Lääketieteellinen tiedekunta

 

Recent Submissions

  • Metsäniitty, Mari (Helsingin yliopisto, 2019)
    Assessment of an individual’s age has important applications in forensics. From developing countries, the possibility to gather reliable reference data for forensic age estimation may be difficult. The aim was 1) to analyse the validity of the Greulich and Pyle method (1959), and other skeletal and dental methods; 2) to analyse forensic age assessments of asylum seekers in Finland, and the Finnish legislation; 3) to compare a created Somali dental development model (SM) on lower left permanent teeth (PT) from 31 to 37 with the Willems et al. model (WM; 2001); and 4) to study whether the addition of information on the development of third molars (TM) with PT increases the accuracy of age assessment of young Somalis. Dental and skeletal radiographic age-assessment methods were compared using Finnish child victim data (N=47). Information on forensic age assessment was collected from Finnish legislation texts, EU statistics, and public statistics by Immigration Authorities on asylum seekers in Finland. Analysis was made of forensic age assessments in Finland in 2015. The dental development of Somalis, born and living in Finland, was analysed, staging the PT according to Demirjian et al. (1973) and TM according to Köhler et al. (1994). First, both SM and WM on PT were validated on 635 Somalis, aged 4–18 years. Secondly, the age prediction performances of PT and TM development were tested separately and combined on 803 Somalis, aged 3–23 years, using a Bayesian approach. Of the compared dental and skeletal methods, development of PT showed the smallest deviation from the chronological age. In 2015, 149 asylum seekers, originating most often from Afghanistan, Iraq, and Somalia, were assessed for age using methods authorised by the Finnish legislation. Comparing the performances of the WM and SM, small but statistically significant differences in mean error were detected: -0.07 years in males and 0.16 years in females. The approach combining PT and TM predicted the age with the highest accuracy. In conclusion, dental methods, except using only TM, override skeletal methods in accuracy. The current Finnish legislation on forensic age assessment has been successfully implemented in Finland. In age assessment, the WM performs well for Somali children. The age prediction performance improves by combining the information of PT and TM, especially in 12- to 15-year-olds, when both PT and TM are still developing.
  • Äyräväinen, Leena (Helsingin yliopisto, 2019)
    Background. Patients with rheumatoid arthritis (RA) suffer from an autoimmune disease with an increased susceptibility to extra-articular inflammation. The purpose of this study was to clarify the oral health in patients with early (ERA) and chronic (CRA) stage of RA. 53 ERA and 28 CRA patients were recruited to this prospective follow-up study at Helsinki University Hospital between 2005 and 2014. ERA patients were naïve to conventional disease- modifying antirheumatic drugs (cDMARDs). CRA patients had a long history of RA and currently an inadequate response to cDMARDs. CRA patients were starting biologic DMARDs mostly combined with cDMARDs. A group of 43 control subjects of age-, gender- and place of residence- matched volunteers was included. Methods. Dental and medical examinations were conducted twice (follow-up mean 16 months) in RA patients and once in controls. Dental examinations included evaluation of periodontitis, prevalence of periodontopathic bacteria from plaque samples, salivary and serum inflammatory biomarkers MMP-8, TIMP-1 and IL-6, saliva flow, Decayed Missing Teeth (DMFT), Decayed Missing Filled Surfaces (DMFS) and Total Dental Index. Dental data comprised also bite-wing and tomogram x-rays. Medical examinations consisted of clinical rheumatological status by disease activity score DAS 28 (28-joint count), total number of swollen (66) and tender (68) joints, blood tests [rheumatoid factor (RF), antibodies against cyclic citrullinated peptide (CCPAb), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA) and antibodies for anti-SSA/SSB (anti-Ro/La) and ribonucleoprotein (RNPAb)], radiographs of hands and feet and general function by Health Assessment Questionnaire (HAQ). Results. At baseline RA patients had significantly more periodontitis: 78.8 % of ERA and 85.7 % of CRA patients vs. 44.1 % of controls suffered from periodontitis (p=0.001). Periodontal findings were more common in RA patients than in controls. Antirheumatic medication seemed to have no influence on periodontal parameters. Salivary inflammatory biomarker MMP-8 was associated with periodontal parameters. MMP-8 (p=0.010) and also IL-6 (p=0.010) in saliva were significantly increased in ERA patients compared with CRA patients and controls at baseline, while MMP-8 and IL-6 in serum were significantly elevated in CRA patients during the study. Salivary MMP-8 and MMP-8/TIMP-1 ratio associated with Periodontal Inflammatory Burden Index (PIBI) in CRA patients at baseline (MMP-8: p<0.001; MMP-8/TIMP-1: p<0.001) and after follow-up (MMP-8: p=0.002; MMP-8/TIMP-1: p=0.003). A similar association between MMP-8 and MMP-8/TIMP1 ratio in saliva was observed also in controls (MMP-8: p=0.010; MMP-8/TIMP-1: p=0.010). Total Dental Index (TDI) was significantly elevated in ERA and CRA patients vs. controls [ERA: 2 (2-3); CRA 2 (1-3); controls 1 (1-3), p=0.045]. RA disease activity (DAS28) associated positively with DMFT (p=0.002) and DMFS (p=0.001) in CRA patients at baseline and further after follow-up (DMFT: p=0.001; DMFS: p= 0.001), while in ERA patients such association was observed after follow-up (DMFT: p=0.016; DMFS: p= 0.038). Conclusions. RA patients even already at the early stage of disease had more periodontitis than control subjects. This was reflected also in elevated salivary inflammatory biomarker (MMP-8, IL-6) levels. Further DMFT and DMFS correlated positively with RA disease activity in CRA patients throughout the study.
  • Grotenfelt, Nora Elisabeth (Helsingin yliopisto, 2019)
    The global prevalence of gestational diabetes (GDM) is around 14%, with increasing numbers over the last decades. In 2017, 19% of all pregnancies in Finland were affected by GDM. Despite treatment, GDM is associated with several short- and long-term adverse health outcomes for both the mother and the child. The short-term effects include an increased risk of large-for-gestational-age babies, birth injuries, Caesarean sections, and neonatal hypoglycemia. The long-term consequences include an increased risk of type 2 diabetes for the mother, and an increased risk of overweight, obesity, metabolic syndrome, and type 2 diabetes for the offspring of GDM pregnancies. Over the recent years, several studies designed to reduce GDM have been published. So far the results are inconclusive. Moreover, there is a shortage of studies assessing the effects of prevention of GDM on the long-term health of the offspring. The aim of this study was to assess women at high risk for GDM considering their clinical characteristics, genetic variance, and time of GDM diagnosis, and to determine the effect of a lifestyle intervention aiming at GDM prevention on long-term offspring health outcomes. This thesis includes four studies. Studies I and II are substudies and Study II is a secondary study of the RADIEL GDM prevention trial, conducted in 2004-2008, assessing maternal outcomes until delivery. Study III includes assessment of neonatal data. In the original RADIEL trial, a total of 720 women with a body mass index (BMI) ≥ 30 kg/m2 and/or a history of GDM in a previous pregnancy were enrolled either before conception or in early pregnancy and allocated either to a lifestyle intervention or a conventional-care group. The intervention focused on both diet and physical activity. Study IV is a substudy of the RADIEL five-year follow-up study (2013-2017), into which all participants of the original RADIEL trial with a viable singleton pregnancy and at least one study visit during pregnancy were invited five years after delivery along with their children. We detected pronounced differences in GDM occurrence between participants with different clinical characteristics. In addition, the effect of the intervention on GDM occurrence differed according to genetic variance. The findings suggest that GDM is a heterogenous disorder, consisting of subgroups that differ markedly regarding both fenotype and genotype. Our lifestyle intervention, delivered by trained nurses to a heterogeneous group of high-risk women enrolled either in early pregnancy or before conception, was not associated with positive effects on metabolic health in the offspring. The value of these findings is the increased knowledge of GDM heterogeneity, useful when improving the screening of GDM and the targeting and cost-effectiveness of future interventions and treatment.
