Use of CT and MR imaging in radiation therapy planning of imaging-diagnosed canine intracranial meningioma achieves better tumor coverage than CT alone.

The aim of this retrospective, secondary analysis study was to quantify the dosimetric impact of the lack of interobserver agreement on gross tumor volume (GTV) delineation for canine meningioma. This study used a previously reported population of 13 dogs with GTVs contoured on CT alone and on registered CT-MR by 18 radiation oncologists. The "true" GTV was generated for each dog using a simultaneous truth and performance-level estimation algorithm, and "true" brain was defined as the whole brain minus true GTV. Treatment plans were generated for each dog and observer combination, using criteria applied to the observer's GTV and brain contours. Plans were then categorized as a pass (met all planning criteria for true GTV and true brain) or fail. A mixed-effects linear regression was performed to examine differences in metrics between CT and CT-MR plans and mixed-effects logistic regression was performed to examine differences in percentages of pass/fail between CT and CT-MRI plans. The mean percent coverage of true GTV by prescribed dose was higher for CT-MR plans than for CT plans (mean difference 5.9%; 95% CI, 3.7-8.0; P < 0.001). There was no difference in the mean volume of true brain receiving ≥24 Gy and in maximum true brain dose between CT plans and CT-MR plans (P ≥ 0.198). CT-MR plans were significantly more likely to pass the criteria for true GTV and true brain than CT plans (OR 1.75; 95% CI, 1.02-3.01; P = 0.044). This study demonstrated significant dosimetric impact when GTV contouring was performed on CT alone compared with CT-MR.

Dichotomous effects of in vivo and in vitro ionizing radiation exposure on lymphatic function.

On the one hand, lymphatic dysfunction induces interstitial edema and inflammation. On the other hand, the formation of edema and inflammation induce lymphatic dysfunction. However, informed by the earlier reports of undetected apoptosis of irradiated lymphatic endothelial cells (LECs) in vivo, lymphatic vessels are commonly considered inconsequential to ionizing radiation (IR)-induced inflammatory injury to normal tissues. Primarily because of the lack of understanding of the acute effects of IR exposure on lymphatic function, acute edema and inflammation, common sequelae of IR exposure, have been ascribed solely to blood vessel damage. Therefore, in the present study, the lymphatic acute responses to IR exposure were quantified to evaluate the hypothesis that IR exposure impairs lymphatic pumping. Rat mesenteric lymphatic vessels were irradiated in vivo or in vitro, and changes in pumping were quantified in isolated vessels in vitro. Compared with sham-treated vessels, pumping was lowered in lymphatic vessels irradiated in vivo but increased in vessels irradiated in vitro. Furthermore, unlike in blood vessels, the acute effects of IR exposure in lymphatic vessels were not mediated by nitric oxide-dependent pathways in either in vivo or in vitro irradiated vessels. After cyclooxygenase blockade, pumping was partially restored in lymphatic vessels irradiated in vitro but not in vessels irradiated in vivo. Taken together, these findings demonstrated that lymphatic vessels are radiosensitive and LEC apoptosis alone may not account for all the effects of IR exposure on the lymphatic system.NEW & NOTEWORTHY Earlier studies leading to the common belief that lymphatic vessels are radioresistant either did not characterize lymphatic pumping, deemed necessary for the resolution of edema and inflammation, or did it in vivo. By characterizing pumping in vitro, the present study, for the first time, demonstrated that lymphatic pumping was impaired in vessels irradiated in vivo and enhanced in vessels irradiated in vitro. Furthermore, the pathways implicated in ionizing radiation-induced blood vessel damage did not mediate lymphatic responses.

Safety and feasibility of short course pre-operative radiation therapy followed by surgical excision for canine solid tumours.

Surgical resection of solid tumours, especially in early stages of disease, remains a cornerstone of cancer treatment in dogs and cats. There are numerous publications that show a strong association between local tumour control and outcome. To achieve local control in some cases radiation therapy and surgery are combined, with radiation therapy being delivered in the neoadjuvant or adjuvant setting. The objective of the study was to report acute toxicity and surgical site complication data in dogs that received a short-course pre-operative (SCPO) radiation therapy protocol, followed by surgical excision for various solid tumours. Medical records were reviewed, and data was analysed retrospectively. Dogs were included if a dermal or subcutaneous solid tumour was treated with SCPO radiation therapy and then was resected on the last day of radiation or 2-3 weeks later. A total of 34 dogs with 35 primary tumours were included. Acute radiation toxicity was diagnosed in 14 sites (40%). VRTOG scores were grade 1 in 50%, grade 2 in 43%, and grade 3 in 7%. Surgical site complications were identified in 17% of dogs with an overall surgical site infection rate of 11%. According to the Clavien-Dindo classification, two dogs required medical intervention (grade 2), 1 dog required surgical intervention under general anaesthesia (grade 3b), and 1 dog died as a result of complications (grade 5). Logistic regression analysis found that anatomic site was significantly associated with complications, where tumours located on the extremity was protective (P = .02; OR 0.06).

