240 research outputs found
A joint frailty model to assess the relationship between time to curative treatment and biochemical recurrence in Prostate Cancer patients
No full textObjectives: Conflicting evidence exists regarding the effect of delaying prostate cancer (PCa) treatment on outcomes after curative treatment. Ideally, modelling this would require a joint analysis of the time to treatment initiation and the time to PCa recurrence. However, traditional Cox models are limited to analysing a single time-to-event outcome. In this study, we build a joint frailty model to assess the effect of delayed or expedited primary curative treatment (surgery or radiotherapy) on the risk of biochemical recurrence (BCR).
Methods: We used HUS (Helsinki Metropolitan Hospital District) data lake for data mining and to categorise PCa patients by Gleason grade group (1- 5), treatment, and biochemical recurrence for a final sample size of n=9934
patients (1993–2019). A broader definition of BCR was established considering secondary treatments as an additional indicator of relapse alongside traditional PSA cut-offs. We applied the INLA method for Bayesian inference, utilising the INLAJoint R package, to fit a shared frailty joint survival model. This model was used to analyse the relationship between the time from diagnosis to curative treatment (treatment risk) and the time from diagnosis to biochemical recurrence (relapse risk).
Results: Conditional on covariates, including age at diagnosis and Gleason grade group, our joint survival model revealed a significant association γ = -1.32 [-1.50, -1.14] between the risk of treatment and risk of BCR. As an example, regardless of the grade group, patients within the top 5% with the lowest risk of receiving treatment (i.e., the longest time to treatment) exhibited an HR=5.27 [4.28, 6.62] fold (increased) risk of recurrence compared to the average patient.
Conclusion: We successfully employed a joint frailty model to simultaneously model the effect of time to curative primary treatment on time to biochemical recurrence. We show that the time to curative treatment is associated with the risk of relapse. Patients of the same age, same diagnostic PSA, and same grade group who are treated early are less likely to develop biochemical recurrence.This work was supported by grants from the Cancer Society Finland (Tuomas Mirtti and Antti Rannikko), Academy of Finland (Tuomas Mirtti and Antti Rannikko), Sigrid Jusélius Foundation (Tuomas Mirtti), Jane and Aatos Erkko Foundation (Antti Rannikko) and state funding for universitylevel health research (Tuomas Mirtti and Antti Rannikko). The funding sources did not play any role in the study design, execution, data analyses, writing of the report, or submission of the article for publication
Altered Glycosylation of PSA in Prostate Cancer Tissue
No full textBackground: The glycosylation of proteins is commonly altered in cancer. This offers novel opportunities for cancer biomarker development. As prostate-specific antigen (PSA) is a glycoprotein, identification of cancer-specific PSA-glycoforms is feasible. Such PSA-glycoforms may provide valuable diagnostic and prognostic information. Methods: PSA-glycoforms were studied in tissues, using in situ proximity-ligation assay (PLA)-based detection with a PSA-specific antibody and 25 different glycan-binding lectins. Results: Using 25 different lectins and a small tissue microarray (TMA), we showed that glycosylation of PSA in cancerous tissues is different from that in benign prostate. In a larger TMA with samples from 162 patients, PSA-glycoforms detected by succinylated wheat germ (WGA(succ)) and Vicia villosa (VVA) lectins were enriched in cancerous tissues as compared to adjacent benign tissues from the same patients (p < 10(-4) for both, Kruskal-Wallis H test), although strong total PSA staining was more often found in benign tissues (p = 6*10(-14)). Conclusions: We showed here that glycosylation of PSA is changed in situ in prostate cancer. The identified lectins, showing preferential binding to cancer-associated PSA-glycoforms, will aid the future development of a diagnostic serum test of prostate cancer. Such a test has potential to revolutionize prostate cancer diagnostics.Peer reviewe
Tekoäly patologian kudosleikkeiden tulkinnassa
No full textKonenäkö ja koneoppiminen ovat vauhdilla tulossa lääketieteeseen, erityisesti radiologiaan ja patologiaan. Hermoverkkojen avulla voidaan jo luokitella tautiryhmiä oikein sekä tunnistaa esimerkiksi syövän erilaistumisasteita. Konenäön odotetaan nopeuttavan lääkärin työtä ja vähentävän subjektiivisista arvioinneista johtuvaa vaihtelua diagnostiikassa, mikä johtaa laadukkaampaan diagnostiikkaan. Tekoäly ei korvaa lääkäriä, mutta oikein hyödynnettynä sille voidaan antaa rutiinitehtäviä ja vapauttaa näin luova ihmismieli vaikeampiin, parempaa kognitiota vaativiin tehtäviin sekä uuden kehittämiseen.Peer reviewe
Re : Fatemeh Seyednasrollah, Mehrad Mahmoudian, Liisa Rautakorpi, et al. How Reliable are Trial-based Prognostic Models in Real-world Patients with Metastatic Castration-resistant Prostate Cancer? Eur Urol. 2017;71:838-40
