Oral melphalan for the treatment of relapsed canine lymphoma.

Oral melphalan has been included in multi-agent rescue protocols for canine lymphoma but its activity as a single-agent for this purpose has not been established. Inexpensive cost, ease of administration and tolerability make oral melphalan an attractive candidate for single-agent rescue therapy of canine lymphoma. Retrospective evaluation of 19 cases of relapsed canine lymphoma treated with oral melphalan was performed. Melphalan was primarily administered (n = 16) via a high dose protocol (HDM) with a median dosage of 19.4 mg m-2 . Fifteen dogs (78.9%) were treated concurrently with corticosteroids. Response evaluation was possible for all dogs with a calculated overall clinical benefit (partial response [PR] + stable disease [SD]) of 31.6% (PR 3/19; SD 3/19). Times to progression following melphalan (TTP-M) were 14, 24 and 34 days for responders and 20, 28 and 103 days for dogs experiencing SD. Twelve of 17 dogs evaluable for toxicity experienced an adverse event (AE) with only 3 dogs experiencing a grade III or higher AE. Haematologic toxicity was common (11/17) while gastrointestinal toxicity was rare (1/17). Although treatment resulted in limited clinical benefit and non-durable responses, oral melphalan was well-tolerated and may be a reasonable rescue option in cases where minimal effective agents remain.

Canine acute leukaemia: 50 cases (1989-2014).

Acute leukaemia (AL) is a bone marrow malignancy of hematopoietic progenitors that historically is poorly responsive to treatment. With the widespread adoption of dose-intense chemotherapy, more human patients attain long-term survivals, but whether comparable progress has been made in canine AL is unknown. To investigate this question, medical records from three academic veterinary hospitals were reviewed. Fifty dogs met the criteria for AL, having excess circulating or marrow blasts, a major cytopenia(s), and no substantial lymphadenopathy. Thirty-six dogs received cytotoxic chemotherapy; 23 achieved a complete or partial response for a median of 56 days (range, 9-218). With failure or relapse, 14 dogs were rescued. Median survival with treatment was poor at 55 days (range, 1-300). Untreated (n = 6) and palliatively-treated (n = 8) dogs lived a median of 7.5 days. Most dogs developed chemoresistance within weeks of initiating treatment, and consequently, survival times for AL remain disappointingly short.

Development of an ELISA to detect circulating anti-asparaginase antibodies in dogs with lymphoid neoplasia treated with Escherichia coli l-asparaginase.

Resistance to Escherichia coli l-asparaginase in canine lymphoma occurs frequently with repeated administration, a phenomenon often attributed, without substantiation, to the induction of neutralizing antibodies. To test the hypothesis that treated dogs develop antibodies against the drug, we created an enzyme-linked immunosorbent assay (ELISA) to measure plasma anti-asparaginase immunoglobulin G responses. Using samples from dogs that had received multiple doses, specific reactivity against l-asparaginase was demonstrated, while naïve patients' samples were negative. The optimized ELISA appeared sensitive, with endpoint titers >1 600 000 in positive control dogs. Intra- and inter-assay coefficients of variation were 3.6 and 14.5%. The assay was supported by the observation that ELISA-positive plasma could immunoprecipitate asparaginase activity. When clinical patients were evaluated, 3/10 dogs developed titers after a single injection; with repeated administration, 4/7 dogs were positive. l-asparaginase antibodies showed reduced binding to the PEGylated drug formulation. The ELISA should prove useful in investigating the potential correlation of antibody responses with resistance.

Chronic lymphocytic leukaemia in the cat: 18 cases (2000-2010).

There is little information regarding the presentation, biologic behaviour, treatment and prognosis in cats with chronic lymphocytic leukaemia (CLL), and further investigation is needed to characterize this disease in cats. The goal of this study was to describe the clinical presentation, response to treatment and prognosis of feline CLL. A multi-institutional retrospective study of 18 cats diagnosed with CLL between 2000 and 2010 was performed. CLL was defined as the presence of a mature lymphocytosis (>9000 lymphocytes µL(-1) ) and confirmation of an immunophenotypically monomorphic or clonal lymphoid population. Each patient was required to also have at least one of the two following criteria: (1) concurrent cytopenia of at least one cell line and/or (2) >15% mature lymphocytes in the bone marrow. Data on signalment, history, clinical signs, clinicopathologic features and response to treatment were reviewed. Median age of the cats at initial presentation was 12.5 years (range: 5-20 years). The most common presenting complaint was chronic weight loss, which was present in 8/18 (44%) cats. Sixteen of 18 (89%) cats were treated with chlorambucil and prednisolone; four of these cats also received vincristine. Two (11%) cats were treated with multi-agent injectable chemotherapy (L-CHOP, l-asparaginase, cyclophosphamide, doxorubicin, vincristine, prednisolone). Eighty-eight percent of cats evaluable for response achieved a complete (nine cats) or partial (six cats) remission. Median overall remission was 15.7 months (range: 1.3-22.8 months). The median overall survival in the 17 cats with follow-up data was 14.4 months (range: 0.9-25.3 months). Results of this study suggest that CLL affects older-aged cats and responds favourably to treatment with oral chlorambucil and prednisolone.

