Search

Objective To validate Vergouwe's prediction model using the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) RETROP database and to define its clinical utility. Materials and methods Vergouwe's prediction model for benign histopathology in post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) uses the following variables: presence of teratoma in orchiectomy specimen; pre-chemotherapy level of alpha-fetoprotein; β-Human chorionic gonadotropin and lactate dehydrogenase; and lymph node size pre- and post-chemotherapy. Our validation cohort consisted of patients included in RETROP, a prospective population-based database of patients in Sweden and Norway with metastatic nonseminoma, who underwent PC-RPLND in the period 2007–2014. Discrimination and calibration analyses were used to validate Vergouwe's prediction model results. Calibration plots were created and a Hosmer–Lemeshow test was calculated. Clinical utility, expressed as opt-out net benefit (NBopt-out), was analysed using decision curve analysis. Results Overall, 284 patients were included in the analysis, of whom 130 (46%) had benign histology after PC-RPLND. Discrimination analysis showed good reproducibility, with an area under the receiver-operating characteristic curve (AUC) of 0.82 (95% confidence interval 0.77–0.87) compared to Vergouwe's prediction model (AUC between 0.77 and 0.84). Calibration was acceptable with no recalibration. Using a prediction threshold of 70% for benign histopathology, NBopt-out was 0.098. Using the model and this threshold, 61 patients would have been spared surgery. However, only 51 of 61 were correctly classified as benign. Conclusions The model was externally validated with good reproducibility. In a clinical setting, the model may identify patients with a high chance of benign histopathology, thereby sparing patients of surgery. However, meticulous follow-up is required.

Background:Epstein–Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL).Methods:Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case–control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models.Results:IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glycoprotein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types.Conclusions:Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis.Impact:Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer.

Supplementary Table S2 shows summary of participant characteristics

Supplementary Methods S1 expands upon data and statistical methods.

Background: Epstein–Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL). Methods: Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case–control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models. Results: IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glycoprotein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types. Conclusions: Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis. Impact: Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer.

Childbirth rates in classical Hodgkin lymphoma (cHL) survivors have historically been reduced compared to the general population. Understanding if contemporary treatment protocols are associated with reduced fertility is crucial as treatment guidelines shift toward more liberal use of intensive chemotherapy. We identified 2834 individuals aged 18-40 years with cHL in Swedish and Danish lymphoma registers, and in the clinical database at Oslo University Hospital diagnosed 1995-2018, who were linked to national medical birth registers. Cox regression adjusted for stage, performance status, year, and age at diagnosis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) contrasting time to first childbirth by treatment groups (ABVD, 2-4 BEACOPP, 6-8 BEACOPP) up to 10 years after diagnosis. Overall, 74.8% of patients were treated with ABVD, 3.1% with 2-4 BEACOPP and 11.2% with 6-8 BEACOPP. Adjusted HRs comparing childbirth rates in individuals treated with 6-8 BEACOPP, and 2-4 BEACOPP to ABVD were 0.53 (CI: 0.36-0.77) and 0.33 (CI: 0.12-0.91) for males, and 0.91 (CI: 0.61-1.34) and 0.38 (CI: 0.12-1.21) for females. Cumulative incidence of childbirths after 10 years was 19.8% (CI: 14.5%-27.0%) for males and 34.3% (CI: 25.8%-45.6%) for females treated with 6-8 BEACOPP. Proportions of children born after assisted reproductive technique (ART) treatments were 77.4% (CI: 60.2-88.6%) for males following 6-8 BEACOPP, and Childbirth rates in classical Hodgkin lymphoma (cHL) survivors have historically been reduced compared to the general population. Understanding if contemporary treatment protocols are associated with reduced fertility is crucial as treatment guidelines shift toward more liberal use of intensive chemotherapy. We identified 2834 individuals aged 18-40 years with cHL in Swedish and Danish lymphoma registers, and in the clinical database at Oslo University Hospital diagnosed 1995-2018, who were linked to national medical birth registers. Cox regression adjusted for stage, performance status, year, and age at diagnosis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) contrasting time to first childbirth by treatment groups (ABVD, 2-4 BEACOPP, 6-8 BEACOPP) up to 10 years after diagnosis. Overall, 74.8% of patients were treated with ABVD, 3.1% with 2-4 BEACOPP and 11.2% with 6-8 BEACOPP. Adjusted HRs comparing childbirth rates in individuals treated with 6-8 BEACOPP, and 2-4 BEACOPP to ABVD were 0.53 (CI: 0.36-0.77) and 0.33 (CI: 0.12-0.91) for males, and 0.91 (CI: 0.61-1.34) and 0.38 (CI: 0.12-1.21) for females. Cumulative incidence of childbirths after 10 years was 19.8% (CI: 14.5%-27.0%) for males and 34.3% (CI: 25.8%-45.6%) for females treated with 6-8 BEACOPP. Proportions of children born after assisted reproductive technique (ART) treatments were 77.4% (CI: 60.2-88.6%) for males following 6-8 BEACOPP, and

