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Lars Christian Haugli Bråten,1 Elisabeth Gjefsen,1,2 Kristina Gervin,1 Are Hugo Pripp,3 Jan Sture Skouen,4 Elina Schistad,5 Linda Margareth Pedersen,1 Monica Wigemyr,1 Kaja Kristine Selmer,1 Hans Christian Dalsbotten Aass,6 Guro Goll,7 Jens Ivar Brox,5 Ansgar Espeland,8,9 Lars Grøvle,10 John-Anker Zwart,1,2 Kjersti Storheim1,11 On behalf of The AIM-study group1Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital HF, Oslo, Norway; 2Faculty of Medicine, University of Oslo, Oslo, Norway; 3Oslo Centre of Biostatistics and Epidemiology Research Support Services, Oslo University Hospital Ulleval, Oslo, Norway; 4Department of Physical Medicine and Rehabilitation, Haukeland University Hospital, Bergen, Norway; 5Department of Physical Medicine and Rehabilitation, Oslo University Hospital HF, Oslo, Norway; 6Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; 7Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway; 8Department of Radiology, Haukeland University Hospital, Bergen, Norway; 9Department of Clinical Medicine, University of Bergen, Bergen, Norway; 10Department of Rheumatology, Østfold Hospital Trust, Grålum, Norway; 11Oslo Metropolitan University, Department of Physiotherapy, Oslo, NorwayCorrespondence: Lars Christian Haugli Bråten, Tel +4722117769, Email l.c.h.braten@studmed.uio.noObjective: Randomized trials testing the effect of antibiotics for chronic low back pain (LBP) with vertebral bone marrow changes on MRI (Modic changes) report inconsistent results. A proposed explanation is subgroups with low grade discitis where antibiotics are effective, but there is currently no method to identify such subgroups. The objective of the present study was to evaluate whether distinct patterns of serum cytokine levels predict any treatment effect of oral amoxicillin at one-year follow-up in patients with chronic low back pain and Modic changes at the level of a previous lumbar disc herniation.Design: We used data from an overpowered, randomized, placebo-controlled trial (the AIM study) that tested 100 days of oral 750 mg amoxicillin vs placebo three times daily in hospital outpatients with chronic (> 6 months) LBP with pain intensity ≥ 5 on a 0– 10 numerical rating scale and Modic changes type 1 (oedema type) or 2 (fatty type). We measured serum levels of 40 inflammatory cytokines at baseline and analysed six predefined potential predictors of treatment effect based on cytokine patterns in 78 randomized patients; three analyses with recursive partitioning, one based on cluster analysis and two based on principal component analyses. The primary outcome was the Roland–Morris Disability Questionnaire score at one-year follow-up in the intention to treat population. The methodology and overall results of the AIM study were published previously.Results: The 78 patients were 25– 62 years old and 47 (60%) were women. None of the three recursive partitioning analyses resulted in any suggested subgroups. Of all main analyses, the largest effect estimate (mean difference between antibiotic and placebo groups) was seen in a subgroup not predefined as of main interest (Cluster category 3+4; − 2.0, 95% CI: − 5.2– 1.3, RMDQ points; p-value for interaction 0.54).Conclusion: Patterns of inflammatory serum cytokine levels did not predict treatment effect of amoxicillin in patients with chronic LBP and Modic changes.Clinical Trial Registration Number: ClinicalTrials.gov (identifier: NCT02323412).Keywords: low back pain, Modic changes, infection, cytokines, inflammation

Berit Taraldsen Valeberg,1 Linda Margareth Pedersen,2,3 Valentina Girotto,3,4 Vivi Lycke Christensen,5 Audun Stubhaug3,6 1Department of Nursing and Health promotion, Oslo and Akershus University College of Applied Sciences, 2Research and communication unit for musculoskeletal health (FORMI), 3Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway; 4Faculty of Medicine and Surgery, University of Turin, Turin, Italy; 5Division of Emergencies and Critical Care, Department of Research and Development, Oslo University Hospital, 6Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway Background and purpose: There is a large variation in people’s reactions to painful stimuli. Although some conditions are more painful, the variation between people is larger than the reaction to pain across conditions. Induced experimental pain is one way to assess some aspects of these differences in pain perception. Experimental nociceptive testing is time consuming and not always feasible in a clinical setting. In order to overcome the obstacles of assessing pain sensitivity using experimental stimulation, the Pain Sensitivity Questionnaire (PSQ) was developed. The purpose of this study is to validate the Norwegian version of the PSQ. Methods: Construct validity was examined through an exploratory principal component factor analysis with varimax rotation. Internal consistency was measured by Cronbach’s alpha reliability for subscales and the total PSQ. As confounding variables such as age and gender may contribute to the experience of pain, a regression analysis was performed with demographic variables and PSQ scores as independent variables and the experimental measures of pain as the dependent variable. Results: The factor analysis yielded at two factor solution, with an eigenvalue greater than one, explain 58% of the variance. Cronbach’s alpha for the PSQ was 0.92. In the regression analysis, only PSQ scores contributed to explain the experimental pain intensity and tolerance. Gender only influenced the experimental pain threshold, as men had statistically significant higher heat pain threshold than women. Conclusion: This study shows that PSQ is a valid and reliable questionnaire and might be a promising instrument for assessing pain sensitivity in Norwegian clinical settings. Further studies are needed to examine whether the PSQ can be used in clinical settings to predict postoperative pain and the development of chronic pain. Keywords: experimental pain, pain sensitivity questionnaire, factor analysis, gender

