Browsing by Author "Štrumfa, Ilze"

Now showing 1 - 20 of 27
  • No Thumbnail Available
    Item
    Association of Epithelial Mesenchymal Transition, Stemness and Inflammation in Colorectal Carcinoma. Doctoral Thesis
    (Rīga Stradiņš University, 2022) Briede, Inese; Gardovskis, Jānis; Štrumfa, Ilze
    Colorectal cancer (CRC) and its treatment is one of the hot topics in medicine, as there is a still a high number of patients with CRC and deaths from CRC. In the era of personalized medicine, a huge field of research is devoted to inflammation, a process that plays an important dual role in carcinogenesis. Survival studies have highlighted the prognostic significance of peritumoural inflammation in CRC. The current theoretical background allows us to link inflammation, the epithelial-mesenchymal transition (EMT), and the closely associated stem cell differentiation in CRC. However, there is scarce direct morphological evidence. The aim of this work was to investigate the role of inflammation in cancer growth and invasion by analyzing the association between inflammation and known morphological prognostic features of CRC, EMT, and mismatch repair (MMR) protein expression. Materials and methods: This retrospective, morphological, and immunohistochemical investigation involved 553 consecutive cases of surgically treated CRC. Besides histopathological CRC assessment, peritumoural inflammation, EMT-characterizing molecular parameters, and MMR protein immunohistochemical detection within CRC tissue was performed. Descriptive statistical analysis was done. The research was carried out in accordance with the Declaration of Helsinki and received approval from the Committee of Ethics of Riga Stradins University [No E-9 (2), 04.09.2014].Results: The tumours of the 553 CRC cases were predominantly located in the left part of the bowel (70.9 %), and were significantly associated with an annular appearance and smaller size (p < 0.05). Mucinous and signet ring cell carcinomas detected within this study were associated with a larger tumour size and significant local structure involvement. Locally advanced tumours predominated within this study: pT3 comprised 49.6 % of cases, pT4 comprised 35.6 % of cases, and pN + comprised 40.5 % of cases. The extent of necrosis was significantly higher in tumours with higher pT, grade, and pN+. There were significant associations between high-grade inflammation and lower pT (p = 0.002), the absence of lymph node metastases (p< 0.001), and less frequent local structure involvement (p< 0.05). Expression of EMT markers and MMR proteins yielded no significant associations with peritumoural inflammation based on the Klintrup-Mäkinen score or the density of lymphoid follicles. Nevertheless, E-cadherin expression was significantly associated with the eosinophil density (p = 0.007), and lower N-cadherin expression was significantly associated with the presence of synchronous CRC. Lower MMR protein expression was associated with changes in E-cadherin and CD44 expression (p< 0.05). Lower MLH1 expression was associated with a lower neutrophil density within the CRC (p = 0.02).Conclusion: High-grade peritumoural inflammation is associated with beneficial morphologic CRC features, including less frequent invasion, and is not secondary to tissue damage and necrosis. Crohn’s disease-like lymphoid reaction (CLR) is not associated with cancer spread by pTN; this finding indirectly suggests an independent role of CLR in carcinogenesis. Further, inflammation based on the Klintrup-Mäkinen score and CLR are not dependent on EMT and stem cell differentiation. MMR protein expression is a marker for EMT within CRC, indicating the need to perform these tests on routine examination to detect patients who might need more advance treatment. MLH1 expression within CRC affects the density of neutrophils within peritumoural inflammation, showing a potential role for the MMR status in anti-tumour immunity. This research highlights the complex associations between inflammation, tumour morphology, EMT, and MMR protein expression in human CRC tissues.
