Elham Kharazmi

Pregnancy loss and risk of cardiovascular disease: a prospective population-based cohort study (EPIC-Heidelberg)

Objectives To examine whether pregnancy loss (miscarriage, abortion or stillbirth) is associated with a higher risk of myocardial infarction (MI) and stroke. Design Population-based prospective cohort study. Setting The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort in Heidelberg, Germany (mean follow-up 10.8u2005years). Participants All 11u2008518 women who had ever been pregnant (aged 35–66). Results Out of the participants, 2876 (25%) had at least one miscarriage, 2053 (18%) had at least one abortion and 209 (2%) had at least one stillbirth. During the follow-up, 82 cases of MI and 112 of stroke (confirmed by medical records) occurred in these women. Each stillbirth increased the risk of MI 2.65 times (95% CI for age-adjusted HR 1.37 to 5.12; HR adjusted for age, smoking, alcohol consumption, body mass index, waist to hip ratio, physical activity, education, number of pregnancies, hypertension, hyperlipidaemia and diabetes mellitus: HR 2.32 95% CI 1.19 to 4.50, 95% CI). Recurrent miscarriage (>3) was associated with about nine times higher risk of MI (age-adjusted HR=8.90, 95% CI 3.18 to 24.90; fully adjusted HR 5.06, 95% CI 1.26 to 20.29). No significant association was found between abortion and MI or between any type of pregnancy loss and stroke. Conclusions These results suggest that women who experience spontaneous pregnancy loss are at a substantially higher risk of MI later in life. Recurrent miscarriage and stillbirth are strong sex-specific predictors for MI and thus should be considered as important indicators for cardiovascular risk factors monitoring and preventive measures. Further research is suggested to elucidate underlying risk factors of pregnancy loss that at the same time strongly predispose to cardiovascular disease.

Familial risk of early and late onset cancer: nationwide prospective cohort study

Objective To determine whether familial risk of cancer is limited to early onset cases. Design Nationwide prospective cohort study. Setting Nationwide Swedish Family-Cancer Database. Participants All Swedes born after 1931 and their biological parents, totalling >12.2 million individuals, including >1.1 million cases of first primary cancer. Main outcome measures Familial risks of the concordant cancers by age at diagnosis. Results The highest familial risk was seen for offspring whose parents were diagnosed at an early age. Familial risks were significantly increased for colorectal, lung, breast, prostate, and urinary bladder cancer and melanoma, skin squamous cell carcinoma, and non-Hodgkin’s lymphoma, even when parents were diagnosed at age 70-79 or 80-89. When parents were diagnosed at more advanced ages (≥90), the risk of concordant cancer in offspring was still significantly increased for skin squamous cell carcinoma (hazard ratio 1.9, 95% confidence interval 1.4 to 2.7), colorectal (1.6, 1.2 to 2.0), breast (1.3, 1.0 to 1.6), and prostate cancer (1.3, 1.1 to 1.6). For offspring with a cancer diagnosed at ages 60-76 whose parents were affected at age <50, familial risks were not significantly increased for nearly all cancers. Conclusion Though the highest familial risks of cancer are seen in offspring whose parents received a diagnosis of a concordant cancer at earlier ages, increased risks exist even in cancers of advanced ages. Familial cancers might not be early onset in people whose family members were affected at older ages and so familial cancers might have distinct early and late onset components.

Effect of a Detailed Family History of Melanoma on Risk for Other Tumors: A Cohort Study Based on the Nationwide Swedish Family-Cancer Database

Using the Swedish Family-Cancer Database, we assessed the effect of a detailed family history of melanoma on risk for other tumors (other than melanoma). Among 248,011 individuals with a family history of melanoma, 43,931 other tumors were diagnosed from 1958 to 2010. Standardized incidence ratios (SIRs) were calculated for other tumors in patients who had a family history of melanoma, as compared with those without. A detailed family history of melanoma was investigated according to an increasing number of melanomas in either 1 or ≥ 2 first-degree relatives (FDRs). Associations were considered significant when there were at least two independently significant SIRs or a statistically significant trend of increasing SIRs with increasing number of melanomas in relatives. The applied criteria for significant associations were convincingly met by pancreatic, breast, prostate, and squamous cell skin tumors and ependymoma, although there was significant but not overwhelming evidence for thyroid, parathyroid, lung, and unknown primary tumors, meningioma, mycosis fungoides, and myeloid leukemia. To our knowledge, no studies have previously considered a detailed family history of melanoma and the use of internal validation to assess familial associations of melanoma with other tumors. We established associations for 12 other tumors, and the associations for myeloid leukemia, parathyroid, and unknown primary tumors are, to our knowledge, previously unreported.

