Impact of tumor growth rate during preceding treatment on tumor response to nivolumab or irinotecan in advanced gastric cancer.

BACKGROUND: Nivolumab (NIVO) and irinotecan (IRI) are standard treatments for refractory advanced gastric cancer (AGC); however, it is unclear which drug should be administered first or in which cases. The tumor growth rate (TGR) during preceding treatment is reported to be associated with tumor response in metastatic colorectal cancer patients treated with regorafenib or trifluridine/tipiracil, suggesting that TGR may be useful for drug selection. Therefore, we evaluated the association between TGR during preceding treatment and the tumor response to NIVO or IRI. PATIENTS AND METHODS: We retrospectively evaluated consecutive AGC patients treated with NIVO or IRI and divided them into slow-growing (Slow) and rapid-growing (Rapid) groups according to TGR and the presence or absence of new lesions (NL+/NL-, respectively) during preceding treatment (Slow group: NL- with low TGR <0.30%/day; Rapid group: NL+ or high TGR ≥0.30%/day). RESULTS: A total of 117 patients (Rapid/Slow groups, 72/45; NIVO/IRI groups, 32/85) were eligible. All baseline characteristics except peritoneal metastases were similar between patients treated with NIVO and IRI in the Rapid and Slow groups. The response rate was significantly higher in patients treated with NIVO compared with IRI [31%/3%; odds ratio (OR), 13.8; P = 0.01; adjusted OR, 52; P = 0.002] in the Slow group, but there was no difference between patients treated with NIVO and IRI (5%/8%; OR, 0.68; P = 0.73; adjusted OR, 0.94; P = 0.96) in the Rapid group. Disease control rate, progression-free survival, and overall survival were consistent with these results. CONCLUSIONS: Our findings suggest that NIVO treatment is a more favorable option for patients with slow-growing tumors, and NIVO and IRI are similarly recommended for patients with rapid-growing tumors in refractory AGC. TGR and NL emergence during preceding treatment may be helpful for drug selection and warrant further investigation.

Persistent truncus arteriosus with an anomalous coronary artery in a cat.

A 6-month-old, female, domestic shorthair cat weighing 1.8 kg presented with cardiomegaly seen on radiographs taken at a primary care veterinary center. Echocardiography revealed a single enlarged vessel overriding a ventricular septal defect and severe hypertrophy of the right ventricular free wall. There was no evidence of a pulmonary arterial trunk originating from the heart. The blood flow through the ventricular septal defect exhibited right-to-left shunting. The cat suddenly experienced dyspnea and died at home, and a postmortem examination was performed. A single large vessel was noted leaving the heart, from which the right and left pulmonary arteries arose separately; a main pulmonary artery was absent. There was only one single anomalous coronary ostium that arose from the brachiocephalic artery and divided into two branches. The walls of the extracardiac coronary artery were thick, but neither infarcts nor narrowing was observed within the coronary arteries. There were no abnormalities in the intracardiac coronary artery. These findings revealed a persistent truncus arteriosus with an anomalous coronary artery. A combination of these anomalies might have contributed to the early death of the cat.

Pathological Features of Complete Atrioventricular Block in Dogs with Lymphocytic Myocarditis.

The cardiac conduction system was examined histologically in 12 canine cases of lymphocytic myocarditis with complete atrioventricular (AV) block. Histological analysis showed active myocarditis characterized by intense infiltration of mononuclear cells, primarily lymphoid, associated with degeneration and necrosis of the adjacent cardiomyocytes. Additionally, there was healing or healed myocarditis manifested by disappearance of cardiomyocytes and replacement fibrosis. This destructive inflammatory process of lymphocytic myocarditis involved the whole of the AV conduction system, resulting in loss and deletion of the conduction fibres, as well as the myocardium of all chambers. Such total or subtotal destruction of the AV conduction system caused by the inflammatory changes was thought to have set the stage for blocking AV conduction of cardiac impulses, but the aetiology of the lymphocytic myocarditis was not elucidated.

Pathological Features and Pathogenesis of the Endomyocardial Form of Restrictive Cardiomyopathy in Cats.