Previous data show that spinal cord long-term potentiation (LTP) can be induced by electrical high-frequency stimulation (HFS) conditioning applied to the sciatic nerve. It has been suggested that the cellular events leading to this form of plasticity may contribute to central hyperalgesia. In the present study, extracellular recordings from single dorsal horn neurons and quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) on rat dorsal horn tissue were used to examine whether maintenance of spinal LTP is associated with changes in gene expression of the proinflammatory interleukin-1beta (IL-1beta), glial cell-line derived neurotrophic factor (GDNF), inducible nitric oxide synthase (iNOS), p38 mitogen-activated protein kinase (p38 MAPK), cyclooxygenase 2 (COX2) and tumor necrosis factor alpha (TNFalpha). The data demonstrated that the HFS conditioning induced a robust increase in the dorsal horn C-fibre responses, which outlasted the duration of the experiments of 6h (p<0.05, HFS vs. control). Moreover, a significant increase in the expression of mRNA for IL-1beta, GDNF and iNOS were observed 6h following the HFS conditioning (p<0.05, HFS vs. control). For the first time we show that spinal cord LTP is associated with an increased dorsal horn expression of the genes for IL-1beta, GDNF and iNOS. [ABSTRACT FROM AUTHOR]

Abstract: Secondary central nervous system lymphoma (SCNSL) is a rare manifestation of diffuse large B-cell lymphoma (DLBCL) with a poor prognosis. We present updated data from a nationwide study on the incidence and clinical characteristics of SCNSL. The incidence of SCNSL was calculated considering death or relapse without SCNSL as competing risks. Risk factors associated with SCNSL were identified using a cause-specific Cox proportional hazards model. A total of 1972 patients with DLBCL were included, of which 68 (3.4%) experienced SCNSL at the first relapse. The crude 1- and 2-year cumulative incidence of SCNSL was 2.0% (95% confidence interval [CI], 1.5-2.7) and 2.6% (95% CI, 2.0-3.4), respectively. For patients with a high-risk central nervous system international prognostic index (CNS-IPI) score, the 1- and 2-year cumulative incidence was 6.4% and 7.5%, respectively. The number and location of extranodal (EN) sites were the most significant predictors of SCNSL. Specific EN sites associated with an increased risk were the bone marrow, heart, kidneys/adrenal glands, ovaries, testes, and uterus. The median overall survival (OS) after SCNSL was 3.2 months. SCNSL within 6 months after the end of treatment (EOT) was associated with a higher baseline CNS-IPI score and worse OS than SCNSL >6 months after EOT. Patients with a combination of low-risk CNS-IPI and late-onset SCNSL had the most favorable prognosis. In conclusion, updated real-world population-based data on SCNSL at first relapse, adjusted for competing risks, demonstrated a lower incidence of SCNSL than previously reported, with the number and location of EN sites being the most significant predictors of SCNSL., (© 2025 American Society of Hematology. Published by Elsevier Inc. 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.)

Chronic low back pain (cLBP) lacks clear physiological explanations, and the treatment options are of limited effect. We aimed to elucidate the underlying biology of cLBP in a subgroup of patients with Modic changes type I (suggestive of inflammatory vertebral bone marrow lesions) by correlating gene expression in blood with patient-reported outcomes on disability and pain intensity and explore sex differences. Patients were included from the placebo group of a clinical study on patients with cLBP and Modic changes. Blood was collected at the time of inclusion, after three months, and after one year, and gene expression was measured at all time points by high-throughput RNA sequencing. The patients reported disability using the Roland-Morris Disability Questionnaire, and pain intensity was assessed as a mean of three scores on a 0-10 numeric rating scale: current LBP, worst LBP within the last two weeks, and mean LBP within the last two weeks. The gene expression profiles were then correlated to the reported outcomes. Changes in gene expression over time correlated significantly with changes in both disability and pain. The findings showed distinct patterns in men and women, with negligible overlap in correlated genes between the sexes. The genes involved were enriched in immunological pathways, particularly T cell receptor complex and immune responses related to neutrophils. Several of the genes harbour polymorphisms that previously have been found to be associated with chronic pain. Taken together, our results indicate gender differences in the underlying biology of disability and pain intensity in patients with low back pain.

