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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.

Survival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapy-based treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high-risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients withTP53missense mutations and the prognostic impact of overexpression and mutations in a Swedish population-based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 andTP53status among 137 cases divided over the two-cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression andTP53mutations on survival (hazard ratio of 3 center dot 1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population-based setting.

For most patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), R-CHOP immunochemotherapy leads to complete remission and 60–70% of patients remain progression-free after 5 years. Given a median age of 65, it is relevant to disentangle how DLBCL and DLBCL therapy influence health care use among the survivors. In this nationwide study, the health care use among Danish DLBCL patients diagnosed in 2007–2015, who achieved complete remission after R-CHOP(-like) therapy, was explored and compared to matched comparators from the Danish general population. The post-remission 5-year risk of hospitalization was significantly higher among DLBCL survivors (55%) compared to matched comparators (49%, P P

Ovarian cancer is influenced by reproductive factors, with a reduced risk of epithelial ovarian cancer in parous women. Nonepithelial ovarian cancer frequently affects young women and often precedes or occurs during the childbearing years. However, the impact of reproductive factors on ovarian cancer survival remains unclear: in epithelial ovarian cancer, data are conflicting, and subtype-specific associations have not been examined, and in nonepithelial ovarian cancer, it has not been studied. Using Swedish registers, we evaluated associations between women's reproductive history and cancer-specific mortality by subtype of epithelial and nonepithelial ovarian cancer in 3791 women born 1953 and later, diagnosed from 1990 to 2018. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated using Cox-proportional hazard models. Parity was associated with a 78% decreased risk of cause-specific mortality in 243 women with germ cell tumors (GCTs) (parous vs nulliparous, adjusted for age at diagnosis: HR: 0.22 [95% CI 0.07-0.62]), with a decreased risk with increasing number of births (per birth: HR: 0.60 [95% CI 0.38-0.95]). We found no evidence of associations between parity and cause-specific mortality among the 334 patients with sex-cord stromal tumors, nor among the 3214 patients with epithelial ovarian cancer; neither overall, nor by subtype. In conclusion, in our large, population-based study, parity was associated with a clearly better prognosis in GCTs but not in the other ovarian cancer subtypes. Future research on how hormone exposure impacts GCT development may lead to a better understanding of mechanisms affecting survival. What's new? While risk of epithelial ovarian cancer is known to be influenced by pregnancy, the mechanisms underlying this association remain unclear. In this population-based study, the impact of reproductive history on ovarian cancer prognosis was evaluated by ovarian cancer subtype. Among women with germ cell tumors, parity was associated with 78 percent reduction in risk of cause-specific mortality. No associations were detected between parity and prognosis among women with sex-cord stromal tumors or epithelial ovarian cancer. These observations raise new questions about relationships between ovarian cancer prognosis and reproductive factors, including possible impacts of hormone exposure in pregnancy.

PURPOSE The majority of young adults with Hodgkin lymphoma (HL) are cured, but chemotherapy-induced infertility can have profound psychosocial consequences. Providing data on parenthood rates and use of assisted reproductive techniques (ARTs) after contemporary HL treatment is important for patient counseling and survivorship care. MATERIALS AND METHODS All Danish patients with HL diagnosed during 2000-2015 at the ages 18-40 years who achieved remission after first-line therapy were included and matched on age, sex, and parenthood status to five random persons from the general population. Parenthood rates were defined as the rate of first live birth per 1,000 person years, starting 9 months after HL diagnosis. Nationwide birth and patient registers were used to capture parenthood outcomes and ARTs use. RESULTS A total of 793 HL survivors and 3,965 comparators were included (median follow-up 8.7 years). Similar parenthood rates were observed for male and female HL survivors when compared with matched comparators (56.2 v 57.1; P = .871 for males and 63.8 v 61.2; P = .672 for females). For male HL survivors, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) therapy was associated with lower parenthood rates as compared to the matched comparators (28.1 v 60.8; P = .020). Live birth after ARTs were more common for HL survivors than for comparators (males 21.6% v 6.3%; P < .001; females 13.6% v 5.5%; P = .001). There were no differences in gestational age, Apgar score, or newborn measurements between HL survivors and matched comparators. CONCLUSION The parenthood rates for HL survivors who have not experienced relapse were generally similar to the general population. However, ARTs were used more often before the first live birth in HL survivors, which is relevant information when discussing possible long-term side effects and fertility-preserving treatment options.

When treating limited stage classical Hodgkin lymphoma (cHL), balancing treatment efficacy and toxicity is important. Toxicities after extended-field radiotherapy are well documented. Investigators have aimed at reducing toxicity without compromising efficacy, mainly by using combined modality treatment (CMT), i.e. chemotherapy and limited-field radiotherapy. In some clinical trials, radiotherapy has been omitted. We evaluated 364 patients with stage I-IIA cHL treated between 1999 and 2005. Patients were treated with two or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) according to presence of risk factors, followed by 30 Gy limited-field (reduced compared to involved-field) radiotherapy. After a median follow-up of 16 years for survival, freedom from progression at five and ten years was 93% and overall survival at 5 and 10 years was 98% and 96%, respectively. Only two relapses, out of 27, occurred after more than 5 years. There was no excess mortality compared to the general population. Of the analysed subgroups, only patients with progression within five years showed significant excess mortality. The absence of excess mortality questions the concept of omitting radiotherapy after short-term chemotherapy, a strategy that has been associated with an elevated risk of relapse but not yet with a proven reduced long-term excess mortality.

The burden of late effects among Hodgkin lymphoma (HL) survivors treated according to contemporary protocols remains poorly characterized. We used nation‐wide registers to assess number of inpatient bed‐days and specialist outpatient visits among 1048 HL‐patients (

Routine follow-up for diffuse large B-cell lymphoma have been shortened to 2 years when event-free survival at 24 months (EFS24) emerged as a new milestone. In the present study, we aimed to determine whether the achievement of this milestone affected overall survival (OS). We compared OS to that of an age- and sex-matched population, analysed other factors governing OS, and reviewed the causes of death. Data were collected from the Swedish Cancer Registry and from individual patient's records. We included 1169 adult patients from five counties between the years 2001 and 2014. The median (range) age was 64·6 (18-91) years, 56·6% were men and the median follow-up was 82·3 months. For early stages, the achievement of EFS12 did not improve OS. More than two-thirds of the patients (n = 837, 71·6%) achieved EFS24, of which 190 (22·7%) died during follow-up. Lymphoma (20%), cardiovascular disease (22·4%) and malignancies (16%) contributed to causes of death. Patients aged 60 years significantly affected OS after EFS24 compared with the standard population. We concluded that follow-up beyond EFS24 should be considered for patients aged >60 years. Amal Abu Sabaa and Charlott Mörth share first authorship

