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  • Riska, Annika (Helsingin yliopisto, 2007)
    The aim of the study was to clarify the occurrence, and etiological and prognostic factors of primary fallopian tube carcinoma (PFTC). We studied the sociodemographic determinants of the incidence of PFTC in Finland and the role of chlamydial infections and human papillomavirus infections as risk factors for PFTC. Serum tumor markers were studied as prognostic factors for PFTC. We also evaluated selected reproductive factors (parity, sterilization and hysterectomy) as risk or protective factors of PFTC. The risks of second primary cancers after PFTC were also studied. The age-adjusted incidence of PFTC in Finland increased to 5.4 / 1,000,000 in 1993 97. The incidence rate was higher in the cities, but the relative rise was higher in rural areas. Women in the two highest social classes showed a 1.8 fold incidence compared with those in the lowest. Women in agriculture and those not working outside the home showed only half the PFTC incidence of those in higher socioeconomic occupations. Pretreatment serum concentrations of hCGβ, CA125 and TATI were evaluated as prognostic markers for PFTC. Elevated hCGβ values (above the 75th percentile, 3.5 pmol/L; OR 2.49, 95% CI 1.22 5.09), stage and histology were strong independent prognostic factors for PFTC. The effects of parity, sterilization and hysterectomy on the risk of PFTC were studied in a case control-study with 573 PFTC cases from the Finnish Cancer Registry. In multivariate analysis parity was the only significant protective factor as regards PFTC, with increasing protection associated with increasing number of deliveries. In univariate analysis sterilization gave borderline protection against PFTC and the protective effect increased with time since the operation. In multivariate analysis the protection did not reach statistical significance. Chlamydial and human papillomavirus (HPV) infections were studied in two separate seroepidemiological case-control studies with 78 PFTC patients. The incidence of women with positive HPV or chlamydial serology was the same in PFTC patients and in the control group and was not found to be a risk factor for PFTC. Finally, the possible risk of a second primary cancer after diagnosis and treatment of PFTC in a cohort of 2084 cases from 13 cancer registries followed for second primary cancers within the period 1943 2000 was studied. In PFTC patients, second primary cancers were 36% more common than expected (SIR 1.36, 95% CI 1.13 1.63). In conclusion, the incidence of PFTC has increased in Finland, especially in higher social classes and among those in certain occupations. Elevated serum hCGβ reflect a worsened prognosis. Parity is a clear protective factor, as is previous sterilization. After PFTC there is a risk of second primary cancers, especially colorectal, breast, lung and bladder cancers and non-lymphoid leukemia. The excess of colorectal and breast cancers after PFTC may indicate common effects of earlier treatments, or they could reflect common effects of lifestyle or genetic, immunological or environmental background.
  • Mäkelä, Keijo (Helsingin yliopisto, 2010)
    The first aim of the current study was to evaluate the survival of total hip arthroplasty (THA) in patients aged 55 years and older on a nation-wide level. The second aim was to evaluate, on a nation wide-basis, the geographical variation of the incidence of primary THA for primary OA and also to identify those variables that are possibly associated with this variation. The third aim was to evaluate the effects of hospital volume: on the length of stay, on the numbers of re-admissions and on the numbers of complications of THR on population-based level in Finland. The survival of implants was analysed based on data from the Finnish Arthroplasty Register. The incidence and hospital volume data were obtained from the Hospital Discharge Register. Cementless total hip replacements had a significantly reduced risk of revision for aseptic loosening compared with cemented hip replacements. When revision for any reason was the end point in the survival analyses, there were no significant differences found between the groups. Adjusted incidence ratios of THA varied from 1.9- to 3.0-fold during the study period. Neither the average income within a region nor the morbidity index was associated with the incidence of THA. For the four categories of volume of total hip replacements performed per hospital, the length of the surgical treatment period was shorter for the highest volume group than for the lowest volume group. The odds ratio for dislocations was significantly lower in the high volume group than in the low volume group. In patients who were 55 years of age or older, the survival of cementless total hip replacements was as good as that of the cemented replacements. However, multiple wear-related revisions of the cementless cups indicate that excessive polyethylene wear was a major clinical problem with modular cementless cups. The variation in the long-term rates of survival for different cemented stems was considerable. Cementless proximal porous-coated stems were found to be a good option for elderly patients. When hip surgery was performed on with a large repertoire, the indications to perform THAs due to primary OA were tight. Socio-economic status of the patient had no apparent effect on THA rate. Specialization of hip replacements in high volume hospitals should reduce costs by significantly shortening the length of stay, and may reduce the dislocation rate.
