ACVR and ECVDI consensus statement: Reporting elements for toxicity criteria of the veterinary radiation therapy oncology group v2.0.

The toxicity criteria of the veterinary radiation therapy oncology group (VRTOG) version 2 guidelines are a substantial update to reflect significant advances in radiation oncology over the last three decades. Radiation therapy techniques provide precise and spatially accurate radiation delivery, which facilitates treating tumors in more anatomic locations and incorporating hypofractionated protocols. The purpose of this update is to aid radiation oncology teams in capturing and grading clinically relevant data that impacts the decision-making process in everyday practice and the assessment of clinical trials involving radiation therapy. A dedicated committee initially updated the criteria to include more anatomical sites and grades to characterize a broad spectrum of possible radiation-induced acute and late tissue changes. Through the revision process, which solicited and incorporated feedback from all radiation oncologists within the American College of Veterinary Radiology (ACVR) and specialists outside the ACVR, the authors endeavored to create a grading structure reflective of clinical decision-making in daily radiation oncology. The updated VRTOG v2 toxicity criteria guideline complements the updated Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) guidelines. Because radiation oncology continues to progress rapidly, the VRTOG toxicity criteria should be regularly updated as adverse event data that will be collected following this update further informs the practice of radiation oncology.

CT features of subcutaneous, intermuscular, and intramuscular mast cell tumors in dogs.

Surgical removal is the treatment of choice for subcutaneous (SC), intermuscular (InterM), and intramuscular (IntraM) mast cell tumors (MCTs). Advanced imaging (CT or MRI) is frequently used for presurgical planning, but InterM and IntraM MCTs can be difficult to identify and delineate on CT. Aims of the current retrospective, diagnostic accuracy, observer agreement study were to describe the imaging features of SC, InterM, and IntraM MCTs on CT and to assess the limitation of CT to identify the full local extent of the MCT. Inclusion criteria for the study were dogs with a cytologically or histologically diagnosed MCTs determined to be SC, InterM, or IntraM MCT based on histology and/or a CT scan performed in the gross disease setting. Two board-certified veterinary radiologists reviewed the CT images and recorded location, contrast enhancement pattern, and delineation between the normal and abnormal tissue. Sensitivity and specificity of CT for determining location (SC/InterM versus IntraM) was 85.71% and 55.56%, respectively, when compared to consensus location based on surgical pathology report/CT/MRI review. There was a low inter-rater agreement for delineation (kappa: 0.150 (-0.070 to 0.370) and measurement had a low/moderate correlation (rho: 0.4667 to 0.5792). Upon review by a surgical oncologist, CT findings were deemed insufficient for curative surgical planning in 13 of 16 due to inadequate definition of tumor depth, compartment boundary (fascial plane) or MCT margins. The use of CT for presurgical planning of SC/InterM/IntraM MCT dogs has limitations, especially when differentiating MCT from the adjacent muscle.

The hypoattenuating ocular lens on CT is not always due to cataract formation.

Hypoattenuating ocular lenses on CT have been described with cataract formation in humans, however published studies are currently lacking regarding this finding in veterinary patients. The purpose of this retrospective and prospective study was to describe the varying CT appearances of the ocular lens in vivo, and investigate the causes for CT density variations in a population of cats and dogs. A total of 102 canine and feline patients with CT of the head acquired at the authors' hospital between May 2011 and March 2019 were included. A bilateral hypoattenuating halo surrounding an isoattenuating to mildly hypoattenuating core was described in the ocular lens center of every cat in which a Philips brand proprietary image construction filter was used. A similar but more varied hypoattenuating region was noted in the lenses of 45.8% of dogs where the same filter was applied, as well as 43.8% of dogs with a second, similar filter. Ophthalmic examination of three live cats and one dog with hypoattenuating lenses demonstrated normal lens translucency, excluding the presence of cataract. The effect of different proprietary filters on lens appearance was also described in three fresh cadavers with normal lenses identified on ophthalmic, macroscopic, and microscopic examination. Etiology of the hypoattenuating areas within the ocular lens was not conclusively determined. Recognition that such a variant may be seen in the absence of cataract is important, in order to prevent misdiagnosis.

Definitive-intent intensity-modulated radiation therapy provides similar outcomes to those previously published for definitive-intent three-dimensional conformal radiation therapy in dogs with primary brain tumors: A multi-institutional retrospective study.