We characterised patients with mantle cell lymphoma (MCL) with poor prognosis based on differences in immune infiltration. Different expressions of the tumour cell markers Cyclin D1 and sex-determining region Y-box transcription factor 11 (SOX11), and the immune markers cluster of differentiation 3 (CD3), CD4, CD8, CD25, forkhead box protein P3 (FoxP3), T-box transcription factor TBX21 (T-bet), programmed cell death protein 1 (PD-1), programmed-death ligand 1 (PD-L1) and CD163 were investigated for all-cause mortality in 282 patients with MCL and time-to-progression (TTP) in 106 clinical trial patients. With increasing age, a significantly lower infiltration of CD3(+) T lymphocytes was seen. T-cell infiltration was independent of cellular tumour antigen p53 (p53) expression, Ki-67, morphology and frequency of tumour cells. The all-cause mortality was higher in patients with PD-L1-expression above cut-off [hazard ratio (HR) 1 center dot 97, 95% confidence interval (CI) 1 center dot 18-3 center dot 25, adjusted for sex and MCL International Prognostic Index (MIPI)] and a higher frequency of CD163(+) cells (continuously, HR 1 center dot 51, 95% CI 1 center dot 03-2 center dot 23, adjusting for age, sex, morphology, Ki-67 and p53). In patients treated within the Nordic Lymphoma Group MCL2/3 trials, TTP was shorter in patients with a higher frequency of FoxP3(+) cells (HR 3 center dot 22, 95% CI 1 center dot 40-7 center dot 43) and CD163(+) cells (HR 6 center dot 09, 95% CI 1 center dot 84-20 center dot 21), independent of sex and MIPI. When combined a higher frequency of CD163(+) macrophages and PD-L1(+) cells or high CD163(+) macrophages and FoxP3(+) regulatory T cells indicated worse outcome independent of established risk factors. The T-cell infiltrate was in turn independent of molecular characteristics of the malignant cells and decreased with age.

Purpose With excellent cure rates for young patients with Hodgkin lymphoma (HL), there is an increasing number of female survivors of HL interested in becoming pregnant. Here, we report childbearing among contemporarily treated HL survivors in comparison with the general population. Material and Methods Using Swedish registers, 449 women (ages 18 to 40 years) diagnosed with HL between 1992 and 2009 and in remission 9 months after diagnosis were identified. Patients were age- and calendar-year–matched to 2,210 population comparators. Rates of first postdiagnosis childbirth were calculated. Hazard ratios (HRs) with 95% CIs were estimated for different follow-up periods using Cox regression. Cumulative probabilities of first childbirth were calculated in the presence of the competing risk of death or relapse. Results Twenty-two percent of relapse-free patients with HL had a child during follow-up, and first childbirth rates increased over time, from 40.2 per 1,000 person-years (1992 to 1997) to 69.7 per 1,000 person-years (2004 to 2009). For comparators, childbirth rates remained stable (70.1 per 1,000 person-years). Patients diagnosed between 2004 and 2009 had a cumulative probability of childbirth similar to comparators. Three years or more after diagnosis, no differences in childbirth rates were observed between patients and comparators, regardless of stage or treatment. Patients who received six to eight courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone had a lower childbirth rate than comparators during the first 3 years (HR, 0.23; 95% CI, 0.06 to 0.94), as did patients who received six to eight courses of chemotherapy and radiotherapy (HR, 0.21; 95% CI, 0.07 to 0.65). Conclusion Childbearing potential among female survivors of HL has improved over time, and childbirth rates 3 years after diagnosis in contemporarily treated patients are, in the absence of relapse, similar to those in the general population, regardless of stage and treatment.

Epithelial ovarian cancer is a fatal disease of largely unknown etiology. Higher parity is associated with reduced risk of ovarian cancer. However, among parous women, the impact of pregnancy-related factors on risk is not well understood. This population-based case–control study included all parous women with epithelial ovarian cancer in Denmark, Finland, Norway and Sweden during 1967–2013 (n = 10,957) and up to 10 matched controls (n = 107,864). We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for pregnancy-related factors and ovarian cancer risk by histological subtype. Preterm delivery was associated with an increased risk [pregnancy length (last pregnancy) ≤30 vs. 39–41 weeks, OR 1.33 (95% CI 1.06–1.67), adjusted for number of births]; the OR increased as pregnancy length decreased (p for trend < 0.001). Older age at first and last birth was associated with a decreased risk [first birth: 30–39 vs. heterogeneity < 0.001]. No associations were observed for multiple pregnancies, preeclampsia or offspring size. In conclusion, in addition to high parity, full-term pregnancies and pregnancies at older ages were associated with decreased risk of ovarian cancer. Our findings favor the cell clearance hypothesis, i.e. a recent pregnancy provides protection by clearing of precancerous cells from the epithelium of the ovary/fallopian tubes, mediated by placental or ovarian hormones.

Objective Forty percent of Hodgkin lymphoma (HL) patients are older than 50 years at diagnosis, a fact which is not commonly recognized. Older patients do significantly worse than younger patients and are rarely included in clinical trials. Methods Using data from Swedish Cancer and Lymphoma Registries, we estimated relative survival ratios (RSRs) for 7997 HL patients (diagnosed 1973-2013; 45% ≥50 years). Results The 1-year RSRs (95% confidence interval; CI) for males aged 45-59, 60-69, 70-80, and 81 years and over, diagnosed in 2013, were 0.95 (0.91-0.97), 0.88 (0.81-0.92), 0.74 (0.63-0.81), and 0.52 (0.35-0.67), respectively. The corresponding 1-year RSRs for females were 0.97 (0.94-0.98), 0.91 (0.85-0.95), 0.82 (0.73-0.88), and 0.66 (0.50-0.77). No improvements in 1-year of 5-year relative survival from 2000 to 2013 were observed for patients aged 45-59 or 60-69 but there were modest improvements for patients aged 70 years and older. Importantly, we saw no changes in the distribution of disease or patient characteristics between 2000 and 2013. Conclusions Elderly patients constitute a large group with clearly unmet medical needs. Our findings motivate a more active approach to including elderly patients in clinical trials. Our study provides a baseline for outcome comparison after the broader introduction of targeted drugs.

Background: High birthweight may predispose children to acute lymphoid leukemia, whereas low birthweight is associated with childhood morbidity and mortality. Low and high birthweight have been inconsistently associated with mortality in children with leukemia. Material and methods: In a cohort of childhood and adolescent leukemia (0–19 years) patients from registries in Denmark, Norway, Sweden, and Washington State in the United States (1967–2015), five-year all-cause mortality was assessed by birthweight and other measures of fetal growth using the cumulative incidence function and Cox regression with adjustment for sex, diagnosis year, country, the presence of Down’s syndrome or other malformations, and type of leukemia. Results: Among 7148 children and adolescents with leukemia (55% male), 4.6% were low (1–2 years old; 1.0 (95% CI: 0.6, 1.5) for 3–8 years old; 1.0 (95% CI: 0.6, 1.8) for 9–13 years old; and 1.2 (95% CI: 0.7, 2.1) for 14–19 years old, and were similar for size for gestational age and Ponderal index. In analyses restricted to children born full term (37–41 weeks of gestation), results were only slightly attenuated but risk was markedly increased for infants aged ≤1 year (HR for low birthweight = 3.2, 95% CI: 1.2, 8.8). Conclusion: This cohort study does not suggest that low birthweight or SGA is associated with increased five-year all-cause mortality risk among children with any type of childhood leukemia or acute lymphoblastic leukemia, specifically, beyond infancy.

