Nutrition exerts profound effects on health and dietary interventions are commonly used to treat diseases of metabolic etiology. Although cancer has a substantial metabolic component 1 , the principles that define whether nutrition may be used to influence tumour outcome are unclear 2. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. In contrast, whether specific dietary interventions could influence the metabolic pathways that are targeted in standard cancer therapies is not known. We now show that dietary restriction of methionine (MR), an essential amino acid, and the reduction of which has anti-aging and anti-obesogenic properties, influences cancer outcome through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and further is the target of a host of cancer interventions Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Improved breast cancer risk models enable targeted screening strategies that achieve earlier detection and less screening harm than existing guidelines. To bring deep learning risk models to clinical practice, we need to further refine their accuracy, validate them across diverse populations, and demonstrate their potential to improve clinical workflows. We developed Mirai, a mammography-based deep learning model designed to predict risk at multiple timepoints, leverage potentially missing risk factor information, and produce predictions that are consistent across mammography machines. Mirai was trained on a large dataset from Massachusetts General Hospital (MGH) in the United States and tested on held-out test sets from MGH, Karolinska University Hospital in Sweden, and Chang Gung Memorial Hospital (CGMH) in Taiwan, obtaining C-indices of 0.76 (95% confidence interval, 0.74 to 0.80), 0.81 (0.79 to 0.82), and 0.79 (0.79 to 0.83), respectively. Mirai obtained significantly higher 5-year ROC AUCs than the Tyrer-Cuzick model (P < 0.001) and prior deep learning models Hybrid DL (P < 0.001) and Image-Only DL (P < 0.001), trained on the same dataset. Mirai more accurately identified high-risk patients than prior methods across all datasets. On the MGH test set, 41.5% (34.4 to 48.5) of patients who would develop cancer within 5 years were identified as high risk, compared with 36.1% (29.1 to 42.9) by Hybrid DL (P = 0.02) and 22.9% (15.9 to 29.6) by the Tyrer-Cuzick model (P < 0.001).

PURPOSE Accurate risk assessment is essential for the success of population screening programs in breast cancer. Models with high sensitivity and specificity would enable programs to target more elaborate screening efforts to high-risk populations, while minimizing overtreatment for the rest. Artificial intelligence (AI)-based risk models have demonstrated a significant advance over risk models used today in clinical practice. However, the responsible deployment of novel AI requires careful validation across diverse populations. To this end, we validate our AI-based model, Mirai, across globally diverse screening populations. METHODS We collected screening mammograms and pathology-confirmed breast cancer outcomes from Massachusetts General Hospital, USA; Novant, USA; Emory, USA; Maccabi-Assuta, Israel; Karolinska, Sweden; Chang Gung Memorial Hospital, Taiwan; and Barretos, Brazil. We evaluated Uno's concordance-index for Mirai in predicting risk of breast cancer at one to five years from the mammogram. RESULTS A total of 128,793 mammograms from 62,185 patients were collected across the seven sites, of which 3,815 were followed by a cancer diagnosis within 5 years. Mirai obtained concordance indices of 0.75 (95% CI, 0.72 to 0.78), 0.75 (95% CI, 0.70 to 0.80), 0.77 (95% CI, 0.75 to 0.79), 0.77 (95% CI, 0.73 to 0.81), 0.81 (95% CI, 0.79 to 0.82), 0.79 (95% CI, 0.76 to 0.83), and 0.84 (95% CI, 0.81 to 0.88) at Massachusetts General Hospital, Novant, Emory, Maccabi-Assuta, Karolinska, Chang Gung Memorial Hospital, and Barretos, respectively. CONCLUSION Mirai, a mammography-based risk model, maintained its accuracy across globally diverse test sets from seven hospitals across five countries. This is the broadest validation to date of an AI-based breast cancer model and suggests that the technology can offer broad and equitable improvements in care.

PURPOSE Low-dose computed tomography (LDCT) for lung cancer screening is effective, although most eligible people are not being screened. Tools that provide personalized future cancer risk assessment could focus approaches toward those most likely to benefit. We hypothesized that a deep learning model assessing the entire volumetric LDCT data could be built to predict individual risk without requiring additional demographic or clinical data. METHODS We developed a model called Sybil using LDCTs from the National Lung Screening Trial (NLST). Sybil requires only one LDCT and does not require clinical data or radiologist annotations; it can run in real time in the background on a radiology reading station. Sybil was validated on three independent data sets: a heldout set of 6,282 LDCTs from NLST participants, 8,821 LDCTs from Massachusetts General Hospital (MGH), and 12,280 LDCTs from Chang Gung Memorial Hospital (CGMH, which included people with a range of smoking history including nonsmokers). RESULTS Sybil achieved area under the receiver-operator curves for lung cancer prediction at 1 year of 0.92 (95% CI, 0.88 to 0.95) on NLST, 0.86 (95% CI, 0.82 to 0.90) on MGH, and 0.94 (95% CI, 0.91 to 1.00) on CGMH external validation sets. Concordance indices over 6 years were 0.75 (95% CI, 0.72 to 0.78), 0.81 (95% CI, 0.77 to 0.85), and 0.80 (95% CI, 0.75 to 0.86) for NLST, MGH, and CGMH, respectively. CONCLUSION Sybil can accurately predict an individual's future lung cancer risk from a single LDCT scan to further enable personalized screening. Future study is required to understand Sybil's clinical applications. Our model and annotations are publicly available.

Screening programs must balance the benefits of early detection against the costs of over screening. Achieving this goal relies on two complementary technologies: (1) the ability to assess patient risk, (2) the ability to develop personalized screening programs given that risk. While methodologies for assessing patient risk have significantly improved with new advances in deep learning applied to imaging and genetics, our ability to personalize screening policies still lags behind. Here, we introduce a novel reinforcement learning-based framework for personalized screening, Tempo, and demonstrate its efficacy in the context of breast cancer. We trained our risk-based screening policies on a large screening mammography dataset from Massachusetts General Hospital (MGH) USA and validated them on held-out patients from MGH, and on external datasets from Emory USA, Karolinska Sweden and Chang Gung Memorial Hospital (CGMH) Taiwan. Across all test sets, we found that a Tempo policy combined with an image-based AI risk model was significantly more efficient than current regimes used in clinical practice in terms of simulated early detection per screen frequency. Moreover, we showed that the same Tempo policy can be easily adapted to a wide range of possible screening preferences, allowing clinicians to select their desired early detection to screening cost trade-off without training a new policy. Finally, we demonstrated Tempo policies based on AI-based risk models out performed Tempo policies based on less accurate clinical risk models. Altogether, our results show that pairing AI-based risk models with agile AI-designed screening policies has the potential to improve screening programs, advancing early detection while reducing over-screening.