Radiotherapy with or without surgery is a common choice for brain tumors in dogs. Although numerous studies have evaluated use of three-dimensional conformal radiotherapy, reports of definitive-intent, IMRT for canine intracranial tumors are lacking. Intensity-modulated radiation therapy has the benefit of decreasing dose to nearby organs at risk and may aid in reducing toxicity. However, increasing dose conformity with IMRT calls for accurate target delineation and daily patient positioning, in order to decrease the risk of a geographic miss. To determine survival outcome and toxicity, we performed a multi-institutional retrospective observational study evaluating dogs with brain tumors treated with IMRT. Fifty-two dogs treated with fractionated, definitive-intent IMRT at four academic radiotherapy facilities were included. All dogs presented with neurologic signs and were diagnosed via MRI. Presumed radiological diagnoses included 37 meningiomas, 12 gliomas, and one peripheral nerve sheath tumor. One dog had two presumed meningiomas and one dog had either a glioma or meningioma. All dogs were treated in the macroscopic disease setting and were prescribed a total dose of 45-50 Gy (2.25-2.5 Gy per fraction in 18-20 daily fractions). Median survival time for all patients, including seven cases treated with a second course of therapy was 18.1 months (95% confidence of interval 12.3-26.6 months). As previously described for brain tumors, increasing severity of neurologic signs at diagnosis was associated with a worse outcome. Intensity-modulated radiation therapy was well tolerated with few reported acute, acute delayed, or late side effects.

Proposed expansion margins for planning organ at risk volume for lenses during radiation therapy of the nasal cavity in dogs and cats.

Radiation therapy protocols for the feline or canine nasal cavity can damage epithelial cells of the posterior pole of the lens and lead to the development of cataracts. Aims of this retrospective, descriptive study were to calculate movements of the lens during radiation therapy of the nasal cavity in a sample of cats and dogs, and to propose species-specific expansion margins for planning organ at risk volume (PRV) to minimize radiation doses to the lens. All included patients were immobilized with an indexed bite block and positioned in a vacuum positioning cushion for head irradiation. On-board cone beam CT (CBCT) imaging was used for patient alignment. Both ocular lenses were contoured on the therapeutic CBCTs. Coregistration (fusion) between the planning CT and CBCTs was used to measure the movements of the lens. Two measurements were made: the differences between the centroid point of each lens as well as the displacement of the coregistrations. A total of 496 different observations were recorded from 14 cats and 52 dogs. Using the displacement results, we calculated how often the lens would be within the lens-PRV contour. We proposed that an optimal expansion margin from the lens volume of 2 mm in cats and 3 mm in dogs may be necessary in generating PRV expansion for the lens. From our results, we expect the lens would therefore be within these proposed PRV expansions in 92% of the feline measurements and 95% of the canine measurements.

Mycobacterium tuberculosis promotes anti-apoptotic activity of the macrophage by PtpA protein-dependent dephosphorylation of host GSK3α.

Mycobacterium tuberculosis tyrosine phosphatase PtpA inhibits two key cellular events in macrophages required for the elimination of invading organisms, phagosome acidification, and maturation. Kinome analysis revealed multiple PtpA-dependent changes to the phosphorylation status of macrophage proteins upon M. tuberculosis infection. Among those proteins we show that PtpA dephosphorylates GSK3α on amino acid Tyr(279), which leads to modulation of GSK3α anti-apoptotic activity, promoting pathogen survival early during infection.

The efficacy and adverse event profile of dexamethasone, melphalan, actinomycin D, and cytosine arabinoside (DMAC) chemotherapy in relapsed canine lymphoma.

In this retrospective study, a chemotherapy protocol using dexamethasone, melphalan, actinomycin D, and cytosine arabinoside (DMAC) was evaluated for efficacy and adverse event profile as a first line rescue protocol in 86 client-owned dogs previously treated with a CHOP-based protocol. Forty-three dogs (43%) achieved remission (16% complete remission, 27% partial remission), and 57% were non-responders. The median overall progression-free survival (PFS) was 24 days. Adverse events included thrombocytopenia in 41% of dogs, neutropenia in 17% of dogs, and gastrointestinal toxicity in 13% of dogs. Overall, 16% (13/79) dogs experienced grade III to IV thrombocytopenia, 8% (6/74) dogs grade III to IV neutropenia and 1% (1/79) dogs grade III to IV gastrointestinal toxicity. The efficacy of the DMAC protocol is similar to that of other rescue protocols in dogs with relapsed lymphoma but is associated with shorter PFS. The main toxicity is thrombocytopenia, which may limit treatment.