Background Non-epithelial ovarian cancers are divided into sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Whereas parity and other pregnancy-related factors are protective for epithelial ovarian cancer, their associations with SCSTs and GCTs remains unclear. Methods Using data from the medical birth registries from Denmark, Finland, Norway and Sweden, we compared all parous women with a diagnosis of SCSTs (n = 420) or GCTs (n = 345) 1970–2013 with up to 10 parous controls (SCSTs n = 4041; GCTs n = 2942) matched on the cases’ birth year and country. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of associations between pregnancy-related factors and SCSTs and GCTs. Results The risk of SCSTs, but not GCTs, decreased with higher age at last birth [≥40 versus Conclusions We found a decreased risk of SCSTs with higher age at last birth and shorter time since last birth. The risk of SCSTs (but not GCTs) may be influenced by the woman’s reproductive history.

ObjectiveTo examine associations between birth defects and cancer from birth into adulthood.DesignPopulation based nested case-control study.SettingNationwide health registries in Denmark, Finland, Norway, and Sweden.Participants62 295 cancer cases (0-46 years) and 724 542 frequency matched controls (matched on country and birth year), born between 1967 and 2014.Main outcome measuresRelative risk of cancer in relation to major birth defects, estimated as odds ratios with 99% confidence intervals from logistic regression models.ResultsAltogether, 3.5% (2160/62 295) of cases and 2.2% (15 826/724 542) of controls were born with major birth defects. The odds ratio of cancer for people with major birth defects compared with those without was 1.74 (99% confidence interval 1.63 to 1.84). For individuals with non-chromosomal birth defects, the odds ratio of cancer was 1.54 (1.44 to 1.64); for those with chromosomal anomalies, the odds ratio was 5.53 (4.67 to 6.54). Many structural birth defects were associated with later cancer in the same organ system or anatomical location, such as defects of the eye, nervous system, and urinary organs. The odds ratio of cancer increased with number of defects and decreased with age, for both non-chromosomal and chromosomal anomalies. The odds ratio of cancer in people with any non-chromosomal birth defect was lower in adults (≥20 years: 1.21, 1.09 to 1.33) than in adolescents (15-19 years: 1.58, 1.31 to 1.90) and children (0-14 years: 2.03, 1.85 to 2.23). The relative overall cancer risk among adults with chromosomal anomalies was markedly reduced from 11.3 (9.35 to 13.8) in children to 1.50 (1.01 to 2.24). Among adults, skeletal dysplasia (odds ratio 3.54, 1.54 to 8.15), nervous system defects (1.76, 1.16 to 2.65), chromosomal anomalies (1.50, 1.01 to 2.24), genital organs defects (1.43, 1.14 to 1.78), and congenital heart defects (1.28, 1.02 to 1.59) were associated with overall cancer risk.ConclusionsThe increased risk of cancer in individuals with birth defects persisted into adulthood, both for non-chromosomal and chromosomal anomalies. Further studies on the molecular mechanisms involved are warranted.

Increasing prevalence of chronic lymphocytic leukemia with an estimated future rise : a nationwide population-based study

Many pregnancy‐related factors are associated with reduced endometrial cancer risk. However, it remains unclear whether pregnancy‐related complications (e.g., hypertensive conditions) are associated with risk and whether these associations vary by endometrial cancer subtype. Thus, we evaluated the risk of endometrial cancer, overall and by subtype, in relation to pregnancy‐related factors, pregnancy complications and birth characteristics. Utilizing population‐based register data from four Nordic countries, we conducted a nested case–control analysis of endometrial cancer risk. We included 10,924 endometrial cancer cases and up to 10 matched controls per case. Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models. We further evaluated associations by individual histology (i.e., endometrioid, serous, etc.) or, for rare exposures (e.g., pregnancy complications), by dualistic type (Type I [n = 10,343] and Type II [n = 581]). Preexisting and pregnancy‐related hypertensive conditions were associated with increased endometrial cancer risk (OR [95% CI]: preexisting hypertension 1.88 [1.39–2.55]; gestational hypertension 1.47 [1.33–1.63]; preeclampsia 1.43 [1.30–1.58]), with consistent associations across dualistic type. Increasing number of pregnancies (≥4 vs. 1 birth: 0.64 [0.59–0.69]) and shorter time since last birth (

Background Because of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk. Methods and findings In this nationwide register study, all singletons born in Sweden 1994–2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19–1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment–to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54–1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25–4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995–2000—both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited. Conclusions No additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients., Yahia Al-Jebari and colleagues reveal no increased risk of congenital malformations in children of men treated for testicular germ cell cancer., Author summary Why was this study done? Chemotherapy and radiotherapy have both been shown to cause mutations and genetic damage in animal studies, leading to fears that men being treated with these therapies might be more prone to have children with genetic diseases and birth defects. This study investigates whether receiving treatment for testicular cancer, being the most common cancer among young men (in child-having ages), leads to a higher risk of fathering a child with a birth defect. What did the researchers do and find? By accessing data from Swedish national registries, we gathered data on more than 2 million newborns and their fathers. Among them, 2,380 fathers had testicular cancer and they had, in total, 4,207 children. When comparing the children conceived after the father received cancer treatment to the children born before treatment, we could not find any evidence showing that chemotherapy or radiotherapy leads to an increased risk of birth defects. We did see that there was, irrespectively of cancer treatment, a small risk increase associated with the fathers’ testicular cancer itself, meaning that men with testicular cancer have an approximately 30% higher relative risk of having a child with a birth defect (an increase from 3.5% to 4.4%). What do these findings mean? There was no risk increase due to cancer therapies. The risk increase detected was associated with testicular cancer. However, this risk increase is very small and relates to rare conditions. Because the risk increase is small, we therefore do not consider this cause for concern and wish this reassuring information to be passed on to patients.

Background: The prognosis for mantle cell lymphoma (MCL) remains poor, particularly for elderly patients. Our aim was to assess the impact of comorbidities on MCL outcome and causes of death. Methods: For all 1,385 MCL patients (1,009 males, 376 females) diagnosed 2000-2014 in Sweden (median age 71 years, range 22-96) comorbidities within 10 years prior to diagnosis were classified according to the Charlson comorbidity index (CCI; 0, 1, 2+). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using flexible parametric models to compare rates of lymphoma-specific and all-cause-mortality by comorbidities. Model-based predictions were used to obtain probabilities of death from lymphoma/other causes. Findings: Severe comorbidity was independently associated with higher all-cause (HR=1·52; 95% CI:1·24-1·85) and lymphoma-specific mortality (HR=1·.31; 95% CI:1·04-1·65), particularly among patients with connective tissue, renal, psychiatric diseases, and dementia. 606 patients (44%) had any comorbidity (CCI 1+) and 388 (28%) severe comorbidity (CCI 2+). Over a median follow-up of 3.7 years (range 0-16), 633 patients (46%) died, the majority (76%) from their lymphoma. Among females with comorbidities, non-lymphoma deaths represented a larger proportion of all deaths, as compared to comorbid males. Interpretation: Since most MCL patients (including comorbid patients) died from lymphoma, more efficient and tolerable lymphoma treatments need to be considered also to patients with severe comorbidity. Patients with renal, psychiatric, or connective tissue disorders need particular attention. However, among females with comorbidities, the likelihood of dying from disorders other than MCL was still considerable, perhaps favoring a more liberal use of a "wait-and-watch" approach. Funding Statement: This study was supported by the Swedish Cancer Society CAN (2012/774). I. Glimelius was supported by The Swedish Cancer Society (CAN 2016/440) and the Swedish Society of Medicine. Declaration of Interests: MJ: Honoraria from Janssen, Gilead, Celgene, Roche, Acerta. Research support from Janssen, Celgene, Abbvie and Gilead. KES: Honoraria from Celgene. Research support from Janssen. IG Honoraria from Janssen. SE has an ongoing role as project manager in a publicprivate real world evidence collaboration between Karolinska Institutet and Janssen Pharmaceuticals NV (contract: 5-63/2015) Ethics Approval Statement: The study was approved by the Regional Board of the Ethical Committee in Stockholm, Sweden (2007/1335-31/4, 2010/1624-32).

