Browsing by Subject "cancer"

Objective: The aim of this study was to assess the cancer risk in a cohort of Finnish systemic lupus erythematosus (SLE) patients when followed long-term. Methods: The cohort consisted of 182 female and 23 male SLE patients treated at the Helsinki University Central Hospital, from 1967 to 1987. The cohort was linked to the Finnish Cancer Registry and followed for cancer incidence from 1967 to 2013. Standardized incidence ratios (SIRs) were calculated by dividing the number of observed cases with the number of expected cases for different types of cancer. Results: The mean duration of follow-up was 25.7 years. 45 patients out of 205 were diagnosed with cancer, with an increased risk of overall malignancy (SIR 1.90, 95% CI 1.39 to 2.54, p<0.001). The incidence for soft-tissue sarcoma (SIR 12.1, 95% CI 1.47 to 43.7, p<0.05), non-Hodgkin lymphoma (SIR 12.1, 95% CI 5.82 to 22.3, p<0.001) and kidney cancer (SIR 7.79, 95% CI 2.53 to 18.2, p<0.01) were significantly elevated. Conclusion: This long-term study confirms that patients with SLE have an increased risk of cancer, particularly non-Hodgkin lymphoma and kidney cancer.

The current 5-year survival rate of OSCC patients is around 50%. There are no diagnostic tests or markers and the diagnosis is based on histopathologic samples only, which postpones the time of detection and worsens the prognosis of the patient greatly. New diagnostic methods and tools are required to improve the survival rate. This study aimed to find possible biomarkers and develop a new diagnostic method for OSCC by comparing the serum proteomic expression of tongue cancer patients and healthy controls with label-free liquid-chromatography mass spectrometry. The results showed small, but statistically significant difference in protein expression between the patients and healthy controls, as well as a clear separation between the groups based on the peptide data. In addition, no specific networks or cellular pathways were highlighted for OSCC compared to other types of cancers. These results didn’t introduce considerable advances into the diagnostics of OSCC but showed a possibility for finding further distinctive differences between the OSCC patients and healthy controls.

