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Childhood acute lymphoblastic leukemia (ALL) has an origin in the fetal period which may distinguish it from ALL diagnosed later in life. We wanted to test whether familial risks differ in ALL diagnosed in the very early childhood from ALL diagnosed later. The Swedish nation-wide family-cancer data were used until year 2016 to calculate standardized incidence ratios (SIRs) for familial risks in ALL in three diagnostic age-groups: 0-4, 5-34 and 35 + years. Among 1335 ALL patients diagnosed before age 5, familial risks were increased for esophageal (4.78), breast (1.42), prostate (1.40) and connective tissue (2.97) cancers and leukemia (2.51, ALL 7.81). In age-group 5-34 years, rectal (1.73) and endometrial (2.40) cancer, myeloma (2.25) and leukemia (2.00, ALL 4.60) reached statistical significance. In the oldest age-group, the only association was with Hodgkin lymphoma (3.42). Diagnostic ages of family members of ALL patients were significantly lower compared to these cancers in the population for breast, prostate and rectal cancers. The patterns of increased familial cancers suggest that BRCA2 mutations could contribute to associations of ALL with breast and prostate cancers, and mismatch gene PMS2 mutations with rectal and endometrial cancers. Future DNA sequencing data will be a test for these familial predictions. ; The study was supported by the European Union's Horizon 2020 research and innovation program, Grant No 856620, the Swedish Research Council (2016-01176; 2018-02400) and the ALF project grant, Region Skane/ Lund University, Sweden.

BACKGROUND: Previous population-based studies on second primary cancers (SPCs) in urothelial cancers have focused on known risk factors in bladder cancer patients without data on other urothelial sites of the renal pelvis or ureter. AIMS: To estimate sex-specific risks for any SPCs after urothelial cancers, and in reverse order, for urothelial cancers as SPCs after any cancer. Such two-way analysis may help interpret the results. METHODS: We employed standardized incidence ratios (SIRs) to estimate bidirectional relative risks of subsequent cancer associated with urothelial cancers. Patient data were obtained from the Swedish Cancer Registry from years 1990 through 2015. RESULTS: We identified 46 234 urinary bladder cancers (75% male), 940 ureteral cancers (60% male), and 2410 renal pelvic cancers (57% male). After male bladder cancer, SIRs significantly increased for 9 SPCs, most for ureteral (SIR 41.9) and renal pelvic (17.2) cancers. In the reversed order (bladder cancer as SPC), 10 individual FPCs were associated with an increased risk; highest associations were noted after renal pelvic (21.0) and ureteral (20.9) cancers. After female bladder cancer, SIRs of four SPCs were significantly increased, most for ureteral (87.8) and pelvic (35.7) cancers. Female bladder, ureteral, and pelvic cancers associated are with endometrial cancer. CONCLUSIONS: The risks of recurrent urothelial cancers were very high, and, at most sites, female risks were twice over the male risks. Risks persisted often to follow-up periods of >5 years, motivating an extended patient follow-up. Lynch syndrome-related cancers were associated with particularly female urothelial cancers, calling for clinical vigilance. ; O.H. was supported by Biomedicum Helsinki-säätiö and Finska läkaresällskapet grants. G.Z was a doctoral student supported by the China Scholarship Council (201606100057). The study was supported by the European Union's Horizon 2020 research and innovation program, Grant No. 856620 (Chaperon) and The Swedish Research Council.

Background: Familial cancer can be defined through the occurrence of the same cancer in two or more family members. We describe a nationwide landscape of familial cancer, including its frequency and the risk that it conveys, by using the largest family database in the world with complete family structures and medically confirmed cancers. Patients/methods: We employed standardized incidence ratios (SIRs) to estimate familial risks for concordant cancer among first-degree relatives using the Swedish Cancer Registry from years 1958 through 2016. Results: Cancer risks in a 20–84 year old population conferred by affected parents or siblings were about two-fold compared to the risk for individuals with unaffected relatives. For small intestinal, testicular, thyroid and bone cancers and Hodgkin disease, risks were higher, five-to-eight-fold. Novel familial associations included adult bone, lip, pharyngeal, and connective tissue cancers. Familial cancers were found in 13.2% of families with cancer; for prostate cancer, the proportion was 26.4%. High-risk families accounted for 6.6% of all cancer families. Discussion/Conclusion: High-risk family history should be exceedingly considered for management, including targeted genetic testing. For the major proportion of familial clustering, where genetic testing may not be feasible, medical and behavioral intervention should be indicated for the patient and their family members, including screening recommendations and avoidance of carcinogenic exposure. ; Supported by the European Union's Horizon 2020 research and innovation program, grant No 856620 (Chaperon), the German Jose Carreras Leukemia Foundation, The Swedish Research Council, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Finnish Cancer Organizations, University of Helsinki and Helsinki University Central Hospital.

