Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors.

Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

COMP report: CPQR technical quality control guidelines for radiation treatment centers.

The Canadian Organization of Medical Physicists (COMP), in close partnership with the Canadian Partnership for Quality Radiotherapy (CPQR) has developed a series of Technical Quality Control (TQC) guidelines for radiation treatment equipment. These guidelines outline the performance objectives that equipment should meet in order to ensure an acceptable level of radiation treatment quality. The TQC guidelines have been rigorously reviewed and field tested in a variety of Canadian radiation treatment facilities. The development process enables rapid review and update to keep the guidelines current with changes in technology. This announcement provides an introduction to the guidelines, describing their scope and how they should be interpreted. Details of recommended tests can be found in separate, equipment specific TQC guidelines published in the JACMP (COMP Reports), or the website of the Canadian Partnership for Quality Radiotherapy (www.cpqr.ca).

PRELIMINARY INVESTIGATION OF RADIATION DOSE TO PATIENTS FROM CARDIOVASCULAR INTERVENTIONAL PROCEDURES IN TANZANIA.

Although contemporary cardiac X-ray exams are typically set so benefits outweighs the risk, the growing use and increasing complexity of the cardiovascular interventional radiological (CVIR) procedures does increase the risk of radiation-related tissue effects and stochastic effects to the individual patients and the population. In view of these radiological concerns there is a need to investigate factors that influence the doses received by the patients and enable optimisation needed. The air kerma area product (KAP), cumulative air kerma (CAK) and fluoroscopy time (FT) to patients from two major CVIR procedures: coronary angiography (CA) and percutaneous coronary interventions (PCI), were obtained from two major hospitals in Tanzania. The CAK and KAP were determined using ionisation chambers equipped in each angiographic unit. The median values of the KAP, CAK and FT for the CA procedures were 37.8 Gy cm2, 425.5 mGy and 7.6 min, respectively, while for the PCI were 86.5 Gy cm2, 1180.3 mGy and 19.0 min, respectively. The overall differences among individual KAP, CAK and FT values across the two hospitals investigated differed by factors of up to 33.5, 58.7 and 26.3 for the CA, while for the PCI procedures differed by factors of up to 10.9, 25.3 and 13.8, respectively. The mean values of KAP and FT for both CA and PCI were mostly higher than those reported values for Ireland, Belgium, Greece, France, China and Australia. The third quartiles of the KAP, CAK and FT for both CA and PCI were relatively above the preliminary diagnostic reference levels proposed by the IAEA, DIMOND III and SENTINEL. The observed substantial variations of mean values of technical parameters and patient doses (KAP, CAK and FT values) observed for the CA and PCI procedures inter and intra-hospitals were mainly explained by the complexity of the CVIR procedures, the nature of pathology, patient-specific characteristics, the variation in levels of skills and experiences among IC personnel, and the different procedural protocols employed among interventional cardiologists and hospitals. The observed great variations of procedural protocols and patient doses within and across the hospitals and relative higher dose than reported values from the literature call for the need to optimise radiation dose to patient from IC procedures.

[Thoracic inflammatory pseudotumors : A rare differential diagnosis]. / Thorakale inflammatorische Pseudotumoren : Eine seltene Differenzialdiagnose.