This study reports pathological and molecular features in 41 cases of feline restrictive cardiomyopathy (RCM). Grossly, there were patchy or diffuse areas of endocardial thickening affecting the left ventricle. The more common patchy endocardial lesions occurred as large trabecular or irregular broad bands of fibrous tissue bridging the left ventricular free wall and ventricular septum. Microscopically, regardless of the gross pattern, the thickened endocardium contained various numbers of stellate, spindle-shaped or elongated mesenchymal cells surrounded by fibrous connective tissue. Immunohistochemical findings were indicative of smooth muscle differentiation in mesenchymal cells. These cells proliferated vigorously and produced alcian blue-positive ground substance and collagen fibres; it was considered that the mesenchymal cells contributed to the formation of the endocardial lesions. In addition, multiple left ventricular 'false tendons' were invariably included within the trabecular or broad fibrous bands, providing a framework for formation of those bands. Evidence of endocarditis or endomyocarditis was lacking in all 41 cases, and no viral genomes were detected in any of the DNA or RNA samples obtained from 14 of the hearts. These observations suggest that any relationship between feline RCM and a virus-induced inflammatory response seems unlikely.

Spermatogonial Nature of the Germ Cell Component of Canine Testicular Mixed Germ Cell-Sex Cord Stromal Tumours.

The present study has characterized the germ cell component of canine testicular mixed germ cell-sex cord stromal tumours (MGSCTs) by examining the histological nature and histochemical and immunohistochemical features using gonocytic and spermatogonial cellular markers, c-Kit, placental alkaline phosphatase (PLAP), protein gene product 9.5 (PGP9.5), Sal-like protein 4 (SALL4), and the periodic acid-Schiff (PAS) reaction. Histologically, all 45 examples of MGSCTs were classified as spermatocytic seminomas (SSs) and Sertoli cell tumours in combination. The germ cell component of all MGSCTs was negative by PAS staining. Immunohistochemically, PLAP immunoreactivity was lacking in the germ cell component of all MGSCTs, which is not consistent with a gonocytic origin. The germ cell component was positive for PGP9.5 and SALL4 in all MGSCTs and positive for c-Kit in 53% of MGSCTs, which is consistent with the phenotype of spermatogonia. Furthermore, the germ cell component in 71% of MGSCTs had moderate immunoreactivity for SALL4, which is suggestive of a spermatogonial phenotype. Conversely, 29% of cases had a minor population of germ cells showing strong SALL4 immunoreactivity, suggesting a phenotype similar to prespermatogonia. The results suggest that the germ cell component of canine MGSCTs is morphologically classified as SS, with the majority of cases showing the spermatogonial phenotype and some cases containing a small population of prespermatogonia.

Incidence, Distribution and Morphology of Left Ventricular False Tendons in Cat Hearts.

The incidence, distribution, and macro- and microscopic structures of left ventricular false tendons (LVFTs) in the cat heart were studied using 25 normal and 57 diseased hearts. The fibrous bands were observed in the left ventricle of all 82 cat hearts examined and most commonly extended between the papillary muscles and the ventricular septum. Histologically, the LVFTs were composed of central Purkinje fibres and surrounding dense collagenous fibres covered by endothelium. There was no appreciable difference in the incidence, distribution or morphology of LVFTs between the normal and the diseased hearts, indicating that LVFTs are a common anatomic variant in the cat heart.

Comparative effect of carperitide and furosemide on left atrial pressure in dogs with experimentally induced mitral valve regurgitation.