  • Liu, Zehua (Helsingin yliopisto, 2019)
    Considerable efforts have been made to fabricate nano-sized drug delivery systems (DDS) with unique and advanced features in comparison to conventional DDS. Yet, challenges still lay ahead requesting for more controllable, even on-demand drug release profiles from the DDS. Moreover, the emerging concept of personalized treatment further urges the combining of therapy and imaging regimes into a single nanocarrier. Among all the nanomaterials studied so far, porous silicon (PSi) draws increasing interest for constructing DDS due to its good biocompatibility, non-immunogenicity, large pore size/surface area and easily changeable surface properties. Herein, the aim of this thesis was to explore PSi-based DDS for multiple biomedical applications, which were designed and synthesized with specific on-demand features. Moreover, simultaneous incorporation of imaging modalities and drugs enables real-time visualization of drug release and/or cellular/tissue level disease condition, which are expected to be beneficial for personalized treatment regime. First, the potential of PSi nanoparticles for hydrophilic drug loading and on-demand release were evaluated by adapting a dynamic non-covalent bonding method. Different ligands were synthesized and applied for modifying the PSi, and the hydrophilic anti-cancer drug doxorubicin (DOX) was sequentially loaded into the fabricated DDS for pH-responsive release profiles. Meanwhile, the fluorescence spectrum of DOX can be dynamically shifted or quenched, depending on the loading and releasing process, thus facilitating the in situ visualization of the drug releasing process. For hydrophobic drugs, a physical encapsulation method was applied to seal the pores of the PSi by a polymeric matrix. Microfluidic-assisted nanoprecipitation method was applied to synthesize batches of nanohybrids with identical PSi-core/polymer-shell structures, and the release behavior was feasibly tailored by the degradation behavior of the outer polymeric matrix. The first trial was set to fabricate a core/shell nanohybrid, with PSi and gold nanoparticles co-encapsulated in a pH-responsive polymer to simultaneously deliver hydrophobic drug and increase the computed tomography signal for acute liver failure theranostics. The newly established single-step co-encapsulation of different particles endowed a system with multi-functionalities, and the polymeric shell precisely tailored the drug release behavior in a pH-dependent manner. Similarly, an acid/oxidation dual-responsive polymer was designed and further applied in encapsulating atorvastatin-loaded PSi nanoparticles. The meticulously designed system not only obtained a dynamic drug release behavior, but also showed an orchestrated cascade that facilitated bio-mimetic diabetic wound healing. To better elucidate the biocompatibility of PSi for DDS fabrication, the biological effects and immunogenicity of different PSi nanoparticles were evaluated at pre-existing lesion sites, which provided insights for further applications of PSi in DDS fabrication. In conclusion, multiple PSi-based nanohybrids with different on-demand responses were fabricated and applied as DDSs for different diseases. The newly developed nanosystems tailored drug release and obtained multiple modalities, ranging from real-time bio-imaging to bio-mimetic/bio-response alteration, as such, represent promising platforms for future therapy regimes.
  • Silander, Katariina (Helsingin yliopisto, 2019)
    Background and aims: In healthcare, both the need to increase patient-centered care and customization, and simultaneously reduce costs has been recognized. Mass customization and its key means, modularization, are operations management models that are suggested to have potential to tackle this conundrum by enabling simultaneous standardization and customization of services. However, more knowledge of the applicability of modularization and mass customization is needed. This thesis focuses on modularization of hospital healthcare delivery. It aims to identify enablers, constraints, and outcomes related to the modularization of healthcare services focusing on specialized healthcare from the perspective of hematology care, and to identify patient preferences related to day hospital service delivery and number of treating nurses in a hematology and oncology care context. Data and methods: Both mixed methods and data were used in the study. Data were gathered from the Helsinki University Hospital´s (HUS) Comprehensive Cancer Center, Meilahti Triangle Hospital´s day hospital, and hospital-wide databases. Quantitative data including service usage, bed count, and personnel resource information from the hematology unit and Meilahti Triangle Hospital were obtained between 2009-2010 and 2013-2014. Semi-structured interviews (n=16) of personnel members of the oncology and hematology units and the Meilahti Triangle Hospital´s day hospital were conducted. In addition, unstructured interviews of key hematology personnel members were conducted. A questionnaire survey to oncology and hematology patients was carried out. Field visits were organized. In addition, treatment instructions from both the hematology and oncology unit and scheduling instructions of the independent day hospital (Meilahti Triangle Hospital´s day hospital) were analyzed. Reference data on changes in hematology care were obtained from Oulu University Hospital (Oulu). Results: Six enablers and two constraints affecting the modularization of hospital care were identified. The findings indicate that healthcare characteristics such as the requirement to treat all, information asymmetry, professional autonomy, hierarchy, and fragmented service delivery may challenge modularization. However, by applying design activities that support modularization, these challenges may be overcome. Modularization may have both positive and challenging outcomes to healthcare service delivery. The findings indicate that modularization may be an applicable method to support the change from inpatient- to outpatient-focused care in a hospital context. In addition, modularization may streamline service production and communication, and increase replaceability among personnel. However, modularization may not increase customization or patient involvement in care delivery design and might restrict communication. Both patient groups, oncology patients treated in a traditional specialty-specific day hospital with named nurses, and hematology patients treated in a multispecialty modularized day hospital without named nurses, were satisfied with their day hospital care. Oncology patients preferred named nurses and a maximum of three treating nurses in day hospital care more often than hematology patients. In addition, the number of treating day hospital nurses and annual visits affected preferences. Conclusions: The findings indicate that modularization may be an applicable method to support the change from inpatient- to outpatient-focused care in a hospital context. However, organizations need to balance the requirement of customization versus standardization in order to increase the success and applicability of the operating model. This is important as modularization may not increase customization or patient involvement in care delivery design and might restrict communication. The findings indicate that when applied to the care of right patient groups, patients may be satisfied with modularized care. However, this study indicates that not all patient groups may be in favor of modularization, especially if it means that patients would not have a named nurse in outpatient care. In addition, healthcare characteristics should be taken into account, as they may constrain modularization and affect the outcomes of modularized services. As not all outcomes are merely positive, organizations should carefully consider in which situations modularization could enhance service production. Altogether, more research is needed to understand when and in what situations modularization is applicable and most likely successful in developing healthcare service delivery.