  • No Thumbnail Available
    Item
    Association of Epithelial Mesenchymal Transition, Stemness and Inflammation in Colorectal Carcinoma. Summary of the Doctoral Thesis
    (Rīga Stradiņš University, 2022) Briede, Inese; Gardovskis, Jānis; Štrumfa, Ilze
    Colorectal cancer (CRC) and its treatment is one of the hot topics in medicine, as there is a still a high number of patients with CRC and deaths from CRC. In the era of personalized medicine, a huge field of research is devoted to inflammation, a process that plays an important dual role in carcinogenesis. Survival studies have highlighted the prognostic significance of peritumoural inflammation in CRC. The current theoretical background allows us to link inflammation, the epithelial-mesenchymal transition (EMT), and the closely associated stem cell differentiation in CRC. However, there is scarce direct morphological evidence. The aim of this work was to investigate the role of inflammation in cancer growth and invasion by analyzing the association between inflammation and known morphological prognostic features of CRC, EMT, and mismatch repair (MMR) protein expression. Materials and methods: This retrospective, morphological, and immunohistochemical investigation involved 553 consecutive cases of surgically treated CRC. Besides histopathological CRC assessment, peritumoural inflammation, EMT-characterizing molecular parameters, and MMR protein immunohistochemical detection within CRC tissue was performed. Descriptive statistical analysis was done. The research was carried out in accordance with the Declaration of Helsinki and received approval from the Committee of Ethics of Riga Stradins University [No E-9 (2), 04.09.2014].Results: The tumours of the 553 CRC cases were predominantly located in the left part of the bowel (70.9 %), and were significantly associated with an annular appearance and smaller size (p < 0.05). Mucinous and signet ring cell carcinomas detected within this study were associated with a larger tumour size and significant local structure involvement. Locally advanced tumours predominated within this study: pT3 comprised 49.6 % of cases, pT4 comprised 35.6 % of cases, and pN + comprised 40.5 % of cases. The extent of necrosis was significantly higher in tumours with higher pT, grade, and pN+. There were significant associations between high-grade inflammation and lower pT (p = 0.002), the absence of lymph node metastases (p< 0.001), and less frequent local structure involvement (p< 0.05). Expression of EMT markers and MMR proteins yielded no significant associations with peritumoural inflammation based on the Klintrup-Mäkinen score or the density of lymphoid follicles. Nevertheless, E-cadherin expression was significantly associated with the eosinophil density (p = 0.007), and lower N-cadherin expression was significantly associated with the presence of synchronous CRC. Lower MMR protein expression was associated with changes in E-cadherin and CD44 expression (p< 0.05). Lower MLH1 expression was associated with a lower neutrophil density within the CRC (p = 0.02).Conclusion: High-grade peritumoural inflammation is associated with beneficial morphologic CRC features, including less frequent invasion, and is not secondary to tissue damage and necrosis. Crohn’s disease-like lymphoid reaction (CLR) is not associated with cancer spread by pTN; this finding indirectly suggests an independent role of CLR in carcinogenesis. Further, inflammation based on the Klintrup-Mäkinen score and CLR are not dependent on EMT and stem cell differentiation. MMR protein expression is a marker for EMT within CRC, indicating the need to perform these tests on routine examination to detect patients who might need more advance treatment. MLH1 expression within CRC affects the density of neutrophils within peritumoural inflammation, showing a potential role for the MMR status in anti-tumour immunity. This research highlights the complex associations between inflammation, tumour morphology, EMT, and MMR protein expression in human CRC tissues.
  • No Thumbnail Available
    Item
    Benign Notochordal Cell Tumours : Case Report and Literature Review
    (2024-07) Grabovska, Dagnija; Štrumfa, Ilze; Ositis, Janis; Liepniece-Karele, Inta; Balodis, Arturs; Department of Pathology; Department of Radiology
    Background: Benign notochordal cell tumours (BNCTs) represent a rare entity within the spectrum of bone neoplasms, which typically arise in the axial skeleton. Although these tumours are often benign, their diagnosis and management pose significant challenges due to their histological similarity to more aggressive lesions, such as chordomas. Understanding of the clinical behaviour, diagnostic nuances, and optimal management strategies for BNCTs continues to evolve. Case Report: Benign notochordal cell tumours of the vertebra are usually asymptomatic and identified on imaging and should be distinguished from chordomas, which has a more aggressive clinical course. This report describes a 15-year-old girl with lumbosacral pain and a diagnosis of a benign notochordal cell tumour, which affects a large part of the S1 vertebra in the lumbar spine, highlighting the diagnostic challenges encountered, the role of radiological and histological investigations, and the ultimate determination of the benign nature of the tumour. Conclusions: This report highlights the approach taken for the diagnosis of a benign notochordal cell tumour of the vertebra and the importance of excluding differential diagnoses. By exploring the intricacies of this case, we contribute to the growing body of literature surrounding BNCTs, with the aim of improving clinical awareness and management strategies for this uncommon bone tumour.
  • No Thumbnail Available
    Item
    Challenges in the management of a patient with Cowden syndrome : Case report and literature review
    (2012-04-14) Melbarde-Gorkuša, Inga; Irmejs, Arvids; Berziņa, Dace; Štrumfa, Ilze; Aboliņš, Arnis; Gardovskis, Andris; Subatniece, Signe; Trofimovičs, Genadijs; Gardovskis, Janis; Miklaševičs, Edvins; Pārmantotā vēža pētniecības nodaļa
    We would like to present a patient with a classical phenotype of a rare disorder - Cowden syndrome, its diagnostics and management challenges. A breast surgeon has to be aware of this rare condition when treating a patient with breast manifestations of Cowden syndrome and has to refer the patient to a clinical geneticist for further evaluation. Sequencing of the PTEN gene showed the Asp24Gly mutation. According to the latest literature data, the lifetime risk of breast cancer for Cowden syndrome patients is 81% and surgery is a justified option to reduce the risk of breast cancer. Bilateral risk-reducing mastectomy with immediate reconstruction was performed to eliminate further risk of breast cancer. 3 years after the risk-reducing breast surgery the patient is satisfied with the outcome. This is to our best knowledge the first reported Cowden syndrome case with follow-up data after risk-reducing measures have been taken.
