Publications by authors named "Ken-Ichi Watanabe"

115 Publications

Analysis of the bone morphogenetic protein 6 gene promoter region in young beef cattle affected by enzootic bovine leukosis.

J Vet Med Sci 2021 Apr 9. Epub 2021 Apr 9.

Veterinary Medical Center, Graduate School of Agricultural and Life Sciences, The University of Tokyo.

Enzootic bovine leukosis (EBL) is typically observed in cattle over 3 years old. However, some cases of EBL onset in young beef cattle have been reported in Japan. The mechanism for early EBL onset is unclear. In Japan, beef cattle are given large amounts of concentrated feed with low vitamin A. Bone morphogenetic proteins (BMPs) are regulators of cell proliferation, differentiation, and apoptosis, and thought to represent one of the key players in tumor malignancy. The purpose of this study was to evaluate the differences in BMP-6 methylation status between EBL beef cattle under 3 years old and other cattle. We investigated the methylation status of the BMP-6 promoter region in 32 EBL beef cattle under 3 years old. We also compared the methylation status of EBL dairy cattle to that of healthy cattle. Median methylation rate of the BMP-6 promoter region in EBL beef cattle under 3 years old was 8.9%, which was significantly higher than that of other groups. Hypermethylation of the BMP-6 promoter region might contribute to early onset of EBL in beef cattle under 3 years old, and animal feeding management practices specific to beef cattle may affect the methylation status of the BMP-6 promoter region.
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http://dx.doi.org/10.1292/jvms.20-0663DOI Listing
April 2021

A clinical case of acute myelomonocytic leukemia in a Holstein cow.

J Vet Med Sci 2021 Mar 22. Epub 2021 Mar 22.

Veterinary Medical Center, Graduate School of Agricultural and Life Sciences, The University of Tokyo.

A 2-year, 3-month-old Holstein cow presented with anorexia and enlarged superficial lymph nodes. Fine needle aspiration cytology of the superficial lymph nodes revealed large blast cells. Hematological examination revealed anemia, neutropenia, and blast cells in peripheral blood. Blast cells were the predominant cell type in bone marrow aspirates. Of the non-erythroid cells, 26%, 58%, and 18% were positive for myeloperoxidase, α-naphthyl acetate esterase, and naphthol AS-D chloroacetate esterase, respectively. Pathological examination revealed the proliferation of neoplastic cells, which were positive for monocytic markers, in the affected lymph nodes. The cow was diagnosed with acute myelomonocytic leukemia based on these findings. This report highlights the importance of performing bone marrow aspiration cytology and cytochemical staining when diagnosing bovine myeloid leukemia.
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http://dx.doi.org/10.1292/jvms.20-0618DOI Listing
March 2021

A Correlation Analysis Between Metabolism-related Genes and Treatment Response to S-1 as First-line Chemotherapy for Metastatic Breast Cancer: The SELECT BC-EURECA Study.

Clin Breast Cancer 2021 Feb 1. Epub 2021 Feb 1.

National Cancer Center Hospital East, Kashiwa, Japan.

Introduction: The previous randomized phase 3 trial (SELECT BC) showed that S-1 as a first-line chemotherapy for metastatic breast cancer (MBC) is non-inferior to taxane with respect to overall survival. This study aimed to identify the usefulness of metabolism-related genes as predictive biomarkers for the response to S-1 compared with taxane using tumor tissue samples from the previous trial.   PATIENTS AND METHODS: In this SELECT BC-EURECA study, 147 patients with human epidermal growth factor 2 (HER2)-negative MBC who received either S-1 or taxane were evaluated. Formalin-fixed paraffin-embedded specimens were collected, and 14 genes involved in the pyrimidine metabolic pathway, estrogen receptor, progesterone receptor, HER2, Ki67, and beta-tubulin were measured using reverse transcription polymerase chain reaction in microdissected tumor specimens. The expression of each gene was categorized as low, intermediate, and high by tertile values.   RESULTS: Interaction tests to identify biomarkers for the response to S-1 compared with taxane, revealed the following as the top 3 biomarkers: RRM1 (P value = 0.24), GGH (P value = 0.25), and MTHFR (P value = 0.28). In the S-1 group, lower GGH and higher MTHFR expression were significantly correlated with better time to treatment failure. In the taxane group, there was no gene that was identified as a significant indicator of treatment failure.

Conclusion: This biomarker analysis from SELECT BC did not identify any predictive biomarkers for the response to S-1 compared with taxane. Future studies with larger sample size and information on not only mRNA, but also protein and DNA for broad functional analyses are needed.
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http://dx.doi.org/10.1016/j.clbc.2021.01.018DOI Listing
February 2021

New cell delivery system CellSaic with adipose-derived stromal cells promotes functional angiogenesis in critical limb ischemia model mice.

J Artif Organs 2021 Mar 3. Epub 2021 Mar 3.

Department of Cardiovascular Surgery, Osaka University, 2-15 Yamadaoka, Suita, Osaka, Japan.