  • Vakkilainen, Svetlana (Helsingin yliopisto, 2019)
    Cartilage-hair hypoplasia (CHH) is a rare chondrodysplasia with short stature, hair hypoplasia, variable degree of immunodeficiency and increased risk of malignancy. The non-coding RNA gene RMRP is mutated in CHH. The gene has multiple functions, including cell cycle regualtion. Several aspects of CHH remain inadequately explored, including the pathogenesis, detailed characteristics of immunologic phenotype, correlations of clinical and laboratory features, as well as disease course and prognosis. To address these questions, we recruited and carefully examined a large cohort of Finnish children and adults with CHH. We performed detailed immunologic evaluation, explored the prevalence of bronchiectasis and compared the diagnostic performance of lung high-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI). We also conducted a prospective 30-year follow-up study to identify factors associated with adverse outcomes. In addition, we investigated the role of telomere machinery in the pathogenesis of CHH by measuring relative telomere length (RTL). Study patients (n=56) demonstrated specific abnormalities in B and T cell compartments: 1) decreased thymic naive, naive CD4+ and CD8+ T cells; 2) increased activated CD4+, central memory CD4+ and effector memory CD8+ T cells; 3) normal regulatory T cells; 4) decreased naive, transitional and memory B cells; and 5) increased activated B cells. Specific antibody deficiency was demonstrated in the majority of patients immunized with unconjugated pneumococcal vaccine. No significant correlations were observed between clinical and laboratory features. Children with CHH demonstrated significantly shorter median RTL compared with healthy controls. HRCT showed bronchiectasis in 10/34 patients (29%), justifying lung evaluation also in those without apparent immunodeficiency. Lung MRI was comparable to HRCT in the assessment of bronchiectasis and could be implemented in the follow-up of lung changes. In the prospective study of 80 subjects with CHH, in a significant proportion of patients (17/79, 22%) clinical features of immunodeficiency progressed over time, including six cases of adult-onset immunodeficiency. Of the 15 subjects with non-skin malignancy, eight demonstrated no preceding symptoms of immunodeficiency. These findings call for careful follow-up and screening for cancer even in asymptomatic patients. Altogether 20/80 patients had died during the follow-up, and causes of death included pneumonia (n = 4), malignancy (n = 7) and pulmonary disease (n = 4). Increased mortality was associated with severe short stature at birth, Hirschsprung disease, pneumonia, autoimmunity and symptoms of combined immunodeficiency. In addition, warts in adulthood and actinic keratosis were associated with the development of skin cancer. The study findings should be considered when establishing management guidelines for patients with CHH.
  • Saavalainen, Liisu (Helsingin yliopisto, 2019)
    The aim of this thesis was to assess the risk of cancer according to the types of endometriosis and the risk of death among women with surgically verified endometriosis. In first register-based cohort study, all women with an initial endometriosis diagnosis (49 956 women) undergoing a relevant surgical procedure were identified from the Finnish Hospital Discharge Register from 1987 to 2012. The cohort was divided into sub-cohorts of ovarian (n=23 222), peritoneal (n=20 197), and deep infiltrating endometriosis (n=2372) according to the procedural diagnosis. Between 1987 and 2012 the median age at index surgery decreased 38.8-34.0 years (interquartile range 32.3–43.6; 28.9–41.0) and the age-standardized incidence rate decreased from 116-45 (95% confidence interval [CI] 112–120; 43-48) per 100 000 women. In second and third study, all female cancer cases were identified from the Finnish Cancer Registry until the end of 2014 (840 000 person-years). The overall risk of cancer mirrored that of the Finnish general female population (standardized incidence ratio 0.98; 95%CI 0.95–1.01). Of all gynecological cancers, the risk of ovarian cancer increased (1.76; 1.47–2.08). It was highest among women with ovarian endometriosis and especially for endometrioid and clear-cell ovarian cancer. In contrast, the incidence of precancerous lesions of the uterine cervix (0.81; 0.71–0.92) and that of invasive squamous cell cervical cancer (0.46; 0.20–0.91) decreased. Of all non-gynecological cancers, the risk of thyroid cancer (1.43; 1.23–1.64) and that of basal cell carcinoma increased (1.18; 1.10–1.25). In comparison, the risk of mouth and pharynx cancers (0.60; 0.41–0.80) and of pancreatic cancer (0.76; 0.58–0.96) decreased. In fourth study, the data on the deaths was obtained from Statistics Finland until the end of 2014. The reference cohort (n=98 824) included two age- and municipality-matched women for each woman in the endometriosis cohort. The risk of death from any cause decreased (adjusted mortality rate ratio [MRR] 0.73; 0.69–0.77) in the endometriosis cohort. Furthermore, the adjusted MRR difference remained significant during 24 years of follow-up. Mortality was lower due to cardiovascular diseases (0.57; 0.50–0.65), including ischemic heart and cerebrovascular diseases, as well as due to accidents and violence, diseases of the respiratory and digestive systems, alcohol-related causes, and other causes. In conclusion, only a few types of cancer carry an increased or decreased risk with mid-life women among surgically diagnosed endometriosis. Ovarian endometriosis was most strongly associated with increased risk of ovarian cancer. The overall mortality and cardiovascular mortality were decreased among these women.
