Late effects of cancer at a young age: Registry-based studies of the health of cancer patients and their off-spring

Modern cancer therapy has resulted in increased survival among patients diagnosed with cancer at a young age. These improvements have led to the investigation of late morbidity and mortality associated with cancer and its treatments. The aim of this study was to evaluate late effects of cancer treated at a young age on the health of patients and their offspring. Utilising the nationwide population-based registries in Finland, we evaluated the risk of hypothyroidism and the probability of parenthood in cancer survivors as well as preterm birth, neonatal outcomes, and the risk of cancer among offspring of patients. The survivor cohort, identified from the Finnish Cancer Registry, consisted of 25,784 cancer patients diag-nosed between ages 0 and 34 in 1953–2004. By linkage to the population register, siblings of these patients were identified for comparison. The prevalence of hypothyroidism was higher among former childhood cancer (aged 0–16) patients than in the general population. The probability of parenthood following early onset cancer was overall significantly reduced compared to siblings. Offspring of female cancer survivors were at an increased risk of preterm birth, this risk being highest among patients diagnosed in childhood and early adulthood (aged 20–34 years). The offspring were not, however, at a significantly increased risk of neonatal death or stillbirth, though they were more likely to need monitoring or intensive care in the neonatal period. The risk of sporadic cancer among offspring of male and female cancer survivors was not elevated in comparison to the general population. The study showed that former cancer patients are at risk of certain adverse endocrine and reproductive health outcomes and should be followed for timely intervention. The offspring of cancer survivors do not appear to be at risk for adverse health outcomes.

Impact of global warming on potato late blight : risk, yield loss and control

Selostus: Ilmaston lämpenemisen vaikutus perunaruttoon

Antenatal inflammation and brain pathology in preterm infants

Chorioamnionitis is known to be an important risk factor underlying preterm delivery, and it has also been suggested to associate with brain lesions and deviant neurological development in both preterm and term infants. Cytokines are believed to be the link causing the deleterious effects of inflammation to the nervous system. Their genetic regulation has also been suggested to play a role, as interleukin (IL)-6 -174 and -572 genotypes, which partly regulate IL-6 synthesis responses, have been connected with deviant neurological development in preterm infants. We evaluated the association of histological chorioamnionitis with brain lesions, regional brain volumes, and the functioning of the auditory pathway in very low birth weight/very low gestational age (VLBW/VLGA) infants. In addition, we investigated the association between IL-6 -174 and -572 genotypes and histological chorioamnionitis, neonatal infections, and brain lesions and regional brain volumes in VLBW/VLGA infants. This study is a part of a larger multidisciplinary project PIPARI (Development and Functioning of Very Low Birth Weight Infants from Infancy to School Age), in which the survivors of a 6-year cohort of VLBW/VLGA infants (n=274) are being followed until school age in Turku University Central Hospital, Finland. Placental samples were collected in the delivery room, and were analyzed for histological inflammatory findings. Blood samples from the infants were collected and DNA was genotyped for IL-6-174 and -572 polymorphisms (GG/GC/CC). Brain ultrasound examinations were performed repeatedly in the neonatal intensive care unit and at term age, and were analysed for structural brain lesions. Brain magnetic resonance imaging was performed at term age, and was analysed for regional brain volumes. In addition, diffusion tensor imaging was performed at term, and was used to analyse fractional anisotrophy and the apparent diffusion coefficient of inferior colliculus. The brainstem auditory evoked potential recordings were carried out according to the routine clinical procedure at median age of 30 days after term age. In our study, we found that histological chorioamnionitis was not an independent risk factor for brain lesions, reduced regional brain volumes or abnormal functioning of the auditory pathway in VLBW/VLGA infants. In addition, we found that IL-6 -174 GG and -572 GC genotypes were associated with a higher incidence of histological chorioamnionitis, and that -174 CC genotype associated with higher incidence of septicaemia. The analysed IL-6 genotypes were not associated with other brain lesions, but a reduced volume of basal ganglia and thalami was associated with IL-6 -174 CC and -572 GG genotypes. In conclusion, our findings suggest that histological chorioamnionitis is not an independent risk factor for the brain development of VLBW/VLGA infants, or that the risk caused by inflammation does not exceed the risks attributed to other underlying pathologies behind preterm deliveries. In addition, our findings give reason to propose that IL-6 promoter genotypes have a role in the defence against serious infections and in the brain development of VLBW/VLGA infants.

