Patient-Reported Outcome Measures in Cancer Care: An Updated Systematic Review and Meta-Analysis.

Importance: Patient-reported outcome measures (PROMs) come directly from the patient, without clinician interpretation, to provide a patient-centered perspective. Objective: To understand the association of PROM integration into cancer care with patient-related, therapy-related, and health care utilization outcomes. Data Sources: Searches included MEDLINE and MEDLINE Epub ahead of print, in-process, and other nonindexed citations; Embase databases (OvidSP); PsychINFO; CENTRAL; and CINAHL from January 1, 2012 to September 26, 2022. Study Selection: Randomized clinical trials (RCTs) that enrolled adult patients (ages 18 years and older) with active cancer receiving anticancer therapy using a PROM as an intervention. Data Extraction and Synthesis: Pairs of review authors, using prepiloted forms, independently extracted trial characteristics, disease characteristics, and intervention details. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline was followed. Random-effects analyses were conducted. Main Outcomes and Measures: Overall mortality, health-related quality of life (HRQoL) measures, and hospital utilization outcomes. Results: From 1996 to 2022, 45 RCTs including 13 661 participants addressed the association of PROMs with outcomes considered important to patients. The addition of a PROM likely reduced the risk of overall mortality (HR, 0.84; 95% CI, 0.72-0.98; moderate certainty), improved HRQoL (range 0-100) at 12 weeks (mean difference [MD], 2.45; 95% CI, 0.42-4.48; moderate certainty). Improvements of HRQoL at 24 weeks were not significant (MD, 1.87; 95% CI, -1.21 to 4.96; low certainty). There was no association between the addition of a PROM and HRQoL at 48 weeks. The addition of a PROM was not associated with reduced ED visits (OR, 0.74; 95% CI, 0.54-1.02; low certainty) or hospital admissions (OR, 0.86; 95% CI, 0.73-1.02; low certainty). Conclusion and Relevance: The findings of this study suggest that the integration of PROMs into cancer care may improve overall survival and quality of life.

Breast cancer learning health system: Patient information from a data and analytics platform characterizes care provided.

Purpose: In a learning health system (LHS), data gathered from clinical practice informs care and scientific investigation. To demonstrate how a novel data and analytics platform can enable an LHS at a regional cancer center by characterizing the care provided to breast cancer patients. Methods: Socioeconomic information, tumor characteristics, treatments and outcomes were extracted from the platform and combined to characterize the patient population and their clinical course. Oncologists were asked to identify examples where clinical practice guidelines (CPGs) or policy changes had varying impacts on practice. These constructs were evaluated by extracting the corresponding data. Results: Breast cancer patients (5768) seen at the Juravinski Cancer Centre between January 2014 and June 2022 were included. The average age was 62.5 years. The commonest histology was invasive ductal carcinoma (74.6%); 77% were estrogen receptor-positive and 15.5% were HER2 Neu positive. Breast-conserving surgery (BCS) occurred in 56%. For the 4294 patients who received systemic therapy, the initial indications were adjuvant (3096), neoadjuvant (828) and palliative (370). Metastases occurred in 531 patients and 495 patients died. Lowest-income patients had a higher mortality rate. For the adoption of CPGs, the uptake for adjuvant bisphosphonate was very low, 8% as predicted, compared to 64% for pertuzumab, a HER2 targeted agent and 40.2% for CD4/6 inhibitors in metastases. During COVID-19, the provincial cancer agency issued a policy to shorten the duration of radiation after BCS. There was a significant reduction in the average number of fractions to the breast by five fractions. Conclusion: Our platform characterized care and the clinical course of breast cancer patients. Practice changes in response to regulatory developments and policy changes were measured. Establishing a data platform is important for an LHS. The next step is for the data to feedback and change practice, that is, close the loop.

Potential of artificial intelligence in reducing energy and carbon emissions of commercial buildings at scale.

