Cardiovascular medication after cancer at a young age in Finland: A nationwide registry linkage study.

Despite improved survival rates, childhood and young adult (YA) cancer survivors face elevated risks for life-threatening morbidities, especially cardiovascular complications. Our nationwide Finnish registry study investigated the purchases of cardiovascular medication from 1993 to 2011 in patients diagnosed with cancer aged below 35 years (N = 8,197) between 1993 and 2004 compared to siblings (N = 29,974) via linkage to the drug purchase registry. The cumulative incidence for purchasing cardiovascular medications was higher in childhood and YA cancer patients compared to siblings with a rising trend over time. After childhood cancer, the highest hazard ratio (HR) was found for purchasing anticoagulants (HR 19.8, 95% CI 8.5-45.9). The HRs for any cardiovascular medication (HR 7.2, 95% CI 5.1-10.1) and cardiac medication (HR 4.8, 95% CI 3.3-6.9) were markedly elevated after childhood cancer as well. Regarding YA cancer patients, the respective HRs were 2.5 (95% CI 2.0-3.2) for anticoagulants, HR 1.7 (95% CI 1.5-1.9) for any cardiovascular medication and HR 1.5 (95% CI 1.3-1.7) for cardiac medication. Among cancer patients, highest HRs for cardiovascular medication were observed after childhood acute lymphoblastic leukemia (ALL) and bone tumors (HR 10.2, 95% CI 6.8-15.5 and HR 7.4, 95% CI 4.0-13.7) and YA ALL and acute myeloid leukemia (HR 5.1, 95% CI 3.5-7.1 and HR 2.8, 95% CI 1.8-4.0). Our study demonstrated increased HRs for purchasing cardiovascular medication after early-onset cancer compared to siblings reflecting elevated cardiovascular morbidity. Thus, the implementation of long-term cardiovascular disease screening is imperative to prevent, detect and adequately treat cardiovascular late effects after cancer at a young age.

Cardiovascular morbidity in long-term survivors of early-onset cancer: a population-based study.

Improvements in cancer therapy have resulted in an expanding population of early-onset cancer survivors. In contrast to childhood and adolescent cancer survivors, there is still a lack of data concerning late morbidities among young adult (YA) cancer survivors. Thus, our aim was to investigate cardiac and vascular morbidity among early-onset cancer survivors with a special interest in YA cancer survivors. In a population-based setting, we explored the risk of cardiovascular disease in early-onset cancer survivors compared to healthy siblings. Patients diagnosed with cancer below 35 years of age since 1975 were identified from the Finnish Cancer Registry, and 5-year survivors were included in our study (N = 13,860). Information on cardiovascular morbidity was collected from the national hospital discharge registry. Compared to siblings, cancer survivors aged 0-19 and 20-34 at diagnosis had significantly elevated hazard ratios (HRs) for the studied outcomes: HR 13.5 (95% CI 8.9-20.4) and 3.6 (95% CI 2.8-4.6) for cardiomyopathy/cardiac insufficiency; HR 3.4 (95% CI 2.3-5.1) and 1.7 (95% CI 1.4-2.0) for atherosclerosis/brain vascular thrombosis; HR 3.3 (95% CI 1.7-6.5) and 1.8 (95% CI 1.5-2.1) for myocardial infarction/cardiac ischemia and HR 1.7 (95% CI 1.2-2.6) and 1.4 (95% CI 1.2-1.7) for cardiac arrhythmia. In both groups, depending on the outcome, the HR for adverse events was highest among lymphoma, brain tumor, leukemia and testicular malignancy survivors. Our results regarding late effects of childhood cancer survivors confirmed previous findings. Additionally, our study provides novel information concerning the YA cancer survivor population. Hence, our data may help in planning the risk-based long-term follow-up of early-onset cancer survivors.

Serum HE4 concentration is not dependent on menstrual cycle or hormonal treatment among endometriosis patients and healthy premenopausal women.

