Lääketieteellinen tiedekunta

 

Recent Submissions

  • 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.
  • 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.
  • 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).
  • Tolppanen, Heli (Helsingin yliopisto, 2019)
    Acute heart failure (AHF) is a leading cause of hospitalizations in patients over the age of 65 worldwide, and is associated with high mortality. Cardiogenic shock (CS), the most severe form of AHF, is characterized by hypotension and end-organ hypoperfusion. Acute coronary syndrome (ACS) precipitates a third of all cases of AHF, and up to 80% of CS. Objective and timely risk assessment in AHF is challenging due to the heterogeneity in its pathophysiology and clinical picture. Risk assessment has traditionally relied on clinical parameters, which may remain subjective or become evident too late, after end-organ dysfunction has become irreversible. Considering the costs and possible adverse effects, application of the most aggressive therapies should be limited to those that most likely procure benefit. The aim of this thesis is to evaluate the prognostic value of electrocardiographic changes and biomarkers in AHF and CS. The patient data come from three cohorts of AHF and two cohorts of CS. All cohorts are independent, prospective, observational, investigator-initiated European cohorts. Study I compared the prognostic value of ventricular conduction blocks (VCB) in patients with new-onset (de novo) AHF and in patients with acutely decompensated chronic heart failure (ADCHF). Study II investigated the role of VCBs in ACS-related CS. Half the patients had a VCB in their baseline ECG, and the presence of any VCB predicted mortality independently of baseline clinical variables or angiographic findings. Studies III-IV investigated the role of two novel biomarkers, sST2 and bio-ADM, in cariogenic shock. Study III showed that sST2 provide strong and complementary prognostic value to NT-proBNP in ACS-related CS, and can help in stratification of patients into low, intermediate and high-risk groups as early as 12 hours after detection of shock. Study IV evaluated in CS patients the prognostic value and association with haemodynamic parameters of bio-ADM compared to lactate. Whereas lactate had good prognostic value in the early phase, its levels normalized during the first 24 hours in the majority of patients, with a decreasing prognostic value thereafter. In contrast, levels of bio-ADM stayed elevated in non-survivors during the first 4 days of intensive care, and bio-ADM had good prognostic value when measured on days 2 to 4. In conclusion, in patients with AHF or CS, electrocardiographic alterations may prove useful in early risk assessment on top of clinical parameters. In addition, biomarkers provide a novel approach in CS risk assessment.
  • Kerola, Anna (Helsingin yliopisto, 2019)
    Background. Biliary atresia (BA) is a destructive, obliterative fibroinflammatory cholangiopathy of infancy, affecting around 1 in 20 000 newborns a year. Despite successful surgical restoration of bile flow by portoenterostomy (PE), liver fibrosis progresses into liver failure and the need for liver transplantation (LTx) before adulthood in most patients. Pathogenesis underlying progressive liver fibrosis after successful PE is unclear. Aims. The aim of this study was to investigate the molecular mechanisms underlying persistent liver fibrogenesis after successful PE and to address the predictors of outcomes. Patients and methods. Three cross-sectional studies investigated gene and protein expression of liver biopsies and serum levels of profibrogenic growth factors, proinflammatory cytokines and extracellular matrix mediators from 25–28 BA patients treated in Helsinki University Hospital between 1991 and 2013, taken at PE and over three years of follow-up after successful operation. The change in survival rates before and after centralization and predictive values were analyzed in BA patients treated in Helsinki between 1987 and 2016 (n=61). Results. During three years following successful PE, serum bilirubin levels remained low [median 10 (interquartile range 4–17) µmol/L]. Despite the resolution of histologic cholestasis and reduction in inflammation, liver fibrosis persisted. Ductular proliferation prevailed and periportal hepatocyte cytokeratin 7 immunopositivity, indicating hepatocyte-to-cholangiocyte metaplasia, increased. If clearance of jaundice (COJ) was not achieved, both histologic cholestasis and inflammation persisted, and progression of liver fibrosis was faster. Of the matrix metalloproteinases (MMPs) studied, MMP-7 was uniquely upregulated in BA when compared to both non-fibrotic and fibrotic control biopsies at protein, gene and serum levels. MMP-7 localized to the biliary epithelium and was related to liver fibrosis stage. Serum MMP-7 showed significant predictive value for portal fibrosis after successful PE. Protein expression of collagen 1, alfa-smooth muscle actin (α-SMA, indicator of activated myofibroblasts), transforming growth factor-beta (TGF-β)-1 and TGF-β2 were all increased at PE and at follow-up compared to non-fibrotic controls. After successful PE, protein expression of TGF-β1, but not that of TGF-β2, decreased. Expression of TGF-β1 and TGF-β2 correlated with Metavir fibrosis stage. Gene expression of platelet-derived growth factor (PDGF) was elevated compared to fibrotic and non-fibrotic controls. Gene expression of proinflammatory cytokines was decreased or comparable when compared to controls. After the centralization of treatment in Helsinki (2005), the median caseload increased from 1 to 3–4 per year. There was an increase in COJ rate from 42% to 80%, a five-year native liver survival from 38% to 70%, and a five-year overall survival rate from 68% to 94%. In multivariate analysis, the only predictor of COJ was high-grade portal inflammation at PE, and the normalization of bilirubin within 3 months predicted native liver survival. Conclusions. After successful PE, a molecular signature of active fibrogenesis prevails, while histologic portal inflammation and expression of proinflammatory cytokines decreases. An increased hepatic expression of MMP-7 is unique to BA and offers a potential follow-up and therapeutic target to extend native liver survival after COJ. TGF-β2 and PDGF might be essentially involved with BA liver fibrogenesis after cholestasis has resolved.
