Gallstones, Cholecystectomy, and Kidney Cancer: Observational and Mendelian Randomization Results Based on Large Cohorts.

BACKGROUND & AIMS: Gallstones (cholelithiasis) constitute a major health burden with high costs related to surgical removal of the gallbladder (cholecystectomy), generally indicated for symptomatic gallstones. The association between gallstones and cholecystectomy and kidney cancer is controversial. We comprehensively investigated this association, considering age at cholecystectomy and time from cholecystectomy to kidney cancer diagnosis, and assessed the causal effect of gallstones on kidney cancer risk by Mendelian randomization (MR). METHODS: We compared the risk of kidney cancer in cholecystectomized and noncholecystectomized patients (16.6 million in total) from the Swedish nationwide cancer, census, patient, and death registries using hazard ratios (HRs). For 2-sample and multivariable MR, we used summary statistics based on 408,567 UK Biobank participants. RESULTS: During a median follow-up of 13 years, 2627 of 627,870 cholecystectomized Swedish patients developed kidney cancer (HR, 1.17; 95% CI, 1.12-1.22). Kidney cancer risk was particularly increased in the first 6 months after cholecystectomy (HR, 3.79; 95% CI, 3.18-4.52) and in patients cholecystectomized before age 40 years (HR, 1.55; 95% CI, 1.39-1.72). MR results based on 18,417 patients with gallstones and 1788 patients with kidney cancer from the United Kingdom revealed a causal effect of gallstones on kidney cancer risk (9.6% risk increase per doubling in gallstone prevalence; 95% CI, 1.2%-18.8%). CONCLUSIONS: Both observational and causal MR estimates based on large prospective cohorts support an increased risk of kidney cancer in patients with gallstones. Our findings provide solid evidence for the compelling need to diagnostically rule out kidney cancer before and during gallbladder removal, to prioritize kidney cancer screening in patients undergoing cholecystectomy in their 30s, and to investigate the underlying mechanisms linking gallstones and kidney cancer in future studies.

Risk of prostate cancer in relatives of prostate cancer patients in Sweden: A nationwide cohort study.

BACKGROUND: Evidence-based guidance for starting ages of screening for first-degree relatives (FDRs) of patients with prostate cancer (PCa) to prevent stage III/IV or fatal PCa is lacking in current PCa screening guidelines. We aimed to provide evidence for risk-adapted starting age of screening for relatives of patients with PCa. METHODS AND FINDINGS: In this register-based nationwide cohort study, all men (aged 0 to 96 years at baseline) residing in Sweden who were born after 1931 along with their fathers were included. During the follow-up (1958 to 2015) of 6,343,727 men, 88,999 were diagnosed with stage III/IV PCa or died of PCa. The outcomes were defined as the diagnosis of stage III/IV PCa or death due to PCa, stratified by age at diagnosis. Using 10-year cumulative risk curves, we calculated risk-adapted starting ages of screening for men with different constellations of family history of PCa. The 10-year cumulative risk of stage III/IV or fatal PCa in men at age 50 in the general population (a common recommended starting age of screening) was 0.2%. Men with ≥2 FDRs diagnosed with PCa reached this screening level at age 41 (95% confidence interval (CI): 39 to 44), i.e., 9 years earlier, when the youngest one was diagnosed before age 60; at age 43 (41 to 47), i.e., 7 years earlier, when ≥2 FDRs were diagnosed after age 59, which was similar to that of men with 1 FDR diagnosed before age 60 (41 to 45); and at age 45 (44 to 46), when 1 FDR was diagnosed at age 60 to 69 and 47 (46 to 47), when 1 FDR was diagnosed after age 69. We also calculated risk-adapted starting ages for other benchmark screening ages, such as 45, 55, and 60 years, and compared our findings with those in the guidelines. Study limitations include the lack of genetic data, information on lifestyle, and external validation. CONCLUSIONS: Our study provides practical information for risk-tailored starting ages of PCa screening based on nationwide cancer data with valid genealogical information. Our clinically relevant findings could be used for evidence-based personalized PCa screening guidance and supplement current PCa screening guidelines for relatives of patients with PCa.

Risk-adapted starting age of breast cancer screening in women with a family history of ovarian or other cancers: A nationwide cohort study.