Background: Favorable survival in malignant cutaneous melanoma (melanoma) has increased the likelihood of second primary cancer (SPC). We assess the influence of patient characteristics at diagnosis of first melanoma and the type of SPC (second melanoma and other SPC) on overall survival. Methods: We used the Swedish Cancer Registry data to assess overall survival in melanoma for the period 1990 to 2015. Kaplan-Meier curves were plotted and hazard ratios (HRs) were estimated with Cox regression models by considering SPC diagnosis as a time-dependent variable. Results: A total of 46,726 patients were diagnosed with melanoma, and 15.3% of them developed SPC, among which, two thirds were other SPCs. Second melanomas were diagnosed early (31% during the first year) compared to non-melanoma SPCs (9.5%). Survival for women with second melanoma or other SPC (56 and 21% alive after 25 years of follow-up, respectively) exceeded the male rates (21 and 10%, respectively) but all these figures were lower than for females (60% alive) or males (48%) without SPC. Time dependent analysis showed vastly increased HRs for cancer types that are fatal also as first cancers, but SPC-specific HRs remained relatively uniform, irrespective of SPC diagnosed soon or late after first melanoma. In early-onset melanoma, SPC diagnosis after 10 years may not negatively influence overall survival. Conclusions: As the overall survival of patients with many types of SPCs is unfavorable, advice about health lifestyle should benefit smoking patients and early detection methods may be recommended for SPCs of the breast, prostate and colorectum. ; G.Z is a doctoral student supported by the China Scholarship Council (201606100057). This work is supported by European Union's Horizon 2020 research and innovation programme, grant No 856620, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, The Swedish Research Council, Finnish Cancer Organizations, University of Helsinki and Helsinki University Central Hospital. Open Access funding enabled and ...

Background: Second primary cancers (SPCs) are increasing, which may negatively influence patient survival. Gastric cancer (GC) has poor survival and when it is diagnosed as SPC it is often the cause of death. We wanted to analyze the risk of SPCs after GC and the risk of GC as SPC after any cancer. Such bidirectional analysis is important in relation to fatal cancers because SPCs may be under-reported in the short-term survival period. Methods: Cancers were obtained from the Swedish Cancer Registry from years 1990 through 2015. Standardized incidence ratios (SIRs) were used to estimate bidirectional relative. Results: We identified 23,137 GC patients who developed 1042 SPCs (4.5%); 2158 patients had GC as SPC. While the risk for three SPCs was increased after GC, seven first primary cancers were followed by an increased risk of GC as SPC, including esophageal, colorectal, bladder, squamous cell skin and breast cancers and non-Hodgkin lymphoma. Breast cancer, which was followed by a diagnosis of second GC, showed an excess of lobular histology. Conclusion: Multiple primary cancers in the same individuals may signal genetic predisposition. Accordingly, the association of GC with breast cancer may be related to mutations in the CDH1 gene, and clustering of colorectal, small intestinal and bladder cancers could be related to Lynch syndrome. The third line of findings supports a contribution of immune dysfunction on the increased risk of GC as SPC after skin cancer and non-Hodgkin lymphoma. Early detection of GC in the risk groups could save lives. ; Supported by the European Union's Horizon 2020 research and innovation programme, grant No 856620 (Chaperon), the Swedish Research Council, the Swedish Research Council, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Finnish Cancer Organizations, University of Helsinki, Helsinki University Central Hospital, Novo Nordisk Foundation, Päivikki and Sakari Sohlberg Foundation.

