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Introduction Medical error is common and has a significant impact on physicians, learners, and patients’ perception of the medical system; however, residents receive little formal training on this topic. This curriculum aims to foster sharing of personal medical error stories, review and practice error management and coping strategies, and impact error response factors. Methods Faculty identified factors related to effective physician error management and recovery in order to develop a targeted curriculum for family medicine residents. The curriculum consisted of three 1-hour didactic sessions in a medium-sized, urban program. Instructional methods included guided reflection after mentor storytelling, small-group discussion, role-play, and self-reflection. Results Twenty-two out of 30 (73%) residents completed the premodule survey, and 15 out of 30 (50%) residents completed the post module survey. Fewer than half of residents reported they knew what to do when faced with medical error, but this increased to 93% after curriculum delivery, as did rates of reported error story sharing. Resident reported self-efficacy (I can be honest about the errors I make as a doctor.) and self-awareness (I acknowledge when I am at increased risk for making errors) also increased following the curriculum. Discussion Family medicine residents are receptive to learning from peers and mentors about error management and recovery. A brief curriculum can impact the culture around disclosure and support. Future iterations should focus on the impact of targeted curricular interventions on patient-oriented outcomes related to medical error.

I am a healer, yet sometimes I do more harm than good…David Hilfiker, 1984: Objectives Medical error is common and significantly impacts patients, physicians, learners, and public perception of the medical system; however, residents receive little formal training on this topic. Research on error response in practicing physicians is limited, and even more so on medical education interventions to improve this. This study evaluates a curriculum developed to foster the sharing of faculty medical error stories, practice of constructive coping strategies, and growth in resident confidence in managing error. Methods Researchers identified factors related to effective physician error management and recovery to develop a targeted intervention for family medicine residents. The intervention consisted of three one hour didactic sessions in a medium-sized midwestern, urban family medicine residency program over the course of 6 months. Instructional methods included guided reflection after mentor storytelling, small group discussion, role play, and self-reflection. Results Of the 30 residents, 22 (73%) completed the preintervention survey, and 15 (50%) completed the postintervention survey. While most residents reported having experienced error (55%), fewer than half of the residents reported they knew what to do when faced with medical errors (46%). This increased to 93% after intervention. Personal error stories from mentors were the most desired type of training reported by residents preintervention, but this was surpassed by legal and malpractice concerns in the postintervention survey. Rates of reported error story sharing increased after the intervention. Residents reported self-efficacy (I can be honest about errors) and self-awareness (I acknowledge when I am at increased risk for error) also increased with intervention. However, these changes did not reach statistical significance. Conclusions Family medicine residents are receptive to learning from peers and mentors about error management and recovery. A brief intervention can impact the culture around disclosure and support. Future research should focus on the impact of targeted interventions on patient-oriented outcomes related to medical error.

Complications occurring after lymphodepleting chemotherapy (LDC) may delay chimeric antigen receptor (CAR) T-cell infusion. The effect of these delays on clinical outcomes is unclear. We performed a retrospective analysis of 240 patients with relapsed/refractory large B-cell lymphoma treated with standard-of-care axicabtagene ciloleucel (axi-cel) and identified 40 patients (16.7%) who had delay in axi-cel infusion. Of these, 85% had delay due to infection. At time of LDC initiation, patients with delayed infusion had lower absolute neutrophil count (P=0.006), lower platelets (P=0.004), lower hemoglobin (P5 days (4.6 vs. 8.2 months; P=0.036), but not 1 day (5.7 vs. 8.2 months; P=0.238). Following propensity score matching, patients with delayed infusion continued to have shorter median PFS (3.5 vs. 6.0 months; P=0.015). Levels of pro-inflammatory cytokines on day of infusion were significantly higher in patients with delayed infusion. Together, these findings suggest that delays in CAR T-cell administration after initiation of LDC are associated with inferior outcomes. Further studies are needed to guide strategies to improve efficacy in such patients.

This study aimed to enhance public awareness regarding conflict identification and encourage the adoption of suitable resolution strategies. The community service initiative employed a training approach, engaging a group of 52 women on Laiya Island, Pangkep Regency, South Sulawesi, Indonesia. Furthermore, this activity was a collaboration between CPCD (Center for Peace, Conflict, and Democracy) Hasanuddin University and the Pangkep District Fisheries Service. The results showed that an effective measure for conflict prevention entailed the empowerment of women. Therefore, there had been a notable improvement in community understanding of appropriate conflict resolution techniques. This activity introduced a novel approach where the empowerment of women through the utilization of marine products and the establishment of micro, small, and medium enterprises (MSMEs) as well as home industries played a vital role in conflict resolution strategies. In conclusion, the conflicts experienced on Laiya Island were minimal, and the community successfully resolved disputes through meaningful discussions.

This community service aims to empower fishermen's families in Karanrang Island through fish processing to produce Bajabu shredded typical of Bugis Makassar. The service method used initial observation, assistance with partner conditions, field data collection, and implementation of alternative solutions for product creation and evaluation. The service partners were a group of fishermen from Karanrang Island. This service created a product in the form of a Fish Smoking House (FSH) made entirely of stainless steel. It also created the Bajabu product, a roasted shredded Bugis Makassar delicacy packed and labeled for increased marketability.

Abstract Background Drug use is a growing concern in Ghana. People who inject drugs (PWID) are highly vulnerable to HIV and other infectious diseases. Ghana’s National Strategic Plan for HIV/AIDS 2016–2020 identifies PWID as a key population, but efforts to address the needs of PWID have lagged behind those targeting sex workers and men who have sex with men. Lack of information about PWID is a critical barrier to implementing effective HIV prevention and treatment. We aimed to learn more about the vulnerability of the PWID population in order to inform much-needed harm reduction interventions. Methods From April to July 2018, we conducted a mixed methods study in Kumasi, Ghana, to identify all major drug using locations, count the numbers of PWID to obtain rough population size estimations, and administer anonymous surveys to 221 PWID regarding drug use and sexual behavior. We also tested for HIV, HCV, and HBV from syringes used by survey participants. Results Key informants identified five major drug using locations and estimated the total PWID population size to be between 600 and 2000. Enumerators counted between 35 and 61 individuals present at each of the five bases. Sharing syringes and reusing discarded syringes are common practices. Over half of survey participants (59%) reported past-month syringe sharing (34% used a used syringe and 52% gave away a used syringe). Individuals with higher injection frequency (≥ 21 times weekly) and who injected with four or more people had higher odds of syringe sharing. Of the survey participants reporting sex in the last month (23%), most reported having one partner, but only 12% used condoms. Nearly all women (11/13) reported exchanging sex for drugs and 6/13 reported exchanging sex for money in the last six months. Fifteen percent of participants (all men) reported paying for sex using drugs or money. Of the used syringes, prevalence estimates were 3% (HIV), 2% (HCV), and 9% (HBV). Conclusions Our findings confirm the urgent need to implement harm reduction interventions targeting PWID and to build a strong and enabling legal and policy environment in Ghana to support these efforts.

The recent development and clinical implementation of novel immunotherapies for the treatment of Hodgkin and non-Hodgkin lymphoma have improved patient outcomes across subgroups. The rapid introduction of immunotherapeutic agents into the clinic, however, has presented significant questions regarding optimal treatment scheduling around existing chemotherapy/radiation options, as well as a need for improved understanding of how to properly manage patients and recognize toxicities. To address these challenges, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in lymphoma to develop a clinical practice guideline for the education of healthcare professionals on various aspects of immunotherapeutic treatment. The panel discussed subjects including treatment scheduling, immune-related adverse events (irAEs), and the integration of immunotherapy and stem cell transplant to form recommendations to guide healthcare professionals treating patients with lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 may be associated with long-term adverse effects such as cytopenia and immune deficiency. In order to characterize these late events, we analyzed 31 patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at our institution on two clinical trials, ZUMA-1 (clinicaltrials gov. Identifier: NCT02348216) and ZUMA-9 (clinicaltrials gov. Identifier: NCT03153462). Complete blood counts, lymphocyte subsets, and immunoglobulin levels were measured serially until month 24 or progression. Fifteen (48%) patients had grade 3-4 cytopenia, including anemia (five, 16%), neutropenia (nine, 29%), or thrombocytopenia (13, 42%) at day 30. Cytopenia at day 30 was not significantly associated with later diagnosis of myelodysplasia. Among patients with ongoing remission, grade 3-4 cytopenia was observed in one of nine (11%) at 2 years. While peripheral CD8+ T cells recovered early, CD4+ T-cell recovery was delayed with a count of

Over the past decade, chimeric antigen receptor (CAR) T-cell therapy has significantly improved the outlook for many patients with relapsed and/or refractory B-cell malignancies. The use of CAR T-cell therapy and other therapeutic immune effector cells will likely continue to expand with the development of other targets and use in solid tumors. Although these therapies have shown significant promise in the treatment of some malignancies, they can be associated with unique toxicities including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome which can be fatal if not identified early and treated appropriately. An understanding of how best to manage the toxicities associated with CAR T-cell therapy is continually evolving. Institutions providing CAR T-cell therapy have undergone changes in infrastructure and staffing models in order to safely care for patients receiving this novel therapy. As members of a multi-disciplinary health care team, advanced practice providers play significant roles in caring for this patient population and must be well-versed in the recognition, grading, and appropriate management of CAR T-cell therapy-related toxicities as these providers care for patients in multiple settings across the continuum of care.

In this review we describe the status of development for a new class of magnetic resonance (MR) contrast agents, based on chemical exchange saturation transfer (CEST). The mathematics and physics relevant to the description of the CEST effect in MR are presented in an appendix published in the online version only. We discuss the issues arising when translating in vitro results obtained with CEST agents to using these MR agents in in vivo model studies and in humans. Examples are given on how these agents are imaged in vivo. We summarize the status of development of these CEST agents, and speculate about the next steps that may be taken towards the demonstration of CEST MR imaging in clinical applications. [ABSTRACT FROM AUTHOR]

Purpose: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC)., Methods: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures., Results: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy ( P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS., Conclusion: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.