Artificial intelligence has emerged as a technology to enhance productivity and improve life quality. However, its role in building energy efficiency and carbon emission reduction has not been systematically studied. This study evaluated artificial intelligence's potential in the building sector, focusing on medium office buildings in the United States. A methodology was developed to assess and quantify potential emissions reductions. Key areas identified were equipment, occupancy influence, control and operation, and design and construction. Six scenarios were used to estimate energy and emissions savings across representative climate zones. Here we show that artificial intelligence could reduce cost premiums, enhancing high energy efficiency and net zero building penetration. Adopting artificial intelligence could reduce energy consumption and carbon emissions by approximately 8% to 19% in 2050. Combining with energy policy and low-carbon power generation could approximately reduce energy consumption by 40% and carbon emissions by 90% compared to business-as-usual scenarios in 2050.

Pharmacologic ascorbate induces transient hypoxia sensitizing pancreatic ductal adenocarcinoma to a hypoxia activated prodrug.

Hypoxic tumor microenvironments pose a significant challenge in cancer treatment. Hypoxia-activated prodrugs like evofosfamide aim to specifically target and eliminate these resistant cells. However, their effectiveness is often limited by reoxygenation after cell death. We hypothesized that ascorbate's pro-oxidant properties could be harnessed to induce transient hypoxia, enhancing the efficacy of evofosfamide by overcoming reoxygenation. To test this hypothesis, we investigated the sensitivity of MIA Paca-2 and A549 cancer cells to ascorbate in vitro and in vivo. Ascorbate induced a cytotoxic effect at 5 mM that could be alleviated by endogenous administration of catalase, suggesting a role for hydrogen peroxide in its cytotoxic mechanism. In vitro, Seahorse experiments indicated that the generation of hydrogen peroxide consumes oxygen, which is offset at later time points by a reduction in oxygen consumption due to hydrogen peroxide's cytotoxic effect. In vivo, photoacoustic imaging showed pharmacologic ascorbate treatment at sublethal levels triggered a complex, multi-phasic response in tumor oxygenation across both cell lines. Initially, ascorbate generated transient hypoxia within minutes through hydrogen peroxide production, via reactions that consume oxygen. This initial hypoxic phase peaked at around 150 s and then gradually subsided. However, at longer time scales (approximately 300 s) a vasodilation effect triggered by ascorbate resulted in increased blood flow and subsequent reoxygenation. Combining sublethal levels of i. p. Ascorbate with evofosfamide significantly prolonged tumor doubling time in MIA Paca-2 and A549 xenografts compared to either treatment alone. This improvement, however, was only observed in a subpopulation of tumors, highlighting the complexity of the oxygenation response.

High-Dose Intravenous Vitamin C Combined with Docetaxel in Men with Metastatic Castration-Resistant Prostate Cancer: A Randomized Placebo-Controlled Phase II Trial.

High-dose intravenous vitamin C (HDIVC) administered to produce pharmacologic concentrations shows promise in preclinical models and small clinical trials, but larger prospective randomized trials are lacking. We evaluated the clinical benefit of combining HDIVC with docetaxel in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). In this double-blind, placebo-controlled phase II trial, 47 patients were randomized 2:1 to receive docetaxel (75 mg/m2 i.v.) with either HDIVC (1 g/kg) or placebo. Coprimary endpoints were PSA50 response and adverse event rates. Secondary endpoints included overall survival, radiographic progression-free survival, and quality of life measured using the Functional Assessment of Cancer Therapy-Prostate instrument. Correlative analyses included pharmacokinetics and oxidative stress markers. Eighty-nine percent of patients previously had three or more lines of therapy. The PSA50 response rate was 41% in the HDIVC group and 33% in the placebo group (P = 0.44), with comparable adverse event rates in both groups. There were no significant differences in Functional Assessment of Cancer Therapy-Prostate scores. The median radiographic progression-free survival was not significantly different between the HDIVC and placebo groups, with durations of 10.1 and 10.0 months (HR, 1.35; 95% confidence interval, 0.66-2.75; P = 0.40), respectively. The median overall survival was 15.2 months in the HDIVC group and 29.5 months in the placebo group (HR, 1.98; 95% confidence interval, 0.85-4.58; P = 0.11). HDIVC did not decrease F2-isoprostanes, indicators of oxidative stress. The study was suspended after prespecified interim analysis indicated futility in achieving primary endpoints. In this patient population, combining HDIVC with docetaxel did not improve PSA response, toxicity, or other clinical outcomes compared with docetaxel alone. Findings do not support the routine use of HDIVC in mCRPC treatment outside of clinical trials. SIGNIFICANCE: This is the first randomized, placebo-controlled, double-blind trial to evaluate HDIVC in cancer treatment. The addition of HDIVC to docetaxel in patients with mCRPC does not improve PSA response, toxicity, or other clinical outcomes compared with docetaxel alone. The routine use of HDIVC in mCRPC treatment is not supported outside of clinical trials.

