Treatment Of Mast Cell Tumors Research Articles

Comparison of Nucleosome, Ferritin and LDH Levels in Blood with Clinical Response before and after Electrochemotherapy Combined with IL-12 Gene Electrotransfer for the Treatment of Mast Cell Tumours in Dogs

Comparison of Nucleosome, Ferritin and LDH Levels in Blood with Clinical Response before and after Electrochemotherapy Combined with IL-12 Gene Electrotransfer for the Treatment of Mast Cell Tumours in Dogs

반려동물의 표적치료제에 대한 고찰

Advances in bioinformatics using next-generation sequencing have dramatically identified new molecules involved in the pathogenesis of various diseases. As a result, many molecularly targeted therapeutics have been developed in medicine including veterinary medicine. In the field of veterinary medicine, toceranib, a multikinase inhibitor was approved 2009 following masitinib, which was the first molecularly target drug approved in 2008. Toceranib is originally approved as a treatment for mast cell tumors, but has been shown to be effective in other tumors as well. Therefore, there is a lot of potential for approved anti-cancer drugs to be used to treat other another type of diseases such as neurodegenerative diseases. Immunotherapies and cancer vaccine are also emerging as targeted therapeutics. In this review, we will discuss the approved molecularly targeted drugs and high potential drugs currently in clinical trials.

Clinical treatment of mast cell tumor in dog

Clinical treatment of mast cell tumor in dog

Superficial kilovoltage x-ray radiotherapy for the treatment of cutaneous mast cell tumors on the head in three dogs and one cat: a limited retrospective case series.

To report preliminary findings of hypofractionated superficial radiotherapy for treatment of cutaneous mast cell tumors (MCTs) and report the acute and late toxicity associated with its use. 3 dogs and 1 cat. In this retrospective study, medical records from January 2021 through July 2022 were searched for animals that received superficial radiation therapy for MCTs of the head. 4 patients with 5 MCTs were included. Three of the masses were periocular and required protection of the globe with a tungsten eye shield. One patient did not complete the intended protocol due to diffuse metastatic spread noted after the second fraction. Of the 3 patients that completed their protocol, 100% had a complete response. Two canine patients were treated adjunctively with toceranib. Two of the 4 patients experienced grade 1 acute veterinary radiation therapy oncology group (VRTOG) toxicity, and the 3 patients that completed their protocol experienced grade 1 late VRTOG toxicity. No radiation effects were documented to the cornea or lens in any patient. Superficial radiation therapy was effective in our limited study population, and patients experienced minimal side effects for treatment of cutaneous MCTs.

Abstract 5122: Electrochemotherapy and IL-12 gene electrotransfer in treatment of mast cell tumors in companion dogs

Abstract When cells or tissues are exposed to an electric field, structural changes can be induced in the cell membrane, allowing molecules to flow into the cells. This condition is useful for delivering cytotoxic drugs whose transport into cells is impeded, such as bleomycin and cisplatin. This is referred to as electrochemotherapy (ECT). When DNA or RNA molecules are transported into cells, the approach is called gene electrotransfer (GET). ECT is an effective local treatment for tumors, but it lacks the systemic component of treatment that is essential for fighting metastatic disease. Cancer progression and metastasis are closely related to an inadequate antitumor immune response. Therefore, the antitumor efficacy of interleukin 12 (IL -12), a cytokine that stimulates the innate and adaptive immune response, has been tested in preclinical studies using plasmid DNA encoding IL -12 delivered into the tumor by gene electrotransfer (IL -12 GET). In addition, the combined treatment of ECT and IL -12 GET has already been shown to be effective in the treatment of mouse tumors and has been used in clinical trials in companion dogs to treat various histological types of spontaneous tumors. The results of these studies showed that the treatment is safe and effective. However, in these clinical trials, IL -12 GET was administered by different routes, either intratumorally (i.t.) or peritumorally (peri.t.). Therefore, the aim of this study was to compare the two IL -12 GET routes of administration in combination with ECT and to determine their contribution to the enhanced response to ECT. In the clinical trial, 59 dogs with spontaneous mast cell tumors (MCT) were divided into two groups: one group was treated with the combination of ECT and GET peri.t. (29 dogs) and the other with the combination of ECT + GET i.t. (30 dogs). The efficacy of the treatment was compared with the group of 18 dogs treated with ECT alone. In addition, immunohistochemical studies of tumor samples before treatment and flow cytometric studies of PMBC before and after treatment were performed to determine immunological aspects of the treatment. The results of this study showed that local tumor control was significantly better in the ECT + GET i.t. group (p < 0.05) than in the ECT + GET peri.t. and ECT groups. In addition, the disease-free interval (DFI) and progression-free survival (PFS) were significantly longer in the ECT + GET i.t. group than in the other two groups (p < 0.05). The data on local tumor response, DFI and PFS were consistent with immunological studies, as we detected increased infiltration of antitumor immune cells after treatment in the ECT + GET i.t. group, also suggesting a systemic effect. Citation Format: Maja Cemazar, Ursa Lampreht Tratar, Nina Milevoj, Katarina Znidar, Katja Ursic Valentinuzzi, Andreja Brozic, Gregor Sersa, Natasa Tozon. Electrochemotherapy and IL-12 gene electrotransfer in treatment of mast cell tumors in companion dogs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5122.

Treatment of multiple synchronous canine mast cell tumours using intratumoural tigilanol tiglate.

Mast cell tumours (MCTs) are common canine skin neoplasia. While they generally occur as single tumours, multiple synchronous MCTs (msMCTs) of de novo/non-metastatic origin are reported in a proportion of the patient population. Where there is no evidence of metastasis or lymphatic spread, MCTs are effectively controlled by surgery and other local therapies. However, treatment of de novo msMCTs can be more challenging, especially when they occur in surgically difficult locations. Here, we report the use of tigilanol tiglate, a novel small molecule registered as a veterinary pharmaceutical for the local treatment of non-metastatic MCTs, in the treatment of patients with msMCTs presenting at three Australian specialist referral centres. We also present a meta-analysis of the literature to provide a better understanding of the prevalence of canine msMCTs. Notably, nine patients with a total of 32 MCTs were treated during the study. A complete response was recorded in 26 (81%) of the individual MCTs on Day 28 after a single tigilanol tiglate injection. Of the 6 initially non-responsive MCTs, one achieved a complete response after a further tigilanol tiglate treatment. A complete response was reported at 6 months in all 22 of the tumours that were evaluable and that had recorded a complete response at Day 84. For the literature meta-analysis, 22 studies were found with prevalence estimates of msMCTs ranging from 3 to 40%; when combined, these studies yielded 3,745 patients with a prevalence of 13% (95% CI 10; 16). Overall, the results demonstrate the utility of intratumoural tigilanol tiglate as an option for the treatment of multiple MCTs where multiple surgical resections would have been required.

Imatinib Mesylate for the Treatment of Canine Mast Cell Tumors: Assessment of the Response and Adverse Events in Comparison with the Conventional Therapy with Vinblastine and Prednisone.

Mast cell tumors (MCTs) are common neoplasms in dogs, and treatments for these diseases include surgery, polychemotherapy and targeted therapy with tyrosine kinase inhibitors. This study aimed to evaluate the response and the adverse events of treatment with imatinib mesylate (IM) compared to conventional therapy using vinblastine and prednisolone (VP) in canine cutaneous MCTs. Twenty-four dogs were included in the study; 13 animals were treated with IM and 11 with VP. Tumor tissue samples were submitted for histological diagnosis, grading and KIT immunostaining. The response to treatment was assessed by tomographic measurements according to VCOG criteria. Adverse events were classified according to VCOG-CTCAE criteria. The IM and VP groups had dogs with similar breeds, gender, ages, MCT localization, WHO stages and lymph node metastasis profiles. Most MCTs were grade 2/low and had KIT- patterns 2 and 3. The objective response rate (ORR) was significantly higher (30.79%) in the IM group then in VP group (9.09%). Adverse events (AE) in IM group were all grade 1, significantly different from VP. In conclusion, IM presented better ORR and less severe adverse events when compared to VP, representing a suitable option for the treatment of low-grade canine MCTs.

Outcomes of adjunctive radiation therapy for the treatment of mast cell tumors in dogs and assessment of toxicity: A multicenter observational study of 300 dogs.

BackgroundRadiation therapy is commonly used as an adjunct to incomplete surgical excision in dogs with mast cell tumors (MCT), but the optimal dose and fractionation regimen have yet to be determined.HypothesisWe assessed outcomes (time to local recurrence, patient survival and toxicity) of a large population of dogs with MCT that received adjunctive radiation therapy.AnimalsThree hundred dogs with 302 MCT treated using adjunctive radiation therapy.MethodsRetrospective observational study. Clinical records of 4 veterinary radiation centers were reviewed.ResultsLocal recurrence rates were similar regardless of radiation protocol with 6.6% of patients developing recurrent cutaneous MCT at a median of 526 days. Local recurrence rate was similar between high and low‐risk MCT. Mast cell tumor related death was reported in 19% of all dogs, with 13% of dogs with low‐risk MCT dying of their disease compared to 29% of dogs with high‐risk MCT. No SC MCT (SCMCT) recurred after radiation therapy and only 7% of dogs with SCMCT were reported to have died of their disease. Mild late toxicity was common in both protocols and severe late toxicity occurred in 1.9% of dogs many years after treatment.Conclusions and Clinical ImportanceOur study supports the use of adjunctive radiation for the long‐term control of incompletely or narrowly excised cutaneous and SCMCT in dogs. More moderate dose and fractionation protocols may be appropriate in the adjunctive treatment of low‐risk MCT in dogs. Large multicenter prospective studies are required to establish the optimal dose and fractionation for MCT of different risk categories.

Effects of Tyrosine Kinase Inhibitor-masitinib Mesylate on Canine Mammary Tumour Cell Lines.

IntroductionMasitinib mesylate, a selective tyrosine kinase inhibitor of the c-KIT receptor, is used for the treatment of mast cell tumours in dogs. Masitinib has previously been investigated in various cancers; however, its potential anticancer effect in canine mammary tumours (CMTs) is unknown. In the present paper, we investigated the antiproliferative effect of masitinib in CMT cells and its possible mechanisms of action.Material and MethodsThe effect of masitinib on the proliferation of CMT-U27 and CMT-U309 cells was assessed by MTT assay and DNA fragmentation. Flow cytometric analysis was used to measure the effect of masitinib on apoptosis and the cell cycle. Additionally, vascular endothelial growth factor levels (VEGF) were measured, and the proliferation marker Ki-67 was visualised in immunocytochemical stainings in CMT cells.ResultsTreatment with masitinib inhibited the proliferation of CMT cells in a concentration-dependent manner. Maximal apoptotic activity and DNA fragmentation were observed at approximately IC50 of masitinib in both cell lines. In addition, cell cycle distribution was altered and VEGF levels and Ki-67 proliferation indices were decreased in masitinib-treated cells in comparison with control cells.ConclusionIn this study, masitinib suppressed cell proliferation concomitantly via induction of apoptosis and cell cycle arrest by decreasing VEGF levels and the Ki-67 proliferation index in CMT-U27 and CMT-U309 cells in vitro, suggesting its potential as a therapeutic tool in the clinical setting of mammary cancer treatment in dogs.

Evaluation of scar revision after inadequate primary excision of cutaneous mast cell tumors in 85 dogs (2000-2013).