PURPOSE Estimates of short- and long-term survival for young patients with classic Hodgkin lymphoma (cHL) are of considerable interest. We investigated cHL prognosis in the era of contemporary treatment at different milestones during the follow-up. PATIENTS AND METHODS On the basis of a Nordic cohort of 2,582 patients diagnosed at ages 18 to 49 years between 2000 and 2013, 5-year relapse risks and 5-year restricted losses in expectation of lifetime were estimated for all patients and for patients who achieved event-free survival (EFS) for 12 (EFS12), 24 (EFS24), 36 (EFS36) or 60 (EFS60) months. The median follow-up time was 9 years (range, 2.9 to 16.8 years). RESULTS The 5-year overall survival was 95% (95% CI, 94% to 96%). The 5-year risk of relapse was 13.4% (95% CI, 12.1% to 14.8%) overall but decreased to 4.2% (95% CI, 3.8% to 4.6%) given that patients reached EFS24. Relapse risk for patients treated with six to eight courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) was comparable to that of patients treated with six to eight courses of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) despite more adverse risk criteria among patients treated with BEACOPP. Both from diagnosis and if EFS24 was reached, the losses in expectation of lifetime during the following 5 years were small (from diagnosis, 45 days [95% CI, 35 to 54 days] and for patients who reached EFS24, 13 days [95% CI, 7 to 20 days]). In stage-stratified analyses of 5-year restricted loss in expectation of lifetime, patients with stages I to IIA disease had no noteworthy excess risk of death after they reached EFS24, whereas risk remained measurable for patients with stages IIB to IV cHL. CONCLUSION Real-world data on young patients with cHL from the Nordic countries show excellent outcomes. The outlook is particularly favorable for patients who reach EFS24, which supports limited relapse-oriented clinical follow-up.

With today's excellent cure rates for Hodgkin lymphoma (HL), the number of long-term survivors is increasing. This study aims to provide a global assessment of late adverse effects for working-age HL survivors treated with contemporary protocols (combination chemotherapy and limited radiotherapy). From Swedish nationwide registers we identified 1017 HL survivors diagnosed in 2000-2009, aged 18-60 years (median 32) and surviving at least one year post-diagnosis, and 4031 age-, sex-, and calendar-year-matched population comparators. Incidence rate ratios (IRR) and 95% confidence intervals (95%CI) for outpatient visits and inpatient bed-days after the first year up to 14 years post-diagnosis (through 2013) were estimated across treatment subgroups, considering relapse-free time and using negative binomial regression. Scheduled outpatient visits for HL were excluded. The rate of outpatient visits was nearly double (IRR = 1.8, 95%CI: 1.6-2.0) that among comparators and higher rates persisted up to 10 years post-diagnosis. The rate of inpatient bed-days among relapse-free survivors was more than three-fold (IRR = 3.6, 95%CI: 2.7-4.7) that of comparators and the increase persisted up to four years post-diagnosis. Patients requiring 6-8 chemotherapy courses had higher rates of outpatient visits (IRR = 1.4, 95%CI: 1.1-1.7) and bed-days (IRR = 4.7, 95%CI: 2.9-7.8) than patients treated with 2-4 courses + radiotherapy. Previously seldom reported reasons for the excess healthcare use included chest pain, keratitis, asthma, diabetes mellitus, and depression. Contemporary treatment, chemotherapy in particular, was associated with excess healthcare use among HL survivors during the first decade postdiagnosis. The reasons for healthcare visits reflected a wide range of disorders, indicating the need of broad individualized care in addition to specific screening programs.

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.

The susceptibility to Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) may be affected by the human leukocyte antigen (HLA) type. We investigated HLA-A and HLA-B allele frequencies, focusing on HLA-A1 and -A2, in a population-based case series of EBV + (n = 60) and EBV- (n = 44) PTLD after solid organ transplantation. The proportion of EBV + PTLD was highest in HLA-A1 homozygotes (100%), lower in carriers of HLA-A1/AX (79%), HLA-A1/A2 (55%), HLA-A2/AX (54%), and lowest in HLA-A2 homozygotes (37%). HLA-A1 type was overrepresented (22% versus 7%, p = 0.05) and HLA-A2 type underrepresented (57% versus 80%, p = 0.01) in patients with EBV + compared with EBV - PTLD. EBV + PTLD in HLA-A1 carriers developed almost exclusively in already EBV-seropositive individuals. EBV status of PTLD was not related to any other HLA-A or HLA-B type. Our findings suggest that HLA-A1 carriers may have an increased risk of EBV + PTLD due to a decreased ability to control the latent EBV infection.

Background: Comorbidity impacts overall survival amongst patients with diffuse large B-cell lymphoma (DLBCL). However, associations of comorbidity with lymphoma characteristics, treatment selection and lymphoma-specific mortality are less well known. Objective: To examine the impact of comorbidity on DLBCL characteristics, treatment intent and cause of death. Methods: We identified 3905 adult patients diagnosed with DLBCL 2007–2013 through the Swedish Lymphoma Register. We assessed comorbid disease history according to the Charlson comorbidity index (CCI). Comorbidity data and causes of death were collected through register linkage. Associations were estimated using multinomial regression and flexible parametric survival models. Results: Overall, 45% of the patients (n = 1737) had a history of at least one comorbidity at DLBCL diagnosis (cardiovascular disease, diabetes and solid cancer were most frequent), and 997 (26%) had a CCI score of ≥2. The relative probability of presenting with poor performance status (PS > 2) was higher amongst comorbid patients [Relative Risk Ratio (RRR)PS >2: 2.02, 95% CI: 1.63–2.51]. Comorbid patients had a substantially lower relative probability of receiving curative treatment (RRR: 0.48, 95% CI: 0.38–0.61). Amongst all patients, CCI ≥ 1 was associated with a significantly increased risk of all-cause and lymphoma-specific death after adjustments. Amongst patients selected for curative treatment, comorbidity was associated with an increased risk of all-cause death (HRCCI >1: 1.54, 95% CI: 1.32–1.80), but not with lymphoma-specific death (HRCCI >1: 1.05, 95% CI: 0.86–1.28). Conclusion: Comorbidity is associated with inferior DLBCL outcome, mainly due to a lower likelihood of receiving treatment with curative intent. Possibly, more comorbid DLBCL patients could be treated with curative intent if comorbid conditions were optimized in parallel.