Introduction: Large B-cell lymphoma (LBCL) exhibits striking clinical and molecular heterogeneity. New approaches have emerged to explore tumor heterogeneity and classify LBCL into biological categories. Consequently, the informational requirements from diagnostic samples to provide the necessary information have increased, but the adequacy of single-site biopsies to provide such information is largely unknown. Here we describe spatial and temporal intra-patient variations in the mutational landscape of paired biopsies., Methods: Paired biopsies from 30 patients with LBCL were obtained from spatially distinct sites at the time of primary diagnosis before treatment and/or at a subsequent relapse. The samples were sequenced using a custom designed 59-gene next generation sequencing (NGS) lymphoma panel., Results: Differences in detected mutations of pathogenic or likely pathogenic significance were frequent both when comparing paired diagnostic biopsies, 2/6 (33%), and when comparing paired biopsies at primary diagnosis and relapse, 8/16 (50%). Mutational heterogeneity tended to increase with longer time interval between biopsies. Analysis of paired diagnostic and relapse biopsies revealed that certain clones present at diagnosis disappeared, while new clones emerged at relapse. Notably, TP53 mutations were detected in six out of seven patients in an extranodal location. In two cases, TP53 mutation was only detected in the relapse biopsy. Several of the mutations identified in this study are used or under investigation as targets for cancer treatments., Conclusion: Multi-site biopsies revealed spatial and temporal mutational heterogeneity in patients with LBCL. Our findings indicate that mutational differences between biopsy pairs can occur at all timepoints examined. This underscores the necessity of performing repeat biopsies with each relapse to capture the full spectrum of genetic aberrations., Competing Interests: Declarations. Ethical approval: The study was performed in accordance with the Declaration of Helsinki and approved by the Danish Regional Committee on Health Research Ethics, Capital Region of Denmark (case number: H-20058846) and the Danish Capital Region Knowledge Center for Data Reviews (Case number: P-2020- 1212). Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Large B-cell lymphoma (LBCL) taxonomy has moved in the direction of a molecular classification, but further clinical experience is needed. We present high-risk gene mutations, which predict outcome in an exploratory study of a consecutive real-world cohort of patients with primary LBCL treated with R-CHOP or R-CHOP-like therapy., Methods: The study was a Registry Study Research Project. Sixty-one patients with LBCL, who had a diagnostic tumor sample successfully examined with a 59-gene next-generation sequencing (NGS) panel as a part of routine clinical work, were included in an otherwise unselected cohort. Data were extracted from patient files and pathology reports., Results: Mutations in NOTCH2 (HR 9.69; 95% CI [2.46-38.11]; p = 0.0012), PRDM1 (HR 3.54; 95% CI [1.03-12.22]; p = 0.045), and TP53 (HR 5.89; 95% CI [1.71-20.32]; p = 0.005) were significantly associated with inferior survival in patients with primary LBCL treated with intention to cure with at least three series of R-CHOP or R-CHOP-like therapy. Neither MYD88 (HR 0.66; 95% CI (0.17-2.49), p = 0.54) nor CD79B (HR 0.84;95% CI (0.18-3.88), p = 0.82) mutations were associated with inferior survival., Conclusion: With a targeted gene panel and NGS methodology feasible in daily diagnostic routine, we identified high-risk gene mutations with a significant prognostic impact of which TP53 mutations were reproducible across validation cohorts., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Despite advances in treatment, approximately 15% of patients with diffuse large B-cell lymphoma (DLBCL) who achieve complete remission (CR) after first-line therapy will experience a relapse. However, there is no consensus on the optimal follow-up strategies for detecting relapse after achieving CR. This population-based study, based on the Danish Lymphoma Registry (LYFO), identified a total of 1634 patients diagnosed with DLBCL between 2010 and 2017, including 105 patients who achieved CR following first-line R-CHOP-like therapy and subsequently relapsed. The median follow-up time was 6 years (range 3-8 years). Most cases of relapse were symptomatic (83%), with B symptoms and peripheral lymphadenopathy being the most common. Asymptomatic relapses were identified through physical examination (1%), blood tests (3%), or imaging findings (13%). The proportion of relapses identified outside routine visits was 70%. Only 5% of scheduled routine visits led to a relapse diagnosis, whereas 74% of unscheduled visits initiated by the patient outside routine follow-up resulted in relapse detection. Our findings highlight that systematic, scheduled monitoring of patients in remission after first-line treatment contributes only modestly to the early detection of disease recurrence. Future studies should explore alternative methods of relapse surveillance rather than relying solely on pre-scheduled clinical follow-up., (© 2025 Wiley Periodicals LLC.)

Introduction: Extramedullary disease (EMD) is a rare manifestation of Waldenström macroglobulinemia (WM), and its clinical and prognostic implications are poorly understood., Methods: In this single-center study, we investigated the clinical significance of EMD in a cohort of 469 WM patients., Results: EMD was identified in 30 (6.4%) patients, with the central nervous system, kidneys, and lungs being the most frequently affected sites. The cumulative incidence of EMD was 12.6% at 15 years. Median overall survival rates at 5 and 10 years for patients with EMD were 63% and 37%, respectively., Conclusion: Our findings indicate a persistent risk of EMD throughout the disease course, with no significant impact on long-term survival., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Objective: This study explores the epidemiology, incidence, and survival outcomes associated with lymphomas of the submandibular gland (SMG) and examines the influence of autoimmune diseases on these parameters., Methods: This retrospective nationwide cohort study analysed data from patients diagnosed with SMG lymphomas in Denmark between 2000 and 2020. Information was extracted from medical records, the National Pathology Register, and the Danish Lymphoma Database. Survival analyses were conducted using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models, focusing on lymphoma subtypes and autoimmune diseases., Results: The cohort consisted of 101 patients with a lymphoma diagnosis and involvement of the SMG. Large B-cell lymphoma (LBCL) was diagnosed in 33 cases (32.7%), follicular lymphoma (FL) in 29 cases (28.7%), extranodal marginal zone lymphoma (EMZL) in 27 cases (26.7%), and 12 cases (11.9%) with other subtypes. EMZL had a significantly longer overall survival (OS) compared to other subtypes, with a median OS of 12.4 years (95% CI 11.2-12.4) vs. 8.4 years (95% CI 6.0-12.2). EMZL and FL showed favourable 5-year OS rates of 95% and 89%, respectively. LBCL had a 5-year OS rate of 65%. Age over 60 significantly negatively impacted OS. Traditional poor prognostic indicators did not significantly affect OS. A notable association between EMZL and autoimmune diseases was observed, particularly with Sjögren's syndrome, indicated by an increased relative risk of 2.67 (CI 95% 0.45-16.01)., Conclusions: Lymphomas of the SMG are rare and have ambiguous clinical presentations. This study provides novel epidemiological, clinical, and prognostic information., (© 2024. The Author(s).)

Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) carries a dismal prognosis and most clinical guidelines recommend CNS prophylaxis to patients deemed at high risk of CNS relapse. However, results from observational studies investigating the effect of CNS prophylaxis have yielded conflicting results. The aims of this study were to evaluate: (i) whether addition of prophylactic intravenous high-dose methotrexate (HD-MTX) reduces the risk of CNS relapse in high-risk DLBCL patients treated with R-CHOP or similar, and (ii) whether HD-MTX prophylaxis confers an overall survival benefit, irrespective of CNS relapse. We performed a systematic search of MEDLINE/PubMed and EMBASE for data on DLBCL patients at high risk of CNS relapse treated with R-CHOP or similar who received HD-MTX as an intervention and a comparator arm of patients who did not receive prophylaxis and/or intrathecal prophylaxis. A risk of bias was estimated using the ROBINS-I tool and the quality of the evidence was assessed by the GRADE approach. Finally, a meta- analysis based on the systematic review was conducted. A total of 1,812 studies were screened. No randomized controlled trials were identified. Seven observational studies comprising 1,661 patients met the inclusion criteria. We found a statistically non-significant relative risk of 0.54 (95% confidence interval: 0.27-1.07) of CNS relapse for patients receiving HD-MTX versus controls. The meta-analysis investigating mortality demonstrated a relative risk of death of 0.70 (95% confidence interval: 0.44-1.11) for patients treated with HD-MTX versus controls. The overall risk of bias was adjudged as "serious" and the quality of the evidence was rated as "low". In conclusion, our data indicate that HD-MTX does not prevent or, at best, only slightly reduces the risk of CNS relapse and confers no survival benefit.

Patients with chronic lymphocytic leukemia (CLL) are at high risk of developing severe COVID-19. The present study was undertaken to elucidate COVID-19 related morbidity and mortality in CLL patients treated with venetoclax. We present a single-center study of 108 patients with small lymphocytic lymphoma or CLL treated with venetoclax. Primary outcome was 30-day COVID-19 mortality. Secondary outcomes included COVID-19 severity and hospitalization rate. Forty-eight (44%) patients had PCR-verified SARS-COV-2 between March 2020 and January 2023. Thirty-six patients (75%) presented with asymptomatic/mild COVID-19 and 12 (25%) with severe/critical disease. The hospitalization rate was 46% with a 30-day mortality rate of only 4% and severe comorbidities as the primary cause of death. COVID-19 severity and mortality were similar before and during the Omicron era. High CIRS-scores (P < 0.02) and thrombocytopenia (P < 0.01) were more frequent in patients with severe/critical disease. In real-world data, most venetoclax treated patients presented with mild COVID-19. Hospitalization and mortality rates were low compared to data of general CLL populations. Our data indicate that venetoclax was a safe treatment option for CLL patients during the pandemic., (© 2024. The Author(s).)