Profil de l'efficacité et des événements indésirables de la chimiothérapie à la déxaméthasone, au melphalan, à l'actinomycine D et à la cytosine arabinoside (DMAC) pour les rechutes du lymphome canin. Dans cette étude rétrospective, un protocole de chimiothérapie utilisant la dexaméthasone, le melphalan, l'actinomycine D et le cytosine arabinoside (DMAC) a été évalué pour le profil d'efficacité et d'événements indésirables en tant que protocole de secours de première ligne chez 86 chiens, appartenant à des clients, antérieurement traités à l'aide d'un protocole CHOP. Quarante-trois chiens (43 %) sont parvenus à la rémission (16 % rémission complète, 27 % en rémission partielle) et 57 % n'ont pas répondu au traitement. La survie globale médiane sans progression était de 24 jours. Les événements indésirables incluaient la thrombocytopénie chez 41 % des chiens, la neutropénie chez 17 % des chiens et la toxicité gastro-intestinale chez 13 % des chiens. Dans l'ensemble, 16 % (13/79 chiens) ont eu une thrombocytopénie de grade III à IV, 8 % (6/74 chiens) une neutropénie de grades III à IV et 1 % (1/79 chiens) une toxicité gastro-intestinale de grade III à IV. L'efficacité du protocole DMAC est semblable à celle d'autres protocoles de secours chez les chiens atteints d'une rechute de lymphome, mais elle est associée à une survie globale médiane sans progression réduite. La principale toxicité est la thrombocytopénie, qui peut limiter le traitement.(Traduit par Isabelle Vallières).

Diagnosis and treatment of a periocular myxosarcoma in a bearded dragon (Pogona vitticeps).

A 5-year-old male Australian bearded dragon (Pogona vitticeps) was presented with a 2-month history of a periocular mass. The clinical evaluation included a physical examination, hematology, biochemistry, and radiographs. The mass was treated surgically and diagnosed as myxosarcoma. Strontium-90 plesiotherapy was attempted, but the mass recurred 5 mo later.

Diagnostic et traitement d'un myosarcome périoculaire chez un dragon barbu(Pogona vitticeps) . Un dragon barbu mâle âgé de 5 ans (Pogona vitticeps) a été présenté avec une anamnèse de masse périoculaire apparue depuis 2 mois. L'évaluation clinique a inclus un examen physique, une hématologie, une biochimie et des radiographies. La masse a été traitée par chirurgie et diagnostiquée comme un myosarcome. Une plésiothérapie au strontium-90 a été tentée, mais la masse est revenue 5 mois plus tard.(Traduit par Isabelle Vallières).

Reason for euthanasia in dogs with urothelial carcinoma treated with chemotherapy or radiation therapy or both: A retrospective observational study.

BACKGROUND: Clients want to know the ultimate cause of death in their pet after cancer treatment. The cause of euthanasia and investigation of urinary obstruction in treated dogs with urothelial carcinoma (UC) has not been specifically reported in veterinary literature. HYPOTHESIS/OBJECTIVES: Our hypothesis was that the majority of treated dogs with UC are euthanized secondary to primary tumor factors, such as urinary obstruction. ANIMALS: Fifty-nine client-owned dogs diagnosed with UC. METHODS: Retrospective observational study on clinical signs and disease at euthanasia of dogs with UC treated by radiation therapy or chemotherapy or both. RESULTS: The median overall survival time (OST) of all dogs was 339 days (range, 17-1996; 95% confidence interval [CI], 185-392; interquartile range [IQR], 112-505). Of dogs deemed to have been euthanized because of UC (50/59, 85%), the primary cause was considered to be local progression in 31/50 (62%), most often because of perceived complete or partial urinary obstruction (24/31, 77%). No variables were found to be predictive of urinary obstruction. The overall documented metastatic rate was 56%. In dogs euthanized because of UC, metastasis was deemed to be the cause in 19/50 (38%) dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Regardless of the type of treatment, UC in dogs has a poor prognosis and there is a continuing need to improve treatments that focus on local control of the primary tumor, given its high contribution to the decision for euthanasia. Proactive management to avoid the high frequency of urinary obstruction may be worthy of future investigation.