BACKGROUND: There is a lack of evidence-based recommendations for the age at which women with a family history of cancers other than breast cancer should start breast cancer screening. METHODS: Using Swedish family cancer data sets, the authors conducted a nationwide cohort study including 5,099,172 Swedish women born after 1931 (follow-up, 1958-2015). Accounting for calendar time, they calculated the relative risk of breast cancer for women with a family history of a discordant cancer in 1 first-degree relative. Furthermore, the authors used 10-year cumulative risk to determine the ages at which women with a family history of discordant cancer reached risk thresholds at which women in the general population were recommended to start breast cancer screening. RESULTS: A family history of cancer at 15 sites was associated with an increased risk of breast cancer. Among women younger than 50 years, the highest risk of breast cancer was observed for those with a family history of ovarian cancer (standardized incidence ratio, 1.44; 95% confidence interval, 1.26-1.64). In these women, the risk of breast cancer associated with a family history at other cancer sites ranged from 1.08-fold for prostate cancer to 1.18-fold for liver cancer. When breast cancer screening was recommended to be started at the age of 50 years for the general population, women with 1 first-degree relative with ovarian cancer attained the threshold risk for screening at the age of 46 years. Women with a family history of other discordant cancers did not reach the risk thresholds for screening at younger ages. CONCLUSIONS: Many cancers showed familial associations with breast cancer, but women with a family history of these cancers (except for ovarian cancer) did not reach risk thresholds for screening at younger ages.

Calculating the Starting Age for Screening in Relatives of Patients With Colorectal Cancer Based on Data From Large Nationwide Data Sets.

BACKGROUND & AIMS: Although colorectal cancer (CRC) screening guidelines acknowledge the need for earlier screening for high-risk individuals, such as those with family history of CRC, there is limited information on how many years earlier these high-risk individuals should be screened; current practice is based on weak evidence. We aimed to provide risk-adapted recommendations on the starting age of CRC screening for individuals with different family histories. METHODS: We collected data from nationwide family-cancer data sets in Sweden and calculated risk-adapted starting ages of screening for individuals with different family histories of CRC. Family history was defined as a dynamic (time-dependent) variable, allowing for changes during the follow-up period of 1958 through 2015. RESULTS: During a follow-up of 12,829,251 individuals with genealogy information, 173,796 developed CRC. The 10-year cumulative risk for the average-risk population at age 50 years (the guideline-recommended age for screening) was 0.44%. Individuals with different family histories of CRC attained this equivalent 0.44% risk 3-29 years earlier than their peers in the general population without such a family history. For example, individuals with 1 affected first-degree relative diagnosed before age 45 years reached the corresponding risk level 16 years earlier. CONCLUSIONS: We determined risk-adapted starting ages of CRC screening for close or distant relatives of patients with CRC, using high quality nationwide data sets. These findings might be used in counselling individuals about the appropriate age to start CRC screening, to optimize screening practice, and to supplement guidelines for CRC screening.

Importance of Family History of Colorectal Carcinoma In Situ Versus Invasive Colorectal Cancer: A Nationwide Cohort Study.

BACKGROUND: The aim of this study was to explore the risk of invasive colorectal cancer (CRC) in relatives of patients with colorectal carcinoma in situ (CCIS), which is lacking in the literature. PATIENTS AND METHODS: We collected data from Swedish family-cancer datasets and calculated standardized incidence ratio (SIR) and cumulative risk of CRC in family histories of CCIS in first- and second-degree relatives. Family history was defined as a dynamic (time-dependent) variable allowing for changes during the follow-up period from 1958 to 2015. Of 12,829,251 individuals with available genealogical data, 173,796 were diagnosed with CRC and 40,558 with CCIS. RESULTS: The lifetime (0-79 years) cumulative risk of CRC in first-degree relatives of patients with CCIS was 6.5%, which represents a 1.6-fold (95% CI, 1.5-1.7; n=752) increased risk. A similarly increased lifetime cumulative risk (6.7%) was found among first-degree relatives of patients with CRC (SIR, 1.6; 95% CI, 1.6-1.7; n=6,965). An increased risk of CRC was also found in half-siblings of patients with CCIS (SIR, 1.9; 95% CI, 1.1-3.0; n=18) and also in half-siblings of patients with CRC (SIR, 1.7; 95% CI, 1.3-2.1; n=78). Moreover, the increased risk of CRC was higher for younger age at diagnosis of CCIS in the affected first-degree relative and for younger age at diagnosis of CRC in the index person. CONCLUSIONS: Results of this study show that first-degree relatives and half-siblings of patients with CCIS have an increased risk of CRC, which is comparable in magnitude to the risk of those with a family history of invasive CRC. These findings extend available evidence on familial risk of CRC and may help to refine guidelines and recommendations for CRC screening.