BACKGROUND: The effects of carperitide on left atrial pressure (LAP) in dogs with mitral valve disease (mitral regurgitation, MR) have not been documented. OBJECTIVE: The objective was to compare the short-term effects of carperitide versus furosemide on LAP and neurohumoral factors in MR dogs. ANIMALS: Six healthy Beagle dogs weighing 9.8-12.6 kg (2 males and 4 females; aged 3 years) were used. METHODS: Experimental, randomized, cross-over, and interventional study. Carperitide 0.1 µg/kg/min or furosemide 0.17 mg/kg/h (1 mg/kg/6 h) was administered to dogs with surgically induced MR for 6 hours, and after a 14 day wash-out period, the other drug was administered. LAP, plasma renin activity, plasma aldosterone, and echocardiographic variables were measured. RESULTS: Left atrial pressure was decreased similarly after the administration of carperitide 0.1 µg/kg/min and furosemide 0.17 mg/kg/h (1 mg/kg/6 h) compared with baseline in dogs with MR (Baseline 14.75 ± 3.74 mmHg, carperitide 10.24 ± 4.97 mmHg, P < .01, furosemide 10.77 ± 5.06 mmHg, P < .05). Plasma renin activity and plasma aldosterone were significantly lower after the administration of carperitide than after the administration of furosemide (P < .05, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Carperitide significantly decreased LAP in dogs with acute MR caused by experimental chordal rupture. Carperitide can have additional benefits from the viewpoint of minimal activation of neurohumoral factors in the treatment of dogs with MR. Additional studies in dogs with spontaneous disease are warranted.

Improvement of hepatocyte recovery from rat liver subjected to 1-hour warm ischemic injury by using citrate phosphate dextrose added to euro-collins perfusion solution.

Warm ischemia (WI)-related injury interferes with recovery of primary hepatocyte after collagenase digestion of surgically resected or non-heart-beating donor livers as human cell sources. We speculated that digestion is impaired due to reduced microcirculation, caused by microembolism after WI. We sought to improve hepatocyte recovery after WI using a rat model. Anesthetized 9-week-old male Sprague-Dawley rats underwent a midline abdominal incision to insert a 22-gauge cannula into the portal vein. WI was initiated by ligating both the cannula and the hepatic artery. We compared Euro-Collins (EC) perfusion solution with 2 anticoagulants-heparin or citrate phosphate dextrose (CPD)-versus ethylene glycol tetraacetic acid (EGTA) combined with Ca(2+)- and Mg(2+)-free Hank's solution (CM-free Hank's solution). Use of CM-free Hank's solution yielded only 0.75 ± 0.15 × 10(8) and 0.82 ± 0.20 × 10(8) cells at 30 and 60 minutes WI respectively. However, CPD, but not heparin, added to the EC solution produced the best cell recovery (CPD: 2.15 ± 0.38 × 10(8); heparin: 1.63 ± 0.31 × 10(8)). During macroscopic observation, CPD added to EC solution also demonstrated best blood flushing. CPD added to EC solution achieved greater hepatocyte recovery than CM-free Hank's solution by restoring microcirculation during flushing of blood from liver tissue subjected to WI.

Mixed form of pericardial mesothelioma with osseous differentiation in a dog.

An 8-year-old female Yorkshire terrier was referred for evaluation and treatment of recurrent pericardial effusion. Echocardiographic examination revealed a markedly and irregularly thickened pericardial sac with frequent hyperechoic areas with acoustic shadows. Pericardiocentesis produced only a small amount of thick serosanguineous fluid. The dog underwent subtotal pericardiectomy, but died during surgery. At necropsy examination, the heart was encased by voluminous, grey-white to red-tan, soft to firm proliferative tissue arising from the pericardial sac. The pericardial cavity was obliterated. Microscopically, the tissue was predominantly sarcomatoid with osseous differentiation and epithelioid elements were admixed with bundles of spindle cells. Immunohistochemically, the constituent cells, especially those that were epithelioid, co-expressed cytokeratin and vimentin. A diagnosis of mixed form pericardial mesothelioma with osseous differentiation was made. This appears to be the first report of such a tumour in a dog.

Tumour endothelial marker-1 is expressed in canine Haemangiopericytomas.

