Palliative radiation therapy as a treatment for feline urinary bladder masses in four cats.

CASE SERIES SUMMARY: Urinary bladder masses in four cats were treated with palliative radiation therapy (RT). Three cats were previously diagnosed with chronic kidney disease (CKD): International Renal Interest Society (IRIS) stage 2 in two cats and IRIS stage 3 in one cat. One cat had a diagnosis of hyperthyroidism and inflammatory bowel disease. Three cats had urinary tract infections diagnosed by urine culture and susceptibility testing prior to or during treatment. All patients had urine cytospin cytology performed; one case showed suspect urothelial carcinoma and three had no cytological evidence of neoplasia. All clients declined further sampling from the bladder masses. Therefore, cytologic/histologic diagnosis in all cases was not available. An abdominal ultrasound was performed in all cats, which revealed urinary bladder mass(es) prior to referral for RT. Three cats had pretreatment thoracic radiographs, which revealed no evidence of pulmonary metastasis. An abdominal CT was performed in all cases and one case had thoracic CT performed for staging. The thoracic CT showed a focal lesion of unknown etiology in the right caudal lung lobe. Palliative RT was performed with four weekly 6 Gy fractions (24 Gy in total). The urinary signs in all cats resolved over the course of RT: after the first RT treatment in two cats and after the second RT treatment in two cats. There were two Veterinary Radiation Therapy Oncology Group grade 1 gastrointestinal and one grade 2 genitourinary acute RT side effects. RELEVANCE AND NOVEL INFORMATION: This is the first report in the literature of a standardized RT protocol as a treatment option for feline urinary bladder masses.

Ultrasonographic features of presumed gastric wall edema in 14 dogs with pancreatitis.

BACKGROUND: Gastric wall edema has not been reported as a complication of acute pancreatitis in dogs. OBJECTIVE: To describe the ultrasonographic features of gastric wall thickening in dogs with acute pancreatitis. ANIMALS: Fourteen dogs with ultrasonographic evidence and clinical diagnosis of acute pancreatitis, with ultrasonographic evidence of increased gastric wall thickness (>5 mm). METHODS: A retrospective search in the medical records from 2014 to 2016 was performed to identify dogs that had ultrasonographic evidence of acute pancreatitis, that had increased thickness of the gastric wall and that were diagnosed with acute pancreatitis clinically. The gastric wall changes such as thickness, layering appearance, echogenicity, distribution of lesions, and perigastric changes were recorded. Serial ultrasonographic examination and histopathological findings were recorded if available. RESULTS: Mean gastric wall thickness was 9.9 ± 4.0 mm (SD). A complete loss of wall layering was observed in 2 dogs. Thickening of the submucosal layer was observed in 12 dogs, and 5 of them had concurrent muscularis layer thickening. The echogenicity of thickened submucosal layer was intermediate hyperechoic. Lacy appearances were present within the thickened submucosal layer in 7 dogs and in the muscularis layer of 1 dog. Thickening was focal in 12 dogs and adjacent to the diseased pancreas. Subsequent resolution of gastric wall thickening was observed in 3 dogs (range 3-28 days) via follow-up ultrasound. One dog underwent necropsy, and gastric wall edema was confirmed histopathologically. CONCLUSIONS AND CLINICAL IMPORTANCE: Findings indicated that gastric wall thickening presumably because of edema could be a complication of acute pancreatitis.

Folic Acid-Conjugated Radioluminescent Calcium Tungstate Nanoparticles as Radio-Sensitizers for Cancer Radiotherapy.

Radiation therapy is a primary treatment modality for many forms of cancer. Normally, the highest tolerable dose of ionizing radiation is used to treat tumors, but limitations imposed by normal tissue complications present challenges for local tumor control. In light of this, a class of compounds called radio-sensitizers have been developed to enhance the effectiveness of radiation. Many of these are small molecule drugs found to interact favorably with radiation therapy, but recent advances have been made using nanoparticles as radio-sensitizers. Herein, we report the utilization of radio-luminescent calcium tungstate nanoparticles that emit photoelectrons, UV-A, and visible light during X-ray irradiation, acting as effective radio-sensitizers ("Radio Luminescence Therapy"). In addition, a folic acid-functionalized form of these nanoparticles was shown to enhance radio-sensitization in vitro and in murine models of head and neck cancer. Folic acid-functionalized particles were found to decrease UV-A-induced clonogenic cell survival relative to nonfunctionalized particles. Several possible mechanisms were explored, and the folic acid-functionalized particles were found to mediate this increase in efficacy likely by activating pro-proliferative signaling through folate's innate mitogenic activity, leading to decreased repair of UV-A-induced DNA lesions. Finally, a clinical case study of a canine sarcoma patient demonstrated the initial safety and feasibility of translating these folic acid-functionalized particles into the clinic as radio-sensitizers in the treatment of spontaneous tumors.