  • No Thumbnail Available
    Item
    Cicatricial Changes in the Kidneys and Their Link to Renal Tumours. Summary of the Doctoral Thesis
    (Rīga Stradiņš University, 2015) Sperga, Māris; Štrumfa, Ilze
    Over the last twenty years, the incidence of renal tumours has been increasing year on year by approximately 2%. A significant increase in tumour incidence can be seen in Latvia as well. In European countries, the overall mortality rates tend to decrease, while in Latvia the mortality rate is not decreasing. In accordance with data from the Centre for Disease Prevention and Control of Latvia, in 2012, the incidence of renal cancer in Latvia was 10.2 cases per 100,000 inhabitants (an 11% increase over seven years). So far, studies have not been carried out in Latvia into whether nephrosclerotic processes affect the incidence, morphological type and grade of renal tumours. Clear cell renal cell carcinoma, which accounted for 67.8% of the diagnosed tumours, was the most common morphological type of renal tumour in the present study. Renal oncocytary adenoma accounted for 9.9% of the cases, papillary renal cell carcinoma for 7.2% of the cases, and chromophobe renal cell carcinoma for 7.5% of the cases. When studying renal tissues adjacent to the tumours mentioned above, the author of the study found new tumors in them, and these were papillary renal adenomas (in 67 cases, or 22%), clear cell renal carcinomas (in 21 cases, or 6.3%), and oncocytary adenomas (in 10 cases, or 3.3%). There were pronounced nephrosclerotic changes in the tissues adjacent to these tumours, as well as cystic changes in the tubules. Also at the same time, while studying a group of kidneys with various degrees of nephrosclerosis, the author found that the most common tumours were papillary renal adenoma and clear cell renal carcinoma. In comparison to the control group, the author found that tumour incidence was 53 times higher among the group of nephrosclerotically altered kidneys and that the incidence of these tumors increased with greater severity of nephrosclerosis. Similarly, the author also found that in kidneys with tumours and nephrosclerosis, the incidence rates of the most common histological types of new tumours significantly differed from the incidence rates of histological types occurring randomly among the general population.This suggests that tumour initiating factors might have different effects on the emergence mechanisms of tumours of various histological types, and that these factors might also possibly affect prognostic factors. When comparing the immunohistochemical prognostic factor expression in three groups of different histological tumour types, differences were observed in prognostic factor expression in tumours of high levels and stages of malignancy. There was a different expression of protein p16 in the tumour groups with and without nephrosclerosis. An increased p16 expression in renal tumours with nephrosclerosis in adjacent tissues indicates a better prognosis. The author also observed changes in immunohistochemical reactions in nephrosclerotically altered kidneys outside of tumours, which suggests that background changes might play a role during the tumour formation stage. There is an increased risk of developing renal tumours in tissues altered by nephrosclerosis of any genesis type, and it increases rapidly when nephrosclerosis reaches more advanced stages.
  • No Thumbnail Available
    Item
  • No Thumbnail Available
    Item
  • No Thumbnail Available
    Item
    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.
  • No Thumbnail Available
    Item
    Epiteliāli mezenhimālas transformācijas, iekaisuma un cilmes šūnu diferenciācijas saistība kolorektālā vēzī. Promocijas darba kopsavilkums
    (Rīgas Stradiņa universitāte, 2022) Briede, Inese; Gardovskis, Jānis; Štrumfa, Ilze