Certain features of pregnancy are important risk factors for breast cancer, such as protection afforded by young age at first birth. Preeclampsia, a pregnancy complication, is associated with reduced maternal breast cancer risk. However, questions remain regarding causality, biological mechanisms and the relation of other hypertensive conditions to risk. We conducted a population-based case–control study of breast cancer cases (n = 116,196) in parous women identified through linkage of birth and cancer registries in Denmark, Finland, Norway and Sweden (1967–2013), including up to 10 matched controls per case (n = 1,147,192) sampled from the birth registries (complete data were not available on all variables). Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models including matching factors (country, maternal birth year) and parity. Hypertension diagnosed before pregnancy (OR 0.87; 95% CI 0.78–0.97), gestational hypertension (OR 0.90; 95% CI 0.86–0.93) and preeclampsia (OR 0.91; 95% CI 0.88–0.95) were associated with reduced breast cancer risk. Results remained similar after adjustment for smoking and maternal body mass index before first pregnancy, and were generally similar stratified by parity, age at breast cancer diagnosis, time since first and last birth, sex of the offspring and calendar time. Except for retained placenta (OR 1.14; 95% CI 0.98–1.32), no other pregnancy complication appeared associated with breast cancer risk. The mechanisms mediating the modest risk reductions for history of preeclampsia or hypertension preceding or arising during pregnancy, and possible increased risk with history of retained placenta are unknown and warrant further laboratory, clinical and epidemiological investigation.

Plasma cells are important prognostic actors in different malignancies. The tumour microenvironmental composition in classic Hodgkin lymphoma (cHL) is a major prognostic key element; however, clinicopathological studies regarding plasma cells in cHL are lacking. The aim of this study was to investigate CD138+ (also termed SDC1+) plasma cell and IgG4 producing (IgG4+) plasma cells infiltration in the microenvironment of cHL. Immunohistochemistry with anti-CD138 and IgG4 antibodies was performed on diagnostic tumour biopsies from 124 patients with cHL, on tissue micro array (TMA). In 120 cases, CD138+ plasma cell-infiltration was associated with the presence of B-symptoms (P = 0·028) and advanced stage, IIB-IVB (P = 0·009). In multivariate analysis, CD138+ plasma cells correlated with eosinophil infiltration (P = 0·013). The subgroup of IgG4+ plasma cells was analysed in 122 cases and only correlated to CD138+ plasma cells (P = 0·004). Patients with high proportion of tumour infiltrating CD138+ plasma cells (defined as ≥10%), had a more inferior event-free survival (P = 0·007) and overall survival (P = 0·004) than patients with a low proportion of infiltrating CD138+ plasma cells (

Purpose Many patients and clinicians are worried that pregnancy after the diagnosis of Hodgkin lymphoma (HL) may increase the risk of relapse despite a lack of empirical evidence to support such concerns. We investigated if an association exists between pregnancy and relapse in women with a diagnosis of HL. Materials and Methods Using Swedish healthcare registers combined with medical records, we included 449 women who received a diagnosis of HL between 1992 and 2009 and who were age 18 to 40 years at diagnosis. Follow-up started 6 months after diagnosis, when the patients' condition was assumed to be in remission. Pregnancy-associated relapse was defined as a relapse during pregnancy or within 5 years after delivery. Hazard ratios (HRs) with 95% CIs were estimated by using the Cox proportional hazards model. Results Among the 449 women, 144 (32%) became pregnant during follow-up. Overall, 47 relapses were recorded, of which one was a pregnancy-associated relapse. The adjusted HR for the comparison of the pregnancy-associated relapse rate to the non–pregnancy-associated relapse rate was 0.29 (95% CI, 0.04 to 2.18). The expected number of relapses in women with a recent pregnancy, given that they would experience the same relapse rate as that of women without a recent pregnancy, was 3.76; the observed-to-expected ratio was 0.27 (95% exact CI, 0.01 to 1.51). Conclusion We found no evidence that a pregnancy after diagnosis increases the relapse rate among women whose HL is in remission. Survivors of HL need to consider a range of factors when deciding about future reproduction. However, given the results of this study, the risk of pregnancy-associated relapse does not need to be considered.

Objective Appendectomy remains one of the most common surgical procedures, but possible long-term consequences for health and disease are incompletely investigated. The appendix forms part of the secondary lymphoid system and appendectomy has been associated with increased risks of hematolymphoproliferative malignancies in some studies. Materials and methods We examined the risk of lymphoid neoplasms in a large cohort of 337,437 appendectomised patients Results There was no increased risk of NHL (SIR = 0.97, 95%CI 0.88–1.06), major NHL subtypes, CLL (SIR = 0.87, 95%CI 0.70–1.06), myeloma (SIR = 1.14, 95%CI 0.96–1.33) or ALL (SIR = 1.10, 95%CI 0.80–1.47) following appendectomy. An increased risk of HL was observed among patients diagnosed with appendicitis (SIR = 1.29, 95%CI 1.07–1.54, p=0.007), especially individuals aged Conclusion Appendectomy is not associated with any notable increase in risk of lymphoid neoplasms. A small increased risk of HL following appendicitis (rather than appendectomy per se) could reflect a true association, or shared susceptibility to infection/inflammation among individuals prone to develop HL. The association observed for myeloma may be explained by chance or surveillance bias.

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.

The aim of the present study was to examine the risk of lost workdays due to sick leave and disability pension by treatment modality and relapse in a population-based cohort of cervical cancer survivors versus matched comparators. We identified 1971 cervical cancer patients aged ≤60 years (median 42) at diagnosis in Sweden 2003–2009 and 9254 population comparators. Information on sociodemographic and clinical characteristics, sick leave, and disability pension was retrieved from nationwide prospective registers. Differences in the annual mean number of lost workdays were calculated by linear regression, and hazard ratios (HRs) of disability pension were calculated by Cox regression analysis, with follow-up through September 2013. Cervical cancer patients had more lost workdays annually than comparators up to 8 years following diagnosis. Relapse-free patients had more lost workdays than comparators up to 4 years. Risk of disability pension during follow-up was increased among the relapse-free patients treated with hysterectomy (HR 1.8 [95 % confidence interval (CI) 1.1–2.8]), hysterectomy plus chemotherapy and/or radiotherapy (HR 2.5 [95 % CI 1.2–5.4]), or chemotherapy and/or radiotherapy alone (HR 3.0 [95 % CI 1.3–6.8]), compared with the population. Women treated with fertility-sparing surgery did not have more lost workdays than the population beyond the first year and were not at increased risk of disability pension. We observed a long-standing increased risk of lost workdays among cervical cancer patients, overall, as well as among relapse-free patients. Extensive but not limited treatment was associated with increased risk of lost workdays, possibly reflecting an association between treatment side effects and work ability.

Results from previous investigations have shown associations between the risk of Hodgkin lymphoma (HL) and a history of autoimmune and atopic diseases, but it remains unknown whether these associations apply to all types of HL or only to specific subtypes. We investigated immune diseases and the risk of classical HL in a population-based case-control study that included 585 patients and 3,187 controls recruited from October 1999 through August 2002. We collected information on immune diseases through telephone interviews and performed serological analyses of specific immunoglobulin E reactivity. Tumor Epstein-Barr virus (EBV) status was determined for 498 patients. Odds ratios with 95% confidence intervals were calculated using logistic regression analysis. Rheumatoid arthritis was associated with a higher risk of HL (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.47, 4.70), especially EBV-positive HL (OR = 3.18; 95% CI: 1.23, 8.17), and with mixed-cellularity HL (OR = 4.25; 95% CI: 1.66, 10.90). HL risk was higher when we used proxies of severe rheumatoid arthritis, such as ever having received daily rheumatoid arthritis medication (OR = 3.98; 95% CI: 2.08, 7.62), rheumatoid arthritis duration of 6-20 years (OR = 3.80; 95% CI: 1.72, 8.41), or ever having been hospitalized for rheumatoid arthritis (OR = 7.36; 95% CI: 2.95, 18.38). Atopic diseases were not associated with the risk of HL. EBV replication induced by chronic inflammation in patients with autoimmune diseases might explain the higher risk of EBV-positive HL.

