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Low-grade canine cutaneous mast cell tumour (cMCT) with metastasis at the time of treatment is uncommonly reported, with few studies focusing on this specific clinical entity. The specific objective of this study was to systematically review the veterinary literature and perform a meta-analysis summarizing the clinical presentation, treatments reported and clinical outcomes from dogs with histologically low-grade cMCT and metastasis present at initial treatment. A total of 980 studies were screened with eight publications providing data on 121 dogs ultimately included. The most common treatments were surgery with adjuvant chemotherapy in 83/121 (69%) dogs; combined surgery, radiation and chemotherapy in 17/121 (14%) dogs; chemotherapy alone in 12/121 (10%) dogs and surgery alone in 7/121 (6%) dogs. Dogs with distant metastasis (n = 22) experienced significantly shorter survival compared with those with regional lymph node (RLN) metastasis (n = 99; median 194 vs 637 days; P < .01). Two variables were significantly associated with increased risk of death: presence of distant (vs RLN) metastasis (hazard ratio = 2.60; P < .01) and not receiving surgery as a component of treatment (hazard ratio = 3.79; P < .01). Risk of bias was judged to be low in terms of selection and performance bias but high in terms of detection and exclusion bias. In conclusion, dogs with cMCT and RLN metastasis can be expected to live significantly longer than those with distant metastasis, and surgery appears to have a role in extending survival of metastatic low-grade cMCT., (© 2020 John Wiley & Sons Ltd.)

The medical records of 4 dogs with histologically confirmed intranasal mast cell tumors (MCTs) were retrospectively evaluated to determine their biological behavior. Information on signalment, presenting clinical signs, tumor grade, treatment administered, and survival times was obtained from the medical record. All 4 patients had high grade tumors and received chemotherapy. Survival times ranged from 27 to 134 days. All 4 dogs showed signs of local or distant disease progression, suggestive of an aggressive behavior of intranasal MCTs.

A 2-tiered histologic grading scheme for canine cutaneous mast cell tumors (MCTs) is based on morphologic characteristics of neoplastic cells, including karyomegaly, multinucleation, nuclear pleomorphism, and mitotic figures. Aspirates from MCTs may provide the same information more quickly, inexpensively, and less invasively. This study used these criteria to develop a cytologic grading scheme for canine MCTs to predict outcome. Three anatomic pathologists graded histologic samples from 152 canine MCTs. Three clinical pathologists evaluated aspirates from these masses using similar criteria. A cytologic grading scheme was created based on correlation with histologic grade and evaluated with a kappa statistic. Survival was evaluated with Kaplan-Meier survival curves. Cox proportional hazards regression was used to estimate hazard ratios for tumor grades and individual grading components. Simple logistic regression tested for relationships between risk factors and mortality. The cytologic grading scheme that best correlated with histology (kappa = 0.725 ± 0.085) classified a tumor as high grade if it was poorly granulated or had at least 2 of 4 findings: mitotic figures, binucleated or multinucleated cells, nuclear pleomorphism, or >50% anisokaryosis. The cytologic grading scheme had 88% sensitivity and 94% specificity relative to histologic grading. Dogs with histologic and cytologic high grade MCTs were 39 times and 25 times more likely to die within the 2-year follow-up period, respectively, than dogs with low grade MCTs. High tumor grade was associated with increased probability of additional tumors or tumor regrowth. This study concluded that cytologic grade is a useful predictor for treatment planning and prognostication., (© The Author(s) 2016.)

Advanced SM is an incurable neoplasm with short survival time. So far, no effective therapy is available for these patients. We and others have shown recently that neoplastic MC in ASM and MCL express antiapoptotic Mcl-1, Bcl-2, and Bcl-xL. In this study, we examined the effects of the pan-Bcl-2 family blocker obatoclax (GX015-070) on primary neoplastic MC, the human MC leukemia cell line HMC-1, and the canine mastocytoma cell line C2. Obatoclax was found to inhibit proliferation in primary human neoplastic MC (IC₅₀: 0.057 μM), in HMC-1.2 cells expressing KIT D816V (IC₅₀: 0.72 μM), and in HMC-1.1 cells lacking KIT D816V (IC₅₀: 0.09 μM), as well as in C2 cells (IC₅₀: 0.74 μM). The growth-inhibitory effects of obatoclax in HMC-1 cells were accompanied by an increase in expression of Puma, Noxa, and Bim mRNA, as well as by apoptosis, as evidenced by microscopy, TUNEL assay, and caspase cleavage. Viral-mediated overexpression of Mcl-1, Bcl-xL, or Bcl-2 in HMC-1 cells was found to introduce partial resistance against apoptosis-inducing effects of obatoclax. We were also able to show that obatoclax synergizes with several other antineoplastic drugs, including dasatinib, midostaurin, and bortezomib, in producing apoptosis and/or growth arrest in neoplastic MC. Together, obatoclax exerts major growth-inhibitory effects on neoplastic MC and potentiates the antineoplastic activity of other targeted drugs. Whether these drug effects can be translated to application in patients with advanced SM remains to be determined.