OBJECTIVE: Human epididymal secretory protein E4 (HE4) is a new promising tumor marker developed for the diagnostics and follow up of ovarian cancer. It has yet to become widely accepted in clinical practice, and its biological properties have not been inclusively studied. The aim of this study was to investigate whether serum HE4 concentration varies within the normal menstrual cycle and whether common gynecological hormonal treatments have an effect on HE4 values. METHODS: Our study population consisted of 180 women, including 126 endometriosis patients and 54 healthy women. We measured their serum HE4 and CA125 concentrations and evaluated the effect of the menstrual cycle and the possible hormonal medication on these marker concentrations. RESULTS: We found no significant variation in serum HE4 concentrations in samples taken at different phases of the menstrual cycle. The median HE4 concentrations in proliferative, secretory and menstrual phase were 41.5, 45.1 and 35.3 pM in healthy women, and 43.4, 44.3 and 43.0 pM in endometriosis patients, respectively. The use of combined estrogen and progestin contraceptives did not affect serum HE4 levels significantly. CONCLUSIONS: The present study shows that the HE4 measurement in healthy premenopausal women as well as in women with endometriosis can be carried out at any phase of the menstrual cycle, and irrespective of hormonal medication, extending the benefits of HE4 use in clinical practice.

Effect of antenatal growth and prematurity on brain white matter: diffusion tensor study.

BACKGROUND: White matter maturation is characterised by increasing fractional anisotropy (FA) and decreasing mean diffusivity (MD). Contradictory results have been published on the effect of premature birth on white matter maturation at term-equivalent age. OBJECTIVE: To assess the association of gestational age and low birth-weight-for-gestational-age (z-score) with white matter maturation. MATERIALS AND METHODS: Infants (n = 76, 53 males) born at different gestational ages were imaged at term-equivalent age. Gestational age and birth weight z-score were used as continuous variables and the effect on diffusion parameters was assessed. Brain maturation was studied using regions-of-interest analysis in several white matter areas. RESULTS: Gestational age showed no significant effect on white matter maturation at term-equivalent age. Children with low birth weight z-score had lower FA in the genu and splenium of the corpus callosum (regression, P = 0.012 and P = 0.032; correlation, P = 0.009 and P = 0.006, respectively), and higher MD in the splenium of the corpus callosum (regression, P = 0.002; correlation, P = 0.0004) compared to children whose birth weight was appropriate for gestational age. CONCLUSION: Children with low birth weight relative to gestational age show delay and/or anomaly in white matter maturation at term-equivalent age.

Internationally adopted children in Finland: parental evaluations of symptoms of reactive attachment disorder and learning difficulties - FINADO study.

OBJECTIVE: This study investigated the association between psychological symptoms, such as features of reactive attachment disorder (RAD), and learning difficulties among international adoptees in Finland. METHODS: The data for this study came from the FINnish ADOption (FINADO) study covering all internationally adopted children in Finland (n= 1450), with a response rate of 55.7%. The subsample consisted of 395 adopted children aged 9-15 (51.6% girls, 48.4% boys). Learning difficulties were evaluated by a screening questionnaire 'Five To Fifteen' and symptoms of RAD by FINADO RAD scale. RESULTS: The parents estimated that one-third (33.4%) of the internationally adopted children had some, and 12.7% had severe learning difficulties, i.e. three and six times more than in normal population, respectively. RAD symptoms at the time of adoption were associated with learning difficulties at school age (OR 4.57, 95% CI 2.57-8.13). CONCLUSIONS: Learning difficulties are common among internationally adopted children in Finland and symptoms of RAD are associated with a child's learning difficulties.

Abnormal antenatal Doppler velocimetry and cognitive outcome in very-low-birth-weight infants at 2 years of age.

OBJECTIVE: To study neurodevelopmental outcome at 2 years of corrected age in very-low-birth-weight (VLBW) (< or = 1500 g) preterm infants with abnormal fetoplacental flow. METHODS: A total of 258 VLBW infants were born at Turku University Hospital between 2001 and 2006. Of these, 99 had undergone, within 1 week of delivery, antenatal Doppler assessment of blood flow in the umbilical artery (UA), fetal middle cerebral artery (MCA), descending aorta (DAo), aortic isthmus and ductus venosus and were eligible for inclusion in the study. Postnatally brain pathology was assessed by serial ultrasound and magnetic resonance imaging in 86 of the neonates and brain volume was measured in 80. Cognitive development was evaluated at 2 years of corrected age in 83 infants using the Bayley Scales of Infant Development-II. Motor development was assessed using the Hammersmith Infant Neurological Examination. RESULTS: On univariate analysis, abnormal pulsatility index (PI) in the UA and an abnormal UA-PI/MCA-PI ratio (P = 0.04 and P = 0.003, respectively) as well as increases in both the DAo-PI and in the DAo-PI/MCA-PI ratio (P = 0.03 and P = 0.02, respectively), were associated with adverse cognitive outcome at 2 years of age. However, when controlling for cerebral volume using multivariate analysis, the association between abnormal antenatal Doppler characteristics and cognitive outcome became statistically non-significant, which indicated the determinant role of the volume reduction. Motor development was not associated with antenatal Doppler indices. CONCLUSION: Abnormal antenatal Doppler indices are associated with adverse cognitive outcome at 2 years in VLBW infants. Our findings suggest that this association may be mediated through brain volume.