The aim of this study was to characterize immunohistochemically 18 cases of canine haemangiopericytoma (CHP) using two new candidate markers for pericytes, tumour endothelial marker (TEM)-1 and new glue (NG)-2, as well as the conventional mesenchymal cellular markers, vimentin, α-smooth muscle actin (α-SMA), desmin and von Willebrand factor (vWF). Because pericytes may have the same origin as endothelial or smooth muscle cells or the same differentiation potential as myofibroblasts, 17 cases of leiomyosarcoma (LMS), 20 cases of haemangiosarcoma (HS) and three cases of myofibroblastic sarcoma (MFS) were also examined. Expression of TEM-1 by >10% of the neoplastic population was observed in 94.4% (17/18) of haemangiopericytomas, 23.5% (4/17) of LMSs, 30.0% (6/20) of HSs and 66.7% (2/3) of MFSs. NG-2 expression by >10% of the neoplastic population was observed in 16.7% (3/18) of haemangiopericytomas, 52.9% (9/17) of LMSs, 0% (0/20) of HSs and 33.3% (1/3) of MFSs. Vimentin was expressed by all of tumours. In haemangiopericytoma, the incidence of positive immunoreactivity in >10% of the neoplastic population was 5.6% (1/18) for both α-SMA and desmin and 0% (0/18) for vWF. Considering the phenotypic features of cells expressing TEM-1, CHPs are thought to originate from immature vascular mural cells sharing their phenotype with myofibroblasts. NG-2 expression may be a phenotype of smooth muscle cells rather than pericytes in dogs.

Histopathological and immunohistochemical evaluation of malignant potential in canine aortic body tumours.

In order to verify the malignant potential of aortic body tumours (ABTs) in dogs, 13 cases of canine ABT were studied histopathologically and immunohistochemically. The cases were divided into two groups according to the presence or absence of metastases to other organs at necropsy examination (metastasis group [n = 9] and non-metastasis group [n = 4]). The mean tumour weight:body weight ratio (TW:BW; g/kg) in the metastasis group (9.3 ± 6.7) was significantly higher than that in the non-metastasis group (1.5 ± 1.7) (P <0.05). In both groups, the neoplastic cells had malignant features including pleomorphism, anisocytosis and anisokaryosis, and mononuclear giant cells were present, showing invasion through the capsule and into the vascular lumen and other adjacent tissues. The mitotic index (MI), mean nuclear area (NA) for size value and coefficient of variation of the nuclear area (CVNA) for anisonucleosis did not differ significantly between the two groups. These findings show that anaplastic characteristics are present regardless of the tumour size or the presence or absence of metastases, suggesting that these tumours are generally malignant or potentially malignant. Immunohistochemical analysis using neuroendocrine markers including neuron-specific enolase, chromogranin A and S100 revealed no obvious differences in labelling intensity of neoplastic cells related to the presence or absence of metastases or associated with the mean TW:BW, MI, NA or CVNA value, indicating that immunohistochemistry has no practical value for determining the tumour grade of canine ABTs.

The anatomical basis of bradycardia-tachycardia syndrome in elderly dogs with chronic degenerative valvular disease.

The hearts of seven elderly dogs in which bradycardia-tachycardia syndrome (BTS) had been diagnosed electrocardiographically were examined post mortem. The clinical basis of the underlying heart disease was invariably mitral or mitral and tricuspid regurgitation. Microscopical examination of the sinoatrial (SA) node and the SA junctional region consistently revealed depletion of SA nodal cells, with a corresponding increase in fibrous or fibro-fatty tissue that interrupted contiguity between the SA node and the surrounding atrial myocardium. The left and right atrial walls showed an increased amount of fibrous tissue in the myocardium and disruption of the muscle bundle architecture (interstitial myocardial fibrosis) to varying degrees. Qualitatively, these changes in the SA node and the SA node region resembled those associated with ageing in elderly people with or without BTS. Thus, it is possible that the pathological process affecting the SA node in these dogs was fundamentally related to ageing and may have caused BTS, in combination with atrial myocardial lesions caused by mitral and tricuspid regurgitation.

The effect of pimobendan on left atrial pressure in dogs with mitral valve regurgitation.