To determine the frequency of residual tumor, and factors associated with local recurrence and disease progression in dogs with incompletely excised mast cell tumors (MCT) following scar revision surgery. Retrospective study. Eighty-five dogs. Medical records from January 2000 to April 2013 were reviewed. Dogs with scar revision surgery after incomplete primary MCT excision were included. Recorded were signalment; initial tumor size, location and grade; time interval between primary excision and scar revision surgery; presence of MCT in the resected scar; local recurrence, lymph node metastasis, systemic metastasis, and cause of death. Eighty six tumors in 85 dogs were studied. Residual MCT was found in 23 (27%) resected scars. Seven (8%) scars with residual MCT had incomplete or narrow margins. Follow-up was available for 68 dogs (69 tumors; median 403 days; range 4-2939). Local recurrence was reported in three (4%) dogs at 212, 555, and 993 days. Disease progressed in 10 dogs (14.5%) with regional or systemic metastasis at a median of 207 days (64-1583). Margin status and presence of MCT in the resected scar were not associated with local recurrence or disease progression. Lymph node metastasis (p = .004), locoregional recurrence (p = .013), and disease progression (p = .001) were significantly more likely in Grade III tumors. Twenty-seven percent of resected scars contained residual MCT, but recurrence was uncommon after surgical revision. Clinicians should primarily consider tumor grade when estimating the likelihood of local recurrence and disease progression and determining the need for ancillary treatment of MCT after scar resection.

Wound formation, wound size, and progression of wound healing after intratumoral treatment of mast cell tumors in dogs with tigilanol tiglate

BackgroundTigilanol tiglate (TT) is a novel small molecule for intratumoral treatment of nonmetastatic mast cell tumors (MCTs) in dogs. In a randomized controlled clinical study, 75% of dogs that received a single TT treatment achieved complete resolution of the MCT by 28 days, with no recurrence in 93% of dogs at 84 days. Critical to TT's efficacy was the area of the wound (tissue deficit) after slough of the necrotic tumor relative to pretreatment tumor volume.ObjectivesTo analyze data collected during the previous study to (a) describe wounds after slough of treated MCTs and (b) identify determinants of wound area and speed of wound healing.MethodsWound presence, condition, and area were determined from clinical records of 117 dogs over 84 days after a single intratumoral TT treatment.ResultsTumor slough occurred 3 to 14 days after treatment, exposing granulation tissue in the wound bed. Wound area after tumor slough in general was related to pretreatment tumor volume, with maximal recorded wound area fully evident in 89% of dogs by day 7. In dogs achieving complete tumor resolution, all wounds were left to heal by secondary intention. Bandaging and other wound management interventions only were required in 5 dogs. Time to healing (ie, full re‐epithelialization of treatment site) depended on wound area and location on the body, with most wounds being fully healed between 28 and 42 days after treatment.ConclusionsWound area and healing after slough of TT‐treated tumors follow a consistent clinical pattern for most dogs.

Recurrence-free interval 12 months after local treatment of mast cell tumors in dogs using intratumoral injection of tigilanol tiglate.

BackgroundTigilanol tiglate (TT) is a novel small molecule approved by the European Medicines Agency for intratumoral treatment of mast cell tumors (MCTs) in dogs. In a randomized controlled clinical efficacy and safety study in the United States, 85 of 116 dogs that received a single TT injection achieved complete response (CR) of the treated MCT by day 28.ObjectiveTo evaluate the durability of the TT treatment response achieved at day 28 in the U.S. study by assessing MCT recurrence at the treatment site 6 and 12 months after TT administration.AnimalsEighty‐five dogs previously treated with TT.MethodsDogs that achieved CR at day 28 were assessed retrospectively for the presence or absence of MCT at the treatment site using records from clinical visits and telephone interviews with owners. Dogs unavailable at an assessment time were considered lost‐to‐follow‐up and data for their last assessment used in the final analysis.ResultsBy 12 months after TT treatment, 64 dogs remained evaluable, with 21 unavailable. Of evaluable patients, 57 (89%) remained tumor free at the treatment site and 7 (11%) had developed recurrence. All recurrences occurred within the first 6 months, predominantly (5/7, 71%) within the first 12 weeks.Conclusions and Clinical ImportanceTigilanol tiglate provided a durable long‐term local response for the treatment of MCT in dogs.