Current therapies for patients with critical limb ischemia have not reduced amputation risk owing to poor cell engraftment. The recombinant peptide Cellnest increases the engraftment rate of administered cells by forming a complex with the cells (CellSaic). We hypothesized that CellSaic containing adipose-derived stromal cells (ADSCs) could improve lower limb blood flow better than ADSCs alone, resulting in better transplanted cell engraftment. ADSCs were extracted from 8-week-old C57BL/6N mice. Thirty-two critical limb ischemia model mice were established by ligating femoral arteries. They were divided into CellSaic (n = 11), ADSC (n = 10), saline (n = 9), and Cellnest (n = 9) groups. Blood flow rate (affected side blood flow / healthy side blood flow × 100%) was evaluated using a laser Doppler blood flow meter every week. Mice were euthanized on day 28 for histological evaluation. Compared with the ADSC group (54.5 ± 17.2%), treated side blood flow rate of the CellSaic group (78.0 ± 24.9%) showed significant improvement on day 28 after administration (p < 0.05). CD31 staining showed significantly higher number of capillary vessels in the CellSaic group (53.0 ± 8.9 cells/mm) than in the ADSC group (43.0 ± 6.8 cells/mm) (p < 0.05). Fluorescent staining showed significantly higher number of arterioles containing both CD31 and αSMA double-positive cells in the CellSaic group than in the ADSC group (p < 0.05). CellSaic containing ADSCs exhibited superiority to ADSC transplantation alone in promoting functional angiogenesis, suggesting its potential in improving clinical outcomes of angiogenic therapy for ischemic limbs.
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http://dx.doi.org/10.1007/s10047-021-01254-8DOI Listing
March 2021

Prospective cohort study of febrile neutropenia in breast cancer patients administered with neoadjuvant and adjuvant chemotherapies: CSPOR-BC FN study.

Breast 2021 Apr 16;56:70-77. Epub 2021 Feb 16.

Division of Oncology/Hematology, National Cancer Center Hospital East, Chiba, Japan.

Background: As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G).

Patients And Methods: Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians' discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors.

Results: Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 μl (0.8) remained significant.

Conclusions: FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC.
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http://dx.doi.org/10.1016/j.breast.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907535PMC
April 2021

A clinical case of single left ventricle in a Holstein calf.

J Vet Med Sci 2021 Apr 9;83(4):609-612. Epub 2021 Feb 9.

Veterinary Medical Center, Graduate School of Agriculture and Life Science, The University of Tokyo, Tokyo 113-8657, Japan.

A 15-day-old Holstein calf with lethargy and tachypnea presented to the Veterinary Teaching Hospital at Obihiro University of Agriculture and Veterinary Medicine for evaluation of suspected congenital heart defect. A Levine grade 6 systolic murmur was noted at right apical site auscultation and phonocardiogram also recorded systolic a murmur. Electrocardiography findings include increased R and S waves, R wave split, and negative T waves without arrhythmia. Echocardiography revealed a single ventricle with a trace of the right ventricular wall, atrioventricular valve regurgitation, and turbulent in a single ventricle. Arterial blood analysis showed a marked decrease in oxygen saturation of 78% and oxygen partial pressure of 44 mmHg. Post-mortem examination confirmed the diagnosis of a single left ventricle.
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http://dx.doi.org/10.1292/jvms.20-0588DOI Listing
April 2021

Secondary endpoints analysis in patients with estrogen receptor-positive metastatic breast cancer treated with everolimus and exemestane enrolled in Oral Care-BC.

BMC Cancer 2021 Jan 7;21(1):34. Epub 2021 Jan 7.

Department of Dentistry and Oral and Maxillofacial Surgery, Tokai University School of Medicine, Tokyo, Japan.

Background: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE.

Methods: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months.

Results: There were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI <  25 mg/m and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial.

Conclusions: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI <  25 mg/m, and who did not receive BMA while receiving EVE and EXE may have better prognoses.

Trial Registration: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov ( NCT02376985 ).
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http://dx.doi.org/10.1186/s12885-020-07746-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791872PMC
January 2021

A clinical case of presumed cerebellar medulloblastoma in a Japanese Black calf with increased neuron-specific enolase in cerebrospinal fluid.

J Vet Med Sci 2020 Oct 3;82(10):1436-1439. Epub 2020 Aug 3.

Veterinary Medical Center, Graduate School of Agriculture and Life Science, The University of Tokyo, Tokyo 113-8657, Japan.

A 2-day-old Japanese Black male calf that presented with opisthotonos with spastic extension of all four limbs and nystagmus was presented. Evaluation of cranial neurology revealed a horizontal slow nystagmus and absence of menace response in the left eye. Necropsy revealed a mass located between the posterior margin of the cerebrum and anterior margin of the cerebellum, and continuously with the cerebellar lesion. The brainstem was severely compressed by those lesions. Original structures of the cerebellum were mostly replaced by grayish-white and brownish tissues. Those lesions were diagnosed as presumed cerebellar medulloblastoma by histopathological and immunohistochemical examination. As neuron-specific enolase in the cerebrospinal fluid which is a biomarker for neuronal damage was increased compared with healthy calves.
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http://dx.doi.org/10.1292/jvms.20-0295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653316PMC
October 2020

Characteristic imaging findings of the respiratory system in penguins with suspected aspergillosis in an aquarium.

J Vet Med Sci 2020 Sep 13;82(9):1260-1266. Epub 2020 Jul 13.

Azabu University, Sagamihara, Kanagawa 252-5201, Japan.