BACKGROUND: Inflammatory pseudotumors are a rare and in the main benign tumor entity but infiltrative growth, recurrence and metastases are described. Generally, a complete resection is needed to exclude lung cancer. This study analyzed our data and experiences with this rare tumor entity. MATERIAL AND METHODS: We performed a retrospective study of all our patients who had been operated on between 2002 and 2016 in our institution for an inflammatory pseudotumor of the lungs. The extent of resection, morbidity, mortality and long-term results were analyzed. RESULTS: Altogether, in this period 13 patients were operatively treated (5 women and 8 men). The median age was 52 years (range 34-74 years). A reoperation was carried out in one patient for recurrence after enucleation of the tumor in another hospital. In no case could lung cancer be excluded prior to complete resection. In total, 11 pulmonary, 1 tracheal and 1 chest wall pseudotumor could be resected by thoracotomy (9×) and thoracoscopy (3×) and 1 by ventral chest wall resection. In eight patients the resections were performed by standard resection (wedge resection or anatomic resection) and five times by extended resection. In all cases a R0 resection was achieved. Due to one case of postoperative pneumonia the morbidity and mortality rates were 7.7% and 0%, respectively. CONCLUSION: The differential diagnosis between inflammatory pseudotumors and lung cancer cannot be definitely made preoperatively. For an exact diagnosis by the pathologist a complete histological preparation is needed. Due to infiltrative growth and recurrence, extended resection can be necessary for a R0 resection. This can be achieved with low morbidity and mortality. Important is an en bloc R0 resection, which is associated with good long-term results.

Streamlined open-source gel dosimetry analysis in 3D slicer.

Three dimensional dosimetry is being used in an increasingly wide variety of clinical applications as more gel and radiochromic plastic dosimeters become available. However, accessible 3D dosimetry analysis tools have not kept pace. 3D dosimetry data analysis is time consuming and laborious, creating a barrier to entry for busy clinical environments. To help in the adoption of 3D dosimetry, we have produced a streamlined, open-source dosimetry analysis system by developing a custom extension in 3D Slicer, called the Gel Dosimetry Analysis slicelet, which enables rapid and accurate data analysis. To assist those interested in adopting 3D dosimetry in their clinic or those unfamiliar with what is involved in a 3D dosimeter experiment, we first present the workflow of a typical gel dosimetry experiment. This is followed by the results of experiments used to validate, step-wise, each component of our software. Overall, our software has made a full 3D gel dosimeter analysis roughly 20 times faster than previous analysis systems.

Best Practice Recommendations for the Retention of Radiotherapy Records.

This paper offers best practice recommendations for the maintenance and retention of radiotherapy health records and technical information for cancer programmes. The recommendations are based on a review of the published and grey literature, feedback from key informants from seven countries and expert consensus. Ideally, complete health records should be retained for 5 years beyond the patient's lifetime, regardless of where they are created and maintained. Technical information constituting the radiotherapy plan should also be retained beyond the patient's lifetime for 5 years, including the primary images, contours of delineated targets and critical organs, dose distributions and other radiotherapy plan objects. There have been increased data storage and access requirements to support modern image-guided radiotherapy. Therefore, the proposed recommendations represent an ideal state of radiotherapy record retention to facilitate ongoing safe and effective care for patients as well as meaningful and informed retrospective research and policy development.

Initial Investigation of Factors Influencing Radiation Dose to Patients Undergoing Barium-Based Fluoroscopy Procedures in Tanzania.

The aim of this study was to investigate the nature and causes of radiation dose imparted to patients undergoing barium-based X-ray fluoroscopy procedures in Tanzania and to compare these doses to those reported in the literature from other regions worldwide. The air kerma area product (KAP) to patient undergoing barium investigations of gastrointestinal tract system was obtained from four consultant hospitals. The KAP was determined using a flat transparent transmission ionization chamber. Mean values of KAP for barium swallow (BS), barium meal (BM) and barium enema (BE) were 2.79, 2.62 and 15.04 Gy cm2, respectively. The mean values of KAP per hospital for the BS, BM and BE procedures varied by factors of up to 7.3, 1.6 and 2.0, respectively. The overall difference between individual patient doses across the four consultant hospitals investigated differed by factors of up to 53, 29.5 and 12 for the BS, BM and BE procedures, respectively. The majority of the mean values of KAP was lower than the reported values for Ghana, Greece, Spain and the UK, while slightly higher than those reported for India. The observed wide variation of KAP values for the same fluoroscopy procedure within and among the hospitals was largely attributed to the dynamic nature of the procedures, the patient characteristics, the skills and experience of personnel, and the different examination protocols employed among hospitals. The observed great variations of procedural protocols and patient doses within and across the hospitals call for the need to standardize examination protocols and optimize barium-based fluoroscopy procedures.