Early relationship between very preterm infant and mother: The role of infant, maternal and dyadic factors

Pienipainoisen keskosen ja äidin varhainen suhde: Lapsen, äidin ja dyadisten muuttujien vaikutus Tämän tutkimuksen tavoitteena oli tutkia keskosvauvan ja äidin varhaista suhdetta. Tutkimuksessa selvitettiin myös vauvan itkukäyttäytymisen, vauvan sylissä olon ja äidin masentuneisuuden yhteyttä äidin ja keskosvauvan varhaiseen suhteeseen. Tutkimusryhmät koostuivat 32:sta (tutkimus I-II) ja 38:sta (tutkimus III-IV) keskosena syntyneestä vauvasta (syntymäpaino < 1501 g tai GI < 32 viikkoa) sekä 46:sta täysiaikaisena syntyneestä terveestä verrokkivauvasta. Lapsen ja äidin vuorovaikutusta arvioitiin 6 ja 12 kuukauden iässä (korjattu ikä) PCERAmenetelmällä. Äidin mielikuvia lapsestaan tutkittiin WMCI-haastattelulla, kun lapsi oli 12 kuukautta. Baby Day Diary -menetelmää käytettiin vauvan itkukäyttäytymisen ja sylissä olon keston mittaamisessa vauvan ollessa 5 kuukautta. Äidin masentuneisuutta arvioitiin EDPS-lomakkeella, kun lapsi oli 6 kuukautta. Tulokset osoittivat, että turvallisten kiintymyssuhdemielikuvien määrä tai vuorovaikutuksen laatu eivät keskosvauvan äideillä eronneet täysiaikaisina syntyneiden vauvojen äitien vastaavista. Ryhmien välillä ei löytynyt eroja myöskään dyadisen vuorovaikutuksen laadussa. Keskosena syntyneet lapset olivat kuitenkin vetäytyvämpiä ja heillä oli laadullisesti heikommat keskittymisen ja leikin taidot vuorovaikutustilanteessa 12 kuukauden iässä täysiaikaisina syntyneisiin lapsiin nähden. Lisäksi äidin masentuneisuus ja lapsen pitkittynyt itkuisuus olivat negatiivisessa yhteydessä vuorovaikutuksen laatuun keskosvauvojen ryhmässä. Vauvan itkukertojen määrän, sylissä olon keston sekä äidin ja vauvan vuorovaikutuksen laadun välillä löytyi positiivinen yhteys ainoastaan keskosena syntyneiden lasten ryhmässä. Tulostemme perusteelle toteamme, että lapsen ennenaikainen syntymä itsessään ei näytä muodostavan riskiä äidin vuorovaikutuksen laadulle tai turvalliselle kiintymyssuhteelle. Yhdessä muiden riskitekijöiden kanssa keskosuus kuitenkin altistaa vauvat ja heidän äitinsä varhaisen vuorovaikutuksen ongelmille. Lisäksi tuloksemme viittaavat siihen, että vauvan itku ja siitä seuraava sylissä olo toimivat suojaavana mekanismina pienipainoisen keskosen ja äidin varhaisessa suhteessa.

