Hepatotoxicity and Recurrent NSTEMI While on Pembrolizumab for Metastatic Giant Cell Bone Tumor.

We present the first reported case showing metastatic giant bone cell tumor being treated successfully with pembrolizumab after failing prior tyrosine kinase inhibitor therapy. Of note, the patient developed multiple systemic effects associated with checkpoint inhibitor use. One year after starting the checkpoint inhibitor (ICI), the patient also developed hepatitis that was confirmed by liver biopsy and pathology to be, in part, due to drug-mediated toxicity similar to prior ICI toxicity cases that have been reported. Additionally, although the patient had vascular risk factors (hypertension, diabetes and smoking), it was notable from a cardiology perspective that the patient developed 2 subsequent non-ST-elevation myocardial infarctions, with rapid progression of stenosis of the left circumflex artery 2 months apart. The first left heart catheterization showing minimal disease of the left circumflex, but 2 months later, presenting with chest pain, a repeat left heart catheterization showed significant stenosis of the left proximal circumflex, raising the possibilities that either ICI can promote plaque rupture and/or accelerated atherosclerosis; both phenomena have been shown to occur in animal models. The patient also developed thyroiditis with subsequent hypothyroidism, now on thyroid replacement from checkpoint inhibitor use. This case demonstrates the multiorgan adverse effects this new antioncologic agent can have and yet also its promising antitumor effects. Awareness of the side effects among primary care doctors and all specialists will be helpful in managing these potential side effects and research will help elucidate ways to prevent the adverse effects.

Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.

Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin- and stromal cell-derived factor 1 (SDF-1)-rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1(+) vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.