Novel prognostic factors for advanced melanoma and localized renal cell carcinoma

This study aimed to evaluate prognostic and predictive factors in melanoma and renal cell carcinoma to tailor optimal treatment and follow-up for cancer patients. Chemotherapy was the standard treatment for advanced melanoma before immune checkpoint inhibitors and targeted therapies. The median overall survival was 8.9 months (95% CI 7.5–10.4) and the five-year survival rate 13% in 146 patients who had received BOLD-IFN chemoimmunotherapy at Turku University Hospital in 1991─2010. Long-term survivors were found especially in patients without visceral metastases (five-year survival rate 28%). The Finnish Melanoma Group conducted a prospective, multicenter trial enrolling 38 patients who received TOL-IFN (temozolomide, lomustine, vincristine, and interferone-alpha) ± vemurafenib for the first-line treatment of advanced cutaneous melanoma. Elevated LDH was associated with shorter overall survival unlike asymptomatic brain metastases. Undetectable circulating tumor DNA in baseline plasma samples correlated with longer progression-free survival and baseline ctDNA levels were inversely associated with overall survival. Patients with persistent detectable ctDNA during treatment had the shortest overall survival. One-third of patients will develop disease recurrence after surgery for localized renal cell carcinoma. Tumor size, tumor grade (Fuhrman), and microvascular invasion were sufficient for the accurate prediction of metastasis-free survival in 196 patients operated for localized clear cell RCC. The three-feature prediction model was validated in an external cohort of 714 patients. It retained similar prediction accuracy as the Leibovich model (C-index 0.836 vs. 0.848, p=0.106) and had better prognostic value for long-term prediction in both cohorts In conclusion, undetectable ctDNA is a novel biomarker indicating favourable prognosis in advanced melanoma. This study suggests that patients with persistent detectable ctDNA may require more frequent monitoring of treatment response and perhaps more intensive therapy. We also introduced a three-feature prediction model for metastasis-free survival as a tool for optimizing postoperative follow-up of localized RCC patients.Edenneen melanooman ja paikallisen munuaissyövän uudet ennustetekijät Tämän väitöskirjatutkimuksen tavoitteena oli löytää uusia ennustetekijöitä, jotka voivat auttaa suunnittelemaan melanooma- ja munuaissyöpäpotilaiden yksilöllistä hoitoa ja seurantaa. Ensimmäisessä osatyössä tutkittiin solunsalpaajahoidon ja alfainterferonin (DOBC-IFN) hyötyä ennustavia tekijöitä. 146 potilasta oli saanut DOBC-IFN-hoitoa TYKS:ssä edenneen ihomelanooman vuoksi vuosina 1991–2010. Potilaiden eliniän mediaani oli 8,9 kuukautta (95 prosentin luottamusväli 7,5–10,4 kk) ja viiden vuoden kohdalla elossa olevien potilaiden osuus oli 13 prosenttia. Jopa 28 prosenttia potilaista, joilla ei ollut todettu sisäelinetäpesäkkeitä, pysyi elossa viisi vuotta. Toisessa ja kolmannessa osatyössä raportoitiin tulokset Suomen Melanoomaryhmän toteuttamasta prospektiivisesta kansallisesta monikeskustutkimuksesta, jossa annettiin 38:lle edennyttä ihomelanoomaa sairastavalle potilaalle solunsalpaajien, alfainterferonin (TOL-IFN) ja vemurafenibin yhdistelmähoitoa. Korkea plasman laktaattidehydrogenaasipitoisuus ennusti lyhyempää elinaikaa, kun taas oireettomat aivometastaasit eivät olleet yhteydessä lyhyempään elinaikaan. Veressä kiertävä kasvain-DNA ennusti nopeampaa taudin etenemistä ja kasvain- DNA:n määrä oli kääntäen verrannollinen elinajan pituuteen. Lyhyin elinaika todettiin potilailla, joilla kasvain-DNA ei hävinnyt hoidon aikana toistetusti otetuista plasmanäytteistä. Neljännessä osatyössä osoitettiin, että syöpäkasvaimen koko, syöpäsolujen erilaistumisaste ja leviäminen hiusverisuoniin ennustavat luotettavasti etäpesäkkeiden ilmaantumista paikallisen kirkassoluisen munuaissyövän leikkauksen jälkeen. Johtopäätöksenä voidaan todeta, että veressä kiertävä kasvain-DNA ennustaa melanoomapotilaiden elinaikaa. Mikäli kiertävä kasvain-DNA ei häviä hoidon aikana, voidaan harkita hoidon tehostamista. Neljännessä osatyössä esitellyn uuden nomogrammin avulla voidaan arvioida potilaan riskiä sairastua levinneeseen munuaissyöpään ja tätä luokittelua voidaan käyttää, kun suunnitellaan potilaan seurantaa paikallisen kirkassoluisen munuaissyövän leikkauksen jälkeen

