Browsing by Subject "melanooma"

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  • Uoti, Arttu (Helsingin yliopisto, 2021)
    Background and objectives: Cancer is one of the leading causes of death worldwide, and resistance to current treatments demands the continuous development of novel cancer therapies. Cancer immunotherapy aims to induce anticancer immune responses that selectively target cancer cells. Viruses can also be harnessed to elicit tumor-specific immune responses and to improve the response rates of other concomitant cancer therapies. The purpose of this study was to develop a novel viral vector-based cancer vaccine for intratumoral immunotherapy. By using the previously developed PeptiENV cancer vaccine platform, the vector viruses were coated with cell-penetrating peptide (CPP) sequence-containing tumor peptides in an attempt to further drive the immune responses elicited by the vector against cancer cells. The efficacy of the PeptiENV complex as a cancer vaccine was assessed by following its effects on tumor growth and the development of local and systemic antitumor immune responses. Methods: The PeptiENV complex formation was assessed by a surface plasmon resonance (SPR) analysis. Dendritic cell (DC) activation and antigen cross-presentation were studied using the murine JAWS II dendritic cell line. The development of cellular immune responses against tumor antigens was first studied by immunizing mice with the PeptiENV complex. The antitumor efficacy and immunity of intratumoral PeptiENV administration were then studied using the murine melanoma models B16.OVA and B16.F10.9/K1. In addition to intratumoral PeptiENV treatment, some of the B16.F10.9/K1-implanted mice were also treated with an anti-PD-1 immune checkpoint inhibitor (ICI) to study the PeptiENV complex as a biological adjuvant for ICIs. Results: The SPR analysis confirmed that CPP-containing peptides can be stably anchored onto the viral envelope of the viral vector. The in vitro results showed that the PeptiENV complex does not hamper the presentation of antigens at the surface of DCs. Additionally, the viral vector was found to activate DCs seen as a change in the cells’ morphology and surface protein expression. Immunizing mice with the PeptiENV complex induced a robust antigen-specific cytotoxic T cell response. Upon intratumoral administration in vivo, the PeptiENV cancer vaccine was not capable of inducing tumor growth control against B16.OVA melanoma, although it did still elicit robust systemic and local antitumor T cell responses. In the treatment of B16.F10.9/K1 melanoma, however, the PeptiENV complex induced efficient tumor growth control, which resulted in a significant survival benefit. Additionally, co-administration of anti-PD-1 resulted in an additive therapeutic effect. Discussion and conclusions: The present study describes a novel, highly immunogenic viral vector-based cancer vaccine that has the potential to be used as an adjuvant treatment for ICI therapy. Subsequent studies could be conducted to gain a deeper understanding of the immunological mechanisms underlying the antitumor efficacy of the cancer vaccine complex. Moreover, this novel PeptiENV complex could also be further developed as an infectious disease vaccine platform against emerging pandemics. However, the effects of pre-existing antiviral immunity on the efficacy of the cancer vaccine should be explored in future studies.
  • Mauno, Mikael; Övermark, Meri; Frisk, Oskari; Isoherranen, Kirsi; Keinonen, Anne; Koskenmies, Sari; Pitkänen, Sari (Helsingin yliopisto, 2019)
    BACKGROUND. In this study we looked at patients, who were referred to the Skin and Allergy Hospital for a diagnosed or suspected premalignant or malignant skin lesion during a single year. These patients’ whole skin was examined, and all additional malignant or premalignant lesions were noted. PATIENTS AND METHODS. This research included 4037 patients, and their average age was 69 years. The patients’ whole skin was examined by a dermatologist, and all lesions that weren’t mentioned in the referral were recorded. RESULTS. Whole body examination revealed additional skin cancer or precancerous lesions in 1542 patients (38,2% of the material). Of these patients 54% were men and almost half of them were over 70-years old. CONCLUSIONS. A significant portion of patients had cancerous or precancerous lesions, that weren’t mentioned in the referral. Primary healthcare units should examine patients’ whole skin, especially if there are multiple risk factors. During a short reception, the examination should be focused on the trunk.
