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Osimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer. However, clinical data and reliable prognostic biomarkers are insufficient.We performed a retrospective multicentre cohort study for 538 EGFR mutation-positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS).The median observation period was 14.7 months (interquartile range 11.4-20.0). The median PFS was 20.5 months (95% confidence interval [CI] 18.6-not reached). Multivariate analysis showed that sex (male) (hazard ratio [HR] 1.99, 95% CI 1.35-2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11-2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03-2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04-2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01-2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70-5.83, P 0.001) were associated with PFS. PD-L1 expression of 1-49% (HR 1.66, 95% CI 1.05-2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17-4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05-2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%).During initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation.

Background Social determinants of health (SDHs) are social factors that affect human health; loneliness and social isolation are core SDH factors. There is a possibility that SDHs are related to passive decisionmaking. However, few studies have evaluated SDHs, especially social isolation and loneliness, among lung cancer patients. This study aims to investigate the effects of social isolation and loneliness on the diagnosis and treatment of Japanese lung cancer patients. Methods This is a prospective cohort study that was conducted in a tertiary referral hospital in Japan (University Hospital Medical Information Network registration: UMIN000031810). The enrollment period was between April 2018 and March 2020. Patients with clinical and/or pathological diagnosis of lung cancer were enrolled in this study. Exposures were social isolation and loneliness, and main outcomes were diagnosis methods and whether the initial treatment involved active therapy or best supportive care (BSC). The confounding factors were defined as sex, age, smoking status, respiratory symptoms, weight loss, presentation with any symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, tumor nodes metastasis (TNM) classification, driver gene mutations [i.e., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK)], and programmed death-ligand 1 (PD-L1) tumor proportion score. Results The study enrolled 264 patients who were divided into quartiles according to their loneliness scores and into two groups according to the social isolation level. Univariate analysis, complete case analysis, and multivariate analysis with multiple imputation failed to detect significant differences in diagnostic method or initial treatment strategy according to loneliness or social isolation level. Conclusions Physicians may not need to consider a patient's loneliness and/or social isolation when diagnosing lung cancer and selecting treatment under universal health insurance coverage. Further studies are needed to understand the influences of loneliness and social isolation on the prognosis of lung cancer patients.

Pulmonary hypertension (PH) is a common comorbidity in dogs with myxomatous mitral valve disease (MMVD), and can induce various changes in the right heart, such as right ventricular (RV) hypertrophy, dilatation, and dysfunction. We hypothesized that RV function, not only systolic function but also diastolic function, could be worsened with PH progression. We aimed to compare RV systolic and diastolic function in dogs with MMVD. Twenty healthy dogs and sixty-eight dogs with MMVD were enrolled. Dogs with MMVD were classified into the probability of PH. Two-dimensional and Doppler echocardiographic indices for right heart and two-dimensional speckle tracking echocardiography indices were measured. The morphological indicators of the right heart were significantly higher only in the high probability of PH group. The RV strain, early-diastolic and systolic strain rates were significantly lower in the high probability of PH group than those in the low and intermediate probability of PH groups. Multivariate analysis showed that increased RV internal dimension normalized by body weight and RV myocardial performance index were significantly associated with the presence of right-sided congestive heart failure. Speckle tracking echocardiography-derived RV systolic and diastolic function were activated in the low and intermediate probability of PH groups. However, dogs with high probability of PH showed RV myocardial dysfunction and dilatation. Increased RV myocardial performance index and end-diastolic RV internal dimension normalized by body weight were significantly associated with the presence of right-sided congestive heart failure in dogs with MMVD.

Objective: This study aimed to explore the predictors of morphine efficacy in the alleviation of dyspnea in COPD. Background: Dyspnea is prevalent in patients with chronic obstructive pulmonary disease (COPD) and often persists despite conventional treatment. Methods: A secondary analysis of a multi-institutional prospective before-after study was conducted focusing on morphine use for alleviating dyspnea in COPD patients. Subjects included COPD patients with dyspnea at seven hospitals in Japan. Patients received 12 mg/day of oral morphine (or 8 mg/day if they had low body weight or renal impairment). Univariate and multivariate logistic regression analyses were performed with numerical rating scale (NRS) score of the current dyspnea intensity in the evening of day 0, Eastern Cooperative Oncology Group Performance Status (ECOG PS; ≤2 or ≥3), age, and partial arterial pressure of carbon dioxide (PaCO2) as independent factors; an improvement of ≥1 in the evening NRS score of dyspnea from day 0 to 2 was the dependent factor. Results: Thirty-five patients were enrolled in this study between October 2014 and January 2018. Excluding one patient who did not receive the treatment, data from 34 patients were analyzed. In the multivariate analysis, lower PaCO2 was significantly associated with morphine efficacy for alleviating dyspnea (odds ratio [OR] 0.862, 95% confidence interval [CI] 0.747-0.994), whereas the NRS of dyspnea intensity on day 0 (OR 1.426, 95% CI 0.836-2.433), ECOG PS (OR 4.561, 95% CI 0.477-43.565), and patients' age (OR 0.986, 95% CI 0.874-1.114) were not. Discussion: Morphine can potentially alleviate dyspnea in COPD patients with lower PaCO2. Trial registration: UMIN000015288 (http://www.umin.ac.jp/ctr/index.htm).

Background Tricuspid annular plane systolic excursion (TAPSE) is a common right ventricular (RV) function indicator. However, TAPSE was not decreased in dogs with myxomatous mitral valve disease (MMVD) and postcapillary pulmonary hypertension (PH) because of its load, angle, and body weight dependency, and TAPSE was considered a preload‐dependent index. Objectives To evaluate the utility of TAPSE normalized by RV size in dogs with postcapillary PH. Animals Twenty healthy dogs and 71 MMVD dogs with or without PH. Methods In this prospective observational study, end‐diastolic RV internal dimension (RVIDd), end‐diastolic and end‐systolic RV area, and end‐diastolic RV wall thickness were measured as RV size indices. The TAPSE was measured using B‐mode and M‐mode methods. Normalized TAPSE was calculated by dividing TAPSE by each RV size index. The RV strain was obtained as the detailed RV function using 2‐dimensional speckle tracking echocardiography. All indices were compared among the PH severity groups and in the presence of right‐sided congestive heart failure (R‐CHF). Results Although nonnormalized TAPSE was higher with PH severity progression, each normalized TAPSE showed a significant decrease in the severe PH group (P

Purpose Recently, fecal microbiota transplantation (FMT) has been tested in veterinary medicine as a treatment option for multiple gastrointestinal (GI) diseases, such as inflammatory bowel disease (IBD). However, there are no reports of changes in the microbial diversity of fecal microbiome after treatment with FMT in canine IBD cases. Moreover, little is known about the long-term efficacy and safety of FMT treatment for dogs. Herein, we present a case of canine intractable IBD treated with repeated, long-term FMT. Patients and methods The patient was a 10-year-old, neutered, male, 4-kg Toy Poodle with a prolonged history of vomiting and diarrhea. Fecal examination for pathogens was negative. Despite treatment with multiple antibacterial and antidiarrheal agents, the patient showed no improvement. Endoscopic mucus sampling diagnosed a case of lymphocytic-plasmacytic duodenitis, ie, idiopathic IBD. Eventually, we performed periodic, long-term fecal microbiota transplantation of fresh donor feces collected from a 4-year-old, 32.8-kg, neutered male Golden Retriever by rectal enema. Additionally, we performed 16S rRNA sequence analysis, before and after FMT, to evaluate the microbiome diversity. Results Fecal microbiome diversity after FMT resembled that of the healthy donor dog’s fecal microbiome, before FMT, which led us to conclude that the fecal microbiome in our patient normalized with FMT. Moreover, the clinical symptoms improved remarkably with regard to the changes in the fecal microbiome. Additionally, we noted no observable side effects during FMT treatment. Conclusion This report indicates the efficacy and safety of long-term, periodic FMT for a case of canine IBD based on attenuation of clinical symptoms and changes in fecal microbiome diversity. Therefore, FMT could be chosen as a treatment option for IBD in canines in the future.

