Retrospective outcome evaluation for dogs with surgically excised, solitary Kiupel high-grade, cutaneous mast cell tumours.

Published outcomes for dogs with specifically high-grade mast cell tumours (MCTs), controlled for clinical stage, are few. Clinical outcomes for 49 dogs with Kiupel high-grade, clinical stage I, cutaneous MCTs were evaluated. Median survival time (MST) was 1046 days; 1 and 2-year survival rates were 79.3% and 72.9%, respectively. At study end 24 dogs had died, 23 dogs were alive (median follow-up 980 days) and 2 dogs were lost to follow-up. Death was considered MCT-related in 14 of 20 dogs with a known cause of death. Local tumour recurrence developed in nine dogs (18.4%); regional lymph node metastasis occurred in six dogs (12.2%); and a new MCT developed in 15 dogs (30.1%). Tumour location, histologic margin size and use of chemotherapy did not affect MST; increasing mitotic count (P = .001) and increasing tumour diameter (P = .024) were independently negatively prognostic. Six dogs that developed lymph node metastasis after surgery had worse MST (451 days) than 42 dogs that did not develop metastasis (1645 days); (P < .001). Our study suggests that dogs with local surgical control of clinical stage I histologically high Kiupel grade cutaneous MCT may have a long survival time; especially those with smaller tumours and a lower mitotic count. Our results suggest that evaluation of staging information and mitotic count may be equally helpful as histologic grading when making a prognosis; and highlight the importance of not relying on histologic grade alone when predicting survival for dogs with MCT.

Rapid clinical progression of B-cell chronic lymphocytic leukemia in a horse.

CASE DESCRIPTION: A 17-year-old Friesian gelding was examined at a referral hospital because of a 1-month history of mild exercise intolerance and marked lymphocytosis. CLINICAL FINDINGS: Physical examination revealed no peripheral lymphadenopathy or other abnormalities. Results of an abdominal palpation examination per rectum and thoracic and abdominal ultrasonographic examinations were unremarkable. B-cell chronic lymphocytic leukemia (CLL) was diagnosed on the basis of severe lymphocytosis and positive expression of the B-cell marker CD20 by lymphocytes in the bone marrow and peripheral blood. TREATMENT AND OUTCOME: Treatment with prednisolone (2 mg/kg [0.9 mg/lb], PO, every other day) and chlorambucil (20 mg/m2, PO, every 3 weeks for 2 doses, then every 2 weeks) was initially associated with improvement in clinical signs and a decrease in the lymphocyte count. However, 3 weeks after administration of the first dose of chlorambucil, the lymphocyte count began to increase. One week later, the horse developed episodes of recurrent fever and the lymphocyte count continued to increase. Despite continued administration of the prednisolone-chlorambucil protocol, the horse's clinical condition deteriorated rapidly, and it was euthanized 6 weeks after initial examination at the referral hospital because of a poor prognosis. A necropsy was not performed. CLINICAL RELEVANCE: B-cell CLL has been infrequently described in horses. This report was the first to describe the use of chemotherapy, albeit unsuccessful, for the treatment of B-cell CLL in a horse. This information should be useful for guiding expectations for prognosis and management of other horses affected with the disease.

Retrospective evaluation of clinical outcome after chemotherapy for lymphoma in 15 equids (1991-2017).

BACKGROUND: Prognosis associated with lymphoma in horses is poorly characterized, and treatment is often palliative. Long-term outcome after chemotherapy for horses with lymphoma is not well documented. OBJECTIVE: To report long-term outcome of horses with lymphoma treated with chemotherapy. ANIMALS: Fifteen equids. METHODS: Retrospective case series. Medical record search and call for cases on the ACVIM listserv for horses treated with chemotherapy for lymphoma. RESULTS: Fifteen cases with adequate data were identified. Complete remission was achieved in 5 horses (33.3%), partial response was achieved in 9 equids (60%), and stable disease was achieved in 1 horse. Overall response rate was 93.3% (14/15). Overall median survival time was 8 months (range, 1-46 months). Nine horses experienced a total of 14 adverse effects attributable to chemotherapy. Adverse effects were graded according to the Veterinary Cooperative Oncology Group common terminology criteria for adverse events grading system (grade 1 alopecia, n = 2; grade 1 neutropenia, n = 2; grade 1 lymphopenia, n = 3; grade 1 lethargy, n = 1; grade 2 neurotoxicity, n = 1; grade 2 colic, n = 1; grade 1 hypersensitivity, n = 1; grade 2 hypersensitivity, n = 2; grade 5 hypersensitivity, n = 1). Higher grade adverse effects most commonly were associated with doxorubicin administration (n = 4), including 1 horse that died 18 hours post-administration. CONCLUSIONS AND CLINICAL IMPORTANCE: Chemotherapy can be used successfully for treatment of horses with lymphoma. Adverse effects, most commonly mild, occurred in approximately two-thirds of treated horses.