BACKGROUND: The effects of pimobendan on left atrial pressure (LAP) in dogs with mitral valve disease (MR) have not been documented in a quantitative manner. OBJECTIVE: The objective was to document and study the short-term effects of pimobendan on LAP and echocardiographic parameters in MR dogs. ANIMALS: Eight healthy Beagle dogs weighing 10.0-14.7 kg (3 males and 5 females; aged 2 years) were used. METHODS: Experimental, cross-over, and interventional study. Dogs with surgically induced MR received pimobendan at either 0.25 mg/kg or 0.50 mg/kg p.o. q12h for 7 days and then, after a 7-day wash-out period, the other dosage. LAP was measured for 30 minutes at baseline and again on days 1, 2, 4, and 7 of pimobendan administration. RESULTS: Mean LAP was significantly decreased after the administration of 0.25 mg/kg (15.81 ± 5.44 mmHg to 12.67 ± 5.71 mmHg, P < .001) and 0.50 mg/kg (15.76 ± 5.45 mmHg to 10.77 ± 5.23 mmHg, P < .001). Also, the 0.50 mg/kg group led to a significantly lower LAP (P < .01) compared with the 0.25 mg/kg group. Significant reduction was seen for the first time 4 days after the administration of 0.25 mg/kg and a day after the administration of 0.50 mg/kg. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan decreased LAP in a dose-dependent manner in dogs with acute MR caused by experimental chordal rupture. This study did not evaluate adverse effects of high-dose pimobendan, and additional studies in clinical patients are warranted.

The effect of furosemide on left atrial pressure in dogs with mitral valve regurgitation.

BACKGROUND: The effects of furosemide on left atrial pressure (LAP) in dogs with mitral regurgitation (MR) have not been documented in a quantitative manner and between different routes of administration. OBJECTIVE: To document LAP and echocardiographic parameters in MR dogs administered furosemide IV or PO, in order to document changes in LAP after furosemide treatment. ANIMALS: Five healthy Beagle dogs (3 males and 2 females; aged 2 years) were used. METHODS: Experimental, cross-over, and interventional study. LAP was measured before the administration of furosemide, and 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours after administration. Furosemide 1, 2, or 4 mg/kg IV, PO or placebo was administered. RESULTS: LAP was significantly decreased with all administrations of furosemide but not after placebo (P < .05, respectively). The max reduction was observed 1 hour (1 mg/kg IV, 15.04 ± 7.02 mmHg), 3 hours (2, 4 mg/kg IV, 13.28 ± 8.01, 9.23 ± 4.92 mmHg), 4 hours (1 mg/kg PO, 14.68 ± 11.51 mmHg), and 5 hours (2, 4 mg/kg PO, 13.19 ± 10.52, 10.70 ± 7.69 mmHg). E wave and E/Ea were significantly decreased corresponding to the reduction of LAP after administration of 2 and 4 mg/kg (P < .05, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: LAP was decreased in proportion to the dosage of furosemide, which did not significantly differ between IV and PO of the same dosages. E wave and E/Ea might be useful for the treatment evaluation of furosemide.

Complete atrioventricular block associated with lymphocytic myocarditis of the atrioventricular node in two young adult dogs.

A histological investigation of the atrioventricular (AV) conduction system was performed in two young adult dogs with complete AV block. In both cases, infiltration of lymphocytes and plasma cells into the AV node and loss and disappearance of the conduction fibres were observed. Such inflammatory lesions of the AV conduction system were associated with complete AV block. The aetiology of these changes and the cause of its location at the AV node were not elucidated.

A histological study of the cardiac conduction system in canine cases of mitral valve endocardiosis with complete atrioventricular block.

The cardiac conduction system was examined histologically in four canine cases of endocardiosis of the mitral valve (MV) with complete atrioventricular (AV) block. In all cases, moderate to severe reduction of the conduction fibres due to fibrous or fibro-fatty replacement was observed in the penetrating and branching portions of the AV bundle. In addition, degenerative and fibrotic lesions were commonly seen at the upper portions of the left and right bundle branches. These changes in the AV conduction system were associated with marked degeneration and fibrosis of the base of the central fibrous body and the upper part of the ventricular septum. The degenerative and sclerotic changes of the AV junctional region, affecting the AV bundle and bundle branches, were qualitatively similar to those in age-matched control dogs, but were more severe. It is possible that the pathological process occurred as a result of ageing and may have been exaggerated or accelerated by the abnormal mechanical forces created by excessive motion of the prolapsed MV and the long-term haemodynamic stresses of mitral regurgitation, resulting in interruption of the AV conduction system to produce complete AV block. Conduction abnormalities represent a possible complication in some canine cases of MV endocardiosis.

