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Teema : päivystäjän kaikukuvau

GATA-transkriptiotekijöiden säätely ja toiminta lisämunuaisen kuorikerroskasvaimissa ja granuloosasoluissa

Transcription factors play a key role in tumor development, in which dysfunction of genes regulating tissue growth and differentiation is a central phenomenon. The GATA family of transcription factors consists of six members that bind to a consensus DNA sequence (A/T)GATA(A/G) in gene promoters and enhancers. The two GATA factors expressed in the adrenal cortex are GATA-4 and GATA-6. In both mice and humans, GATA-4 can be detected only during the fetal period, whereas GATA-6 expression is abundant both throughout development and in the adult. It is already established that GATA factors are important in both normal development and tumorigenesis of several endocrine organs, and expression of GATA-4 and GATA-6 is detected in adrenocortical tumors. The aim of this study was to elucidate the function of these factors in adrenocortical tumor growth. In embryonal development, the adrenocortical cells arise and differentiate from a common pool with gonadal steroidogenic cells, the urogenital ridge. As the adult adrenal cortex undergoes constant renewal, it is hypothesized that undifferentiated adrenocortical progenitor cells reside adjacent to the adrenal capsule and give rise to daughter cells that differentiate and migrate centripetally. A diverse array of hormones controls the differentiation, growth and survival of steroidogenic cells in the adrenal gland and the gonads. Factors such as luteinizing hormone and inhibins, traditionally associated with gonadal steroidogenic cells, can also influence the function of adrenocortical cells in physiological and pathophysiological states. Certain inbred strains of mice develop subcapsular adrenocortical tumors in response to gonadectomy. In this study, we found that these tumors express GATA-4, normally absent from the adult adrenal cortex, while GATA-6 expression is downregulated. Gonadal markers such as luteinizing hormone receptor, anti-Müllerian hormone and P450c17 are also expressed in the neoplastic cells, and the tumors produce gonadal hormones. The tumor cells have lost the expression of melanocortin-2 receptor and the CYP enzymes necessary for the synthesis of corticosterone and aldosterone. By way of xenograft studies utilizing NU/J nude mice, we confirmed that chronic gonadotropin elevation is sufficient to induce adrenocortical tumorigenesis in susceptible inbred strains. Collectively, these studies suggest that subcapsular adrenocortical progenitor cells can, under certain conditions, adopt a gonadal fate. We studied the molecular mechanisms involved in gene regulation in endocrine cells in order to elucidate the role of GATA factors in endocrine tissues. Ovarian granulosa cells express both GATA-4 and GATA-6, and the TGF-β signaling pathway is active in these cells. Inhibin-α is both a target gene for, and an atypical or antagonistic member of the TGF-β growth factor superfamily. In this study, we show that GATA-4 is required for TGF-β-mediated inhibin-α promoter activation in granulosa cells, and that GATA-4 physically interacts with Smad3, a TGF-β downstream protein. Apart from the regulation of steroidogenesis and other events in normal tissues, TGF-β signaling is implicated in tumors of multiple organs, including the adrenal cortex. Another signaling pathway found often to be aberrantly active in adrenocortical tumors is the Wnt pathway. As both of these pathways regulate the expression of inhibin-α, a