  • Pulkka, Olli-Pekka (Helsingin yliopisto, 2019)
    Background: Gastrointestinal stromal tumor (GIST) is one of the most common types of soft tissue sarcoma. The molecular mechanisms of GISTs are incompletely understood though the importance of KIT or platelet-derived growth factor α (PDGFRA) signaling in GIST is evident. The molecular mechanisms beyond KIT and PDGFRA signaling are incompletely understood. Tyrosine kinase inhibitors and especially imatinib, an inhibitor of KIT, PDGFRA and BCL-ABL, revolutionized the systemic treatment of GIST. However, advanced GISTs usually eventually progress on tyrosine kinase inhibitors, often because of secondary KIT mutations. There is a need for novel effective agents for the treatment of patients with GIST. Experimental design: The GIST gene expression profile was investigated in an in silico transcriptome database comprising of human tissue and cancer samples. Two GIST cell lines were screened for sensitivity to 217 anti-cancer compounds. SLUG, ITGA4, PDE3A and PDE3B expression was studied using immunohistochemistry on tissue microarrays (TMA). We used three different clinical cancer patient series: the first was a series that consisted of samples from 630 tumors from the archives of the Department of Pathology, Helsinki University Hospital; the second was a population-based cohort consisting of GIST patients who were treated with surgery in Western Sweden from 1983 through 2000; and the third series consisted of high risk GIST patients who were entered to the Scandinavian Sarcoma Group (SSG) XVIII/Arbeitsgemeinschaft Internistische Onkologie (AIO) adjuvant trial. The effects of SLUG, ITGA4 and PDE3 knockdown and selective ITGA4 and PDE3 inhibitors were investigated in three GIST cells lines. The efficacy of a PDE3 inhibitor, anagrelide, was investigated in patient-derived xenograft mouse models. Results: SLUG was expressed in 25.0 %, ITGA4 in 52.3 %, PDE3A in 90.9 % and PDE3B in 60.0 % of the GISTs investigated. Expression of these proteins were also detected in some other human tumor types, but usually much less frequently. SLUG and ITGA4 expression were associated several factors linked with unfavorable prognosis. SLUG expression was associated significantly also with unfavorable recurrence-free survival both when the patients were treated with surgery alone and when treated with surgery followed by adjuvant imatinib. ITGA4 expression was associated with unfavorable GIST-specific survival and overall survival in a patient population treated with surgery alone. PDE3A and PDE3B expression had no significant associations with the clinicopathological factors studied, RFS or overall survival. SLUG and PDE3 downregulation inhibited cell proliferation and induced apoptosis in GIST cell lines, whereas ITGA4 inhibition decreased GIST cell invasion. Anagrelide reduced or stabilized tumor growth in several GIST xenograft mouse models. Conclusions: SLUG, ITGA4 and PDE3s are frequently expressed in GISTs. They are likely important factors in the molecular pathogenesis of GIST, and may influence their clinical behavior. As ITGA4 and PDE3s can be targeted with specific inhibitors, they could potentially be therapeutic targets in GIST. SLUG may mediate pro-survival signaling in GIST. Some PDE3 inhibitors, such as anagrelide, warrant more study as potential therapeutic agents in GIST.