Urinary iodine clearance after iodinated contrast administration to healthy cats.

BACKGROUND: Exogenous iodine interferes with the uptake of radioactive iodine (131I) by the thyroid gland. This has potential implications for the treatment of cats with hyperthyroidism that have recently undergone computed tomography (CT) with IV administration of iodinated contrast medium (ICM). HYPOTHESIS: To determine the time to normalize urinary iodine clearance after administration of ICM. We hypothesized that it would require 4 weeks for urinary iodine concentration (UIC) to decrease to baseline after IV administration of ICM. ANIMALS: Ten healthy adult neutered male cats. METHODS: All cats were sedated and received Iopamidol at a dose of 2 mL/kg (600 mg/kg). Urinary iodine and creatinine concentrations were measured before administration of Iopamidol and on days 1, 2, 3, 7, 10 and weeks 2 to 6 after administration. The urinary iodine-to-creatinine ratio (UICR) was calculated. Outcome variables were modeled using a linear mixed-effects model. RESULTS: Urinary iodine concentration increased 37- to 884-fold on Day 1 after ICM injection and returned to baseline during Week 2. Compared with baseline, UIC was significantly increased for Days 1 to 7 (all P < .001); UC was significantly lower for Days 1 to 10 (all P < .03); and UICR was significantly increased from Days 1 to 10 (all P < .001, except Day 10 P = .05). CONCLUSIONS: Urinary clearance of iodine after IV administration of ICM requires 10 days to return to baseline in healthy cats. A 2-week interval between the iodinated contrast study and 131I treatment could be appropriate but needs to be confirmed in hyperthyroid cats.

Surgery and postoperative definitive radiotherapy for management of canine soft tissue sarcoma: a multi-institutional retrospective study of 272 dogs (2010-2020).

OBJECTIVE: To report local progression and survival in dogs following surgery and postoperative definitive radiotherapy (dRT) for management of soft tissue sarcoma (STS) and to evaluate risk factors for local progression and survival. METHODS: Records were retrospectively reviewed at 9 referral hospitals for dogs managed with postoperative dRT between January 1, 2010, and January 1, 2020, following surgery for STS. Data related to presentation, surgery, dRT, systemic therapy, and outcome were abstracted. Selected variables were assessed for association with local progression and overall survival. RESULTS: 272 dogs were included. Histologic grade was reported in 249 dogs: 102 were grade 1 (40.9%), 120 were grade 2 (48.2%), and 27 were grade 3 (10.8%). Local progression was suspected or confirmed in 56 dogs. Local progression rates were similar for grade 1 (24 of 89 [26.7%]), grade 2 (23 of 111 [20.7%]), and grade 3 tumors (6 of 22 [27.3%]). Previous recurrence (P = .010) and subsequent distant metastasis (P = .014) were associated with more frequent local progression; intensity-modulated radiotherapy was associated with decreased local progression (P = .025) compared to other forms of delivery. Age (P = .049), grade (P = .009), previous recurrence (P = .009), and institution type for surgery (P = .043) were associated with overall survival. CONCLUSIONS: Outcomes for most dogs were good; however, the frequency of local progression indicates an ongoing need to critically appraise local management strategies, particularly for low-grade STS. Intensity-modulated radiotherapy was associated with lower rates of local progression and may be preferred to less precise forms of delivery. CLINICAL RELEVANCE: These data may guide clinicians when making decisions regarding dRT for management of STS.

Successful long-term outcome with radiation and prednisolone following a postoperative feline vertebral angiomatosis relapse.

Case summary: A 1-year-old male castrated domestic shorthair cat was presented to the Ontario Veterinary College for a week-long history of lethargy and reluctance to walk. CT and MRI revealed a monostotic T5 compressive vertebral lesion that was excised in surgery via pediculectomy. Histology and advanced imaging were consistent with feline vertebral angiomatosis. The cat relapsed both clinically and on CT 2 months postoperatively and was therefore treated with an intensity-modulated radiation therapy protocol (45 Gy over 18 fractions) and tapering doses of prednisolone. On follow-up CT and MRI at 3 and 6 months post-radiation, the lesion was static and then improved at 19 months post-radiation, with no signs of pain reported. Relevance and novel information: To our knowledge, this is the first described case of a postoperative relapse of feline vertebral angiomatosis treated with radiation therapy and prednisolone with a successful long-term follow-up.

Modulation of mTOR signaling by radiation and rapamycin treatment in canine mast cell cancer cells.

Rapamycin has been reported to reduce cancer cell survival in certain tumors following radiation therapy, but the mechanisms driving this phenomenon are unclear. Rapamycin inhibits mTOR signaling, a pathway responsible for several essential cell functions. The objective of this study was to investigate the effects of rapamycin and radiation on the activation and inhibition of mTOR signaling and the relationship between mTOR signaling and DNA damage response in vitro using canine mast cell tumor (MCT) cancer cell lines. Rapamycin rapidly inhibited S6K phosphorylation in a dose-dependent manner. Ionizing radiation (3, 6, or 10 Gy) was able to activate mTOR signalling, but the combination of radiation and rapamycin maintained mTOR inhibition. The comet assay revealed that co-treatment with rapamycin induced modest increases in the severity of DNA damage to MCT cells, but that these differences were not statistically significant. Although the relationship between mTOR and DNA damage response in MCT cancer cell lines remains unclear, our findings suggest the possibility of interaction, leading to enhancement of radiation response.

Il a été rapporté que la rapamycine réduisait la survie des cellules cancéreuses dans certaines tumeurs après une radiothérapie, mais les mécanismes à l'origine de ce phénomène ne sont pas clairs. La rapamycine inhibe la signalisation mTOR, une voie responsable de plusieurs fonctions cellulaires essentielles. L'objectif de cette étude était d'étudier les effets de la rapamycine et des radiations sur l'activation et l'inhibition de la signalisation mTOR et la relation entre la signalisation mTOR et la réponse aux dommages à l'ADN in vitro à l'aide de lignées cellulaires cancéreuses de tumeurs mastocytaires canines (MCT). La rapamycine a rapidement inhibé la phosphorylation de S6K de manière dose-dépendante. Le rayonnement ionisant (3, 6 ou 10 Gy) a pu activer la signalisation mTOR, mais la combinaison de rayonnement et de rapamycine a maintenu l'inhibition de mTOR. Le test des comètes a révélé que le co-traitement avec la rapamycine induisait des augmentations modestes de la gravité des dommages à l'ADN des cellules MCT, mais que ces différences n'étaient pas statistiquement significatives. Bien que la relation entre mTOR et la réponse aux dommages à l'ADN dans les lignées cellulaires cancéreuses MCT reste incertaine, nos résultats suggèrent la possibilité d'une interaction, conduisant à une amélioration de la réponse aux radiations.(Traduit par Docteur Serge Messier).

A retrospective comparison of first and second opinion histopathology with patient outcomes in veterinary oncology cases (2011-2019).

Mandatory second opinion histopathology is common practice in human surgical pathology. It is intended to confirm the original diagnosis or identify clinically significant discrepancies, which could alter the course of disease, cost of treatment, patient management or prognosis. This retrospective analysis aimed to evaluate agreement between first and second opinion histopathology cases, examine their correlation with natural history of disease and investigate the rationale for pursuing this test. Medical records from 2011 to 2019 were reviewed, identifying 109 cases where second opinion histopathology was sought. Reasons for seeking second opinion and clinical disease course were also reviewed to determine whether case progression favoured first or second opinion findings in cases of diagnostic disagreement. Diagnostic disagreement was found in 49.5% of cases. Complete diagnostic disagreement (a change in degree of malignancy or tumour type) occurred in 15.6% cases and partial disagreement (a change in tumour subtype, grade, margins and mitotic count) occurred in 33.9%. Major disagreement (a change in diagnosis resulting in alteration of treatment recommendations) occurred in 38.5% of cases. The most common reasons for seeking second opinion were an atypical/poorly differentiated tumour (31.2%; 34/109) or a discordant clinical picture (24.8%; 27/109). Among cases with any form of disagreement, natural history of disease favoured second opinion findings in 33.3%. The first opinion was favoured over the second in a single case. These findings reinforce previous literature supporting a role for second opinion histopathology in optimizing therapy and predicting outcomes in veterinary oncology, particularly in cases where diagnosis is in question based on the overall clinical picture.

