Increasing age and severe intraoperative hypotension associated with nonsurvival in dogs with gallbladder mucocele undergoing cholecystectomy.

OBJECTIVE: To identify prognostic indicators and inflammatory markers associated with nonsurvival in dogs with gallbladder mucoceles (GBMs) following cholecystectomy and to evaluate C-reactive protein (CRP) and haptoglobin concentrations in dogs with GBMs compared to healthy controls. ANIMALS: 25 dogs that underwent cholecystectomy for removal of GBM and 20 healthy control dogs. METHODS: A prospective, multicenter cohort study. Survival outcomes to hospital discharge and 2 weeks postdischarge were recorded from medical records. Laboratory variables, inflammatory markers (CRP and haptoglobin), and 25-hydroxyvitamin(OH) D (25[OH]D) concentrations were measured preoperatively. Associations between signalment, clinicopathologic variables, acute patient physiologic and laboratory evaluation (APPLEFAST) scores, inflammatory markers, 25(OH)D concentration, and survival were analyzed using logistic regression. RESULTS: 76% (19/25) and 68% (17/25) of dogs survived to hospital discharge and 2 weeks postdischarge, respectively. For each additional year of age, the odds of nonsurvival in hospital and 2 weeks postdischarge increased by 2.2 (P = .01; 95% CI, 1.2 to 5.0) and 1.7 (P = .04; 95% CI, 1.0 to 3.2), respectively. Intraoperative systolic blood pressure ≤ 65 mm Hg increased the probability of nonsurvival in hospital (P < .04). Gallbladder perforation, APPLEFAST scores, and preoperative serum concentrations of CRP, haptoglobin, and 25(OH)D were not associated with survival. Serum CRP and haptoglobin concentrations were greater in dogs with GBM compared to controls (P < .001). CLINICAL RELEVANCE: Increasing age and intraoperative systolic blood pressure ≤ 65 mm Hg were associated with nonsurvival in dogs with GBM undergoing cholecystectomy. Serum CRP, haptoglobin, and 25(OH)D were not associated with nonsurvival postcholecystectomy in this sample population.

Pegylated-l-asparaginase therapy for feline large cell lymphoma: 82 cases (2017-2020).

OBJECTIVES: The present study aimed to investigate pegylated-l-asparaginase monotherapy for feline large cell lymphoma as a potential alternative to palliative corticosteroids treatment in animals whose owners declined cytotoxic chemotherapy. METHODS: A retrospective, descriptive case series of cats treated initially with pegylated-l-asparaginase as a sole therapy for feline large cell lymphoma is reported. The treatment protocol consisted of 12 intramuscular injections of pegylated-l-asparaginase with increasing intervals. If cats were unresponsive to pegylated-l-asparaginase monotherapy, a second-line treatment was initiated. Signalment, origin of lymphoma, staging, treatment, possible adverse events and follow-up data were extracted from the medical records. Responses and survival data were analysed. RESULTS: Eighty-two cats with lymphoma of five different anatomic types were included: alimentary, abdominal extra-alimentary, peripheral nodal, nasal/nasopharyngeal and other (mediastinal, renal [solitary] and miscellaneous combined in one group for analytical purposes). The response rate was 74.1% (95% confidence interval = 63.4-83.5) with 38.3% (95% confidence interval = 27.8-48.8) in complete remission. The median disease-free period and calculated overall survival time were 70 days (12-1702+) and 79 days (1-1715+), respectively. The response rate was significantly correlated with the origin of the lymphoma and the combined group had a significantly lower response rate (P = 0.035). Twenty-four cats were also treated with corticosteroids. There was no significant difference in outcomes between the group treated with or without corticosteroids. Adverse events were present in a small number of cats (14/82). The majority of these adverse events were mild to moderate in 5/14 cats; however, the adverse events were severe enough to cause discontinuation of therapy. CONCLUSIONS AND RELEVANCE: Based on the response rate and median disease-free period, treatment with pegylated-l-asparaginase is inferior when compared with historical chemotherapy protocols. However, some cats demonstrated an exceptional long disease-free period. Therefore, pegylated-l-asparaginase could be offered as an alternative to corticosteroid therapy alone. Further studies are needed to evaluate the additional benefit over palliative corticosteroid monotherapy.