No full textNon peer reviewe
Tekoäly patologian kudosleikkeiden tulkinnassa
No full textTiivistelmäKonenäkö ja koneoppiminen ovat vauhdilla tulossa lääketieteeseen, erityisesti radiologiaan ja patologiaan. Hermoverkkojen avulla voidaan jo luokitella tautiryhmiä oikein sekä tunnistaa esimerkiksi syövän erilaistumisasteita. Konenäön odotetaan nopeuttavan lääkärin työtä ja vähentävän subjektiivisista arvioinneista johtuvaa vaihtelua diagnostiikassa, mikä johtaa laadukkaampaan diagnostiikkaan. Tekoäly ei korvaa lääkäriä, mutta oikein hyödynnettynä sille voidaan antaa rutiinitehtäviä ja vapauttaa näin luova ihmismieli vaikeampiin, parempaa kognitiota vaativiin tehtäviin sekä uuden kehittämiseen.AbstractArtificial intelligence in interpretation of tissue pathologyThe progress in medical computer vision and artificial intelligence is accelerating, especially in radiology and pathology. The use of neural networks, disease classification and cancer grading is possible already. It is expected that computer vision will help medical experts to work faster and make more consistent and reproducible diagnoses, i.e. increase the diagnostic quality. Artificial intelligence is not going to replace a physician but, when applied correctly, routine procedures performed by AI may free humans to work with more creative and demanding tasks, as well as to develop diagnostics further. Tiivistelmä
Konenäkö ja koneoppiminen ovat vauhdilla tulossa lääketieteeseen, erityisesti radiologiaan ja patologiaan. Hermoverkkojen avulla voidaan jo luokitella tautiryhmiä oikein sekä tunnistaa esimerkiksi syövän erilaistumisasteita. Konenäön odotetaan nopeuttavan lääkärin työtä ja vähentävän subjektiivisista arvioinneista johtuvaa vaihtelua diagnostiikassa, mikä johtaa laadukkaampaan diagnostiikkaan. Tekoäly ei korvaa lääkäriä, mutta oikein hyödynnettynä sille voidaan antaa rutiinitehtäviä ja vapauttaa näin luova ihmismieli vaikeampiin, parempaa kognitiota vaativiin tehtäviin sekä uuden kehittämiseen.Abstract
Artificial intelligence in interpretation of tissue pathology
The progress in medical computer vision and artificial intelligence is accelerating, especially in radiology and pathology. The use of neural networks, disease classification and cancer grading is possible already. It is expected that computer vision will help medical experts to work faster and make more consistent and reproducible diagnoses, i.e. increase the diagnostic quality. Artificial intelligence is not going to replace a physician but, when applied correctly, routine procedures performed by AI may free humans to work with more creative and demanding tasks, as well as to develop diagnostics further
Abstract 5732: PI3K/Akt activity regulates androgen receptor expression and predicts poor clinical outcome in non-metastatic hormone-naïve prostate cancer
No full textAbstract
Activation of PI3K/Akt pathway is associated with adverse outcome and aggressive disease in many cancers. In prostate cancer (PCa), the activity of this pathway has been shown to promote disease progression and metastasis. However, it is still controversial how PI3K/Akt regulates androgen receptor (AR), a central signaling molecule in prostate pathophysiology, and whether it has an active role in hormone naïve non-metastatic PCa. Here, we show using immunohistochemistry (IHC) and advanced quantitative multiplexed IHC that the expression of phosphorylated-Akt(S473) and AR are highly correlated in clinical PCa, even at the cellular level. Furthermore, we found that high expression of p-Akt(S473) predicts poor clinical outcome in two independent hormone-naïve non-metastatic PCa cohorts. To study whether PI3K/Akt regulates AR expression, we performed an in vitro drug screen with 32 PI3K/Akt/mTOR inhibitors in PC346C, an AR expressing cell line derived from a hormone-naïve primary tumor of prostate. We observed a strong correlation between p-Akt(S473) and AR also in vitro in individual cells independent of the inhibitor used. Although both PI3K and Akt specific inhibition reduced cell viability, the response in nuclear expression of AR was highly dependent on the target of inhibition: Akt specific inhibition reduced AR nuclear expression and resulted in large, spindle-shaped cells, whereas PI3K specific inhibition increased AR nuclear expression and resulted in smaller, round-shaped cells. These data suggest that PI3K and Akt have different roles in sustaining AR activity in PCa as perturbations of the two components leads to differential responses in terms of AR nuclear expression and cell morphology. In conclusion, activated Akt associates with AR expression and predicts poor clinical outcome in hormone-naïve non-metastatic PCa. Furthermore, the differing roles of PI3K and Akt in AR regulation warrants for further studies as it may have implications in the design of PCa therapy targeting PI3K/Akt, especially when the inhibitors are administered in combination with anti-androgens.
