Marked paraneoplastic basophilia in a cat with alimentary T-cell lymphoma.

An 8-year-old, spayed female domestic shorthair cat was presented for acute weight loss, hyporexia, intermittent vomiting, and loose stools. A caudal abdominal mass and thickened intestinal loops were palpated on initial examination. An abdominal ultrasound identified a circumferential intramural jejunal mass with complete loss of wall layering, diffuse thickening of the jejunal muscularis, and jejunal and ileocecal lymphadenomegaly. Initial routine bloodwork revealed mild monocytosis and minimal lymphopenia with reactive lymphocytes. Cytologic evaluation of the jejunal mass and enlarged lymph nodes was consistent with lymphoma (intermediate cell size), and PCR for antigen receptor rearrangement revealed a clonal T-cell receptor rearrangement consistent with T-cell lymphoma. Chemotherapy (CHOP protocol) was initiated, but despite initial improvement of clinical signs, a repeat ultrasound examination 5 weeks after initiation of treatment revealed no improvement in the lymphadenomegaly or reduction in the size of the jejunal mass. At this visit, the cat also developed a marked basophilia (basophils 12.28 × 103 /µL, RI 0.00-0.10) with low numbers of circulating atypical lymphocytes; no concurrent eosinophilia was noted. Heartworm disease, ectoparasites, and allergic diseases were evaluated for and considered unlikely. The chemotherapy protocol was changed to L-asparaginase, followed by lomustine. The basophilia was significantly reduced 2 days after the initial dose of L-asparaginase and remained within the reference interval for 40 days before an eventual decline in the cat's health. To the authors' knowledge, this is the first report of paraneoplastic basophilia without concurrent eosinophilia in a cat with T-cell lymphoma.

Veterinary oncologists and pet owners differ in their perceptions of chemotherapy-related adverse events in cancer-bearing dogs.

OBJECTIVE: Chemotherapy is widely used in veterinary oncology but carries real and perceived risks of adverse events (AEs). Human cancer patients perceive AEs from chemotherapy as more severe than do their attending physicians. It is currently unknown whether this discrepancy exists in veterinary oncology. This survey study's aim was to assess differences in the ways that pet owners and veterinary oncologists perceive chemotherapy-related AEs. We hypothesized that veterinary oncologists would accept higher grade AEs and tolerate a greater risk of AEs of any grade than pet owners. SAMPLE: 152 pet owners and 111 veterinary oncologists. METHODS: Separate surveys were derived for pet owners and veterinary oncologists. Respondents were asked to define maximally acceptable AE scores and risks of AEs given 3 hypothetical outcomes of treatment: (1) cure, (2) extension of life, and (3) improved quality of life. Statistical tests were used to compare responses between groups. RESULTS: Veterinary oncologists accepted higher grade AEs if the hypothetical goal of chemotherapy was cancer cure (P = .003) or extension of life (P = .026), but owners accepted higher grade AEs if the goal of chemotherapy was to improve quality of life (P = .002). Owners accepted greater risk of moderate (P < .0001) or serious (P < .0001) AEs across the 3 treatment outcomes. CLINICAL RELEVANCE: This was the first study to assess how pet owners and veterinary oncologists differ in their perception of chemotherapy-related AEs. These initial results may help to frame discussions with pet owners on the expectations of chemotherapy.

Self-paced acceptance and commitment training reduces burden transfer, stress, and burnout in veterinary healthcare teams.

OBJECTIVE: An acceptance and commitment training (ACT) educational program targeting reaction to difficult client interactions recently demonstrated efficacy in reducing burden transfer, stress, and burnout in veterinary healthcare teams. The current noninferiority trial compared effectiveness of the original program with a self-paced version. SAMPLE: Employees of 2 corporate veterinary groups were randomized to live (n = 128) or self-paced (124) conditions. The workshop and assessments were completed by 137 (55 live and 82 self-paced). PROCEDURES: Asynchronous modules containing the same content as the original program were placed on in-house veterinary clinic learning systems. Participants of this parallel arms trial completed pretest measures of burden transfer, stress, and burnout. Following assessment, the 3-week ACT program was delivered via videoconferencing (live) or asynchronous modules (self-paced). At post-test and 1-month follow-up, measures were repeated, with added assessment of knowledge, helpfulness ratings, and usage of techniques. A subset (n = 33) of participants repeated measures 9 to 12 months as an extended follow-up. RESULTS: Program helpfulness was rated more highly by live versus self-paced participants. Self-paced showed better program retention. No differences in knowledge or use of program techniques (> 5 times daily) emerged. Relative to pretest, both conditions showed reduced burden transfer, stress, and burnout at post-test and follow-up; no differences by condition emerged. Participants completing extended follow-up maintained improvement from baseline. CLINICAL RELEVANCE: Findings suggest a learning system-based version of this program can improve occupational distress in veterinary healthcare teams, with gains maintained over time. The flexibility of this format promotes program completion and allows broader dissemination.