The effect of the birth hospital and the time of birth on the outcome of Finnish very preterm infants

The purpose of this study was to evaluate the effect of the birth hospital and the time of birth on mortality and the long-term outcome of Finnish very low birth weight (VLBW) or very low gestational age (VLGA) infants. This study included all Finnish VLBW/VLGA infants born at <32 gestational weeks or with a birth weight of ≤1500g, and controls born full-term and healthy. In the first part of the study, the mortality of VLBW/VLGA infants born in 2000–2003 was studied. The second part of the study consisted of a five-year follow-up of VLBW/VLGA infants born in 2001–2002. The study was performed using data from parental questionnaires and several registers. The one-year mortality rate was 11% for live-born VLBW/VLGA infants, 22% for live-born and stillborn VLBW/VLGA infants, and 0% for the controls. In live-born and in all (including stillbirths) VLBW/VLGA infants, the adjusted mortality was lower among those born in level III hospitals compared with level II hospitals. Mortality rates of live-born VLBW/VLGA infants differed according to the university hospital district where the birth hospital was located, but there were no differences in mortality between the districts when stillborn infants were included. There was a trend towards lower mortality rates in VLBW/VLGA infants born during office hours compared with those born outside office hours (night time, weekends, and public holidays). When stillborn infants were included, this difference according to the time of birth was significant. Among five-year-old VLBW/VLGA children, morbidity, use of health care resources, and problems in behaviour and development were more common in comparison with the controls. The health-related quality of life of the surviving VLBW/VLGA children was good but, statistically, it was significantly lower than among the controls. The median and the mean number of quality-adjusted life-years were 4.6 and 3.6 out of a maximum five years for all VLBW/VLGA children. For the controls, the median was 4.8 and the mean was 4.9. Morbidity rates, the use of health care resources, and the mean quality-adjusted life-years differed for VLBW/VLGA children according to the university hospital district of birth. However, the time of birth, the birth hospital level or university hospital district were not associated with the health-related quality of life, nor with behavioural and developmental scores of the survivors at the age of five years. In conclusion, the decreased mortality in level III hospitals was not gained at the expense of long-term problems. The results indicate that VLBW/VLGA deliveries should be centralized to level III hospitals and the regional differences in the treatment practices should further be clarified. A long-term follow-up on the outcome of VLBW/VLGA infants is important in order to recognize the critical periods of care and to optimise the care. In the future, quality-adjusted life-years can be used as a uniform measure for comparing the effectiveness of care between VLBW/VLGA infants and different patient groups

Very preterm infants in Finland - Use of health care services and economic consequences during the first five years of life

The aim of this thesis was to study the health, the hospitalisations, and the use of communal health care services in very preterm children during the first five years of life. In addition, the effect of very preterm birth and prematurity-related morbidities on the costs of hospitalisations, other health care services and the cost per quality adjusted life years (QALY) were studied. This population-based study included all very preterm children (gestational age (GA) <32 weeks or birth weight<1501g, N=2 064) and full-term controls (GA 37+0−41+6, N=200 609) born in Finland during 2000-2003. The data sources included national register data, costing data from the participating hospitals and parental questionnaires. This study showed that most very preterm infants born in Finland survived without prematurity-related morbidities diagnosed during the first years of life. They required relatively little hospital care after the initial discharge, which accounted for the vast majority of the total four-year hospitalisation costs. However, a minority of children born very preterm later developing morbidities had a long initial length of stay and more re-admissions and outpatient visits during the five-year follow-up period. In particular, the number and costs of non-emergency outpatient visits were considerable in individuals with prematurity-related morbidities. The need and costs of hospitalisations decreased clearly with each follow-up year, even in individuals with morbidities. The health-care related costs during the fifth year of life in children born very preterm without prematurity-related morbidities were close to the costs in infants born healthy at term. The cost per QALY of 19,245 € was at an acceptable level already by four years of age in the very preterm population as a whole. Prematurity-related later morbidities and decreasing GA increased the costs per QALY. As the initial hospital stay accounted for a great majority of the total four-year costs, and the costs of hospitalisation decreased with each follow-up year, the cost per QALY is likely to decrease with age. In conclusion, the majority of costs arising after the initial hospitalisation were associated with morbidities related to prematurity. Therefore offering high-quality neonatal care to prevent later morbidities in very preterm survivors has a long-term impact on the cost per QALY. In addition, this study indicates that when estimating the costs of prematurity after the first year of life, one should calculate not only the hospitalisation costs, but also other costs for social welfare services, primary care, and therapies, as these exceed the hospitalisation costs in very preterm infants during the fifth year of life.