  • Hyvärinen, Kati (Helsingin yliopisto, 2013)
    Atherosclerotic vascular diseases (ASVDs) affect the heart and circulatory system. One of the most common forms is coronary artery disease (CAD) which may eventually lead to acute coronary syndrome (ACS). ASVDs are currently the leading cause of mortality worldwide, and account for 47% of all deaths in Europe. The underlying mechanism is atherosclerosis, a progressive disease that manifests in several tissues. Common chronic infections, including periodontal disease and Chlamydia pneumoniae, may promote atherosclerosis and are associated with an increased risk of ASVDs. The general aims of this thesis project were to investigate the role of bacteria associated with periodontal disease in CAD, and the mechanisms by which common chronic infections promote proatherogenic alterations. More specifically, we aimed to: I) study the effects of Aggregatibacter actinomycetemcomitans and C. pneumoniae infections on the liver and adipose tissue lipid homeostasis and inflammation status in mice; II) develop and validate a quantitative PCR (QPCR) method to analyze the levels of periodontal disease-associated bacteria in saliva; and III) determine the association between salivary pathogen levels and CAD. The animal studies were conducted in atherosclerosis-susceptible apolipoprotein E-deficient mice. They were infected intravenously with viable A. actinomycetemcomitans and intranasally with viable C. pneumoniae. Consequently, the pathogens were recovered in the liver and C. pneumonia also in the lungs. Both infections induced systemic and hepatic inflammation, which were seen as an elevation of inflammation markers. Chronic C. pneumoniae infection induced hepatic microvesicular formations, which may promote steatosis. The recurrent A. actinomycetemcomitans infection disturbed the lipid homeostasis of adipose tissue: the proportion of saturated fatty acids was increased and that of polyunsaturated fatty acid decreased. The alterations in adipose tissue transcriptomes were depot-specific, and the inguinal adipose tissue was especially prone to inflammation-related responses. Single-copy gene-based QPCR assays were developed for five periodontal disease-associated bacteria: A. actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola, and Tannerella forsythia. The assays were validated in a case-control population including periodontally diseased and healthy subjects, and the diagnostic ability was found to be potent. The association of these pathogens with CAD was determined by analyzing saliva samples from the Parogene cohort (n = 492), consisting of patients with stable CAD, ACS, and no significant CAD as the reference group. All CAD diagnoses were verified by coronary angiography. The increased salivary levels of A. actinomycetemcomitans strongly associated with both stable CAD and ACS. Systemic exposure to the pathogen was seen as elevated serum antibody levels against the pathogen. The findings from the animal study indicate that A. actinomycetemcomitans and C. pneumoniae infections induce inflammation and disturbances in lipid and fatty acid homeostasis in the liver and adipose tissue. The potential tissue dysfunction may further augment the progression of atherosclerosis. The results from the Parogene study demonstrate that high salivary levels and systemic exposure to A. actinomycetemcomitans are associated with the risk of CAD and its acute manifestation. The findings from the thesis study are of common interest, because the studied pathogens are highly prevalent among the general population and their persistence may increase the overall risk of ASVDs.
