Browsing by Subject "oncology"

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  • Zafar, Sadia (Helsingin yliopisto, 2021)
    Dendritic cells (DCs) are the sentinels of the immune system and are specialized in initiating adaptive immune responses by presenting foreign antigens to T cells. Thus, dendritic cells are critical regulators of immune responses and accordingly have been a focus of cancer immunotherapy research. DC therapy is considered as a promising approach in cancer immunotherapy. However, DC-based vaccines have shown limited efficacy in clinical trials. Oncolytic adenovirus replicates and lyses only cancer cells. Virus-mediated lysis of cancer cells also induces danger signals and exposes tumor epitopes that promote immune system activation against cancer. This study investigated the oncolytic adenovirus 3 coding for CD40 Ligand: Ad3-hTERT-CMV-CD40L (also known as TILT-234) as an enhancer of DC therapy. In the first study, human cancer patient data suggested that intravenous adenovirus administration is able to transduce distant tumors and virally-produced CD40L can activate DCs in situ. Studies with mice suggested that the virus possesses potent antitumor activity. In the second study, treatment with Ad3-hTERT-CMV-CD40L and DCs showed 100% survival of humanized mice and resulted in greater antitumor efficacy than either approach as monotherapy. The third study focused on the treatment of prostate cancer. In this study, treatment with companion therapy (i.e. Ad3-hTERT-CMV-CD40L and DC therapy) was shown to induce greater antitumor immune responses in vivo and in established prostate cancer histocultures. In the fourth study, we focused on the interaction of a chimeric adenovirus Ad5/3 with human lymphocytes and erythrocytes. This study showed that the binding of Ad5/3 with human lymphocytes and erythrocytes occurs in a reversible manner, which enables the virus to transduce different tumors and to retain oncolytic potency both in vitro and in vivo, with or without neutralizing antibodies. In summary, the first three studies demonstrated the ability of Ad3-hTERT-CMV-CD40L to modulate the tumor microenvironment and that local delivery of CD40L is safe and efficient regarding DC therapy. In conclusion, Ad3-hTERT-CMV-CD40L was shown to be a potential enabler of DC therapy. The fourth study revealed the ability of a chimeric Ad5/3 adenovirus to transduce non-injected tumors through blood, even in the presence of neutralizing antibodies.
  • Galluzzi, Lorenzo; Vitale, Ilio; Warren, Sarah; Adjemian, Sandy; Agostinis, Patrizia; Martinez, Aitziber Buqué; Chan, Timothy A; Coukos, George; Demaria, Sandra; Deutsch, Eric; Draganov, Dobrin; Edelson, Richard L; Formenti, Silvia C; Fucikova, Jitka; Gabriele, Lucia; Gaipl, Udo S; Gameiro, Sofia R; Garg, Abhishek D; Golden, Encouse; Han, Jian; Harrington, Kevin J; Hemminki, Akseli; Hodge, James W; Hossain, Dewan Md Sakib; Illidge, Tim; Karin, Michael; Kaufman, Howard L; Kepp, Oliver; Kroemer, Guido; Lasarte, Juan Jose; Loi, Sherene; Lotze, Michael T; Manic, Gwenola; Merghoub, Taha; Melcher, Alan A; Mossman, Karen L; Prosper, Felipe; Rekdal, Øystein; Rescigno, Maria; Riganti, Chiara; Sistigu, Antonella; Smyth, Mark J; Spisek, Radek; Stagg, John; Strauss, Bryan E; Tang, Daolin; Tatsuno, Kazuki; van Gool, Stefaan W; Vandenabeele, Peter; Yamazaki, Takahiro; Zamarin, Dmitriy; Zitvogel, Laurence; Cesano, Alessandra; Marincola, Francesco M (2020)
    Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
  • Vähäaho, Niina (Helsingin yliopisto, 2018)
    Background and objectives: Currently in Finland, there are over 66 000 women living with breast cancer. The five-year survival rate is 90.6 %. Breast cancer and its treatments are known to impair patients’ health-related quality of life (HRQoL). The current study is a part of an open prospective randomized Breast cancer and exercise (BREX) -study in Finland conducted to investigate whether supervised exercise training shortly after the adjuvant treatments of breast cancer patients could prevent osteoporosis and improve patient’s quality of life. This master thesis examines cross-sectional and prospective associations between the sense of coherence (SOC) and the HRQoL of breast cancer survivors. Methods: 537 long-term breast cancer survivors and controls who participated in a prospective randomized physical exercise intervention with twelve months of supervised exercise training were followed up five years. 406 participants who finished the 5-year follow-up and filled the SOC questionnaire were included in the final analyzes. The SOC was measured by 13-item Finnish and Swedish short forms of Orientation to life Questionnaire (SOC-13) at 3 years. Cancer-specific HRQoL was measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) version 3 and general HRQoL by the 15D. Associations between the SOC and the HRQoL were studied by logistic regression analyze. Results and conclusion: The SOC was associated with the cancer-specific and the general HRQoL at the 3-year (p < .001) and at the 5-year follow-up (p < .001). The relationship was the most significant for the general HRQoL, global health / quality of life and emotional and cognitive functions. Weak SOC increases the risk of low cancer-specific and low general HRQoL after the adjuvant treatments of breast cancer. Strong SOC as an inner resource may serve as a protective psychological factor in the adaptation process of breast cancer survivors. The SOC-13 questionnaire might be useful in targeting patients vulnerable to decrease in the HRQoL and in planning psychosocial interventions.
  • Pemovska, Tea (Helsingin yliopisto, 2015)
    Adult acute myeloid leukemia (AML) effectively illustrates the challenges of contemporary cancer drug discovery and development, as molecularly targeted therapies have not yet been translated in clinical practice. In fact the standard therapy (cytarabine and an anthracycline) for AML has not been changed in over 40 years. As a consequence, outcome remains poor with overall survival of 30-40%. The genetic alterations that are associated with AML have been mapped, but the underlying disease mechanism is poorly defined due to large inter-patient heterogeneity. In contrast, chronic myeloid leukemia (CML) is strictly driven by BCR-ABL1 and drugs targeting the ABL1 kinase activity have paved the way for oncoprotein targeting drugs in the treatment of cancer. In CML the main clinical challenge is instead the emergence of resistance to ABL1-directed therapy. This resistance typically occurs through point mutations in the kinase domain of ABL1 such as the clinically challenging T315I mutation. Hence, in both leukemia types there is an unmet need for novel therapeutic strategies. This study focused on development and implementation of an Individualized Systems Medicine (ISM) platform to identify novel therapeutic strategies for leukemia patients. The ISM strategy incorporated functional ex vivo drug sensitivity and resistance testing (DSRT), deep molecular profiling and clinical information to facilitate identification of personalized therapy approaches. A large number of approved and investigational anti-cancer compounds were tested and individualized selective responses were quantified with drug sensitivity scores (DSS). RNA and exome sequencing data was used to identify genetic alterations that enabled associating drug sensitivities with genetic alterations and biomarkers. The DSRT approach enabled functional taxonomy of AML patient samples based on drug responses, provided insights into disease biology, and identified effective drugs and drug combinations for individual patients and thus facilitated drug repurposing. In addition, integration of DSRT and molecular data identified phenotype to genotype links that has a potential for rapid translation of results. Clinical implementation of ISM data was plausible in approximately 80% of relapsed and refractory AML patient cases, and meaningful and evaluable responses were achieved in approximately 40% of cases. Notably, emergence of in vivo resistance to targeted therapy was mirrored in the DSRT profile of the relapsed samples, highlighting a solid correlation between ex vivo and in vivo drug responses. Finally, this study identified a number of kinase inhibitors that can be repositioned for specific subtypes of AML and CML, such as dasatinib in combination with a FLT3 inhibitor for AML patients with FLT3-ITD mutations and axitinib for patients with BCR-ABL1(T315I)-driven leukemia. The results of this thesis demonstrate how unbiased drug sensitivity profiling of patient-derived cancer cells is a powerful way to discern unforeseen drug-disease and drug-target links with clinical implications and provides a workable concept that can be implemented in routine clinical care of cancer patients in the future.
