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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]

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: 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: Computed tomography (CT), a strong diagnostic tool, delivers higher radiation doses than most imaging modalities. As CT use has increased rapidly, radiation protection is important, particularly among children. We evaluate leukemia and brain tumor risk following exposure to low-dose ionizing radiation from CT scans in childhood.Methods: For a nationwide retrospective cohort of 168 394 children who received one or more CT scans in a Dutch hospital between 1979 and 2012 who were younger than age 18 years, we obtained cancer incidence, vital status, and confounder information by record linkage with external registries. Standardized incidence ratios were calculated using cancer incidence rates from the general Dutch population. Excess relative risks (ERRs) per 100 mGy organ dose were calculated with Poisson regression. All statistical tests were two-sided.Results: Standardized incidence ratios were elevated for all cancer sites. Mean cumulative bone marrow doses were 9.5 mGy at the end of follow-up, and leukemia risk (excluding myelodysplastic syndrome) was not associated with cumulative bone marrow dose (44 cases). Cumulative brain dose was on average 38.5 mGy and was statistically significantly associated with risk for malignant and nonmalignant brain tumors combined (ERR/100 mGy: 0.86, 95% confidence interval = 0.20 to 2.22, P = .002, 84 cases). Excluding tuberous sclerosis complex patients did not substantially change the risk.Conclusions: We found evidence that CT-related radiation exposure increases brain tumor risk. No association was observed for leukemia. Compared with the general population, incidence of brain tumors was higher in the cohort of children with CT scans, requiring cautious interpretation of the findings. [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]

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare but serious complication in patients with breast implants, Patients are at risk of BIA-ALCL whether they receive breast implants for cosmetic reasons or for reconstructive purposes after surgery for breast cancer or prophylactic mastectomy. During the past decade, an increased number of reports have addressed BIA-ALCL. Herein, we describe BIA-ALCL in a transgender woman. The patient received breast implants as part of her gender transition and was diagnosed with BIA-ALCL 20 years later. The patient underwent several revisional operations in the 20 years after her primary breast surgery to treat unexplained pain with low-grade fever, severe capsular contracture (Baker grade III-IV), and several instances of implant rupture. In July 2016, the patient presented to our office with "late-onset" periprosthetic seroma 5 years after her last revisional breast surgery. She was diagnosed with BIA-ALCL without capsular invasion based on results of cytologic analysis of the periprosthetic seroma and histologic evaluation of the periprosthetic capsule. This diagnosis was verified further by results of immunohistochemical testing, which indicated expression of CD30 and T-cell markers in the periprosthetic seroma only. Our intentions with this case report are to demonstrate that all patients who undergo breast implantation, including transgender women, are at risk of BIA-ALCL and to highlight the importance of cytomorphologic and immunohistochemical screening of seroma fluid in patients with late-onset periprosthetic seroma.Level Of Evidence: 5. [ABSTRACT FROM AUTHOR]

Background: The primary aim of the study was to investigate prognosis and long-term survival in young breast cancer patients with a BRCA1 or BRCA2 germline mutation compared with noncarriers. The secondary aim was to investigate whether differences in survival originate from associations with tumor characteristics, second cancers, and/or treatment response.Methods: We established a cohort of invasive breast cancer patients diagnosed younger than age 50 years in 10 Dutch hospitals between 1970 and 2003. BRCA1/2 testing of most prevalent mutations was mainly done using DNA isolate from formalin-fixed paraffin-embedded nontumor tissue. Survival estimates were derived using Cox regression and competing risk models.Results: In 6478 breast cancer patients, we identified 3.2% BRCA1 and 1.2% BRCA2 mutation carriers. BRCA1 mutation carriers had a worse overall survival independent of clinico-pathological/treatment characteristics, compared with noncarriers (adjusted hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 0.97 to 1.47), though only statistically significant in the first five years of follow-up (adjusted HR = 1.40, 95% CI = 1.07 to 1.84). A large part of the worse survival was explained by incidence of ovarian cancers. Breast cancer-specific, disease-free, and metastasis-free survival results were less pronounced and mostly statistically nonsignificant but in the same direction with those of overall survival. Overall survival was worse, although not statistically significantly, within the ER-negative or ER-positive, grade 3, and small tumor subgroups. The worse survival was most pronounced in non-chemotherapy-treated patients (adjusted HR = 1.54, 95% CI = 1.08 to 2.19). Power for BRCA2 mutation carriers was limited; only after five years' follow-up overall survival was worse (adjusted HR = 1.47, 95% CI = 1.00 to 2.17).Conclusions: BRCA1/2 mutation carriers diagnosed with breast cancer before age 50 years are prone to a worse survival, which is partly explained by differences in tumor characteristics, treatment response, and second ovarian cancers. [ABSTRACT FROM AUTHOR]

