Oligodendroglioma with Neuronal Differentiation in Two Boxer Dogs.

Two cases of high-grade glioma comprising sheets of oligodendroglial cells multifocally disrupted by regions of remarkable neuronal differentiation are described. These tumours morphologically resemble 'oligodendroglioma with ganglioglioma-like maturation', a rare tumour of man, but appear to be phenotypically more aggressive. Neuronal markers (synaptophysin, neuron-specific enolase and ßIII-tubulin) effectively highlight neuronal elements within these tumours and could potentially help to further investigate the prevalence and biological significance of neuronal differentiation in canine oligodendroglioma.

Fatty acid synthase as a potential therapeutic target in feline oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is an aggressive and treatment-resistant malignancy in both feline and human patients. Recent work has demonstrated aberrant expression of fatty acid synthase (FASN) and an increased capacity for lipogenesis in human OSCC and other cancers. In human OSCC, inhibition of FASN decreased cell viability and growth in vitro, and diminished tumour growth and metastasis in murine preclinical models. This study aimed to characterize FASN as a therapeutic target in feline OSCC. Immunohistochemistry revealed high FASN expression in primary feline OSCC tumours, and FASN expression was detected in OSCC cell lines (3 feline and 3 human) by immunoblotting and quantitative real-time-polymerase chain reaction (qRT-PCR). Orlistat, a FASN inhibitor, substantially reduced cell viability in both feline and human OSCC lines, although feline cell lines consistently displayed higher sensitivity to the drug. FASN mRNA expression among cell lines mirrored sensitivity to orlistat, with feline cell lines expressing higher levels of FASN. Consistent with this observation, diminished sensitivity to orlistat treatment and decreased FASN mRNA expression were observed in feline OSCC cells following incubation under hypoxic conditions. Treatment with orlistat did not potentiate sensitivity to carboplatin in the cell lines investigated; instead, combinations of the 2 drugs resulted in additive to antagonistic effects. Our results suggest that FASN inhibition is a viable therapeutic target for feline OSCC. Furthermore, cats may serve as a spontaneous large animal model for human oral cancer, although differences in the regulation of lipogenesis between these 2 species require further investigation.

CFTR is a tumor suppressor gene in murine and human intestinal cancer.

This corrects the article DOI: 10.1038/onc.2015.483.

Establishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T-Cell Lymphoma, Large Cell Type.

The pathogenesis of canine T-cell lymphoma remains incompletely understood, partly because there are no well-established in-vivo models to study these malignancies. For this study, we generated a patient-derived tumour xenograft (PDTX) from a 10-year-old neutered male golden retriever dog with enteropathy-associated intestinal T-cell lymphoma, large cell type. One of two female, 15-week-old beige/nude/XID mice developed a visible tumour 7 weeks after sections of tumour material from the spleen were surgically implanted. The histological appearance, immunophenotype and clonal antigen receptor rearrangements of the tumour from the recipient mouse showed that it was derived from the primary canine tumour. Our results indicate that immunodeficient mice are receptive hosts to develop in-vivo PDTX models to study the pathogenesis and management of canine T-cell lymphomas.

CFTR is a tumor suppressor gene in murine and human intestinal cancer.

CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt ß-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival.

The role of KCNQ1 in mouse and human gastrointestinal cancers.

Kcnq1, which encodes for the pore-forming α-subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. To confirm that Kcnq1 has a functional role in GI tract cancer, we created Apc(Min) mice that carried a targeted deletion mutation in Kcnq1. Results demonstrated that Kcnq1 is a tumor suppressor gene as Kcnq1 mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, and some of these tumors progressed to become aggressive adenocarcinomas. Gross tissue abnormalities were also observed in the rectum, pancreas and stomach. Colon organoid formation was significantly increased in organoids created from Kcnq1 mutant mice compared with wild-type littermate controls, suggesting a role for Kcnq1 in the regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of Kcnq1, we carried out microarray studies in the colon and proximal small intestine. We identified altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, epidermal growth factor receptor and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis. To investigate the role of KCNQ1 in human colorectal cancer (CRC), we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival.