Validation of the Burden Transfer Inventory-abbreviated and examination across veterinary medicine positions and settings in the United States.

Background: Burden transfer, when veterinary client caregiver burden underlies stressful encounters with providers, elevates risk for occupational distress in veterinary medicine. To date, burden transfer has been primarily examined in veterinarians working in general practice, using methods that are time consuming. The current work validates an abbreviated Burden Transfer Inventory (BTI-A) and explores burden transfer across positions of employment and veterinary settings. Methods: Participants completed online measures of burden transfer, stress and burnout. A BTI-A with items representing each BTI domain was created with an initial validation sample (n = 1151 veterinarians). Confirmatory psychometric analyses were conducted in a cross-validation sample (n = 440 veterinarians and support staff), followed by exploration of the BTI and BTI-A across veterinary settings and position of employment. Results: The BTI-A correlated with the full-length BTI (r = 0.89-0.96) shows good internal consistency (α = 0.72-0.88) and 1-month test-retest reliability (r = 0.69-0.74). The BTI-A correlated significantly (p < 0.001) with stress and burnout. Exploratory comparisons suggested group differences including greater reactivity in general compared to specialty referral/emergency practice (p = 0.02). Conclusion: The BTI-A can be used in place of the original measure when brevity is important. Use of the BTI-A may help guide allied mental health professionals in providing support for wellbeing in veterinary healthcare team members.

Identification of a naturally-occurring canine model for early detection and intervention research in high grade urothelial carcinoma.

Background: Early detection and intervention research is expected to improve the outcomes for patients with high grade muscle invasive urothelial carcinoma (InvUC). With limited patients in suitable high-risk study cohorts, relevant animal model research is critical. Experimental animal models often fail to adequately represent human cancer. The purpose of this study was to determine the suitability of dogs with high breed-associated risk for naturally-occurring InvUC to serve as relevant models for early detection and intervention research. The feasibility of screening and early intervention, and similarities and differences between canine and human tumors, and early and later canine tumors were determined. Methods: STs (n=120) ≥ 6 years old with no outward evidence of urinary disease were screened at 6-month intervals for 3 years with physical exam, ultrasonography, and urinalysis with sediment exam. Cystoscopic biopsy was performed in dogs with positive screening tests. The pathological, clinical, and molecular characteristics of the "early" cancer detected by screening were determined. Transcriptomic signatures were compared between the early tumors and published findings in human InvUC, and to more advanced "later" canine tumors from STs who had the typical presentation of hematuria and urinary dysfunction. An early intervention trial of an oral cyclooxygenase inhibitor, deracoxib, was conducted in dogs with cancer detected through screening. Results: Biopsy-confirmed bladder cancer was detected in 32 (27%) of 120 STs including InvUC (n=29, three starting as dysplasia), grade 1 noninvasive cancer (n=2), and carcinoma in situ (n=1). Transcriptomic signatures including druggable targets such as EGFR and the PI3K-AKT-mTOR pathway, were very similar between canine and human InvUC, especially within luminal and basal molecular subtypes. Marked transcriptomic differences were noted between early and later canine tumors, particularly within luminal subtype tumors. The deracoxib remission rate (42% CR+PR) compared very favorably to that with single-agent cyclooxygenase inhibitors in more advanced canine InvUC (17-25%), supporting the value of early intervention. Conclusions: The study defined a novel naturally-occurring animal model to complement experimental models for early detection and intervention research in InvUC. Research incorporating the canine model is expected to lead to improved outcomes for humans, as well as pet dogs, facing bladder cancer.

Atypical multiple myeloma in 3 young dogs.

