SPINAL MAST CELL TUMORS IN DOGS: IMAGING FEATURES AND CLINICAL OUTCOME OF FOUR CASES.

Published information regarding canine vertebral column mast cell tumors (MCTs) is limited. The objectives of this study were to report clinical and advanced imaging findings for a group of dogs with confirmed spinal MCT. Inclusion criteria for this retrospective case series were dogs with spinal magnetic resonance imaging (MRI) or computed tomography (CT) scans and a histological diagnosis of spinal MCT. Clinical, imaging, treatment, and outcome data were recorded. Four dogs met inclusion criteria. One dog had primary spinal MCT and three dogs had metastatic spinal MCT. All four dogs presented for paraspinal hyperesthesia and subacute progressive or acute myelopathy. All CT and MRI lesions were extradural. Two cases exhibited distinct masses in the epidural space. In one case, an epidural tumor invaded from the paravertebral musculature. One case exhibited polyostotic lesions indistinguishable from multiple myeloma by MRI. One dog with a primary epidural low-grade MCT remains clinically normal 4 years postoperatively, following adjunctive lomustine. An epidural high-grade MCT, metastatic from a cutaneous tumor, recurred within 2 months of surgery despite adjunctive vinblastine. Two high-grade cases with concurrent visceral involvement were euthanized immediately after imaging. In dogs, MCT should be considered as a differential diagnosis for a progressive painful myelopathy and CT or MRI evidence of an extradural spinal lesion (epidural, paravertebral, or polyostotic). While more often associated with cutaneous or disseminated disease, MCT may also occur as a primary tumor of the epidural space in dogs.

Evaluation of osseous-associated cervical spondylomyelopathy in dogs using kinematic magnetic resonance imaging.

Osseous-associated cervical spondylomyelopathy in dogs is characterized by both static and dynamic spinal cord compression; however, standard MRI methods only assess static compression. In humans with cervical spondylotic myelopathy, kinematic MRI is commonly used to diagnose dynamic spinal cord compressions. The purpose of this prospective, analytical study was to evaluate kinematic MRI as a method for characterizing the dynamic component of osseous-associated cervical spondylomyelopathy in dogs. We hypothesized that kinematic MRI would allow visualization of spinal cord compressions that were not identified with standard imaging. Twelve client-owned dogs with osseous-associated cervical spondylomyelopathy were enrolled. After standard MRI confirmed a diagnosis of osseous-associated cervical spondylomyelopathy, a positioning device was used to perform additional MRI sequences with the cervical vertebral column flexed and extended. Morphologic and morphometric (spinal cord height, intervertebral disc width, spinal cord width, vertebral canal height, and spinal cord area) assessments were recorded for images acquired with neutral, flexion, and extension imaging. A total of 25 compressions were seen with neutral positioning, while extension identified 32 compressions. There was a significant association between extension positioning and presence of a compressive lesion at C4-C5 (p = 0.02). Extension was also associated with a change in the most severe site of compression in four out of 12 (33%) dogs. None of the patients deteriorated neurologically after kinematic imaging. We concluded that kinematic MRI is a feasible method for evaluating dogs with osseous-associated cervical spondylomyelopathy, and can reveal new compressions not seen with neutral positioning.

A CLN8 nonsense mutation in the whole genome sequence of a mixed breed dog with neuronal ceroid lipofuscinosis and Australian Shepherd ancestry.