The anatomical basis of complete atrioventricular block in cats with hypertrophic cardiomyopathy.

The cardiac conduction system was examined histologically in 13 feline cases of hypertrophic cardiomyopathy (HCM) with complete atrioventricular (AV) block. Marked degeneration and fibrous replacement of the AV conduction system were consistently observed in the combined regions of the branching portion of the AV bundle and the upper portion of the left bundle branch. These changes were associated with extensive fibrosis of the central fibrous body and endocardial and myocardial fibrosis in the upper border of the ventricular septum. Chondrometaplastic lesions or osseous lesions, or both, present in the base of the central fibrous body, compressed the underlying penetrating or branching (or both) portions of the AV bundle, causing apparent reduction of the conduction fibres. The pathological process and the nature and predilection sites of the lesions resembled those associated with ageing in human patients with complete AV block. It is possible that the pathological process in the cats was fundamentally related to the normal ageing phenomenon and may have been exacerbated by mechanical forces created by the cardiac hypertrophy associated with HCM.

Surgical management of a double-chambered right ventricle and chylothorax in a Labrador retriever.

A 22-month-old, male Labrador retriever was presented with anorexia, dyspnoea, and fainting. The dog was diagnosed with a double-chambered right ventricle and tricuspid valve dysplasia using echocardiography and cardiac catheterisation. A marked bilateral pleural effusion was also present and chemical analysis of the fluid confirmed the diagnosis of chylothorax. Using echocardiography, a pressure gradient of 87.1 mmHg was found between the proximal and distal chambers of the double-chambered right ventricle. Initiation of cardiopulmonary bypass allowed the anomalous muscle bundle that divided the right ventricle into two chambers to be resected via a right ventriculotomy. The fainting completely resolved postoperatively, and this treatment seemed quite effective in the reduction of pressure overload ascribable to ejection disturbance. Because the tricuspid dysplasia was not corrected in the first operation, the postoperative chyle effusion was reduced but did not cease. A combination of thoracic duct ligation and passive pleuroperitoneal shunting was effective in the resolution of the chyle effusion.

A histological study of the cardiac conduction system in a heifer with complete atrioventricular block.

A case of complete atrioventricular (AV) block of congenital origin in a 16-month-old Holstein heifer was studied histologically with serial sectioning of the cardiac conduction system. The heart was enlarged and showed moderate dilatation of the left and right ventricles. Histologically, the abnormally placed and poorly formed AV bundle was observed in association with abnormality in the tricuspid extension of the central fibrous body, suggesting that the pathological state of the AV bundle had been responsible for the complete AV block. This type of anatomical fault in the AV bundle is considered to be part of an embryological, developmental malformation of the central fibrous body.

Thyroid lesions and dioxin accumulation in the livers of jungle crows (Corvus macrorhynchos) in urban and suburban Tokyo.

Wild jungle crows (Corvus macrorhynchos) captured from three different areas of Tokyo were examined to evaluate environmental contamination of dioxins. In addition to the pathologic examination of their whole body, accumulation of dioxins, mRNA expression of the aryl hydrocarbon receptor (AhR), and pentoxyresorufin-O-depenthylase (PROD) activity in the liver were determined. Marked histopathologic changes were observed in the thyroid glands, especially in the crows from the urban downtown area. Levels of dioxins and their toxic equivalents (TEQs) and AhR mRNA expression in the livers of the crows from the urban area were higher than those from the suburban area. There was a high correlation between the levels of TEQs and PROD activity. The results of the present study demonstrated that jungle crows possess AhR-mediated toxicologic pathways similar to those of mammals and suggest the possibility that the thyroidal changes observed in the adult crows from the urban areas are one of the toxic manifestations resulting from exposure to dioxins and other environmental chemicals.