Risk of colorectal cancer in patients with diabetes mellitus: A Swedish nationwide cohort study.

BACKGROUND: Colorectal cancer (CRC) incidence is increasing among young adults below screening age, despite the effectiveness of screening in older populations. Individuals with diabetes mellitus are at increased risk of early-onset CRC. We aimed to determine how many years earlier than the general population patients with diabetes with/without family history of CRC reach the threshold risk at which CRC screening is recommended to the general population. METHODS AND FINDINGS: A nationwide cohort study (follow-up:1964-2015) involving all Swedish residents born after 1931 and their parents was carried out using record linkage of Swedish Population Register, Cancer Registry, National Patient Register, and Multi-Generation Register. Of 12,614,256 individuals who were followed between 1964 and 2015 (51% men; age range at baseline 0-107 years), 162,226 developed CRC, and 559,375 developed diabetes. Age-specific 10-year cumulative risk curves were used to draw conclusions about how many years earlier patients with diabetes reach the 10-year cumulative risks of CRC in 50-year-old men and women (most common age of first screening), which were 0.44% and 0.41%, respectively. Diabetic patients attained the screening level of CRC risk earlier than the general Swedish population. Men with diabetes reached 0.44% risk at age 45 (5 years earlier than the recommended age of screening). In women with diabetes, the risk advancement was 4 years. Risk was more pronounced for those with additional family history of CRC (12-21 years earlier depending on sex and benchmark starting age of screening). The study limitations include lack of detailed information on diabetes type, lifestyle factors, and colonoscopy data. CONCLUSIONS: Using high-quality registers, this study is, to our knowledge, the first one that provides novel evidence-based information for risk-adapted starting ages of CRC screening for patients with diabetes, who are at higher risk of early-onset CRC than the general population.

Familial risk of breast cancer by dynamic, accumulative, and static definitions of family history.

BACKGROUND: Familial breast cancer risk studies usually overlook the dynamic nature of family history. METHODS: The authors assessed the effect of incorporating the timing of cancer diagnosis events into the assessment of familial risks of breast cancer in first-degree and second-degree relatives in a nationwide cohort study of 5,099,172 women (follow-up was between 1958-2015). Family history was assessed using 3 approaches: 1) as a static variable (ever having a relative with breast cancer); 2) as accumulative history; and 3) as a dynamic variable (time-dependent variable). RESULTS: For women aged <50 years, familial risk was mostly higher when family history was assessed as a dynamic variable compared with using a static or accumulative family history. For example, the cumulative risk of receiving a breast cancer diagnosis until age 50 years for women with a history of breast cancer in 1 first-degree relative was 2.6% (95% CI, 2.5%-2.7%) using the static method, 2.4% (95% CI, 2.3%-2.4%) using the accumulative method, and 3.1% (95% CI, 3.0%-3.2%) using the dynamic method. Relative risk in women aged <50 years with a breast cancer diagnosis in a sister was 1.40-fold (95% CI, 1.31-fold to 1.48-fold) using the static method, 1.66-fold (95% CI, 1.57-fold to 1.76-fold) using the accumulative method, and 2.28-fold (95% CI, 2.07-fold to 2.51-fold) using the dynamic method. CONCLUSIONS: The results of the current study demonstrated that assessing family history as static, accumulative, or dynamic results in different familial risk estimates. The answer as to which method to use for family history assessment depends on the implications of the study, with the dynamic method appearing to be better suited for risk stratification studies, the accumulative method being the most convenient in practice and the least favored for risk prediction, and the static method being suitable for etiological impact and risk attribution studies.

Risk of invasive prostate cancer and prostate cancer death in relatives of patients with prostatic borderline or in situ neoplasia: A nationwide cohort study.