Associations between treatment outcomes of immune checkpoint inhibitors and metastatic sites in advanced non-small cell lung cancer (NSCLC) are not well known. Therefore, this multicenter retrospective study aimed to investigate the predictive factors of metastatic sites after first-line pembrolizumab treatment for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. We retrospectively analyzed advanced NSCLC patients with a PD-L1 TPS ≥50% who underwent first-line pembrolizumab therapy at 11 institutions between February 2017 and April 2018. Clinical data collected from medical records included metastatic sites at the time of pembrolizumab treatment. Treatment outcomes of pembrolizumab were assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 213 patients were included in the study. The median age was 71 years (range 39-91 years). Of the 213 patients, 176 (83%) were men and 172 (81%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0-1. The most common metastases were thoracic lymph node metastasis (77%), intrapulmonary metastasis (31%), bone metastasis (28%), and malignant pleural effusion (26%). On multivariate analysis, a poor ECOG-PS score (hazard ratio: 1.95, 95.0% confidence interval: 1.25-3.04; P = 0.003) and malignant pleural effusion (hazard ratio: 1.52, 95.0% confidence interval: 1.01-2.29; P = 0.043) were independent predictors of shorter progression-free survival in patients treated with pembrolizumab. For NSCLC patients with malignant pleural effusion, pembrolizumab monotherapy is not a suitable first-line treatment because of its insufficient effectiveness, even though their PD-L1 TPS was high.

Congestive heart failure (CHF) is a life-threatening condition in cats with cardiomyopathy. We hypothesized that myocardial dysfunction may induce progression to CHF pathophysiology in cats with cardiomyopathy. However, no previous studies have evaluated the involvement of myocardial dysfunction in cats with CHF. In this study, we aimed to evaluate the relationship between CHF and myocardial function assessed using two-dimensional speckle-tracking echocardiography (2D-STE). Sixteen client-owned healthy cats and 32 cats with cardiomyopathy were enrolled in this study. Cats were classified into three groups: healthy cats, cardiomyopathy without CHF (CM group), and cardiomyopathy with CHF (CHF group). Left ventricular (LV) longitudinal and circumferential strains (SL and SC, respectively), and right ventricular (RV) SL were measured using 2D-STE. Logistic regression analysis was performed to assess the relationship between CHF and echocardiographic variables, including 2D-STE. Results comparing the healthy cats and CM vs. CHF groups showed that increased left atrial to aortic diameter ratio and decreased LV apical SC were significantly associated with the existence of CHF (odds ratio [95% confidence interval]: 1.40 [1.16–1.78] and 1.59 [1.06–2.36], respectively). Results comparing the CM vs. CHF group showed that increased end-diastolic RV internal dimension and decreased RV SL were significantly associated with the existence of CHF (odds ratio: 1.07 [1.00–1.13] and 1.34 [1.07–1.68], respectively). Left atrial enlargement and depressed LV apical myocardial function may be useful tools for predicting the progression to CHF in cats. Furthermore, RV enlargement and dysfunction may lead to the onset of CHF in asymptomatic cats with cardiomyopathy.

OBJECTIVE To evaluate the influence of manual ventilation-controlled respiration on right ventricular (RV) pressure-volume loop–derived and echocardiographic variables in dogs. ANIMALS 8 healthy, anesthetized Beagles. PROCEDURES In a prospective experimental study, pressure-volume catheters were percutaneously inserted into the right ventricle of each dog, and manual ventilation was performed; RV pressure-volume loop (hemodynamic) data and conventional echocardiographic variables were assessed. Two-dimensional speckle tracking echocardiography–derived RV strain (RVS) and RV systolic strain rate (RVSR) were obtained with RV free wall–only analysis (free wall) and RV global analysis (RVGA; interventricular septum). Variables were compared between end-inspiratory and end-expiratory phases of respiration by statistical methods. Multiple regression analysis was used to assess associations between selected hemodynamic and echocardiographic variables. RESULTS The RV pressure significantly increased, and RV volume, stroke volume, tricuspid annular plane systolic excursion, RV fractional area change, peak myocardial systolic velocity of the lateral tricuspid annulus, and RV free wall only–assessed RVS and RVSR significantly decreased in the inspiratory phase, compared with the expiratory phase. There were no significant differences in end-systolic elastance or RVGA-assessed RVS or RVSR between respiratory phases. The RVGA-assessed RVSR was significantly associated with stroke volume and end-systolic elastance. CONCLUSIONS AND CLINICAL RELEVANCE Specific RV echocardiographic variables were significantly affected by respiration. In contrast, RVS and RVSR determined with RVGA were not affected by respiration and were associated with hemodynamic indicators of RV contractility.

Post-capillary pulmonary hypertension (PH) is a life-threatening complication in dogs with myxomatous mitral valve disease (MMVD). An increase in pulmonary vascular resistance (PVR) is associated with post-capillary PH progression. In humans, PVR estimated by echocardiography (PVRecho) enables the non-invasive assessment of PVR in patients with PH. This study aimed to evaluate the clinical utility of PVRecho in dogs with MMVD, PH probability, and right-sided congestive heart failure (R-CHF). Dogs with MMVD and detectable tricuspid valve regurgitation were included in the study. Dogs were classified into three PH probability groups (low/intermediate/high) and according to the presence or absence of R-CHF. All dogs underwent echocardiographic measurements for right ventricular (RV) morphology and function. PVRecho was calculated by two methods using tricuspid valve regurgitation velocity and velocity–time integral of the pulmonary artery flow (PVRecho and PVRecho2). RV size indicators were significantly higher with a higher probability of PH. RV strain and velocity–time integral of the pulmonary artery flow in the high probability group were significantly lower than those in the other groups. Tricuspid valve regurgitation velocity, PVRecho, and PVRecho2 were significantly higher with an increase in PH probability. Logistic regression analysis revealed a significant association between the presence of R-CHF and increased PVRecho2 and end-diastolic RV internal dimension normalized by body weight. PVRecho and PVRecho2 showed significant differences among the PH probability groups. These non-invasive variables may be useful for the diagnosis and stratification of PH and the determination of the presence of R-CHF in dogs with MMVD.