Three dogs under 12 months old were diagnosed with atypical multiple myeloma (MM), having an aggressive multifocal anaplastic round cell sarcoma in bone marrow, viscera, and/or peripheral blood, which were confirmed by cytology and immunohistochemistry to be of plasma cell origin. The intramedullary sarcomas caused myelophthisis, osteolysis, and hypercalcemia. Complete or free light chain monoclonal gammopathy in the serum and/or urine was demonstrated by protein electrophoresis and immunofixation. The polymerase chain reaction for antigen receptor rearrangement assay performed on 2 cases identified a clonally rearranged immunoglobulin gene. Neoplastic cells lacked expression of CD45, CD3, CD18, CD21, CD34, and MHCII by flow cytometry. Immunohistochemistry revealed MUM1 immunoreactivity of the neoplastic cells. Combining all data, the diagnosis was MM. An aggressive form of MM in young dogs should be a differential diagnosis for patients with an immunoglobulin-productive, B cell-clonal, CD45-negative, MUM1-positive discrete cell neoplasm arising from the bone marrow.

Ultrasonographic detection of apex nodules in the urinary bladder of Scottish Terriers.

An apex nodule was recently identified in the urinary bladder of Scottish Terriers being screened for bladder cancer at our institution. This prospective, single-center, case series study was performed to better characterize the apex nodule and assess the clinical importance of the nodule. Scottish Terriers ≥6 years of age with no evidence of urinary tract disease underwent urinary tract ultrasonography and urinalysis at 6-month intervals. In dogs with evidence of the apex nodule, ultrasound features such as location, margins, number, echogenicity, size, and shape of the lesion were recorded by a veterinary oncologist and veterinary radiologist. The apex nodule was identified in eight (6%) of 134 dogs in the absence of other detectable bladder disease. Features of the nodules included the following: one nodule per dog, triangular to an oval shape, smooth mucosal covering, well-defined margins, isoechoic to the bladder wall, 2-4 mm at the base, and 4-6 mm protruding into the bladder lumen. In five dogs undergoing multiple ultrasonographic examinations, the nodule did not appear to change over time (up to 3.5 years). Cystoscopy performed in three dogs revealed a column of tissue covered by normal mucosa protruding into the bladder lumen. Histological features consistent with a neoplastic growth were absent. Five dogs remained free of any bladder disease. Three dogs developed urothelial carcinoma at sites distant to the nodule at 8-53 months after the nodule was first observed. Findings indicated that incidental apex nodules could mimic neoplasia and other bladder diseases in Scottish Terriers.

A prospective, randomized, placebo-controlled, double-blinded clinical trial comparing the incidence and severity of gastrointestinal adverse events in dogs with cancer treated with piroxicam alone or in combination with omeprazole or famotidine.

OBJECTIVE: To assess the impact of prophylactic omeprazole and famotidine on the incidence and severity of gastrointestinal (GI) adverse events (AEs) in dogs with cancer treated with single agent piroxicam. ANIMALS: 39 dogs with a cytologic or histologic diagnosis of cancer with no history of GI disease and received piroxicam. PROCEDURES: A prospective, randomized, placebo-controlled, double-blinded clinical trial was performed. All dogs received piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h) and either omeprazole (1 mg/kg [0.45 mg/lb], PO, q 12 h), famotidine (1 mg/kg, PO, q 12 h), or placebo (lactose; PO, q 12 h). Monthly assessments of GI AEs were performed and scored by using the Veterinary Comparative Oncology Group's Common Terminology Criteria for Adverse Events (version 1.1). RESULTS: Compared with dogs in the placebo group, more dogs in the omeprazole group (84.6% vs 36.4%) and famotidine group (80.0% vs 36.4%) experienced GI AEs by day 56. The severity of GI AEs was higher in the omeprazole group, compared with the placebo group. CONCLUSIONS AND CLINICAL RELEVANCE: Omeprazole was not helpful in reducing the frequency or severity of GI AEs and was associated with more frequent and severer GI AEs in dogs with cancer treated with single agent piroxicam. Proton-pump inhibitors and H2-receptor antagonists should not be prescribed as prophylaxis with NSAIDs for dogs with cancer.

Phase I/II Trial of Vemurafenib in Dogs with Naturally Occurring, BRAF-mutated Urothelial Carcinoma.