transcriptional target for GATA-4 and GATA-6, we wanted to investigate whether GATA factors are associated with the components of these signaling cascades in human adrenocortical tumors. We found that the expression of Wnt co-receptors LRP5 and LRP6, Smad3, GATA-6 and SF-1 was diminished in adrenocortical carcinomas with poor outcome. All of these factors drive inhibin-α expression, and their expression in adrenocortical tumors correlated with that of inhibin-α. The results support a tumor suppressor role previously suggested for inhibin-α in the mouse adrenal cortex, and offer putative pathways associated with adrenocortical tumor aggressiveness. Unraveling the role of GATA factors and associated molecules in human and mouse adrenocortical tumors could ultimately contribute to the development of diagnostic tools and future therapies for these diseases.Lisämunuainen on parillinen sisäerityselin, jonka kuorikerros erittää steroidihormoneja hypotalamuksen ja aivolisäkkeen säätelemänä. Lisämunuaisen pahanlaatuinen kuorikerroskasvain on harvinainen, mutta aggressiivinen syöpä. Hyvänlaatuiset lisämunuaisen kuorikerroskasvaimet ovat sitä vastoin melko tavallisia. Transkriptiotekijät ovat proteiineja, jotka sitoutuvat DNA:han säädellen sitä, mitkä geenit kyseisessä solussa ilmentyvät. Kasvainsolussa geenit ilmentyvät sille epänormaalisti, mikä johtaa solun normaalin jakautumisen ja erilaistumisen häiriintymiseen. Onkin ilmeistä, että transkriptiotekijöillä on kasvainten kehittymisessä keskeinen rooli. Tässä väitöskirjassa selvitettiin GATA-transkriptiotekijäperheen toimintaa hiirellä ja ihmisellä lisämunuaisen kuorikerroskasvaimissa ja granuloosasoluissa. GATA-perheen kuudesta jäsenestä kaksi, GATA-4 ja GATA-6, ilmentyy lisämunuaiskuoren soluissa. Osan hiirikannoista tiedetään kehittävän lisämunuaisen kuorikerroskasvaimia, kun niiden sukurauhaset poistetaan, ja havaitsimme, että nämä kasvaimet ilmentävät GATA-4:ää, joka normaalisti ilmentyy lisämunuaiskuoressa vain sikiöaikana. Kasvaimet ilmentävät poikkeavasti myös luteinisoivan hormonin reseptoria ja muita normaalisti sukurauhasten somaattisissa soluissa ilmentyviä geenejä. Toisella hiirimallilla pystyimme istukkahormonia erittävillä kudossiirteillä osoittamaan, että krooninen sukurauhasten toimintaa stimuloivan hormonin ylimäärä on riittävä näiden lisämunuaiskasvainten kehittymiseen sille alttiilla hiirikannoilla. Munasarjojen granuloosasoluja tutkimalla selvitettiin molekyylitason mekanismeja, joiden kautta GATA-transkriptiotekijät vaikuttavat geenien ilmentymiseen sisäerityselinten soluissa. TGF-β kasvutekijäperheen solunsisäistä viestintää tutkimalla havaitsimme, että GATA-4 osallistuu inhibiini-α geenin aktivointiin sitoutumalla solun sisällä Smad3-proteiiniin. Viimeisessä osatyössä tutkimme, miten TGF-β reitti ja toinen kasvutekijäperhe Wnt ilmentyvät suhteessa GATA-tekijöihin ja muihin transkriptiotekijöihin ihmisen lisämunuaiskuoren hyvän- ja pahanlaatuisissa kasvaimissa. Havaitsimme, että kuolemaan johtaneissa lisämunuaisen kuorikerrossyövissä sekä inhibiini-α proteiinin että sitä säätelevien transkriptiotekijöiden ja signaalireittien ilmentyminen oli vähentynyttä. Inhibiini-α voi siis olla kasvaimen kasvua estävä tekijä. GATA-transkriptiotekijöillä on tämän väitöstutkimuksen perusteella toiminnallinen rooli granuloosasoluissa ja lisämunuaisen kuorikerroskasvaimissa. Parempi ymmärrys molekyylitason mekanismeista, jotka säätelevät kudosten kasvua ja voivat johtaa kasvainten muodostumiseen, on tarpeen jotta jatkossa olisi mahdollista parantaa diagnostiikkaa ja kehittää uusia hoitomuotoja lisämunuaissyöpään