Oncologists' Satisfaction with Virtual Care: A Questionnaire.

INTRODUCTION: Although virtual care (VC) has become an integral part of oncology care and healthcare delivery, clinicians' perspectives on and satisfaction with this modality are not well understood. METHODS: Using a National Network Forum framework and expert panel review, we developed a questionnaire to measure oncologists' satisfaction with VC. The questionnaire was distributed to Canadian oncologists through medical society email lists (n = 1541). We used a 5-point Likert scale to capture their responses, which included strongly disagree (1), disagree (2), undecided (3), agree (4), and strongly agree (5). RESULTS: A total of 61 oncologists and/or oncology trainees, of 768 (7.9%) who opened their email, completed questionnaires between October 2022 and January 2023. Every questionnaire item had a response rate greater than 98%. Seventy-two percent of the respondents were satisfied with VC. Oncologists who were less comfortable with technology were more likely to report lower levels of satisfaction (p < 0.001, Wilcoxon rank-sum). The questionnaire items that received the highest levels of agreement were related to VC reducing costs and improving access for patients and concerns about missing a diagnosis and assessing patients' functional status. The questionnaire items that received the greatest disagreement were related to VC improving access for patients with language barriers, VC being associated with time-savings for clinicians, improvements in clinical efficacy, and more readily available lab tests. CONCLUSIONS: Most of the oncologists surveyed are satisfied with VC; however, there are some concerns with VC that need to be addressed. Future research on optimizing VC should address clinicians' concerns, in addition to addressing the patient experience.

Plasma Ascorbic Acid Levels in Critically Ill Pediatric Patients.

Ascorbic acid, or vitamin C, is a physiological antioxidant that has been found to be deficient in critically ill adults with sepsis and acute respiratory distress system. In adults, ascorbic acid supplementation has been shown to reduce the need for vasopressors and mechanical ventilation. This study aimed to describe the prevalence of ascorbic acid deficiency in critically ill pediatric patients. This prospective, single-centered study analyzed 34 patients aged 1 month to 18 years old with septic shock and/or acute respiratory failure requiring mechanical ventilation in a quaternary, urban, pediatric intensive care unit. Plasma ascorbic acid levels were measured by high-performance liquid chromatography within 24 hours of meeting eligibility criteria. The median level was 23.34 µM (IQR [11.45, 39.14]). Twenty-three patients had repeat samples that were collected 3 to 5 days later. The median for repeat samples was higher at 42.41 µM (IQR [13.08, 62.43]). Patients who were enterally fed had significantly higher levels than those who were not (62.4 ± 7.7 µM vs. 32.4 ± 7.1 µM; p = 0.03). Ascorbic acid levels vary widely among critically ill children with septic shock and/or respiratory failure requiring mechanical ventilation, but one-half of our patients had deficient levels that are typically seen in scurvy. Further studies are warranted to investigate the significance of low levels as well as the impact of normalizing levels through nutritional support.

Pediatric Esophageal Button Battery Protocol Reduces Time From Presentation to Removal.