Twenty penguins, including the King penguin (Aptenodytes patagonicus), Gentoo penguin (Pygoscelis papua), and African penguin (Spheniscus demersus), housed at an aquarium in Hokkaido, Japan, underwent regular health screening via blood test, and five penguins with suspected aspergillosis were extracted. In cases 1 and 2, a thickened membrane and/or fluid level and/or calcification in the air sac were observed on both radiography and computed tomography (CT). These two penguins died after 19 and 43 days, respectively. At the time the radiographic changes were observed, the disease had likely progressed to a point at which it was too late for recovery. Aspergillus fumigatus infection was confirmed by nucleotide sequence analysis in case 1. In case 3, infiltration in the pulmonary parenchyma was observed on CT, and the infiltration disappeared following oral administration of itraconazole as diagnostic therapy for 8 months. In case 4, defects in the pulmonary parenchyma were observed only on CT. These defects remained unchanged in size for 7 months despite the lack of any treatment, and were not considered clinically significant. However, the blood antigen level in case 5 was increased, both radiography and CT were unremarkable. The combination of a screening blood test and CT examination could be useful clues for an early diagnosis of aspergillosis as well as for initiating treatment.
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http://dx.doi.org/10.1292/jvms.20-0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538335PMC
September 2020

Acute monoblastic leukemia in a feline leukemia virus-negative cat.

J Vet Med Sci 2020 Jul 22;82(7):1000-1005. Epub 2020 May 22.

Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan.

A 12-year-old female domestic short-haired cat was presented due to weight loss, anorexia, and tachypnea. Complete blood count revealed severe anemia, leukocytosis with massive undifferentiated blast cells, and thrombocytopenia. Bone marrow aspiration showed acute myeloid leukemia, subclassified as monoblastic leukemia (M5a) based on the outcomes of the cytochemistry examinations. The SNAP feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) test using whole blood was negative. In addition, FeLV/FIV proviral polymerase chain reaction test using bone marrow aspirate was also negative. Although the cat was treated with doxorubicin, cytosine arabinoside, and prednisolone, anemia did not improve without blood transfusion. The owner declined further treatment after 2 months, and the cat died a few days later.
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http://dx.doi.org/10.1292/jvms.20-0157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399316PMC
July 2020

Intramedullary spinal nephroblastoma in a mixed breed dog.

J Vet Med Sci 2020 Jul 18;82(7):917-921. Epub 2020 May 18.

Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Inada, Obihiro, Hokkaido 080-8555, Japan.

A 1-year-old male mixed breed dog presented for the evaluation of progressive hindlimb paresis. Neurological examination indicated a spinal cord lesion between the 3rd thoracic and 3rd lumbar vertebrae. Magnetic resonance imaging (MRI) revealed an intramedullary spinal cord lesion located at the level of the 1st and 2nd lumbar vertebrae. Following cytoreductive surgery of the mass, palliative radiation therapy was administered. A diagnosis of nephroblastoma was made based on histological examination. After radiation therapy, the disappearance of the spinal lesion was confirmed by MRI. The dog was improved from gait abnormality and alive at 16 months postoperatively, with slight signs of neurological dysfunction.
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http://dx.doi.org/10.1292/jvms.20-0068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399307PMC
July 2020

Quantitative analysis of the BRAF V595E mutation in plasma cell-free DNA from dogs with urothelial carcinoma.

PLoS One 2020 24;15(4):e0232365. Epub 2020 Apr 24.

Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan.

Circulating tumor DNA (ctDNA), which carries tumor-specific mutations, is an emerging candidate biomarker for malignancies and for monitoring disease status in various human tumors. Recently, BRAF V595E mutation has been reported in 80% of dogs with urothelial carcinoma. This study investigates the BRAF V595E allele concentration in circulating cell-free DNA (cfDNA) and assesses the clinical significance of BRAF-mutated ctDNA levels in canines with urothelial carcinoma. A total of 15 dogs with urothelial carcinoma were included. cfDNA concentration was measured using a real-time polymerase chain reaction (PCR) of the LINE-1 gene. To measure the concentration of the mutated BRAF gene in cfDNA, allele-specific real-time PCR with a locked nucleic acid probe was performed. BRAF mutations were detected in 11 (73%) of the 15 tested tumor samples. BRAF-mutated ctDNA concentrations were significantly higher in dogs with the BRAF mutation (14.05 ± 13.51 ng/ml) than in wild-type dogs (0.21 ± 0.41 ng/ml) (p = 0.031). The amount of BRAF-mutated ctDNA in plasma increased with disease progression and responded to treatment. Our results show that BRAF-mutated ctDNA can be detected using allele-specific real-time PCR in plasma samples of canines with urothelial carcinoma with the BRAF V595E mutation. This ctDNA analysis may be a potentially useful tool for monitoring the progression of urothelial carcinoma and its response to treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232365PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182225PMC
July 2020

Oral Care Evaluation to Prevent Oral Mucositis in Estrogen Receptor-Positive Metastatic Breast Cancer Patients Treated with Everolimus (Oral Care-BC): A Randomized Controlled Phase III Trial.

Oncologist 2020 02 8;25(2):e223-e230. Epub 2019 Oct 8.

Department of Dentistry and Oral and Maxillofacial Surgery, Tokai University School of Medicine, Tokyo, Japan.

Background: The incidence of oral mucositis (any grade) after everolimus treatment is 58% in the general population and 81% in Asian patients. This study hypothesized that professional oral care (POC) before everolimus treatment could reduce the incidence of everolimus-induced oral mucositis.