    Kolorektālais vēzis (KRV) joprojām ir viena no aktuālākajām problēmām medicīnā, jo novērojama tā augsta izplatība un augsts nāves gadījumu skaits. Personalizētās medicīnas laikmetā arvien lielāku nozīmi pievēršot imūnajai atbildei KRV gadījumā, liela nozīme ir arī iekaisuma izpētei. Peritumorozs iekaisums, lai arī tam ir divējāda loma kanceroģenēzē, ir pierādīts kā viens no KRV prognozē nozīmīgajiem faktoriem. Teorētiskajos pētījumos ir raksturota saistība starp iekaisumu, epiteliāli mezenhimālo transformāciju un cilmes šūnu diferenciāciju KRV, bet šobrīd tam ir maz tiešu morfoloģisku pierādījumu.Šī pētījuma mērķis bija raksturot iekaisuma nozīmi kolorektālā vēzī, analizējot tā saistību ar KRV morfoloģiskajiem prognostiskajiem faktoriem, epiteliāli mezenhimālo transformāciju (EMT) un DNS labotājgēnu proteīnu ekspresiju. Materiāli un metodes. Retrospektīvā pētījumā tika izvērtēti 553 secīgi ķirurģiski operēti KRV gadījumi. Tika veikta morfoloģiska un imūnhistoķīmiska izmeklēšana, nosakot KRV morfoloģiskos parametrus, kā audzēja izplatības dziļums (pT), metastātisku limfmezglu klātesamība (pN +), invāzija lokālajās struktūrās, nekrozes plašums. Tika novērtēts peritumorozs iekaisums, kā arī EMT un DNS labotājgēnu kodējošo proteīnu raksturojošo IHĶ marķieru ekspresija KRV audos. Tika veikta deskriptīva statistiska analīze. Pētījums veikts saskaņā ar Helsinku deklarāciju un ir saņēmis Rīgas Stradiņa universitātes Ētikas komitejas atļauju (izsniegta 04.09.2014., E-9 (2)). Rezultāti. Pētījumā tika iekļauti 553 secīgi KRV gadījumi. Lielākā daļa audzēju bija lokalizēti kreisajā zarnu pusē (70,9 %), un tos raksturoja cirkulārs (gredzenveida) izskats, kā arī mazs audzēja izmērs (< 0,05). Pētījumā iekļautajiem KRV gadījumiem ar mucinozu un gredzenšūnu morfoloģiju bija raksturīgs liels audzēja izmērs un statistiski nozīmīga lokālo struktūru iesaiste. Pētījumā dominēja KRV gadījumi ar augstu lokālu izplatību: pT3 audzēji veidoja 49,6 %, pT4 35,6 % un pN + 40,5 % no pētāmās grupas. Audzējos ar augstu pT, pN un zemu diferenciācijas pakāpi tika novērota statistiski nozīmīgi plašāka nekrozes izplatība. Tika atrasta statistiski nozīmīga asociācija ar izteiktu lokālu iekaisumu un zemāku pT (p = 0,002), pN0 (p< 0,001), kā arī retākām lokālo struktūru invāzijām (p< 0,05). EMT (CD44, -katenīna, N-kadherīna un E-kadherīna), kā arī DNS labotājgēnu raksturojošo marķieru (MSH2, MSH6, PMS2 un MLH1) IHĶ ekspresija statistiski nozīmīgi neatšķīrās audzējos ar dažādas intensitātes peritumorozu iekaisumu un Krona slimībai līdzīgo limfocitāro reakciju. Tomēr, analizējot iekaisuma šūnu subpopulācijas, tika atrasta statistiski nozīmīga atšķirība E-kadherīna izteiktākā ekspresijā pie palielināta eozinofilo leikocītu daudzuma (p = 0,007). Zemāka N-kadherīna ekspresija bija raksturīga multifokāliem KRV gadījumiem. DNS labotājgēnu ekspresija statistiski ticami atšķīrās audzējos ar izmaiņām E-kadherīna un CD44 ekspresijā (p< 0,05). MLH1 proteīna zemāka ekspresija statistiski ticami saistījās ar zemāku neitrofilo leikocītu klātbūtni KRV (p = 0,02). Secinājumi. Audzējiem ar izteiktu peritumorozo iekaisumu ir raksturīga mazāka izplatība un lokālo struktūru invāzija. Krona slimībai līdzīgā limfocitārā reakcija neietekmē audzēja izplatību (pTN), tas netieši norāda uz šīs reakcijas neatkarīgu lomu kanceroģenēzē. Iekaisums, noteikts pēc Klintrupa–Makinena skalas (Klintrup-Makinen score), un Krona slimībai līdzīgā limfoīdā reakcija nav atkarīgi no EMT un cilmes šūnu diferenciācijas KRV. DNS labotājgēnu (MSH2, MSH6, PMS2 un MLH1) samazināta ekspresija KRV ir norāde par EMT procesu, kas potenciāli var ietekmēt terapijas izvēli KRV. MLH1 ekspresija KRV ietekmē neitrofilo leikocītu daudzumu peritumorozā iekaisumā, netieši norādot potenciālo DNS labotājgēnu nozīmi audzēja imunitātē. Šajā pētījumā raksturota iekaisuma, KRV morfoloģijas, EMT un DNS labotājgēnu mijiedarbība.