Retrospective study of survival time and prognostic factors for dogs with small intestinal adenocarcinoma treated by tumor excision with or without adjuvant chemotherapy.

OBJECTIVE To estimate survival time for dogs with small intestinal adenocarcinoma (SIACA) following tumor excision with or without adjuvant chemotherapy and to identify factors associated with survival time. DESIGN Retrospective case series with a nested cohort study. ANIMALS 29 client-owned dogs with surgically resected, histologically diagnosed SIACA. PROCEDURES Medical records were reviewed and data collected regarding dog signalment; clinical signs; physical examination findings; PCV; serum total solids concentration; diagnostic imaging results; tumor size, location, and histologic characteristics (serosal extension, lymphatic invasion, surgical margins, and lymph node metastasis); type of adjuvant chemotherapy; NSAID administration; and survival time. Variables were assessed for associations with survival time and hazard rate via Kaplan-Meier and Cox proportional hazards analyses. RESULTS Overall median survival time for dogs with SIACA following tumor excision was 544 days (95% confidence interval, 369 to 719 days). Based on Kaplan-Meier estimates, the 1- and 2-year survival rates were 60% and 36%, respectively. On multivariate analysis, only age category was an independent predictor of survival over the follow-up period. Dogs < 8 years of age had a significantly longer median survival time (1,193 days) than dogs ≥ 8 years (488 days). Lymph node metastasis, adjuvant chemotherapy, NSAID administration, and other assessed variables were not associated with survival time. CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that SIACA in dogs carries a fair prognosis following excision, even when lymph node metastasis is present. Prospective studies are warranted to better characterize the effects of adjuvant chemotherapy or NSAID administration on survival time.

Usefulness of chemotherapy for the treatment of very elderly dogs with multicentric lymphoma.

OBJECTIVE To evaluate factors for associations with duration of first remission and survival time in dogs ≥ 14 years of age with stage III to V multicentric lymphoma. DESIGN Retrospective cohort study. ANIMALS 29 dogs ≥ 14 years of age with multicentric lymphoma treated with a chemotherapy protocol at dosages used for younger dogs (n = 22) or with prednisolone alone (7). PROCEDURES Various data were collected from the medical records, including treatment response and related adverse events. Survival analysis was performed to determine duration of first remission and survival time (from start of chemotherapy), and these outcomes were compared between various groupings. RESULTS The 7 (24%) dogs that received prednisolone alone had a median survival time of 27 days and were excluded from further analysis. Complete clinical remission was achieved in 21 of the 22 (95%) remaining dogs; 1 (5%) achieved partial remission. Median duration of first remission was 181 days. Anemic dogs had a briefer remission period (median, 110 days) than nonanemic dogs (median, 228 days). Median survival time for all 22 dogs was 202 days, with estimated 1- and 2-year survival rates of 31% and 5%, respectively. Six (27%) dogs had adverse events of chemotherapy classified as grade 3 or worse. CONCLUSIONS AND CLINICAL RELEVANCE Survival time was substantially longer in dogs treated with a chemotherapy protocol versus prednisolone alone. Findings suggested that the evaluated chemotherapy protocols for lymphoma were beneficial for and tolerated by very elderly dogs, just as by younger dogs, and need not be withheld, or dosages adjusted, because of age alone.

Clinical outcome and prognosis of dogs with histopathological features consistent with epitheliotropic lymphoma: a retrospective study of 148 cases (2003-2015).

