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The aim of this study was to clarify the clinical significance of bone metabolism in the mandibular condyles in determining condylar resorptive changes. Twelve condyles of patients with idiopathic condylar resorption and degenerative joint disease were analysed using

Intestinal lymphangiectasia (IL) is a common complication in dogs. Since nitric oxide (NO) is known to relax the lymphatic vessel, we evaluated inducible NO synthase (iNOS) expression using immunohistochemistry in 13 dogs with lymphoplasmacytic enteritis (LPE) with or without IL. The duodenal iNOS expressing cells were significantly increased in dogs with IL-negative or IL-positive LPE dogs (P=0.025, P=0.007) compared with control dogs. However, there was no significant difference in iNOS expression between IL-positive and IL-negative tissues. Based on these results, there is no clear evidence for the NO overproduction in the pathogenesis of IL in dogs with LPE. Factors other than NO could, thus, contribute to IL in dogs with LPE.

OBJECTIVE: To retrospectively evaluate the clinical outcomes of pre-operative endovascular coil embolisation (ECE) for chronic pulmonary aspergillosis (CPA).METHODS: We evaluated surgical patients with CPA between November 2016 and April 2020. Pre-operative ECE for CPA with severe adhesions was selectively performed to reduce intra-operative blood loss. ECE procedures, operative procedures, intra-operative blood loss and complications were evaluated.RESULTS: Twenty-eight patients (21 males and 7 females; median age: 55 years) were included in the study. Of the 28 patients, 8 (28.6%) underwent pre-operative ECE. Technical success rate in pre-operative ECE was 100%. The median time required for ECE procedures was 123 min. The median number of vessels embolised per procedure was 2.5. The median period between embolisation and surgery was 5 days. Major complications were observed in three patients (10.7%). There were no significant differences between patients with and without pre-operative ECE in operative time (284 vs. 365 min, respectively, P = 0.7602) and intra-operative blood loss (294 vs. 228 mL, respectively, P = 0.8987).CONCLUSIONS: Pre-operative ECE for CPA appears to be feasible and safe; however, its role in reducing intra-operative blood loss needs further investigation.

Protein-losing enteropathy (PLE) is known to induce hypercoagulability and resultant thromboembolism in dogs. We hypothesized that hypercoagulability would improve if remission was obtained in dogs with PLE after treatment. This study aimed to evaluate the changes in the coagulation parameters after treatment in dogs diagnosed with PLE. As coagulation parameters, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, thrombin-antithrombin complex (TAT), D-dimer, and antithrombin (AT) were measured. In addition to these parameters, rotational thromboelastometry (ROTEM), which evaluates the comprehensive coagulation and fibrinolysis reactions of whole blood, was conducted and the data of clotting time (CT), clot formation time (CFT), α angle (α), maximum clot firmness (MCF) and lysis index at 60 min (LI60) were obtained. Eleven of the 14 dogs diagnosed with PLE were classified as responders to the treatment based on the changes in their plasma albumin (ALB) concentration after treatment. Significant increase in CFT and decrease of α and MCF indicating the resolution of hypercoagulability were found after treatment in responder dogs; however, there was no significant change in the coagulation and fibrinolysis parameters other than those measured by ROTEM. This study demonstrated that the hypercoagulability detected by ROTEM was significantly improved after treatment in dogs with PLE.

There has been an increase in the number of Jack Russell Terriers (JRTs) diagnosed with adenomas and adenocarcinomas of the gastrointestinal tract in Japan. This study retrospectively investigated the clinical and histopathological features and prognosis of adenocarcinomas arising in the gastrointestinal tract in JRT dogs. Seven JRTs and 39 dogs of other breeds diagnosed with gastrointestinal adenocarcinoma were included in the study. The most common sites of gastrointestinal adenocarcinoma in JRTs were the pylorus and rectum. On histopathological examination, these adenocarcinomas showed a papillary or tubular growth pattern, and the lesions were confined within the mucosal epithelium and poorly invasive. Among all dogs with gastric adenocarcinoma, the median survival time (MST) for five of the JRTs could not be determined because more than half of the cases remained alive, while the MST for nine non-JRT dogs was 34 days. Among all dogs with adenocarcinoma in the large intestine, the MST for three of the JRTs could not be determined, while the MST for nine non-JRT dogs was 1,973 days. The difference in MST between JRT and non-JRT dogs with gastric adenocarcinoma was significant (P=0.0220). Since gastrointestinal adenocarcinomas in JRTs show distinct characteristics with respect to their clinical features, treatment course, and prognosis, a different surgical and medical treatment plan should be considered compared to the management of gastrointestinal adenocarcinomas in other dog breeds.