Background Merkel Cell Carcinoma (MCC) is a rare neuroendocrine tumor that is associat-ed with old age and immunosuppressive condition. It has two distinct sub-groups differentiated with their Merkel Cell Polyomavirus (MCPyV) positivi-ty/negativity. While both groups are considered aggressive, the Merkel cell Pol-yomavirus negative group has significantly worse prognosis. Traditionally MCC cases have been diagnosed based on their physiological appearance and im-munohistochemical markers such as cytokeratin 20 and tumor transcription factor-1, which differentiate MCCs from small cell carcinomas. It still requires skilled personnel such as dermatologists and pathologists to identify MCCs. More precise and effective biomarkers are required to improve MCC diagnos-tics, to enhance patient survival and in the development of personalized medi-cine for MCC. Neurocan (NCAN) is a chondroitin sulphate proteoglycan that is found mainly in central nervous tissue in adults. The core protein of Neurocan is formed of 3 domains, G1 containing a single immunoglobulin domain, the glycosamino-glycan binding backbone and G3 domain containing regulatory protein-like sequences and epidermal growth factor/lectin-like domains. It is produced mainly by reactive astrocytes and its main function is to guide the growth of ax-ons and to participate in the formation of neural extracellular matrix. Neurocan is linked to inhibition of axonal regeneration and glial scarring in case of neu-ral injury. There are few mentions of Neurocan changes related to cancer out-side of the central nervous system, however, there is clear evidence of chon-droitin sulphate proteoglycan involvement in tumor invasiveness and potential-ly promotion of malignant tumor phenotype. Aim of the study and experimental design This thesis is a part of a project studying novel biomarkers and therapeutic tar-gets for MCC. The aim of the study was to identify a novel cancer specific gene (Neurocan) that would be either a potential biomarker or therapeutic target, and to set up the pipeline for further expanding the parent project. Neurocan was first identified from outlier gene detection methods applied to MCC sample series containing samples of 141 MCC patients. After this Neu-rocan expression levels were studied at protein level using immunohistochem-istry for MCC sample series. NCAN expression levels in MCC cell lines were investigated at mRNA and protein level with qPCR and Western blotting re-spectively. Functional studies of Neurocan such as an effect on cell prolifera-tion were performed with siRNA knockdown assays, and analyzed with West-ern blotting and qPCR. Results 144 FFPE samples in TMA (tissue microarray) format were stained for Neu-rocan protein expression; 31 samples expressed NCAN at low level, 60 at in-termediate level and 53 cases had high NCAN expression. The low NCAN ex-pression correlated with poor MCC specific survival (5-year survival 44%) when compared to intermediate and high expression groups (5-year survival 73% and 65% respectively). Kaplan-Meier survival analysis also implicated a signifi-cant difference in survival between the groups, p-value 0.044. NCAN expres-sion levels had a strong association with Merkel Cell Polyomavirus (MCPyV) status (Pearson Chi-square, p-value = 0.006) with 83% of high NCAN expres-sion cases being MCPyV positive, where as 55% of low NCAN expression cases were MCPyV negative. Cox proportional hazards model revealed that NCAN is unlikely to be an independent variable in patient survival. NCAN expression correlated with the MCPyV status of 9 tested MCC cell lines (Student’s t-test, p-value = 0.041). Protein level studies were inconclusive due to lack of specific antibodies and testing methods. 4 cell lines were tested for NCAN functionality in cell cultures. siRNA knock-down of NCAN did not affect the survival of MCC cell lines, however, it had a reducing effect on Large T-antigen expression of the MCPyV positive cell lines. Likewise, siRNA knockdown of Large T-antigen reduced the expression of NCAN mRNA in MCPyV positive cell lines. No such interactions were found in the MCPyV negative cell lines. siRNA knockdown of sT-antigen significantly reduced the growth of MCPyV positive WaGa cell line (Student’s t-test, p-value = 0.01). NCAN and large T-antigen targeting siRNAs had only a minor growth reducing effect on WaGa cell lines, and MKL1 cell line saw only minor growth reduction with all of the different siRNA treatments. These were not statistically significant findings. Whether Neurocan expression is directly controlled by MCPyV T-antigens, or whether the regulation is due to a signaling cascade of sorts, is still unknown.

Diffuse large B-cell lymphoma (DLBCL) represents the most common diagnostic entity of lymphoid malignancies. As only 60% of the patients are cured with the current standard of care R-CHOP immunochemotherapy, the quest for better biomarkers and targeted therapies continues. Non-synonymous mutations in the WWE1 domain of an uncharacterized E3 ubiquitin ligase Deltex-1 have been associated with poor outcomes in DLBCL patients. Thus, to elucidate molecular features underlying this observation, this Master’s thesis set out to characterize the expression and subcellular localization of Deltex-1 in a panel of DLBCL cell lines, and to investigate the interaction partners of Deltex-1 in the activated B-cell like (ABC) DLBCL cell line context. The study aimed to gain further knowledge to understand the role that Deltex-1 plays in the pathogenesis of DLBCL, which could be used for inspecting its future possibilities as a prognostic marker or a drug target. Western blot analysis of the cell lysates revealed variable levels of Deltex-1 expression, especially between the ABC-DLBCL cell lines in comparison to germinal centre B-cell like (GCB) DLBCL cell lines. Western blots of separate cytoplasmic and nuclear fractions of the cells showed that Deltex-1 was expressed both in the cytoplasmic and the nuclear fractions of the cells, and the expression levels were reflecting the levels of the whole cell lysates of the same cell lines. The more exact localization of Deltex-1 was observed with immunofluorescence staining and microscopy of fixed cells from a few chosen cell lines. A distinct plasma membrane localization was detected in an ABC-DLBCL cell line U2932. The protein-protein interaction partners of Deltex-1 in the U2932 cell line were screened using proximity-dependent biotin labelling and affinity purification mass spectrometry. The experiments revealed novel associations between Deltex-1 and B-cell receptor signalling regulators, such as B- lymphocyte antigen CD20 and tyrosine protein kinase Lck. Though additional research is needed to define the functional mechanisms of these interactions, these findings might lead to the discovery of the connection between Deltex-1 and lymphomagenesis. In conclusion, this study provides novel information on Deltex-1 expression in the DLBCL context and describes previously unidentified associations of Deltex-1 with B-cell receptor signalling. Yet, more functional experiments are required to clarify the nature of these interactions.

