Obesity Is an Independent Predictor of Poor Survival in Metastatic Breast Cancer: Retrospective Analysis of a Patient Cohort Whose Treatment Included High-Dose Chemotherapy and Autologous Stem Cell Support

The purpose of the study was to identify predictors of long-term survival in metastatic breast cancer (MBC). A cohort of 96 patients, who received high-dose chemotherapy with autologous stem cell support (HD-ASCT) as part of their treatment, was analyzed. Percent long-term survival at 10 years was 24.5% (CI 17.2–34.9%) when metastasis was diagnosed and 14.4% (CI 8.7–23.9%) when MBC was diagnosed. Survival was impacted significantly by body mass index (BMI). Median overall survival from initial diagnosis or from time of metastasis for patients with BMIs ≤30 and >30 (obese) was 7.1 (CI 4.4–8.7) and 3.2 years (2.41–6.75), respectively, or 3.2 or 2.3 years (all P = 0.02). Also, obesity was the only independent patient-related predictor of time to metastasis and of survival. While obesity is linked with poor outcomes in earlier stages of breast cancer, this has not been previously reported for MBC

Musculoskeletal ultrasound for intra-articular bleed detection: a highly sensitive imaging modality compared with conventional magnetic resonance imaging.

Essentials The best imaging modality for joint blood detection in hemophilia is unknown. Blood appearance and detection thresholds were studied with ultrasound and conventional MRI. Ultrasound is sensitive to low volume and concentration of blood, whereas conventional MRI is not. The findings establish the validity of ultrasound for rapid bleed detection in hemophilia care. SUMMARY:Background There is increasing demand for musculoskeletal ultrasound (MSKUS) to detect hemophilic joint bleeding, but there is uncertainty regarding blood detection concentration thresholds or if magnetic resonance imaging (MRI) is more accurate. Aims Compare the sensitivity of blood detection by MSKUS and MRI. Methods Increasing blood concentrations in plasma were imaged with MSKUS and MRI 1-2 h, 3-4 days and 7 days after blood withdrawal in vitro, and after injection into cadaveric pig joints. Additionally, effusions in the joints of two patients with hemophilia joints were imaged, followed by aspiration. MSKUS was performed using an 8-18-MHz linear transducer; MRI was performed at 3T using T1-weighted and T2-weighted fat-suppressed sequences. Images were reviewed by a hematologist certified in MSKUS and a musculoskeletal radiologist. Results MSKUS permitted the detection of blood in vitro and in pig joint spaces at concentrations as low as 5%, demonstrated by the presence of echogenic signals that were absent with plasma alone. In contrast, no differences between fluids were discernible on the T1-weighted or T2-weighted MRI images. Results were confirmed in the two patients with hemophilia. Blood clots demonstrated varying and dynamic echogenicity patterns over time and, using MRI, were visualized best with T2 sequences. Conclusion MSKUS is extremely sensitive in detecting low concentrations of intra-articular blood and in discriminating between bloody and non-bloody fluid, whereas conventional MRI is not. These observations demonstrate the advantages of MSKUS over MRI in detecting intra-articular blood, and show that MSKUS is ideal for rapid bleed detection in the clinic

Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis

Antibodies confer humoral immunity but can also be harmful when they target an autoantigen, alloantigen, allergen, or biotherapeutic. New strategies are needed for antigen-specific suppression of undesired antibody responses, particularly to T cell–dependent protein antigens, because they elicit T cell help. Here we show that liposomal nanoparticles, displaying both antigen and glycan ligands of the inhibitory coreceptor CD22, induce a tolerogenic program that selectively causes apoptosis in mouse and human B cells. These SIGLEC-engaging tolerance-inducing antigenic liposomes (STALs, where SIGLEC is defined as sialic acid–binding Ig-like lectin) induced robust antigen-specific tolerance to protein antigens in mice, preventing subsequent immune response to challenge with the same antigen. Since development of inhibitory antibodies to FVIII is a serious problem in treatment of hemophilia A patients, we investigated the potential of this approach for inducing tolerance to FVIII in a hemophilia mouse model. STALs prevented formation of inhibitory FVIII antibodies, allowing for effective administration of FVIII to hemophilia mice to prevent bleeding. These findings suggest that STALs could be used to eliminate or prevent harmful B cell–mediated immune responses

