Browsing by Subject "Melanoma"

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  • Alve, Sanni; Gramolelli, Silvia; Ojala, Päivi M. (Humana press, 2021)
    Methods in Molecular Biology
    Three-dimensional (3D) cell culture has allowed a deeper understanding of complex pathological and physiological processes, overcoming some of the limitations of 2D cell culture on plastic and avoiding the costs and ethical issues related to experiments involving animals. Here we describe a protocol to embed single melanoma cells alone or together with primary human lymphatic endothelial cells in a 3D crosslinked matrix, to investigate the invasion and molecular crosstalk between these two cell types, respectively. After fixation and staining with antibodies and fluorescent conjugates, phenotypic changes in both cell types can be specifically analyzed by confocal microscopy.
  • Eggermont, Alexander MM; Meshcheryakov, Andrey; Atkinson, Victoria; Blank, Christian U.; Mandala, Mario; Long, Georgina V.; Barrow, Catherine; Di Giacomo, Anna Maria; Fisher, Rosalie; Sandhu, Shahneen; Kudchadkar, Ragini; Ortiz Romero, Pablo Luis; Svane, Inge Marie; Larkin, James; Puig, Susana; Hersey, Peter; Quaglino, Pietro; Queirolo, Paola; Stroyakovskiy, Daniil; Bastholt, Lars; Mohr, Peter; Hernberg, Micaela; Chiarion-Sileni, Vanna; Strother, Matthew; Hauschild, Axel; Yamazaki, Naoya; van Akkooi, Alexander CJ; Lorigan, Paul; Krepler, Clemens; Ibrahim, Nageatte; Marreaud, Sandrine; Kicinski, Michal; Suciu, Stefan; Robert, Caroline (2021)
    Background: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I–V and of grade III–V immune-related adverse events (irAEs) was 37% and 7%, respectively. Methods: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. Results: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over (‘crossover’). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 (‘rechallenge’). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7–15.2) and the 3-year PFS rate was 32% (95% CI 25–40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48–83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6–NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I–IV irAE and 11 (6%) had a grade III–IV irAE. Conclusions: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged.
  • Aly, Ashraf A.; El-Sheref, Essmat M.; Bakheet, Momtaz E. M.; Mourad, Mai A. E.; Bräse, Stefan; Ibrahim, Mahmoud A. A.; Nieger, Martin; Garvalov, Boyan K.; Dalby, Kevin N.; Kaoud, Tamer S. (2019)
    Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Herein, we report the design and synthesis of novel series of fused naphthofuro[3,2-c] quinoline-6,7,12-triones 3a-f and pyrano[3,2-c]quinoline-6,7,8,13-tetraones 5a,b and 6, as potential ERK inhibitors. New inhibitors were synthesized and identified by different spectroscopic techniques and X-ray crystallography. They were evaluated for their ability to inhibit ERK1/2 in an in vitro radioactive kinase assay. 3b and 6 inhibited ERK1 with IC50s of 0.5 and 0.19 mu M, and inhibited ERK2 with IC50s of 0.6 and 0.16 mu M respectively. Kinetic mechanism studies revealed that the inhibitors are ATP-competitive inhibitors where 6 inhibited ERK2 with a K-i of 0.09 mu M. Six of the new inhibitors were tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Compound 3b and 6 were the most potent against most of the human tumor cell lines tested. Moreover, 3b and 6 inhibited the proliferation of the BRAF mutant A375 melanoma cells with IC50s of 3.7 and 0.13 mu M, respectively. In addition, they suppressed anchorage-dependent colony formation. Treatment of the A375 cell line with 3b and 6 inhibited the phosphorylation of ERK substrates p-90RSK and ELK-1 and induced apoptosis in a dose dependent manner. Finally, a molecular docking study showed the potential binding mode of 3b and 6 within the ATP catalytic binding site of ERK2.
  • Wouters, Michel W.; Michielin, Olivier; Bastiaannet, Esther; Beishon, Marc; Catalano, Orlando; del Marmol, Veronique; Delgado-Bolton, Roberto; Dendale, Remi; Trill, Maria Die; Ferrari, Andrea; Forsea, Ana-Maria; Kreckel, Hannelore; Lövey, Jozsef; Luyten, Gre; Massi, Daniela; Mohr, Peter; Oberst, Simon; Pereira, Philippe; Paiva Prata, Joao Paulo; Rutkowski, Piotr; Saarto, Tiina; Sheth, Sapna; Spurrier-Bernard, Gilly; Vuoristo, Meri-Sisko; Costad, Alberto; Naredi, Peter (2018)
    Background ECCO essential requirements for quality cancer care (ERQCC) are explanations and descriptions of challenges, organisation and actions that are necessary to give high-quality care to patients who have a specific type of cancer. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Melanoma: essential requirements for quality care: Melanoma, the most-deadly skin cancer, is rising in incidence among fair-skinned people in Europe. Increasing complexity of care for advanced disease in clinical areas such as staging and new therapies requires attention to a number of challenges and inequalities in a diverse patient group. Care for advanced melanoma must only be carried out in, or in collaboration with, specialist melanoma centres which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries. It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis to treatment and follow-up, to improve survival and quality of life for patients. Conclusion: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for melanoma. The ERQCC expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams and specialised treatments is guaranteed to all patients with melanoma.