Canine intracranial gliomas: relationship between magnetic resonance imaging criteria and tumor type and grade.

Limited information is available to assist in the ante-mortem prediction of tumor type and grade for dogs with primary brain tumors. The objective of the current study was to identify magnetic resonance imaging (MRI) criteria related to the histopathological type and grade of gliomas in dogs. A convenience sample utilizing client-owned dogs (n=31) with gliomas was used. Medical records of dogs with intracranial lesions admitted to two veterinary referral hospitals were reviewed and cases with a complete brain MRI and definitive histopathological diagnosis were retrieved for analysis. Each MRI was independently interpreted by five investigators who were provided with standardized grading instructions and remained blinded to the histopathological diagnosis. Mild to no contrast enhancement, an absence of cystic structures (single or multiple), and a tumor location other than the thalamo-capsular region were independently associated with grade II tumors compared to higher grade tumors. In comparison to oligodendrogliomas, astrocytomas were independently associated with the presence of moderate to extensive peri-tumoral edema, a lack of ventricular distortion, and an isointense or hyper-intense T1W-signal. When clinical and MRI features indicate that a glioma is most likely, certain MRI criteria can be used to inform the level of suspicion for low tumor grade, particularly poor contrast enhancement. Information obtained from the MRI of such dogs can also assist in predicting an astrocytoma or an oligodendroglioma, but no single imaging characteristic allows for a particular tumor type to be ruled out.

Lipopolysaccharide enhances mouse lung tumorigenesis: a model for inflammation-driven lung cancer.

The association between pulmonary inflammation and lung cancer is well established. However, currently there are no appropriate models that recapitulate inflammation-related lung cancer in humans. In the present study, we examined, in 2 tumor bioassays, enhancement by bacterial lipopolysaccharide (LPS) of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice. Mice that were treated with NNK alone developed 29.6 ± 9.8 and 36.2 ± 4.1 lung tumors per mouse in experiments 1 and 2, respectively. Chronic intranasal instillation of LPS to NNK-treated mice increased the multiplicity of lung tumors to 47.3 ± 16.1 and 51.2 ± 4.8 lung tumors per mouse in experiments 1 and 2, corresponding to a significant increase by 60% and 41%, respectively. Moreover, administration of LPS to NNK-pretreated mice significantly increased the multiplicity of larger tumors and histopathologically more advanced lesions (adenoma with dysplasia and adenocarcinoma), macrophage recruitment to the peritumoral area, and expression of inflammation-, cell proliferation-, and survival-related proteins. Overall, our findings demonstrated the promise of the NNK-LPS-A/J mice model to better understand inflammation-driven lung cancer, dissect the molecular pathways involved, and identify more effective preventive and therapeutic agents against lung cancer.

Transitional cell carcinoma of the upper ureter metastatic to the thoracic spine presenting as a spinal cord compression.

We performed a left nephroureterectomy for a gentleman with transitional cell carcinoma of the upper ureter. Histological analysis revealed it to be a T1 lesion, but to be highly mitotically active. The gentleman defaulted on adjuvant therapy and defaulted on follow-up. He represented with symptoms of acute spinal cord compression and magnetic resonance imaging demonstrated a lesion at T6/7. Neurosurgical resection of the lesion showed it to be a metastatic deposit from the ureteric primary. Despite surgical debulking and subsequent radiotherapy to the lesion, the patient died secondary to metastatic complications. This case report is of interest to the surgeon as it demonstrates both the high metastatic potential of upper tract carcinomas and educates the surgeon on the presentation of acute spinal cord compression.

Uterine infarctions in cynomolgus monkeys (Macaca fascicularis).

