Randomized Phase III Trial of Piroxicam in Combination with Mitoxantrone or Carboplatin for First‐Line Treatment of Urogenital Tract Transitional Cell Carcinoma in Dogs

Background

Reported response rates of transitional cell carcinoma (TCC) in dogs to piroxicam in combination with either mitoxantrone or carboplatin are similar; however, it is unknown whether either drug might provide superior duration of response.

Hypothesis/Objectives

To determine if the progression‐free interval (PFI) of dogs with TCC treated with mitoxantrone and piroxicam was different than that of dogs receiving carboplatin and piroxicam. The hypothesis was that the efficacy of mitoxantrone is no different from carboplatin.

Animals

Fifty dogs with TCC without azotemia.

Methods

Prospective open‐label phase III randomized study. Either mitoxantrone or carboplatin was administered every 3 weeks concurrently with piroxicam with restaging at 6‐week intervals. Twenty‐four dogs received carboplatin and 26 received mitoxantrone.

Results

Response was not different between groups (P = .56). None of the dogs showed complete response. In the mitoxantrone group, there were 2 (8%) partial responses (PR) and 18 (69%) dogs with stable disease (SD). In the carboplatin group, there were 3 PR (13%) and 13 (54%) dogs with SD. The PFI was not significantly different between groups (mitoxantrone = 106 days; carboplatin = 73.5 days; P = .62; hazard ratio 0.86; 95% confidence interval 0.47–1.56). Dogs with prostatic involvement experienced a shorter survival (median, 109 days) compared to dogs with urethral, trigonal, or apically located tumors; this difference was significant (median 300, 190, and 645 days, respectively; P = .005).

Conclusions and Clinical Importance

This study did not detect a different in outcome in dogs with TCC treated with either mitoxantrone or carboplatin in combination with piroxicam.     

犬低分化鳞状细胞癌的病理特点

运用病理组织学方法,观察了3例犬低分化鳞癌的病理特点,结果显示,在犬低分化鳞状细胞癌组织中,癌细胞类似于棘细胞、基底细胞,癌组织中形成癌腔,在一些癌腔内可见角化不全细胞,无癌珠形成。癌腔是低分化鳞状细胞癌的病理特点之一,可作为诊断低分化鳞状细胞癌的依据。     

Pharmacokinetics of Oleandomycin in Dogs After Intravenous or Oral Administration Alone and After Pretreatment With Metamizole or Dexamethasone

The pharmacokinetics of oleandomycin OLD) after intravenous and oral administration, both alone and after intramuscular pretreatment with metamizole or dexamethasone, were studied in healthy dogs. After intravenous injection of OLD alone 10 mg/kg as bolus), the elimination half-life t _1/2, volume of distribution V _{d, area}), body clearance CL_B) and area under the concentration-time curve AUC) were 1.60 h, 1.11 L/kg, 7.36 ml/kg)/min and 21.66 µg h/ml, respectively. There were no statistically significant differences following pretreatment with metamizole or dexamethasone. After oral administration of OLD alone, the t _frac12;, maximum plasma concentrations C _max), time of C _max t _max), mean absorption time MAT) and absolute bioavailability F _abs) were 1.68 h, 5.34 µg/ml, 1.5 h, 1.34 h and 84.29%, respectively. Pretreatment with metamizole caused a significantly decreased value for C _max 2.93 µg/ml) but the MAT value 2.23 h) was significantly increased. Statistically significant changes in the pharmacokinetic parameters of OLD following oral administration were also observed as a result of pretreatment with dexamethasone. The C _max was increased 8.24 µg/ml) and the t _max 0.5 h) and MAT 0.45 h) were lower.     

Comparison of Adrenocorticotropic Hormone Stimulation Test Results Started 2 versus 4 Hours after Trilostane Administration in Dogs with Naturally Occurring Hyperadrenocorticism

Background

Trilostane medical treatment of naturally occurring hyperadrenocorticism (NOH) in dogs is common, as is use of the adrenocorticotropic hormone (ACTH) stimulation test (ACTHst) in monitoring response to treatment. There is uncertainty regarding when the ACTHst should be started relative to time of trilostane administration.

Objective

To compare ACTHst results in dogs being treated for NOH with trilostane when the test is begun 2 versus 4 hours after trilostane administration.

Animals

Twenty‐one privately owned dogs with NOH, each treated with trilostane for at least 30 days.

Methods

Each dog had 2 ACTHst completed, 1 started 2 hours and the other 4 hours after trilostane administration. The second test was started no sooner than 46 hours and no later than 74 hours after the first.