Feasibility and safety of whole lung irradiation in the treatment of canine appendicular osteosarcoma.

Whole lung irradiation (WLI) has been used successfully in humans as an adjuvant treatment for osteosarcoma. The aim of this study is to describe the feasibility and safety of WLI in dogs with appendicular osteosarcoma. Twelve client-owned dogs with appendicular osteosarcoma that had successfully completed amputation and four doses of carboplatin without evidence of gross metastasis were enrolled in this prospective clinical trial. Ten once-daily fractions of 1.75 Gy were administered to the planning target volume encompassing the lungs. Overall, WLI was well tolerated in these patients. No dogs developed symptoms of pneumonitis or pulmonary fibrosis. Haematopoietic toxicity evaluated during radiation therapy was found to be mild. The median disease free interval for WLI treated dogs was not significantly different than the median DFI for a group of historic control dogs (376 days for WLI treated dogs versus 304.5 days for control dogs; p = 0.5461). Although no significant improvement in outcome was observed with this study, WLI appears to be safe in dogs and warrants further investigation to characterize the efficacy and toxicity.

Transient Activation of the Hedgehog-Gli Pathway Rescues Radiotherapy-Induced Dry Mouth via Recovering Salivary Gland Resident Macrophages.

Irreversible hypofunction of salivary glands is a common side effect of radiotherapy for head and neck cancer and is difficult to remedy. Recent studies indicate that transient activation of Hedgehog signaling rescues irradiation-impaired salivary function in animal models, but the underlying mechanisms are largely unclear. Here, we show in mice that activation of canonical Gli-dependent Hedgehog signaling by Gli1 gene transfer is sufficient to recover salivary function impaired by irradiation. Salivary gland cells responsive to Hedgehog/Gli signaling comprised small subsets of macrophages, epithelial cells, and endothelial cells, and their progeny remained relatively rare long after irradiation and transient Hedgehog activation. Quantities and activities of salivary gland resident macrophages were substantially and rapidly impaired by irradiation and restored by Hedgehog activation. Conversely, depletion of salivary gland macrophages by clodronate liposomes compromised the restoration of irradiation-impaired salivary function by transient Hedgehog activation. Single-cell RNA sequencing and qRT-PCR of sorted cells indicated that Hedgehog activation greatly enhances paracrine interactions between salivary gland resident macrophages, epithelial progenitors, and endothelial cells through Csf1, Hgf, and C1q signaling pathways. Consistently, expression of these paracrine factors and their receptors in salivary glands decreased following irradiation but were restored by transient Hedgehog activation. These findings reveal that resident macrophages and their prorepair paracrine factors are essential for the rescue of irradiation-impaired salivary function by transient Hedgehog activation and are promising therapeutic targets of radiotherapy-induced irreversible dry mouth. SIGNIFICANCE: These findings illuminate a novel direction for developing effective treatment of irreversible dry mouth, which is common after radiotherapy for head and neck cancer and for which no effective treatments are available. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5531/F1.large.jpg.See related commentary by Coppes, p. 5462.

A case report of total skin photon radiation therapy for cutaneous epitheliotropic lymphoma in a dog.

BACKGROUND: Total skin electron beam radiation therapy (TSEBT) is an effective treatment for primary diffuse cutaneous lymphomas in humans. While several techniques exist, they all require significant commitment of staff time and resources. In veterinary medicine, canine-specific techniques and strategies have been adapted and delivered but deemed not "realistically" clinically implementable given the time commitment of over 2.5 h plus per fraction or have been relegated to palliative intent. Leveraging these technologies of helical tomotherapy and 3D printing, we developed and clinically implemented a radiotherapeutic treatment strategy for the management of medically refractory diffuse cutaneous lymphoma in the dog. CASE PRESENTATION: A 13.5-year-old female spayed Bichon Frise presented to the Oncology service at Texas A&M University, College of Veterinary Medicine due to the progression of diffuse cutaneous epitheliotropic lymphoma (CEL) that had failed medical management. Twenty-seven gray were delivered to the patient with a treatment time requirement under 40 min including real time monitoring of anesthesia during setup and treatment. A partial response was noticeable after four fractions and the tumor completely regressed progressively over the entire treated area by the end of therapy. A grade 1 lethargy, fatigue, weight loss, and oral mucositis and grade 2 alopecia, nail/claw changes, pruritus, scaling, anorexia, and diarrhea were noted during treatment. Additionally, a grade 3 thrombocytopenia developed after fraction eight requiring a treatment interruption of 6 weeks and prescription modification prior to treatment continuation and completion. From the beginning of total skin photon radiation therapy (TSPT) treatment until the time of the patient was euthanized unrelated to cutaneous epitheliotropic lymphoma (123 days), only one new lesion on the head was identified and confirmed by histopathology within the treated fields. CONCLUSIONS: The proposed technique is an acceptable alternative to TSEBT that is actually clinically implementable within a palliative or definitive setting and clinical constraints, however further testing and refinement is needed to reduce hematological complications and to confirm and expand on preliminary findings.

Reduced risk of pneumonia after changes in anesthetic procedures for dogs receiving repeated anesthesia for radiation treatment.

Radiation therapy requires repeated anesthetic administration to patients who often have multiple comorbidities contributing to an increased rate of anesthetic complications such as pneumonia. This is a retrospective observational study in which data were collected from 146 medical records of dogs receiving repeat anesthesia for radiation treatment from prior to management changes and compared to data from 149 cases treated after completion of management changes. The objective was to determine if changes in case management protocol that were put in place decreased the risk of pneumonia development among these patients. Management changes that were made included the following: decrease in anticholinergic and pure-mu opioid use, change in positioning during intubation and recovery, prophylactic treatment of nausea, timing of cuff inflation and deflation, and aseptic handling of intubation equipment. There was a significant association between diagnosis of pneumonia and the following: pre- vs. post-changes to protocol, presence of a neurologic tumor, presence of respiratory disease, presence of megaesophagus, and number of radiation fractions completed. Diagnosis of pneumonia did not vary significantly by age group, body weight category, or sex. In a multivariable logistic regression model that controlled for the effects of the three concurrent diseases and fractions completed, the odds of being diagnosed with pneumonia were approximately 10 times greater among dogs anesthetized prior to management changes (odds ratio = 9.9, 95% CI = 2.0-48.7, P = 0.005).

Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice.

BACKGROUND & AIMS: Transmembrane protein 173 (TMEM173 or STING) signaling by macrophage activates the type I interferon-mediated innate immune response. The innate immune response contributes to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). We investigated whether STING regulates diet-induced in hepatic steatosis, inflammation, and liver fibrosis in mice. METHODS: Mice with disruption of Tmem173 (STINGgt) on a C57BL/6J background, mice without disruption of this gene (controls), and mice with disruption of Tmem173 only in myeloid cells were fed a standard chow diet, a high-fat diet (HFD; 60% fat calories), or a methionine- and choline-deficient diet (MCD). Liver tissues were collected and analyzed by histology and immunohistochemistry. Bone marrow cells were isolated from mice, differentiated into macrophages, and incubated with 5,6-dimethylxanthenone-4-acetic acid (DMXAA; an activator of STING) or cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Macrophages or their media were applied to mouse hepatocytes or human hepatic stellate cells (LX2) cells, which were analyzed for cytokine expression, protein phosphorylation, and fat deposition (by oil red O staining after incubation with palmitate). We obtained liver tissues from patients with and without NAFLD and analyzed these by immunohistochemistry. RESULTS: Non-parenchymal cells of liver tissues from patients with NAFLD had higher levels of STING than cells of liver tissues from patients without NAFLD. STINGgt mice and mice with disruption only in myeloid cells developed less severe hepatic steatosis, inflammation, and/or fibrosis after the HFD or MCD than control mice. Levels of phosphorylated c-Jun N-terminal kinase and p65 and mRNAs encoding tumor necrosis factor and interleukins 1B and 6 (markers of inflammation) were significantly lower in liver tissues from STINGgt mice vs control mice after the HFD or MCD. Transplantation of bone marrow cells from control mice to STINGgt mice restored the severity of steatosis and inflammation after the HFD. Macrophages from control, but not STINGgt, mice increased markers of inflammation in response to lipopolysaccharide and cGAMP. Hepatocytes and stellate cells cocultured with STINGgt macrophages in the presence of DMXAA or incubated with the medium collected from these macrophages had decreased fat deposition and markers of inflammation compared with hepatocytes or stellate cells incubated with control macrophages. CONCLUSIONS: Levels of STING were increased in liver tissues from patients with NAFLD and mice with HFD-induced steatosis. In mice, loss of STING from macrophages decreased the severity of liver fibrosis and the inflammatory response. STING might be a therapeutic target for NAFLD.