Background Aspects of survivorship, such as long-term ability to work, are increasingly relevant owing to the improved survival of patients with rectal cancer. The aim of this study was to assess risk and determinants of disability pension (DP) in this patient group. Methods Using Swedish national clinical and population-based registers, patients with stage I–III rectal cancer aged 18–61 years in 1995–2009 were identified at diagnosis and matched with population comparators. Prospectively registered records of DP during follow-up were retrieved up to 2013. Non-proportional and proportional hazards models were used to estimate the incidence rate ratio (IRR) for DP annually and overall. Potential variations in risk by demographic and clinical factors were calculated, with relapse as a time-varying exposure. Results A total of 2815 patients were identified and compared with 13 465 population comparators. During a median follow-up of 6·0 (range 0–10) years, 23·3 per cent of the relapse-free patients and 10·3 per cent of the population comparators received DP (IRR 2·40, 95 per cent c.i. 2·17 to 2·65). An increased annual risk of DP was evident almost every year until the tenth year of follow-up. Abdominoperineal resection was associated with an increased DP risk compared with anterior resection (IRR 1·44, 1·19 to 1·75). Surgical complications (IRR 1·33, 1·10 to 1·62) and reoperation (IRR 1·42, 1·09 to 1·84), but not radiotherapy or chemotherapy, were associated with risk of DP. Conclusion Relapse-free patients with rectal cancer of working age are at risk of disability pension.

An understanding of the origin of cancer is critical for cancer prevention and treatment. Complex biological mechanisms promote carcinogenesis, and there is increasing evidence that pregnancy-related exposures influence fetal growth cell division and organ functioning and may have a long-lasting impact on health and disease susceptibility in the mothers and offspring. Nulliparity is an established risk factor for breast, ovarian, endometrial, and possibly pancreatic cancer, while the risk of kidney cancer is elevated in parous compared with nulliparous women. For breast, endometrial and ovarian cancer, each pregnancy provides an additional risk reduction. The associations of parity with thyroid and colorectal cancers are uncertain. The timing of reproductive events is also recognized to be important. Older age at first birth is associated with an increased risk of breast cancer and older age at last birth is associated with a reduced risk of endometrial cancer. The risks of breast and endometrial cancers increase with younger age at menarche and older age at menopause. The mechanisms, and hormone profiles, that underlie alterations in maternal cancer risk are not fully understood and may differ by malignancy. Linking health-registries and pooling of data in the Nordic countries have provided opportunities to conduct epidemiologic research of pregnancy exposures and subsequent cancer. We review the maternal risk of several malignancies, including those with a well-known hormonal etiology and those with less established relationships. The tendency for women to have fewer pregnancies and at later ages, together with the age-dependent increase in the incidence of most malignancies, are expected to affect the incidence of pregnancy-associated cancer. This article is protected by copyright. All rights reserved.

Background: Hodgkin lymphoma (HL) treatment protocols for children, adolescents and young adults traditionally differ, but the biological and clinical justification for this remains uncertain. Material and methods: We compared age-dependent clinical presentation and treatment and outcome for 1072 classical HL patients 0–24 years diagnosed in Denmark (1990–2010) and Sweden (1992–2009) in pediatric (n = 315, Denmark 2-test and Mantel–Haenszel trend test. The Kaplan–Meier method was used for survival analyses. Hazard ratios (HR) were used to compare the different treatment groups and calculated using Cox regression. Results: Children (0–9 years) less often presented with advanced disease than adolescents (10–17 years) and young adults (18–24 years) (stage IIB-IV: children 32% vs. adolescents 50%, and adults 55%; p

High expression of programmed death receptor 1 (PD-1) and its ligand (PD-L1) by leukocytes in primary classical Hodgkin lymphoma (cHL) is associated with inferior outcome. However, it is unclear how expression varies during disease progression, and in the event of relapse. Our aim was to study PD-1 and PD-L1 in consecutive biopsies from untreated and treated cHL patients. We screened pathology registries from 3500 cHL patients. Eleven patients had a diagnostic cHL biopsy and a previous benign lymph node biopsy reclassified as cHL when reviewed and designated as the untreated. Thirty patients had a primary and a relapse biopsy, designated as the treated. Biopsies were immunostained to detect PD-1+ and PD-L1+ leukocytes, and PD-L1+ tumor cells. In the untreated, none of the markers were statistically significantly different when biopsies 1 and 2 were compared. In the treated, 19, 22, and 18 of 30 cases had increased proportions of PD-1+ leukocytes, PD-L1+ leukocytes and PD-L1+ tumor cells, respectively, and were all statistically significantly increased when primary and relapse biopsies were compared. PD-1 and PD-L1 most likely increase due to primary treatment with chemotherapy and radiotherapy, which could have implications regarding treatment with PD-1 inhibitors.

The classical Hodgkin lymphoma (cHL) tumor microenvironment shows an ongoing inflammatory response consisting of varying degrees of infiltrating eosinophils, mast cells, macrophages, regulatory T lymphocytes (Tregs), and activated lymphocytes surrounding the malignant cells. Herein, different immune signatures are characterized and correlated with treatment outcome.Tumor-infiltrating leukocytes were phenotyped in biopsies from 459 patients with cHL. Time to progression (TTP) (primary progression, relapse, or death from cHL) and overall survival were analyzed using Cox proportional hazards regression.The leukocyte infiltration in the microenvironment was highly diverse between patients and was categorized in 4 immune signatures (active, anergic, innate, or mixed). A high proportion of Tregs (anergic) resulted in shorter TTP (median 12.9-year follow-up) in age-adjusted analyses (hazard ratio = 1.82; 95% confidence interval 1.05-3-15). Epstein-Barr virus (EBV)-positive cases had higher proportions of macrophages and activated lymphocytes than EBV negative, but neither of those leukocytes predicted prognosis.Abundant Tregs (anergic signature) indicate a shorter TTP, particularly in younger patients. This is probably due to a reduced ability of the immune system to attack the tumor cells. Our data warrant further investigation if these suggested immune signatures could predict outcome of immunotherapy such as immune checkpoint inhibitors.

Aim A population-based cohort and four randomized trials enriched with long-term register data were used to clarify if radiotherapy in combination with rectal cancer surgery is associated with increased risks of cardiovascular disease (CVD). Methods We identified 14,901 rectal cancer patients diagnosed 1995–2009 in Swedish nationwide registers, of whom 9227 were treated with preoperative radiotherapy. Also, we investigated 2675 patients with rectal cancer previously randomized to preoperative radiotherapy or not followed by surgery in trials conducted 1980–1999. Risks of CVD overall and subtypes were estimated based on prospectively recorded hospital visits during relapse-free follow-up using multivariable Cox regression. Maximum follow-up was 18 and 33 years in the register and trials, respectively. Results We found no association between preoperative radiotherapy and overall CVD risk in the register (Incidence Rate Ratio, IRR = 0.99, 95% confidence interval (CI) 0.92–1.06) or in the pooled trials (IRR = 1.07, 95% CI 0.93–1.24). We noted an increased risk of venous thromboembolism among irradiated patients in both cohorts (IRRregister = 1.41, 95% CI 1.15–2.72; IRRtrials = 1.41, 95% CI 0.97–2.04), that remained during the first 6 months following surgery among patients treated 2006–2009, after the introduction of antithrombotic treatment (IRR6 months = 2.30, 95% CI 1.01–5.21). However, the absolute rate difference of venous thromboembolism attributed to RT was low (10 cases per 1000 patients and year). Discussion Preoperative radiotherapy did not affect rectal cancer patients’ risk of CVD overall. Although an excess risk of short-term venous thromboembolism was noted, the small increase in absolute numbers does not call for general changes in routine prophylactic treatment, but might do so for patients already at high risk of venous thromboembolism.

