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Epidemiologic studies conducted to quantify the impact of radiation dose d on an outcome typically model the hazard ratio (HR) for association using a linear term, HR(d)=1+βd, via a linear excess relative risk (ERR) model, based on biological considerations. To study associations of risk of a second cancer with radiation treatment for a first cancer, several nested case‐control designs to estimate β have been proposed that use refined doses received by different locations in the organ of interest. Here we first evaluated the small sample bias in maximum likelihood estimates of β for the linear ERR model using location‐specific radiation doses in simulations. As we found substantial upward bias for studies of realistic sample sizes (more than 50% relative bias for studies with 75 cases), we also proposed and investigated several approaches to correct this bias. We studied first and second order jackknife bias corrections and we derived a modified set of score functions under retrospective case‐control sampling, from which we directly obtained bias‐corrected estimates. In simulations based on doses from a study of stomach cancer among testicular cancer survivors and synthetically generated data, neither the first nor second order jackknife bias correction performed well. Estimates based on the modified score equations corrected the bias much better, albeit not completely, and were numerically much more stable. [ABSTRACT FROM AUTHOR]

Suspicion has been raised about an increased cancer risk among Balkan veterans because of alleged exposure to depleted uranium. The authors conducted a historical cohort study to examine cancer incidence among Dutch Balkan veterans. Male military personnel (n = 18,175, median follow-up 11 years) of the Army and Military Police who had been deployed to the Balkan region (1993-2001) was compared with their peers not deployed to the Balkans (n = 135,355, median follow-up 15 years) and with the general Dutch population of comparable age and sex. The incidence of all cancers and 4 main cancer subgroups was studied in the period 1993-2008. The cancer incidence rate among Balkan deployed military men was 17% lower than among non-Balkan deployed military men (hazard ratio 0.83 (95% confidence interval 0.69, 1.00)). For the 4 main cancer subgroups, hazard ratios were statistically non-significantly below 1. Also compared to the general population cancer rates were lower in Balkan deployed personnel (standardised incidence rate ratio (SIR) 0.85 (0.73, 0.99). The SIR for leukaemia was 0.63 (0.20, 1.46). The authors conclude that earlier suggestions of increased cancer risks among veterans are not supported by empirical data. The lower risk of cancer might be explained by the 'healthy warrior effect'. [ABSTRACT FROM AUTHOR]

Background: Female survivors of Hodgkin's disease (HD) have a strongly elevated risk of breast cancer, but factors responsible for the increased risk are not well known. Methods: We investigated the effects of radiation dose, chemotherapy (CT), and reproductive factors on breast cancer risk in a nested case-control study in The Netherlands in a cohort of 770 female patients who had been diagnosed with HD before age 41. Detailed treatment information and data on reproductive factors were collected for 48 case patients who developed breast cancer 5 or more years after diagnosis of HD and 175 matched control subjects. The radiation dose was estimated to the area of the breast where the case patient's tumor had developed and to a comparable location in matched control subjects. Relative risks (RRs) of breast cancer were calculated by conditional logistic regression. Statistical tests were two-sided. Results: The risk of breast cancer increased statistically significantly with radiation dose (P[sub trend] = .01); patients who received 38.5 Gy or more had an RR of 4.5 (95% confidence interval [CI] = 1.3 to 16) times that of patients who received less than 4 Gy. Patients who received both CT and radiotherapy (RT) had a statistically significantly lower risk than those treated with RT alone (RR = 0.45, 95% CI = 0.22 to 0.91). Breast cancer risk increased with increasing radiation dose among patients who received RT only (RR = 12.7, 95% CI = 1.8 to 86, for patients receiving ≥38.5 Gy) but not among patients treated with CT and RT. Sixty-nine percent of control subjects treated with RT and more than six cycles of CT, but only 9% of those who received RT alone, reached menopause before age 41. Reaching menopause before age 36 was associated with a strongly reduced risk of breast cancer (RR = 0.06, 95% CI = 0.01 to 0.45). Conclusion: Breast cancer risk increases with increasing radiation dose up to at least 40 Gy. The substantial risk reduction associated with CT may... [ABSTRACT FROM AUTHOR]

Evaluates the relationship between a history of induced or spontaneous abortion and risk for breast cancer. Examination of reporting bias by comparing risks between two geographic areas; Comparison of reporting bias in data on induced abortion with reporting bias in data on oral contraceptive use.

Investigates the effects of radiation dose, chemotherapy and smoking on the risk of lung cancer after treatment of Hodgkin's disease. Description of the method used in the study; Increase in lung cancer risk caused by smoking and radiation dose.

Assesses the effect of timing and duration of oral contraceptives (OC) use on the risk of developing breast cancer in women 20 to 54 years old. Selection of subjects; Data collection methods; Statistical analyses of data; Effect of long-term OC use; Association between breast cancer and specific brands of OC; Implications of the findings.

Supports the hypothesis that the use of tamoxifen increases the risk of endometrial cancer. Characteristics of case patients with endometrial cancer after breast cancer and matched controls; Relative risks (RR) of endometrial cancer according to total duration of tamoxifen use and cumulative dose; Characteristics of patients with endometrial cancer according to use of tamoxifen.

This multi-center cohort-study examined late mortality among 6,165 Dutch five-year childhood cancer survivors diagnosed 1963–2001. Clinical details and cause of death were based on medical records. Mortality was 12-fold that of the general population, with 51.3 additional deaths per 10,000 person-years (21.9 yrs median follow-up). Cumulative mortality 15 yrs post-diagnosis was 6.9%, predominantly from late recurrences; thereafter the absolute contribution of other health outcomes increased. Cumulative all-cause and recurrence-related mortality were highest for Central Nervous System and bone tumor survivors. All-cause, but not subsequent tumor and circulatory disease-related cumulative mortality, was highest for patients diagnosed 1963–1979 vs. later (p-trend <0.001). [ABSTRACT FROM AUTHOR]

Women treated at young ages with supra-diaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rsl 21 9648, which annotates the FGFR2 gene, was associated with risk in both series (combined per-allele odds ratio = 1.59, 95% confidence interval: 1.26-2.02; P= .000111). These data provide evidence that genetic variation in FGFR2 influences radiation-induced breast cancer risk. (Blood. 2012;119(4): 1029-1031) [ABSTRACT FROM AUTHOR]

Background: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era.Methods: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis.Results: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m2 platinum dose administered (Ptrend  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure.Conclusions: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality. [ABSTRACT FROM AUTHOR]