Maladaptive lymphangiogenesis is associated with synovial iron accumulation and delayed clearance in factor VIII–deficient mice after induced hemarthrosis

BackgroundMechanisms of iron clearance from hemophilic joints are unknown.ObjectivesTo better understand mechanisms of iron clearance following joint bleeding in a mouse model of hemophilia.MethodsHemarthrosis was induced by subpatellar puncture in factor VIII (FVIII)-deficient (FVII-/-) mice, +/- periprocedural recombinant human FVIII, and hypocoagulable (HypoBALB/c) mice. HypoBALB/c mice experienced transient FVIII deficiency (anti-FVIII antibody) at the time of injury combined with warfarin-induced hypocoagulability. Synovial tissue was harvested weekly up to 6 weeks after injury for histological analysis, ferric iron and macrophage accumulation (CD68), blood and lymphatic vessel remodeling (αSMA; LYVE1). Synovial RNA sequencing was performed for FVIII-/- mice at days 0, 3, and 14 after injury to quantify expression changes of iron regulators and lymphatic markers.ResultsBleed volumes were similar in FVIII-/- and HypoBALB/c mice. However, pronounced and prolonged synovial iron accumulation colocalizing with macrophages and impaired lymphangiogenesis were detected only in FVIII-/- mice and were prevented by periprocedural FVIII. Gene expression changes involved in iron handling (some genes with dual roles in inflammation) and lymphatic markers supported proinflammatory milieu with iron retention and disturbed lymphangiogenesis.ConclusionAccumulation and delayed clearance of iron-laden macrophages were associated with defective lymphangiogenesis after hemarthrosis in FVIII-/- mice. The absence of such findings in HypoBALB/c mice suggests that intact lymphatics are required for removal of iron-laden macrophages and that these processes depend on FVIII availability. Studies to elucidate the biological mechanisms of disturbed lymphangiogenesis in hemophilia appear critical to develop new therapeutic targets

Pulmonary Embolism Does Not Have an Unusually High Incidence Among Hospitalized COVID19 Patients

IntroductionAcute respiratory illnesses from COVID19 infection are increasing globally. Reports from earlier in the pandemic suggested that patients hospitalized for COVID19 are at particularly high risk for pulmonary embolism (PE). To estimate the incidences of PE during hospitalization for COVID19, we performed a rigorous systematic review of published literature.MethodsWe searched for case series, cohort studies and clinical trials from December 1, 2019 to July 13, 2020 that reported the incidence of PE among consecutive patients who were hospitalized for COVID19 in ICUs and in non-ICU hospital wards. To reflect the general population of hospitalized COVID19 patients, we excluded studies in which subject enrollment was linked to the clinical suspicion for venous thromboembolism (VTE).ResultsFifty-seven studies were included in the analysis. The combined random effects estimate of PE incidence among all hospitalized COVID19 patients was 7.1% (95% CI: 5.2%, 9.1%). Studies with larger sample sizes reported significantly lower PE incidences than smaller studies (r2 = 0.161, p = 0.036). The PE incidence among studies that included 400 or more patients was 3.0% (95% CI: 1.7%, 4.6%). Among COVID19 patients admitted to ICUs, the combined estimated PE incidence was 13.7% (95% CI: 8.0%, 20.6%). The incidence of ICU-related PE also decreased as the study sample sizes increased. The single largest COVID19 ICU study (n = 2215) disclosed a PE incidence of 2.3% (95% CI: 1.7%, 3.0%).ConclusionPE incidences among hospitalized COVID19 patients are much lower than has been previously postulated based on smaller, often biased study reports. The incidence of "microthrombosis," leading to occlusion of microscopic blood vessels, remains unknown