Targeted Therapy Possibilities for Metastatic Melanoma

The incidence of malignant melanoma of the skin has been steadily rising worldwide during the past decades. Most early detected primary tumors can be removed surgically and the prognosis is good. However, at the same time there still is no permanent cure for metastatic melanoma and its prognosis is poor, although lately new effective drugs have emerged. In this thesis, four different approaches of experimental therapy for metastatic melanoma were studied. Endogenous cis-Urocanic acid (UCA) is found in every individual’s skin, where exposure to UV light from the sun generates it from its inactive trans conformation. Cis- UCA was found to destroy malignant melanoma cells in culture under an acidified pH and sufficient concentration through caspase-3 mediated apoptosis. Furthermore, cis-UCA is able to considerably diminish the growth rate in human melanoma tumors on living SCID mice. Using replication-competent Semliki Forest viruses, human melanoma tumors grown in SCID mice were dramatically shrunken as the fulminant production of viruses in melanoma cells leads them to apoptosis within 72 hours. Small oligopeptides attaching to melanoma cells were identified using in vivo phage display. The melanoma-specific peptides found were further tested in vitro on adenoviruses. Ultimately, the adenoviral retargeting using the peptides was tested in vivo. One peptide homed to human transferring receptor upregulated on melanoma cells. In order to kill the malignant melanoma cells with the retargeted adenoviruses, the viruses should carry genetic material producing apoptotic proteins in the cancer tissue. TIMP-3 has been identified as a good candidate for such a protein, as it inhibits malignant cell adhesion as well as promotes apoptosis through a caspase-8 pathway. It is further shown here that adenovirally delivered TIMP-3 is even more potent, as it could kill non-adherent cancer cells, lacking the fully functional death receptor signalling pathway. Adenovirally delivered TIMP-2 also showed marked antitumor effects in human malignant melanoma xenografts on SCID mice both in ex vivo and systemic delivery.

Vuotasapainon hallinta kokosiltasyötetyssä muuntajassa

Keskitaajuudella toimivia muuntajia käytetään laajalti tehoelektroniikkasovelluksissa kuten DC/DC-konverttereissa ja muissa hakkuriteholähteissä. Muuntaja on induktiivinen komponentti, jonka magneettisen tasapainon säilyttäminen hakkuriteholähteissä on laitteen virheettömän toiminnan kannalta tärkeää. Muuntajaa syöttävän virtapiirin on muodostettava symmetrinen syöttöjännite, jotta muuntajan vuo ei ajaudu positiiviseen tai negatiiviseen kyllästykseen. Tässä diplomityössä esitetään muuntajan sähkömagneettinen toimintaperiaate, kyllästymisen syyt hakkuriteholähteissä sekä kehitetään aktiivinen ohjaus vuotasapainon säilyttämiseksi. Hakkuriteholähteissä käytettävissä muuntajissa on monesti useampi kuin kaksi käämiä. Tässä työssä tutkittavassa muuntajassa on useita ensiöitä ja useita toisioita ja muuntajaa syötetään keskitaajuudella. Tämä tuo uusia ongelmia verrattuna perinteiseen yksivaiheiseen DC/DC-konvertteriin. Näihin ongelmiin esitetään ratkaisut diplomityön tutkimuksessa.

Operative Treatment of Ovarian Cancer and Borderline Tumors in Different Hospital Categories in Finland

Surgery is the cornerstone of ovarian cancer treatment and maximal cytoreduction is important. In the early 1980’s primary surgical treatment of ovarian cancer was performed in over 80 hospitals in Finland. The significance of the operative volume of the hospital, of the training of the surgeons and of centralization of surgical treatment has been widely discussed. The aim of the present study was to evaluate the outcome of surgical treatment of ovarian cancer in different hospital categories retrospectively and prospectively, and to analyze if any differences are reflected in survival. The retrospective study included 3851 ovarian cancer patients operated between 1983 and 1994 in Finland. The data was analyzed according to hospital category (university, central, and other) and by quartiles of the hospital operative volume. The results showed that patients operated in the highest operative volume hospitals had the best relative survival. When stratifying the analysis by the period of diagnosis (1983-1988 and 1989-1994), the university hospitals improved their performance the most. The prospective part of the thesis was initiated in 1999 and included 307 patients with invasive ovarian cancer and 65 patients with an ovarian borderline tumor. The baseline and 5-year surveys used a questionnaire that was filled in by the operating surgeons. For analysis of the 5-year followup data, the hospitals were divided into three categories (<10, 10-20, or >20 patients operated in 1999). The effect of the surgical volume was analyzed also as a continuous variable (1-47 operations per year). In university hospitals, pelvic lymphadenectomy was performed in 88 %, and para-aortic lymphadenectomy in 73 %, of the patients with stage I disease. The corresponding figures ranged from 11 % to 21 % in the other hospitals. For stage III ovarian cancer patients operated by gynecological oncologists, the estimated odds ratio for no macroscopic residual tumor was 3.0 times higher (95 % CI 1.2-7.5) than for those operated by general gynecologists. In the university and other hospitals 82% of the patients received platinum-based chemotherapy. Platinum + taxane combination was given to 63 % of the patients in the university and in 49 % in the other hospitals (p = 0.0763). Only a minority of the patients with tumors of borderline malignancy were staged according to recommendations, most often multiple peritoneal biopsies and omentectomy were neglected. FIGO stage, patient age, and residual tumor were independent prognostic factors of cancer-specific 5-year survival. A higher hospital operative volume was also a significant prognostic factor for better cancer-specific survival (p = 0.036) and disease-free survival (p = 0.048). In conclusion, ovarian cancer patients operated in high-volume university hospitals were more often optimally debulked and had a significantly better cancer-specific survival than patients operated in other hospitals. These results favor centralization of primary surgical treatment of ovarian cancer.