Introduction: Overweight and obesity constitute a major concern among patients treated at forensic psychiatric departments. The present clinical feasibility study aimed at investigating the extent to which glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with once-daily liraglutide 3.0 mg could be a feasible pharmacological treatment of these conditions in patients with schizophrenia spectrum disorders hospitalised in forensic psychiatry., Methods: The 26-week, open-label feasibility study included participants aged 18-65 years diagnosed with a severe mental illness and hospitalised at a forensic psychiatric department. At the time of inclusion, all participants fulfilled the indication for using liraglutide as a treatment for overweight and obesity. Participants' baseline examinations were followed by a 26-week treatment period with liraglutide injection once daily according to a fixed uptitration schedule of liraglutide, with a target dose of 3.0 mg. Each participant attended seven visits to evaluate the efficacy and adverse events. The primary endpoint was the number of "completers", with adherence defined as >80% injections obtained in the period, weeks 12-26. Determining whether liraglutide is a feasible treatment was pre-defined to a minimum of 75% completers., Results: Twenty-four participants were included in the study. Sex, male = 19 (79.2%). Mean age: 42.3 [25th and 75th percentiles: 39.1; 48.4] years; body mass index (BMI): 35.7 [31.7; 37.5] kg/m 2 ; glycated haemoglobin (HbA1c): 37 [35; 39] mmol/mol. Eleven out of 24 participants (46%) completed the study. For the completers, the median net body weight loss after 26 weeks of participation was -11.4 kg [-15.4; -5.9]. The net difference in HbA1C and BMI was -2.0 mmol/mol [-4; -1] and -3.6 kg/m 2 [-4.7; -1.8], respectively. The weight change and reduction in HbA1c and BMI were all statistically significant from baseline., Conclusion: The study did not confirm our hypothesis that liraglutide is a feasible treatment for a minimum of 75% of the patients initiating treatment with liraglutide while hospitalised in a forensic psychiatric department. The high dropout rate may be due to the non-naturalistic setting of the clinical trial. For the proportion of patients compliant with the medication, liraglutide 3.0 mg was an efficient treatment for overweight., (© 2024 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Advancements in lymphoma treatment have increased the number of long-term survivors who may experience late effects such as impaired sexual function and testosterone deficiency. The aim of this review was to determine the prevalence of testosterone deficiency and sexual dysfunction among male lymphoma survivors; and associations between the two. A systematic search identified 20 articles for inclusion. The prevalence of low total testosterone was 0%-50 %, with mean values within reference levels, and for luteinizing hormone above reference levels in 0%-80 %. Four studies included SHBG and free testosterone, with mixed results. Compromised sexual health was found in 23%-61 %. Overall, total testosterone and sexual health were associated. The risk of bias (ROBINS-E and RoB 2) was high/very high, leading to low/very low overall confidence in the bulk of evidence (GRADE). Longitudinal studies evaluating biologically active testosterone and sexual health are needed, to develop evidence based standard procedures for follow-up of sexual health., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interestsSigne Micas Pedersen reports equipment, drugs, or supplies was provided by Besins Healthcare. Peter de Nully Brown reports a relationship with Roche that includes: consulting or advisory. Peter de Nully Brown reports a relationship with Gilead Sciences Inc that includes: consulting or advisory. Peter de Nully Brown reports a relationship with Swedish Orphan Biovitrum that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Cancer and side effects from cytostatic treatment commonly affect nutritional status manifested as a decrease in muscle mass. We aimed to investigate the impact of nutrition and lifestyle-related factors on muscle mass in patients with hematological cancer., Methods: Dietary intake, food preferences, quality of life (QoL), and physical activity level (PAL) were monitored during 1-2 cytostatic treatment series. Body composition was estimated using bioelectrical impedance analysis (BIA)., Results: 61 patients were included. Weight loss and loss of muscle mass were detected in 64% and 59% of the patients, respectively. Muscle mass was significantly positively correlated to increasing PAL ( p = 0.003), while negatively correlated to increasing age ( p = 0.03), physical QoL ( p = 0.007), functional QoL ( p = 0.05), self-perceived health ( p = 0.004), and self-perceived QoL ( p = 0.007). Weight was significantly positively correlated to increased intake of soft drinks ( p = 0.02) as well as the favoring of bitter grain and cereal products ( p = 0.03), while negatively correlated to increasing age ( p = 0.03) and increasing meat intake ( p = 0.009) Conclusions: Several nutritional and lifestyle-related factors affected change in body composition. The clinical significance of these changes should be investigated in controlled, interventional studies.

In the current study, we report the prevalence of male testosterone deficiency in a cohort of 60 male long-term survivors of malignant lymphoma with normal total testosterone but in the lower part of the reference level. Testosterone deficiency was defined as subnormal concentrations of total testosterone or subnormal concentrations of calculated free testosterone. The aim was to clarify whether total testosterone was sufficient for identification of testosterone deficiency in male survivors of malignant lymphoma. Hormonal analyses taken at follow-up were compared with samples taken at diagnosis for a subgroup of 20 survivors, for evaluation of changes in hormones over time. Another group of 83 similar survivors of malignant lymphoma with testosterone in the high end of reference levels were also used for comparison, to identify groups of increased risk of testosterone deficiency. A total group of 143 survivors were therefore included in the study. Our findings indicate that for screening purposes an initial total testosterone is sufficient in some survivors because sexual hormone binding globulin concentration was found stable over time. However, 15% were found with subnormal calculated free testosterone. Survivors intensely treated for Hodgkin lymphoma and older survivors were identified as high-risk groups for testosterone deficiency necessitating endocrinological attention during follow-up. Some evidence of pituitary downregulation was also found, because of uncompensated decreases in testosterone concentration over time. In conclusion, longitudinal measurements of total testosterone alone do not seem adequate for the screening of testosterone deficiency for all long-term lymphoma survivors., (© 2023. The Author(s).)

