Publications

The transition from screen-film to digital mammography may have altered diagnostic evaluation of women following a positive screening examination. This study compared the use and timeliness of diagnostic imaging and biopsy for women screened with screen-film or digital mammography. Data were obtained from 35,321 positive screening mammograms on 32,087 women aged 40-89 years, from 22 breast cancer surveillance consortium facilities in 2005-2008. Diagnostic pathways were classified by their inclusion of diagnostic mammography, ultrasound, magnetic resonance imaging, and biopsy. We compared time to resolution and frequency of diagnostic pathways by patient characteristics, screening exam modality, and radiology facility. Between-facility differences were evaluated by computing the proportion of mammograms receiving follow-up with a particular pathway for each facility and examining variation in these proportions across facilities. Multinomial logistic regression adjusting for age, calendar year, and facility compared odds of follow-up with each pathway. The median time to resolution of a positive screening mammogram was 10 days. Compared to screen-film mammograms, digital mammograms were more frequently followed by only a single diagnostic mammogram (46 vs. 36 %). Pathways following digital screening mammography were also less likely to include biopsy (16 vs. 20 %). However, in adjusted analyses, most differences were not statistically significant (p = 0.857 for mammography only; p = 0.03 for biopsy). Substantial variability in diagnostic pathway frequency was seen across facilities. For instance, the frequency of evaluation with diagnostic mammography alone ranged from 23 to 55 % across facilities. Differences in evaluation of positive digital and screen-film screening mammograms were minor, and appeared to be largely attributable to substantial variation between radiology facilities. To guide health systems in their efforts to eliminate practices that do not contribute to effective care, we need further research to identify the causes of this variation and the best evidence-based approach for follow-up.

Pneumocystis jirovecii dihydropteroate synthase (DHPS) gene mutations are well-reported. Although sulfa prophylaxis generally is associated with DHPS mutant infection, whether mutant infection is associated with poorer clinical outcomes is less clear. The differing definitions of sulfa prophylaxis and the different mortality endpoints used in these studies may be one explanation for the conflicting study results. Applying different definitions of prophylaxis, mortality endpoints and DHPS mutant to 301 HIV-infected patients with Pneumocystis pneumonia, we demonstrate that prophylaxis, irrespective of definition, increased the risk of infection with pure mutant (any prophylaxis: AOR 4.00, 95% CI: 1.83-8.76, P < 0.001) but not mixed genotypes (any prophylaxis: AOR 0.78, 95% CI: 0.26-2.36, P = 0.65). However, infection with mutant DHPS, irrespective of definition, was not associated with increased mortality (all-cause or PCP death) at the three time-intervals examined (all P > 0.05). Future studies should standardize key variables associated with DHPS mutant infection as well as examine DHPS mutant subtypes (pure mutant vs. mixed infections) - perhaps even individual DHPS mutant genotypes - so that data can be pooled to better address this issue.

New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety.