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Ludvigsson JF, Appelros P, Askling J, et al. Clin Epidemiol. 2021;13:21–41. The authors have advised that the Charlson Comorbidity Index (CCI) scripts linked to this paper have been updated accordingly and are available for R, SAS, and STATA (https://github.com/bjoroeKI/Charlson-comorbidity-index-revisited). Mild liver disease (international classification of disease, ICD) code version 10: in Table 1 on page 30, K70.3 is listed twice. In the revised script, one of these have been replaced by K70.9 (hence both K70.3 and K70.9 are now listed in the CCI scripts). Cancer, ICD-9: the code 173 in Table 1 on page 33 is not relevant and has been deleted from the CCI scripts. AIDS, ICD-10: the code Z11.4 represents health check-up for HIV but the diagnosis may not have been confirmed. Z11.4 in Table 1 on page 37 has hence been deleted from the CCI scripts. Also, the code Z71.1 (“no diagnosis”) in Table 1 on page 37 has been replaced by Z71.7 (counselling for HIV).

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

Jonas F Ludvigsson,1– 4 Peter Appelros,5 Johan Askling,6,7 Liisa Byberg,8 Juan-Jesus Carrero,1 Anna Mia Ekström,9,10 Magnus Ekström,11 Karin Ekström Smedby,6 Hannes Hagström,12– 14 Stefan James,15,16 Bengt Järvholm,17 Karl Michaelsson,8 Nancy L Pedersen,18 Helene Sundelin,19,20 Kristina Sundquist,21 Johan Sundström22– 24 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 2Department of Pediatrics, Orebro University Hospital, Orebro, Sweden; 3Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK; 4Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA; 5University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro SE-701 82, Sweden; 6Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 7Rheumatology, Theme Inflammation and Infection, Karolinska University Hospital, Stockholm, Sweden; 8Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; 9Global & Sexual Health Research Group (GloSH), Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden; 10Faculty of Medicine, Department of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 11Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; 12Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden; 13Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; 14Department of Medicine, Karolinska Huddinge, Institutet, Stockholm, Sweden; 15Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden; 16Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; 17Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; 18Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden; 19Neuropediatric Unit, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; 20Division of Children’s and Women’s Health, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; 21Center for Primary Health Care Research, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden; 22Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 23The George Institute for Global Health, University of New South Wales, Sydney, Australia; 24Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 25Center for Community-Based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, JapanCorrespondence: Jonas F LudvigssonDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, SwedenEmail jonasludvigsson@yahoo.comPurpose: Comorbidity indices are often used to measure comorbidities in register-based research. We aimed to adapt the Charlson comorbidity index (CCI) to a Swedish setting.Methods: Four versions of the CCI were compared and evaluated by disease-specific experts.Results: We created a cohesive coding system for CCI to 1) harmonize the content between different international classification of disease codes (ICD-7,8,9,10), 2) delete incorrect codes, 3) enhance the distinction between mild, moderate or severe disease (and between diabetes with and without end-organ damage), 4) minimize duplication of codes, and 5) briefly explain the meaning of individual codes in writing.Conclusion: This work may provide an integrated and efficient coding algorithm for CCI to be used in medical register-based research in Sweden.Keywords: Charlson comorbidity score, comorbidity, disease, epidemiology, public health, Sweden