Background Both testicular germ cell tumours (TGCT) and neurodevelopmental disorders are associated with urogenital malformations. Few studies have investigated the association between psychiatric disorders and TGCT. We investigated whether history of any psychiatric or neurodevelopmental disorder is associated with increased risk or mortality of TGCT. Method This is a nested case–control study including 6166 TGCT patients diagnosed during 1992–2014, individually matched for age and calendar period to 61,660 controls. We calculated odds ratios (ORs) for the association between type of psychiatric diagnoses and TGCT risk. Among the cases, we used a cohort design and calculated hazard ratios (HRs) of the association between psychiatric diagnose and all-cause and TGCT-specific death. Results History of a neurodevelopmental disorder (attention deficit hyperactivity disorder, autism spectrum disorder and intellectual disabilities) was associated with an increased risk of seminoma (OR: 1.54; 1.09–2.19). Seminoma patients with neurodevelopmental disorders were younger (34 versus 38 years, p = 0.004) and had more stage IV disease (5.4% versus 1.2%) than those without. Psychiatric history overall was not associated with TGCT. Patient history of any psychiatric disorder was associated with an increased all-cause and TGCT-specific death. Conclusions We report an association between neurodevelopmental disorders and testicular seminoma, and an increased TGCT-specific mortality for TGCT patients with psychiatric disorders.

Supplementary Figure S1. Annual distribution of patients by extent of annual work loss (0, 1-180, 181-359 and >360 days) from two years before to five years after rectal cancer diagnosis for relapse-free patients without pre-diagnostic work loss before diagnosis (n=2529) and with pre-diagnostic work loss (sick leave only n=500, or disability pension n=409).

Supplementary Table S1. Summary of results for rs6457715 in total classical Hodgkin lymphoma and subgroups. Supplementary Table S2. Regression analysis of EBV-positive cHL risk and rs6457715 genotype. Supplementary Table S3. Association between risk score comprising rs2734986, rs6904029, and rs6457715 and EBV+ Hodgkin lymphoma in the GWAS population. Supplementary Table S4. HLA-DPB1 significant eQTLs and their effect on EBV-positive cHL risk. Supplementary Table S5. Subjects included in the genome-wide association imputation analysis and independent replication of classical Hodgkin lymphoma. Supplementary Table S6. Concordance rates between HLA imputed and directly genotyped data across 334 UK and 284 Dutch individuals. Supplementary Figure S1. Association between genetic variants and HL and Epstein-Barr virus (EBV)-negative HL within an approximately 6.5 Mb region of the extended major histocompatibility complex located at 6p21.

Supplementary Table S1. Numbers of patients at risk and mean days of work loss for clinical subgroups among relapse-free patients without pre-diagnostic work loss between 2 years before diagnosis and 5 years after diagnosis. Supplementary Table S2. Incidence rate ratio of work loss related to demographic covariates following diagnosis among relapse-free rectal cancer patients stratified by pre-diagnostic work loss Supplementary Table S3. Incidence rate ratio (IRR) of work loss following rectal cancer diagnosis associated with clinical covariates among relapse-free rectal cancer patients with pre-diagnostic sick leave (SL) only or disability pension (DP).

Background: The number of working-age rectal cancer survivors is increasing due to early detection and improved treatment. However, work loss duration and predictors among them have not been studied thoroughly.Methods: We identified 3,438 patients with stage I–III rectal cancer, 18 to 61 years of age in the Swedish Colorectal Cancer Register 1996–2009. Information on work loss due to sick leave or disability pension was collected from 2 years before diagnosis to 5 years after (until December 31st, 2013). Incidence rate ratios (IRR) of work loss were estimated in a negative binominal model by clinical characteristics for the 1st and 2nd–5th years after diagnosis. Patients were stratified by prediagnostic work loss.Results: Patients without prediagnostic work loss (74%) experienced median 147 days (25th and 75th percentile: 55 and 281) of work loss during the 1st year after diagnosis. Work loss rates (2nd–5th years) were significantly increased among relapse-free patients diagnosed in stage III [IRR = 1.92; 95% confidence interval (CI), 1.52–2.43], operated with abdominoperineal resection (IRR = 1.26; 95% CI, 1.03–1.56), and treated with neoadjuvant (chemo)radiotherapy (IRR = 1.46; 95% CI, 1.06–2.02). Patients with prediagnostic work loss (26%) experienced median 336 days (25th and 75th percentile: 183 and 365) of work loss during the 1st year, and rates did not vary clinically till 5 years.Conclusion: Without prediagnostic work loss, disease- and treatment-related factors could help identify rectal cancer patients in need of early interventions to facilitate return to work.Impact: Clinical awareness around prediagnostic and postdiagnostic work loss and individualized cancer rehabilitation programs should be emphasized among cancer survivors. Cancer Epidemiol Biomarkers Prev; 25(6); 987–94. ©2016 AACR.

