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The antiphospholipid syndrome (APS) is characterized by thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Complement is a system of enzymes and regulatory proteins of the innate immune system that plays a key role in the inflammatory response to pathogenic stimuli. The complement and coagulation pathways are closely linked, and expanding data indicate that complement may be activated in patients with aPL and function as a cofactor in the pathogenesis of aPL-associated clinical events. Complement activation by aPL generates C5a, which induces neutrophil tissue factor-dependent procoagulant activity. Beta-2-glycoprotein I, the primary antigen for pathogenic aPL, has complement regulatory effects . Moreover, aPL induce fetal loss in wild-type mice but not in mice deficient in specific complement components (C3, C5). Antiphospholipid antibodies also induce thrombosis in wild type mice and this effect is attenuated in C3 or C6 deficient mice, or in the presence of a C5 inhibitor. Increased levels of complement activation products have been demonstrated in sera of patients with aPL, though the association with clinical events remains unclear. Eculizumab, a terminal complement inhibitor, has successfully been used to treat catastrophic APS and prevent APS-related thrombotic microangiopathy in the setting of renal transplant. However, the mechanisms of complement activation in APS, its role in the pathogenesis of aPL related complications in humans, and the potential of complement inhibition as a therapeutic target in APS require further study.

BackgroundThromboembolism (TE) in cancer significantly contributes to morbidity and mortality. Little is known about the incidence of arterial TE (ATE) and venous TE (VTE) in patients with melanoma on immune checkpoint inhibitor (ICI) therapy.MethodsWe conducted a retrospective cohort study of patients with melanoma receiving ICI from July 2015 through December 2017 at the Cleveland Clinic. TE, including VTE events of deep venous thrombosis, pulmonary embolism, visceral vein thrombosis, and ATE events of myocardial infarction, stroke, peripheral arterial embolism, or transient ischemic attack after ICI initiation were identified. Overall survival (OS) from ICI initiation was estimated by Kaplan-Meier and Cox hazard models; associations between TE, ICI regimen, and clinical risk factors were evaluated using log-rank test.ResultsThe study population comprised 228 patients with median age of 65 years (23–91 years), 67% male, and median follow-up of 27.3 months. Pembrolizumab was most commonly used (38.7%), followed by combination of ipilimumab plus nivolumab (29.4%), ipilimumab (20%), and nivolumab (12.3%). Most had stage IV disease (81.1%) and 11% had brain metastases (BM) at treatment initiation. Fifty-one TE events occurred in 47 patients (20.6%), including 37 (16.2%) VTE and 14 (6.1%) ATE. Cumulative incidence of TE after ICI initiation was 9.3% (95% CI: 6.0% to 13.6%) at 6 months, and 16.0% (95% CI: 11.6% to 21.2%) at 12 months. The 6-month and 12-month VTE cumulative incidence rates were higher with combination ICI than single agent (16.7% vs 5.0% and 21.3% vs 9.5%, respectively; p=0.02). Risk factors significantly associated with VTE in multivariate analysis included combination ICI (HR 2.70; 95% CI: 1.28 to 5.70; p=0.009), Khorana Score ≥1 (HR 2.24; 95% CI: 1.06 to 4.74; p=0.03), history of coronary artery disease (HR 2.71; 95% CI: 1.16 to 6.29); p=0.02), and anticoagulation at treatment start (HR 4.14; 95% CI: 1.60 to 10.7; p=0.003). Of patients without BM, OS was worse in patients with TE compared with those without (2-year OS 50.8% vs 71.3%; HR 2.27; 95% CI: 1.36 to 3.79; p=0.002), when adjusted for age and stage.ConclusionsICI is associated with a high incidence of TE in patients with melanoma, with higher rates with combination therapy; TE is associated with substantial worsening of survival. Further studies are needed to identify pathophysiology, biomarkers, and preventive approaches.