Parents as Pain Killers in the Pain Management of Preterm Infants

Vanhemmat keskoslasten kivun lievittäjinä Tutkimuksen tarkoituksena oli kehittää uusi kivunlievitysmenetelmä, Vanhempien käsikapalo, keskoslasten kivunhoitoon vastasyntyneiden teho-osastolla. Vanhempien käsikapalon tehokkuutta verrattiin kahdessa satunnaistetussa kontrolloidussa crossover-tutkimusasetelmassa ei-lääkkeelliseen näyttöön perustuvaan hoitoon (P.O. glukoosiliuos), lääkkeelliseen menetelmään (I.V. oksikodoni) ja lumeeseen (P.O. vesi) tai kontrolli hoitoon kantapääpiston ja hengitysteiden imemisen aikana. Lisäksi mitattiin kivunhoidon lyhytaikaisia sivuvaikutuksia (hapetuksen- ja pulssinlasku) ja pidempiaikaisia vaikutuksia uneen. Tutkittujen lasten ikä oli 28 raskausviikkoa (n = 20) ja 28 1/7 (n = 20). Toimenpidekipua arvioitiin Premature Infant Pain Profile (PIPP) -kipumittarilla. Interventioiden jälkeen unen rakenne analysoitiin 13 tunnin polysomnografia-rekisteröinneistä. Viimeisessä vaiheessa haastateltiin äitejä (n = 23), jotka olivat käyttäneet vanhempien käsikapaloa 2–4 viikkoa vastasyntyneiden teho-osastolla, strukturoidulla the Clinical Interview for Parents of High-Risk Infants -haastattelulla, johon oli lisätty kysymyksiä lapsen kivunhoidosta. Kantapääpiston aikana PIPP–pisteet olivat merkitsevästi matalampia P.O. glukoosiliuoksella (ka 4,85 ± 1,73, p ≤ 0,001) ja vanhempien käsikapalolla (ka 5,20 ± 1,70, p = 0,004) verrattuna lumeeseen (ka 7,05 ± 2,16). Hengitysteiden imemisen yhteydessä PIPP–pisteet olivat matalampia P.O. glukoosiliuoksella (ka 11,05 ± 2,31, p = 0,014) ja vanhempien käsikapalolla (ka 11,25 ± 2,47, p = 0,034) verrattuna lumeeseen (ka 12,40 ± 2,06). Oksikodonin teho oli verrattavissa lumeeseen kummankin toimenpiteen aikana. P.O. glukoosiliuoksen (21,3 %) ja lumeen (12,5 %) annosteluun liittyi merkittävästi enemmän lyhytaikaisia sivuvaikutuksia verrattuna oksikodoniin (5 %) tai vanhempien käsikapaloon (5 %). Oksikodoni muutti keskoslasten unen rakennetta vähentämällä merkittävästi aktiivisen unen määrää verrattuna muihin hoitoihin. Vanhemmat suhtautuivat positiivisesti käsikapalon käyttöön. Äitien osallistuminen kivunhoitoon voitiin jaotella kolmeen eri tyylin, jotka selittyivät äidin kiintymyksen tunteilla ja lapsen tehohoitoon liittyvällä stressillä. Vanhempien käsikapalo on suositeltavampi lyhyen toimenpidekivun lievittäjä kuin P.O. glukoosiliuos tai I.V. oksikodoni, kun tehokkuus, turvallisuus ja perhe otetaan huomioon.

The Vulnerable Brain and Very Preterm Infants - Findings from the PIPARI-Study

Preterm birth is a risk for normal brain development. Brain maturation that normally happens in the uterus is in very preterm infants a developmental challenge during their stay in a neonatal intensive care unit (NICU). Typical brain injuries of preterm infants include ischemic injuries, brain haemorrhages, ventricular dilatation (VD), and reduced brain volumes. Brain injury is a serious complication of prematurity leading to possible long term consequences for the neurodevelopment of the very low birth weight (VLBW) infant, such as cerebral palsy (CP), hearing impairments, vision problems, and delay in cognitive development.There is a need for further studies to ascertain the potential risk factors and their causal relationships to brain vulnerability, growth and development in the increasing number of surviving VLBW infants. This thesis consists of four studies evaluating the definitions, causes and consequences of brain lesions in VLBW(<1500g) or very low gestationalage (VLGA) (gestational age <32 gestational weeks) infants. We showed that the redistribution of fetal blood flow is a risk factor for smaller brain volumes at term. In addition,we showed that brain lesions related to prematurity are not associated with increased spontaneous crying behaviour or circadian rhythm development in infancy. However, the preterm infants began to fuss more often and were held more than term infants at five months of age. Furthermore, we showed that VD is associated with brain lesions and smaller brain volumes. Therefore, brain magneticresonance imaging can be recommended for infants with VD. VD together with other brain pathology is a risk factor for the onset of developmental impairments in VLBW/VLGA infants at two years of age.

The Sedimentology, Ichnology and Hydrogeochemistry of the Late Miocene, Marginal Marine, Upper Pebas and Nauta Formations, Amazonian Foreland Basin, Peru

This thesis includes detailed sedimentological and ichnological studies on two geological units: the Pebas Formation, with a special focus in its informal upper member, and the Nauta Formation. Both formations were deposited during the Miocene in Northeastern Peruvian Amazonia, in the Amazon retroarc foreland basin. The Pebas and Nauta successions mainly consist of non-consolidated, clastic sedimentary deposits arranged into sand- to mud-dominated heterolithic successions, which can be upward-coarsening to upward-fining. Sediments in both the Pebas and Nauta successions range from mud to fine- to medium-grained sand. The main facies observed were 1) mud-dominated horizontal heterolithic couplets; 2) rooted brownish mud; 3) lenticular, mud-draped, cross-stratified sand; 4) mud- to sand-dominated, inclined heterolithic stratification; 5) sand-dominated horizontal heterolithic couplets; and 6) mud-draped, trough cross-stratified sand. Locally, tidal rhythmites were documented. The facies are interpreted as: 1) muddy, shallow, subaqueous flats/shoals; 2) palaeosols; 3) secondary tidal channels or run-off creeks; 4) tidally influenced point bars; 5) shoreface deposits; and 6) subtidal compound dunes. Thalassinoides-dominated Glossifungites ichnofacies, low-diversity expressions of the Skolithos ichnofacies and depauperate suites consisting of elements common to the Cruziana ichnofacies strongly indicate brackish-water conditions. However, continental trace fossil assemblages, with possible elements common to the Scoyenia ichnofacies, have also been identified. In addition to the palaeoenvironmental study, a local hydrogeochemical characterisation of the Pebas and Nauta formations was also conducted. The geochemistry of the groundwaters reflects the characteristics and the soil geochemistry of the geological formations studied. The Pebas formation has low hardness, acid to neutral waters, whereas the upper Pebas has high hardness, acid to neutral waters. In both units, the arsenic content is locally high. The Nauta formation has low hardness acid groundwaters. A regional review of the Pebas and Nauta formations placed the local observations into a continental perspective and suggests that the whole Pebas-Nauta system was a probably shallow (some tens of metres at maximum), brackish- to freshwater, tidally-influenced epicontinental embayment with a probable semi-diurnal to mixed tidal regime and a microtidal range, surrounded by continental environments such as forest floors, lagoons, rivers and their flood plains, and lakes.

