The impact of self- and physician-administered cancer treatment on work productivity and healthcare utilization.

BACKGROUND: Lost productivity in the workplace represents a significant portion of the economic burden of cancer in the United States. Cancer treatments have historically been physician-administered, while recent innovations have led to the development of self-administered, usually oral, agents. Self-administered treatments have the potential to reduce healthcare utilization and time away from work, but the magnitude of these effects is unknown. OBJECTIVE: To compare the effects of self- and physician-administered cancer treatment on work productivity and health care utilization. METHODS: Cancer subtypes with self- and physician-administered treatment options were selected. Patients with female breast, or lung or bronchus cancer diagnosed in 2004-2013 were identified in the Truven Health Analytics Commercial Claims and Encounters and Health and Productivity Management databases. Using multivariate regression models, work productivity and healthcare utilization were compared for patients receiving self- versus physician-administered treatment in the 12 months after initial diagnosis. Work productivity outcomes included the number of sick days and short-term disability claims. RESULTS: One month of self- versus physician-administered treatment significantly reduced cancer-related outpatient services, doctor visits, and infusions in the 12 months after initial diagnosis for both cancers of interest. In addition, breast and lung or bronchus cancer patients who received self-administered treatment were less likely to have short-term disability claims, and breast cancer patients with non-metastatic disease who received self-administered treatment had significantly fewer sick days. CONCLUSIONS: Self-administered cancer treatment was associated with fewer cancer-related outpatient services and reduced time away from work compared to physician-administered cancer treatment.

Cost-effectiveness of minimally invasive sacroiliac joint fusion.

BACKGROUND: Sacroiliac joint (SIJ) disorders are common in patients with chronic lower back pain. Minimally invasive surgical options have been shown to be effective for the treatment of chronic SIJ dysfunction. OBJECTIVE: To determine the cost-effectiveness of minimally invasive SIJ fusion. METHODS: Data from two prospective, multicenter, clinical trials were used to inform a Markov process cost-utility model to evaluate cumulative 5-year health quality and costs after minimally invasive SIJ fusion using triangular titanium implants or non-surgical treatment. The analysis was performed from a third-party perspective. The model specifically incorporated variation in resource utilization observed in the randomized trial. Multiple one-way and probabilistic sensitivity analyses were performed. RESULTS: SIJ fusion was associated with a gain of approximately 0.74 quality-adjusted life years (QALYs) at a cost of US$13,313 per QALY gained. In multiple one-way sensitivity analyses all scenarios resulted in an incremental cost-effectiveness ratio (ICER) <$26,000/QALY. Probabilistic analyses showed a high degree of certainty that the maximum ICER for SIJ fusion was less than commonly selected thresholds for acceptability (mean ICER =$13,687, 95% confidence interval $5,162-$28,085). SIJ fusion provided potential cost savings per QALY gained compared to non-surgical treatment after a treatment horizon of greater than 13 years. CONCLUSION: Compared to traditional non-surgical treatments, SIJ fusion is a cost-effective, and, in the long term, cost-saving strategy for the treatment of SIJ dysfunction due to degenerative sacroiliitis or SIJ disruption.

HOXA methylation in normal endometrium from premenopausal women is associated with the presence of ovarian cancer: a proof of principle study.

DNA methylation of polycomb group target (PCGT) genes is an early step in carcinogenesis and could potentially be assayed to determine cancer risk prediction. To assess whether methylation changes in PCGT genes in normal tissue is able to predict the presence of cancer, we studied HOXA gene methylation in normal endometrium from premenopausal ovarian cancer patients and age-matched healthy controls without ovarian cancer. DNA methylation of HOXA9 and HOXA11 genes in normal endometrium was associated with ovarian cancer in an initial test set and this was subsequently confirmed in independent validation sample sets. The overall risk of ovarian cancer was increased 12.3-fold by high HOXA9 methylation for all stages, and 14.8-fold for early stage ovarian cancers, independent of age, phase of the menstrual cycle and histology of the cancer. The results of this proof of principle study demonstrate the potential to detect ovarian cancer via analysis of normal endometrial cells and provide insight into the possible contribution of this novel approach in ovarian cancer risk prediction and prevention.

Association between common genetic variation in Cockayne syndrome A and B genes and nucleotide excision repair capacity among smokers.