BACKGROUND: Limited information is available regarding the treatment and outcome of dogs with epitheliotropic lymphoma. The disease typically has a poor prognosis. OBJECTIVES: To characterize the clinical signs, identify prognostic factors and evaluate the treatment outcome of dogs with epitheliotropic lymphoma. METHODS: A retrospective review of medical records from 2003 to 2015. Treatment details, tumour response and survival time were recorded for 148 dogs. Potential prognostic factors were evaluated for their statistical effect on median survival time. RESULTS: The overall median survival time for dogs was 264 days (cutaneous: 130 days; mucocutaneous/mucosal: 491 days). On multivariate analysis, a shorter median survival time was associated with the cutaneous form (P < 0.001) and the presence of multiple lesions (P < 0.001). Among 80 dogs with cutaneous lesions, chemotherapy treatment (P < 0.001) and having a solitary lesion (P < 0.001) were associated with longer median survival. In 72 dogs with multiple cutaneous lesions, chemotherapy intervention (P < 0.001), retinoid treatment (P = 0.001) and complete remission (P = 0.001) were associated with longer median survival. In 68 dogs with mucocutaneous/mucosal lesions, decreasing age (P = 0.020) and a solitary lesion (P = 0.015) were associated with longer median survival. CONCLUSION: Canine epitheliotropic lymphoma may be divided into cutaneous and mucocutaneous/mucosal forms. Solitary lesions have a better prognosis. Dogs with multiple lesions appear to benefit from chemotherapy and retinoid treatment, with those attaining complete remission having longer survival times. Multi-agent chemotherapy could be considered in dogs with cutaneous lesions that fail to respond to single-agent chemotherapy.

Evaluation of clinical and histologic factors associated with survival time in dogs with stage II splenic hemangiosarcoma treated by splenectomy and adjuvant chemotherapy: 30 cases (2011-2014).

OBJECTIVE To determine histologic and clinical factors associated with survival time in dogs with stage II splenic hemangiosarcoma treated by splenectomy and a chemotherapy protocol in which an anthracycline was alternated with lomustine. DESIGN Retrospective case series. ANIMALS 30 dogs with stage II splenic hemangiosarcoma. PROCEDURES Medical records of 3 facilities were reviewed to identify dogs treated for stage II splenic hemangiosarcoma between June 2011 and October 2014. Information collected included signalment, disease staging data, whether anemia was present, date of splenectomy, chemotherapy protocol, adverse effects, and date of death or last follow-up. Histologic slides were reviewed and scored by pathologists. Associations between variables of interest and survival data were evaluated statistically. RESULTS Median survival time for all dogs was 158 days (range, 55 to 560 days), and the 1-year survival rate was 16%. On multivariate analysis, only the histologically determined mitotic score was significantly associated with survival time. The median survival time of 292 days for dogs with a mitotic score of 0 (< 11 mitoses/10 hpf; n = 9) was significantly longer than that for dogs with higher scores (indicating higher mitotic rates); the 1-year survival rate for these dogs was 42%. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that future studies should take histologic factors, particularly mitotic rate, as well as tumor stage into account when assessing treatment effects on survival time of dogs with splenic hemangiosarcoma.

Ovarian carcinomatosis in a dog managed with surgery and intraperitoneal, systemic, and intrapleural chemotherapy utilizing indwelling pleural access ports.

A 3-year-old Weimaraner dog was presented with bilateral papillary ovarian carcinoma and abdominal carcinomatosis. Treatment included ovariectomy, intraperitoneal cisplatin, and systemic carboplatin. Pleural carcinomatosis 473 days following surgery was treated with intrapleural cisplatin through indwelling pleural access ports. Euthanasia occurred 1154 days following surgery due to malignant pleural effusion without peritoneal effusion.

Carcinomatose ovarienne chez une chienne gérée par chirurgie et chimiothérapie intrapleurale, systémique et intrapéritonéale en utilisant des ports d'accès à demeure. Une chienne Weimaraner âgée de 3 ans a été présentée avec un carcinome papillaire bilatéral et une carcinomatose abdominale. Le traitement a inclus l'ovariectomie, de la cisplatine intrapéritonéale et de la carboplatine systémique. Une carcinomatose pleurale 473 jours après la chirurgie a été traitée avec de la cisplatine intrapleurale par des ports d'accès pleuraux à demeure. L'euthanasie a été réalisée 1154 jours après la chirurgie en raison d'une effusion pleurale maligne sans épanchement péritonéal.(Traduit par Isabelle Vallières).

Incidence of sterile hemorrhagic cystitis in tumor-bearing dogs concurrently treated with oral metronomic cyclophosphamide chemotherapy and furosemide: 55 cases (2009-2015).