  • No Thumbnail Available
    Item
    The first evidence of hereditary and familial gastric cancer in Latvia : Implications for prevention
    (2012) Vanags, Andrejs; Štrumfa, Ilze; Gardovskis, Andris; Aboliņs, Arnis; Simtniece, Zane; Trofimovičs, Genadijs; Gardovskis, Janis; Department of Surgery; Department of Pathology
    Background and Objective: Gastric cancer is a frequent cause of cancer mortality. The prognosis of established tumor is unfavorable due to the propensity to spread and limited treatment efficiency. Therefore, prevention has a high significance. We tested a population screening approach in order to identify families with an increased gastric cancer load for further surveillance. Material and Methods: Population screening was performed by questionnaire reaching 76.6% of the population. Hereditary gastric cancer (HGC) syndrome was diagnosed if 3 mutually first-degree relatives with gastric cancer were reported in the kindred. Additional group (HGC2) of families with 2 first-degree relatives affected by gastric cancer was identified. Results: The HGC syndrome was diagnosed in 0.11%, but HGC2 syndrome, in 0.4% probands. The gastric cancer frequency among blood relatives was 25.2% (95% CI, 20.6%-30.4%) in HGC, but 16.0% (95% CI, 13.8%-18.5%) in HGC2 families. The mean age at diagnosis of cancer was 56.9 years (95% CI, 53.4-60.3) in HGC and 62.5 years (95% CI, 60.1-64.8) in HGC2. The mean survival was 2.6 years (95% CI, 1.2-4.0). Conclusions: Population screening identifies reasonable number of families with a high frequency of gastric cancer. The frequency of gastric cancer and an unfavorable course characterized by low survival justify surveillance in families with 2 or 3 first-degree relatives affected by gastric cancer. Population screening provides the age characteristics of the respective tumors in order to adjust the surveillance schedule.
  • No Thumbnail Available
    Item
    High expression of miR-214 is associated with a worse disease-specific survival of the triple-negative breast cancer patients
    (2015-02-08) Kalniete, Dagnija; Nakazawa-Miklaševiča, Miki; Štrumfa, Ilze; Abolinš, Arnis; Irmejs, Arvids; Gardovskis, Janis; Miklaševičs, Edvins; Onkoloģijas institūts; Rīga Stradiņš University
    Background: Hereditary triple-negative breast cancer patients have better recurrence-free survival than triple-negative sporadic ones. High expression of some of the miRNAs is related to worse overall and disease-free survival of triple-negative breast cancer patients. The attempt to associate expression level of some miRNA in triple-negative hereditary and sporadic breast cancers to disease specific survival was performed in this study. Material and methods: Study group was made of 18 triple-negative breast cancer patients harboring the BRCA1 gene mutations and 32 triple-negative sporadic breast cancer patients. Quantitative amount of mir-10b, mir-21, mir-29a, mir-31, and mir-214 by real-time PCR was assessed. The disease-specific survival in relation of high and low levels of some of the miRNAs was analyzed using Log-rank (Mantel-Cox) test. Results: MiR-214 showed significantly higher expression level in sporadic tissues than in hereditary ones (p=0.0005). Triple-negative breast cancer patients with high level of miR-214 showed significantly worse disease-specific survival than patients with low level (p=0.0314). Conclusions: Our finding suggests that miR-214 possibly could be used as a potential prognostic biomarker for triple-negative breast cancer patients.
  • No Thumbnail Available
    Item
    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.
  • No Thumbnail Available
    Item
    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.
  • No Thumbnail Available
    Item
    Krūts vēža molekulāro apakštipu un imūnhistoķīmiskā profila raksturojums. Promocijas darba kopsavilkums
    (Rīgas Stradiņa universitāte, 2013) Āboliņš, Arnis; Gardovskis, Jānis; Štrumfa, Ilze
    Promocijas darbs “Krūts vēža molekulāro apakštipu un imūnhistoķīmiskā profila raksturojums” veltīts krūts vēža morfoloģiskajai un imūnhistoķīmiskajai izpētei. Krūts vēzis ir viens no biežākajiem ļaundabīgajiem audzējiem Rietumu valstu populācijās un visbiežākais ļaundabīgais audzējs sievietēm. Tā izplatība Latvijā saglabājas augsta. Krūts vēzim raksturīgās heterogenitātes dēļ Pasaules Veselības organizācijas apstiprinātā morfoloģiskā klasifikācija nespēj atklāt visus audzēja parametrus, kas raksturo audzēja bioloģisko potenciālu un ļauj izvēlēties personalizētu terapiju, tādēļ krūts audzēju raksturojumam izmantojama molekulārā klasifikācija. Molekulārie apakštipi sākotnēji tika noteikti, analizējot gēnu ekspresiju ar mikrokartēšanas tehnoloģiju. Šobrīd imūnhistoķīmija tiek pieņemta kā atbilstošākā aizvietojošā tehnoloģija. Promocijas darbā detalizēti raksturoti krūts vēža 5 molekulārie subtipi (lumināls A, lumināls B (HER2 negatīvs), lumināls B (HER2 pozitīvs), HER2 pozitīvs un trīskārši negatīvs) atbilstoši St. Gallēnas klasifikācijai (2011), kas ir novatoriska pieeja arī pasaules praksē, kā arī veikti pētījumi jaunu prognostisku faktoru atklāšanai, analizējot molekulas, kas nosaka audzēja galvenās bioloģiskās īpašības – iesaistās šūnu proliferācijā un šūnu cikla kontrolē (ciklīns D1), ļauj audzēja šūnām izvairīties no apoptozes (BCL2 onkoproteīns), saistīti ar mutācijām proto-onkogēnos (p53) un angioģenēzi (ciklooksigenāze-2). Pētījuma teorētiskās bāzes izstrādei izmantoti 247 literatūras avoti. Promocijas darbā izvirzīts mērķis klasificēt krūts vēža gadījumus pēc molekulāriem apakštipiem un izvērtēt minētos jaunos potenciālos prognostiskos faktorus krūts vēža audos. Izmantojot morfoloģiskas, imūnhistoķīmiskās vizualizācijas un in situ hibridizācijas tehnoloģijas, izpētīti 383 secīgi invazīva krūts vēža gadījumi. Pētījuma rezultātā izveidotas 4 imūnhistoķīmiskās vizualizācijas tehnoloģijas p53 proteīna, BCL2 proteīna, ciklooksigenāzes-2 un ciklīna D1 noteikšanai, detalizēti raksturoti krūts vēža 5 molekulārie apakštipi, iegūts p53, BCL2, ciklooksigenāzes-2 un ciklīnu D1 ekspresējošu krūts vēžu molekulārais portrets un noteikts šo faktoru sastopamības biežums. Kompleksi izvērtējot daudzu parametru prognostisko nozīmi, kā dzīvildzi ietekmējoši faktori identificēti krūts vēža lokālā izplatība (pT) un reģionālo limfmezglu metastātisks bojājums (pN), audzēja diferenciācijas pakāpe, molekulārais subtips, kā arī p53 un BCL2 ekspresija.