  • Bruun, Tanja (Helsingfors universitet, 2018)
    Marine organisms can be regarded as a diverse source of bioactive compounds with the possibility to discover novel drug lead molecules. Sea sponges produce bromine containing alkaloids, bromotyrosines, from which several are active against cancer. Some bromotyrosines have spirocyclic structure and the innate three-dimensionality and structural novelty of spirocycles make them an interesting option in drug design. Clavatadine C, extracted from sponge Suberea clavata, is a bromine containing spirocyclohexa-dienylisoxazoline alkaloid. It’s symmetric spirocyclic core can be viewed as a restricted derivative of open chain oximes, such as purpurealidin I, a bromotyrosine extracted from Pseudoceratina purpurea. Earlier work with purpurealidin I derivatives against melanoma cell line has had some promising results. Inspired by these earlier results, eight spirocyclic clavatadine C derivatives were synthesized according the published synthesis route. The activities of seven synthesized clavatadine C derivatives were tested on A375 melanoma cell line. All spiro derivatives were active with CC50 values ranging between 1.0 μM and 3.4 μM. Also, the activities of 10 earlier synthesized bromotyrosine derivatives were tested, from which four open chain oximes had CC50 values between 13.5 μM and 27.8 μM. Interestingly, the most active compounds were chlorinated and unhalogenated spirocyclic derivatives. In general, the spirocyclic compounds were 2- to 8-fold more active than the corresponding open chain oximes. The selectivity of active compounds was determined as cytotoxicity against Hs27 fibroblasts and by comparing the CC50 values of these two cell lines. The most selective compound was brominated derivative which had three times better selectivity against melanoma cells. The weak selectivity was consistent with the trend with open chain oxime analogs. Despite the selectivity issue, the improved activity of spirocyclic derivatives are promising and support for further investigation of marine-based spirocyclic bromotyrosine derivatives against melanoma.
  • Hellman, Anni (Helsingin yliopisto, 2021)
    Tutkimuksessa havainnointiin HUS Syöpäkeskuksessa vuosina 2008–2017 ihomelanooman diagnoosin saaneiden potilaiden seurantaa, taudin uusiutumista ja selviytymistä. Potilaiden tietoja kerättiin vuoden 2019 syyskuuhun saakka. Tutkimuksen tarkoituksena oli havainnoida HUS Syöpäkeskuksessa hoidettujen potilaiden ihomelanoomadiagnooseja, tapahtunutta seurantaa ja sen ominaisuuksia. Tutkimus analysoi seurannan eri vaiheita ja uusiutuman diagnostiikkatapoja. HUS Syöpäkeskuksessa hoidettiin 808 mainittuina vuosina diagnosoitua melanoomapotilasta, joista 783 saatiin kerättyä levinneisyysluokittelun mahdollistava määrä tietoa. Levinneisyysasteen III ihomelanoomissa potilaiden keski-ikä oli 60 vuotta ja potilaista 59 % oli miehiä. Evakuaatiotoimenpide tehtiin diagnoosivaiheessa näissä taudeissa 74 prosentille. Uusiutuvista levinneisyysasteen III ihomelanoomista suurin osa oli alaluokkaa IIIC. TT-tutkimus havaitsi luokan III ihomelanoomien kaikista uusiutumista lähes puolet ja sen hyöty korostui systeemisissä uusiutumissa. Levinneisyysasteen IIIC ensimmäisistä uusiutumista suurin osa havaittiin ensimmäisenä seurantavuotena, kun taas IIIA potilailla uusiutumia todettiin suhteellisesti enemmän toisena seurantavuotena ja IIIB potilailla toisena ja kolmantena seurantavuotena. Systeemisten uusiutumien osuus oli 41 %, joista merkittävä osa ilmeni jo ensimmäisenä seurantavuotena. Systeemiset ensimmäiset uusiutumat esiintyivät keskimäärin noin puoli vuotta myöhemmin kuin paikalliset ja ne ilmaantuivat tasaisemmin kahden ensimmäisen seurantavuoden aikana. Tulokset sekä viisivuotisseurannassa että kokonaisselviytymisestä vuosien 2008–2019 aikana vastaavat suuruusluokaltaan AJCC8-luokituksen elossaololukuja. Selviytymisen havaittiin myös heikkenevän odotetusti riskiluokan mukaan. Eri alaluokkien ennusteet taudin uusiutumisen toteamisen jälkeen olivat samansuuntaisia. Tutkimus havainnollistaa HUS-alueen levinneisyysasteen III potilaiden seurannan toteutumista ja sen eri osa-alueiden diagnostista merkittävyyttä havaita uusiutumia tässä potilasryhmässä. Melanoomapotilaista ei ole vielä kattavaa rekisteriä HUS-alueella eikä kansallisella tasolla. Tutkimus vastaa osaltaan tähän puutteeseen ja tarjoaa tietoa melanooman esiintymisestä ja ennusteesta kotimaisten hoitosuositusten valossa. Tätä tietoa voidaan jatkossa käyttää arvioitaessa melanoomapotilaiden hoidon tehokkuutta ja seurannan tarpeita Suomessa. Avainsanat: Melanoma / Diagnostic imaging; Melanoma / Pathology; Follow-Up Studies; Neoplasm Recurrence; Population Surveillance, Prognosis, Posoperative Period