  • Saijonmaa, Oskar (Helsingin yliopisto, 2021)
    Medulloblastom (MB) är den vanligaste maligna hjärtumören inom pediatrin och omfattar 63% av intrakraniella embryonala tumörer hos barn. Insidensnivån ligger globalt kring 0.7 fall per 100 000 invånare och medianåldern för diagnosen är 6 år. Tumören ligger i den bakre skallgropen och kan potentiellt spridas leptomeningealt. Vården är en kombination av kirurgi, intrakraniell bestrålning och cytostatikavård. Prognosen varierar enligt kliniska och molekylära riskgruppen, men den totala 5- års överlevnaden ligger kring 70-80%. Symptomen vid diagnos är icke-specifika och inkluderar bl.a. illamående, motorisk klumpighet och andra neurologiska fynd. Diagnosen ställs m.h.a. magnetröntgen (MRI) samt molekylära och histologiska prov. Denna studie kartlägger överlevnaden av patienter vårdade inom HUS-området mellan åren 2000 och 2020. Materialet utgjordes av 32 patienter som indelades i två riskgrupper enligt s.k. Chang’s kriterier. Datainsamlingen gjordes rakt från patientjournaler. Överlevnaden jämfördes mellan grupperna och analyserades m.h.a Kaplan-Meier metoden på SPSS. Av 32 patienter var 19 indelade i standard risk- gruppen (SR) och 13 i gruppen med sämre prognos, d.v.s high risk- gruppen (HR). 5-årsöverlevnaden i SR- gruppen var 84.6% och i HR- gruppen 61.5%. 5-årsöverlevnaden för hela kohorten blev 73.9%. Undersökningen påvisar att överlevnaden förblir sämre i den högre riskgruppen och hos patienter med subtotal kirurgisk resektion. Därutöver ser vi att överlevnaden inom båda grupperna ligger på internationell nivå och att SR-gruppen dessutom har en gynnsammare överlevnad inom HUS-området jämförelsevis med internationella resultat.
  • Alabi, Rasheed Omobolaji; Hietanen, Päivi; Elmusrati, Mohammed; Youssef, Omar; Almangush, Alhadi; Mäkitie, Antti A. (2021)
    Objectives: The purpose of this study was to provide a scoping review on how to address and mitigate burnout in the profession of clinical oncology. Also, it examines how artificial intelligence (AI) can mitigate burnout in oncology. Methods: We searched Ovid Medline, PubMed, Scopus, and Web of Science, for articles that examine how to address burnout in oncology. Results: A total of 17 studies were found to examine how burnout in oncology can be mitigated. These interventions were either targeted at individuals (oncologists) or organizations where the oncologists work. The organizational interventions include educational (psychosocial and mindfulness-based course), art therapies and entertainment, team-based training, group meetings, motivational package and reward, effective leadership and policy change, and staff support. The individual interventions include equipping the oncologists with adequate training that include—communication skills, well-being and stress management, burnout education, financial independence, relaxation, self-efficacy, resilience, hobby adoption, and work-life balance for the oncologists. Similarly, AI is thought to be poised to offer the potential to mitigate burnout in oncology by enhancing the productivity and performance of the oncologists, reduce the workload and provide job satisfaction, and foster teamwork between the caregivers of patients with cancer. Discussion: Burnout is common among oncologists and can be elicited from different types of situations encountered in the process of caring for patients with cancer. Therefore, for these interventions to achieve the touted benefits, combinatorial strategies that combine other interventions may be viable for mitigating burnout in oncology. With the potential of AI to mitigate burnout, it is important for healthcare providers to facilitate its use in daily clinical practices. Conclusion: These combinatorial interventions can ensure job satisfaction, a supportive working environment, job retention for oncologists, and improved patient care. These interventions could be integrated systematically into routine cancer care for a positive impact on quality care, patient satisfaction, the overall success of the oncological ward, and the health organizations at large.
  • De Santis, Ilaria; Tasnadi, Ervin; Horvath, Peter; Bevilacqua, Alessandro; Piccinini, Filippo (2019)
    Featured Application The main goal of this work is to provide an overview of open-source tools available for researchers interested in estimating the volume of 3D multicellular aggregates (e.g., spheroids, organoids), besides introducing a new version of the Reconstruction and Visualization from Multiple Sections (ReViMS) tool (http://sourceforge.net/p/revims). Abstract The volume is one of the most relevant features that define the treatment of an in vivo tumour. When using cancer 3D in vitro models in pre-clinical studies, it becomes important to evaluate the macroscopic effects of drugs and radiotherapy treatments. Depending on the nature of the 3D in vitro model used, different open-source solutions can be used for measuring the volume by starting from microscope-acquired images. In this work, we introduced several open-source tools today available for estimating the volume of 3D multicellular aggregates (e.g., spheroids, organoids), also giving hints for defining the best software by analysing characteristics of 3D in vitro models and limits of the tools. Finally, using several cancer organoids imaged by a fluorescent microscope, we compared volume estimations obtained with different tools, besides presenting a new version of the Reconstruction and Visualization from Multiple Sections (ReViMS version 2.0) tool. This work aims to be the reference for researchers interested in estimating the volume of 3D multicellular aggregates through an open-source tool.
