Wild-type and innate immune-deficient mice are not susceptible to the Middle East respiratory syndrome coronavirus.

The Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging highly pathogenic virus causing almost 50 % lethality in infected individuals. The development of a small-animal model is critical for the understanding of this virus and to aid in development of countermeasures against MERS-CoV. We found that BALB/c, 129/SvEv and 129/SvEv STAT1 knockout mice are not permissive to MERS-CoV infection. The lack of infection may be due to the low level of mRNA and protein for the MERS-CoV receptor, dipeptidyl peptidase 4 (DPP4), in the lungs of mice. The low level of DPP4 in the lungs likely contributes to the lack of viral replication in these mouse models and suggests that a transgenic mouse model expressing DPP4 to higher levels is necessary to create a mouse model for MERS-CoV.

Induction of alternatively activated macrophages enhances pathogenesis during severe acute respiratory syndrome coronavirus infection.

Infection with severe acute respiratory syndrome coronavirus (SARS-CoV) causes acute lung injury (ALI) that often leads to severe lung disease. A mouse model of acute SARS-CoV infection has been helpful in understanding the host response to infection; however, there are still unanswered questions concerning SARS-CoV pathogenesis. We have shown that STAT1 plays an important role in the severity of SARS-CoV pathogenesis and that it is independent of the role of STAT1 in interferon signaling. Mice lacking STAT1 have greater weight loss, severe lung pathology with pre-pulmonary-fibrosis-like lesions, and an altered immune response following infection with SARS-CoV. We hypothesized that STAT1 plays a role in the polarization of the immune response, specifically in macrophages, resulting in a worsened outcome. To test this, we created bone marrow chimeras and cell-type-specific knockouts of STAT1 to identify which cell type(s) is critical to protection from severe lung disease after SARS-CoV infection. Bone marrow chimera experiments demonstrated that hematopoietic cells are responsible for the pathogenesis in STAT1(-/-) mice, and because of an induction of alternatively activated (AA) macrophages after infection, we hypothesized that the AA macrophages were critical for disease severity. Mice with STAT1 in either monocytes and macrophages (LysM/STAT1) or ciliated lung epithelial cells (FoxJ1/STAT1) deleted were created. Following infection, LysM/STAT1 mice display severe lung pathology, while FoxJ1/STAT1 mice display normal lung pathology. We hypothesized that AA macrophages were responsible for this STAT1-dependent pathology and therefore created STAT1/STAT6(-/-) double-knockout mice. STAT6 is essential for the development of AA macrophages. Infection of the double-knockout mice displayed a lack of lung disease and prefibrotic lesions, suggesting that AA macrophage production may be the cause of STAT1-dependent lung disease. We propose that the control of AA macrophages by STAT1 is critical to regulating immune pathologies and for protection from long-term progression to fibrotic lung disease in a mouse model of SARS-CoV infection.

Postmenopausal mixed gestational trophoblastic neoplasia with complete response to immunotherapy - A case report.

•Mixed GTN.•GTN in a post-menopausal woman.•Treatment of GTN with immunotherapy.

Case Report: Collision Tumour of Colon Leiomyosarcoma and Adenocarcinoma.

The colon is an exceedingly rare site of primary leiomyosarcoma and only a few cases have been published to date. Of the reported cases of collision tumours, collision tumours that specifically occurred in the colon have consisted of combinations of adenoma or adenocarcinoma with lymphomas or neuroendocrine tumours. Here, not only do we report a case of colon leiomyosarcoma, but we report, what is to our knowledge, the first case of collision tumour consisting of colon leiomyosarcoma and adenocarcinoma. Cause, prognosis, and treatment of colon collision tumours vary and are yet to be understood.

Biliary stent-related alterations can be distinguished from adenocarcinoma on bile duct brushings using a limited number of cytologic features.