Allelic diversity at the DLA-88 locus in Golden Retriever and Boxer breeds is limited.

In the dog, previous analyses of major histocompatibility complex class I genes suggest a single polymorphic locus, dog leukocyte antigen (DLA)-88. While 51 alleles have been reported, estimates of prevalence have not been made. We hypothesized that, within a breed, DLA-88 diversity would be restricted, and one or more dominant alleles could be identified. Accordingly, we determined allele usage in 47 Golden Retrievers and 39 Boxers. In each population, 10 alleles were found; 4 were shared. Seven novel alleles were identified. DLA-88*05101 and *50801 predominated in Golden Retrievers, while most Boxers carried *03401. In these breeds, DLA-88 polymorphisms are limited and largely non-overlapping. The finding of highly prevalent alleles fulfills an important prerequisite for studying canine CD8+ T-cell responses.

Steroid-responsive, cervical, pyogranulomatous pachymeningitis in a dog.

Syndromes of steroid-responsive meningitis have been described in the dog and typically are characterized by neutrophilic pleocytosis and an elevated protein concentration of the cerebrospinal fluid. In a minority of cases, histopathology has demonstrated suppurative leptomeningeal (i.e., arachnoid and pia) inflammation. A case of compressive, cervical, pyogranulomatous inflammation of undetermined cause affecting the dura mater (i.e., pachymeningitis), accompanied by fever and hyperpathia, is presented. The pachymeningitis ultimately regressed with long-term immunosuppressive therapy. This case shares features with hypertrophic spinal pachymeningitis of humans, an uncommon, frequently idiopathic, chronic inflammatory disorder causing dural hypertrophy, radiculopathy, and spinal cord compression.

Management of portal hypertension and its consequences.

Increased pressure in the protal venous system results from impedance to blood flow at any point along it's course from the splanchnic circulation through the liver to the right heart. Typical manifestations of sustained increases in portal venous pressure commonly may include accumulation of abdominal fluid and development of acquired portosystemic shunts. Pathophysiology of altered portal vascular dynamics, diagnostic approach for animals suspected of having an intra-abdominal source of portal hypertension and treatment options are discussed.

Effect of neonatal infraorbital nerve transection on substance P- and leucine enkephalin-like immunoreactivities in trigeminal subnucleus caudalis of the rat.

The distributions of substance P-like immunoreactivity (SPLI) and leucine-enkephalin-like immunoreactivity (LENKLI) in subnucleus caudalis of normal adult rats were compared with those observed in the adult rats that sustained transection of the infraorbital (IO) nerve either on the day of birth or in adulthood. All immunocytochemical experiments in the neonatally nerve damaged rats were carried out at least 60 d after the nerve transection. In the animals that sustained nerve transections as adults, brains were processed for immunohistochemistry between 7 and 60 d after the lesions. In the rats that sustained IO nerve transections as adults, there was a transient reduction in the density of the SPLI in layers I and II of ipsilateral subnucleus caudalis. It was most apparent about 2 weeks after the nerve transection and returned to near normal values by 60 d after the lesion. In the rats that sustained IO nerve transections on the day of birth, there was no reduction in the density of SPLI in caudalis, and the band of staining on the deafferented side of the brain stem was actually 40% wider than that on the intact side. Neither neonatal nor adult IO nerve transection had appreciable effects upon the distribution of LENKLI in the rat's trigeminal brain-stem complex. In another series of experiments, rats that sustained neonatal transection of the IO nerve had this same nerve recut in adulthood. Twelve days after the second lesion, the brains of these animals were processed for SPLI. There was a marked reduction in the density of the staining for this peptide on the deafferented side. This last result is consistent with the interpretation that the increased distribution of SPLI in the neonatally nerve damaged rats is due, at least partially, to reorganization of primary afferents.

The projection from the superficial to the deep layers of the superior colliculus: an intracellular horseradish peroxidase injection study in the hamster.

Intracellular recording and horseradish peroxidase (HRP) injection techniques were employed to examine the projections of superficial layer [stratum griseum superficiale (SGS) and stratum opticum (SO)] superior collicular (SC) neurons in the hamster that sent axon collaterals into the deep laminae (those ventral to the SO) of this structure. Sixty-nine neurons were studied, selected from a sample of over 185 HRP-filled superficial layer cells on the basis of having heavily stained axons. Of the 69 cells included in the study, 43.4% (n = 30) sent at least one axon collateral to the deep laminae. Not all cell types in the superficial layers contributed equally to this interlaminar projection: 78.6% (n = 11) of the recovered wide-field vertical cells, 55.0% (n = 11) of the narrow-field vertical cells, 16.7% (n = 2) of the stellate cells, 40.0% (n = 2) of the marginal cells, 18.2% (n = 2) of the horizontal cells, and 28.6% (n = 2) of neurons we could not classify on the basis of their somadendritic morphology projected to the deep layers. Within a given cell class, there were no significant morphological or physiological differences between the neurons that possessed deep axon collaterals and those that did not. The deep axon collaterals of most of the interlaminar projection neurons were restricted to the stratum griseum intermediate (SGI). In this layer, the largest segment of the axon arbor was located lateral to a projection line that was orthogonal to the SC surface and that passed through the soma of the cell in question. These results, along with those of a previous study (Mooney et al., 1984), which demonstrated that the dendrites of deep layer cells may extend through the SO and into the SGS, indicate that there is an extensive anatomical substrate by which sensory information may be communicated from superficial to deep layer SC neurons.