Materials And Methods: This randomized, multicenter, open-label, phase III study evaluated the efficacy of POC in preventing everolimus-induced mucositis. Patients were randomized into POC and control groups (1:1 ratio) and received everolimus with exemestane. Patients in the POC group underwent teeth surface cleaning, scaling, and tongue cleaning before everolimus initiation and continued to receive weekly POC throughout the 8-week treatment period. Patients in the control group brushed their own teeth and gargled with 0.9% sodium chloride solution or water. The primary endpoint was the incidence of all grades of oral mucositis. We targeted acquisition of 200 patients with a 2-sided type I error rate of 5% and 80% power to detect 25% risk reduction.

Results: Between March 2015 and December 2017, we enrolled 175 women from 31 institutions, of which five did not receive the protocol treatment and were excluded. Over the 8 weeks, the incidence of grade 1 oral mucositis was significantly different between the POC group (76.5%, 62 of 82 patients) and control group (89.7%, 78 of 87 patients; p = .034). The incidence of grade 2 (severe) oral mucositis was also significantly different between the POC group (34.6%, 28 of 82 patients) and control group (54%, 47 of 87 patients; p = .015). As a result of oral mucositis, 18 (22.0%) patients in the POC group and 28 (32.2%) in the control group had to undergo everolimus dose reduction.

Conclusion: POC reduced the incidence and severity of oral mucositis in patients receiving everolimus and exemestane. This might be considered as a treatment option of oral care for patients undergoing this treatment. Clinical trial identification number: NCT02069093.

Implications For Practice: The Oral Care-BC trial that prophylactically used professional oral care (POC), available worldwide, did not show a greater than 25% difference in mucositis. The 12% difference in grade 1 or higher mucositis and especially the ∼20% difference in grade 2 mucositis are likely clinically meaningful to patients. POC before treatment should be considered as a treatment option of oral care for postmenopausal patients who are receiving everolimus and exemestane for treatment of hormone receptor-positive, HER2-negative advanced breast cancer and metastatic breast cancer. However, POC was not adequate for prophylactic oral mucositis in these patients, and dexamethasone mouthwash prophylaxis is standard treatment before everolimus.
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http://dx.doi.org/10.1634/theoncologist.2019-0382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011665PMC
February 2020

Molecular diagnosis of bovine B-cell lymphoma using polymerase chain reaction for immunoglobulin heavy chain gene.

J Vet Med Sci 2020 Jan 4;82(1):61-63. Epub 2019 Dec 4.

United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan.

We performed a clonality analysis using polymerase chain reaction (PCR) for immunoglobulin heavy chain (IgH) gene rearrangement, specifically with regard to its utility as a method to diagnose bovine B-cell lymphoma. PCR for IgH gene rearrangement indicated monoclonal proliferation of B-cells in 24 of 35 cattle with B-cell lymphoma. In contrast, PCR for IgH gene rearrangement in lymph nodes and tumor tissues from 65 cattle diagnosed with tumors other than B-cell lymphoma and non-tumors revealed polyclonal population of B-cells. Sensitivity, specificity, positive predictive value, and negative predictive value for PCR for IgH gene rearrangement for bovine B-cell lymphoma were 68.6%, 100%, 100%, and 85.5%, respectively. Clonality analysis using PCR for IgH gene rearrangement may be useful for adjunctive diagnosis of bovine B-cell lymphoma.
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http://dx.doi.org/10.1292/jvms.19-0418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983668PMC
January 2020

Oral Care Evaluation to Prevent Oral Mucositis in Estrogen Receptor-Positive Metastatic Breast Cancer Patients Treated with Everolimus (Oral Care-BC): A Randomized Controlled Phase III Trial.

Oncologist 2019 Oct 8. Epub 2019 Oct 8.

Department of Dentistry and Oral and Maxillofacial Surgery, Tokai University School of Medicine, Tokyo, Japan.

Background: The incidence of oral mucositis (any grade) after everolimus treatment is 58% in the general population and 81% in Asian patients. This study hypothesized that professional oral care (POC) before everolimus treatment could reduce the incidence of everolimus-induced oral mucositis.

Materials And Methods: This randomized, multicenter, open-label, phase III study evaluated the efficacy of POC in preventing everolimus-induced mucositis. Patients were randomized into POC and control groups (1:1 ratio) and received everolimus with exemestane. Patients in the POC group underwent teeth surface cleaning, scaling, and tongue cleaning before everolimus initiation and continued to receive weekly POC throughout the 8-week treatment period. Patients in the control group brushed their own teeth and gargled with 0.9% sodium chloride solution or water. The primary endpoint was the incidence of all grades of oral mucositis. We targeted acquisition of 200 patients with a 2-sided type I error rate of 5% and 80% power to detect 25% risk reduction.

Results: Between March 2015 and December 2017, we enrolled 175 women from 31 institutions, of which five did not receive the protocol treatment and were excluded. Over the 8 weeks, the incidence of grade 1 oral mucositis was significantly different between the POC group (76.5%, 62 of 82 patients) and control group (89.7%, 78 of 87 patients; = .034). The incidence of grade 2 (severe) oral mucositis was also significantly different between the POC group (34.6%, 28 of 82 patients) and control group (54%, 47 of 87 patients; = .015). As a result of oral mucositis, 18 (22.0%) patients in the POC group and 28 (32.2%) in the control group had to undergo everolimus dose reduction.