  • Pérez Tanoira, Ramón (Helsingin yliopisto, 2019)
    Prosthetic infection represents a major problem in the outcome of patients after implantation of a foreign body. The presence of biomaterial in the body provides a substratum to host either tissue-cell integration or bacterial colonization. In obliteration of an infected bone, artificial bone substitutes and rigid fixation materials are usually necessary to fill bone cavity and to restore the properties of the bone respectively. This study attempted to discover the effect of bioactive glass bone substitute granules (BAG) S53P4 on bacterial and human-cell adhesion on other implant used simultaneously (I, II). During development of new infection-resistant biomaterials, adherence and colonization of either bacterial cells or tissue cells on biomaterials must be evaluated in parallel. A methodology allowing study of the simultaneous growth of bacteria and tissue cells on the same biomaterial surface was developed. This will allow discovery of the effect of various bacterial concentrations on host-cell viability and integration with an implant surface, and their relation to increasing reactive oxygen species (ROS) levels and cell apoptosis (III). Finally, considering our first results and that microorganisms frequently infect an implant surface during surgery and start to compete for the surface before tissue integration, it was hypothesized that incubation of implants with host cells before implantation may be one way to reduce the bacterial living space available and would prevent bacterial adhesion and consequently the infection of biomaterials (IV). Bacterial and human osteoblast-like osteosarcoma cells (SaOS-2) or primary osteoblast (hOB) cells were incubated for 4.5 hours, 2 days, or 4 days at 37°C. As substratum, titanium (Ti), polytetrafluoroethylene (PTFE), polydimethyl-siloxane (PDMS), or bioactive glass plates (IV) were used. The study was done separately (I, II), in competition with SaOS-2 or hOB (III), or in competition with SaOS-2 after 24-hour pre-incubation with SaOS-2 (IV). The effect of BAG S53P4 on bacteria (I) and cell (II) adhesion was studied in either a normal atmosphere or in hypoxia-simulating atmospheric conditions of the middle ear, mastoid cavity, or sinuses. Human osteoblast-like SaOS-2 cells or primary osteoblast (hOB) cells (III) (both, 1x105cells/mL), and collection strains of Staphylococcus aureus and Staphylococcus epidermidis (I) [108 colony forming units (CFU) (I) or (serial 1:10 dilutions of 108 CFU (III, IV)] were employed. The bacteria and cell proliferation, cytotoxicity (III, IV), and production of reactive oxygen species (ROS) (III) were evaluated by colorimetric (MTT, LDH, and crystal violet) (III, IV) as well as by fluorometric methods (fluorescent microscopy and flow cytometry) (III). Bacterial cell viability was studied by use of a drop-plate method after sonication. Effects of BAG S53P4 on cell adhesion were linked intimately with modifications of cellular attachment organs (vinculin containing focal adhesions), rearrangement of the actin cytoskeleton, and cellular spreading. The presence of bioglass under normoxic and hypoxic conditions prevented bacterial and biofilm adhesion for most of the materials and promoted integration of SaOS-2 cells with various biomaterial surfaces, especially under hypoxic conditions, in which S53P4 granules cause increased pH (I, II). In the competitive study, the presence of bacteria resulted in reduced adherence of human cells to the surface of the biomaterials, increased production of ROS, and increased apoptosis. The presence of either type of human cell was associated with a reduction in bacteria compared with that for the materials incubated with S. aureus only (III). Pretreatment with human cells was also associated with a reduction in bacterial colonization of the biomaterial compared with that of the non-pretreated materials, but the presence of bacteria produced a decrease in viable human cells for all materials (IV). In conclusion, the presence of S53P4 granules may both protect implants from bacterial colonization and promote their osteointegration. In the presence of bacteria and cells, colonization of the surface by one reduces colonization by the other. The bacteria produce cellular oxidative stress in human cells, which may be related to the cellular death. The preoperative incubation of prostheses with host cells could be a new way to prevent infection of biomaterials and lessen the risk for bacterial antibiotic resistance.
  • Sälevaara, Mari (Helsingin yliopisto, 2019)
    The use of donated gametes has made parenthood possible for those women and men who are unable to conceive with their own gametes. Every year 150-200 children are born after oocyte donation treatment and 300 children after sperm donation treatment. Parental psychological health has scarcely been addressed during pregnancy and soon after delivery. One of the most important questions in gamete donation is whether the child should be informed about his/her genetic background. The aim of the first questionnaire study was to compare fear of childbirth and delivery experience among women who conceived with donated oocytes (n=26), women after IVF treatment with own gametes (n=52) and spontaneous conception (n=52). The level of fear of childbirth and pregnancy related anxiety was lower among oocyte donation mothers compared with controls. Delivery experience did not differ between the groups. Acute operative delivery associated with dissatisfaction only among oocyte donation mothers. In the second study we compared mental health symptoms between parents after oocyte donation, IVF/ICSI with own gametes and after spontaneous pregnancy. The study group was the same as in the first study. The parents filled in General Health Questionnaire (GHQ-36) during 2nd trimester, 8 weeks and 1 year postpartum. Oocyte donation mothers showed fewer mental health symptoms in early parenthood than controls. No differences were found during pregnancy and among fathers at any time point. The third study examined parents´ plans of disclosure to their child after oocyte donation treatment. A questionnaire was sent to 160 couples who had 231 donor conceived children. 60% of parents had already told or intended to inform the child about his/her genetic background. Of children aged 3-14, 26% had received information about the way of conception. Parents with younger children were more willing to tell the child compared to parents with older children. The fourth questionnaire study examined parents´ disclosure plans after sperm donation treatment and their experiences of donor treatment. Answers provided information on 240 children. Of parents, 40% intended to tell or had already told the child (16 %) about his/her genetic background. Parents with younger children were more inclined to openness than parents with older children. Noteworthy finding was that less than half of the parents (42%) were satisfied with the psychological counselling they received to discuss importance of disclosure to the child.
  • Puhakka, Laura (Helsingin yliopisto, 2019)
    Cytomegalovirus (CMV) is the most common congenital infection in developed countries. Only about 10% of the infected infants have symptoms due to CMV at birth. About half of these symptomatic infants will develop long-term sequelae, such as hearing loss or neurological impairment. Most congenitally infected infants are asymptomatic, and their prognosis is clearly better. The aim of this doctoral thesis was to evaluate the burden of congenital CMV infection (cCMV) in Finland. In the first study, we evaluated the CMV seroprevalence in Finland. We examined CMV antibodies of 200 randomly collected samples from the Finnish Maternity Cohort serum bank at three time points: 1992, 2002, and 2012. The seropositivity rate decreased significantly from 84.5% (95% CI 78.7–89.2) in 1992 to 71.5% (95% CI 64.7–77.6) in 2012. The outcome of symptomatic cCMV infection was evaluated retrospectively from a cohort of 26 children diagnosed in Finnish tertiary hospitals from 2000 to 2012. Long-term sequelae occurred in 58% (15/26), neurologic abnormality in 50% (12/24), and hearing loss in 42% (8/19) of the children. Of the children whose mothers had suffered from primary CMV infections in the first trimester, 86% (6/7) developed long-term sequelae. Of the children whose mothers had experienced non-primary CMV infections during the pregnancy, 64% (9/14) developed long-term sequelae. None of the 5 children whose mothers had had primary CMV infections in the second or third trimester had developed any long-term sequelae. To evaluate the prevalence of cCMV, and the outcome of asymptomatic cCMV, we screened 19,868 infants with a saliva CMV PCR test in four Helsinki area hospitals from September 2012 to January 2015. Confirmed cCMV infection occurred in 40 children, corresponding to a prevalence of 2 in 1,000 (95% CI 1.4–2.6). No differences in the Griffiths Mental Development Scales or hearing outcome could be found between cCMV positive and healthy controls at 18 months age. In addition, no CMV-related findings were detected in the ophthalmologic examinations. Among cCMV positive children, viral shedding to urine was more persistent than to saliva. At 18 months age all urine samples tested (33/33) were positive for CMV culture, but only 24% (9/37) saliva samples had positive CMV PCR. In conclusion, the disease burden of cCMV was relatively low in Finland. The prevalence was only 2 in 1,000, and the outcome of the asymptomatic infants was favourable. However, the morbidity of the symptomatic infection was remarkable. Over half of the infants from the retrospective cohort with CMV-related symptoms at birth developed long-term sequelae. In the positive screening samples, the genotype distribution for CMV glycoproteins gB, gH, and gN was similar to that reported from other populations and does not therefore explain the low burden of the disease in Finland.
