Treatment of Ezetimibe lowers total and low-density lipoprotein cholesterol in hypercholesterolemic dogs with hyperadorenocorticism.

Ezetimibe is a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol, thereby lowering primarily low density lipoprotein-cholesterol (LDL-chol) in human studies. This study aimed to investigate the effects of ezetimibe on dyslipidemia control in nine dogs with hypercholesterolemia. Changes in total cholesterol (T-chol) and each lipoprotein fractions were evaluated at 0, 2, and 4 months following initiation of ezetimibe treatment. A significant decrease in T-chol was observed, and a mean T-chol concentration below 400 mg/dL was achieved at 2 and 4 months. Furthermore, a significant decrease in LDL-chol was observed (-53.3% and -64.3% at 2 and 4 months, respectively). Taken together, treatment of ezetimibe could lower LDL-chol levels in dogs with hypercholesterolemia.

Pulmonary solid adenocarcinoma in a dog.

A 12-year-old castrated male Beagle dog presented with a 1-month history of progressive loss of appetite and cough. One month after the initial visit, a detailed clinical examination was performed due to weight loss and persistent cough. Computed tomography demonstrated diffuse opacification of the entire right lung and cranial lobe of the left lung. Samples of the pulmonary lesions obtained by fine-needle aspiration (FNA) were highly cellular with scattered and clustered foci of large round cells, suggestive of a round cell tumour. Ten days after the FNA, the dog was euthanized due to decreased activity and severe respiratory symptoms. At necropsy, enlargement of the entire right lung and cranial lobe of the left lung was seen. The external and cut surfaces of the lungs were homogeneously grey-white. Histopathological examination of sections of the right lung and the cranial lobe of the left lung revealed proliferation of large round or polygonal neoplastic cells arranged in nests of variable size separated by a thin fibrous stroma. Neoplastic cells were immunopositive for cytokeratin and thyroid transcription factor-1 but negative for vimentin, CD204, chromogranin A and synaptophysin. On the basis of these findings, the tumour was diagnosed as pulmonary solid adenocarcinoma.

Successful treatment of feline hyperadrenocorticism with pituitary macroadenoma using radiation therapy: a case study.

A 10-year-old castrated male cat showing behavioral (irritation, prowling, and tumbling) and cutaneous abnormalities such as dermal fragility was diagnosed as hyperadrenocorticism with pituitary macroadenoma, concurrent with insulin dependent diabetes mellitus. Pituitary enlargement (18.0 mm) was observed during magnetic resonance imaging. High endogenous adrenocorticotropic hormone levels (>2,500 pg/ml) were also observed. Although trilostane treatment (5-10 mg/head, daily) was commenced, the clinical signs did not disappear. Insulin and trilostane treatment were discontinued on day 86 after first day of radiation therapy (4 Gy/12 fractions). After radiation therapy, a decreased pituitary tumor size (10.7 mm) was observed on day 301; neurological and dermatological signs exhibited remission. Radiation therapy is the treatment of choice for feline hyperadrenocorticism with pituitary macroadenoma with neurological signs.

Relationship between anti-insulin antibody production and severe insulin resistance in a diabetic cat.

A 5-year-old castrated male domestic shorthair cat was diagnosed with diabetic ketoacidosis and severe insulin resistance. Although the conventional treatment for diabetic ketoacidosis was provided, the cat required frequent hospitalization because of severe dehydration and repeated diabetic ketoacidosis. We detected anti-insulin antibodies for human in this cat. Serum insulin-binding IgG levels were markedly elevated compared with those in healthy cats and other diabetic cats. We initiated prednisolone to suppress the effects of anti-insulin antibodies. After initiation of prednisolone, the cat was gradually recovered with increasing activity and appetite. Furthermore, satisfactory glycemic control was achieved with combined subcutaneous injection of insulin detemir and insulin degludec.

Relationship between anti-insulin antibody production and severe insulin resistance in a diabetic cat.

