Collagen molecular phenotypic switch between non-neoplastic and neoplastic canine mammary tissues.

In spite of major advances over the past several decades in diagnosis and treatment, breast cancer remains a global cause of morbidity and premature death for both human and veterinary patients. Due to multiple shared clinicopathological features, dogs provide an excellent model of human breast cancer, thus, a comparative oncology approach may advance our understanding of breast cancer biology and improve patient outcomes. Despite an increasing awareness of the critical role of fibrillar collagens in breast cancer biology, tumor-permissive collagen features are still ill-defined. Here, we characterize the molecular and morphological phenotypes of type I collagen in canine mammary gland tumors. Canine mammary carcinoma samples contained longer collagen fibers as well as a greater population of wider fibers compared to non-neoplastic and adenoma samples. Furthermore, the total number of collagen cross-links enriched in the stable hydroxylysine-aldehyde derived cross-links was significantly increased in neoplastic mammary gland samples compared to non-neoplastic mammary gland tissue. The mass spectrometric analyses of type I collagen revealed that in malignant mammary tumor samples, lysine residues, in particular those in the telopeptides, were markedly over-hydroxylated in comparison to non-neoplastic mammary tissue. The extent of glycosylation of hydroxylysine residues was comparable among the groups. Consistent with these data, expression levels of genes encoding lysyl hydroxylase 2 (LH2) and its molecular chaperone FK506-binding protein 65 were both significantly increased in neoplastic samples. These alterations likely lead to an increase in the LH2-mediated stable collagen cross-links in mammary carcinoma that may promote tumor cell metastasis in these patients.

Response-based modification of CHOP chemotherapy for canine B-cell lymphoma.

Despite high initial response rates, a subset of dogs with B-cell lymphoma responds less robustly to CHOP-based chemotherapy and experiences shorter survival. One hundred and four dogs with nodal B-cell lymphoma were treated with a response-based CHOP (RBCHOP) protocol modified based on response to individual drugs during the first chemotherapy cycle. Dogs achieving complete (CR) or partial response (PR) at week 3, following treatment with vincristine and cyclophosphamide, received RBCHOP 1 (n = 72), a protocol sequentially rotating vincristine, cyclophosphamide, and doxorubicin. Dogs without a detectable response at week 3 that subsequently achieved CR or PR following treatment with doxorubicin received RBCHOP 2 (n = 14), in which four doses of doxorubicin were given consecutively followed by vincristine and cyclophosphamide. Dogs that failed to respond at week 3 and then to doxorubicin at week 5 assessment were offered rescue chemotherapy (RBCHOP 3, n = 18). Median progression free survival (PFS) and overall survival time (OST) were similar between RBCHOP 1 (PFS 210 days, OST 354 days) and RBCHOP 2 (PFS 220 days, OST 456 days), but significantly shorter for RBCHOP 3 (PFS 34 days, OST 80.5 days, P < 0.001). No presenting signalment nor hematologic variable differentiated patient cohort, however, dogs in RBCHOP 2 and RBCHOP 3 were more likely to have a lymphocytosis at diagnosis (P = 0.02 and 0.04, respectively). Protocol modification based on response during the first cycle resulted in similar toxicity profiles and outcomes to previously published variants of CHOP, and prognosis remained poor for dogs failing to respond during the first treatment cycle.

Factors influencing complications following mastectomy procedures in dogs with mammary gland tumors: 140 cases (2009-2015).

OBJECTIVE: To evaluate complication rates for various types of mastectomy procedures, identify factors associated with an increased risk of complications, and determine the consequences of such complications. ANIMALS: 140 female dogs that underwent 154 separate mastectomy procedures to treat mammary gland tumors. PROCEDURES: Medical records of dogs in the Penn Vet Shelter Canine Mammary Tumor Program from July 2009 to March 2015 were reviewed. Data regarding signalment, tumor characteristics (ie, number and size, benign or malignant, and bilateral or unilateral), mastectomy type, anesthesia time, concurrent ovariohysterectomy or ovariectomy, surgeons' qualifications, antimicrobial administration after surgery, postoperative placement of surgical drains, and complications (seroma, abscess, dehiscence, or infection) were collected. Complications that required hospitalization were recorded. Fisher exact tests were used to evaluate associations between variables of interest and complications. Multivariable analysis was used to identify factors independently associated with an increased risk of complications. RESULTS: Complication rate following all mastectomy procedures was 16.9% (26/154); of these, 9 (34.6%) required hospitalization. High body weight, undergoing bilateral mastectomy, and postoperative antimicrobial administration were associated with significantly increased odds of complications. The odds of complications associated with postoperative antimicrobial administration, however, varied according to mastectomy type; dogs undergoing chain mastectomy that did not receive antimicrobials postoperatively had the highest odds of developing complications. Dogs undergoing concurrent ovariohysterectomy or ovariectomy had significantly decreased odds of complications. CONCLUSIONS AND CLINICAL RELEVANCE: Previously spayed dogs with a large body size that underwent the most extensive mastectomy procedures had increased odds of having postoperative complications.

