Background
The risk of arterial thromboembolism in patients with cancer is incompletely understood.
Objectives
The authors aimed to better define this epidemiological relationship, including the effects of cancer stage.
Methods
Using the Surveillance Epidemiology and End Results-Medicare linked database, we identified patients with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, pancreatic, or gastric cancer or non-Hodgkin lymphoma from 2002 through 2011. They were individually matched by demographics and comorbidities to a Medicare enrollee without cancer, and each pair was followed through 2012. Validated diagnosis codes were used to identify arterial thromboembolism, defined as myocardial infarction or ischemic stroke. Cumulative incidence rates were calculated using competing risk survival statistics. Cox hazards analysis was used to compare rates between groups at discrete time points.
Results
We identified 279,719 pairs of patients with cancer and matched controls. The 6-month cumulative incidence of arterial thromboembolism was 4.7% (95% confidence interval [CI]: 4.6% to 4.8%) in patients with cancer compared to 2.2% (95% CI: 2.1% to 2.2%) in controls (HR: 2.2; 95% CI: 2.1 to 2.3). The 6-month cumulative incidence of myocardial infarction was 2.0% (95% CI: 1.9% to 2.0%) in patients with cancer compared with 0.7% (95% CI: 0.6% to 0.7%) in controls (HR: 2.9; 95% CI: 2.8 to 3.1). The 6-month cumulative incidence of ischemic stroke was 3.0% (95% CI: 2.9% to 3.1%) in patients with cancer compared to 1.6% (95% CI: 1.6% to 1.7%) in controls (HR: 1.9; 95% CI: 1.8 to 2.0). Excess risk varied by cancer type (greatest for lung), correlated with cancer stage, and generally had resolved by 1 year.
Conclusions
Patients with incident cancer face a substantially increased short-term risk of arterial thromboembolism.
Diffuse gliomas comprise the most common malignant brain tumors in adults and include glioblastomas (GBM) and World Health Organization (WHO) grade II and grade III tumors, sometimes referred to as lower-grade gliomas (LGGs). Genetic tumor profiling is used for disease classification and to guide therapy
1
,
2
, but involves brain surgery for tissue collection and repeated tumor biopsies may be necessary for accurate genotyping over the course of the disease
3
–
10
. While detection of circulating tumor DNA (ctDNA) in blood remains challenging for patients with primary brain tumors
11
,
12
, sequencing of cerebrospinal fluid (CSF) ctDNA may provide an alternative to genotype glioma at lower morbidity and cost
13
,
14
. We therefore evaluated the representation of the glioma genome in CSF from 85 glioma patients who underwent a lumbar puncture for evaluation of neurological signs or symptoms. Tumor-derived DNA was detected in CSF from 42/85 (49.4 %) patients and was associated with disease burden and adverse outcome. The genomic landscape of glioma in CSF contained a broad spectrum of genetic alterations and closely resembled the genome in tumor biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes
isocitrate dehydrogenase 1 (IDH1)
or
IDH2
1
,
2
, were shared in all matched ctDNA-positive CSF/tumor pairs, whereas we observed considerable evolution in growth factor receptor signaling pathways. The ability to monitor evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.
Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with Nuclear factor kappa B (NF-κB). The role of BTK in primary CNS lymphoma (PCNSL) is unknown. We performed a Phase 1 clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS Lymphoma. Clinical responses to ibrutinib occurred in 10/13 (77%) PCNSL patients, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of Caspase Recruitment Domain Family Member 11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-Cell Antigen Receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with Phosphatidylinositol 3-kinase (PI3K)/mTOR activation markers. Inhibition of the PI3K-isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.
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