Objective: To assess the usefulness of histologic evaluation of surgical margins to predict local recurrence of cutaneous malignant tumors in dogs and cats treated by means of surgical excision., Design: Prospective case series., Animals: 40 dogs and 20 cats., Procedures: 60 surgically excised tumors (20 soft tissue sarcomas [STSs], 20 mast cell tumors [MCTs], and 20 carcinomas) were examined histologically. Margins were classified as clean, close, or infiltrated; histologic grade was assessed in STSs and MCTs. Recurrence rates and recurrence-free intervals (RFIs) during a 24-month follow-up period were recorded, and method accuracy was calculated., Results: Surgical margins were clean in 29 of 60 (48%) tumors, close in 11 (18%), and infiltrated in 20 (33%). Tumors recurred in 27 of 60 (45%) animals, with a mean ± SD RFI of 229 ± 173 days. Recurrence rates for animals that had tumors with infiltrated (16/20) or close (8/11) margins were significantly higher than recurrence rate for animals that had tumors with clean margins (3/29). Margin classification was a significant predictor of RFI. Accuracy of the method to predict recurrence was 94% for carcinomas, 87% for STSs, and 76% for MCTs., Conclusions and Clinical Relevance: Histologic assessment of margin status was useful for predicting local recurrence of cutaneous malignant tumors in dogs and cats treated by means of excision alone. Method accuracy varied among tumor types and grades. Recurrence times suggested postsurgical follow-up should continue for ≥ 2 years. Results were similar for animals with infiltrated and close tumor margins, and careful postsurgical management is recommended for both.

This study reports the outcomes of dogs with grade 3 mast cell tumors (MCTs). Clinical and histopathological data were available for 43 dogs. Median progression-free survival (PFS) and overall survival (OS) were 133 and 257 days, respectively. Tumor size, lymph node (LN) status, and mitotic index (MI) significantly influenced PFS in univariate analysis. Tumor size and LN status remained significant in the multivariate analysis. Lymph node status, local tumor control, LN treatment, and MI significantly influenced OS in univariate analysis but only LN status remained significant in multivariate analysis. These results confirm that locoregional control improves outcomes in patients with grade 3 MCTs.

Objective: To evaluate the effectiveness of masitinib for the treatment of nonresectable mast cell tumors (MCTs) in dogs at 12 and 24 months after onset of treatment., Animals: 132 dogs with nonresectable grade 2 or 3 MCTs., Procedures: Dogs received masitinib (12.5 mg/kg/d, PO; n = 106) or a placebo (26). After 6 months, treatment was extended with tumor assessments at 3-month intervals until detection of disease progression. Endpoints were tumor response and overall survival rate and time., Results: In dogs with nonresectable MCTs, masitinib significantly improved survival rate, compared with results for the placebo, with 59 of 95 (62.1%) and 9 of 25 (36.0%) dogs alive at 12 months and 33 of 83 (39.8%) and 3 of 20 (15.0%) dogs alive at 24 months, respectively. Median overall survival time was 617 and 322 days, respectively. Tumor control at 6 months had a high predictive value for 24-month survival, with high specificity (88%) and sensitivity (76%), whereas short-term tumor response (within 6 weeks) had a poor predictive value. Complete responses at 24 months were observed in 6 of 67 (9.0%) dogs with nonresectable MCTs treated with masitinib., Conclusions and Clinical Relevance: Masitinib significantly increased survival rates at 12 and 24 months in dogs with nonresectable MCTs. Control of disease at 6 months, but not best response at 6 weeks, was predictive of long-term survival in dogs treated with masitinib, which suggested that short-term response may be irrelevant for assessing clinical efficacy of tyrosine kinase inhibitors for treatment of MCTs.

The purpose of this retrospective cohort study is to describe the association of cytological assessment of lymph node metastasis with survival and tumour grade in dogs with mast cell tumours. Regional lymph node aspirates of 152 dogs diagnosed with a mast cell tumour were reviewed and classified according to specific cytological criteria for staging. 97 dogs (63.8%) had stage I tumours, and 55 (36.2%) had stage II tumours. Stage II dogs had a significantly shorter survival time than dogs with stage I disease (0.8 and 6.2 years, respectively; P < 0.0001). Dogs with grade III mast cell tumours were more likely to have stage II disease (P = 0.004). These results suggest that cytological evaluation of lymph nodes in dogs with mast cell tumours provides useful and valuable clinical information, and the results correlate with tumour grade and outcome thus providing a practical and non-invasive method for staging.

Objectives: To evaluate the response of measurable canine mast cell tumours unsuitable for other treatment modalities to a chemotherapy protocol comprising chlorambucil and prednisolone., Methods: Dogs bearing measurable mast cell tumours, unsuitable for treatment by surgery or radiotherapy, were treated with orally administered prednisolone and chlorambucil, and their responses assessed., Results: Twenty-one dogs were enrolled in the study; 13 had intermediate-grade mast cell tumour, six were high grade and two were diagnosed by cytology alone. Eight dogs had multiple tumours and 13 dogs had single tumours, and six dogs had lymph node metastases and no dogs had visceral metastases detected. Three dogs achieved complete remission, five achieved partial remission (overall response rate 38 per cent), nine had static disease and four dogs had progressive disease. Median progression-free interval for the eight responders was 533 days, and median survival time for all dogs in the study was 140 days. Progression-free interval and median survival time were not influenced by the age, sex, weight or neutering status of the patient, by the grade or stage of the tumour or whether the patient had single or multiple tumours. No toxicity was detected., Clinical Significance: Response and survival rates of inoperable canine MCT to chlorambucil and prednisolone are comparable to previously described protocols, with no apparent toxicity.