Background: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein–Barr virus (EBV) status, particularly within the MHC region.Methods: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls.Results: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83–2.97; P = 7 × 10–12], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92–1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10−8). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL.Conclusions: rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL.Impact: This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease. Cancer Epidemiol Biomarkers Prev; 24(12); 1838–43. ©2015 AACR.

Thyroid cancer incidence is higher in women than men, especially during the reproductive years, for reasons that remain poorly understood. Using population-based registry data from 4 Nordic countries through 2015, we examined associations of perinatal characteristics with risk of maternal thyroid cancer. Cases were women diagnosed with thyroid cancer ≥2 years after last birth (n = 7,425, 83% papillary). Cases were matched to controls (n = 67,903) by mother’s birth year, country, and county of residence. Odds ratios (ORs) were estimated using conditional logistic regression models adjusting for parity. Older age at first pregnancy, postpartum hemorrhage (OR = 1.18, 95% (confidence interval) CI: 1.08, 1.29), and benign thyroid conditions (ORs ranging from 1.64 for hypothyroidism to 10.35 for thyroid neoplasms) were associated with increased thyroid cancer risk, as were higher offspring birth weight (per 1-kg increase, OR = 1.17, 95% CI: 1.12, 1.22) and higher likelihood of offspring being large for gestational age (OR = 1.26, 95% CI: 1.11, 1.43). Unmarried/noncohabiting status (OR = 0.91, 95% CI: 0.84, 0.98), maternal smoking (OR = 0.75, 95% CI: 0.67, 0.84), and preterm birth (OR = 0.90, 95% CI: 0.83, 0.98) were associated with reduced risk. Several factors (e.g., older age at first pregnancy, maternal smoking, goiter, benign neoplasms, postpartum hemorrhage, hyperemesis gravidarum, and neonatal jaundice) were associated with advanced thyroid cancer. These findings suggest that some perinatal exposures may influence maternal thyroid cancer risk.

Studies on late effects in mantle cell lymphoma (MCL) patients are increasingly important as survival is improving and novel targeted drugs are being introduced, however knowledge about late effects is limited. The aim of this population-based study was to describe the magnitude and panorama of late effects among patients treated with or without high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT). The study cohort included all MCL patients, recorded in the Swedish Lymphoma Register, 18-69 years old, diagnosed 2000-2014 (total n=620, treated with HD-ASCT n=247) and 1:10 matched healthy comparators. Patients and comparators were followed via the national Patient Register and Cause-of-Death-Register, from 12 months after diagnosis/matching until December 2017. Incidence rate ratios of numbers of outpatient visits, hospitalizations and bed days were estimated using negative binomial regression models. In relation to the matched comparators, the rate of specialist and hospital visits was significantly higher among MCL patients (IRR 2.0, 95% CI: 1.8-2.2 and 7.2, 95% CI: 6.3-8.3, respectively). MCL patients had especially high relative risks of infectious, respiratory and blood disorders. Within this observation period, no difference in rate of these complications, including secondary neoplasms, was observed between HD-ASCT and non-HD-ASCT treated patients. The majority of patients died from their lymphoma and not from another cause or treatment complication. Taken together, our results imply that the vast majority of the post-treatment healthcare needs are related to the lymphoma disease itself, thus, indicating the need for more efficient treatment options.

Hodgkin lymphoma is among the most curable cancers. For patients in remission for 24 months, residual lifetime becomes close to that of the background population. However, late relapses can occur after several years and, as shown by Andersen et al., the outcomes are not always good. Commentary on: Andersen MD, Hamilton-Dutoit S, Modvig L, Vase M, Christiansen I, Christensen JH, et al. Late recurrence of lymphoid malignancies after initial treatment for Hodgkin lymphoma – A study from the Danish Lymphoma Registry. Br J Haematol 2022;198:50-61.

Treatment for patients 60 years with classical Hodgkin lymphoma (cHL) is problematic; there is no gold standard, and outcome is poor. Using the Swedish Lymphoma Registry, we analysed all Swedish patients diagnosed with cHL between 2000 and 2014 (

Not available.