OBJECTIVE: Evaluate implementation of an institutional protocol to reduce the time to removal of esophageal button battery (BB) and increase use of mitigation strategies. METHODS: We developed a protocol for esophageal BB management [Zakai's Protocol (ZP)]. All cases of esophageal BB impaction managed at a tertiary care center before and after implementation from 2011 to 2023 were reviewed. Time to BB removal, adherence to critical steps, and use of mitigation strategies (honey/sucralfate, acetic acid) were evaluated. RESULTS: Fifty-one patients (38 pre-ZP, 13 post-ZP) were included. Median age was 2.3 years (IQR 1.3-3.4). After implementation, the time from arrival at the institution to arrival in the operating room (OR) reduced by 4.2 h [4.6 h (IQR 3.9-6.5) to 0.4 h (IQR 0.3-0.6), p < 0.001] and there was improvement in all management steps. The number of referrals direct to otolaryngology increased from 51% to 92%, arrival notification increased from 86% to 100%, avoidance of second x-ray increased from 63% to 100%, and direct transfer to OR increased from 92% to 100%. Adherence to mitigation strategies such as preoperative administration of honey or sucralfate increased from 0% to 38%, intraoperative use of acetic acid from 3% to 77%, and nasogastric tube insertion from 53% to 92%. CONCLUSION: Implementation of ZP substantially reduced the time to BB removal and the use of mitigation strategies in our tertiary care institution. Additional strategies focused on prevention of BB ingestion, and shortening the transfer time to the tertiary care hospital are required to prevent erosive complications. LEVEL OF EVIDENCE: Level 3 Case-series Laryngoscope, 2024.

Surgical waitlist management: Perspectives from surgeons on surgical prioritization at a paediatric hospital.

Globally exacerbated surgical waitlists have provided the opportunity to reflect on prioritization and resource allocation decisions. The unique circumstances of paediatric surgery and consequences of surgical delay prompted the study reported in this paper. As part of a larger project to attend to prioritization in our surgical waitlists, we conducted a Quality Improvement study, the purpose of which is to understand surgeon's perspectives regarding the ethical and practical realities of surgical prioritization at our institution. The study comprises semi-structured interviews with nine full-time paediatric surgeons from a variety of subspecialties conducted at our institution, which is a tertiary paediatric hospital with ten surgical subspecialties in a publicly funded healthcare system. Participants articulated how they prioritize their waitlists, and how they understand ethical prioritization. These findings resonate with the growing public concern for ethical practice in healthcare delivery and transparency in prioritization and resource allocation practices. Specifically, more transparency, consistency, and support is required in prioritization practices. This work highlights the importance of institutional dialogue regarding surgical case prioritization. Because quality improvement work is necessarily site-specific, concrete generalizations cannot be offered. However, the insights gleaned from these interviews and the process by which they were gleaned are a valuable knowledge-sharing resource for any institution that is interested in ongoing quality improvement work. The objectives here were to clarify the goals of prioritization within the institution, improve prioritization practices, and make them more ethical and transparent.

LUMINA: Using molecular biomarkers to guide decision making for breast radiotherapy.

In this opinion piece, we respond to comments about the LUMINA trial by Meattini and colleagues in the Journal. LUMINA was a prospective cohort study which evaluated the omission of radiotherapy after breast conserving surgery (BCS) in patients treated with endocrine therapy with low risk clinico-pathologic features and luminal A breast cancer. We address their areas of concern including the single cohort design that required careful patient selection, the relatively short follow-up period of 5 years, and the limited follow-up on younger patients. The Ki67 biomarker was key to defining the luminal A phenotype. We clarify the evidence supporting the Ki67 criteria used. The compliance with endocrine therapy was high and similar to other contemporary trials. Based on the results of LUMINA, and mounting evidence from other trials, we feel comfortable offering our patients the option of no radiotherapy after BCS if they fit the trial eligibility criteria from LUMINA and have decided to receive adjuvant endocrine therapy. We concur that a patient-centered approach to treatment decision making should be used to make patients aware of all available information including the results of the LUMINA trial when deciding on post-operative breast radiotherapy.

Visual digital data, ethical challenges, and psychological science.