An experimental model for calcium carbonate urolithiasis in goats.

BACKGROUND: Calcium carbonate is a common urolith type in small ruminants with no high-yield experimental model to evaluate animal susceptibility or preventative measure response. HYPOTHESIS: That novel plastic winged implants would allow accumulation and quantification of calcium carbonate calculus formation in goats on a high-calcium diet and identify individual variation between goats in the mass of calculi produced. ANIMALS: Eight nonpregnant 3- and 4-year-old Boer-cross does, weighing 22.3-39.5 kg, determined to be healthy based on physical examination, were used in these experiments. METHODS: Prospective cohort study for in vivo experimental model development. Implants were placed into the urinary bladder lumen in 8 goats over 2 evaluation periods. The alfalfa-based ration had a total ration Ca : P of 3.29 and 3.84 : 1, respectively. Urine was collected at 0, 28, 56, and 84 days in the 1st experiment; blood and urine at those timepoints in the 2nd experiment. For each evaluation period, the implants were removed 84 days after implantation and weighed. Accumulated calculi mass was calculated and compared between goats and was analyzed for composition. RESULTS: Implant retention was 100% and 86% in the 2 studies. All goats with retained implants accumulated calcium carbonate at a mean implant gain per day across studies ranging from 0.44 to 57.45 mg. Two goats accumulated (0.44-7.65 mg/day and 33.64 & 57.45 mg/day) significantly more urolith material than the cohort across both studies (P = .047). No routine analytes on blood or urine were found to be explanatory for the difference observed. CONCLUSIONS AND CLINICAL IMPORTANCE: These findings form a basis for implant and diet selection for use in future studies of urolithiasis development and for studies regarding individual susceptibility to urolithiasis.

Delivery of Sonic Hedgehog Gene Repressed Irradiation-induced Cellular Senescence in Salivary Glands by Promoting DNA Repair and Reducing Oxidative Stress.

Rationale: Irreversible hypofunction of salivary glands or xerostomia is common in head and neck cancer survivors treated with radiotherapy even when various new techniques are applied to minimize the irradiation (IR) damage. This condition severely impairs the quality of life of patients and can only be temporarily relieved with current treatments. We found recently that transient expression of Sonic Hedgehog (Shh) in salivary glands after IR rescued salivary function, but the underlying mechanisms are not totally clear. Methods: We generated a mouse model of IR-induced hyposalivation, and delivered adenoviral vectors carrying Shh or control GFP gene into submandibular glands (SMGs) via retrograde ductal instillation 3 days after IR. The cellular senescence was evaluated by senescence-associated beta-galactosidase assay and the expression of senescence markers. The underlying mechanisms were explored by examining DNA damage, oxidative stress, and the expression of related genes by qRT-PCR, Western blot and immunofluorescent staining. Results: Shh gene transfer repressed IR-induced cellular senescence by promoting DNA repair and decreasing oxidative stress, which is mediated through upregulating expression of genes related to DNA repair such as survivin and miR-21 and repressing expression of pro-senescence gene Gdf15 likely downstream of miR-21. Conclusion: Repressing cellular senescence contributes to the rescue of IR-induced hyposalivation by transient activation of Hh signaling, which is related to enhanced DNA repair and decreased oxidative stress in SMGs.

Functional genomics screening utilizing mutant mouse embryonic stem cells identifies novel radiation-response genes.