Diabetic nephropathy, included in diabetic kidney disease (DKD), is the primary disease leading to end-stage renal disease (ESRD) or dialysis treatment, accounting for more than 40% of all patients with ESRD or receiving dialysis. Developing new therapeutics to prevent the transition to ESRD or dialysis treatment requires an understanding of the pathophysiology of DKD and an appropriate animal model for drug efficacy studies. In this study, we investigated the pathophysiology of diabetic kidney disease with type 2 diabetes in uninephrectomized db/db mice. In addition, the nephrectomized db/db mice from 10 weeks to 42 weeks were used to assess the efficacy of long-term administration of the angiotensin-II–receptor antagonist losartan. The blood and urinary biochemical parameters and the blood pressure which is a main pharmacological endpoint of the losartan therapy, were periodically measured. And at the end, histopathological analysis was performed. Uninephrectomized db/db mice clearly developed obesity and hyperglycemia from young age. Furthermore, they showed renal pathophysiological changes, such as increased urinary albumin-creatinine ratio (UACR) (the peak value 3104±986 in 40-week-old mice), glomerular hypertrophy and increased fibrotic areas in the tubulointerstitial tubules. The blood pressure in the losartan group was significantly low compared to the normotensive Vehicle group. However, as expected, Losartan suppressed the increase in UACR (829±500) indicating the medication was sufficient, but the histopathological abnormalities including tubular interstitial fibrosis did not improve. These results suggest that the uninephrectomized db/db mice are useful as an animal model of the severe DKD indicated by the comparison of the efficacy of losartan in this model with the efficacy of losartan in clinical practice.

Cancer vaccines induce cancer-specific T-cells capable of eradicating cancer cells. The impact of cancer peptide vaccines (CPV) on the tumor microenvironment (TME) remains unclear. S-588410 is a CPV comprising five human leukocyte antigen (HLA)-A*24:02-restricted peptides derived from five cancer testis antigens, DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC1, which are overexpressed in esophageal cancer. This exploratory study investigated the immunologic mechanism of action of subcutaneous S-588410 emulsified with MONTANIDE ISA51VG adjuvant (median: 5 doses) by analyzing the expression of immune-related molecules, cytotoxic T-lymphocyte (CTL) response and T-lymphocytes bearing peptide-specific T-cell receptor (TCR) sequencing in tumor tissue or blood samples from 15 participants with HLA-A*24:02-positive esophageal cancer. Densities of CD8+, CD8+ Granzyme B+, CD8+ programmed death-1-positive (PD-1+) and programmed death-ligand 1-positive (PD-L1+) cells were higher in post- versus pre-vaccination tumor tissue. CTL response was induced in all patients for at least one of five peptides. The same sequences of peptide-specific TCRs were identified in post-vaccination T-lymphocytes derived from both tumor tissue and blood, suggesting that functional peptide-specific CTLs infiltrate tumor tissue after vaccination. Twelve (80%) participants had treatment-related adverse events (AEs). Injection site reaction was the most frequently reported AE (grade 1, n = 1; grade 2, n = 11). In conclusion, S-588410 induces a tumor immune response in esophageal cancer. Induction of CD8+ PD-1+ tumor-infiltrating lymphocytes and PD-L1 expression in the TME by vaccination suggests S-588410 in combination with anti-PD-(L)1 antibodies may offer a clinically useful therapy. Trial registration UMIN-CTR registration identifier: UMIN000023324. Electronic supplementary material The online version of this article (10.1007/s00262-020-02619-3) contains supplementary material, which is available to authorized users.

Inflammatory colorectal polyps (ICRPs) are frequently observed in miniature dachshunds in Japan and treated by prednisolone and immunosuppressive drugs such as cyclosporine and leflunomide. The purpose of this retrospective study was to compare the treatment efficacy, such as response rate, response interval, recurrence rate, and adverse events between cyclosporine and leflunomide. While the response rates were significantly higher in dogs treated with leflunomide, no significant differences were observed in the response interval or recurrence rate. Two of the 11 dogs treated with leflunomide showed hematological or gastrointestinal adverse events, while no dog treated with cyclosporine showed any adverse events. A case-controlled prospective study to compare the treatment efficacy of leflunomide with that of cyclosporine should be conducted.

