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Very few studies, often with very small cohorts, have proven chemotherapy efficacy against canine aggressive mammary carcinomas, either in terms of metastasis or median survival, in dogs after surgery and chemotherapy, with such outcomes not being confirmed by other studies. As a result, we lack efficient standardized protocols, which exist in human cases, according to the grade and stage of the tumor in dogs. In this case report, we describe a relapsing grade III solid mammary carcinoma evolving into prominent lymphatic intravascular invasion with multifocal nodal extension (stage IV); we applied an intensive treatment combining radical surgery and intensive adjuvant chemotherapy. The latter combined carboplatin maximal-tolerated-dose chemotherapy, with doses adjusted as necessary, and metronomic chemotherapy with firocoxib, toceranib and chloraminophene, progressively administered and carefully monitored. Adapting the doses prevented adverse events and resulted in 218 days of survival with good quality of life. To our knowledge, this is the first description of such a treatment combination. Our result should be confirmed with a large-scale prospective study.

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)., (© 2024 The Authors. Veterinary and Comparative Oncology published by John Wiley & Sons Ltd.)

Background: Myeloma-related disorders (MRDs) are rare and poorly documented neoplasms of cats., Hypothesis/objectives: To describe clinical, clinicopathologic, and imaging findings, response to treatment, and survival time and to identify factors associated with shorter outcomes in cats with MRD., Animals: Fifty cats with a diagnosis of MRD., Methods: Cats with paraproteinemia confirmed by serum protein electrophoresis (SPE) and either intramedullary plasmacytosis >10%, marked cytonuclear atypia with intramedullary plasmacytosis that ranged between 5% and 10%, or cytologically or histologically confirmed visceral infiltration were retrospectively included from several veterinary referral centers., Results: Bone marrow plasmacytosis and splenic or hepatic involvement were present in 17/27 cats (63%), 36/42 cats (86%), and 27/38 cats (71%), respectively. Anemia was reported in 33/49 cats (67%) and thrombocytopenia in 16/47 cats (34%). Some of the treatments that the cats received included melphalan and prednisolone (n = 19), cyclophosphamide and prednisolone (n = 10), chlorambucil and prednisolone (n = 4), prednisolone (n = 4), or other (n = 4). The overall response rates to melphalan, cyclophosphamide, and chlorambucil in combination with prednisolone were 87%, 90%, and 100%, respectively. Adverse events to melphalan or cyclophosphamide occurred in 65% and 23% of cats, respectively. Median survival time was 122 days (range, 0-1403) and was not significantly associated with chemotherapy protocol. Anemia (hazard ratio [HR], 3.1; 95% confidence interval [CI], 1.0-9.8) and thrombocytopenia (HR, 2.7; 95% CI, 1.2-6.0) were risk factors for shorter survival., Conclusions and Clinical Importance: Our study confirmed the guarded prognosis of MRD in cats and identified risk factors for shorter survival times., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

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., Competing Interests: AF, KMK, JAT, LMM, JMR, PCF, GEH, FM, PN, CAR-P, DMF, TJ, RM-P, KW, ALM-W, DSG, AP, KM, SCH, KML, LH, JC, IC, and DWYT are employed by or affiliated with PetDx; and receive compensation from PetDx and/or hold vested or unvested equity in PetDx. Drs. Flesner and Leibman are members of the PetDx clinical advisory board and receive compensation and equity. Dr. Borgatti has ownership interest (including patents) in a patent entitled “Reduction of EGFR therapeutic toxicity” filed by the University of Minnesota Office of Technology Commercialization. Drs. Cahalane, Phillips, and Aiken are investors in PetDx. Drs. Jensen, van den Boom, Dharajiya, and Diaz are advisors for PetDx and hold vested or unvested equity in PetDx. Drs. Chorny, Kruglyak, Grosu, Marass, Ruiz-Perez and Tsui hold pending patent applications related to technology described in this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Female dogs, especially intact or neutered lately, are at increased risk for reproductive disorders including mammary tumors (MTs). This retrospective study evaluated the prevalence of reproductive pathology and associated mortality in a cohort of female dogs presented at a single veterinary clinic. The medical records of female dogs born in 2000-2003 were reviewed. The study included 599 cases, of which 293 were followed up until death. Causes of death were analyzed according to the spaying status. Among the 599 female dogs, 306 were intact (51%), 50 (8%) had been spayed before 2 years of age (ES, early spaying), and 243 (41%) after 2 years (LS, late spaying). During their lifetime, 79 dogs (13.2%) developed pyometra, and 160 (26.7%) a mammary tumor. Among the 293 dogs with complete follow-up, 103 (35.1%) had at least one MT during their lifetime, of which 53 (51.5%) died of their mammary cancer. Spayed (ES + LS) female dogs had a 4-fold decreased risk of dying from mammary cancer (OR = 0.23, 95% CI 0.11-0.47, p < 0.0001) compared to intact females. In this low-sterilization rate population, MTs developed in 35.1% of female dogs over their lifetime and was the cause of death in half of them.

