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

Editorial: Disaster resilience: Building the Jigsaw

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New solutions of Heun general equation

We show that in four particular cases the derivative of the solution of Heun general equation can be expressed in terms of a solution to another Heun equation. Starting from this property, we use the Gauss hypergeometric functions to construct series solutions to Heun equation for the mentioned cases. Each of the hypergeometric functions involved has correct singular behavior at only one of the singular points of the equation; the sum, however, has correct behavior

Approximate Quantum Fourier Transform and Decoherence

We discuss the advantages of using the approximate quantum Fourier transform (AQFT) in algorithms which involve periodicity estimations. We analyse quantum networks performing AQFT in the presence of decoherence and show that extensive approximations can be made before the accuracy of AQFT (as compared with regular quantum Fourier transform) is compromised. We show that for some computations an approximation may imply a better performance.Comment: 14 pages, 10 fig. (8 *.eps files). More information on http://eve.physics.ox.ac.uk/QChome.html http://www.physics.helsinki.fi/~kasuomin http://www.physics.helsinki.fi/~kira/group.htm

The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis

This article is available open access through the publisher’s website at the link below. Copyright @ 2013 The American Society of Gene & Cell Therapy.Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.Imperial College London, the Wellcome Trust, and Brunel University