Randomized controlled clinical study evaluating the efficacy and safety of intratumoral treatment of canine mast cell tumors with tigilanol tiglate (EBC-46).

ObjectiveTo evaluate the efficacy and safety of tigilanol tiglate (TT) for local intratumoral treatment of mast cell tumors (MCTs) in dogs.MethodsA randomized controlled clinical study in 2 phases involving 123 dogs with cytologically diagnosed MCT. Phase 1 compared 81 TT‐treated dogs with 42 control dogs; phase 2 allowed TT treatment of control dogs and retreatment of dogs that failed to achieve tumor resolution after TT treatment in phase 1. Tigilanol tiglate (1 mg/mL) was injected intratumorally with dose based on tumor volume. Concomitant medications were used to minimize potential for MCT degranulation. Modified response evaluation criteria in solid tumors were used to evaluate treatment response at 28 and 84 days. Adverse events and quality of life were also assessed.ResultsA single TT treatment resulted in 75% complete response (CR) (95% confidence interval [CI] = 61‐86) by 28 days, with no recurrence in 93% (95% CI = 82‐97) of dogs by 84 days. Eight TT‐treated dogs that did not achieve CR in phase 1 achieved CR after retreatment, increasing the overall CR to 88% (95% CI = 77‐93). Control dogs had 5% CR (95% CI = 1‐17) at 28 days. Wound formation after tumor slough and wound size relative to tumor volume were strongly associated with efficacy. Adverse events typically were low grade, transient, and directly associated with TT's mode of action.ConclusionsTigilanol tiglate is efficacious and well tolerated, providing a new option for the local treatment of MCTs in dogs.

Comparison of Two Different Vinblastine Dosages for Treatment of Cutaneous Mast Cell Tumor in Dogs

Background: Mast cell tumors (MCT) are among the most common malignant cutaneous neoplasm in dogs with variable biologic behavior and remain a therapeutic challenge in high-grade cases. Surgery remains the primary treatment for canine MCT; however, chemotherapy and radiation therapy are commonly used to treat aggressive cases. The combination of vinblastine (VBL) at a dose of 2 mg/m² and prednisone is the classically described protocol for MCT treatment. Studies have shown the safety of higher VBL doses for dogs with MCT, but there is a lack of information regarding dose intensity and outcome as a goal after chemotherapy. This study aimed to evaluate the impact of a higher dose of VBL on MCT treatment outcome.Materials, Methods & Results: This was an observational and comparative study conducted in two different Veterinary Teaching Hospitals. Client-owned dogs with histopathological diagnosis of grade II or III MCT were selected and underwent at least four chemotherapy sessions with VBL and prednisone. The experimental group (EG) consisted of 18 dogs that received a dose of 3 mg/m² VBL treated in one institution. The control group (CG) included 31 dogs that received a dose of 2 mg/m² VBL treated at the other institution. All dogs treated in both groups had a clinical and complete blood count (CBC) evaluation performed previous the start of chemotherapy (T0) and before each weekly treatment (T1, T2, T3, and T4). After treatment, dogs in both groups were followed-up for the recurrence rate and overall survival time after diagnosis. There was no significant difference in clinical variables between EG and CG. During treatment, dogs of EG showed a significant reduction in erythrocyte, hemoglobin, and hematocrit values between T0 and T1, T2, T3, and T4 (P < 0.001). Comparatively, the CG showed significant reduction in hemoglobin (P = 0.02) and total leucocytes (P = 0.001) values in the same period. Despite these findings, these hematological parameters did not exceed the lower limit for the species in both groups. There was a higher-grade neutropenia one week after the first VBL application (T2) in both groups, with no statistical difference in neutrophil counts at T2 or during the whole treatment. There were discrete and self-limited episodes of anorexia, vomiting, and diarrhea in both groups. After chemotherapy, dogs in EG showed a significantly lower rate of recurrence than dogs in CG (P = 0.02). There was no significant difference in the overall survival time between groups.Discussion: The absence of significant differences in clinical variables (e.g. sex, age, histological grading, and tumor location) between EG and CG suggests that the groups may be similar regarding these parameters. All dogs included in this study had a recommendation for MCT post-operative chemotherapy treatment. VBL action is non-selective and anemia is not a commonly described adverse effect associated with its administration. Despite that, EG dogs exhibited a reduction in erythrocytes, hematocrit, and hemoglobin, and CG dogs in hemoglobin throughout T0 to T4. The highest number of neutropenia episodes occurred during T2, after the first VBL application in both groups with a trend of stabilization after T2, which is compatible with findings described in the literature. Any dog of EG or CG had to interrupt the treatment due to hematological or gastrointestinal toxicity or died during treatment. The role of VBL dose intensity in outcome is still debatable for dogs with MCT, once it is a multifactorial disease with variable presentation. In this study, there was no difference in overall survival time after diagnosis between groups, and EG dogs treated with a higher VBL dose showed significantly less tumor recurrence than CG.