Qianwei Liu,1 Therese ML Andersson,2 Anna Jöud,3,4 Qing Shen,2 Maria EC Schelin,3,5 Patrik KE Magnusson,2 Karin E Smedby,6 Fang Fang1 1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 3Lund University, Department of Clinical Sciences Lund, Orthopaedics, Lund, Sweden; 4Lund University, Department of Laboratory Medicine, Occupational and Environmental Medicine, Lund, Sweden; 5Institute for Palliative Care, IKVL, Lund University and Region Skåne, Lund, Sweden; 6Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, SwedenCorrespondence: Fang FangInstitute of Environmental Medicine, Karolinska Institutet, Box 23109, 104 35, Stockholm, SwedenTel +46 8 52486131Email fang.fang@ki.seBackground: Little attention has been given to the risk of cardiovascular and psychiatric comorbidities during the clinical evaluation of a suspected hematological malignancy.Methods: Based on Skåne Healthcare Register, we performed a population-based cohort study of 1,527,449 individuals residing during 2005–2014 in Skåne, Sweden. We calculated the incidence rate ratios (IRRs) of cardiovascular diseases or psychiatric disorders during the diagnostic workup of 5495 patients with hematological malignancy and 18,906 individuals that underwent a bone marrow aspiration or biopsy or lymph node biopsy without receiving a diagnosis of any malignancy (“biopsied individuals”), compared to individuals without such experience (i.e., reference).Results: There was a higher rate of cardiovascular diseases during the diagnostic workup of patients with hematological malignancy (overall IRR, 3.3; 95% CI, 2.9 to 3.8; greatest IRR for embolism and thrombosis, 8.1; 95% CI, 5.2 to 12.8) and biopsied individuals (overall IRR, 4.9; 95% CI, 4.6 to 5.3; greatest IRR for stroke, 37.5; 95% CI, 34.1 to 41.2), compared to reference. Similarly, there was a higher rate of psychiatric disorders during the diagnostic workup of patients with hematological malignancy (IRR, 2.1; 95% CI, 1.5 to 2.8) and biopsied individuals (IRR, 3.1; 95% CI, 2.9 to 3.4). The rate increases were greater around the time of diagnosis or biopsy, compared to thereafter, for both outcomes.Conclusion: There were higher rates of cardiovascular diseases and psychiatric disorders during the diagnostic workup of a suspected hematological malignancy, regardless of the final diagnosis.Keywords: hematological malignancy, cardiovascular diseases, psychiatric disorders, diagnostic workup

Objective: In the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome (pSS), pre-existing lymphoma is not an exclusion criterion for pSS diagnosis, as in earlier criteria. We aimed to explore whether there are differences between pSS patients with and without pre-existing lymphoma at pSS diagnosis.Method: Patients with ICD-7-10 codes for Sjögren's syndrome (SS) and a diagnosis of malignant lymphoma before or after SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n = 224). Clinical data were collected from medical records. Lymphoma diagnoses were evaluated by tissue review. Characteristics of pSS patients with and without pre-existing lymphoma were compared.Results: We identified 107 patients with pSS as the reason for an SS diagnosis code and a verified lymphoma. Of these, 18 (17%) had a pre-existing lymphoma at pSS diagnosis, defined as lymphoma diagnosed before or within 6 months of pSS diagnosis. Male gender (39% vs 10%, p = 0.006), enlarged lymph nodes during the pSS disease (61% vs 27%, p = 0.01), mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs 22%, p = 0.02), and salivary gland lymphoma (61% vs 26%, p = 0.006) were more common in patients with a pre-existing lymphoma at pSS diagnosis. Other pSS characteristics were similar.Conclusion: In a substantial proportion of patients, particularly in men, pSS remains undiagnosed until after lymphoma diagnosis. The study highlights the importance of pSS investigation in patients with lymphoma, especially MALT lymphoma, in the salivary glands. [ABSTRACT FROM AUTHOR]

Purpose: Studies of smoking and risk of non-Hodgkin lymphoma (NHL) have yielded inconsistent results, possibly due to subtype heterogeneity and/or genetic variation impacting the metabolism of tobacco-derived carcinogens, including substrates of the N-acetyltransferase enzymes NAT1 and NAT2.Methods: We conducted a pooled analysis of 5,026 NHL cases and 4,630 controls from seven case-control studies in the international lymphoma epidemiology consortium to examine associations between smoking, variation in the N-acetyltransferase genes NAT1 and NAT2, and risk of NHL subtypes. Smoking data were harmonized across studies, and genetic variants in NAT1 and NAT2 were used to infer acetylation phenotype of the NAT1 and NAT2 enzymes, respectively. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for risk of NHL and subtypes were calculated using joint fixed effects unconditional logistic regression models.Results: Current smoking was associated with a significant 30 % increased risk of follicular lymphoma (n = 1,176) but not NHL overall or other NHL subtypes. The association was similar among NAT2 slow (OR 1.36; 95 % CI 1.07-1.75) and intermediate/rapid (OR 1.27; 95 % CI 0.95-1.69) acetylators (p (interaction) = 0.82) and also did not differ by NAT1*10 allelotype. Neither NAT2 phenotype nor NAT1*10 allelotype was associated with risk of NHL overall or NHL subtypes.Conclusion: The current findings provide further evidence for a modest association between current smoking and follicular lymphoma risk and suggest that this association may not be influenced by variation in the N-acetyltransferase enzymes. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification.Methods: We conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided.Results: Two novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 × 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 × 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 × 10(-4)) and replication series (P = .03).Conclusion: Overall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients. [ABSTRACT FROM AUTHOR]

