Lasten primaariset pahanlaatuiset aivokasvaimet : mitä olemme oppineet?

publishedVersionPeer reviewe

Polysialic acid is associated with better prognosis and IDH1-mutation in diffusely infiltrating astrocytomas

Peer reviewe

Glioomien diagnoosi ja ennuste - molekyylidiagnostiikan mahdollisuudet

Glioomat ovat aivojen tukisolukasvaimia ja primaarisista aivokasvaimista yleisimpiä. Diffuusien glioomien hoito perustuu kasvaimen kirurgiseen poistoon sekä säde- ja solunsalpaajahoitoon. Diagnoosi tehdään kasvaimen histopatologisesta tutkimuksesta, jota voidaan nykyisin täydentää molekyylidiagnostisilla tutkimuksilla. Esitämme Tampereen yliopistollisessa sairaalassa vuosina 1983-2009 hoidettujen glioomapotilaiden ennustetta kuvaavia uusia menetelmiä, joista tärkeimpiä ovat IDH-mutaation ja 1p/19q-kodeleetion osoitukset. Tulevaisuudessa voi olla mahdollista räätälöidä hoitoa potilaskohtaisesti glioomien profiloinnin perusteella

Method for the Intraoperative Detection of IDH Mutation in Gliomas with Differential Mobility Spectrometry

Isocitrate dehydrogenase (IDH) mutation status is an important factor for surgical decision-making: patients with IDH-mutated tumors are more likely to have a good long-term prognosis, and thus favor aggressive resection with more survival benefit to gain. Patients with IDH wild-type tumors have generally poorer prognosis and, therefore, conservative resection to avoid neurological deficit is favored. Current histopathological analysis with frozen sections is unable to identify IDH mutation status intraoperatively, and more advanced methods are therefore needed. We examined a novel method suitable for intraoperative IDH mutation identification that is based on the differential mobility spectrometry (DMS) analysis of the tumor. We prospectively obtained tumor samples from 22 patients, including 11 IDH-mutated and 11 IDH wild-type tumors. The tumors were cut in 88 smaller specimens that were analyzed with DMS. With a linear discriminant analysis (LDA) algorithm, the DMS was able to classify tumor samples with 86% classification accuracy, 86% sensitivity, and 85% specificity. Our results show that DMS is able to differentiate IDH-mutated and IDH wild-type tumors with good accuracy in a setting suitable for intraoperative use, which makes it a promising novel solution for neurosurgical practice.Peer reviewe

The tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a group of medulloblastomas and supratentorial primitive neuroectodermal tumours: an association of CA IX with poor prognosis

Peer reviewe

Impact of Timing of Surgery and Adjuvant Treatment on Survival of Adult IDH–wild-type Glioblastoma : A Single-center Study of 392 Patients

Background: The purpose of our study was to analyze the impact of time interval from referral to surgery and from surgery to adjuvant treatment on survival of adult isocitrate dehydrogenase–wild-type (IDH-wt) glioblastomas. Methods: Data on 392 IDH-wt glioblastomas diagnosed at the Tampere University Hospital in 2004–2016 were obtained from the electronic patient record system. Piecewise Cox regression was used to calculate hazard ratios for different time intervals between referral and surgery, as well as between surgery and adjuvant treatments. Results: The median survival time from primary surgery was 9.5 months (interquartile range: 3.8–16.0). Survival among patients with an interval exceeding 4 weeks from referral to surgery was no worse compared to <2 weeks (hazard ratio: 0.78, 95% confidence interval: 0.54–1.14). We found indications of poorer outcome when the interval from surgery to radiotherapy exceeded 30 days (hazard ratio: 1.42, 95% confidence interval: 0.91–2.21 for 31–44 days; and 1.59, 0.94–2.67 for over 45 days). Conclusions: Interval from referral to surgery in the range of 4–10 weeks was not associated with decreased survivals in IDH-wt glioblastomas. In contrast, delay exceeding 30 days from surgery to adjuvant treatment may decrease long-term survival.Peer reviewe