  • Stamatova, Iva (Helsingin yliopisto, 2010)
    Yogurt consumption has been related to longevity of some populations living on the Balkans. Yogurt starter L. delbrueckii subsp. bulgaricus and Str. thermophilus have been recognized as probiotics with verified beneficial health effects. The oral cavity emerges as a arget for probiotic applications. Probiotics have demonstrated promising results in controlling dental diseases and oral yeast infections. However, L. bulgaricus despite its broad availability in dairy products has not been evaluated for probiotic activity in the mouth. These series of studies investigated in vitro properties of L. bulgaricus to outline its potential as an oral probiotic. Prerequisite probiotic properties in the mouth are resistance to oral defense mechanisms, adherence to saliva-coated surfaces, and inhibition of oral pathogens. L. bulgaricus strains showed a strain-dependent inhibition of oral streptococci and Aggregatibacter actinomycetemcomitans, whereas none of the dairy starter strains could affect growth of Porphyromonas gingivalis and Fusobacterium nucleatum. Adhesion is a factor contributing to colonization of the species at the target site. Radiolabeled L. bulgaricus strains and L. rhamnosus GG were tested for their ability to adhere to saliva-coated surfaces. The effects of lysozyme on adhesion and adhesion of Streptococcus sanguinis after lactobacilli pretreatment were also assessed. Adhesion of L. bulgaricus remained lower in comparison to L. rhamnosus GG. One L. bulgaricus strain showed binding frequency comparable to S. sanguinis. Lysozyme pretreatment significantly increased Lactobacillus adhesion. Low gelatinolytic activity was observed for all strains and no conversion of proMMP-9 to its active form was induced by L. bulgaricus. Safety assessment ruled out deleterious effects of L. bulgaricus on extracellular matrix structures. Cytokine response of oral epithelial cells was assessed by measuring IL-8 and TNF-α in cell culture supernatants. The effect of P. gingivalis on cytokine secretion after lactobacilli pretreatment was also assessed. A strain- and time-dependent induction of IL-8 was observed with live bacteria inducing the highest levels of cytokine secretion. Levels of TNF-α were low and only one of ten L. bulgaricus strains stimulated TNF-α secretion similar to positive control. The addition of P. gingivalis produced immediate reduction of cytokine levels within the first hours of incubation irrespective of lactobacilli strains co-cultured with epithelial cells. According to these studies strains among the L. delbrueckii subsp. bulgaricus species may have beneficial probiotic properties in the mouth. Their potential in prevention and management of common oral infectious diseases needs to be further studied.
  • Kukkonen, Anna Kaarina (Helsingin yliopisto, 2008)
    The rapid increase in allergic diseases in developed, high-income countries during recent decades is attributed to several changes in the environment such as urbanization and improved hygiene. This relative lack of microbial stimulation is connected to a delay in maturation of the infantile immune system and seems to predispose especially genetically prone infants to allergic diseases. Probiotics, which are live ingestible health-promoting microbes, may compensate for the lack of microbial stimulation of the developing gut immune system and may thus be beneficial in prevention of allergies. Prebiotics, which are indigestible nutrients by us, promote the growth and activity of a number of bacterial strains considered beneficial for the gut. In a large cohort of 1 223 infants at hereditary risk for allergies we studied in a double-blind placebo-controlled manner whether probiotics administered in early life prevent allergic diseases from developing. We also evaluated their safety and their effects on common childhood infections, vaccine antibody responses, and intestinal immune markers. Pregnant mothers used a mixture of four probiotic bacteria or a placebo, from their 36th week of gestation. Their infants received the same probiotics plus prebiotic galacto-oligosaccharides for 6 months. The 2-year follow-up consisted of clinical examinations and allergy tests, fecal and blood sampling, and regular questionnaires. Among the 925 infants participating in the 2-year follow-up the cumulative incidence of any allergic disease (food allergy, eczema, asthma, rhinitis) was comparable in the probiotic (32%) and the placebo (35%) group. However, eczema, which was the most common manifestation (88%) of all allergic diseases, occurred less frequently in the probiotic (26%) than in the placebo group (32%). The preventive effect was more pronounced against atopic (IgE-associated) eczema which, of all atopic diseases, accounted for 92%. The relative risk reduction of eczema was 26% and of atopic eczema 34%. To prevent one case of eczema, the number of mother-infant pairs needed to treat was 16. Probiotic treatment was safe without any undesirable outcome for neonatal morbidity, feeding-related behavior, serious adverse events, growth, or for vaccine-induced antibody responses. Fewer infants in the probiotic than in the placebo group received antibiotics during their first 6 months of life and thereafter to age 2 years suffered from fewer respiratory tract infections. As a novel finding, we discovered that high fecal immunoglobulin A (IgA) concentrations at age 6 months associated with reduced risk for atopic (IgE-associated) diseases by age 2 years. In conclusion, although feeding probiotics to high-risk newborn infants showed no preventive effect on the cumulative incidence of any allergic diseases by age 2, they apparently prevented eczema. This probiotic effect was more pronounced among IgE-sensitized infants. The treatment was safe and seemed to stimulate maturation of the immune system as indicated by increased resistance to respiratory infections and improved vaccine antibody responses.