Elucidating the genetic determinants of radiation response is crucial to optimizing and individualizing radiotherapy for cancer patients. In order to identify genes that are involved in enhanced sensitivity or resistance to radiation, a library of stable mutant murine embryonic stem cells (ESCs), each with a defined mutation, was screened for cell viability and gene expression in response to radiation exposure. We focused on a cancer-relevant subset of over 500 mutant ESC lines. We identified 13 genes; 7 genes that have been previously implicated in radiation response and 6 other genes that have never been implicated in radiation response. After screening, proteomic analysis showed enrichment for genes involved in cellular component disassembly (e.g. Dstn and Pex14) and regulation of growth (e.g. Adnp2, Epc1, and Ing4). Overall, the best targets with the highest potential for sensitizing cancer cells to radiation were Dstn and Map2k6, and the best targets for enhancing resistance to radiation were Iqgap and Vcan. Hence, we provide compelling evidence that screening mutant ESCs is a powerful approach to identify genes that alter radiation response. Ultimately, this knowledge can be used to define genetic variants or therapeutic targets that will enhance clinical therapy.

Molecular imaging biomarkers of resistance to radiation therapy for spontaneous nasal tumors in canines.

PURPOSE: Imaging biomarkers of resistance to radiation therapy can inform and guide treatment management. Most studies have so far focused on assessing a single imaging biomarker. The goal of this study was to explore a number of different molecular imaging biomarkers as surrogates of resistance to radiation therapy. METHODS AND MATERIALS: Twenty-two canine patients with spontaneous sinonasal tumors were treated with accelerated hypofractionated radiation therapy, receiving either 10 fractions of 4.2 Gy each or 10 fractions of 5.0 Gy each to the gross tumor volume. Patients underwent fluorodeoxyglucose (FDG)-, fluorothymidine (FLT)-, and Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM)-labeled positron emission tomography/computed tomography (PET/CT) imaging before therapy and FLT and Cu-ATSM PET/CT imaging during therapy. In addition to conventional maximum and mean standardized uptake values (SUV(max); SUV(mean)) measurements, imaging metrics providing response and spatiotemporal information were extracted for each patient. Progression-free survival was assessed according to response evaluation criteria in solid tumor. The prognostic value of each imaging biomarker was evaluated using univariable Cox proportional hazards regression. Multivariable analysis was also performed but was restricted to 2 predictor variables due to the limited number of patients. The best bivariable model was selected according to pseudo-R(2). RESULTS: The following variables were significantly associated with poor clinical outcome following radiation therapy according to univariable analysis: tumor volume (P=.011), midtreatment FLT SUV(mean) (P=.018), and midtreatment FLT SUV(max) (P=.006). Large decreases in FLT SUV(mean) from pretreatment to midtreatment were associated with worse clinical outcome (P=.013). In the bivariable model, the best 2-variable combination for predicting poor outcome was high midtreatment FLT SUV(max) (P=.022) in combination with large FLT response from pretreatment to midtreatment (P=.041). CONCLUSIONS: In addition to tumor volume, pronounced tumor proliferative response quantified using FLT PET, especially when associated with high residual FLT PET at midtreatment, is a negative prognostic biomarker of outcome in canine tumors following radiation therapy. Neither FDG PET nor Cu-ATSM PET were predictive of outcome.

The Modellers' Halting Foray into Ecological Theory: Or, What is This Thing Called 'Growth Rate'?

This discussion paper describes the attempt of an imagined group of non-ecologists ("Modellers") to determine the population growth rate from field data. The Modellers wrestle with the multiple definitions of the growth rate available in the literature and the fact that, in their modelling, it appears to be drastically model-dependent, which seems to throw into question the very concept itself. Specifically, they observe that six representative models used to capture the data produce growth-rate values, which differ significantly. Almost ready to concede that the problem they set for themselves is ill-posed, they arrive at an alternative point of view that not only preserves the identity of the concept of the growth rate, but also helps discriminate between competing models for capturing the data. This is accomplished by assessing how robustly a given model is able to generate growth-rate values from randomized time-series data. This leads to the proposal of an iterative approach to ecological modelling in which the definition of theoretical concepts (such as the growth rate) and model selection complement each other. The paper is based on high-quality field data of mites on apple trees and may be called a "data-driven opinion piece".

Mobile applications for dermatology.

The number of available mobile applications has increased by 500% over the past 3 years. Searching for useful dermatology applications may be overwhelming. The following summary may help both advanced and budding dermatologists select useful programs.

Spatially resolved regression analysis of pre-treatment FDG, FLT and Cu-ATSM PET from post-treatment FDG PET: an exploratory study.

