Features and prognostic impact of distant metastases in 45 dogs with de novo stage IV cutaneous mast cell tumours: A prospective study

BACKGROUND: Distant metastases in dogs with cutaneous mast cell tumors (cMCT) are rare and incurable. The aims of this prospective study were to clarify the clinico-pathological features of stage IV cMCTs and to identify possible prognostic factors for progression-free interval (PFI) and survival time (ST). MATERIAL AND METHODS: Dogs were eligible for recruitment if they had a previously untreated, histologically confirmed cMCT and if they underwent complete staging demonstrating stage IV disease. Dogs were uniformly followed-up, whereas treatment was not standardized and included no therapy, surgery, radiation therapy, chemotherapy, tyrosine-kinase inhibitors or a combination of these. RESULTS: 45 dogs with stage IV cMCT were enrolled. All dogs had distant metastatic disease, and 41 (91.1%) dogs had also metastasis in the regional lymph node. Histopathological grade and mutational status greatly varied among dogs. Median ST was 110 days. Notably, PFI and ST were independent of well-known prognostic factors, including anatomic site, histological grade, and mutational status. Conversely, tumor diameter >3\u2009cm, more than 2 metastatic sites, bone marrow infiltration, and lack of tumor control at the primary site were confirmed to be negative prognostic factors by multivariate analysis. CONCLUSION: Currently, there is no satisfactory treatment for stage IV cMCT. Asymptomatic dogs with tumor diameter <3\u2009cm and a low tumor burden, without bone marrow infiltration may be candidates for multimodal treatment. Stage IV dogs without lymph node metastasis may enjoy a surprisingly prolonged survival. The achievement of local tumor control seems to predict a better outcome in dogs with stage IV cMCT

Array-based comparative genomic hybridization analysis reveals chromosomal copy number aberrations associated with clinical outcome in canine diffuse large B-cell lymphoma

Canine Diffuse Large B-cell Lymphoma (cDLBCL) is an aggressive cancer with variable clinical response. Despite recent attempts by gene expression profiling to identify the dog as a potential animal model for human DLBCL, this tumor remains biologically heterogeneous with no prognostic biomarkers to predict prognosis. The aim of this work was to identify copy number aberrations (CNAs) by high-resolution array comparative genomic hybridization (aCGH) in 12 dogs with newly diagnosed DLBCL. In a subset of these dogs, the genetic profiles at the end of therapy and at relapse were also assessed. In primary DLBCLs, 90 different genomic imbalances were counted, consisting of 46 gains and 44 losses. Two gains in chr13 were significantly correlated with clinical stage. In addition, specific regions of gains and losses were significantly associated to duration of remission. In primary DLBCLs, individual variability was found, however 14 recurrent CNAs (&gt;30%) were identified. Losses involving IGK, IGL and IGH were always found, and gains along the length of chr13 and chr31 were often observed (&gt;41%). In these segments, MYC, LDHB, HSF1, KIT and PDGFR alpha are annotated. At the end of therapy, dogs in remission showed four new CNAs, whereas three new CNAs were observed in dogs at relapse compared with the previous profiles. One ex novo CNA, involving TCR, was present in dogs in remission after therapy, possibly induced by the autologous vaccine. Overall, aCGH identified small CNAs associated with outcome, which, along with future expression studies, may reveal target genes relevant to cDLBCL

Transformation of canine lymphoma/leukemia to more aggressive diseases : anecdotes or reality?

Transformation is the evolution of an indolent lymphoma/leukemia to an aggressive lymphoma, typically harboring a very poor prognosis. This phenomenon is well described in humans, but underestimated in dogs although recognized as a possible evolution of indolent lymphomas/leukemias. In canine chronic leukemias, blast crisis (mainly in myeloid) and Richter syndrome (transformation into a high grade lymphoma) (mainly in B-cell lymphocytic leukemia) have been reported. Transformation is a possible event also in canine low grade lymphomas, although rare. The increased knowledge has also generated new questions and posed challenges that need to be addressed to improve outcome, including the recognition of the clinical characteristics at diagnosis associated with a higher risk of transformation in an attempt of anticipating the typical evolution

Conformity and controversies in the diagnosis, staging and follow-up evaluation of canine nodal lymphoma: a systematic review of the last 15 years of published literature

Diagnostic methods used in the initial and post-treatment evaluation of canine lymphoma are heterogeneous and can vary within countries and institutions. Accurate reporting of clinical stage and response assessment is crucial in determining the treatment efficacy and predicting prognosis. This study comprises a systematic review of all available canine multicentric lymphoma studies published over 15 years. Data concerning diagnosis, clinical stage evaluation and response assessment procedures were extracted and compared. Sixty-three studies met the eligibility criteria. Fifty-five (87.3%) studies were non-randomized prospective or retrospective studies. The survey results also expose variations in diagnostic criteria and treatment response assessment in canine multicentric lymphoma. Variations in staging procedures performed and recorded led to an unquantifiable heterogeneity among patients in and between studies, making it difficult to compare treatment efficacies. Awareness of this inconsistency of procedure and reporting may help in the design of future clinical trials

Prognostic role of non-neoplastic lymphocytes in lymph node aspirates from dogs with diffuse large B-cell lymphoma treated with chemo-immunotherapy