Citation Format: Sami Blom, Petra Mäki-Teeri, Andrew Erickson, Lassi Paavolainen, Tuomas Mirtti, Antti Rannikko, Swapnil Potdar, Päivi Östling, Wytske van Weerden, Olli Kallioniemi, Teijo Pellinen. PI3K/Akt activity regulates androgen receptor expression and predicts poor clinical outcome in non-metastatic hormone-naïve prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5732. doi:10.1158/1538-7445.AM2017-5732</jats:p
Abstract 5730: Increased FGFRL1 expression is associated with prostate cancer progression
No full textAbstract
Prostate cancer (PCa) is the most diagnosed cancer in men in developed countries. Fibroblast growth factor receptors (FGFRs) have been demonstrated to play an important role in PCa initiation and progression. Fibroblast growth factor receptor like 1 (FGFRL1) is the most recently identified member of the FGFR family. Its extracellular domain shares high similarity to FGFR1-4 but it lacks the cytoplasmic domain with tyrosine kinase activity. Thus, FGFRL1 is able to bind FGF ligands but the subsequent intracellular signaling cascade is defective. We observed up-regulation of FGFRL1 mRNA expression in PCa in a public genome-wide cancer transcriptome data base (cBioPortal). To validate the expression data and to investigate the putative role of upregulated FGFRL1 protein in normal prostate and PCa, tissue microarrays containing different types of benign and malignant prostate tissue were used. Altered FGFRL1 protein expression was correlated with clinical parameters; and both in vitro and in vivo experiments were applied to study the biological functions FGFRL1 in PCa cell lines. Our results confirmed that FGFRL1 expression is upregulated in PCa compared to normal prostate. More specifically, increased cytoplasmic and nuclear FGFRL1 expression was associated with high Gleason score and Ki67 expression, while membrane-associated FGFRL1 showed the opposite correlation. To investigate the effects of androgens on FGFRL1 in vitro, PCa cells were treated with dihydrotestosterone and/or MDV3100, an androgen receptor inhibitor. Dihydrotestosterone increased FGFRL1 expression and MDV3100 inhibited endogenous FGFRL1 expression, but not when stimulated by dihydrotestosterone, suggesting indirect androgen-mediated regulation. The in vitro studies also showed that FGFRL1 is able to attenuate the phosphorylation of FRS2α and ERK1/2 by FGF ligands, providing evidence for the assumed decoy function of membranous FGFRL1. However, knock-down of FGFRL1 in PC3M cells resulted in reduced cell growth in tumor xenografts. Additionally, mRNA sequencing on PC3M cells with FGFRL1 knock-down revealed differential expression of about 250 molecules, including several metalloproteinases and FGFR1, compared to control cells (FDR&lt;0.1 and -1&gt;logFC&gt;1). In conclusion, we suggest that upregulation and altered subcellular localization of FGFRL1, in PCa, directly or indirectly, promotes tumor growth and progression. The results suggest that FGFRL1 is a potent regulator of gene expression and may be involved in diverse functions depending on its cellular localization.
