Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors

Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents.

Intestinal atresia and ectopia in a bovine fetus

A 2-year-old Red Holstein cow was presented with uterine torsion at 235 days of pregnancy. The fetus extracted by cesarean section had weak vital signs and marked abdominal distention. An edematous pouch that contained tubular structures with peristaltic activity was associated with the umbilical cord. Because of poor prognosis, both dam and fetus were euthanized. At necropsy, the fetus had severe distention of the forestomachs, abomasum, and proximal small intestine; absence of distal small intestine, cecum, and proximal colon; atresia of the 2 blind ends of the intestine; and atrophy of distal colon and rectum. The tubular structures associated with the umbilical cord were identified as the segments of intestine that were absent in the fetus. Intestinal atresia combined with ectopia may be caused by local ischemia during temporary herniation and rotation of the fetal gut into the extraembryonic coelom. The close connection between ectopic intestine and amniotic sheath of the umbilical cord in this case may have facilitated vascularization and allowed development and viability of the ectopic intestine.

Glomerulonephropathy in Aged Captive Key Largo Woodrats (Neotoma floridana smalli)

A retrospective review of mortality records of Key Largo woodrats (Neotoma floridana smalli) in a captive breeding program revealed chronic renal disease in 5 of 6 woodrats older than 4 years of age. Two of the 5 woodrats with chronic renal disease also had clinical evidence of diabetes mellitus. Kidneys from all 5 woodrats were examined via light microscopy, histochemical staining, immunohistochemical staining, and transmission electron microscopy. The dietary histories of the affected animals were examined as well. The most striking histopathologic abnormality in the affected kidneys was the presence of large protein casts within cortical and medullary tubules in combination with lesions of membranous glomerulopathy and glomerulosclerosis. Transmission electron microscopy revealed thickening and undulation of the tubular and glomerular mesangial basement membranes with the variable presence of electron-dense deposits within the capillary endothelial basement membrane. Patchy glomerular immunoreactivity for IgG was noted in 2 cases, but IgA and IgM immunoreactivity were not present. The pathologic changes in the kidneys of the Key Largo woodrats mirrored many of the features of chronic progressive nephropathy commonly diagnosed in laboratory rats. Woodrats in the captive population were fed an ad libitum high-protein diet similar to diets that have been shown in laboratory rats to exacerbate the development and progression of chronic progressive nephropathy. It is concluded that Key Largo woodrats develop glomerulonephropathy with features similar to chronic progressive nephropathy described in laboratory rats. Age, concomitant disease, and dietary factors may contribute to the development and severity of this potentially age-limiting disease in Key Largo woodrats.

Comparison of brain PrPd distribution in ovine BSE and scrapie

Scrapie and bovine spongiform encephalopathy (BSE) are both prion diseases affecting ruminants, and these diseases do not share the same public health concerns. Surveillance of the BSE agent in small ruminants has been a great challenge, and the recent identification of diverse prion diseases in ruminants has led to the development of new methods for strain typing. In our study, using immunohistochemistry (IHC), we assessed the distribution of PrP(d) in the brains of 2 experimentally BSE-infected sheep with the ARQ/ARQ genotype. Distribution of PrP(d) in the brain, from the spinal cord to the frontal cortex, was remarkably similar in the 2 sheep despite different inoculation routes and incubation periods. Comparatively, overall PrP(d) brain distribution, evaluated by IHC, in 19 scrapie cases with the ARQ/ARQ, ARQ/VRQ, and VRQ/VRQ genotypes, in some cases showed similarities to the experimentally BSE-infected sheep. There was no exclusive neuroanatomical site with a characteristic and specific PrP(d) type of accumulation induced by the BSE agent. However, a detailed analysis of the topography, types, and intensity of PrP(d) deposits in the frontal cortex, striatum, piriform cortex, hippocampus, mesencephalon, and cerebellum allowed the BSE-affected sheep group to be distinguished from the 19 scrapie cases analyzed in our study. These results strengthen and emphasize the potential interest of PrP(d) brain mapping to help in identifying prion strains in small ruminants.