A 5-year-old castrated male domestic shorthair cat was diagnosed with diabetic ketoacidosis and severe insulin resistance. Although the conventional treatment for diabetic ketoacidosis was provided, the cat required frequent hospitalization because of severe dehydration and repeated diabetic ketoacidosis. We detected anti-insulin antibodies for human in this cat. Serum insulin-binding IgG levels were markedly elevated compared with those in healthy cats and other diabetic cats. We initiated prednisolone to suppress the effects of anti-insulin antibodies. After initiation of prednisolone, the cat was gradually recovered with increasing activity and appetite. Furthermore, satisfactory glycemic control was achieved with combined subcutaneous injection of insulin detemir and insulin degludec.

Comparison of cholesterol levels among lipoprotein fractions separated by anion-exchange high-performance liquid chromatography in periparturient Holstein-Friesian dairy cows.

Changes in lipoprotein profiles occur in dairy cows during the periparturient period and in cows with transition cow disease. Here, the lipoprotein profiles of Holstein-Friesian dairy cows during the periparturient period were obtained by anion-exchange, high-performance liquid chromatography to evaluate the usefulness of lipoprotein profile evaluation during the periparturient period and in cows with fatty liver and milk fever. Lipoprotein levels (including total and high- (HDL-C) and low-density lipoprotein (LDL-C) cholesterol) in 10 healthy cows were low 4 weeks prepartum, with the lowest values at calving or within 1 week of calving; the values increased at 8 weeks postpartum. The lipoprotein levels were measured in 16 cows diagnosed with fatty liver (n=10) or milk fever (n=6) and compared to 10 healthy dairy cows. A significant difference was observed in HDL-C between healthy cows (at calving and 1 week postpartum), and the fatty liver and milk fever cows. Cows with fatty liver and milk fever had a lower mean HDL-C than the 10 healthy dairy cows at calving and 1 week postpartum. HDL-C might be a good indicator of energy balance for differentiating healthy cows from those with transition cow disease.

The effect of Insulin Degludec on glycemic control in diabetic cats over a 12-month period.

Insulin degludec (IDeg) is a long-acting basal insulin recently developed for use in humans. This study aimed to investigate the effects of IDeg on glycemic control in diabetic cats. Changes in body weight, IDeg dosage, and glycated albumin (GA) were evaluated at 0, 1, 3, 6, 9, and 12 months following initiation of IDeg. A significant decrease in GA was observed and a mean GA level below 25% was achieved between 3 and 12 months. Furthermore, a significant increase in body weight was observed between 3 and 12 months. The mean IDeg dose was 0.75 ± 0.68 IU/kg/day at 12 months. Taken together, long-term glycemic control was successfully achieved in diabetic cats using IDeg.

Comparison of the effects of four commercially available prescription diet regimens on the fecal microbiome in healthy dogs.

The effects of prescription diets on canine intestinal microbiota are unknown. In this study, we used next generation sequencing to investigate the impact of four commercially available prescription diet regimens on the fecal microbiome in six healthy dogs. The diet regimens used were as follows: weight-loss diet, low-fat diet, renal diet, and anallergenic diet. We found a significantly decreased proportion of phylum Actinobacteria with the weight-loss diet compared to the anallergenic diet. There were no significant differences in the proportion of phylum Bacteroidetes between the four diets. The proportion of phylum Firmicutes was significantly decreased with the weight-loss diet compared to the anallergenic diet. The proportion of phylum Fusobacteria was significantly increased with the weight-loss diet compared to the anallergenic diet. There were no significant differences in the proportion of phylum Proteobacteria after consumption of the four diets. We therefore demonstrated that commercial prescription diet influences the fecal microbiome in healthy dogs. These results might be useful when choosing a prescription diet for targeting a disease.

Appropriateness of the revised Japanese guidelines' risk classification for the prognosis of papillary thyroid carcinoma: a retrospective analysis of 5,845 papillary thyroid carcinoma patients.