There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983-2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Patients with rheumatoid arthritis (RA), in particular those with the most severe disease, are at increased risk of developing malignant lymphoma. Whether this increase is entirely a consequence of the RA disease and/or its treatment or is reflective of shared susceptibility to the two diseases remains unclear. We undertook this study to assess whether patients with RA are already at increased risk of lymphoma or of other cancers before the diagnosis of RA, and if the relative risk increases with time since RA diagnosis. METHODS: Patients with incident RA (symptom duration <1 year) (n = 6,745) registered in the Swedish Early Arthritis Registry from 1997 through 2006 were identified. For each patient, 5 general population controls were randomly matched by sex, age, marital status, and residence (n = 33,657). For all study subjects, inclusion in the nationwide Swedish Cancer Register in 1958-2006 was determined. Relative risks (RRs) (with 95% confidence intervals [95% CIs]) of lymphoma and of cancer overall, before and after diagnosis of RA, were estimated using conditional logistic regression and Cox regression, respectively. RESULTS: Before diagnosis of RA, there was no observed increase in the risk of lymphoma (RR [odds ratio] 0.67 [95% CI 0.37-1.23]) or other cancers (RR 0.78 [95% CI 0.70-0.88]). During the first 10 years following diagnosis of RA, the overall RR (hazard ratio) of lymphoma development was 1.75 (95% CI 1.04-2.96). CONCLUSION: These findings indicate that overall, a history of cancer, including lymphoma, does not increase the risk of subsequent RA development. Shared susceptibility to RA and lymphoma may thus be of limited importance. In contrast, increased lymphoma risks were observed within the first decade following RA diagnosis. [ABSTRACT FROM AUTHOR]

As specific autoimmune disorders now constitute established risk factors for malignant lymphomas, we describe this association. We review reported risk levels, risk determinants, lymphoma subtypes and biological mechanisms in autoimmunity/inflammation, emphasizing on recent findings. Whilst numerous reports describe average lymphomarisks in large patient groups, there's a recent shift of focus to risk determinants and the role of inflammatory activity. Studies highlight associations with diffuse large B-cell lymphoma, apart from lymphoma development in target organs of inflammation. Future studies of high-risk patient subsets using detailed assessments of autoimmunity/inflammation and lymphoma may give important clues to lymphomagenesis. [ABSTRACT FROM AUTHOR]

