Feline high-grade and large granular lymphocyte alimentary lymphomas treated with COP- or CHOP-based chemotherapy: A multi-centric retrospective study of 57 cases.

Specific data regarding outcome of cats with high-grade and large granular lymphocyte alimentary lymphoma (HGAL and LGL, respectively) treated with multi-agent chemotherapy are scarce. The aims of this multi-centric, retrospective study were to describe the outcome of cats with HGAL and LGL treated with COP- or CHOP-based chemotherapy and to identify potential prognostic factors. Cats with a cytological or histological diagnosis of HGAL or LGL lymphoma treated with COP- or CHOP-based protocol as first-line chemotherapy were included. Data regarding diagnosis, staging, treatment and follow-up were collected. Fifty-seven cats treated with CHOP (n = 37) or COP (n = 20) protocols were included. Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were observed in 20%, 22%, 36% and 22% of cats, respectively, for an overall response rate of 42%. Median progression-free interval (PFI) was 148 days and overall median survival time (OST) was 131 days. Cats achieving CR, PR or SD showed significantly longer PFI (p < .01) and OST (p < .015) compared with cats with PD. Other positive prognostic factors in multi-variate analysis were rescue treatment (p < .001) and absence of lymph node involvement (p < .03). Negative prognostic factors were diffuse infiltration of the gastrointestinal tract (p = .035) and infiltration of a non-haematopoietic organ (p < .01).

Outcome of dogs treated with chemotherapy for mesothelioma: A retrospective clinical study on 40 cases and a literature review.

Mesothelioma is an uncommon cancer in dogs for which there is no established standard of care. Chemotherapy is often suggested despite no definitive proof of efficacy. The aim of this study was to evaluate the impact of chemotherapy on survival of dogs with mesothelioma. A retrospective multicentric study was carried out. To be included, dogs needed to present an evocative clinical evolution and a morphological diagnosis of mesothelioma. Exclusion of other cause of effusion and complete clinical follow-up were also required. Fourty dogs were included, 27 received chemotherapy (group 1) and 13 did not (group 2). Groups were heterogeneous regarding the proportion of animals undergoing surgery as part of their treatment (16 in group 1, 2 in group 2; p = .016) and homogeneous otherwise. Univariate analysis showed that dogs from group 1 survived significantly longer than dogs from group 2 (MST: 366 vs. 74 days; p < .001). Complete resolution of effusion after the first chemotherapy administration positively correlated with survival in group 1 (MST: 415 vs. 160 days; p < .01). All other variable tested had no significant impact on survival in univariate analysis, but dogs undergoing surgery and dogs having serous membranes' modification at medical imaging tended to survive longer. Multivariate analysis confirmed that chemotherapy was the sole variable independently associated with survival in our study (odds ratio 5.57-6.12; p < .01).

Clinical validation of a next-generation sequencing-based multi-cancer early detection "liquid biopsy" blood test in over 1,000 dogs using an independent testing set: The CANcer Detection in Dogs (CANDiD) study.

Cancer is the leading cause of death in dogs, yet there are no established screening paradigms for early detection. Liquid biopsy methods that interrogate cancer-derived genomic alterations in cell-free DNA in blood are being adopted for multi-cancer early detection in human medicine and are now available for veterinary use. The CANcer Detection in Dogs (CANDiD) study is an international, multi-center clinical study designed to validate the performance of a novel multi-cancer early detection "liquid biopsy" test developed for noninvasive detection and characterization of cancer in dogs using next-generation sequencing (NGS) of blood-derived DNA; study results are reported here. In total, 1,358 cancer-diagnosed and presumably cancer-free dogs were enrolled in the study, representing the range of breeds, weights, ages, and cancer types seen in routine clinical practice; 1,100 subjects met inclusion criteria for analysis and were used in the validation of the test. Overall, the liquid biopsy test demonstrated a 54.7% (95% CI: 49.3-60.0%) sensitivity and a 98.5% (95% CI: 97.0-99.3%) specificity. For three of the most aggressive canine cancers (lymphoma, hemangiosarcoma, osteosarcoma), the detection rate was 85.4% (95% CI: 78.4-90.9%); and for eight of the most common canine cancers (lymphoma, hemangiosarcoma, osteosarcoma, soft tissue sarcoma, mast cell tumor, mammary gland carcinoma, anal sac adenocarcinoma, malignant melanoma), the detection rate was 61.9% (95% CI: 55.3-68.1%). The test detected cancer signal in patients representing 30 distinct cancer types and provided a Cancer Signal Origin prediction for a subset of patients with hematological malignancies. Furthermore, the test accurately detected cancer signal in four presumably cancer-free subjects before the onset of clinical signs, further supporting the utility of liquid biopsy as an early detection test. Taken together, these findings demonstrate that NGS-based liquid biopsy can offer a novel option for noninvasive multi-cancer detection in dogs.

