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The aim of this study was to evaluate the use of cathepsin-activated intraoperative near-infrared (NIR) imaging to detect insulinomas in dogs, a spontaneous large animal model for human disease. A prospective, pilot clinical trial was performed on dogs with naturally occurring insulinomas undergoing exploratory laparotomy. Each dog underwent routine preoperative diagnostic assessment, and a cathepsin-activated fluorophore (VGT-309) was administered intravenously 1-2 days preoperatively. All intraoperative findings with visible light and NIR imaging were recorded and mean NIR fluorescence intensity of tumors and grossly normal pancreas were quantified. Excision of any identified primary tumor and suspected metastatic lesions was performed. All excised tissues underwent histologic evaluation and immunohistochemistry (IHC) for cathepsin B expression. Descriptive statistics were calculated, and differential fluorescence intensity and cathepsin B expression between the pancreatic mass and adjacent grossly normal pancreatic tissue were assessed for statistical significance via paired t tests with p < 0.05 used for significance. Six dogs were enrolled. No adverse events occurred secondary to administration of the imaging agent. In situ, insulinomas had significantly greater mean fluorescence intensities than the surrounding pancreas, and the median tumor to background ratio was 1.906 (range 1.286-2.556). One dog had an occult pancreatic mass that was identified intraoperatively with NIR guidance. Background fluorescence of liver and lymph nodes was observed in all cases, and one dog was diagnosed with nodal and hepatic metastasis. Histologic tumor margins correlated with margins of NIR fluorescence. Cathepsin B expression was determined to be significantly greater in the pancreatic tumor compared to adjacent non-neoplastic pancreas via IHC, and there was no overlap in the range of median IHC-positive proportion values for these tissues. However, there was overlap in the range of IHC-positive proportion values for neoplastic pancreatic samples and lymph node and liver tissues. The findings of this pilot study support further investigation of cathepsin-activated NIR imaging to enhance intraoperative canine insulinoma localization and margin evaluation. Future studies are needed to further characterize and optimize the utility of targeted NIR imaging, particularly to identify metastatic lesions, for canine insulinoma, which may serve as an effective translational model for humans with pancreatic neuroendocrine tumors.

Abstract Background Insulinoma is the most commonly diagnosed endocrine tumor of the pancreas in dogs. Current literature has predominately focused on referral management of insulinoma in dogs. Hypothesis/Objectives To describe clinical signs, management, and survival and to explore risk factors associated with clinical management undertaken for insulinoma in dogs under primary veterinary care in the United Kingdom. Animals Two hundred seventy-eight insulinoma cases identified from 225 0741 VetCompass study dogs within the United Kingdom in 2019. Methods Nested cohort study. Insulinoma cases were identified by manual review of electronic health records. Multivariable logistic regression was used to identify risk factors associated with clinical management. The Kaplan–Meier method with log rank test and multivariable Cox regression were used to identify risk factors associated with survival. Results Epileptiform seizures, weakness, collapse/syncope, and muscle fasciculations were the most commonly reported clinical signs. Spaniel breed dogs (OR 2.43, 95% CI 1.02-5.79), dogs with epileptiform seizures (OR 2.15, 95% CI 1.15-4.02) and referred dogs (OR 4.85, 95% CI 2.42-9.72) had increased odds of undergoing surgery, compared to non-spaniel breed dogs, dogs without epileptiform seizures, and non-referred dogs. Compared to dogs treated solely medically, dogs treated surgically had a lower hazard (HR 0.49, 95% CI 0.32-0.77) of dying. Referred dogs had a longer median survival time (673 days, IQR 221-1139) than non-referred dogs (275 days, IQR 55-735) (P < .001). Conclusions and clinical importance This study identified that referral and surgical treatment are associated with improved clinical outcomes for dogs with insulinoma presenting to primary veterinary care.

Insulinoma is the most common pancreatic tumor diagnosed in dogs. This study aimed to report incidence risk, breed predispositions and other demographic risk factors for insulinoma diagnosed in dogs under primary veterinary care in the UK. The VetCompass Program supports research on anonymized electronic health records (EHRs) from dogs under UK veterinary care. This study included all VetCompass EHRs from dogs under primary veterinary care during 2019. Multivariable logistic regression analysis was used to evaluate demographic risk factors for insulinoma diagnosis. Of 2,250,741 study dogs, 278 were confirmed as insulinoma cases at any date. The estimated 2019 incidence risk was 0.003% (95% CI 0.002–0.004%). Compared to crossbreeds, predisposed breeds included Dogue de Bordeaux, German Pointer, Flat Coated Retriever, Boxer and West Highland White Terrier. The Labrador Retriever showed decreased odds for insulinoma diagnosis. Additionally, being a terrier breed and being a breed predisposed to other endocrine cancers were associated with increased odds for insulinoma diagnosis. Other risk factors associated with increased odds for insulinoma diagnosis included being female neutered, being 9 - <15 years of age, having an adult median bodyweight of 20 - <30 kg and having a bodyweight above the median for the sex/breed. This is the first study to report the epidemiology of canine insulinoma in dogs under primary veterinary care, resulting in crucial leads for further research in the epidemiology and etiology of canine insulinoma and possible links of canine insulinoma with other canine endocrine cancers. Additionally, the results can aid veterinarians to identify dogs at greater risk of insulinoma.