Purpose: Prior evidence suggests a progression-free survival (PFS) benefit from adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy for patients with some oligometastatic solid tumors. Randomized trials testing this hypothesis in breast cancer have yet to be published. We sought to determine whether adding MDT to SOC systemic therapy improves PFS in oligometastatic breast cancer., Methods: EXTEND is a multicenter phase II randomized basket trial testing the addition of MDT to SOC systemic therapy in patients with ≤5 metastases (NCT03599765). Patients were randomized 1:1 to MDT (definitive local treatment to all sites of disease, plus SOC systemic therapy) or to SOC systemic therapy only. Primary endpoint was PFS, and secondary endpoints included overall survival (OS), time to subsequent line of systemic therapy, and time to the appearance of new metastases. Exploratory analyses included quality of life (QOL) and systemic immune response measures., Results: From September 2018 through July 2022, 22 and 21 patients were randomized to the MDT and no-MDT arms, respectively. At a median follow-up of 24.8 months, PFS was not improved with the addition of MDT to SOC systemic therapy (median PFS 15.6 months MDT vs 24.9 months no-MDT [hazard ratio {HR} 0.91; 95% CI 0.34-2.48, p=0.86]). Similarly, MDT did not improve OS, time to subsequent line of systemic therapy, or time to the appearance of new metastases (all p>0.05). No significant differences were found in QOL measures, systemic T-cell activation, or T-cell stimulatory cytokine concentration., Conclusion: Among patients with oligometastatic breast cancer, the addition of MDT to SOC systemic therapy did not improve PFS. These findings suggest that MDT may have no systemic benefit in otherwise unselected oligometastatic breast cancer patients, although this trial was limited by a heterogenous and small sample size and overperformance of both treatment arms., Competing Interests: Declaration of competing interest Mr Fellman reported receiving grants from the National Institutes of Health (NIH) to The University of Texas MD Anderson Cancer Center during the conduct of the study. Dr Haymaker reported receiving grants from Avenge Bio, Sanofi, Dragonfly, BTG, Iovance Biotherapeutics, and TriSalus Life Sciences; receiving personal fees from Nanobiotix; receiving speaker honoraria from the Southwest Oncology Group and the Society for Immunotherapy of Cancer; and receiving stock options from BriaCell as a member of the scientific advisory board outside the submitted work. Dr Smith reported receiving salary support from Varian Medical Systems for a strategic alliance between MD Anderson Cancer Center and Varian Medical Systems outside the submitted work and royalty and equity interest in Oncora Medical. Dr Shaitelman reported funding from the Emerson Collective Foundation and contracted research agreements with Alpha Tau, Exact Sciences, TAE Life Sciences, and Artios Pharmaceuticals, outside the submitted work. Dr. Chun declares in the past 36 months support from grants or contracts from NIH R50 CA275822 and MD Anderson; consulting fees from Curio Science, Norton Healthcare, and AstraZeneca; honoraria from Binaytara Foundation, Curio Science, Henry Ford Health Systems, Japanese Society for Radiation Oncology and Hong Kong Precision Oncology society; and support for attending meetings and/or travel from ViewRay, American Board of Radiology, Binaytara Foundation, Japanese Society for Radiation Oncology, and AstraZeneca outside the submitted work. Dr Reuben reported receiving consulting fees and honoraria from Adaptive Biotechnologies outside the submitted work. Dr Ghia reported receiving consulting fees and honoraria from Brainlab outside the submitted work. Dr. Woodward reported personal fees from Exact Sciences and Epic Sciences, outside the submitted work. Dr Gomez reported receiving grants from AstraZeneca, Merck, Varian, and Bristol Myers Squibb and receiving consulting fees and honoraria from Grail, AstraZeneca, Olympus, Johnson & Johnson, Varian, Medtronic, and Med Learning Group outside the submitted work. Dr Tang reported receiving grants from the Cancer Prevention & Research Institute of Texas (CPRIT) and the Andrew Sabin Family Foundation and being an Andrew Sabin Scholar during the conduct of the study and receiving royalties from Wolters Kluwer and consulting fees and honoraria from Bayer, Diffusion Pharmaceuticals, and The Osler Institute Lecture Series outside the submitted work. No other disclosures were reported., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses., Experimental Design: Clinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals., Results: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 [23.8%; 95% confidence interval (CI), 19.7%, 28.5%] comparisons. In multivariable analysis, non-overall survival endpoints [OR, 2.16 (95% CI, 1.21, 3.87); P = 0.009] were associated with higher odds of PHVs, and immunotherapy comparisons [OR 1.94 (95% CI, 0.98, 3.86); P = 0.058] were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) prespecified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with restricted mean survival time or maximum combination test, of which 10 (71%) reported negative results., Conclusions: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting nonproportional hazards to be misinterpreted., (©2024 American Association for Cancer Research.)

Purpose: The primary results of phase III oncology trials may be challenging to interpret, given that results are generally based on P value thresholds. The probability of whether a treatment is beneficial, although more intuitive, is not usually provided. Here, we developed and released a user-friendly tool that calculates the probability of treatment benefit using trial summary statistics., Methods: We curated 415 phase III randomized trials enrolling 338,600 patients published between 2004 and 2020. A phase III prior probability distribution for the treatment effect was developed on the basis of a three-component zero-mean mixture distribution of the observed z-scores. Using this prior, we computed the probability of clinically meaningful benefit (hazard ratio [HR] <0.8). The distribution of signal-to-noise ratios and power of phase III oncology trials were compared with that of 23,551 randomized trials from the Cochrane Database., Results: The signal-to-noise ratios of phase III oncology trials tended to be much larger than randomized trials from the Cochrane Database. Still, the median power of phase III oncology trials was only 49% (IQR, 14%-95%), and the power was <80% in 65% of trials. Using the phase III oncology-specific prior, only 53% of trials claiming superiority (114 of 216) had a ≥90% probability of clinically meaningful benefits. Conversely, the probability that the experimental arm was superior to the control arm (HR <1) exceeded 90% in 17% of trials interpreted as having no benefit (34 of 199)., Conclusion: By enabling computation of contextual probabilities for the treatment effect from summary statistics, our robust, highly practical tool, now posted on a user-friendly webpage, can aid the wider oncology community in the interpretation of phase III trials.

Objectives: Randomized noncomparative trials (RNCTs) promise reduced accrual requirements vs randomized controlled comparative trials because RNCTs do not enroll a control group and instead compare outcomes to historical controls or prespecified estimates. We hypothesized that RNCTs often suffer from two methodological concerns: (1) lack of interpretability due to group-specific inferences in nonrandomly selected samples and (2) misinterpretation due to unlicensed between-group comparisons lacking prespecification. The purpose of this study was to characterize RNCTs and the incidence of these two methodological concerns., Study Design and Setting: We queried PubMed and Web of Science on September 14, 2023, to conduct a meta-epidemiological analysis of published RNCTs in any field of medicine. Trial characteristics and the incidence of methodological concerns were manually recorded., Results: We identified 70 RNCTs published from 2002 to 2023. RNCTs have been increasingly published over time (slope = 0.28, 95% CI 0.17-0.39, P < .001). Sixty trials (60/70, 86%) had a lack of interpretability for the primary endpoint due to group-specific inferences. Unlicensed between-group comparisons were present in 36 trials (36/70, 51%), including in the primary conclusion of 31 trials (31/70, 44%), and were accompanied by significance testing in 20 trials (20/70, 29%). Only five (5/70, 7%) trials were found to have neither of these flaws., Conclusion: Although RNCTs are increasingly published over time, the primary analysis of nearly all published RNCTs in the medical literature was unsupported by their fundamental underlying methodological assumptions. RNCTs promise group-specific inference, which they are unable to deliver, and undermine the primary advantage of randomization, which is comparative inference. The ongoing use of the RNCT design in lieu of a traditional randomized controlled comparative trial should therefore be reconsidered., Plain Language Summary: The typical way that doctors can learn whether new drugs are helpful is through a clinical trial. Often, doctors compare these new treatments to the control treatment being used in standard clinical practice. When researchers want to compare different treatments, they may decide to randomly assign one treatment or the other to trial participants. Like flipping a coin, randomly deciding which treatment to use can help researchers make the best comparisons between the new and control treatment by limiting certain biases. These trials are called "randomized comparative trials" and are the most common way researchers can improve medicine. A newer type of trial, called a "randomized noncomparative trial," has become increasingly popular in medicine. Like randomized comparative trials, this type of trial randomly decides which treatment participants receive. However, the "randomized noncomparative trial" is not designed to evaluate whether the new treatment results in better outcomes compared with the control treatment. Instead, the results of each randomized arm in the trial are compared to other patients, who are not a part of the trial, or to another measure set ahead of time by the researchers. This is justified by some researchers, who say that fewer participants are needed for such trials, which helps to finish the trial faster. However, directly comparing the results of patients after receiving a treatment on a clinical trial is one of the most important parts of the trial and the main reason why researchers would want to randomly assign treatments in the first place. To better understand how RNCTs are used in practice, we reviewed all such trials that have been completed in medicine to date. We found that more than half of RNCTs actually ended up comparing their patients anyway, despite saying they would not. This is a problem because these comparisons are not prespecified and may therefore be only reported when the result is what the researchers wanted. Furthermore, the main outcome of each trial was difficult to interpret in most trials because there was no effort to show that the enrolled patients were representative of any prespecified population that would facilitate comparisons with historical information. Overall, only five trials, or just 7% of the "randomized noncomparative trials" published in the medical literature, did not have either of these issues. As a result, this type of clinical trial does not seem to be a good way to improve medical care. If researchers want to learn which treatments are better, they should stick to the standard way to learn this-randomized comparative trials., Competing Interests: Declaration of competing interest A.D.S. reports honoraria from Sermo. P.M. reports honoraria for scientific advisory board membership for Mirati Therapeutics, Bristol-Myers Squibb, and Exelixis; consulting fees from Axiom Healthcare; nonbranded educational programs supported by Exelixis, Pfizer, and DAVA Oncology; leadership or fiduciary roles as a Medical Steering Committee Member for the Kidney Cancer Association and a Kidney Cancer Scientific Advisory Board Member for KCCure; and research funding from Takeda, Bristol-Myers Squibb, Mirati Therapeutics, and Gateway for Cancer Research (all unrelated to this manuscript's content). There are no competing interests for any other author., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: A previous study demonstrated that power against the (unobserved) true effect for the primary end point (PEP) of most phase III oncology trials is low, suggesting an increased risk of false-negative findings in the field of late-phase oncology. Fitting models with prognostic covariates is a potential solution to improve power; however, the extent to which trials leverage this approach, and its impact on trial interpretation at scale, is unknown. To that end, we hypothesized that phase III trials using multivariable PEP analyses are more likely to demonstrate superiority versus trials with univariable analyses., Methods: PEP analyses were reviewed from trials registered on ClinicalTrials.gov. Adjusted odds ratios (aORs) were calculated by logistic regressions., Results: Of the 535 trials enrolling 454,824 patients, 69% (n = 368) used a multivariable PEP analysis. Trials with multivariable PEP analyses were more likely to demonstrate PEP superiority (57% [209 of 368] v 42% [70 of 167]; aOR, 1.78 [95% CI, 1.18 to 2.72]; P = .007). Among trials with a multivariable PEP model, 16 conditioned on covariates and 352 stratified by covariates. However, 108 (35%) of 312 trials with stratified analyses lost power by categorizing a continuous variable, which was especially common among immunotherapy trials (aOR, 2.45 [95% CI, 1.23 to 4.92]; P = .01)., Conclusion: Trials increasing power by fitting multivariable models were more likely to demonstrate PEP superiority than trials with unadjusted analysis. Underutilization of conditioning models and empirical power loss associated with covariate categorization required by stratification were identified as barriers to power gains. These findings underscore the opportunity to increase power in phase III trials with conventional methodology and improve patient access to effective novel therapies.