Validation of biobanks and large cancer cohorts is essential in ensuring high-quality research results. We examined the coverage, generalisability and validity of the lymphoma collection of the Uppsala-Umeå Comprehensive Cancer Consortium (U-CAN) biobank in Sweden, one of the largest cancer biobanks in Europe. Up until 2022, 889 lymphoma patients in U-CAN Uppsala had available samples, and 329 in U-CAN Umeå. Patients diagnosed in the U-CAN Uppsala area 2011-2021 (n = 843) were linked to the nationwide Swedish Lymphoma Register, and a subset diagnosed before 2019 (n = 727) to population-based registers. The coverage was 39% of all lymphoma patients between 2011 and 2019 diagnosed in the U-CAN Uppsala area, with a pandemic decline to 10% during 2020-2021. The patients included had superior overall survival (hazard ratio = 0.70 [95% confidence interval, CI: 0.60-0.82]) than all lymphoma patients in Sweden. They had better performance status, were younger (odds ratio [OR] = 0.21 [95% CI: 0.13-0.34]) and had less comorbidities (OR = 0.66 [95% CI: 0.56-0.78]). However, cause-specific survival and stage distribution were similar. The questionnaire data captured less comorbidities compared to the national registers. Evaluations of biobanks are important, as even population-based biobanks such as U-CAN select younger patients with higher socioeconomical status and better performance status. However, the similar cause-specific survival as in the registries suggests U-CANs usefulness for prognostic biomarker studies., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Etoposide to standard R-CHOP is used for high-risk diffuse large B-cell lymphoma (DLBCL) in some countries. Due to the lack of randomized trials, a real-world data study using matching methods was used to test the potential effectiveness of R-CHOEP over R-CHOP., Patients and Methods: This study included patients from the Danish Lymphoma Register diagnosed between 2006 and 2020 at the age of 18-60 years with de novo DLBCL and age-adjusted IPI ≥2. R-CHOEP treated patients were matched 1:1 without replacement to R-CHOP treated patients using a hybrid exact and genetic matching technique. Primary endpoints were progression-free survival (PFS) and overall survival (OS)., Results: In total, 396 patients were included; 213 received R-CHOEP and 183 received R-CHOP. Unadjusted 5-year PFS and OS for R-CHOEP were 69% (95% Confidence intervals [CI]; 63%-76%) and 79% (CI;73%-85%) versus 62% (CI;55%-70%) and 76% (CI;69%-82%) for R-CHOP (log-rank test, PFS p = .25 and OS p = .31). A total of 127 patients treated with R-CHOEP were matched to 127 patients treated with R-CHOP. Matching-adjusted 5-year PFS and OS were 65% (CI; 57%-74%) and 79% (CI; 72%-84%) for R-CHOEP versus 63% (CI; 55%-73%) and 79% (CI;72%-87%) for R-CHOP (log-rank test, PFS p = .90 and OS p = .63)., Conclusion: The present study did not confirm superiority of R-CHOEP over R-CHOP for young patients with high-risk DLBCL., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Purpose: To examine health-related quality of life (HRQoL) and supportive care needs among young adult (YA) cancer survivors up to 3 years post-diagnosis., Methods: A national cohort of individuals diagnosed at 18-39 years with breast, cervical, ovarian, or testicular cancer, lymphoma or brain tumor was approached with surveys at 1.5 (n = 1010, response rate 67%) and 3 (n = 722) years post-diagnosis. HRQoL was measured using the EORTC QLQ-C30. Scores were dichotomized using cut-off scores to predict supportive care needs in the Supportive Care Needs Survey-Long Form 59 (SCNS-LF59). Swedish cancer quality registers provided clinical data. Factors predicting need of support at 1.5 and 3 years post-diagnosis were identified using logistic regression., Results: HRQoL improvements over time were trivial to small. At both time points, a majority of respondents rated HRQoL levels indicating supportive care needs. At 1.5 years post-diagnosis, the risk of having support needs was lower among survivors with testicular cancer (compared to lymphoma) or university-level education, and higher among those on treatment (predominantly endocrine therapy). At 3 years post-diagnosis, when controlling for previous HRQoL scores, most correlations persisted, and poor self-rated household economy and chronic health conditions were additionally associated with supportive care needs., Conclusion: A majority of YAs diagnosed with cancer rate HRQoL at levels indicating support needs up to 3 years post-diagnosis. Testicular cancer survivors are at lower risk of having support needs. Concurrent health conditions and poor finances are linked to lower HRQoL. More efforts are needed to provide adequate, age-appropriate support to YA cancer survivors., (© 2024. The Author(s).)

Massively parallel sequencing helps create new knowledge on genes, variants and their association with disease phenotype. This important technological advancement simultaneously makes clinical decision making, using genomic information for cancer patients, more complex. Currently, identifying actionable pathogenic variants with diagnostic, prognostic, or predictive impact requires substantial manual effort. Objective: The purpose is to design a solution for clinical diagnostics of lymphoma, specifically for systematic variant filtering and interpretation. Methods: A scoping review and demonstrations from specialists serve as a basis for a blueprint of a solution for massively parallel sequencing-based genetic diagnostics. Results: The solution uses machine learning methods to facilitate decision making in the diagnostic process. A validation round of interviews with specialists consolidated the blueprint and anchored it across all relevant expert disciplines. The scoping review identified four components of variant filtering solutions: algorithms and Artificial Intelligence (AI) applications, software, bioinformatics pipelines and variant filtering strategies. The blueprint describes the input, the AI model and the interface for dynamic browsing. Conclusion: An AI-augmented system is designed for predicting pathogenic variants. While such a system can be used to classify identified variants, diagnosticians should still evaluate the classification's accuracy, make corrections when necessary, and ultimately decide which variants are truly pathogenic., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RR received honoraria from Abbvie, AstraZeneca, Janssen, Illumina and Roche.