Correction: Serum 25-hydroxyvitamin D concentrations in dogs with gallbladder mucocele.

[This corrects the article DOI: 10.1371/journal.pone.0244102.].

Serum 25-hydroxyvitamin D concentrations in dogs with gallbladder mucocele.

Gallbladder mucocele (GBM) is a common biliary disorder in dogs. Gallbladder hypokinesia has been proposed to contribute to its formation and progression. The specific cause of gallbladder stasis in dogs with GBM as well as viable treatment options to resolve dysmotility remains unknown. Vitamin D deficiency is one of the many potential causes of gallbladder hypokinesia in humans and repletion results in complete resolution of stasis. Improving our understanding of the relationship between serum vitamin D and GBM could help identify dogs as a model for humans with gallbladder hypokinesia. Furthermore, this relationship could provide insight into the pathogenesis of GBM and support the need for future studies to investigate vitamin D as a novel treatment target. Therefore, goals of this study were i) to determine if serum 25-hydroxyvitamin(OH)D concentrations were decreased in dogs with GBM, ii) if serum 25(OH)D concentrations were different in clinical versus dogs subclinical for GBM, and iii) to determine if serum 25(OH)D concentrations could predict the ultrasonographic type of GBM. Sixty-two dogs (clinical, n = 26; subclinical, n = 36) with GBM and 20 healthy control dogs were included in this prospective observational study. Serum 25(OH)D concentrations were measured with a competitive chemiluminescence immunoassay. Overall, dogs with GBM had lower serum 25(OH)D concentrations than control dogs (P = 0.004). Subsequent subgroup analysis indicated that this difference was only significant in the subclinical group compared to the control dogs (P = 0.008), and serum 25(OH)D concentrations did not significantly differ between dogs clinical for GBM versus subclinical or control dogs, indicating that inflammatory state in clinical dogs was not the major constituent of the observed findings. Decreasing serum 25(OH)D concentrations, but not clinical status, was associated with a more advanced developmental stage of GBM type determined by ultrasonography. Our results indicate that vitamin D has a role in dogs with GBM. Additional studies are needed to assess if reduced vitamin D in dogs with GBM is a cause or effect of their biliary disease and to investigate if vitamin D supplementation could be beneficial for dogs with GBM.

Genome-wide based model predicting recovery from portosystemic shunting after liver shunt attenuation in dogs.

BACKGROUND: In dogs with congenital portosystemic shunt (CPSS), recovery after surgical CPSS attenuation is difficult to predict. OBJECTIVES: Our aim was to build a model with plasma albumin concentration and mRNA expression levels of hepatic gene products as predictors of recovery from portosystemic shunting after surgery. ANIMALS: Seventy-three client-owned dogs referred for surgical attenuation of CPSS. METHODS: A prediction model was constructed using 2 case-control studies of recovered and nonrecovered dogs after surgical CPSS attenuation. In the 1st study, a dog-specific gene expression microarray analysis was used to compare mRNA expression in intraoperatively collected liver tissue between 23 recovered and 23 nonrecovered dogs. In the 2nd study, preoperative plasma albumin concentration and the expression of microarray-selected genes were confirmed by RT-qPCR in intraoperatively collected liver samples of 31 recovered and 31 nonrecovered dogs, including 35 dogs from the 1st study. RESULTS: In the 1st study, 43 genes were differently expressed in recovered and nonrecovered dogs. The mean preoperative plasma albumin concentration in recovered dogs was higher compared to nonrecovered dogs (23 and 19 g/L, respectively; P = .004). The best fitting prediction model in the 2nd study included preoperative plasma albumin concentration and intraoperative DHDH, ERLEC1, and LYSMD2 gene expression levels. CONCLUSION AND CLINICAL IMPORTANCE: A preclinical model was constructed using preoperative plasma albumin concentration and intraoperative hepatic mRNA expression of 3 genes that were unbiasedly selected from the genome to predict recovery from portosystemic shunting after shunt ligation. Further development is essential for clinical application.