The revised Japan Association of Endocrine Surgeons (JAES)/Japanese Society of Thyroid Surgery (JSTS) guidelines for patients with papillary thyroid carcinoma (PTC) describe four risk classes: very-low-risk, low-risk, intermediate-risk, and high-risk. Here we conducted a retrospective analysis to evaluate the appropriateness of these guidelines' risk classification of PTCs. Lymph node recurrence-free, distant recurrence-free and cause-specific survivals at 15-year of high-risk group were significantly poorer than those at 15-year of intermediate-group and these survivals of intermediate-group were poorer than of low- or very-low-risk patients. In the subset analyses based on patient age (≥55 years and <55 years), we obtained the same results in both subsets. Age significantly worsen the whole prognosis of high-risk patients and cause-specific survival of intermediate-risk patients, but not the prognosis of low- or very-low-risk patients. Therefore, the risk classification of the revised JAES/JSTS guidelines is appropriate, and therapeutic strategies should be decided based on the risk class together with the patients' age.

Natural history of papillary thyroid microcarcinoma: Kinetic analyses on tumor volume during active surveillance and before presentation.

BACKGROUND: We report on the growth of papillary microcarcinoma during active surveillance and before clinical presentation. METHODS: We conducted a retrospective study of 169 patients with papillary microcarcinoma who were enrolled in active surveillance at our hospital between 2000 and 2004. Patients were followed for a median of 10.1 years using serial ultrasonography (median, 12 examinations), used to calculate the tumor doubling time. To contextualize tumor growth rates during active surveillance, we calculated the hypothetical tumor doubling time before clinical presentation. To resolve the limitations in tumor doubling time, tumor doubling rates were inversely transformed into doubling rates. RESULTS: The doubling rates (per year) during active surveillance (median: 0.0) were >0.5, 0.1 to 0.5, -0.1 to 0.1, and <-0.1 in 5, 38, 97, and 29 cases, respectively. The proportions of tumors with rather rapid growth, slow growth, stable, and a decrease in size were 3%, 22%, 57%, and 17%, respectively. CONCLUSION: Tumor growth of papillary microcarcinomas varies from rather rapid growth to a decrease in size during active surveillance.

Spontaneous Deceleration and Acceleration of Growth Rate in Medullary Thyroid Carcinomas Suggested by Changes in Calcitonin Doubling Times Over Long-Term Surveillance.

BACKGROUND: Based on our long-term observation of medullary thyroid carcinoma (MTC) patients, we hypothesized that some MTCs have spontaneous deceleration or regression of tumor growth over a long term and that a minority may acquire growth acceleration. We thus compared the calcitonin doubling time (Ct-DT) in the earlier and later half-periods of MTC patients' postoperative course. METHODS: We followed 26 MTC patients (14 hereditary and 12 sporadic MTCs) with postoperative hypercalcitoninemia with periodic measurements of serum calcitonin (Ct) for >10 years without major interventions. The median period of Ct measurements was 18.3 years (range 10.6-30.2 years). We divided the individual patients' study periods into the earlier and later halves and calculated the Ct-DTs for both periods. RESULTS: In the hereditary group, the Ct-DT in the later half-period (Later-Ct-DT) was significantly longer than that in the earlier half-period (Earlier-Ct-DT) (median 20.0 years vs. 7.1 years, p = 0.013). These values in the sporadic group were 20.0 years versus 11.1 years, respectively (p =0.774). Twelve patients (seven hereditary and five sporadic) had Later-Ct-DTs significantly longer than their Earlier-Ct-DTs (median 27.4 years vs. 4.9 years) and good prognoses. Two patients (one hereditary, one sporadic) had Later-Ct-DTs significantly shorter than their Earlier-Ct-DTs, and both developed structural recurrence and died of the disease. CONCLUSION: Many of the hereditary and some of the sporadic MTC patients had elongated Ct-DTs over a long period, suggesting spontaneous deceleration and regression of tumor growth. A minority of the MTC patients showed Ct-DT shortening, suggesting tumor growth acceleration.

Long-term management and postmortem examination in a diabetic cat with acromegaly treated with two courses of radiation therapy.