Miscarriage and risk of cardiovascular disease

In a nationally representative sample (the Health 2000 Survey) comprising 3,937 Finnish women aged 30–99 years, we examined the association of miscarriage (assessed by questionnaire) with risk of cardiovascular disease (assessed by physicians examination and linkages to hospital discharge and drug reimbursement registers). We considered age, smoking, body mass index, waist/hip ratio, physical activity, education, number of previous pregnancies, blood pressure, and fasting blood glucose and cholesterol as potentially confounding factors in the analysis. In women 50–74 years of age who had experienced pregnancy, history of miscarriage tended to be associated with a higher risk of myocardial infarction (age‐adjusted odds ratio (OR): 2.1, 95% confidence interval (CI): 1.0–4.3), and the risk increased significantly with the number of miscarriages (age‐adjusted OR per miscarriage: 1.4, 95% CI: 1.1–1.8). These results suggest that women who experience repeated miscarriages may be at an increased risk of cardiovascular disease later in life.

Familial risk of small intestinal carcinoid and adenocarcinoma.

BACKGROUND & AIMSnSmall intestinal cancer (SIC) is rare, and its etiology is poorly understood. We compared clusters of families with SICs of different histologic subtypes.nnnMETHODSnBy using the nationwide family cancer data sets of Sweden and Finland, we identified a cohort of 9964 first-degree relatives of 1799 patients with SIC, diagnosed from 1961 through 2009. Data were collected from time periods as long as 47 years (mean, 35.4 y), and cancer incidence was determined. Standardized incidence ratios (SIRs) were calculated and stratified by sex, age, time period, and cancer type, using the incidence rates for the entire national population as the reference.nnnRESULTSnAmong the 1799 SIC cases, 1.1% had a sibling with SIC, so the SIR was 11.8 (95% confidence interval [CI], 7.2-18.2); 1.1% had a parent or child with SIC (SIR, 3.5; 95% CI, 2.0-5.6). The SIR of concordant carcinoid histology of SIC among siblings was 28.4 (95% CI, 14.7-49.6; n = 12) and in parent-child pairs was 9.9 (95% CI, 5.4-16.6; n = 14). The familial risk of concordant histologic subtypes increased for siblings diagnosed with adenocarcinoma, but only 2 familial cases were identified. In family members of patients with SIC of the adenocarcinoma subtype, risks of colorectal and bladder cancer were modestly but significantly increased compared with the general population. Family members of patients with SIC of the carcinoid subtype had an increased risk for kidney cancer and polycythemia vera.nnnCONCLUSIONSnBased on data from our population-based study, first-degree relatives of patients with small intestinal carcinoid tumors have developed these tumors with high incidence. Because of the rareness of this tumor, the absolute risk remains moderate even within families. Gastroenterologists could inform patients with small intestinal carcinoids about the familial risk and encourage counseling for their first-degree relatives. Studies are needed to identify genetic factors that affect susceptibility to SIC.

Does pregnancy or pregnancy loss increase later maternal risk of diabetes

Evidence that childbearing is associated with future development of diabetes remains conflicting and the role of pregnancy loss in this association has not been investigated. We aimed to examine whether pregnancy and/or pregnancy loss (miscarriage, abortion, or stillbirth) are associated with maternal higher risk of diabetes later in life, using a population-based prospective cohort study (mean follow-upxa0=xa010.7xa0years), including 13,612 women (aged 35–65 at baseline). We found pregnancy per se did not change the risk of diabetes after considering the effect of education, smoking, alcohol consumption, physical activity, BMI, waist/hip ratio, hypertension, and hyperlipidemia (fully-adjusted OR: 1.04, 95xa0% CI: 0.82–1.31). Having more than four live births was associated with around two times higher risk of diabetes later in life (fully-adjusted OR: 1.77, 95xa0% CI: 1.12–2.80). Having more than two miscarriages was associated with about two-fold higher risk of diabetes (fully-adjusted Odd ratio (OR): 1.85, 95xa0% CI: 1.17–2.93). After further adjustment for parity, the higher risk of diabetes in those who had history of more than two miscarriages did not change substantially (OR: 1.82; 95xa0% CI: 1.15–2.88), but the association between more than four live births and diabetes disappeared when the role of pregnancy loss was considered (fully-adjusted HR: 1.06; 95xa0% CI: 0.54–2.08). No significant association was found between abortion, stillbirth and risk of maternal diabetes. Pregnancy per se did not increase risk of diabetes. Women who experience more than two miscarriages are at around two times higher risk of diabetes later in life. The association between high parity and diabetes is mediated by history of miscarriages and known risk factors of diabetes. The underlying reason for association between miscarriage and diabetes needs further investigation.