BRAF-targeted therapies including vemurafenib (Zelboraf) induce dramatic cancer remission; however, drug resistance commonly emerges. The purpose was to characterize a naturally occurring canine cancer model harboring complex features of human cancer, to complement experimental models to improve BRAF-targeted therapy. A phase I/II clinical trial of vemurafenib was performed in pet dogs with naturally occurring invasive urothelial carcinoma (InvUC) harboring the canine homologue of human BRAF V600E The safety, MTD, pharmacokinetics, and antitumor activity were determined. Changes in signaling and immune gene expression were assessed by RNA sequencing and phosphoproteomic analyses of cystoscopic biopsies obtained before and during treatment, and at progression. The vemurafenib MTD was 37.5 mg/kg twice daily. Anorexia was the most common adverse event. At the MTD, partial remission occurred in 9 of 24 dogs (38%), with a median progression-free interval of 181 days (range, 53-608 days). In 18% of the dogs, new cutaneous squamous cell carcinoma and papillomas occurred, a known pharmacodynamic effect of vemurafenib in humans. Upregulation of genes in the classical and alternative MAPK-related pathways occurred in subsets of dogs at cancer progression. The most consistent transcriptomic changes were the increase in patterns of T lymphocyte infiltration during the first month of vemurafenib, and of immune failure accompanying cancer progression. In conclusion, the safety, antitumor activity, and cutaneous pharmacodynamic effects of vemurafenib, and the development of drug resistance in dogs closely mimic those reported in humans. This suggests BRAF-mutated canine InvUC offers an important complementary animal model to improve BRAF-targeted therapies in humans.

Anal sacculiths may be an incidental finding in dogs.

Mineral-attenuating material is occasionally seen in the anal sacs of dogs during abdominal CT studies. This retrospective, descriptive study was performed to estimate the prevalence and CT appearance of this mineral-attenuating material. A total of 357 abdominal CTs were reviewed retrospectively. The mineral-attenuating material was most easily identifiable using the brain window setting (window width: 120 HU; window level: 40 HU). In the current study, the prevalence of mineral-attenuating material in the anal sacs was 7.6% (95% confidence interval, 5.0-10.8%) with 48.1% bilateral involvement and equal distribution in the right and left in dogs with unilateral involvement. Successful collection and material analysis were performed in three dogs. The material was determined to be 100% dried blood, 100% waxy matter, and a "small amount of fat enmeshed in unidentified noncrystallined material." Given the CT appearance and the Hounsfield unit of these mineral-attenuating material within the anal sacs, the term "anal sacculiths" is proposed. All dogs with anal sacculiths within this study population did not have any reported disease of the anal sacs.

Early caregiver burden in owners of pets with suspected cancer: Owner psychosocial outcomes, communication behavior, and treatment factors.

BACKGROUND: Owners of companion animals with serious illnesses are likely to experience "caregiver burden." This topic has not been fully evaluated in veterinary oncology. OBJECTIVES: To examine owners of a dog or cat with suspected cancer for relationships between early caregiver burden and (a) psychosocial factors: depression, stress, and quality of life; (b) owner communication behavior; and (c) specific pet treatment plan factors. ANIMALS: None. METHODS: This cross-sectional, observational study recruited 164 owners of a cat or dog presenting for evaluation by a veterinary oncology service at a single referral institution. Measures of caregiver burden, psychosocial function, treatment plan elements, and demographics were collected online via owner self-report. Medical records were reviewed to identify factors including diagnosis, medications, treatment schedules, and owner communications. RESULTS: Caregiver burden correlated with higher stress (rs = 0.40, P < .001), greater symptoms of depression (rs = 0.50, P < .001), and lower quality of life (rs = 0.39, P < .001). Pet treatment plan factors related to caregiver burden included changes in care routines, perception that compliance with new routines was challenging, and difficulty adhering to medication routines. There was low correlation between caregiver burden and owner-driven communications (rs = 0.15, P = .07). CONCLUSIONS AND CLINICAL IMPORTANCE: Findings suggest caregiver burden is similar in owners of pets with cancer and owners of pets with other diseases. Caregiver burden is present in the earliest stages of disease. Major correlates of burden including life-disruptive treatments and schedules provide key areas for potential intervention by veterinary teams.