Antioxidative Enzymes, Carbonic Anhydrases and Claudins in Pediatric Brain Tumors: Prognostic and predictive value

Uusia työkaluja lasten aivokasvainten tutkimukseen ja hoitoon Aivokasvaimet ovat suurin kasvainkuolleisuuden syy lapsilla ja toiseksi yleisin kasvaintyyppi leukemian jälkeen. Erityisesti hoitojen kehityttyä potilaiden ennuste on parantunut selvästi viime vuosikymmenten aikana. Tauti ja hoidot aiheuttavat kuitenkin elämänlaadun heikkenemistä, vammautumista, sekä myös kustannuksia. Uusia hoitokeinoja tutkitaan jatkuvasti, mutta selviä läpimurtoja ei ole toistaiseksi saavutettu. Tämän väitöskirjan tavoitteena oli etsiä uusia molekyylejä, joita voitaisiin hyödyntää lasten yleisimpien aivokasvainten diagnostiikassa, ennusteen arvioimisessa sekä seurannassa. Pilosyyttinen astrosytooma on lasten yleisin aivokasvain. Se on histologisesti hyvänlaatuinen, mutta saattaa olla sijainnista riippuen tappava tauti. Väitöskirjassa tutkittiin antioksidatiivisten entsyymien (AOE) sekä peroksiredoksiinien (Prx) esiintymistä pilosyyttisissä astrosytoomissa. Kaikki AOE:t ilmentyivät laajasti viitaten oksidatiivisen vaurion ja sen korjausmekanismien osallisuuteen kasvaimen kehittymisessä. Mielenkiintoinen havainto oli, että Prx VI oli tilastollisesti merkittävä tekijä arvioitaessa kasvaimen uusiutumista. Tutkimuksessa selvitettiin AOE:n yhteyttä lapsille tyypillisen ependymooman kliinispatologisiin muuttujiin. Useimmat kasvaimet ilmensivät entsyymejä. Kiinnostava löytö oli Trx:n vähäisyyden yhteys huonoon ennusteeseen. Tällä havainnolla voi olla kliinistä merkitystä potilaiden hoidon ja seurannan suunnittelussa. Lisäksi tutkittiin klaudiinien (CLDN) esiintymistä ependymoomissa. Kaikki klaudiinit, lukuunottamatta CLDN4, esiintyivät ependymoomissa. CLDN5:llä oli yhteys kasvaimen aggressiivisuuteen, kun taas CLDN2:llä ja 10:llä oli trendi parempaan erilaistumiseen ja ennusteeseen. Tuloksista voi päätellä, että klaudiinit vaikuttavat ependymoomien kasvuun ja erilaistumiseen. Väitöskirjassa käsiteltiin myös hiilihappoanhydraasien (CA) esiintymistä embryonaalisissa medulloblastoomissa ja primitiivisissä neuroektodermaalisissa tuumoreissa (PNET). Medulloblastooma on lasten yleisin pahanlaatuinen aivokasvain. CA II esiintyi syöpäkudoksessa uudisverisuonten endoteelissä ja muut hiilihappoanhydraasit syöpasolujen sytoplasmassa. CA IX oli huonon ennusteen tekijä sekä yksimuuttuja, -että monimuuttujamalleissa. CA IX on osoittautunut lupaavaksi syöpähoidon kohdemolekyyliksi muissa kasvaimissa, ja tutkimuksen perusteella näin voisi olla myös medulloblastoomissa ja PNET:ssa. Väitöskirjan tulokset osoittavat, että antioksidatiiviset entsyymit, mukaan luettuna peroksiredoksiinit, sekä hiilihappoanhydraasit ja klaudiinit esiintyvät lasten yleisimmissä aivokasvaimissa. Tutkimuksen perusteella molekyylejä voidaan hyödyntää kasvaindiagnostiikassa, hoidon suunnittelussa ja ennusteen arvioimisessa.Brain tumors are the second most common tumor type in children after leukemia. The outcome of the patients has become more favorable over the past few decades due to improved treatment modalities. Nowadays, the 5-year prognosis is from less than 60% to 90% depending on the tumor type. Nevertheless, the tumor itself and its treatment reduce quality of life, increase the risk of being handicapped, and raise expenses. Novel treatment modalities are under intense investigation, although a major breakthrough has yet to be discovered. The aim of this thesis was to find new molecules to be used in the process of diagnosing and evaluating the predictivity, prognosis and follow-up of children with the most common pediatric brain tumors, including pilocytic astrocytomas, ependymomas, medulloblastomas (MBS), and primitive neuroectodermal tumors (PNETs). In this thesis, antioxidative