BACKGROUND: The question of whether having a family history of prostatic borderline or in situ neoplasia (PBISN) is associated with an increased risk of invasive prostate cancer (PCa) or death from PCa remains unanswered. The objective of the current study was to provide an evidence-based risk estimation for the relatives of patients with PBISN. METHODS: Nationwide Swedish family cancer data sets were used for the current study, including data regarding all residents of Sweden who were born after 1931 and their parents. Standardized incidence ratios (SIRs), standardized mortality ratios (SMRs), and lifetime cumulative risks of PCa were calculated for men with different constellations of family history. Family history was defined as a dynamic (time-dependent) variable considering changes during follow-up (1958-2015). RESULTS: Of the 6,343,727 men in the current study, a total of 238,961 developed invasive PCa and 5756 were diagnosed with PBISN during the follow-up. Men with 1 first-degree relative who was diagnosed with PBISN had a 70% increased risk of invasive PCa (SIR, 1.7; 95% confidence interval, 1.5-1.9) and PCa death (SMR, 1.7; 95% confidence interval, 1.3-2.2) compared with men with no family history of PBISN or invasive PCa. These were rather close to estimates in men with 1 first-degree relative diagnosed with invasive PCa (SIR, 2.1 and SMR, 1.8). A higher risk of PCa in family members was found among patients with a family history of PBISN and/or PCa diagnosed before age 60 years. The results in terms of cumulative risk resembled this trend. CONCLUSIONS: A family history of PBISN appears to be as important as a family history of invasive PCa with regard to an increased risk of invasive PCa or PCa mortality. Such a history should not be overlooked in PCa screening recommendations or in future research regarding familial PCa.

Personal History of Diabetes as Important as Family History of Colorectal Cancer for Risk of Colorectal Cancer: A Nationwide Cohort Study.

INTRODUCTION: Diabetes mellitus (DM) and colorectal cancer (CRC) share some risk factors, including lifestyle and metabolic disturbances. We aimed to provide in-depth information on the association of CRC risk, especially early-onset CRC, with DM, family history of CRC, and age at DM diagnosis. METHODS: A nationwide cohort study was conducted using Swedish family cancer data sets, inpatient, and outpatient registers (follow-up: 1964-2015), including all individuals born after 1931 and their parents (12,614,256 individuals; 559,375 diabetic patients; 162,226 CRC patients). RESULTS: DM diagnosis before the age of 50 years was associated with a 1.9-fold increased risk of CRC before the age of 50 years (95% CI for standardized incidence ratio: 1.6-2.3) vs 1.3-fold risk of CRC at/after the age of 50 years (1.2-1.4). DM diagnosis before the age of 50 years in those with a family history of CRC was associated with 6.9-fold risk of CRC before the age of 50 years (4.1-12) and 1.9-fold risk of CRC at/after the age of 50 years (1.4-2.5). Diabetic patients had a similar lifetime risk of CRC before the age of 50 years (0.4%, 95% CI: 0.3%-0.4%) to those with only a family history of CRC (0.5%, 0.5%-0.5%), double that of the population (0.2%, 0.2%-0.2%). DISCUSSION: Our large cohort with valid information on DM and family history of cancer showed that DM is associated with increased risk of CRC in a magnitude close to having family history of CRC. Associations of DM and CRC family history with increased CRC risk were most prominent in young adults. These findings warrant further studies on harms, benefits, and cost-effectiveness of CRC screening in patients with diabetes, especially type 2, at earlier ages than in the general population.

Risk of invasive breast cancer in relatives of patients with breast carcinoma in situ: a prospective cohort study.

BACKGROUND: Wide implementation of mammography screening has resulted in increased numbers of women diagnosed with breast carcinoma in situ. We aimed to determine the risk of invasive breast cancer in relatives of patients with breast carcinoma in situ in comparison to the risk in relatives of patients with invasive breast cancer. METHODS: We analyzed the occurrence of cancer in a nationwide cohort including all 5,099,172 Swedish women born after 1931 with at least one known first-degree relative. This was a record linkage study of Swedish family cancer datasets, including cancer registry data collected from January 1, 1958, to December 31, 2015. We calculated standardized incidence ratios (SIRs) and 10-year cumulative risk of breast cancer diagnosis for women with a family history of in situ and invasive breast cancer. RESULTS: Having one first-degree relative with breast carcinoma in situ was associated with 50% increased risk of invasive breast cancer (SIR = 1.5, 95% CI 1.4-1.7) when compared to those who had no family history of invasive breast cancer or breast carcinoma in situ in either first- or second-degree relatives. Similarly, having one first-degree relative with invasive breast cancer was associated with 70% (1.7, 1.7-1.8) increased risk. The 10-year cumulative risk for women at age 50 with a relative with breast carcinoma in situ was 3.5% (2.9-3.9%) and was not significantly different from 3.7% (3.6-3.8%) risk for 50-year-old women with a relative with invasive breast cancer (95% confidence intervals overlapped). CONCLUSIONS: The risk of invasive breast cancer for women with a family history of breast carcinoma in situ was comparable to that for women with a family history of invasive breast cancer. Therefore, family history of breast carcinoma in situ should not be overlooked in recommendations for breast cancer prevention for women with a family history of breast cancer.