Ultrasonographic features of colonic B-cell lymphoma with mesenteric lymphomatosis in a cat.

A 10-year-old male neutered Domestic Shorthair cat was referred for chronic inappetence, weight loss, and hematochezia and an abdominal mass. Abdominal ultrasonography revealed a heterogeneously hypoechoic transmural colonic mass, which extended beyond the serosa and into the adjacent mesentery. Cytology and clonality assays of fine needle aspirates of the mass and mesenteric nodules yielded a diagnosis of B-cell lymphoma. Colonic lymphoma with mesenteric involvement can have a similar appearance to carcinomatosis, therefore a definitive diagnosis requires sampling and further testing of the mesenteric lesions.

Naturally-Occurring Invasive Urothelial Carcinoma in Dogs, a Unique Model to Drive Advances in Managing Muscle Invasive Bladder Cancer in Humans.

There is a great need to improve the outlook for people facing urinary bladder cancer, especially for patients with invasive urothelial carcinoma (InvUC) which is lethal in 50% of cases. Improved outcomes for patients with InvUC could come from advances on several fronts including emerging immunotherapies, targeted therapies, and new drug combinations; selection of patients most likely to respond to a given treatment based on molecular subtypes, immune signatures, and other characteristics; and prevention, early detection, and early intervention. Progress on all of these fronts will require clinically relevant animal models for translational research. The animal model(s) should possess key features that drive success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). Experimental animal models, while essential in bladder cancer research, do not possess these collective features to accurately predict outcomes in humans. These key features, however, are present in naturally-occurring InvUC in pet dogs. Canine InvUC closely mimics muscle-invasive bladder cancer in humans in cellular and molecular features, molecular subtypes, immune response patterns, biological behavior (sites and frequency of metastasis), and response to therapy. Thus, dogs can offer a highly relevant animal model to complement other models in research for new therapies for bladder cancer. Clinical treatment trials in pet dogs with InvUC are considered a win-win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. In addition, the high breed-associated risk for InvUC in dogs (e.g., 20-fold increased risk in Scottish Terriers) offers an unparalleled opportunity to test new strategies in primary prevention, early detection, and early intervention. This review will provide an overview of canine InvUC, summarize the similarities (and differences) between canine and human InvUC, and provide evidence for the expanding value of this canine model in bladder cancer research.

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).

Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs.

Genomic analyses are defining numerous new targets for cancer therapy. Therapies aimed at specific genetic and epigenetic targets in cancer cells as well as expanded development of immunotherapies are placing increased demands on animal models. Traditional experimental models do not possess the collective features (cancer heterogeneity, molecular complexity, invasion, metastasis, and immune cell response) critical to predict success or failure of emerging therapies in humans. There is growing evidence, however, that dogs with specific forms of naturally occurring cancer can serve as highly relevant animal models to complement traditional models. Invasive urinary bladder cancer (invasive urothelial carcinoma (InvUC)) in dogs, for example, closely mimics the cancer in humans in pathology, molecular features, biological behavior including sites and frequency of distant metastasis, and response to chemotherapy. Genomic analyses are defining further intriguing similarities between InvUC in dogs and that in humans. Multiple canine clinical trials have been completed, and others are in progress with the aim of translating important findings into humans to increase the success rate of human trials, as well as helping pet dogs. Examples of successful targeted therapy studies and the challenges to be met to fully utilize naturally occurring dog models of cancer will be reviewed.

A Nonselective Cyclooxygenase Inhibitor Enhances the Activity of Vinblastine in a Naturally-Occurring Canine Model of Invasive Urothelial Carcinoma.