Modeling molecular development of breast cancer in canine mammary tumors.

Understanding the changes in diverse molecular pathways underlying the development of breast tumors is critical for improving diagnosis, treatment, and drug development. Here, we used RNA-profiling of canine mammary tumors (CMTs) coupled with a robust analysis framework to model molecular changes in human breast cancer. Our study leveraged a key advantage of the canine model, the frequent presence of multiple naturally occurring tumors at diagnosis, thus providing samples spanning normal tissue and benign and malignant tumors from each patient. We showed human breast cancer signals, at both expression and mutation level, are evident in CMTs. Profiling multiple tumors per patient enabled by the CMT model allowed us to resolve statistically robust transcription patterns and biological pathways specific to malignant tumors versus those arising in benign tumors or shared with normal tissues. We showed that multiple histological samples per patient is necessary to effectively capture these progression-related signatures, and that carcinoma-specific signatures are predictive of survival for human breast cancer patients. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we provide FREYA, a robust data processing pipeline and statistical analyses framework.

Intratumoral collagen signatures predict clinical outcomes in feline mammary carcinoma.

Breast cancer is the most common cause of cancer-related deaths in women worldwide. Identification of reliable prognostic indicators and therapeutic targets is critical for improving patient outcome. Cancer in companion animals often strongly resembles human cancers and a comparative approach to identify prognostic markers can improve clinical care across species. Feline mammary tumors (FMT) serve as models for extremely aggressive triple negative breast cancer (TNBC) in humans, with high rates of local and distant recurrence after resection. Despite the aggressive clinical behavior of most FMT, current prognostic indicators are insufficient for accurately predicting outcome, similar to human patients. Given significant heterogeneity of mammary tumors, there has been a recent focus on identification of universal tumor-permissive stromal features that can predict biologic behavior and provide therapeutic targets to improve outcome. As in human and canine patients, collagen signatures appear to play a key role in directing mammary tumor behavior in feline patients. We find that patients bearing FMTs with denser collagen, as well as longer, thicker and straighter fibers and less identifiable tumor-stromal boundaries had poorer outcomes, independent of the clinical variables grade and surgical margins. Most importantly, including the collagen parameters increased the predictive power of the clinical model. Thus, our data suggest that similarities with respect to the stromal microenvironment between species may allow this model to predict outcome and develop novel therapeutic targets within the tumor stroma that would benefit both veterinary and human patients with aggressive mammary tumors.

Treating the locoregional lymph nodes with radiation and/or surgery significantly improves outcome in dogs with high-grade mast cell tumours.

High-grade canine mast cell tumours (HG-MCT) have a high rate of locoregional relapse. In this study, dogs with HG-MCT treated with radiation therapy (RT) were retrospectively evaluated to determine the benefit associated with treating the locoregional lymph nodes (LNs). Forty-two dogs were included. Variables assessed for association with overall survival (OS) and progression-free survival (PFS) included WHO stage, tumour location and size, LN irradiation (prophylactic, therapeutic or none), LN treatment (yes or no), LN status at RT (metastatic or nonmetastatic) and RT intent (definitive vs palliative). Lower-stage disease at irradiation was significantly associated with prolonged median PFS (425 vs 125 days for stage 0 vs 1-4), and OS (615 vs 314 days for stage 0 vs 1-4). Having any LN treatment and definitive RT were both significantly associated with prolonged OS. In order to evaluate the role of LN irradiation, dogs were divided into subgroups: (a) stage 0 at irradiation with no LN treatment (n = 14), (b) stage 0 at irradiation with prophylactic LN irradiation (n = 6), (c) stage 0 at irradiation but previously stage 2 (n = 5) and (d) stage >0 at irradiation (n = 17). Prophylactic LN irradiation significantly prolonged PFS (>2381 vs 197 days; group B vs A). Interestingly, dogs that were stage 2 and had LN treatment (C) had prolonged OS vs dogs with negative LNs and no LN treatment (A) (1908 vs 284 days; P = .012). This study confirms that prophylactic and therapeutic LN irradiation in dogs with HG-MCT is beneficial and improves outcome.

The estrogen effect; clinical and histopathological evidence of dichotomous influences in dogs with spontaneous mammary carcinomas.

The purpose of this study was to investigate the associations and explore the relationships between hormonal factors (serum estrogen, estrogen receptors and ovariohysterectomy) and other clinical/histological prognostic factors and their impact on outcome in dogs with mammary carcinomas. Data from two separate prospective studies on dogs with spontaneous mammary carcinomas were used for this research. All dogs underwent standardized diagnostic testing, staging, surgery and follow-up examinations. Serum estrogen was analyzed by competitive enzyme immunoassay or radioimmunoassay, and tumor estrogen receptor (ER) expression was analyzed by immunohistochemistry. A total of 159 dogs were included; 130 were spayed and 29 remained. High serum estrogen was associated with an overall longer time to metastasis (p = 0.021). When stratifying based on spay group, the effect was only significant in spayed dogs, (p = 0.019). Positive tumor ER expression was also associated with a longer time to metastasis (p = 0.025), but similar to above, only in dogs that were spayed (p = 0.049). Further subgroup analysis revealed that high serum estrogen was significantly associated with improved survival in dogs with ER positive tumors, but only in spayed dogs (p = 0.0052). Interestingly, the effect of spaying was the opposite in dogs with ER negative tumors; here, intact dogs with high serum estrogen but ER negative tumors had a significantly longer time to metastasis (p = 0.036). Low serum estrogen was associated with increased risk for the development of non-mammary tumors in the post-operative period (p = 0.012). These results highlight the dual effect of estrogen in cancer: Estrogen acts as a pro-carcinogen in ER positive mammary tumors, but a may have a protective effect in ER negative tumors, potentially via non-receptor mechanisms. The latter is supported by the decreased risk for non-mammary tumors in dogs with high serum estrogen, and explains the increased incidence of certain non-mammary tumors in in dogs spayed at an early age.

Developing and testing prognostic bio-scoring systems for canine mammary gland carcinomas.

Canine mammary carcinomas (CMC) represent a range of histolopathological subtypes with diverse biological behaviours. Several individual factors, including stage, grade, subtypes and presence of invasion, predict outcome. Less is known how these factors interact and impact prognosis. The purpose of this work was to develop and test comprehensive bio-scoring systems in CMCs. Clinical and histopathological data from 127 dogs with MCs treated through two prospective studies were obtained. All dogs underwent standardized pre-surgical staging, treatments and regular follow-up visits. All tumours were evaluated, classified and graded according to published guidelines. Time to primary metastasis was the main endpoint in this study. Two bio-scoring systems were developed: The multivariate scoring (MVS) was based on traditional statistical analysis where only factors significant in the multivariate analysis (tumour size and grade) were kept for the final model. The refined flexible scoring (RFS) system was based on results from subgroup analysis, which guided the development of a flexible system. Progressive worsening prognosis was observed with increasing bio-scores in both systems. MVS: Median primary metastasis-free survival (TTM1 days) was not reached in dogs with bio-scores 0 to 5, 10, 15 and 648, 149, 317, in MVS groups 25, 30, 40, respectively. Similarly, TTM1 was not reached in dogs with RFS 0, 1, 2 and 374, 407 and 149, in dogs with bio-scores 3, 4, 5, respectively. However, a more distinct separation between dogs with high risk vs low risk for metastasis was observed with RFS, suggesting superior overall prognostication regarding the risk for metastasis.

Diagnosis and Multimodal Treatment of Metastatic Maxillofacial Juvenile Embryonal Rhabdomyosarcoma in a Young Golden Retriever.

A 2 yr old male castrated golden retriever was evaluated for a rapidly progressing maxillofacial spindle cell tumor. On examination, an ill-defined left maxillary mass, a 2 cm swelling under the left eye, and an enlarged left mandibular lymph node were noted. The dog was bright and alert but appeared painful upon jaw extension. Cytology from the lymph node revealed metastatic disease. Thoracic radiographs and computed tomography scan revealed pulmonary nodules. Computed tomography of the head and neck revealed a 6.7 × 4.1 × 6.5 cm mass at the rostral aspect of the left zygomatic arch invading the orbit. A second opinion of the biopsy specimen in conjunction with positive immunohistochemical staining for desmin led to a revised diagnosis of rhabdomyosarcoma. Treatment consisted of three doses of palliative radiation therapy, in 8 Gy fractions, and chemotherapy with vincristine, cyclophosphamide, and doxorubicin. A rapid clinical response was noted shortly after treatment initiation; however, the response was temporary, and the dog was euthanized due to widespread metastatic disease and associated clinical signs 74 days after initial therapy. This is one of the first reports describing positive results from multimodal treatment with chemotherapy and radiation therapy of a maxillofacial juvenile rhabdomyosarcoma in the veterinary literature.

Investigating Associations Between Proliferation Indices, C-kit, and Lymph Node Stage in Canine Mast Cell Tumors.

Previous studies have evaluated cellular proliferation indices, KIT expression, and c-kit mutations to predict the clinical behavior of canine mast cell tumors (MCTs). The study purpose was to retrospectively compare mitotic index, argyrophilic nucleolar organizer regions (AgNORs)/nucleus, Ki-67 index, KIT labeling pattern, and internal tandem duplication mutations in c-KIT between stage I and stage II grade II MCTs. Medical records and tumor biopsy samples from dogs with Grade II MCTs with cytological or histopathological regional lymph node evaluation were included. Signalment, tumor location and stage, and presence of a recurrent versus de novo tumor were recorded. Mitotic index, AgNORs/nucleus, Ki-67, KIT staining pattern, and internal tandem duplication mutations in exon 11 of c-KIT were evaluated. Sixty-six tumors (51 stage I; 15 stage II) were included. Only AgNORs/nucleus and recurrent tumors were significantly associated with stage (odds ratio 2.8, 95% confidence interval [CI] 1.0-8.0, P = .049; odds ratio 8.8, 95% CI 1.1-69.5; P = .039). Receiver-operator characteristic analysis showed that the sensitivity and specificity of AgNORs/cell ≥ 1.87 were 93.3% and 27.4%, respectively, (area under the curve: 0.65) for predicting stage. Recurrent tumors and higher AgNORs/nucleus are associated with stage II grade II MCTs; however, an AgNOR cutoff value that reliably predicts lymph node metastasis was not determined.

Identification of prognostic collagen signatures and potential therapeutic stromal targets in canine mammary gland carcinoma.

Increasing evidence indicates that the tumor microenvironment plays a critical role in regulating the biologic behavior of breast cancer. In veterinary oncology, there is a need for improved prognostic markers to accurately identify dogs at risk for local and distant (metastatic) recurrence of mammary gland carcinoma and therefore would benefit from adjuvant therapy. Collagen density and fiber organization have been shown to regulate tumor progression in both mouse and human mammary tumors, with certain collagen signatures predicting poor outcomes in women with breast cancer. We hypothesized that collagen signatures in canine mammary tumor biopsies can serve as prognostic biomarkers and potential targets for treatment. We used second harmonic generation imaging to evaluate fibrillar collagen density, the presence of a tumor-stromal boundary, tumor associated collagen signatures (TACS) and individual collagen fiber characteristics (width, length and straightness) in grade I/II and grade III canine mammary tumors. Collagen density, as well as fiber width, length and straightness, were inversely correlated with patient overall survival time. Notably, grade III cases were less likely to have a tumor-stromal boundary and the lack of a boundary predicted poor outcome. Importantly, a lack of a defined tumor-stromal boundary and an increased collagen fiber width were associated with decreased survival even when tumor grade, patient stage, ovariohysterectomy status at the time of mammary tumor excision, and histologic evidence of lymphovascular invasion were considered in a multivariable model, indicating that these parameters could augment current methods to identify patients at high risk for local or metastatic progression/recurrence. Furthermore, these data, which identify for the first time, prognostic collagen biomarkers in naturally occurring mammary gland neoplasia in the dog, support the use of the dog as a translational model for tumor-stromal interactions in breast cancer.

Association between macroscopic appearance of liver lesions and liver histology in dogs with splenic hemangiosarcoma: 79 cases (2004-2009).