Adaptive radiation therapy using weekly hypofractionation for thymoma treatment: A retrospective study of 10 rabbits.

Radiation therapy (RT) is being utilized more commonly for rabbit thymomas due to high perioperative mortality rates with surgery. Median overall survival times reported for rabbit thymomas treated with a variety of RT protocols and techniques range from 6 months to greater than 2 years. As thymomas are radiation-responsive tumours and may shrink rapidly after RT, adaptive radiotherapy (ART) is often warranted. The purpose of this single-institution retrospective case series was to investigate the tumour volume reduction during RT, the frequency of replanning during RT, and survival time in rabbit thymomas treated using intensity-modulated/image-guided radiation therapy (IMRT/IGRT) and a weekly hypofractionated protocol delivering a total dose of 30 Gy. Ten rabbits met the inclusion criteria from October 2014 to October 2019. The median progression-free survival was 561 days and the median overall survival was 634 days (range: 322-1118 days). The tumour volume gradually decreased with each RT fraction. On post-hoc analysis, only the first RT fraction was associated with a significant GTV reduction (of more than 50% on average, p < .001). All subsequent RT fractions did not further reduce the GTV significantly (p > .06). Hypofractionated RT using a weekly protocol of 5 fractions of 6 Gy is a reasonable option to treat rabbit thymomas and replanning should be anticipated. The results of this study support the use of RT to rapidly relieve thymoma-induced dyspnoea in rabbits.

Protein kinase and phosphatase signaling in Mycobacterium tuberculosis physiology and pathogenesis.

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), evades the antimicrobial defenses of the host and survives within the infected individual through a complex set of strategies. These include active prevention of host cellular killing processes as well as overwhelming adaptive gene expression. In the past decade, we have gained an increased understanding of how mycobacteria not only have the ability to adapt to a changing host environment but also actively interfere with the signaling machinery within the host cell to counteract or inhibit parts of the killing apparatus employed by the macrophage. Mtb is able to sense its environment via a set of phospho-signaling proteins which mediate its response and interaction with the host in a coordinated manner. In this review, we summarize the current knowledge about selected Mtb serine, threonine, and tyrosine kinase and phosphatase signaling proteins, focusing on the protein kinases, PknG and PtkA, and the protein phosphatase, PtpA.

Received dose variability after administration of I-131 for treatment of hyperthyroidism in cats.

BACKGROUND: Injectable radioactive iodine (I-131) frequently is used to treat hyperthyroidism in cats. In human medicine, residual activity after injection of radionuclides has been reported, and the actual quantity administered is recorded after administration. OBJECTIVE: Our aim was to evaluate actual administered dose variability after administration of preprepared I-131 single unit doses for the treatment of hyperthyroidism in cats. ANIMALS: Twenty-seven cats with hyperthyroidism treated with I-131 between April 2017 and March 2019. METHODS: Retrospective observational study of cats treated with preprepared single unit I-131 doses. For each dose, the measured activity before administration and residual activity were recorded. The measured dose and the actual dose administered were compared to the prescribed dose. RESULTS: Measured activity before administration ranged from 88.4% to 103.3% of the prescribed dose. Mean residual activity was 5.2 ± 3.0 MBq (ranging from 1.5% to 15% of the prescribed dose). The actual dose administered (measured activity - residual activity) ranged from 79.1% to 100.2% of the prescribed dose. Seventeen of 28 (60.7%) of the actual administered doses differed between 10% and 20% of the prescribed dose. One administered dose had a >20% difference compared to the prescribed dose (79.10% of the prescribed dose). CONCLUSION AND CLINICAL IMPORTANCE: Our study identified variability in the residual and actual administered activity of I-131 as compared to the prescribed dose, which should be taken into consideration when treating cats with (predrawn) I-131.

Patterns of local residual disease and local failure after intensity modulated/image guided radiation therapy for sinonasal tumors in dogs.

