Optimal Use of Treatment Modalities and Treatment Results of Osteosarcoma and Soft Tissue Sarcomas

Soft tissue sarcomas are malignant tumours of mesenchymal origin. Because of infiltrative growth pattern, simple enucleation of the tumour causes a high rate of local recurrence. Instead, these tumours should be resected with a rim of normal tissue around the tumour. Data on the adequate margin width are scarce. At Helsinki University Central Hospital (HUCH) a multidisciplinary treatment group started in 1987. Surgical resection with a wide margin (2.5 cm) is the primary aim. In case of narrower margin radiation therapy is necessary. The role of adjuvant chemotherapy remains unclear. Our aims were to study local control by the surgical margin and to develop a new prognostic tool to aid decision-making on which patients should receive adjuvant chemotherapy. Patients with soft tissue sarcoma of the extremity or the trunk wall referred to HUCH during 1987-2002 form material in Studies I and II. External validation material comes from the Lund university sarcoma registry. The smallest surgical margin of at least 2.5 centimetres yielded local control of 89 per cent at five years. Amputation rate was 9 per cent. The proposed prognostic model with necrosis, vascular invasion, size on a continuous scale, depth, location and grade worked well both in Helsinki material and in the validation material, and it also showed good calibration. Based on the present study, we recommend the smallest surgical margin of 2-3 centimetres in soft tissue sarcoma irrespective of grade. Improvement in local control was present but modest in margins wider than 1 centimetre. In cases where gaining a wider margin would lead to a considerable loss of function, smaller margin is to be considered combined to radiation therapy. Patients treated with inadequate margins should be offered radiation therapy irrespective of tumour grade. Our new prognostic model to estimate 10-year survival probability in patients with soft tissue sarcoma of the extremities or trunk wall showed good dicscrimination and calibration. For time being the prognostic model is available for scientific use and further validations. In the future, the model may aid in clinical decision-making. For operable osteosarcoma, neoadjuvant multidrug chemotherapy followed by delayed surgery and multidrug adjuvant chemotherapy is the treatment of choice. Overall survival rates at five years are approximately 75 per cent in modern trials with classical osteosarcoma. All patients diagnosed and reported to the Finnish Cancer Registry with osteosarcoma in Finland during 1971-2005 form the material in Studies III and IV. Limb-salvage rate increased from 23 per cent to 78 per cent during 1971-2005. The 10-year sarcoma-specific survival for the whole study population improved from 32 per cent to 62 per cent. It was 75 per cent for patients with a local high-grade osteosarcoma of the extremity diagnosed during 1991-2005. This study outlines the improved prognosis of osteosarcoma patients in Finland with modern chemotherapy. The 10-year survival rates are good also in an international scale. Nonetheless, their limb-salvage rate remains inferior to those seen for highly selected patient series. Overall, the centralisation of osteosarcoma treatment would most likely improve both survival and limb-salvage rates even further.

Myoblast Sheet Transplantation for Treatment of Heart Failure after Myocardial Infarction

Heart failure is a common, severe, and progressive condition associated with high mortality and morbidity. Because of population-aging in the coming decades, heart failure is estimated to reach epidemic proportions. Current medical and surgical treatments have reduced mortality, but the prognosis for patients has remained poor. Transplantation of skeletal myoblasts has raised hope of regenerating the failing heart and compensating for lost cardiac contractile tissue. In the present work, we studied epicardial transplantation of tissue-engineered myoblast sheets for treatment of heart failure. We employed a rat model of myocardial infarction-induced acute and chronic heart failure by left anterior descending coronary artery ligation. We then transplanted myoblast sheets genetically modified to resist cell death after transplantation by expressing antiapoptotic gene bcl2. In addition, we evaluated the regenerative capacity of myoblast sheets expressing the cardioprotective cytokine hepatocyte growth factor in a rat chronic heart failure model. Furthermore, we utilized in vitro cardiomyocyte and endothelial cell culture models as well as microarray gene expression analysis to elucidate molecular mechanisms mediating the therapeutic effects of myoblast sheet transplantation. Our results demonstrate that Bcl2-expression prolonged myoblast sheet survival in rat hearts after transplantation and induced secretion of cardioprotective, proangiogenic cytokines. After acute myocardial infarction, these sheets attenuated left ventricular dysfunction and myocardial damage, and they induced therapeutic angiogenesis. In the chronic heart failure model, inhibition of graft apoptosis by Bcl-2 improved cardiac function, supported survival of cardiomyocytes in the infarcted area, and induced angiogenesis in a vascular endothelial growth factor receptor 1- and 2-dependent mechanism. Hepatocyte growth factor-secreting myoblast sheets further enhanced the angiogenic efficacy of myoblast sheet therapy. Moreover, myoblast-secreted paracrine factors protected cardiomyocytes against oxidative stress in an epidermal growth factor receptor- and c-Met dependent manner. This protection was associated with induction of antioxidative genes and activation of the unfolded protein response. Our results provide evidence that inhibiting myoblast sheet apoptosis can enhance the sheets efficacy for treating heart failure after acute and chronic myocardial infarction. Furthermore, we show that myoblast sheets can serve as vehicles for delivery of growth factors, and induce therapeutic angiogenesis in the chronically ischemic heart. Finally, myoblasts induce, in a paracine manner, a cardiomyocyte-protective response against oxidative stress. Our study elucidates novel mechanisms of myoblast transplantation therapy, and suggests effective means to improve this therapy for the benefit of the heart failure patient.