Abstract Background Information regarding outcome of dogs undergoing surgical management for insulinoma is based on studies of a small number of dogs. Objectives To report the outcomes of dogs undergoing surgery as treatment for insulinoma, the prevalence of postoperative diabetes mellitus (DM) in this group and to determine if development of DM can be predicted. Animals Forty-eight client-owned dogs, with a histopathological diagnosis of insulinoma, from three European referral hospitals. Methods Retrospective observational study. Dogs were identified from a search of electronic hospital records. Cox's regression was used to determine factors associated with postoperative survival and relapse, and logistic regression was used to determine factors associated with the development of DM. Results Median survival time (MST) was 372 days (range 1-1680 days), with dogs with stage I disease having the longest survival time. Stage I dogs had MST of 652 days (range 2-1680 days), whereas dogs with either stage II or III disease had MST of 320 days (range 1-1260 days; P = 0.045). Postoperative hyperglycemia was identified in 33% (16/48) of the dogs, of which 9 (19% of the total population) developed persistent DM. No factors that could be used as predictors for development of DM were identified. Conclusions and clinical importance Stage of disease and postoperative hypoglycemia were associated with greater odds of relapse and decreased survival time; these could be used when discussing prognosis. In this study, postoperative DM developed more commonly than previously reported, but no factors were identified that might be useful predictors.

Insulinomas (INS) are the most common human and canine functioning pancreatic neuroendocrine tumours. The long-term prognosis for malignant INS is poor, because micrometastases are frequently missed during surgery. As human and canine malignant INS share clinical and histopathological features, dogs have been proposed as models for INS research. Using RNA-sequencing, we conducted a pilot study to better understand the underlying molecular mechanisms of canine INS. Normal canine pancreas and lymph node control tissues were compared with primary INS and INS-metastatic lymph nodes, revealing more than 3,000 genes differentially expressed in normal pancreas compared to primary INS. Only 164 genes were differentially expressed between primary INS and INS-metastatic lymph nodes. Hierarchical clustering analysis demonstrated similar genetic profiles in normal pancreas and early clinical stage primary INS, whereas late clinical stage primary INS resembled the genetic profile of INS-metastatic lymph nodes. These findings suggest that markers of malignant behaviour could be identified at the primary site of the disease. Finally, using the REACTOME pathways database, we revealed that an active collagen metabolism, extracellular matrix remodelling, beta-cell differentiation and non-beta-cell trans-differentiation might cause disease progression and hyperinsulinism in INS, identifying major pathways worthy of future research in this currently poorly controlled disease.

Abstract Background Information regarding serum insulin concentration in dogs newly diagnosed with insulinoma and its association with clinical stage and survival time is lacking. Objective Examine association between serum insulin concentration and survival and clinical disease stage in dogs with insulinoma. Animals Fifty-nine client-owned dogs with a diagnosis of insulinoma from 2 referral hospitals. Method Retrospective observational study. The χ2 test was used to compare the proportion of dogs with increased insulin concentration in groups with or without metastasis at the time of diagnosis. Linear mixed-effect models were built to compare differences in insulin concentration between dogs with and without evidence of metastasis at the time of original diagnosis. Cox's proportional hazards regression and Kaplan-Meier graphs were used to evaluate the association between insulin concentration and insulin groups and survival. Results Median serum insulin concentration was 33 mIU/L (range, 8-200 mIU/L) in dogs with World Health Organization (WHO) stage I disease and 45 mIU/L (range, 12-213 mIU/L) in dogs with WHO stage II and III disease. No difference was found in the proportion of dogs with increased insulin concentration with or without metastasis (P = .09). No association was identified between insulin concentration and survival (P = .63), and between dogs grouped by insulin concentration and survival (P = .51). Conclusions and Clinical Importance Serum insulin concentrations were not different between dogs with or without metastasis at diagnosis. The degree of insulinemia does not provide further information regarding the stage of the disease and is not associated with survival time in dogs with insulinoma.