An ultrasound based platform for image-guided radiotherapy in canine bladder cancer patients.

BACKGROUND AND PURPOSE: Ultrasound (US) is a non-invasive, non-radiographic imaging technique with high spatial and temporal resolution that can be used for localizing soft-tissue structures and tumors in real-time during radiotherapy (RT) (inter- and intra-fraction). A comprehensive approach incorporating an in-house 3D-US system within RT is presented. This system is easier to adopt into existing treatment protocols than current US based systems, with the aim of providing millimeter intra-fraction alignment errors and sensitivity to track intra-fraction bladder movement. MATERIALS AND METHODS: An in-house integrated US manipulator and platform was designed to relate the computed tomographic (CT) scanner, 3D-US and linear accelerator coordinate systems. An agar-based phantom with measured speed of sound and densities consistent with tissues surrounding the bladder was rotated (0-45°) and translated (up to 55 mm) relative to the US and CT coordinate systems to validate this device. After acquiring and integrating CT and US images into the treatment planning system, US-to-US and US-to-CT images were co-registered to re-align the phantom relative to the linear accelerator. RESULTS: Statistical errors from US-to-US registrations for various patient orientations ranged from 0.1 to 1.7 mm for x, y, and z translation components, and 0.0-1.1° for rotational components. Statistical errors from US-to-CT registrations were 0.3-1.2 mm for the x, y and z translational components and 0.1-2.5° for the rotational components. CONCLUSIONS: An ultrasound-based platform was designed, constructed and tested on a CT/US tissue-equivalent phantom to track bladder displacement with a statistical uncertainty to correct and track inter- and intra-fractional displacements of the bladder during radiation treatments.

Occult tonsillar squamous cell carcinoma in 2 dogs presenting for treatment of primary oral squamous cell carcinoma.

Canine non-tonsillar oral squamous cell carcinoma (OSCC) is generally regarded as locally invasive with low rates of metastasis. Two cases of canine non-tonsillar OSCC with occult tonsillar squamous cell carcinoma (TSCC) detected with tonsillar biopsies are reported. Tonsillar biopsies and detection of occult TSCC changed the therapeutic plan and may have contributed to long-term tumor control.

Carcinome squameux tonsillaire occulte chez 2 chiens présentés pour le traitement d'un carcinome squameux buccal primaire. Le carcinome squameux buccal (CSB) non tonsillaire canin est généralement considéré comme localement invasif avec de faibles taux de métastase. Deux cas de CSB non tonsillaire canin avec un carcinome squameux tonsillaire (CST) occulte détectés lors de biopsies tonsillaires ont été signalés. Les biopsies tonsillaires et la détection du CST occulte ont modifié le régime thérapeutique et peuvent avoir contribué au contrôle de la tumeur à long terme.(Traduit par Isabelle Vallières).

IMAGING DIAGNOSIS -ANTEMORTEM DETECTION OF OLIGODENDROGLIOMA "CEREBROSPINAL FLUID DROP METASTASES" IN A DOG BY SERIAL MAGNETIC RESONANCE IMAGING.

An English Bulldog underwent radiation therapy of an intracranial, left lateral ventricle mass. Following resolution of the primary mass, an intraventricular fourth ventricle lesion developed. Subsequently, multiple lesions developed from the cervical central canal and leptomeninges. Serial magnetic resonance imaging documented the propagation of lesions along the cerebrospinal fluid (CSF) pathways, known as "CSF drop metastasis." Histopathology confirmed multifocal intraventricular and leptomeningeal oligodendroglioma. Oligodendroglioma should be included in the differential diagnosis for an intraventricular tumor exhibiting apparent CSF drop metastasis.