  • Lehtoranta, Liisa (Helsingin yliopisto, 2012)
    Viral respiratory and gastrointestinal infections are a major health problem, in particular among children. A large range of etiologic agents and increasing antiviral and antibiotic resistance, challenge the development of efficient therapies. Accumulating evidence suggests that specific probiotic bacteria are able to decrease the risk and symptoms of these infections. This thesis investigated the effects of specific probiotics, in particular Lactobacillus rhamnosus GG, on respiratory and gastrointestinal virus infections in a cell model in vitro, in a rat model in vivo, and in children. A particular focus was on questions, whether viability of a probiotic is an important factor in probiotic-virus interaction, and whether a combination of probiotics is more effective than single strains. A novel colorimetric neutralization assay was developed for measuring influenza virus antibodies in human sera. The method was applied to measure antibody response after the administration of a seasonal, inactivated, trivalent influenza vaccine. The results were compared with those obtained with a traditional hemagglutinin inhibition test. The results obtained with both assays correlated well. Moreover, neutralization test proved to be more sensitive and specific than the hemagglutinin inhibition test. Thus, the method is valid for influenza virus research, and it could be applied for studying immune adjuvant effects of probiotics on serum influenza antibody titers in the future. Immunomodulatory effects of probiotics were screened in human macrophage model in vitro. After 24 hours of bacterial stimulation, probiotic combination of L. rhamnosus GG and L. rhamnosus Lc705 was not able to significantly induce higher macrophage cytokine and chemokine production (TNF-α, IL-1β, IL-6, IL-10, and IL-12, MCP-1, IP-10) over individual L. rhamnosus strains. However, cytokine responses induced by this combination were stronger than responses induced by traditional starter culture bacterium Lactococcus lactis ARH74, highlighting that immunomodulatory effects of probiotics are strain specific. The effects of viable and unviable L. rhamnosus GG in rotavirus infection were investigated in a neonatal rat model. Consistency of feces, animal weight, colon weight and the rotavirus colonization of plasma and intestinal tissues were considered as indexes of infection severity. Nonviable L. rhamnosus GG had beneficial effects in rotavirus infection in terms of reducing rotavirus induced body weight reduction and colon weight increase. However, viable L. rhamnosus GG was more effective in reducing significantly viral load in the gastrointestinal tract. The effects of L. rhamnosus GG alone or probiotic combination containing L. rhamnosus GG on the occurrence of viral respiratory infections was assessed in a six month intervention trial in children or in otitis-prone children. Children receiving only L. rhamnosus GG had fewer days with respiratory tract symptoms during the intervention period. However, L. rhamnosus GG did not reduce viral occurrence in the nasopharynx, suggesting that L.rhamnosus GG is able to reduce respiratory virus symptoms through enhancing immune response. In otitis-prone children, L. rhamnosus GG in a combination with L. rhamnosus Lc705, Bifidobacterium breve 99, and Propionibacterium freudenreichii ssp. shermanii JS significantly reduced human bocavirus load in the nasopharynx three to six months after intervention. In conclusion, probiotics and their combinations differ in their ability to elicit immunomodulatory effects in vitro. Viability of a probiotic is an important factor in virus infection. The probiotic L. rhamnosus GG reduced days with respiratory tract symptoms. In children, L. rhamnosus GG alone was not effective in reducing viral occurrence in the nasopharynx. However in otitis-prone children, L. rhamnosus GG in a combination reduced the numbers of human bocavirus.