Data collection by mailing questionnaires to the study population is one of the main research methods in epidemiologic studies. As participation rates are decreasing, easy-to-implement and cost-effective strategies to increase survey participation are needed. In this study, we tested the effect of a pragmatic combination of evidence-based interventions. We conducted a two-armed randomized controlled trial, nested in a cohort of breast cancer survivors (n = 1000) in the setting of a health outcomes survey. The intervention arm received a postal pre-notification, a non-monetary incentive (ballpoint with the study logo) and an alternative invitation letter in which several lay-out and textual adjustments were implemented according to behavioural science techniques. The alternative invitation letter also contained a QR-code through which an information video about the study could be accessed. The control arm was invited according to standard practice. Participants had the option to fill-out a questionnaire either on paper or online. A questionnaire with more than 50% of the questions answered classified as participation. Overall participation rate was 62.9%. No significant difference in participation rate was observed between intervention and control arm (64.5% vs 61.3%, Risk Ratio (RR) 1.05, 95% CI [0.96 – 1.16]). Older age at study (>65 vs <51 years), and high socio-economic status (highest vs lowest quartile) were associated with higher participation rates (RR 1.30, 95% CI [1.07 – 1.57] and 1.24, 95% CI [1.09 – 1.42] respectively). In-situ carcinoma compared to invasive cancer and longer interval since treatment were associated with lower participation (RR 0.86, 95% CI [0.74 – 0.99] and RR 0.92, 95% CI [0.87 – 0.99] per 5 year increase, respectively). Overall, the combination of four interventions tested in this study did not improve survey participation among breast cancer survivors. The overall participation rate was relatively high, possibly due to the study population of cancer survivors. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to evaluate how cumulative burden of clinically relevant, self‐reported outcomes in childhood cancer survivors (CCSs) compares to a sibling control group and to explore how the burden corresponds to levels of care proposed by existing risk stratifications. Methods: The authors invited 5925 5‐year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS LATER) cohort and their 1066 siblings to complete a questionnaire on health outcomes. Health outcomes were validated by self‐reported medication use or medical record review. Missing data on clinically relevant outcomes in CCSs for whom no questionnaire data were available were imputed with predictive mean matching. We calculated the mean cumulative count (MCC) for clinically relevant outcomes. Furthermore, we calculated 30‐year MCC for groups of CCSs based on primary cancer diagnosis and treatment, ranked 30‐year MCC, and compared the ranking to levels of care according to existing risk stratifications. Results: At median 18.5 years after 5‐year survival, 46% of CCSs had at least one clinically relevant outcome. CCSs experienced 2.8 times more health conditions than siblings (30‐year MCC = 0.79; 95% confidence interval [CI], 0.74–0.85 vs. 30‐year MCC = 0.29; 95% CI, 0.25–0.34). CCSs' burden of clinically relevant outcomes consisted mainly of endocrine and vascular conditions and varied by primary cancer type. The ranking of the 30‐year MCC often did not correspond with levels of care in existing risk stratifications. Conclusions: CCSs experience a high cumulative burden of clinically relevant outcomes that was not completely reflected by current risk stratifications. Choices for survivorship care should extend beyond primary tumor and treatment parameters, and should consider also including CCSs' current morbidity. Survivors of childhood cancer experience a high cumulative burden of clinically relevant outcomes. Choices for survivorship care should extend beyond primary tumor and treatment parameters and should also consider including the current morbidity of childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Background: Although colorectal adenomas serve as prime target for colorectal cancer (CRC) surveillance in other high-risk groups, data on adenoma risk after childhood cancer are lacking. We evaluated the risk of histologically confirmed colorectal adenomas among childhood cancer survivors. A secondary aim was to assess CRC risk.Methods: The DCOG-LATER cohort study includes five-year Dutch childhood cancer survivors and a sibling comparison group (n = 883). Colorectal tumors were identified from the population-based Dutch Pathology Registry (PALGA). We calculated cumulative incidences of adenomas/CRCs for survivors and siblings. For adenomas, multivariable Cox regression models were used to evaluate potential risk factors. All statistical tests were two-sided.Results: Among 5843 five-year survivors (median follow-up = 24.9 years), 78 individuals developed an adenoma. Cumulative incidence by age 45 years was 3.6% (95% confidence interval [CI] = 2.2% to 5.6%) after abdominopelvic radiotherapy (AP-RT; 49 cases) vs 2.0% (95% CI = 1.3% to 2.8%) among survivors without AP-RT (28 cases; Pdifference = .07) and vs 1.0% (95% CI = 0.3% to 2.6%) among siblings (6 cases) (Pdifference = .03). Factors associated with adenoma risk were AP-RT (hazard ratio [HR] = 2.12, 95% CI = 1.24 to 3.60), total body irradiation (TBI; HR = 10.55, 95% CI = 5.20 to 21.42), cisplatin (HR = 2.13; 95% CI = 0.74 to 6.07 for <480 mg/m²; HR = 3.85, 95% CI = 1.45 to 10.26 for ≥480 mg/m²; Ptrend = .62), a hepatoblastoma diagnosis (HR = 27.12, 95% CI = 8.80 to 83.58), and family history of early-onset CRC (HR = 20.46, 95% CI = 8.10 to 51.70). Procarbazine was statistically significantly associated among survivors without AP-RT/TBI (HR = 2.71, 95% CI = 1.28 to 5.74). Thirteen CRCs occurred.Conclusion: We provide evidence for excess risk of colorectal adenomas and CRCs among childhood cancer survivors. Adenoma risk factors include AP-RT, TBI, cisplatin, and procarbazine. Hepatoblastoma (familial adenomatous polyposis-associated) and family history of early-onset CRC were confirmed as strong risk factors. A full benefit-vs-harm evaluation of CRC screening among high-risk childhood cancer survivors warrants consideration. [ABSTRACT FROM AUTHOR]

Implant-based breast reconstructions contribute considerably to the quality of life of breast cancer patients. A knowledge gap exists concerning the potential role of silicone breast implants in the development of so-called "breast implant illness" (BII) and autoimmune diseases in breast cancer survivors with implant-based reconstructions. BII is a constellation of non-specific symptoms reported by a small group of women with silicone breast implants. The Areola study is a multicenter retrospective cohort study with prospective follow-up aiming to assess the risk of BII and autoimmune diseases in female breast cancer survivors with and without silicone breast implants. In this report, we set out the rationale, study design, and methodology of this cohort study. The cohort consists of breast cancer survivors who received surgical treatment with implant-based reconstruction in six major hospitals across the Netherlands in the period between 2000 and 2015. As a comparison group, a frequency-matched sample of breast cancer survivors without breast implants will be selected. An additional group of women who received breast augmentation surgery in the same years will be selected to compare their characteristics and health outcomes with those of breast cancer patients with implants. All women who are still alive will be invited to complete a web-based questionnaire covering health-related topics. The entire cohort including deceased women will be linked to population-based databases of Statistics Netherlands. These include a registry of hospital diagnostic codes, a medicines prescription registry, and a cause-of-death registry, through which diagnoses of autoimmune diseases will be identified. Outcomes of interest are the prevalence and incidence of BII and autoimmune diseases. In addition, risk factors for the development of BII and autoimmune disorders will be assessed among women with implants. The Areola study will contribute to the availability of reliable information on the risks of BII and autoimmune diseases in Dutch breast cancer survivors with silicone breast implants. This will inform breast cancer survivors and aid future breast cancer patients and their treating physicians to make informed decisions about reconstructive strategies after mastectomy. This study is registered at ClinicalTrials.gov on June 2, 2022 (NCT05400954). [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors are at risk for developing long‐term adverse health outcomes. To identify the risk of and risk factors for specific health outcomes, well‐established cohorts are needed with detailed information on childhood cancer diagnosis, treatment, and health outcomes. We describe the design, methodology, characteristics, and data availability of the Dutch Childhood Cancer Survivor Study LATER cohort (1963–2001) part 1; questionnaire and linkage studies. Methods: The LATER cohort includes 5‐year childhood cancer survivors, diagnosed in the period 1963–2001, and before the age of 18 in any of the seven former pediatric oncology centers in the Netherlands. Information on health outcomes from survivors and invited siblings of survivors was collected by questionnaires and linkages to medical registries. Results: In total, 6165 survivors were included in the LATER cohort. Extensive data on diagnosis and treatment have been collected. Information on a variety of health outcomes has been ascertained by the LATER questionnaire study and linkages with several registries for subsequent tumors, health care use, and hospitalizations. Conclusion: Research with data of the LATER cohort will provide new insights into risks of and risk factors for long‐term health outcomes. This can enhance risk stratification for childhood cancer survivors and inform surveillance guidelines and development of interventions to prevent (the impact of) long‐term adverse health outcomes. The data collected will be a solid baseline foundation for future follow‐up studies. [ABSTRACT FROM AUTHOR]