Study Question: Does long-term exogenous testosterone administration result in polycystic ovarian morphology (PCOM), determined by (3D) transvaginal ultrasound (TVU) in female-to-male transsexuals (FtMs).Summary Answer: Long-term exogenous testosterone administration in FtMs does not result in PCOM determined by (3D) TVU.What Is Known Already: The role of androgens in the pathophysiology of polycystic ovary syndrome (PCOS) is still unclear. From animal studies, intra-ovarian androgens have been suggested to disturb folliculogenesis, through a pro-atretic effect on growing follicles. It remains debatable whether exogenous androgens induce PCOM in humans. In the past histomorphologic studies indicated that androgen administration in FtMs could cause PCO-like changes. However, ultrasound morphology is an established criterion for PCOS, TVU data of ovaries after prolonged androgen exposure are lacking.Study Design, Size, Duration: Prospective, observational, case-control study, in an academic setting, performed in 2014-2015, including 56 FtMs and 80 controls.Participants/materials, Setting, Methods: The study population consisted of adult FtMs treated with long-term testosterone, as part of their cross-sex hormone treatment, and scheduled for sex-reassignment surgery (bilateral salpingo-oophorectomy). Prior to the operation, under anaesthetics TVU measurements (3D transvaginal probe 3-9 MHz; HD11, Philips Ultrasound, Inc.) of the ovaries were performed. The control group consisted of females from a general population who underwent the same TVU and analysis. Antral follicle count (AFC) (3D) and ovarian volume (3D) were calculated using specialized software. PCOM was defined as AFC of 12 or more follicles (2-10 mm) in at least one ovary.Main Results and the Role Of Chance: Prevalence rates of PCOM were not significantly different in the FtMs compared to controls, determined by (3D) TVU: 32.1% (17/53) versus 30.7% (23/75), P = 0.87.Limitations, Reasons For Caution: Testosterone levels in FtMs are supraphysiological, and may not be comparable to the testosterone levels in women with PCOS. However, we applied a unique and ethically acceptable opportunity of exploring the effects of androgens on human ovaries.Wider Implications Of the Findings: This first explorative study shows that long-term exogenous testosterone administration in adult women does not seem to induce PCOM determined by TVU.Study Funding/competing Interest(s): None.Trial Registration Number: The trial was registered at the Dutch Trial Register (www.trialregister.nl), registration number NTR4784. [ABSTRACT FROM AUTHOR]

Study Question: Do patients present different adjustment trajectories during and after IVF treatment?Summary Answer: Most women show resilient trajectories during and after IVF treatment but 37% show temporary or chronic maladjustment during IVF and 10% are maladjusted 11-17 years after treatment.What Is Known Already: Research on patient psychosocial adjustment during treatment has contributed to identifying the most distressful stages of IVF treatment and profiling patients at risk for emotional maladjustment at these specific stages. This knowledge is currently driving the deliverance of psychosocial care at fertility clinics by tailoring it to patients' risk profiles and specific treatment stages. However, current care does not take into consideration how individuals adjust across the entire treatment pathway. This can be assessed by profiling individual adjustment trajectories.Study Design, Size, Duration: A longitudinal cohort study with five assessment moments that combines data from two different studies, the STRESSIVF and OMEGA projects. Participants enrolled in the STRESSIVF study (started IVF in 1998-2000) were assessed before and after the first IVF treatment cycle and 6 months and 2.5 years after the last IVF cycle. A subset participated in the OMEGA project (started IVF in 1995-2000) and reported on their mental health 11-17 years after treatment.Participants/materials, Setting, Methods: Three hundred and forty-eight women participated in the STRESSIVF project and 108 of these in the OMEGA. Anxiety was measured with the State and Trait Anxiety Inventory, depression with the Beck Depression Inventory and mental health with the Mental Health Inventory. Latent class growth mixed modelling was carried out to identify distinct anxiety and depression trajectories over the four STRESSIVF study assessment moments. Multinominal logistic regressions were conducted to investigate predictors of trajectory membership, and stepwise linear regressions were performed to investigate if adjustment trajectories predicted mental health 11-17 years after IVF treatment.Main Results and the Role Of Chance: A total of 67 and 86% of women showed normal levels of anxiety and depression, respectively, throughout treatment (resilient trajectories), 24 and 33% experienced anxiety and depression only during treatment (recovery trajectories), 4.6 and 4.9% experienced anxiety and depression only after treatment (delayed trajectories), and 4.3% showed chronic anxiety (chronic trajectory, not identified for depression). Non-resilient trajectories were associated with unsuccessful treatment, marital dissatisfaction, lack of social support and negative infertility cognitions. One in 10 women had a delayed or chronic trajectory and these trajectories predicted serious mental health impairment 11-17 years after treatment.Limitations, Reasons For Caution: The study only focuses on women. In the OMEGA project adjustment was assessed using a mental health measure. Although we could investigate how trajectories predicted mental health, it would have been preferable to map anxiety and depression trajectories up to 11-17 years after treatment. Missing analysis showed selective dropout from the study but this was accounted for by using mixed models and imputation procedures. Finally, data on other life stressors were not collected; therefore any contribution from these events cannot be assessed.Wider Implications Of the Findings: Fertility health-care providers have been called upon considering their responsibility in supporting patients in the aftermath of treatment. Results show it is possible to profile different groups of at-risk women at the start of the treatment and tailor psychosocial support to risk profile to promote health adjustment during treatment and thereafter.Study Funding/competing Interests: This study was supported by a grant from the Dutch Cancer Society (2006-3631) and the Praeventiefonds (28-3012). No competing interests exist. [ABSTRACT FROM AUTHOR]