enzymes were investigated in pilocytic astrocytomas and ependymomas, as well as peroxiredoxins in pilocytic astrocytomas. In addition, the role of carbonic anhydrases was studied in medulloblastomas and PNETs. Finally, claudins were analysed in ependymomas. The first study analysed the antioxidative enzymes (AOEs), including manganese superoxide dismutase (MnSOD), gamma glutamyl cysteinyl synthetase catalytic and regulatory subunits (GLCL-C, GLCL-R), thioredoxin (Trx), thioredoxin reductase (TrxR) and peroxiredoxins (Prx) I-VI in a series of 105 pilocytic astrocytomas. All of them were expressed in pilocytic astrocytomas, suggesting that oxidative damage and consequent defence take place during the progression of the tumors. AOEs correlated with the degenerative features and angiogenesis, possibly associating with reactive oxygen species-derived cellular damage. Moreover, the expression of the AOEs was associated with each other in terms of concurrent activation of the enzymes. With the exception of MnSOD, a strong expression of AOEs was generally associated with higher cell proliferation. Prx VI seemed to have a positive association with a longer recurrence-free interval. The second study investigated the relationship between AOE (MnSOD, GLCL-C, GLCL-R, Trx, TrxR) expression and clinicopathological features in 67 ependymal tumors. Most of the tumors expressed AOEs. Lower GLCL-C and GLCL-R expression was associated with higher tumor grade. MnSOD, GLCL-C and TrxR expressions were significantly higher in tumors located in the spinal cord compared with those in the brain. Interestingly, decreased expression of Trx predicted worse outcome for the patients. This finding may have clinical relevance when planning treatment modalities and follow-up for patients. The aim of the third study was to analyse the expression of carbonic anhydrases (CAs) II, IX, and XII in a set of 39 medulloblastomas and PNETs. Interestingly, CA II was expressed in both the neovessel endothelium and tumour cell cytoplasm. CA IX was mainly expressed in the tumor cells located in perinecrotic areas. CA XII showed the most homogenous distribution within the tumors. Importantly, CA IX expression predicted poor prognosis in both univariate and multivariate analyses. CA IX has been previously found to be a promising target molecule for anticancer treatment in other tumors. The results suggest that this could also be the case for medulloblastomas and PNETs. In the fourth study, expression of claudins (CLDNs) 2-5, 7, and 10 was investigated in a set of 61 ependymomas. According to the results, all CLDNs except for CLDN4 were expressed in these tumors. CLDN5 was related to more aggressive tumors compared with CLDN2 and 10. Tumors expressing these two claudins displayed a better degree of differentiation and a better prognosis. There were also differences in the expression of claudins associated with location of the tumor and between primary and recurrent tumors, CLDNs 3 and 5 were more often found in the cerebrum than in other sites and CLDN7 in primary tumors compared with recurrent ones. Evidently claudins influence the growth and differentiation in ependymomas. In summary, the studied antioxidative enzymes, peroxiredoxins, carbonic anhydrases, and claudins were expressed in the most common pediatric brain tumors, including pilocytic astrocytomas, ependymomas, medulloblastomas, and PNETs. Prx VI was associated with longer recurrence-free interval in patients with pilocytic astrocytoma, whereas decreased Trx expression predicted worse prognosis of patients with ependymoma. CA IX correlated with worse outcome in patients with medulloblastoma or PNET. Claudins had no significant association with prognosis, nevertheless CLDN5 was related to more aggressive ependymomas