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.

Clinical outcomes of perioptic tumors treated with hypofractionated stereotactic radiotherapy using CyberKnife® stereotactic radiosurgery.

INTRODUCTION: Stereotactic radiation technique is widely reported as an effective treatment for various types of benign intracranial tumors. However, single fraction radiosurgery (SRS) is not recommended for tumors located close to the optic apparatus due to the restricted radiation tolerance dose of the optic pathway. Recent advances in radiotherapy include advanced frameless radiosurgery using hypofractionated stereotactic radiotherapy (HSRT), and this has become an attractive treatment option for perioptic tumors within 2-3 mm of the optic pathway. Accordingly, the aim of this study was to investigate the clinical outcomes of perioptic tumors treated with HSRT using CyberKnife® (CK) robotic radiosurgery system relative to tumor control, vision preservation and toxicity. METHODS: This retrospective analysis of prospectively collected data included consecutive 100 patients that were diagnosed with and treated for perioptic tumor at the Radiosurgery center, Ramathibodi Hospital during the January 2009 to December 2012 study period. RESULTS: The median tumor volume was 6.81 cm3 (range 0.37-51.6), and the median prescribed dose was 25 Gy (range 20-35) in 5 fractions (range 3-5). After the median follow-up time of 37.5 months (range 21-103), two patients developed tumor progression at 6 and 34 months post-HSRT. The 5-year overall survival was 97%, and the 5-year local control was 97.5%. At the last follow-up, no vision deterioration or newly developed hypopituitarism was detected in our study. CONCLUSIONS: Although a longer follow-up is needed, HSRT yields a high level of local control and vision preservation, and should be considered a treatment of choice for perioptic tumor located close to the optic apparatus.

PREDICTORS OF TREATMENT RESPONSE OF VASOPROLIFERATIVE RETINAL TUMORS TO RUTHENIUM-106 BRACHYTHERAPY.

PURPOSE: To identify predictors of treatment response by evaluating long-term outcomes of vasoproliferative retinal tumors after ruthenium-106 brachytherapy. METHODS: In a retrospective case series, 39 eyes of 38 patients with vasoproliferative retinal tumors received ruthenium-106 brachytherapy between 2001 and 2013. Baseline clinical and morphologic parameters were analyzed regarding posttreatment tumor activity status. RESULTS: Within a median follow-up period of 2.9 ± 2.9 years, overall, a tumor inactivation was achieved in 72% of cases and visual acuity remained stable in 69%. The mean apex dose was 90 ± 23 Gy (range, 51-140 Gy). Mean tumor thickness decreased significantly, from 2.9 ± 0.9 mm to 1.5 ± 1.0 mm (P < 0.001; paired t-test). Persistence or recurrence of tumor activity occurred in 28% of cases, requiring secondary intervention with intravitreal drug injections, vitrectomy, cryotherapy, or repeated brachytherapy. Comparison of inactive and active vasoproliferative retinal tumors revealed significant correlation between both initial basal tumour diameter and area and subsequent tumour activity status. In particular, a diameter >7.5 mm was associated with an 8-fold risk of persistent or recurrent activity, whereas basal area >40 mm demonstrated a 6-fold risk (P = 0.009 and 0.021, respectively; Fisher's exact-test). In contrast, tumor thickness was not found to be of prognostic relevance. CONCLUSION: Ruthenium-106 brachytherapy is an effective and safe therapeutic option for vasoproliferative retinal tumors. Additionally, tumor diameter and area are efficient predictors of persistence or recurrence of tumor activity.

Laser treatment of dark skin: an updated review.