  • Javanainen, Mervi (Helsingin yliopisto, 2019)
    Since 1975, the prevalence of obesity has nearly tripled, and 39% of the world’s population is now overweight. Bariatric surgery has proven to be the most effective treatment for obesity and obesity-related diseases. Roux-en-Y gastric bypass (RYGB) is one the most popular and well-studied operation types worldwide. However, in recent years, the popularity of sleeve gastrectomy (SG) has risen rapidly, surpassing the RYGB. Bariatric surgery has proven to be safe; however, there is still limited information about some of the complication types. The complications that occur after bariatric surgery can be divided into early complications (under 30 days after the operation) and late ones (over 30 days after the operation); late complications can further be divided into surgical and non-surgical complications. This thesis consists of four different studies on the common complication types related to bariatric surgery. Study I analyses the relationship between bleeding/venous thromboembolic complications and different enoxaparin protocols, and Study II reviews the changes in pulmonary complications under different perioperative protocols. The last two studies compare late complications, vitamin deficiencies, and fractures between RYGB and SG operations. In Study IV, we also compare the number of fractures that occur after surgery to fractures in non-surgically treated patients. All the data from the patients were collected between 2007 and 2016 at Peijas Hospital, affiliated to Helsinki University Hospital. The patient characteristics and the data from the first two years were collected prospectively and later retrospectively. In addition to analyzing the patients who underwent operations, Study IV includes 199 non-surgically treated obese patients as a control group. In Studies I and II, the follow-up times were 30 days. In Study III, the follow-up time was two years, and, in Study IV, the follow-up time was at least six years. The results of Study I showed that enoxaparin was safest when administered in a 40-mg dose once a day. Study II revealed that, alongside avoiding the use of drains and urinary catheters, fast mobilization was favorable to prevent postoperative pneumonia and shorten the hospital stay. The last two studies compared RYGB to SG. It was observed that, compared to the SG patients, the RYGB patients had more late complications treated surgically or endoscopically. In Study IV, vitamin D, albumin, and B12 levels were at an acceptable level two years after either operation. It was shown that the bariatric patients had a higher risk of fractures compared to the non-surgically treated patients. Higher age, bariatric surgery, and lower body mass index (BMI) at the two-year control mark increased the risk of fracture after obesity treatment.
  • Kivelä, Jesper (Helsingin yliopisto, 2019)
    Liver transplantation has been an accepted treatment modality for end-stage liver disease in both children and adults for over 30 years. More than 100 children and adolescents have undergone liver transplantation in Finland; one tenth of them have undergone combined liver-kidney transplantation. Life expectancy after pediatric liver transplantation has improved during the years, and six to seven out of ten patients are expected to be alive twenty years later. Vascular complications, like hepatic artery thrombosis, increase patient morbidity and mortality early after liver transplantation however, the less severe form, late hepatic artery thrombosis, can be asymptomatic. The human leukocyte antigen system is responsible for immune responses against all foreign material, like liver allografts, via various mechanisms. These include production of antibodies, some of which can be directed against the donor, namely donor-specific human leukocyte antigen antibodies. These are harmful to allografts, especially kidneys, but their role in pediatric liver transplantation is less well defined. Long-term complications, including renal impairment, can lead to chronic kidney disease after liver transplantation. Glomerular filtration rate provides an indicator of kidney function more reliably when measured instead of being estimated from surrogate markers. The aims of this study were to investigate prevalences of late hepatic artery thrombosis with magnetic resonance imaging in 34 patients and donor-specific human leukocyte antigen antibodies with One Lambda LabScreen® antigen immunoassays in 50 patients after pediatric liver transplantation conducted between 1987 and 2007. Long-term renal function was studied with measurement of glomerular filtration rate using plasma clearance of 51-chromium-labeled ethylenediamine tetraacetic acid in 57 pediatric patients who received liver grafts between 1987 to 2007 as well as in 34 pediatric and adult patients who received simultaneously a liver and a kidney between 1993 and 2011. A decade after pediatric liver transplantation, 44% had late hepatic artery thrombosis and 52% had donor-specific human leukocyte antigen antibodies. Renal function remained stable up to five years and declined thereafter to a mean measured glomerular filtration rate of 66 mL/min/1.73 m2 at 15 years after pediatric liver transplantation. In contrast, renal function was stable during the follow-up, with a mean measured glomerular filtration rate of 70 mL/min/1.73 m2 at ten years after pediatric combined liver-kidney transplantation. Instead, renal function was impaired in adult patients after combined liver-kidney transplantation. In conclusion, late hepatic artery thrombosis and donor-specific human leukocyte antigen antibodies are common after pediatric liver transplantation. Longitudinal renal function remains stable for at least five years after pediatric liver and liver-kidney transplantation, but declines in adult combined liver-kidney transplant patients.
  • Tiittala, Paula (Helsingin yliopisto, 2019)
    Migrants are over-represented among the incident cases of hepatitis B (HBV) and C (HCV), human immunodeficiency virus (HIV) and syphilis in many low-prevalence countries including Finland. Current knowledge of the epidemiology of these infections among migrants is limited to guide the public health response. This thesis aims to describe the feasibility of screening in a population-based survey, to estimate the burden of infections, to evaluate the implementation of screening, and to assess HIV-related health literacy among specific migrant populations. Seroprevalence rates of HBV, HCV, HIV and syphilis were assessed in a population-based survey among adult Kurdish, Russian and Somali-origin migrants. Survey non-participation and previous notifications were evaluated through register-linkage. HBV, HIV and syphilis seroprevalence and implementation of screening among all asylum seekers in Finland in 2015–2016 were examined based on register information of healthcare procurements. HIV-related knowledge, attitudes and practices of young adult asylum seekers were compared to those of age-matched general population in two separate surveys. Non-participation analysis observed no differences in the notification prevalence of HBV, HCV, HIV or syphilis between participants and non-participants of the survey. The majority of survey participants accepted the multiphasic opt-in provider-initiated screening. Acceptability of HIV testing was increased by enhanced pre-test counselling. Seroprevalence of HBV, HCV, HIV and syphilis among Kurdish, Russian and Somali-origin migrants and among asylum seekers were comparable or lower than in countries of origin. Prevalence of HCV and syphilis was higher in older age-groups. The burden of HBV was highest among Somali-origin migrants and that of HCV and syphilis among Russian migrants. Of all test-positive cases among Kurdish, Russian and Somali-migrants, 61% had not been previously notified and were considered missed diagnoses. Coverage of after arrival screening of HBV, HIV and syphilis was 88% among eligible Kurdish, Russian and Somali migrants, and 61% among asylum seekers. Previous HIV testing was reported by 31% of the Kurdish, Russian and Somali-origin migrants and 23% of the young adult asylum seekers. HIV-related knowledge among asylum seekers was below the international target level. Asylum seekers preferred passive sources of HIV information to interpersonal strategies of health education. In conclusion, although asylum and integration processes are windows of opportunity for health education, prevention and screening, barriers hindering their implementation exist. Missed HBV diagnoses among Somali-origin migrants suggest missed opportunities for vaccinations. Limitations of the current screening programme explain missed hepatitis C and syphilis diagnoses among Russian migrants. Findings from this study suggest opportunities for public health response: extending after-arrival screening of HBV, HIV and syphilis to all at-risk migrants, inclusion of HCV screening, describing and addressing barriers that hinder implementation of screening, enhancing provider-initiated screening and investing in health literacy.