Slicing Sets and Measures, and the Dimension of Exceptional Parameters

We consider the problem of slicing a compact metric space \Omega with sets of the form \pi_{\lambda}^{-1}\{t\}, where the mappings \pi_{\lambda} \colon \Omega \to \R, \lambda \in \R, are \emph{generalized projections}, introduced by Yuval Peres and Wilhelm Schlag in 2000. The basic question is: assuming that \Omega has Hausdorff dimension strictly greater than one, what is the dimension of the 'typical' slice \pi_{\lambda}^{-1}{t}, as the parameters \lambda and t vary. In the special case of the mappings \pi_{\lambda} being orthogonal projections restricted to a compact set \Omega \subset \R^{2}, the problem dates back to a 1954 paper by Marstrand: he proved that for almost every \lambda there exist positively many $t \in \R$ such that \dim \pi_{\lambda}^{-1}{t} = \dim \Omega - 1. For generalized projections, the same result was obtained 50 years later by J\"arvenp\"a\"a, J\"arvenp\"a\"a and Niemel\"a. In this paper, we improve the previously existing estimates by replacing the phrase 'almost all \lambda' with a sharp bound for the dimension of the exceptional parameters.Comment: 31 pages, three figures; several typos corrected and large parts of the third section rewritten in v3; to appear in J. Geom. Ana

Super star clusters and Supernovae in interacting LIRGs unmasked by NIR adaptive optics

We report on an on-going near-IR adaptive optics survey targeting interacting luminous IR galaxies. High-spatial resolution NIR data are crucial to enable interpretation of kinematic, dynamical and star formation (SF) properties of these very dusty objects. Whole progenitor nuclei in the interactions can be missed if only optical HST imaging is used. Here we specifically present the latest results regarding core-collapse supernovae found within the highly extincted nuclear regions of these galaxies. Direct detection and study of such highly obscured CCSNe is crucial for revising the optically-derived SN rates used for providing an independent measurement of the SF history of the Universe. We also present thus-far the first NIR luminosity functions of super star cluster (SSC) candidates. The LFs can then be used to constrain the formation and evolution of SSCs via constraints based on initial mass functions and cluster disruption models.Comment: 6 pages. To appear in proceedings of 'Galaxies and their Masks' (Namibia, April 2010), published by Springer, New York, eds. D.L. Block, K.C. Freeman, I. Puerar

Child perspectives on income and time use in Finnish families in the 1990s

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Porosities and dimensions of measures

We introduce a concept of porosity for measures and study relations between dimensions and porosities for two classes of measures: measures on $R^n$ which satisfy the doubling condition and strongly porous measures on $R$.Comment: Jarvenpaa = J\"arvenp\"a\"

The Core-Collapse Supernova Rate in Arp299 Revisited

We present a study of the CCSN rate in nuclei A and B1 of the luminous infrared galaxy Arp299, based on 11 years of Very Large Array monitoring of their radio emission at 8.4 GHz. Significant variations in the nuclear radio flux density can be used to identify the CCSN activity in the absence of high-resolution very long baseline interferometry observations. In the case of the B1-nucleus, the small variations in its measured diffuse radio emission are below the fluxes expected from radio supernovae, thus making it well-suited to detect RSNe through flux density variability. In fact, we find strong evidence for at least three RSNe this way, which results in a lower limit for the CCSN rate of 0.28 +/- 0.16 per year. In the A-nucleus, we did not detect any significant variability and found a SN detection threshold luminosity which allows only the detection of the most luminous RSNe known. Our method is basically blind to normal CCSN explosions occurring within the A-nucleus, which result in too small variations in the nuclear flux density, remaining diluted by the strong diffuse emission of the nucleus itself. Additionally, we have attempted to find near-infrared counterparts for the earlier reported RSNe in the Arp299 nucleus A, by comparing NIR adaptive optics images from the Gemini-N telescope with contemporaneous observations from the European VLBI Network. However, we were not able to detect NIR counterparts for the reported radio SNe within the innermost regions of nucleus A. While our NIR observations were sensitive to typical CCSNe at 300 mas from the centre of the nucleus A, suffering from extinction up to A_v~15 mag, they were not sensitive to such highly obscured SNe within the innermost nuclear regions where most of the EVN sources were detected. (abridged)Comment: 12 pages, 4 figures and 7 tables. Accepted for publication in MNRA

WH2 domain: a small, versatile adapter for actin monomers

The actin cytoskeleton plays a central role in many cell biological processes. The structure and dynamics of the actin cytoskeleton are regulated by numerous actin-binding proteins that usually contain one of the few known actin-binding motifs. WH2 domain (WASP homology domain-2) is a similar to35 residue actin monomer-binding motif, that is found in many different regulators of the actin cytoskeleton, including the beta-thymosins, ciboulot, WASP (Wiskott Aldrich syndrome protein), verprolin/WIP (WASP-interacting protein), Srv2/CAP (adenylyl cyclase-associated protein) and several uncharacterized proteins. The most highly conserved residues in the WH2 domain are important in beta-thymosin's interactions with actin monomers, suggesting that all WH2 domains may interact with actin monomers through similar interfaces. Our sequence database searches did not reveal any WH2 domain-containing proteins in plants. However, we found three classes of these proteins: WASP, Srv2/CAP and verprolin/WIP in yeast and animals. This suggests that the WH2 domain is an ancient actin monomer-binding motif that existed before the divergence of fungal and animal lineages. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved