Incorporating intensity modulated total body irradiation into a Children's Oncology Group trial: Rationale, techniques, and safeguards.

Historically, total body irradiation (TBI) has been delivered using static, parallel opposed photon beams (2D-TBI). Recently, centers have increasingly used intensity-modulated radiation therapy (IMRT) techniques for TBI. Relative to 2D-TBI, IMRT can reduce doses to critical organs (i.e., lungs and kidneys) while delivering myeloablative doses to the rest of the body, so it may decrease the risk of toxicity while maintaining oncologic outcomes. Despite these potential benefits, delivering TBI using IMRT introduces new challenges in treatment planning and delivery. We describe the extensive experience with IMRT-based TBI at Stanford University and City of Hope Cancer Center. These groups, and others, have reported favorable clinical outcomes and have developed methods to optimize treatment planning and delivery. A critical next step is to evaluate the broader adoption of this approach. Therefore, IMRT-based TBI will be incorporated into a prospective, multi-institutional Children's Oncology Group study with careful procedures and safeguards in place.

Children's Oncology Group's 2023 blueprint for research: Radiation oncology.

Radiation oncology is an integral part of the multidisciplinary team caring for children with cancer. The primary goal of our committee is to enable the delivery of the safest dose of radiation therapy (RT) with the maximal potential for cure, and to minimize toxicity in children by delivering lower doses to normal tissues using advanced technologies like intensity-modulated RT (IMRT) and proton therapy. We provide mentorship for y ators and are actively involved in educating the global radiation oncology community. We are leaders in the effort to discover novel radiosensitizers, radioprotectors, and advanced RT technologies that could help improve outcomes of children with cancer.

Multitarget Stool RNA Test for Colorectal Cancer Screening.

Importance: Noninvasive tests for colorectal cancer screening must include sensitive detection of colorectal cancer and precancerous lesions. These tests must be validated for the intended-use population, which includes average-risk individuals 45 years or older. Objective: To evaluate the sensitivity and specificity of a noninvasive, multitarget stool RNA (mt-sRNA) test (ColoSense) test compared with results from a colonoscopy. Design, Setting, and Participants: This phase 3 clinical trial (CRC-PREVENT) was a blinded, prospective, cross-sectional study to support a premarket approval application for a class III medical device. A total of 8920 participants were identified online using social media platforms and enrolled from June 2021 to June 2022 using a decentralized nurse call center. All participants completed the mt-sRNA test, which incorporated a commercially available fecal immunochemical test (FIT), concentration of 8 RNA transcripts, and participant-reported smoking status. Stool samples were collected prior to participants completing a colonoscopy at their local endoscopy center. The mt-sRNA test results (positive or negative) were compared with index lesions observed on colonoscopy. Over the course of 12 months, individuals 45 years and older were enrolled in the clinical trial using the decentralized recruitment strategy. Participants were enrolled from 49 US states and obtained colonoscopies at more than 3800 different endoscopy centers. Main Outcomes and Measures: The primary outcomes included the sensitivity of the mt-sRNA test for detecting colorectal cancer and advanced adenomas and the specificity for no lesions on colonoscopy. Results: The mean (range) age of participants was 55 (45-90) years, with 4% self-identified as Asian, 11% as Black, and 7% as Hispanic. Of the 8920 eligible participants, 36 (0.40%) had colorectal cancer and 606 (6.8%) had advanced adenomas. The mt-sRNA test sensitivity for detecting colorectal cancer was 94%, sensitivity for detecting advanced adenomas was 46%, and specificity for no lesions on colonoscopy was 88%. The mt-sRNA test showed significant improvement in sensitivity for colorectal cancer (94% vs 78%; McNemar P = .01) and advanced adenomas (46% vs 29%; McNemar P < .001) compared with results of the FIT. Conclusions and Relevance: In individuals 45 years and older, the mt-sRNA test showed high sensitivity for colorectal neoplasia (colorectal cancer and advanced adenoma) with significant improvement in sensitivity relative to the FIT. Specificity for no lesions on colonoscopy was comparable to existing molecular diagnostic tests. Trial Registration: ClinicalTrials.gov Identifier: NCT04739722.

The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression.

Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF-NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF-NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF-NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ-TEAD transcriptional target. We also discovered that VEGF-NRP2-YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF-NRP2 or YAP/TAZ. These findings reveal roles for VEGF-NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF-NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.

A Review of Immunotherapy for Stage III and Metastatic Non-Small Cell Lung Cancer and the Rationale for the ECOG-ACRIN EA5181 Study.

ECOG-ACRIN EA5181 is a phase III prospective, randomized trial that randomizes patients undergoing chemo/radiation for locally advanced non-small cell lung cancer (LA-NSCLC) to concomitant durvalumab or no additional therapy, with both arms receiving 1 year of consolidative durvalumab. Radiation dose escalation failed to improve overall survival in RTOG 0617. However, conventionally fractionated radiation to 60 Gy with concomitant chemotherapy is associated with a high risk of local failure (38%-46%). It is hoped that concomitant immunotherapy during chemo/radiation can help decrease the risk of local failure, thereby improving overall survival and progression-free survival with acceptable toxicity. In this article, we review conventional chemo/radiation therapy for LA-NSCLC, as well as the quickly evolving world of immunotherapy in the treatment of non-small cell lung cancer and discuss the rationale and study design of EA5181. IMPLICATIONS FOR PRACTICE: This article provides an up-to-date assessment of how immunotherapy is reshaping the landscape of metastatic non-small cell lung cancer (NSCLC) and how the impact of this therapy is now rapidly moving into the treatment of patients with locally advanced NSCLC who are presenting for curative treatment. This article reviews the recent publications of chemo/radiation as well as those combining immunotherapy with chemotherapy and chemo/radiation, and provides a strategy for improving overall survival of patients with locally advanced NSCLC by using concomitant immunotherapy with standard concurrent chemo/radiation.

Quality assurance in radiation oncology.

The Children's Oncology Group (COG) has a strong quality assurance (QA) program managed by the Imaging and Radiation Oncology Core (IROC). This program consists of credentialing centers and providing real-time management of each case for protocol compliant target definition and radiation delivery. In the International Society of Pediatric Oncology (SIOP), the lack of an available, reliable online data platform has been a challenge and the European Society for Paediatric Oncology (SIOPE) quality and excellence in radiotherapy and imaging for children and adolescents with cancer across Europe in clinical trials (QUARTET) program currently provides QA review for prospective clinical trials. The COG and SIOP are fully committed to a QA program that ensures uniform execution of protocol treatments and provides validity of the clinical data used for analysis.

Dopaminergic basis for signaling belief updates, but not surprise, and the link to paranoia.

Distinguishing between meaningful and meaningless sensory information is fundamental to forming accurate representations of the world. Dopamine is thought to play a central role in processing the meaningful information content of observations, which motivates an agent to update their beliefs about the environment. However, direct evidence for dopamine's role in human belief updating is lacking. We addressed this question in healthy volunteers who performed a model-based fMRI task designed to separate the neural processing of meaningful and meaningless sensory information. We modeled participant behavior using a normative Bayesian observer model and used the magnitude of the model-derived belief update following an observation to quantify its meaningful information content. We also acquired PET imaging measures of dopamine function in the same subjects. We show that the magnitude of belief updates about task structure (meaningful information), but not pure sensory surprise (meaningless information), are encoded in midbrain and ventral striatum activity. Using PET we show that the neural encoding of meaningful information is negatively related to dopamine-2/3 receptor availability in the midbrain and dexamphetamine-induced dopamine release capacity in the striatum. Trial-by-trial analysis of task performance indicated that subclinical paranoid ideation is negatively related to behavioral sensitivity to observations carrying meaningful information about the task structure. The findings provide direct evidence implicating dopamine in model-based belief updating in humans and have implications for understating the pathophysiology of psychotic disorders where dopamine function is disrupted.

Practice patterns and recommendations for pediatric image-guided radiotherapy: A Children's Oncology Group report.

This report by the Radiation Oncology Discipline of Children's Oncology Group (COG) describes the practice patterns of pediatric image-guided radiotherapy (IGRT) based on a member survey and provides practice recommendations accordingly. The survey comprised of 11 vignettes asking clinicians about their recommended treatment modalities, IGRT preferences, and frequency of in-room verification. Technical questions asked physicists about imaging protocols, dose reduction, setup correction, and adaptive therapy. In this report, the COG Radiation Oncology Discipline provides an IGRT modality/frequency decision tree and the expert guidelines for the practice of ionizing image guidance in pediatric radiotherapy patients.

Specifying a Causal Role for Angular Gyrus in Autobiographical Memory.