Lithostratigraphy and age of pre-Late Weichselian sediments in the Suupohja area, western Finland

Different types of laterally extensive sand- and gravel-dominated deposits, up to several tens of metres thick, were investigated in the Suupohja area of western Finland. The studied sediments were deposited in glacial, ice-marginal, glaciofluvial, sea or lake, littoral and terrestrial environments during several glacial-non-glacial cycles. Seventeen pre-Late Weichselian and three Late Weichselian/Holocene sedimentary units were identified. These were divided into ten formally and two informally defined formations that were together termed the Suupohja Group. Every unit are nevertheless not detectable throughout the study area. The informally defined “Karhukangas lower deposits” represent the lowest units in the Suupohja Group. The Karhukangas lower deposits with 5 till units, 3 glaciolacustrine/-marine units and 2 sand units, were interpreted as having been deposited during possibly four glacial-non-glacial cycles before the Late Pleistocene Subepoch (MIS 6 or earlier). The Kankalo Sand above the Karhukangas lower deposits comprises glaciofluvial and aeolian sands of Late Saalian, Eemian or Early Weichselian origin (MIS 6–MIS 5c). The Kariluoma Till above the Kankalo Sand was possibly deposited during the Late Saalian glacial advance, although an Early Weichselian origin is also possible. The Harrinkangas Formation, with glaciofluvial and quiet-water sediments, is interpreted as having been deposited during the Late Saalian and Eemian Stages (MIS 6–MIS 5e). The uppermost units in the deposits studied, the Kodesjärvi Formation (shore deposit), Isojoki Sand (aeolian), Rävåsen Formation (glaciofluvial), Vanhakylä Formation (shore line deposit), Dagsmark Till and Kauhajoki Till, were deposited during the Weichselian Stage (MIS 5d–MIS 2). In addition, Early Holocene (MIS 1) eskers without till cover were informally termed the “Holocene esker deposits”. The Lumikangas Formation represents gravelly shore deposits formed in the Holocene Epoch, when these areas last emerged from the sea. The first Weichselian ice expansion possibly reached the western part of Suupohja in the Early Weichselian Substage (MIS 5d?), but it did not expand further to the east. The second Weichselian glaciation of relatively short duration occupied the southern part of Finland in the later part of Middle Weichselian (MIS 3). Thus, the southern half of the country remained ice-free for the majority (~65–75%) of the Weichselian Stage. Instead, both humid temperate and periglacial conditions alternated. In the initial part of Middle Weichselian, this area was partly submerged, which indicates eastward expansion of the Scandinavian ice sheet(s), depressing the lithosphere. The exceptionally thick sediment cover, multiple lithofacies, relict landscape and preserved preglacially weathered bedrock are evidence of weak glacial erosion in the Suupohja area during the latest as well as earlier glaciations, making this area one of the key areas in Quaternary research.

Diffusion Tensor Imaging as a Diagnostic and Research Tool: A Study on Preterm Infants

Diffusion tensor imaging (DTI) is an advanced magnetic resonance imaging (MRI) technique. DTI is based on free thermal motion (diffusion) of water molecules. The properties of diffusion can be represented using parameters such as fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, which are calculated from DTI data. These parameters can be used to study the microstructure in fibrous structure such as brain white matter. The aim of this study was to investigate the reproducibility of region-of-interest (ROI) analysis and determine associations between white matter integrity and antenatal and early postnatal growth at term age using DTI. Antenatal growth was studied using both the ROI and tract-based spatial statistics (TBSS) method and postnatal growth using only the TBSS method. The infants included to this study were born below 32 gestational weeks or birth weight less than 1,501 g and imaged with a 1.5 T MRI system at term age. Total number of 132 infants met the inclusion criteria between June 2004 and December 2006. Due to exclusion criteria, a total of 76 preterm infants (ROI) and 36 preterm infants (TBSS) were accepted to this study. The ROI analysis was quite reproducible at term age. Reproducibility varied between white matter structures and diffusion parameters. Normal antenatal growth was positively associated with white matter maturation at term age. The ROI analysis showed associations only in the corpus callosum. Whereas, TBSS revealed associations in several brain white matter areas. Infants with normal antenatal growth showed more mature white matter compared to small for gestational age infants. The gestational age at birth had no significant association with white matter maturation at term age. It was observed that good early postnatal growth associated negatively with white matter maturation at term age. Growth-restricted infants seemed to have delayed brain maturation that was not fully compensated at term, despite catchup growth.

BORIS – It’s never too late to start a repository

Presentation at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014