  • Hatakka, Katja (Helsingin yliopisto, 2007)
    Infectious diseases put an enormous burden on both children and the elderly in the forms of respiratory, gastrointestinal and oral infections. There is evidence suggesting that specific probiotics may be antagonistic to pathogens and may enhance the immune system, but the clinical evidence is still too sparce to make general conclusions on the disease-preventive effects of probiotics. This thesis, consisting of four independent, double-blind, placebo-controlled clinical trials, investigated whether Lactobacillus GG (LGG) or a specific probiotic combination containing LGG would reduce the risk of common infections or the prevalence of pathogens in healthy and infection-prone children and in independent and institutionalised elderly people. In healthy day-care children, the 7-month consumption of probiotic milk containing Lactobacillus GG appeared to postpone the first acute respiratory infection (ARI) by one week (p=0.03, adjusted p=0.16), and to reduce complicated infections (39% vs. 47%, p<0.05, adjusted p=0.13), as well as the need for antibiotic treatment (44% vs. 54%, p=0.03, adjusted p=0.08) and day-care absences (4.9 vs. 5.8 days, p=0.03, adjusted p=0.09) compared to the placebo milk. In infection-prone children, the 6-month consumption of a combination of four probiotic bacteria (LGG, L. rhamnosus LC705, Propionibacterium freudenreichii JS, Bifidobacterium breve 99) taken in capsules appeared to reduce recurrent ARIs (72% vs. 82%, p<0.05; adjusted p=0.06), and the effect was particularly noticeable in a subgroup of children with allergic diseases (12% vs. 33%, p=0.03), although no effect on the presence of nasopharyngeal rhinovirus or enterovirus was seen. The 5-month consumption of the same probiotic combination did not show any beneficial effects on the respiratory infections in frail, institutionalised elderly subjects. In healthy children receiving Lactobacillus GG, the reduction in complications resulted in a marginal reduction in the occurrence of acute otitis media (AOM) (31% vs. 39%, p=0.08; adjusted p=0.19), and the postponement of the first AOM episode by 12 days (p=0.04; adjusted p=0.09). However, in otitis-prone children, a probiotic combination did not reduce the occurrence of AOM or the total prevalence of common AOM pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis), except in the case of children with allergic diseases, in whom probiotics reduced recurrent AOM episodes (0% vs. 14%, p=0.03). In addition, interaction between probiotics and bacterial carriage was seen: probiot-ics reduced AOM in children who did not carry any bacterial pathogens (63% vs. 83%), but the effect was the reverse in children carrying bacteria in the nasopharynx (74% vs 62%) (p<0.05). Long-term probiotic treatment, either LGG given in milk to healthy children for 7 months or a combination of probiotics given in capsules to institutionalised elderly subjects for 5 months, did not reduce the occurrence of acute diarrhoea. However, when the probiotic combination (LGG, L. rhamnosus LC705, Propionibacterium JS) was given in cheese to independent elderly subjects for 4 months, the oral carriage of high Candida counts was reduced in the probiotic group vs. the placebo group (21% vs. 34%, p=0.01, adjusted p=0.004). The risk of hyposalivation was also reduced in the probiotic group (p=0.05). In conclusion, probiotics appear to slightly alleviate the severity of infections by postponing their appearance, by reducing complications and the need for antimicrobial treatments. In addition, they appear to prevent recurrent infections in certain subgroups of children, such as in infection-prone children with allergic diseases. Alleviating ARI by probiotics may lead to a marginal reduction in the occurrence of AOM in healthy children but not in infection-prone children with disturbed nasopharyngeal microbiota. On the basis of these results it could be supposed that Lactobacillus GG or a specific combination containing LGG are effective against viral but not against bacterial otitis, and the mechanism is probably mediated through the stimulation of the immune system. A specific probiotic combination does not reduce respiratory infections in frail elderly subjects. Acute diarrhoea, either in children or in the elderly, is not prevented by the continuous, long-term consumption of probiotics, but the consumption of a specific probiotic combination in a food matrix is beneficial to the oral health of the elderly, through the reduction of the carriage of Candida.