Background: Pulmonary hypertension (PH) is a life-threatening disease in dogs characterized by an increase in pulmonary arterial pressure (PAP) and/or pulmonary vascular resistance. Right ventricle adapts to its pressure overload through various right ventricular (RV) compensative mechanisms: adaptive and maladaptive remodeling. The former is characterized by concentric hypertrophy and increased compensatory myocardial contractility, whereas the latter is distinguished by eccentric hypertrophy associated with impaired myocardial function.Objectives: To evaluate the RV adaptation associated with the increase of PAP using two-dimensional speckle tracking echocardiography.Animals: Seven experimentally induced PH models.Methods: Dogs were anesthetized and then a pulmonary artery catheter was placed via the right jugular vein. Canine models of PH were induced by the repeated injection of microspheres through the catheter and monitored pulmonary artery pressure. Dogs were performed echocardiography and hemodynamic measurements in a conscious state when baseline and systolic PAP (sPAP) rose to 30, 40, 50 mmHg, and chronic phase. The chronic phase was defined that the sPAP was maintained at 50 mmHg or more for 4 weeks without injection of microspheres.Results: Pulmonary artery to aortic diameter ratio, RV area, end-diastolic RV wall thickness, and RV myocardial performance index were significantly increased in the chronic phase compared with that in the baseline. Tricuspid annular plane systolic excursion was significantly decreased in the chronic phase compared with that in the baseline. The RV longitudinal strain was significantly decreased in the sPAP30 phase, increased in the sPAP40 and sPAP50 phases, and decreased in the chronic phase.Conclusions: Changes in two-dimensional speckle tracking echocardiography-derived RV longitudinal strain might reflect the intrinsic RV myocardial contractility during the PH progression, which could not be detected by conventional echocardiographic parameters.

The incidence of real-world pneumonitis and durvalumab rechallenge during chemoradiotherapy and durvalumab consolidation for non-small cell lung cancer is unknown.We retrospectively evaluated the medical records of 302 consecutive patients diagnosed with non-small cell lung cancer who started chemoradiotherapy between May 2018 and May 2019.Median age was 70 (range: 40-87) years. Volume of lung parenchyma that received 20 Gy (V20) exceeded 35% in 2% and mean lung dose exceeded 20 Gy in 1% of patients. Durvalumab consolidation was delivered to 225 patients (75%). Overall, 83% (n = 251), 34% (n = 103), 7% (n = 21), and 1% (n = 4) of the patients developed any grade of pneumonitis, symptomatic pneumonitis, ≥grade 3 pneumonitis, and fatal (grade 5) pneumonitis, respectively. Corticosteroids were administered to 25% of the patients to treat pneumonitis. Multivariate analysis identified the predictive factors for the development of symptomatic pneumonitis: V20 Gy or more ≥ 25% (odds ratio [OR]: 2.37, P = 0.008) and mean lung dose (MLD) ≥ 10 Gy (OR: 1.93, P 0.0047). Of the 52 patients who received corticosteroids for pneumonitis after durvalumab initiation, 21 were rechallenged with durvalumab. Overall, 81% of patients met the PACIFIC study's rechallenge criteria and did not experience a severe pneumonitis relapse.High V20 and MLD were independent risk factors of symptomatic pneumonitis. More than 80% of the patients who were rechallenged with durvalumab after pneumonitis met the PACIFIC study's rechallenge criteria. Consequently, severe relapse did not occur. Cooperation between radiation and medical oncologists is important for safe chemoradiotherapy and the safe completion of durvalumab consolidation therapy.

Simple Summary The endomyocardial form of restrictive cardiomyopathy, a primary disorder of the myocardium, is one of the diseases with poor prognosis in cats. While two-dimensional speckle-tracking echocardiography has been known to identify myocardial deformations, its function relative to cats with the endomyocardial form of restrictive cardiomyopathy has yet to be characterized. We hypothesized that both the left and right myocardial functional abnormalities may occur in cats with the endomyocardial form of restrictive cardiomyopathy, causing this disease pathophysiology and clinical status. In the current study, cats were assessed for layer-specific myocardial function (whole, endocardial, and epicardial) in the left ventricular longitudinal and circumferential directions, and right ventricular longitudinal direction, via two-dimensional speckle-tracking echocardiography. Our study indicated that cats with restrictive cardiomyopathy have reduced left ventricular myocardial function. Notably, left ventricular systolic circumferential endocardial strain and circumferential endocardial-to-epicardial strain ratio were lower in cats with restrictive cardiomyopathy. Furthermore, some right ventricular myocardial deformations were also differerent in cats with restrictive cardiomyopathy. Myocardial function assessed by two-dimensional speckle-tracking echocardiography could reveal left and right myocardial dysfunction. Abstract The endomyocardial form of restrictive cardiomyopathy (EMF-RCM), a primary disorder of the myocardium, is one of the diseases with poor prognosis in cats. We hypothesized that both the left and right myocardial functional abnormalities may occur in cats with EMF-RCM, causing this disease pathophysiology and clinical status. Out of the 25 animals included in this study, 10 were client-owned cats with EMF-RCM, and 15 were healthy cats. In this study, cats were assessed for layer-specific myocardial function (whole, endocardial, and epicardial) in the left ventricular longitudinal and circumferential directions, and right ventricular longitudinal direction, via two-dimensional speckle-tracking echocardiography (2D-STE). Cats with EMF-RCM had depressed left ventricular myocardial deformations both in systole (whole longitudinal strain, epicardial longitudinal strain, and endocardial circumferential strain) and diastole (early and late diastolic longitudinal strain rates, and late diastolic circumferential strain rate) compared to controls. Furthermore, some right ventricular myocardial deformations (systolic longitudinal strain in epicardial layers, and endocardial-to-epicardial strain ratio) were significantly differerent in cats with EMF-RCM. Myocardial function assessed by 2D-STE could reveal left and right myocardial dysfunction.

Objectives As first line therapy, pembrolizumab provides longer progression free survival (PFS) and overall survival (OS) than platinum doublets in programmed death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) with tumor propensity scores (TPS) ≥50%. However, clinical trials do not represent real-world patients. Materials and Methods This multicenter retrospective study conducted across 11 medical centers in Japan analyzed clinical data from patients receiving first-line pembrolizumab for NSCLC between February 1, 2017 and April 30, 2018. The efficacy, safety, and suitability of pembrolizumab monotherapy were evaluated. Results The median age of the 213 enrolled patients was 71 (range: 39–91) years. Among them, 176 (82.6%) were male, 20 (9.4%) were never smokers (median Brinkman index: 900), 172 (80.8%) had an ECOG PS of 0–1, 55 (25.8%) had squamous-cell carcinoma (SQ). PD-L1 TPS were 50–74%, 75–89%, and 90–100% in 97 (45.5%), 47 (22.1%), and 69 (32.4%) patients, respectively. Adverse events (AEs) of grades ≥3 were observed in 39 (18.3%) patients. Pneumonitis was the most common severe AE, occurring in 10 patients (4.7%) including 1 with grade 4 toxicity; no severe AE-related deaths occurred. The overall response rate, median PFS, and median OS was 51.2%, 8.3 months, and 17.8 months, respectively. On multivariate analysis, ECOG PS (0–1 vs. ≥2: HR: 1.69, 95.0% CI: 1.05–2.72; p = 0.03138), CRP/Alb (

To identify reference values for the Schirmer tear test I (STT I) in Japanese black cattle, investigate the effects of variables (sex, age, time of day, and environment in the barn including environmental temperature, humidity, illuminance, and ammonia concentration) on tear production, and determine total tear protein concentration. One-hundred-and-thirty-seven Japanese black cattle (67 females and 70 males, age 3-90 days) were evaluated. The mean STT I values was 18.9 ± 2.9 mm/min (n=263) and significant effects were age and ammonia concentration in the barn. Mean total tear protein concentration was 1.18 ± 0.30 mg/ml in healthy cattle older than 15 days (n=38). It was suggested that age and ammonia concentration are related to fluctuation of tear volume.