Background: Hodgkin lymphoma (HL) survivors are at increased risk for developing valvular heart disease (VHD). We evaluated the determinants of the risk and the radiation dose-response. Methods: A case-control study was nested in a cohort of 1852 five-year HL survivors diagnosed at ages 15 to 41 years and treated between 1965 and 1995. Case patients had VHD of at least moderate severity as their first cardiovascular diagnosis following HL treatment. Control patients were matched to case patients for age, gender, and HL diagnosis date. Treatment and follow-up data were abstracted from medical records. Radiation doses to heart valves were estimated by reconstruction of individual treatments on representative computed tomography datasets. All statistical tests were two-sided. Results: Eighty-nine case patients with VHD were identified (66 severe or life-threatening) and 200 control patients. Aortic (n = 63) and mitral valves (n = 42) were most frequently affected. Risks increased more than linearly with radiation dose. For doses to the affected valve(s) of less than or equal to 30, 31-35, 36-40, and more than 40 Gy, VHD rates increased by factors of 1.4, 3.1, 5.4, and 11.8, respectively (Ptrend < .001). Approximate 30-year cumulative risks were 3.0%, 6.4%, 9.3%, and 12.4% for the same dose categories. VHD rate increased with splenectomy by a factor of 2.3 (P = .02). Conclusions: Radiation dose to the heart valves can increase the risk for clinically significant VHD, especially at doses above 30 Gy. However, for patients with mediastinal involvement treated today with 20 or 30 Gy, the 30-year risk will be increased by only about 1.4%. These findings may be useful for patients and doctors both before treatment and during follow-up. [ABSTRACT FROM AUTHOR]

Background Mammographic screening has led to a proportional shift toward earlier-stage breast cancers at presentation. We assessed whether the method of detection provides prognostic information above and beyond standard prognostic factors and investigated the accuracy of predicted overall and breast cancer–specific survival by the computer tool Adjuvant! among patients with screen-detected, interval, and nonscreening-related carcinomas. Methods We studied 2592 patients with invasive breast cancer who were treated at the Netherlands Cancer Institute from January 1, 1990, through December 31, 2000. Overall and breast cancer–specific survival probabilities among patients with mammographically screen-detected (n = 958), interval (n = 417), and nonscreening-related (n = 1217) breast carcinomas were compared. Analyses were adjusted for clinicopathologic characteristics and adjuvant systemic therapy. Because of gradual implementation of population-based screening in the Netherlands, analyses were stratified a priori according to two periods of diagnosis. All statistical tests were two-sided. Results Screen detection was associated with reduced mortality (adjusted hazard ratio for all-cause mortality = 0.74, 95% confidence interval = 0.63 to 0.87, P < .001, and adjusted hazard ratio for breast cancer–specific mortality = 0.62, 95% confidence interval = 0.50 to 0.78, P < .001, respectively) compared with nonscreening-related detection. The absolute adjusted reduction in breast cancer–specific mortality was 7% at 10 years. The prognostic value of the method of detection was independent of the period of diagnosis and was similar across tumor size and lymph node status categories, indicating its prognostic value beyond stage migration. Adjuvant! underestimated breast cancer–specific survival in patients with screen-detected (−3.2%) and interval carcinomas (−5.4%). Conclusions Screen detection was found to be independently associated with better prognosis for overall and breast cancer–specific survival and to provide prognostic information beyond stage migration among patients with invasive breast cancer. We propose that the method of detection should be taken into account when estimating individual prognosis. [ABSTRACT FROM PUBLISHER]

Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer. [ABSTRACT FROM PUBLISHER]

Information on clinically verified stroke and transient ischemic attack (TIA) following Hodgkin lymphoma is scarce. We quantified the long-term risk of cerebrovascular disease associated with the use of radiotherapy and chemotherapy in survivors of Hodgkin lymphoma and explored potential pathogenic mechanisms. We performed a retrospective cohort study among 2201 five-year survivors of Hodgkin lymphoma treated before age 51 between 1965 and 1995. We compared incidence rates of clinically verified stroke and TIA with those in the general population. We used multivariable Cox regression techniques to study treatment-related factors and other risk factors. All statistical tests were two-sided. After a median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 strokes, 31 TIAs, and 10 with both hA and stroke; median age = 52 years). Most ischemic events were from large-artery atherosclerosis (36%) or cardioembolisms (24%). The standardized incidence ratio for stroke was 2.2 (95% confidence interval [Cl] = 1.7 to 2.8), and for TIA, it was 3.1 (95% Cl = 2.2 to 4.2). The risks remained elevated, compared with those in the general population, after prolonged follow-up. The cumulative incidence of ischemic stroke or TIA 30 years after Hodgkin lymphoma treatment was 7% (95% Cl = 5% to 8%). Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (hazard ratio = 2.5, 95% Cl = 1.1 to 5.6 vs without radiotherapy). Treatment with chemotherapy was not associated with an increased risk. Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not. Patients treated for Hodgkin lymphoma experience a substantially increased risk of stroke and TIA, associated with radiation to the neck and mediastinum. Physicians should consider appropriate risk-reducing strategies. [ABSTRACT FROM AUTHOR]

Background.Survivors of hereditary retinoblastoma have an elevated risk of developing second malignancies, but data on the risk in middle-aged retinoblastoma survivors (ie, those with more than 40 years of follow-up) are scarce. Method.s Data from the Dutch retinoblastoma registry were used to analyze risks of second malignancies in 668 retinoblastoma survivors, diagnosed from 1945 to 2005 (median age = 24.9 years) and classified as having had hereditary or nonhereditary disease based on the presence of family history, bilateral disease, or a germllne RB1 mutation. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) of subsequent cancers in patients with hereditary and nonhereditary disease were estimated by comparison with Dutch sex-, age-, and calendar year-specific rates. Multivariable Cox regression and competing risk analyses were used to determine associations of treatment with risks of second malignancies. All statistical tests were two-sided. Results. After a median follow-up of 21.9 years, the risk of second malignancies in survivors of hereditary retinoblastoma (SIR = 20.4, 95% confidence interval [Cl) = 15.6 to 26.1) far exceeded the risk of survivors of nonhereditary retinoblastoma (SIR = 1.86, 95% Cl = 0.96 to 3.24). Among patients with hereditary disease, treatment with radiotherapy was associated with a further increase in the risk of a subsequent cancer (hazard ratio = 2.81, 95% Cl = 1.28 to 6.19). After 30 years of follow-up, elevated risks f epithelial cancers (lung, bladder, and breast) were observed among survivors of hereditary retinoblastoma. After 40 years of follow-up, the AER of a second malignancy among survivors of hereditary retinoblastoma had increased to 26.1 excess cases per 1000 person-years. The cumulative incidence of any second malignancy 40 years after retinoblastoma diagnosis was 28.0% (95% Cl = 21.0% to 35.0%) for patients with hereditary disease. Conclusion Our analysis of middle-aged hereditary retinoblastoma survivors suggests that these individuals have an excess risk of epithelial cancer. Lifelong follow-up studies are needed to evaluate the full spectrum of subsequent cancer risk in hereditary retinoblastoma survivors. [ABSTRACT FROM AUTHOR]