BACKGROUND: Most dogs with sinonasal tumors (SNT) treated with radiation therapy (RT) died because of local disease progression. HYPOTHESIS/OBJECTIVES: Our hypothesis is that the majority of local failure and residual disease would occur within the radiation field. ANIMALS: Twenty-two dogs with SNT treated with RT. METHODS: Retrospective cohort study. INCLUSION CRITERIA: dogs with SNT receiving 10 daily fractions of 4.2 Gy with intensity modulated radiation therapy (IMRT)/image guided radiation therapy (IGRT) and follow-up cone beam computed tomography (CBCT). Each CBCT was registered with the original radiation planning CT and the gross tumor volume (GTV) contoured. The GTV was classified as residual (GTVr) or a failure (GTVf). The dose statistic for each GTV was calculated with the original IMRT plan. For GTVf, failures were classified as "in-field," "marginal," or "out-field" if at least 95, 20-95, or less than 20% of the volume of failure was within 95% (D95) of the total prescription dose, respectively. RESULTS: There were 52 follow-up CBCT/CTs. Overall there was a GTVr for 20 dogs and GTVf for 16 dogs. The majority of GTVr volume was within the original GTV. GTVf analysis showed that 75% (12/16) were "in-field," 19% (3/16) were "marginal" and 6% (1/16) were "out-field." CONCLUSION AND CLINICAL IMPORTANCE: In-field failures are the main pattern for local recurrence, and there is evidence of radioresistant subvolumes within the GTV.

Inhibition of Mycobacterium tuberculosis tyrosine phosphatase PtpA by synthetic chalcones: kinetics, molecular modeling, toxicity and effect on growth.

Tuberculosis (TB) is a major cause of morbidity and mortality throughout the world, and it is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis. Among a series of tested compounds, we have recently identified five synthetic chalcones which inhibit the activity of M. tuberculosis protein tyrosine phosphatase A (PtpA), an enzyme associated with M. tuberculosis infectivity. Kinetic studies demonstrated that these compounds are reversible competitive inhibitors. In this work we also carried out the analysis of the molecular recognition of these inhibitors on their macromolecular target, PtpA, through molecular modeling. We observed that the predominant determinants responsible for the inhibitory activity of the chalcones are the positions of the two methoxyl groups at the A-ring, that establish hydrogen bonds with the amino acid residues Arg17, His49, and Thr12 in the active site of PtpA, and the substitution of the phenyl ring for a 2-naphthyl group as B-ring, that undergoes pi stacking hydrophobic interaction with the Trp48 residue from PtpA. Interestingly, reduction of mycobacterial survival in human macrophages upon inhibitor treatment suggests their potential use as novel therapeutics. The biological activity, synthetic versatility, and low cost are clear advantages of this new class of potential tuberculostatic agents.

Clinical-dosimetric relationship between lacrimal gland dose and keratoconjunctivitis sicca in dogs with sinonasal tumors treated with radiation therapy.

BACKGROUND: Dogs with sinonasal tumor can develop keratoconjunctivitis sicca (KCS) after radiation therapy (RT). In humans, the incidence of xerophtalmia is associated with the mean radiation dose received by the ipsilateral lacrimal gland (LG). HYPOTHESIS/OBJECTIVES: The eyes receiving a higher mean LG dose are more likely to develop KCS. The aim of the study was to determine a starting threshold dose to use as dose constraint for intensity-modulated radiation therapy (IMRT). ANIMALS: Dogs with nasal tumors treated with RT between August 2013 and December 2016. METHODS: Case control retrospective study of dogs with sinonasal tumor treated with 42 Gray (Gy) in 10 fractions using IMRT. Dogs were included if development of KCS after RT was documented (cases) or adequate follow-up information with Schirmer tear test (STT) result for ≥6 months after RT was available (controls). Lacrimal glands were contoured and dose distribution was calculated using the original treatment plan to determine prescribed doses to LGs. RESULTS: Twenty-five dogs were treated with RT and 5 dogs (20%) developed KCS. Fifteen dogs met the inclusion criteria including 5 unilateral KCS and 10 control dogs, resulting in 5 KCS eyes and 25 control eyes. KCS developed at a median of 111 days (84-122) after 1st RT. The mean LG dose reached using a 4.2 Gy per fraction was 33.08 Gy (range: 23.75-42.33) for KCS eyes and 10.33 Gy (1.8-24.77) for control eyes (P < .001). The minimum LG mean dose for developing KCS was 23.75 Gy. No eyes that received a mean LG dose <20 Gy developed KCS versus 5/7 (71%) developed with >20 Gy. CONCLUSION AND CLINICAL IMPORTANCE: Contouring and applying a dose constraint on LGs should be performed when using IMRT in dogs with sinonasal tumors to reduce the risk of KCS.