Interobserver reliability of computed tomographic contouring of canine tonsils in radiation therapy treatment planning.

In radiation therapy (RT) treatment planning for canine head and neck cancer, the tonsils may be included as part of the treated volume. Delineation of tonsils on computed tomography (CT) scans is difficult. Error or uncertainty in the volume and location of contoured structures may result in treatment failure. The purpose of this prospective, observer agreement study was to assess the interobserver agreement of tonsillar contouring by two groups of trained observers. Thirty dogs undergoing pre- and post-contrast CT studies of the head were included. After the pre- and postcontrast CT scans, the tonsils were identified via direct visualization, barium paste was applied bilaterally to the visible tonsils, and a third CT scan was acquired. Data from each of the three CT scans were registered in an RT treatment planning system. Two groups of observers (one veterinary radiologist and one veterinary radiation oncologist in each group) contoured bilateral tonsils by consensus, obtaining three sets of contours. Tonsil volume and location data were obtained from both groups. The contour volumes and locations were compared between groups using mixed (fixed and random effect) linear models. There was no significant difference between each group's contours in terms of three-dimensional coordinates. However there was a significant difference between each group's contours in terms of the tonsillar volume (P < 0.0001). Pre- and postcontrast CT can be used to identify the location of canine tonsils with reasonable agreement between trained observers. Discrepancy in tonsillar volume between groups of trained observers may affect RT treatment outcome.

Safety and feasibility of stereotactic radiotherapy using computed portal radiography for canine intracranial tumors.

Stereotactic radiotherapy is a highly conformal treatment option for intracranial and extracranial malignancies. Stereotactic radiotherapy utilizes specialized equipment specifically designed to avoid normal tissue while delivering ablative treatments with submillimeter precision and accuracy. Linear accelerator based stereotactic radiotherapy incorporates on-board image guidance utilizing cone beam computed tomography (CT). Many institutions lack the ability to provide image guidance with cone beam CT but delivery of highly conformal treatments with submillimeter precision and accuracy is still feasible. The purpose of this retrospective, pilot study was to describe clinical outcomes for a group of dogs with neurological disease that were treated with an stereotactic radiotherapy technique utilizing intensity modulated radiation therapy, megavoltage computed portal radiography, a bite plate, thermoplastic mold, and mask based positioning system. Twelve dogs with neurological clinical signs were included. The diagnosis of intracranial tumor was made based on advanced imaging (12/12) and confirmed via histopathology (3/12). Twelve courses of stereotactic radiotherapy, utilizing three fractions of 8.0 Gy, were delivered on alternating days. Self-resolving neurological deterioration was observed in two patients during stereotactic radiotherapy. Neurological progression free interval and median survival time were 273 days (range: 16-692 days) and 361 days (range: 25-862 days). Stereotactic radiotherapy using computed portal radiography may be a safe treatment option for dogs with intracranial tumors.

Design, construction, and in vivo feasibility of a positioning device for irradiation of mice brains using a clinical linear accelerator and intensity modulated radiation therapy.

PURPOSE: The goal of this study was to design a positioning device that would allow for selective irradiation of the mouse brain with a clinical linear accelerator. METHODS: We designed and fabricated an immobilization fixture that incorporates three functions: head stabilizer (through ear bars and tooth bar), gaseous anesthesia delivery and scavenging, and tissue mimic/bolus. Cohorts of five mice were irradiated such that each mouse in the cohort received a unique dose between 1000 and 3000 cGy. DNA damage immunohistochemistry was used to validate an increase in biological effect as a function of radiation dose. Mice were then followed with hematoxylin and eosin (H&E) and anatomical magnetic resonance imaging (MRI). RESULTS: There was evidence of DNA damage throughout the brain proportional to radiation dose. Radiation-induced damage at the prescribed doses, as depicted by H&E, appeared to be constrained to the white matter consistent with radiological observation in human patients. The severity of the damage correlated with the radiation dose as expected. CONCLUSIONS: We have designed and manufactured a device that allows us to selectively irradiate the mouse brain with a clinical linear accelerator. However, some off-target effects are possible with large prescription doses.