Studies have shown higher survival rates for patients with Hodgkin lymphoma (HL) treated within clinical trials compared to patients treated outside clinical trials. However, endpoints are often limited to overall survival (OS). In this retrospective cohort study, we investigated the effect of trial participation on OS, the incidence of relapse, second cancer, and cardiovascular disease (CVD). The study population consisted of patients with HL, aged between 14 and 51 years at diagnosis, who started their treatment between 1962 and 2002 at three Dutch cancer centres. Patients were either included in the EORTC Lymphoma Group trials (H1–H9) or treated according to standard guidelines at the time. After adjusting for differences in baseline characteristics, trial participation was associated with longer OS (median OS: 29.4 years [95%CI: 27.0–31.6] for treatment inside trials versus 27.4 years [95%CI: 26.0–28.5] for treatment outside trials, p =.046), a lower incidence of relapse (HR = 0.79, 95%CI: 0.63–0.98, p =.036) and a higher incidence of CVD (HR = 1.49, 95%CI: 1.23–1.79, p <.001). The trial effect for CVD was present only for patients treated before 1983. No evidence of differences in the incidence of second cancer was found. Consequently, essential results from clinical trials should be implemented into standard practice without undue delay. [ABSTRACT FROM AUTHOR]

Background: There is concern that assisted reproductive technology (ART) may increase ovarian cancer risk, but previous studies are inconclusive. We compared ovarian cancer risk for women who gave birth after ART vs natural conception. Methods: Through linkage of nationwide registry data, we followed 3,303,880 initially nulliparous women in Denmark (1994–2014), Finland (1990–2014), Norway (1984–2015) and Sweden (1985–2015) from first pregnancy ≥22 weeks to ovarian cancer, emigration, death or end of follow-up (2014/2015). We estimated hazard ratios (HRs), adjusting for age, parity, maternal birth year and country, and for body mass index and smoking in subsamples. Results: Mean age at first birth was 27.7 years. During a mean follow-up of 14.4 person-years, 2683 participants (0.08%) developed ovarian cancer; 135 after ART and 2548 after natural conception only (incidence rates 11.6 and 5.5 per 100,000 person-years, respectively). The risk was higher for women who ever gave birth after ART (HR 1.70, 95% confidence interval 1.42–2.03) compared to natural conception. Associations were stronger for conventional in vitro fertilisation than for intracytoplasmic sperm injection. Conclusions: Among parous women, ART-conception was associated with a higher risk of ovarian cancer than natural conception. Further studies should decipher whether this is causal or confounded by infertility or other factors. [ABSTRACT FROM AUTHOR]

The article presents a response by Doctor Daphne de Jong to a letter to the editor discussing her article "Anaplastic large-cell lymphoma in women with breast implants," by D de Jong, WL Vasmel, and JP De Boer, published in a previous issue.

A letter to the editor is presented in response to an article about compensation for diethylstilbestrol injury by Graham Dukes and Ellen 't Hoen in the January 20, 2007 issue.

Presents a letter to the editor about the effects of estrogen-only treatment in postmenopausal women.

Presents a letter to the editor about the design of the MWS research on breast cancer and HRT.

Background: Hodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit BC treatment options. It is unknown how treatment adaptations affect BC and CVD outcomes. Methods: The authors compared 195 BC patients treated with chest/axillary radiotherapy for HL (BC‐HL) with 5988 age‐ and calendar year‐matched patients with first primary BC (BC‐1). Analyses included cumulative incidence functions and Cox regression models, accounting for tumor characteristics and BC treatment. Results: Compared to BC‐1 patients, BC‐HL patients received anthracycline‐containing chemotherapy (23.7% vs. 43.8%, p <.001) and breast‐conserving surgery followed by radiotherapy (7.1% vs. 57.7%, p <.001) less often. BC treatment considerations were reported for 71% of BC‐HL patients. BC‐HL patients had a significantly higher risk of 15‐year overall mortality than BC‐1 patients (61% vs. 23%). Furthermore, risks of BC‐specific mortality and nonfatal BC events were significantly increased among BC‐HL patients, also when accounting for tumor and treatment characteristics (2.2‐ to 4.5‐fold). BC‐HL patients with a screen‐detected BC had a significantly reduced (61%) BC‐specific mortality. One‐third of BC‐HL patients had CVD at BC‐diagnosis, compared to <0.1% of BC‐1 patients. Fifteen‐year CVD‐specific mortality and CVD incidence were significantly higher in BC‐HL patients than in BC‐1 patients (15.2% vs. 0.4% and 40.4% vs. 6.8%, respectively), which was due to HL treatment rather than BC treatment. Conclusions: BC‐HL patients experience a higher burden of CVD and worse BC outcomes than BC‐1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors. Lay summary: Patients with breast cancer after Hodgkin lymphoma (BC‐HL) may have limited options for BC treatment, due to earlier HL treatment and an associated increased risk of cardiovascular disease (CVD).BC treatment considerations were reported for 71% of BC‐HL patients.We examined whether BC‐HL patients have a higher risk of CVD or BC events (recurrences/metastases) compared to patients with breast cancer that had no earlier tumors (BC‐1).We observed a higher burden of CVD and worse BC outcomes in HL patients compared to BC‐1 patients.Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors. Hodgkin lymphoma survivors with radiation‐induced breast cancer experience a higher burden of cardiovascular disease and worse breast cancer outcomes than first primary breast cancer patients. Clinicians should be aware of increased cardiovascular disease risk when selecting breast cancer treatment for Hodgkin lymphoma survivors. [ABSTRACT FROM AUTHOR]

Background: Non-seminoma testicular cancer survivors (TCS) have an increased risk of developing colorectal cancer (CRC) when they have been treated with platinum-based chemotherapy. Previously we demonstrated that among Hodgkin lymphoma survivors (HLS) there is enrichment of rare mismatch repair (MMR) deficient (MMRd) CRCs with somatic hits in MMR genes. We speculate that this phenomenon could also occur among other cancer survivors. We therefore aim to determine the MMR status and its underlying mechanism in CRC among TCS (TCS-CRC).Methods: Thirty TCS-CRC, identified through the Dutch pathology registry, were analysed for MMR proteins by immunohistochemistry. Next-generation sequencing was performed in MMRd CRCs without MLH1 promoter hypermethylation (n = 4). Data were compared with a male cohort with primary CRC (P-CRC, n = 629).Results: MMRd was found in 17% of TCS-CRCs vs. 9% in P-CRC (p = 0.13). MMRd was more often caused by somatic double or single hit in MMR genes by mutation or loss of heterozygosity in TCS-CRCs (3/30 (10%) vs. 11/629 (2%) in P-CRCs (p < 0.01)).Conclusions: MMRd CRCs with somatic double or single hit are more frequent in this small cohort of TCS compared with P-CRC. Exposure to anticancer treatments appears to be associated with the development of these rare MMRd CRC among cancer survivors. [ABSTRACT FROM AUTHOR]