Neurofibrillary tangles of tau constitute one of the key biological hallmarks of Alzheimer's disease. Currently, the assessment of regional tau accumulation requires intravenous administration of radioactive tracers for PET imaging. A noninvasive MRI-based solution would have significant clinical implications. Herein, we utilized an MRI technique known as chemical exchange saturation transfer (CEST) to determine the imaging signature of tau in both its monomeric and pathologic fibrillated conformations. Three sets of purified recombinant full-length (4R) tau protein were prepared for collection of CEST spectra using a 9.4 T NMR spectrometer at varying temperatures (25, 37, and 42 °C) and RF intensities (0.7, 1.0, 1.5, and 2.2 μT). Monomeric and fibrillated tau were readily distinguished based on their Z-spectrum profiles. Fibrillated tau demonstrated a less prominent peak at 3.5 ppm with additional peaks near 0.5 and 1.5 ppm. No significant differences were identified between fibrillated tau prepared using heparin versus seed-competent tau. In conclusion, monomeric and fibrillated tau can be readily detected and distinguished based on their CEST-derived Z-spectra, pointing to the potential utility of CEST-MRI as a noninvasive biomarker of regional pathologic tau accumulation in the brain. Further testing and validation in vitro and in vivo will be necessary before this can be applied clinically., (© 2024 John Wiley & Sons Ltd.)

Purpose: Increasing data suggest that radiation therapy, particularly ablative radiation therapy, alters the natural history of metastatic disease. For patients with metastatic disease enrolled in prospective trials testing systemic therapy, the use of off-protocol radiation therapy to improve clinical symptoms or extend the duration of study systemic therapy may influence study endpoints. We sought to evaluate how often off-protocol radiation therapy was permitted among systemic therapy phase 3 trials, how often off-protocol radiation therapy is used, and whether off-protocol radiation therapy correlated with study outcomes., Methods and Materials: Two-arm, superiority-design, phase 3 randomized trials testing systemic therapy were screened from ClinicalTrials.gov. Protocol availability was required to assess the trial approach to off-protocol radiation therapy if not described in the manuscript. Adjusted odds ratios with 95% CI were calculated by logistic regression., Results: A total of 112 trials enrolling 80,134 patients were included, with publication dates between 2010 and 2019. Of these, off-protocol radiation therapy was allowed, not discussed, or prohibited during study systemic therapy in 52% (N =58), 25% (N = 28), and 23% (N = 26) of trials, respectively. However, only 2% (2 of 112) of trials reported off-protocol radiation therapy utilization rates, although no data were reported on the use of ablative off-protocol radiation therapy. No trials evaluated or adjusted for the potential influence of off-protocol radiation therapy on study endpoints. Among the subset of open-label studies, trials permissive toward off-protocol radiation therapy were more likely to meet their primary endpoint (adjusted odds ratio, 4.50; 95% CI, 1.23-20.23; P = .04)., Conclusions: Although most trials allowed off-protocol radiation therapy during the receipt of the study systemic therapy, the influence of off-protocol radiation therapy, especially ablative radiation therapy, on study outcomes is underevaluated among phase 3 systemic therapy trials., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Disease progression in clinical trials is commonly defined by radiologic measures. However, clinical progression may be more meaningful to patients, may occur even when radiologic criteria for progression are not met, and often requires a change in therapy in clinical practice. The objective of this study was to determine the utilization of clinical progression criteria within progression-based trial endpoints among phase III trials testing systemic therapies for metastatic solid tumors. The primary manuscripts and protocols of phase III trials were reviewed for whether clinical events, such as refractory pain, tumor bleeding, or neurologic compromise, could constitute a progression event. Univariable logistic regression computed odds ratios (OR) and 95% CI for associations between trial-level covariates and clinical progression. A total of 216 trials enrolling 148,190 patients were included, with publication dates from 2006 through 2020. A major change in clinical status was included in the progression criteria of 13% of trials (n = 27), most commonly as a secondary endpoint (n = 22). Only 59% of trials (n = 16) reported distinct clinical progression outcomes that constituted the composite surrogate endpoint. Compared with other disease sites, genitourinary trials were more likely to include clinical progression definitions (16/33 [48%] vs. 11/183 [6%]; OR, 14.72; 95% CI, 5.99 to 37.84; p < .0001). While major tumor-related clinical events were seldom considered as disease progression events, increased attention to clinical progression may improve the meaningfulness and clinical applicability of surrogate endpoints for patients with metastatic solid tumors., (© 2024 UICC.)

