Cancer-associated thrombocytosis and high concentrations of circulating transforming growth factor–β1 (TGF-β1) are frequently observed in patients with progressive cancers. Using genetic and pharmacological approaches, we show a direct link between thrombin catalytic activity and release of mature TGF-β1 from platelets. We found that thrombin cleaves glycoprotein A repetitions predominant (GARP), a cell surface docking receptor for latent TGF-β1 (LTGF-β1) on platelets, resulting in liberation of active TGF-β1 from the GARP–LTGF-β1 complex. Furthermore, systemic inhibition of thrombin obliterates TGF-β1 maturation in platelet releasate and rewires the tumor microenvironment toward favorable antitumor immunity, which translates into efficient cancer control either alone or in combination with programmed cell death 1–based immune checkpoint blockade therapy. Last, we demonstrate that soluble GARP and GARP–LTGF-β1 complex are present in the circulation of patients with cancer. Together, our data reveal a mechanism of cancer immune evasion that involves thrombin-mediated GARP cleavage and the subsequent TGF-β1 release from platelets. We propose that blockade of GARP cleavage is a valuable therapeutic strategy to overcome cancer’s resistance to immunotherapy.

The radiologic findings in three cases of meningovascular syphilis are presented. Angiography demonstrated varying degrees of narrowing and ectasia of the supraclinoid carotid, basilar, and proximal anterior and middle cerebral arteries, as well as distal branches. Computed tomography (CT) showed multifocal infarction with variable enhancement. Similarly, in the one case studied with magnetic resonance (MR), several regions of high signal intensity on T2-weighted sequences were found, which were compatible with foci of ischemia. Although the radiologic findings are nonspecific, the diagnosis of meningovascular syphilis should be considered in patients with vasculitis of uncertain etiology.

Seventy consecutive patients were examined with magnetic resonance (MR) and computed tomography (CT) of the brain. Each study was independently reviewed. Focal abnormalities were detected by one or both modalities in 51 patients. Neoplastic, infectious, vascular, demyelinating, metabolic, and congenital disorders of the brain were included. The MR pulse sequence that best detected these abnormalities was a spin-echo multisection technique that used a long interval between RF excitations (TR = 1500 or 2000 msec). Forty-eight of 51 patients showed focal lesions with this technique. A supplementary MR pulse sequence with a short TR (500 msec) was useful in helping to characterize certain lesions with a long T1 relaxation component, but in 10 of 26 positive cases in which this sequence was added it would have missed the abnormality had it been the sole sequence used. MR missed focal lesions in 3 of 51 patients. These were lesions that required thin-section (1.5 mm) CT techniques. Two were intrasellar, and one was an intracanalicular neurinoma. In 17 of 48 patients, CT missed the focal lesion seen with MR. Based on this experience, it is concluded that the long TR multisection spin-echo sequence is the optimal MR screening technique for detection of most brain abnormalities, and is more sensitive than CT. Currently, CT remains the screening modality of choice when high-resolution, thin-section studies in the pituitary, inner ear, and orbital regions are indicated.

Twenty-six patients with primary intracranial tumors were evaluated by magnetic resonance (MR) and a comparison was made with CT findings. The SE technique with TR = 2,000 ms and TE = 56 ms was most useful in delineating normal anatomy, in differentiating gray and white matter, and in optimizing the visualization of edema. The use of TR = 500 ms optimized sensitivity to T1 relaxation time differences in disparate tissue and best defined the cerebrospinal fluid spaces. Although prolongation of T1 and T2 relaxation values was seen with most malignant lesions, several cases produced no obvious prolongation of T1. Separation of tumor from surrounding edema was possible in several instances. In 16/26 patients information not available on CT was obtained with MR. This included detection of altered tissue characteristics where CT showed only mass effect, more accurate depiction of full extent and location of tumor, and visualization of associated abnormalities. However, a small inner ear epidermoid tumor seen with high-resolution CT (1.5-mm sections) was difficult to identify with certainty on MR, and in two other cases punctate foci of calcification were not identified on MR.