Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
Add more filters










Database
Language
Publication year range
1.
Radiother Oncol ; 196: 110277, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38670264

ABSTRACT

Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical knowledge and enabled effective cancer treatment to date. Remarkable advances in technology, computing, and experimental biology now create opportunities to incorporate this knowledge into enhanced computational models. The ESTRO DREAM (Dose Response, Experiment, Analysis, Modelling) workshop brought together experts across disciplines to pursue the vision of personalized radiotherapy for optimal outcomes through advanced modelling. The ultimate vision is leveraging quantitative models dynamically during therapy to ultimately achieve truly adaptive and biologically guided radiotherapy at the population as well as individual patient-based levels. This requires the generation of models that inform response-based adaptations, individually optimized delivery and enable biological monitoring to provide decision support to clinicians. The goal is expanding to models that can drive the realization of personalized therapy for optimal outcomes. This position paper provides their propositions that describe how innovations in biology, physics, mathematics, and data science including AI could inform models and improve predictions. It consolidates the DREAM team's consensus on scientific priorities and organizational requirements. Scientifically, it stresses the need for rigorous, multifaceted model development, comprehensive validation and clinical applicability and significance. Organizationally, it reinforces the prerequisites of interdisciplinary research and collaboration between physicians, medical physicists, radiobiologists, and computational scientists throughout model development. Solely by a shared understanding of clinical needs, biological mechanisms, and computational methods, more informed models can be created. Future research environment and support must facilitate this integrative method of operation across multiple disciplines.


Subject(s)
Neoplasms , Radiobiology , Humans , Neoplasms/radiotherapy , Precision Medicine/methods
2.
Radiat Res ; 196(1): 23-30, 2021 07 01.
Article in English | MEDLINE | ID: mdl-33914890

ABSTRACT

Currently, all soft tissue sarcomas (STS) are irradiated by the same regimen, disregarding possible subtype-specific radiosensitivities. To gain further insight, cellular radiosensitivity was investigated in a panel of sarcoma cell lines. Fourteen sarcoma cell lines, derived from synovial sarcoma, leiomyosarcoma, fibrosarcoma and liposarcoma origin, were submitted to clonogenic survival assays. Cells were irradiated with single doses from 1-8 Gy and surviving fraction (SF) was calculated from the resulting response data. Alpha/beta (α/ß) ratios were inferred from radiation-response curves using the linear-quadratic (LQ)-model. Cellular radiosensitivities varied largely in this panel, indicating a considerable degree of heterogeneity. Surviving fraction after 2 Gy (SF2) ranged from 0.27 to 0.76 with evidence of a particular radiosensitive phenotype in only few cell lines. D37% on the mean data was 3.4 Gy and the median SF2 was 0.52. The median α/ß was 4.9 Gy and in six cell lines the α/ß was below 4 Gy. A fairly homogeneous radiation response was observed in myxoid liposarcoma cell lines with SF2 between 0.64 and 0.67. Further comparing sarcomas of different origin, synovial sarcomas, as a group, showed the lowest SF2 values (mean 0.35) and was significantly more radiosensitive than myxoid liposarcomas and leiomyosarcomas (P = 0.0084 and 0.024, respectively). This study demonstrates a broad spectrum of radiosensitivities across STS cell lines and reveals subtype-specific radiation responses. The particular cellular radiosensitivity of synovial sarcoma cells supports consideration of the different sarcoma entities in clinical studies that aim to optimize sarcoma radiotherapy.


Subject(s)
Radiation Tolerance , Sarcoma/radiotherapy , Cell Line, Tumor , Cell Survival/radiation effects , Humans , Sarcoma/pathology
3.
BMC Cancer ; 19(1): 901, 2019 Sep 10.
Article in English | MEDLINE | ID: mdl-31500595

ABSTRACT

BACKGROUND: Poly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited. METHODS: Olaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for pharmacokinetic and pharmacodynamic analyses. DISCUSSION: We designed three parallel phase 1 trials to assess the safety and tolerability of the PARP inhibitor olaparib in combination with radical (chemo-)radiotherapy treatment regimens. PARP inhibitors have the potential to improve outcomes in patients treated with radical (chemo-)radiotherapy, by achieving higher locoregional control rates and/or less treatment associated toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).


Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/radiotherapy , Phthalazines/therapeutic use , Piperazines/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/radiotherapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/radiotherapy , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Maximum Tolerated Dose , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Radiotherapy, Adjuvant
4.
Radiother Oncol ; 138: 17-24, 2019 09.
Article in English | MEDLINE | ID: mdl-31146069

ABSTRACT

BACKGROUND AND PURPOSE: Preclinical models are much needed to assess the effect of novel radio-sensitizers or mitigators on radiation dose limiting lung toxicity. Albeit showing radiation-induced lung pathologies, current mouse models lack the sensitivity to do so. Using micro image-guided radiotherapy (µIGRT) techniques, we aimed to establish murine models which enable the sensitive detection of lung damage aggravation and characterized functional, radiological and histological responses. MATERIALS AND METHODS: Right lungs of C57Bl/6J mice were irradiated using µIGRT with doses from 15 to 27 Gy and with 21 Gy and cisplatin as a radio-sensitizer in a second study. Mice were sacrificed for histological and pathological assessment at different time-points post-IR. Lung density was determined using the integrated micro cone-beam CT (µCBCT). Lung function was measured by double-chamber-plethysmography. RESULTS: µIGRT resulted in accurate deposition of the radiation dose in the right lung only as determined by É£H2AX staining. Lung fibrosis was confirmed by pathological assessments and increased significantly at 21 Gy as determined by automated quantification of histochemical analyses. Lung function was affected in a dose-dependent manner. µCBCT-determined lung densities increased significantly over time in the irradiated lungs and showed a strong radiation dose-dependence. Importantly, the µCBCT analyses allowed the detection of additional lung damage caused by 3 Gy dose increments or by the combination with cisplatin. CONCLUSION: µCBCT after right lung µIGRT enables the sensitive detection of effects inflicted by relative small dose increments or radio-sensitizers. Our preclinical model therefore facilitates the determination of lung damage exacerbation for the safety assessment of novel RT-drug combinations.


Subject(s)
Cone-Beam Computed Tomography/methods , Lung Injury/diagnostic imaging , Lung/diagnostic imaging , Lung/radiation effects , Radiation Injuries/diagnostic imaging , Animals , Disease Models, Animal , Dose Fractionation, Radiation , Lung Injury/etiology , Male , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis
5.
Radiat Res ; 157(6): 734-9, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12005553

ABSTRACT

To test modifications in sensitization to radiation or drugs in preclinical studies of cancer therapy, the colony-forming assay is regarded as the gold standard. Because this assay is time consuming, somewhat laborious, and unsuitable for rapid screening, development of other assays is desirable. We describe here an assay based on the detection of enhanced green fluorescence protein (EGFP) with flow cytometry that is particularly suitable for genetic manipulation studies in which the gene of interest is introduced together with EGFP as reporter. It is easily adaptable to other reporters, however, whether naturally fluorescent or requiring immunochemical staining. Cells are irradiated as mixed populations of a known standard cell line (nonfluorescent) together with the genetically manipulated cell line expressing EGFP. Ratios of fluorescent and nonfluorescent cells are measured before treatment and several days after treatment. If the cell populations have equal radiosensitivities, the ratio remains unchanged. Changes in the ratio indicate changes in radiosensitivity. The assay was validated for two situations in which dominant negative peptides inhibiting DNA repair were expressed in A549 human lung cells and affected radiosensitivity.


Subject(s)
Flow Cytometry/methods , Fluorescence , Radiation Tolerance , Cell Death/radiation effects , Cell Survival/radiation effects , DNA Polymerase beta/metabolism , DNA Repair , Dose-Response Relationship, Radiation , Green Fluorescent Proteins , Humans , Luminescent Proteins/metabolism , Tumor Cells, Cultured
7.
FASEB J ; 13(14): 2071-82, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10544190

