Local treatment of a pleural mesothelioma tumor with ONCOS-102 induces a systemic antitumor CD8(+) T-cell response, prominent infiltration of CD8(+) lymphocytes and Th1 type polarization

Peer reviewe

Gene expression analysis of tumors demonstrates an induction of Th1 type immune response following intratumoral administration of ONCOS-102 in refractory solid tumor patients

2014-11-0

Phase I study with ONCOS-102 for the treatment of solid tumors - an evaluation of clinical response and exploratory analyses of immune markers

Peer reviewe

Mechanisms influencing activation and survival of normal and malignant lymphoid cells in the testis

Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy and the testis is the third most common site of relapse after treatment. Testicular function is regulated by pituitary hormones, but the testicular microenvironment is also locally regulated through cell-cell interactions and by paracrine factors. Such factors could be of importance for the tendency for testicular relapse of ALL. The aim of this thesis was to obtain a better understanding of the contribution of testicular paracrine factors to the tendency for relapse of treated childhood ALL. Seminiferous tubules were shown to produce factors that inhibit lymphocyte proliferation in a stage related way. The characteristics of these factors indicate that they could be isoforms or multimers of bioactive transforming growth factor beta (TGFbeta). Seminiferous tubule extracts contain a factor that showed response in the CCL-64 mink lung epithelial cell line TGFbeta bioassay, indicating that the factor was TGFbeta. Neutralizing TGFbeta antibodies could reverse suppression of lymphocyte proliferation induced by testis protein extracts as further evidence that the activity is mediated by TGFbeta. TGFbeta dose-dependently inhibited rat testicular interleukin-1 (IL-1) driven proliferation in a mouse thymocyte IL-1 bioassay and polyclonal mitrogen stimulated rat PBL proliferation. In co-cultures, Leydig cells suppressed polyclonal mitogen induced lymphocyte proliferation and suppressed recombinant IL-1alpha and IL-1beta as well as rat testicular IL-1alpha bioactivity in a mouse thymocyte IL-1 bioassay. The suppressive effect was not mediated by testosterone. A single injection of hCG induces a rapid surge of expression of pro-inflammatory cytokines in the rat testis. The reaction was not detectable in Leydig cell depleted rats, confirming that this inflammatory reaction is hormonally regulated and mediated via hypophyseal hormonal regulation of Leydig cells. As has been previously shown, this acute reaction can be mimicked by testicular injection of IL-1beta but not IL-1alpha. IL-1beta was detectable in macrophages but not in Leydig cells after hCG dosing, indicating that Leydig cells can regulate inflammatory responses by activation of macrophages in the testis. Using a rat leukaemia model and human leukaemic cells recovered from patients with childhood leukaemia, we could demonstrate that leukaemic cell proliferation can be regulated by testicular constitutive factors. In conclusion, the present data suggest that testicular proteins can influence proliferation of normal as well as malignant lymphocytes. In the present study IL-1 and TGFbeta have been especially implicated - IL-1 as a proliferation-inducing factor and TGFbeta as a proliferation suppressive factor that might render malignant lymphocytes less sensitive to cytotoxic effects of chemotherapy. Production of such factors is, at least in part, under hormonal regulation by pituitary hormones. These results support a role for the testicular paracrine factors in the tendency for testicular relapse of ALL

Relationship between functional disability and costs one and two years post stroke.

BACKGROUND AND PURPOSE:Stroke affects mortality, functional ability, quality of life and incurs costs. The primary objective of this study was to estimate the costs of stroke care in Sweden by level of disability and stroke type (ischemic (IS) or hemorrhagic stroke (ICH)). METHOD:Resource use during first and second year following a stroke was estimated based on a research database containing linked data from several registries. Costs were estimated for the acute and post-acute management of stroke, including direct (health care consumption and municipal services) and indirect (productivity losses) costs. Resources and costs were estimated per stroke type and functional disability categorised by Modified Rankin Scale (mRS). RESULTS:The results indicated that the average costs per patient following a stroke were 350,000SEK/€37,000-480,000SEK/€50,000, dependent on stroke type and whether it was the first or second year post stroke. Large variations were identified between different subgroups of functional disability and stroke type, ranging from annual costs of 100,000SEK/€10,000-1,100,000SEK/€120,000 per patient, with higher costs for patients with ICH compared to IS and increasing costs with more severe functional disability. CONCLUSION:Functional outcome is a major determinant on costs of stroke care. The stroke type associated with worse outcome (ICH) was also consistently associated to higher costs. Measures to improve function are not only important to individual patients and their family but may also decrease the societal burden of stroke

Sex as predictor for achieved health outcomes and received care in ischemic stroke and intracerebral hemorrhage : A register-based study

Background: Differences in stroke care and health outcomes between men and women are debated. The objective of this study was to explore the relationship between patients' sex and post-stroke health outcomes and received care in a Swedish setting. Methods: Patients with a registered diagnosis of acute intracerebral hemorrhage (ICH) or ischemic stroke (IS) within regional administrative systems (ICD-10 codes I61∗or I63∗) and the Swedish Stroke Register during 2010-2011 were included and followed for 1 year. Data linkage to multiple other data sources on individual level was performed. Adjustments were performed for age, socioeconomic factors, living arrangements, ADL dependency, and stroke severity in multivariate regression analyses of health outcomes and received care. Health outcomes (e.g., survival, functioning, satisfaction) and received care measures (regional and municipal resources and processes) were studied. Results: Study population: 13,775 women and 13,916 men. After case-mix adjustments for the above factors, we found women to have higher 1-year survival rates after both IS (ORfemale = 1.17, p < 0.001) and ICH (ORfemale = 1.65, p < 0.001). Initial inpatient stay at hospital was, however, shorter for women (β female, IS = - 0.05, p < 0.001; β female, ICH = - 0.08, p < 0.005). For IS, good function (mRS ≤ 2) was more common in men (ORfemale = 0.86, p < 0.001) who also received more inpatient care during the first year (β female = - 0.05, p < 0.001). Conclusions: A lower proportion of women had good functioning, a difference that remained in IS after adjustments for age, socioeconomic factors, living arrangements, ADL dependency, and stroke severity. The amount of received hospital care was lower for women after adjustments. Whether shorter hospital stay results in lower function or is a consequence of lower function cannot be elucidated. One-year survival was higher in men when no adjustments were made but lower after adjustments. This likely reflects that women were older at time of stroke, had more severe strokes, and more disability pre-stroke - factors that make a direct comparison between the sexes intricate

Additional file 1: of Sex as predictor for achieved health outcomes and received care in ischemic stroke and intracerebral hemorrhage: a register-based study

Table S1. Study outcomes stratified by sex, 95% CI. Table S2. Analysis population sizes and p values from multivariate regression analyses. (DOCX 29 kb