  • Stenius-Ayoade, Agnes (Helsingin yliopisto, 2019)
    Being homeless is a stressful life-situation that complicates everyday life in many ways. Previous studies from other countries have shown that homelessness is associated with increased morbidity and mortality, as well as increased use of hospital and emergency department services. Yet, the health situation of the homeless in Finland has not been extensively studied before. The aim of this study was to examine the housing situation, morbidity, mortality and healthcare service use of the homeless shelter population in Helsinki, Finland. By combining data from both local and national registers three cohorts of shelter users (in total 1458 persons) were followed for up to ten years. The housing situation, morbidity and overall as well as cause-specific mortality and health care service use were assessed and compared with an age-matched control group from the general population. The results show that homeless shelter users had high morbidity compared with the control group, and that especially psychiatric morbidity was high. During the ten-year follow-up period about half of those who had stayed in shelter died, which means a fivefold risk of death for the homeless compared with the controls. The risk of death from diseases and medical conditions was more than threefold compared with the control group, and the risk of death from external causes was over tenfold. The large majority of those still alive at the end of the ten year follow-up were staying in supported housing, with only a small group being still or again homeless. Six per cent of the homeless were independently housed. Compared with controls, the homeless had over 40 times more hospital days in psychiatric hospitals, 10 times more hospital emergency department visits and over six times more medical/surgical hospital days. Also those who had stayed only temporarily in shelter had a high use of emergency department and hospital services. Mental disorders were strongly associated with primary healthcare service use. The homeless visited primary care for mental health- and substance use-related problems, traumas and infections, but undertreatment of chronic conditions such as hypertension and diabetes was detected. This study shows that, also in the Finnish setting, having experienced homelessness is strongly associated with adverse health outcomes and that the prognosis for the homeless in shelters is poor both in terms of being independently housed and mortality. The high use of hospital and emergency services and relatively low use of outpatient care, as well as undertreatment of chronic conditions, indicate that access to timely and appropriate care is insufficient, leading to high use of specialized care. Better, targeted healthcare services are needed to prevent avoidable hospitalizations, ill health and premature death.
  • Heinola, Ivika (Helsingin yliopisto, 2019)
    Background. Abdominal aortic infections are dreaded disorders in vascular surgery, linked to high morbidity and mortality. Mycotic aneurysm as a primary infection of the abdominal aorta (MAAA) and an aortic graft infection (AGI) are different entities; however, due to bacterial presence in aorta and perivascular tissue, the principles of management are the same. Due to low incidence and complexity of disease, the high-quality evidence is lacking to define whether prosthetic aortic reconstructions in infectious conditions are utterly safe or whether biological reconstruction material should be preferred despite some shortcomings in durability. In complex abdominal surgery encompassing visceral aorta, prolonged aortic clamping above renal arteries is a risk factor for acute ischaemic kidney injury. In such situations, renal protection is recommended in order to avoid irreversible damage and renal replacement therapy. Aims. The aim of current study was to evaluate the infection resistance and durability of biological grafts as an aortic reconstruction material in abdominal aortic infections and to estimate the mortality after such reconstructions. Furthermore, efficacy of temporary axillo-renal bypass in prevention of renal ischaemic damage from major aortic surgery was estimated. Materials. The study comprises two parts. In the first part, 132 patients were analysed after being treated for aorto-iliac infections with arterial resection and reconstruction with a biological graft. Study I included patients treated due to AGI with femoral vein grafts, Study II included patients in whom the arterial infection was treated using cryopreserved venous allografts, and Study III included patients who were treated with various biological grafts for a primary aortic infection. The primary endpoints were postoperative mortality and reinfection rates, secondary endpoints were treatment-related mortality, overall mortality and graft reinterventions. During the second part of the study, (Study IV) patients who underwent temporary axillo-renal bypass during a major aortic intervention were retrospectively analysed. Outcome measures were postoperative kidney injury and 30-day mortality. Studies I, II and IV entailed retrospective analyses of patients treated at Helsinki University Hospital, while Study II was multicentre retrospective analysis of patients from six countries. Results. Sixty-four percent (64%, n=85) of the patients underwent surgery for an abdominal aortic infection with autologous femoral veins (FV), 17% (n=23) with cryopreserved venous allografts (CVA), 9% (n=12) with xenopericardial tube grafts, 5% (n=7) with cryopreserved arterial allografts, and 4% (n=5) with fresh arterial allografts. Most common indications for operation were aortic graft infection with an incidence of 51% (n=67) and mycotic abdominal aneurysm with 45% (n=60). The 30-day mortality was 9% for patients treated with FV for an AGI, 9% for patients treated for mixed infectious indications with cryopreserved venous allografts, and 5% for patients treated with various biological reconstructions due to MAAA,. The respective treatment-related mortality rates in these cohorts were 18%,13% and 9%. The reinfection rate was 2% (n=3) and 11% (n=14) of the grafts needed reinterventions at the mid-term follow-up, with stenotic lesions in femoral veins as the most common indication (n=9/14). Kaplan-Meier estimation of survival at 5 years was 59% (95% confidence interval, [CI] 43% – 73%) for patients treated with FV due to AGI and 71% (95% CI 52% –89%) for patients treated with mixed biological materials for MAAA. For patients treated with cryopreserved allografts for mixed indications, estimated survival at 2-years was 70% (95% CI 49% – 91%). Sixteen patients were operated with temporary axillo-renal bypass during aortic surgery. Despite short median renal ischaemia time of 24.5 minutes, 6 (38%) patients suffered acute kidney injury (AKI), of whom 4 had renal insufficiency preoperatively. One patient needed temporary renal replacement therapy, at one-month follow-up, however, renal function had returned to its baseline level or improved in all patients. The 30-day and in-hospital mortality was nil. Conclusions. Biological reconstruction material is infection resistant and reasonably durable in midterm analysis. Early postoperative and overall mortality rates are acceptable after treatment of such a complex entity as abdominal aortic infections. Furthermore, temporary axillo-renal bypass is safe and feasible in diminishing acute kidney injury during major aortic surgery.
