Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas

Background: Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality. Methods and Findings: Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity’s associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed. Conclusions: To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types

Clinical pharmacokinetics and pharmacodynamics of cerliponase alfa, enzyme replacement therapy for CLN2 disease by intracerebroventricular administration

Cerliponase alfa is recombinant human TPP1 delivered by intracerebroventricular (ICV) infusion for CLN2, a pediatric neurodegenerative disease caused by deficiency in lysosomal enzyme TPP1. We report the PK and PD of cerliponase alfa, the first ICV enzyme replacement therapy, characterized in a Phase 1/2 study. Escalating doses (30-300 mg every two weeks, Q2W) followed by 300 mg Q2W for ≥48 weeks were administered in 24 patients aged ≥3 years. Concentrations peaked in CSF at the end of ~4-hour ICV infusion and 8 hours thereafter in plasma. Plasma exposure was 300-1000 fold lower than in CSF, with no correlation in the magnitude of Cmax or AUC between body sites. There was no apparent accumulation in CSF or plasma exposure with Q2W dosing. Inter- and intra-patient variability of AUC, respectively, were 31-49% and 24% in CSF versus 59-103% and 80% in plasma. PK variability was not explained by baseline demographics, as gender, age, weight, and CLN2 disease severity score did not appear to impact CSF or plasma PK. No apparent correlation was noted between CSF or plasma PK and incidence of adverse events (pyrexia, hypersensitivity, seizure, and epilepsy) or presence of antidrug antibodies in CSF and serum. There was no relationship between magnitude of CSF exposure and efficacy (change in CLN2 score from baseline), indicating maximum benefit was obtained across the range of exposures with 300 mg Q2W. Data from this small trial of ultra-rare disease were leveraged to adequately profile cerliponase alfa and support 300 mg ICV Q2W for CLN2 treatment

Baseline cerebral oximetry values in cardiac and vascular surgery patients: a prospective observational study

<p>Abstract</p> <p>Aim</p> <p>This study was conducted to evaluate baseline INVOS values and identify factors influencing preoperative baseline INVOS values in carotid endarterectomy and cardiac surgery patients.</p> <p>Methods</p> <p>This is a prospective observational study on 157 patients (100 cardiac surgery patients, 57 carotid endarterectomy patients). Data were collected on factors potentially related to baseline INVOS values. Data were analyzed with student's t-test, Chi-square, Pearson's correlation or Linear Regression as appropriate.</p> <p>Results</p> <p>100 cardiac surgery patients and 57 carotid surgery patients enrolled. Compared to cardiac surgery, carotid endarterectomy patients were older (71.05 ± 8.69 vs. 65.72 ± 11.04, P < 0.001), with higher baseline INVOS (P < 0.007) and greater stroke frequency (P < 0.002). Diabetes and high cholesterol were more common in cardiac surgery patients. Right side INVOS values were strongly correlated with left-side values in carotid (r = 0.772, P < 0.0001) and cardiac surgery patients (r = 0.697, P < 0.0001). Diabetes and high cholesterol were associated with significantly (P < 0.001) lower INVOS and smoking was associated with higher INVOS values in carotid, but not in cardiac surgery patients. Age, sex, CVA history, Hypertension, CAD, Asthma, carotid stenosis side and surgery side were not related to INVOS. Multivariate analysis showed that diabetes is strongly associated with lower baseline INVOS values bilaterally (P < 0.001) and explained 36.4% of observed baseline INVOS variability in carotid (but not cardiac) surgery.</p> <p>Conclusion</p> <p>Compared to cardiac surgery, carotid endarterectomy patients are older, with higher baseline INVOS values and greater stroke frequency. Diabetes and high cholesterol are associated with lower baseline INVOS values in carotid surgery. Right and left side INVOS values are strongly correlated in both patient groups.</p

Serum Proteome and Cytokine Analysis in a Longitudinal Cohort of Adults with Primary Dengue Infection Reveals Predictive Markers of DHF

10.1371/journal.pntd.0001887PLoS Neglected Tropical Diseases611

Use of Biomarkers in the Evaluation and Treatment of Hypertensive Patients

The current definition of hypertension is based on blood pressure values, and blood pressure also drives treatment decisions, is the most important treatment monitoring tool and helps estimating risk of hypertension related organ damage. In an era of precision medicine additional biomarkers are needed in the diagnosis and management of patients with hypertension. In this review we outline the areas in which functional, imaging and circulating biomarkers could help in a more individualised definition of hypertension and associated risk. We will cover biomarkers for diagnosis; of pathophysiology and prediction of hypertension; response to treatment, organ damage; and to monitor treatment. A clear focus is on the vasculature, the heart and the kidneys, whereas we see a need to further develop biomarkers of cerebral function in order to diagnose cognition deficits and monitor changes in cognition in the future to support addressing the growing burden of hypertension associated vascular dementia