Suun mukosiitti on suun limakalvon inflammaatiotila, joka aiheutuu syöpähoidoista. Se on yksi yleisimmistä haittavaikutuksista kemoterapiaa, sädehoitoa tai kemosädehoitoa saavilla syöpää sairastavilla potilailla. Sen patofysiologia perustuu syöpähoitojen kykyyn inhiboida nopeasti jakautuvia soluja, joita syöpäkudoksen lisäksi on myös esimerkiksi suun limakalvolla. Kliinisesti suun mukosiitti aiheuttaa suun limakalvolla turvotusta, punoitusta ja kivuliaita haavaumia, joiden päälle muodostuu herkästi bakteerien muodostama plakkikerros. Pahentuessaan suun mukosiitti vaikuttaa potilaan kykyyn syödä, voi aiheuttaa keskeytyksiä syöpähoitoihin ja voi jopa johtaa sepsikseen sekä kuolemaan. Suun mukosiittia hoidetaan ennaltaehkäisemällä sitä sekä hoitamalla jo olemassa olevia oireita. Ennaltaehkäisyssä tärkeää on potilaan hyvä suuhygienia ja sen lisäksi käytetään esimerkiksi kemoterapian aikana annettua jääpalahoitoa. Erilaisia lääkkeitä sekä suuhuuhteita on tutkittu suun mukosiitin ennaltaehkäisevänä sekä oireenmukaisena hoitona, mutta toistaiseksi niistä ei ole saatu merkittävää hyötyä. Yksittäisistä hoitomuodoista hyvä teho erityisesti ennaltaehkäisevänä hoitona on saatu matala- asteisesta laserterapiasta (LLLT: low-level lasertherapy), mutta sen laaja-alaista käyttöä rajoittaa sen saatavuus ja käytännön toteutus. Koska on huomattu, että suun mukosiitin vakavuusasteeseen vaikuttavat haavaumien päälle muodostuvat bakteeripesäkkeet, on alettu tutkia erilaisia antibakteerisia hoitoja. Antibakteerinen fotodynaaminen terapia (aPDT: antibacterial photodynamic therapy) sekä antibakteerinen sinivalo (aBL: antibacterial blue light) ovat hoitomuotoja, joiden teho perustuu bakteerien epäselektiiviseen tappamiskykyyn. Kaksoisvaloterapia perustuu aPDT:n sekä aBL:n yhteisvaikutukseen. Tämä tutkielma koostuu kirjallisuuskatsauksesta suun mukosiittiin, sen patofysiologiaan ja sen eri hoitokeinoihin sekä tutkimuskatsauksesta, jossa on tutkittu kaksoisvalon antibakteerista tehokkuutta Streptococcus Oralista vastaan. Tutkimuksessa altistettiin S. Oralis pesäkkeitä kaksoisvalolle, samalla kun aPDT:n sekä aBL:n suhteellisia valon energioita muutettiin ja näin selvitettiin onko tällä vaikutusta antibakteriaaliseen tehoon. Kaksoisvalon avulla saatiin hävitettyä kaikki S. Oralis pesäkkeet huolimatta aPDT:n ja aBL:n suhteellisista valon energioista. Tutkielman lopussa liitteenä on käsitelista tutkielmassa käytetyistä lääketieteellisistä termeistä.