The growing diversification of the patient population coupled with the increasing demand for cosmetic laser rejuvenation has highlighted the need to develop cutaneous laser systems and establish treatment protocols for patients with a wide range of skin conditions and phototypes. Recent technologic advancements have provided viable treatment options to achieve clinical outcomes that were previously only attainable in patients with lighter skin tones. This review provides an updated discussion of the range of laser treatments available for pigmented skin and sets the stage for further advancements. Pigment-specific laser technology with green, red, or near-infrared light targets a variety of pigmented lesions such as lentigines, ephelides, café-au-lait macules, and melanocytic nevi as well as tattoos and unwanted hair. Short-pulsed alexandrite, ruby, and neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers are used for pigmented lesions and tattoos, whereas their longer pulse-width laser counterparts are used for laser-assisted hair removal. Vascular lesions and hypertrophic scars can be treated with a variety of vascular-specific lasers, but it is the pulsed dye laser (PDL) that has long been the gold standard treatment for these lesions due to its high specificity for hemoglobin and its ability to improve skin surface texture in children and adults. Laser skin resurfacing techniques for photodamaged skin and atrophic scars have been optimized with fractional technology to produce excellent clinical outcomes and minimal complication risks. Radiofrequency and nonablative lasers are also used to provide skin tightening and collagen remodeling with virtually no postoperative recovery.

Laser therapy of vascular lesions.

Since the first construction of a laser by Maiman in 1960 and the first clinical application of a laser in the therapy of skin lesions by Leon Goldman, laser therapy has become an important therapeutic modality in dermatology. Various lasers can be used for the treatment of different vascular and non-vascular lesions. According to our results, vascular lesions constitute the most important indication for laser therapy in dermatology.

Ruthenium-106 plaque brachytherapy for symptomatic vasoproliferative tumours of the retina.

AIM: To investigate the safety and efficacy of beta ray brachytherapy in treatment of vasoproliferative tumours of the retina (VTR). METHODS: 35 consecutive patients with symptomatic VTR were treated with a ruthenium-106 ((106)Ru) plaque. Three tumours had been treated previously (two with cryotherapy; one with transpupillary thermotherapy). 32 VTR (91.4%) were located in the lower half of the retina and all of them were found between the mid-periphery and the ora serrata. The mean tumour thickness was 2.8 mm. An exudative retinal detachment was present in 25 eyes (71.4%) and in 15 cases (42.9%) hard exudates were found in the macula. The major symptom was loss of vision (77.1%). RESULTS: Brachytherapy was well tolerated by every patient. The mean applied dose was 416 Gy at the sclera and 108 Gy at the tumour apex. In all but four eyes (88.6%), it was possible to control the VTR activity. The median follow up time was 24 months. Three of the above mentioned four eyes with treatment failure had had secondary glaucoma before therapy. There was no case of radiation induced neuropathy or retinopathy. Cataract surgery was necessary for five patients. The development of epiretinal gliosis was the most common event during follow up (n = 10, 28.6%). The mean visual acuity decreased slightly (0.33 before and 0.29 after brachytherapy). Multivariate analysis showed that the presence of macular pathology before treatment was associated with a 6.1-fold risk of vision of 0.25 or better (p = 0.03). CONCLUSIONS: beta ray brachytherapy with (1106)Ru plaques was able to control the activity of VTR and retain vision. Cases with secondary glaucoma before treatment had a very poor prognosis.

Targeting the tumor blood vessel network to enhance the efficacy of radiation therapy.

It has been well established that the vascularization of solid tumors is a prerequisite if a clinically relevant size is to be reached. For progressive tumor growth, the vessel network must continuously expand to satisfy the neoplastic cells' nutritional needs and waste product removal requirements. This utter reliance of the tumor on its vasculature provides a logical target for new approaches to cancer therapy. Indeed, there currently exists a great deal of enthusiasm for the development of interventions that compromise the growth and/or function of the tumor neovasculature. Two primary directions are being pursued. Inhibitors of angiogenesis seek to interrupt the angiogenic process to prevent new vessel formation. Antivascular approaches aim to cause direct damage to the tumor endothelium and thus lead to extensive secondary neoplastic cell death. The application of such strategies as adjuvants to conventional radiation treatments offers unique opportunities to develop more effective cancer therapies.

Spindle cell angiosarcoma following irradiation therapy for cervical carcinoma.

