Cardiovascular disease in Adult Life after Childhood Cancer in Scandinavia: A population‐based cohort study of 32,308 one‐year survivors

The lifetime risk for cardiovascular disease in a large cohort of childhood cancer survivors has not been fully assessed. In a retrospective population‐based cohort study predicated on comprehensive national health registers, we identified a cohort of 32,308 one‐year survivors of cancer diagnosed before the age of 20 in the five Nordic countries between the start of cancer registration in the 1940s and 1950s to 2008; 211,489 population comparison subjects were selected from national population registers. Study subjects were linked to national hospital registers, and the observed numbers of first hospital admission for cardiovascular disease among survivors were compared with the expected numbers derived from the population comparison cohort. Cardiovascular disease was diagnosed in 2,632 childhood cancer survivors (8.1%), yielding a standardized hospitalization rate ratio (RR) of 2.1 (95% CI 2.0–2.2) and an overall absolute excess risk (AER) of 324 per 100,000 person‐years. At the end of follow‐up 12% of the survivors were ≥ 50 years of age and 4.5% ≥ 60 years of age. Risk estimates were significantly increased throughout life, with an AER of ～500–600 per 100,000 person‐years at age ≥ 40. The highest relative risks were seen for heart failure (RR, 5.2; 95% CI 4.5–5.9), valvular dysfunction (4.6; 3.8–5.5) and cerebrovascular diseases (3.7; 3.4–4.1). Survivors of hepatic tumor, Hodgkin lymphoma and leukemia had the highest overall risks for cardiovascular disease, although each main type of childhood cancer had increased risk with different risk profiles. Nordic childhood cancer survivors are at markedly increased risk for cardiovascular disorders throughout life. These findings indicate the need for preventive interventions and continuous follow‐up for this rapidly growing population.     

Cancer incidence among priests: 45?years of follow-up in four Nordic countries

Previously published studies on the risk of cancer among male priests have been based on cancer mortality with the exception of one case–control study. The aim of this study was to present estimates of cancer incidence among Nordic male priests. The study cohort for our analyses consisted of 6.5 million men aged 30–64 years old who had participated in any computerised population census in four Nordic countries in 1990 or earlier. Follow-up was done by drawing linkages with the national population and cancer registries. 13,491 priests were identified by their job title codes. We estimated the standardised incidence ratio (SIR) and 95% confidence intervals (95% CI) for the priests using the male population as a reference. Priests had a lower cancer incidence than the general population (overall SIR 0.85, 95% CI: 0.82–0.88). The majority of smoking- and alcohol-related cancers were associated with decreased SIR estimates. Increased risks were observed for skin melanoma (SIR 1.34, 95% CI: 1.11–1.62), acute myeloid leukemia (SIR 1.75, 95% CI: 1.20–2.47) and thyroid cancer (SIR 1.86, 95% CI: 1.22–2.73). This is the first cohort study regarding the incidence of cancer among priests. The lower incidence of smoking and alcohol-related cancers among Nordic male priests can be explained by their lower exposure to cigarettes and alcohol when compared to the general population. A greater risk of melanoma is typical of highly-educated people, but it is unclear why priests should have an increased risk of acute myeloid leukemia or thyroid cancer.     

Adverse life experiences and common mental health problems in pregnancy: a causal pathway analysis

Risk factors for antenatal common mental problems include a history of depression, lack of social support and a history of both childhood and adulthood sexual and physical abuse. However, it is less clear whether pregnancy is a time of particular susceptibility to mental disorders due to prior childhood experiences. The aim of the paper was to investigate the potential pathways to antenatal mental health problems. A total of 521 women attending prenatal care attended a clinical interview and answered psychological questionnaires. Univariate analysis, sequential binary logistic regression and structural equation modelling (SEM) were used to analyse the relationships between variables. Having experienced parental maladjustment, maltreatment and serious physical illness in childhood and domestic violence, financial difficulties and serious spousal substance abuse in adulthood significantly predicted antenatal common mental health symptoms. SEM showed that history of depression and adverse experiences in adulthood had mediating effects on the relationship between adverse childhood events and symptoms of antenatal common mental disorders. Adverse childhood experiences are distal risk factors for antenatal common mental health problems, being significant indicators of history of depression and adverse experiences in adulthood. We therefore conclude that pregnancy is not a time of particular susceptibility to common mental health problems as a result of childhood abuse, but rather, these childhood experiences have increased the risk of adulthood trauma and prior mental disorders. Women at risk for antenatal common mental disorders include those with a history of depression, domestic violence, financial difficulties, spousal substance abuse and lack of social support.