A 12-year-old, castrated male cat with diabetes mellitus was diagnosed with acromegaly and examined with magnetic resonance imaging (enlarged pituitary gland, 8 mm); serum hormone concentrations were measured. After the first course of radiation therapy (4 Gy, 12 fractions), insulin administration was not required from day 420 after diagnosis. Enlarged pituitary tumor (8 mm) recurred, and insulin dosage amount of the cat was increased on day 1,065. The second course of radiation therapy (6 Gy, 4 fractions) was performed on day 1,201 and insulin administration was again discontinued. However, the cat died from lymphoma on day 1,397. Postmortem examination revealed pituitary adenoma. Most tumor cells were positive for chromogranin A, synaptophysin, and growth hormone immunohistochemistry. The pancreatic islet cells revealed diffuse hyperplasia. We achieved long-term successful management of an acromegalic cat with two courses of RT. However, a protocol for a second course of RT for feline recurrent pituitary tumor should be further discussed.

Time-action profiles of insulin degludec in healthy dogs and its effects on glycemic control in diabetic dogs.

Insulin degludec (IDeg) is a new insulin formulation that facilitates long-term control of glucose level in humans. In this study, we investigated the effects of IDeg on glycemic control in dogs. Its time-action profiles were monitored in healthy dogs using an artificial pancreas apparatus under euglycemic conditions. At 9.0-13.5 hr post-IDeg injection, an indistinct peak of glucose level was detected. Moreover, the action of IDeg was persistent for >20 hr. Both IDeg and neutral protamine Hagedorn insulin (NPH) lowered blood glucose concentrations in diabetic dogs, but IDeg caused postprandial hyperglycemia and a somewhat lower preprandial glucose level than that caused by NPH. IDeg might be ineffective in concurrently preventing postprandial hyperglycemia and preprandial hypoglycemia in a single-agent administration.

Prognostic value of the 8th edition of the tumor-node-metastasis classification for patients with papillary thyroid carcinoma: a single-institution study at a high-volume center in Japan.

The tumor-node-metastasis (TNM) staging system is most commonly adopted to evaluate the prognosis of patients with thyroid carcinoma. The 8th edition of the TNM staging system, an extensively revised version of the 7th edition, was recently released. We aimed to investigate whether and how well the 8th edition reflects the cause-specific survival (CSS) of patients with papillary thyroid carcinoma by analyzing the cases in 5,892 patients who underwent initial surgery at Kuma Hospital between 1987 and 2005. The median postoperative follow-up duration was 178 months (range: 6-357 months). One patient with T4b disease was excluded from the analysis. Overall, 116 (2.0%) patients died of thyroid carcinoma. The proportion of variance explained (PVE) for CSS in the 7th and 8th editions was 10.69 and 10.97, respectively. Using the 7th edition, CSS of patients with stage IVA and stage III disease was similar (p = 0.32). In contrast, using the 8th edition, CSS was poorer in stage II than in stage I (p < 0.001), in stage III than in stage II (p < 0.001), and in stage IVB than in stage III (p < 0.001). Similar results were observed for disease-free survival. Although we could not establish any objective evidence that the 8th edition is superior to the 7th edition, the 8th edition is simpler and more convenient, as it includes fewer stages and addresses the issue of the 7th edition where stage IVA and III patients had similar prognoses.

Prognostic value of the 8th tumor-node-metastasis classification for follicular carcinoma and poorly differentiated carcinoma of the thyroid in Japan.

Follicular thyroid carcinoma (FTC), a form of differentiated thyroid carcinoma, is the second most common malignancy arising from thyroid follicular cells. Recently, the tumor-node-metastasis (TNM) classification for differentiated thyroid carcinoma was revised from the 7th to the 8th edition. The diagnostic criteria for poorly differentiated carcinoma (PDC) were also updated in the latest World Health Organization (WHO) classification. In this study, we investigated whether these changes are appropriate for accurately predicting prognosis. Three hundred and twenty-nine patients diagnosed with postoperative pathologically confirmed FTC, who underwent initial surgery at our hospital between 1984 and 2004, were enrolled. For this study, patients were re-evaluated and diagnosed with FTC (N = 285) or PDC (N = 44) without typical nuclear findings of papillary thyroid carcinoma. For FTC, the 8th TNM classification was a more accurate predictor of prognosis than the 7th TNM classification. In the 8th TNM classification, cause-specific survival became significantly poorer from Stage I to IVB. The cause-specific survival of PDC based on the latest WHO classification was worse than, but did not significantly differ from, that of PDC based only on the former WHO classification. For PDC, neither of the TNM classifications could accurately predict prognosis. Taken together, we conclude that (1) the 8th TNM classification more accurately reflects the prognosis of FTC than the 7th TNM classification; (2) PDC based on the former WHO classification should be retained, at least in Japan; and (3) the TNM classification may not be suitable for predicting the prognosis of PDC.