  • Andersson, Stefan S. (Helsingin yliopisto, 2019)
    Rare earth elements (REE) are important metals used in green and low-carbon energy and information technologies and are widely used for geological petrogenetic studies. It is becoming increasingly evident that the REE can be mobile in certain hydrothermal fluids and even form hydrothermal REE deposits. This study focuses on the formation of hydrothermal REE deposits rich in the REE-phosphates (monazite [(LREE,Y)PO4] and xenotime [(Y,HREE)PO4]). The main objective of the study was to characterise the Olserum-Djupedal REE-phosphate mineralisation in SE Sweden. Based on this, the study evaluates different sources of REE and P in hydrothermal deposits and assesses how REE and P are transported in hydrothermal fluids. To characterise the Olserum-Djupedal REE mineralisation, this study combines fieldwork, petrographical and textural analysis, major and trace element mineral chemistry of REE-bearing minerals and the main gangue phases, stable Cl isotopic and halogen analysis of fluorapatite, and fluid inclusion microthermometry and LA-ICP-MS analysis. The primary Olserum-Djupedal REE mineralisation comprises co-existing monazite-(Ce), xenotime-(Y) and fluorapatite. These occur mainly within veins dominated by biotite, magnetite, gedrite and quartz forming within metasedimentary rocks in or close to the contact aureole of a peraluminous alkali feldspar granite. The veins are also hosted by the granite within the outermost part of this granite. Primary REE-minerals formed by granitic-derived NaCl-FeCl2-KCl-CaCl2-HF-H2O fluids at high temperatures of ~600 °C at c. 1.8 Ga. Subsequently, the ore assemblages were variably modified during cooling by CaCl2-NaCl to NaCl-CaCl2 brines, and partly, CO2-rich fluids down to temperatures of ~300 °C and to at least 1.75 Ga. Hydrothermal REE deposits rich in REE-phosphates are commonly associated with alkaline magmatism, particularly in silicate-carbonatitic systems. This is because REE and P both exhibit strong chemical affinities with carbonatitic systems and the potential for mobilisation of REE and P are high. This study shows that REE deposits can also form by hydrothermal activity related to subalkaline magmatic rocks. Peraluminous granites exhibit the greatest potential to exsolve fluids carrying REE and P, which can lead to the formation of hydrothermal REE deposits rich in REE-phosphates. The general understanding on how hydrothermal REE-phosphate deposits form is that REE and P are transported in separate fluids and that the REE-phosphates form when these two fluids mix, or the REE-phosphates form when REE-bearing fluids interact with P-rich rocks. The lack of rocks pre-enriched in P in the Olserum-Djupedal district and the co-crystallisation of fluorapatite, monazite-(Ce) and xenotime-(Y), however, suggest that such scenarios not necessarily account for all occurrences of hydrothermal REE-phosphate deposits. As an alternative, REE and P can have been transported by the same fluid. This study demonstrates that the most probable conditions for co-transport of REE and P are at temperatures exceeding 400 °C and with increasing salinity of the fluids, conditions that agree well with that of the Olserum-Djupedal system. The most effective co-transport of REE and P would occur at acidic conditions by REE-Cl, REE-F or REE-SO4 complexes. Yet, co-transport of REE and P may also be feasible at neutral to alkaline conditions by REE-OH complexes. In low-temperature hydrothermal systems, the interaction of REE-bearing fluids with P-rich rocks or fluids is probably the most efficient mechanism for precipitating REE-phosphates. In high-temperature magmatic-hydrothermal systems, REE and P probably share a common origin and were transported by the same fluid. In such systems, pH changes, cooling and the destabilisation of the chief REE transporting complexes jointly contribute to the precipitation of REE-phosphates.
  • Mars, Nina (Helsingin yliopisto, 2019)
    Rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA) and axial spondyloarthritis (AxSpA; including ankylosing spondylitis) are inflammatory rheumatic diseases contributing to a substantial burden on both the patient and society. During the past couple of decades, active treatment strategies and pharmacological advancements have altered their cost structures, with scarce data existing on modern cohorts. Particularly for JIA in adulthood, the cost outcomes and clinical outcomes remain poorly documented. For these four rheumatic diseases, we set out to explore the health service-related costs, with emphasis on both costs of the index rheumatic disease and the costs of comorbidities. We investigated unmet needs by identifying disease-related factors attributable to distinct healthcare utilization patterns. We linked two population-based databases: a longitudinal clinical dataset with high diagnostic validity from the Jyväskylä Central Hospital rheumatology unit, and administrative data covering all public healthcare in the area. Collection of the clinical data took place between May 2007 and March 2016, and health service-related costs in euros (€) were available for fiscal year 2014. We studied the clinical outcomes in 218 adult JIA patients, with health service-related costs available for 119 adult patients with JIA, 213 with PsA, 1086 with RA, and 277 with AxSpA. We compared their cost distributions and high healthcare utilization patterns. Despite being heterogeneous, particularly regarding age, JIA, RA, PsA, and AxSpA shared similar patterns of healthcare resource utilization, both in terms of costs incurred by the rheumatic disease and by comorbidities. The majority of patients are doing overall well both in terms of patient-reported outcomes and health service-related costs, reflecting the effects of modern anti-rheumatic treatment. However, a tenth was recognizable as high healthcare utilizers (for JIA, 15%). Particularly pain, fatigue and disability, but also comorbidity and disease activity emerged as key factors affecting healthcare resource utilization. For all diseases, comorbidities accounted for two thirds of the total costs. This study supports the existing evidence that active treatment of rheumatic diseases has entailed good outcomes and low healthcare resource utilization for the majority. Particularly chronic pain, fatigue, and disability seem to be important areas needing attention in treatment of rheumatic diseases.