Previous solid organ transplantation has been associated with worse survival among colorectal cancer (CRC) patients. This study investigates the contribution of CRC characteristics and treatment-related factors to the differential survival. Using the Swedish register-linkage CRCBaSe, all patients with solid organ transplantation before CRC diagnosis were identified and matched with non-transplanted CRC patients. Associations between transplantation history and clinical CRC factors and survival were estimated using the Kaplan-Meier estimator and logistic, multinomial, and Cox regression, respectively. Ninety-eight transplanted and 474 non-transplanted CRC patients were followed for 5 years after diagnosis. Among patients with stage I-III cancer, transplanted patients had lower odds of treatment with abdominal surgery [odds ratio (OR):0.27, 95% confidence interval (CI):0.08-0.90], than non-transplanted patients. Among those treated with surgery, transplanted colon cancer patients had lower odds of receiving adjuvant chemotherapy (OR:0.31, 95% CI:0.11-0.85), and transplanted rectal cancer patients had higher rate of relapse (hazard ratio:9.60, 95% CI:1.84-50.1), than non-transplanted patients. Five-year cancer-specific and overall survival was 56% and 35% among transplanted CRC patients, and 68% and 57% among non-transplanted. Accordingly, transplanted CRC patients were treated less intensely than non-transplanted patients, and had worse cancer-specific and overall survival. These patients might benefit from multidisciplinary evaluation including transplantation specialists., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Benoni, Nordenvall, Hellström, Dietrich, Martling, Smedby and Eloranta.)