Summary: Chronotype is frequently assessed in human observational studies using various morningness–eveningness questionnaires. An alternative single‐item chronotype question has been proposed for its reduced administration time and its accessibility to all types of populations. We investigated whether this single‐item chronotype is associated with dim light melatonin onset, the "gold standard" for estimating the endogenous circadian phase. We used data from a randomised trial in 166 (non‐)Hodgkin lymphoma survivors with cancer‐related fatigue. All participants completed a questionnaire, including a single‐item chronotype question. A subsample of 47 participants also provided saliva samples before sleep onset for melatonin measurement. Using multiple linear regression, we examined whether chronotype based on a single question was associated with dim light melatonin onset. The subsample of 47 participants had a mean age of 44.6 years. The mean (SD) dim light melatonin onset was at 8:42 (1:19) p.m. and the most common chronotype was more evening than morning person (29.2%). A gradual increase in dim light melatonin onset with later chronotype (i.e. evening preference) was observed, with a mean ranging from 7:45 p.m. in definite morning persons to 9:16 p.m. in definite evening persons. Our study shows that single‐item chronotype is associated with dim light melatonin onset as a marker of the endogenous circadian phase of fatigued lymphoma survivors. This type of chronotype assessment can therefore be a useful alternative for more extensive morningness–eveningness questionnaires. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) risk is increased among Hodgkin lymphoma (HL) survivors treated with chest radiotherapy. Case-control studies showed a linear radiation dose-response relationship for estimated dose to the breast tumor location. However, these relative risks cannot be used for absolute risk prediction of BC anywhere in the breasts. Furthermore, the independent and joint effects of radiation dose and irradiated volumes are unclear. Therefore, we examined the effects of mean breast dose and various dose-volume parameters on BC risk in HL patients.Methods: We conducted a nested case-control study of BC among 5-year HL survivors (173 case patients, 464 matched control patients). Dose-volume histograms were obtained from reconstructed voxel-based 3-dimensional dose distributions. Summary parameters of dose-volume histograms were studied next to mean and median breast dose, Gini index, and the new dose metric mean absolute difference of dose, using categorical and linear excess odds ratio (EOR) models. Interactions between dose-volume parameters and mean dose were also examined.Results: Statistically significant linear dose-response relationships were observed for mean breast dose (EOR per Gy = 0.19, 95% confidence interval [CI] = 0.05 to 1.06) and median dose (EOR/Gy = 0.06, 95% CI = 0.02 to 0.19), with no statistically significant curvature. All metrics except Gini and mean absolute difference were positively correlated with each other. These metrics all showed similar patterns of dose-response that were no longer statistically significant when adjusting for mean dose. No statistically significant modification of the effect of mean dose was observed.Conclusion: Mean breast dose predicts subsequent BC risk in long-term HL survivors. [ABSTRACT FROM AUTHOR]

Introduction: The risk of developing gastric cancer is increased in patients treated with radiotherapy for Hodgkin lymphoma (HL) or testicular cancer (TC). This study aims to assess if gastric adenocarcinoma after treatment for HL/TC (t-GC) is molecularly different from gastric adenocarcinoma in the general population. Methods: Patients were diagnosed with t-GC ≥5 years after treatment for HL/TC. Four molecular subtypes were identified using immunohistochemical and molecular analyses: Epstein-Barr virus (EBV), mismatch repair (MMR) deficiency or microsatellite instability (MSI), aberrant p53 staining as surrogate for chromosomal instability (sCIN), and a surrogate for genomic stability (sGS) without these aberrations. Results were compared with gastric cancer in the general population (p-GC) described in literature. Results: Molecular subtyping of 90 t-GCs resulted in 3% EBV, 8% MSI, 36% sCIN and 53% sGS. 3/6 of MSI t-GCs had MLH1 promoter methylation and 2/6 were explained by double somatic mutations in MMR genes. T-GCs were more frequently sGS than p-GCs (53% vs. 38%, p = 0.04). T-GC was more frequently sGS in HL/TC patients diagnosed before 1990, than after 1990 (63% vs. 38%, p = 0.03). T-GCs located in the antrum, an area that receives high irradiation doses, were more frequently sGS (61% vs. 28% in p-GCs, p = 0.02). Conclusion: Our results demonstrate that t-GCs are more frequently of the sGS subtype than p-GCs. An association of t-GC of the sGS subtype with prior anticancer treatment is suggested by the high frequency in HL/TC patients who were treated before 1990, a time period in which HL/TC treatments were more extensive. [ABSTRACT FROM AUTHOR]

Background: To help BRCA1 and 2 mutation carriers make informed decisions regarding use of combined-type oral contraceptive preparation (COCP), absolute risk-benefit estimates are needed for COCP-associated cancer.Methods: For a hypothetical cohort of 10 000 women, we calculated the increased or decreased cumulative incidence of COCP-associated (breast, ovarian, endometrial) cancer, examining 18 scenarios with differences in duration and timing of COCP use, uptake of prophylactic surgeries, and menopausal hormone therapy.Results: COCP use initially increased breast cancer risk and decreased ovarian and endometrial cancer risk long term. For 10 000 BRCA1 mutation carriers, 10 years of COCP use from age 20 to 30 years resulted in 66 additional COCP-associated cancer cases by the age of 35 years, in addition to 625 cases expected for never users. By the age of 70 years such COCP use resulted in 907 fewer cancer cases than the expected 9093 cases in never users. Triple-negative breast cancer estimates resulted in 196 additional COCP-associated cases by age 40 years, in addition to the 1454 expected. For 10 000 BRCA2 mutation carriers using COCP from age 20 to 30 years, 80 excess cancer cases were estimated by age 40 years in addition to 651 expected cases; by the age of 70 years, we calculated 382 fewer cases compared with the 6156 cases expected. The long-term benefit of COCP use diminished after risk-reducing bilateral salpingo-oophorectomy followed by menopausal hormone therapy use.Conclusion: Although COCP use in BRCA1 and BRCA2 mutation carriers initially increases breast, ovarian, and endometrial cancer risk, it strongly decreases lifetime cancer risk. Risk-reducing bilateral salpingo-oophorectomy and menopausal hormone therapy use appear to counteract the long-term COCP-benefit. [ABSTRACT FROM AUTHOR]

Background: Cancer‐related fatigue is a debilitating late effect after treatment for childhood cancer. The prevalence of fatigue in childhood cancer survivors (CCSs) and associated factors for fatigue has varied widely in previous studies. Two important aspects of cancer‐related fatigue, its severity and chronicity, are often not assessed. This study investigated the prevalence of, and risk factors for, severe chronic fatigue (CF) in a national cohort of Dutch CCSs. Methods: In this study, 2810 CCSs (5‐year survivors of all childhood malignancies diagnosed between 1963 and 2001 with a current age of 12‐65 years) and 1040 sibling controls were included. CF was assessed with the Short Fatigue Questionnaire and was defined as a score ≥ 18 and persistence of fatigue for ≥6 months. Cancer‐ and treatment‐related characteristics, current health problems, and demographic and lifestyle variables were assessed as potential risk factors for CF via multivariable logistic regression analyses. Results: In adult CCSs and sibling controls (≥18 years old), the prevalence of CF was 26.1% and 14.1%, respectively (P <.001). In adolescent CCSs and sibling controls (<18 years old), the prevalence of CF was 10.9% and 3.2%, respectively. Female gender (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.73‐2.62), unemployment (OR, 2.18; 95% CI, 1.67‐2.85), having 1 or more health problems (OR for 1‐2, 1.48; 95% CI, 1.18‐1.87; OR for >2, 2.20; 95% CI, 1.50‐3.21), and a central nervous system diagnosis (OR, 1.74; 95% CI, 1.17‐2.60) were significantly associated with CF in adult CCSs. Conclusions: This study shows that CCSs, regardless of their cancer diagnosis, report CF more often than sibling controls. This study provides new evidence for the prevalence of fatigue in CCSs. One in 4 childhood cancer survivors reports chronic fatigue. Current health problems increase the risk of reporting chronic fatigue. [ABSTRACT FROM AUTHOR]