Higher risk of primary cancers after polycythaemia vera and vice versa

To our knowledge, there are no population-based epidemiological data concerning whether individuals with polycythaemia vera (PV) are at an elevated risk of developing solid tumours and vice versa. This study aimed to systematically quantify the risk of all primary cancers after PV and vice versa for the first time. Since the mid-1950s, patients with haematological disorders in Sweden are primarily diagnosed, treated, and followed clinically by physicians at hospital-based haematology/oncology centres and each incident case of cancer is reported to the nationwide Swedish Cancer Registry. In Sweden, the criteria for PV diagnosis have changed from those of the Polycythaemia Vera Study Group (mid-1970s–late-1990s) to the World Health Organization criteria (Landgren et al, 2008). The Swedish Family Cancer Database contains >11Æ8 million individuals born after 1932, 1 062 820 survivors of first primary cancers including 3530 patients with PV, and >110 000 second primary cancers (Hemminki et al, 2010). The International Classification of Disease, 7th revision was used to retrieve patients with first and second primary cancer from the Swedish Cancer Registry (1958–2006). Standardized incidence ratios (SIRs, adjusted for covariates age group, sex, socioeconomic status, residential region, and period) and 95% confidence intervals (95% CIs, assuming a Poisson distribution) were calculated using sas software version 9.2 (SAS Institute Inc., Cary, NC, USA). In line with other studies (Landolfi et al, 2010), we confirmed the markedly higher risk of myelofibrosis (40 times) and leukaemia (13–25 times) in PV patients (Table I). The molecular mechanisms of this association have been discussed elsewhere (Vannucchi et al, 2009a), and so this report concentrates mainly on solid tumours. We found a significant higher risk of PV after thyroid cancer (men six times; women two times; Table I), which showed a long lag time between diagnosis of thyroid cancer and subsequent PV (median 13 years) in line with cancers after radiotherapy. To our knowledge, there is no similar finding in the literature. Moreover, PV is known to be highly associated with leukaemia and the risk of leukaemia is higher after radioiodine therapy for thyroid cancer, therefore PV occurrence after thyroid cancer might be related to radiotherapy treatment for the solid tumour. We found a higher risk of parathyroid tumours (mostly adenomas) after PV (males SIR = 5Æ4, 95% CI = 2Æ0–11Æ8; females 1Æ6, 0Æ6–3Æ2) and more than twice the risk of PV after parathyroid adenoma. These associations are in line with a few studies suggesting a link between hyperparathyroidism and the growth of haematopoietic stem cells (Weinstein, 1991; Pizzolito et al, 1997). One study suggested that nonparaneoplastic hypercalcaemia due to primary hyperparathyroidism may increase the risk of these malignancies (Pizzolito et al, 1997). The risk of kidney cancer was 2Æ4 times higher among PV survivors. A series of 300 PV patients treated and evaluated over 12 years showed an abnormal association between PV and kidney cancer (Najean, 1991). Our study confirmed and quantified this association in a substantially larger sample. The risk of cutaneous melanoma among survivors of PV was about twice the level in the general population and vice versa. There is only one relevant case report, of a man with three melanomas and a subsequent PV (Hayne et al, 1985). This two-way association warrants further investigation on the potential effect of sun exposure on the development of PV. After PV, the risk of non-melanoma skin cancers (mostly squamous cell carcinoma) doubled, while no association was found for non-melanoma skin cancer following PV. This is consistent with other studies reporting squamous cell carcinoma as the most severe cutaneous side effect after treatment of PV patients with hydroxycarbamide (Sanchez-Palacios & Guitart, 2004). It is important to ensure that physicians and patients are aware of the specific risks of this treatment. PV patients that receive hydroxycarbamide or ultraviolet therapy should be monitored closely by dermatologists for early detection and treatment of cutaneous side-effects. A 14Æ7 times higher incidence of PV was found after adrenal tumours only in males (95% CI = 1Æ8–53Æ0). Risk of multiple myeloma after PV was significantly elevated in females (2Æ7, 1Æ1–5Æ5), but not in males (0Æ9, 0Æ2–2Æ5). These associations need to be confirmed in other independent datasets. In contrast with an Italian study of 345 patients (Vannucchi et al, 2009b), we did not find an increased risk of nonHodgkin lymphoma after PV. This association needs further investigation in an independent dataset with larger sample size and high diagnostic accuracy. Although providing 95% CI for SIRs minimizes to some extent the role of chance in our findings, a limitation of this study could be the possibility of chance findings due to multiple comparisons. However, the study has the strength that two independent analyses were performed for each cancer pair, one among PV survivors to find their risk of developing other types of malignancies, and the other among other cancer survivors to estimate risk of PV. Therefore, if both showed increase, the findings are most likely unbiased and indicative of Correspondence