  • Kuivanen, Antti (Helsingin yliopisto, 2020)
    Melanooma on ihosyöpä, jonka ennuste on ihon syövistä huonoin. Melanooman paksuus on merkittävin ennustetekijä metastasoinnin suhteen. Pinnallisiin melanoomiin lasketaan kuuluvaksi paksuudeltaan enintään 1 mm paksut melanoomat. Pinnalliset melanoomat metastasoivat harvoin, mutta metastasoidessa potilaan ennuste huonontuu selkeästi. Melanooma metastasoi tavallisimmin imuteitä pitkin ensiksi paikallisiin imusolmukkeisiin. Mahdollista metastasointia pyritään selvittämäänvartijaimusolmuketutkimuksella. Tämän tutkielman tavoitteena oli selvittää vuosina 2010-2013 Helsingin ja Uudenmaan sairaanhoitopiirissä (HUS) todettujen pinnallisten melanoomapotilaiden selviytymistä ja vartijaimusolmuketutkimuksen tuloksia. 599 potilaalla todettiin pinnallinen melanooma. Näistä potilaista 192:lle (32,1%) tehtiin vartijaimusolmuketutkimus. Positiivisia löydöksiä oli 10 (5,2%). Positiivisen tuloksen saaneista neljällä (40,0%) tauti metastasoi seuranta-aikana, negatiivisen tuloksen saaneista kolmella (1,6%). Komplikaatioita vartijaimusolmuketutkimuksesta todettiin sairauskertomusmerkintöjen perusteella 39 potilaalla (20,3%). Systeemimetastasointi todettiin 11 potilaalla (1,8%). Imusolmukemetastasoinnin riskitekijöiksi nousivat Breslow-luokka > 0,8 mm sekä korkea Clark-luokitus (IV-V). Ohuissa pinnallisissa, <0.8mm paksuissa melanoomissa ulseraatio ja regressio vaikuttaisivat nostavan metastasointiriskiä. Pinnallinen melanooma metastasoi harvoin vartijaimusolmukkeeseen, mutta systeemimetastaasin todennäköisyys vaikuttaa kasvavan positiivisen vartijalöydöksen myötä huomattavasti. Aineiston pienen koon vuoksi tarkkoja päätelmiä vartijaimusolmuketutkimuksen kriteereistä ei ole mahdollista tehdä. Rajatapauksissa potilastapaukset on syytä käydä läpi moniammatillisen ryhmän toimesta. (166 sanaa)
  • Ikonen, Miika (Helsingin yliopisto, 2021)
    Suun limakalvon pigmentaatioita aiheuttavat syyt ovat moninaiset ja pigmenttimuutosten taustalla voi olla jopa systeeminen sairaus. Pigmentaatiota voivat aiheuttaa ulkopuolinen materiaali, joka on päässyt limakalvon sisälle, kuten amalgaamitatuoinnissa, tai muutos voi olla fysiologista, melaniinin tuotannon lisääntymisestä johtuvaa, jolloin ne eivät vaadi hoitotoimia. Pigmentaatioita aiheuttavien muutosten joukossa on myös joitakin henkeä uhkaavia tiloja, kuten melanooma, Addisonin tauti tai Peutz-Jeghersin syndrooma. Pigmentaatioiden väri vaihtelee vaalean ruskeasta mustaan, ja ne voivat esiintyä eri muotoisina yksittäisinä plakkeina tai laaja-alaisina diffuusirajaisina muutoksina. Tutkielman tarkoituksena oli laatia kattava katsaus suun limakalvojen pigmentaatioita aiheuttavista muutoksista tämänhetkiseen tietämykseen perustuen käyttäen lähdeaineistona uusimpia tutkimustuloksia. Tiedonlähteenä on käytetty Pubmed tietokantaa ja Käypä hoito -suosituksia. Pigmentaatioiden moninaisuus ja niitä aiheuttavien taustatekijöiden laaja kirjo luo haasteen diagnostiikalle. Diagnoosiin tarvitaan perehtymistä hoitohistoriaan sekä tuntemusta suun limakalvoilla pigmentaatioita aiheuttavista syistä. On tärkeää merkitä kaikki pigmenttimuutokset potilasasiakirjoihin. Muutosten kohdalla tulisi aina varmistaa diagnoosi. Yksittäiset pigmenttimuutokset tulisi aina poistaa histolopatologista tutkimusta varten pahanlaatuisuuden (melanooma) poissulkemiseksi, ellei muutoksen luonne muutoin ole selkeä. Laaja-alaisten ja symmetrisen pigmentaatiomuutosten kohdalla koepalasta ei yleensä ole hyötyä, vaan näissä tapauksissa on syytä tarkentaa anamneesia (esim. lääkeaineiden aiheuttamat pigmentaatiot) tai lähettää potilas jatkotutkimuksiin.