The association between malignancy and venous thromboembolic disease (VTE) is well established. The independent impact of VTE, both symptomatic and incidental, on survival in patients with prostate cancer is not known. We conducted a retrospective cohort study to evaluate the effect of VTE of survival in prostate cancer. Data regarding clinical characteristics, treatment and outcomes of 453 consecutive prostate cancer patients were collected. Fisher exact (categorical variables) and t-test (continuous variables) were utilized to test associations with VTE and mortality. Survival was estimated using the Kaplan Meier method. A Cox regression model was used to model the mortality hazard ratio (HR). At diagnosis, 358 (83%) patients had early stage disease, 43 (10%) had locally advanced disease and 32 (7%) had metastatic disease. During the follow up period, 122 (27%) patients died and 41 (9%) developed VTE (33 deep vein thrombosis, 5 pulmonary embolism, and 3 patients with both DVT and PE). Twenty-five VTE events were symptomatic and 16 were incidentally diagnosed on CT scans obtained for other reasons. VTE was associated with increased mortality [HR 6.89 (4.29-11.08), p<0.001] in a multivariable analysis adjusted for cancer stage, performance status, treatments and co-morbidities. There was no difference in survival between patients who had symptomatic and incidental VTE. Venous thromboembolic disease, both symptomatic and incidental, is a predictor of poor survival in patients with prostate cancer, especially those with advanced disease. Further studies are needed to evaluate the benefit of prophylactic and therapeutic anticoagulation in this population.

Thrombolysis remains the only effective therapy to reverse acute ischaemic stroke. However, delayed treatment may cause serious complications including hemorrhagic transformation and reperfusion injury. The level of lipocalin‐2 (LCN2) is elevated in the plasma of ischaemic stroke patients, but its role in stroke is unknown. Here, we show that LCN2 was acutely induced in mice after ischaemic stroke and is an important mediator of reperfusion injury. Increased levels of LCN2 were observed in mouse serum as early as 1 hr after transient middle cerebral artery occlusion (tMCAO), reaching peak levels at 23 hrs. LCN2 was also detected in neutrophils infiltrating into the ipsilateral hemisphere, as well as a subset of astrocytes after tMCAO, but not in neurons and microglia. Stroke injury, neurological deficits and infiltration of immune cells were markedly diminished in LCN2 null mice after tMCAO, but not after permanent MCAO (pMCAO). In vitro, recombinant LCN2 protein induced apoptosis in primary cultured neurons in a dose‐dependent manner. Our results demonstrate that LCN2 is a neurotoxic factor secreted rapidly in response to cerebral ischaemia, suggesting its potential usage as an early stroke biomarker and a novel therapeutic target to reduce stroke‐reperfusion injury.

Key Clinical Message Our case depicts a challenging diagnosis of catastrophic antiphospholipid syndrome in a young patient with a heterogenous presentation with extensive clinical course, a wide range of investigations, including multimodality imaging, and multidisciplinary expertise, to initiate prompt treatment addressing multiorgan thrombotic injury. Multimodality imaging evaluation of CAPS. Top: CTA demonstrating filling defects and thrombosis of (A) superior vena cava and (B) left brachiocephalci vein with (C) chest wall collaterals and (D) prominent azygos vein, There is also (E) splenic infarct, (F) and (G) signs of aortitis affecting infrarenal abdominal aorta and right common iliac artery, which in (H) appears to resolve on follow‐up CTA. Bottom: MRI evaluation showing late gadolinium enhancement imaging on (A)–(C) short axis, (D) 2‐chamber, (E) 3‐chamber and (F) 4‐chamber views, illustrating mid‐myocardial and subendocardial enhancement of multiple segments suspicious for multi‐vessel coronary embolic infarcts or myocarditis.

