diagnostic samples (84%) by screening for rearranged immunoglobulin (IG) and T-cell receptor (TCR) genes. Allele-specific oligonucleotides were designed, and the sensitivity and quantitative level was determined for each target. Overall, clonal IG/TCR rearrangements were detected in 97% (236/244) of B-cell precursor ALL (BCP ALL) and 94% (33/35) of T-ALL. A sensitive RQ-PCR analysis (< or = 10(-4)) was obtained in 89% (216/244) of BCP ALL and in 74% (26/35) of T-ALL, whereas two sensitive targets were only available in 47% (115/244) of BCP ALL and 29% (10/35) of T-ALL cases. With the stratification threshold of > or = 10(-3), which is applied in the current Nordic treatment protocol (NOPHO-ALL 2008) for the identification of high-risk patients, 93% of BCP ALL and 86% of T-ALL reached this quantitative range by at least one target gene. Taken together, this national retrospective study demonstrates that an IG/TCR target for MRD monitoring can be identified in the majority of childhood ALL cases, whereas identification of a second sensitive target gene needs to be improved.

The aim of the present cross-sectional study was to investigate psychological distress, changes in life, adherence to surveillance programs and satisfaction with cancer genetic counseling based on Swedish participants' self-reported data. A total of 218 probands (72% response rate) affected by breast, breast/ovarian or colorectal cancer and/or a family history of cancer were surveyed 3-7 years after receiving cancer genetic counseling. Participants reported a relatively high level of anxiety and a low level of depression. Probands affected by colorectal cancer reported a higher level of depression than did non-affected individuals with a family history of colorectal cancer. Overall, the participants reported moderate changes in family relations, priorities and appreciation of daily life activities. The majority of at-risk probands reportedly adhered to recommended surveillance programs. The mean level of satisfaction with cancer genetic counseling was high. About half of the participants would have accepted additional counseling sessions, contact with a psychologist or further help concerning informing family members. The present results indicate no adverse effects of genetic counseling, but they do suggest that typical counseling procedures could be improved by provision of additional psychosocial support.