Background: Hodgkin's lymphoma (HL) survivors treated with abdominal radiotherapy and/or procarbazine have an increased risk of developing colorectal neoplasia. Aims: We evaluated the clinicopathological characteristics and risk factors for developing (advanced) neoplasia (AN) in HL survivors. Methods: In all, 101 HL survivors (median age 51 years, median age of HL diagnosis 25 years) underwent colonoscopy and 350 neoplasia and 44 AN (classified as advanced adenomas/serrated lesions or colorectal cancer), mostly right‐sided, were detected, as published previously. An average‐risk asymptomatic cohort who underwent screening colonoscopy were controls (median age 60 years). Clinicopathological characteristics of AN were evaluated in both groups. Mismatch repair (MMR) status was assessed using immunohistochemistry (MLH1/MSH2/MSH6/PMS2). Logistic regression analysis was performed to evaluate the risk factors for AN in HL survivors, including age at HL diagnosis and interval between HL and colonoscopy. Results: In 101 colonoscopies in HL survivors, AN was primarily classified based on polyp size ≥10 mm, whereas (high‐grade)dysplasia was more often seen in AN in controls. An interval between HL diagnosis and colonoscopy >26 years was associated with more AN compared with an interval of <26 years, with an odds ratio for AN of 3.8 (95% confidence interval 1.4–9.1) (p < 0.01). All 39 AN that were assessed were MMR proficient. Conclusions: Colorectal neoplasia in HL survivors differ from average‐risk controls; classification AN was primarily based on polyp size (≥10 mm) in HL survivors. Longer follow‐up between HL diagnosis and colonoscopy was associated with a higher prevalence of AN in HL survivors. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the self-reported psychosocial well-being of 11- to 18-year-old adolescents who were conceived by in vitro fertilization (IVF) and examine the role of IVF conception on behavior. Design: Youth Self-Report (YSR) of 86 IVF and 97 control adolescents. Setting: VU University Medical Center, Amsterdam. Patient(s): Adolescents of ages 11 to 18 years; mean age 15.71 (± 2.06) years in IVF and 15.07 (± 2.11) years in controls. Intervention(s): None. Main Outcome Measure(s): Behavior and socioemotional functioning reported by the children themselves. Result(s): The YSR scores were all within the normal range. No statistically significant differences were found between the IVF and control groups on the different scales. Conclusion(s): Behavior and socioemotional functioning as reported by 11- to 18-year-old adolescents conceived by IVF were found to be normal. Previously found reduced behavior of externalizing nature and more withdrawn/depressed behavior reported by parents and teachers could not be reproduced in this study. We found no significant influence of IVF conception on behavior in adolescence. [ABSTRACT FROM AUTHOR]

Background: Amsterdam Airport Schiphol is a major source of complaints about aircraft noise, safety risks and concerns about long term adverse health effects, including cancer. We investigated whether residents of the area around Schiphol are at higher risk of developing cancer than the general Dutch population. Methods: In a population-based study using the regional cancer registry, we estimated the cancer incidence during 1988-2003 in residents of the area surrounding Schiphol. We defined a study area based on aircraft noise contours and 4-digit postal code areas, since historical data on ambient air pollution were not available and recent emission data did not differ from the background urban air quality. Results: In residents of the study area 13 207 cancer cases were diagnosed, which was close to the expected number, using national incidence rates as a reference (standardized incidence ratio [SIR] 1.02). We found a statistically significantly increased incidence of hematological malignancies (SIR 1.12, 95% confidence interval [CI]: 1.05, 1.19), mainly due to high rates for non-Hodgkin lymphoma (SIR 1.22, 95% CI: 1.12, 1.33) and acute lymphoblastic leukemia (SIR 1.34, 95% CI: 0.95, 1.83). The incidence of cancer of the respiratory system was statistically significantly decreased (SIR 0.94, 95% CI: 0.90, 0.99), due to the low rate in males (SIR 0.89). In the core zone of the study area, cancer incidence was slightly higher than in the remaining ring zone (rate ratio of the core zone compared to the ring zone 1.05, 95% CI 1.01, 1.10). This was caused by the higher incidence of cancer of the respiratory system, prostate and the female genital organs in the core zone in comparison to the ring zone. Conclusion: The overall cancer incidence in the Schiphol area was similar to the national incidence. The moderately increased risk of hematological malignancies could not be explained by higher levels of ambient air pollution in the Schiphol area. This observation warrants further research, for example in a study with focus on substances in urban ambient air pollution, as similar findings were observed in Greater Amsterdam. [ABSTRACT FROM AUTHOR]

Discusses various biases that may occur in studies that estimate the risk reduction after prophylactic surgery for BRCA1 and BRCA2 mutation. Illustration of decision-making process within a family; Biases associated with selection of study subjects; Survival bias; Cancer-induced testing bias; Familial event bias.

Simple Summary: It is well-established that hereditary retinoblastoma survivors have a substantially increased risk of developing subsequent malignant neoplasms (SMNs). Although clinicians have long suspected that this population is also at increased risk for developing benign neoplasms, the evidence is unclear. Benign tumors can substantially impact health status and quality of life, while raising questions for clinicians, when faced with a mass in a retinoblastoma survivor. By 60 years following retinoblastoma diagnosis, 17.6% of hereditary survivors had developed a benign tumor, with lipomas and leiomyomas being the most frequently diagnosed types. Additionally, we report both an increased risk of benign tumors after SMNs and a reciprocal increased risk of SMNs after benign tumors among hereditary retinoblastoma survivors. If confirmed, the large magnitude of the absolute risks and the association between benign tumors and SMNs in this population may have implications for long-term surveillance. Hereditary retinoblastoma survivors have substantially increased risk of subsequent malignant neoplasms (SMNs). The risk of benign neoplasms, a substantial cause of morbidity, is unclear. We calculated the cumulative incidence of developing benign tumors at 60 years following retinoblastoma diagnosis among 1128 hereditary (i.e., bilateral retinoblastoma or unilateral with family history, mutation testing was not available) and 924 nonhereditary retinoblastoma survivors diagnosed during 1914–2006 at two US medical centers with follow-up through 2016. Using Cox proportional hazards regression, we compared benign tumor risk by hereditary status and evaluated the association between benign tumors and SMNs. There were 100 benign tumors among 73 hereditary survivors (cumulative incidence = 17.6%; 95% confidence interval [CI] = 12.9–22.8%) and 22 benign tumors among 16 nonhereditary survivors (cumulative incidence = 3.9%; 95%CI = 2.2–6.4%), corresponding to 4.9-fold (95%CI = 2.8–8.4) increased risk for hereditary survivors. The cumulative incidence after hereditary retinoblastoma was highest for lipoma among males (14.0%; 95%CI = 7.7–22.1%) and leiomyoma among females (8.9%; 95%CI = 5.2–13.8%). Among hereditary survivors, having a prior SMN was associated with 3.5-fold (95%CI = 2.0–6.1) increased risk of developing a benign tumor; the reciprocal risk for developing an SMN after a benign tumor was 1.8 (95%CI = 1.1–2.9). These large-scale, long-term data demonstrate an increased risk for benign tumors after hereditary versus nonhereditary retinoblastoma. If confirmed, the association between benign tumors and SMNs among hereditary patients may have implications for long-term surveillance. [ABSTRACT FROM AUTHOR]

Meningiomas are the most frequent brain tumours occurring after pediatric cranial radiotherapy (CrRT). Data on course of disease, to inform clinical management of meningiomas, are sparse. This study reports the clinical characteristics of histologically confirmed meningiomas in childhood cancer survivors (CCS) in the Netherlands. In total, 6015 CCS from the Dutch Long-Term Effects After Childhood Cancer (LATER) cohort were eligible, including 1551 with prior CrRT. These CCS were diagnosed with cancer age <18 y (between 1963 and 2002) and are not subject to brain tumour screening. We identified histologically confirmed meningiomas by record linkage with the Dutch Pathology Registry (PALGA; 1991–2018), and in the Dutch LATER registry. We extracted details regarding diagnosis, treatment, and follow-up from medical records. We described 93 CCS with meningioma, of whom 89 (95.7%) were treated with CrRT (5.7% of 1551 with prior CrRT; OR = 68). Median age at diagnosis was 31.8 y (range: 13.2–50.5). Thirty survivors (32.3%) had synchronous meningiomas; 84 (90.3%) presented with symptoms. Only 16.1% of meningioma was detected at late effects clinics. Over time, all survivors had surgery; one-third also received radiotherapy. During follow-up 38 (40.9%), survivors developed new meningiomas, 22(23.7%) recurrences and at least four died due to the meningioma. Histologically confirmed meningiomas after childhood cancer are mostly diagnosed with symptoms and not during routine follow-up at late effects clinics. The meningiomas occur at a median of 20–25 y younger age than incidental meningiomas, are frequently multiple and recurrence after treatment is high. It is crucial to inform CCS and healthcare providers about risk and symptoms of subsequent meningiomas. • Histologically confirmed meningioma in childhood cancer survivors (CCS) are presented at young age with symptoms. • Synchronous and metachronous meningiomas and recurrences are common in CCS. • It is crucial to inform CCS and healthcare providers about risk and symptoms. [ABSTRACT FROM AUTHOR]