Introduction: Integration of molecular characterization of lymphomas in clinical diagnostics may improve subclassification and risk-stratification, and we implemented a next generation sequencing (NGS) analysis as part of routine diagnostic work-up of all mature B-cell non-Hodgkin's lymphoma (B-NHL). Here, we present data of mutational profiles with potential complementary diagnostic, prognostic, and predictive value detected in our consecutive non-selected cohort of B-NHL patients., Methods: NGS results from 298 patients with both newly diagnosed and relapsed/refractory disease were included as a single center study. NGS was performed as routine analysis together with standard diagnostic work-up using a custom-made amplicon PCR-based multiplex NGS panel covering all coding exons and consensus splice sites in 59 genes., Results: Mutations were detected in 94% of the 298 samples. Most lymphomas could be classified definitively, but 24 cases were classified as small B-cell lymphomas without defining characteristics. Of these, 50% (12/24 cases) could retrospectively be assigned a likely diagnostic subtype according to mutational findings., Conclusion: Implementation of a 59 gene exome sequencing panel added diagnostic value to 50% of unclassified cases and provided in 94% of the cases possible biomarkers for disease monitoring as well as potential diagnostic, prognostic, and predictive markers for future studies., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, both regarding clinical presentation, response to treatment and outcome. Recently, subclassification of DLBCL based on mutational profile has been suggested, and next generation sequencing (NGS) analysis may be relevant as part of the diagnostic workflow. This will, however, often be based on analysis of one tumor biopsy. Here, we present a prospective study where multi-site sampling was performed prior to treatment in patients with newly diagnosed DLBCL. Two spatially different biopsies from 16 patients were analyzed using NGS with an in-house 59-gene lymphoma panel. In 8/16 (50%) patients, mutational differences were found between the two biopsy sites, including differences in TP53 mutational status. Our data indicate that a biopsy from the extra-nodal site may represent the most advanced clone, and an extra-nodal biopsy should be preferred for analysis, if safely accessible. This will help ensure a standardized stratification and treatment decision.

Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients ( n = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study. Gene expression and DNA methylation were investigated at a genome-wide level at screening, after 100 days of treatment, and at one-year follow-up. We identified intra-individual longitudinal changes in gene expression and DNA methylation in patients receiving amoxicillin, while few changes were observed in patients receiving placebo. After 100 days of amoxicillin treatment, 28 genes were significantly differentially expressed, including the downregulation of 19 immunoglobulin genes. At one-year follow-up, the expression levels were still not completely restored. The significant changes in DNA methylation ( n = 4548 CpGs) were mainly increased methylation levels between 100 days and one-year follow-up. Hence, the effects on gene expression occurred predominantly during treatment, while the effects on DNA methylation occurred after treatment. In conclusion, unrecognized side effects of long-term amoxicillin treatment were revealed, as alterations were observed in both gene expression and DNA methylation that lasted long after the end of treatment.

Background: Lymphomas constitute 2% of all salivary gland tumors and are the second most common group of malignancies in the head and neck region., Objectives: In this systematic review, the demographics and characteristics of salivary gland lymphomas are presented., Methods: All types of studies that involve data of salivary gland lymphomas between 1990 and 2020 were identified and screened., Results: A total of 169 articles with 1640 patients were identified. The median age of the patients was 59 years with a range between 10 and 87 years. The anatomic locations of salivary gland lymphomas were distributed with 88% in the parotid glands, 9% in the submandibular glands, 1% in the minor salivary glands, and 0.3% in the sublingual glands. The overall survival at 12 months is high and in line with the outcome of indolent lymphomas in general. The predominant indolent subtypes were extranodal marginal zone lymphomas and follicular lymphomas, whereas the more aggressive subtypes were mainly diffuse large B-cell lymphomas, mantle cell lymphomas, and T-cell lymphomas., Conclusion: In conclusion, lymphomas occur in all salivary glands and mainly in elderly female patients. Sjögren's syndrome is frequently associated. Depending on the anatomical location, the lymphoma subtypes vary in aggressiveness, stage, and prognosis.