Dogs with Diffuse Large B-Cell Lymphoma (DLBCL) benefit from the addition of active immunotherapy to traditional chemotherapy. We hypothesized that immune cells within neoplastic lymph nodes (LNs) may play a role in the tumor pathobiology and treatment response. The present study describes the composition and prognostic role of non-neoplastic lymphocytes in LNs of 59 dogs with treatment-naive DLBCL receiving chemo-immunotherapy. The percentage of small non-neoplastic cells and of CD5+, CD21+, CD4+ and CD8+ small cells was recorded via flow cytometry. CD4+/CD8+ and CD5+/large CD21+ cell ratios were calculated. The likelihood of progression significantly diminished with increasing percentage of small cells, CD5+ and CD8+ small cells, and CD5+/large CD21+ cell ratio, with decreasing CD4+/CD8+ ratio and in non-anemic dogs. Active immunotherapy is more effective in dogs with higher percentage of non-neoplastic lymphocytes at diagnosis. We lay the ground for future studies assessing the role of the immune system in the pathobiology of canine DLBCL

Prognostic significance of peripheral blood and bone marrow infiltration in newly-diagnosed canine nodal marginal zone lymphoma

Canine nodal marginal zone lymphoma (nMZL) is infrequent and is typically diagnosed at an advanced disease stage. However, it is currently unknown whether different levels of peripheral blood (PB) and bone marrow (BM) infiltration may provide prognostic stratification in dogs with nMZL. The aims of the present prospective study were to assess the influence of PB and BM infiltration detected by flow cytometry (FC) on time to progression (TTP) and lymphoma-specific survival (LSS) in dogs with newly-diagnosed multicentric nMZL, and to establish a cut-off value of prognostic significance. Forty-five completely staged and treatment-na\ueff dogs with histologically-confirmed nMZL were enrolled. After staging, dogs received chemo-immunotherapy or chemotherapy. PB infiltration was significantly associated with TTP (p = 0.001): dogs with PB infiltration <30% had a median TTP of 186 days, whereas dogs with PB infiltration 6530% had a median TTP of 43 days. Additionally, vaccinated dogs had a significantly (p = 0.012) longer TTP (399 days) compared with dogs receiving chemotherapy only (211 days). BM infiltration was significantly associated with LSS (p < 0.001): dogs with BM infiltration <1% had a median LSS of 1403 days, those with BM infiltration 1\u201320% of 337 days, and those with BM infiltration 6520% of 188 days. Normal LDH levels and the administration of chemo-immunotherapy also significantly improved LSS (560 vs 211 days, and 399 vs 211 days, respectively; p < 0.001). PB and BM flow cytometric evaluation is an integral part of staging work-up in dogs with nMZL and has prognostic relevance

Canine presumed glial brain tumours treated with radiotherapy: Is there an inferior outcome in tumours contacting the subventricular zone?

Post-treatment outcome in canine glial tumours is described with a broad range of survival times between 2 and 28 months. After surgery or radiation therapy, the tumours may progress locally or spread within the central nervous system. It is unknown if tumour- or patient-specific factors influence prognosis. In humans, glioblastoma involving the subventricular zone has been found to recur distantly, with shortened time to progression and overall survival. We included 32 dogs irradiated for a presumptive primary glial brain tumour in this retrospective cohort study. Tumours were grouped relative to subventricular zone contact and overt ventricular invasion assessing pre-treatment magnetic resonance images. Median time to progression (TTP) for all cases was 534 days (95%CI, 310–758), with a significantly shorter TTP in dogs with lesions at the subventricular zone (median TTP, 260 vs. 687 days; p&nbsp;=.049). Tumours at the subventricular zone progressed more often (p&nbsp;=.001), and more likely as CNS-metastasis (52.9% vs. 13.3%, p&nbsp;=.028). Median overall survival (OS) was 489 days (95%CI, 147–831) and median tumour-specific survival 609 days (95%CI, 382–835). Involvement of the subventricular zone was significantly associated with a shorter tumour-specific survival (median, 306 vs. 719 days; p&nbsp;=.044). Glial tumours contacting the subventricular zone in dogs have a shorter tumour-specific survival and a higher rate of progression and CNS-metastasis. Despite local tumour control, metastasis must be considered and should prompt further treatment approaches

Design of the new electromagnetic measurement system for RFX-mod upgrade

A major modification of the RFX-mod toroidal load assembly has been decided in order to improve passive MHD control and to minimize the braking torque on the plasma, thus extending the operational space in both RFP and Tokamak configurations. With the removal of the vacuum vessel, the support structure will be modified in order to obtain a new vacuum-tight chamber and the first wall tiles will be directly in front of the passive stabilizing shell inside of it, so increasing both the poloidal cross section and the plasma-shell proximity. This implies the design of a new vacuum fit electromagnetic measurement system. The new local probes will be installed in vacuum onto the copper shell, behind the graphite tiles, and shall operate up to a maximum temperature of 180\ub0C to allow for baking cycles for first wall conditioning. Because of the reduced room available, tri-axial pickup probes have been designed, with the additional advantage of allowing the minimization of alignment errors. The paper describes the detailed design of the new probe set, in particular highlighting advantages and effectiveness of different probe solutions. Preliminary tests carried out on local probe prototypes to characterize their electromagnetic behaviour are also reported