Development of a coupled simulation toolkit for computational radiation biology based on Geant4 and CompuCell3D.

Understanding and designing clinical radiation therapy is one of the most important areas of state-of-the-art oncological treatment regimens. Decades of research have gone into developing sophisticated treatment devices and optimization protocols for schedules and dosages. In this paper, we presented a comprehensive computational platform that facilitates building of the sophisticated multi-cell-based model of how radiation affects the biology of living tissue. We designed and implemented a coupled simulation method, including a radiation transport model, and a cell biology model, to simulate the tumor response after irradiation. The radiation transport simulation was implemented through Geant4 which is an open-source Monte Carlo simulation platform that provides many flexibilities for users, as well as low energy DNA damage simulation physics, Geant4-DNA. The cell biology simulation was implemented using CompuCell3D (CC3D) which is a cell biology simulation platform. In order to couple Geant4 solver with CC3D, we developed a 'bridging' module, RADCELL, that extracts tumor cellular geometry of the CC3D simulation (including specification of the individual cells) and ported it to the Geant4 for radiation transport simulation. The cell dose and cell DNA damage distribution in multicellular system were obtained using Geant4. The tumor response was simulated using cell-based tissue models based on CC3D, and the cell dose and cell DNA damage information were fed back through RADCELL to CC3D for updating the cell properties. By merging two powerful and widely used modeling platforms, CC3D and Geant4, we delivered a novel tool that can give us the ability to simulate the dynamics of biological tissue in the presence of ionizing radiation, which provides a framework for quantifying the biological consequences of radiation therapy. In this introductory methods paper, we described our modeling platform in detail and showed how it can be applied to study the application of radiotherapy to a vascularized tumor.

Intravitreal bevacizumab in the treatment of vasoproliferative retinal tumours.

AIM: To evaluate the efficacy of intravitreal bevacizumab in the treatment of retinal vasoproliferative tumours (VPT). MATERIALS AND METHODS: Six eyes of 6 patients with VPT who received intravitreal bevacizumab were retrospectively reviewed. All patients received between one and three injections of intravitreal bevacizumab depending upon response to treatment. Best-corrected visual acuity (BCVA), tumour size, and presence of co-pathology or sequelae were noted pre- and postoperatively and then analysed. Subsequent retreatments were performed in patients with recurrent or persistent VPT according to the ophthalmologist's discretion. Retreatments included photodynamic therapy with verteporfin, ruthenium-106 plaque brachytherapy, or endoresection of tumour. RESULTS: The mean follow-up duration was 33.3 months (range 10-66 months). At baseline, the mean logMAR BCVA was 1.45 (Snellen equivalent of 6/165); range 0.10-1.90 (6/8-CF). Following bevacizumab treatment the mean logMAR BCVA was 0.98 (Snellen equivalent of 6/57); range 0.5-1.9 (Snellen equivalent of 6/19 to CF). Therefore, there was no statistically significant change in visual acuity. The mean tumour thickness reduced from 2.4 to 2.1 mm following treatment with bevacizumab. However, this did not reach the statistical significance of P<0.05. Despite the visual improvement following bevacizumab therapy, five out of six patients had recurrence of tumour activity during the follow-up period and required further intervention in order to achieve sustained regression. CONCLUSIONS: Intravitreal bevacizumab appeared to result in temporary reduction of tumour thickness in 3 out of 6 VPT patients. However, neither the reduction in tumour thickness nor the change in visual acuity were statistically significant and intravitreal bevacizumab monotherapy had limited effectiveness in causing long-term regression of the lesions. Additional therapy was indicated in five out of six patients to establish long-term regression. The efficacy of bevacizumab as an adjunct is as yet undetermined and further studies are needed. Presently, we recommend other treatment modalities in the long-term management of VPTs.

From pericytes to perivascular tumours: correlation between pathology, stem cell biology, and tissue engineering.