  • Vihinen, Pia; Mäkelä, Siru; Hernberg, Micaela; Tyynelä-Korhonen, Kristiina; Koivunen, Jussi (2017)
  • Hernberg, Micaela; Mäkelä, Siru; Vihinen, Pia (2017)
  • Saavalainen, Liisu; Lassus, Heini; Härkki, Päivi; Tiitinen, Aila; Pukkala, Eero; Heikinheimo, Oskari (2021)
    Aiempien tutkimusten mukaan endometrioosia sairastavien naisten kokonaissyöpäriski ei poikkea muista samanikäisistä naisista. Munasarjasyöpää, kilpirauhassyöpää ja ihomelanoomaa on todettu hieman useammin ja kohdunkaulasyöpää esiastemuutoksineen hieman harvemmin kuin muilla naisilla. Uuden suomalaistutkimuksen perusteella näyttää siltä, että suurentunut munasarjasyöpäriski liittyy vain munasarjan endometrioosiin.
  • Peippo, Minna; Gardberg, Maria; Lamminen, Tarja; Kaipio, Katja; Carpen, Olli; Heuser, Vanina D. (2017)
    The functional properties of actin-regulating formin proteins are diverse and in many cases cell-type specific. FHOD1, a formin expressed predominantly in cells of mesenchymal lineage, bundles actin filaments and participates in maintenance of cell shape, migration and cellular protrusions. FHOD1 participates in cancer associated epithelial to mesenchymal transition (EMT) in oral squamous cell carcinoma and breast cancer. The role of FHOD1 in melanomas has not been characterized. Here, we show that FHOD1 expression is typically strong in cutaneous melanomas and cultured melanoma cells while the expression is low or absent in benign nevi. By using shRNA to knockdown FHOD1 in melanoma cells, we discovered that FHOD1 depleted cells are larger, rounder and have smaller focal adhesions and inferior migratory capacity as compared to control cells. Importantly, we found FHOD1 depleted cells to have reduced colony-forming capacity and attenuated tumor growth in vivo, a finding best explained by the reduced proliferation rate caused by cell cycle arrest. Unexpectedly, FHOD1 depletion did not prevent invasive growth at the tumor margins. These results suggest that FHOD1 participates in key cellular processes that are dysregulated in malignancy, but may not be essential for melanoma cell invasion.
  • Arasu, Uma Thanigai; Deen, Ashik Jawahar; Pasonen-Seppänen, Sanna; Heikkinen, Sami; Lalowski, Maciej; Kärnä, Riikka; Härkönen, Kai; Mäkinen, Petri; Lazaro-Ibañez, Elisa; Siljander, Pia R-M; Oikari, Sanna; Levonen, Anna-Liisa; Rilla, Kirsi (2020)
    Intercellular communication is fundamental to the survival and maintenance of all multicellular systems, whereas dysregulation of communication pathways can drive cancer progression. Extracellular vesicles (EVs) are mediators of cell-to-cell communication that regulate a variety of cellular processes involved in tumor progression. Overexpression of a specific plasma membrane enzyme, hyaluronan synthase 3 (HAS3), is one of the factors that can induce EV shedding. HAS3, and particularly its product hyaluronan (HA), are carried by EVs and are known to be associated with the tumorigenic properties of cancer cells. To elucidate the specific effects of cancerous, HAS3-induced EVs on target cells, normal human keratinocytes and melanoma cells were treated with EVs derived from GFP-HAS3 expressing metastatic melanoma cells. We found that the HA receptor CD44 participated in the regulation of EV binding to target cells. Furthermore, GFP-HAS3-positive EVs induced HA secretion, proliferation and invasion of target cells. Our results suggest that HAS3-EVs contains increased quantities of IHH, which activates the target cell hedgehog signaling cascade and leads to the activation of c-Myc and regulation of claspin expression. This signaling of IHH in HAS3-EVs resulted in increased cell proliferation. Claspin immunostaining correlated with HA content in human cutaneous melanocytic lesions, supporting our in vitro findings and suggesting a reciprocal regulation between claspin expression and HA synthesis. This study shows for the first time that EVs originating from HAS3 overexpressing cells carry mitogenic signals that induce proliferation and epithelial-to-mesenchymal transition in target cells. The study also identifies a novel feedback regulation between the hedgehog signaling pathway and HA metabolism in melanoma, mediated by EVs carrying HA and IHH.