Production, review, and impact of technical quality control guidelines in a national context.

A close partnership between the Canadian Partnership for Quality Radiotherapy (CPQR) and the Canadian Organization of Medical Physicist's (COMP) Quality Assurance and Radiation Safety Advisory Committee (QARSAC) has resulted in the development of a suite of Technical Quality Control (TQC) guidelines for radiation treatment equipment; they outline specific performance objectives and criteria that equipment should meet in order to assure an acceptable level of radiation treatment quality. The adopted framework for the development and maintenance of the TQCs ensures the guidelines incorporate input from the medical physics com-munity during development, measures the workload required to perform the QC tests outlined in each TQC, and remain relevant (i.e., "living documents") through subsequent planned reviews and updates. The framework includes consolidation of existing guidelines and/or literature by expert reviewers, structured stages of public review, external field-testing, and ratification by COMP. This TQC develop-ment framework is a cross-country initiative that allows for rapid development of robust, community-driven living guideline documents that are owned by the com-munity and reviewed to keep relevant in a rapidly evolving technical environment. Community engagement and uptake survey data shows 70% of Canadian centers are part of this process and that the data in the guideline documents reflect, and are influencing, the way Canadian radiation treatment centers run their technical quality control programs. For a medium-sized center comprising six linear accelerators and a comprehensive brachytherapy program, we evaluate the physics workload to 1.5 full-time equivalent physicists per year to complete all QC tests listed in this suite.

Radiotherapeutic Management of Non-Small Cell Lung Cancer in the Minimal Resource Setting.

Lung cancer is the most common cancer worldwide and the fifth most common cause of death globally. Its incidence continues to increase, especially within low- and middle-income countries (LMICs), which have limited capacity to address the growing need for treatment. The standard of care for lung cancer treatment often involves radiation therapy (RT), which plays an important therapeutic role in curative-intent treatment of early-stage to locally advanced disease, as well as in palliation. The infrastructure, equipment, and human resources required for RT may be limited in LMICs. However, this narrative review discusses the scope of the problem of lung cancer in LMICs, the role of RT technologies in lung cancer treatment, and RT capacity in developing countries. Strategies are presented for maximizing the availability and impact of RT in settings with minimal resource availability, and areas for potential future innovation are identified. Priorities for LMICs involve increasing access to RT equipment and trained health care professionals, ensuring quality of care, providing guidance on priority setting with limited resources, and encouraging innovation to increase the economic efficiency of RT delivery. Several international initiatives are currently under way and represent important first steps toward scaling up RT in LMICs to treat lung cancer.

Leuco-crystal-violet micelle gel dosimeters: II. Recipe optimization and testing.

In this study, recipe optimization of Leuco Crystal Violet (LCV) micelle gels made with the surfactant Cetyl Trimethyl Ammonium Bromide (CTAB) and the chemical sensitizer 2,2,2-trichloroethanol (TCE) was aided by a two-level three-factor designed experiment. The optimized recipe contains 0.75 mM LCV, 17.0 mM CTAB, 120 mM TCE, 25.0 mM tri-chloro acetic acid (TCAA), 4 wt% gelatin and ~96 wt% water. Dose sensitivity of the optimized gel is 1.5 times higher than that of Jordan's standard LCV micelle gel. Spatial integrity of the 3D dose distribution information in 1L phantoms filled with this recipe is maintained for >120 d. Unfortunately, phantoms made using the optimized recipe showed dose-rate dependence (14% difference in optical attenuation at the peak dose using electron beam irradiations at 100 and 400 MU min(-1)). Further testing suggests that the surfactant CTAB is the cause of this dose rate behaviour.

Leuco-crystal-violet micelle gel dosimeters: I. Influence of recipe components and potential sensitizers.