Background Radiotherapy for breast cancer as delivered in the 1970s has been associated with increased risk of cardiovascular disease, but recent studies of associations with modern regimens have been inconclusive. Few data on long-term cardiovascular disease risk according to specific radiation fields are available, and interaction with known cardiovascular risk factors has not been examined. Methods We studied treatment-specific incidence of cardiovascular disease in 4414 10-year survivors of breast cancer who were treated from 1970 through 1986. Risk of cardiovascular disease in these patients was compared with general population rates and evaluated in Cox proportional hazards regression models. All statistical tests were two-sided. Results After a median follow-up of 18 years, 942 cardiovascular events were observed (standardized incidence ratio = 1.30, 95% confidence interval (CI) = 1.22 to 1.38; corresponding to 62.9 excess cases per 10000 patient-years). Breast irradiation only was not associated with increased risk of cardiovascular disease. However, radiotherapy to either the left or right side of the internal mammary chain was associated with increased cardiovascular disease risk for the treatment period 1970-1 979 (for myocardial infarction, hazard ratio [HR] = 2.55, 95% CI = 1.55 to 4.19; P<.001; for congestive heart failure, HR = 1.72, 95% CI = 1.22 to 2.41; P = .002) compared with no radiotherapy. Among patients who received internal mammary chain radiotherapy after 1979, risk of myocardial infarction declined over time toward unity, whereas the risks of congestive heart failure (HR = 2.66, 95% CI = 1.27 to 5.61; P= .01) and valvular dysfunction (HR = 3.17, 95% CI = 1.90 to 5.29; P<.001) remained increased. Patients who underwent radiotherapy plus adjuvant chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) after 1979 had a higher risk of congestive heart failure than patients who were treated with radiotherapy only (HR = 1.85, 95% CI = 1.25 to 2.73; P = .002). Smoking and radiotherapy together were associated with a more than additive effect on risk of myocardial infarction (HR = 3.04, 95% CI = 2.03 to 4.55; P for departure from additivity = .039). Conclusions Radiotherapy as administered from the 1980s onward is associated with an increased risk of cardiovascular disease. Irradiated breast cancer patients should be advised to refrain from smoking to reduce their risk for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Many women develop breast cancer after treatment for Hodgkin lymphoma (HL) at a young age. We estimated this future risk, taking into account age and calendar year of HL diagnosis, HL treatment information, population breast cancer incidence rates, and competing causes of death. Methods: Relative risks of breast cancer for categories defined by radiation dose to the chest (0, 20–«40 Gy, or ≥40 Gy) and use of alkylating agents (yes or no) were estimated from a case-control study conducted within an international population-based cohort of 3817 female 1-year survivors of HL diagnosed at age 30 years or younger from January 1, 1965, through December 31, 1994. To compute cumulative absolute risks of breast cancer, we used modified standardized incidence ratios to relate cohort breast cancer risks to those in the general population, enabling application of population-based breast cancer rates, and we allowed for competing risks by using population-based mortality rates in female HL survivors. Results: Cumulative absolute risks of breast cancer increased with age at end of follow-up, time since HL diagnosis, and radiation dose. For an HL survivor who was treated at age 25 years with a chest radiation dose of at least 40 Gy without alkylating agents, estimated cumulative absolute risks of breast cancer by age 35, 45, and 55 years were 1.4% (95% confidence interval [CI] = 0.9% to 2.1%), 11.1% (95% CI = 7.4% to 16.3%), and 29.0% (95% CI = 20.2% to 40.1%), respectively. Cumulative absolute risks were lower in women treated with alkylating agents. Conclusions: Breast cancer projections varied considerably by type of HL therapy, time since HL diagnosis, and age at end of follow-up. These estimates are applicable to HL survivors treated with regimens of the past and can be used to counsel such patients and plan management and preventive strategies. Projections should be used with caution, however, in patients treated with more recent approaches, including limited-field radiotherapy and/or ovary-sparing chemotherapy. [ABSTRACT FROM AUTHOR]

The authors assessed the accuracy of cause(s) of subfertility as reported by women in a self-administered questionnaire in comparison with medical record information, in a nationwide cohort study of women receiving in vitro fertilization treatment in the Netherlands (n = 9,164) between 1983 and 1995. Validity was expressed as sensitivity and specificity, and reliability was expressed by the kappa statistic and overall agreement between self-reports and medical records for various subfertility categories. The sensitivity for subfertility attributed to tubal, male, hormonal, cervical, uterine, and idiopathic factors and for endometriosis was 84%, 78%, 65%, 40%, 46%, 59%, and 83%, respectively. The corresponding kappas were 0.79, 0.71, 0.38, 0.34, 0.13, 0.50, and 0.52, respectively. For 54% of all women who reported two or more causes of subfertility, the medical record revealed only one major factor. Conversely, for 43% of all women whose subfertility was attributed to two or more major factors in the record, only one factor was reported by the women. Older age at the time of filling out the questionnaire, low educational level, long duration of subfertility, and pre–in vitro fertilization treatment were associated with less accurate reporting. The results indicate that the validity of self-reports for tubal and male subfertility is satisfactory. For unexplained subfertility, the validity is moderate; for other causes of subfertility and when two causes of subfertility play a role, the validity is low. [ABSTRACT FROM AUTHOR]