PURPOSE: To quantify associations between pre-radiotherapy and post-radiotherapy PET parameters via spatially resolved regression. MATERIALS AND METHODS: Ten canine sinonasal cancer patients underwent PET/CT scans of [(18)F]FDG (FDG(pre)), [(18)F]FLT (FLT(pre)), and [(61)Cu]Cu-ATSM (Cu-ATSM(pre)). Following radiotherapy regimens of 50 Gy in 10 fractions, veterinary patients underwent FDG PET/CT scans at 3 months (FDG(post)). Regression of standardized uptake values in baseline FDG(pre), FLT(pre) and Cu-ATSM(pre) tumour voxels to those in FDG(post) images was performed for linear, log-linear, generalized-linear and mixed-fit linear models. Goodness-of-fit in regression coefficients was assessed by R(2). Hypothesis testing of coefficients over the patient population was performed. RESULTS: Multivariate linear model fits of FDG(pre) to FDG(post) were significantly positive over the population (FDG(post) ~ 0.17 · FDG(pre), p = 0.03), and classified slopes of RECIST non-responders and responders to be different (0.37 vs. 0.07, p = 0.01). Generalized-linear model fits related FDG(pre) to FDG(post) by a linear power law (FDG(post) ~ FDG(pre)(0.93),p<0.001). Univariate mixture model fits of FDG(pre) improved R(2) from 0.17 to 0.52. Neither baseline FLT PET nor Cu-ATSM PET uptake contributed statistically significant multivariate regression coefficients. CONCLUSIONS: Spatially resolved regression analysis indicates that pre-treatment FDG PET uptake is most strongly associated with three-month post-treatment FDG PET uptake in this patient population, though associations are histopathology-dependent.

Feasibility of dose painting using volumetric modulated arc optimization and delivery.

PURPOSE: Dose painting strategies are limited by optimization algorithms in treatment planning systems and physical constraints of the beam delivery. We investigate dose conformity using the RapidArc optimizer and beam delivery technique. Furthermore, robustness of the plans with respect to positioning uncertainties are evaluated. METHODS: A head & neck cancer patient underwent a [(61)Cu]Cu-ATSM PET/CT-scan. PET-SUVs were converted to prescribed dose with a base dose of 60 Gy, and target mean dose 90 Gy. The voxel-based prescription was converted into 3, 5, 7, 9, and 11 discrete prescription levels. Optimization was performed in Eclipse, varying the following parameters: MLC leaf width (5 mm and 2.5 mm), number of arcs (1 and 2) and collimator rotation (0, 15, 30 and 45 degrees). Dose conformity was evaluated using quality volume histograms (QVHs), and relative volumes receiving within ±5% of prescribed dose (Q(0.95-1.05)). Deliverability was tested using a Delta4(®) phantom. Robustness was tested by shifting the isocenter 1 mm and 2 mm in all directions, and recalculating the dose. RESULTS: Good conformity was obtained using MLC leaf width 2.5 mm, two arcs, and collimators 45/315 degrees, with Q(0.95-1.05)=92.8%, 91.6%, 89.7% and 84.6%. Using only one arc or increasing the MLC leaf width had a small deteriorating effect of 2-5%. Small changes in collimator angle gave small changes, but large changes in collimator angle gave a larger decrease in plan conformity; for angles of 15 and 0 degrees (two arcs, 2.5 mm leaf width), Q(0.95-1.05) decreased by up to 15%. Consistency between planned and delivered dose was good, with ∼90% of gamma values <1. For 1 mm shift, Q(0.95-1.05) was decreased by 5-15%, while for 2 mm shift, Q(0.95-1.05) was decreased to 55-60%. CONCLUSIONS: Results demonstrate feasibility of planning of prescription doses with multiple levels for dose painting using RapidArc, and plans were deliverable. Robustness to positional error was low.

Feasibility and sensitivity study of helical tomotherapy for dose painting plans.