Abstract Background Enlargement of the European Union has caused worries about the possibility of increased migration from its new members, the former Soviet countries, and consequently increased demands on the health care systems of the host countries. This study investigated whether or not earlier immigrants from the former Soviet Bloc have poorer self-reported mental health, measured as self-reported psychiatric illness and psychosomatic complaints, than the host population in Sweden. It also examined the particular factors which might determine the self-reported mental health of these immigrants. Methods The cross-sectional national sample included 25–84-year-old Swedish-born persons (n = 35,459) and immigrants from Poland (n = 161), other East European countries (n = 164), and the former Soviet Union (n = 60) who arrived in Sweden after 1944 and were interviewed during 1994–2001. Unconditional multivariate logistic regression was used in the analyses. Results The findings indicated that the country of birth had a profound influence on self-reported mental health. Polish and other East European immigrants in general had a twofold higher odds ratio of reporting psychiatric illness and psychosomatic complaints, which fact could not be explained by adjustments for the demographic and socioeconomic variables. However, immigrants from the former Soviet Union had odds similar to those of the Swedish-born reference group. Adjustments for migration-related variables (language spoken at home and years in Sweden) changed the association between the country of birth and the outcomes only to a limited extent. Conclusion Since poor mental health may hinder acculturation, the mental health of immigrants from Poland and other East European countries should be acknowledged, particularly with the expansion of the European Union and inclusion of nine former Soviet Bloc countries by 2007.

BACKGROUND: Enlargement of the European Union has caused worries about the possibility of increased migration from its new members, the former Soviet countries, and consequently increased demands on the health care systems of the host countries. This study investigated whether or not earlier immigrants from the former Soviet Bloc have poorer self-reported mental health, measured as self-reported psychiatric illness and psychosomatic complaints, than the host population in Sweden. It also examined the particular factors which might determine the self-reported mental health of these immigrants. METHODS: The cross-sectional national sample included 25-84-year-old Swedish-born persons (n = 35,459) and immigrants from Poland (n = 161), other East European countries (n = 164), and the former Soviet Union (n = 60) who arrived in Sweden after 1944 and were interviewed during 1994-2001. Unconditional multivariate logistic regression was used in the analyses. RESULTS: The findings indicated that the country of birth had a profound influence on self-reported mental health. Polish and other East European immigrants in general had a twofold higher odds ratio of reporting psychiatric illness and psychosomatic complaints, which fact could not be explained by adjustments for the demographic and socioeconomic variables. However, immigrants from the former Soviet Union had odds similar to those of the Swedish-born reference group. Adjustments for migration-related variables (language spoken at home and years in Sweden) changed the association between the country of birth and the outcomes only to a limited extent. CONCLUSION: Since poor mental health may hinder acculturation, the mental health of immigrants from Poland and other East European countries should be acknowledged, particularly with the expansion of the European Union and inclusion of nine former Soviet Bloc countries by 2007.

BACKGROUND: Head and neck cancers (HNCs) encompass a heterogeneous group of cancers between the mouth and larynx. Familial clustering in HNCs has been described, but how it influences individual sites and to which extent known risk factors, such as human papilloma virus (HPV) infection, may contribute is not well established. PATIENTS/METHODS: We employed standardized incidence ratios (SIRs) to estimate familial risks for HNC with same (concordant) and different (discordant) cancers among first-degree relatives using data from the Swedish Cancer Registry from 1958 to 2018. RESULTS: Incidence for male and female oropharyngeal cancer increased close to four-fold in the past 39 years. Familial HNC was found in 3.4% of the study population, with an overall familial SIR of 1.78. Patients with concordant nasopharyngeal cancer showed a high risk of 23.97, followed by hypopharyngeal cancer (5.43). The husbands of wives with cervical cancer had an increased risk of oropharyngeal cancer. DISCUSSION/CONCLUSION: Nasopharyngeal cancers lacked associations with lifestyle or HPV associated cancers, suggesting a role for germline genetics, which was also true for the high-risk families of three HNC patients. In the Swedish population with low smoking levels, HPV is becoming a dominant risk factor, emphasizing the need for sexual hygiene and HPV vaccination. ; The study was supported by the European Union's Horizon 2020 research and innovation program, grant no. 856620; the Swedish Research Council (2020-01175; 2018-02400); and the ALF project grant, Region Skane/Lund University, Sweden.