Trends in the Implementation of Active Surveillance for Low-Risk Papillary Thyroid Microcarcinomas at Kuma Hospital: Gradual Increase and Heterogeneity in the Acceptance of This New Management Option.

BACKGROUND: Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PMC) was adopted as a management modality in both the Japanese guidelines in 2011 and the American Thyroid Association guidelines in 2015. AS was initiated at Kuma Hospital in 1993 but was not immediately accepted by all physicians. This study investigated the history of acceptance of AS at Kuma Hospital over time. The results should assist in the implementation of AS at other hospitals in Japan and other countries. METHODS: This study included 4023 patients who were cytologically diagnosed with low-risk PMC at Kuma Hospital during the 24-year period between October 1993 and June 2016. The trend in the frequency of AS use over time was analyzed, dividing the 24-year study period into five parts based on the change in frequency of AS use: 1993-1997, 1998-2002, 2003-2006, 2007-2013, and 2014-2016. RESULTS: The frequency of AS use in the present cohort was 65%. The frequency gradually increased from 30% in 1993-1997 to 88% in 2014-2016, with a slight decrease from 51% in 1998-2002 to 42% in 2003-2006. Until 2007, patients were mostly seen by surgeons, and the frequency of AS use varied remarkably among individual surgeons. Since 2007, the number of patients whose therapeutic strategies are determined by endocrinologists has increased, and the frequency of AS use for low-risk PMC by endocrinologists has been higher than that by surgeons. CONCLUSIONS: At Kuma Hospital, acceptance of AS for low-risk PMC gradually increased over the 24-year study period, but AS was not equally accepted by all physicians. Such variations in the acceptance of AS among individual physicians are also expected to exist in other hospitals. However, due to increasing evidence of the safety and superiority of AS over immediate surgery for this indolent disease, it is expected that AS will gain faster acceptance in other hospitals in Japan and around the world.

Successful treatment of refractory demodicosis and transient papules with a single dose of fluralaner in a dog with uncontrolled severe endocrine disease.

A 12-year-old female Shih-Tzu with hyperadrenocorticism and hypothyroidism developed concurrent refractory generalized demodicosis that did not respond to doramectin treatment. Although amitraz treatment was effective, the dog developed severe diabetes, which resulted in the cessation of amitraz and trilostane. Attempts to control the diabetes were unsuccessful, and its hyperadrenocorticism was left untreated, leading to the recurrence of demodicosis. However, demodicosis went into complete remission with a single dose of fluralaner. Transient erythematous papules appeared on the trunk three days after the administration of fluralaner, but no other adverse reactions were noted. We demonstrated that fluralaner is a potent treatment for demodicosis, and skin eruptions are possible after the first dose of the drug.

Pituitary size alteration and adverse effects of radiation therapy performed in 9 dogs with pituitary-dependent hypercortisolism.

The purpose of this study was to determine the therapeutic and/or adverse effects of radiation therapy (RT) against pituitary tumors in dogs with pituitary-dependent hypercortisolism, as monitored by frequent post-RT detailed MRI examinations, clinical signs, and changes in hormone concentrations. Nine dogs with an adrenocorticotropic hormone (ACTH)-secreting pituitary mass diagnosed by magnetic resonance imaging (MRI) underwent RT for 4weeks (total of 48Gy in 4-Gy fractions). Pituitary height/brain area (P/B) value, clinical signs, basal plasma ACTH concentrations, serum cortisol concentrations (pre- and post-ACTH stimulation test) and adverse effects of RT were evaluated before and post-RT. The P/B value was significantly lower in all nine dogs post-RT. One dog lacking any neurological signs demonstrated no change in clinical signs pre and post-RT. Out of 8 dogs which exhibited neurological signs pre-RT, half of them demonstrated complete resolution of their signs, whereas the other half showed transient resolution. In all animals with recurrence of neurological signs, pituitary tumor regrowth was not observed; however, MRI revealed moderate to severe pituitary hemorrhage. Late adverse effect (bilateral otitis media) was observed in three of nine dogs post-RT. RT did not induce any significant changes in the dogs' basal plasma ACTH concentration and pre- and post-ACTH serum cortisol concentrations. In conclusion, RT is effective to reduce pituitary size and the mass effect, but does not appear to affect blood hormone concentrations, necessitating additional medical treatment against hypercortisolism. Periodic MRI imaging post-RT enables early detection of adverse effects of RT.