Citation Format: Lan Yu, Mervi Toriseva, Andrew Erickson, Heikki Seikkula, Martti Nurmi, Pekka Taimen, Peter Boström, Tuomas Mirtti, Kalle Alanen, Markku Kallajoki, Johanna Tuomela, Mattias Nees, Pirkko Härkönen. Increased FGFRL1 expression is associated with prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5730. doi:10.1158/1538-7445.AM2017-5730</jats:p
Abstract 3854: Precision medicine approach: analysis of renal cancer patient-derived cells with phenomics, genomics and drug sensitivity profiling
No full textAbstract
We have built up the precision medicine approach for solid tumors to understand biological heterogeneity and driver signalling pathways in cancer, to develop pharmacogenomic biomarkers and to ultimately tailor effective treatments for patients. In addition to genetic profiling of original tumor tissues, we have developed patient -derived tumor cell (PDC) models, and characterized these models with genomics, image-based phenotyping (phenomics) and high throughput drug profiling.
Here, we describe our approach for a clear cell renal cell carcinoma (ccRCC) patient. PDC cultures were initiated using conditional reprogramming method from fresh primary tumor, protrusion to vena cava, and the benign tissue samples. The exome-sequencing of tissues and PDCs showed that several copy number variations and somatic driver mutations were shared between the cancer tissue and corresponding cell models, including TSC2 and VHL mutations. Using image-based phenotyping, the PDCs from the benign tissue were observed to be strongly positive to cytokeratin 7 (CK7), while original tumor tissue and PDCs from tumor tissue were predominantly CK7 negative. The PDCs expressed vimentin, a mesenchymal marker, but the epithelial marker E-cadherin was downregulated, suggesting for epithelial-mesenchymal transition. The PDCs from primary tumor were exposed to drug sensitivity profiling with a library of 525 approved and investigational oncology compounds in five different concentrations and imaged for proliferation with Ki-67. PI3K/mTOR pathway inhibitors were found to be among the drugs inhibiting the cell proliferation, in agreement with detected somatic mutations affecting these pathways. In addition, our image-based drug sensitivity testing revealed the intra-sample heterogeneity in drug responses and resistance, and we are now further investigating the mechanisms of most potent drugs and their combinations in PDCs at single cell level.
As a conclusion, our results implicate the importance of comprehensive characterization of PDCs and their drug responses in translational research. We also foresee that these approaches may potentially improve the translation of results back to clinic and support the design of combination therapies in cancer.
Citation Format: Vilja M. Pietiäinen, Piia Mikkonen, Khalid Saeed, Lassi Paavolainen, Teijo Pellinen, Swapnil Potdar, John Mpindi, Harry Nisén, Antti Rannikko, Tuomas Mirtti, Peter Horvath, Päivi Östling, Olli Kallioniemi. Precision medicine approach: analysis of renal cancer patient-derived cells with phenomics, genomics and drug sensitivity profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3854. doi:10.1158/1538-7445.AM2017-3854</jats:p
Systeeminen tulehdusvaste kolorektaalisyövässä : Sytokiinien ja endostatiinin merkitys
No full textAbstractColorectal cancer (CRC) is among the most common cancers in Finland. Prognostic factors are important for predicting disease outcome and adjusting optimal treatment. The currently used prognostic methods for CRC have their limitations and consequently several biomarkers have been studied to find potential prognostic markers, but none have been adapted for routine use so far. In the present study, the relationships between the components of the immune system and other factors modulating tumor growth were assessed and their suitability to be used for use as prognostic tools in CRC were studied.The study material consisted of blood samples and surgical specimens collected from 148 CRC patients operated on in Oulu University Hospital and blood samples of 86 healthy controls. Concentrations of endostatin and 27 cytokines were measured from preoperative serum samples and control samples. Immunohistochemical methods were used for collagen XVIII and inflammatory cell analyses.The levels of several cytokines were altered in CRC patients compared to the controls. The serum cytokine profile achieved an excellent accuracy in discriminating CRC patients from healthy controls. Advanced CRCs were associated with elevated cytokine levels and a metastasized disease was linked to an orientation