Objective: To evaluate efficacy of hypotonic water as adjuvant therapy after marginal resection of canine mast cell tumors (MCT)., Study Design: Double-blinded, placebo-controlled, prospective, randomized study., Animals: Dogs (n=30) with spontaneous, cutaneous, solitary MCT., Methods: The wound bed of MCT, resected with margins <0.5 cm, was injected with either hypotonic or isotonic water according to a standardized protocol. Follow-up was obtained by clinical examination at 1, 2, 3, 6, and 12 months and annual telephone contact with the owner., Results: Eighteen dogs were treated with isotonic lactated Ringer's solution and 12 dogs with hypotonic distilled water. All MCT were stage 0 tumors and most grade II. Six tumors (4 isotonic, 2 hypotonic) recurred locally, 3 of these dogs died from disease-related reasons within 4 months. The surviving 3 dogs were alive with a median survival time (ST) of 1092 days. The calculated 2-year recurrence-free rate was 92.7%; the 2-year disease-free rate 79.1%; and the 2-year survival rate 89.5%. No significant differences in local recurrence and ST were observed between treatment groups. Histologic grading was the only significant prognosticator for ST and recurrence-free periods., Conclusion: No significant differences in local recurrence and ST were observed between adjunctive hypotonic water and placebo treatment after marginal resection of solitary MCT., Clinical Relevance: Hypotonic water does not decrease the rate of local recurrence in dogs with solitary MCT after marginal surgical excision.

The purpose of this study was to evaluate the short-term adverse events (AEs) in dogs with mast cell tumours (MCT) receiving prednisone and dose-escalating vinblastine (VBL). Twenty-four dogs were treated with intravenous VBL starting at 2 mg m(-2) and then escalating in weekly increments to 2.33, 2.67 and 3 mg m(-2). AEs were graded using a standardized scoring system. No dogs receiving 2 or 2.33 mg m(-2) experienced grade 3 or 4 AEs. Among the dogs, 9.5 and 5.9% had grade 3 or 4 AEs at dosages of 2.67 and 3 mg m(-2), respectively. Serious AEs included neutropaenia (n = 3) and vomiting (n = 1), only one of which required hospitalization. These data indicate that VBL chemotherapy may be safe to administer at higher than the traditional 2 mg m(-2) dosage for dogs with MCT. Randomized prospective trials are necessary to establish whether dose escalation will translate into improved response rates when compared with the standard 2 mg m(-2) dosage.

Objective: To determine the efficacy of strontium 90 beta irradiation in the management of cutaneous mast cell tumors (CMCTs) in cats., Study Design: Retrospective case series., Animals: 35 client-owned cats with CMCTs., Procedure: Medical records of cats with CMCTs in which tumors were radiated by use of a strontium 90 ophthalmic applicator from 1992 to 2002 were reviewed. Cats were included if CMCT was diagnosed, there were no other sites of MCT involvement at the time of treatment, and records contained adequate follow-up information to permit retrospective assessment of local tumor control., Results: 54 tumors in 35 cats were treated with a median dose of 135 Gy of strontium 90 beta irradiation, resulting in local tumor control in 53 of 54 (98%) tumors with a median follow-up time of 783 days after treatment. Median survival time was 1,075 days. Adverse effects of treatment appeared to be infrequent and of mild severity., Conclusions and Clinical Relevance: Results indicated that strontium 90 beta irradiation resulted in long-term tumor control and should be considered an effective alternative to surgical resection in management of CMCTs in cats.

Between 1997 and 1999, 280 dogs with mast cell tumours were identified, of which 59 (21 per cent) had multiple tumours. Follow-up data for survival analysis were available for 145 dogs with single tumours and 50 dogs with multiple tumours. There was no significant difference between the survival times of the two groups; the survival rates after 12 and 24 months were 88 per cent and 83 per cent, respectively, for the dogs with single tumours, and 86 per cent at both intervals for the dogs with multiple tumours. Eight of the dogs with single tumours had lymph node metastases (stage II disease) and these dogs had a median survival time of 431 days, whereas the 50 dogs with multiple tumours (classified as stage III disease) and the dogs with single tumours (classified as stage I disease) had not reached their median survival times. Golden retrievers appeared to be predisposed to developing multiple tumours in the population studied, with an odds ratio of 3.8. This study found no evidence that dogs with multiple tumours had different survival times than those with single tumours, although there was evidence that the presence of lymph node metastasis generally carried a poorer prognosis.

