Yukino Machida

A 10-year-old spayed mixed breed dog presented with severe neurological signs. Computed tomography revealed a cranial mediastinal mass, osteolysis of the right second rib and second thoracic vertebra, tracheobronchial and mesenteric lymph node enlargement, pneumonia and pleural effusion. Magnetic resonance imaging detected lesions in the white matter of the right frontal lobe and left cerebral hemisphere with contrast-enhanced T1-weighted images showing demarcated enhancement. On cut section, the surface of the right cerebral frontal lobe and left cerebral hemisphere corticomedullary junctions were indistinct and the white matter was discoloured. Microscopically, multicentric granulomatous inflammation was seen in the brain, cranial mediastinal mass, masses on the right second rib, tracheobronchial and mesenteric lymph nodes, heart, kidneys, lungs and oesophagus. Necrosis and hyaline fungal structures were frequently observed in the centre of the granulomas. These fungi had septae, Y-shaped branching and were 2-3 μm in width. Sequence analysis of DNA from formalin-fixed paraffin-embedded samples identified the fungi as Schizophyllum commune. Based on these findings, this case was diagnosed as disseminated S. commune infection. This is the first report of granulomatous encephalitis caused by S. commune in a dog.

A 16-year-old male mixed-breed dog presented with a mass with hemorrhage at the right conjunctiva. Five months after the initial visit, the right eye protruded and had a firm and irregular mass measuring approximately 1.00 cm in diameter with conjunctival hemorrhage. Microscopically, the mass was comprised polygonal or round tumor cells with distinct cell borders arranged in a nested and diffuse pattern. The tumor cells had round-to-oval fine hyperchromatic nuclei containing distinct multiple nucleoli and abundant eosinophilic or pale cytoplasm. Multiple giant cells were frequently observed. The mitotic index was 12.60/high power field. Extensive necrosis, hemorrhage and part of the cord-like and papillary epithelioid cells were observed in the intra-tumor tissue. Immunohistochemically, the tumor cells were positive for vimentin and α-smooth muscle actin and negative for cytokeratin, desmin and PNL2. On the other hand, the cord-like and papillary epithelioid cells were positive for vimentin, S100 and neuron-specific enolase. The tumor was diagnosed as an epithelioid leiomyosarcoma. This case considered to have occurred in the ocular region, although the ocular structure was destroyed.

The chromatin-associated AAA+ ATPases Tip48 and Tip49 are the core components of various complexes implicated in diverse nuclear events such as DNA repair and gene regulation. Although they are frequently overexpressed in many human cancers, their functional significance remains unclear. Here, we show that loss of Tip49 triggered p53-dependent apoptosis and inhibited leukemia development in vivo. To examine the impact of chemical inhibition of this complex on leukemia, we have developed the novel compound DS-4950, which interferes with the ATPase activity of the Tip48/49. Administration of DS-4950 was well-tolerated in healthy mice, and the drug effectively reduced tumor burden and improved survival. We also provide evidence that the dependency on Tip48/49 is widely conserved in non-hematologic malignancies with wild type p53. These results demonstrated that the Tip48/49 ATPases are functionally necessary and therapeutically targetable for the treatment of human cancers.

Abstract Patient-derived xenograft (PDX) tumor models are known to maintain the genomic and phenotypic profiles, including the histopathological structures, of the parental tumors. On the other hand, unique enrichment of single-nucleotide variants or copy number aberrations has been reported in several types of tumors. However, an understanding of endometrial carcinoma PDXs is limited. The purpose of the present study was to clarify the presence or absence of the molecular properties of endometrial carcinomas in PDXs passaged up to eight times. Established PDXs of endometrioid carcinomas maintained their histopathological characteristics, but those of carcinosarcomas predominantly consisted of sarcomatous components when compared to the parental tumors. Alterations in the proportion of cells with positive/negative immunohistochemical staining for estrogen receptor, PTEN, PAX8, and PAX2 were observed, whereas the proportions of cells with AE1/AE3, TP53, ARID1A, PMS2, and MSH6 staining were unchanged. Variants of cancer-associated genes were compared between PDXs and parental tumors. Mutations in POLE and a frameshift deletion in BRCA1 were observed in the parental tumor tissue in each of the six cases, and additional genomic alterations, which were not apparently related to histopathological and immunohistochemical alterations, were found in the PDXs of these cases. The genomic and phenotypic alterations observed between endometrial carcinoma PDXs and parental tumors were partly associated with endometrial cancer-specific characteristics related to cellular differentiation and gene mutations.