  • Ilveskero, Sorella (Helsingin yliopisto, 2005)
  • Uittamo, Johanna (Helsingin yliopisto, 2012)
    Oral cancer is the seventh most common cancer worldwide and its incidence is increasing. The most important risk factors for oral cancer are chronic alcohol consumption and tobacco smoking, up to 80 % of oral carcinomas are estimated to be caused by alcohol and tobacco. They both trigger an increased level of salivary acetaldehyde, during and after consumption, which is believed to lead to carcinogenesis. Acetaldehyde has multiple mutagenic features and it has recently been classified as a Group 1 carcinogen for humans by the International Agency for Research on Cancer. Acetaldehyde is metabolized from ethanol by microbes of oral microbiota. Some oral microbes possess alcohol dehydrogenase enzyme (ADH) activity, which is the main enzyme in acetaldehyde production. Many microbes are also capable of acetaldehyde production via alcohol fermentation from glucose. However, metabolism of ethanol into acetaldehyde leads to production of high levels of this carcinogen. Acetaldehyde is found in saliva during and after alcohol consumption. In fact, rather low ethanol concentrations (2-20mM) derived from blood to saliva are enough for microbial acetaldehyde production. The high acetaldehyde levels in saliva after alcohol challenge are explained by the lack of oral microbiota and mucosa to detoxify acetaldehyde by metabolizing it into acetate and acetyl coenzymeA. The aim of this thesis project was to specify the role of oral microbes in the in vitro production of acetaldehyde in the presence of ethanol. In addition, it was sought to establish whether microbial metabolism could also produce acetaldehyde from glucose. Furthermore, the potential of xylitol to inhibit ethanol metabolism and acetaldehyde production was explored. Isolates of oral microbes were used in the first three studies. Acetaldehyde production was analyzed after ethanol, glucose and fructose incubation with gas chromatography measurement. In studies I and III, the ADH enzyme activity of some microbes was measured by fluorescence. The effect of xylitol was analyzed by incubating microbes with ethanol and xylitol. The fourth study was made ex vivo and microbial samples obtained from different patient groups were analyzed. This work has demonstrated that isolates of oral microbiota are able to produce acetaldehyde in the presence of clinically relevant ethanol and glucose concentrations. Significant differences were found between microbial species and isolates from different patient groups. In particular, the ability of candidal isolates from APECED patients to produce significantly more acetaldehyde in glucose incubation compared to healthy and cancer patient isolates is an interesting observation. Moreover, xylitol was found to reduce their acetaldehyde production significantly. Significant ADH enzyme activity was found in the analyzed high acetaldehyde producing streptococci and candida isolates. In addition, xylitol was found to reduce the ADH enzyme activity of C. albicans. Some results from the ex vivo study were controversial, since acetaldehyde production did not correlate as expected with the amount of microbes in the samples. Nevertheless, the samples isolated from patients did produce significant amounts of acetaldehyde with a clinically relevant ethanol concentration.
  • Siironen, Päivi (Helsingin yliopisto, 2005)
  • Koskensalo, Selja (Helsingin yliopisto, 2013)
    Background and aims: The most important prognostic factor in colorectal cancer (CRC) is tumour stage. Prognosis of local tumours is good, but in tumours with lymph node or distant metastasis, the prognosis is worse. Patients with stage III (Dukes C) tumours usually receive adjuvant chemotherapy. Patients with stage IV (Dukes D) tumours cannot be treated curatively by surgery alone and usually receive chemotherapy. In stage II (Dukes B) disease, adjuvant chemotherapy is recommended for patients at risk for recurrence, such as with tumours with vascular or perineural invasion, or in cases with emergency surgery or insufficient lymph-node harvest. In order to identify better those patients requires additional prognostic factors like biomarkers. Material and methods: Clinical data came from 643 consecutive patients who underwent surgery for colorectal cancer at the Department of Surgery, Meilahti Hospital, Helsinki University Central Hospital, between 1982 and 1998. Clinical data and archival tissue specimens were available from 623 cases. For MMP-9, a validation series of 213 patients treated between 1998 and 2001 was included. Survival data came from the Population Register Centre of Finland and Statistics Finland. Tissue microarray (TMA) blocks were prepared from re-evaluated histological archive blocks. TMA slides were stained with MMP-2, MMP-7, MMP-8, MMP-9, TATI, trypsinogen-1, trypsinogen-2, p53, Ki-67, and EGFR antibodies. Correlation of immunoexpression of markers with clinicopathological variables was assessed. Survival analysis was performed by the Kaplan-Meier method, and multivariate Cox proportional hazards model. Results: Study I showed strong MMP-7 to be an independent prognostic marker for 5-year survival, but later the difference faded. In Study II, no association was observable between p53 or Ki-67 expression and survival. In Study III, TATI immunoexpression was an independent prognostic marker for improved survival, particularly in subgroups of trypsinogen-1- and trypsinogen-2-positive patients, although trypsinogen-1 and trypsinogen-2 were not prognostic factors. In Study IV, MMP-9 expression was an independent prognostic marker of favourable survival in Dukes B patients, but the validation series did not confirm these results. MMP-2 and MMP-8 immunoexpression lacked any correlation with prognosis. In Study V, EGFR+TATI+ patients had significantly better prognosis than did those with EGFR+TATI-, EGFR-TATI+, or EGFR-TATI-. Conclusion: MMP-7, MMP-9, TATI, and the TATI-EGFR combination can all serve as prognostic biomarkers in CRC.