Radiochromic leuco crystal violet (LCV) micelle gel dosimeters are promising three-dimensional radiation dosimeters because of their spatial stability and suitability for optical readout. The effects of surfactant type and surfactant concentration on dose sensitivity of LCV micelle gels are tested, demonstrating that dose sensitivity and initial colour of the gel increases with increasing Triton x-100 (Tx100) concentration. Using Cetyl Trimethyl Ammonium Bromide (CTAB) in place of Tx100 produces gels that are nearly colourless prior to irradiation, but reduces the dose sensitivity. The separate effects of Tri-chloro acetic acid concentration and pH are investigated, revealing that controlling the pH near 3.6 is crucial for achieving high dose sensitivity. The sensitizing effect of chlorinated species on dose sensitivity is tested using 2,2,2-trichloroethanol (TCE), chloroform, and 1,1,1-trichloro-2-methyl-2-propanol hemihydrate. TCE gives the largest improvement in dose sensitivity and is recommended for use in micelle gel dosimeters because it is less volatile and safer to use than chloroform. Preliminary experiments on a new gel containing CTAB as the surfactant and TCE show that this new gel gives a dose sensitivity that is 24% higher than that of previous LCV micelle gels and is nearly colourless prior to irradiation.

Pretubulysin: a new option for the treatment of metastatic cancer.

Tubulin-binding agents such as taxol, vincristine or vinblastine are well-established drugs in clinical treatment of metastatic cancer. However, because of their highly complex chemical structures, the synthesis and hence the supply issues are still quite challenging. Here we set on stage pretubulysin, a chemically accessible precursor of tubulysin that was identified as a potent microtubule-binding agent produced by myxobacteria. Although much simpler in chemical structure, pretubulysin abrogates proliferation and long-term survival as well as anchorage-independent growth, and also induces anoikis and apoptosis in invasive tumor cells equally potent to tubulysin. Moreover, pretubulysin posseses in vivo efficacy shown in a chicken chorioallantoic membrane (CAM) model with T24 bladder tumor cells, in a mouse xenograft model using MDA-MB-231 mammary cancer cells and finally in a model of lung metastasis induced by 4T1 mouse breast cancer cells. Pretubulysin induces cell death via the intrinsic apoptosis pathway by abrogating the expression of pivotal antiapoptotic proteins, namely Mcl-1 and Bcl-xL, and shows distinct chemosensitizing properties in combination with TRAIL in two- and three-dimensional cell culture models. Unraveling the underlying signaling pathways provides novel information: pretubulysin induces proteasomal degradation of Mcl-1 by activation of mitogen-activated protein kinase (especially JNK (c-Jun N-terminal kinase)) and phosphorylation of Mcl-1, which is then targeted by the SCF(Fbw7) E3 ubiquitin ligase complex for ubiquitination and degradation. In sum, we designate the microtubule-destabilizing compound pretubulysin as a highly promising novel agent for mono treatment and combinatory treatment of invasive cancer.

Cobalt-60 tomotherapy: clinical treatment planning and phantom dose delivery studies.

PURPOSE: Investigations have shown that a Cobalt-60 (Co-60) radioactive source has the potential to play a role in intensity modulated radiation therapy (IMRT). In this paper, Co-60 tomotherapy's conformal dose delivery potential is evaluated by delivering conformal dose plans on a cylindrical homogeneous phantom containing clinical structures similar to those found in a typical head and neck (H&N) cancer. Also, the clinical potential of Co-60 tomotherapy is investigated by generating 2D clinical treatment plans for H&N and prostate anatomical regions. These plans are compared with the 6 MV based treatment plans for modalities such as linear accelerator-based tomotherapy and broad beam IMRT, and 15 MV based 3D conformal radiation therapy (3DCRT). METHODS: For experimental validation studies, clinical and nonclinical conformal dose patterns were delivered on circular, homogeneous phantoms containing GafChromic film. For clinical planning study, dose calculations were performed with the EGSnrc Monte Carlo program, where a Theratronics 780C Co-60 unit and a 6 MV linear accelerator were modeled with a MIMiC binary multileaf collimator. An inhouse inverse treatment planning system was used to optimize tomotherapy plans using the same optimization parameters for both Co-60 and 6 MV beams. The IMRT and 3DCRT plans for the clinical cases were generated entirely in the Eclipse treatment planning system based on inhouse IMRT and 3DCRT site specific protocols. RESULTS: The doses delivered to the homogeneous phantoms agreed with the calculations, indicating that it is possible to deliver highly conformal doses with the Co-60 unit. The dose distributions for Co-60 tomotherapy clinical plans for both clinical cases were similar to those obtained with 6 MV based tomotherapy and IMRT, and much more conformal compared to 3DCRT plans. The dose area histograms showed that the Co-60 plans achieve the dose objectives for the targets and organs at risk. CONCLUSIONS: These results confirm that Co-60 tomotherapy is capable of providing state-of-the-art conformal dose delivery and could be used for the treatment of targets in both small and larger separation anatomical regions.