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSIs) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood., Experimental Design: We applied targeted cell-free DNA sequencing to 126 mCRPC patients from three academic cancer centers, and separately performed genome-wide cell-free DNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome-positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 mCRPC patients, respectively, to develop and validate a stem-like signature, which we inferred from cell-free DNA., Results: Targeted cell-free DNA sequencing detected AR/enhancer alterations prior to first-line ARSIs which correlated with significantly worse PFS (p = 0.01; HR = 2.12) and OS (p = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (p < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cell-free DNA revealed enrichment for stemness-associated transcription factors in lethal mCRPC patients. The resulting stemness signature was then validated in a completely held-out cohort of 80 mCRPC patients profiled by tumor RNA sequencing., Conclusions: We analyzed a total of 220 mCRPC patients, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.

Secondary endpoints (SEP) provide crucial information in the interpretation of clinical trials, but their features are not yet well understood. Thus, we sought to empirically characterize the scope and publication rate of SEPs among late-phase oncology trials. We assessed SEPs for each randomized, published phase III oncology trial across all publications and ClinicalTrials.gov, performing logistic regressions to evaluate associations between trial characteristics and SEP publication rates. After screening, a total of 280 trials enrolling 244,576 patients and containing 2,562 SEPs met the inclusion criteria. Only 22% of trials (62/280) listed all SEPs consistently between ClinicalTrials.gov and the trial protocol. The absolute number of SEPs per trial increased over time, and trials sponsored by industry had a greater number of SEPs (median 9 vs. 5 SEPs per trial; P < 0.0001). In total, 69% of SEPs (1,770/2,562) were published. The publication rate significantly varied by SEP category [X2 (5, N = 2,562) = 245.86; P < 0.001]. SEPs that place the most burden on patients, such as patient-reported outcomes and translational correlatives, were published at 63% (246/393) and 44% (39/88), respectively. Trials with more SEPs were associated with lower overall SEP publication rates. Overall, our findings are that SEP publication rates in late-phase oncology trials are highly variable based on the type of SEP. To avoid undue burden on patients and promote transparency of findings, trialists should weigh the biological and clinical relevance of each SEP together with its feasibility at the time of trial design., Significance: In this investigation, we characterized the utilization and publication rates of SEPs among late-phase oncology trials. Our results draw attention to the proliferation of SEPs in recent years. Although overall publication rates were high, underpublication was detected among endpoints that may increase patient burden (such as translational correlatives and patient-reported outcomes)., (©2024 The Authors; Published by the American Association for Cancer Research.)

Most oncology trials define superiority of an experimental therapy compared to a control therapy according to frequentist significance thresholds, which are widely misinterpreted. Posterior probability distributions computed by Bayesian inference may be more intuitive measures of uncertainty, particularly for measures of clinical benefit such as the minimum clinically important difference (MCID). Here, we manually reconstructed 194,129 individual patient-level outcomes across 230 phase III, superiority-design, oncology trials. Posteriors were calculated by Markov Chain Monte Carlo sampling using standard priors. All trials interpreted as positive had probabilities > 90% for marginal benefits (HR < 1). However, 38% of positive trials had ≤ 90% probabilities of achieving the MCID (HR < 0.8), even under an enthusiastic prior. A subgroup analysis of 82 trials that led to regulatory approval showed 30% had ≤ 90% probability for meeting the MCID under an enthusiastic prior. Conversely, 24% of negative trials had > 90% probability of achieving marginal benefits, even under a skeptical prior, including 12 trials with a primary endpoint of overall survival. Lastly, a phase III oncology-specific prior from a previous work, which uses published summary statistics rather than reconstructed data to compute posteriors, validated the individual patient-level data findings. Taken together, these results suggest that Bayesian models add considerable unique interpretative value to phase III oncology trials and provide a robust solution for overcoming the discrepancies between refuting the null hypothesis and obtaining a MCID.