Uterine infarctions have not been reported in domestic animals, and there are few reports in the human medical literature. In a retrospective study, uterine infarctions were identified in 9 of 323 (2.8%) female cynomolgus monkeys (Macaca fascicularis) necropsied over a 13-year period. The infarctions were grossly visible, after fixation, on the serosal surface of the uterus in 2 monkeys; the remainder were first recognized in histologic sections. Histologically, the lesions consisted of well-demarcated regions of endometrial and myometrial necrosis and of hemorrhage. All affected monkeys had histologic evidence of a previous pregnancy, which included enlarged myometrial vessels with an expanded perivascular matrix. In all monkeys with uterine infarctions, there was clinical evidence of severe systemic illness, which included trauma, diarrhea, hypovolemia, or septicemia. The major pathologic findings in affected monkeys included cutaneous or skeletal muscle necrosis (n = 5), enterocolitis (n = 4), pulmonary edema or diffuse alveolar damage (n = 3), and intestinal amyloidosis (n = 1). Histopathologic evidence of intravascular fibrin thrombi in multiple organs of 5 monkeys was consistent with a diagnosis of disseminated intravascular coagulopathy (DIC). Based on these findings, it appears that uterine infarction is an uncommon finding in cynomolgus monkeys and may occur secondary to a severe systemic illness, predisposing to DIC.

Intracranial tuberculoma -- a diagnostic dilemma.

The characteristics of intracranial tuberculoma on computed tomography (CT) and magnetic resonance imaging (MRI) are not well known. The authors present a patient with an intracranial tuberculoma in whom the diagnosis was confirmed only after surgical excision.

S100beta and nitric oxide product concentrations following cerebral aneurysm clipping in patients with subarachnoid haemorrhage: a pilot study.

OBJECTIVE: The objective of this investigation was to determine the efficacy of S100beta and nitric oxide product (nitrate and nitrite [NOx]) concentrations as markers of brain injury following cerebral aneurysm clipping in patients with spontaneous subarachnoid haemorrhage. METHODS: Fifteen patients with spontaneous subarachnoid haemorrhage were studied. Blood samples were obtained for estimation of serum S100beta (microg/L) and nitric oxide product (nitrate and nitrite [NOx]) (microM) concentrations immediately preoperatively (baseline) and then 10 minutes, 2, 6 and 12 hr postoperatively and daily thereafter for five days. Neurological outcome was assessed three months after surgery by the Glasgow Outcome Scale (GOS) (poor outcome, grade 1 - 3 and good outcome as grade 4 - 5). Data were analysed using the Mann-Whitney-U-test. RESULTS: S100beta concentrations were greater at two hours postoperatively compared to baseline (0.33 +/- 0.16 vs 0.25 +/- 0.04)(P = 0.02). S100beta concentrations were similar in good and poor neurological outcome groups as defined by GOS at three months. NOx concentrations were less at 12 hours postoperatively compared to baseline (9.81 +/- 3.25 vs 12.74 +/- 2.9)(P = 0.03). NOx concentrations were greater on the fourth and fifth postoperative days compared to baseline (t0) (17.22 +/- 7.9, 12.74 +/- 2.9 vs 9.81 +/- 3.25) (P < 0.05). NOx concentrations were greater in patients with a poor neurological outcome (n = 4) compared to the good outcome group (n = 11) (24.7 +/- 4.9 vs. 11.3 +/- 3.3)(P = 0.04). CONCLUSIONS: S100beta and NOx concentrations increase after cerebral aneurysm clipping in patients with spontaneous SAH. Increased nitric oxide product concentrations were associated with subsequent poor neurological outcome.

Intramedullary capillary haemangioma.

Intramedullary capillary haemangioma is extremely rare and only four cases have been previously reported. We describe a further case, outlining the clinical, radiological, surgical and pathological features.

Shoulder tip pain: an under-reported complication of ventriculoperitoneal shunt.

