Person:

Rotenstein, Lisa

Objective: The hippocampus is crucial for paired-associate learning. Obesity is associated with increased MR activity in peripheral and possibly central tissues, decreased hippocampal size in humans and impaired hippocampal learning in rodents. The MR is expressed in hippocampal neurons and MR blockade improves hippocampal learning in obese animals. We sought to determine whether MR blockade would modulate paired-associate learning in obese men and women. Design and Methods Men and women ages 20-61 years with BMIs between 30-45 kg/m2 were randomly assigned to placebo (n=11; 7 women) or 50 mg spironolactone daily (n=12; 7 women) for six weeks. At baseline and post treatment, subjects underwent a clinical and hormonal evaluation. They also underwent a computerized task that assesses paired-associate learning and has been shown by functional magnetic resonance imaging to activate the hippocampus. Results: In an ANCOVA model that adjusted for baseline paired-associate learning, age, and race, spironolactone treatment was associated with a significant (p=0.043) improvement in hippocampal memory as compared to placebo treatment. Conclusions: Our findings demonstrate, for the first time, that blocking MR with chronic, low-dose spironolactone treatment improves paired-associate learning in obese individuals, suggesting that MR activation contributes to hippocampal memory modulation in humans.

Background: Clinical pathways increase compliance with treatment guidelines, improve outcomes, and reduce costs. Evidence around treatment of complicated bone metastases is increasingly nuanced and although the American Society of Radiation Oncology and the American Association of Hospice and Palliative Medicine recommend single fraction radiation therapy (SFRT) for uncomplicated bone metastases, implementation is variable. We sought to determine the effects of a bone metastases-focused clinical pathway on Brigham and Women’s/Dana Farber Cancer Center’s (BW/DFCC) palliative radiation treatment patterns, which are determined by a dedicated palliative radiation consult service (SPRO) at the main BW/DFCC campus, and network physicians who treat more than one disease type at community-based affiliated sites. We hypothesized that pathway implementation would augment data-driven use of palliative radiation for bone metastases, including use of SFRT for uncomplicated metastases. It would also enhance physician efficiency and confidence.

Methods: Using published literature, clinical guidelines, and expert input, we designed a comprehensive clinical pathway for bone metastases radiation. This was translated to a secure electronic interface as a decision support tool and integrated into daily workflows. Providers were surveyed pre and post implementation to assess expectations and elicit feedback. Rates of pathway compliance and reasons for non-compliance were assessed. Rates of appropriate SFRT use (defined as the number of times SFRT was delivered versus the number of times it was recommended) were compared pre and post implementation.

Results: The final pathway includes twenty endpoints and integrates several validated scoring systems, including assessments of life expectancy, spinal stability, and appropriateness of surgical management. It has been used 265 times since launch in March 2016, representing a 35% utilization rate. Appropriate SFRT prescription rates averaged 47% after the pathway was introduced, versus 24% prior to pathway use but post-implementation of SPRO and 23% prior to SPRO’s introduction, representing a significant increase versus both periods (p < 0.01). Major reasons for denying pathway recommendations included clinicians disagreeing with the pathway’s life expectancy prognostication and needing to alter radiation courses for convenience of timing. In qualitative surveys, clinicians felt the pathway increased their confidence with providing guideline concordant care, enhanced their decision-making efficiency, and increased their comfort with treating uncomplicated bone metastases. Workflow disruptions and the inability of the pathway to guide the complicated, nuanced decisions often made at a tertiary care center emerged as pathway limitations.

Conclusions: Our experience suggests the feasibility and utility of pathways-based decision support for bone metastases in a complex academic practice setting. Next steps include increasing the pathway’s ease of use to enhance utilization, refining the pathway’s prognostic abilities, and measuring patient reported outcomes and cost savings related to the pathway.