Results

For all 21 dogs, the mean post‐ACTH serum cortisol concentration from tests started 2 hours after trilostane administration (5.4 ± 3.7 μg/dL) was significantly lower (P = .03) as compared with results from the tests started 4 hours after administration (6.5 ± 4.5 μg/dL).

Conclusions

Results of ACTHst started at different times yield significantly different results. Dogs with NOH, treated with trilostane, and monitored with ACTHst results should have all of their subsequent ACTHst tests begun at or about the same time after trilostane administration.     

Reduced Response to Intravenous Endotoxin Injections Following Repeated Oral Administration of Endotoxin in the Pig

Three prepubertal gilts were each given 100 mg of endotoxin (ET) in their ordinary feed rations, twice daily for 6 days; 3 other gilts received standard feed. Following ET feeding, all animals were injected intravenously (i.v.) with ET (1.0 µg/kg b.w.) once daily for 5 days. Blood samples were collected and analysed for hematology and total serum bile acids (S-BA), glutamate dehydrogenase (S-GLDH), calcium (S-Ca), iron (S-Fe), zinc (S-Zn) and a blood plasma metabolite (15-ketodihy-dro-PGF2a; P-PG) of prostaglandin F2a. The animals showed no apparent clinical symptoms following ET-feeding, neither did the blood analyses reveal effects of oral ET. However, when iv ET injections were given, the ET-fed animals showed fewer clinical signs of endotoxemia following the 2nd to 5th injection. S-BA and S-GLDH increased markedly in the standard-fed group following the first injection, while the ET-fed animals showed a much smaller increase in S-BA and no change in S-GLDH on that day. The difference in response may be explained by a direct uptake of ET from the gastrointestinal tract in the ET-fed pigs, making them less sensitive to the injected ET     

磷—32玻璃微球肝动脉注射对猪肝脏毒性反应的电镜观察

为观察猪肝动脉注射磷-32 玻璃微球(32P-GMS)对肝脏急性、亚急性反应的超微结构损伤及修复过程。用7 只健康猪经切皮肝动脉内接受由选择性导管注射直径为46～76μm 的玻璃微球。其中4 只猪注射放疗性32P-GMS;3 只猪注射31P-GMS(对照)。术后2、4、8 或16 周分批取不同部位的肝组织进行电镜常规制样及电镜观察。结果选择性导管注射32P-GMS,内放射急性期(2 周时)肝细胞均出现明显的异常和严重损伤;亚急性期(4 周时)大部分肝细胞核基本正常,胞浆细胞器仍有变化;恢复期(8 周时)大部分肝细胞已修复,肝细胞基本正常,但胶原和贮脂细胞增多。内放射16 周时,肝细胞全部修复正常。观察结果表明,当吸收剂量每次不超过200Gy 的32P-GMS经肝动脉给药时,肝细胞的损伤是短期而可逆性的。     

Early diagnosis may hold the key to the successful treatment of nasal and paranasal sinus neoplasia in the horse

Intrasinus neoplasia remains a rare but difficult condition to diagnose and treat in the horse, comprising approximately 8–19% of sinonasal disorders. There are, however, only a few case series upon which to base an approach to diagnosis and management ( Cotchin 1967, 1977 ; Madewell et al. 1976 ; Stunzi and Hauser 1976 ; Sundberg et al. 1977 ; Priester and McKay 1980 ; Boulton 1985 ; Hilbert et al. 1988 ; Dixon and Head 1999 ; Head and Dixon 1999 ; Tremaine and Dixon 2001a,b ). Squamous cell carcinoma (SCC) is the most common neoplasm observed in the equine paranasal sinuses. Evidence from other species would indicate that early recognition of SCC is crucial to the success of treatment and the ideal treatment remains complete excision with margins. Sinus involvement generally precludes this and we must often settle for surgical debulking, with or without adjunctive radio‐ or chemotherapy. In horses, as in other species, early recognition is difficult because clinical signs are nonspecific. Treatment is, therefore, often not attempted due to the extensive nature of lesions at presentation and the limited surgical access. The accompanying article by Kowalczyk et al. (2011 ) showed how 3‐dimensional (3D) imaging can identify the hallmark changes associated with aggressive neoplasia in the equine sinuses ( Kowalczyk et al. 2011 ). The value of computed tomography (CT) and magnetic resonance imaging (MRI) lies in noninvasive early diagnosis as well as lesion monitoring post intervention. Where CT can be performed with the horse in the standing position, avoidance of general anaesthesia offers further value, especially as standing surgical techniques now allow thorough, minimally invasive evaluation and biopsy of the equine sinuses. In combination, standing CT and minimally invasive sinus surgery allow accurate and early diagnosis and monitoring of disease progression, opening the door for advances in surgical and adjunctive treatments for this complex condition.