Abstract: Patients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are the established standard treatment at first relapse, but their effectiveness compared with chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes among patients at first, late POD beyond 24 months. The primary objective was progression-free survival from the time of second-line therapy (PFS-2) of BTKi vs CIT. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 years (range, 19-70), and 77% were male. Median follow-up from the time of second-line therapy was 53 months (range, 12-144). Overall, 114 patients had second-line BTKi, whereas 271 had CIT, consisting of rituximab-bendamustine (R-B; n = 101), R-B and cytarabine (R-BAC; n = 70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone]- or platinum-based; n = 100). The 2 groups were balanced in clinicopathological features and median time to first relapse. Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT (not reached [NR] vs 26 months, respectively; P = .0003) and overall survival (NR and 56 months, respectively; P = .03). Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio, 0.41 for R-B and 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in patients with BTKi-naïve MCL., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease. Whereas some patients have an indolent disease, others experience an aggressive course and early death. Our aim was to investigate if modifiable and non-modifiable medical history and lifestyle factors prior to diagnosis had an impact on the natural course of the disease., Method: In 1154 CLL patients, we assessed if the weight, physical activity, smoking, and alcohol consumption or non-modifiable characteristics including family history of lymphoid malignancy and medical history were associated with time-to-first-treatment (TTFT) and adjusted all results for the CLL-International Prognostic Index (CLL-IPI)., Results: TTFT was shorter for patients with high/very high-risk CLL-IPI than those with low/intermediate risk CLL-IPI. In the adjusted analysis we did not find additional impact on TTFT besides CLL-IPI from any environmental characteristics assessed., Conclusions: We found limited impact of environmental factors on the natural course of CLL (measured as the TTFT in treatment naïve patients) providing valuable knowledge, and potential relief, to share with patients at the time of diagnosis., Competing Interests: Karin E. Smedby: received honoraria from Celgene and research support from Janssen. Ingrid Glimelius received honoraria from Janssen and participated in a real‐world data study sponsored by Takeda. Richard Rosenquist received honoraria from AbbVie, AstraZeneca, Illumina, Janssen, and Roche. DSMC (Data Safety Monitoring Committee) for Agios Pharm, Astra Zeneca, Cytomx Therapeutics, Rigel. Advisory Board for Cytomx Therapy, Pharmacyclics, Dava Oncology, Juno Therapeutics, Oncotracker, and Abbvie. Sameer A. Parikh: Research funding has been provided to the institution (Mayo Clinic) from Janssen, AstraZeneca, Merck, and Genentech for clinical studies in which Sameer A. Parikh is a principal investigator. Honoraria has been provided to the institution (Mayo Clinic) from Pharmacyclics, Merck, AstraZeneca, Janssen, Genentech, Amgen, MingSight Pharmaceuticals, TG Therapeutics, Novalgen Limited, Kite Pharma, and AbbVie for Sameer A. Parikh's participation in consulting activities/advisory board meetings. Carsten Utofth Niemann received honoraria and/or research support from AstraZeneca, Abbvie, Janssen, Beigene, Genmab, CSL Behring, Takeda, Octapharma, and MSD. The rest of the authors declare no conflict of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Advancements in treatments have significantly improved the prognosis for mantle cell lymphoma (MCL), and there is a growing population of survivors with an increased susceptibility to infections. We assessed the incidence of infections by clinical characteristics and treatment both before and after MCL diagnosis in Sweden. Patients with a diagnosis of MCL ≥ 18 years between 2007 and 2019 were included, along with up to 10 matched comparators. Infectious disease diagnosis and anti-infective drug dispensation were identified by the National Patient and the Prescribed Drug Registers, respectively. Patients and comparators were followed from the diagnosis/matching date until death, emigration, or June 30, 2020. Overall, 1559 patients and 15,571 comparators were followed for a median duration of 2.9 and 5 years, respectively. The infection rate among patients was twofold higher, RRadj = 2.14 (2.01-2.27), contrasted to the comparator group. There was a notable rise in infection rates already 4 years before MCL diagnosis, which reached a fourfold increase in the first year after diagnosis and persisted significantly increased for an additional 8 years. Among patients, 69% ( n  = 1080) experienced at least one infection during the first year of follow-up. Influenza, pneumonia, other bacterial infections, urinary tract infections, and acute upper respiratory infections were the most frequent. Notably, MCL remained to be the primary leading cause of death among patients (57%, n  = 467/817). Infections as the main cause of death were rare (2.6%, n  = 21). Our study highlights the importance of thoroughly assessing infectious morbidity when appraising new treatments. Further investigations are warranted to explore strategies for reducing infectious disease burden., Competing Interests: Mats Jerkeman received honoraria from Abbvie, AstraZeneca, BMS, Kite/Gilead, Pierre Fabre, Roche, Sobi, and Takeda and research support from Abbvie, AstraZeneca, BMS, and Roche. Ingrid Glimelius received research support from Takeda and participated in educational sessions arranged by Janssen Cilag, Abbvie, and Kite Gilead. Karin E. Smedby received honoraria from Incyte and Celgene, and research support from Janssen Cilag. The other authors have no relevant financial or nonfinancial interests to disclose., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Follicular lymphoma (FL) is a clinically heterogeneous disease. The need for treatment, treatment sequencing, number of treatment lines, and its association with survival have not been described in a population-based setting. We identified all patients diagnosed with FL in the Swedish Lymphoma register from 2007 to 2014, followed until 2020, with detailed data on progression/relapse, transformation, and 2nd and further lines of therapy. During a median follow-up of 6.8 years, 1226 patients (69%) received 1st systemic treatment, 358 patients (20%) were managed with watch-and-wait (WaW) only, and 188 (10%) patients were treated with radiotherapy and did not require additional therapy during the study period. Among patients starting systemic treatment, 496 (40%), 224 (18%), and 88 (7%) received 2nd-, 3rd-, or 4th-line therapy, respectively. The 10-year cause-specific cumulative incidence of transformation was 13%. Among patients managed with 1 st line R-single, R-CHOP, or BR, 54%, 33%, and 29% required 2nd line, respectively. The cumulative probability of starting subsequent treatment within 2 years was 26% after 1st line and 35% after 2nd line treatment. Two-year OS following 1st, 2nd, 3rd, and 4th line systemic treatment was 84%, 70%, 52%, and 36%, respectively, and remained similar when excluding transformations. We conclude that a substantial proportion of FL patients can be managed with WaW for a long period of time, while patients who require multiple treatment lines constitute a group with a large clinical unmet need. These results constitute valuable real-world reference data for FL., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background & Purpose: The COVID-19 pandemic posed a large challenge for healthcare systems across the world. Comprehensive data on the impact of the COVID-19 pandemic on incidence and mortality in lymphoma are lacking., Patients/methods: Using data from the Swedish lymphoma register, we compare incidence and 1-year survival of lymphoma patients in Sweden before (2017-2019) and during the pandemic (2020 and 2021)., Results: Fewer patients were diagnosed with lymphomas during March-June 2020, but the annual incidence rates for 2020 and 2021 were similar to those of 2017-2019. A larger proportion of patients presented with stage IV disease during 2021. There were no differences in other base-line characteristics nor application of active treatment in pre-pandemic and pandemic years. One-year overall survival was not inferior among lymphoma patients during the pandemic years compared to pre-pandemic years i.e., 2017-2019., Interpretation: The COVID-19 pandemic had limited impact on the incidence and mortality of lymphoma in Sweden.