  • Veija, Tuukka (Helsingin yliopisto, 2019)
    Merkel cell carcinoma (MCC) is a rare aggressive skin cancer categorized into two subgroups according to presence of Merkel cell polyomavirus (MCV). Around 20% of the tumors are polyomavirus negative and associate with worse prognosis than MCV-positive tumors. Current treatment modalities for advanced MCC are scarce, and new targeted therapies are warranted. Therefore, we need to further examine the molecular pathology of MCC with respect to the polyomavirus status of the tumor to seek potential therapeutic targets. We hypothesized that there could be significant differences in microRNA, gene mutation and RNA expression patterns of MCV-positive and MCV-negative tumors. In this study, we utilized formalin- fixed paraffin-embedded primary MCC samples to investigate molecular aberrations of MCV-negative and MCV-positive MCC. Microarrays and quantitative reverse transcription PCR were used to determine microRNA expression, while next-generation sequencing was applied for analyzing mutational and RNA expression patterns of MCC tumors. Tumor protein expression was examined by immunohistochemistry. Further, clinical details of MCC patients were statistically correlated to molecular alterations. Regarding microRNA patterns, we uncovered different expressions of four miRNAs in MCV-negative tumors compared to MCV-positive tumors. The most notable of these miRNAs was miRNA-34a, a known tumor suppressor, which was underexpressed in MCV-negative tumors and therefore might contribute to the pathogenesis of that MCC subgroup. In our sequencing projects, we observed generally higher mutational frequency in MCV- negative tumors. Notably, we recorded unprecedented EGFR mutations in 22% of the MCC tumors studied. In addition, there was overexpression of ALK and EZH2 at RNA level in MCC tumors. We then proceeded to investigate the expression of ALK, EGFR and EZH2 at protein level by immunohistochemistry and found frequent expression of ALK and EZH2. Interestingly, ALK expression by immunohistochemistry correlated strongly with MCV positivity of the tumor. EGFR expression was detected in 7/31 MCV-negative tumors, while none of the MCV-positive tumors expressed EGFR. There was no significant correlation between the alterations and clinical parameters of the patients. We concluded that the relationship of ALK and MCV needs further investigation, while EZH2 could be a potential therapeutic target in MCC since it is frequently expressed, regardless of the MCV status of the tumor. In addition, the subgroup of EGFR positive MCC-negative tumors might benefit from EGFR inhibitor treatment. Our results provide evidence that there are distinct molecular aberrations in MCV-negative and MCV-positive MCC.
  • Siren, Reijo (Helsingin yliopisto, 2019)
    Mortality from coronary heart disease (CHD) among the working-age population has declined by 70% during the past 50 years in Finland. Factors contributing to this development include both advances in health policy and the improvement of medical care. Despite this favourable trend, cardiovascular disease (CVD), especially ischaemic heart disease, is still the leading cause of death among the working-age male population in Finland. One of the substantial risk factors for CVD and type 2 diabetes is obesity, predominantly abdominal – that is the accumulation of fat in the visceral adipose tissue. When the subcutaneous adipose tissue's ability to store fat is exceeded, the excess fat accumulates in the visceral adipose tissue and ectopic depositions in organs, such as skeletal muscles, liver, pancreas, and heart. This aberrant fat accumulation strongly correlates with an adverse cardiometabolic profile. We studied the association between visceral adiposity and cardiac steatosis in 70 non-diabetic obese middle-aged men. The amount of visceral adipose tissue, abdominal subcutaneous tissue and epicardial and pericardial fat depositions was measured by magnetic resonance imaging. Cardiac steatosis correlated with the amount of abdominal subcutaneous fat tissue and visceral adiposity; the correlation was stronger with visceral adiposity. Furthermore, of all the cardiometabolic risk factors measured, WC correlated strongest with visceral adiposity as well as epicardial and pericardial fat. WC is an indirect measure, but it is considered to be a reliable measure of visceral adiposity. Thus, it can serve as a tentative means when assessing the risk for CVD and type 2 diabetes. To study the predictive value of WC to assess the risk for CVD and type 2 diabetes in middle-aged men, we used data from 200 men from a community-based screening programme in the city of Helsinki. Our results show that a cut-off point for a WC of ≥ 94 cm identifies those with increased risk for CVD and/or type 2 diabetes with a sensitivity of 84.4% and specificity of 78.2%. Yearly, from 2006 onwards, all men aged 40 living in Helsinki have been invited to a CVD risk evaluation and health counselling visit at their local healthcare centre. Men who were found to be at high risk received lifestyle counselling aiming at risk reduction. We conducted two prospective follow-up studies among the men who were at high risk in the year 2006 screening. In the first study, our aim was to determine whether the impact of lifestyle counselling on health behaviour and total CVD risk during the two years of follow-up depended on educational attainment. In 2008, a total of 430 initially high-risk men were identified and invited to a follow-up visit; 200 participated. Subjects were categorised into three groups according to their educational attainment: low (≤ 9 years), middle (10 to 12 years) and high (≥ 13 years). We observed a positive trend in lifestyles in all three groups. In the low educational attainment group, the change in lifestyle did not lead to a significant reduction in the overall risk for CVD, whereas the risk reduction was statistically significant in the two higher educational attainment groups during follow-up. In our second prospective study, we aimed to determine whether the continuation of risk communication would lead to and sustain lifestyle changes and maintain the possibly achieved lower CVD risk during the five-year follow-up. In 2011, a total of 389 initially high-risk men were identified and invited to a follow-up visit; of these, 159 participated. We observed that the participants’ self-reported lifestyles improved regardless of the continuation of risk communication, while the overall risk for CVD improved only among those who were continuing risk communication during the five-year follow-up. If lifestyle behaviour has not been optimal during early adulthood, a person may have been exposed to one or more CVD risk factors before reaching middle age. Often, an easily recognisable indication of such exposure is abdominal obesity. In everyday practice in primary healthcare, abdominal obesity and a low level of education should trigger a comprehensive risk evaluation and, when appropriate, an offer of health counselling. Achieving sustainable lifestyle changes and risk reduction requires ongoing risk communication between parties.