Digital visual data afford psychologists with exciting research possibilities. It becomes possible to see real-life interactions in real time and to be able to analyze this behavior in a fine-grained and systematic manner. However, the fact that faces (and other personally identifying physical characteristics) are captured as part of these data sets means that this kind of data is at the highest level of sensitivity by default. When this is combined with the possibility of automatic collection and processing, then the sensitivity risks are compounded. Here we explore the ethical challenges that face psychologists wishing to take advantage of digital visual data. Specifically, we discuss ethical considerations around data acquisition, data analysis, data storage, and data sharing. We begin by considering the challenges of securing visual data from both public space security systems and social media sources. We then explore the dangers of bias and discrimination in automatic data processing, as well as the dangers to human analysts. We set out the ethical requirements for secure data storage, the dangers of "function creep," and the challenges of the right of the individual to withdraw from databases. Finally, we consider the tensions that exist between sensitive visual data that require extra protections and the recent open science movement, which advocates data transparency and sharing. We conclude by offering a practical route map for tackling these complex ethical issues in the form of a Privacy and Data Protection Impact Assessment template for researchers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Evaluating the Outcomes and Trainee Performance of a Canadian Medical Imaging Clinician Investigator Program.

Purpose: To measure the research productivity of trainees from the University of Toronto's Medical Imaging Clinician Investigator Program (MI-CIP) and comparing it with the research productivity of trainees from MI-non-CIP and General Surgery (GSx) Clinician Investigator Program. Methods: We identified residents who completed an MI-CIP, MI-non-CIP and GSx-CIP from 2006-2016. In each group of trainees, we assessed 3 research productivity outcomes with non-parametric tests before residency and at 7 years post-CIP completion/post-graduation. Research productivity outcomes include the number of total publications, the number of first-author publications, and the publication's average journal impact factor (IF). Results: We identified 11 MI-CIP trainees (male/female: 9 [82%]/2 [18%]), 74 MI-non-CIP trainees (46 [62%]/28 [38%]) and 41 GSx-CIP trainees (23 [56%]/18 [44%]). MI-CIP trainees had statistically significant higher research productivity than MI-non-CIP in all measured outcomes. The median (interquartile range, IQR) number of total publications of MI-CIP vs MI-non-CIP trainees was 5.0 (8.0) vs 1.0 (2.0) before residency and 6.0 (10.0) vs .0 (2.0) at 7 years post-CIP completion/post-graduation. The median (IQR) first-author publications of MI-CIP vs MI-non-CIP trainees was 2.0 (3.0) vs .0 (1.0) before residency and 2.0 (4.0) vs (.0) (1.0) at 7 years post-CIP completion/post-graduation. The median (IQR) average journal IF of MI-CIP vs MI-non-CIP trainees was 3.2 (2.0) vs .3 (2.4) before residency and 3.9 (3.2) vs .0 (2.6) at 7 years post-CIP completion/post-graduation. Between MI-CIP and GSx-CIP trainees, there were no significant differences in research productivity in all measured outcomes. Conclusion: MI-CIP trainees actively conducted research after graduation. These trainees demonstrated early research engagement before residency. The similar research productivity of MI-CIP vs GSx-CIP trainees shows initial success of MI-CIP trainees.

"Are we in this together?": embedding social identity detection in drones improves emergency coordination.

Autonomous systems, such as drones, are critical for emergency mitigation, management, and recovery. They provide situational awareness and deliver communication services which effectively guide emergency responders' decision making. This combination of technology and people comprises a socio-technical system. Yet, focusing on the use of drone technology as a solely operational tool, underplays its potential to enhance coordination between the different agents involved in mass emergencies, both human and non-human. This paper proposes a new methodological approach that capitalizes on social identity principles to enable this coordination in an evacuation operation. In the proposed approach, an adaptive drone uses sensor data to infer the group membership of the survivors it encounters during the operation. A corpus of 200 interactions of survivors' talk during real-life emergencies was computationally classified as being indicative of a shared identity or personal/no identity. This classification model, then, informed a game-theoretic model of human-robot interactions. Bayesian Nash Equilibrium analysis determined the predicted behavior for the human agent and the strategy that the drone needs to adopt to help with survivor evacuation. Using linguistic and synthetic data, we show that the identity-adaptive architecture outperformed two non-adaptive architectures in the number of successful evacuations. The identity-adaptive drone can infer which victims are likely to be helped by survivors and where help from emergency teams is needed. This facilitates effective coordination and adaptive performance. This study shows decision-making can be an emergent capacity that arises from the interactions of both human and non-human agents in a socio-technical system.