The etiology of classical Hodgkin lymphoma (cHL) is largely unknown. High serum CD30-levels are associated with increased risk of cHL. Epstein-Barr virus (EBV) is detectable in the tumor cells in 1/3 of cHL cases in the Western world. The PD-1 pathway (T-cell inflamed immune response) might contribute to the pathogenesis by enabling pre-malignant CD30+ or EBV + cells to evade immune surveillance. We aimed to investigate if high infiltrations of CD30+, PD-1+, PD-L1+ and EBV + cells in benign lymph nodes from patients that later develop cHL (cases) (n = 15) were associated with risk of cHL compared to controls (n = 45) with benign lymph nodes from patients that did not develop cHL. Pathology registries including 3500 cH L patients were screened. Lymph nodes were stained with immunohistochemistry and in situ hybridization and the risk for cHL calculated with logistic regression. High CD30-expression by B- and T-cells was associated with a decreased risk of cHL [(OR = 0.10, 95 % CI:0.03-0.39) and (OR = 0.13, 95 % CI:0.01-0.71), respectively], which remained significant for CD30 + B-cells (OR = 0.15, 95 % CI:0.03-0.60) in multivariate analyses. Amount of PD-1+, PD-L1+ and EBV + cells were not statistically significantly associated with risk of cHL. However, the amount of PD-L1+ leukocytes tended to be higher in cases later developing cHL (OR = 2.84, 95 % CI:0.61-12.61). High proportions of potential precursors to cHL, i.e. CD30 + B-cells in benign lymph nodes are not associated with an increased risk of cHL, while a tendency for a T-cell inflamed immune response, i.e. abundant PD-L1+ cells, was observed in biopsies taken prior to the cHL diagnosis.

BACKGROUND: Data are conflicting regarding the role of endogenous sex hormones in colorectal carcinogenesis. In this large population-based study, we pooled data from birth and cancer registries in four Nordic countries, to evaluate the risk of colorectal adenocarcinoma in relation to women's reproductive history.METHODS: We conducted a population-based case-control study among women registered in Nordic birth registries. The study included colorectal adenocarcinoma cases diagnosed in Denmark, Finland, Norway, and Sweden during 1967-2013 and up to 10 matched controls per case, in total 22 185 cases and 220 246 controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were derived from conditional logistic regression models. We had limited information available on possible confounders.RESULTS: We found no evidence for associations between colorectal adenocarcinoma and parity, age at first and last birth, and time since first and last birth. The risk estimates were also close to unity for specific cancer subsites (proximal and distal colon and rectum). As well, when the analyses were stratified on menopausal status, parity, and mother's year of birth, no indication of associations was found.CONCLUSIONS: In this large, Nordic population-based study, no evidence for associations was found between women's reproductive history and colorectal adenocarcinoma in parous women.British Journal of Cancer advance online publication 4 October 2016; doi:10.1038/bjc.2016.315 www.bjcancer.com.

High parental age at childbirth has repeatedly been linked to childhood malignancies, while few studies have focused on the offspring's risk of adult cancer. In this population-based case-control study, we identified 32,000 patients with lymphoid neoplasms, diagnosed at ages 0-79 years during the period 1987-2011, and 160,000 matched controls in Sweden. Using prospectively registered data on their first-degree relatives, we evaluated the impact of parental age on the risk of lymphoid neoplasms by subtype. Overall, each 5-year increment in maternal age was associated with a 3% increase in incidence of offspring lymphoid neoplasms (hazard ratio = 1.03, 95% confidence interval: 1.02, 1.04). The association was similar for paternal age and present even among individuals older than 70 years of age at diagnosis. Stratified analyses further revealed that the association was limited to certain subtypes, mostly of indolent nature. Risks of chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma were 5%-10% higher per 5-year increment in maternal age, but no associations were observed for acute lymphoblastic leukemia, plasma cell neoplasms, or diffuse large B-cell lymphoma. These findings indicated that prenatal genetic or epigenetic changes influence risk of adult lymphoid neoplasms and suggest a difference in this association between aggressive and indolent lymphoma subtypes.

Follicular lymphoma (FL) risk is strongly associated with germline genetic variation in human leukocyte antigen (HLA) class II. Cigarette smoking has been suggested to increase FL risk, primarily among women. We hypothesized that amino acids in HLA-antigen D-related β1 subunit (DRB1) interact with smoking in FL risk, as shown for rheumatoid arthritis. We analyzed 373 patients with FL and 818 controls from 2 population-based case-control studies in Sweden and Denmark (1999-2003). Haplotypes in HLA-DRB1 were imputed at amino acid positions 11, 13, 28, 30, and 70-74 (shared epitope). We estimated the relative risk of FL as odds ratios with 95% confidence intervals for different smoking status/haplotype combinations. Interaction was defined as departure from additivity of effects and quantified by the attributable proportion (AP). Relative to never-smokers carrying no shared epitope alleles, smoking was associated with the risk of FL among all subjects (for former smokers, odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.10, 4.41; ORcurrent = 3.56, 95% CI: 1.60, 7.92) and women (ORformer = 2.95, 95% CI: 1.18, 7.37; ORcurrent = 5.63, 95% CI: 2.07, 15.3) carrying 2 shared epitope alleles but not among those carrying zero or 1 shared epitope allele. Smoking and shared epitope status interacted significantly as measured by AP (overall, AP = 0.6, 95% CI: 0.15, 1.0; for women, AP = 0.5, 95% CI: 0.005, 1.0). These results suggest a possible interaction between smoking and HLA-DRB1-associated antigen presentation in FL risk and provide a model to further unravel FL etiology.

OBJECTIVES: To study Hodgkin lymphoma (HL) microenvironment in a Swedish paediatric population and its relation to clinical parameters. METHODS: Tumour tissue from classical HL (cHL) (n=87) and nodular lymphocyte predominant HL (NLPHL) (n=11) was investigated for Epstein-Barr Virus (EBV) and analysed for eosinophils, mast cells and macrophages. RESULTS: In cHL, EBV positivity was more common in low age (pBoth last authors contributed equally.