  • Isoherranen, Kirsi; Tolkki, Lauri; Salava, Alexander (2022)
    • Ihokoepalan tutkimus on kustannustehokas ja informatiivinen, mutta sen virhemahdollisuudet tulee tunnistaa. • Ottokohdan valinnalla on suuri vaikutus diagnostiseen osuvuuteen, ja siksi on hyvä muodostaa etukäteen työdiagnoosi. • Tulkintavirheitä pystytään estämään lähetteen hyvillä esitiedoilla ja ottamalla leesiosta valokuva. • Koepalavastaus tulee aina suhteuttaa kliiniseen kuvaan.
  • Mattila, Kalle; Mäkelä, Siru; Hernberg, Micaela; Vihinen, Pia (2018)
    Immuuniaktivaation vapauttajat ovat uusia syöpälääkkeitä, joiden haittavaikutuksena voi ilmaantua tulehduksia. Jos päivystyspotilasta on hoidettu näillä lääkkeillä, hänen oireitaan tulee epäillä lääkkeen haittavaikutuksiksi, kunnes toisin on osoitettu. Samanaikainen infektio on mahdollinen.
  • Rousi, Emma K.; Kallionpää, Roope A.; Kallionpää, Roosa E.; Juteau, Susanna M.; Talve, Lauri A.; Hernberg, Micaela M.; Vihinen, Pia P.; Kähäri, Veli-Matti; Koskivuo, Ilkka O. (2022)
    Background Changes in the incidence of melanoma in children and adolescents have been reported in Europe and in the USA in the recent decades. Aims The aim of this study was to examine the incidence of paediatric and adolescent melanomas in Finland in 1990-2014, and the associated clinical and histopathological characteristics to reveal temporal trends, such as changes in diagnostic sensitivity of Spitzoid melanomas. Methods Information on 122 patients diagnosed with cutaneous melanoma at 0-19 years of age in Finland in 1990-2014 were retrieved from the Finnish Cancer Registry. 73 primary melanoma archival samples were re-evaluated by two dermatopathologists to allow comparability over time. Results A 5.6% annual increase was observed in the incidence of melanoma among children and adolescents during the study period. Fifty-six tumours were confirmed as malignant melanomas in the re-evaluation. After correction for tumour misclassification in the Cancer Registry, the age-adjusted annual incidence was estimated to have increased from 1.4/1 000 000 in 1990-1994 to 5.8/1 000 000 in 2010-2014. The change in incidence was most prominent among adolescents and in Spitzoid melanoma subtype. Melanomas diagnosed 1990-2002 and 2003-2014 did not differ in terms of their clinicopathological characteristics or prognosis (hazard ratio for melanoma-related death 1.53, 95% CI 0.30 to 7.88). Spitzoid melanomas were diagnosed at a younger age, were of higher stage and had higher Clark level than other melanomas, yet the hazard ratio for death was 0.52 (95% CI 0.10 to 2.58) for Spitzoid versus other melanomas. Conclusions The incidence of cutaneous melanoma has clearly increased among the young in Finland, especially among adolescents. No evidence for overdiagnosis of Spitzoid melanomas as the underlying cause of the increased incidence was observed. Key message A nationwide retrospective re-evaluation of the cutaneous melanomas recorded in the Finnish Cancer Registry among patients aged 0-19 years in Finland in 1990-2014 revealed an approximately 4-fold increase in the incidence. The increase in the incidence was most prominent among adolescents and in the Spitzoid melanoma subtype. Our results contrast those reported in other countries, where the incidence of melanoma among adolescents has declined.
  • Bolomsky, Arnold; Vogler, Meike; Köse, Murat C; Heckman, Caroline A.; Ehx, Grégory; Ludwig, Heinz; Caers, Jo (BioMed Central, 2020)
    Abstract Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.
  • Bolomsky, Arnold; Vogler, Meike; Kose, Murat Cem; Heckman, Caroline A.; Ehx, Gregory; Ludwig, Heinz; Caers, Jo (2020)
    Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.
  • Vuoristo, Meri-Sisko; Mäkelä, Siru; Nores, Marja; Bouchard, Laura; Koulu, Leena (2017)