  • No Thumbnail Available
    Item
    Molecular Subtypes and Immunohistochemical Profiles in Breast Cancer. Doctoral Thesis
    (Rīga Stradiņš University, 2013) Āboliņš, Arnis; Gardovskis, Jānis; Štrumfa, Ilze
    The doctoral thesis “Molecular subtypes and immunohistochemical profiles in breast cancer” is devoted to morphological and immunohistochemical research on breast cancer. Breast cancer is one of the most common malignant tumours in the European population and the most frequent malignancy in female. In Latvia, the incidence of breast cancer remains significant. Breast cancer is a heterogeneous disease including several entities with different clinical behaviour. The classics of breast cancer characteristics are represented in the classification of breast tumours by the World Health Organization. However, even tumours belonging to the same histologic type can have different clinical course. Additional information can be obtained from molecular subtyping of breast cancer thus disclosing subgroups with different biological properties and response to treatment. The molecular subtypes initially were discovered by gene expression profiling in high throughput microarray technologies. At present, immunohistochemistry is accepted as adequate surrogate marker. In the present work, 5 molecular subtypes of breast cancer (luminal A, luminal B (HER2 positive), luminal B (HER2 negative), HER2 positive and triple negative) are detected according to novel St. Gallen (2011) classification and characterised in detail. Further, new potential prognostic factors are analysed, targeting proteins that are involved in the cardinal tumour features as cell proliferation and cell cycle control (cyclin D1), evasion of apoptosis (BCL2 oncoprotein), expression of oncoproteins due to mutations in proto-oncogenes (p53) and angiogenesis (cyclooxygenase-2). The theoretical basis of the doctoral thesis employs 247 literature sources. The aim of the doctoral thesis was to classify breast cancer by molecular subtypes and to evaluate the above listed novel prognostic factors by immunohistochemistry. Within the research work, 383 patients with primary invasive breast cancer were enrolled. The tumour tissues were evaluated by morphological, immunohistochemical visualisation and in situ hybridisation technologies. In the result, 4 immunohistochemical technologies for the detection of p53, BCL2 protein, cyclooxygenase-2 and cyclin D1 have been developed, 5 molecular subtypes of breast cancer are characterised in detail and the molecular portraits of p53, BCL2, cyclooxygenase-2 and cyclin D1-positive breast cancers are obtained. The complex evaluation of the prognostic value of several factors, revealed that the local spread (pT) of breast cancer, regional lymph nodes status (pN) cancer grade and molecular subtype as well as expression of p53 and BCL2 influences the survival.