Background: Second primary cancers (SPCs) are important clinically as they may negatively influence patient survival and they may tell about therapeutic side effects and general causes of cancer. Population-based literature concerning SPCs after hepatobiliary cancers is limited and here we assess risks of SPCs after hepatocellular cancer (HCC), and cancers of the gallbladder, bile ducts and ampulla of Vater. In reverse order, we consider the risk of hepatobiliary cancers as SPCs after any cancer. Methods: We used standardized incidence ratios (SIRs) to estimate bidirectional relative risks of subsequent cancers associated with hepatobiliary cancers. Cancer diagnoses were obtained from the Swedish Cancer Registry from years 1990 through 2015. Results: We identified 9997 primary HCCs, 1365 gallbladder cancers and 4721 bile duct cancers. After HCC, risks of four SPCs were increased: gallbladder (SIR = 4.38; 95% confidence interval 1.87-8.67), thyroid (4.13; 1.30-9.70), kidney (2.92; 1.66-4.47) and squamous cell skin (1.55; 1.02-2.26) cancers. In reverse order, HCC as SPC, in addition to the above cancers, associations included upper aerodigestive tract, esophageal, small intestinal and bladder cancers and non-Hodgkin lymphoma. For gallbladder and bile duct cancers, associations were found with small intestinal and pancreatic cancers. Conclusion: The results suggested that HCC is associated with two types of SPC, one related to shared environmental risk factors, such as alcohol, exemplified by upper aerodigestive tract and esophageal cancer, and the other related to immune dysfunction, exemplified by squamous cell skin cancer. SPCs associated with gallbladder and bile duct cancers suggest predisposition to mutations in the mismatch repair gene MLH1. ; Supported by the European Union's Horizon 2020 research and innovation programme, grant No 856620 (Chaperon), The Swedish Research Council, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Finnish Cancer Organizations, University of Helsinki and Helsinki ...

Sleep apnea is increasing in prevalence and an important cause of cardiometabolic diseases and mortality worldwide. Its only established modifiable risk factor is obesity; however, up to half of all sleep apnea cases may occur in non-obese persons, and hence there is a pressing need to identify other modifiable risk factors to facilitate more effective prevention. We sought to examine, for the first time, cardiorespiratory fitness (CRF) in relation to risk of sleep apnea, independent of obesity. A national cohort study was conducted to examine CRF in all 1,547,478 Swedish military conscripts during 1969–1997 (97–98% of all 18-year-old men) in relation to risk of sleep apnea through 2012 (maximum age 62 years). CRF was measured as maximal aerobic workload in Watts, and sleep apnea was identified from nationwide outpatient and inpatient diagnoses. A total of 44,612 (2.9%) men were diagnosed with sleep apnea in 43.7 million person-years of follow-up. Adjusting for age, height, weight, socioeconomic factors, and family history of sleep apnea, low CRF at age 18 years was associated with a significantly increased risk of sleep apnea in adulthood (lowest vs. highest CRF tertile: incidence rate ratio [IRR], 1.44; 95% CI, 1.40–1.49; P<0.001; continuous CRF per 100 Watts: IRR, 0.71; 95% CI, 0.70–0.73; P<0.001). An increased risk was observed even among men with normal body mass index (lowest vs. highest CRF tertile: IRR, 1.30; 95% CI, 1.26–1.35; P<0.001). These findings identify low CRF early in life as a new modifiable risk factor for development of sleep apnea in adulthood.

OBJECTIVE: Low physical fitness and obesity have been associated with higher risk of developing heart failure (HF), but their interactive effects are unknown. Elucidation of interactions among these common, modifiable factors may help facilitate more effective primary prevention. METHODS: We conducted a national cohort study to examine interactive effects of aerobic fitness, muscular strength, and body mass index (BMI) among 1,330,610 military conscripts in Sweden during 1969–1997 (97–98% of all 18-year-old males) on risk of HF identified from inpatient and outpatient diagnoses through 2012 (maximum age 62 years). RESULTS: There were 11,711 men diagnosed with HF in 37.8 million person-years of follow-up. Low aerobic fitness, low muscular strength, and obesity were independently associated with higher risk of HF, after adjusting for each other, socioeconomic factors, other chronic diseases, and family history of HF. The combination of low aerobic fitness and low muscular strength (lowest vs. highest tertiles) was associated with a 1.7-fold risk of HF (95% CI, 1.6–1.9; P<0.001; incidence rates per 100,000 person-years, 43.2 vs. 10.8). These factors had positive additive and multiplicative interactions (P<0.001), and were associated with increased risk of HF even among men with normal BMI. CONCLUSIONS: Low aerobic fitness, low muscular strength, and obesity at age 18 were independently associated with higher risk of HF in adulthood, with interactive effects between aerobic fitness and muscular strength. These findings suggest that early-life interventions may help reduce the long-term risk of HF and should include both aerobic fitness and muscular strength, even among persons with normal BMI.

