Pegylated asparaginase in feline high-grade lymphoma: clinical results of single injection and continued incorporation into a modified COP regimen.

OBJECTIVES: The aim of this retrospective study was to determine the response to a single injection of pegylated asparaginase ('pegaspargase') and to assess the tolerability and outcome of prolonged incorporation of pegaspargase into a modified COP (cyclophosphamide, vincristine, prednisolone) regimen in pegaspargase sensitive cats. METHODS: Fifty-six client-owned cats with confirmed macroscopic high-grade lymphoma at any anatomical site were included. Treatment was commenced with a single pegaspargase injection. Cats showing an objective response were eligible to continue therapy with pegaspargase incorporated into a modified COP protocol and had their survival analysed using the Kaplan-Meier method and log-rank test. RESULTS: Objective response to pegaspargase was reported in 46 cats (82%), including 21 (38%) complete and 25 (44%) partial responses. Thirty-four responders continued therapy with pegaspargase-COP as the first-line treatment. Of these, 31 cats (92%) achieved complete remission with a median duration of the first remission (disease-free survival [DFS]) of 816 days. The median overall survival time (OST) for all 34 cats treated with pegaspargase-COP was 181 days. Response to the initial pegaspargase injection before COP initiation was significantly associated with DFS (P = 0.04) and OST (P = 0.001). Median DFS/OST for cats with complete response to initial pegaspargase injection was significantly longer compared with those with partial remission (>1273 days/>2066 days vs 77 days/108 days, respectively). Cats with gastric lymphoma showed a significantly longer survival (OST 854 days, 1- and 2-year survival rate 57.1%) compared with cats with intestinal lymphoma (OST 102 days, 1-year survival rate 0%). The pegaspargase-COP protocol was generally well tolerated, but two deaths were likely attributable to treatment-related toxicity during the maintenance phase. Importantly, none of the cats experienced hypersensitivity, despite multiple repeated treatments with pegaspargase. CONCLUSION AND RELEVANCE: Pegaspargase is an effective agent for feline lymphoma. Its incorporation into a COP chemotherapy protocol may confer a survival benefit, especially in cats with complete response to pegaspargase. Treatment is generally well tolerated, but careful monitoring is recommended. Further studies are required to assess the benefits of pegaspargase as monotherapy or as part of different multi-agent chemotherapy regimens.

Familial follicular cell thyroid carcinomas in a large number of Dutch German longhaired pointers.

Thyroid carcinomas (TCs) originating from follicular cells of the thyroid gland occur in both humans and dogs, and they have highly similar histomorphologic patterns. In dogs, TCs have not been extensively investigated, especially concerning the familial origin of TCs. Here, we report familial thyroid follicular cell carcinomas (FCCs) confirmed by histology in 54 Dutch origin German longhaired pointers. From the pedigree, 45 of 54 histopathologically confirmed cases are closely related to a pair of first-half cousins in the past, indicating a familial disease. In addition, genetics contributed more to the thyroid FCC than other factors by an estimated heritability of 0.62 based on pedigree. The age of diagnosis ranged between 4.5 and 13.5 years, and 76% of cases were diagnosed before 10 years of age, implying an early onset of disease. We observed a significant higher pedigree-based inbreeding coefficient in the affected dogs (mean F, 0.23) compared to unaffected dogs (mean F, 0.14), suggesting the contribution of inbreeding to tumour development. The unique occurrence of familial thyroid FCC in this dog population and the large number of affected dogs make this population an important model to identify the genetic basis of familial thyroid FCC in this breed and may contribute to the research into pathogenesis, prevention and treatment in humans.

Test/Retest Variability of the eCAP Threshold in Advanced Bionics Cochlear Implant Users.

OBJECTIVE: The reliability of the electrically evoked compound action potential (eCAP) threshold depends on its precision and accuracy. The precision of the eCAP threshold reflects its variability, while the accuracy of the threshold shows how close it is to the actual value. The objective of this study was to determine the test/retest variability of the eCAP threshold in Advanced Bionics cochlear implant users, which has never been reported before. We hypothesized that the test/retest variability is dependent on the presence of random noise in the recorded eCAP waveforms. If this holds true, the recorded error should be reduced by approximately the square-root of the number of averages. As secondary objectives, we assessed the effects of the slope of the amplitude growth function (AGF), cochlear location, and eCAP threshold on eCAP threshold precision. We hypothesized that steeper slopes should result in better precision of the linearly extrapolated eCAP threshold. As other studies have shown that apical regions have steeper slopes and larger eCAPs, we recorded eCAPs in three different cochlear locations. The difference of the precision between two commonly applied stimulus-artifact reduction paradigms on eCAP threshold precision was compared, namely averaging of alternating stimulus polarities (AP averaging) and forward masking (FM). FM requires the addition of more waveforms than AP averaging, and hence we expected FM to have lower precision than AP. DESIGN: This was an unmasked, descriptive, and observational study with a cross-over (repeated measures) design that included 13 subjects. We recorded eCAPs on three electrode contacts: in the base, middle, and apex of the cochlea at 10 stimulus intensities. Per stimulus level, 256 eCAP waveforms were recorded. eCAP thresholds were determined by constructing AGFs and linear extrapolation to zero-amplitude. The precision of the eCAP threshold was calculated as the SD using a Monte Carlo simulation, as a function of the number of waveform averages. RESULTS: The SD of the eCAP threshold was reduced by approximately the square root of two when the number of averages in the eCAP waveforms was doubled. The precision was significantly better when the slope of the AGF was steeper and was more favorable in the cochlear base than in the apex. Precision was better when AP averaging was used. Absolute eCAP threshold did not significantly affect precision. At the default number of 32 waveform averages in the Advanced Bionics system, we report a median SD of the eCAP threshold of 2 to 3 µA, with a range of 1 to 11 µA across the cochlea. Previous studies have shown that the total error, based on the 95% confidence bounds of the linear extrapolation, can be as high as -260 to +120 µA. CONCLUSIONS: The median variability in the eCAP threshold proved to be small compared with the total variability introduced by the linear extrapolation method. Yet there was substantial intersubject variability. Therefore, we recommend monitoring the SD during eCAP recording to facilitate informed decisions when to terminate waveform collection. From a precision perspective, AP averaging is preferable over FM as it has better precision, while fewer recordings are needed, making it the more time-efficient method of the two.