Incidence of necrotizing enterocolitis in very-low-birth-weight infants related to the use of Lactobacillus GG.

BACKGROUND: One of the five level III neonatal intensive care units (NICU) in Finland has used prophylactic Lactobacillus GG (LGG) for very-low-birth-weight (VLBW) infants since 1997. AIM: To examine retrospectively the incidence of necrotizing enterocolitis (NEC) in all five university hospital NICUs in Finland in relation to the use of LGG during the years each unit has belonged to the Vermont Oxford Network (VON). METHODS: The incidence of NEC was analysed from the national database and from the VON databases separately in all five level III NICUs and additionally in three groups according to the probiotic practice in the hospitals: prophylactic LGG group, probiotics 'on demand' group and no probiotics group. RESULTS: The incidence of NEC was 4.6% vs. 3.3% vs. 1.8% in the prophylactic LGG group, the no probiotics group and the probiotics 'on demand' group [corrected] respectively; p = 0.0090, chi-square. LGG had no influence on the clinical course of NEC. CONCLUSIONS: The results of this retrospective report failed to show that LGG prophylaxis protects VLBW infants from the occurrence of NEC, in contrast to previously published results. Our results call for more research regarding effective ways to administer probiotics, including data on appropriate bacteria, strain, dose and timing of administration to achieve clinically robust effects.

Effects of serum-free in vitro maturation of bovine oocytes on subsequent embryo development and cell allocation in two developmental stages of day 7 blastocysts.

Maturation of oocytes and the subsequent outcome of the in vitro production (IVP) are affected by the composition of in vitro maturation (IVM) medium. To determine the use of serum interfering with effects of single molecules, we aimed at developing simplified IVM medium. The experimental IVM media were: (1) M199-medium supplemented with hormones and serum (control), (2) as 1 but serum was substituted with fatty acid-free serum albumin (FAFBSA) and (3) M199-medium without hormonal and serum supplementation (M199). The quality of embryos was assessed on day 7 by morphology and cryotolerance, as well as by Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) and differential staining. Results showed that the nuclear maturation was suppressed in M199 group alone. Embryo cleavage and development rates, and the proportion of quality 1 blastocysts were lower in the FAFBSA and M199 groups compared to the control. Differences in the cell allocation of fresh embryos were observed at the blastocyst stage, but not at the expanded blastocyst stage. The control group blastocysts had larger number of cells allocated to the inner cell mass (ICM), and the FAFBSA group blastocysts larger apoptotic cell proportion compared to the blastocysts derived from other groups. After cryopreservation, the reduction of ICM proportion and increase of apoptotic cell proportion of embryos were equal between the experimental groups. In conclusion, exclusion of serum from the IVM media reduces embryo development and may cause perturbations in blastocyst development. Differences in the cell allocation of blastocysts between IVM media may appear only when the developmental stages are taken into account.

Do the early development of gestures and receptive and expressive language predict language skills at 5;0 in prematurely born very-low-birth-weight children?

