Lessons learned from routine, targeted assessment of liquid biopsies for EGFR T790M resistance mutation in patients with EGFR mutant lung cancers.

Background: Plasma cfDNA evaluation at acquired resistance to targeted therapies in lung cancer is routine, however, reports of extended clinical application and pitfalls in laboratory practice are still limited. In this study we describe our experience with cfDNA testing using EGFR T790M as a prototype.Methods: Patients with metastatic EGFR-mutant NSCLC patients who underwent plasma EGFR T790M testing at acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) from January 2016 through August 2017 were identified. Molecular laboratory records were reviewed to assess performance of testing by digital PCR, concordance between plasma and tissue testing, turnaround time (TAT), plasma T790M variant allele frequency (VAF), and its correlations with metastatic sites and clinical outcomes.Results: 177 patients underwent T790M cfDNA testing during this period. Plasma T790M was positive in 32% of patients. The median TAT was shorter for plasma T790M compared to tissue PCR (9 vs. 15 days, p < .0001), and led to osimertinib use in 84% of positive patients. In 52 patients with plasma and tissue T790M evaluation, the concordance was 77%. Plasma T790M VAF did not correlate with time to osimertinib discontinuation (p = .4). Plasma T790M status correlated with a higher number of metastatic sites (4 vs. 3, p < .001) and bone metastases (p = .0002).Conclusion: Plasma EGFR T790M testing had shorter TAT compared to tissue testing, however, it was longer than anticipated. Test sensitivity is higher in patients with osseous metastases and with higher metastatic burden suggesting a more limited role for early detection. T790M VAF was not associated with clinical outcomes.

Household air pollution and cancers other than lung: a meta-analysis.

Household air pollution (HAP) from solid fuel combustion contributes to 2.6% of the global burden of disease. HAP emissions are an established lung carcinogen; however, associations with other cancer sites have not been fully explored. We conducted a meta-analysis of 18 case-control studies. Using fixed-effects models, utilizing the adjusted odds ratios (OR) and 95% confidence intervals (95% CI) from each study, we evaluated the association between HAP and cervical neoplasia (663 cases and 1747 controls) and upper aero-digestive tract cancers (6022 cases and 15 325 controls). We found that HAP was associated with cervical neoplasia (OR = 6.46; 95% CI = 3.12-13.36; 4 studies); oral (OR = 2.44; 95% CI = 1.87-3.19; 4 studies; 1000 cases/3450 controls); nasopharyngeal (OR = 1.80; 95% CI = 1.42-2.29; 6 studies; 2231 cases/2160 controls); pharyngeal (OR = 3.56; 95% CI = 2.22-5.70; 4 studies; 1036 cases/3746 controls); and laryngeal (OR = 2.35; 95% CI = 1.72- 3.21; 5 studies; 1416 cases/4514 controls) cancers. The elevated risk for esophageal cancer (OR = 1.92; 95% CI = 0.82-4.49; 2 studies; 339 cases/1455 controls) was non-significant. HAP was associated with cervical neoplasia among studies that accounted for HPV infection (OR = 9.60; 95% CI = 3.79-24.32) and smoking (OR = 4.72; 95% CI = 1.84-12.07). Similarly, our observed associations between HAP and upper aero-digestive tract cancers remained significantly elevated when analyses were restricted to studies that controlled for smoking. No significant publication bias was detected. Our results suggest that the carcinogenic effect of HAP observed for lung cancer may extend to other cancers, including those of the cervix and the upper aero-digestive tract. Further research is needed to confirm these associations in prospective studies.

Hypoalbuminemia in hemodialyzed end stage renal disease patients: risk factors and relationships--a 2 year single center study.

BACKGROUND: Malnutrition affects 1/3 of hemodialysis patients and associates with a higher risk of morbidity and mortality. Serum albumin is a marker of nutrition and inflammation, and predicts mortality, particularly when <3.8 g/dL. This study was performed to identify risk factors for hypoalbuminemia (<3.8 g/dL) and the particular temporal relationship and strength of association between protein intake (nPCR) and serum albumin when confounding variables are taken into account. METHODS: Demographic, clinical, and dialysis-related data of 57 ESRD patients on hemodialysis over 24 months in 6 temporal segments were analyzed with serum albumin as a continuous, and categorical outcome (with 3.8 g/dl as cut-off) variable , against 13 potential independent variables [4 demographic factors, 3 nutrition-related, and 5 morbidity-related parameters, and % urea reduction ratio (URR)]. The temporal relationships between albumin and nPCR were analyzed for the concurrent & 3 subsequent months in each temporal segment. RESULTS: The impact of nPCR on serum albumin (p < 0.05) was significant but with no discernible temporal relationship. Advancing age, longer vintage, female gender, diabetes mellitus, nPCR, serum phosphate and ferritin had significant correlation with albumin <3.8 g/dl (p < 0.05). Serum phosphate levels correlated positively, and fever, bacteremia, hospital stay and weight loss negatively, with mean serum albumin but did not negate the effect of nPCR. Regression analysis showed that mean albumin associated with nPCR, fever, hospital stay, bacteremia, dialysis vintage, age, sex, and diabetes mellitus; and that an albumin level of <3.8 g/dl associated with age, female sex, diabetes, lower nPCR, and higher ferritin. CONCLUSION: Suggested target albumin levels were not met in elderly, female, and diabetic patients. The association of nPCR with albumin was not nullified by confounding demographic or morbidity-related factors. nPCR had no demonstrable temporal relationship with albumin.

The nervous system's potential role in multiple sclerosis associated bone loss.

Osteoporosis is a degenerative bone disease that causes significant morbidity and mortality in multiple sclerosis (MS) patients; the pathogenesis of this disease being poorly understood in the context of MS. Osteoporosis is seen more frequently in MS patients than in healthy controls matched for age and sex. Extensively studied factors, including impaired ambulation and the use of steroids, do not appear to completely account for the phenomenon. This review summarizes common risk factors, physiologic and genetic, that may contribute to the etiology and progression of osteoporosis in MS patients as well as providing insight into nervous system control of bone metabolism and homeostasis.

Cognitive impairment is associated with reduced bone mass in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) has been associated with reduced bone mineral density (BMD), yet the underlying causes are not fully known. The recent discovery that bone homeostasis is directly regulated by the brain led us to hypothesize that it may be impaired by MS pathology. As cognitive impairment (CI) is a well-documented correlate of MS-related brain pathology, we tested the hypothesis that it is associated with reduced BMD. OBJECTIVE: We aimed to determine if CI is associated with reduced BMD in patients with MS. METHODS: We retrospectively studied the medical records of 56 patients with MS, ≤50 years old, with Expanded Disability Status Scale score ≤4.5 and with dual X-ray absorptiometry (DEXA) BMD measurement within 1 year of neuropsychological testing with a standard battery (MACFIMS). RESULTS: In total, 23 (41.1%) MS patients had osteopenia or osteoporosis. Mean femur BMD was significantly lower in patients with MS with CI (0.89±0.12 g/cm(2)) compared with intact patients (0.99±0.17 g/cm(2), p=0.009). In the cognitively impaired group, 59.3% had either osteopenia or osteoporosis, compared with 24.1% in the non-cognitively impaired group (odds ratio=4.57, p=0.008). CONCLUSION: CI is associated with reduced BMD in patients with MS, suggesting that central mechanisms involved in bone homeostasis may be directly impaired by MS-related inflammatory and neurodegenerative processes.