Omitting Radiotherapy after Breast-Conserving Surgery in Luminal A Breast Cancer.

BACKGROUND: Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information. METHODS: We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years. RESULTS: Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1). CONCLUSIONS: Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).

Vitamin C Urinary Loss and Deficiency in Human Immunodeficiency Virus (HIV): Cross-sectional Study of Vitamin C Renal Leak in Women With HIV.

BACKGROUND: Reduced plasma vitamin C (vitC) concentrations in human immunodeficiency virus (HIV) may result from abnormal urinary excretion: a renal leak. VitC renal leak indicates underlying nutritional dysregulation independent of diet. We hypothesized that increased renal leak prevalence in HIV would be associated with deficient vitC concentrations. METHODS: We conducted an outpatient cross-sectional study of 96 women (40 HIV [PWH] and 56 without HIV [PWOH]) at the National Institutes of Health and Georgetown University. Renal leak was defined as abnormal urinary vitC excretion at fasting plasma concentrations <43.2µM, 2 SDs below vitC renal threshold in healthy women. To determine the primary outcome of renal leak prevalence, matched urine and plasma samples were collected the morning after overnight fast. Secondary outcomes assessed group differences in mean plasma vitC concentrations and prevalence of vitC deficiency. Exploratory outcomes assessed clinical parameters associated with renal leak. VitC was measured by high-performance liquid chromatography with coulometric electrochemical detection. RESULTS: PWH had significantly higher renal leak prevalence (73%vs14%; OR (odds ratio):16; P<.001), lower mean plasma vitC concentrations (14µMvs50µM; P<.001), and higher prevalence of vitC deficiency (43%vs7%; OR:10; P<.001) compared with PWOH, unchanged by adjustments for confounding factors. Significant predictors of renal leak included antiretroviral therapy (ART), Black race, older age, and metabolic comorbidities but not viral load or CD4 count. When compared with other chronic disease cohorts, PWH had the highest prevalence of renal leak and vitC deficiency (P<.001). CONCLUSIONS: High prevalence of vitC renal leak in HIV was associated with vitC deficiency, ART use, and race/ethnicity differences.

Impact of 18F-Labeled Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography Versus Conventional Staging in Patients With Locally Advanced Breast Cancer.

PURPOSE: Patients with locally advanced breast cancer (LABC) typically undergo staging tests at presentation. If staging does not detect metastases, treatment consists of curative intent combined modality therapy (neoadjuvant chemotherapy, surgery, and regional radiation). Positron emission tomography-computed tomography (PET-CT) may detect more asymptomatic distant metastases, but the evidence is based on uncontrolled studies. METHODS: For inclusion, patients had histological evidence of invasive ductal carcinoma of the breast and TNM stage III or IIb (T3N0, but not T2N1). Consenting patients from six regional cancer centers in Ontario were randomly assigned to 18F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of the chest/abdomen and pelvis). The primary end point was upstaging to stage IV. A key secondary outcome was receiving curative intent combined modality therapy (ClinicalTrials.gov identifier: NCT02751710). RESULTS: Between December 2016 and April 2022, 184 patients were randomly assigned to whole-body PET-CT and 185 patients to conventional staging. Forty-three (23%) PET-CT patients were upstaged to stage IV compared with 21 (11%) conventional staged patients (absolute difference, 12.3% [95% CI, 3.9 to 19.9]; P = .002). Consequently, treatment was changed in 35 (81.3%) of 43 upstaged PET-CT patients and 20 (95.2%) of the 21 upstaged conventional patients. Subsequently, 149 (81%) patients in the PET-CT group received combined modality treatment versus 165 (89.2%) patients in the conventional staging group (absolute difference, 8.2% [95% CI, 0.1 to 15.4]; P = .03). CONCLUSION: In patients with LABC, PET-CT detected more distant metastases than conventional staging, and fewer PET-CT patients received combined modality therapy. Our randomized trial demonstrates the utility of the PET-CT staging strategy.

Vitamin C Urinary Loss in Fabry Disease: Clinical and Genomic Characteristics of Vitamin C Renal Leak.