Insights into the Management of Papillary Microcarcinoma of the Thyroid.

BACKGROUND: Rapid increases in the incidence of thyroid carcinoma with stable mortality rates from thyroid carcinoma have been reported from many countries, and these increases are thought to be due mostly to the increased detection of small papillary thyroid carcinomas (PTCs), including papillary microcarcinomas (PMCs; i.e., PTCs ≤10 mm). Some researchers have suggested that small PTCs have been overdiagnosed and overtreated. In Japan, the active surveillance of patients with low-risk PMCs was initiated by Kuma Hospital (1993) and Tokyo's Cancer Institute Hospital (1995) based on the extremely higher incidences of both latent thyroid carcinomas in autopsy studies and small PTCs detected in mass screening studies using ultrasound examinations compared to the prevalence of clinical thyroid carcinomas. METHODS: The above two institutions' data are summarized regarding the active surveillance of low-risk PMCs, and future prospects for their management are discussed. RESULTS: At 10-year observations in the Kuma Hospital series of 1235 patients, only 8% and 3.8% of the PMC patients showed size enlargement by ≥3 mm and the novel appearance of node metastasis, respectively. In contrast to clinical PTC, PMCs are most unlikely to grow in older patients (≥60 years). In the Kuma Hospital series, the 974 patients who underwent immediate surgery had significantly higher incidences of unfavorable events than the 1179 patients who chose active surveillance. The total cost of immediate surgery, including the costs for salvage surgery and postoperative care for 10 years, was 4.1 times the total cost of 10-year management by active surveillance. Only 8% of the 51 PMC patients showed tumor enlargement during pregnancy, and the rescue surgeries after delivery were successful. In the Cancer Institute Hospital series of 230 patients with 300 lesions, only 7% and 1% of the patients showed size enlargement and novel node metastasis, respectively, and that institution's analysis also revealed that macroscopic or rim calcification and poor vascularity were correlated with non-progressing disease. In both series, none of the patients who underwent rescue surgery after progression signs were detected showed significant recurrence or died of PTC. CONCLUSION: Active surveillance of low-risk PMC can be the first-line management. Interestingly, older patients with low-risk PMCs are the best candidates for active surveillance.

Estimation of the lifetime probability of disease progression of papillary microcarcinoma of the thyroid during active surveillance.

BACKGROUND: We reported that a minority of patients with low-risk papillary microcarcinoma of the thyroid showed disease progression during active surveillance and that older patients had significantly lower disease progression rates than younger patients. Here, we estimated lifetime (≤85 years old) probabilities of disease progression during active surveillance according to the age at presentation based on age decade-specific disease progression rates. METHODS: From 1993-2013, 1,211 low-risk papillary microcarcinoma patients aged 20-79 years underwent active surveillance at Kuma Hospital. We calculated the disease progression rate at the 10-year point of active surveillance for each age-decade group (20s to 70s) with the Kaplan-Meier method. The lifetime disease progression probability for each age group was calculated as (1 - cumulative probability of progression-free survival calculated with age decade-specific disease progression rates) until the patients reached their 80s (i.e., 85 years on average). RESULTS: The age decade-specific disease progression rates at 10 years of active surveillance were 36.9% (20s), 13.5% (30s), 14.5% (40s), 5.6% (50s), 6.6% (60s), and 3.5% (70s); the respective lifetime disease progression probabilities were 60.3%, 37.1%, 27.3%, 14.9%, 9.9% and 3.5% according to the age at presentation. CONCLUSION: The estimated lifetime disease progression probabilities of papillary microcarcinoma during active surveillance vary greatly according to the age at presentation.