The goal of this study was to determine the significance of tumour depth, tumour location and multiple synchronous tumour masses for the prognostic evaluation of canine cutaneous mast cell tumours (MCTs). The study population consisted of 100 formalin-fixed, paraffin-embedded cutaneous MCTs that had been surgically removed from 100 dogs and submitted to the Diagnostic Center of Population and Animal Health at Michigan State University between 1998 and 2001. None of the dogs had received chemotherapy or radiation therapy. For each case the following data were obtained from the referring veterinarians: sex, breed, weight, age at diagnosis, diagnostics performed, adjunct medications given at the time of surgery, tumour location, number of tumour masses, tumour recurrence (development of MCTs at the surgical site), development of additional MCTs at distant sites (outside the surgical margins), tumour duration before removal, survival time and cause of death, if applicable. Tumour depth was determined through microscopic evaluation of 5 microm sections stained with haematoxylin and eosin. Based on univariable and multivariable survival analysis, dogs with multiple synchronous cutaneous MCTs at the time of diagnosis have a worse prognosis compared with dogs with single tumours. Additional treatment beyond surgical excision alone should be considered for these animals. Older dogs and Boxers with cutaneous MCTs were at higher risk to develop additional MCTs at distant sites (outside the surgical margins), and older and male dogs with cutaneous MCTs had significantly shorter survival times. Univariable analysis also determined that dogs with cutaneous MCTs located on the head and neck had an increased risk of additional MCT development at distant sites and that sterilized dogs with cutaneous MCTs had shorter survival times. However, these findings were not confirmed by multivariable analysis. Tumour depth was of no prognostic significance for dogs with cutaneous MCTs.

Objective: To determine the prognostic factors for survival and tumor recurrence in dogs with cutaneous mast cell tumors (MCTs) in the perineal and inguinal regions treated surgically with or without adjunctive radiation therapy, chemotherapy, or both., Design: Retrospective study., Animals: 68 dogs., Procedure: Medical records of dogs with histologically confirmed MCTs in the perineal region, inguinal region, or both treated surgically with or without adjunctive radiation therapy, chemotherapy, or both were reviewed., Results: Mean tumor-free interval was 1,635 days (median not reached), and 1- and 2-year tumor-free rates were 79% and 71%, respectively. Median survival time was 1,111 days (mean, 1,223 days), and 1- and 2-year survival rates were 79% and 61%, respectively. Factors that negatively influenced survival time were age at diagnosis, tumor recurrence, and treatment with lomustine., Conclusions and Clinical Relevance: Results indicated that dogs with MCTs in the inguinal and perineal regions, if appropriately treated, may have survival times and tumor-free intervals similar to dogs with MCTs in other locations.

Cutaneous mast cell tumors (MCTs) are one of the most common tumors in dogs. Currently, prognostic and therapeutic determinations for MCTs are primarily based on the histologic grade of the tumor, but a vast majority of MCTs are of an intermediate grade, and the prognostic relevance is highly questioned. A more detailed prognostic evaluation, especially of grade 2 canine MCTs, is greatly needed. To evaluate the prognostic significance of KIT and tryptase expression patterns in canine cutaneous MCTs, we studied 100 cutaneous MCTs from 100 dogs that had been treated with surgery only. The total survival and disease-free survival time and the time to local or distant recurrence of MCTs were recorded for all dogs. Using immunohistochemistry, 98 of these MCTs were stained with anti-KIT and antitryptase antibodies. Three KIT- and three tryptase-staining patterns were identified. The KIT-staining patterns were identified as 1) membrane-associated staining, 2) focal to stippled cytoplasmic staining with decreased membrane-associated staining, and 3) diffuse cytoplasmic staining. The tryptase-staining patterns were identified as 1) diffuse cytoplasmic staining, 2) stippled cytoplasmic staining, and 3) little to no cytoplasmic staining. Based on univariate and multivariate survival analysis, increased cytoplasmic KIT staining was significantly associated with an increased rate of local recurrence and a decreased survival rate. The tryptase-staining patterns were not significantly associated with any survival parameter. On the basis of these results, we propose a new prognostic classification of canine cutaneous MCTs, according to their KIT-staining pattern, that can be used for the routine prognostic evaluation of canine cutaneous MCTs.

The histological grade of 340 cutaneous mast cell tumours derived from 280 dogs was determined by an established histological grading system; 87 of the tumours (26 per cent) were well differentiated, 199 (59 per cent) were intermediately differentiated and 54 (16 per cent) were poorly differentiated. The one-year survival rates for the dogs with tumours of these three grades were significantly different (P = 0.0001), being 100 per cent, 92 per cent and 46 per cent, respectively. The median survival time for the dogs with poorly differentiated tumours was 278 days, significantly shorter than that for the dogs with either intermediately or well-differentiated tumours, which were both over 1300 days. Regrowth of the tumours was identified in 10 (19 per cent) of the dogs with poorly differentiated tumours, 12 (6 per cent) of the dogs with intermediately differentiated tumours and one of the dogs with well-differentiated tumours; only three of the tumours which regrew had initially had complete margins. The results suggest that wide surgical margins are not a prerequisite for a successful long-term outcome in dogs with well-differentiated cutaneous mast cell tumours.