UNLABELLED: It is unclear what the predictive value of very early development of gestures and language is on later language ability in prematurely born very-low-birth-weight (VLBW; birth weight ≤1500g) children. The aim of the present study was to analyse the predictive value of early gestures and a receptive lexicon measured between the ages of 0;9 and 1;3, as well as the predictive value of receptive and expressive language ability at 2;0 for language skills at 5;0 in VLBW children. The subjects were 29 VLBW children and 28 full-term children whose language development has been followed intensively between the ages of 0;9 and 2;0 using the Finnish version of the MacArthur Developmental Inventory and the Reynell Developmental Language Scales (RDLS III). At 5;0, five selected verbal subtests of the Nepsy II test and the Boston Naming Test (BNT) were used to assess children's language skills. For the first time in VLBW children, the development of gestures measured between the ages of 0;9 and 1;3 was shown to correlate significantly and positively with language skills at 5;0. In addition, both receptive and expressive language ability measured at 2;0 correlated significantly and positively with later language skills in both groups. Moreover, according to the hierarchical regression analysis, the receptive language score of the RDLS III at 2;0 was a clear and significant predictor for language skills at 5;0 in both groups. The findings particularly underline the role of early receptive language as a significant predictor for later language ability in VLBW children. The results provide evidence for a continuity between early language development and later language skills. LEARNING OUTCOMES: After reading this article, readers will understand the associations between the very early (≤2 years of age) development of gestures and language (i.e. early receptive lexicon, expressive lexicon at 2;0, receptive and expressive language ability at 2;0) and the language skills at 5;0 in prematurely born very-low-birth-weight (VLBW) children. In addition, readers will understand the heterogeneity of the group of VLBW children. The information presented in this article is informative for those who work in a clinical context and who want to be able to identify those VLBW children who need support for their language development at an early age.

Health conditions associated with metabolic syndrome after cancer at a young age: A nationwide register-based study.

PURPOSE: Childhood cancer survivors are at risk for developing metabolic syndrome (MetS), which subsequently leads to cardiovascular morbidity and excess mortality. Our aim was to investigate the purchases of medications associated with MetS among 7551 early onset cancer patients compared to siblings. METHODS: Our nationwide Finnish population-based registry study analyzed the drug purchase of medication among early onset cancer patients diagnosed with cancer below the age of 35 years between 1994 and 2004 compared to siblings by linkage to the drug purchase registry, allowing for a maximal follow-up of 18 years. RESULTS: The hazard ratios (HRs) for purchasing antihypertensives and diabetes drugs were higher after both childhood (HR 4.6, 95%CI 3.1-7.0; HR 3.0, 95%1.5-6.1) and young adulthood (YA) cancer (HR 1.5, 95%CI 1.3-1.8; HR 1.6, 95%CI 1.1-2.2) compared to siblings. The HRs for purchasing lipid-lowering drugs were elevated both after childhood (HR 4.3,95%CI 0.9-19.5) and YA cancer (HR 1.6, 95%CI 1.04-2.5), but only reached significance in YA cancer patients. Among specific cancer diagnosis groups, highest HR values for antihypertensives were found in childhood acute lymphoblastic leukemia (ALL) (HR 6.1, 95%CI 3.7-10.3) and bone tumor (HR 4.3, 95%CI 1.9-9.4), and YA ALL (HR 4.8, 95%CI 3.1-7.0) and acute myeloid leukemia (AML) (HR 3.4, 95%CI 2.5-5.1) patients. Moreover, childhood ALL (HR 6.3, 95%CI 2.7-14.8), AML (HR 7.6, 95%CI 1.9-24.5) and central nervous system (CNS)-tumor (HR 3.5, 95%CI 1.3-9.2) and YA ALL (HR 3.7, 95%CI 1.2-9.5) patients showed the strongest likelihood of purchasing diabetes drugs compared to siblings. CONCLUSION: The purchase of medications associated with MetS was increased after early onset cancer and highly dependent on the age at cancer diagnosis and the cancer diagnosis. Prevention strategies are imperative for reducing potentially life-threatening cardiovascular complications after early onset cancer.

Prevalence of Pain Symptoms Suggestive of Endometriosis Among Finnish Adolescent Girls (TEENMAPS Study).