Considerable recent evidence indicates that angular gyrus dysfunction in humans does not result in amnesia, but does impair a number of aspects of episodic memory. Patients with parietal lobe lesions have been reported to exhibit a deficit when freely recalling autobiographical events from their pasts, but can remember details of the events when recall is cued by specific questions. In apparent contradiction, inhibitory brain stimulation targeting angular gyrus in healthy volunteers has been found to have no effect on free recall or cued recall of word pairs. The present study sought to resolve this inconsistency by testing free and cued recall of both autobiographical memories and word-pair memories in the same healthy male and female human participants following continuous theta burst stimulation (cTBS) of angular gyrus and a vertex control location. Angular gyrus cTBS resulted in a selective reduction in the free recall, but not cued recall, of autobiographical memories, whereas free and cued recall of word-pair memories were unaffected. Additionally, participants reported fewer autobiographical episodes as being experienced from a first-person perspective following angular gyrus cTBS. The findings add to a growing body of evidence that a function of angular gyrus within the network of brain regions responsible for episodic recollection is to integrate memory features within an egocentric framework into the kind of first-person perspective representation that enables the subjective experience of remembering events from our personal pasts.SIGNIFICANCE STATEMENT In seeking to understand the role played by the angular gyrus region of parietal cortex in human memory, interpreting the often conflicting findings from neuroimaging and neuropsychology studies has been hampered by differences in anatomical specificity and localization between methods. In the present study, we address these limitations using continuous theta burst stimulation in healthy volunteers to disrupt function of angular gyrus and a vertex control region. With this method, we adjudicate between two competing theories of parietal lobe function, finding evidence that is inconsistent with an attentional role for angular gyrus in memory, supporting instead an account in terms of integrating memory features within an egocentric framework into a first-person perspective representation that enables the subjective experience of remembering.

Sequential inference as a mode of cognition and its correlates in fronto-parietal and hippocampal brain regions.

Normative models of human cognition often appeal to Bayesian filtering, which provides optimal online estimates of unknown or hidden states of the world, based on previous observations. However, in many cases it is necessary to optimise beliefs about sequences of states rather than just the current state. Importantly, Bayesian filtering and sequential inference strategies make different predictions about beliefs and subsequent choices, rendering them behaviourally dissociable. Taking data from a probabilistic reversal task we show that subjects' choices provide strong evidence that they are representing short sequences of states. Between-subject measures of this implicit sequential inference strategy had a neurobiological underpinning and correlated with grey matter density in prefrontal and parietal cortex, as well as the hippocampus. Our findings provide, to our knowledge, the first evidence for sequential inference in human cognition, and by exploiting between-subject variation in this measure we provide pointers to its neuronal substrates.

Feasibility and accuracy of UF/NCI phantoms and Monte Carlo retrospective dosimetry in children treated on National Wilms Tumor Study protocols.

PURPOSE: This pilot study was done to determine the feasibility and accuracy of University of Florida/National Cancer Institute (UF/NCI) phantoms and Monte Carlo (MC) retrospective dosimetry and had two aims: (1) to determine the anatomic accuracy of UF/NCI phantoms by comparing 3D organ doses in National Wilms Tumor Study (NWTS) patient-matched UF/NCI phantoms to organ doses in corresponding patient-matched CT scans and (2) to compare infield and out-of-field organ dosimetry using two dosimetry methods-standard radiation therapy (RT) treatment planning systems (TPS) and MC dosimetry in these two anatomic models. METHODS: Twenty NWTS patient-matched Digital Imaging and Communications in Medicine (DICOM) files of UF/NCI phantoms and CT scans were imported into the Pinnacle RT TPS. The NWTS RT fields (whole abdomen, flank, whole lung, or a combination) and RT doses (10-45 Gy) were reconstructed in both models. Both TPS and MC dose calculations were performed. For aim 1, the mean doses to the heart, kidney, thyroid gland, testes, and ovaries using TPS and MC in both models were statistically compared. For aim 2, the TPS and MC dosimetry for these organs in both models were statistically compared. RESULTS: For aim 1, there was no significant difference between phantom and CT scan dosimetry for any of the organs using either TPS or MC dosimetry. For aim 2, there was a significant difference between TPS and MC dosimetry for both CT scan and phantoms for all organs. Although the doses for infield organs were similar for both TPS and MC, the doses for near-field and out-of-field organs were consistently higher for 90% to 100% of MC doses; however, the absolute dose difference was small (<1 Gy). CONCLUSIONS: This pilot study has demonstrated that the patient-matched UF/NCI phantoms together with MC dosimetry is an accurate model for performing retrospective 3D dosimetry in large-scale epidemiology studies such as the NWTS.