Simple Summary: Currently survival from retinoblastoma exceeds 95% in high-income/resource countries. Life expectancy within the heritable retinoblastoma population is mainly threatened by trilateral retinoblastoma in early childhood and subsequent malignant neoplasms throughout life. In this review the risks of specific subsequent malignant neoplasms and trilateral Rb, age at onset and influence of therapy are examined. Furthermore, long-term surveillance guidelines in the heritable retinoblastoma survivors are discussed. Retinoblastoma (Rb) is a pediatric malignant eye tumor. Subsequent malignant neoplasms (SMNs) and trilateral Rb (TRb) are the leading cause of death in heritable Rb patients in developed countries. The high rate of SMNs in heritable Rb patients is attributed to the presence of a mutation in the RB1 tumor suppressor gene. In addition, Rb therapy choices also influence SMN incidence in this patient group. The incidence rates and age of occurrence for the most frequent SMNs and TRb will be discussed. In addition, the impact of genetic predisposition and Rb treatments on the development of SMNs will be evaluated. Furthermore, screening and other prevention methods will be reviewed. [ABSTRACT FROM AUTHOR]

Background: Testicular cancer (TC) survivors have an increased risk of various second primary malignancies. A recent cohort study detected an increased risk of colorectal cancer (CRC) in TC survivors treated with platinum-based chemotherapy with a hazard ratio of 3.9. CRC risk increased with higher cisplatin-dose. We know that colonoscopy surveillance in high-risk populations results in reduced incidence and mortality of CRC. TC survivors treated with platinum-based chemotherapy can potentially benefit from colonoscopy surveillance; however, to which extent is unknown. Furthermore, the pathogenesis of these secondary CRCs is unknown, and better insights into the carcinogenesis may affect surveillance decisions.Methods: This prospective multicenter study will be performed in four Dutch hospitals. TC survivors are eligible if treated with ≥ 3 cycles of cisplatin before age 50. Colonoscopy will be performed ≥ 8 years after initial treatment (minimum and maximum ages at colonoscopy, 35 and 75 years, respectively). The primary aim of the study is the diagnostic yield of advanced neoplasia detected during colonoscopy. As secondary aim, we will evaluate the molecular profile of advanced colorectal neoplasia and will assess current platinum levels in blood and urine and correlate blood-platinum levels with prevalence of colorectal lesions. Furthermore, we will investigate effectiveness of fecal immunochemical testing (FIT) and burden of colonoscopy by two questionnaires. Demographic data, previous history, results of colonoscopy, hemoglobin level of FIT and results of molecular and platinum levels will be obtained. Yield of colonoscopy will be determined by detection rate of adenoma and serrated lesions, advanced adenoma detection rate and CRC detection rate. The MISCAN model will be used for cost-effectiveness analyses of CRC surveillance. With 234 participants undergoing colonoscopy, we can detect an absolute difference of 6% of advanced neoplasia with 80% power.Discussion: TC survivors treated with cisplatin-based chemotherapy can benefit from CRC surveillance. Evaluation of the diagnostic performance and patient acceptance of CRC surveillance is of importance to develop surveillance recommendations. Insight into the carcinogenesis of cisplatin-related advanced colorectal lesions will contribute to CRC prevention in the increasing number of TC survivors. The results may also be important for the many other cancer survivors treated with platinum-based chemotherapy.Trial Registration: Clinical Trials: NCT04180033, November 27, 2019, https://clinicaltrials.gov/ct2/show/NCT04180033 . [ABSTRACT FROM AUTHOR]

Cancer-related fatigue has been related to circadian disruptions and lower levels of sleep quality. However, it is unknown whether the circadian phase, which is associated with chronotype and timing of sleep, is related to fatigue after cancer. The aims of this study were to investigate the associations between (1) chronotype and cancer-related fatigue and (2) sleep quality and cancer-related fatigue. In this cross-sectional questionnaire study, 458 (non-)Hodgkin lymphoma survivors (n = 231 female, mean age 49.7 years) completed a Visual Analogue Scale for fatigue (VAS-fatigue) from 0 (no fatigue) to 10 (worst imaginable fatigue), the Munich Chronotype Questionnaire (MCTQ), and the Pittsburgh Sleep Quality Index (PSQI) between October 2018 and July 2019. A hierarchical linear regression analysis was used to evaluate the associations between the dependent variable fatigue and chronotype (based on early, intermediate, or late average midsleep) in Model 1, and fatigue and sleep quality in Model 2. The results showed no indications for an association between chronotype and fatigue (all p values ≥ 0.50). There were associations between two (out of seven) aspects of sleep quality and fatigue: subjective sleep quality (p < 0.001) and daily dysfunctioning (p < 0.001). Therefore, it is more likely that fatigue is associated with self-reported sleep quality rather than with chronotype. However, experimental studies with objective, physiological data on circadian phase and sleep quality are necessary to confirm the conclusions of this cross-sectional study. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL) survivors are at increased risk of developing second primary esophageal squamous cell cancer (ESCC). We aimed to gain insight in the driving events of ESCC in HL survivors (hESCC) by using RNA sequencing and NanoString profiling. Objectives were to investigate differences in RNA signaling between hESCC and sporadic ESCC (sESCC), and to look for early malignant changes in non-neoplastic esophageal tissue of HL survivors (hNN-tissue). We analyzed material of 26 hESCC cases, identified via the Dutch pathology registry (PALGA) and 17 sESCC cases from one academic institute and RNA sequencing data of 44 sESCC cases from TCGA. Gene expression profiles for the NanoString panel PanCancer IO 360 were obtained from 16/26 hESCC and four hNN-tissue, while non-neoplastic squamous tissue of four sporadic cases (sNN-tissue) served as reference profile. Hierarchical clustering, differential expression and pathway analyses were performed. Overall, the molecular profiles of hESCC and sESCC were similar. There was increased immune, HMGB1 and ILK signaling compared to sNN-tissue. The profiles of hNN-tissue were distinct from sNN-tissue, indicating early field effects in the esophagus of HL survivors. The BRCA1 pathway was upregulated in hESCC tissue, compared to hNN tissue. Analysis of expression profiles reveals overlap between hESCC and sESCC, and differences between hESCC and its surrounding hNN-tissue. Further research is required to validate our results and to investigate whether the changes observed in hNN-tissue are already detectable before development of hESCC. In the future, our findings could be used to improve hESCC patient management. [ABSTRACT FROM AUTHOR]

To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma. We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence. Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center. Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations. Diagnosis and mortality from subsequent neoplasm. Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent. This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members. [ABSTRACT FROM AUTHOR]