Magneettikuvauksen tehosteaineet

Teema : Magneettikuvaus. English summaryPeer reviewe

Neoadjuvant therapy offers longer survival than upfront surgery for poorly differentiated and higher stage pancreatic cancer

Background: Neoadjuvant therapy for pancreatic cancer remains controversial. Our aim was to assess differences in survival, disease recurrence and histopathological tumor characteristics between patients treated with neoadjuvant therapy followed by subsequent surgery and patients undergoing upfront surgery.Material and methods: Out of 399 consecutive pancreatic ductal adenocarcinoma (PDAC) patients operated at Helsinki University Hospital in 2000-2015, 75 borderline resectable patients were treated with neoadjuvant therapy. Resectable propensity scored patients (n=150) underwent upfront surgery. Neoadjuvant therapy consisted of folfirinox, single gemcitabine or combined with cisplatin, nab-paclitaxel or capecitabine with or without radiation. Survival was calculated with Kaplan-Meier and compared with the Breslow test. Survival was determined from the start of treatment, being the first day of treatment for patients treated with neoadjuvant therapy and the date of surgery for others.Results: Between 2000 and 2015 median disease-specific survival (DSS) [34 vs. 26 months, p=.016] and disease-free survival (DFS) [22 vs. 13 months, p=.001] were longer in patients treated with neoadjuvant therapy than in those undergoing upfront surgery. Survival differences were not significant in the 2000s but were, in turn, among patients treated in the 2010s with better survival for patients treated with neoadjuvant therapy [DSS 35 vs. 26 months, p=.008 and DFS 25 vs. 13 months, p=.001]. Especially patients with poorly differentiated G3 tumors [DSS 30 vs. 11 months, p=.004 and DFS 21 vs. 7 months, p=.001] and higher stage IIB-III [DSS 34 vs. 20 months, p=.006 and DFS 21 vs. 10 months, p=.001] had longer survival when treated with neoadjuvant therapy.Conclusions: PDAC patients treated with neoadjuvant therapy had longer DSS and DFS than those undergoing upfront surgery. Neoadjuvant therapy benefits especially borderline resectable patients with higher stage and poorly differentiated tumors.Peer reviewe

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Biliary Anomalies in Patients With HNF1B Diabetes

Context: The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined. Objective: To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP). Setting and Patients: Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype. Main Outcome Measure(s): Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia. Results: Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant. Conclusions: Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.Peer reviewe

Adrenocortical carcinoma: presentation and outcome of a contemporary patient series

Background: Adrenocortical carcinoma (ACC) is a rare endocrine carcinoma with poor 5-year survival rates of Design and methods: We studied all patients (n = 47, four children) from a single centre during years 2002–2018. We re-evaluated radiologic and histopathological findings and assessed treatments and outcome. We searched for possible TP53 gene defects and assessed nationwide incidence of ACC.Results: In adults, incidental radiologic finding led to diagnosis in 79% at median age of 61 years. ENSAT stage I, II, III and IV was 19%, 40%, 19% and 21%, respectively. Nonenhanced CT demonstrated > 20 Hounsfield Units (HU) for all tumours (median 34 (21–45)), median size 92 mm (20–196), Ki67 17% (1–40%), Weiss score 7 (4–9) and Helsinki score 24 (4–48). ACC was more often found in the left than the right adrenal (p  5 to > 10 years was achieved after repeated surgery of metastases. Overall 5-year survival was 67%, and 96% vs. 26% for ENSAT stage I–II vs. III–IV (p Conclusions: Contemporary ACC predominantly presents as an incidental imaging finding, characterised by HU > 20 on nonenhanced CT but variable tumour size (20–196 mm). Malignancy cannot be ruled out by small tumour size only. The 5-year survival of 96% in ENSAT stage I–III compares favourably to previous studies.</p

Inter- and Intra-Observer Variability and the Effect of Experience in Cine-MRI for Adhesion Detection

Cine-MRI for adhesion detection is a promising novel modality that can help the large group of patients developing pain after abdominal surgery. Few studies into its diagnostic accuracy are available, and none address observer variability. This retrospective study explores the inter- and intra-observer variability, diagnostic accuracy, and the effect of experience. A total of 15 observers with a variety of experience reviewed 61 sagittal cine-MRI slices, placing box annotations with a confidence score at locations suspect for adhesions. Five observers reviewed the slices again one year later. Inter- and intra-observer variability are quantified using Fleiss’ (inter) and Cohen’s (intra) κ and percentage agreement. Diagnostic accuracy is quantified with receiver operating characteristic (ROC) analysis based on a consensus standard. Inter-observer Fleiss’ κ values range from 0.04 to 0.34, showing poor to fair agreement. High general and cine-MRI experience led to significantly (p &lt; 0.001) better agreement among observers. The intra-observer results show Cohen’s κ values between 0.37 and 0.53 for all observers, except one with a low κ of −0.11. Group AUC scores lie between 0.66 and 0.72, with individual observers reaching 0.78. This study confirms that cine-MRI can diagnose adhesions, with respect to a radiologist consensus panel and shows that experience improves reading cine-MRI. Observers without specific experience adapt to this modality quickly after a short online tutorial. Observer agreement is fair at best and area under the receiver operating characteristic curve (AUC) scores leave room for improvement. Consistently interpreting this novel modality needs further research, for instance, by developing reporting guidelines or artificial intelligence-based methods.</p