Background Osimertinib, the third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has become the standard treatment in cases where rebiopsy reveals T790M mutation after the first-line EGFR-TKI treatment. However, the prognosis of patients after rebiopsy, the most important outcome for cancer patients, has not been described sufficiently. This systematic review aimed to clarify whether rebiopsy contributes to improved prognosis in the first- or second-generation EGFR-TKI refractory patients. Methods Using free word and control terms related to “non-small cell lung cancer” and “rebiopsy,” we searched studies from Medical Literature Analysis and Retrieval System Online via PubMed, Embase, Cochrane Central Register of Controlled Trials, and World Health Organization International Clinical Trials Registry Platform. We included cohort studies and case reports written in English and judged whether each study answers our research questions. Results Of the 144 studies included, only one reported the prognosis of patients with/without rebiopsy showing that in EGFR-TKI refractory non-small cell lung cancer patients, the post-progression survival (PPS) was significantly longer in patients who received rebiopsy and treatment based on a resistant mechanism (median PPS 24.2 months) than those who received rebiopsy and salvage regimen (median PPS 15.2 months, p = 0.002) and who did not receive rebiopsy (median PPS 9.7 months, p

Background Hypertrophic cardiomyopathy (HCM), a primary disorder of the myocardium, is the most common cardiac disease in cats. However, determination of layer-specific myocardial function with 2D speckle-tracking echocardiography in cats with asymptomatic HCM has not yet been reported. Objectives To quantitatively measure layer-specific myocardial function of asymptomatic cats with HCM. Animals Ten client-owned, asymptomatic cats with obstructive HCM and 13 healthy cats. Methods A retrospective, case-control study. Cats underwent assessment of layer-specific myocardial function (whole, endocardial, and epicardial) in the longitudinal and circumferential directions by using 2D speckle-tracking echocardiography. Results Longitudinal strains were significantly lower in cats with HCM than controls in the whole (-15.5% vs -19.1%), endocardial (-18.3% vs -21.8%), and epicardial (-13.1% vs -16.8%) layers. Circumferential strains in whole and epicardial layers also were significantly lower in cats with HCM as compared with controls (-15.0% vs -20.2% and - 4.4% vs -9.4%, respectively). However, no significant difference was found between cats with HCM and controls in the global circumferential strain in the endocardial layer (-31.2% vs -34.2%). The circumferential endocardial-to-epicardial strain ratio was significantly higher in cats with HCM than in controls (6.1 vs 3.5). Conclusions and clinical importance Layer-specific myocardial function assessed by 2D speckle-tracking echocardiography differed in asymptomatic cats with obstructive HCM compared to controls despite their apparently normal systolic function, as determined by conventional echocardiography. The maintained endocardial circumferential strain and higher circumferential endocardial-to-epicardial strain ratio may reflect compensation for occult systolic dysfunction in cats with obstructive HCM.

Background Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved. Methods We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions. Results Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR. Conclusions Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.

In human medicine, fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridioides difficile infection. It has also been tested as a treatment for multiple gastrointestinal diseases, including inflammatory bowel disease (IBD). However, only a few studies have focused on the changes in the microbiome following FMT for canine IBD. Here, we performed FMT in nine dogs with IBD using the fecal matter of healthy dogs and investigated the subsequent changes in the fecal microbiome and clinical signs. In three dogs, the fecal microbiome was examined by 16S rRNA sequencing. Fusobacteria were observed at a low proportion in dogs with IBD. However, the post-FMT microbiome became diverse and showed a significant increase in Fusobacteria proportion. Fusobacterium was detected in the nine dogs by quantitative polymerase chain reaction. The proportion of Fusobacterium in the post-FMT fecal microbiome was significantly increased (p

The potential of mesenchymal stem cells (MSCs) to differentiate into nonmesodermal cells such as pancreatic beta cells has been reported. New cell-based therapy using MSCs for diabetes mellitus is anticipated as an alternative treatment option to insulin injection or islet transplantation in both human and veterinary medicine. Several protocols were reported for differentiation of MSCs into insulin-producing cells (IPCs), but no studies have reported IPCs generated from canine MSCs. The purpose of this study was to generate IPCs from canine adipose tissue-derived MSCs (AT-MSCs) in vitro and to investigate the effects of IPC transplantation on diabetic mice in vivo. Culturing AT-MSCs with the differentiation protocol under a two-dimensional culture system did not produce IPCs. However, spheroid-like small clusters consisting of canine AT-MSCs and human recombinant peptide μ-pieces developed under a three-dimensional (3D) culture system were successfully differentiated into IPCs. The generated IPCs under 3D culture condition were stained with dithizone and anti-insulin antibody. Canine IPCs also showed gene expression typical for pancreatic beta cells and increased insulin secretion in response to glucose stimulation. The blood glucose levels in streptozotocin-induced diabetic mice were decreased after injection with the supernatant of canine IPCs, but the hyperglycemic states of diabetic mice were not improved after transplanting IPCs subcutaneously or intramesenterically. The histological examination showed that the transplanted small clusters of IPCs were successfully engrafted to the mice and included cells positive for insulin by immunofluorescence. Several factors, such as the transplanted cell number, the origin of AT-MSCs, and the differentiation protocol, were considered potential reasons for the inability to improve the hyperglycemic state after IPC transplantation. These findings suggest that canine AT-MSCs can be differentiated into IPCs under a 3D culture system and IPC transplantation may be a new treatment option for dogs with diabetes mellitus.

Lysophosphatidic acids (LysoPAs) and lysophosphatidylserine (LysoPS) are emerging lipid mediators proposed to be involved in the pathogenesis of acute coronary syndrome (ACS). In this study, we attempted to elucidate how LysoPA and LysoPS become elevated in ACS using human blood samples collected simultaneously from culprit coronary arteries and peripheral arteries in ACS subjects. We found that: 1) the plasma LysoPA, LysoPS, and lysophosphatidylglycerol levels were not different, while the lysophosphatidylcholine (LysoPC), lysophosphatidylinositol, and lysophosphatidylethanolamine (LysoPE) levels were significantly lower in the culprit coronary arteries; 2) the serum autotaxin (ATX) level was lower and the serum phosphatidylserine-specific phospholipase A1 (PS-PLA1) level was higher in the culprit coronary arteries; 3) the LysoPE and ATX levels were significant explanatory factors for the mainly elevated species of LysoPA, except for 22:6 LysoPA, in the peripheral arteries, while the LysoPC and LysoPE levels, but not the ATX level, were explanatory factors in the culprit coronary arteries; and 4) 18:0 and 18:1 LysoPS were significantly correlated with PS-PLA1 only in the culprit coronary arteries. In conclusion, the origins of LysoPA and LysoPS might differ between culprit coronary arteries and peripheral arteries, and substrates for ATX, such as LysoPC and LysoPE, might be important for the generation of LysoPA in ACS.

Introduction Previous studies have described an association between immune-related adverse events (irAEs) and better outcomes in patients administered nivolumab for advanced non–small-cell lung cancer. However, the patients in previous studies were not stratified by potential predictive factors, such as programmed cell death ligand 1 status and treatment lines. Additionally, little is known of whether the timing and type of irAEs can inform the prediction of outcomes. Patients and Methods We prospectively investigated the association between irAEs and outcomes in the single-center cohort that included patients administered nivolumab in the second or later line of therapy. Subsequently, we confirmed these findings in a retrospective multicenter cohort that included patients with programmed cell death ligand 1 tumor proportion score of ≥ 50% who had received first-line pembrolizumab. The primary outcome was progression-free survival (PFS). Results In the prospective cohort (n = 76), the median PFS was significantly longer for the patients experiencing irAEs within 2 weeks of beginning nivolumab compared with the PFS for those who did not (median, 5.0 months [95% confidence interval (CI), 2.1-8.6 months] vs. median, 2.0 months [95% CI, 1.9-2.5 months]; P = .046). The association was stronger with earlier (within 2 weeks) than with later (within 6 weeks) irAEs. In the retrospective cohort (n = 148), the median PFS was significantly longer for the patients with early irAEs (within 3 weeks) than for those without (median, not reached [95% CI, 5.9 months to not reached] vs. median, 6.9 months [95% CI, 4.2-9.7 months]; P = .04). Rash was common and a better predictor of outcomes in both cohorts. Conclusion Our results have provided firmer evidence of the association between the occurrence of irAEs and outcomes and suggest that early irAEs (especially rash) might better predict outcomes.