Trends in Hodgkin lymphoma (HL) survival among patients treated outside of clinical trials provide real-world benchmark estimates of prognosis and help identify patient subgroups for targeted trials. In a Swedish population-based cohort of 1947 HL patients diagnosed in 1992-2009 at ages 18-59 years, we estimated relative survival (RS), cure proportions (CP), and median survival times using flexible parametric cure models. Overall, the CP was 89% (95% CI: 0.87-0.91) and median survival of the uncured was 4.6 years (95% CI: 3.0-6.3). For patients aged 18-50 years diagnosed after the year 2000, CP was high and stable, whereas for patients of 50-59 years, cure was not reached. The survival of relapse-free patients was similar to that of the general population (RS5-year : 0.99; 95% CI: 0.98-0.99, RS15-year : 0.95; 95% CI: 0.92-0.97). The excess mortality of relapsing patients was 19 times (95% CI: 12-31) that of relapse-free patients. Despite modern treatments, patients with adverse prognostic factors (e.g., advanced stage) still had markedly worse outcomes [CP stage: IIIB 0.82 (95% CI: 0.73-0.89); CP stage: IVB 0.72, (95% CI: 0.60-0.81)] and patients with international prognostic score (IPS) ≥3 had 2.7 times higher excess mortality (95% CI: 1.0-7.0, p = 0.04) than patients with IPS3. High-risk patients selected for 6-8 courses of BEACOPP (bleomycin, etoposide, doxorubicin, cyclofosphamide, vincristine, procarbazine, prednisone)-chemotherapy had a 15-year relative survival of 87%, (95% CI: 0.80-0.92), whereas the corresponding estimate for patients selected for 6-8 courses of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) was 93% (95% CI: 0.88-0.97). These population-based results indicate limited fatal side-effects in the 15-year perspective with contemporary treatments, while the unmet need of effective relapse treatment remains of concern. BEACOPP-chemotherapy was still not sufficient in high-risk HL patients.

ContextSecond cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk.ObjectiveTo quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD.Design, Setting, and SubjectsMatched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998.Main Outcome MeasuresRelative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents.ResultsBreast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P

This study seeks to investigate the long-term public health burden of Hodgkin lymphoma (HL) in terms of work loss following contemporary treatment protocols and associations with established treatment complications and lymphoma relapse.We identified 1,989 Swedish HL patients (1,082 with clinical information) aged 18-60 (median 33) years at diagnosis 1992-2009, and matched 1:4 to population comparators. Sick leave, disability pension (work loss), and comorbidity were retrieved through September 2013. Relative risks (RR) with 95% confidence intervals (CI) were calculated using Poisson regression, and mean lost work days were estimated yearly during follow-up.The risk of annual work loss was elevated in HL survivors versus comparators up to the 15th year post-diagnosis (RR(5th year) 1.64, 95% CI 1.46-1.84; RR(10th year) 1.33, 95% CI 1.15-1.34; and RR(15th year) 1.30, 95% CI 1.04-1.62). The risk remained elevated up to the 10th year after adjustment for secondary malignancies and cardiovascular disease (RR(10th year) 1.31, 95% CI 1.13-1.52). Advanced-stage patients had more lost days than comparators (mean number(5th year) 66 versus 33, mean difference 34, 95% CI 20-48) as did patients receiving 6-8 chemotherapy courses (62 versus 33, mean difference(5th year) 30, 95 % CI 17-43). Among patients in the first complete remission, a difference was still observed for advanced-stage (51 versus 33, mean difference(5th year) 19, 95% CI 5-34) but not early-stage disease.Advanced-stage HL survivors treated with full-dose chemotherapy were at increased risk of work loss, not only explained by relapse, secondary malignancies, or cardiovascular disease.The results call for increased awareness and evaluation of reasons for long-term work disability following intensive chemotherapy among young HL survivors.

Ultraviolet radiation (UVR) exposure has been inversely associated with Hodgkin lymphoma (HL) risk, but only inconsistently, only in a few studies, and without attention to HL heterogeneity. We conducted a pooled analysis of HL risk focusing on type and timing of UVR exposure and on disease subtypes by age, histology, and tumor-cell Epstein-Barr virus (EBV) status. Four case-control studies contributed 1320HLcasesand 6381 controls. We estimated lifetime, adulthood, and childhood UVR exposure and history of sunburn and sunlamp use. We used 2-stage estimation with mixed-effects models and weighted pooled effect estimates by inverse marginal variances. We observed statistically significant inverse associations with HL risk for UVR exposures during childhood and adulthood, sunburn history, and sunlamp use, but we found no significant doseresponse relationships. Risks were significant only for EBV-positive HL (pooled odds ratio, 0.56; 95% confidence interval, 0.35 to 0.91 for the highest overall UVR exposure category), with a significant linear trend for overall exposure (P 5.03). Pooled relative risk estimates were not heterogeneous across studies. Increased UVR exposure may protect against HL, particularly EBV-positive HL. Plausible mechanisms involving UVR induction of regulatory T cells or the cellular DNA damage response suggest opportunities for new prevention targets. © 2013 by The American Society of Hematology.

Cancer research has moved from solely investigating the tumour cells to also including analysis of the tumour microenvironment; however, the methods utilized have not been evaluated for this change. The aim of this study was to compare tissue microarrays (TMA) to whole tissue sections (WS) with regard to cells in the tumour microenvironment. Manual evaluation and digital image analyses (DIA) were utilized and also compared.TMA slides from 117 Hodgkin lymphoma patients were immunostained for forkhead box protein 3 (FoxP3) [identifying regulatory T cells (T(reg) )], and 39 corresponding WS were also analysed. Manual evaluation and DIA were utilized for all patients on both the TMA and the WS. A correlation coefficient of 0.83 was obtained for the proportion of T(reg) in TMA versus WS using manual evaluation and a correlation coefficient of 0.77 with DIA. T(reg) counts using manual evaluation correlated in turn with DIA, with a coefficient of 0.79 for the 117 TMA sections and 0.65 for the 39 WS.Because a high correlation was observed between TMA and WS, TMA can be utilized when evaluating cells in the tumour microenvironment. DIA appears to provide a reliable measurement method, provided that manual control of the tumour slides is conducted.

Classical Hodgkin's lymphoma (HL) lesions comprise few tumour cells, surrounded by numerous inflammatory cells. Like in other malignancies, the microenvironment is presumed to be clinically important in HL; however, microenvironment predictors remain poorly characterised. The aim of this study was to investigate how selected patient characteristics and genetic factors affect HL phenotype, in particular tissue eosinophilia, mast cell counts and HL histological subtype.In a population-based study, patients with HL were interviewed about potential HL risk factors. Available tumours, n=448, were classified histologically; the number of eosinophils and mast cells were estimated, and eosinophil cationic protein (ECP) and eosinophil protein-x (EPX) gene polymorphisms were determined. Associations were assessed in regression models.Self-reported history of asthma was predictive of having tumour eosinophilia [≥200 eosinophils/10 high power fields, univariate odds ratio (OR)=2.22, 95% CI 1.06-4.64, P=0.03]. High numbers of eosinophils were predominantly seen in patients carrying the genotype ECP434GG [multivariate relative levels (RLs)=1.84, 95% CI 1.02-3.30, P=0.04]. Lower number of eosinophils was seen in Epstein-Barr virus (EBV)-positive tumours (univariate RL=0.52, 95% CI 0.3-0.9, P=0.02) and in older patients (univariate RL=0.85, 95% CI 0.73-0.99, P=0.03). Well-known factors such as young age, female sex and EBV-negative status predicted nodular sclerosis histology.The number of eosinophils in HL tumours is influenced by patient traits such as asthma, ECP genotype and EBV status. EBV status was predictive of histology.