  • Kozłowska, Emilia (Helsingin yliopisto, 2019)
    Cancer is one of the world’s most lethal diseases. Although our understanding of this disease is expanding continuously, treatments for many types of cancers are still ineffective. The main reason for the high mortality of cancer patients is resistant to therapy. Since resistance to therapy is a complex and dynamical process, an interdisciplinary approach is necessary to understand it. The emergence of a new field called integrative mathematical oncology can tackle many urgent clinical problems in the treatment of cancer that are impossible to address using, for example, an in vitro or in vivo approach. The primary goal of this new field is to translate the biological complexity of a tumor into a precise language, such as mathematical formulas, and to perform model simulations. Therefore, integrative mathematical oncology allows for biological experiments to be performed inexpensively and rapidly. This thesis applies the integrative mathematical oncology approach to investigate resistance to treatment in solid tumors at the molecular and cellular levels. A mathematical model of the most commonly dysregulated pathway in cancer (the p53 signaling pathway) underwent a bifurcation analysis to investigate the possibility of restoring its proper dynamics in two types of cancer: osteosarcoma and breast cancer. Next, a stochastic model of resistance to platinum compounds was developed to improve our understanding of chemo-resistance to this group of drugs in advanced high-grade serous ovarian cancer (HGSOC). Finally, virtual clinical trial simulations (VCTS) were performed to identify a novel drug combination in ovarian cancer. The application of integrative mathematical oncology deepened our understanding of radio- and chemo-resistance in solid tumors. Firstly, the results from the bifurcation analysis of the p53 signaling pathway suggested silencing Mdm2 using siRNA to overcome radio-resistance in breast cancer and osteosarcoma. Next, the stochastic model of platinum resistance was utilized to answer two urgent clinical questions about ovarian cancer: i) how many platinum resistance mechanisms are active at diagnosis, and ii) how many drug-resistance mechanisms must be targeted to improve patient outcomes. Finally, the clinical trial simulations suggested a novel drug combination to overcome platinum resistance in advanced high-grade serous ovarian cancer.
  • Tuomi, Taru (Helsingin yliopisto, 2019)
    This thesis consists of cohort studies to evaluate the reliability of methods that are presently accessible for the risk profiling of endometrial cancer treatment and to augment contemporary ways that might be clinically usable. Cohort studies were based on a sample of 1166 women who were surgically treated for endometrial cancer at the Department of Obstetrics and Gynecology, Helsinki University Hospital, between January 2007 and December 2013. In the first study, previously recognized risk factors for advanced stage and poor outcome were used to create a calculatory score to predict lymph node and distant metastasis in endometrial cancer (EC). The association of advanced stage disease with demographic factors, biochemical factors, preoperative histology and tumor size was examined. The model predicted stage IIIC–IV carcinomas with a sensitivity of 100%, specificity of 38.0%, PPV of 17.1% and NPV of 100%. A subgroup analyses suggests that the model predicts lymph node metastases (LNM) in addition to distant metastases. In the second study the risk scoring system developed in study I was evaluated by comparing its performance characteristics with two other risk models in predicting lymphatic dissemination. The models had similar accuracies. Survival analyses suggest that variables included in the models predict patient outcome independently of tumor stage. The third study was conducted to investigate the correlation of predictors of advanced disease and/or poor outcome with the manifestation of tumor relapses in different anatomical sites in early stage endometrioid EC. A relapse was diagnosed in 98 patients (10.5%). Of these, 15 were vaginal, 27 pelvic, 27 intra-abdominal and beyond the pelvis and 29 extra-abdominal. Poor differentiation, myometrial invasion (MI) 50% or higher, a tumor size of 3 cm or greater and abnormal peritoneal cytology were associated with an increased risk of intra-abdominal relapses. A tumor size of 3 cm or greater and abnormal peritoneal cytology predicted intra-abdominal relapses beyond the pelvis whereas poor differentiation, MI ≥ 50% and abnormal peritoneal cytology predicted extra-abdominal relapses. In the fourth study, the incidence of surgical site infection and its risk factors in EC were evaluated. In all, 78.4% had had a hysterectomy by minimally invasive surgery. Ninety‐four women (8.1%) were diagnosed with a surgical site infection. The associations clinicopathologic and surgical variables were tested. Obesity, diabetes and long operative time were associated with a higher risk of incisional infection, whereas minimally invasive surgery was associated with a smaller risk. Smoking, conversion to laparotomy, and lymphadenectomy were associated with a higher risk of organ/space infection.

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