Use of Electrically Evoked Compound Action Potentials for Cochlear Implant Fitting: A Systematic Review.

OBJECTIVES: The electrically evoked compound action potential (eCAP) is widely used in the clinic as an objective measure to assess cochlear implant functionality. During the past decade, there has been increasing interest in applying eCAPs for fitting of cochlear implants. Several studies have shown that eCAP-based fitting can potentially replace time-consuming behavioral fitting procedures, especially in young children. However, a closer look to all available literature revealed that there is no clear consensus on the validity of this fitting procedure. This study evaluated the validity of eCAP-based fitting of cochlear implant recipients based on a systematic review of the recent literature. DESIGN: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were used to search the PubMed, Web of Science, and Cochrane Library databases. The term "eCAP" was combined with "cochlear implants," "thresholds," and "levels," in addition to a range of related terms. Finally, 32 studies met the inclusion criteria. These studies were evaluated on the risk of bias and, when possible, compared by meta-analysis. RESULTS: Almost all assessed studies suffered from some form of risk of bias. Twenty-nine of the studies based their conclusion on a group correlation instead of individual subject correlations (analytical bias); 14 studies were unclear about randomization or blinding (outcome assessment bias); 9 studies provided no clear description of the populations used, for example, prelingually or postlingually implanted subjects (selection bias); and 4 studies had a high rate of loss (>10%) for patients or electrodes (attrition bias). Meta-analysis of these studies revealed a weak pooled correlation between eCAP thresholds and both behavioral T- and C-levels (r = 0.58 and r = 0.61, respectively). CONCLUSIONS: This review shows that the majority of the assessed studies suffered from substantial shortcomings in study design and statistical analysis. Meta-analysis showed that there is only weak evidence to support the use of eCAP data for cochlear implant fitting purposes; eCAP thresholds are an equally weak predictor for both T- and C-levels. Based on this review, it can be concluded that research on eCAP-based fitting needs a profound reflection on study design and analysis to draw well-grounded conclusions about the validity of eCAP-based fitting of cochlear implant recipients.

Determination of platinum originating from carboplatin in human urine and canine excretion products by inductively coupled plasma mass spectrometry.

We present highly sensitive, rapid methods for the determination of Pt originating from carboplatin in human urine and canine urine, feces, and oral fluid. The methods are based on the quantification of Pt by inductively coupled plasma mass spectrometry, and allow quantification of 7.50 ng/L Pt in human and canine urine (in 15 µL of matrix), 15.0 ng/L Pt in canine oral fluid (in 15 µL of matrix), and 0.105 ng/g Pt in canine feces (in 5 µg of matrix). Sample pretreatment mainly involved dilution with appropriate diluents. The performance of the methods fulfilled the most recent FDA guidelines for bioanalytical method validation. Validated ranges of quantification were 7.50 to 1.00 × 10(4) ng/L Pt in human and canine urine, 0.105-30.0 ng/g Pt in canine feces, and 15.0 to 1.00 × 10(4) ng/L Pt in canine oral fluid. Canine urine and oral fluid cannot be easily obtained. Therefore, we also investigated the validity of the usage of human matrix samples for the preparation of calibration standards and quality control samples as alternatives, to be used in future clinical studies. The assays are used to support biomonitoring studies and pharmacokinetic studies in pet dogs treated with carboplatin.

Determination of platinum originating from carboplatin in canine sebum and cerumen by inductively coupled plasma mass spectrometry.

We present highly sensitive, reliable methods for the determination of platinum originating from carboplatin in canine sebum and cerumen. The methods are based on the measurement of platinum by inductively coupled plasma mass spectrometry and allow quantification of 0.15 pg platinum per cm² body surface in canine sebum and of 7.50 pg platinum per sampled ear canal. The sample pretreatment procedure involved extraction of wipe samples followed by dilution with appropriate diluents. The performance of the methods, in terms of accuracy and precision, fulfilled the most recent FDA guidelines for bioanalytical method validation. Validated ranges of quantification were 15.0-1.00 x 104 ng L⁻¹ for platinum in canine sebum extraction solution (corresponding to 15.0 pg per wipe sample or 0.15 pgcm⁻²) and 7.50-1.00 x 104 ng L⁻¹ for platinum in canine cerumen extraction solution (corresponding to 7.50 pg per sampled external acoustic meatus). Canine matrices may not always be obtained in sufficient quantities. Therefore, we also confirmed the legitimacy of the application of human matrix samples for the preparation of calibration standards and quality control samples as alternatives, to be used in future clinical studies. The assays are used to support human biomonitoring studies and pharmacokinetic oncology studies in pet dogs treated with carboplatin.