Summary Background Thyroid cancer tends to be diagnosed at a younger age (median age 51 years) compared with most other malignancies (such as breast cancer [62 years] or lung cancer [71 years]). The incidence of thyroid cancer is higher in women than men diagnosed from early adolescence. However, few in-utero and early life risk exposures associated with increased risk of thyroid cancer have been identified. Methods In this population-based nested case-control study we used registry data from four Nordic countries to assess thyroid cancer risk in offspring in relation to maternal medical history, pregnancy complications, and birth characteristics. Patient with thyroid cancer (cases) were individuals born and subsequently diagnosed with first primary thyroid cancer from 1973 to 2013 in Denmark, 1987 to 2014 in Finland, 1967 to 2015 in Norway, or 1973 to 2014 in Sweden. Each case was matched with up to ten individuals without thyroid cancer (controls) based on birth year, sex, country, and county of birth. Cases and matched controls with a previous diagnosis of any cancer, other than non-melanoma skin cancer, at the time of thyroid cancer diagnosis were excluded. Cases and matched controls had to reside in the country of birth at the time of thyroid cancer diagnosis. Conditional logistic regression models were used to calculate odds ratios (ORs) with 95% CIs. Results Of the 2437 cases, 1967 (81·4%) had papillary carcinomas, 1880 (77·1%) were women, and 1384 (56·7%) were diagnosed before age 30 years (range 0–48). Higher birth weight (OR per kg 1·14 [95% CI 1·05–1·23]) and congenital hypothyroidism (4·55 [1·58–13·08]); maternal diabetes before pregnancy (OR 1·69 [0·98–2·93]) and postpartum haemorrhage (OR 1·28 [1·06–1·55]); and (from registry data in Denmark) maternal hypothyroidism (18·12 [10·52–31·20]), hyperthyroidism (11·91 [6·77–20·94]), goiter (67·36 [39·89–113·76]), and benign thyroid neoplasms (22·50 [6·93–73·06]) were each associated with an increased risk of thyroid cancer in offspring. Interpretation In-utero exposures, particularly those related to maternal thyroid disorders, might have a long-term influence on thyroid cancer risk in offspring. Funding Intramural Research Program of the National Cancer Institute (National Institutes of Health).

There is a lack of data regarding treatment and prognosis for the growing group of oldest old patients with lymphoma. Therefore, we studied 2347 patients aged >= 85 years from the Danish and Swedish lymphoma registers 2000-2016 (Denmark) and 2007-2013 (Sweden). Outcome was assessed using relative survival (RS). The 2-year RS overall for patients with aggressive lymphomas was 38% [95% confidence interval (CI) 35-42%], of whom 845 (66%) patients received active treatment (chemotherapy, radiotherapy, immunotherapy, other). For aggressive lymphomas, not receiving active treatment was associated with an inferior 2-year RS of 12% (95% CI 9-17%) compared to 49% (95% CI 45-53%) for patients who received active treatment (excess mortality rate ratio 2 center dot 84, 95% CI 2 center dot 3-3 center dot 5; P < 0 center dot 0001). For patients with indolent lymphoma, the 2-year RS was 77% (95% CI 72-82%). Here, 383 (46%) patients received active treatment at diagnosis, but did not have better 2-year RS (75%, 95% CI 67-81%) compared to those who did not receive active treatment (83%, 95% CI 74-89%). We conclude that outcomes for the oldest old patients with lymphoma are encouraging for several subtypes and that active treatment is associated with improved outcome amongst the oldest old patients with aggressive lymphomas, indicating that age itself should not be a contraindication to treatment.

The abundant hepatocyte-expressed plasma protein histidine-rich glycoprotein (HRG) enhances antitumor immunity by polarizing inflammatory and immune cells in several mouse models, however, the clinical relevance of HRG in human cancer is poorly explored. The expression and role of HRG in human B-cell lymphomas was investigated in order to find new tools for prognosis and treatment.Immunohistochemical (IHC) analysis and RNA hybridization of tissue microarrays showed that (i) HRG was expressed by tumor cells in marginal zone lymphoma (MZL), in 36% of 59 cases. Expression was also detected in follicular lymphoma (22%), mantle cell lymphoma (19%), and indiffuse large B-cell lymphoma (DLBCL;5%) while primary CNS lymphoma (PCNSL) lacked expression of HRG. (ii) MZL patients positive for HRG showed a superior overall survival outcome (HR = 0.086, 95% CI = 0.014-0.518,HRG expression by MZL tumor cells correlates with an altered transcription profile and improved overall survival.