Timing of adjuvant chemotherapy after limb amputation and effect on outcome in dogs with appendicular osteosarcoma without distant metastases.

OBJECTIVE: To determine an optimal time interval between amputation and initiation of adjuvant chemotherapy (TIamp-chemo) in dogs with appendicular osteosarcoma without distant metastases and whether TIamp-chemo was associated with outcome. ANIMALS: 168 client-owned dogs treated at 9 veterinary oncology centers. PROCEDURES: Data were collected from the dogs' medical records concerning potential prognostic variables and outcomes. Dogs were grouped as to whether they received chemotherapy within 3, 5, 7, 10, 15, 20, 30, or > 30 days after amputation of the affected limb. Analyses were performed to identify variables associated with time to tumor progression and survival time after limb amputation and to determine an optimal TIamp-chemo. RESULTS: Median TIamp-chemo was 14 days (range, 1 to 210 days). Median time to tumor progression for dogs with a TIamp-chemo ≤ 5 days (375 days; 95% CI, 162 to 588 days) was significantly longer than that for dogs with a TIamp-chemo > 5 days (202 days; 95% CI, 146 to 257 days). Median overall survival time for dogs with a TIamp-chemo ≤ 5 days (445 days; 95% CI, 345 to 545 days) was significantly longer than that for dogs with a TIamp-chemo > 5 days (239 days; 95% CI, 186 to 291 days). CONCLUSIONS AND CLINICAL RELEVANCE: Findings indicated that early (within 5 days) initiation of adjuvant chemotherapy after limb amputation was associated with a significant and clinically relevant survival benefit for dogs with appendicular osteosarcoma without distant metastases. These results suggested that the timing of chemotherapy may be an important prognostic variable.

Prostate artery chemoembolization in prostate cancer: A proof of concept study in spontaneous prostate cancer in a canine model.

PURPOSE: The purpose of this study was to assess the feasibility and efficacy of docetaxel-loaded bead chemoembolization in spontaneous prostate cancer in a canine model. MATERIALS AND METHODS: Five pet dogs with histopathologically proven prostate cancer were referred for prostate artery chemoembolization (PACE). After PACE, all animals were followed, including pharmacokinetic study and clinical and biological evolution, until death. Pelvic contrast-enhanced computed tomography examination was performed at one and two months. Animals were subjected to pathological examination after death. RESULTS: Both prostate arteries were successfully chemoembolized in all dogs. A median dose of 18 mg (Q1, Q3; 11.8, 20 mg) docetaxel loaded in 3 mL of 50-100 µm super absorbent polymer beads was injected into each dog. At one month, four of the five dogs were still alive and the median prostate volume was 51% lower (prePACE median prostate volume, 18.4 mL [Q1, Q3; 12, 32.1 mL] vs. postPACE median prostate volume, 6.2 mL [Q1, Q3; 6.2, 11 mL]). At two months, three dogs died because of disease progression. The two remaining dogs showed a 70% median decrease in prostate volume. Prostate pathological examination showed 73% of necrosis. No worsening of urinary symptoms was observed. Pharmacokinetic analysis showed limited systemic passage of docetaxel. All dogs died of metastatic spread at nine months. CONCLUSION: This study suggests that PACE is feasible and safe for the treatment of spontaneous prostate cancer in a canine model and may provide a new approach to treat selected patients with prostate cancer.

Prognostic value of pretreatment plasma D-dimer level in dogs with intermediate to high-grade non-Hodgkin lymphoma.

Pretreatment D-dimer levels have been reported to predict survival in several types of malignancies in human patients. The objective of this study was to evaluate the prognostic value of pretreatment D-dimer level in dogs with intermediate to high-grade non-Hodgkin lymphoma (NHL). In a prospective, randomized, double-blind study of F14512 vs etoposide phosphate, we assessed the prognostic value of pretreatment plasma D-dimer level in 48 client-owned dogs diagnosed with intermediate to high-grade NHL. The correlation between pretreatment plasma D-dimer level and various clinical features, progression-free survival (PFS) and overall survival (OS) was analysed. The median value of pretreatment plasma D-dimer level was 0.4 µg/mL (range: 0.1-14.3 µg/mL). High pretreatment plasma D-dimer level (>0.5 µg/mL) was detected in 44% (21/48) of dogs. High D-dimer levels were not correlated with naive vs relapsed lymphoma, clinical stage, substage, immunophenotype or treatment group. D-dimer levels >0.5 µg/mL were significantly associated with inferior median PFS (54 vs 104 days, P = .011) and OS (93 vs 169 days, P = .003). In the multivariate analysis, high D-dimer levels remained an independent predictor for worse PFS (HR: 3.21, 95% CI: 1.57-6.56, P = .001) and OS (HR: 3.87, 95% CI: 1.88-7.98; P < .001). This study suggests that pretreatment plasma D-dimer level can serve as a predictor of prognosis in dogs with intermediate to high-grade NHL. Further studies are warranted to confirm these findings.

Phase I dose escalation study of 12b80 (hydroxybisphosphonate linked doxorubicin) in naturally occurring osteosarcoma.

PURPOSE: 12b80 combines doxorubicin bound to a bone targeting hydroxybisphosphonate vector using a pH-sensitive linker, designed to specifically trigger doxorubicin release in an acidic bone tumor microenvironment. This phase I study aimed to determine the safety and toxicity profiles of 12b80 in dogs with naturally occurring osteosarcoma, with the objective to translate findings from dogs to humans. EXPERIMENTAL DESIGN: Ten client-owned dogs with osteosarcoma were enrolled in an accelerated dose-titration design followed by 3 + 3 design. Dogs received three cycles of 12b80 intravenous injection at 4 mg/kg (n = 1), 6 mg/kg (n = 2), 8 mg/kg (n = 3), and 10 mg/kg (n = 4). Endpoints included safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicity (DLT). RESULTS: The MTD of 12b80 was 8 mg/kg (i.e., equivalent dose of doxorubicin of 110 mg/m2, range: 93-126). Most adverse events included grade ≤ 2 gastrointestinal disorders and hypersensitivity reactions. No hematological or cardiac DLT were observed at any dose tested. CONCLUSIONS: In dogs, 12b80 is overall well tolerated and expends the MTD of doxorubicin up to four times the standard dose of 30 mg/m2. These results demonstrate the potential therapeutic benefit of 12b80 in canine and human osteosarcoma.

Randomized, double-blind trial of F14512, a polyamine-vectorized anticancer drug, compared with etoposide phosphate, in dogs with naturally occurring lymphoma.

Purpose: F14512 is an epipodophyllotoxin derivative from etoposide, combined with a spermine moiety introduced as a cell delivery vector. The objective of this study was to compare the safety and antitumor activity of F14512 and etoposide phosphate in dogs with spontaneous non-Hodgkin lymphoma (NHL) and to investigate the potential benefit of F14512 in P-glycoprotein (Pgp) overexpressing lymphomas. Experimental Design: Forty-eight client-owned dogs with intermediate to high-grade NHL were enrolled into a randomized, double-blind trial of F14512 versus etoposide phosphate. Endpoints included safety and therapeutic efficacy. Results: Twenty-five dogs were randomized to receive F14512 and 23 dogs to receive etoposide phosphate. All adverse events (AEs) were reversible, and no treatment-related death was reported. Hematologic AEs were more severe with F14512 and gastrointestinal AEs were more frequent with etoposide phosphate. F14512 exhibited similar response rate and progression-free survival (PFS) as etoposide phosphate in the global treated population. Subgroup analysis of dogs with Pgp-overexpressing NHL showed a significant improvement in PFS in dogs treated with F14512 compared with etoposide phosphate. Conclusion: F14512 showed strong therapeutic efficacy against spontaneous NHL and exhibited a clinical benefice in Pgp-overexpressing lymphoma superior to etoposide phosphate. The results clearly justify the evaluation of F14512 in human clinical trials.

Evaluation of intracavitary carboplatin chemotherapy for treatment of pleural carcinomatosis in cats: a retrospective study of eight cases.

OBJECTIVES: The aim of this study was to evaluate the benefit of intracavitary carboplatin chemotherapy in cats with malignant pleural effusion of epithelial origin. METHODS: The medical records of cats with a cytological diagnosis of neoplastic pleural effusion of epithelial origin were reviewed at three referral institutions between January 2013 and June 2018. Only cats treated with intracavitary carboplatin chemotherapy were enrolled. Data collection included signalment, medical history, clinical signs, pleural effusion analysis, diagnostic imaging findings, intracavitary carboplatin chemotherapy protocol, adverse events, response to chemotherapy, outcome and underlying primary tumour, if possible. RESULTS: Eight cats met the inclusion criteria. Three cats had previous surgical removal of a tumour, including a poorly differentiated primary lung carcinoma, a uterine adenocarcinoma and a benign mammary tumour. The main clinical signs were tachypnoea and/or dyspnoea, inappetence and weight loss. Thoracic radiographs revealed marked bilateral pleural effusion in all cats. Pleural fluid analysis was consistent with a modified transudate, with malignant epithelial cells on cytology, leading to a diagnosis of pleural carcinomatosis. All cats received only one cycle of intracavitary carboplatin chemotherapy at a dose of 200-240 mg/m2. Recurrence of pleural effusion was reported in 7/8 cats within 4-15 days of chemotherapy, and death was recorded in all cats within 5-16 days, owing to recurrent pleural effusion or poor general condition. The primary cancer was suspected to be of pulmonary, mammary and pancreatic origin in four cats, two cats and one cat, respectively, and of unknown origin in the remaining cat. CONCLUSIONS AND RELEVANCE: In this study, intracavitary carboplatin chemotherapy seems ineffective in managing neoplastic pleural effusion of epithelial origin in cats with pleural carcinomatosis. Other cytotoxic drugs and/or techniques should be investigated in the future to improve the quality of life and survival of cats with pleural carcinomatosis.