Conclusion: POC reduced the incidence and severity of oral mucositis in patients receiving everolimus and exemestane. This might be considered as a treatment option of oral care for patients undergoing this treatment. : NCT02069093.

Implications For Practice: The Oral Care-BC trial that prophylactically used professional oral care (POC), available worldwide, did not show a greater than 25% difference in mucositis. The 12% difference in grade 1 or higher mucositis and especially the ∼20% difference in grade 2 mucositis are likely clinically meaningful to patients. POC before treatment should be considered as a treatment option of oral care for postmenopausal patients who are receiving everolimus and exemestane for treatment of hormone receptor-positive, HER2-negative advanced breast cancer and metastatic breast cancer. However, POC was not adequate for prophylactic oral mucositis in these patients, and dexamethasone mouthwash prophylaxis is standard treatment before everolimus.
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http://dx.doi.org/10.1634/theoncologist.2019-0382DOI Listing
October 2019

Disseminated thymic B-cell lymphoma in a Holstein heifer.

J Vet Diagn Invest 2019 Nov 24;31(6):852-855. Epub 2019 Sep 24.

Central Region Veterinary Laboratory, Department of Veterinary Service, Selangor, Malaysia (Hishamunuri).

A 19-mo-old Holstein heifer was inactive and dyspneic. Physical examination revealed wheezing, exophthalmos, a cervical mass, and lymphadenopathy. Cytology of the cervical mass and lymph nodes showed predominantly large atypical lymphocytes. Lactate dehydrogenase and thymidine kinase activities were elevated. Although nested PCR for bovine leukemia virus (BLV) using blood was positive, quantitative PCR showed a low number of provirus copies. Autopsy revealed enlargement of most lymph nodes examined, as well as white masses of various sizes in muscles of the left hindlimb and thoracic and abdominal organs. Histopathology revealed severe infiltration with neoplastic lymphocytes in these organs. The cervical mass was immune-positive for B-cell markers. The final diagnosis was thymic B-cell lymphoma with BLV infection.
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http://dx.doi.org/10.1177/1040638719875501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900721PMC
November 2019

Chronic Inflammatory and Proliferative Lesions of the Gallbladder in Aged Pigs.

Vet Pathol 2020 01 24;57(1):122-131. Epub 2019 Sep 24.

Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.

Primary epithelial tumors of the gallbladder are rarely reported in animals. In this study, 9 aged pigs (6-12 years old) were histopathologically examined for gallbladder proliferative lesions. At necropsy, a large gallstone occupied the lumen of the gallbladder of 3 pigs. Histopathological examination revealed chronic cholecystitis in all 9 pigs, mucosal hyperplasia in 2 pigs, adenoma in 1 pig, and adenocarcinoma in 2 pigs. Bacilli were detected in the gallbladder lumen of 6 pigs by Warthin-Starry stain. Mucosal hyperplasia, adenoma, and adenocarcinoma were characterized by papillary projections of the mucosa with occasional acinar structures. Tumor invasion of the surrounding tissue was observed in the cases of adenocarcinoma. On Alcian blue and periodic acid-Schiff double-stained sections, the acinar structure of gallbladder mucosa in chronic cholecystitis and mucosal hyperplasia was stained in a mosaic pattern, indicating pyloric gland metaplasia. The results of immunohistochemistry revealed a CD10-positive epithelial brush border and mucin (MUC) 2-positive goblet cells in chronic cholecystitis, adenoma, and adenocarcinomas, indicating intestinal metaplasia. Immunoreactivity of MUC5 AC and cytokeratin 19 was weaker in adenoma and adenocarcinomas compared with the normal and hyperplastic gallbladder mucosa. The number of p53-positive nuclei and the Ki-67 index were higher in adenocarcinomas compared with benign lesions. These results suggest that chronic cholecystitis associated with gallstones and/or bacterial infections may contribute to metaplastic changes and development of gallbladder tumors in aged pigs. Alteration of mucin, cytokeratin, and p53 profiles in gallbladder proliferative lesions in pigs were similar to that in humans, suggesting a common pathogenesis in tumor development.
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http://dx.doi.org/10.1177/0300985819875749DOI Listing
January 2020

Distinct gene expression profiles between primary breast cancers and brain metastases from pair-matched samples.

Sci Rep 2019 09 16;9(1):13343. Epub 2019 Sep 16.

Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Sixteen pair-matched samples from primary breast cancers and brain metastases diagnosed were collected from the Japan Clinical Oncology Group Breast Cancer Study Group. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Potential therapeutic target genes of 41 FDA-approved or under-investigation agents for brain metastases were explored. Immune-related signatures exhibited significantly lower gene expression in brain metastases than in primary breast cancers. No significant differences were detected for the majority of genes associated with brain metastases and EMT in the two groups. Among 41 therapeutic target candidates, VEGFA and DNMT3A demonstrated significantly higher gene expression in brain metastases. We found that distinct patterns of gene expression exist between primary breast cancers and brain metastases. Further studies are needed to explore whether these distinct expression profiles derive from or underlie disease status and compare these features between metastases to the brain and other sites.
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http://dx.doi.org/10.1038/s41598-019-50099-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746866PMC
September 2019

Endarterectomy Using the Lateral Approach with an Ultrasonic Surgical Aspirator Device for Heavily Calcified Peripheral Arterial Occlusive Disease.

Ann Vasc Dis 2019 Jun;12(2):216-221

Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

: To present a new and easy technique for performing endarterectomy in patients with peripheral arterial occlusive disease (PAD) having dollop calcification at the common femoral artery (CFA). : We developed a procedure for angioplasty for PAD using a supersonic surgical suction device, based on the new concept of "to create a new lumen to dig tunnel in calcification." Ultrasonic surgical aspiration device was inserted into the intravascular space from outside the area of the target lesion and only internal calcification was removed. : We performed this technique in three patients who had PAD with dollop calcification at CFA. We succeeded in performing endarterectomy easily and safely. This method does not require vascular wall closure suture at calcified lesion or intimal fixation suture of dollop calcification. : We address the technical difficulty in treating highly calcified lesions that could not be dealt with conventional endarterectomy. Our new method is one of the options for revascularization of heavily calcified lesions.
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http://dx.doi.org/10.3400/avd.oa.19-00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600106PMC
June 2019

Polyradiculoneuropathy in dourine-affected horses.

Neuromuscul Disord 2019 06 18;29(6):437-443. Epub 2019 Mar 18.

Research Center for Global Agromedicine, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11, Inada-cho, Obihiro, Hokkaido 080-8555, Japan.

Dourine is an equine protozoan disease caused by Trypanosoma equiperdum. Dourine-afflicted animals die after developing neurological clinical signs, such as unilateral paresis. The disease has been a problem for many years; however, the pathogenesis regarding the neurological clinical signs of dourine has been unclear. In the present study, we conducted a histopathological examination in order to investigate the mechanisms by which dourine-afflicted horses develop the accompanying neurological clinical signs. Four dourine-afflicted horses in Mongolia were evaluated. An apparently healthy horse exhibited multifocal neuritis without axonal or myelin degeneration. The other horses, which had obvious neurological clinical signs, also exhibited multifocal neuritis. In particular, the nerves that innervated areas associated with neurological clinical signs exhibited neuritis with demyelination in the latter horses. Inflamed, non-demyelinating nerves were infiltrated with B lymphocytes and T lymphocytes; while inflamed, demyelinating nerves were infiltrated with mononuclear phagocytes. Our observations revealed lesion progression in the nerves, such that polyradiculoneuropathy could explain the accompanying neurological clinical signs of dourine. To our knowledge, this is the first report to describe a pathogenic mechanism for the development of the neurological clinical signs found in dourine-afflicted horses.
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http://dx.doi.org/10.1016/j.nmd.2019.03.005DOI Listing
June 2019

Thrombectomy and reconstruction of the left vertebral artery after total arch replacement: never give up on postoperative stroke.

Gen Thorac Cardiovasc Surg 2020 May 14;68(5):534-537. Epub 2019 Mar 14.

Department of Thoracic and Cardiovascular Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.

The patient was a 64-year-old man who had aortic regurgitation, ischemic heart disease, a transverse aortic aneurysm, and an abdominal-common iliac aneurysm. Concomitant operations including aortic valve replacement, coronary artery bypass grafting, and total aortic arch replacement with elephant trunk technique were performed successfully. The patient developed postoperative cardiac tamponade on the 5th postoperative day, resulting in bulbar palsy due to occlusion of the dominant left vertebral artery. Thrombectomy of the vertebral artery with reconstruction by a saphenous vein was performed. The patient's neurological symptoms improved after the operation. Revascularization of ischemic stroke may yield neurological improvement even in patients after cardiovascular surgery.
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http://dx.doi.org/10.1007/s11748-019-01106-6DOI Listing
May 2020

Coinfection of a lingual lesion with bovine papular stomatitis virus and bovine papillomavirus.

Arch Virol 2019 May 7;164(5):1441-1444. Epub 2019 Mar 7.

Department of Veterinary Medical Science, Shandong Vocational Animal Science and Veterinary College, Weifang, 261061, China.

To date, there have been no reports of coinfection with bovine papular stomatitis virus (BPSV) and bovine papillomavirus (BPV) in the same lesion. In the present study, one lingual papilloma-like sample was collected at an abattoir from the tongue of a 31-month-old Japanese black cow. Coinfection with BPSV and BPV was confirmed by histopathology, immunohistochemistry, PCR and RT-PCR. The evidence for coinfection with BPSV and BPV in the same lesion and an association of BPV with lingual papillomatosis will contribute to future epidemiological studies of these two viruses.
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http://dx.doi.org/10.1007/s00705-019-04199-9DOI Listing
May 2019

Rhinocerebral Zygomycosis Due to a Lichtheimia ramosa Infection in a Calf: Neural Spread Through the Olfactory Nerves.

Mycopathologia 2019 Feb 30;184(1):141-146. Epub 2018 Aug 30.

Research Center for Global Agromedicine, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11, Obihiro-Shi, Hokkaido, 080-8555, Japan.

Here, we report a case of rhinocerebral zygomycosis due to a Lichtheimia ramosa infection in a calf. A histopathological examination revealed that a fungus had invaded the brain through the olfactory nerves. Lichtheimia ramosa was detected by polymerase chain reaction analysis of DNA extracted from formalin-fixed paraffin-embedded samples of the affected tissue. This is the first case of rhinocerebral zygomycosis to involve cattle. Also, this is the first such case to involve fungal invasion into the central nervous system through the cranial nerve itself, rather than through perineural tissue.
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http://dx.doi.org/10.1007/s11046-018-0296-zDOI Listing
February 2019

Histopathological study of encephalomalacia in neonatal calves and application of neuronal and axonal degeneration marker.