Investigation of photon shielding property changes in curing high density concrete.

High density concrete is usually used for radiation shielding around radiotherapy treatment rooms. Because the concrete is specified differently at the design, construction, and verification stages, the relationship between the intended performance and the actual performance of the shielding material might not be entirely clear. In this study, cylindrical samples of high density shielding concrete were taken as each section of a new radiotherapy bunker was poured. The shielding performance of each sample [measured by beam attenuation and tenth-value layers (TVL)] was evaluated for 15 MV and 6 MV x-ray beams and for the 1.25 MeV monoenergetic gamma beam from a Co source. Transmission curves to 3 TVL were mapped for a representative sample. The samples were also imaged and analyzed using Co Cone Beam Computed Tomography (CoCBCT). Results indicate no significant change in the TVL of high density concrete samples as they cure. The minor fluctuations in shielding properties observed are explained by the heterogeneous structure of the samples as indicated in the CoCBCT images.

Evaluation of the potential for diacetylenes as reporter molecules in 3D micelle gel dosimetry.

Radiochromic micelle gel dosimeters are promising for three-dimensional (3D) radiation dosimetry because they can be read out by optical CT techniques and they have superior spatial stability compared to polymer and Fricke gel dosimeters. This study evaluates the use of diacetylenes as reporter molecules in micelle gel dosimeters. Several gels containing pentacosa-10,12-diynoic acid (PCDA) emulsified using sodium dodecyl sulfate (SDS) changed from colourless to blue upon irradiation. Unfortunately, all phantoms that experienced a colour change were turbid and would be unsuitable for 3D dosimetry. Two techniques (use of organic solvent and aqueous-phase additives) were successful in increasing colloidal stability to prevent the turbidity problem, but none of the resulting transparent gels changed colour in response to radiation. Transparent PCDA emulsions were prepared using NaOH solutions with no SDS or other emulsifier, but these transparent emulsions also did not change colour. Only turbid gels and emulsions with precipitated particles responded to radiation. These results indicate that the colour change was due to the oligomerization within precipitated PCDA crystals, and that liquid-phase emulsified PCDA did not undergo oligomerization. As a result, PCDA is not suitable for use in micelle gel dosimeters, and other radiochromic reporter molecules will need to be identified.

Anti-angiogenic effects of the tubulysin precursor pretubulysin and of simplified pretubulysin derivatives.