Background: With improved survival in patients with lymphoma, long-term toxicity and quality of life (QoL), including sexual health, have become increasingly important., Aim: We aimed to (1) determine the prevalence of erectile dysfunction (ED) in adult male lymphoma survivors; (2) determine whether testosterone deficiency, comorbidities, or lifestyle factors were associated; and (3) evaluate their impact on QoL., Methods: A cross-sectional study including 172 male survivors of Hodgkin lymphoma or diffuse large B cell lymphoma diagnosed in adulthood between 2008 and 2018 was performed. Patients were in complete metabolic remission after first-line treatment and remained in remission at follow-up (3-13 years after diagnosis). Participants completed 3 questionnaires measuring sexual health and general QoL. Serum concentrations of total testosterone were measured and thorough medical history and sociodemographic factors were obtained. The Danish SEXUS Project, European Male Ageing Study, and European Organization of Research and Treatment of Cancer (EORTC) Reference Manual were used as reference values of the general population., Outcomes: Patient reported outcome measures including the 5-item International Index of Erectile Function, EORTC C30, and EORTC 22-item Sexual Health Questionnaire., Results: ED was reported by 55.2%, which was higher than in an age-matched Danish population cohort (17.5%). Erectile function score (5-item International Index of Erectile Function) was negatively associated with comorbidity, body mass index, smoking, and age and positively with the number of children conceived before treatment and serum concentration of total testosterone. Overt testosterone deficiency in combination with ED was detected in 10 (5.7%) of 176 survivors, including excluded survivors in hormonal treatment, which is higher than for the general population (0.1%-3.2% for men <70 years of age). Mean EORTC C30 global health score for survivors with ED was lower (67.7) than for survivors without ED (80.1) but was comparable to the general population (71.2). Furthermore, a positive association was seen between sexual function and both sexual and general QoL., Clinical Implications: Sexual health is important for QoL and related to comorbidities. The focus on improving QoL requires that both sexual health and comorbidities are addressed in the follow-up of lymphoma patients., Strengths and Limitations: Despite the relatively high number of included survivors, the cross-sectional design of this study warrants longitudinal studies to clarify the specific underlying causes of sexual dysfunction., Conclusion: ED was highly prevalent and associated with comorbidity in lymphoma survivors, and more focus on sexual health and treatment related comorbidity is needed to improve sexual and general QoL., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Objectives: To explore serum cytokine levels over time in patients with chronic low back pain (cLBP) and Modic changes (MCs), difference in change between treatment groups in the Antibiotics in Modic Changes (AIM) study and associations between change in cytokines and low back pain., Methods: Serum concentrations of 39 cytokines were measured at baseline and 1 year from 73 participants in the AIM study; 30 randomized to placebo, 43 to Amoxicillin. Low back pain intensity was measured by numeric rating scale. Change in cytokine levels over time were assessed by paired t-tests. Difference in change in cytokine levels between treatment groups and associations between changes in LBP and cytokine levels were assessed by linear regression models. Networks of cytokine changes in each treatment groups were explored by Pearson's correlations., Results: Five cytokines changed from baseline to 1 year, (mean change, log transformed values with CI) C-X-C motif chemokine ligand (CXCL) 10 (IP-10) (0.11 (0.01-0.20)), CXCL13 (0.61 (0.00-0.12)), C-C motif chemokine ligand (CCL)26 (0.05 (0.01-0.1)), granulocyte macrophage-colony stimulating factor (GM-CSF) (-0.12 (-0.23 to 0.00)) and CXCL11 (0.12 (0.03-0.22)). Treatment group only influenced change in CCL21 (β 0.07 (0.01-0.12)), and IL-6 (β -0.17 (-0.30 to -0.03)). Change in CXCL13 (β 2.43 (0.49-4.38)), CCL27 (β 3.07 (0.46-5.69)), IL-8 (β 1.83 (0.08-3.58)) and CCL19 (β 3.10 (0.86-5.43)) were associated with change in LBP. The correlation networks of cytokine changes demonstrate small differences between treatment groups., Conclusions: Cytokine levels are relatively stable over time in our sample, with little difference between treatment groups. Some cytokines may be associated with LBP intensity. The differences between the correlation networks suggest that long-term Amoxicillin-treatment may have longstanding effects to be further explored., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Social capital is an acknowledged theoretical concept in work environment research focusing on collective resources that arise from social networks between employees in the workplace. Social capital is divided into bonding (in the work unit), bridging (between work units), and linking social capital (between the work units and management). However, only a few studies have investigated the relationship between social capital and the quality of health care, which is the key outcome of hospital services., Objective: We investigated the associations between bonding, bridging and two types of linking social capital with the self-reported quality of health care services among Danish hospital employees. Next, we directly compared how social capital, workload and work pace each affected the quality of health care., Design: A cross-sectional study at Regional Hospital West Jutland, Denmark., Data: Questionnaire data were collected from 1589 Danish hospital employees. We used validated scales for social capital, workload, and work pace and self-developed scales for clinical quality, quality of patient involvement, and overall professional quality., Methods: Binary logistic regression analyses were conducted., Results: The analyses showed significant, positive associations of bonding and bridging social capital with all types of quality and negative associations between workload and all types of quality. The work pace was negatively associated with clinical quality. When covariates were included in the model, the associations remained statistically significant and showed no decrease in odds ratios. The marginal effects showed that when bonding and bridging social capital were increased by a single scale point, the predicted probability for a high clinical quality increased by an average of 0.5 percentage points. This increase corresponds to a change in the predicted probability of self-reported high clinical quality from 10% for the lowest reported bridging social capital to 54% for the highest reported bridging social capital. For workload and work pace, the effects were -0.2 and -0.3 percentage points, respectively., Discussion & Conclusions: This study adds to the literature on positive work environment factors by focusing on social capital and the importance of well-functioning relationships within and especially between hospital units for high-quality health care. Hence, bridging and bonding social capital should be included in theoretical frameworks, as well as in hospital strategies and work environment guidelines to potentially improve the quality of health care services. However, further studies are needed to develop and test the effects of specific social capital interventions on the quality of health care services., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Bone involvement is a rare extranodal manifestation in patients with malignant lymphoproliferative diseases and has also been noted as a rare event in patients with Waldenstrom macroglobulinemia (WM). However, the actual prevalence has not been previously reported. We describe an unusual case of a patient with WM who presented with lower back pain and focal bone lesions at initial diagnosis. Magnetic resonance imaging (MRI) revealed multiple vertebral fractures. Positron emission tomography (PET) detected only nodal changes without pathological skeletal-related metabolic activity. Lymph node and bone marrow biopsies combined with an immunoglobulin M (IgM) M component revealed the diagnosis of WM. A next-generation sequencing (NGS) analysis using a targeted lymphoma panel of 59 recurrently mutated genes in lymphoid neoplasms showed mutations in the MYD88 and CD79B genes. After treatment with rituximab and bendamustine, the patient achieved a partial remission and pain relief. After 3 years of stable disease, a spontaneous subcapital fracture at the base of the femoral neck and new vertebral compression fractures occurred. Whole-body low-dose computed tomography (WB-LDCT) and bone density (dual energy X-ray absorptiometry (DEXA)) scan revealed marked osteopenia. After insertion of a hip prosthesis, examination of the removed hip showed infiltration of clonal lymphoplasmacytic cells. Our case confirms that one must be aware that bone involvement in patients with WM can occur as a rare manifestation. Interestingly, the MYD88/CD79B -mutated (MCD) genotype in diffuse large B-cell lymphoma is characterized by extranodal involvement and may also be involved in the pathogenesis of skeletal-related disease in the present case. As a follow-up to this unusual case, we have carried out an analysis based on the Danish Lymphoma Registry (LYFO) covering the entire national population in the period 2000 - 2020. The registry study included a cohort of 2,459 patients with WM and lymphoplasmacytic lymphoma. Our data revealed that primary bone involvement at diagnosis occurs in 1.75% of adults with WM. To the best of our knowledge, this is the first report of the prevalence of skeletal-related disease in a large nationwide cohort and defines bone involvement as an exceedingly rare event in WM., Competing Interests: The authors have no conflict of interest to declare., (Copyright 2022, Bhatti et al.)