BACKGROUND: Reduced plasma vitamin C concentrations in chronic diseases may result from abnormal urinary excretion of vitamin C: a renal leak. We hypothesized that vitamin C renal leak may be associated with disease-mediated renal dysregulation, resulting in aberrant vitamin C renal reabsorption and increased urinary loss. OBJECTIVES: We investigated the prevalence, clinical characteristics, and genomic associations of vitamin C renal leak in Fabry disease, an X-linked lysosomal disease associated with renal tubular dysfunction and low plasma vitamin C concentrations. METHODS: We conducted a non-randomized cross-sectional cohort study of men aged 24-42 y, with Fabry disease (n = 34) and controls without acute or chronic disease (n = 33). To match anticipated plasma vitamin C concentrations, controls were placed on a low-vitamin C diet 3 wk before inpatient admission. To determine the primary outcome of vitamin C renal leak prevalence, subjects were fasted overnight, and matched urine and fasting plasma vitamin C measurements were obtained the following morning. Vitamin C renal leak was defined as presence of urinary vitamin C at plasma concentrations below 38 µM. Exploratory outcomes assessed the association between renal leak and clinical parameters, and genomic associations with renal leak using single nucleotide polymorphisms (SNPs) in the vitamin C transporter SLC23A1. RESULTS: Compared with controls, the Fabry cohort had 16-fold higher odds of renal leak (6% vs. 52%; OR: 16; 95% CI: 3.30, 162; P < 0.001). Renal leak was associated with higher protein creatinine ratio (P < 0.01) and lower hemoglobin (P = 0.002), but not estimated glomerular filtration rate (P = 0.54). Renal leak, but not plasma vitamin C, was associated with a nonsynonymous single nucleotide polymorphism in vitamin C transporter SLC23A1 (OR: 15; 95% CI: 1.6, 777; P = 0.01). CONCLUSIONS: Increased prevalence of renal leak in adult men with Fabry disease may result from dysregulated vitamin C renal physiology and is associated with abnormal clinical outcomes and genomic variation.

Vitamin E Induces Liver Iron Depletion and Alters Iron Regulation in Mice.

BACKGROUND: Vitamin E (vit E) is an essential nutrient that functions as a lipophilic antioxidant and is used clinically to treat nonalcoholic fatty liver disease, where it suppresses oxidative damage and impedes the progression of steatosis and fibrosis. Mice lacking a critical liver iron-trafficking protein also manifest steatosis because of iron-mediated oxidative damage and are protected from liver disease by oral vit E supplements. OBJECTIVES: We aimed to examine the role of dietary vit E supplementation in modulating iron-sensing regulatory systems and nonheme iron levels in mouse liver. METHODS: C57Bl/6 male mice, aged 6 wk, were fed purified diets containing normal amounts of iron and either control (45 mg/kg) or elevated (450 mg/kg) levels of 2R-α-tocopherol (vit E) for 18 d. Mouse plasma and liver were analyzed for nonheme iron, levels and activity of iron homeostatic proteins, and markers of oxidative stress. We compared means ± SD for iron and oxidative stress parameters between mice fed the control diet and those fed the vit E diet. RESULTS: The Vit E-fed mice exhibited lower levels of liver nonheme iron (38% reduction, P < 0.0001) and ferritin (74% reduction, P < 0.01) than control-fed mice. The levels of liver mRNA for transferrin receptor 1 and divalent metal transporter 1 were reduced to 42% and 57% of the control, respectively. The mRNA levels for targets of nuclear factor erythroid 2-related factor (Nrf2), a major regulator of the oxidative stress response and iron-responsive genes, were also suppressed in vit E livers. Hepcidin, an iron regulatory hormone, levels were lower in the plasma (P < 0.05), and ferroportin (FPN), the iron exporter regulated by hepcidin, was expressed at higher levels in the liver (P < 0.05). CONCLUSIONS: Oral vit E supplementation in mice can lead to depletion of liver iron stores by suppressing the iron- and redox-sensing transcription factor Nrf2, leading to enhanced iron efflux through liver FPN. Iron depletion may indirectly enhance the antioxidative effects of vit E.