A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges

<p>Abstract</p> <p>Background</p> <p>Advances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper describes the design and encountered methodological challenges of a nationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarian reserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOG LATER-VEVO study.</p> <p>Methods</p> <p>The study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical, menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonal analyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-year survivors of childhood cancer treated in the Netherlands, whereas the control group consists of age-matched sisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participate in both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges were encountered involving the study population: dealing with bias due to the differences in characteristics of several types of (non-) participants and finding an adequately sized and well-matched control group. Moreover, the challenges related to the data collection process included: differences in response rates between web-based and paper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of women using hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements.</p> <p>Discussion</p> <p>The DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning to conduct large cohort studies on late effects may encounter similar challenges as those encountered during this study. The solutions to these challenges described in this paper may be useful to these investigators.</p> <p>Trial registration</p> <p>NTR2922; <url>http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922</url></p

The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state

We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page

Longer sleep is associated with lower BMI and favorable metabolic profiles in UK adults: Findings from the National Diet and Nutrition Survey

Ever more evidence associates short sleep with increased risk of metabolic diseases such as obesity, which may be related to a predisposition to non-homeostatic eating. Few studies have concurrently determined associations between sleep duration and objective measures of metabolic health as well as sleep duration and diet, however. We therefore analyzed associations between sleep duration, diet and metabolic health markers in UK adults, assessing associations between sleep duration and 1) adiposity, 2) selected metabolic health markers and 3) diet, using National Diet and Nutrition Survey data. Adults (n = 1,615, age 19–65 years, 57.1% female) completed questions about sleep duration and 3 to 4 days of food diaries. Blood pressure and waist circumference were recorded. Fasting blood lipids, glucose, glycated haemoglobin (HbA1c), thyroid hormones, and high-sensitivity C-reactive protein (CRP) were measured in a subset of participants. We used regression analyses to explore associations between sleep duration and outcomes. After adjustment for age, ethnicity, sex, smoking, and socioeconomic status, sleep duration was negatively associated with body mass index (-0.46 kg/m2 per hour, 95% CI -0.69 to -0.24 kg/m2, p < 0.001) and waist circumference (-0.9 cm per hour, 95% CI -1.5 to -0.3cm, p = 0.004), and positively associated with high-density lipoprotein cholesterol (0.03 mmol/L per hour, 95% CI 0.00 to 0.05, p = 0.03). Sleep duration tended to be positively associated with free thyroxine levels and negatively associated with HbA1c and CRP (p = 0.09 to 0.10). Contrary to our hypothesis, sleep duration was not associated with any dietary measures (p ≥ 0.14). Together, our findings show that short-sleeping UK adults are more likely to have obesity, a disease with many comorbidities

Second primary malignancies after treatment for malignant lymphoma

To determine the incidence and possible causes of second primary malignancies after treatment for Hodgkin's and Non-Hodgkin's lymphoma (HL and NHL). A cohort of 3764 consecutive patients diagnosed with HL or NHL between January 1970 and July 2001 was identified using the Sheffield Lymphoma Group database. A search was undertaken for all patients diagnosed with a subsequent primary malignancy. Two matched controls were identified for each case. Odds ratios were calculated to detect and quantify any risk factors in the cases compared to their matched controls. Mean follow-up for the cohort was 5.2 years. A total of 68 patients who developed second cancers at least 6 months after their primary diagnosis were identified, giving a crude incidence of 1.89% overall: 3.21% among the patients treated for HL, 1.32% in those treated for NHL. Most common were bronchial, breast, colorectal and haematological malignancies. High stage at diagnosis almost reached statistical significance in the analysis of just the NHL patients (odds ratio=3.48; P=0.068) after adjustment for other factors. Treatment modality was not statistically significant in any analysis. High stage at diagnosis of NHL may be a risk factor for developing a second primary cancer

Risk and temporal changes of heart failure among 5-year childhood cancer survivors: a DCOG-LATER study