Ventriculoperitoneal (VP) shunt insertion is the commonest form of treatment for hydrocephalus. Shoulder tip pain after VP shunt insertion is unusual and has only recently been reported. We present a case of excruciating shoulder tip pain due to diaphragmatic irritation after VP shunt insertion.

Cranio-orbital approach for complex aneurysmal surgery.

Certain aneurysms of the anterior circulation continue to offer a technical challenge for safe exposure and clipping. The purpose of this paper was to describe the cranio-orbital approach for surgical clipping of complex aneurysms and to evaluate prospectively the associated complications of this approach. Prospective audit of all patients undergoing cranio-orbital approach for aneurysm surgery from 1997 to 2004 by the senior author. Twenty-five patients, eight male and 17 female, median age of 52 years, range 28-73. All patients had a standard pterional approach supplemented by an orbital osteotomy. In the 7-year period 367 patients underwent treatment for their aneurysms (169 clipped and 198 coiled). Of the 169 patients who were operated on, 29 had a skull base approach, of which 25 were cranio-orbital. The aneurysm location was as follows: 16 middle cerebral artery (MCA), three carotid bifurcation, four anterior communicating artery (ACOMM), one ophthalmic and one basilar. There were no approach-related complications. The cranio-orbital craniotomy can be a useful adjunct in the surgical treatment of giant or complex aneurysms. It offers the following advantages over a standard pterional approach: reduces operative distance; allows easy splitting of the sylvian fissure; and provides a wide arc of exposure with multiple working corridors.

Sensory and chemical assessment of pork supplemented with iron and vitamin E.

Pork muscle samples (M. longissimus dorsi and M. psoas major) were obtained from pigs given one of four dietary treatments, (1) control diet, (2) supplemental iron (7g iron (II) sulphate/kg feed), (3) supplemental vitamin E (200 mg dl-α-tocopheryl acetate/kg of feed) and (4) supplemental vitamin E+supplemental iron. Vitamin C was supplemented to all dietary treatments to facilitate iron uptake. Vitamin E and iron tissue levels were determined for each treatment. Warmed-over flavour (WOF) was evaluated by a trained sensory panel (n=8) for the four treatments which were cooked and refrigerated at 4 °C for up to 5 days. Thawing loss, driploss and thiobarbituric acid reactive substances (TBARS) were also determined. Vitamin E muscle tissue levels were greatest in the Iron/vitamin E-treated group followed by the vitamin E group, control and iron treated groups, respectively for M. longissimus dorsi. Whereas, for M. psoas major vitamin E tissue levels were in order of magnitude, vitamin E>iron/vitamin E>iron>control group. Iron tissue levels were in the order vitamin E>iron/vitamin E>control>iron for M. longissimus dorsi and iron>vitamin E>control>iron/vitamin E for M. psoas major. Thus, vitamin E and vitamin C promoted non-supplemental iron absorption in the vitamin E-treated group for M. longissimus dorsi and to a lesser extent for M. psoas major. M. psoas major was more susceptible to warmed-over flavour development than M. longissimus dorsi for all treatments as determined by sensory profiling, due to higher tissue iron levels. From sensory profiling, WOF development in M. longissimus dorsi and M. psoas major was highest in the iron-supplemented groups followed by the control and vitamin E-supplemented groups.

Excision of large solid haemangioblastomas of the cerebellopontine angle by a skull base approach.

Solid haemangioblastomas can be difficult to treat surgically because of their hypervascularity and requirement for circumferential dissection. We report two cases of large solid cerebellopontine angle haemangioblastomas that were safely resected utilizing wide transtemporal posterolateral skull-base exposures. In both cases, good tumour exposure was achieved with trans-cochlear approaches and division of the sigmoid sinus. These were large tumours and we felt that the added complexity of the approach was justified by providing panoramic exposure to allow safe resection.

Health-related quality of life in patients with skull base tumours.