Social and material deprivation among youth in Finland : causes, consequences, and coping.

Background: Social and material deprivation is associated with poor health, decreased subjective well-being, and limited opportunities for personal development. To date, little is known about the lived experiences of Finnish low-income youths and the general purpose of this study is to fill this gap. Despite the extensive research on socioeconomic income disparities, only a few scholars have addressed the question of how low socioeconomic position is experienced by disadvantaged people themselves. Little is known about the everyday social processes that lead to decreased well-being of economically and socially disadvantaged citizens. Data: The study is based on the data of 65 autobiographical essays written by Finnish low-income youths aged 14-29 (M=23.51, SD=3.95). The research data were originally collected in a Finnish nationwide writing contest “Arkipäivän kokemuksia köyhyydestä” [Everyday Experiences of Poverty] between June and September of 2006. The contest was partaken by 850 Finnish writers. Methods and key concepts: Autobiographical narratives (N=65) of low-income youths were analyzed based on grounded theory methodology (GTM). The analysis was not built on specific pre-conceived categorizations; it was guided by the paradigm model and so-called “sensitizing concepts”. The concepts this study utilized were based on the research literature on socioeconomic inequalities, resilience, and coping. Socioeconomic inequalities refer to unequal distribution of resources, such as income, social status, and health, between social groups. The concept of resilience refers to an individual’s capacity to cope despite existing risk factors and conditions that are harmful to health and well-being. Coping strategies can be understood as ways by which a person tries to cope with psychological stress in a situation where internal or externals demands exceed one’s resources. The ways to cope are cognitive or behavioral efforts by which individual tries to relieve the stress and gain new resources. Lack of material and social resources is associated with increased exposure to health-related stressors during the life-course. Aims: The first aim of this study is to illustrate how youths with low socioeconomic status perceive the causes and consequences of their social and material deprivation. The second aim is to describe what kind of coping strategies youths employ to cope in their everyday life. The third aim is to build an integrative conceptual framework based on the relationships between causes, consequences, and individual coping strategies associated with deprivation. The analysis was carried out through systematic coding and orderly treatment of the data based on the grounded theory methodology. Results: Finnish low-income youths attributed the primary causes of deprivation to their family background, current socioeconomic status, sudden life changes, and contextual factors. Material and social deprivation was associated with various kinds of negative psychological, social, and material consequences. Youths used a variety of coping strategies that were identified as psychological, social, material, and functional-behavioral. Finally, a conceptual framework was formulated to link the findings together. In the discussion, the results were compared and contrasted to the existing research literature. The main references of the study were: Coping: Aldwin (2007); Lazarus & Folkman (1984); Hobfoll (1989, 2001, 2002). Deprivation: Larivaara, Isola, & Mikkonen (2007); Lister (2004); Townsend (1987); Raphael (2007). Health inequalities: Dahlgren & Whitehead (2007); Lynch. et al. (2000); Marmot & Wilkinson (2006); WHO (2008). Methods: Charmaz (2006); Flick (2009); Strauss & Corbin (1990). Resilience: Cutuli & Masten (2009); Luthar (2006).