Important limitations for dose painting are due to treatment planning and delivery constraints. The purpose of this study was to develop a methodology for creating voxel-based dose painting plans that are deliverable using the clinical TomoTherapy Hi-Art II treatment planning system (TPS). Material and methods. Uptake data from a head and neck patient who underwent a [(61)Cu]Cu-ATSM (hypoxia surrogate) PET/CT scan was retrospectively extracted for planning. Non-uniform voxel-based prescriptions were converted to structured-based prescriptions for compatibility with the Hi-Art II TPS. Optimized plans were generated by varying parameters such as dose level, structure importance, prescription point normalization, DVH volume, min/max dose, and dose penalty. Delivery parameters such as pitch, jaw width and modulation factor were also varied. Isodose distributions, quality volume histograms and planning target volume percentage receiving planned dose within 5% of the prescription (Q(0.95-1.05)) were used to evaluate plan conformity. Results. In general, the conformity of treatment plans to dose prescriptions was found to be adequate for delivery of dose painting plans. The conformity was better as the dose levels increased from three to nine levels (Q(0.95-1.05): 69% to 93%), jaw decreased in width from 5.0cm to 1.05cm (Q(0.95-1.05): 81% to 93%), and modulation factor increased up to 2.0 (Q(0.95-1.05): 36% to 92%). The conformity was invariant to changes in pitch. Plan conformity decreased as the prescription DVH constraint (Q(0.95-1.05): 93% vs. 89%) or the normalization point (Q(0.95-1.05): 93% vs. 90%) deviated from the means. Conclusion. This investigation demonstrated the ability of the Hi-Art II TPS to create voxel-based dose painting plans. Results indicated that agreement in prescription dose and planned dose distributions for all plans were sensitive to physical delivery parameter changes in jaw width and modulation factors, but insensitive to changes in pitch. Tight constraints on target structures also resulted in decreased plan conformity while under a relaxed set of optimization parameters, plan conformity was increased.

Dosimetric impact of daily setup variations during treatment of canine nasal tumors using intensity-modulated radiation therapy.

Intensity-modulated radiation therapy (IMRT) can be employed to yield precise dose distributions that tightly conform to targets and reduce high doses to normal structures by generating steep dose gradients. Because of these sharp gradients, daily setup variations may have an adverse effect on clinical outcome such that an adjacent normal structure may be overdosed and/or the target may be underdosed. This study provides a detailed analysis of the impact of daily setup variations on optimized IMRT canine nasal tumor treatment plans when variations are not accounted for due to the lack of image guidance. Setup histories of ten patients with nasal tumors previously treated using helical tomotherapy were replanned retrospectively to study the impact of daily setup variations on IMRT dose distributions. Daily setup shifts were applied to IMRT plans on a fraction-by-fraction basis. Using mattress immobilization and laser alignment, mean setup error magnitude in any single dimension was at least 2.5 mm (0-10.0 mm). With inclusions of all three translational coordinates, mean composite offset vector was 5.9 +/- 3.3 mm. Due to variations, a loss of equivalent uniform dose for target volumes of up to 5.6% was noted which corresponded to a potential loss in tumor control probability of 39.5%. Overdosing of eyes and brain was noted by increases in mean normalized total dose and highest normalized dose given to 2% of the volume. Findings suggest that successful implementation of canine nasal IMRT requires daily image guidance to ensure accurate delivery of precise IMRT distributions when non-rigid immobilization techniques are utilized. Unrecognized geographical misses may result in tumor recurrence and/or radiation toxicities to the eyes and brain.

Radiobiological and treatment planning study of a simultaneously integrated boost for canine nasal tumors using helical tomotherapy.

Feasibility of delivering a simultaneously integrated boost to canine nasal tumors using helical tomotherapy to improve tumor control probability (TCP) via an increase in total biological equivalent uniform dose (EUD) was evaluated. Eight dogs with varying size nasal tumors (5.8-110.9 cc) were replanned to 42 Gy to the nasal cavity and integrated dose boosts to gross disease of 45.2, 48.3, and 51.3 Gy in 10 fractions. EUD values were calculated for tumors and mean normalized total doses (NTD(mean)) for organs at risk (OAR). Normal Tissue Complication Probability (NTCP) values were obtained for OARs, and estimated TCP values were computed using a logistic dose-response model and based on deliverable EUD boost doses. Significant increases in estimated TCP to 54%, 74%, and 86% can be achieved with 10%, 23%, and 37% mean relative EUD boosts to the gross disease, respectively. NTCP values for blindness of either eye and for brain necrosis were < 0.01% for all boosts. Values for cataract development were 31%, 42%, and 46% for studied boost schemas, respectively. Average NTD(mean) to eyes and brain for mean EUD boosts were 10.2, 11.3, and 12.1 Gy3, and 7.5, 7.2, and 7.9 Gy2, respectively. Using helical tomotherapy, simultaneously integrated dose boosts can be delivered to increase the estimated TCP at 1-year without significantly increasing the NTD(mean) to eyes and brain. Delivery of these treatments in a prospective trial may allow quantification of a dose-response relationship in canine nasal tumors.