F cycles. RESULTS: The unadjusted results showed a slight but non‐significant decrease in the number of retrieved oocytes over six IVF cycles. The change in cycle 6 compared with cycle 1 was –0.06 oocytes (5.8% decrease) (P = 0.21). When adjusting for the number of ampoules and the stimulation protocol (fertility drug used combined with use of GnRH agonists), there was a considerable and highly significant decrease from cycle 1 to cycle 6 [change in cycle 6 compared with cycle 1: –0.19 oocytes (17.4% decrease), (P < 0.0001)]. However, when adjusting for age of the women, this decrease almost completely disappeared [change in cycle 6 compared with cycle 1: –0.05 oocytes (5% decrease), (P = 0.50)]. CONCLUSION: The results suggest that there is no decrease in the number of retrieved oocytes over subsequent cycles when simultaneously accounting for the increasing age of the women, differences in the number of ampoules of gonadotrophins used, type of stimulation protocol and year of IVF treatment. [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]

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.

Background: Our aim was to examine whether women who had a low number of retrieved oocytes at their first IVF attempt reach the menopausal transition and/or the natural menopause earlier than women of similar ages with a high number of retrieved oocytes.Methods: We conducted a retrospective cohort study among women in The Netherlands who received IVF treatment between 1983 and 1995. For the present study, we selected all cohort members who had a regular menstrual cycle at the time of the first visit to the gynaecologist (n = 4601). After a median follow-up of 5.5 years, 3871 (84%) women still had a regular menstrual cycle pattern, 547 (12%) women had entered the menopausal transition (i.e. no menses for 3-11 months, use of HRT or irregular menstrual cycles) and 27 (1%) women had reached natural menopause. We examined whether the quantity and the quality of the retrieved oocytes were related to an early menopausal transition and early menopause. The live birth rate per embryo transfer was used as indicative of the quality of the oocytes.Results: The age-adjusted odds ratio (OR) for having entered the menopausal transition/natural menopause for women with a poor response (0-3 oocytes) at their first IVF attempt was 3.1 [95% confidence interval (CI) 2.4-3.8] compared with women with a normal response (>3 oocytes). Women who were stimulated with gonadotrophins during IVF treatment but did not undergo an IVF puncture because of an anticipated poor response (cancelled IVF cycle) had an age-adjusted OR of 3.2 (95% CI 2.3-4.3). There was no significant difference in the odds of reaching the menopausal transition/natural menopause, after adjustment for age and the number or retrieved oocytes, between women who did and did not have a live birth following their first embryo transfer (OR = 1.3; 95% CI 0.95-1.7).Conclusions: These results indicate that a low remaining quantity of oocytes, as reflected by a low number of retrieved oocytes at first IVF treatment, is an important predictor of the risk of an early menopausal transition/natural menopause. The quality of the oocytes did not affect the risk of an early menopausal transition/natural menopause once the number of retrieved oocytes had been taken into account. Our findings support the concept that the number of remaining follicles in the ovaries is one of the main aspects of reproductive ageing. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use.Methods: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided.Results: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment.Conclusions: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco. [ABSTRACT FROM AUTHOR]

Presents information on a study which examined the association between physical activity and the risk of breast cancer on women in Netherlands. Methodology; Results; Discussion on the study findings.

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.

To investigate whether breast tumors developing through a pathway with p53 protein overexpression (p53+) show different risk factor associations compared with breast tumors without p53 overexpression (p53−), the authors determined p53 overexpression in tissue sections of 528 patients with invasive breast cancer by using immunohistochemistry. These patients and 918 healthy controls aged 20–54 years participated in a Netherlands population-based case-control study on oral contraceptives in 1986–1989. A total of 142 tumors (27%) demonstrated clear p53 overexpression (p53+). Most risk factors did not show different associations with p53+ and p53− tumors. However, use of oral contraceptives for 9 or more years was associated with a 2.5-fold increase in the risk of p53+ tumors (95% confidence interval 1.4–4.4; test for trend with months of use, p = 0.01), whereas such use increased the risk of p53− tumors only 1.4-fold (95% confidence interval 0.9–2.1; test for trend, p = 0.06). Prolonged lactation (≥25 weeks) was associated with a 40% reduction in risk of p53+ tumors (odds ratio = 0.6; 95% confidence interval 0.3–1.0; test for trend with weeks of lactation, p = 0.09), whereas the risk of p53− tumors was not associated with lactation. The authors conclude that p53+ and p53− breast tumors are not associated with very distinct risk profiles but that the stronger associations of p53+ tumors with oral contraceptive use and lactation suggest differences in risks that deserve further investigation. If these findings can be confirmed and possible molecular mechanisms explored, this may help to elucidate the associations between these risk factors and breast cancer in general. Am J Epidemiol 1996; 144: 924-33. [ABSTRACT FROM AUTHOR]