BACKGROUND: Angiosarcomas arise in the scalp and face in the elderly, in association with chronic lymphedema (Stewart-Treves syndrome), and in irradiated areas. Rarely in these settings, angiosarcomas exhibit pure spindle cell phenotype. METHODS: Herein, the clinicopathologic features of a 72-year-old-woman with spindle cell angiosarcoma are described. RESULTS: A 72-year-old woman presented with numerous nodules and diffuse induration from the lower abdomen to the right buttock, corresponding to the area exposed to 60Co-irradiation during treatment for cervical carcinoma 10 years earlier. Histopathological examination revealed inflitrative, atypical, spindle cells that labeled with antibodies to CD31, CD34, and factor VIII-related antigen. Ultrastructurally, these malignant spindle cells contained Weibel-Palade bodies. No features suggesting radiation dermatitis (sclerosis or bizarre, large fibroblasts) were identified, but lymphangiectases and widely spaced collagen bundles(lymphedema) were prominent in the skin surrounding the angiosarcoma. Computed tomographic scan of the abdomen highlighted this histologic finding by demonstrating tumor masses limited to areas of lymphedema. Treatment with intravenous and local injections of recombinant interleukin 2 (rIL 2) followed by electron beam irradiation were initially effective with tumor remission for 2 months. However, the recurrent tumor did not respond to a second course of one-shot injection of rIL 2 through the abdominal aorta and the patient succumbed to her angiosarcoma 19 months after diagnosis. CONCLUSIONS: Radiation-induced lymphedema may be a factor in angiosarcoma associated with radiotherapy.

Multiple glomus cell tumours--treatment by infra-red coagulation.

This report describes the successful use of infra-red coagulation in the treatment of multiple glomus tumours. Glomus cell tumours are usually solitary and an excisional diagnostic biopsy therefore provides effective treatment. Such an approach is, however, impractical in the rarer condition of multiple glomus cell tumours where up to 400 lesions have been described in one patient. We describe a case of multiple glomus cell tumours in which more than 30 tumours were treated quickly and effectively by infra-red coagulation.

Radiation therapy for nonsquamous tumors of the head and neck.

Recent advances in the understanding of the natural history and modes of spread of the nonsquamous malignancies of the head and neck region have delineated an important role for radiotherapy in their management. The indications for primary radiotherapy include malignant lymphoma of the thyroid, idiopathic midline granuloma, midline malignant reticulosis, extramedullary plasmacytomas, esthesioneuroblastomas, and locally aggressive benign tumors, such as glomus tumors, angiofibromas, and hemangiomas. Although the traditional treatment for malignant melanoma is surgery, indications are emerging for high-dose radiotherapy, either as the only modality or in addition to surgery. Combined radiotherapy and chemotherapy is the treatment choice for nonHodgkin's lymphomas of the Waldeyer's ring and for Ewing's sarcomas. High-grade soft tissue sarcomas and salivary gland malignancies are best treated with surgery and postoperative radiotherapy. The use of megavoltage photons and electrons, custom-made blocks delineating the treatment volume, tissue compensators, patient immobilization devices, and simulator-aided treatment planning are mandatory to achieve loco-regional control and to minimize the treatment-related morbidity.

Radon seed implants. Residual radioactivity after 33 years.

Radon seeds, formerly used for vascular and neoplastic tumors, acne, and other dermatological disorders, are rarely, if ever, used today. Because the half-life of radon is 3.83 days, these hollow gold seeds filled with radon gas are usually left in situ permanently. A case is reported of a woman who had seeds implanted 33 years ago for a vascular lesion. The seeds were removed and found to have minute amounts of residual radiation but not sufficient to cause radiation damage. Since seeds are foreign bodies, removal is recommended if they are easily accessible.

[Advances in the clinical application of quantum and electron irradiation (author's transl)]. / Fortschritte in der klinischen Anwendung von Quanten- und Elektronenstrahlen

The technical perequisites for irradiation with fast electrons and high-energy photons are described in the introduction and the physical and biological development of megavoltage therapy is discussed. The role of exact treatment planning is mentioned and new developments avising from introduction of ultrasound and computer-dosimetry are demonstrated. Finally, emphasis is placed on the progress actieved with modern radiotherapeutic in the treatment of tumours in certain selected clinical fields, which appear suited to the application of electron- and photon-beam therapy. Further improvement in therapeutic results is expected with the introduction of chemotherapeutic agents, radiation sensitizers and combined surgical-radiotherapeutic biological methods. The importance of collaboration amongst various suspecialities engaged in oncology is stressed.