Active Inference: A Process Theory.

This article describes a process theory based on active inference and belief propagation. Starting from the premise that all neuronal processing (and action selection) can be explained by maximizing Bayesian model evidence-or minimizing variational free energy-we ask whether neuronal responses can be described as a gradient descent on variational free energy. Using a standard (Markov decision process) generative model, we derive the neuronal dynamics implicit in this description and reproduce a remarkable range of well-characterized neuronal phenomena. These include repetition suppression, mismatch negativity, violation responses, place-cell activity, phase precession, theta sequences, theta-gamma coupling, evidence accumulation, race-to-bound dynamics, and transfer of dopamine responses. Furthermore, the (approximately Bayes' optimal) behavior prescribed by these dynamics has a degree of face validity, providing a formal explanation for reward seeking, context learning, and epistemic foraging. Technically, the fact that a gradient descent appears to be a valid description of neuronal activity means that variational free energy is a Lyapunov function for neuronal dynamics, which therefore conform to Hamilton's principle of least action.

Readiness to Vaccinate Critical Personnel During an Influenza Pandemic, United States, 2015.

OBJECTIVES: To assess the readiness to vaccinate critical infrastructure personnel (CIP) involved in managing public works, emergency services, transportation, or any other system or asset that would have an immediate debilitating impact on the community if not maintained. METHODS: We analyzed self-reported planning to vaccinate CIP during an influenza pandemic with data from 2 surveys: (1) the Program Annual Progress Assessment of immunization programs and (2) the Pandemic Influenza Readiness Assessment of public health emergency preparedness programs. Both surveys were conducted in 2015. RESULTS: Twenty-six (43.3%) of 60 responding public health emergency preparedness programs reported having an operational plan to identify and vaccinate CIP, and 16 (26.2%) of 61 responding immunization programs reported knowing the number of CIP in their program's jurisdictions. CONCLUSIONS: Many programs may not be ready to identify and vaccinate CIP during an influenza pandemic. Additional efforts are needed to ensure operational readiness to vaccinate CIP during the next influenza pandemic.

2015 Pandemic Influenza Readiness Assessment Among US Public Health Emergency Preparedness Awardees.

OBJECTIVES: To assess how US Public Health Emergency Preparedness (PHEP) awardees plan to respond to an influenza pandemic with vaccination. METHODS: The Centers for Disease Control and Prevention developed the Pandemic Influenza Readiness Assessment, an online survey sent to PHEP directors, to analyze, in part, the readiness of PHEP awardees to vaccinate 80% of the populations of their jurisdictions with 2 doses of pandemic influenza vaccine, separated by 21 days, within 16 weeks of vaccine availability. RESULTS: Thirty-eight of 60 (63.3%) awardees reported being able to vaccinate their populations within 16 weeks; 38 (63.3%) planned to allocate more than 20% of their pandemic vaccine supply to points of dispensing (PODs). Thirty-four of 58 (58.6%) reported staffing as a challenge to vaccinating 80% of their populations; 28 of 60 (46.7%) reported preparedness workforce decreases, and 22 (36.7%) reported immunization workforce decreases between January 2012 and July 2015. CONCLUSIONS: Awardees relied on PODs to vaccinate segments of their jurisdictions despite workforce decreases. Planners must ensure readiness for POD sites to vaccinate, but should also leverage complementary sites and providers to augment public health response.

Cross-modal effects of value on perceptual acuity and stimulus encoding.

Cross-modal interactions are very common in perception. An important feature of many perceptual stimuli is their reward-predicting properties, the utilization of which is essential for adaptive behavior. What is unknown is whether reward associations in one sensory modality influence perception of stimuli in another modality. Here we show that auditory stimuli with high-reward associations increase the sensitivity of visual perception, even when sounds and reward associations are both irrelevant for the visual task. This increased sensitivity correlates with a change in stimulus representation in the visual cortex, indexed by increased multivariate decoding accuracy in simultaneously acquired functional MRI data. Univariate analysis showed that reward associations modulated responses in regions associated with multisensory processing in which the strength of modulation was a better predictor of the magnitude of the behavioral effect than the modulation in classical reward regions. Our findings demonstrate a value-driven cross-modal interaction that affects perception and stimulus encoding, with a resemblance to well-described modulatory effects of attention. We suggest that multisensory processing areas may mediate the transfer of value signals across senses.

Neural signals encoding shifts in beliefs.