OBJECTIVE To determine the incidence of sterile hemorrhagic cystitis (SHC) in tumor-bearing dogs concurrently treated with oral metronomic cyclophosphamide chemotherapy and furosemide. DESIGN Retrospective case series. ANIMALS 55 dogs. PROCEDURES Record databases of 2 specialty practices were searched to identify dogs treated with oral metronomic cyclophosphamide chemotherapy in conjunction with furosemide for a minimum of 28 days between January 2009 and December 2015. Information extracted from the records included signalment, tumor diagnosis, cyclophosphamide and furosemide dosages, and concurrent medications. Confirmed SHC was defined as the presence of gross or microscopic hematuria and clinical signs associated with lower urinary tract disease in the absence of infection or neoplasia of the urinary tract; the definition for suspected SHC was the same, except the absence of infection or neoplasia of the urinary tract was not confirmed. RESULTS Cyclophosphamide dosage varied from 6.5 to 18.6 mg/m2 once daily to 6.3 to 49.2 mg/m2 every other day. Median duration of cyclophosphamide administration was 272 days (range, 28 to 1,393 days). Median cumulative dose of cyclophosphamide administered was 2,898 mg/m2 (range, 224 to 14,725 mg/m2). Median furosemide dose was 1.4 mg/kg (0.64 mg/lb). Confirmed or suspected SHC was identified in 2 of 55 (3.6%) dogs. Cyclophosphamide administration was discontinued for the dog with confirmed SHC but not the dog with suspected SHC. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that oral administration of furosemide in conjunction with oral metronomic cyclophosphamide chemotherapy was associated with a low incidence of SHC, which suggested that furosemide may protect against cyclophosphamide-induced SHC.

Treatment of canine non-indolent T cell lymphoma using the VELCAP-TSC protocol: A retrospective evaluation of 70 dogs (2003-2013).

The immunophenotype of canine non-indolent lymphoma has prognostic value; dogs with T cell lymphoma have a poorer response rate and shorter survival times than dogs with B cell lymphoma. This study sought to retrospectively evaluate prognostic factors for complete remission (CR), progression free survival (PFS) and overall survival time (OST) in 70 dogs with T cell lymphoma treated with an alkylator-rich, combination protocol. The overall remission was 72.9%; 45 dogs (64.3%) achieved CR and six (8.6%) achieved partial remission. Dogs that were neutropenic at diagnosis were significantly more likely to achieve CR. The median overall PFS was 175 days; 1, 2 and 3 year PFS were 26.8%, 15.8%, and 12.6%, retrospectively, after commencing chemotherapy. Median PFS was significantly longer for dogs that achieved CR. Median OST was 237 days. The 1, 2 and 3 year survival rates were 31%, 20.2% and 11.5%, retrospectively, after commencing chemotherapy. The median OST was significantly longer for dogs that achieved CR and significantly shorter for Boxers and those in substage b at diagnosis. More than 30% of dogs treated with this protocol survived >1 year, suggesting that favourable outcomes and longer survival are possible for a proportion of dogs with T cell lymphoma.

Canine Osteosarcoma Treated by Post-Amputation Sequential Accelerated Doxorubicin and Carboplatin Chemotherapy: 38 Cases.

Canine appendicular osteosarcoma is an important clinical problem in veterinary medicine. Current standard therapy includes amputation followed by chemotherapy, which improves outcomes; however the percentage of long-term survival is still relatively low at 15-20%. Established prognostic factors include serum alkaline phosphatase level, histologic grade, and lymphocyte and monocyte counts. We used a protocol with shorter inter-treatment intervals than standard, but which we expected to still be well-tolerated, based on drugs known to be active agents, with the aim of improving outcomes by increasing dose intensity. Thirty-eight dogs with confirmed appendicular osteosarcoma and no pulmonary metastases that underwent amputation followed by this chemotherapy protocol were retrospectively evaluated. The median survival time was 317 days and 1- and 2-yr survival percentages were 43.2% and 13.9%, respectively. Toxicity was comparable to that seen with other standard dose protocols, with 5.2% of dogs hospitalized for complications that resolved with supportive care and no chemotherapy-related mortality. Serum alkaline phosphatase level (normal or high) (p = 0.004) and whether or not chemotherapy was completed (p = 0.001) were found to significantly impact survival time on multivariate analysis. Outcomes were similar to those reported with most other published chemotherapy protocols for dogs with this disease.

Doxorubicin and carboplatin trials in Tasmanian devils (Sarcophilus harrisii) with Tasmanian devil facial tumor disease.

The devil facial tumor disease (DFTD) is having a devastating impact on Tasmanian devils (Sarcophilus harrisii) (devils) in the wild. Only a single study has been published regarding treatment of DFTD, where vincristine was not found to be an effective chemotherapeutic agent. In the current study, devils were treated with escalating dosages of carboplatin (8-26 mg/kg) (n = 13) and doxorubicin (0.75-1.0 mg/kg) (n = 5). Dosages for carboplatin (20 mg/kg) and doxorubicin (1.0 mg/kg) were identified as maximally tolerated dosages. Limiting toxicities for carboplatin were anorexia and weight loss (gastrointestinal signs) and azotemia. Limiting toxicities for doxorubicin were neutropenia, anorexia and weight loss. None of the treated devils responded to either drug, suggesting that, based on the clonality of this tumour, it is unlikely that either drug individually or in combination would be effective treatments for DFTD. These results, however, provide valuable information for practitioners who may choose to treat other neoplastic diseases in the devil or other marsupials. In addition, these results show that even drugs that are metabolized and excreted in the same manner can be tolerated to different degrees by the same species.