  • Dogrusoz, Mehmet; Brouwer, Niels J.; de Geus, Stefan J. R.; Ly, Long; Böhringer, Stefan; van Duinen, Sjoerd G.; Kroes, Wilma G. M.; van der Velden, Pieter A.; Haasnoot, Geert W.; Marinkovic, Marina; Luyten, Gregorius P. M.; Kivelä, Tero T.; Jager, Martine J. (2020)
    PURPOSE. A subgroup of uveal melanoma (UM) gives rise to metastases at a late stage. Our objective was to identify patient and tumor characteristics that are associated with UM-related death in patients who survived 5 years following enucleation. METHODS. A retrospective analysis was performed in 583 primary UM cases, enucleated at the Leiden University Medical Center between 1983 and 2013. Univariable and multivariable Cox regression analyses were performed in the total cohort and separately in those surviving more than 5 years (n = 297). RESULTS. In the total cohort, the median age was 62.6 years, and the median tumor diameter was 12.0 mm. Monosomy 3 was detected in 53% of cases and gain of 8q in 47%. In the cohort surviving 5 years, the median age was 59.5 years, and the median tumor diameter was 11.0 mm. Monosomy 3 and gain of 8q were detected in 33% and 31% of cases, respectively. In the total cohort, male gender (P = 0.03), tumor diameter (P <0.001), mitotic count (P <0.001), extravascular matrix loops (P = 0.03), extraocular growth (P <0.001), and gain of 8q (P <0.001) were independently associated with UM-related death. In patients surviving 5 years after enucleation, univariable analysis revealed that age (P = 0.03), tumor diameter (P <0.001), monosomy 3 (P = 0.04), and 8q gain (P = 0.003) were associated with subsequent UM-related death. Using a multivariable analysis, only male gender (P = 0.03) and gain of 8q (P = 0.01) remained significant. CONCLUSIONS. Predictors of UM-related death change over time. Among UM patients who survived the initial 5 years following enucleation, male gender and chromosome 8q status were the remaining factors related to UM-related death later on.
  • Karihtala, Peeter; Jaaskelainen, Anniina; Roininen, Nelli; Jukkola, Arja (2021)
    Objectives Being either young or old at the time of breast cancer diagnosis has been suggested as an indicator of a poor prognosis. We studied the effect of age at breast cancer onset in relation to survival, focusing in particular on biological subtypes and reproductive anamnesis. Design, setting and participants Patients with early breast cancer (n=594) treated in a Finnish University Hospital during 2003-2013 were prospectively collected and followed in median 102 months. Results Patients with luminal A-like breast cancer were older than the patients with luminal B-like (HER2-positive) (p=0.045) or patients with the HER2-positive (non-luminal) subtype (p=0.029). Patients >= 70 years received substantially less adjuvant chemotherapy (p=1.5x10(-9)) and radiotherapy (p=5.9x10(-7)) than younger women. Nevertheless, the estimated 10-year breast cancer-specific rates of survival were 84.2%, 92.9% and 87.0% in age groups = 70 years, respectively, with no statistical difference (p=0.115). Survival rates were also comparable between the three age groups when assessed separately in different biological subtypes, and for patients with metastatic breast cancer there was similarly no difference between the age groups. Later menarche (p=5.7x10(-8)) and high parity (p=0.000078) correlated with increased age at breast cancer diagnosis, but, according to the patients' oestrogen receptor (ER) status, only among ER-positive patients. Conclusions Despite the suggested undertreatment of older patients, we report excellent long-term outcomes in all age groups in this prospective cohort. Later endogenous endocrine exposure may cause delay in breast cancer onset, but the exact biology behind this phenomenon is so far unclear.