  • Tilli, Irene (Helsingfors universitet, 2017)
    Melanoma is the most severe case of skin cancer and there is no curative treatment if it has progressed. Despite the recent advances in drug therapy tens of thousands of patients die of melanoma annually. There is still need for new antimelanoma drugs for which marine compounds are a potential source. Halogens are common elements in drug molecules as they enhance their molecular properties. So far most of the halogenated drugs contain fluorine and/or chlorine but the role of bromine and iodine is probably growing in the future due to halogen bonding. Bromotyrosines are originally isolated from Verongiida-order sponges but whether they are truly of bacterial origin is under controversy. All bromotyrosine compounds consist of brominated tyrosine and/or tyramine residues or their derivatives. Purpurealidin I is one of the newest bromotyrosine derivatives extracted from Pseudoceratina purpurea and it has shown activity against melanoma. In this study eight new purpurealidin I derivatives were synthesized following a successful route previously designed. All synthesized derivatives contained the original N-oxime structure which's stereochemistry was determined to be E by X-ray crystallography. Cytotoxicity against A375 melanoma cells was determined for seven compounds synthesized here and for 15 compounds synthesized previously. All seven compounds and one previously synthesized purpurealidin I analog were active with CC50 values between 4,7 and 22,1 µM. The previously synthesized bromotyrosine derivative intermediates and aerophobin-1 analogs were not active. The selectivity of the active compounds was calculated by determining their CC50 value against Hs27 fibroblast cells. None of the compounds showed remarkable selectivity the most selective 2-pyridin containing derivative having four times better selectivity against melanoma. The tyrosine part and N-oxime seem to be important parts to preserve while the tyramine part can be modified more freely and maintain the activity. Still more derivatives need to be synthesized and tested to confirm these observations. More data is also needed considering the selectivity of the compounds.
  • Merikallio, Sini (Helsingin yliopisto, 2021)
    Canine uveal melanoma (UM) usually manifests as a slowly developing, darker pigmented and well distinguishable mass in the iris. Less than a third of them are considered malignant, which is much less than with other melanocytic cancers. In contrast, in humans, 90% of UM occurs in the choroid and half of the patients eventually develop aggressive and often lethal metastases. Understanding the disease process and genetic background in dogs might also help us further the knowledge and improve the treatment options of humans. There is a hereditary component to the oncogenesis of the UM: the disease is more common in a Caucasian race and is also found in certain families. It is also more prevalent in certain dog breeds; Labrador Retrievers seem to be overrepresented. Several susceptibility genes have been identified in humans. One with the strongest association with UM is a tumor suppressor gene BAP1, which is dysfunctional or missing in nearly half of the human uveal melanomas. This gene is a so-called secondary driver of the UM and mutations in it spark the metastasizing process. There is a germline mutation of BAP1 in fourth of Finnish UM families and these mutations are also connected to various other cancers. Moreover, BAP1 shows over 98% protein product homology and almost 80% mRNA homology between dogs and humans, making it an appealing study target also for canines. Should a single variant account for high UM risk, a DNA test could be developed to be used in breeding and veterinary diagnostics. In this work, I mapped the BAP1 germline mutations of seven Labrador Retrievers with diagnosed uveal melanomas or melanocytomas. It was found that four dogs shared the same set of five heterozygous single nucleotide variants (SNV). One of the SNVs within exon 17 was synonymous, g.37,363,076G>A, p.(Ser721Ser), while the other four SNVs were intronic, residing close to exons 4, 10, 11 and 14. In the future, variant comparisons with healthy Labradors are needed to study the role of the identified variants for the development of UM, as the SNVs now found could also just be a part of a common variation in the Labrador Retriever gene pool. To grasp a bigger picture of the UM tumor development, the tumors themselves should also be analyzed for somatic mutations. Moreover, when we know that the disease is likely affected by over a hundred genes, studying just one gene is unnecessarily self-restricting. Modern full genome sequencing techniques should be used for catching all the predisposing genes simultaneously.