A combination chemotherapy protocol with dose intensification and autologous bone marrow transplant (VELCAP-HDC) for canine lymphoma.

Twenty-eight dogs with lymphoma were treated with a 12-week, 5-drug chemotherapy protocol concluding with high-dose cyclophosphamide supported by autologous bone marrow transplants. A dose escalation design was used to determine the maximum tolerated cyclophosphamide dose (MTD) in this setting. Three cyclophosphamide dose levels were given: 300 mg/ m2 IV (groupl, 3 dogs), 400 mg/m2 IV (group 2, 12 dogs), and 500 mg/m2 IV (group 3, 13 dogs); and the MTD was 500 mg/m2 IV. Toxicity was common but mild, and the dose-limiting toxicity was myelosuppression, specifically neutropenia. No dog died as a result of treatment-related toxicity. One dog in group 3 developed fever, neutropenia, and presumed sepsis and responded promptly to routine management. No other dog required hospitalization. Lower stage and higher cyclophosphamide dose (both increasing dose [study groups 1-3], and the highest dose [group 3]) compared with the lower doses combined (groups 1 and 2) were significantly associated with longer remission duration (all P < .0001). Median remission duration for dogs in group 3 was 54 weeks, compared with 21 weeks for dogs in groups 1 and 2 combined. Factors associated with longer survival time were lower stage (P = .042) and higher cyclophosphamide dose (both increasing dose [study groups 1-3], and the highest dose [group 3] compared with the lower doses combined [groups 1 and 2]) (P = .027). Median survival time for dogs in group 3 was 139 weeks, compared with 43 weeks and 68 weeks for dogs in groups 1 and 2, respectively.

Prognostic factors for survival of dogs with inguinal and perineal mast cell tumors treated surgically with or without adjunctive treatment: 68 cases (1994-2002).

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.

H2-mismatched transplantation with repetitive cell infusions and CD40 ligand antibody infusions without myeloablation.

Graft rejection and graft-versus-host disease are major problems in mismatched marrow transplants along with toxicity from standard myeloablative host treatments. We have established a tolerization model, using 1 Gy irradiation, which reduces stem cell capacity to < 10% of control while causing minimal myelosuppression, donor antigen pre-exposure (spleen cells), CD40-ligand antibody blockade and high levels of marrow (40 x 106 cells), which allows for stable long-term multilineage engraftment in H2-mismatched murine marrow transplants. We now show that the establishment of 'microchimaerism' (0.5-3.8%) sets the stage for macrochimaerism, with subsequent marrow infusions in H2-mismatched mice with CD40-ligand blockade only. Neither irradiation nor spleen cell exposure were necessary. When 40 x 106 bone marrow cells were infused on weeks 0, 12, 14 and 16, blood engraftment was about seven times the single 40 x 106 control. When marrow cells were given on weeks 0, 3, 4, 5 and 6, engraftment at 24 weeks post transplant was 17.9 +/- 1.2%, compared with 2.7 +/- 0.8% for the single 40 x 106 control (P = 0.009). We have shown stable, long-term multilineage chimaerism and established that the schedule of marrow administration, not the total cell dose, is critical for tolerization. This approach indicates that microchimaerism can tolerize for subsequent marrow infusions and produce macrochimaerism. This strategy could be applied in clinical human transplants.

The new stem cell biology.

Recent studies have indicated that bone marrow stem cells are capable of generating muscle, cardiac, hepatic, renal, and bone cells. Purified hematopoietic stem cells have generated cardiac and hepatic cells and reversed disease manifestations in these tissues. Hematopoietic stem cells also alter phenotype with cell cycle transit or circadian phase. During a cytokine stimulated cell cycle transit, reversible alterations of differentiation and engraftment occur. Primitive hematopoietic stem cells express a wide variety of adhesion and cytokine receptors and respond quickly with migration and podia extensions on exposure to cytokines. These data suggest an "Open Chromatin" model of stem cell regulation in which there is a fluctuating continuum in the stem cell/progenitor cell compartments, rather than a hierarchical relationship. These observations, along with progress in using low dose treatments and tolerization approaches, suggest many new therapeutic strategies involving stem cells and the creation of a new medical specialty; stemology.