towards Th2 cytokine milieu. The presence of systemic inflammation, depicted by a modified Glasgow Prognostic Score (mGPS), correlated to CRC progression. The serum endostatin levels were elevated in CRC and correlated with invasion through muscular layer and systemic inflammation, but not with densities of local inflammatory cells. Collagen XVIII was expressed in tumor stroma and in the muscle layer of bowel wall. The serum cytokines and tumor infiltrating immune cells showed relatively weak associations.In conclusion, CRC is associated with significant alterations in serum cytokine milieu, which underlines the relevance of studying several cytokines and their relative alterations. The serum cytokine profile is a promising tool for discriminating CRC patients from healthy controls, but its clinical value needs to be validated. The elevated endostatin levels may result from invasion-related cleavage of collagen XVIII in the bowel wall, but further studies are needed to determine the value of endostatin in CRC prognosis.TiivistelmäPaksu- ja peräsuolisyöpä (kolorektaalisyöpä) on yleisimpiä syöpämuotoja Suomessa. Sen ennustetta kuvaavat mittarit ovat tärkeitä taudin etenemisen ennustamisessa ja hoidon suunnittelussa. Käytössä olevat kolorektaalisyövän ennusteen arvioinnin menetelmät eivät ole riittäviä. Uusia merkkiaineita onkin kehitetty ja testattu, mutta rutiinikäyttöön soveltuvia menetelmiä ei ole vielä löydetty. Tässä tutkimuksessa selvitettiin immuunijärjestelmän ja muiden kasvaimen kasvua säätelevien tekijöiden keskinäisiä yhteyksiä ja niiden merkitystä kolorektaalisyövän ennusteen arvioinnissa.Tutkimusmateriaali koostui Oulun yliopistollisessa sairaalassa leikattujen kolorektaalisyöpäpotilaiden (n = 148) leikkaus- ja verinäytteistä ja terveiden verrokkihenkilöiden (n = 86) verinäytteistä. Endostatiinin ja 27 sytokiinin pitoisuudet mitattiin seeruminäytteistä. Kollageeni XVIII:n ja tulehdussolujen analysoimiseen käytettiin immunohistokemiallisia menetelmiä.Useiden sytokiinien pitoisuudet olivat korkeammat potilailla kuin verrokeilla, mutta osassa sytokiineista pitoisuudet olivat alentuneet. Seerumin sytokiiniprofiili erotteli luotettavasti potilaat verrokeista. Pidemmälle edenneeseen tautiin liittyi sytokiinien korkeampia pitoisuuksia ja etäpesäkkeitä muodostanut tauti oli yhteydessä Th1-tyypin sytokiinien esiintymiseen. Systeeminen tulehdusreaktio oli yhteydessä syövän etenemiseen. Endostatiinipitoisuudet olivat kohonneet potilailla ja olivat yhteydessä kasvaimen invaasioon suolen seinämän lihaskerroksen läpi. Endostatiinipitoisuudet korreloivat myös systeemisen tulehdusreaktion kanssa, mutta eivät liittyneet paikallisten tulehdussolujen määrään. Kollageeni XVIII ilmentyi kasvaimen stroomassa ja suolen seinämän lihaskerroksessa. Sytokiineilla ja kasvaimen paikallisilla tulehdussoluilla todettiin olevan vain vähän keskinäisiä yhteyksiä.Kolorektaalisyöpään liittyy useita erisuuntaisia muutoksia seerumin sytokiinipitoisuuksissa, joten on olennaista tutkia eri sytokiinien suhteellisia muutoksia. Seerumin sytokiiniprofiili on lupaava potilaita ja verrokeita erotteleva mittari, jolla voi olla diagnostista arvoa. Kohonneet endostatiinipitoisuudet potilailla voivat johtua kasvaimen invaasioon liittyvästä kollageeni XVIII:n hajoamisesta suolen seinämässä, mutta lisätutkimuksia tarvitaan endostatiinin ennustetta kuvaavan arvon määrittämiseksi.Academic dissertation to be presented with the assent of the Doctoral Training Committee of Health and Biosciences of the University of Oulu for public defence in Auditorium F202 of the Faculty of Medicine (Aapistie 5 B), on 8 January 2016, at 12 noonAbstract
Colorectal cancer (CRC) is among the most common cancers in Finland. Prognostic factors are important for predicting disease outcome and adjusting optimal treatment. The currently used prognostic methods for CRC have their limitations and consequently several biomarkers have been studied to find potential prognostic markers, but none have been adapted for routine use so far. In the present study, the relationships between the components of the immune system and other factors modulating tumor growth were assessed and their suitability to be used for use as prognostic tools in CRC were studied.
The study material consisted of blood samples and surgical specimens collected from 148 CRC patients operated on in Oulu University Hospital and blood samples of 86 healthy controls. Concentrations of endostatin and 27 cytokines were measured from preoperative serum samples and control samples. Immunohistochemical methods were used for collagen XVIII and inflammatory cell analyses.