ObjectivesDyspnoea in patients with chronic obstructive pulmonary disease (COPD) is frequent and often persists despite conventional treatment. This study aimed to evaluate the efficacy and safety of oral morphine for dyspnoea in Japanese COPD patients.MethodsWe conducted a multi-institutional, prospective, before–after study of morphine in COPD patients with dyspnoea at rest in seven hospitals. Patients received 12 mg of oral morphine per day (or 8 mg per day if low body weight or renal impairment). Primary outcome was change in the numerical rating scale (NRS) of current dyspnoea in the evening from Day 0 to Day 2. Secondary outcomes included changes in dyspnoea intensity in the evening from Day 0 to Day 1, dyspnoea intensity between the morning from Day 0 to Day 1 and Day 2, vital signs, nausea, somnolence, anorexia and other adverse events (AEs).ResultsA total of 35 patients were enrolled in this study between October 2014 and January 2018. One patient did not receive study treatment. Data from 34 patients was analysed. The NRS of dyspnoea intensity in the evening significantly decreased from 3.9 on Day 0 (95% CI: 3.1 to 4.8) to 2.4 on Day 2 (95% CI: 1.7 to 3.1; p=0.0002). Secondary outcomes significantly improved in a similar manner. There were no apparent changes in the mean scores of the opioid-related AEs and vital signs. One patient experienced grade 3 lung infection not associated with morphine. Other AEs were mild.ConclusionOral morphine is effective in alleviating dyspnoea in Japanese COPD patients.Trial registrationUMIN000015288 (http://www.umin.ac.jp/ctr/index.htm).

Beta-blockers are used to treat cats with hypertrophic obstructive cardiomyopathy (HOCM). However, there are various hemodynamic responses to beta-blockers. This retrospective study aimed to explore the relationship between the response to carvedilol and the presence of geometric abnormalities. Medical records were reviewed for 16 cats diagnosed with HOCM. Cats were divided into two groups based on the velocity of the left-ventricular outflow-tract after carvedilol treatment (responder: eight cats, non-responder: eight cats). Baseline intergroup comparison revealed that anterior mitral valve leaflet length and diastolic left-ventricular posterior-wall thickness were significantly greater in the non-responder group. Longer anterior mitral valve leaflet and thicker left-ventricular posterior-wall may cause poor response to carvedilol. Thus, these properties may predict a lack of response to carvedilol therapy.

Lysophosphatidic acid (LPA) is a blood-derived bioactive lipid with numerous biological activities exerted mainly through six defined G protein-coupled receptors (LPA1-LPA6). LPA was first identified as a vasoactive compound because it induced transient hypertension when injected intravenously in rodents. Here, we examined the molecular mechanism underlying the LPA-induced hypertensive response. The LPA-induced hypertensive response was significantly attenuated by pretreatment with a Rho kinase inhibitor, which blocks Gα12/13 signaling. Consistent with this, the response was weakened in KO mice of LPA4, a Gα12/13-coupling LPA receptor. KO mice of another Gα12/13-coupling LPA receptor, LPA6, also showed an attenuated LPA-induced hypertensive response. However, LPA6 KO mice also displayed attenuated pressor responses to an adrenergic agent and abnormal blood vessel formation. Using several LPA analogs with varied affinity for each LPA receptor, we found a good correlation between the hypertensive and LPA4 agonistic activities. Incubated mouse plasma, which contained abundant LPA, also induced a hypertensive response. Interestingly the response was completely abolished when the plasma was incubated in the presence of an ATX inhibitor. Together, these results indicate that circulating LPA produced by ATX contributes to the elevation of blood pressure through multiple LPA receptors, mainly LPA4.

Background Vitamin D-dependent rickets is rare in animals and humans. Several types of this condition are associated with genetic variants related to vitamin D metabolism. This is the first report of type 1B vitamin D-dependent rickets in a cat. Case presentation Here, we describe the case of a 3-month-old female domestic short-haired cat previously fed on commercial kitten food that presented at our clinic with seizures, lethargy, and generalized pain. Serum and ionized calcium concentrations and 1,25-dihydroxycholecalciferol in this cat were low, and radiographs showed skeletal demineralization and abnormally wide growth plates on the long bones. Initially, simple vitamin D deficiency was suspected; however, the cat’s profile, which included fed a well-balanced commercial diet, together with the findings of additional laboratory tests and the cat’s unresponsiveness to various treatments, raised the suspicion of vitamin D-dependent rickets. Examination of the DNA sequences of CYP2R1 and CYP27B1 genes, which are genes linked with vitamin D metabolism, showed a CYP2R1 frameshift mutation in exon 5 (where T is deleted at position c.1386). This mutation alters the amino acid sequence from position 462, while the stop codon introduced at position 481 prematurely truncates the 501 amino acid full-length protein. With this knowledge, a new treatment regime based on a standard dose of calcitriol was started and this markedly improved the cat’s condition. Conclusions To the best of our knowledge, the present case is the first description of type 1B vitamin D-dependent rickets linked with a genetic variant of CYP2R1 in a cat. Electronic supplementary material The online version of this article (10.1186/s12917-019-1784-1) contains supplementary material, which is available to authorized users.

Background Inconsistency of treatment response in cats with obstructive hypertrophic cardiomyopathy is well recognized. We hypothesized that the difference in response to beta-blockers may be caused by myocardial functional abnormalities. This study was designed to compare myocardial function in cats with obstructive hypertrophic cardiomyopathy with and without response to beta-blockers. Twenty-one, client-owned, hypertrophic cardiomyopathy cats treated with carvedilol were analyzed. After carvedilol treatment, cats with decreased left ventricular outflow tract velocity were categorized as responders (n = 10); those exhibiting no response (no decrease in the left ventricular outflow tract velocity) were categorized as non-responders (n = 11). The cats were examined using layer-specific assessment of the myocardial function (whole, endocardial, and epicardial layers) longitudinally and circumferentially by two-dimensional speckle-tracking echocardiography, before and after carvedilol treatment. Results The non-responder cats had a significantly higher age, end-diastolic left ventricular posterior-wall thickness, peak velocity of left ventricular outflow tract, and dose of carvedilol than the responders (p = 0.04, p p p p p = 0.006). According to the multivariate analysis, circumferential strain in the epicardial layer was the only independent correlate of treatment response with carvedilol. Conclusions Myocardial function, assessed by two-dimensional speckle-tracking echocardiography, differed in cats with hypertrophic cardiomyopathy with and without response to beta-blockers. The determination of layer-specific myocardial function may facilitate detailed pathophysiologic assessment and treatment response in cats with hypertrophic cardiomyopathy.

