Publications

Persistent pain after breast cancer surgery is a common clinical problem. Given the role of potassium channels in modulating neuronal excitability, coupled with recently published genetic associations with preoperative breast pain, we hypothesized that variations in potassium channel genes will be associated with persistent postsurgical breast pain. In this study, associations between 10 potassium channel genes and persistent breast pain were evaluated. Using growth mixture modeling (GMM), 4 distinct latent classes of patients, who were assessed before and monthly for 6 months after breast cancer surgery, were identified previously (ie, No Pain, Mild Pain, Moderate Pain, Severe Pain). Genotyping was done using a custom array. Using logistic regression analyses, significant differences in a number of genotype or haplotype frequencies were found between: Mild Pain vs No Pain and Severe Pain vs No Pain classes. Seven single-nucleotide polymorphisms (SNPs) across 5 genes (ie, potassium voltage-gated channel, subfamily A, member 1 [KCNA1], potassium voltage-gated channel, subfamily D, member 2 [KCND2], potassium inwardly rectifying channel, subfamily J, members 3 and 6 (KCNJ3 and KCNJ6), potassium channel, subfamily K, member 9 [KCNK9]) were associated with membership in the Mild Pain class. In addition, 3 SNPs and 1 haplotype across 4 genes (ie, KCND2, KCNJ3, KCNJ6, KCNK9) were associated with membership in the Severe Pain class. These findings suggest that variations in potassium channel genes are associated with both mild and severe persistent breast pain after breast cancer surgery. Although findings from this study warrant replication, they provide intriguing preliminary information on potential therapeutic targets.

A key objective of the 1993 National Institutes of Health (NIH) Revitalization Act was to ensure inclusion of minorities in clinical research. We conducted a literature search for the period from 1993 to 2013 to examine whether racial/ethnic minorities are adequately represented in published research studies of pulmonary diseases, particularly NIH-funded studies. We found a marked underrepresentation of minorities in published clinical research on pulmonary diseases. Over the last 20 years, inclusion of members of racial or ethnic minority groups was reported (in MeSH terms, journal titles, and MEDLINE fields) in less than 5% of all NIH-funded published studies of respiratory diseases. Although a secondary analysis revealed that a larger proportion of NIH-funded studies included any minorities, this proportional increment mostly resulted from studies including relatively small numbers of minorities (which precludes robust race- or ethnic-specific analyses). Underrepresentation or exclusion of minorities from NIH-funded studies is likely due to multiple reasons, including insufficient education and training on designing and implementing population-based studies of minorities, inadequate motivation or incentives to overcome challenges in the recruitment and retention of sufficient numbers of members of racial/ethnic minorities, underrepresentation of minorities among respiratory scientists in academic medical centers, and a dearth of successful partnerships between academic medical centers and underrepresented communities. This problem could be remedied by implementing short-, medium-, and long-term strategies, such as creating incentives to conduct minority research, ensuring fair review of grant applications focusing on minorities, developing the careers of minority scientists, and facilitating and valuing research on minorities by investigators of all backgrounds.

BACKGROUND

Next-generation tumor sequencing (NGTS) panels, which include multiple established and novel targets across cancers, are emerging in oncology practice, but lack formal positive coverage by US payers. Lack of coverage may impact access and adoption. This study identified challenges of NGTS coverage by private payers.

METHODS

We conducted semi-structured interviews with 14 NGTS experts on potential NGTS benefits, and with 10 major payers, representing more than 125,000,000 enrollees, on NGTS coverage considerations. We used the framework approach of qualitative research for study design and thematic analyses and simple frequencies to further describe findings.

RESULTS

All interviewed payers see potential NGTS benefits, but all noted challenges to formal coverage: 80% state that inherent features of NGTS do not fit the medical necessity definition required for coverage, 70% view NGTS as a bundle of targets versus comprehensive tumor characterization and may evaluate each target individually, and 70% express skepticism regarding new evidence methods proposed for NGTS. Fifty percent of payers expressed sufficient concerns about NGTS adoption and implementation that will preclude their ability to issue positive coverage policies.

CONCLUSIONS

Payers perceive that NGTS holds significant promise but, in its current form, poses disruptive challenges to coverage policy frameworks. Proactive multidisciplinary efforts to define the direction for NGTS development, evidence generation, and incorporation into coverage policy are necessary to realize its promise and provide patient access. This study contributes to current literature, as possibly the first study to directly interview US payers on NGTS coverage and reimbursement.

RATIONALE

β2-Agonists are the most common form of treatment of asthma, but there is significant variability in response to these medications. A significant proportion of this responsiveness may be heritable.

OBJECTIVES

To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma.

METHODS

We performed a GWAS of acute bronchodilator response (BDR) to inhaled β2-agonists. A total of 444,088 single-nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals.

MEASUREMENTS AND MAIN RESULTS

The combined P value for four SNPs reached statistical genome-wide significance aftercorrecting for multiple comparisons. Combined P values for rs350729, rs1840321, rs1384918, and rs1319797 were 2.21 × 10(-10), 5.75 × 10(-8), 9.3 × 10(-8), and 3.95 × 10(-8), respectively. The significant variants all map to a novel genetic region on chromosome 2 near the ASB3 gene, a region associated with smooth muscle proliferation. As compared with the wild type, the presence of the minor alleles reduced the degree of BDR by 20% in the original population and by a similar percentage in the confirmatory population.

CONCLUSIONS

These GWAS findings for BDR in subjects with asthma suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma.

Human papillomavirus (HPV) infection is associated with essentially all cervical cancers, 80-90 % of anal cancers, and a high proportion of oropharyngeal, vaginal, penile, and vulvar cancers. Malignancy is preceded by the development of precancerous lesions termed high-grade squamous intraepithelial lesions (HSIL). Men and women with human immunodeficiency virus (HIV) infection are at high risk of HPV-related malignancies. The incidence of anal cancer in particular has markedly risen during the antiretroviral era due to the increased longevity of patients with HIV and the absence of anal malignancy screening programs. HIV infection may facilitate initial HPV infection by disrupting epithelial cell tight junctions. Once infection is established, HIV may promote HSIL development via the up-regulation of HPV oncogene expression and impairment of the immune response needed to clear the lesion. HIV-infected women should be screened for cervical HSIL and cancer, and HIV-infected men and women should be considered for anal screening programs.