INTRODUCTION: Although it is widely accepted that cytologic alterations secondary to a biliary stent can be difficult to distinguish from adenocarcinoma in pancreatobiliary exfoliative cytology, no systematic study has been undertaken to identify the cytologic features that best distinguish these entities. MATERIALS AND METHODS: A training set of 29 bile duct brushings (14 with biliary stents, originally classified as atypical or suspicious, with >6 months of benign clinical follow-up; and 15 diagnosed as adenocarcinoma with histologic confirmation) was evaluated for the following: nuclear enlargement, nuclear contour, nuclear overlap, chromatin distribution, nuclear-cytoplasmic ratio, anisonucleosis, macronucleoli, mitoses, acute inflammation, disorganization, necrosis, cell borders, single atypical cells, and 2 distinct cell populations. A distinct validation set of 31 equivocal stented brushings-13 later diagnosed with carcinoma and 18 with ≥6 months of benign follow-up-were similarly evaluated. Cases were categorized as benign or malignant using a scoring algorithm based on statistically significant features. RESULTS: Five features achieved statistical significance: atypical single cells (P = 0.0001), 2 distinct cell populations (P = 0.0007), and anisonucleosis (P = 0.0422) favored malignancy; distinct cell borders (P = 0.0018) and acute inflammation (P = 0.0035) favored benign. The algorithm correctly classified 12 of 14 benign and 15 of 15 malignant cases in the training set and 16 of 18 benign and 7 of 13 malignant cases in the validation set. CONCLUSIONS: Most bile duct brushings from patients with biliary stents could be definitively and correctly classified as either benign or malignant using 5 morphologic features: single atypical cells, binary cell population, anisonucleosis, distinct cell borders, and acute inflammation.

Lymphoepithelioma-like carcinoma of the breast presenting as breast abscess.

Lymphoepithelioma-like carcinoma (LELC) is a rare type of neoplasm in which only twenty cases have been reported in the breast. This type of tumor can be difficult to distinguish from other breast tumors particularly medullary carcinoma and lymphoma in the breast. We present a case of LELC of the breast presenting as an abscess along with a review of the literature. This is the 21(st) reported case of LELC of the breast and the first case to present as an abscess. Her clinical picture could have been mistaken for other infectious or inflammatory diseases. Given the potential for favorable outcome, early detection and general knowledge of this neoplasm are essential to expedite treatment for this rare tumor type.

Automated quantification of Ki-67 proliferative index of excised neuroendocrine tumors of the lung.

BACKGROUND: The histopathologic distinction between typical carcinoid (TC) and atypical carcinoid (AC) of the lung is based largely on mitotic index. Ki-67 may aid in separation of these tumors, as well as the distinction from large cell neuroendocrine carcinoma (LCNEC). METHODS: We identified 55 surgically resected primary neuroendocrine lung tumors (39 TC, 7 AC, 9 LCNEC) based on mitotic rate and histologic features. Ki-67 proliferative index based on automated image analysis, tumor necrosis, nodal metastases, local or distant recurrence, and survival were compared across groups. RESULTS: The mean mitotic count and Ki-67 index for TC, AC, and LCNEC were 0.1 and 2.3%, 3.4 and 16.8%, and 56.1 and 81.3% respectively. The Ki-67 index did not overlap among groups, with ranges of 0-6.7% for TC, 9.9-25.7% for AC, and 63.2-91.9% for LCNEC. Nodal metastases were identified in 4/39 (10%) TC, 2/7 (22%) AC, and 2/8 (25%) LCNEC. There was no survival difference between TC and AC, but there was a significant survival difference between LCNEC and TC and AC combined (p<0.001). There was a step-wise increase in disease free survival with tumor grade: no TC recurred, 2/7 AC recurred or progressed (median interval 35.5 months), and all LCNEC recurred or progressed (median interval 10.1 months). No patient with TC or AC died of disease, compared to 7/8 LCNEC with follow-up data. CONCLUSIONS: We conclude that Ki-67 index is a useful diagnostic marker for neuroendocrine tumors, with 7% a divider between AC and TC, and 50% a divider between LCNEC and AC. LCNEC is biologically different from AC and TC, with a much more aggressive course, and a high Ki-67 index. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_174.