  • No Thumbnail Available
    Item
    Molecular Subtypes and Immunohistochemical Profiles in Breast Cancer. Summary of the Doctoral Thesis
    (Rīga Stradiņš University, 2013) Āboliņš, Arnis; Gardovskis, Jānis; Štrumfa, Ilze
    The doctoral thesis “Molecular subtypes and immunohistochemical profiles in breast cancer” is devoted to morphological and immunohistochemical research on breast cancer. Breast cancer is one of the most common malignant tumours in the European population and the most frequent malignancy in female. In Latvia, the incidence of breast cancer remains significant. Breast cancer is a heterogeneous disease including several entities with different clinical behaviour. The classics of breast cancer characteristics are represented in the classification of breast tumours by the World Health Organization. However, even tumours belonging to the same histologic type can have different clinical course. Additional information can be obtained from molecular subtyping of breast cancer thus disclosing subgroups with different biological properties and response to treatment. The molecular subtypes initially were discovered by gene expression profiling in high throughput microarray technologies. At present, immunohistochemistry is accepted as adequate surrogate marker. In the present work, 5 molecular subtypes of breast cancer (luminal A, luminal B (HER2 positive), luminal B (HER2 negative), HER2 positive and triple negative) are detected according to novel St. Gallen (2011) classification and characterised in detail. Further, new potential prognostic factors are analysed, targeting proteins that are involved in the cardinal tumour features as cell proliferation and cell cycle control (cyclin D1), evasion of apoptosis (BCL2 oncoprotein), expression of oncoproteins due to mutations in proto-oncogenes (p53) and angiogenesis (cyclooxygenase-2). The theoretical basis of the doctoral thesis employs 247 literature sources. The aim of the doctoral thesis was to classify breast cancer by molecular subtypes and to evaluate the above listed novel prognostic factors by immunohistochemistry. Within the research work, 383 patients with primary invasive breast cancer were enrolled. The tumour tissues were evaluated by morphological, immunohistochemical visualisation and in situ hybridisation technologies. In the result, 4 immunohistochemical technologies for the detection of p53, BCL2 protein, cyclooxygenase-2 and cyclin D1 have been developed, 5 molecular subtypes of breast cancer are characterised in detail and the molecular portraits of p53, BCL2, cyclooxygenase-2 and cyclin D1-positive breast cancers are obtained. The complex evaluation of the prognostic value of several factors, revealed that the local spread (pT) of breast cancer, regional lymph nodes status (pN) cancer grade and molecular subtype as well as expression of p53 and BCL2 influences the survival.
  • No Thumbnail Available
    Item
    Operēta aizkuņģa dziedzera vēža prognostiskie faktori. Promocijas darba kopsavilkums
    (Rīgas Stradiņa universitāte, 2015) Simtniece, Zane; Gardovskis, Jānis; Štrumfa, Ilze
    Pēc Veselības Ekonomikas centra datiem, saslimstība ar aizkuņģa dziedzera vēzi pieaug: 2007. gadā atklāti 360, bet 2010. gadā – 405 gadījumi. Analogu incidences pieaugumu novēro arī citviet pasaulē. Aizkuņģa dziedzera vēža 5 gadu izdzīvotība, pacientam saņemot labāko iespējamo ārstēšanu, t.sk. radikālu ķirurģisku terapiju, ir 15%, bet kopējā aizkuņģa dziedzera vēža grupā 5 gadu izdzīvotība ir tikai 5%, pie tam rezultāti nav būtiski uzlabojušies 30 gadu laikā. Līdz ar to ir būtiski pētīt aizkuņģa dziedzera audzēju bioloģisko potenciālu un to noteicošos mehānismus, lai varētu rast mērķa molekulas iespējamai terapijai un precizēt katra pacienta individuālo prognozi. Pētījuma mērķis ir noteikt potenciāli radikāli operētu aizkuņģa dziedzera duktālu adenokarcinomu (ADDA) un aizkuņģa dziedzera endokrīnu audzēju (AEA) morfoloģisko un imūnhistoķīmisko profilu un šo pacientu prognozi. Materiāli un metodes. Pētījums ir retrospektīvs, uz pierādījumiem balstīts potenciāli radikāli operētu ADDA un AEA morfoloģisks un imūnhistoķīmisks izvērtējums, nosakot 14 morfoloģiskus un 21 imūnhistoķīmiskus parametrus un iekļaujot izdzīvotības analīzi. Datu statistiskai apstrādei tika izmantota aprakstošā un analītiskā metode. Pētījums ir veikts saskaņā ar Helsinku deklarāciju un Rīgas Stradiņa universitātes ētikas komitejas atļauju. Rezultāti. Pētījumā iekļauti 78 potenciāli radikāli operētu ADDA pacientu un 16 AEA pacientu gadījumi. ADDA pacientu vidējais vecums bija 63,4 gadi, AEA pacientiem – 59,4 gadi. ADDA raksturīgas šādas pazīmes: liels audzēja izmērs (vidējais izmērs 3,6 cm), biežs pT3 – 98,7%, pN1 – 67,5%, vidēja vai zema diferenciācijas pakāpe – 46,2% un 35,9% gadījumos