J Vet Med Sci 2018 Jul 4;80(7):1116-1124. Epub 2018 May 4.

Laboratory of Veterinary Pathology, Department of Basic Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan.

Five calves that had shown neurological symptoms within 9 days after birth were histopathologically diagnosed as encephalomalacia. Two calves showed bilateral laminar cerebrocortical necrosis and neuronal necrosis in the corpus striatum and hippocampus. Since the distributional pattern of the lesions was consistent with that of global ischemia in other species, the lesions were probably hypoxic/ischemic encephalopathy consistent with the history of dystocia and perinatal asphyxia. One calf also showed bilateral laminar cerebrocortical necrosis. However, the lesions were chronic ones, because the calf had survived for long time and necropsied at postnatal day 118. Additionally, the lesions did not involve the corpus striatum and hippocampus. The other two calves showed multifocal necrosis with vascular lesions characterized by fibrin thrombi, perivascular edema and perivascular hyaline droplets in the cerebral cortex, corpus striatum, thalamus, brain stem and cerebellum. Considering the age of onsets and histopathological appearance, it was possible that latter three calves were also hypoxic/ischemic encephalopathy, however, exact cause of them was not revealed. In all calves, degenerated/necrotic neurons showed positive reactions for Fluoro-Jade C and degenerated axons showed immunoreactivity for Alzheimer precursor protein A4. Therefore, these markers were applicable to examination of brain injury in neonatal calves.
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http://dx.doi.org/10.1292/jvms.18-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068296PMC
July 2018

Bi-weekly eribulin therapy for metastatic breast cancer: a multicenter phase II prospective study (JUST-STUDY).

Breast Cancer 2018 Jul 12;25(4):438-446. Epub 2018 Feb 12.

Department of Surgery, Breast Oncology, NHO Osaka National Hospital, Chu-ouku Hoenzaka 2-1-14, Osaka-shi, Osaka, Japan.

Background: This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule.

Methods: Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated.

Results: Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events.

Conclusion: This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule.

Clinical Trial Registration: University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491).
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http://dx.doi.org/10.1007/s12282-018-0843-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996009PMC
July 2018

Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer.

Oncotarget 2017 Nov 27;8(61):103671-103681. Epub 2017 Oct 27.

Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Background: Immune checkpoint inhibitors are reported to be effective in patients with brain metastases. However, detailed characteristics of the brain metastasis immune microenvironment remain unexplored.

Results: The median tumor-infiltrating lymphocyte (TIL) category in brain metastases was 5% (1-70%). In 46 pair-matched samples, the percentages of TILs were significantly higher in primary breast tumors than in brain metastases (paired t-test, < 0.01). The numbers of CD4/CD8/Foxp3-positive cells were significantly higher in primary breast tumors than in brain metastases (paired -test, < 0.05 for all antibodies). In patients with triple-negative breast cancer specifically, low TIL numbers were associated with significantly shorter overall survival compared to high TIL numbers (log-rank test, = 0.04).

Materials And Methods: We retrospectively identified 107 patients with breast cancer and brain metastases who had undergone surgery between 2001 and 2012 at 8 institutions, and collected 191 samples including brain metastases alone and primary tumors with pair-matched brain metastasis samples. Hematoxylin and eosin-stained slides were evaluated for TILs and categorized according to the extent of staining. Immunohistochemistry for CD4, CD8, Foxp3, PD-L1, PD-L2, and HLA class I was also performed.

Conclusions: There are significantly fewer TILs in brain metastases than in primary breast tumors.
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http://dx.doi.org/10.18632/oncotarget.22110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732758PMC
November 2017

Variation of amino acid sequences of serum amyloid a (SAA) and immunohistochemical analysis of amyloid a (AA) in Japanese domestic cats.

J Vet Med Sci 2018 Feb 4;80(1):164-172. Epub 2017 Dec 4.

Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences. The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.

Amyloid A (AA) amyloidosis, a fatal systemic amyloid disease, occurs secondary to chronic inflammatory conditions in humans. Although persistently elevated serum amyloid A (SAA) levels are required for its pathogenesis, not all individuals with chronic inflammation necessarily develop AA amyloidosis. Furthermore, many diseases in cats are associated with the elevated production of SAA, whereas only a small number actually develop AA amyloidosis. We hypothesized that a genetic mutation in the SAA gene may strongly contribute to the pathogenesis of feline AA amyloidosis. In the present study, genomic DNA from four Japanese domestic cats (JDCs) with AA amyloidosis and from five without amyloidosis was analyzed using polymerase chain reaction (PCR) amplification and direct sequencing. We identified the novel variation combination of 45R-51A in the deduced amino acid sequences of four JDCs with amyloidosis and five without. However, there was no relationship between amino acid variations and the distribution of AA amyloid deposits, indicating that differences in SAA sequences do not contribute to the pathogenesis of AA amyloidosis. Immunohistochemical analysis using antisera against the three different parts of the feline SAA protein-i.e., the N-terminal, central, and C-terminal regions-revealed that feline AA contained the C-terminus, unlike human AA. These results indicate that the cleavage and degradation of the C-terminus are not essential for amyloid fibril formation in JDCs.
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http://dx.doi.org/10.1292/jvms.17-0447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797877PMC
February 2018

Clinical and bacteriological differences of deep neck infection in pediatric and adult patients: Review of 123 cases.