Evaluation of cell death mechanisms induced by the vascular disrupting agent OXi4503 during a phase I clinical trial

OXi4503 is a tubulin-binding vascular disrupting agent that has recently completed a Cancer Research UK-sponsored phase I trial. Preclinical studies demonstrated early drug-induced apoptosis in tumour endothelial cells at 1-3 h and secondary tumour cell necrosis between 6 and 72 h.

Hereditary hydrocephalus in laboratory-reared golden hamsters (Mesocricetus auratus)

A colony of golden hamsters had an ongoing problem with hydrocephalus. In an attempt to clear the colony of the problem, new breeders from another supplier had been purchased. At termination of a behavioral study, the brain was collected from 35 animals (four of which had died with hydrocephalus during the study) and was examined macroscopically and by light microscopy. Although no animals manifested obvious behavioral changes, 31 of 35 (88.6%, 13/15 males and 18/20 females in control and manipulated groups) had hydrocephalus. Twenty-five animals had macroscopically identifiable hydrocephalus, and six had hydrocephalus identified microscopically. Neither teratogenic concentrations of metals nor mycotoxins were detected in tissues or food, and sera from breeders tested negative for antibodies to Sendai virus, reovirus 3, and lymphocytic choriomeningitis virus. Trial matings of breeders expected to produce hydrocephalic offspring resulted in affected offspring, and mating of breeders expected to produce normal offspring resulted in normal or less-affected offspring. Hydrocephalus was confirmed retrospectively in some breeders. Hereditary hydrocephalus appears to be widespread in hamster stocks in Central Europe. Affected animals do not manifest signs of disease and usually die without obvious premonitory signs. Despite severe hydrocephalus, the animals can breed, and animal handlers do not identify motor deficits or abnormal behavioral activity. This entity is unlike the previously described, hereditary hydrocephalus of hamsters that is phenotypically identifiable and usually is lethal before they attain breeding age.

Two independent cases of spontaneously occurring branchioblastomas in koi carp (Cyprinus carpio)

This report documents 2 cases of branchioblastomas in koi carp (Cyprinus carpio). Macroscopically, both cases were characterized by well-demarcated, pale red nodular masses located at the left first branchial arch and the right pseudobranch, respectively. Histologically, the neoplasias were composed of blast-like cells that differentiated into cartilage and branchial lamellae embedded in abundant fibrous connective tissue. Based on these findings, a branchioblastoma was diagnosed.

Immunohistochemical demonstration of the putative canine distemper virus receptor CD150 in dogs with and without distemper

Signaling lymphocyte activation molecule (SLAM) or CD150 can function as a receptor for the canine distemper virus (CDV) in vitro. The expression of SLAM was studied using immunohistochemistry in order to evaluate the presence and distribution of the receptor in dogs in vivo. Additionally, receptor expression was assessed after experimental infection of dogs with CDV. In 7 control dogs without distemper virus, the receptor was found in various tissues, mostly on cells morphologically identified as lymphocytes and macrophages. In 7 dogs with early distemper lesions characterized by presence of the virus, higher numbers of SLAM-expressing cells were found in multiple tissues recognized as targets of CDV compared with those in control dogs. These findings suggest that SLAM, a putative distemper receptor, is expressed in dogs in vivo. Additionally, virus infection is associated with up-regulation of SLAM, potentially causing an amplification of virus in the host.

A mixed epithelial and stromal tumor of the kidney in a ringtail lemur (Lemur catta)

Primary renal tumors are rare neoplasms in nonhuman primates. This report describes a mixed epithelial and stromal tumor of the kidney (MESTK) in a 14.5-year-old female ringtail lemur. The well-demarcated, solid, and cystic mass was located in the pelvis of the left kidney and consisted histologically of both epithelial and mesenchymal components. The mesenchymal cells were arranged in fascicles around cysts lined by a well-differentiated epithelium. Neither the mesenchymal nor the epithelial parts showed significant nuclear atypia or mitotic figures. To our knowledge, only 1 similar case, classified as adenoleiomyofibromatous hamartoma, has been reported in a ringtail lemur. In humans this tumor affects predominantly perimenopausal women and can express estrogen and progesterone receptors. However, neither estrogen nor progesterone receptors could be identified by immunohistochemistry in the tumor of the present ringtail lemur. Therefore, a hormonal mechanism could not be demonstrated in this case.