Objective: To determine the efficacy (durations of remission and survival) of an alternating-day radiation protocol for incompletely excised histologic grade-III solitary mast cell tumors (MCTs) in dogs., Design: Retrospective study., Animals: 31 dogs., Procedure: Radiation (52 Gy in an 18-fraction alternating-day protocol) was delivered to an area bordered by margins > or = 3 cm around the surgical scar and to the associated local-regional lymph nodes. Dogs were not given chemotherapeutic agents concurrently or after radiation. Information on signalment, duration of remission, and survival time was obtained from medical records., Results: Median and mean durations of remission were 27.7 and 17.0 months, respectively (range, 1 to 47 months). Median and mean durations of survival were 28 and 20 months, respectively (range, 3 to 52 months). Dogs with tumors located on the skin of the pinna, perineum, and prepuce had a median duration of remission greater than dogs with tumors located at other sites (27.7 and 14.4 months, respectively). Dogs with tumors < or = 3 cm in maximum diameter before surgery survived longer than dogs with tumors > 3 cm (31 and 24 months, respectively). The remission rate was 65% and survival rate was 71% at 1 year after treatment. Sixteen dogs that were euthanatized had complications associated with local-regional tumor progression. Systemic metastases to liver, spleen, intestine, and bone marrow were detected in 1 dog., Conclusions and Clinical Relevance: Without further treatment, incompletely excised grade-III mast cell tumors have high local-regional recurrence; local-regional treatment with radiation may effectively be used to manage many such tumors.

Objective: To characterise the types of canine soft tissue sarcoma and mast cell tumour treated surgically at the University Veterinary Centre, Sydney. To evaluate the success of surgical treatment of these tumours and identify variables predictive of local recurrence and survival. To establish whether conclusions drawn from previous international studies are applicable to the University Veterinary Centre, Sydney, dog population and vice versa., Design: Clinical presentation and results of surgical excision of 54 soft tissue sarcomas and 70 mast cell tumours affecting the trunk and limbs of dogs at the University Veterinary Centre, Sydney, between 1989 and 2001 were reviewed retrospectively., Results: Cross-bred dogs and Rhodesian Ridgebacks were at significantly greater risk of developing soft tissue sarcomas, and Boxers, Australian Cattle Dogs and Staffordshire Bull Terriers were at significantly greater risk of developing mast cell tumours than other breeds. Fine needle aspiration biopsy yielded a correct diagnosis in 62.5% of soft tissue sarcomas and 96% of mast cell tumours. Local recurrence was encountered after surgical excision in 7.4% of soft tissue sarcomas and 7.3% of mast cell tumours. Metastasis occurred in 6% of soft tissue sarcomas and 12% of mast cell tumours. The most significant risk factors for local recurrence were contaminated surgical margins (soft tissue sarcomas) and histological grade (mast cell tumours). Due to the low number of animals experiencing metastasis, no conclusions could be drawn about significant risk factors., Conclusions: Aggressive surgical management of soft tissue sarcomas and mast cell tumours is associated with a low incidence of local recurrence. The type, location and behaviour of mast cell tumours and soft tissue sarcomas in the population of dogs presented to the University Veterinary Centre, Sydney are similar to those reported by others.

The weakly immunogenic murine P1A Ag is a useful experimental model for the development of new vaccination strategies that could potentially be used against human tumors. An i.m. DNA-based immunization procedure, consisting of three inoculations with the P1A-coding pBKCMV-P1A plasmid at 10-day intervals, resulted in CTL generation in all treated BALB/c mice. Surprisingly, gene gun skin bombardment with the pBKCMV-P1A vector did not induce CTL, nor was it protective against a lethal challenge with the syngeneic P1A-positive J558 tumor cell line. To speed up the immunization procedure, we pretreated the tibialis anterior muscles with cardiotoxin, which induces degeneration of myocytes while sparing immature satellite cells. The high muscle-regenerative activity observable after cardiotoxin inoculation was associated with infiltration of inflammatory cells and expression of proinflammatory cytokines. A single pBKCMV-P1A plasmid inoculation in cardiotoxin-treated BALB/c mice allowed for sustained expansion of P1A-specific CTL and the induction of strong lytic activity in <2 wk. Cardiotoxin adjuvanticity could not be replaced by another muscle-degenerating substance, such as bupivacaine, or by MF59, a Th1 response-promoting adjuvant. Although this vaccination schedule failed to induce tumor rejection in all immunized mice, the analysis of CD8 T cell responses at an individual mouse level disclosed that the cytotoxic activity of P1A-specific CTL was correlated to the antitumor efficacy. These results highlight the critical need to identify reliable, specific immunological parameters that may predict success or failure of an immune response against cancer.

The medical records of 24 dogs with histologically confirmed mast cell tumors (MCT) of the muzzle were retrospectively evaluated to determine their biologic behavior and prognostic factors. Information on signalment, tumor grade and stage, treatment methods, and pattern of and time to failure and death was obtained from the medical record. Twenty-three dogs were treated with combinations of radiotherapy, surgery, and chemotherapy; 1 dog received no treatment. There were 2 Grade 1, 15 Grade 11, and 7 Grade III tumors. Tumors were stage 0 (n = 8), stage 1 (5), stage 2 (6), stage 3 (4), and stage 4 (1). Mean and median survival times of treated dogs were 36 and 30 months, respectively. Prognostic factors affecting survival time included tumor grade and presence of metastasis at diagnosis. Dogs with Grade I and II tumors survived longer than dogs with Grade III tumors. Variables, including sex, age, gross versus microscopic disease, and treatment type were not found to affect survival. Local control rate was 75% at 1 year and 50% at 3 years. Tumor grade was the only variable found to affect local control. Dogs with Grade I tumors had longer disease-free intervals than those with Grade II tumors, and dogs with Grade II tumors had longer disease-free intervals than dogs with Grade III tumors. Eight of 9 dogs dying of MCT had local or regional disease progression. Muzzle MCT a rebiologically aggressive tumors with higher regional metastatic rates than previously reported for MCT in other sites.