e21076 Background: PD-L1 inhibitor, durvalumab has been approved since the PACIFIC study showed its efficacy as consolidation therapy after CCRT for locally advanced NSCLC. But predictive factor for the efficacy of CCRT on this post PACIFIC era have not been known. LIPI has been proposed as a new biomarker for the anti-PD-1 therapy of advanced NSCLC. In this study, we investigated the usefulness of LIPI as a predictive marker in multicenter cohort of patients with locally advanced NSCLC who received CCRT as initial treatment. Methods: 219 patients with available baseline LIPI were reviewed. The progression free survival (PFS) was estimated by the Kaplan-Meier method, and LIPI were calculated at baseline. Kaplan-Meier estimates of PFS and recurrence were compared using the log-rank test for trend. Multivariable analysis was conducted using the Cox and logistic regression models, respectively, adjusted for age, sex, ECOG-PS, smoking, histology, TNM stage, chemotherapy regimens, Body mass index (BMI), PD-L1 status, EGFR or ALK mutation, and baseline LIPI. Results: 62.5% (n = 137) of the patients had a good (0 factors) LIPI, while 37.5% (n = 82) had intermediate (1 factor) and poor (2 factors) LIPI respectively. In multivariable analysis, good LIPI (0 factors) were significantly associated with longer PFS (HR = 0.46, 95% CI 0.28-0.75; P < 0.01) as did ECOG-PS0 (P < 0.01), ≤stageIIIA (P < 0.01), being treated with durvalumab after CRT (P = 0.04). There were no difference in the patient characteristics between good LIPI and intermediate/poor LIPI, significantly. Higher LIPI (1 or 2 factors) were strongly prognostic factor for recurrence after CCRT in multivariate analysis (P = 0.04), along with ECOG-PS1≤ (P < 0.01), stage IIIB≤ (P < 0.01). Conclusions: The good LIPI predictive value for PFS and disease control in patients treated with CCRT was confirmed. Although a strong statistical significance, we needs to be confirmed further with longer follow-up and prospective study.

9039 Background: Durvalumab was approved as a consolidation therapy after chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (NSCLC) and established as the standard of care. However, since the approval of durvalumab, little has been reported on the frequency, severity, or clinical course of pneumonitis/radiation pneumonitis throughout the course of CRT. Methods: We conducted a 17-center, retrospective cohort study of consecutive patients with locally advanced NSCLC who received concurrent chemoradiotherapy (CCRT) with platinum-based chemotherapy between May 2018 and May 2019. Results: A total of 275 patients were included; their median age was 69.9 (range, 40.3-87.5), mean V20 was 19.4% (range, 1.4-37.9), and mean "mean lung dose" was 10.9 Gy (range, 1.5-31.3). Of these, 204 patients received durvalumab consolidation therapy (74.2%). Median follow-up time from the initiation of CCRT was 8.4 months (range, 1.5-15.7). During follow-up, 225 patients (81.8%) developed any-grade pneumonitis/radiation pneumonitis. Of these, more than half (134 of 225) were asymptomatic (grade 1), 18 (6.5%) were ≥grade 3, and 4 patients (1.5%) had fatal pneumonitis/radiation pneumonitis. By the time of initial assessment of response to CCRT, 64 (23.3%) patients had developed radiation pneumonitis. Logistic regression revealed that only V20 ≥25 % was an independent risk factor of symptomatic (≥grade 2) pneumonitis/radiation pneumonitis (OR: 2.74, 95% CI: 1.35-5.53, p = 0.0045). Of the 275 patients, 67 were treated with corticosteroids for pneumonitis/radiation pneumonitis (24.7%), and 14 (5.1%) needed home oxygen therapy after the treatment of pneumonitis/radiation pneumonitis. Among patients treated with corticosteroids, 21 patients received durvalumab rechallenge. Of the 21 patients, 6 (29%) showed pneumonitis/radiation pneumonitis relapse, of which 3 (14%) resulted in suspension of durvalumab rechallenge, but none were fatal. Conclusions: Although over four-fifths of the patients treated with CCRT after the approval of durvalumab developed pneumonitis/radiation pneumonitis, more than half of them were asymptomatic, and ≥grade 3 events accounted for 6.5%. Sometimes patients needed corticosteroid therapy, which was in many occasions effective, and some also underwent durvalumab rechallenge. V20 was an independent risk factor of symptomatic pneumonitis/radiation pneumonitis.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness and safety of third‐line chemotherapy in patients with small cell lung cancer (SCLC), compared to conventional supportive care.

Case summary A 6-month-old female cat with a history of chronic regurgitation presented with weight loss. CT angiography (CTA) showed severe constriction of the oesophagus due to an aberrant right subclavian artery and Kommerell’s diverticulum. The cat was surgically treated and remained clinically normal. More than 1 year after surgery, the general condition of the cat was stable and body weight had increased. Relevance and novel information This case report describes the clinical findings and surgical management of a cat diagnosed with severe oesophageal constriction caused by an aberrant right subclavian artery with Kommerell’s diverticulum (markedly dilated origin of the aberrant right subclavian artery), which are rare vascular anomalies in veterinary medicine and specifically in cats. The Kommerell’s diverticulum compressed the oesophagus and contributed to the severe oesophageal constriction in this case. Preoperative CTA was useful in the diagnosis and treatment planning.

We investigated the clinical effectiveness of subcutaneous (SC) administration of recombinant feline interferon-omega (rFeIFN-ω) at a dose of 1 M unit (MU)/kg body weight (bw) for the treatment of feline chronic gingivitis-stomatitis (FCGS) in cats infected with feline calicivirus (FCV). Among the 17 cats used in this study, there were 13 FCV-positive cats (FCVI group), which were subcutaneously injected with rFeIFN-ω. The remaining four FCV-positive cats (FCVC group) were treated with SC corticosteroid. SC injection of rFeIFN-ω was given once daily on days 1, 2, 3, 7, 8, 9, 14, and 21. Corticosteroid was subcutaneously injected at a dose of 1.0 mg/kg bw, at the same intervals as rFeIFN-ω. Clinical symptoms (salivation, pain at opening the mouth, halitosis, mandibular lymphadenopathy, and all four symptoms combined [defined as “total clinical symptoms”]) and stomatitis (the degree and extent of inflammation, bleeding from the lesion, and all three items combined [defined as “total stomatitis”]) were scored on days 0, 7, 14, 21, and 28. FCV RNAs was quantified by real-time polymerase chain reaction and the percent increase in viral copy numbers was calculated using the values on days 0 and 28. In the FCVI group, significant differences were observed in the score for clinical symptom (salivation) score and in the total clinical symptom score within the group (P = 0.018 and 0.008, respectively). Significant differences within the group were also observed in the scores for the degree and extent of inflammation in stomatitis and in the total stomatitis score (P = 0.003, 0.007, and 0.003, respectively). The total score, defined as the clinical score plus the stomatitis score, was on days 7, 14, 21 and 28 than on day 0 (p = 0.006, .0003, 0.002 and 0.002, respectively). In the FCVI group, significant difference was observed between on days 0 and on 21 (p = 0.023). The percentage change in the number of polymerase chain reaction cycles required to amplify the viral RNA was positive (indicating viral reduction) in the FCVI group, but was negative in the FCVC group. These results demonstrate that SC administration of rFeIFN-ω under the current protocol improves stomatitis by inhibiting FCV proliferation in FCV-positive cats with FCGS.