Medical records for 79 dogs with confirmed splenic hemangiosarcoma (HSA) following splenectomy were reviewed for information regarding either the presence or absence of macroscopic liver lesions and the histopathological characteristics of the liver. Only 29 of 58 dogs (50%) with grossly abnormal livers had HSA metastasis. No dogs with grossly normal livers had metastasis detected on liver pathology. Gross lesions in the liver such as multiple nodules, dark-colored nodules, and active bleeding nodules were highly associated with malignancy. For the dogs in this study, performing biopsy in a grossly normal liver was a low-yield procedure in dogs with splenic HSA.

Evaluation of Clostridium novyi-NT spores in dogs with naturally occurring tumors.

OBJECTIVE: To establish the maximum tolerated dose of Clostridium novyi-NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. ANIMALS: 6 client-owned dogs. PROCEDURES: A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C. novyi-NT spores i.v.. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. RESULTS: The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C. novyi-NT infection; both required surgical intervention. Clostridium novyi-NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that C. novyi-NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology.

Prognostic significance of weight changes during treatment of feline lymphoma.

The study purpose was to determine the prognostic significance of weight changes during feline lymphoma treatment. A secondary purpose was to compare weight changes according to baseline body weight, cell type and location. Records of 209 cats treated for lymphoma with chemotherapy from 1995 to 2007 were evaluated. Signalment, cell type, lymphoma location, baseline body weight, weight during treatment, and outcome information were collected. Lymphoma specific survival (LSS) was compared according to baseline weight and weight changes during treatment. Weight change over time was compared according to cell type (small versus large), location (gastrointestinal versus non-gastrointestinal) and baseline weight. Cats with large cell lymphoma that lost ≥ 5% body weight at 1 month had significantly shorter LSS than those that gained or had stable weight (P = 0.004). Percentage weight change over time differed significantly according to baseline weight group. These findings demonstrate the prognostic importance of weight loss in feline large cell lymphoma.

CD40-activated B cell cancer vaccine improves second clinical remission and survival in privately owned dogs with non-Hodgkin's lymphoma.

Cell-based active immunotherapy for cancer is a promising novel strategy, with the first dendritic cell (DC) vaccine achieving regulatory approval for clinical use last year. Manufacturing remains arduous, especially for DC vaccines, and the prospect of using cell-based immunotherapy in the adjuvant setting or in combination with chemotherapy remains largely untested. Here, we used a comparative oncology approach to test the safety and potential efficacy of tumor RNA-loaded, CD40-activated B cells in privately owned dogs presenting with non-Hodgkin's lymphoma (NHL), a clinical scenario that represents not only a major problem in veterinary medicine but also a bona fide spontaneous animal model for the human condition. When administered to NHL dogs in remission after induction chemotherapy, CD40-B cells electroporated ex vivo with autologous tumor RNA safely stimulated immunity in vivo. Although chemotherapy plus CD40-B vaccination did not improve time-to-progression or lymphoma-specific survival compared to dogs treated with chemotherapy alone, vaccination potentiated the effects of salvage therapy and improved the rate of durable second remissions as well as subsequent lymphoma-specific survival following salvage therapy. Several of these relapsed dogs are now long-term survivors and free of disease for more than a year. Overall, these clinical and immunological results suggest that cell-based CD40 cancer vaccination is safe and synergizes with chemotherapy to improve clinical outcome in canine NHL. More broadly, our findings underscore the unique value of clinical investigations in tumor-bearing companion animals.

Outcomes of dogs with grade 3 mast cell tumors: 43 cases (1997-2007).

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.

Case-control study to evaluate risk factors for the development of sepsis (neutropenia and fever) in dogs receiving chemotherapy.

OBJECTIVE-To identify risk factors for development of sepsis in dogs treated with chemotherapeutics and to evaluate the impact of sepsis on outcome. DESIGN-Case-control study. ANIMALS-Client-owned dogs with various cancers undergoing standard chemotherapeutic treatment at the University of Pennsylvania veterinary hospital. PROCEDURES-39 dogs with sepsis (cases) were identified through a search of the medical record database. Controls (n = 77) were randomly selected from dogs admitted during the same time period. Variables analyzed included patient demographics, tumor type, stage, remission status, treatment phase, chemotherapeutics used, and outcome. RESULTS-Dogs that weighed less and dogs with lymphoma were significantly more likely to become septic, compared with larger dogs or dogs with solid tumors. Septic dogs were also significantly more likely to have received doxorubicin (odds ratio [OR], 12.5; 95% confidence interval [CI], 2.4 to 66.0) or vincristine (OR, 9.0; 95% CI, 1.6 to 52.0) than controls. Of the 39 cases, 28 (71.8%) were in the induction phase of their protocol, and 19 of 39 (48.7%) became septic after receiving the chemotherapeutic drug for the first time. Median survival time of the cases (253 days) was not significantly different from that of the controls (371 days). CONCLUSIONS AND CLINICAL RELEVANCE-Dogs that weighed less were at increased risk for chemotherapy-induced sepsis. Tumor type and chemotherapeutic drug used were also important risk factors. These results may lead to the implementation of prophylactic measures, especially when doxorubicin or vincristine is used in the induction phase in small dogs with lymphoma.