The purpose of this study was to determine if the presence of histopathologically tumor-free versus nontumor-free margins was prognostic for relapse or tumor-related death in dogs following surgical excision of single or multiple cutaneous mast cell tumors confined to the skin without evidence of metastasis to lymph nodes or other noncutaneous sites. Differences in tumor-related death or frequency of relapse between the two groups were not significant. Failure to achieve histopathological tumor-free margins frequently did not lead to local relapse. All tumor-related deaths occurred following local relapse. The lack of statistical support for an association between prognosis and histopathological tumor-free versus nontumor-free margins may be a result of small sample size.

The records of 19 dogs with cutaneous mast cell tumor and regional lymph node metastasis (WHO Stage 2) were reviewed to determine the efficacy of radiation therapy in this population. Dogs with grade I (n = 1), grade II (n = 16), and grade III (n = 2) cutaneous mast cell tumor were included in this study. All dogs were treated with a combination of pre-irradiation surgical cytoreduction of the primary tumor, irradiation of the primary tumor and regional lymph node, and oral prednisone. Total radiation dose to the primary tumor and regional lymph node ranged from 48 to 57 Gray (Gy). The medial iliac and hypogastric lymph nodes were irradiated prophylactically in 11 dogs with primary tumor of the pelvic limb and positive ipsilateral popliteal lymph node. Total radiation dose to these lymph nodes ranged from 48 to 57 Gy. For all radiation fields, dose per fraction was 3 Gy, and therapy was administered on a Monday through Friday schedule. Acute and late radiation side effects observed in this study were considered acceptable. The median disease-free survival was 1,240 days (95% confidence interval 256 to 2,391 days). The disease-free survival in dogs with stage 2 mast cell tumor suggests that the combination of surgery, irradiation, and prednisone for the primary tumor along with irradiation of the positive lymph node is effective.

One hundred twenty-six cutaneous mast cell tumors obtained by excisional biopsy from 106 dogs were evaluated using immunohistochemical staining for the presence of p53 protein. A standard avidin-biotin immunohistochemical protocol was used incorporating a polyclonal antibody of rabbit origin (CM-1) as the primary antibody. Histopathologic grading of tumors was performed on hemotoxylin and eosin-stained samples. There was a significant difference in the percentage of cells staining positive for p53 for the histopathologic grades (P = 0.0005). Grade III tumors had a significantly greater p53 content than did grade I or II tumors (P < 0.05). Clinical data obtained retrospectively was available for 54 dogs. Tumor recurred in 19 of 54 (35.2%) dogs. Twenty-nine dogs died by the end of the study; 9 of 29 (31.0%) died of mast cell tumor disease. Histopathologic grade showed a significant negative association with survival time. Both clinical stage and histopathologic grade showed a significant negative association with time to recurrence. The percentage of cells staining positive for p53 did not significantly improve the forward analysis. Immunohistochemical detection of p53 did not appear useful in characterizing the clinical association between cutaneous mast cell tumor cellular features and survival time or time to tumor recurrence in dogs.

Eighty-three canine cutaneous mast cell tumors were graded histologically and evaluated immunohistochemically for p53 tumor-suppressor protein expression. An avidin-biotin immunohistochemical protocol incorporated a rabbit polyclonal antibody (CM-1) directed against normal and mutant p53 protein. Positive staining was observed in 44.6% (37/83) of tumors and included 50% (12/24) of grade I (well differentiated) tumors, 46.9% (23/49) of grade II (intermediate differentiation) tumors, and 20% (2/10) of grade III (poorly differentiated) tumors. A statistically significantly higher proportion (P < 0.019) of tumors from the head and neck (83.3%, 10/12), stained positive for p53 than tumors from the thorax, back, abdomen, and axilla (39.4%, 13/33), legs (35.7%, 10/28), or prepuce, scrotal, or inguinal areas (44.4%, 4/9). No statistically significant difference between p53 labeling and histologic grade, breed, or tumor size was present. Survival data were available for 53/83 (63.9%) of dogs. Positive reactivity for p53 was observed in 47% (25/53) of tumors within this group, with 57.9% (11/19) of grade I, 43.3% (13/30) of grade II, and 25% (1/4) of grade III tumors labeled. Mean survival time for the 53 dogs was 12.1 months. The median survival time for dogs with grade III tumors or tumors >5 cm was statistically significantly shorter (P < 0.0001) than for dogs with grades I and II or smaller tumors. Although p53 protein abnormalities may play a role in tumor development or behavior in some canine cutaneous mast cell tumors, immunoreactivity was not associated with lack of tumor differentiation, tumor locations previously shown to demonstrate aggressive biological behavior, breed predisposition, or survival times.

