Protein-coding differences between mammals often fail to explain phenotypic diversity, suggesting involvement of enhancers, often rapidly evolving regions that regulate gene expression. Identifying associations between enhancers and phenotypes is challenging because enhancer activity is context-dependent and may be conserved without much sequence conservation. We developed TACIT (Tissue-Aware Conservation Inference Toolkit) to associate open chromatin regions (OCRs) with phenotypes using predictions in hundreds of mammalian genomes from machine learning models trained to learn tissue-specific regulatory codes. Applying TACIT for motor cortex and parvalbumin-positive interneurons to neurological phenotypes revealed dozens of new OCR-phenotype associations. Many associated OCRs were near relevant genes, including brain size-associated OCRs near genes mutated in microcephaly or macrocephaly. Our work creates a forward genomics foundation for identifying candidate enhancers associated with phenotype evolution.

Protein-coding differences between species often fail to explain phenotypic diversity, suggesting the involvement of genomic elements that regulate gene expression such as enhancers. Identifying associations between enhancers and phenotypes is challenging because enhancer activity can be tissue-dependent and functionally conserved despite low sequence conservation. We developed the Tissue-Aware Conservation Inference Toolkit (TACIT) to associate candidate enhancers with species’ phenotypes using predictions from machine learning models trained on specific tissues. Applying TACIT to associate motor cortex and parvalbumin-positive interneuron enhancers with neurological phenotypes revealed dozens of enhancer–phenotype associations, including brain size–associated enhancers that interact with genes implicated in microcephaly or macrocephaly. TACIT provides a foundation for identifying enhancers associated with the evolution of any convergently evolved phenotype in any large group of species with aligned genomes.

External dose rates were measured 1 m away from 230 Lu-177 patients to characterise the variability in normalised dose rates as a function of administered activity, body mass index (BMI) and sex. The largest dose rate observed was 0.07 mSv/h associated with an administered activity of 7.2 GBq. Substantial variability was found in the distribution of the normalised dose rate associated that had an average of 0.0037 mSv/h per GBq and a 95% confidence interval of 0.0024–0.0058 mSv/h per GBq. Based on this study, estimating the patient dose rate based on the Lu-177 gamma exposure factor overestimates the dose rate by a factor of 2. A statistically significant inverse relationship was found between the patient dose rate and patient BMI and an empirically derived equation relating these two quantities was reported. On average, male patient dose rates were 3.5% lower than female dose rates, which may be attributed to the larger average BMI of the male patient group.

OBJECTIVE Recurrence of previously-irradiated brain metastases (BrM) presents a significant challenge. We describe our initial experience using salvage resection with Cs131 brachytherapy in previously-irradiated BrM. METHODS Between September 2019 and April 2020, 9 patients with recurrent BrM underwent maximally-safe metastatectomy. Following pathological confirmation of viable recurrence, cavities were implanted with permanent Cs131 brachytherapy (GammaTile, GT Medical Technologies). Prescribed dose was 60Gy at 5mm from the cavity. Postimplant dosimetry (V100) was calculated on postoperative day 1 fused CT/MRI. Intraoperative team exposure was recorded using intraoperative ring dosimetry, and patient dose-rates measured postoperatively informed patient, family and medical-staff exposure modeling. RESULTS Nine patients (55% female, median age 54) underwent 10 implantations (6 supratentorial, 4 infratentorial). Median preoperative maximum diameter was 3.5cm (2.3–6.3) and histologies included breast, gastrointestinal, lung, kidney and oral cavity squamous cell carcinomas. Five had undergone prior resection or laser ablation. All lesions received >/=1 prior course of stereotactic irradiation a median of 10.1 months (3.7–15.9) earlier. Eight lesions were gross-totally resected. Median number of implanted Cs131 seeds was 16 (12–28) with median seed strength of 61.8U (42.4–98.0). Median postoperative cavity size was well-correlated with the number of implanted seeds (Pearson R=0.75, p=0.03). Median V100 dose coverage of the cavities and uniform 5mm expansion of the cavities were 99% (79–100%) and 79% (51–95%), respectively. Median measured exposure rates were 90mR/hr (28–152) on contact, 9.15mR/hr (2.7–13.9) at 30cm and 1.4mR/hr (0.6–2.3) at 1 meter from the patient. Mean ring dose was 6.83mrem (0–18) for the radiation oncologist and 9.17mrem (0–15) for the neurosurgeon. Modeled lifetime family-member and visitor exposure was 116mrem (52-193mrem), and healthcare worker exposure was 39mrem (17-64mrem), all well below regulatory limits. There were no immediate wound complications or unanticipated neurologic injuries. CONCLUSION In our early experience, salvage interstitial Cs131 implantation was safely employed for recurrent brain metastases.

No abstract