The levels of several cytokines were altered in CRC patients compared to the controls. The serum cytokine profile achieved an excellent accuracy in discriminating CRC patients from healthy controls. Advanced CRCs were associated with elevated cytokine levels and a metastasized disease was linked to an orientation towards Th2 cytokine milieu. The presence of systemic inflammation, depicted by a modified Glasgow Prognostic Score (mGPS), correlated to CRC progression. The serum endostatin levels were elevated in CRC and correlated with invasion through muscular layer and systemic inflammation, but not with densities of local inflammatory cells. Collagen XVIII was expressed in tumor stroma and in the muscle layer of bowel wall. The serum cytokines and tumor infiltrating immune cells showed relatively weak associations.
In conclusion, CRC is associated with significant alterations in serum cytokine milieu, which underlines the relevance of studying several cytokines and their relative alterations. The serum cytokine profile is a promising tool for discriminating CRC patients from healthy controls, but its clinical value needs to be validated. The elevated endostatin levels may result from invasion-related cleavage of collagen XVIII in the bowel wall, but further studies are needed to determine the value of endostatin in CRC prognosis.Tiivistelmä
Paksu- ja peräsuolisyöpä (kolorektaalisyöpä) on yleisimpiä syöpämuotoja Suomessa. Sen ennustetta kuvaavat mittarit ovat tärkeitä taudin etenemisen ennustamisessa ja hoidon suunnittelussa. Käytössä olevat kolorektaalisyövän ennusteen arvioinnin menetelmät eivät ole riittäviä. Uusia merkkiaineita onkin kehitetty ja testattu, mutta rutiinikäyttöön soveltuvia menetelmiä ei ole vielä löydetty. Tässä tutkimuksessa selvitettiin immuunijärjestelmän ja muiden kasvaimen kasvua säätelevien tekijöiden keskinäisiä yhteyksiä ja niiden merkitystä kolorektaalisyövän ennusteen arvioinnissa.
Tutkimusmateriaali koostui Oulun yliopistollisessa sairaalassa leikattujen kolorektaalisyöpäpotilaiden (n = 148) leikkaus- ja verinäytteistä ja terveiden verrokkihenkilöiden (n = 86) verinäytteistä. Endostatiinin ja 27 sytokiinin pitoisuudet mitattiin seeruminäytteistä. Kollageeni XVIII:n ja tulehdussolujen analysoimiseen käytettiin immunohistokemiallisia menetelmiä.
Useiden sytokiinien pitoisuudet olivat korkeammat potilailla kuin verrokeilla, mutta osassa sytokiineista pitoisuudet olivat alentuneet. Seerumin sytokiiniprofiili erotteli luotettavasti potilaat verrokeista. Pidemmälle edenneeseen tautiin liittyi sytokiinien korkeampia pitoisuuksia ja etäpesäkkeitä muodostanut tauti oli yhteydessä Th1-tyypin sytokiinien esiintymiseen. Systeeminen tulehdusreaktio oli yhteydessä syövän etenemiseen. Endostatiinipitoisuudet olivat kohonneet potilailla ja olivat yhteydessä kasvaimen invaasioon suolen seinämän lihaskerroksen läpi. Endostatiinipitoisuudet korreloivat myös systeemisen tulehdusreaktion kanssa, mutta eivät liittyneet paikallisten tulehdussolujen määrään. Kollageeni XVIII ilmentyi kasvaimen stroomassa ja suolen seinämän lihaskerroksessa. Sytokiineilla ja kasvaimen paikallisilla tulehdussoluilla todettiin olevan vain vähän keskinäisiä yhteyksiä.