Effects of ibrutinib on proliferation and histamine release in canine neoplastic mast cells.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is effective in the treatment of human chronic lymphocytic leukaemia and mantle cell lymphoma. Recent data have shown that ibrutinib also blocks IgE‐dependent activation and histamine release in human basophils (BAs) and mast cells (MCs). The aim of this study was to investigate whether BTK serves as a novel therapeutic target in canine mast cell tumours (MCTs). We evaluated the effects of ibrutinib on two canine MC lines, C2 and NI‐1 and on primary MCs obtained from canine MCTs (n = 3). Using flow cytometry, we found that ibrutinib suppresses phosphorylation of BTK and of downstream STAT5 in both MC lines. In addition, ibrutinib decreased proliferation of neoplastic MCs, with IC50 values ranging between 0.1 and 1 μM in primary MCT cells and between 1 and 3 μM in C2 and NI‐1 cells. In C2 cells, the combination “ibrutinib + midostaurin” produced synergistic growth‐inhibitory effects. At higher concentrations, ibrutinib also induced apoptosis in both MC lines. Finally, ibrutinib was found to suppress IgE‐dependent histamine release in primary MCT cells, with IC50 values ranging from 0.05 to 0.1 μM in NI‐1 cells, and from 0.05 to 1 μM in primary MCT cells. In summary, ibrutinib exerts anti‐proliferative effects in canine neoplastic MCs and counteracts IgE‐dependent histamine release in these cells. Based on our data, ibrutinib may be considered as a novel therapeutic agent for the treatment of canine MCT. The value of BTK inhibition in canine MCT patients remains to be elucidated in clinical trials.

Dose Characterization of the Investigational Anticancer Drug Tigilanol Tiglate (EBC-46) in the Local Treatment of Canine Mast Cell Tumors.

Mast cell tumor (MCT) is the most common cutaneous neoplasm in dogs and wide surgical resection is the current first-line treatment. However, recurrence is common and often requires more specialist and expensive therapies. Tigilanol tiglate is a novel small molecule drug delivered by intratumoral injection that is currently under development to provide a new option for treating MCT. The aim of this study was to characterize a safe and effective dose of tigilanol tiglate for canine MCT and to gather preliminary data on the drug's pharmacokinetics. A multicenter, open-label, uncontrolled, non-randomized, dose de-escalation design was used. Eligibility was MCT stage I/IIa and a tumor size of 0.1–6.0 cm3. Dosing was based on tumor size (50% v/v tumor) and 3 drug concentrations (1.0, 0.5, 0.2 mg/mL) were evaluated. Twenty-seven dogs were treated in 3 dose de-escalation cohorts (10, 10, and 7 dogs, respectively). Efficacy at 21 days was defined using international accepted solid tumor response criteria (RECIST). Greatest efficacy (90% complete response) was observed at the highest drug concentration (1.0 mg/mL) and adverse events were generally low grade, mild and transient, and directly associated with the mode of action of the drug. Hematological and serum biochemistry were generally unremarkable with plasma concentration curves typical of a non-intravenous parenteral medication. Intratumoral treatment of MCT with tigilanol tiglate at a concentration of 1.0 mg/mL was highly efficacious and well-tolerated. These results support the drug's further development for the treatment of MCT and other solid tumors.