• 252 oesophageal cancers (488 matched controls) after breast cancer were analysed. • The excess odds-ratio of oesophageal cancer linearly increased with median dose. • At a fixed median dose, larger V30 increased the risk of squamous cell carcinoma. • Median dose and V30 could be relevant metrics in treatment plan optimization. • The study highlights the role of highest doses in oesophageal cancer risk. To investigate the relationship between oesophagus dose-volume distribution and long-term risk of oesophageal cancer after radiation therapy for breast cancer. In a case-control study nested within a cohort of 289,748 ≥5-year survivors of female breast cancer treated in 1943–2003 in five countries, doses to the second primary cancer (D SPC) and individual dose-volume histograms (DVH) to the entire oesophagus were reconstructed for 252 oesophageal cancer cases and 488 matched controls (median follow-up time: 13, range: 5–37 years). Using conditional logistic regression, we estimated excess odds ratios (EOR) of oesophageal cancer associated with DVH metrics. We also investigated whether DVH metrics confounded or modified D SPC -related -risk estimates. Among the DVH metrics evaluated, median dose (D median) to the entire oesophagus had the best statistical performance for estimating risk of all histological types combined (EOR/Gy = 0.071, 95% confidence interval [CI]: 0.018 to 0.206). For squamous cell carcinoma, the most common subtype, the EOR/Gy for D median increased by 31% (95% CI: 3% to 205%) for each increment of 10% of V30 (p = 0.02). Adjusting for DVH metrics did not materially change the EOR/Gy for D SPC , but there was a borderline significant positive interaction between D SPC and V30 (p = 0.07). This first study investigating the relationship between oesophagus dose-volume distribution and oesophageal cancer risk showed an increased risk per Gy for D median with larger volumes irradiated at high doses. While current techniques allows better oesophagus sparing, constraints applied to D median and V30 could potentially further reduce the risk of oesophageal cancer. [ABSTRACT FROM AUTHOR]

Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged <18 years during evaluation received an altered questionnaire without questions regarding pregnancy and pregnancy outcomes. These data were combined with information from medical records. AMH levels were measured in serum samples and were compared with AMH levels from 420 women not treated for cancer. Results: Fifty-six survivors with a median age of 31.0 (interquartile range, IQR, 25.1–39.6) years were evaluated after a median follow-up of 15.4 (IQR 8.3–24.7) years. The median cumulative dose of 131I administered was 7.4 (IQR 3.7–13.0) GBq/200.0 (IQR 100.0–350.0) mCi. Twenty-five of the 55 survivors aged 18 years or older during evaluation reported 64 pregnancies, 45 of which resulted in live birth. Of these 55, 10.9% visited a fertility clinic. None of the survivors reported premature menopause. Age at AMH evaluation did not differ between DTC survivors and the comparison group (p = 0.268). Median AMH levels did not differ between DTC survivors and the comparison group [2.0 (IQR 1.0–3.7) μg/L vs. 1.6 (IQR 0.6–3.1) μg/L, respectively, p = 0.244]. The cumulative dose of 131I was not associated with AMH levels in DTC survivors (rs = 0.210, p = 0.130). Conclusions: Female survivors of DTC who received 131I treatment during childhood do not appear to have major abnormalities in reproductive characteristics nor in predictors of ovarian failure. [ABSTRACT FROM AUTHOR]

Background: Insight in hospitalizations in long-term childhood cancer survivors (CCS) is useful to understand the impact of long-term morbidity. We aimed to investigate hospitalization rates and underlying types of diagnoses in CCS compared to matched controls, and to investigate the determinants. Methods: We linked 5,650 five-year CCS from the Dutch nationwide Dutch LATER cohort and 109,605 age- and sex-matched controls to the Dutch Hospital Discharge register, which contained detailed information on inpatient hospitalizations from 1995–2016. Relative hospitalization rates (RHRs) were calculated using a Poisson regression model. Adjusting for multiple hospitalizations per person via a Poisson model for generalized estimated equations, we investigated determinants for hospitalizations for all types of underlying diagnoses among CCS. Results: CCS were twice as likely to be hospitalized as reference persons (hospitalization rate 178 and 78 per 1,000 person-years respectively; RHR 2.0, 95% confidence interval (CI) 1.9–2.2). Although CCS had more hospitalizations for 17 types of underlying diagnoses, they were especially more likely to be hospitalized for endocrine conditions (RHR: 6.0, 95% CI 4.6–7.7), subsequent neoplasms (RHR: 5.6, 95% CI 4.6–6.7) and symptoms without underlying diagnoses (RHR: 5.2, 95% CI 4.6–5.8). For those types of underlying diagnoses, female sex and radiotherapy were determinants. Conclusion: This study provides new insights in the high risk of hospitalizations for many types of underlying diagnoses in CCS and treatment related determinants. CCS are especially at high risk for hospitalizations for endocrine conditions, subsequent neoplasms and symptoms without an underlying diagnosis. This new knowledge is important for survivorship care and to identify possible preventable hospitalizations among CCS. [ABSTRACT FROM AUTHOR]

• IMC-irradiation was associated with an increased cardiac death rate following an ACS. • Death rate on the day of ACS diagnosis was doubled for IMC- vs. no-IMC-irradiation. • Largest difference in cumulative incidence of cardiac death observed at time of ACS. • Radiotherapy, in case of substantial heart doses, may worsen ACS prognosis. Breast cancer patients treated with radiotherapy are at increased risk of subsequent acute coronary syndromes (ACS). We aimed to study if radiotherapy also influences the prognosis of these ACS. We included all 398 patients diagnosed with ACS following radiotherapy from our hospital-based cohort of early breast cancer patients aged <71 years, treated 1970–2009. Cardiovascular disease incidence and cause of death were acquired through questionnaires to general practitioners and cardiologists. Internal mammary chain (IMC) irradiation delivers the highest heart doses in breast cancer radiotherapy. Hence, we compared ACS prognosis between patients treated with/without IMC-irradiation. ACS prognosis was assessed through cardiac death, death due to ACS and cardiovascular disease incidence, using multivariable Cox proportional hazard models and by estimating cumulative incidence. In total, 62% of patients with ACS had received IMC-irradiation and 38% did not (median age at ACS diagnosis, 67 years). Median time between breast cancer and ACS was 15 years. After ACS, ten-year cumulative risk of cardiac death was 35% for patients who had IMC-irradiation (95% confidence interval [95%CI] 29–41) compared to 24% (95%CI 17–31) for patients without IMC-irradiation (p = 0.04). After correction for confounders, IMC-irradiation remained associated with a less favourable prognosis of ACS compared to no IMC-irradiation (hazard ratio cardiac death = 1.7, 95%CI 1.1–2.5). Our results suggest that radiotherapy, in case of substantial heart doses, may worsen ACS prognosis. This is an important, novel finding that may impact upon the risk-based care for breast cancer survivors with ACS. [ABSTRACT FROM AUTHOR]

Background: We aimed to develop dose-response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies.Methods and Results: A case-control study was performed within a cohort of breast cancer survivors treated during 1980-2009. Cases (n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9-13.7]. MHD was not associated with HF risk overall [excess rate ratio (ERR) = 1%/Gy, 95% confidence interval (CI) -2 to 10]. In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7-21.7) compared to <10% exposed to ≥20 Gy. For cases who received radiotherapy, median cumulative anthracycline dose was 247 mg/m2 (IQR 240-319). A dose-dependent increase was observed after anthracycline without trastuzumab (ERR = 1.5% per mg/m2 , 95% CI 0.5-4.1). After anthracycline and trastuzumab, the rate ratio was 34.9 (95% CI 11.1-110.1) compared to no chemotherapy.Conclusions: In absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies. [ABSTRACT FROM AUTHOR]