Mammary adenocarcinomas in three male cats exposed to medroxyprogesterone acetate (1990-2006).

In this case series, three unrelated male housemate cats were treated repeatedly with injections of medroxyprogesterone acetate (MPA) for intercat aggression and urinary house soiling. All three cats subsequently developed multiple recurrent mammary adenocarcinomas and underwent numerous surgical resections. This report describes the clinical, histopathological and immunohistochemical findings in these three cats and highlights the potential for mammary carcinomas to develop in male cats years after receiving MPA injections. Extended survival times and a long delay between the administration of the progestin injections and the onset of mammary neoplasia are noted. Estrogen and progesterone receptor staining was performed on some of the tumors and the complex role of hormones in the pathogenesis and the prognosis of feline mammary carcinoma is discussed. Clinicians using MPA should institute life-long surveillance of their feline patients for mammary tumors.

Rescue therapy with doxorubicin-based chemotherapy for relapsing or refractory feline lymphoma: a retrospective study of 23 cases.

This study examined the efficacy of doxorubicin-based chemotherapy used for rescue therapy in refractory feline lymphoma. Records of 23 cats with lymphoma treated with chemotherapy who received doxorubicin for the first time in a rescue setting were reviewed. Seventeen (74%) of the 23 cats had only one treatment of doxorubicin. Five (22%) of the 23 cats had a positive response to doxorubicin and were given additional doses. The response to therapy in 4/5 of these responders could be assessed objectively, of which, two cats (9%) achieved partial remission (PR) and two cats (9%) achieved complete remission (CR). The two cats that achieved CR had differing response durations (6 weeks and greater than 47 months). Three of these five (60%) responders had also received concurrent other chemotherapy in addition to doxorubicin. Cell type and the use of concurrent chemotherapy were significant predictors of response. Cats with small-medium cell lymphomas (P=0.001) and cats that received concurrent chemotherapy with doxorubicin rescue (P=0.007) were more likely to respond favorably. This study suggests that doxorubicin-based chemotherapy is not an effective rescue protocol for feline lymphoma.

CCNU for the treatment of dogs with histiocytic sarcoma.

BACKGROUND: Histiocytic sarcoma is an aggressive neoplasm of dendritic cells that carries a grave prognosis. The efficacy of chemotherapy against this disease is unknown. The purpose of this study was to determine the efficacy of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in dogs with incompletely resected or metastatic histiocytic sarcoma, to describe the clinical characteristics of these dogs, and to identify factors affecting prognosis. HYPOTHESIS: Our hypothesis is that CCNU has activity against canine histiocytic sarcoma and can improve survival in dogs with advanced disease. ANIMALS: Included in analysis are dogs diagnosed with histiocytic sarcoma who had gross measurable or residual microscopic disease and who received CCNU. METHODS: A multi-institutional, retrospective, single-arm cohort study was conducted. Available biopsy samples were tested with an antibody against CD18 when possible to confirm the diagnosis of histiocytic sarcoma. RESULTS: Fifty-nine dogs were treated at 8 institutions. Twenty-three tumor specimens were confirmed to be CD18 positive. Treatment with CCNU at 60 to 90 mg/m2 resulted in an overall response rate of 46% in the 56 dogs with gross measurable disease. All 3 dogs with minimal residual disease experienced tumor relapse but lived 433 days or more after starting CCNU. The median survival of all 59 dogs was 106 days. Thrombocytopenia (< 100,000 platelets/microL) and hypoalbuminemia were found to be negatively associated with prognosis and were predictive of < 1 month survival. CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that CCNU is active against canine histiocytic sarcoma and may be useful in the treatment of dogs without negative prognostic factors.