Cancer Risk in Relatives of Testicular Cancer Patients by Histology Type and Age at Diagnosis: A Joint Study from Five Nordic Countries

BACKGROUNDnNone of the population-based epidemiologic studies to date has had a large enough sample size to show the familial risk of testicular cancer (TC) by age at diagnosis for patients and their relatives or for rare histologic subtypes.nnnOBJECTIVEnTo estimate absolute and relative risks of TC in relatives of TC patients by age at diagnosis in patients and their relatives and histological subtypes.nnnDESIGN, SETTING, AND PARTICIPANTSnIn a joint population-based cohort study, 97 402 first-degree relatives of 21 254 TC patients who were diagnosed between 1955 and 2010 in five European countries were followed for cancer incidence.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnStandardized incidence ratios (SIRs) were estimated using histology-, age-, period-, and country-specific incidence rates as references. Lifetime cumulative risks were also calculated.nnnRESULTS AND LIMITATIONSnThe lifetime cumulative risk of TC in brothers of a patient with TC was 2.3%, which represents a fourfold increase in risk (SIR 4.1, 95% confidence interval [CI] 3.6-4.6) compared to the general population. TC in a father increased the risk by up to twofold in his son (95% CI 1.7-2.4; lifetime risk 1.2%) and vice versa. When there were two or more TC patients diagnosed in a family, the lifetime TC risk for relatives was 10-11%. Depending on age at diagnosis, twins had a 9-74% lifetime risk of TC. Family history of most of the histologic subtypes of TC increased the risk of concordant and most discordant subtypes. There was a tendency toward concordant age at diagnosis of TC among relatives.nnnCONCLUSIONSnThis study provides clinically relevant age-specific cancer risk estimates for relatives of TC patients. Familial TC patients tended to develop TC at an age close to the age at diagnosis of TC among their relatives, which is a novel finding of this study.nnnPATIENT SUMMARYnThis joint European population study showed that sons and brothers of testicular cancer patients are at higher risk of developing this cancer at an age close to the age at diagnosis of their relatives.

Familial risks for childhood acute lymphocytic leukaemia in Sweden and Finland: far exceeding the effects of known germline variants

Despite recent successes in the identification of genetic susceptibility loci, no familial risk has been demonstrated for childhood acute lymphoblastic leukaemia (ALL). We identified 3994 childhood ALL cases from two cancer registries; family members were obtained from population registers. The standardized incidence ratio for familial risk in singleton siblings and twins was 3·2 (95% confidence interval 1·5–5·9) and 162·6 (70·2–320·4), respectively. The present data constitute the first demonstration of familial risk for singleton siblings; the high risk for twins is believed to result from shared prenatal blood circulation. The data suggest that currently unidentified genetic loci underlie these observed familial effects.

Risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex: A joint study from five Nordic countries

We aimed to provide the familial risk of classical Hodgkin lymphoma (HL) by relationship, histology, age at diagnosis, and sex. A cohort of 57,475 first-degree relatives of 13,922 HL patients diagnosed between 1955 and 2009 in 5 European countries was observed for HL incidence. The overall lifetime cumulative risk (CR) of HL in first-degree relatives of a patient with HL was 0.6%, which represents a threefold (standardized incidence ratio [SIR], 3.3; 95% confidence interval [CI], 2.8-3.9) increased risk over the general population risk. The risk in siblings (6.0-fold; 95% CI, 4.8- to 7.4-fold) was significantly higher than in parents and/or children (2.1-fold; 95% CI, 1.6- to 2.6-fold). Very high lifetime risk of HL was found for those with multiple affected first-degree relatives (13-fold; 95% CI, 2.8- to 39-fold) and for same-sex twins (57-fold; 95% CI, 21- to 125-fold). We found high familial risks between some concordant histologic subtypes of HL such as lymphocyte-rich (81-fold; 95% CI, 30- to 177-fold) and nodular sclerosis (4.6-fold; 95% CI, 2.9- to 7.0-fold) and also between some discordant subtypes. The familial risk in sisters (9.4-fold; 95% CI, 5.9- to 14-fold) was higher than in brothers (4.5-fold; 95% CI, 2.9- to 6.7-fold) or unlike-sex siblings (5.9-fold; 95% CI, 4.3- to 8.1-fold). The lifetime risk of HL was higher when first-degree relatives were diagnosed at early ages (before age 30 years). This study provides tangible absolute risk estimates for relatives of HL patients, which can be used as a sex-, age-, and family history-based risk calculator for classical HL by oncologists and genetic counselors.