Block Copolymer-Encapsulated CaWO4 Nanoparticles: Synthesis, Formulation, and Characterization.

We envision that CaWO4 (CWO) nanocrystals have the potential for use in biomedical imaging and therapy because of the unique ways this material interacts with high-energy radiation. These applications, however, require development of nanoparticle (NP) formulations that are suitable for in vivo applications; primarily, the formulated nanoparticles should be sufficiently small, chemically and biologically inert, and stable against aggregation under physiological conditions. The present study demonstrates one such method of formulation, in which CWO nanoparticles are encapsulated in bioinert block copolymer (BCP) micelles. For this demonstration, we prepared three different CWO nanocrystal samples having different sizes (3, 10, and 70 nm in diameter) and shapes (elongated vs truncated rhombic). Depending on the specific synthesis method used, the as-synthesized CWO NPs contain different surfactant materials (citric acid or cetyltrimethylammonium bromide or a mixture of oleic acid and oleylamine) in the coating layers. Regardless of the type of surfactant, the original surfactant coating can be replaced with a new enclosure formed by BCP materials using a solvent-exchange method. Two types of BCPs have been tested: poly(ethylene glycol-block-n-butyl acrylate) (PEG-PnBA) and poly(ethylene glycol-block-D,L-lactic acid) (PEG-PLA). Both BCPs are able to produce fully PEGylated CWO NPs that are stable against aggregation under physiological salt conditions for very long periods of time (at least three months). The optical and radio luminescence properties of both BCP-encapsulated and surfactant-coated CWO NPs were extensively characterized. The study confirms that the BCP coating structure does not influence the luminescence properties of CWO NPs.

RADIATION THERAPY COMMUNICATION-REIRRADIATION OF A NASAL TUMOR IN A BRACHYCEPHALIC DOG USING INTENSITY MODULATED RADIATION THERAPY.

A 5-year-old spayed female Shih Tzu was referred for evaluation of a nasal transitional carcinoma. A total lifetime dose of 117 Gy was delivered to the intranasal mass in three courses over nearly 2 years using fractionated intensity modulated radiation therapy (IMRT) to spare normal tissues. Clinically significant late normal tissue side effects were limited to bilaterally diminished tear production. The patient died of metastatic disease progression 694 days after completion of radiation therapy course 1. This case demonstrates that retreatment with radiation therapy to high lifetime doses for recurrent local disease may be well tolerated with IMRT.

Use of three-dimensional conformal radiation therapy for treatment of a heart base chemodectoma in a dog.

CASE DESCRIPTION: A 9-year-old spayed female mixed-breed dog was evaluated because of a progressively worsening, nonproductive cough and gagging of 1 year's duration. CLINICAL FINDINGS: Physical examination results were unremarkable. A cranial mediastinal mass was identified at the heart base with 3-view thoracic radiography. A CT scan of the thorax revealed an invasive mass surrounding major vessels at the heart base that was not considered surgically resectable. Thoracoscopic biopsy specimens of the cranial mediastinal mass were obtained, and histologic evaluation revealed that the tumor was a chemodectoma. TREATMENT AND OUTCOME: On the basis of results of the CT scan, a 3-D conformal radiation therapy plan was generated with computer treatment-planning software. The patient was treated with external beam radiation therapy; a 6-MV linear accelerator was used to deliver a prescribed dose of 57.5 Gy in twenty-three 2.5-Gy fractions. The cough improved following radiation therapy. Prior to treatment, the tumor volume was calculated to be 126.69 cm(3). Twenty-five months following radiation therapy, a follow-up CT scan was performed and there was a >50% reduction in tumor volume at that time. Disease progression causing pericardial, pleural, and peritoneal effusion and syncopal episodes occurred 32 months following radiation therapy, which were treated with pericardectomy and additional radiation therapy. The dog was still alive and doing well 42 months following initial radiation treatment. CLINICAL RELEVANCE: Conformal radiation therapy provided an additional treatment option for a nonresectable heart base chemodectoma in the dog of this report; conformal radiation therapy was reasonably tolerable and safe.

Adenoviral-mediated overexpression of SOCS3 enhances IgG immune complex-induced acute lung injury.