The propensity to develop venous thromboembolism (VTE) on the basis of individual tumor biological features remains unknown. We conducted a whole transcriptome RNA sequencing strategy, focusing on a single cancer type (lung cancer), to identify biomarkers of cancer‐associated VTE. Twelve propensity‐matched patients, 6 each with or without VTE, were identified from a prospective institutional review board–approved registry at the Cleveland Clinic with available tissue from surgical excision of a primary lung mass between 2010 and 2015. Patients were propensity matched based on age, sex, race, history of prior cancer, date of cancer diagnosis, stage, histology, number of lines of chemotherapy, and length of follow‐up. RNA sequencing was performed on tumor tissue, and gene set enrichment analysis (GSEA) was performed on differentially expressed genes. We identified 1037 genes with differential expression. In patients with VTE, 869 genes were overexpressed and 168 were underexpressed compared to patients without VTE. Of these, 276 overexpressed and 35 underexpressed were significantly different (Q < 0.05). GSEA revealed upregulation of genes in complement, inflammation, and KRAS signaling pathways in tumors from patients with VTE. These differentially expressed genes and associated pathways provide biologic insights into cancer‐associated VTE and may provide insignts to develop new risk stratification schemes, prevention, or treatment strategies.

Thrombopoietin receptor agonists (TPO‐RAs) are used to treat primary immune thrombocytopenia (ITP). Some patients have discontinued treatment while maintaining a hemostatic platelet count. To develop expert consensus on when it is appropriate to consider tapering TPO‐RAs in ITP, how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy. We used a RAND/UCLA modified Delphi panel method. Ratings were completed independently by each expert before and after a meeting. Second‐round ratings were used to develop the panel’s guidance. The panel was double‐blinded: The sponsor and nonchair experts did not know each other’s identities. Guidance on when it is appropriate to taper TPO‐RAs in children and adults was developed based on patient platelet count, history of bleeding, intensification of treatment, trauma risk, and use of anticoagulants/platelet inhibitors. For example, it is appropriate to taper TPO‐RAs in patients who have normal/above‐normal platelet counts, have no history of major bleeding, and have not required an intensification of treatment in the past 6 months; it is inappropriate to taper TPO‐RAs in patients with low platelet counts. Duration of ITP, months on TPO‐RA, or timing of platelet response to TPO‐RA did not have an impact on the panel’s guidance on appropriateness to taper. Guidance on how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy is also provided. This guidance could support clinical decision making and the development of clinical trials that prospectively test the safety of tapering TPO‐RAs.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life. We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations). The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash. Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244).

Hereditary hemorrhagic telangiectasia (HHT) is a rare angiogenic disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Pazopanib is an oral multi-kinase angiogenesis inhibitor with promise to treat bleeding in HHT. We analyzed outcomes of HHT patients with the most severe bleeding causing RBC transfusion dependence treated on a predefined institutional pazopanib treatment pathway (with data collected retrospectively). The primary endpoint was achievement of transfusion independence. Secondary endpoints included hemoglobin, epistaxis severity score, RBC transfusion and iron infusion requirements, number of local hemostatic procedures, ferritin and transferrin saturation, compared using paired and repeated measures mean tests. Thirteen transfusion-dependent HHT patients received pazopanib [median (range) dose 150 (25–300) mg daily)] for a median of 22 months. All patients achieved transfusion independence. Compared with pretreatment, pazopanib increased mean hemoglobin by 4.8 (95% CI, 3.6–5.9) g/dL (7.8 vs. 12.7 g/dL, P < 0.0001) and decreased mean epistaxis severity score by 4.77 (3.11–6.44) points (7.20 vs. 2.43 points, P < 0.0001) after 12 months of treatment. Compared with 3 months of pretreatment, RBC transfusions decreased by 93% (median of 16.0 vs. 0.0 units, P < 0.0001) and elemental iron infusion decreased by 92% (median of 4500 vs. 0 mg, P = 0.005) during the first 3 months of treatment; improvements were maintained over time. Pazopanib was well-tolerated: hypertension, lymphocytopenia, and fatigue were the most common TEAEs. In conclusion, pazopanib was safe and effective to manage severe bleeding in HHT, liberating all patients from transfusion dependence and normalizing hematologic parameters at doses lower than used to treat malignancies. These findings require confirmation in a randomized trial.