A number of polyclonal antibodies specific for DNA modified with (±)-7,8-dihydroxy--9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) were obtained from the sera of New Zealand white rabbits immunized with BPDE-DNA, complexed with methylated bovine serum albumin (mBSA). Monoclonal antibodies were developed by fusion of mouse myeloma cells with spleen cells isolated from BALB/c mice immunized with the same complex of BPDE-DNA and mBSA. These antibodies have been characterized for specificity in a highly sensitive, enzyme-linked immunosorbent assay (ELISA). All antibodies showed a very high affinity for single-stranded BPDE-DNA, but had lower affinity towards native BPDE-DNA. The affinity for the free mononucleoside BPDE-dG was at least 100-fold lower than that for BPDE-DNA, and no affinity was detected for BP tetrols or DNA modified with -acetoxy--acetyl-2-aminofluorene. A high cross reactivity was observed with DNA modified with (±)--1,2-dihydroxy--3,4-epoxy-1,2,3,4-tetrahydrochrysene. Using five different antibodies, monoclonal or polyclonal, we observed that the antibody affinity for BPDE-DNA was dependent on the level of modification; in the competitive ELISA as little as 4 fmol BPDE-DNA (50 pmol/μg) was sufficient for 50% inhibition with our best antisera, but 17 fmol of the adduct was required when [H]BPDE-DNA of low modification (1–10 fmol/μg) was used as inhibitor. When samples of [H]BP-DNA isolated from the livers of mice, treated i.p. with different doses of [H]BP were examined by competitive ELISA and calibrated with [H]BPDE-DNA of low modification (1–10 fmol/μg), binding values calculated from the immunoassay were in good agreement with those obtained from radioactivity measurements. In contrast, when this DNA was quantitated in competitive ELISA using highly modified BPDE-DNA as standards, values by ELISA were 20–40% of those obtained by radioactivity. These results indicate that the use of serially diluted BPDE-DNA of high modification as standard competitor in the ELISA will lead to erroneous results in the measurement of adducts in DNAs modified to a low extent (biological samples). The property of antisera specific for BP-DNA, recognizing highly modified DNA more efficiently than DNA modified to a low extent, may be common to all antisera elicited against highly modified DNA immunogens. Therefore we conclude that antibody affinity must be tested also with DNA samples of low modification, obtained either or . [ABSTRACT FROM PUBLISHER]

We have undertaken a study among coke-oven workers to test the feasibility of an enzyme-linked immunosorbent assay with anti-trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahy-dro-benzo[]pyrene-DNA antibodies for monitoring occupational exposure to poly cyclic aromatic hydrocarbons (PAH). Coke-oven workers are occupationally exposed to relatively high levels of PAH and are at increased risk for lung cancer. Three blood samples were collected from each of the 56 coke-oven workers exposed to PAH and 44 unexposed workers employed in a steel-rolling factory of the same plant. In addition, PAH levels were measured in ambient air by personal sampling, and the excretion of 1-hydroxypyrene in urine was also measured on 3 consecutive working days. All participants were interviewed regarding working conditions, personal hygiene, and smoking habits. The results showed that the coke-oven workers were exposed to substantial concentrations of atmospheric PAH [1–186 μg/m), including benzo[]pyrene (0.1–7.8 μg/m) and pyrene (0.6–23.6 μg/m). Both benzo[]pyrene and pyrene were shown to be representative for the whole group of PAH. Forty-seven percent of the coke-oven workers had detectable levels of PAH–DNA adducts in their white blood cells, compared with 30% of the controls. In both groups, smokers had significantly higher levels of PAH-DNA adducts than did nonsmokers. At one site, we found the correlation positive between DNA adducts and the duration of exposure (= .47, = .005). Generally, the correlation was not significant between PAH–DNA adducts in blood and the concentration of PAH in the air and 1-hydroxypyrene in urine. [J Natl Cancer Inst 82: 927–933, 1990] [ABSTRACT FROM PUBLISHER]