     

Identification of phosphorylated residues that affect the activity of the mitotic kinase Aurora-A

The activity of the kinase Aurora-A (Aur-A) peaks during mitosis and depends on phosphorylation by one or more unknown kinases. Mitotic phosphorylation sites were mapped by mass spec sequencing of recombinant Aur-A protein that had been activated by incubation in extracts of metaphase-arrested Xenopus eggs. Three sites were identified: serine 53 (Ser-53), threonine 295 (Thr-295), and serine 349 (Ser-349), which are equivalent to Ser-51, Thr-288, and Ser-342, respectively, in human Aur-A. To ask how phosphorylation of these residues might affect kinase activity, each was mutated to either alanine or aspartic acid, and the recombinant proteins were then tested for their ability to be activated by M phase extract. Mutation of Thr-295, which resides in the activation loop of the kinase, to either alanine or aspartic acid abolished activity. The S349A mutant had slightly reduced activity, indicating that phosphorylation is not required for activity. The S349D mutation completely blocked activation, suggesting that Ser-349 is important for either the structure or regulation of Aur-A. Finally, like human Aur-A, overexpression of Xenopus Aur-A transformed NIH 3T3 cells and led to tumors in nude mice. These results provide further evidence that Xenopus Aur-A is a functional ortholog of human Aur-A and, along with the recently described crystal structure of human Aur-A, should help in future studies of the mechanisms that regulate Aur-A activity during mitotic progression.     

Immune reconstitution after autologous hematopoietic stem cell transplantation in relation to underlying disease, type of high-dose therapy and infectious complications

BACKGROUND AND OBJECTIVES: Autologous peripheral stem cell transplantation (APSCT) is increasingly used for various hematologic malignancies and solid tumors. The objective of this study was to analyze the immune reconstitution after APSCT and see if there was any correlation with diagnosis, age, type of high-dose therapy, CD34(+) selection of the autograft and double vs single APSCT. DESIGN AND METHODS: Lymphocyte subset recovery was studied in 46 consecutive patients with hematologic malignancies and breast cancer, who underwent APSCT. Eleven patients with multiple myeloma received tandem autografts. Thirty-one patients were given total body irradiation (TBI) as part of the high-dose treatment. Eighteen patients received a CD34(+) selected graft. The percentage and absolute numbers of lymphocyte populations, T-cells (CD2(+), CD3(+)), B-cells (CD19(+)), NK cells (CD56(+ )CD3(-) and CD16(+)CD3(-)) and T-cell subpopulations (CD4(+), CD8(+), CD4(+)CD45RA(+), CD4(+ )CD45RO(+), CD4(+)DR(+), CD8(+ )CD45RO(+), CD8(+)DR(+)), were monitored with flow cytometry during the first year after APSCT. RESULTS: The total B-cell (CD19(+)) and T-cell (CD3(+)) counts were reconstituted to normal levels 2-4 months after APSCT. All patients had a low CD4/CD8 ratio during the observation period, related to both a low number of CD4(+) cells and elevated numbers of CD8(+) cells. The low number of CD4(+) cells was due to a persistently low level of naive CD4(+)CD45RA(+) cells. A high proportion of the CD8+ cells displayed a phenotype compatible with activated T-cells (CD8(+)DR(+)) up to 10 months after autografting. The number of NK cells (CD56(+)3(-) or CD16(+)3(-)) reached normal values within one month post-transplant. No single variable, such as diagnoses, age, TBI as part of the high-dose treatment, tandem autografting or CD34(+) selection of the graft, influenced the immune or hematopoietic reconstitution and no correlation with documented infectious complications was found. INTERPRETATION AND CONCLUSIONS: Despite heterogeneity of diseases, age, initial treatment and high-dose regimens, lymphocyte subset analysis did not reveal any differences in hematopoietic or immune reconstitution. All patients had a low CD4(+)/CD8(+) ratio during at least the first year post-transplant, caused by a persistent increase of CD8(+) lymphocytes and a constant reduction of CD4(+) lymphocytes, making the patients susceptible to infections for a prolonged period of time post-transplant.     