Forty-one dogs with mast cell tumors (MCTs) were treated with oral prednisone and injectable vinblastine (VBL), both in the adjuvant setting (23 dogs) and in dogs with gross disease (18 dogs). Adverse effects were noted in 20% (8/41) of the patients, usually after the 1st dose of VBL. Adverse effects were considered mild in 6, and severe, necessitating treatment discontinuation, in 2 (5%). Overall response rate in the evaluable dogs with gross disease was 47% (7/15), consisting of 5 complete responses and 2 partial responses. Median response duration was 154 days (24 to >645 days). As adjuvant therapy to incomplete surgical resection, prednisone and VBL conferred a 57% 1- and 2-year disease-free rate. Median survival time (MST) for the entire patient population was not reached with a median follow-up of 573 days; however, the MST for dogs with grade III MCT was 331 days, with 45% of dogs alive at 1 and 2 years. This is an apparent improvement over historical survival data employing surgery alone. Upon univariate analysis, significant prognostic factors (P < .05) for survival included presence of a locally recurrent tumor, presence of gross disease, argyrophilic nucleolar organizer region frequency, lymph node status, histologic grade, previous chemotherapy, and ulceration of the tumor. Similar criteria were significant when analyzed for time to treatment failure. Response to therapy was also predictive of survival in the gross disease group. Upon multivariate analysis, histologic grade (P = .012) and presence of a locally recurrent tumor (P < .001) were significant factors for survival.

Case records of 32 cats with cutaneous mast cell tumors (CMCTs) were reviewed. Using the Patnaik system for grading canine mast cell tumors, the relationships between histopathological grade and patient survival time and tumor recurrence were examined. Tumor histopathological grade had no prognostic significance. One-, two-, and three-year tumor recurrence rates following surgical excision were 16%, 19%, and 13%, respectively. Incomplete excision was not associated with a higher rate of tumor recurrence.

Objective: To evaluate a group of cats with malignant colonic neoplasia and to identify factors related to survival time., Design: Retrospective study., Animals: 46 cats with malignant colonic neoplasia., Procedure: Information on signalment, diagnostic findings, histopathologic diagnosis, surgical procedure performed, identification of nodal metastasis at surgery, type of chemotherapy administered, and survival time was obtained from the medical record of each cat. A diagnosis of malignant colonic neoplasia had been established by histologic examination of endoscopic biopsy specimens (3 cats), biopsy specimens obtained during laparotomy (38), or necropsy specimens (5)., Results: Mean age of cats was 12.5 years (range, 6 to 18 years). Ultrasonography was useful 84% of the time in localizing the mass to the intestine. Three cats had endoscopic biopsy, 9 had incisional biopsy, 21 had mass resection, and 8 had subtotal colectomy performed. Histopathologic diagnoses included adenocarcinoma (21 cats), lymphoma (19), mast cell tumor (4), and neuroendocrine carcinoma (2)., Clinical Implications: Obtaining clean margins at surgery seems to increase survival time in cats with malignant colonic neoplasia. Metastasis at the time of surgery decreases survival time. Data from this study indicate that the survival time of certain cats with colonic lymphoma may not be affected by chemotherapy. Cats with an unidentified colonic mass should receive a subtotal colectomy to increase survival time. Cats with colonic adenocarcinoma should receive a subtotal colectomy with consideration of doxorubicin administration to increase survival time.

In this study, age, sex, recurrence, metastasis, death rate, and histologic patterns were in agreement with those of previous reports on canine mast cell tumors. Histologic grading, mitotic index, chromosome nucleolar organizer regions stained with silver (AgNORs), and anti-proliferating cell nuclear antigen (PCNA) were evaluated as indicators of prognosis. Histologic grading, AgNORs estimated in 100 cells, and PCNA-labeled fraction estimated in five high power fields (HPFs) were significantly different between recurring and nonrecurring tumors. Those prognostic factors were also significantly different between tumors that metastasized and those that did not. The survival time was lower in dogs with mast cell tumors with histologic grade 3 (Patnaik's), AgNOR counts higher than 2.25, and PCNA count in five HPFs higher than 261. The significance of these factors as markers for prognosis determined by logistic regression analysis differed with the time period considered. By combining the three most significant prognostic factors in a prognostic index, three models were obtained to determine the probability of nonrecurrence at 3, 6, and 9 months after surgery. The models were accurate in the prediction of the outcome of up to 80% of mast cell tumors. The use of these models provides a less subjective means of prognosticating mast cell tumors than the use of any one component alone.

A case of malignant mastocytosis with peripheral blood involvement is presented. The course of the patient's illness was complicated by recurrent hypotensive episodes, presumed to have been caused by mast cell degranulation. Treatment with hydroxyurea was associated with persistent hypotension which resulted in death. It has been proposed that the diagnosis of mast cell leukemia be given to patients presenting with greater than 10% atypical mast cells in the blood. However, review of 16 published cases of malignant mastocytosis with circulating mast cells reveals that the clinical manifestations, complications, and survival do not vary significantly with the percentage of peripheral blood mast cells. Patients with malignant mastocytosis with significant involvement by atypical mast cells in the bone marrow and peripheral blood should be considered as having an aggressive disease, regardless of the percentage of circulating mast cells.

Eighty-three cutaneous mast cell tumors in the dog were classified morphologically into three grades. The neoplasms were excised surgically, and the dogs were followed for 1500 days. Comparison of morphologic grade of tumor with survival time revealed significant differences among the three groups (p less than 0.00010). Comparison of sex and age (above and below ten years) with morphologic grade of tumor revealed no significant differences.

