Publications

PURPOSE OF REVIEW

This review summarizes research on the physiological changes that occur with aging and the resulting effects on fracture healing.

RECENT FINDINGS

Aging affects the inflammatory response during fracture healing through senescence of the immune response and increased systemic pro-inflammatory status. Important cells of the inflammatory response, macrophages, T cells, mesenchymal stem cells, have demonstrated intrinsic age-related changes that could impact fracture healing. Additionally, vascularization and angiogenesis are impaired in fracture healing of the elderly. Finally, osteochondral cells and their progenitors demonstrate decreased activity and quantity within the callus. Age-related changes affect many of the biologic processes involved in fracture healing. However, the contributions of such changes do not fully explain the poorer healing outcomes and increased morbidity reported in elderly patients. Future research should address this gap in understanding in order to provide improved and more directed treatment options for the elderly population.

OBJECTIVES

The expression and activity of the breast cancer resistance protein (ABCG2) contributes toward the pharmacokinetics of endogenous and xenobiotic substrates. The effect of genetic variation on the activity of cis-regulatory elements and nuclear response elements in the ABCG2 locus and their contribution toward ABCG2 expression have not been investigated systematically. In this study, the effect of genetic variation on the in vitro and in vivo enhancer activity of six previously identified liver enhancers in the ABCG2 locus was examined.

METHODS

Reference and variant liver enhancers were tested for their ability to alter luciferase activity in vitro in HepG2 and HEK293T cell lines and in vivo using a hydrodynamic tail vein assay. Positive in vivo single-nucleotide polymorphisms (SNPs) were tested for association with gene expression and for altered protein binding in electrophoretic mobility shift assays.

RESULTS

Multiple SNPs were found to alter enhancer activity in vitro. Four of these variants (rs9999111, rs12508471, ABCG2RE1*2, and rs149713212) decreased and one (rs2725263) increased enhancer activity in vivo. In addition, rs9999111 and rs12508471 were associated with ABCG2 expression in lymphoblastoid cell lines, lymphocytes, and T cells, and showed increased HepG2 nuclear protein binding.

CONCLUSION

This study identifies SNPs within regulatory regions of the ABCG2 locus that alter enhancer activity in vitro and in vivo. Several of these SNPs correlate with tissue-specific ABCG2 expression and alter DNA/protein binding. These SNPs could contribute toward reported tissue-specific variability in ABCG2 expression and may influence the correlation between ABCG2 expression and disease risk or the pharmacokinetics and pharmacodynamics of breast cancer resistance protein substrates.

Background

Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling.

Methods

We performed targeted sequencing across 72 clinically relevant genes in 45 plasma cell-free DNA (cfDNA) samples collected at time of metastatic tissue biopsy. We compared ctDNA alterations with exome sequencing data generated from matched tissue and quantified the concordance of mutations and copy number alterations using the Fisher exact test and Pearson correlations.

Results

Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA. Furthermore, the hierarchy of variant allele fractions for shared mutations was remarkably similar between ctDNA and tissue. Copy number profiles between matched liquid and solid biopsy were highly correlated, and individual copy number calls in clinically actionable genes were 88.9% concordant. Detected alterations included AR amplifications in 22 (64.7%) samples, SPOP mutations in three (8.8%) samples, and inactivating alterations in tumor suppressors TP53 , PTEN , RB1 , APC , CDKN1B , BRCA2 , and PIK3R1 . In several patients, ctDNA sequencing revealed robust changes not present in paired solid biopsy, including clinically relevant alterations in the AR, WNT, and PI3K pathways.

Conclusions

Our study shows that, in the majority of patients, a ctDNA assay is sufficient to identify all driver DNA alterations present in matched metastatic tissue and supports development of DNA biomarkers to guide mCRPC patient management based on ctDNA alone.

Importance

As greater numbers of older patients seek elective surgery, one approach to preventing postoperative complications is enhanced assessment of risks during preoperative evaluation.

Objective

To determine whether a geriatric assessment tool can be implemented in a preoperative clinic and can estimate risk of postoperative complications.

Design, Setting, and Participants

In this prospective cohort study, patients 70 years of age or older were assessed in a preoperative clinic for elective surgery from July 9, 2008, to January 5, 2011. Patients were screened using the Vulnerable Elders Surgical Pathways and Outcomes Assessment (VESPA) tool developed for this study. Patients were assessed on 5 preoperative activities of daily living recommended by the American College of Surgeons (bathing, transferring, dressing, shopping, and meals), history of falling or gait impairment, and depressive symptoms (2-item Patient Health Questionnaire). Patients also underwent a brief cognitive examination (Mini-Cog) and gait and balance assessment (Timed Up and Go test). A novel question was also asked as to whether patients expected they could manage themselves alone after discharge. Comorbidities and work-related relative value units (categorized into low, moderate, and high tertiles) were also collected. Multivariable logistic regression was performed to estimate risk of postoperative complications. Sustainability of VESPA over time was also evaluated. Medical record review was performed from December 11, 2012, to October 2, 2015, and data analysis was performed from November 15, 2015, to May 18, 2016.

Main Outcomes and Measures

Postoperative surgical and geriatric complications.

Results

Of the 770 patients evaluated, 736 (384 women and 352 men; mean [SD] age, 77.7 [5.7] years) underwent 740 operative procedures; of these patients, 711 had complete data for multivariable analysis. In our sample, 105 patients (14.3%) reported 1 or more difficulties with the 5 activities of daily living, and 270 of 707 patients (38.2%) foresaw themselves unable to manage self-care alone. A total of 131 of 740 patients had geriatric complications, and 114 of 740 patients had surgical complications; 187 of 740 patients (25.3%) had either geriatric or surgical complications. On multivariable analysis, the number of difficulties with activities of daily living (odds ratio [OR], 1.3; 95% CI, 1.0-1.6), anticipated difficulty with postoperative self-care (OR, 1.6; 95% CI, 1.0-2.2), Charlson Comorbidity score of 2 or more vs less than 2 (OR, 1.5; 95% CI, 1.0-2.3), male sex (OR, 1.6; 95% CI, 1.1-2.3), and work-related relative value units (moderate vs low: OR, 1.9; 95% CI, 1.1-3.3; high vs low: OR, 8.8; 95% CI, 5.3-14.5) were independently associated with postoperative complications (overall model area under the receiver operating characteristic curve, 0.77). With these results, a whole-point VESPA score used alone to estimate risk of complications also demonstrated excellent fit (area under the curve, 0.76).

Conclusions and Relevance

Preoperative assessment of older geriatric patients is feasible in the general preoperative clinic and can help identify patients at higher risk of postoperative complications.

Social media has become an important tool for physicians and scientists to rapidly share information with colleagues around the world. Use of social media outlets-in particular, Twitter-has risen rapidly in recent years, and it is now customary for national hematology meetings to have thousands of participants who share photographs and textual summaries of data presentations, as well as personal insights and commentary, with virtual audiences. These messages, or "tweets," can be specifically followed using a hashtag ontology which arose organically over the past several years in the context of medical meetings. This system facilitates communication between meeting attendees and those colleagues near and far with similar interests, thus globalizing the conversation between hematology providers, investigators, patient advocates, professional organizations, regulatory agencies, testing companies, and the pharmaceutical industry about cutting-edge developments in the field.