Nivolumab and ipilimumab combination therapy is one of the most promising treatments for patients with melanoma. However, this combination therapy is highly toxic and causes serious adverse events (SAEs) in more than half of the patients.

Introduction There is a wide range of problems associated with ejaculation, including decreased semen volume, vaginal ejaculation problems, premature ejaculation, delayed ejaculation, hematospermia, and pain associated with ejaculation. However, there is no simple questionnaire that can comprehensively evaluate these ejaculatory functions. Objective In this study, we evaluated the overall ejaculation function of the patients in question using an originally developed ejaculation function score (Kimura and Shoji's Ejaculation Function Score). Methods We examined 20 patients who visited our sexual function outpatient clinic with a chief complaint of ejaculation. As a control group, we also examined 20 patients who had undergone vasectomy using the same score. The questionnaire consisted of the following five items (1) Awareness of sufficient momentum, (2) Pleasant sensation during ejaculation, (3) Presence of pain associated with ejaculation, (4) Presence of blood in semen, and (5) Perception of decreased semen volume. The total score was also evaluated. In addition, satisfaction with the current ejaculation was assessed. Results The mean age of the ejaculation disorder group was 43.5±15.1 years. The main complaints were decreased semen volume in 7 cases (35%), vaginal ejaculation disorder in 6 cases (30%), delayed ejaculation in 2 cases (10%), premature ejaculation in 2 cases (10%), lack of orgasm in 1 case (5%), and pain associated with ejaculation in 1 case (5%). The mean scores for each item were 1.5 for item 1, 1.8 for item 2, 3.0 for item 3, 3.0 for item 4, and 2.0 for item 5, resulting in a mean total score of 11.2. On the other hand, the mean age of the vasectomy group was 42.0±9.4 years, item 1 was 2.8, item 2 was 2.9, item 3 was 3.0, item 4 was 3.0, item 5 was 2.9, and the mean total score was 14.6. When the two groups were compared, significant differences were found except for items 3 and 4. There was also a significant difference in satisfaction of present ejaculation with mean scores of 1.3 and 2.9. As a result of examining the clinical severity and the total score, the total score of 5-6 was considered severe, 7-9 moderate, 10-13 mild ejaculation disorder, and 14-15 within the normal range. Conclusion Although our ejaculation function score is still in the developmental stage, we believe that it can be a screening tool for ejaculation function in practical medical care and self-assessment. Disclosure Work supported by industry: no.

Objectives To examine the efficacy and adverse events of continuous L-asparaginase administration in dogs with large cell lymphoma of presumed gastrointestinal origin. Methods We retrospectively reviewed medical records of dogs with large cell lymphoma of presumed gastrointestinal origin treated with continuous L-asparaginase administration from 2009 to 2018. We collected information on the signalment, lesion site, complete blood count, serum biochemical profile, diagnostic imaging findings, cytological and histopathological findings, immunophenotype, L-asparaginase administration frequency, treatment response, adverse events, rescue protocol, and patient outcomes. Clinical outcomes were assessed using medical records or by contacting the owner or referring veterinarian. Results Thirty-two dogs with large cell lymphoma of presumed gastrointestinal origin received weekly L-asparaginase administration. The median number of L-asparaginase injections was seven (range: 1-30). Although two of the 32 dogs had gastrointestinal toxicity of grade 3 or higher, none developed a hypersensitivity reaction. The response rate based on ultrasonographic findings was 18/32 (56%) and that based on clinical signs was 30/32 (94%). The median overall progression-free survival was 50 days (range: 2-214 days), and median overall survival was 147 days (range: 2-482 days). Clinical significance Adverse events associated with continuous L-asparaginase administration were rare. Clinical signs at diagnosis improved in most cases. Based on these results, continuous L-asparaginase administration appears to be a reasonable treatment option for dogs with large cell lymphoma of presumed gastrointestinal origin. This article is protected by copyright. All rights reserved.

Objectives Primary copper-associated hepatopathy (PCH) has been reported in young cats. Although our group recently reported a young cat with PCH harbouring single-nucleotide variations in ATP7B, limited information is available regarding its association with the pathogenesis of feline PCH. The objective of this study was to investigate the prevalence of ATP7B variations in cats with PCH. Methods Rhodanine staining was performed to detect hepatic copper accumulation (HCA) in intraoperative liver tissue specimens from 54 cats. In cats with HCA, variations in ATP7B and COMMD1 and serum ceruloplasmin activity were analysed. Results Based on age, liver histopathological findings and hepatic distribution of accumulated copper, PCH was suspected in 4/54 cats. Sequence analysis of ATP7B and COMMD1 revealed single-nucleotide variations in ATP7B in 3/4 cats with PCH. Among the cats with PCH, one showed remarkably low serum ceruloplasmin activity, while the other three did not. Conclusions and relevance The results of this study suggest that some cats with PCH harbour single-nucleotide variations in ATP7B, suggesting that feline PCH is an equivalent disorder to human Wilson’s disease. This study provides basic evidence facilitating further studies of the pathophysiology and treatment of feline PCH.