It is well established that neurons regulate the properties of both central and peripheral glial cells. Some of these neuro-glial interactions are modulated by the pattern of neuronal electrical activity. In the present work, we asked whether blocking the electrical activity of dorsal root ganglion (DRG) neurons in vitro by a chronic treatment with tetrodotoxin (TTX) would modulate the expression of the T-type Ca(2+) channel by mouse Schwann cells. When recorded in their culture medium, about one-half of the DRG neurons spontaneously fired action potentials (APs). Treatment for 4 days with 1 microM TTX abolished both spontaneous and evoked APs in DRG neurons and in parallel significantly reduced the percentage of Schwann cells expressing Ca(2+) channel currents. On the fraction of Schwann cells still expressing Ca(2+) channel currents, these currents had electrophysiological parameters (mean amplitude, mean inactivation time constant, steady-state inactivation curve) similar to those of control cultures. Co-treatment for 4 days with 1 microM TTX and 2 mM CPT-cAMP, a cAMP analogue that induces the expression de novo of Ca(2+) channel currents in Schwann cells deprived of neurons, maintained the percentage of Schwann cells expressing Ca(2+) channel currents, showing that TTX does not directly affect the expression of Ca(2+) channel currents by Schwann cell. We conclude that blocking spontaneous activity of DRG neurons in vitro downregulates Ca(2+) channel expression by Schwann cells. These results strongly suggest that DRG neurons upregulate Ca(2+) channel expression by Schwann cells via the release of a diffusible factor whose secretion is dependent on electrical activity., (Copyright 2000 Wiley-Liss, Inc.)

Regulation of expression of functional voltage-gated ion channels for inward currents was studied in Schwann cells in organotypic cultures of dorsal root ganglia from E19 mouse embryos maintained in serum-free medium. Of the Schwann cells that did not contact axons, 46.5% expressed T-type Ca2+ conductances (ICaT). Two days or more after excision of the ganglia, and consequent disappearance of neurites, ICaT were detectable in only 10.9% of the cells, and the marker 04 disappeared. On Schwann cells deprived of neurons, T- (but not L-) type Ca2+ conductances were re-induced by weakly hydrolysable analogues of cAMP, and by forskolin (an activator of adenylyl cyclase) after long-term treatment (4 days). With CPT cAMP (0.1-2 mM), 8Br cAMP, db cAMP or forskolin (0.01 or 0.1 mM), the proportion of cells with ICaT was not significantly different from the proportion in the cultures with neurons. These agents also induced expression in some cells of tetrodotoxin-resistant Na+ currents, which were rarely induced by neurons, but 04 was not re-induced by cAMP analogue treatments that re-induced ICaT. Inward currents (Ba2+ or Na+) were partly restored (P < 0.05) on Schwann cells cultured for 6-7 days beneath a filter bearing cultured neurons. In contrast, addition of neuron-conditioned medium was ineffective. The results suggest that neurons activate, via diffusible and degradable factors, a subset of Schwann cell cAMP pathways leading to expression of IcaT, and activate additional non-cAMP pathways that lead to expression of 04.

1. Voltage-dependent K+ conductances on Schwann cells in organotypic cultures of mouse dorsal root ganglia were classified as inactivating or sustained (responsible for currents IA and IK, respectively). IA is known to be much reduced on Schwann cells that contact neurites. 2. In the absence of neurones, IA and IK were present. IA, but not IK, was markedly reduced (by 80% after 105 h of treatment) by 2 mM 8-(4-chlorophenylthio)-cAMP (cpt-cAMP), a weakly hydrolysable analogue of cAMP. The effect did not appear for at least 2 h and was maximal after about 100 h. 3. The effect of 1 mM cpt-cAMP was abolished in the presence of an inhibitor of protein kinases, N-[2-bromocinnamyl(amino)ethyl]-5-isoquinolinesulphonamide (H-89, 10 microM). 4. Other analogues of cAMP, but not an analogue of cGMP (8-bromo-cGMP), also reduced IA. 5. We conclude that IA, but not IK, can be downregulated by activation of the protein kinase A pathway.