Background: Increased risk of neoplastic events after recombinant human growth hormone (rhGH) treatment in childhood has been an ongoing concern but long-term safety data are limited., Methods: A nationwide population-based cohort study in Sweden of patients treated with rhGH during childhood between 1985-2010, due to isolated growth hormone deficiency (GHD), small for gestational age (SGA) and idiopathic short stature (ISS). The comparison group consisted of 15 age-, sex-, and region-matched controls per patient, randomly selected from the general population. Data on neoplastic events and covariates, such as gestational age, birth weight, birth length, socioeconomic status, and height at study start, were collected through linkage with population-based registers. The cohort was followed for neoplastic events until the end of 2020., Results: 53,444 individuals (3,408 patients; 50,036 controls) were followed for up to 35 years, with a median follow-up of 19.8 years and a total of 1,050,977 person-years. Patients showed a moderately increased hazard ratio (HR) for neoplastic events overall compared to controls (HR 1.28, 95% CI: 1.12-1.46), but only significant for males (HR 1.39, 95% CI: 1.17-1.66) and not females (HR 1.15, 95% CI: 0.94-1.41). Longer treatment duration was associated with an increased HR, but no association was found between neoplastic events and mean or cumulative dose. No increased risk of malignant neoplasms was observed for the patients compared to matched controls (HR 0.91 95% CI: 0.66-1.26)., Conclusion: No association was found between rhGH treatment during childhood for GHD, SGA, or ISS and malignant neoplastic events in early to mid-adulthood. A moderate increase in overall neoplastic events was observed due to an increased number of events in male patients., Competing Interests: AT reports participation in advisory board for Pfizer. LS reports lecture honoraria from Merck, Novo Nordisk, and Pfizer, travel support from Novo Nordisk and participation in adjudication committee for Aetherna-Icon and advisory boards for Pfizer and Novo Nordisk. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tidblad, Bottai, Smedby, Albertsson-Wikland and Sävendahl.)

Despite the improvements in clinical outcomes for DLBCL, a significant proportion of patients still face challenges with refractory/relapsed (R/R) disease after receiving first-line R-CHOP treatment. To further elucidate the underlying mechanism of R/R disease and to develop methods for identifying patients at risk of early disease progression, we integrated clinical, genetic and transcriptomic data derived from 2805 R-CHOP-treated patients from seven independent cohorts. Among these, 887 patients exhibited R/R disease within two years (poor outcome), and 1918 patients remained in remission at two years (good outcome). Our analysis identified four preferentially mutated genes (TP53, MYD88, SPEN, MYC) in the untreated (diagnostic) tumor samples from patients with poor outcomes. Furthermore, transcriptomic analysis revealed a distinct gene expression pattern linked to poor outcomes, affecting pathways involved in cell adhesion/migration, T-cell activation/regulation, PI3K, and NF-κB signaling. Moreover, we developed and validated a 24-gene expression score as an independent prognostic predictor for treatment outcomes. This score also demonstrated efficacy in further stratifying high-risk patients when integrated with existing genetic or cell-of-origin subtypes, including the unclassified cases in these models. Finally, based on these findings, we developed an online analysis tool ( https://lymphprog.serve.scilifelab.se/app/lymphprog ) that can be used for prognostic prediction for DLBCL patients., (© 2023. The Author(s).)

Purpose: To describe long-term prescribed drug use after rectal cancer treatment., Methods: We identified 12,871 rectal cancer patients without distant metastasis between 2005 and 2016 and 64,341 matched population comparators using CRCBaSe (a Swedish nationwide register linkage of colorectal cancer patients). Mean defined daily doses (DDDs) of drug dispensing during relapse-free follow-up were calculated by Anatomical Therapeutic Chemical drug categories. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) from negative binomial regression were used to compare drug dispensing between patients and comparators., Results: The overall pattern of drug dispensing was similar among cancer survivors and comparators, although patients had higher mean DDDs of drugs regulating the digestive system. Excess dispensing of drugs for constipation (IRR, 3.35; 95% CI, 3.12-3.61), diarrhea (IRR, 6.43; 95% CI, 5.72-7.22), functional gastrointestinal disorders (IRR, 3.78; 95% CI, 3.15-4.54), and vitamin and mineral supplements (IRR, 1.37; 95% CI, 1.24-1.50) was observed up to 10 years after surgery. Treatment with Hartmann's procedure was associated with higher dispensing rates of digestive drugs compared to surgery with anterior resection and abdominoperineal resection but the association was attributed to higher use of diabetic drugs. Additionally, excess digestive drug dispensing was associated with more advanced cancer stage but not with (chemo)radiotherapy treatment., Conclusions: Excess drug use after rectal cancer is primarily driven by bowel-regulating drugs and is not modified by surgical or oncological treatment., Implications for Cancer Survivors: The excess use of bowel-regulating drugs after rectal cancer indicated long-standing postsurgical gastrointestinal morbidity and need of prophylaxis. Reassuringly, no excess use of other drug classes was noted long term., (© 2024. The Author(s).)