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.

Effect of multiplicity, laterality, and age at onset of breast cancer on familial risk of breast cancer: a nationwide prospective cohort study.

The objective of this nationwide prospective cohort study is to find out the risk of breast cancer (BC) in relatives of patients with multiple BCs by laterality and age at diagnosis of first BC. Having family history of single (HR 1.8; 95 % CI 1.8-1.9) or multiple (HR 2.7; 95 % CI 2.6-2.9) BC was associated with higher risk of BC. Those with an FDR with contralateral BC at any age had the highest risk of familial cancer except at age <40 in which those whose young FDR was affected by multiple ipsilateral BC had the highest risk (HR 9.7; 95 % CI 6.0-15.6). The familial risk of BC in these families decreased as the subject's and FDRs' age at diagnosis of first BC increased. The HR was still significantly increased (2.2) for old individuals (>60) having a FDR with contralateral BC at an advanced age (≥80). Despite the common belief that later onset breast cancer is more associated with sporadic breast cancer, our data suggest that breast cancer at any age in the family is associated with some increase in the familial risk, though that risk decreases as the age of onset increases. Contralateral and multiple ipsilateral breast cancers might be associated with distinct shared familial risk factors. Our results have implication for genetic counseling and urge gene identification studies.

Longer Interval Between First Colonoscopy With Negative Findings for Colorectal Cancer and Repeat Colonoscopy.

Importance: For individuals without a family history of colorectal cancer (CRC), colonoscopy screening every 10 years is recommended to reduce CRC incidence and mortality. However, debate exists about whether and for how long this 10-year interval could be safely expanded. Objective: To assess how many years after a first colonoscopy with findings negative for CRC a second colonoscopy can be performed. Design, Setting, and Participants: This cohort study leveraged Swedish nationwide register-based data to examine CRC diagnoses and CRC-specific mortality among individuals without a family history of CRC. The exposed group included individuals who had a first colonoscopy with findings negative for CRC at age 45 to 69 years between 1990 and 2016. The control group included individuals matched by sex, birth year, and baseline age (ie, the age of their matched exposed individual when the exposed individual's first colonoscopy with findings negative for CRC was performed). Individuals in the control group either did not have a colonoscopy during the follow-up or underwent colonoscopy that resulted in a CRC diagnosis. Up to 18 controls were matched with each exposed individual. Individuals were followed up from 1990 to 2018, and data were analyzed from November 2022 to November 2023. Exposure: A first colonoscopy with findings negative for CRC, defined as a first colonoscopy without a diagnosis of colorectal polyp, adenoma, carcinoma in situ, or CRC before or within 6 months after screening. Main Outcomes and Measures: The primary outcomes were CRC diagnosis and CRC-specific death. The 10-year standardized incidence ratio and standardized mortality ratio were calculated to compare risks of CRC and CRC-specific death in the exposed and control groups based on different follow-up screening intervals. Results: The sample included 110 074 individuals (65 147 females [59.2%]) in the exposed group and 1 981 332 (1 172 646 females [59.2%]) in the control group. The median (IQR) age for individuals in both groups was 59 (52-64) years. During up to 29 years of follow-up of individuals with a first colonoscopy with findings negative for CRC, 484 incident CRCs and 112 CRC-specific deaths occurred. After a first colonoscopy with findings negative for CRC, the risks of CRC and CRC-specific death in the exposed group were significantly lower than those in their matched controls for 15 years. At 15 years after a first colonoscopy with findings negative for CRC, the 10-year standardized incidence ratio was 0.72 (95% CI, 0.54-0.94) and the 10-year standardized mortality ratio was 0.55 (95% CI, 0.29-0.94). In other words, the 10-year cumulative risk of CRC in year 15 in the exposed group was 72% that of the 10-year cumulative risk of CRC in the control group. Extending the colonoscopy screening interval from 10 to 15 years in individuals with a first colonoscopy with findings negative for CRC could miss the early detection of only 2 CRC cases and the prevention of 1 CRC-specific death per 1000 individuals, while potentially avoiding 1000 colonoscopies. Conclusions and Relevance: This cohort study found that for the population without a family history of CRC, the 10-year interval between colonoscopy screenings for individuals with a first colonoscopy with findings negative for CRC could potentially be extended to 15 years. A longer interval between colonoscopy screenings could be beneficial in avoiding unnecessary invasive examinations.