attiecīgi, perineirāla invāzija – 87,2% un R1 – 57,5% gadījumos. AEA raksturīgas mazāk agresīvas pazīmes: pT3 – 37,5%, pN1 – 20,0%, R1 – 27,3% gadījumu; visbiežāk tie bija labi diferencēti endokrīni audzēji ar neskaidru potenciālu (56,3%). Salīdzinot neoplastiskās šūnas ar atbilstošiem labdabīgiem audiem, konstatēta CK 20, CK 5/6 un COX-2 jauna ekspresija ADDA gadījumos, bet AEA gadījumos – CK 7, CK 19, p63, vimentīna un COX-2 ekspresija. ADDA audos pastiprinās Ki-67, p53, p21, ciklīna D1, hromogranīna A un vimentīna ekspresija (salīdzinot vidējo pozitīvo šūnu relatīvos daudzumus), bet AEA – Ki-67 un CD44. Savukārt ADDA šūnās samazinās p27, CK 7, CK 19 un CD56 ekspresija. Mediānais izdzīvotības laiks pēc potenciāli radikālas operācijas bija 11,0 mēneši ADDA pacientiem, bet starp AEA pacientiem 2/ 14 pacienti nomira 1 un 15 mēnešus pēc operācijas. Prognostiska nozīme bija audzēja invāzijai lielajos asinsvados (p = 0,013), nekrozei (p = 0,001), paaugstinātai vimentīna (p = 0,002) un CD44 (p = 0,018) ekspresijai, kā arī p27 izzudumam (p = 0,003) ADDA gadījumos. Secinājumi. Potenciāli radikāli operētu aizkuņga dziedzera duktālas adeno-carcinomas pacientu mediānais izdzīvotības laiks ir īss. Diagnostikas brīdī audzējam bieži ir liels izmērs. Šiem audzējiem raksturīga izteikta invazivitāte un izplatība ārpus aizkuņģa dziedzera audiem. Pēc imūnhistoķīmiskā izvērtējuma, prognostiska nozīme ir epiteliāli-mezenhimālai transformācijai, paaugstinātai CD44 ekspresijai un p27 zudumam. Aizkuņģa dziedzera endokrīni audzēji ir mazāk agresīvi, bet uz agresīvu audzēja progresiju un izplatību norāda samazināta E-kadherīna ekspresija, kā arī iegūta CK 19 un vimentīna ekspresija.
  • No Thumbnail Available
    Item
    Pārmantotā vēža populācijas skrīnings Valkas rajonā. Promocijas darba kopsavilkums
    (Rīgas Stradiņa universitāte, 2010) Vanags, Andrejs; Gardovskis, Jānis; Štrumfa, Ilze
  • No Thumbnail Available
    Item
    Pathological Complete Remission in Young Colon Cancer Patient with a Large Liver Metastasis after FOLFOX-4/Bevacizumab Treatment – A Case Report
    (2012-01-01) Skuja, Elīna; Āboliņš, Arnis; Priedīte, Ilze; Purkalne, Gunta; Štrumfa, Ilze; Vilmanis, Jānis; Kalniete, Dagnija; Miklaševičs, Edvīns; Gardovskis, Jānis; Onkoloģijas institūts
  • No Thumbnail Available
    Item
    Population screening for hereditary and familial cancer syndromes in Valka district of Latvia
    (2010-10-29) Vanags, Andrejs; Štrumfa, Ilze; Gardovskis, Andris; Borošenko, Viktors; Aboliņš, Arnis; Teibe, Uldis; Trofimovičs, Genadijs; Miklaševičs, Edvins; Gardovskis, Janis; Pārmantotā vēža pētniecības nodaļa
    Background: The growing possibilities of cancer prevention and treatment as well as the increasing knowledge about hereditary cancers require proper identification of the persons at risk. The aim of this study was to test the outcome of population screening in the scientific and practical evaluation of hereditary cancer.Methods: Population screening for hereditary cancer was carried out retrospectively in a geographic area of Latvia. Family cancer histories were collected from 18642 adults representing 76.6% of the population of this area. Hereditary cancer syndromes were diagnosed clinically. Molecular testing for BRCA1 founder mutations 300 T/G, 4153delA and 5382insC was conducted in 588 persons who reported at least one case of breast or ovary cancer among blood relatives.Results: Clinically, 74 (0.40%; 95% confidence interval (CI): 0.32 - 0.50%) high-risk and 548 (2.94%, 95% CI: 2.71 - 3.19) moderate-risk hereditary cancer syndromes were detected covering wide cancer spectrum. All syndromes were characterised by high cancer frequency among blood relatives ranging 8.6 - 46.2% in contrast to spouse correlation of 2.5 - 3.6%. The mean age of cancer onset ranged 38.0 - 72.0 years in different syndromes. The BRCA1 gene mutations were identified in 10 (1.7%; 95% CI: 0.9 - 3.1%) probands. Families with established BRCA1 gene founder mutations were identified with the frequency 1:2663 clinically screened persons.Conclusions: Population screening is a useful practical tool for the identification of persons belonging to families with high frequency of malignant tumours. The whole hereditary and familial cancer spectrum along with the age structure was identified adjusting follow-up guidelines. Another benefit of the population screening is the possibility to identify oncologically healthy persons belonging to hereditary and familial cancer families so that appropriate surveillance can be offered. Clinical diagnostics is appropriate for population screening purposes; molecular investigation provides additional information. In collaboration with family doctors, the screening is technically manageable as characterised by high compliance.