BACKGROUND AND PURPOSE: The use of tubulin-binding compounds, which act in part by inhibiting tumour angiogenesis, has become an integral strategy of tumour therapy. Recently, tubulysins were identified as a novel class of natural compounds of myxobacterial origin, which inhibit tubulin polymerization. As these compounds are structurally highly complex, the search for simplified precursors [e.g. pretubulysin (Prt)] and their derivatives is mandatory to overcome supply problems hampering clinical development. We tested the anti-angiogenic efficacy of Prt and seven of its derivatives in comparison to tubulysin A (TubA). EXPERIMENTAL APPROACH: The compounds were tested in cellular angiogenesis assays (proliferation, cytotoxicity, cell cycle, migration, chemotaxis, tube formation) and in vitro (tubulin polymerization). The efficacy of Prt was also tested in vivo in a murine subcutaneous tumour model induced with HUH7 cells; tumour size and vascularization were measured. KEY RESULTS: The anti-angiogenic potency of all the compounds tested ran parallel to their inhibition of tubulin polymerization in vitro. Prt showed nearly the same efficacy as TubA (EC(50) in low nanomolar range in all cellular assays). Some modifications in the Prt molecule caused only a moderate drop in potency, while others resulted in a dramatic loss of action, providing initial insight into structure-activity relations. In vivo, Prt completely prevented tumour growth and reduced vascular density to 30%. CONCLUSIONS AND IMPLICATIONS: Prt, a chemically accessible precursor of some tubulysins is a highly attractive anti-angiogenic compound both in vitro and in vivo. Even more simplified derivatives of this compound still retain high anti-angiogenic efficacy.

Medical physics staffing for radiation oncology: a decade of experience in Ontario, Canada.

The January 2010 articles in The New York Times generated intense focus on patient safety in radiation treatment, with physics staffing identified frequently as a critical factor for consistent quality assurance. The purpose of this work is to review our experience with medical physics staffing, and to propose a transparent and flexible staffing algorithm for general use. Guided by documented times required per routine procedure, we have developed a robust algorithm to estimate physics staffing needs according to center-specific workload for medical physicists and associated support staff, in a manner we believe is adaptable to an evolving radiotherapy practice. We calculate requirements for each staffing type based on caseload, equipment inventory, quality assurance, educational programs, and administration. Average per-case staffing ratios were also determined for larger-scale human resource planning and used to model staffing needs for Ontario, Canada over the next 10 years. The workload specific algorithm was tested through a survey of Canadian cancer centers. For center-specific human resource planning, we propose a grid of coefficients addressing specific workload factors for each staff group. For larger scale forecasting of human resource requirements, values of 260, 700, 300, 600, 1200, and 2000 treated cases per full-time equivalent (FTE) were determined for medical physicists, physics assistants, dosimetrists, electronics technologists, mechanical technologists, and information technology specialists, respectively.

Aperture superposition dose model versus pencil beam superposition dose model for a finite size Cobalt-60 source for tomotherapy deliveries.

PURPOSE: The finite size pencil beam (FSPB) superposition method is a commonly used dose calculation method in intensity modulated radiation therapy (IMRT). The FSPB model assumes that dose for a broad intensity modulated beam can be calculated by superposition of dose from small, pencil-like beams. However, this model is limited to point-like radiation sources and is not valid for finite size sources, such as a Cobalt-60 (Co-60) source of 2 cm diameter. In this paper, the authors present results that show the limitation of this model and propose an alternative model, namely the aperture superposition (AS) model, to calculate photon dose for intensity modulated beams arising from finite size radiation sources. METHODS: The AS model is based on adding beam apertures rather than pencil beams. Each aperture is defined as a series of adjacently opened leaves of a multileaf collimator with no closed leaves in between them. The apertures are calculated using the EGSnrc Monte Carlo program. The accuracy of the AS model was tested for dose calculations of fan beams, as encountered in tomotherapy treatment plans. The results were compared with the FSPB model and GafChromic film measurements. The measurements and simulations were performed for a clinical Theratronics T780C Co-60 unit with MIMiC binary multileaf collimator mounted on it. RESULTS: The comparisons between the AS model and film measurements show agreement better than 1.5% in the high dose regions and 3.7% in the low dose regions. On the contrary, film measurement comparisons to the FSPB model show that the FSPB model underestimates the dose by up to 7% for small field sizes such as 2 × 2 cm(2) and 20% for larger field sizes such as 20 × 2 cm(2). CONCLUSIONS: The results presented in this paper indicate that the AS model provides better accuracy than the FSPB model when calculating dose for fan beams from large radiation sources. The implementation of this model to the current treatment planning systems has the scope of advancing Co-60 based IMRT and tomotherapy.