The intratumoral administration of lipopolysaccharide (LPS) and muramyl dipeptide (MDP) in combination, but not separately, resulted in necrosis and rejection of subcutaneous P815 mastocytoma nodules in DBA/2 mice with 30 to 40% survival. Previous sensibilization of animals by LPS + MDP, treatment by indomethacin, cyclophosphamide or syngeneic lymphocytes did not augment the immunotherapeutic action of LPS + MDP combination. Reinoculation of P815 cells into cured DBA/2 mice 8 months after the disappearance of the primary tumor led to rejection of new nodules with 50% survival rate. In LPS + MDP immunotherapy of these tumors two stages may be distinguished by a thrombo-necrotic stage and that of development of immunity.

A mouse survival assay was evaluated for its suitability to enumerate metastatic P815 tumor cells in the draining lymph node and spleen of a B6D2 F1 (H-2b X H-2d) host bearing a primary intradermal P815 tumor. The mouse survival assay is based on the linear relationship between the log10 number of P815 tumor cells (H-2d) injected i.p. into mice and their mean survival time. It was found that the assay is capable of quantifying as few as 10 tumor cells in lymph node and spleen, but only if cell suspensions of these organs are treated with anti-H-2b serum and complement, in order to selectively destroy H-2bd host cells. This was necessary because host cells from the lymph node and spleen of a tumor-bearing host possessed antitumor functions, in that they were capable of destroying the H-2d P815 tumor cells when admixed with the tumor cells and injected i.p. into 800-rad irradiated test recipients. The kinetics of acquisition and loss of host cells with antitumor function and the Ly phenotype of these host cells suggest that they are the same cells that give the tumor-bearing host the capacity to express concomitant immunity against a tumor implant.

A treatment concept for the control of tumor growth utilized weekday radiotherapy and weekend chemotherapy. Mice were given sc injections of P815X2 mastocytoma cells on the lower back (day 0) and separated into the following treatment groups: 5-day/week X-irradiation, adriamycin alone at either 5 mg/kg body wt (days 6 and 13) or 2 mg/kg (days 5, 12, and 19), and combined radiotherapy and chemotherapy. Untreated controls had a mean tumor volume of 2.77 cm-3 and a mean survival time of 24 days. Adriamycin alone at 5 mg/kg resulted in an eventual tumor of 70 percent of the control value at death, whereas at 2mg/kg the tumor volume was 60 percent of control. After radiotherapy only, tumor size was 52 percent of control. Irradiation plus either 5 or 2 mg drug per kg body wt resulted in tumor volumes of 23 and 30 percent, respectively, of control values. Although no treatment regimen prolonged survival, the marked reduction in local tumor growth with combination therapy indicates that it may be a useful concept in future cancer therapy.

Purified supernatants obtained from human macrophage supernatants or the U937 human macrophage cell line are cytotoxic for tumor cells in vitro, and when tumor bearing animals are injected with these supernatants tumor growth is suppressed in vivo. Tumor growth rate and survival times were assessed for each group of animals. At day 12 after injection of the P815 tumor cells, no difference in tumor size could be demonstrated in any of the groups. However, by day 17 the tumors in the animals treated with macrophage supernatants or the U937 macrophage cell line supernatants did not continue to increase in size as was seen in the case of the control animals. When examining survival times, it appeared that the animals treated with macrophage supernatants survived approximately 8 days longer than did the animals receiving no treatment (35-day vs 27-day survival), and the animals treated with the U937 macrophage cell line supernatants survived approximately 13 days longer than the control animals (40-day vs 27-day survival). Thus, it appears that tumor cell growth can be slowed down in vivo when purified macrophage supernatants as well as the secretions from a human macrophage cell line are injected into the tumor mass.

Subcutaneous transplantation of the syngeneic P815 mastocytoma in DBA/2J mice induced an activation of splenic T cells which resulted in a hyperresponsiveness of the tumor-bearing animal to the unrelated antigens pneumococcal polysaccharide (Pn) and sheep red blood cells (SRBC). These tumor-activated T cells appeared to increase the plaque-forming cell (PFC) potential of suboptimal numbers of spleen cells, caused normal spleen cells to express increased numbers of PFC, and produced lymphokine(s) which also increased PFC responses of normal splenocytes. The tumor-activated T cells responsible for stimulating normal splenocytes in an in vitro antibody response were shown to be Ly+2- cells. The activity of the tumor-activated T-cell supernatants was not genetically restricted and required additional Ly1 T cells in order to induce rigorously clean B cells to produce antibody. The T cells capable of stimulating non-specific antibody responses were also capable of slowing tumor growth when injected with tumor cells in normal recipient mice. These results suggest that T cells activated by tumor antigens release immunostimulatory lymphokines and, at the same time, are capable of leading to inhibition of tumor growth.

Tumor-bearing animals injected with either LPS-activated or control macrophages were capable of suppressing tumor growth in vivo. Tumor growth rate and survival times were assessed for each group of animals. At day 12 after injection of the P815 tumor cells, no difference in tumor size could be demonstrated in any of the groups. However, by day 17 the tumors in the animals treated with 2.5 X 10(6) or 5 X 10(6) control as well as LPS-activated macrophages did not continue to increase in size as was seen in the case of the control animals. When examining survival times, it appeared that the animals treated with control or activated macrophages generally survived approximately 10 days longer than did the animals receiving no treatment (30-day vs 20 day survival). Thus, it appears that tumor cell growth can be slowed down in vivo when control or activated macrophages are injected into the site of the tumor mass.