Aberrant hepatic lipid storage and metabolism in canine portosystemic shunts.

Non-alcoholic fatty liver disease (NAFLD) is a poorly understood multifactorial pandemic disorder. One of the hallmarks of NAFLD, hepatic steatosis, is a common feature in canine congenital portosystemic shunts. The aim of this study was to gain detailed insight into the pathogenesis of steatosis in this large animal model. Hepatic lipid accumulation, gene-expression analysis and HPLC-MS of neutral lipids and phospholipids in extrahepatic (EHPSS) and intrahepatic portosystemic shunts (IHPSS) was compared to healthy control dogs. Liver organoids of diseased dogs and healthy control dogs were incubated with palmitic- and oleic-acid, and lipid accumulation was quantified using LD540. In histological slides of shunt livers, a 12-fold increase of lipid content was detected compared to the control dogs (EHPSS P<0.01; IHPSS P = 0.042). Involvement of lipid-related genes to steatosis in portosystemic shunting was corroborated using gene-expression profiling. Lipid analysis demonstrated different triglyceride composition and a shift towards short chain and omega-3 fatty acids in shunt versus healthy dogs, with no difference in lipid species composition between shunt types. All organoids showed a similar increase in triacylglycerols after free fatty acids enrichment. This study demonstrates that steatosis is probably secondary to canine portosystemic shunts. Unravelling the pathogenesis of this hepatic steatosis might contribute to a better understanding of steatosis in NAFLD.

Estimated incidence rate and distribution of tumours in 4,653 cases of archival submissions derived from the Dutch golden retriever population.

BACKGROUND: A genetic predisposition for certain tumour types has been proven for some dog breeds. Some studies have suggested that this may also be true for the Golden retriever breed. The present study aimed to examine a possible existence of a tumour (type) predisposition in the Dutch population of Golden retrievers by evaluating annual estimated incidence rates compared to incidence rates from previous publications. A second aim was to evaluate whether incidences of various tumours differed as related to the diagnostic method chosen, being either cytology or histology. RESULTS: Tumours submitted to Utrecht University during the period 1998-2004 diagnosed either by means of cytology (n = 2,529) or histology (n = 2,124), were related to an average annual Dutch kennel club population of 29,304 Golden retrievers.Combining individual tumours from both the cytological and the histopathological data-set resulted in an annual estimated incidence rate of 2,242 for 100,000 dog-years at risk regarding tumour development in general.The most common cytological tumor diagnoses were 'fat, possibly lipoma' (35%), mast cell tumour (21%) and non-Hodgkin lymphoma (10%). The most commonly diagnosed tumours by histology were mast cell tumour (26%), soft tissue sarcomas (11%) and melanoma (8%). Both the cytological and histopathological data-sets, showed variation; in patient age distribution, age of onset and incidence of various tumours. CONCLUSION: Comparing our data with previous reports in non-breed-specified dog populations, the Golden retriever breed shows an increased risk for the development of tumours in general, as well as an increased risk for the development of specific tumour types, including the group of soft tissue sarcomas. Variations in age, location and incidence of various tumours were observed between the two data-sets, indicating a selection bias for diagnostic procedure.

Aberrant gene expression in dogs with portosystemic shunts.