The lung inflammatory response caused by intratracheal deposition of IgG immune complexes (IC) includes the production of IL-6, which signals through activation of STAT transcription factors. Recently, suppressor of cytokine signaling 3 (SOCS3) has been shown to be a key negative regulator of IL-6/gp130/Jak/STAT3 signal transduction. Although SOCS3 has been implicated in several inflammatory diseases, very little is known regarding its activation and its function in the lung during acute inflammation. Our previous study showed that IL-6/STAT3 activation was triggered in lungs after intrapulmonary deposition of IgG IC in rats. In the current study, we sought to determine whether SOCS3 is playing a regulatory role in the lung inflammatory response. SOCS3 induction occurred during development of inflammation in the IgG IC model of lung injury. Overexpression of SOCS3 in lung using a recombinant adenovirus encoding murine SOCS3 resulted in substantial increases in lung vascular permeability and lung myeloperoxidase, together with enhanced levels of TNF-alpha, MIP-2, and keratinocyte-activated cytokine in bronchoalveolar lavage fluids. SOCS3 overexpression in lungs led to overproduction of bronchoalveolar lavage IL-6, but not IL-10, in this inflammatory model. We further show that activation of STAT3 was inhibited by SOCS3 overexpression as well as by anti-IL-6 treatment during IgG IC-induced lung injury, as determined by EMSA. In vitro, SOCS3 overexpression abrogated IL-6-induced activation of STAT3 in lung epithelial cells. These findings suggest SOCS3 is an important regulator of lung inflammatory injury after deposition of IgG IC.

Regulatory effects of estrogen on acute lung inflammation in mice.

The role of estrogen in the regulation of the inflammatory response is not well defined. In this study, we investigated the effects of ovarian hormones on the acute inflammatory response in mouse lungs. Acute lung injury was induced by intratracheal instillation of bacterial lipopolysaccharide (LPS) in male, female, and ovariectomized (OVX) mice. End points of injury were polymorphonuclear neutrophil (PMN) content in bronchoalveolar lavage (BAL) fluids, myeloperoxidase activity in whole lung, and leak of albumin into the lung. After intratracheal instillation of LPS, all end points of injury were substantially increased in male and OVX mice compared with the female mice with intact ovaries. BAL fluids of all mice showed similar levels of chemokines (macrophage inflammatory protein MIP-2, KC, and monocyte chemoattractant proteins MCP-1 and MCP-3) and TNF-alpha, but enhanced levels of IL-1beta were found in OVX and male mice. Serum levels of IL-6 and ICAM-1 levels in lung homogenates from OVX and male mice, compared with those in female mice with intact ovaries, were also enhanced after instillation of LPS. Albumin and PMN content in LPS-injured lungs were reduced to levels found in female mice after administration of estradiol in OVX mice and corresponded to reduced IL-1beta, IL-6, and ICAM-1 levels. These data suggest that estrogen suppresses lung inflammatory responses in mice through an effect on vascular cell adhesion molecules and proinflammatory mediators.

Novel chemokine responsiveness and mobilization of neutrophils during sepsis.

Blood neutrophils (PMN) are usually unresponsive to CC chemokines such as monacyte chemotactic protein-1 and macrophage inflammatory protein-1 alpha. In rodents, the lung buildup of PMN as determined by myeloperoxidase (MPO) activity after airway instillation of bacterial lipopolysaccharide (LPS) was independent of MCP-1 and MIP-1 alpha. In striking contrast, during sepsis following cecal ligation and puncture (CLP), blood PMN demonstrated mRNA for CC chemokine receptors. Furthermore, PMN from CLP, but not from sham rodents, bound MCP-1 and MIP-1 alpha and responded chemotactically in vitro to both MCP-1 and MIP-1 alpha. In CCR2(-/-) mice or WT mice treated in vivo with antibodies to either MCP-1 or MIP-1 alpha, MPO activity was greatly attenuated in CLP animals. In CLP mice, increased serum IL-6 levels were found to be dependent on CCR2, MCP-1, and MIP-1 alpha. When PMN from CLP rodents were incubated in vitro with either MCP-1 or MIP-1 alpha, release of IL-6 was also shown. These findings suggest that sepsis fundamentally alters the trafficking of PMN into the lung in a manner that now engages functional responses to CC chemokines.