Case summary A 5-month-old intact female Scottish Fold cat was presented for cardiac evaluation. Careful auscultation detected a slight systolic murmur (Levine I/VI). The findings of electrocardiography, thoracic radiography, non-invasive blood pressure measurements and conventional echocardiographic studies were unremarkable. However, two-dimensional speckle tracking echocardiography revealed abnormalities in myocardial deformations, including decreased early-to-late diastolic strain rate ratios in longitudinal, radial and circumferential directions, and deteriorated segmental systolic longitudinal strain. At the follow-up examinations, the cat exhibited echocardiographic left ventricular hypertrophy and was diagnosed with hypertrophic cardiomyopathy using conventional echocardiography. Relevance and novel information This is the first report on the use of two-dimensional speckle tracking echocardiography for the early detection of myocardial dysfunction in a cat with hypertrophic cardiomyopathy; the myocardial dysfunction was detected before the development of hypertrophy. The findings from this case suggest that two-dimensional speckle tracking echocardiography can be useful for myocardial assessment when conventional echocardiographic and Doppler findings are ambiguous.

Objective— Lysophosphatidic acids (LPA) have important roles in the field of vascular biology and are derived mainly from lysophosphatidylcholine via autotaxin. However, in our previous study, only the plasma LPA levels, and not the serum autotaxin levels, increased in patients with acute coronary syndrome (ACS). The aim of this study was to elucidate the pathway by which LPA is increased in patients with ACS. Approach and Results— We measured the plasma lysophospholipids species in 141 consecutive patients undergoing coronary angiography (ACS, n=38; stable angina pectoris, n=71; angiographically normal coronary arteries, n=32) using a liquid chromatography-tandem mass spectrometry analysis. Among the ACS subjects, notable increases in the 22:6 LPA, 18:2 LPA, and 20:4 LPA levels were observed. The in vitro experiments revealed that serum incubation mainly increased the 18:2 LPA level, whereas platelet activation increased the 20:4 LPA level. Minor lysophospholipids other than LPA were also elevated in ACS subjects and were well correlated with the corresponding LPA species, including 22:6 LPA. A multiple regression analysis also revealed that lysophosphatidylinositol, lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylglycerol were independent explanatory variables for several LPA species. Conclusions— Specific LPA species, especially long-chain unsaturated LPA, were elevated in ACS patients, along with the corresponding minor lysophospholipids. The elevation of these LPA species might be mainly caused by presently unidentified LPA-producing pathway(s). Minor lysophospholipids might be involved in the generation of LPA, especially 22:6 LPA, and in the pathogenesis of ACS.

Objectives Hypertrophic cardiomyopathy, a primary disorder of the myocardium, is the most common cardiac disease in cats. However, determination of myocardial deformation with two-dimensional speckle-tracking echocardiography in cats with various stages of hypertrophic cardiomyopathy has not yet been reported. This study was designed to measure quantitatively multidirectional myocardial deformations of cats with hypertrophic cardiomyopathy. Methods Thirty-two client-owned cats with hypertrophic cardiomyopathy and 14 healthy cats serving as controls were enrolled and underwent assessment of myocardial deformation (peak systolic strain and strain rate) in the longitudinal, radial and circumferential directions. Results Longitudinal and radial deformations were reduced in cats with hypertrophic cardiomyopathy, despite normal systolic function determined by conventional echocardiography. Cats with severely symptomatic hypertrophic cardiomyopathy also had lower peak systolic circumferential strain, in addition to longitudinal and radial strain. Conclusions and relevance Longitudinal and radial deformation may be helpful in the diagnosis of hypertrophic cardiomyopathy. Additionally, the lower circumferential deformation in cats with severe hypertrophic cardiomyopathy may contribute to clinical findings of decompensation, and seems to be related to severe cardiac clinical signs. Indices of multidirectional myocardial deformations by two-dimensional speckle-tracking echocardiography may be useful markers and help to distinguish between cats with hypertrophic cardiomyopathy and healthy cats. Additionally, they may provide more detailed assessment of contractile function in cats with hypertrophic cardiomyopathy.

Trilostane, a competitive inhibitor of 3β-hydroxysteroid dehydrogenase, is often used to treat canine hyperadrenocorticism. In some species, trilostane has been shown to have additional effects on steroid biosynthesis, and it has been postulated that trilostane might have effects on 11β-hydroxysteroid dehydrogenase (11β-HSD) in dogs. To investigate the effect of trilostane on 11β-HSD in canine adrenal glands, healthy Beagle dogs were treated with trilostane for 8 weeks. Trilostane treatment resulted in a significant decrease of the cortisol/cortisone ratio in the serum. The adrenal gland mRNA and protein expression levels of 11β-HSD type 1 and 11β-HSD type 2 were significantly higher and significantly lower respectively in dogs treated with trilostane compared to those in control healthy Beagle dogs. These findings suggest that trilostane may have an effect on 11β-HSD activity in canine adrenal glands.

Pituitary-dependent hyperadrenocorticism (PDH) is mainly caused by pituitary corticotroph tumors in dogs. A characteristic feature of corticotroph tumors is their resistance to negative feedback by glucocorticoids. In some animal species, including dogs, the aberrant expression of 11β-hydroxysteroid dehydrogenase (11HSD), a cortisol metabolic enzyme, is observed in corticotroph tumors. We previously reported that carbenoxolone (CBX), an inhibitor of 11HSD, suppressed ACTH secretion from the pituitary gland, and decreased cortisol concentrations in healthy dogs. Therefore, the aim of this study was to investigate the therapeutic effects of CBX on dogs with PDH. Six dogs with PDH were treated with 60 to 80 mg/kg/day of CBX for 6 weeks, followed by trilostane, which is a commonly used agent for canine PDH. CBX treatment led to a gradual decrease in both basal and in corticotropic releasing hormone (CRH)-stimulated plasma ACTH concentrations and CRH-stimulated serum cortisol concentrations, without side effects. However, basal and stimulated ACTH and cortisol concentrations remained higher than those of healthy dogs, and clinical symptoms such as polydipsia and polyuria were not ameliorated. After a 2-week wash-out interval, trilostane was administered for 2 weeks. Although basal plasma ACTH concentrations were higher after trilostane treatment than CBX treatment, polydipsia and polyuria resolved in all six dogs. The reason for the lack of improvement in polydipsia and polyuria with CBX treatment is unclear. Other mechanisms, in addition to a partial decrease in ACTH secretion, are likely to be involved. In conclusion, this is the first study to report the in vivo effects of CBX in dogs with PDH. The findings suggest that CBX inhibits ACTH secretion from canine pituitary tumors, resulting in lower cortisol concentrations.

Objective The objective of this study was to evaluate the influence of heart rate (HR) on myocardial function assessed by two-dimensional speckle-tracking echocardiography (2D-STE) in healthy dogs. Animals Thirteen healthy beagle dogs. Methods Animals were anesthetized and HR was controlled with right atrial pacing. Myocardial function of each dog was assessed using 2D-STE at pacing rates of 120, 140, 160, and 180 bpm. Results All strain and strain rate variables in the longitudinal, circumferential, and radial directions were not significantly different between pacing rates. Peak early diastolic torsion rate at 180 bpm was significantly increased compared with that at 120 bpm (P = 0.003). Conclusion Torsion rate in early diastole was elevated at 180 bpm, which may reflect improved myocardial relaxation with higher HR. Changes in left ventricular torsion during tachycardia may play an important role in preserving stroke volume in the presence of shortened ejection and filling times.