Background: Chemotherapy is expected to remain an important part of invasive urothelial carcinoma (UC) treatment. Strategies to enhance chemotherapy efficacy are needed. Objective: To determine the chemotherapy-enhancing effects of a nonselective cyclooxygenase (COX) inhibitor on vinblastine in a naturally-occurring canine model of invasive UC. Methods: With IACUC approval, privately-owned dogs with naturally-occurring histologically-diagnosed invasive UC, expected survival ≥6 weeks, and informed owner consent were randomly allocated to receive vinblastine (2.5 mg/m2 intravenously every 2 weeks) plus piroxicam (0.3 mg/kg daily per os) or vinblastine alone (same dose) with the option to receive piroxicam alone when vinblastine failed. Scheduled evaluations included physical exam, standard laboratory analyses, thoracic radiography, abdominal ultrasonography, and standardized measurement of urinary tract tumors. Results: Dogs receiving vinblastine alone (n = 27) and vinblastine-piroxicam (n = 24) were similar in age, sex, breed, tumor stage, and grade. Remission occurred more frequently (P <  0.02) with vinblastine-piroxicam (58.3%) than with vinblastine alone (22.2%). The median progression free interval was 143 days with vinblastine alone and 199 days with the combination. Interestingly, the overall median survival time was significantly longer (P <  0.03) in dogs receiving vinblastine alone followed by piroxicam alone (n = 20, 531 days) than in dogs receiving the combination (299 days). Treatment was well tolerated in both arms. Conclusions: Piroxicam significantly enhanced the activity of vinblastine in dogs with UC where the cancer closely mimics the human condition, clearly justifying further study. The study suggest the potential importance of tracking COX inhibitor use in patients in clinical trials as COX inhibitors could affect treatment response.

Management of transitional cell carcinoma of the urinary bladder in dogs: a review.

Transitional cell carcinoma (TCC), also referred to as urothelial carcinoma, is the most common form of urinary bladder cancer in dogs, affecting tens of thousands of dogs worldwide each year. Canine TCC is usually a high grade invasive cancer. Problems associated with TCC include urinary tract obstruction, distant metastases in >50% of affected dogs, and clinical signs that are troubling both to the dogs and to their owners. Risk factors for TCC include exposure to older types of flea control products and lawn chemicals, obesity, female sex, and a very strong breed-associated risk. This knowledge is allowing pet owners to take steps to reduce the risk of TCC in their dog. The diagnosis of TCC is made by histopathology of tissue biopsies obtained by cystoscopy, surgery, or catheter. Percutaneous aspirates and biopsies should be avoided due to the risk of tumor seeding. TCC is most commonly located in the trigone region of the bladder precluding complete surgical resection. Medical treatment is the mainstay for TCC therapy in dogs. Although TCC is not usually curable in dogs, multiple drugs have activity against it. Approximately 75% of dogs respond favorably to TCC treatment and can enjoy several months to a year or more of good quality life. Many promising new therapies for TCC are emerging and with the close similarity between TCC in dogs and high grade invasive bladder cancer in humans, new treatment strategies found to be successful in canine studies are expected to help dogs and to be subsequently translated to humans.

Mutations in Lyar and p53 are synergistically lethal in female mice.

BACKGROUND: Ly-1 antibody reactive clone (LYAR) is a nucleolar zinc finger protein that has been implicated in cell growth, self-renewal of embryonic stem cells, and medulloblastoma. To test whether LYAR is critical for cell growth and development, we generated Lyar mutant mice. METHODS: Mice carrying the mutant Lyar(gt) allele were generated from embryonic stem cells that contained a gene-trap insertion in the Lyar gene. Phenotypic analyses were performed on Lyar mutant mice and mouse embryonic fibroblasts. Lyar(gt/gt) mice were crossed to mice lacking the p53 tumor suppressor protein and Lyar/p53 compound mutants scored for external abnormalities. RESULTS: Lyar(gt/gt) homozygotes are viable, fertile, and indistinguishable from wild type littermates. However, the growth of Lyar(+/gt) and Lyar(gt/gt) mouse embryonic fibroblasts (MEFs) was impaired, coincident with an increase in the steady-state level of p53 and a key p53 effector of growth arrest, p21, suggesting that a cellular stress response is triggered in the absence of a wild type level of LYAR. Remarkably, the majority of Lyar(+/gt) and Lyar(gt/gt) female mice lacking p53 mice failed to survive. The neural tube defect (NTD) exencephaly was observed in ≈26% and ≈61% of female Lyar(+/gt;) p53(-/-) and Lyar(gt/gt;) p53(-/-) embryos, respectively. CONCLUSIONS: Lyar/p53 mutant mice represent a new digenic model of NTDs. Furthermore, these studies identify Lyar as a novel candidate gene for a role in human NTDs. These results provide new data to support the idea that loss of a p53-mediated developmental checkpoint may increase the risk of NTDs owing to some germline mutations.