  • Kanerva, Jukka (Helsingin yliopisto, 2002)
  • Koljonen, Virve (Helsingin yliopisto, 2004)
  • Ilmonen, Suvi (Helsingin yliopisto, 2005)
  • Taskinen, Minna (Helsingin yliopisto, 2011)
    Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma. It is an indolent and clinically heterogeneous disease, which is generally considered incurable. Currently, immunochemotherapy has significantly improved the outcome of FL patients. This is based on the combination of rituximab, a monoclonal anti-CD20 antibody, with chemotherapy, and is used at present as a standard first-line therapy in FL. Thus far, however, patients have been selected for treatment based on clinical risk factors and indices that were developed before the rituximab era. Therefore, there is a growing need to understand the molecular mechanisms underlying the disease, which would not only provide information to predict survival in the rituximab era, but also enable the design of more targeted therapeutic strategies. In this study, our aim was to identify genes predicting the outcome in FL patients treated with immunochemotherapy. Thus, we performed a cDNA microarray with 24 FL patients. When gene expression differences from diagnostic tumour samples were related to the clinical outcome, we identified novel genes with a prognostic impact on survival. The expression of selected genes was further characterized with quantitative PCR and immunohistochemistry (IHC). Interestingly, the prognostic influence of these genes was often associated with their expression in non-malignant cells instead of tumour cells. Based on the observed gene expression patterns, we analyzed the abundance and prognostic value of non-malignant immune cells in 95-98 FL patients treated with immunochemotherapy. We observed that a high content of tumour-associated macrophages was a marker of a favourable prognosis. In contrast, the accumulation of mast cells correlated with a poor outcome and was further associated with tumour vascularity. Increased microvessel density also correlated with an inferior outcome. In addition, we used the same microarray data with a systems biology approach to identify signalling pathways or groups of genes capable of separating patients with favourable or adverse outcomes. Among the transcripts, there were many genes associated with signal transducers and activators of the transcription (STAT5a) pathway. When IHC was used as validation, STAT5a expression was mostly observed in T-cells and follicular dendritic cells, and expression was found to predict a favourable outcome. In cell cultures, rituximab was observed to induce the expression of STAT5a-associated interleukins in human lymphoma cell lines, which might provide a possible link for the cross-talk between rituximab-induced FL cells and their microenvironment. In conclusion, we have demonstrated that the microenvironment has a prognostic role in FL patients treated with immunochemotherapy. The results also address the importance of re-evaluating the prognostic markers in the rituximab era of lymphoma therapies.
  • Mäkitie, Teemu (Helsingin yliopisto, 2001)
  • Koskinen, Walter (Helsingin yliopisto, 2006)
    Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Well-known risk factors include tobacco smoking and alcohol consumption. Overall survival has improved, but is still low especially in developing countries. One reason for this is the often advanced stage of the disease at the time of diagnosis, but also lack of reliable prognostic tools to enable individualized patient treatment to improve outcome. To date, the TNM classification still serves as the best disease evaluation criterion, although it does not take into account the molecular basis of the tumor. The need for surrogate molecular markers for more accurate disease prediction has increased research interests in this field. We investigated the prevalence, physical status, and viral load of human papillomavirus (HPV) in HNSCC to determine the impact of HPV on head and neck carcinogenesis. The prevalence and genotyping of HPV were assessed with an SPF10 PCR microtiter plate-based hybridization assay (DEIA), followed by a line probe-based genotyping assay. More than half of the patients had HPV DNA in their tumor specimens. Oncogenic HPV-16 was the most common type, and coinfections with other oncogenic and benign associated types also existed. HPV-16 viral load was unevenly distributed among different tumor sites; the tonsils harbored significantly greater amounts of virus than other sites. Episomal location of HPV-16 was associated with large tumors, and both integrated and mixed forms of viral DNA were detected. In this series, we could not show that the presence of HPV DNA correlated with survival. In addition, we investigated the prevalence and genotype of HPV in laryngeal carcinoma patients in a prospective Nordic multicenter study based on fresh-frozen laryngeal tumor samples to determine whether the tumors were HPV-associated. These