Familial risk of small intestinal carcinoid and adenocarcinoma.

BACKGROUND & AIMS: Small intestinal cancer (SIC) is rare, and its etiology is poorly understood. We compared clusters of families with SICs of different histologic subtypes. METHODS: By 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. RESULTS: Among 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. CONCLUSIONS: Based 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.

Race and Ethnicity-Adjusted Age Recommendation for Initiating Breast Cancer Screening.

Importance: Breast cancer (BC) is the second leading cause of cancer death in women, and there is a substantial disparity in BC mortality by race, especially for early-onset BC in Black women. Many guidelines recommend starting BC screening from age 50 years; however, the current one-size-fits-all policy to start screening all women from a certain age may not be fair, equitable, or optimal. Objective: To provide race and ethnicity-adapted starting ages of BC screening based on data on current racial and ethnic disparities in BC mortality. Design, Setting, and Participants: This nationwide population-based cross-sectional study was conducted using data on BC mortality in female patients in the US who died of BC in 2011 to 2020. Exposures: Proxy-reported race and ethnicity information was used. The risk-adapted starting age of BC screening by race and ethnicity was measured based on 10-year cumulative risk of BC-specific death. Age-specific 10-year cumulative risk was calculated based on age group-specific mortality data without modeling or adjustment. Main Outcomes and Measures: Disease-specific mortality due to invasive BC in female patients. Results: There were BC-specific deaths among 415 277 female patients (1880 American Indian or Alaska Native [0.5%], 12 086 Asian or Pacific Islander [2.9%], 62 695 Black [15.1%], 28 747 Hispanic [6.9%], and 309 869 White [74.6%]; 115 214 patients died before age 60 years [27.7%]) of any age in the US in 2011 to 2020. BC mortality per 100 000 person-years for ages 40 to 49 years was 27 deaths in Black females, 15 deaths in White females, and 11 deaths in American Indian or Alaska Native, Hispanic, and Asian or Pacific Islander females. When BC screening was recommended to start at age 50 years for all females with a 10-year cumulative risk of BC death of 0.329%, Black females reached this risk threshold level 8 years earlier, at age 42 years, whereas White females reached it at age 51 years, American Indian or Alaska Native and Hispanic females at age 57 years, and Asian or Pacific Islander females 11 years later, at age 61 years. Race and ethnicity-adapted starting ages for Black females were 6 years earlier for mass screening at age 40 years and 7 years earlier for mass screening at age 45 years. Conclusions and Relevance: This study provides evidence-based race-adapted starting ages for BC screening. These findings suggest that health policy makers may consider a risk-adapted approach to BC screening in which individuals who are at high risk are screened earlier to address mortality due to early-onset BC before the recommended age of mass screening.

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.

C-reactive protein and seizures in focal epilepsy: a video-electroencephalographic study.

PURPOSE: C-reactive protein (CRP) has been studied extensively in many noninflammatory neurologic conditions, but there has been little study of CRP in the context of seizures or epilepsy. The purpose of this study was to examine CRP concentrations in patients with refractory focal epilepsy who were undergoing video-electroencephalography (EEG) monitoring compared with healthy controls, and CRP change during 24 h after a seizure. METHODS: CRP levels were measured in serum at the onset of video-EEG recording (CRP-0h) and at 3, 6, 12, and 24 h after index seizure (the first verified localized-onset seizure) in 31 patients during inpatient video-EEG monitoring by using high sensitivity measurement of CRP concentration. The patients were categorized into two groups: temporal lobe epilepsy (TLE; n = 15) and extratemporal lobe epilepsy (XLE; n = 16). Eighty healthy volunteers served as controls. KEY FINDINGS: CRP-0h concentration was significantly higher in patients with refractory focal epilepsy than in controls (3.5 vs. 0.7 mg/ml, p < 0.001). All five patients with elevated CRP-0h (>mean + 2 standard deviations in controls) had TLE (vs. none in XLE; p = 0.018). Index seizure type was associated with CRP increase from baseline to maximum level after index seizure (p = 0.005). The most important predictor of increase in CRP level was secondarily generalized tonic-clonic seizure (SGTCS; p = 0.030). SIGNIFICANCE: The higher baseline levels in patients with epilepsy compared with healthy controls demonstrates that CRP concentrations are also affected in refractory epilepsy. Our data suggest that SGTCS stimulates CRP production. These results emphasize the association between inflammation and refractory epilepsy.