Background Heart failure is one of the most important late effects after treatment for cancer in childhood. The goals of this study were to evaluate the risk of heart failure, temporal changes by treatment periods, and the risk factors for heart failure in childhood cancer survivors (CCS). Methods and Results The DCOG‐LATER (Dutch Childhood Oncology Group–Long‐Term Effects After Childhood Cancer) cohort includes 6,165 5‐year CCS diagnosed between 1963 and 2002. Details on prior cancer diagnosis and treatment were collected for this nationwide cohort. Cause‐specific cumulative incidences and risk factors of heart failure were obtained. Cardiac follow‐up was complete for 5,845 CCS (94.8%). After a median follow‐up of 19.8 years and at a median attained age of 27.3 years, 116 survivors developed symptomatic heart failure. The cumulative incidence of developing heart failure 40 years after childhood cancer diagnosis was 4.4% (3.4%–5.5%) among all CCS. The cumulative incidence of heart failure grade ≥3 among survivors treated in the more recent treatment periods was higher compared with survivors treated earlier (Gray test, P=0.05). Mortality due to heart failure decreased in the more recent treatment periods (Gray test, P=0.02). In multivariable analysis, survivors treated with a higher dose of mitoxantrone or cyclophosphamide had a higher risk of heart failure than survivors who were exposed to lower doses. Conclusions CCS treated with mitoxantrone, cyclophosphamide, anthracyclines, or radiotherapy involving the heart are at a high risk for severe, life‐threatening or fatal heart failure at a young age. Although mortality decreased, the incidence of severe or life‐threatening heart failure increased with more recent treatment periods

Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer

Background Improved breast cancer (BC) survival and evidence showing beneficial effects of internal mammary chain (IMC) irradiation underscore the importance of studying late cardiovascular effects of BC treatment. Methods We assessed cardiovascular disease (CVD) incidence in 14,645 Dutch BC patients aged <62 years, treated during 1970–2009. Analyses included proportional hazards models and general population comparisons. Results CVD rate-ratio for left-versus-right breast irradiation without IMC was 1.11 (95% CI 0.93–1.32). Compared to right-sided breast irradiation only, IMC irradiation (interquartile range mean heart doses 9–17 Gy) was associated with increases in CVD rate overall, ischaemic heart disease (IHD), heart failure (HF) and valvular heart disease (hazard ratios (HRs): 1.6–2.4). IHD risk remained increased until at least 20 years after treatment. Anthracycline-based chemotherapy was associated with an increased HF rate (HR = 4.18, 95% CI 3.07–5.69), emerging <5 years and remaining increased at least 10–15 years after treatment. IMC irradiation combined with anthracycline-based chemotherapy was associated with substantially increased HF rate (HR = 9.23 95% CI 6.01–14.18), compared to neither IMC irradiation nor anthracycline-based chemotherapy. Conclusions Women treated with anthracycline-based chemotherapy and IMC irradiation (in an older era) with considerable mean heart dose exposure have substantially increased incidence of several CVDs. Screening may be appropriate for some BC patient groups

Rising incidence of breast cancer among female cancer survivors: implications for surveillance

The number of female cancer survivors has been rising rapidly. We assessed the occurrence of breast cancer in these survivors over time. We computed incidence of primary breast cancer in two cohorts of female cancer survivors with a first diagnosis of cancer at ages 30+ in the periods 1975–1979 and 1990–1994. Cohorts were followed for 10 years through a population-based cancer registry. Over a period of 15 years, the incidence rate of breast cancer among female cancer survivors increased by 30% (age-standardised rate ratio (RR-adj): 1.30; 95% CI: 1.03–1.68). The increase was significant for non-breast cancer survivors (RR-adj: 1.41, 95% CI: 1.04–2.75). During the study period, the rate of second breast cancer stage II tripled (RR-adj: 3.10, 95% CI: 1.73–5.78). Non-breast cancer survivors had a significantly (P value=0.005) more unfavourable stage distribution (62% stage II and III) than breast cancer survivors (32% stage II and III). A marked rise in breast cancer incidence among female cancer survivors was observed. Research to optimise follow-up strategies for these women to detect breast cancer at an early stage is warranted