SUMMARYThe aim of this study was to determine C-reactive protein levels in dogs with benign and malignant mammary tumors. Thirty female dogs, with ages ranging between 6 and 15 years and with no distinction of breed were used for this purpose. The animals were divided into 3 different groups of 10 dogs each: Group 1 (control), Group 2 (benign mammary tumor) and Group 3 (malignant mammary tumor). The neoplasias were classified histologically and C-reactive protein (CRP) levels were analyzed using a human turbidimetric immunoassay validated for dogs. Group 3 had the highest values (mean: 8.2 mg/L; median: 7.1 mg/L) of C-reactive protein compared with the other groups (P < 0.05). According to a discriminant analysis, a female dog with a mammary tumor and CRP values ≥ 8 mg/L has a 61% or greater probability of this tumor being malignant.Palabras clave: proteína C-reactiva, neoplasia mamaria, maligna.

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Background Eculizumab, a monoclonal antibody targeting C5, is an effective treatment for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy has been suggested, the optimal treatment schedule is unknown, while eculizumab discontinuation does not universally lead to relapse. Data evaluating risk factors associated with an increased risk of CM-TMA recurrence following eculizumab withdrawal are scarce. Prior to the eculizumab era, complement genetic studies have been used to assess morbidity and mortality in patients with CM-TMA. Our aim was to assess the impact of complement gene variants on CM-TMA relapse rate (RR) after eculizumab discontinuation. Methods Search protocols were developed for the Ovid and PubMed databases to identify existing reports on CM-TMA and eculizumab withdrawal published before February 1st 2020. Cases were cross-referenced to eliminate duplicates. Inclusion criteria included patients diagnosed with CM-TMA who had undergone eculizumab discontinuation. Reasons for exclusion were patients with no follow-up after eculizumab withdrawal and patients lacking complement gene testing. Patients undergoing eculizumab dose extension, but not discontinuation, were not included. Results Fifteen studies including 557 individuals were retrieved. Of these, 363 (65.2%) were excluded as outlined in Figure 1 and 194 cases were included in the final analysis with a global RR of 28.9% (n=56). Distribution based on gene impacted and variant type are presented in Table 1. RR was highest among patients with CFH variants (52.5% to 60%) -particularly if involving exon 22 or nonsense mutations-, MCP/CD46 variants (38.9% to 45%) -particularly if affecting splice regions-, and cases with multiple concomitant variants (57.1%) -particularly those including CFH or a CFH-CFHR1 Hybrid (Table 2). Patients with relapse were more likely to have the presence of a complement variant (p&lt;0.001), history of previously resolved CM-TMA events (p=0.022), younger age (mean age 22.4 years for patients with relapse vs. 32.33 years for patients without relapse; p=0.002) and, within those with detected variants, multiple vs. single variants (p=0.002) and CFH-inclusive variants (p=0.003). On univariate analysis, complement gene variants (OR 4.217 95%CI 1.97-9.026; p&lt;0.001), age &lt;30 years (OR 2.346 95%CI 1.159-4.749; p=0.018), and presence of multiple variants (OR 2.06 95%CI 1.172-3.621; p=0.012) or CFH-inclusive variants (OR 3.111 95%CI 1.443-6.71; p=0.004) were associated with increased odds of CM-TMA relapse, while no prior history of additional CM-TMA events was the only factor associated with lower RR (OR 0.327 95%CI 0.123-0.87; p=0.025). Presence of complement variants (OR 4.48 95%CI 1.132-17.724; p=0.033) and CFH-inclusive variants (OR 3.045 95%CI 1.136-8.159; p=0.027) were independently associated with increased RR on multivariate analysis (Table 3). Conclusion Relapse after eculizumab discontinuation is rare in cases with no genetic variants identified but can increase to more than 80% in high-risk subgroups. Complement genetic testing is not required for CM-TMA diagnosis or for initiation of complement inhibiting therapy; however, our results demonstrate the value of complement genetic testing when stratifying risk of patients for consideration of eculizumab discontinuation. Disclosures Sridharan: Alexion: Honoraria.

Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for acute leukemia (AL) with the potential to achieve long-term remission. Nevertheless, relapse remains the main cause of mortality after allo-HSCT. Isolated extramedullary relapse (iEMR) is defined as the presence of clonal blasts in tissues other than the medullary compartment, in the absence of bone marrow relapse (BMR) and with full donor chimerism. Reports on its prevalence and risk factors are rare and its implications on prognosis and treatment continue to be an area of active study. Our aim was to describe the rates, clinical characteristics, and outcomes of patients with iEMR in the post-allo-HSCT setting. Methods Retrospective multicenter study that included patients ≥15-years-old diagnosed with AL who underwent allo-HSCT with chemotherapy-only conditioning regimens between 1999-2019. Patients referred to participating centers after HSCT and those with incomplete medical records were excluded. The Kaplan-Meier method was used to construct survival curves, differences between groups were analyzed using the log-rank test, and a standard Cox-regression was carried out for multivariate analysis. Results One hundred twenty-four patients were included with a median follow-up of 12 months (1-158) after allo-HSCT. The most common AL phenotype was lymphoblastic (ALL) in 66.1% (n=82). High-risk cytogenetics were present in 23.9% (n= 28). Twenty-three patients (18.5%) had a history of extramedullary disease (EMD) prior to allo-HSCT, CNS being the most common site in 52.2% (n=12). Additional baseline characteristics are presented in Table 1. Median overall survival (OS) for the cohort was 15 months (1-158). Factors related to decreased OS on univariate analysis are shown in Table 2. Independent risk factors for mortality were: belonging to the non-AYA group (HR 4.7,95%CI 1.6-13.3; p=0.004), grade III-IV acute GVHD (HR 3.9, 95%CI 1.6-9.8; p=0.003), and absence of chronic GHVD (HR 10.3, 95%CI 3.4-30.9; p&lt;0.001). Sixty-seven patients (54%) relapsed after allo-HSCT with a median time to relapse of 13 months (1-158). Of these, 19 (28.4%) had EM involvement, of which 16 (23.9%) had iEMR. All cases of iEMR occurred in patients with ALL. The most commonly involved EM sites were CNS in 47.3% (n=9), skin in 26.3% (n=5), and breast in 15.8% (n=3). Of patients with post-allo-HSCT CNS relapse, 85.7% (n=6) had prior history of pre-HSCT CNS EMD. Post-relapse therapy was administered to 76.1% (n=51), including a second allo-HSCT in 25.5% (n=13), the remaining patients transitioned to palliative care. Median relapse free survival (RFS) was 13 months (1-124). Factors demonstrating a protective role are described in Table 2. On multivariate analysis, early disease stage at time of HSCT (HR 0.35, 95% CI 0.18-0.71; p=0.003) and the development of chronic GVHD (HR 0.29, 95% CI 0.15-0.54; p&lt;0.001) had a positive impact on RFS. The median OS after relapse was 4 months (2.6-5.3). Factors related to increased survival on univariate analysis are described in Table 2 and in Figure 1. On multivariate analysis, an iEMR (HR 0.13, 95% CI 0.026-0.67; p= 0.015), as compared to a relapse with a medullary component, and a complete remission after post-relapse therapy (HR 0.095, 95%CI 0.039-0.233; p&lt;0.001) positively impacted OS. Conclusion Isolated EMR was highly prevalent in our population as compared to historical cohorts. This reflects differences in Latin American AL epidemiologic distribution, with high representation of ALL, and our limited access to conditioning regimens based on total body irradiation. Patients that had an iEMR and achieved treatment response had improved survival outcomes which may reflect a more indolent biology allowing the clinician time to implement therapy intensification interventions. Additionally, in our setting, escalation of pre-HSTC therapy to achieve deeper responses and tailoring HSCT, in combination with post-HSCT CNS prophylaxis, are potential strategies that should be pursued further. Disclosures No relevant conflicts of interest to declare.

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