Congenital portosystemic shunts are developmental anomalies of the splanchnic vascular system that cause portal blood to bypass the liver. Large-breed dogs are predisposed for intrahepatic portosystemic shunts (IHPSS) and small-breed dogs for extrahepatic portosystemic shunts (EHPSS). While the phenotype resulting from portal bypass of the liver of the two types of shunt is identical, the genotype and molecular pathways involved are probably different. The aim of this study was to gain insight into the pathways involved in the different types of portosystemic shunting. Microarray analysis of mRNA expression in liver tissue from dogs with EHPSS and IHPSS revealed that the expression of 26 genes was altered in either IHPSS or EHPSS samples compared with that in liver samples from control dogs. Quantitative real-time PCR of these genes in 14 IHPSS, 17 EHPSS, and 8 control liver samples revealed a significant differential expression of ACBP, CCBL1, GPC3, HAMP, PALLD, VCAM1, and WEE1. Immunohistochemistry and Western blotting confirmed an increased expression of VCAM1 in IHPSS but its absence in EHPSS, an increased WEE1 expression in IHPSS but not in EHPSS, and a decreased expression of CCBL1 in both shunt types. Regarding their physiologic functions, these findings may indicate a causative role for VCAM1 in EHPSS [corrected] and WEE1 for IHPSS. CCBL1 could be an interesting candidate to study not yet elucidated aspects in the pathophysiology of hepatic encephalopathy.

Distribution of extrahepatic congenital portosystemic shunt morphology in predisposed dog breeds.

BACKGROUND: An inherited basis for congenital extrahepatic portosystemic shunts (EHPSS) has been demonstrated in several small dog breeds. If in general both portocaval and porto-azygous shunts occur in breeds predisposed to portosystemic shunts then this could indicate a common genetic background. This study was performed to determine the distribution of extrahepatic portocaval and porto-azygous shunts in purebred dog populations. RESULTS: Data of 135 client owned dogs diagnosed with EHPSS at the Faculty of Veterinary Medicine of Utrecht University from 2001 - 2010 were retrospectively analyzed. The correlation between shunt localization, sex, age, dog size and breed were studied. The study group consisted of 54 males and 81 females from 24 breeds. Twenty-five percent of dogs had porto-azygous shunts and 75% had portocaval shunts. Of the dogs with porto-azygous shunts only 27% was male (P = 0.006). No significant sex difference was detected in dogs with a portocaval shunt. Both phenotypes were present in almost all breeds represented with more than six cases. Small dogs are mostly diagnosed with portocaval shunts (79%) whereas both types are detected. The age at diagnosis in dogs with porto-azygous shunts was significantly higher than that of dogs with portocaval shunts (P < 0.001). CONCLUSION: The remarkable similarity of phenotypic variation in many dog breeds may indicate common underlying genes responsible for EHPSS across breeds. The subtype of EHPSS could be determined by a minor genetic component or modulating factors during embryonic development.

Inherited liver shunts in dogs elucidate pathways regulating embryonic development and clinical disorders of the portal vein.

Congenital disorders of the hepatic portal vasculature are rare in man but occur frequently in certain dog breeds. In dogs, there are two main subtypes: intrahepatic portosystemic shunts, which are considered to stem from defective closure of the embryonic ductus venosus, and extrahepatic shunts, which connect the splanchnic vascular system with the vena cava or vena azygos. Both subtypes result in nearly complete bypass of the liver by the portal blood flow. In both subtypes the development of the smaller branches of the portal vein tree in the liver is impaired and terminal branches delivering portal blood to the liver lobules are often lacking. The clinical signs are due to poor liver growth, development, and function. Patency of the ductus venosus seems to be a digenic trait in Irish wolfhounds, whereas Cairn terriers with extrahepatic portosystemic shunts display a more complex inheritance. The genes involved in these disorders cannot be identified with the sporadic human cases, but in dogs, the genome-wide study of the extrahepatic form is at an advanced stage. The canine disease may lead to the identification of novel genes and pathways cooperating in growth and development of the hepatic portal vein tree. The same pathways likely regulate the development of the vascular system of regenerating livers during liver diseases such as hepatitis and cirrhosis. Therefore, the identification of these molecular pathways may provide a basis for future proregenerative intervention.