An 11-year-old spayed female miniature dachshund was evaluated for a 2-month history of chronic vomiting. Abdominal ultrasonography revealed a heterogeneous mass in the pyloric region. Contrast upper gastrointestinal radiography demonstrated impairment of gastric outflow. Endoscopic examination revealed multiple polyps at the gastric pylorus. The pyloric polyps were variable in size, sessile-shaped and pedunculated. Initially, endoscopic polypectomy was attempted, but all the polyps could not be completely resected. Thus, endoscopic polypectomy with argon plasma coagulation was performed to cauterise the lesions. The histopathological diagnosis of the lesions was inflammatory polyps, and a moderate number of Helicobacter spp. was revealed. After the argon plasma coagulation treatment, the dog did not vomit, and improvement of clinical signs was maintained for 13 months. Endoscopic polypectomy with argon plasma coagulation may be useful for mixtures of sessile and pedunculated polyps. The present report may provide a basis for further studies of argon plasma coagulation treatment for canine gastrointestinal polyps.

Background Left ventricular torsional motion plays an important role for effective pump function. However, noninvasive clinical assessment of torsional deformations by two-dimensional speckle-tracking echocardiography (2D-STE) in dogs with myxomatous mitral valve disease (MMVD) has not been reported. Hypothesis Left ventricular torsion is determined by the native orientation of the helical myocardial fibers, such that it might provide better assessment of myocardial function than conventional methods. Animals Sixty-seven client-owned dogs with MMVD were classified into 3 classes based on the International Small Animal Cardiac Health Council classification and 16 weight- and age-matched healthy dogs. Methods Dogs were examined for myocardial deformations by 2D-STE and were evaluated for peak systolic rotation and rotation rate at each basal and apical view. Dogs also were evaluated for peak systolic torsion and torsion rate. Results Peak systolic torsion was higher in class II than in class I (P

Objectives The objective of our study was to quantitatively measure systolic torsional deformations in cats with hypertrophic cardiomyopathy (HCM) and in controls. Animals Twenty-six client-owned cats with HCM and 14 healthy cats. HCM cats were categorized based on their symptoms (asymptomatic and symptomatic) and with or without left ventricular outflow tract obstruction (obstructive and non-obstructive). Methods The cats were examined for myocardial deformations using two-dimensional speckle-tracking echocardiography and were evaluated for peak systolic rotation and the rotation rate at each basal and apical view. Cats were also evaluated for the peak systolic torsion and torsion rate. Results The peak systolic apical rotation and torsion were higher in asymptomatic and symptomatic cats with HCM than in control cats. Also, the peak systolic apical rotation, apical rotation rate, torsion, and torsion rate were higher in cats with obstructive HCM than in control cats. Conclusions Myocardial torsional deformations assessed by two-dimensional speckle-tracking echocardiography may be useful for evaluating compensatory myocardial function of HCM.

Introduction Determine the usefulness of dyssynchrony indices derived from two-dimensional speckle tracking echocardiography for the detection of mechanical dyssynchrony in a canine model of left bundle branch block. Animals Ten healthy beagles. Materials and Methods Segmental, time–radial strain curves were obtained using two-dimensional speckle tracking echocardiography. The maximum difference and standard deviation of the time to peak radial strain for six predefined segments (MaxD-TpSR and 6SD-TpSR) were calculated, together with the left ventricular dyssynchrony by radial strain (DysSR), before and after ablation of the left bundle branch block. Receiver operating characteristic curve analysis was performed using dogs after ablation as positive controls. Results After ablation, all dogs showed multiple peaks in at least one segment on the time–radial strain curve, while all dyssynchrony indices increased significantly (MaxD-TpSR from 16.25 ± 16.04 [mean ± standard deviation] to 44.4 ± 26.18 ms, 6SD-TpSR from 7.59 ± 7.40 to 19.62 ± 11.91 ms, and DysSR from 4.20 ± 2.12 to 10.87± 2.92%, p

Cushing’s disease caused by pituitary corticotroph adenoma is a common endocrine disease in dogs. A characteristic biochemical feature of corticotroph adenomas is their relative resistance to suppressive negative feedback by glucocorticoids. The abnormal expression of 11beta-hydroxysteroid dehydrogenase (11HSD), which is a cortisol metabolic enzyme, is found in human and murine corticotroph adenomas. Our recent studies demonstrated that canine corticotroph adenomas also have abnormal expression of 11HSD. 11HSD has two isoforms in dogs, 11HSD type1 (HSD11B1), which converts cortisone into active cortisol, and 11HSD type2 (HSD11B2), which converts cortisol into inactive cortisone. It has been suggested that glucocorticoid resistance in corticotroph tumors is related to the overexpression of HSD11B2. Therefore it was our aim to investigate the effects of carbenoxolone (CBX), an 11HSD inhibitor, on the healthy dog’s pituitary-adrenal axis. Dogs were administered 50 mg/kg of CBX twice each day for 15 days. During CBX administration, no adverse effects were observed in any dogs. The plasma adrenocorticotropic hormone (ACTH), and serum cortisol and cortisone concentrations were significantly lower at day 7 and 15 following corticotropin releasing hormone stimulation. After completion of CBX administration, the HSD11B1 mRNA expression was higher, and HSD11B2 mRNA expression was significantly lower in the pituitaries. Moreover, proopiomelanocortin mRNA expression was lower, and the ratio of ACTH-positive cells in the anterior pituitary was also significantly lower after CBX treatment. In adrenal glands treated with CBX, HSD11B1 and HSD11B2 mRNA expression were both lower compared to normal canine adrenal glands. The results of this study suggested that CBX inhibits ACTH secretion from pituitary due to altered 11HSD expressions, and is potentially useful for the treatment of canine Cushing’s disease.

Background Systolic dysfunction is associated with poor outcomes in dogs with myxomatous mitral valve disease. However, assessment of systolic variables by conventional echocardiographic methods is difficult in these dogs because of mitral regurgitation (MR). Hypothesis We hypothesized that assessment of systolic function by dobutamine stress may identify systolic dysfunction in dogs with MR, and that 2-dimensional speckle-tracking echocardiography (2D-STE) could quantitatively evaluate myocardial function. Animals Anesthetized dogs with experimentally induced MR. Methods Dogs were examined for systolic myocardial deformations using 2D-STE during dobutamine infusion before and 3 and 6 months after MR induction. We evaluated peak systolic rotation and rotation rate in each basal and apical view; peak systolic torsion and torsion rate were also calculated. Results Invasive peak positive first derivatives of left ventricular pressure (dp/dt) were significantly decreased in dogs 6 months after induction of MR compared with pre-MR results. After 3 and 6 months of MR, dogs had diminished peak systolic torsion values and torsion rates in response to dobutamine infusion compared with pre-MR results (3 months, P

Objectives To evaluate left ventricular geometry in dogs with various stages of myxomatous mitral valve disease. Methods Ninety-seven dogs with myxomatous mitral valve disease classified by the International Small Animal Cardiac Health Council system and 20 weight- and age-matched healthy dogs. Left ventricular long-axis to short-axis ratio, sphericity index in end-diastole and end-systole, left ventricular wall thickness to internal dimension ratio and relative wall thickness were assessed. Results The diastolic sphericity index was lower in classes Ib, II and III than in healthy dogs (P=0·003, P

A four-month-old female Labrador retriever was brought to the Tokyo University of Agriculture and Technology Animal Medical Center for examination of its main symptoms of cough, tachypnea and exercise intolerance. Upon examination, the dog was found to have cyanosis and inadequate growth. Echocardiography revealed tetralogy of Fallot. Cardiac catheterization confirmed that the main pulmonary artery was completely occluded and that blood flowed from the aorta to the pulmonary artery. Accordingly, the animal was diagnosed with extreme tetralogy of Fallot.