patients were also examined and interviewed at diagnosis for known risk factors, such as tobacco smoking and alcohol consumption, and for several other habituations to elucidate their effects on patient survival. HPV analysis was performed with the same protocols as in the first study. Only 4% of the specimens harbored HPV DNA. Heavy drinking was associated with poor survival. Heavy drinking patients were also younger than nonheavy drinkers and had a more advanced stage of disease at diagnosis. Heavy drinkers had worse oral hygiene than nonheavy drinkers; however, poor oral hygiene did not have prognostic significance. History of chronic laryngitis, gastroesophageal reflux disease, and orogenital sex contacts were rare in this series. To clarify why vocal cord carcinomas seldom metastasize, we determined tumor lymph vessel (LVD) and blood vessel (BVD) densities in HNSCC patients. We used a novel lymphatic vessel endothelial marker (LYVE-1 antibody) to locate the lymphatic vessels in HNSCC samples and CD31 to detect the blood microvessels. We found carcinomas of the vocal cords to harbor less lymphatic and blood microvessels than carcinomas arising from sites other than vocal cords. The lymphatic and blood microvessel densities did not correlate with tumor size. High BVD was strongly correlated with high LVD. Neither BVD nor LVD showed any association with survival in our series. The immune system plays an important role in tumorigenesis, as neoplastic cells have to escape the cytotoxic lymphocytes in order to survive. Several candidate HLA class II alleles have been reported to be prognostic in cervical carcinomas, an epithelial malignancy resembling HNSCC. These alleles may have an impact on head and neck carcinomas as well. We determined HLA-DRB1* and -DQB1* alleles in HNSCC patients. Healthy organ donors served as controls. The Inno-LiPA reverse dot-blot kit was used to identify alleles in patient samples. No single haplotype was found to be predictive of either the risk for head and neck cancer, or the clinical course of the disease. However, alleles observed to be prognostic in cervical carcinomas showed a similar tendency in our series. DRB1*03 was associated with node-negative disease at diagnosis. DRB1*08 and DRB1*13 were associated with early-stage disease; DRB1*04 had a lower risk for tumor relapse; and DQB1*03 and DQB1*0502 were more frequent in controls than in patients. However, these associations reached only borderline significance in our HNSCC patients.
  • Jernman, Juha (Helsingin yliopisto, 2015)
    Neuroendocrine tumors of the rectum were regarded as benign, when Oberndorfer originally described the entity in 1907. Later, he acknowledged that some neuroendocrine tumors (or carcinoids, the term at that time) behave in a more aggressive manner, and a few of them even had the potential to metastasize with poor outcome. In the novel World Health Organization (WHO) classification launched in 2010, all neuroendocrine tumors of the gastrointestinal (GI) tract are malignant. In this classification, tumors of every part of the GI tract are graded uniformly according to proliferation index and mitotic frequency, whereas the TNM-classification (tumor, node, metastasis) is specific for each site. Around 10% of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) occur in the rectum. The tumor series comprised 73 rectal NETs, with the main objective being to study the prognostic value of the WHO 2010 classification in rectal NETs: additionally, as the WHO classification has been used for a rather short time, tumor markers were tested to find a good, reliable prognostic tool. The WHO 2010 had excellent prognostic significance; none of the G1-NETs (grade 1) metastasized, whereas G2-NETs were often disseminated, some of them at initial presentation. Metastatic NETs have a poor prognosis. Cell-cycle antigen cyclin A also correlated with prognosis, and G2-NETs with high cyclin A expression were all metastatic. Transcription factor prospero homeobox 1 (PROX1) was immunohistochemically positive in a significant proportion of rectal NETs, and showed a correlation with metastatic potential and survival. It was also possible to conclude that the novel stem cell-associated factor HES77 (human embryonic stem cell factor 77) correlated well with rectal NETs metastatic potential and prognosis. These results support the validity of the WHO 2010 classification in rectal NETs. In view of this study, for patients with a rectal G1-NET, one follow-up endoscopy to exclude local recurrence might suffice. Intensive follow-up does not seem indicated, as metastatic potential is very low. As to G2-NETs, a thorough work-up is recommended, since most of these tumors disseminate eventually, some after several years, and a standard 5-year follow-up may not suffice. PROX1-positivity suggests that colorectal adenocarcinoma and rectal NET may, to some extent, share the same pathway in oncogenesis, which could lead to future therapeutic applications.