Evaluation of serum thymidine kinase 1 activity as a biomarker for treatment effectiveness and prediction of relapse in dogs with non-Hodgkin lymphoma.

BACKGROUND: Serum thymidine kinase 1 (sTK1) activity is closely correlated with DNA synthesis. OBJECTIVES: Evaluate sTK1 activity as a biomarker for treatment response and early detection of relapse in dogs with lymphoma. ANIMALS: Ninety-seven client-owned dogs with naive or relapsed lymphoma and 23 healthy dogs. METHODS: Prospective study. Serum TK1 activity measured by refined ELISA-based method (DiviTum assay, Biovica International) before treatment, at clinical response, and every 4 weeks until relapse or last follow-up. RESULTS: Serum TK1 activity was ≤20 Du/L in 96% (22/23) of healthy dogs. Pretreatment sTK1 activity was >20 Du/L in 88% (85/97) dogs with lymphoma. At clinical response, sTK1 activity was significantly lower in dogs with complete (CR, n = 36) versus partial (PR, n = 29) response (P < .0001). Sensitivity (Se) and specificity (Sp) of sTK1 activity for detecting nonfully responders were 76% and 100%, respectively, with cutoff of 119.5 Du/L (AUC, 0.90; 95%-CI, 0.81-0.98; P < .0001). In dogs with CR, a 5-fold increase in sTK1 activity at a 4-week interval predicted relapse at the subsequent 4-week assessment with a Se 50% and Sp 94% (AUC, 0.72; 95%-CI, 0.55-0.90; P = .02). An increase of sTK1 activity (>2.7-fold value measured at clinical response) predicted relapse at subsequent 4-week assessment with a Se 61% and Sp 88% (AUC, 0.79; 95%-CI, 0.64-0.95; P = .004). CONCLUSIONS AND CLINICAL IMPORTANCE: Monitoring sTK1 activity could help to detect complete responders and early disease progression in dogs with lymphoma.

Computed tomography or rhinoscopy as the first-line procedure for suspected nasal tumor: a pilot study.

There are no evidence-based guidelines as to whether computed tomography (CT) or endoscopy should be selected as the first-line procedure when a nasal tumor is suspected in a dog or a cat and only one examination can be performed. Computed tomography and rhinoscopic features of 17 dogs and 5 cats with a histopathologically or cytologically confirmed nasal tumor were retrospectively reviewed. The level of suspicion for nasal neoplasia after CT and/or rhinoscopy was compared to the definitive diagnosis. Twelve animals underwent CT, 14 underwent rhinoscopy, and 4 both examinations. Of the 12 CT examinations performed, 11 (92%) resulted in the conclusion that a nasal tumor was the most likely diagnosis compared with 9/14 (64%) for rhinoscopies. Computed tomography appeared to be more reliable than rhinoscopy for detecting nasal tumors and should therefore be considered as the first-line procedure.

Examen de première intention lors de suspicion de tumeur nasale: scanner où rhinoscopie? Une étude pilote. Lors de suspicion de tumeur nasale chez le chien et le chat, il n'existe à ce jour aucun consensus quant à l'examen de première intention à privilégier entre la tomodensitométrie et l'endoscopie lorsqu'un seul examen peut être réalisé. Les caractéristiques tomodensitométriques et endoscopiques de 17 chiens et 5 chats avec un diagnostic de tumeur nasale confirmé histologiquement ou cytologiquement ont été analysées rétrospectivement. Le degré de suspicion de tumeur nasale permis par l'endoscopie et/ou le scanner a été comparé au diagnostic final. Un examen tomodensitométrique a été réalisé chez 12 animaux, une rhinoscopie chez 14 et les deux examens ont été couplés dans quatre cas. L'examen scanner a conclu qu'une tumeur nasale était le diagnostic le plus probable dans 11 cas sur 12 (92 %), et la rhinoscopie dans 9 cas sur 14 (64 %). L'examen scanner apparait plus fiable que la rhinoscopie pour détecter les tumeurs nasales, et de ce fait devrait être considéré comme le meilleur examen de première intention.(Traduit par les auteurs).