Aim: The primary aim was to estimate premature infants' spontaneous patent ductus arteriosus closure rate. Secondly, to identify criteria associated with the chance of spontaneous closure., Methods: We performed a retrospective cohort study of 167 infants born before 32 weeks of gestation and diagnosed with a patent ductus arteriosus between 1 January 2008 and 31 December 2017. The spontaneous patent ductus arteriosus closure event rate was evaluated using the Kaplan-Meier estimator., Results: The spontaneous closure rate within the first year of life was 66% (95% CI 58%-73%), increasing to 80% (95% CI 72%-86%) five years after birth. When including both spontaneous closure and closure following treatment, 96% (95% CI 86%-100%) closed within 5 years after birth. The chance of spontaneous closure was reduced in the case of a large patent ductus arteriosus: OR 0.16 (95% CI 0.05-0.52), left atrial enlargement: OR 0.16 (95% CI 0.05-0.51), and pulmonary hypertension: OR 0.23 (95% CI 0.07-0.74)., Conclusion: The chance of spontaneous closure in premature infants born between 23 and 32 weeks of gestation was high, and the incidence continued increasing until 5 years of follow-up., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Chronic lymphocytic leukemia (CLL) patients with unmutated immunoglobulin heavy chain (IgHV) are at risk of early disease progression compared to patients with mutated IgHV. As a preventive strategy, we treated 19 previously untreated CLL patients with unmutated IgHV in a phase 1/2 trial (clinicaltrials.gov, NCT03939234) exploring the efficacy and toxicity of a therapeutic cancer vaccine containing peptides derived from programmed death ligand 1 (PD-L1) and ligand 2 (PD-L2), hoping to restore immunological control of the disease. According to the International Workshop on Chronic lymphocytic Leukemia (iwCLL) response criteria, no patients obtained a response; however, during follow-up, one patient had complete normalization of the peripheral lymphocyte count and remained in biochemical remission after a follow-up time of 15 months. At the end of treatment, one patient had progressed, and 17 patients had stable disease. During follow-up with a median time of 23.5 months since inclusion, seven patients had progressed, and eight patients had stable disease. The median time to first treatment (TTFT) from diagnosis was 90.3 months with a median follow-up time of 50.1 months. This apparent favorable outcome in TTFT needs to be investigated in a randomized setting, as our population may have been biased. More than 80% of patients obtained vaccine-specific immune responses, confirming the immunogenicity of the vaccine. The vaccine was generally well tolerated with only grade I-II adverse events. Although there were some signs of clinical effects, the vaccine seems to be insufficient as monotherapy in CLL, possibly due to a high tumor burden. The efficacy of the vaccine should preferably be tested in combination with novel targeted therapies or as a consolidating treatment., Competing Interests: The first author UK was employed at National Center for Cancer Immune Therapy CCIT-DK, supported by a research agreement with IO biotech APS during the trial. Further, the study is part of a PhD thesis by UK, who answers to MA, his primary supervisor and employer. MA is named as an inventor on various patent applications relating to therapeutic uses of PD-L1 and PD-L2 peptides. These patent applications are assigned to the company IO Biotech, which is developing immune-modulating cancer treatments. MA and IS have cofounded IO Biotech and are shareholders and active advisors in the company. CN received research funding and/or consultancy fees outside this study from AbbVie, AstraZeneca, Janssen, CSL Behring, BeiGene, Genmab, Takeda, and Octapharma. Large parts of the study have taken place at CCIT-DK, which is an organization that has an economical interest in the tested vaccines according to the patent laws in Denmark. JG, SW-B, SA, MH, MOH, and ÖM were employed at CCIT-DK during the trial, answering to either IMS or MHA. EM is an employee at IO Biotech. 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 © 2022 Klausen, Grauslund, Jørgensen, Ahmad, Jonassen, Weis-Banke, Martinenaite, Pedersen, Lisle, Gang, Enggaard, Hansen, Holmström, Met, Svane, Niemann, Pedersen and Andersen.)