In human medicine, computed tomography (CT) is the gold standard for visceral fat measurement. Research shows that the visceral fat area (VFA) of the umbilical slice is significantly correlated with the visceral fat volume (VFV). In veterinary medicine, however, few studies have evaluated visceral fat using CT. This study aimed to evaluate the visceral fat in dogs using CT images, and determine if the slice significantly correlated with VFV to simplify visceral fat measurements. This retrospective study includes data on 90 dogs that underwent whole-body CT scans for diagnostic purposes. VFV was calculated as the product of VFA and thickness in each CT slice; the correlation between VFV and VFA was analyzed at the level of each lumbar vertebra. Visceral fat percentage (VF%) was calculated as the ratio of the product of VFV and fat density to the body weight. Visceral fat area percentage (VFA%) was calculated as the ratio of VFA to the body area, and its correlation with the VF% and the body condition score (BCS) was analyzed. VFA was highly correlated with VFV at the level of each lumbar vertebra, with the highest correlation (r=0.964) at the L3 level. VFA% was significantly correlated with VF% (r=0.930) and weakly correlated with BCS (r=0.523). This study demonstrates that it is sufficient to use only the L3 slice for visceral fat evaluation and that the evaluation can be based on VFA% of the L3 level.

Background/aims An interim analysis of post-marketing surveillance of CT-P13, an infliximab biosimilar, was performed to evaluate its safety and efficacy in Japanese patients with inflammatory bowel disease. Methods Patients were prospectively enrolled between November 2014 and March 2017, after the launch of CT-P13 in Japan, and case report forms of patients followed for at least 4 months were analyzed as of July 2018. Results Of 523 patients in the analysis set, 372 remained on CT-P13 therapy, while 54 (20.2%) of 267 patients with Crohn's disease, and 97 (37.9%) of 256 patients with ulcerative colitis were withdrawn during follow-up. A total of 144 adverse drug reactions (ADRs) were reported in 106 patients (20.3%). Infusion reaction was the most frequent ADR observed in 49 patients (9.4%). Efficacy parameters decreased immediately after the start of treatment in naive patients to anti-tumor necrosis factor-α antibody. In the patients switched from originator infliximab for nonmedical reasons, the decreased parameters due to proceeded treatment with the originator were maintained in low ranges, and the treatment continuation rate was high with low ADR incidence. In contrast, in patients switched for medical reasons such as adverse event or loss of response, the incidence of ADRs was high. However, the efficacy parameters were improved, and the treatment continuation rate was not significantly different from that of the naive patient group. Conclusions In this interim analysis, CT-P13 was comparable to the originator infliximab with respect to ADRs and efficacy, and is therefore considered to be a cost-efficient interchangeable biosimilar for Japanese patients with inflammatory bowel disease.

X-chromosome inactivation pattern (XCIP) analysis can be used to assess the clonality of cell populations of various origin by distinguishing the methylated X chromosome from the unmethylated X chromosome. In this study, the utility of XCIP analysis was improved by incorporating the examination of AC dinucleotide repeats in SLIT and NTRK-like family member 4 (SLITRK4) gene into the previously reported CAG repeat examination of androgen receptor (AR) gene in dogs. The rate of heterozygosity when both genes were analysed (125/150, 83.3%) was higher than AR gene examination alone (86/150, 57.3%). Blood samples from heterozygous dogs in either AC-1 or AC-2 of SLITRK4 gene were examined for the corrected inactivation allele ratio (CIAR), resulting in the determination of a reference range of CIAR3.8 in non-neoplastic cell/tissue samples. Using this analytical method, 49% (21/43) of neoplastic tissue samples from dogs showed a CIAR3.8, indicating the presence of a clonal population. Through the present study, the availability of canine XCIP analysis was improved by incorporating the examination of the SLITRK4 gene, providing a highly useful laboratory examination system for the detection of the clonality of various cell/tissue samples in dogs.