Int J Pediatr Otorhinolaryngol 2017 Aug 5;99:95-99. Epub 2017 Jun 5.

Department of Otolaryngology - Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Objectives: Deep neck infections (DNIs) can lead to life-threatening disease. However, the detailed pathophysiology remains unclear due to its rarity and only a few reports have directly compared DNIs in children and adults. This study aimed to reveal the clinical differences between DNIs in children and adults.

Methods: We retrospectively reviewed 123 patients who suffered from DNIs at Tohoku University Hospital from August 2005 to July 2015. We extracted data on patient sex, age, antecedent illness, extension of infections, operative procedures, and bacteriology results. The patients were categorized into pediatric (≤18 years) and adult (>18 years) groups. Fisher's exact test was performed to determine significant differences between the two groups.

Results: Fifteen children (6 males and 9 females) and 108 adults (71 males and 37 females) were identified. The most common antecedent illness in pediatric patients was lymphadenitis, which was the least common in adult patients (73% vs 7%, p < 0.0001). The incidence of DNIs extending below the hyoid bone was significantly lower in pediatric patients than in adult patients (20% vs 53%, p < 0.05). Regarding bacterial culture analysis, Staphylococcus species was the most common pathogen in children (60%), whereas only 9% of adults were positive for Staphylococcus (p < 0.001). Streptococcus species were significantly less common in children than in adults (27% vs 56%, p = 0.05). Anaerobes were also significantly less common in children than in adults (13% vs 45%, p < 0.01). Concerning surgical intervention, 53% of pediatric patients underwent external incision compared with 70% of adults. Specifically, tracheostomy was significantly less frequently performed in children than in adults (7% vs 54%, p < 0.01).

Conclusion: DNIs in children feature different characteristics from those in adults regarding severity, antecedent illness, bacteriology, and clinical management.
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http://dx.doi.org/10.1016/j.ijporl.2017.05.028DOI Listing
August 2017

The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC).

Breast Cancer 2018 Jan 9;25(1):34-42. Epub 2017 May 9.

Department of Breast Surgery, National Hospital Organization (NHO) Hokkaido Cancer Center, 4-2 Kikusui, Shiroishi-ku, Sapporo, 003-0804, Japan.

Background: The status of tumor-infiltrating lymphocytes (TILs) is a prognostic factor for triple negative breast cancer (TNBC). Recent studies have shown that programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) is expressed on T lymphocytes or tumor cells modulating antitumor immunity. The regulation of immune checkpoints between tumor cells and T lymphocytes may serve as a target for improvement of TNBC prognosis. We investigated TILs and PD-L1 status in TNBCs before or after preoperative systemic therapy (PST) to elucidate the clinical significance of PD-L1 expression.

Methods: Ninety patients received PST, and materials of core needle biopsies (CNB) taken before PST were available for 32 patients. TILs were scored as "% stromal", and tumors were defined as High-TILs (≥30%) or Low-TILs (<30%). The expression of PD-L1 was assessed by immunohistochemistry.

Results: TILs status in CNB is significant in pathological therapeutic grade: 1 vs. 2 or 3 (p = 0.0359). Disease-free survival (DFS) in patients with Low-TIL tumors were significantly worse than those with High-TIL tumors (p = 0.0383), but overall survival (OS) showed no significance (p = 0.0772). However, in patients with Low-TIL tumors, both DFS and OS in patients with High-PD-L1 expression were extremely unfavorable than in patients with Low-PD-L1 expression (p = 0.0032, p = 0.0002).

Conclusion: The patients with TNBCs with combined Low-TILs and High-PD-L1 status in pre-PST situation showed unfavorable prognosis. The subset of TNBCs with Low-TILs and High-PD-L1 status could be the therapeutic target for immune checkpoint inhibitor.
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http://dx.doi.org/10.1007/s12282-017-0781-0DOI Listing
January 2018

A cutaneous mixed tumor in a dog.

J Vet Med Sci 2017 Mar 28;79(3):670-673. Epub 2017 Jan 28.

Department of Veterinary Medicine, Research Center for Global Agromedicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-0834, Japan.

The atypical cutaneous tumor of a 9-year-old mixed breed female dog was examined. The tumor was well-demarcated and histologically composed of a trichoblastic area, tricholemmal area and apocrine glandular area. Neoplastic cells in trichoblastic area and tricholemmal area had PAS-positive granules in the cytoplasm and were positive for pan-cytokeratin, cytokeratin 5/6, 14 and 19 and p63. Neoplastic cells in trichoblastic area were also positive for cytokeratin 15 and CD34. Neoplastic cells in apocrine glandular area were positive for pan-cytokeratin and cytokeratin 7, 18 and 19. Myoepithelial cell proliferation with osteocartilaginous metaplasia was observed in this area. Since neoplastic cells showed multiphenotypic differentiation for hair follicles and apocrine glands, the present case was diagnosed as a cutaneous mixed tumor.
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http://dx.doi.org/10.1292/jvms.16-0610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383195PMC
March 2017