AbstractWe seek to identify factors that facilitate or inhibit transmission of drug abuse (DA) from high-risk parents to their children. In 44,250 offspring of these parents, ascertained from a Swedish national sample for having a mother and/or father with DA, we explored, using Cox models, how the prevalence of DA was predicted by potentially malleable risk factors in these high-risk parents, their spouses and the rearing environment they provided. Analyses of offspring of discordant high-risk siblings and offspring of discordant sibling-in-laws and step-parents aided causal inference. Risk for DA in the children was associated with high-risk and married-in parental externalizing psychopathology, a range of other features of these parents (e.g., low education and receipt of welfare), and aspects of the rearing environment (e.g., neighborhood deprivation and number of nearby drug dealers). Offspring of discordant high-risk siblings, siblings-in-laws and step-parents suggested that nearly all these associations were partly causal. A multivariate analysis utilizing offspring of discordant high-risk siblings identified the six most significant potentially malleable risk factors for offspring DA: (1) criminal behavior (CB) in married-in parent, (2) community peer deviance, (3) broken family, (4) DA in high-risk parent, (5) CB in high-risk parent and (6) number of family moves. Children in the lowest decile of risk had a 50% reduction in their DA prevalence, similar to that seen in the general population. We conclude that transmission of DA from high-risk parents to children partly results from a range of potentially malleable risk factors that could serve as foci for intervention.

Using information from Swedish population registries, we attempt to decompose the shared environment (C) into four subcomponents: close family, family, household, and community. Among pairs differing in their genetic and geographical/household relationships, we examine three externalizing syndromes: drug abuse (DA), criminal behavior (CB), and alcohol use disorders (AUD). The best-fitting common pathway model suggested that total estimates for C were higher for DA (21% for males and 18% for females) than for AUD (16% and 14%) and CB (17% and 10%). Concerning syndrome-specific influences in males, close family effects were stronger for CB and AUD, while community effects were stronger for DA. The two C components in between community experiences and close family experiences (family and household) were estimated to almost entirely derive from the common latent factor. In females, among the four components of C, the community experiences were just slightly above zero, while the C components referred to as the household effect were almost zero. The total close family experiences were similar and most important across syndromes were also divided into common and specific components. For all syndromes, for both males and females, the effects of additive genetic factors were 2–4 times the size of the total effect of the shared environment. Applying standard methods to novel relationships, we expand our understanding of how the shared environment contributes to individual differences in three externalizing syndromes.

Background: Pernicious anemia (PA) is an autoimmune disease (AID) which is caused by lack of vitamin B12 (cobalamin) due to its impaired uptake. PA is a multifactorial disease which is associated with a number of other AID comorbidities and which is manifested as part of autoimmune polyglandular syndrome. Due to the shortage of family studies on PA, we planned to address the problem by assessing familial risks for concordant PA between family members and for discordant PA in families of other AID patients. Methods: We collected data on patients diagnosed with AIDs from the Swedish hospitals and family data from a population register. We calculated standardized incidence ratios (SIRs) in families for concordant and discordant risks. Results: The number of PA patients in the offspring generation (for which the familial risk was calculated) was 7701; 278 (3.6%) patients had a family history of PA. The population prevalence of PA was 0.9/1000. The familial risk for PA was 3.88 when any first-degree relative was the proband, equal for men and women. The familial risk was two times higher between siblings than between offspring and parents which may be due to complex genetic background. Associations of PA with 14 discordant AIDs were significant; these included some AIDs that have previously been described as comorbidities in PA patients and several yet unreported associations, including rheumatoid arthritis and other AIDs. Conclusions: The familial risks for PA were high suggesting multifactorial genetic etiology. The results call for further population-level studies to unravel mechanisms of familial PA which may help to understand the etiology of this disease. ; is study was supported by the European Union's Horizon 2020 Research and Innovation Program (grant no. 856620), Swedish Research Council (2016-01176 (to Jan Sundquist) and 2018-02400 (to Kristina Sundquist)), Swedish Heart- Lung Foundation, and ALF project grant, Lund University, Sweden.