Background: Cure fraction-the proportion of persons considered cured of cancer after long-term follow-up-reflects the total impact of cancer control strategies, including screening, without lead-time bias. Previous studies have not reported stage-stratified cure fraction across the spectrum of cancer types., Methods: Using a mixture cure model, we estimated cure fraction across stages for 21 cancer types and additional subtypes. Cause-specific survival for 2.4 million incident cancers came from 17 US Surveillance, Epidemiology, and End Results registries for adults 40 to 84 years at diagnosis in 2006 to 2015, followed through 2020., Results: Across cancer types, a substantial cure fraction was evident at early stages, followed by either a sharp drop from stages III to IV or a steady decline from stages I to IV. For example, estimated cure fractions for colorectal cancer at stages I, II, III, and IV were 62% (95% confidence interval: 59%-66%), 61% (58%-65%), 58% (57%-59%), and 7% (7%-7%), respectively. Corresponding estimates for gallbladder cancer were 50% (46%-54%), 24% (22%-27%), 22% (19%-25%), and 2% (2%-3%). Differences in 5-year cause-specific survival between early-stage and stage IV cancers were highly correlated with between-stage differences in cure fraction, indicating that survival gaps by stage are persistent and not due to lead-time bias., Conclusions: A considerable fraction of cancer is amenable to cure at early stages, but not after metastasis., Impact: These results emphasize the potential for early detection of numerous cancers, including those with no current screening modalities, to reduce cancer death., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication., Patients and Methods: Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti-CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts)., Results: Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, -1.5 to 4.4; all-pts) and 1.4% (95% CI, -1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup., Conclusion: In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Purpose: With modern treatments, mantle cell lymphoma (MCL) patients more frequently experience long-lasting remission resulting in a growing population of long-term survivors. Follow-up care includes identification and management of treatment-related late-effects, such as secondary malignancies (SM). We conducted a population-based study to describe the burden of SM in MCL patients., Methods: All patients with a primary diagnosis of MCL, aged ≥ 18 years and diagnosed between 2000 and 2017 in Sweden were included along with up to 10 individually matched population comparators. Follow-up was from twelve months after diagnosis/matching until death, emigration, or December 2019, whichever occurred first. Rates of SM among patients and comparators were estimated using the Anderson-Gill method (accounting for repeated events) and presented as hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age at diagnosis, calendar year, sex, and the number of previous events., Results: Overall, 1 452 patients and 13 992 comparators were followed for 6.6 years on average. Among patients, 230 (16%) developed at least one SM, and 264 SM were observed. Relative to comparators, patients had a higher rate of SM, HR adj = 1.6 (95%CI:1.4-1.8), and higher rates were observed across all primary treatment groups: the Nordic-MCL2 protocol, R-CHOP, R-bendamustine, ibrutinib, lenalidomide, and R-CHOP/Cytarabine. Compared to Nordic-MCL2, treatment with R-bendamustine was independently associated with an increased risk of SM, HR adj = 2.0 (95%CI:1.3-3.2). Risk groups among patients were those with a higher age at diagnosis (p < 0.001), males (p = 0.006), and having a family history of lymphoma (p = 0.009). Patients had preferably higher risk of melanoma, other neoplasms of the skin and other hematopoietic and lymphoid malignancies., Conclusions: MCL survivors have an increased risk of SM, particularly if treated with R-bendamustine. The intensive treatments needed for long-term remissions are a concern, and transition to treatment protocols with sustained efficacy but with a lower risk of SM is needed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ingrid Glimelius received research support from Takeda and participated in the educational sessions arranged by Jansen Cilag. Sandra Eloranta received grants or contracts from Swedish Cancer Society, Åke Wiberg Foundations, Karolinska institutet foundations - Grant as PI paid to my institution. Nordic Cancer Union Grant paid to my institution - Support for attending meetings. Other financial or nonfinancial interests - Academic partner to Red Door Analytics. Red Door Analytics is a statistical consulting company operating in Stockholm, Sweden. I have not received financial compensation for my academic partnership at any time point. The other authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)