Inducible nitric oxide synthase and nitrotyrosine in listeric encephalitis: a cross-species study in ruminants

Listeria monocytogenes (LM) is a Gram-positive facultative intracellular bacterium that causes fatal meningoencephalitis in humans and ruminants. A current paradigm predicts that intracellular bacteria are controlled by nitric oxide (NO) whose synthesis is catalyzed by inducible nitric oxide synthase (iNOS). The ability of macrophages (Mphi) to express iNOS shows extreme interspecies variability. Here the expression of iNOS and synthesis of NO was studied in listeric encephalitis of cattle, sheep, and goats. iNOS was expressed by a subset of Mphi in cerebral microabscesses in all three species. The level of iNOS expression and the density of cells per lesion expressing iNOS was highest in cattle, intermediate in sheep, and lowest in goats. The accumulation of nitrotyrosine (NT), an indicator of local NO synthesis, was observed in lesions of cattle but not in those of small ruminants. The density of iNOS-expressing cells in lesions was inversely correlated with the number of bacteria. No species differences were observed in regard to reactive oxygen intermediate (ROI) production by stimulated granulocytes, using the flow cytometric dihydrorhodamine-123 (DHR) method indicating ROI generation. Thus, the marked species differences in iNOS expression, NT accumulation, and LM content in lesions of ruminants with listeric encephalitis are explained by different amounts of ROI produced. It suggests that variations in the ability of Mphi to synthesize NO are of pathophysiological significance in listeriosis.

Nasal acinic cell carcinoma in a cat

This case report describes the clinical, magnetic resonance imaging (MRI)-related, and pathologic features of a nasal acinic cell carcinoma in a cat. A 16-year-old, castrated male, oriental shorthaired cat, weighing 3.8 kg, was presented with history of sneezing, coughing, and nasal discharge persisting several months. Evaluation by MRI revealed an heterogeneous, space-occupying lesion that filled the left nasal cavity and was diagnosed by histopathologic examination as an acinic cell carcinoma arising from a minor salivary gland of the nasal cavity. Acinic cell carcinoma is a rare tumor in veterinary medicine. The tumor is composed mainly of cells resembling serous cells of salivary glands and originates from major or minor salivary glands. Clinicians and pathologists should be aware of the occurrence of acinic cell carcinoma in the sinonasal tract and include the tumor in the differential diagnosis of feline nasal diseases.

Clinical, histologic, and immunohistochemical analyses of feline squamous cell carcinoma in situ

Actinic keratosis (AK) and Bowenoid in situ carcinoma (BISC) are two distinct forms of in situ squamous cell carcinoma in felines. They usually occur on different locations and present with specific clinical and histologic features. However, in some cases, these diseases cannot be distinguished either clinically or histopathologically. The aim of the present study was to determine the accuracy of diagnosis based on clinical or histologic criteria alone, and whether immunohistochemistry for papillomavirus or p53 can improve the accuracy of diagnosis. A series of in situ squamous cell carcinoma cases (n = 45) were selected according to their location and initial histologic classification and subsequently classified as AK (n = 22) or BISC (n = 23) according to the clinical criteria and were reevaluated histologically by 2 dermatopathologists. All BISC cases and most of the AK cases (n = 15) were confirmed histologically. In 7 cases clinically classified as AK, this diagnosis was not unanimously confirmed histologically because of the presence of overlapping features. P53 immunoreactivity was observed in 11/14 (79%) confirmed AK cases and in 4/22 (18%) BISC cases, while papillomavirus antigen was not detected in any confirmed AK case but was detected in 11/23 (48%) BISC cases. It was concluded that BISC can usually be reliably diagnosed histologically. The histologic diagnosis of lesions clinically suggestive of AK might sometimes be difficult. Results of immunohistochemistry for p53 and papillomavirus antigen were supportive for a role of sun exposure and papillomavirus in the pathogenesis of AK and BISC, respectively.