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-up = 10.7 years), 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, 95 % 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, 95 % 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, 95 % 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; 95 % 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; 95 % 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.

Risk of Gynecological Cancers in Cholecystectomized Women: A Large Nationwide Cohort Study.

Background: Gallstones affect women more frequently than men, and symptomatic gallstones are increasingly treated with surgical removal of the gallbladder (cholecystectomy). Breast, endometrial, and ovarian cancer share several risk factors with gallstones, including overweight, obesity, and exposure to female sex hormones. We intended to assess the association between cholecystectomy and female cancer risk, which has not been comprehensively investigated. Methods: We investigated the risk of female cancers after cholecystectomy leveraging the Swedish Cancer, Population, Patient, and Death registries. Standardized incidence ratios (SIRs) adjusted for age, calendar period, socioeconomic status, and residential area were used to compare cancer risk in cholecystectomized and non-cholecystectomized women. Results: During a median follow-up of 11 years, 325,106 cholecystectomized women developed 10,431 primary breast, 2888 endometrial, 1577 ovarian, and 705 cervical cancers. The risk of ovarian cancer was increased by 35% (95% confidence interval (CI) 2% to 77%) in the first 6 months after cholecystectomy. The exclusion of cancers diagnosed in the first 6 months still resulted in an increased risk of endometrial (19%, 95%CI 14% to 23%) and breast (5%, 95%CI 3% to 7%) cancer, especially in women cholecystectomized after age 50 years. By contrast, cholecystectomized women showed decreased risks of cervical (-13%, 95%CI -20% to -7%) and ovarian (-6%, 95%CI -10% to -1%) cancer. Conclusions: The risk of ovarian cancer increased by 35% in a just short period of time (6 months) following the surgery. Therefore, it is worth ruling out ovarian cancer before cholecystectomy. Women undergoing cholecystectomy showed an increased risk of breast and endometrial cancer up to 30 years after surgery. Further evaluation of the association between gallstones or gallbladder removal on female cancer risk would allow for the assessment of the need to intensify cancer screening in cholecystectomized women.

Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy.

PURPOSE: Glutamic acid decarboxylase antibodies (GADAs) have been detected in patients with epilepsy, but the clinical determinants of epilepsy associated with GADA have not been defined. METHODS: We analyzed GADA with a radioimmunoassay in sera of 253 well-characterized patients with epilepsy and 200 control subjects. The positive samples were confirmed by immunohistochemistry and western blotting (WB). Sera were screened for other autoantibodies. RESULTS: GADA were detected in 15 patients (5.9%) and in three control subjects (1.5%) (p = 0.026). Seven patients (2.8%) had high GADA titers [>or=1,000 relative units (RUs)/ml], six of whom had temporal lobe epilepsy (TLE). All three GADA-positive control subjects had low titers. Two of the five patients with high GADA titers and available cerebrospinal fluid (CSF) samples had intrathecal synthesis (IS) of GADA; one patient had CSF oligoclonal bands. The prevalence of increased levels of GADA tended to be higher in patients with TLE than in patients with extra-TLE [odds ratio (OR) 1.32, 95% confidence interval (CI) 0.39-4.42; p = 0.657]. The patients with high GADA titers had significantly higher number of other autoantibodies compared to the patients with low GADA titers (p = 0.001) and the patients with normal GADA (p < 0.001). DISCUSSION: High GADA titers were present in a subgroup of patients; close to 90% had TLE. The immunologic profile of these patients suggests that the most probable origin of their epilepsy is autoimmune. A positive IS of GADA may be a marker of an ongoing immune response that could identify those patients in whom a trial with immunosuppressive therapy might be warranted.