STUDY OBJECTIVE: To evaluate the prevalence of pain symptoms suggestive of endometriosis among adolescent girls aged 15-19 years. DESIGN: Cross-sectional study. SETTING: University hospital. PARTICIPANTS: Adolescent girls aged 15-19 years attending elementary school, high school, or vocational institute at 3 cities in Southwest Finland in 2010-2011. INTERVENTIONS: The school nurses distributed a detailed questionnaire to 2582 girls who were attending school at the time of the study. Completion of the questionnaire was voluntary and anonymous. MAIN OUTCOME MEASURES: Prevalence and severity of dysmenorrhea, acyclic abdominal pain, dyspareunia, dyschezia, and dysuria. Severity was evaluated with an 11-point numerical rating scale (NRS). RESULTS: A total of 1103 eligible answers were analyzed. The prevalence of dysmenorrhea was 68% (738/1092) with mean NRS of 7.0 (SD = 2.0). Acyclic abdominal pain, dyspareunia, dyschezia, and dysuria were less frequent (19% [207/1085], 12% [53/458], 8% [87/1088] and 5% [50/1084], respectively). The prevalence of severe dysmenorrhea (NRS 8-10) was 33% (355/1089). Severe dysmenorrhea was associated with increased risk of concurrent acyclic abdominal pain (odds ratio [OR] = 2.7; 95% confidence interval [CI], 2.0-3.6), dyschezia (OR = 2.5; 95% CI, 1.6-3.9), and regular absenteeism from school or hobbies (OR = 10.0; 95% CI, 4.2-23.6). Using different criteria, 2%-10% (21-106/1103) of all girls could be identified as having symptoms suggestive of endometriosis. Five percent of girls (n = 53/1103) had severe dysmenorrhea, used oral contraceptive pills, and reported inadequate relief from pain medication. CONCLUSION: One-third (355/1089) of 15- to 19-year-old girls had severe menstrual pain and 14% (49/355) of them were regularly absent from school or hobbies. Five percent of all teenage girls (53/1103) were poor responders to conventional therapy for primary dysmenorrhea.

Early relations between language development and the quality of mother-child interaction in very-low-birth-weight children.

BACKGROUND: It is not clearly understood how the quality of early mother-child interaction influences language development in very-low-birth-weight children (VLBW). AIMS: We aim to analyze associations between early language and the quality of mother-child interaction, and, the predictive value of the features of early mother-child interaction on language development at 24 months of corrected age in VLBW children. STUDY DESIGN: A longitudinal prospective follow-up study design was used. METHODS: The participants were 28 VLBW children and 34 full-term controls. Language development was measured using different methods at 6, 12 and at 24 months of age. The quality of mother-child interaction was assessed using PC-ERA method at 6 and at 12 months of age. RESULTS: Associations between the features of early interaction and language development were different in the groups of VLBW and full-term children. There were no significant correlations between the features of mother-child interaction and language skills when measured at the same age in the VLBW group. Significant longitudinal correlations were detected in the VLBW group especially if the quality of early interactions was measured at six months and language skills at 2 years of age. However, when the predictive value of the features of early interactions for later poor language performance was analyzed separately, the features of early interaction predicted language skills in the VLBW group only weakly. CONCLUSIONS: The biological factors may influence on the language development more in the VLBW children than in the full-term children. The results also underline the role of maternal and dyadic factors in early interactions.

Apolipoprotein E, brain injury and neurodevelopmental outcome of children.

Apolipoprotein E plays an important role in neurodegenerative processes in adulthood, whereas its neurodevelopmental role is uncertain. We aimed to study the effect of apolipoprotein E on neurodevelopment in a cohort liable to neurodevelopmental changes. The cohort consisted of very preterm (<32 gestational weeks) and/or very low birth weight (<1500 g) children, and the longitudinal follow-up protocol included sequential cranial ultrasounds during infancy, brain magnetic resonance imaging at term-equivalent age, neurological and cognitive assessment (Mental Developmental Index) at the corrected age of 2 years and cognitive and neuropsychological assessments (Wechsler Preschool and Primary Scale of Intelligence and Developmental NEuroPSYchological Assessment) at the chronological age of 5 years. Apolipoprotein E genotypes were determined from 322 children. Ultrasound and magnetic resonance imaging data were available for 321 (99.7%) and 151 (46.9%) children, respectively. Neurodevelopmental assessment data were available for 138 (42.9%) to 171 (53.1%) children. Abnormal findings in ultrasounds and magnetic resonance imaging were found in 163 (50.8%) and 64 (42.4%) children, respectively. Mild cognitive delay at the corrected age of 2 years and the chronological age of 5 years was suspected in 21 (12.3%) of 171 and 19 (13.8%) of 138 children, respectively. In the Developmental NEuroPSYchological Assessment, 47 (32.6%) of 144 children had significantly impaired performances in more than one study subtest. No associations between the apolipoprotein E genotypes and imaging findings or measured neurodevelopmental variables were found. Apolipoprotein E genotypes do not appear to have major impact on brain vulnerability or neurodevelopment in children.