ABSTRACT

Studies of T lymphocyte activation with mitogenic lectins during spaceflight have shown a dramatic inhibition of activation as measured by DNA synthesis at 72 h, but the mechanism of this inhibition is unknown. We have investigated the progression of cellular events during the first 24 h of activation using both spaceflight microgravity culture and a ground-based model system that relies on the low shear culture environment of a rotating clinostat (clinorotation). Stimulation of human peripheral blood mononuclear cells (PBMCs) with soluble anti-CD3 (Leu4) in clinorotation and in microgravity culture shows a dramatic reduction in surface expression of the receptor for IL-2 (CD25) and CD69. An absence of bulk RNA synthesis in clinorotation indicates that stimulation with soluble Leu4 does not induce transition of T cells from G0 to the G1 stage of the cell cycle. However, internalization of the TCR by T cells and normal levels of IL-1 synthesis by monocytes indicate that intercellular interactions that are required for activation occur during clinorotation. Complementation of TCR-mediated signaling by phorbol ester restores the ability of PBMCs to express CD25 in clinorotation, indicating that a PKC-associated pathway may be compromised under these conditions. Bypassing the TCR by direct activation of intracellular pathways with a combination of phorbol ester and calcium ionophore in clinorotation resulted in full expression of CD25; however, only partial expression of CD25 occurred in microgravity culture. Though stimulation of purified T cells with Bead-Leu4 in microgravity culture resulted in the engagement and internalization of the TCR, the cells still failed to express CD25. When T cells were stimulated with Bead-Leu4 in microgravity culture, they were able to partially express CD69, a receptor that is constitutively stored in intracellular pools and can be expressed in the absence of new gene expression. Our results suggest that the inhibition of T cell proliferative response in microgravity culture is a result of alterations in signaling events within the first few hours of activation, which are required for the expression of important regulatory molecules.


Subject(s)
Lymphocyte Activation , Space Flight , T-Lymphocytes/immunology , Antigens, CD/analysis , Antigens, Differentiation, T-Lymphocyte/analysis , Cell Cycle , DNA/biosynthesis , Humans , Interleukin-1/biosynthesis , Lectins, C-Type , Monocytes/metabolism , Protein Kinase C/physiology , Receptors, Antigen, T-Cell/physiology , Receptors, Interleukin-2/analysis , Rotation , Tetradecanoylphorbol Acetate/pharmacology
8.
J Biotechnol ; 47(2-3): 203-14, 1996 Jun 27.
Article in English | MEDLINE | ID: mdl-9026045

ABSTRACT

This paper presents data on a novel, semi-automatic cell culturing device called 'C5 Unit' (connectable circuit cell culture chamber) which was developed and adapted to the quality and size criteria set by the characteristics of the ESA Biorack. The suitability of the hardware for culturing cells under microgravity conditions was demonstrated by successful culture of primary mouse cells from neonatal cerebellum and testis aboard the Space Shuttle during the IML-2 mission.


Subject(s)
Cell Culture Techniques/instrumentation , Space Flight/instrumentation , Weightlessness , Animals , Biotechnology , Cell Aggregation , Cells, Cultured , Cerebellum/cytology , Equipment Design , Male , Mice , Testis/cytology , Weightlessness/adverse effects
9.
Cell Adhes Commun ; 2(4): 287-98, 1994 Aug.
Article in English | MEDLINE | ID: mdl-7820532

ABSTRACT

We have undertaken aggregation experiments using mouse LMTK(-)-fibroblasts transfected with various isotypes of the neural cell adhesion molecule, NCAM. We found that self-aggregation of NCAM-positive fibroblasts is enhanced compared to control-transfected cells. The aggregation properties are partly dependent on the expressed NCAM isotype. Fibroblasts expressing a NCAM 140 isotype with exons a3 and pi were further tested in primary cerebellum cell re-aggregation experiments. While control-transfected fibroblasts could not be found in forming aggregates, fibroblasts ectopically expressing NCAM were integrated into neural cell aggregates. Time-lapse photography indicated that the nascent primary cell aggregates actively participated in the integration process by migration and attachment to nearby NCAM-positive fibroblasts.


Subject(s)
Cell Adhesion Molecules, Neuronal/physiology , Cerebellum/cytology , Fibroblasts/cytology , Animals , Cell Adhesion Molecules, Neuronal/genetics , Cell Aggregation , Cells, Cultured , Cerebellum/physiology , DNA, Complementary , Exons , Fibroblasts/physiology , Gene Expression , L Cells , Mice , Transfection
SELECTION OF CITATIONS
SEARCH DETAIL
...