English

English

Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry

Masitinib (MST) is an orally administered drug that targets mast cells and macrophages, important cells for immunity, by inhibiting a limited number of tyrosine kinases. It is currently registered in Europe and USA for the treatment of mast cell tumors in dogs. AB Science announced that the European Medicines Agency has accepted a conditional marketing authorization application for MST to treat amyotrophic lateral sclerosis. In our work, we focused on studying in vivo metabolism of MST in Sprague–Dawley rats. Single oral dose of MST (33 mg kg−1) was given to Sprague–Dawley rats (kept in metabolic cages) using oral gavage. Urine was collected and filtered at 0, 6, 12, 18, 24, 48, 72 and 96 h from MST dosing. An equal amount of ACN was added to urine samples. Both organic and aqueous layers were injected into liquid chromatography-tandem mass spectrometry (LC–MS/MS) to detect in vivo phase I and phase II MST metabolites. The current work reports the identification and characterization of twenty in vivo phase I and four in vivo phase II metabolites of MST by LC–MS/MS. Phase I metabolic pathways were reduction, demethylation, hydroxylation, oxidative deamination, oxidation and N-oxide formation. Phase II metabolic pathways were the direct conjugation of MST, N-demethyl metabolites and oxidative metabolites with glucuronic acid. Part of MST dose was excreted unchanged in urine. The literature review showed no previous articles have been made on in vivo metabolism of MST or detailed structural identification of the formed in vivo phase I and phase II metabolites.

Safety and efficacy of intralesional triamcinolone administration for treatment of mast cell tumors in dogs: 23 cases (2005-2011).

OBJECTIVE To evaluate the safety and efficacy of intralesional triamcinolone administration, as a sole or adjuvant treatment, in dogs with mast cell tumors. DESIGN Retrospective case series ANIMALS 23 dogs with mast cell tumors. PROCEDURES Medical records of dogs treated for a confirmed diagnosis of a mast cell tumor between 2005 and 2011 were reviewed. Patients with a confirmed diagnosis and measurable disease (tumor longest dimension ≥ 0.5 cm) that had received ≥ 1 intralesional treatment with triamcinolone, regardless of prior, concurrent, or adjuvant treatments, were eligible for inclusion. Data collected included patient characteristics, results of cytologic and histologic testing and tumor staging, triamcinolone dosage, treatment response, and adverse events. RESULTS 23 dogs with 24 tumors were included. Tumors were treated by means of intralesional triamcinolone administration alone (n = 5), intralesional triamcinolone administration with concurrent oral administration of glucocorticoids (6), and intralesional triamcinolone administration with concurrent cytotoxic chemotherapy, with or without oral administration of corticosteroids and radiation therapy (13). Of 5 dogs treated with intralesional triamcinolone administration alone, 1 achieved a complete response, 3 achieved a partial response, and 1 maintained stable disease. The response rate for all 24 tumors (23 dogs) was 67% (16/24), including 4 with a complete response and 12 with a partial response. The median time to progression was 63 days (range, 6 to 447 days). Three dogs experienced adverse events (local hemorrhage [n = 1]; suspected gastrointestinal ulceration [2]). CONCLUSIONS AND CLINICAL RELEVANCE Intralesional triamcinolone administration may be well tolerated and effective for treatment of nonresectable mast cell tumors in dogs.

Identification and characterization of in vitro phase I and reactive metabolites of masitinib using a LC-MS/MS method: bioactivation pathway elucidation

In vitro phase I metabolic reactions & cyano conjugates of masitinib.