Aims: Anthracyclines increase heart failure (HF) risk, but the long-term prevalence of myocardial dysfunction in young breast cancer (BC) survivors is unknown. Early measures of left ventricular myocardial dysfunction are needed to identify BC patients at risk of symptomatic HF.Methods and Results: Within an established cohort, we studied markers for myocardial dysfunction among 569 women, who were 5-7 years (n = 277) or 10-12 years (n = 292) after BC treatment at ages 40-50 years. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were assessed by echocardiography. N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured in serum. Associations between patient-related and treatment-related risk factors and myocardial dysfunction were evaluated using linear and logistic regression. Median ages at BC diagnosis and cardiac assessment were 46.7 and 55.5 years, respectively. Anthracycline-treated patients (n = 313), compared to the no-anthracycline group (n = 256), more often had decreased LVEF (10% vs. 4%), impaired GLS (34% vs. 27%) and elevated NT-proBNP (23% vs. 8%). GLS and LVEF declined in a linear fashion with increasing cumulative anthracycline dose (GLS: +0.23 and LVEF: -0.40 per cycle of 60 mg/m2 ; P < 0.001) and GLS was worse for patients with left breast irradiation. The risk of NT-proBNP >125 ng/L was highest for patients who received 241-300 mg/m2 anthracycline dose compared to the no-anthracycline group (odds ratio: 3.30, 95% confidence interval: 1.83-5.96).Conclusion: Impaired GLS and increased NT-proBNP levels are present in a substantial proportion of young BC survivors treated with anthracyclines. Whether this will lead to future cardiac disease needs to be evaluated by longitudinal assessment. [ABSTRACT FROM AUTHOR]

The recent UK HL guideline also discusses the advantages and disadvantages of omitting radiotherapy in selected cases.[5] Of note, the omission of radiotherapy may come at a price. In addition, modern radiotherapy regimens include conformal radiotherapy techniques, radiotherapy in deep inspiration, and, if available, proton therapy. [Extracted from the article]

Background: An increasing number of breast cancer (BC) survivors are at risk of developing contralateral breast cancer (CBC). We aimed to investigate the influence of various adjuvant systemic regimens on, subtype-specific, risk of CBC.Methods: This population-based cohort study included female patients diagnosed with first invasive BC between 2003 and 2010; follow-up was complete until 2016. Clinico-pathological data were obtained from the Netherlands Cancer Registry and additional data on receptor status through linkage with PALGA: the Dutch Pathology Registry. Cumulative incidences (death and distant metastases as competing risk) and hazard ratios (HRs) were estimated for all invasive metachronous CBC and CBC subtypes.Results: Of 83 144 BC patients, 2816 developed a CBC; the 10-year cumulative incidence was 3.8% (95% confidence interval [CI] = 3.7% to 4.0%). Overall, adjuvant chemotherapy (HR = 0.70, 95% CI = 0.62 to 0.80), endocrine therapy (HR = 0.46, 95% CI = 0.41 to 0.52), and trastuzumab with chemotherapy (HR = 0.57, 95% CI = 0.45 to 0.73) were strongly associated with a reduced CBC risk. Specifically, taxane-containing chemotherapy (HR = 0.48, 95% CI = 0.36 to 0.62) and aromatase inhibitors (HR = 0.32, 95% CI = 0.23 to 0.44) were associated with a large CBC risk reduction. More detailed analyses showed that endocrine therapy statistically significantly decreased the risk of estrogen receptor (ER)-positive CBC (HR = 0.41, 95% CI = 0.36 to 0.47) but not ER-negative CBC (HR = 1.32, 95% CI = 0.90 to 1.93) compared with no endocrine therapy. Patients receiving chemotherapy for ER-negative first BC had a higher risk of ER-negative CBC from 5 years of follow-up (HR = 2.84, 95% CI = 1.62 to 4.99) compared with patients not receiving chemotherapy for ER-negative first BC.Conclusion: Endocrine therapy, chemotherapy, as well as trastuzumab with chemotherapy reduce CBC risk. However, each adjuvant therapy regimen had a different impact on the CBC subtype distribution. Taxane-containing chemotherapy and aromatase inhibitors were associated with the largest CBC risk reduction. [ABSTRACT FROM AUTHOR]

Study Question: Do children conceived by ART have an increased risk of cancer?Summary Answer: Overall, ART-conceived children do not appear to have an increased risk of cancer.What Is Known Already: Despite the increasing use of ART, i.e. IVF or ICSI worldwide, information about possible long-term health risks for children conceived by these techniques is scarce.Study Design, Size, Duration: A nationwide historical cohort study with prospective follow-up (median 21 years), including all live-born offspring from women treated with subfertility treatments between 1980 and 2001.Participants/materials, Setting, Methods: All offspring of a nationwide cohort of subfertile women (OMEGA study) treated in one of the 12 Dutch IVF clinics or two fertility clinics. Of 47 690 live-born children, 24 269 were ART-conceived, 13 761 naturally conceived and 9660 were conceived naturally or through fertility drugs, but not by ART. Information on the conception method of each child and potential confounders were collected through the mothers' questionnaires and medical records. Cancer incidence was ascertained through linkage with The Netherlands Cancer Registry from 1 January 1989 until 1 November 2016. Cancer risk in ART-conceived children was compared with risks in naturally conceived children from subfertile women (hazard ratios [HRs]) and with the general population (standardized incidence ratios [SIRs]).Main Results and the Role Of Chance: The median follow-up was 21 years (interquartile range (IQR): 17-25) and was shorter in ART-conceived children (20 years, IQR: 17-23) compared with naturally conceived children (24 years, IQR: 20-30). In total, 231 cancers were observed. Overall cancer risk was not increased in ART-conceived children, neither compared with naturally conceived children from subfertile women (HR: 1.00, 95% CI 0.72-1.38) nor compared with the general population (SIR = 1.11, 95% CI: 0.90-1.36). From 18 years of age onwards, the HR of cancer in ART-conceived versus naturally conceived individuals was 1.25 (95% CI: 0.73-2.13). Slightly but non-significantly increased risks were observed in children conceived by ICSI or cryopreservation (HR = 1.52, 95% CI: 0.81-2.85; 1.80, 95% CI: 0.65-4.95, respectively). Risks of lymphoblastic leukemia (HR = 2.44, 95% CI: 0.81-7.37) and melanoma (HR = 1.86, 95% CI: 0.66-5.27) were non-significantly increased for ART-conceived compared with naturally conceived children.Limitations, Reasons For Caution: Despite the large size and long follow-up of the cohort, the number of cancers was rather small for subgroup analyses as cancer in children and young adults is rare.Wider Implications Of the Findings: Overall, ART-conceived children do not appear to have an increased cancer risk after a median follow-up of 21 years. This large study provides important results, enabling physicians to better inform couples considering ART about the long-term safety of ART for their children. However, larger studies with prolonged follow-up are needed to investigate cancer risk in adults and in children conceived by ICSI and/or from cryopreserved embryos.Study Funding/competing Interest(s): This work was supported by The Dutch Cancer Society (NKI 2006-3631) which funded the OMEGA-women's cohort and Children Cancer Free (KIKA;147) which funded the OMEGA-offspring cohort. We declare no competing interests. [ABSTRACT FROM AUTHOR]

Background: Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors.Methods: This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high-grade dysplasia, ≥25% villous component, or ≥10-mm diameter), advanced serrated lesions (dysplasia or ≥10-mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50-75 years old). This study demonstrated the results of a predefined interim analysis.Results: A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45-57 years) than the general population controls (median, 60 years; IQR, 55-65 years; P < .001). The prevalence of advanced neoplasia was higher in HL survivors than controls (25 of 101 [25%] vs 171 of 1426 [12%]; P < .001). Advanced adenomas were detected in 14 of 101 HL survivors (14%) and in 124 of 1426 controls (9%; P = .08). The prevalence of advanced serrated lesions was higher in HL survivors than controls (12 of 101 [12%] vs 55 of 1426 [4%]; P < .001). Serrated polyposis syndrome was present in 6% of HL survivors and absent in controls (P < .001).Conclusions: HL survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered. [ABSTRACT FROM AUTHOR]