Missing visual elements (MVE) in Kaplan-Meier (KM) curves can misrepresent data, preclude curve reconstruction, and hamper transparency. This study evaluated KM plots of phase III oncology trials. MVE were defined as an incomplete y-axis range or missing number at risk table in a KM curve. Surrogate endpoint KM curves were additionally evaluated for complete interpretability, defined by (1) reporting the number of censored patients and (2) correspondence of the disease assessment interval with the number at risk interval. Among 641 trials enrolling 518 235 patients, 116 trials (18%) had MVE in KM curves. Industry sponsorship, larger trials, and more recently published trials were correlated with lower odds of MVE. Only 3% of trials (15 of 574) published surrogate endpoint KM plots with complete interpretability. Improvements in the quality of KM curves of phase III oncology trials, particularly for surrogate endpoints, are needed for greater interpretability, reproducibility, and transparency in oncology research., (© The Author(s) 2024. Published by Oxford University Press.)

Importance: Improving the efficiency of interim assessments in phase III trials should reduce trial costs, hasten the approval of efficacious therapies, and mitigate patient exposure to disadvantageous randomizations., Objective: We hypothesized that in silico Bayesian early stopping rules improve the efficiency of phase III trials compared with the original frequentist analysis without compromising overall interpretation., Design: Cross-sectional analysis., Setting: 230 randomized phase III oncology trials enrolling 184,752 participants., Participants: Individual patient-level data were manually reconstructed from primary endpoint Kaplan-Meier curves., Interventions: Trial accruals were simulated 100 times per trial and leveraged published patient outcomes such that only the accrual dynamics, and not the patient outcomes, were randomly varied., Main Outcomes and Measures: Early stopping was triggered per simulation if interim analysis demonstrated ≥ 85% probability of minimum clinically important difference/3 for efficacy or futility. Trial-level early closure was defined by stopping frequencies ≥ 0.75., Results: A total of 12,451 simulations (54%) met early stopping criteria. Trial-level early stopping frequency was highly predictive of the published outcome (OR, 7.24; posterior probability of association, >99.99%; AUC, 0.91; P < 0.0001). Trial-level early closure was recommended for 82 trials (36%), including 62 trials (76%) which had performed frequentist interim analysis. Bayesian early stopping rules were 96% sensitive (95% CI, 91% to 98%) for detecting trials with a primary endpoint difference, and there was a high level of agreement in overall trial interpretation (Bayesian Cohen's κ, 0.95; 95% CrI, 0.92 to 0.99). However, Bayesian interim analysis was associated with >99.99% posterior probability of reducing patient enrollment requirements ( P < 0.0001), with an estimated cumulative enrollment reduction of 20,543 patients (11%; 89 patients averaged equally over all studied trials) and an estimated cumulative cost savings of 851 million USD (3.7 million USD averaged equally over all studied trials)., Conclusions and Relevance: Bayesian interim analyses may improve randomized trial efficiency by reducing enrollment requirements without compromising trial interpretation. Increased utilization of Bayesian interim analysis has the potential to reduce costs of late-phase trials, reduce patient exposures to ineffective therapies, and accelerate approvals of effective therapies., Key Points: Question: What are the effects of Bayesian early stopping rules on the efficiency of phase III randomized oncology trials? Findings: Individual-patient level outcomes were reconstructed for 184,752 patients from 230 trials. Compared with the original interim analysis strategy, in silico Bayesian interim analysis reduced patient enrollment requirements and preserved the original trial interpretation. Meaning: Bayesian interim analysis may improve the efficiency of conducting randomized trials, leading to reduced costs, reduced exposure of patients to disadvantageous treatments, and accelerated approval of efficacious therapies.

