OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum

Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional sin-gle-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict re-sponses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for ther-apy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy.Molecular tumour pathology - and tumour genetic

Unusual case of bifocal leptomeningeal melanocytoma in the posterior fossa with seeding in the spinal canal.

Item does not contain fulltextA 26-year-old man presented with signs of raised intracranial pressure. CT and MRI of the head demonstrated two separate lesions in the posterior fossa. The radiological differential diagnoses included multiple meningiomas, schwannomas, neurofibromas and subependymomas. Both lesions were surgically resected. Histopathological examination revealed localisations of a leptomeningeal melanocytoma. Leptomeningeal melanocytoma is a rare tumour of the central nervous system. Generally, it has a good prognosis if radical resection can be performed. In cases of subtotal resection, adjuvant radiotherapy should be considered. Local recurrences are common. Less frequently, leptomeningeal metastases and, on rare occasions, distant metastases or progression to malignant melanoma have been described. We describe an unusual case with multiple localisations of melanocytoma in the posterior fossa and spinal canal, with the emphasis being on the radiological findings and diagnosis of this rare tumour. After surgery of the brain, this patient was irradiated on the craniospinal axis

Vorapaxar in the secondary prevention of atherothrombotic events

Item does not contain fulltextBACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)