Preventing regeneration of infraorbital axons does not alter the ganglionic or transganglionic consequences of neonatal transection of this trigeminal branch.

Retrograde and transganglionic tracing with a combination of horseradish peroxidase (HRP) and wheatgerm agglutinin (WGA)-conjugated HRP (WGA-HRP) was employed to determine whether transection of the infraorbital (IO) nerve on the day of birth and prevention of regeneration by retransecting it at weekly intervals until the time of a terminal anatomical experiment had effects upon ganglion cell survival and innervation of the brainstem by this trigeminal (V) branch that differed from those which followed a single transection of the same nerve on the day of birth without any attempt to prevent peripheral regeneration of the cut axons. Counts of labelled ganglion cells and examination of the brainstem labelling produced by application of HRP and WGA-HRP to the IO nerve proximal to the point of transection(s) at 6 weeks of age demonstrated no differential effects of preventing regeneration of the cut nerve. In animals subjected to a single transection of the nerve (n = 9), we counted an average of 5001.2 (S.D. = 1286.9) labelled ganglion cells and these had an average diameter of 22.7 micron (S.D. = 6.3). In the rats (n = 9) that sustained multiple nerve cuts, the average number of labelled ganglion cells was 4447.8 (S.D. = 1060.9). The mean diameter for these primary afferent neurons was 21.5 micron (S.D. = 6.6). Neither of these values were significantly different from those from the rats subjected to a single nerve cut. The cell counts from both of these groups were significantly lower than those obtained after application of HRP and WGA-HRP to the IO nerve in normal rats (n = 3, X = 12,553.3, S.D. = 1454.8), but the average cell diameter in the normals (X = 23.2, S.D. = 6.6) was not significantly greater than that in the nerve-damaged animals. The pattern of brainstem labelling observed in the rats subjected to multiple nerve cuts was the same as that in the rats which sustained a single transection of the IO nerve on the day of birth. Very little terminal labelling was observed in nucleus principalis, subnucleus oralis, subnucleus interpolaris or the magnocellular portion of caudalis. There was, however, very heavy labelling in laminae I and II of the latter nucleus.

Morphological characteristics of low-threshold primary afferents in the trigeminal subnuclei interpolaris and caudalis (the medullary dorsal horn) of the golden hamster.

Intra-axonal recording and horseradish peroxidase (HRP) injection techniques were employed to define the response characteristics of low-threshold, rapidly conducting trigeminal primary afferents and the morphological features of their axon arbors in subnucleus interpolaris and subnucleus caudalis (or the medullary dorsal horn; these last two terms are used synonomously throughout the paper). A total of 61 such afferents were characterized and recovered. Of these, ten gave rapidly adapting (RA) and 17 slowly adapting (SA type I) responses to vibrissa deflection. Twenty were sensitive to guard hair deflection and 14 were responsive to indentation of the hairy skin. The vibrissa-sensitive primary afferents were all quite similar morphologically. Primary collaterals proceeded directly, in a radial fashion, to their zone of termination and gave rise to dense and compact arbors. These tended to be larger in the medullary dorsal horn (MDH) than in interpolaris and they also gave rise to more boutons in the former nucleus. Guard hair afferents generally had smaller arbors and gave rise to fewer boutons than vibrissa-sensitive axons. Like vibrissa afferents, their arbor were generally circumscribed in both interpolaris and MDH, but they were larger in the latter nucleus. Skin-sensitive afferents had arbors that tended to be somewhat larger than those of vibrissa- or guard-hair-related fibers. Unlike the other fiber types, the arbors of skin-sensitive afferents were on average larger in interpolaris than MDH. Quantitative analysis of the morphological data from well-filled examples from each of these four functional types verified our qualitative impressions regarding differences between interpolaris and MDH collaterals of a given fiber-type. Statistical comparison of data from different functional classes indicated trends that supported our qualitative impressions, but none of these was statistically significant. The topography of the trigeminal primary afferent input to interpolaris was organized such that the head was inverted and fibers with caudal receptive fields terminated in the lateral portion of the nucleus. This was true for all of the functional afferent types that we examined. Vibrissa-related fibers differed from nonvibrissa afferents in that they tended to avoid the most rostral portion of interpolaris. In the MDH, the primary afferent representation of the head was also inverted, but fibers with caudal facial receptive fields tended to terminate medially rather than laterally.(ABSTRACT TRUNCATED AT 400 WORDS)