The neuronal ceroid lipofuscinoses (NCLs) are hereditary neurodegenerative diseases characterized by seizures and progressive cognitive decline, motor impairment, and vision loss accompanied by accumulation of autofluorescent lysosomal storage bodies in the central nervous system and elsewhere in the body. Mutations in at least 14 genes underlie the various forms of NCL. One of these genes, CLN8, encodes an intrinsic membrane protein of unknown function that appears to be localized primarily to the endoplasmic reticulum. Most CLN8 mutations in people result in a form of NCL with a late infantile onset and relatively rapid progression. A mixed breed dog with Australian Shepherd and Blue Heeler ancestry developed neurological signs characteristic of NCL starting at about 8months of age. The signs became progressively worse and the dog was euthanized at 21months of age due to seizures of increasing frequency and severity. Postmortem examination of the brain and retinas identified massive accumulations of intracellular autofluorescent inclusions characteristic of the NCLs. Whole genome sequencing of DNA from this dog identified a CLN8:c.585G>A transition that predicts a CLN8:p.Trp195* nonsense mutation. This mutation appears to be rare in both ancestral breeds. All of our 133 archived DNA samples from Blue Heelers, and 1481 of our 1488 archived Australian Shepherd DNA samples tested homozygous for the reference CLN8:c.585G allele. Four of the Australian Shepherd samples tested heterozygous and 3 tested homozygous for the mutant CLN8:c.585A allele. All 3 dogs homozygous for the A allele exhibited clinical signs of NCL and in 2 of them NCL was confirmed by postmortem evaluation of brain tissue. The occurrence of confirmed NCL in 3 of 4 CLN8:c.585A homozygous dogs, plus the occurrence of clinical signs consistent with NCL in the fourth homozygote strongly suggests that this rare truncating mutation causes NCL. Identification of this NCL-causing mutation provides the opportunity for identifying dogs that can be used to establish a canine model for the CLN8 disease (also known as late infantile variant or late infantile CLN8 disease).

Cediranib and Olaparib Combination Compared With Cediranib or Olaparib Alone, or Chemotherapy in Platinum-Resistant or Primary Platinum-Refractory Ovarian Cancer: NRG-GY005.

PURPOSE: We assessed the efficacy of cediranib, olaparib, and cediranib/olaparib compared with standard-of-care chemotherapy (SOC) in platinum-resistant or platinum-refractory epithelial ovarian cancer (PROC). PATIENTS AND METHODS: NRG-GY005 is an open-label, four-arm, phase II/III superiority trial enrolling patients with high-grade serous/endometrioid PROC and one to three previous therapies. Key exclusion criteria included previous receipt of poly(ADP-ribose) polymerase inhibitor or receipt of antiangiogenic therapy in the recurrent setting. Treatment arms (SOC [once weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin], cediranib, olaparib, or cediranib/olaparib) were equally randomized. A preplanned interim futility analysis on the basis of progression-free survival (PFS) selected treatment arms to advance to phase III. PFS and overall survival (OS) were phase III coprimary end points, with hierarchical testing of PFS followed by OS to preserve type 1 error control, designed to have 90% power for a 0.625 PFS hazard ratio (HR). OS was tested after PFS in the multiple hierarchical testing procedure. Secondary end points included objective response rate (ORR) and patient-reported outcomes. RESULTS: Five hundred sixty-two eligible patients were enrolled for phase II/III. Three arms met PFS criteria to carry forward to phase III (SOC, cediranib/olaparib, and cediranib). Median PFS was 3.4, 5.2, and 4 months with SOC, cediranib/olaparib, and cediranib, respectively, with a median follow-up duration of 42.2 months. PFS HR estimates for cediranib/olaparib and cediranib (v SOC) were 0.796 (98.3% CI, 0.597 to 1.060) and 0.972 (98.3% CI, 0.726 to 1.300), respectively. Median OS was 13.6, 12.8, and 10.5 months, and of 443 patients with measurable disease, ORR was 8.6%, 24.7%, and 13.1% for SOC, cediranib/olaparib, and cediranib, respectively. No new safety signals were identified. In patients receiving cediranib/olaparib, no statistically significant difference was observed on the NFOSI-DRS-P subscale compared with SOC (98.3% CI, -1.3 to 1.5, P = .8725). CONCLUSION: The cediranib-containing arms demonstrated clinical activity on the basis of PFS but were not superior compared with SOC.