Dopamine is implicated in a diverse range of cognitive functions including cognitive flexibility, task switching, signalling novel or unexpected stimuli as well as advance information. There is also longstanding line of thought that links dopamine with belief formation and, crucially, aberrant belief formation in psychosis. Integrating these strands of evidence would suggest that dopamine plays a central role in belief updating and more specifically in encoding of meaningful information content in observations. The precise nature of this relationship has remained unclear. To directly address this question we developed a paradigm that allowed us to decompose two distinct types of information content, information-theoretic surprise that reflects the unexpectedness of an observation, and epistemic value that induces shifts in beliefs or, more formally, Bayesian surprise. Using functional magnetic-resonance imaging in humans we show that dopamine-rich midbrain regions encode shifts in beliefs whereas surprise is encoded in prefrontal regions, including the pre-supplementary motor area and dorsal cingulate cortex. By linking putative dopaminergic activity to belief updating these data provide a link to false belief formation that characterises hyperdopaminergic states associated with idiopathic and drug induced psychosis.

The Dopaminergic Midbrain Encodes the Expected Certainty about Desired Outcomes.

Dopamine plays a key role in learning; however, its exact function in decision making and choice remains unclear. Recently, we proposed a generic model based on active (Bayesian) inference wherein dopamine encodes the precision of beliefs about optimal policies. Put simply, dopamine discharges reflect the confidence that a chosen policy will lead to desired outcomes. We designed a novel task to test this hypothesis, where subjects played a "limited offer" game in a functional magnetic resonance imaging experiment. Subjects had to decide how long to wait for a high offer before accepting a low offer, with the risk of losing everything if they waited too long. Bayesian model comparison showed that behavior strongly supported active inference, based on surprise minimization, over classical utility maximization schemes. Furthermore, midbrain activity, encompassing dopamine projection neurons, was accurately predicted by trial-by-trial variations in model-based estimates of precision. Our findings demonstrate that human subjects infer both optimal policies and the precision of those inferences, and thus support the notion that humans perform hierarchical probabilistic Bayesian inference. In other words, subjects have to infer both what they should do as well as how confident they are in their choices, where confidence may be encoded by dopaminergic firing.

Reward-related activity in ventral striatum is action contingent and modulated by behavioral relevance.

Multiple features of the environment are often imbued with motivational significance, and the relative importance of these can change across contexts. The ability to flexibly adjust evaluative processes so that currently important features of the environment alone drive behavior is critical to adaptive routines. We know relatively little about the neural mechanisms involved, including whether motivationally significant features are obligatorily evaluated or whether current relevance gates access to value-sensitive regions. We addressed these questions using functional magnetic resonance imaging data and a task design where human subjects had to choose whether to accept or reject an offer indicated by visual and auditory stimuli. By manipulating, on a trial-by-trial basis, which stimulus determined the value of the offer, we show choice activity in the ventral striatum solely reflects the value of the currently relevant stimulus, consistent with a model wherein behavioral relevance modulates the impact of sensory stimuli on value processing. Choice outcome signals in this same region covaried positively with wins on accept trials, and negatively with wins on reject trials, consistent with striatal activity at feedback reflecting correctness of response rather than reward processing per se. We conclude that ventral striatum activity during decision making is dynamically modulated by behavioral context, indexed here by task relevance and action selection.

Precision and neuronal dynamics in the human posterior parietal cortex during evidence accumulation.

Primate studies show slow ramping activity in posterior parietal cortex (PPC) neurons during perceptual decision-making. These findings have inspired a rich theoretical literature to account for this activity. These accounts are largely unrelated to Bayesian theories of perception and predictive coding, a related formulation of perceptual inference in the cortical hierarchy. Here, we tested a key prediction of such hierarchical inference, namely that the estimated precision (reliability) of information ascending the cortical hierarchy plays a key role in determining both the speed of decision-making and the rate of increase of PPC activity. Using dynamic causal modelling of magnetoencephalographic (MEG) evoked responses, recorded during a simple perceptual decision-making task, we recover ramping-activity from an anatomically and functionally plausible network of regions, including early visual cortex, the middle temporal area (MT) and PPC. Precision, as reflected by the gain on pyramidal cell activity, was strongly correlated with both the speed of decision making and the slope of PPC ramping activity. Our findings indicate that the dynamics of neuronal activity in the human PPC during perceptual decision-making recapitulate those observed in the macaque, and in so doing we link observations from primate electrophysiology and human choice behaviour. Moreover, the synaptic gain control modulating these dynamics is consistent with predictive coding formulations of evidence accumulation.