  • Wikman, Patrik (Helsingin yliopisto, 2019)
    Previous human functional magnetic resonance imaging (fMRI) research has shown that activation in the auditory cortex (AC) is strongly modulated by motor influences. Other fMRI studies have indicated that the AC is also modulated by attention-engaging listening tasks. How these motor- and task-related activation modulations relate to each other has, however, not been previously studied. The current understanding of the functional organization of the human AC is strongly based on primate models. However, some authors have recently questioned the correspondence between the monkey and human cognitive systems, and whether the monkey AC can be used as a model for the human AC. Further, it is unknown whether active listening modulates activations similarly in the human and nonhuman primate AC. Thus, non-human primate fMRI studies are important. Yet, such fMRI studies have been previously impeded by the difficulty in teaching tasks to non-human primates. The present thesis consists of three studies in which fMRI was used both to investigate the relationship between the effects related to active listening and motor responding in the human AC and to investigate task-related activation modulations in the monkey AC. Study I investigated the effect of manual responding on activation in the human AC during auditory and visual tasks, whereas Study II focused on the question whether auditory-motor effects interact with those related to active listening tasks in the AC and adjacent regions. In Study III, a novel paradigm was developed and used during fMRI to investigate auditory task-dependent modulations in the monkey AC. The results of Study I showed that activation in the AC in humans is strongly suppressed when subjects respond to targets using precision or power grips during both visual and auditory tasks. AC activation was also modulated by grip type during the auditory task but not during the visual task (with identical stimuli and motor responses). These manual-motor effects were distinct from general attention-related modulations revealed by comparing activation during auditory and visual tasks. Study II showed that activation in widespread regions in the AC and inferior parietal lobule (IPL) depends on whether subjects respond to target vowel pairs using vocal or manual responses. Furthermore, activation in the posterior AC and the IPL depends on whether subjects respond by overtly repeating the last vowel of a target pair or by producing a given response vowel. Discrimination tasks activated superior temporal gyrus (STG) regions more strongly than 2-back tasks, while the IPL was activated more strongly by 2-back tasks. These task-related (discrimination vs. 2-back) modulations were distinct from the response type effects in the AC. However, task and motor-response-type effects interacted in the IPL. Together the results of Studies I and II support the view that operations in the AC are shaped by its connections with motor cortical regions and that regions in the posterior AC are important in auditory-motor integration. Furthermore, these studies also suggest that the task, motor-response-type and vocal-response-type effects are caused by independent mechanisms in the AC. In Study III, a novel reward-cue paradigm was developed to teach macaque monkeys to perform an auditory task. Using this paradigm monkeys learned to perform an auditory task in a few weeks, whereas in previous studies auditory task training has required months or years of training. This new paradigm was then used during fMRI to measure activation in the monkey AC during active auditory task performance. The results showed that activation in the monkey AC is modulated during this task in a similar way as previously seen in human auditory attention studies. The findings of Study III provide an important step in bridging the gap between human and animal studies of the AC.
  • Alkodsi, Amjad (Helsingin yliopisto, 2019)
    Cancer is a leading cause of death worldwide, and its incidence is increasing due to modern lifestyle that prolonged human life. All cancers originate from a single cell that had acquired genetic aberrations enabling uncontrolled proliferation. Each cancer is unique in its aberrant genetic makeup, which defines, to large extent, its biology, aggressiveness, and vulnerabilities to different treatments. Furthermore, the genetic makeup of each cancer is heterogeneous among its constituent cancer cells, and dynamic with the ability to evolve in order to preserve the survival of cancer cells. Sequencing technologies are currently producing massive amounts of data that, with the help of specialized computational methods, can revolutionize our knowledge on cancer. A key question in cancer research is how to personalize the treatment of cancer patients, so that each cancer is treated according to its molecular characteristics. The first study in this thesis takes a step in that direction through a proposed novel molecular classification system of diffuse large B-cell lymphoma (DLBCL), which is the most common hematological malignancy in adults. The suggested classification, derived from the integrative analysis of gene expression and DNA mutations, stratifies DLBCL into four groups with distinct biology, genetic landscapes, and clinical outcome. These subtypes could help identify patients at high risk who may benefit from an altered treatment plan. Understanding the genomic evolution of cancer that transforms a typically curable primary tumor into an incurable drug-resistant metastasis is another aspect of cancer research under intensive investigation. The second study in this thesis investigates the spreading patterns of metastasis in breast cancer, which is the most common cancer in women. Using phylogenetic analysis of somatic mutations from longitudinal breast cancer samples, the metastasis routes were uncovered. The study revealed that breast cancer spreads either in parallel from primary tumor to multiple distant sites, or linearly from primary tumor to a distant site, and then from that to another. However, in all cases, axillary lymph nodes did not mediate the spreading to distant sites. This provided a genetic-based evidence on the redundancy of lymph node dissection in breast cancer management. Towards a genetic-based diagnostics in cancer, the computational methods used to detect genetic aberrations need to be evaluated for their accuracy. The third study in this thesis performs a comparison of methods for detecting somatic copy number alterations from cancer samples. The study evaluated several commonly used methods for two different sequencing platforms using simulated and real cancer data. The results provided an overview of the weaknesses of the different methods that could be methodologically improved. Altogether, this thesis gives an overview on the field of computational cancer genomics and presents three studies that exemplify the clinical relevance of computational research.
  • Ylitalo, Pekka (Helsingin yliopisto, 2019)
    Abstract Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect. Postoperative patients with TOF are mostly compromised by chronic pulmonary regurgitation and chronic right ventricular volume load. These patients suffer from impaired exercise capacity and have an increased risk of sudden cardiac death (SCD) and heart failure. This thesis investigates the long-term outcome of surgically corrected TOF patients in a population-based setting. It also assesses the effects of long-lasting pulmonary regurgitation (PR) in the postoperative state in children and adolescents with TOF and healthy control subjects. During the period from 1962 to 2007 a total of 600 patients with TOF were surgically corrected in Finland before the age of 15 years. The follow-up time of these patients was 23±12.1 years. We observed that: i. 514 (85%) patients were alive and living in Finland; 82 (14%) had died. Primary repair of TOF was found to predict lower mortality and longer event-free survival when compared with two-stage repair. The need for a transannular patch (TAP) in TOF surgery carried a higher risk of re-operation without impact on late survival. In addition to the population-based follow-up study, we conducted a single‑centre cross-sectional study including 45 patients after repair of tetralogy of Fallot (rTOF) and 45 healthy age- and gender-matched paediatric and adolescent volunteers as controls (CO). Cardiac magnetic resonance (CMR) imaging was performed on all the study subjects. We made the following observations: ii. Late gadolinium enhancement (LGE), detected with CMR after gadolinium contrast agent, was also found outside the surgically affected areas in the right ventricle (RV) of TOF patients. Severity of PR correlated with the degree of LGE. LGE is recognized as a marker of fibrosis, scars, or otherwise abnormal myocardium. iii. In children and adolescents with TOF, severe pulmonary regurgitation importantly affects volume flow through the left atrium. Reduction in left ventricular (LV) preload volume may be an additional factor contributing to LV dysfunction. iv. RV longitudinal strain is increased in paediatric TOF patients with severe pulmonary regurgitation. In comparison with healthy volunteers, all TOF patients demonstrated enhanced and delayed RV circumferential strain that was accentuated in the apical region. In conclusion, the late results of TOF surgery are excellent. Patients operated on in the last two decades can expect to have a life expectancy comparable to their healthy peers. Early primary correction and avoidance of TAP if possible are predictors of superior late outcome. Chronic pulmonary regurgitation has deleterious effects on both right and LV filling and function. Novel methods such as LGE analysis, feature tracking (FT), and evaluation of LV preload may prove valuable when assessing the need for pulmonary valve replacement (PVR).

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