2021. gadā aizstāvētie promocijas darbi un kopsavilkumi

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Browsing 2021. gadā aizstāvētie promocijas darbi un kopsavilkumi by Author "Jakovļevs, Arvīds"

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    Difūzo gliomu imūnhistoķīmiskā klasifikācija. Promocijas darba kopsavilkums
    (Rīgas Stradiņa universitāte, 2021) Jakovļevs, Arvīds; Štrumfa, Ilze; Gardovskis, Jānis
    Glioblastoma (GBM) ir viens no biežākajiem un agresīvākajiem centrālās nervus sistēmas (CNS) audzējiem, kas ir augstākās anaplāzijas pakāpes glioma (4. anaplāzijas pakāpe). Neskatoties uz standartterapiju, kas iekļauj maksimāli iespējamu audzēja rezekciju, kuru papildina ar adjuvantu ķīmijterapiju ar temozolamīdu un radioterapiju, prognoze pacientiem ar GBM ir ļoti slikta. Jaunu potenciālu molekulāru un imūnhistoķīmisku marķieru atklāšanu un pētīšana varētu palīdzēt uzlabot mūsu zināšanas par kādām kritiskām molekulārām izmaiņām, kas veicina audzēja attīstību un šādas zināšanas palielina iespēju izveidot efektīvu uz mērķa molekulu vērstu terapiju nākotnē. Jauni molekulāri un imūnhistoķīmiski prognostiski marķieri var uzlabot ārstēšanu un iespējams arī ļaut sadalīt pacientus vairākās prognostiskās grupās ar atšķirīgu ārstēšanas pieeju, kas padarītu terapiju vairāk personalizētu. Šī pētījuma mērķis ir izvērtēt gliomu- GBM un difūzu astrocitomu (DA), morfoloģisko un imūnhistoķīmisko profilu, kā arī izvērtēt atsevišķus imūnhistoķīmiskus marķierus un iespēju vienkāršoti veikt gliomu subtipēšanu, izmantojot imūnhistoķīmijas (IHĶ) metodi. Pētījums ir retrospektīvs, kurā tika analizēti formalīnā fiksēti parafīnā ieguldīti ķirurģiski rezecētu gliomu audi. Pētījumā veikta plaša morfoloģiska un imūnhistoķīmiska izvērtēšana, kur kopumā tikai vērtēti 8 imūnhistoķīmiskie parametri, iekļaujot izdzīvotības analīzi. Datu statistiskai apstrādei tika izmantota aprakstošā un analītiskā metode. Pētījumā tika iekļauti 172 gliomu pacienti, no tiem 146 GBM un 26 DA pacienti. Pētījumā tika konstatēts, ka GBM pacientiem ir slikta prognoze ar mediāno izdzīvotību 7,9 mēneši, kas ir nedaudz zem dzīvildzes rādītājiem citās valstīs. No pētījumā izmantotajiem marķieriem, tikai izocitrātdehidrogenāzes 1 (IDH1) R132H mutācijas klātbūtne ir visnozīmīgākais prognostiskais faktors gliomām. Pacientiem ar DA, augsta trombocītu atbrīvotā augšanas faktora receptora alfa (PDGFRA) ekspresija arī ir saistīta ar labākiem izdzīvotības rādītājiem. Tika konstatēts, ka daži imūnhistoķīmiskie marķieri, tādi kā CD44, p21, PDGFRA un Ki-67 proliferācijas indekss ir parametri, kas atkarīgi no gliomu anaplāzijas pakāpes, tādējādi augstas anaplāzijas pakāpes gliomas, kā GBM, novēroja augstu CD44, Ki-67 un p21 ekspresiju. Savukārt, p27 un PDGFRA ir daudz zemāka GBM, salīdzinot ar DA. Interesanti, bet dažu marķieru ekspresijai (p27, CD44, Ki-67) bija arī dzimumatšķirības. GBMs, šūnas cikla proteīni, tādi kā p53, p21 un p27 ir arī iesaistīti dažādos mehānismos, kas regulē angioģenēzi un šūnu proliferāciju. Cieša saistība ir atklāta starp PDGFRA un p53 ekspresiju gliomās. DA gadījumos, PDGFRA novēroja negatīvu korelāciju ar CD44 un p21 kā arī mikroasinsvadu blīvumu (MVB). Pētījuma noslēgumā pierādīts, ka gliomu subtipēšana ir iespējama ar IHĶ metodi, izmantojot nelielu marķieru skaitu- PDGFRA, p53, IDH1 R132H un CD44. Ir konstatēts arī tas, ka augsta CD44 ekspresija ir nozīmīgs GBM mezenhimāla subtipa rādītājs, kas ir saistīts ar sliktāku atbildi uz radioterapiju.
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    Immunohistochemical classification of diffuse gliomas. Doctoral Thesis
    (Rīga Stradiņš University, 2021) Jakovļevs, Arvīds; Štrumfa, Ilze; Gardovskis, Jānis
    Glioblastoma (GBM) is one of the most common and aggressive tumours of the central nervous system (CNS) and represents the highest grade (grade IV) of glioma. Despite the standard therapy with maximal possible resection, followed by radiotherapy and chemotherapy with temozolomide, the prognosis for GBM patients remains dismal. Identification and research of potential molecular and immunohistochemical markers will help to increase our awareness of critical molecular changes in tumorigenesis and increase the possibility of effective molecularly targeted therapy in future. New molecular and immunohistochemical prognostic markers can improve the treatment and even allow patients to be stratified into different prognostic groups, which will make the therapy more personalized. The aim of this research was to evaluate the morphological and immunohistochemical profile of gliomas ? glioblastoma (GBM) and diffuse astrocytoma (DA) ? as well as to evaluate the prognostic role of single immunohistochemical markers and the possibility of glioma subtyping by immunohistochemistry (IHC). This work was performed as a retrospective study that is based on the analysis of formalin-fixed, paraffin-embedded, surgically treated human glioma tissues. In the study, a comprehensive morphological and immunohistochemical evaluation was performed including analysis of eight immunohistochemical parameters and survival analysis by applying a wide range of descriptive and analytic statistic methods. A total of 172 patients with gliomas were enrolled in the research work, including 146 GBMs and 26 DAs. It was found that GBM patients were characterized by poor prognosis with a median survival time of 7.9 months, which is slightly below the survival rates reported in other countries. From the selected markers, the presence of isocitrate dehydrogenase 1 (IDH1) R132H mutation was the most significant prognostic factor of better survival in gliomas. However, in patients with DAs, high platelet-derived growth factor receptor alpha (PDGFRA) expression was also associated with significantly better survival. Some immunohistochemical markers, such as CD44, p21, p27, PDGFRA and Ki-67 proliferation, are grade-specific parameters in gliomas, thus CD44, Ki-67 and p21 are significantly upregulated; however, p27 and PDGFRA are downregulated in high-grade gliomas such as GBM. Surprisingly, gender-related differences were found in the expression of some immunohistochemical markers, such as p27, CD44 and Ki-67, in gliomas. In GBMs, cell cycle proteins, such as p53, p21 and p27, are involved in a variety of mechanisms that regulate proliferation and angiogenesis. A strong relationship was also found between the expression of PDGFRA and p53 in gliomas. In DAs, PDGFRA correlated inversely with CD44, p21 and microvascular density (MVD). Finally, it was found that subtyping of gliomas is possible by IHC using a limited number of markers – PDGFRA, p53, IDH1, R132H and CD44. In addition, the expression of CD44 was shown to be a reliable indicator of mesenchymal subtype in GBM, which has a worse response to radiotherapy.
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    Immunohistochemical classification of diffuse gliomas. Summary of the Doctoral Thesis
    (Rīga Stradiņš University, 2021) Jakovļevs, Arvīds; Štrumfa, Ilze; Gardovskis, Jānis
    Glioblastoma (GBM) is one of the most common and aggressive tumours of the central nervous system (CNS) and represents the highest grade (grade IV) of glioma. Despite the standard therapy with maximal possible resection, followed by radiotherapy and chemotherapy with temozolomide, the prognosis for GBM patients remains dismal. Identification and research of potential molecular and immunohistochemical markers will help to increase our awareness of critical molecular changes in tumorigenesis and increase the possibility of effective molecularly targeted therapy in future. New molecular and immunohistochemical prognostic markers can improve the treatment and even allow patients to be stratified into different prognostic groups, which will make the therapy more personalized. The aim of this research was to evaluate the morphological and immunohistochemical profile of gliomas ? glioblastoma (GBM) and diffuse astrocytoma (DA) ? as well as to evaluate the prognostic role of single immunohistochemical markers and the possibility of glioma subtyping by immunohistochemistry (IHC). This work was performed as a retrospective study that is based on the analysis of formalin-fixed, paraffin-embedded, surgically treated human glioma tissues. In the study, a comprehensive morphological and immunohistochemical evaluation was performed including analysis of eight immunohistochemical parameters and survival analysis by applying a wide range of descriptive and analytic statistic methods. A total of 172 patients with gliomas were enrolled in the research work, including 146 GBMs and 26 DAs. It was found that GBM patients were characterized by poor prognosis with a median survival time of 7.9 months, which is slightly below the survival rates reported in other countries. From the selected markers, the presence of isocitrate dehydrogenase 1 (IDH1) R132H mutation was the most significant prognostic factor of better survival in gliomas. However, in patients with DAs, high platelet-derived growth factor receptor alpha (PDGFRA) expression was also associated with significantly better survival. Some immunohistochemical markers, such as CD44, p21, p27, PDGFRA and Ki-67 proliferation, are grade-specific parameters in gliomas, thus CD44, Ki-67 and p21 are significantly upregulated; however, p27 and PDGFRA are downregulated in high-grade gliomas such as GBM. Surprisingly, gender-related differences were found in the expression of some immunohistochemical markers, such as p27, CD44 and Ki-67, in gliomas. In GBMs, cell cycle proteins, such as p53, p21 and p27, are involved in a variety of mechanisms that regulate proliferation and angiogenesis. A strong relationship was also found between the expression of PDGFRA and p53 in gliomas. In DAs, PDGFRA correlated inversely with CD44, p21 and microvascular density (MVD). Finally, it was found that subtyping of gliomas is possible by IHC using a limited number of markers – PDGFRA, p53, IDH1, R132H and CD44. In addition, the expression of CD44 was shown to be a reliable indicator of mesenchymal subtype in GBM, which has a worse response to radiotherapy.