Cancer patients have a manifold risk of suffering from both thrombotic events and anticoagulation-related bleeding complications. For this reason, knowledge of their adequate medication is crucial. The aims of this study were to find out are guidelines being followed regarding the treatment of venous thromboembolisms. The emphasis was on the anticoagulation therapy of cancer patients, but also non-cancer patients were analyzed as controls. Data was collected from the clinical information system Uranus CGI. All patient records (with the diagnostic codes I26.0, I67.6, I74.3, I80*, I81*, I83*, K55, N28.0, 022.3) in the hospital district of Helsinki and Uusimaa (Jorvi, Meilahti, Peijas, Lohja, Porvoo, Tammisaari and Hyvinkää hospitals) during the time period 1.1.2014- 29.4.2016 were reviewed. Statistical analysis was performed using the IBM SPSS Statistics and Microsoft Excel computer softwares. The study included 1667 patients, out of whom 163 (9.8%) had active cancer. The recommendation of using low molecular weight heparins as the primary anticoagulants for patients with malignancies has been practiced. More research is necessary in order to find the optimal duration for treatment of, especially, isolated calf muscle venous thromboses and cancer patients' superficial thrombophlebitides.

Lääketieteessä kuvantamistutkimuksissa hyödynnetään usein kolmiulotteista (3D) mallintamista, jotta tutkittava kohde pystyttäisiin hahmottamaan yksiselitteisemmin. Sen sijaan histopatologiassa kaksiulotteinen (2D) esittämistapa on edelleen vallitseva tapa ilmoittaa esimerkiksi poistetun kasvaimen leikkausmarginaalit. Tutkimuksemme tarkoitus oli esittää leikkauksessa poistetun pehmytkudosresekaatin sisällä olevan kasvaimen dimensiot ja siitä tehtyjen histologisten leikkeiden sijainnit 3D muodossa luomalla resekaatista ja sen leikkeistä digitaalinen 3D-malli. Kehittelimme menetelmän käyttäen yleisesti saatavilla olevia instrumentteja keskittyen kielen levyepiteelikarsinooman mallintamiseen. Loimme menetelmän tunnistamalla ja ratkomalla ongelmia, jotka liittyivät histologisten leikkeiden leikesuuntien valintaan, joka aiemman kirjallisuuden perusteella on ollut keskeinen haaste pehmytkudosresekaatin 3D-mallin luomisessa. Tavanomaiseen resekaatin käsittelyyn verrattuna lisävaiheita olivat ainoastaan leikkausresekaatin skannaaminen ennen histopatologisten leikkeiden keräämistä sekä itse karsinooman mallintaminen digitaaliseksi. Nämä lisävaiheet vaativat ainoastaan 3D pöytäskannerin ja 3D mallinnusohjelmiston. Työssä esittelemme leikkausresekaatin ja histopatologisten leikkeiden mallintamiseen liittyviä haasteita ja niille kehittämiämme ratkaisuja. Työn tuloksena esittelemme valmiin 3D-mallin kielen levyepiteelikarsinooman leikkausresekaatista ja sen sisällä olevasta varsinaisesta kasvaimesta sekä digitaalisena mallina että puoliläpäisevänä valumallina (3D-tuloste). Kuvaamme työssä myös työvaiheet, jotka vaaditaan 3D-mallin luomiseksi. Julkaisuhetkellä tietääksemme työmme on ensimmäinen yritys esittää kielikasvaimen histopatologiset marginaalit 3D muodossa, kun aiemmin vain 2D muoto on ollut saatavilla. 3D-mallin luominen metodillamme ei vaadi ennalta määrättyjä leikesuuntia. Metodimme tarjoaa yksiselitteisemmän ja selkeämmän tavan havainnollistaa kasvaimen marginaalit, topografia ja orientaatio. Metodiamme voitaisiin tulevaisuudessa käyttää työkaluna postoperatiivisessa arvioinnissa sekä adjuvanttihoitojen suunnitelussa.