CT scans and subsequent cancer risk in the Netherlands. Tween pediatric CT scans and subsequent risk of leukemia and brain tumors: And risk of leukemia and brain tumors by cancer susceptibility syndromes. There unmeasured indication bias in radiation-related cancer risk. [Extracted from the article]

The article presents the response of the authors to a reaction by D. L. Longo to their study on the increased risk of stroke and transient ischemic attack following Hodgkin lymphoma. Longo made a criticism on the use of radiotherapy in the treatment of Hodgkin lymphoma. Longo further mentioned that the effectivity of chemotherapy may be compared to combined modality treatment. The authors argue that Longo overestimated the effectivity of chemotherapy alone in the treatment and underestimated its toxicity.

Presents a letter to the editor about the use of radiation therapy in the treatment of Hodgkin's disease.

Comments on an article on the association between oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers, published in a previous issue of the 'Journal of the National Cancer Institute.' No material association between cigarette smoking and breast cancer risk; Potential problems in design and interpretation.

Background: Hodgkin lymphoma (HL) survivors are at increased risk of developing valvular heart disease (VHD). We evaluated the determinants of the risk and the radiation dose-response.Methods: A case-control study was nested in a cohort of 1852 five-year HL survivors diagnosed at ages 15 to 41 years and treated between 1965 and 1995. Case patients had VHD of at least moderate severity as their first cardiovascular diagnosis following HL treatment. Control patients were matched to case patients for age, gender, and HL diagnosis date. Treatment and follow-up data were abstracted from medical records. Radiation doses to heart valves were estimated by reconstruction of individual treatments on representative computed tomography datasets. All statistical tests were two-sided.Results: Eighty-nine case patients with VHD were identified (66 severe or life-threatening) and 200 control patients. Aortic (n = 63) and mitral valves (n = 42) were most frequently affected. Risks increased more than linearly with radiation dose. For doses to the affected valve(s) of less than or equal to 30, 31-35, 36-40, and more than 40 Gy, VHD rates increased by factors of 1.4, 3.1, 5.4, and 11.8, respectively (P trend < .001). Approximate 30-year cumulative risks were 3.0%, 6.4%, 9.3%, and 12.4% for the same dose categories. VHD rate increased with splenectomy by a factor of 2.3 (P = .02).Conclusions: Radiation dose to the heart valves can increase the risk of clinically significant VHD, especially at doses above 30 Gy. However, for patients with mediastinal involvement treated today with 20 or 30 Gy, the 30-year risk will be increased by only about 1.4%. These findings may be useful for patients and doctors both before treatment and during follow-up. [ABSTRACT FROM AUTHOR]

Background Recent concerns about potential overdiagnosis and overtreatment of ductal carcinoma in situ of the breast (DCIS) render evaluation of late effects of treatment, such as cardiovascular disease (CVD), of great importance. We studied cardiovascular morbidity and mortality in a large population-based cohort of DCIS patients. Methods Data on all incident DCIS case patients in the Netherlands between 1989 and 2004 who were diagnosed before the age of 75 years were obtained (n = 10468). CVD data was acquired through linkage with population-based registries. Standardized mortality ratios were calculated by comparing mortality in our cohort with that in the Dutch female population, taking into account person-years of observation. Within-cohort comparisons were based on multivariable competing-risk regression. Results Compared with the general population, 5-year survivors of DCIS had a similar risk of dying due to any cause (standardized mortality ratio [SMR] = 1.04; 95% confidence interval [CI] = 0.97 to 1.11) but a lower risk of dying of CVD (SMR = 0.77; 95% CI = 0.67 to 0.89). No difference in CVD risk was found when comparing 5-year survivors treated with radiotherapy with those treated with surgery only. Left-sided vs right-sided radiotherapy also did not increase this risk (hazard ratio [HR] = 0.94; 95% CI = 0.67 to 1.32). In a subgroup analysis of all DCIS patients diagnosed between 1997 and 2005, we were able to account for history of CVD and did not observe a risk difference between treatment groups (left-sided vs right-sided radiotherapy: HR = 0.94; 95% CI = 0.68 to 1.29). Conclusions After a median follow-up of 10 years, we did not find an increased risk for cardiovascular morbidity or mortality after radiotherapy for DCIS when comparing surgery and radiotherapy vs surgery only, nor when comparing radiotherapy for left-sided vs right-sided DCIS. Compared with the general population, DCIS patients have a decreased risk of cardiovascular death, independent of treatment. [ABSTRACT FROM PUBLISHER]