PURPOSE: Pericytes were once thought only to aid in angiogenesis and blood pressure control. Gradually, the known functions of pericytes and other perivascular stem cells (PSC) have broadly increased. The following review article will summarize the known functions and importance of pericytes across disciplines of pathology, stem cell biology, and tissue engineering. METHODS: A literature review was performed for studies examining the importance of pericytes in pathology, stem cell biology, and tissue engineering. RESULTS: The importance of pericytes most prominently includes the identification of the perivascular identity of mesenchymal stem cells (or MSC). Now, pericytes and other PSC are known to display surface markers and multilineage differentiation potential of MSC. Accordingly, interest in the purification and use of PSC for mesenchymal tissue formation and regeneration has increased. Significant demonstration of in vivo efficacy in bone and muscle regeneration has been made in laboratory animals. Contemporaneously with the uncovering of an MSC identity for pericytes, investigators in tumour biology have found biologically relevant roles for pericytes in tumor formation, lymphovascular invasion, and perivascular tumor spread. As well, the contribution of pericytes to perivascular tumors has been examined (and debated), including glomus tumour, myopericytoma and solitary fibrous tumour/hemangiopericytoma. In addition, an expanding recognition of pericyte mimicry and perivascular tumour invasion has occurred, encompassing common malignancies of the brain and skin. CONCLUSIONS: In summary, pericytes have a wide range of roles in health and disease. Pericytes are being increasingly studied for their role in tumour formation, growth and invasion. Likewise, the application of pericytes/PSC for mesenchymal tissue engineering is an expanding field of interest.

Fetal and placental vascular tumors: persistent fetal hyperdynamic status predisposes to poorer long-term neurodevelopmental outcome.

OBJECTIVE: To evaluate the association between fetal hemodynamic changes seen in the presence of vascular tumors of fetal or placental origin and risk of adverse pregnancy outcome. METHODS: All cases of placental chorioangioma, sacrococcygeal teratoma and pulmonary sequestration during a 10-year period were included. Ultrasound data and pregnancy and long-term neurodevelopmental outcomes were assessed in this cohort. A survival analysis was performed to assess the relationship between the cardiovascular profile score (CVPS) and adverse pregnancy outcome. RESULTS: There were 56 fetal or placental tumors, including 28 chorioangiomas, 10 sacrococcygeal teratomas and 18 pulmonary sequestrations, diagnosed at a median gestation of 23 + 3 weeks. Abnormal CVPS (≤ 8) was seen in 30% of sacrococcygeal teratomas and in 46% of chorioangiomas, but in none of the pulmonary sequestration cases. Adverse pregnancy outcome occurred in 11 cases (three stillbirths, three neonatal deaths and five cases of developmental delay) and only in those cases in which the tumors were associated with a CVPS of ≤ 8. CONCLUSIONS: Certain fetal and placental vascular tumors are associated with cardiac dysfunction in fetal life. When the CVPS is low (≤ 8), these cases are at increased risk of both fetal/neonatal demise as well as overt long-term neurodevelopmental disability. The long-term neurodevelopmental outcome should be formally and prospectively assessed in cases of fetal and placental vascular tumors.

Symptoms, diagnosis, and therapy of primary sarcomas of the pulmonary artery.

Primary sarcoma of the pulmonary artery is a rare tumor which must be considered in differential diagnosis of pulmonary embolism. The data of the 93 cases published up to now is evaluated synoptically after a report on a primary sarcoma of the pulmonary artery. Modern diagnostic imaging methods (pulmonary DSA, perfusion scintigraphy, echocardiography, computer tomography, nuclear magnetic resonance tomography) may corroborate the suspicion of a sarcoma of the pulmonary artery. With a median survival time of 1.5 months, the prognosis of patients with primary sarcomas of the pulmonary artery must be regarded extremely poor. After tumor excision, the median survival time of the patients could be prolonged (statistically significant; p less than 0.01) to ten months. The significance of adjuvant chemotherapy and/or radiotherapy cannot be appraised at present.