The objective of the investigation was to report on the health-related quality of life (HRQoL) of patients diagnosed with skull base tumours using the Short Form Health Survey questionnaire (SF-36). Those patients suffering with vestibular schwannoma were examined to determine the effect facial nerve function had on their quality of life. It took place at the tertiary referral centre at the Department of Clinical Neurosciences, Western General Hospital, Edinburgh. A prospective study of 70 consecutive patients was taken, who harboured the following tumours: 54 vestibular schwannomas, 13 meningiomas, two haemangioblastomas and one hypoglossal schwannoma. Patients were interviewed using the short form 36 (SF-36) questionnaire. Facial nerve function was assessed in those patients who had vestibular schwannomas. The entire cohort of live skull base patients were assessed after a median follow-up time of 38.4 months. Patients with vestibular schwannoma treated conservatively with interval MRI had a quality of life similar to t he normal population. Those who underwent surgery had a significant difference in two of the SF-36 domains. No statistically significant correlation was found at final assessment between the degree of facial nerve functioning and any of the domains of SF-36. Patients with non-vestibular tumours had an impaired HRQoL in seven of the eight domains. Patients with skull base tumours have a significant impairment of their HRQoL. A conservative policy of follow up with interval MRI for patients with small vestibular schwannomas may therefore be more appropriate to preserve their HRQoL. Facial nerve outcome has little influence on quality of life in vestibular schwannoma patients.

Sensory colour assessment of fresh meat from pigs supplemented with iron and vitamin E.

Pork muscle samples (M. longissimus dorsi) were obtained from pigs given one of four dietary treatments: (1) control diet; (2) supplemental iron [7-g iron (II) sulphate/kg feed]; (3) supplemental vitamin E (200-mg dl-α-tocopheryl acetate/kg of feed); and (4) supplemental vitamin E+supplemental iron. Muscle cores were packaged in polythene bags and placed in a retail refrigerated display cabinet at 5±1°C, under fluorescent light (1000 LUX) for up to 5 days. Samples were subjected to visual colour evaluation by a trained sensory panel (n=12) at 0, 1, 3 and 5 days. In addition instrumental L*, a* and b* values and drip loss were measured on each day of analysis. All samples became less red and browner over storage time in the refrigerated display cabinet. The vitamin E treated samples were more red and less brown compared with the other samples on successive days in the cabinet followed by the control, iron/vitamin E and iron treatments. The iron/vitamin E treatment was positioned midway between the vitamin E and iron treatments indicating that the vitamin E in the samples was effective in reducing the pro-oxidative effect of iron in inducing the brown metmyoglobin pigment development. Iron supplementation did not significantly (P<0.05) increase M. longissimus dorsi iron tissue levels, but had a detrimental effect on the visual sensory properties of the iron and iron/vitamin E treatment groups with greater metmyoglobin formation. Vitamin E appears to have promoted non-supplemental iron absorption in the vitamin E treated group without the detrimental sensory colour characteristics associated with ferrous sulphate supplementation. Drip loss increased in all samples during the course of the experiment with no significant (P<0.05) differences between the experimental groups. The panellists were able to differentiate the four experimental groups on each day of the study and were more effective in evaluating the colour quality of samples than instrumental assessment, i.e. the Hunter L* a* b* method.

Colonic adenocarcinoma in rhesus macaques.

Colon cancer is the second most common cause of cancer mortality in human beings, but relatively few cases have been described in macaques. The present report documents two fatal cases of colon cancer in aged rhesus macaques. Case 1 was a 20-year-old female in which extensive invasion of the caecum by a scirrhous adenocarcinoma led to perforation and a severe fibrinopurulent peritonitis. Case 2 was a 32-year-old male with a stricture at the ileocaecal junction, also caused by a scirrhous adenocarcinoma, which had metastasized to a regional lymph node. Both neoplasms showed aggressive local involvement of the proximal large bowel, which appears to be a predilection site in rhesus monkeys. Descriptions of spontaneous cases of colon cancer in non-human primates may lead to the development of models for certain aspects of the disease in man.