Serum 25-hydroxyvitamin D levels and bone mineral density in 16–20 years-old girls: lack of association

Pancreas allograft transplantation (PTX) when successful is an effective modality for the control of glucose metabolism in diabetic patients [1, 2]. Side-effects are mainly related to surgical complications, immunosuppressive therapy and graft rejection. Hypoglycaemia is an unexpected complication that has been reported [3, 4]. We report two patients having recurrent hypoglycaemic events following pancreatic transplantation and review the literature.     

Lack of germline PALB2 mutations in melanoma-prone families with CDKN2A mutations and pancreatic cancer

The presence of pancreatic cancer (PC) in melanoma-prone families has been consistently associated with an increased frequency of CDKN2A mutations, the major high-risk susceptibility gene identified for melanoma. However, the precise relationship between CDKN2A, melanoma and PC remains unknown. We evaluated a recently identified PC susceptibility gene PALB2 using both sequencing and tagging to determine whether PALB2 might explain part of the relationship between CDKN2A, melanoma, and PC. No disease-related mutations were identified from sequencing PALB2 in multiple pancreatic cancer patients or other mutation carrier relatives of PC patients from the eight melanoma-prone families with CDKN2A mutations and PC. In addition, no significant associations were observed between 11 PALB2 tagging SNPs and melanoma risk in 23 melanoma-prone families with CDKN2A mutations or the subset of 11 families with PC or PC-related CDKN2A mutations. The results suggested that PALB2 does not explain the relationship between CDKN2A, melanoma, and pancreatic cancer in these melanoma-prone families.     

Genetic epidemiologic aspects of gastric cancer in Iceland

BACKGROUND: Association between gastric cancer and environmental factors (diet and infections) has been established, and genetic changes are well described in adenocarcinomas of the stomach. Less is known about clinical features of hereditary gastric cancer and whether the disease is associated with family clustering. STUDY DESIGN: Family trees of patients diagnosed with gastric cancer in Iceland between 1955 and 1999 were identified in the Genealogical Database of the University of Iceland. All probands with age of onset younger than 60 years were used in the study. Families of all probands (n = 455 men and 161 women) were traced to third degree. Through linkage of the genealogic data obtained by the Icelandic Cancer Registry (between 1955 and 1999), all reported cancers were identified in those families. The expected number of cases was calculated using age-specific population rates in Iceland. RESULTS: A relative risk (RR) of 2.2 (95% confidence interval [CI] = 1.6-3.0) and 1.3 (95% CI = 1.0-1.7) for the gastric cancer risk was observed among 2,846 first- and 8,658 second-degree relatives of male probands. For female probands the corresponding relative risks were 1.6 (95% CI = 1.1-2.6, n = 7,396) and 1.4 (95% CI = 0.9-2.0, n = 2,764). The increased risk was more pronounced for relatives of men and women diagnosed with gastric cancer before the age of 50 years. A minor difference in relative risk was found between relatives of probands who were diagnosed with intestinal type or diffuse type gastric cancer. Fifty-eight families with two or more relatives with cancer were identified. In 32 families 2 relatives with gastric cancer were identified and in 26 families 3 or more relatives had gastric cancer. CONCLUSIONS: Relatives of gastric cancer patients have two- to three-fold increased risk of developing gastric cancer. The risk is elevated for both genders.