Mutagen sensitivity in in vitro cultured lymphocytes challenged by benzo[a]pyrene diolepoxide (BPDE) has been validated as an intrinsic susceptibility factor for several cancers. Bulky BPDE-DNA adducts are repaired via either transcription-coupled repair or global genome nucleotide excision repair depending on the location of lesions. Cockayne syndrome A (CSA) and B (CSB) play essential roles in integrating the recognition of damage, chromatin remodeling, and the core nucleotide excision repair proteins. This study evaluated the hypothesis that common genetic variation in CSA and CSB is associated with mutagen sensitivity induced by BPDE in 276 cancer-free smokers. Tag single nucleotide polymorphisms (SNP; n = 37) selected across the entire coding and putative regulatory regions of CSA and CSB based on a high-density SNP database were genotyped by the Illumina Golden Gate assay. Major principal components of CSA and CSB that captured the linkage disequilibrium from multiple SNPs were globally associated with the number of breaks per cell at the threshold of 80% (P < or = 0.02 for both genes). Haplotype H125 in CSA and H97 in CSB as well as SNPs in high linkage disequilibrium with these two haplotypes were significantly associated with a 13% to 15% reduction in the mean number of chromatid breaks per cell (P < 0.05). A resampling-based omnibus test supported the significant association between SNPs and haplotypes in CSA and mutagen sensitivity induced by BPDE (P = 0.035). This study implicates transcription-coupled repair in protecting the cell from BPDE-induced DNA damage.

Haplotypes of DNMT1 and DNMT3B are associated with mutagen sensitivity induced by benzo[a]pyrene diol epoxide among smokers.

The mutagen sensitivity assay is an in vitro measure of DNA repair capacity used to evaluate intrinsic susceptibility for cancer. The high heritability of mutagen sensitivity to different mutagens validates the use of this phenotype to predict cancer susceptibility. However, genetic determinants of mutagen sensitivity have not been fully characterized. Recently, several studies found that three major cytosine DNA methyltransferases (DNMTs), especially DNMT1, have a direct role in the DNA damage response, independent of their methyltransferase activity. This study evaluated the hypothesis that sequence variants in DNMT1, DNMT3A and DNMT3B are associated with mutagen sensitivity induced by the tobacco carcinogen benzo[a]pyrene diol epoxide (BPDE) in 278 cancer-free smokers. Single-nucleotide polymorphisms (n = 134) dispersed over the entire gene and regulatory regions of these DNMTs were genotyped by the Illumina Golden Gate Assay. DNA sequence variation in the DNMT1 and DNMT3B loci was globally associated with breaks per cell (P < 0.04 for both). No global association between DNMT3A and breaks per cell was seen (P = 0.09). Two haplotypes in block1 of DNMT1 (H284) and 3B (H70) were associated with 16 and 24% increase in breaks per cell, respectively. Subjects with three or four adverse haplotypes of both DNMT1 and 3B had a 50% elevation in mean level of breaks per cell compared with persons without adverse alleles (P = 0.004). The association between sequence variants of DNMT1 and 3B and mutagen sensitivity induced by BPDE supports the involvement of these DNMTs in protecting the cell from DNA damage.

Double-strand break damage and associated DNA repair genes predispose smokers to gene methylation.

Gene promoter hypermethylation in sputum is a promising biomarker for predicting lung cancer. Identifying factors that predispose smokers to methylation of multiple gene promoters in the lung could affect strategies for early detection and chemoprevention. This study evaluated the hypothesis that double-strand break (DSB) repair capacity and sequence variation in genes in this pathway are associated with a high methylation index in a cohort of current and former cancer-free smokers. A 50% reduction in the mean level of DSB repair capacity was seen in lymphocytes from smokers with a high methylation index, defined as three or more of eight genes methylated in sputum, compared with smokers with no genes methylated. The classification accuracy for predicting risk for methylation was 88%. Single nucleotide polymorphisms within the MRE11A, CHEK2, XRCC3, DNA-PKc, and NBN DNA repair genes were highly associated with the methylation index. A 14.5-fold increased odds for high methylation was seen for persons with seven or more risk alleles of these genes. Promoter activity of the MRE11A gene that plays a critical role in recognition of DNA damage and activation of ataxia-telangiectasia mutated was reduced in persons with the risk allele. Collectively, ours is the first population-based study to identify DSB DNA repair capacity and specific genes within this pathway as critical determinants for gene methylation in sputum, which is, in turn, associated with elevated risk for lung cancer.