Kolorektaalisyöpään liittyy useita erisuuntaisia muutoksia seerumin sytokiinipitoisuuksissa, joten on olennaista tutkia eri sytokiinien suhteellisia muutoksia. Seerumin sytokiiniprofiili on lupaava potilaita ja verrokeita erotteleva mittari, jolla voi olla diagnostista arvoa. Kohonneet endostatiinipitoisuudet potilailla voivat johtua kasvaimen invaasioon liittyvästä kollageeni XVIII:n hajoamisesta suolen seinämässä, mutta lisätutkimuksia tarvitaan endostatiinin ennustetta kuvaavan arvon määrittämiseksi
Syväoppimisen avulla johdetut histologiset piirteet eturauhassyöpäpotilaiden riskitason arvioinnissa
No full textProstate cancer is a common cancer that varies between patients from mild symptoms and slow progressing to an aggressively spreading and metastatic disease. Thereby, accurate prognosis is particularly important for treatment planning. In the case of an aggressive cancer, an early treatment might prevent the disease from spreading, while unnecessary treatments of slowly progressing prostate cancers should be avoided due to side effects. The prognosis of prostate cancer is based on the Gleason grading system. In the Gleason grading system, prostate biopsies are scored based on histological features, focusing on glandular structures. A low score indicates a slowly progressing disease while a high score refers to a more aggressive cancer. However, for patients with an intermediate Gleason score, determining the prognosis is challenging. In this work, I search for histological features that could supplement the Gleason grading system by assisting the risk stratification of the patients with intermediate Gleason scores. I employ artificial intelligence to extract features from histological image data and compose histological clusters. Secondly, I conduct survival analysis to examine the relationships between the clusters and survival outcomes. I discover clusters with significant effects on survival both on a data set covering several Gleason scores, and on a data set mostly covering only intermediate Gleason scores. Accordingly, the histological clusters are suggested to provide additional information to the Gleason grading system which could be beneficial in evaluating the risk for the patients with intermediate Gleason scores. Finally, I investigate the histological features of the significant clusters, focusing on the size of epithelial nuclei. For this, I first segment and classify the nuclei using an artificial intelligence model. The obtained results reveal that clusters with a protective influence contain small epithelial nuclei in terms of the median area, diameter, and perimeter in comparison to clusters that increase the risk of prostate cancer death.Eturauhassyöpä on yleinen sairaus, jonka taudinkuva vaihtelee potilaiden välillä lieväoireisesta ja hitaasti etenevästä taudista aggressiivisesti leviävään ja etäpesäkkeitä muodostavaan tautiin. Näin ollen täsmällisen ennusteen määrittäminen on erityisen tärkeää sopivan hoitosuunnitelman laatimiseksi. Aggressiivisten syöpätapausten kohdalla nopea hoidon aloitus voi estää taudin leviämisen, kun taas hitaasti etenevien eturauhassyöpien tarpeetonta hoitoa tulisi välttää haittavaikutusten vuoksi. Eturauhassyövän diagnostiikka ja ennusteen arvioiminen perustuvat Gleasonin luokitukseen. Siinä potilaan eturauhasesta otetulle koepalalle määritetään pisteytys histologisten piirteiden perusteella, rauhasrakenteisiin keskittyen. Matala pisteytys viittaa hitaasti etenevään syöpään ja korkea pisteytys aggressiivisempaan tautiin. Monissa tapauksissa pistemäärä on kuitenkin keskitasolla, jolloin ennusteen määrittäminen on haastavampaa. Tämän työn tarkoituksena on etsiä histologisia piirteitä, jotka voisivat täydentää Gleasonin luokitusta tarkentamalla keskitason pistemäärän omaavien potilaiden riskitasoarviointia. Työssä poimin piirteitä histologisesta kuvadatasta ja muodostan niistä histologisia klustereita tekoälyä hyödyntäen. Tämän jälkeen suoritan elinaika-analyysin tutkiakseni klustereiden vaikutuksia potilaiden selviytymiseen. Sekä useita eri Gleason-pisteytyksiä sisältävällä datalla, että pääosin keskitason pisteytyksistä koostuvalla datalla löytyi klustereita, joiden vaikutus selviytym-seen oli merkittävä. Histologisten klusterien voidaan siten arvioida sisältävän Gleasonin luokitukseen sisältymätöntä tietoa, joka voisi olla hyödyksi keskitason Gleason-pistemäärän potilaiden ennusteen arvioimisessa. Lopuksi tarkastelen merkityksellisiksi havaittujen klustereiden sisältämiä histologisia piirteitä, keski-tyen epiteelisolujen tumakokoon. Tätä varten tunnistan ja luokittelen tumat tekoälymallin avulla. Saadut tulokset osoittavat, että klustereissa, joilla on suojaava vaikutus, epiteelitumat ovat pienikokoisia mediaanipinta-alan, -halkaisijan ja -piirin suhteen verrattuna klustereihin, jotka lisäävät syöpäkuoleman riskiä
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