Megaesophagus (ME) is a common esophageal disease in dogs and the prognosis is generally poor, especially with aspiration pneumonia (AP). We retrospectively investigated the clinical features and prognosis of canine ME in Japan. Twenty-eight dogs were included in this study, with the Miniature Dachshund breed being significantly overrepresented (odds ratio: 4.33). Most cases (21 of 28) were diagnosed as idiopathic ME and Myasthenia gravis was the most common cause of secondary ME. The overall median survival time (MST) was not reached and the 3-month survival rate was 85.7%. Ten dogs were diagnosed with AP, at least once during the study period, and the MST of ME dogs with AP was 114 days. The survival time overall and even with AP, was notably more prolonged compared to the previous studies. We hypothesized that treatment for canine ME could prolong the survival time, even in those with both ME and AP.

A 9-month-old intact crossbred female cat was presented with jaundice, intermittent anorexia and lethargy, increased hepatic enzyme activities, and hyperammonemia. Abdominal ultrasound and computed tomographic examinations determined that the liver had a rounded and irregular margin, and histopathological examination identified excessive accumulation of copper hepatocytes in the liver. Concentrations of both blood and urine copper were higher than in healthy cats. The patient responded well to treatment with penicillamine. Clinicopathological abnormalities and clinical signs improved within 2 months, and the patient was alive for >9 months after starting treatment. Genetic examination determined that the patient and its littermate had a single-nucleotide variation (SNV, p. T1297R) that impaired the function of the ATP7B gene product; the gene that is mutated in patients with Wilson's disease (WD). Hepatic copper accumulation was believed to be associated with the SNV of the ATP7B gene, and the patient had a genetic disorder of copper metabolism equivalent to WD in humans.

Targeting regulatory T cell (Treg) infiltration is an emerging strategy for cancer immunotherapy. However, the efficacy of this strategy in advanced prostate cancer remains unclear. Here, we describe the therapeutic efficacy of this strategy in a canine model of advanced prostate cancer. We used dogs with naturally occurring prostate cancer to study the molecular mechanism underlying Treg infiltration into tumor tissues and the effect of anti-Treg treatment. We found that tumor-infiltrating Tregs were associated with poor prognosis in dogs bearing spontaneous prostate cancer. RNA sequencing and protein analyses showed that Treg infiltration was mediated by interaction between the tumor-producing chemokine, CCL17, and the receptor CCR4 expressed on Tregs. Dogs with advanced prostate cancer responded to mogamulizumab, a monoclonal antibody targeting CCR4, with improved survival and low incidence of clinically relevant adverse events. Exploratory analyses showed urinary CCL17 concentration and BRAFV595E mutation to be independently predictive of the response to mogamulizumab. Analysis of a publicly available transcriptomic dataset of human prostate cancer showed that the CCL17/CCR4 axis correlated with the Treg marker, Foxp3. In silico survival analyses showed that high expression of CCL17 was associated with poor prognosis. Immunohistochemistry confirmed that tumor-infiltrating Tregs expressed CCR4 in human patients with prostate cancer. These findings suggest that anti-Treg treatment through the blocking of CCR4 is a promising therapeutic approach for advanced prostate cancer.One Sentence SummaryTargeting regulatory T cell infiltration by CCR4 blockade induces objective responses and improves survival in a canine model of prostate cancer.

Funding Acknowledgements Type of funding sources: None. Background Left atrial (LA) function is impaired in heart failure with preserved ejection fraction (HFpEF). However, the association between LA longitudinal strain and heart failure (HF) events in patients with HFpEF is still unknown. We evaluated whether LA strain measurements would be useful to predict hospitalizations for worsening HF in this study. Methods This study included 121 patients (Male 73, Female 48) with HFpEF who had echocardiogram at our institute (Age = 76 ± 14y, Left ventricular ejection fraction; LVEF = 63 ± 8%). Patients with atrial fibrillation were excluded. LA longitudinal strain was measured by speckle-tracking echocardiography, using TOMTEC imaging system. The endpoints were hospitalizations for worsening HF. Results During follow-up period of 319 ± 269 days, 33 patients (27%) experienced hospitalizations for worsening HF. LA strain was markedly lower in patients with HF events at 11.3 ± 5.6, whereas LA strain was higher at 20.3 ± 10.1 in patients without HF events. Kaplan-Meier analysis demonstrated a significant separation of survival curves stratified by median value of LA strain (Figure). Conclusions LA dysfunction in HFpEF is associated with a higher risk of HF hospitalization, and LA strain measurements would be useful to predict HF events. Abstract Figure