Implementing an Evidence-based Hypertension Guideline into Finnish Primary Care Nursing

Kohonneen verenpaineen hoitosuosituksen käyttöönottosuomen perusterveydenhiollon hoitotyössä Tutkimuksen tavoitteena oli tuottaa suosituksia näyttöön perustuvien Käypä hoito -suositusten käytön edistämiseksi perusterveydenhuollon hoitotyössä. Tutkimuksen ensimmäisessä vaiheessa arvioitiin Kohonneen verenpaineen hoitosuosituksen käyttöönottoa terveyskeskuksissa. Toisessa vaiheessa selvitettiin hoitajien hoitosuositusasenteita ja kokemuksia hoitosuosituksen käyttöönotosta. Kolmannessa vaiheessa selvitettiin hoitohenkilöstön näkemyksiä hoitosuosituksen käyttöä edistävistä tekijöistä. Kohonneen verenpaineen hoitosuositus oli ylilääkäreiden ja ylihoitajien mukaan otettu käyttöön lähes kaikissa terveyskeskuksissa, mutta heidän näkemyksensä suositusten käyttöönottoa koskevista terveyskeskuksissa tehdyistä sopimuksista erosivat toisistaan monilta osin. Myös käyttöönoton toteutuksessa oli suurta vaihtelua terveyskeskusten välillä. Toteutustavan perusteella ääripäissä sijaitsevat terveyskeskukset luokiteltiin yksittäisin ja monin keinoin käyttöönottoa tukeneiksi. Hoitajien hoitosuositusasenteet olivat hyvin myönteisiä ja hoitosuosituksia pidettiin luotettavina tiedonlähteinä, ja niiden uskottiin parantavan hoidon laatua. Hoitosuositusten paikallinen soveltaminen sekä johdon ja lääkäreiden tuki olivat hoitajien mielestä keskeisiä käyttöönotossa, vaikkakin tulosten mukaan kaikki käytetyt keinot olivat yhteydessä positiivisempiin hoitosuositusasenteisiin sekä aktiivisempaan hoitajien itsensä ilmaisemaan hoitosuositusten käyttöön. Yhteenvetona voidaan todeta, että Käypä Hoito -suositukset on hyväksytty osaksi kliinistä hoitotyön käytäntöä. Niiden käytön tehostamiseksi tulisi kiinnittää huomiota suositusten paikalliseen soveltamiseen ja eri ammattiryhmien tehtäväkuvien määrittelyyn. Tähän tarvitaan terveyskeskusten johdon ja lääkäreiden selkeää tukea.

The Roots of Neurofibromas in Neurofibromatosis 1 — A Question of Multipotency, Differentiation and Hiding

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome that affects about 1 in 3500 individuals worldwide. NF1 is caused by mutations in the NF1 gene that encodes the tumor suppressor protein neurofibromin, an inactivator of the Ras oncogene. The hallmarks of NF1 include pigmentary lesions of the skin, Lisch nodules of the iris and cutaneous neurofibromas. Cutaneous neurofibromas are benign tumors composed of all the cell types of normal peripheral nerve. The traditional view of neurofibroma development has been that cutaneous neurofibromas arise from the disruption of the small nerve tributaries of the skin and subsequent proliferation of the resident cells. The second hit mutation in the NF1 gene has been considered as a prerequisite for neurofibroma development. The second hit is detectable in a subpopulation of primary Schwann cells cultured from neurofibromas. This thesis challenges the traditional concept of neurofibroma development. The results show that cutaneous neurofibromas are intimately associated with hair follicular structures and contain multipotent precursor cells (NFPs), suggesting that neurofibromas may arise from the multipotent cells which reside in hair follicles. Furthermore, this study presents that neurofibroma-derived Schwann cells that harbor bi-allelic inactivation in the NF1 gene express HLA class II genes and may act as nonprofessional antigen presenting cells. The CD4- and FoxP3-positive cells detected in cutaneous neurofibromas suggest that these cells may represent regulatory T cells (Tregs) which interact with HLA II –positive cells and aid the tumor cells in hiding from the immune system and are thus mediators of immune tolerance. This thesis also investigated neurofibroma development in the oral cavity and the use of different biomarkers to characterize cellular differentiation in neurofibromas. The results revealed that oral neurofibromas are not rare, but they usually appear as solitary lesions contrary to multiple cutaneous neurofibromas and present high heterogeneity within and between tumors. The use of class III beta-tubulin as a marker for neuronal differentiation led to an unexpected finding showing that multiple cell types express class III beta-tubulin during mitosis. The increased understanding of the multipotency of tumor cells, cellular differentiation and ability to hide from immune system will aid in the development of future treatments. Specifically, targeting Tregs in NF1 patients could provide a novel therapeutic approach to interfere with the development of neurofibromas.