Objectives: To determine 1) the sensitivity of contrast-enhanced CT (CECT) for detection of primary canine insulinomas and metastases 2) the sensitivity of CECT to locate canine insulinomas within the pancreas and 3) the CECT attenuation pattern of canine insulinomas and post-contrast phase in which insulinomas have the best visibility. Methods: A retrospective review was performed of the medical records of 27 canine insulinoma patients. Simultaneous occurrence of blood glucose < 3.5 mmol/L (reference interval: 4.2-5.8 mmol/L) and plasma insulin > 10 mIU/L (reference interval: 1.4-24.5 mIU/L) were considered diagnostic for insulinoma. The dogs had a mean age of 9.0 ± 1.7 (SD) years and comprised 11 males and 17 females. Results: Using CECT-scans, 26/27 insulinomas were successfully detected. However, CECT-scans predicted the correct location of insulinomas within the pancreas in only 14/27 dogs. In 9/13 inaccurately located insulinoma cases, the location error was major. There was no significant difference between triple, double and single-phase CECT-scans with location accuracies of 54%, 50% and 50%, respectively. Also, there was no specific post-contrast phase in which insulinomas could be visualised best. Detection of lymph node metastases with CECT-scans had a sensitivity of 67% (10/15 lymph node metastases). Detection of liver metastases had a sensitivity of 75% (6/8 liver metastases). This study highlights that major location errors mainly occurred if single- or double-phase CECT-scans were used (6/9 cases). Conclusion: It is suggested that triple-phase CECT-scans have superior outcome over single- or double-phase CECT-scans in pre-operative imaging of canine insulinomas.

Background Administration of streptozotocin (STZ) at a 21‐day interval has been described in dogs with stage II and III insulinoma. Myelosuppression was not observed, suggesting the possibility of increasing dose intensity by decreasing the interval between doses. Objective To describe the tolerability of a biweekly STZ protocol. A secondary objective was to describe the outcome of dogs treated with this protocol. Animals Nineteen dogs with residual local, metastatic, or recurrent insulinoma. Methods After surgery for insulinoma, or at the time of recurrence, dogs were treated with a previously described STZ and saline diuresis protocol. Treatments were administered every 14 days. All dogs received antiemetic treatment. Adverse events (AEs) were recorded and graded. Outcome endpoints assessed were progression‐free survival (PFS) and survival. Results None of the dogs experienced neutropenia or thrombocytopenia. Mild to moderate gastrointestinal toxicity was the most common AE. Diabetes mellitus was observed in 8 dogs and, in 6, resulted in euthanasia or death. Two dogs developed nephrotoxicity manifested as Fanconi syndrome in 1 and nephrogenic diabetes insipidus in the other. Six dogs developed increased alanine amino transferase activity. Hypoglycemia at the end of the STZ infusion, resulted in collapse in 1 dog and a generalized seizure in another. The median overall PFS and survival time were 196 and 308 days, respectively. Conclusions and Clinical Importance Streptozotocin can be safely administered to dogs with insulinoma, but serious AEs are possible. Additional investigation is required to better define the role of STZ in managing dogs with insulinoma.

Abstract Background Insulinoma is an autonomous insulin-secreting islet cell neoplasm that is rarely diagnosed in cats. The clinical and pathological aspects of feline insulinoma have been described previously, but the molecular characteristics of these tumors have not been investigated. Objectives The study objectives were to characterize peptide hormone production and determine expression of selected genes involved in glucose metabolism and insulin secretion in a feline insulinoma. Methods Immunohistochemistry and RT-PCR were used to examine hormone and gene expression, respectively, by insulinoma cells. Results Immunohistochemistry examination indicated that the tumor cells expressed insulin, chromogranin A, and somatostatin but not glucagon or pancreatic polypeptide. The tumor expressed several genes characteristic of pancreatic beta cells (β cells) including insulin (INS), glucose transporter 2 (GLUT2), and glucokinase (GCK). The tumor also expressed hexokinase 1 (HK1), a glycolytic enzyme not normally expressed in β cells. GCK expression was higher in the insulinoma than in normal pancreas from the same cat. The GCK : HK1 ratio was >20-fold higher in insulinoma tissue than in normal pancreas. Conclusions and Clinical Importance The feline insulinoma produced several peptide hormones and expressed genes consistent with a β-cell phenotype. The pattern of hexokinase gene expression in tumor cells differed from that of normal pancreas. These findings suggest insulinoma cells may have an increased sensitivity to glucose that could contribute to the abnormal insulin secretory response observed at low serum glucose concentrations.

A crossbreed dog with a history of a chronic progressive tetra-paresis had an insulinoma-related peripheral polyneuropathy. Frequent feeding and treatment with corticosteroids resulted in recovery from a non-ambulatory to an almost completely normal clinical state, despite the persistence of hypoglycaemia and hyperinsulinism. After euthanasia for uncontrollable seizures, the presence of a beta-cell carcinoma of the pancreas and extensive axonal degeneration of the peripheral nerves was confirmed by histopathological examination. These findings may indicate an immune-mediated pathogenesis for insulinoma-related peripheral polyneuropathy.