Effects of a novel Nodal-targeting monoclonal antibody in melanoma

Nodal is highly expressed in various human malignancies, thus supporting the rationale for exploring Nodal as a therapeutic target. Here, we describe the effects of a novel monoclonal antibody (mAb), 3D1, raised against human Nodal. In vitro treatment of C8161 human melanoma cells with 3D1 mAb shows reductions in anchorage-independent growth and vasculogenic network formation. 3D1 treated cells also show decreases of Nodal and downstream signaling molecules, P-Smad2 and P-ERK and of P-H3 and CyclinB1, with an increase in p27. Similar effects were previously reported in human breast cancer cells where Nodal expression was generally down-regulated; following 3D1 mAb treatment, both Nodal and P-H3 levels are reduced. Noteworthy is the reduced growth of human melanoma xenografts in Nude mice treated with 3D1 mAb, where immunostaining of representative tumor sections show diminished P-Smad2 expression. Similar effects both in vitro and in vivo were observed in 3D1 treated A375SM melanoma cells harboring the active BRAF(V600E) mutation compared to treatments with IgG control or a BRAF inhibitor, dabrafenib. Finally, we describe a 3D1-based ELISA for the detection of Nodal in serum samples from cancer patients. These data suggest the potential of 3D1 mAb for selecting and targeting Nodal expressing cancers.     

Orthodeoxia without platypnea from interatrial defect associated with persistent left superior vena cava in the absence of pulmonary hypertension

Orthodeoxia-platypnea is a rare but increasingly recognized syndrome of upright hypoxemia usually associated to breathlessness relieved by recumbency. We report the case of isolated orthodeoxia discovered in a military recruit who referred only fatigability as the clinical symptom after a forced march. Transesophageal echocardiography demonstrated the presence of interatrial defect ostium secundum type with the persistence of left superior vena cava draining into coronary sinus. Right-to-left shunt was visualized by peripheral saline contrast infusion, despite normal right hemodynamics at heart catheterization. Hypoxemia recovered after the percutaneous closure of the interatrial defect. Orthodeoxia and platypnea could occur as separate disease manifestations, the latter probably being a rarer acute event, whereas orthodeoxia was underestimated and potentially earlier screenable.     

Low-molecular-weight and unfractionated heparin for prevention of venous thromboembolism in neurosurgery: a meta-analysis

BACKGROUND: Venous thromboembolism is a common, life-threatening complication in neurosurgery, but prophylaxis with anticoagulant agents has not gained wide acceptance because of concern about intracranial bleeding. We performed a meta-analysis of controlled randomized trials on the efficacy and safety of heparin in the prophylaxis of venous thromboembolism in neurosurgery. OBJECTIVE: To review the clinical benefit of prophylaxis of venous thromboembolism with heparin in the controversial setting of neurosurgery. METHODS: Relevant trials evaluating heparin for prophylaxis of venous thromboembolism in neurosurgery were identified by a MEDLINE search, scan of meeting abstracts, and scrutiny of the references of original articles and reviews. Four controlled randomized studies, 3 of which involved low-molecular-weight heparin, were included in the analysis, and 4 uncontrolled studies are commented on in the article. The outcome measure (observed minus expected number of events) and its variance were calculated for each single trial and then summed. Two-tailed P values and 95% confidence intervals (CIs) were calculated. Efficacy was assessed per protocol and safety by intention-to-treat analysis. The homogeneity of the studies was tested with the chi(2) statistic. The results were also expressed as number needed for 1 extra event. RESULTS: A total of 187 thromboembolic events were recorded in 827 patients (22.6%). Heparin prophylaxis resulted in a 45% relative risk reduction of venous thromboembolic events (odds ratio [OR], 0.48; 95% CI, 0.35-0.66; P<. 001). Nineteen major bleedings were recorded in 1022 patients. None were fatal. Heparin treatment resulted in a 71% relative risk increase of major bleeding (OR, 1.72; 95% CI, 0.69-4.27; P =.24). The number needed to treat was 7.7 for venous thromboembolism and 16 for proximal deep vein thrombosis. The number needed to harm was 102 (115 for low-molecular-weight heparin). CONCLUSIONS: Low-molecular-weight and unfractionated heparin have been shown to be effective for prophylaxis of venous thromboembolism in elective neurosurgery without excessive bleeding risk.