Differential censoring, which refers to censoring imbalance between treatment arms, may bias the interpretation of survival outcomes in clinical trials. In 146 phase III oncology trials with statistically significant time-to-event surrogate primary endpoints, we evaluated the association between differential censoring in the surrogate primary endpoints, control arm adequacy, and the subsequent statistical significance of overall survival results. Twenty-four (16%) trials exhibited differential censoring that favored the control arm, whereas 15 (10%) exhibited differential censoring that favored the experimental arm. Positive overall survival was more common in control arm differential censoring trials (63%) than in trials without differential censoring (37%) or with experimental arm differential censoring (47%; odds ratio = 2.64, 95% confidence interval = 1.10 to 7.20; P = .04). Control arm differential censoring trials more frequently used suboptimal control arms at 46% compared with 20% without differential censoring and 13% with experimental arm differential censoring (odds ratio = 3.60, 95% confidence interval = 1.29 to 10.0; P = .007). The presence of control arm differential censoring in trials with surrogate primary endpoints, especially in those with overall survival conversion, may indicate an inadequate control arm and should be examined and explained., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Addition of adjuvant capecitabine improves overall survival for patients with breast cancer lacking pathologic complete response to standard-of-care neoadjuvant chemotherapy. Combining radiosensitizing capecitabine concurrent with radiation may further improve disease control, although the feasibility and tolerability of chemoradiation in this setting is unknown. This study aimed to determine the feasibility of this combination. Secondary objectives included the effect of chemoradiation on physician-reported toxicity, patient-reported skin dermatitis, and patient-reported quality of life compared with patients with breast cancer treated with adjuvant radiation., Methods and Materials: Twenty patients with residual disease following standard neoadjuvant chemotherapy were enrolled in a prospective single-arm trial and treated with adjuvant capecitabine-based chemoradiation. Feasibility was defined as ≥75% of patients completing chemoradiation as planned. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 5.0 and the patient-reported radiation-induced skin reaction scale. Quality of life was measured using the RAND Short-Form 36-Item Health Survey., Results: Eighteen patients (90%) completed chemoradiation without interruption or dose reduction. The incidence of grade ≥3 radiation dermatitis was 5% (1 of 20 patients). Patient-reported radiation dermatitis did not show a clinically meaningful difference following chemoradiation (mean increase, 55 points) compared with published reports of patients with breast cancer treated with adjuvant radiation alone (mean increase, 47 points). On the other hand, patient-reported quality of life demonstrated a clinically meaningful decline at the end of chemoradiation (mean, 46; SD, 7) compared with the reference population of patients treated with adjuvant radiation alone (mean, 50; SD, 6)., Conclusions: Adjuvant chemoradiation with capecitabine is feasible and tolerable in patients with breast cancer. Although current studies using adjuvant capecitabine for residual disease following neoadjuvant chemotherapy have specified sequential treatment of capecitabine and radiation, these results support the conduct of randomized trials in this setting to investigate the efficacy of concurrent radiation with capecitabine and provide patient-reported toxicity estimates for trial design., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This study was designed to test whether the single appended phosphonate group in GdDOTA-1AmP is sufficient for catalyzing the exchange of proton from the single inner-sphere water-exchanging molecule. Unlike the other phosphonate derivatives in this series, GdDOTA-1AmP showed a surprisingly smooth increase in r 1 relaxivity from 3.0 to 6.3 mM -1 s -1 at 20 MHz as the pH was lowered from 9 to 2.5. In comparison to the bis-, tris-, and tetrakis-phosphonate analogues, which all show a biphasic dependence of r 1 with changes in pH, the unique r 1 versus pH characteristics of GdDOTA-1AmP are shown to closely parallel deprotonation of the single appended phosphonate group. Although the tissue biodistribution and clearance rates of GdDOTA-1AmP are more favorable than the other more highly charged phosphonate derivatives, the pH dependency of r 1 is substantially reduced at magnetic fields typically used for small animal imaging (7 and 9.4T), so the attractiveness of this new molecule for quantitative imaging of tissue pH is diminished. However, this study provides some new insights into the feasibility of designing pH-responsive MRI contrast agents based upon fundamental acid-base prototropic mechanisms.

Importance: Subgroup analyses are often performed in oncology to investigate differential treatment effects and may even constitute the basis for regulatory approvals. Current understanding of the features, results, and quality of subgroup analyses is limited., Objective: To evaluate forest plot interpretability and credibility of differential treatment effect claims among oncology trials., Design, Setting, and Participants: This cross-sectional study included randomized phase 3 clinical oncology trials published prior to 2021. Trials were screened from ClinicalTrials.gov., Main Outcomes and Measures: Missing visual elements in forest plots were defined as a missing point estimate or use of a linear x-axis scale for hazard and odds ratios. Multiplicity of testing control was recorded. Differential treatment effect claims were rated using the Instrument for Assessing the Credibility of Effect Modification Analyses. Linear and logistic regressions evaluated associations with outcomes., Results: Among 785 trials, 379 studies (48%) enrolling 331 653 patients reported a subgroup analysis. The forest plots of 43% of trials (156 of 363) were missing visual elements impeding interpretability. While 4148 subgroup effects were evaluated, only 1 trial (0.3%) controlled for multiple testing. On average, trials that did not meet the primary end point conducted 2 more subgroup effect tests compared with trials meeting the primary end point (95% CI, 0.59-3.43 tests; P = .006). A total of 101 differential treatment effects were claimed across 15% of trials (55 of 379). Interaction testing was missing in 53% of trials (29 of 55) claiming differential treatment effects. Trials not meeting the primary end point were associated with greater odds of no interaction testing (odds ratio, 4.47; 95% CI, 1.42-15.55, P = .01). The credibility of differential treatment effect claims was rated as low or very low in 93% of cases (94 of 101)., Conclusions and Relevance: In this cross-sectional study of phase 3 oncology trials, nearly half of trials presented a subgroup analysis in their primary publication. However, forest plots of these subgroup analyses largely lacked essential features for interpretation, and most differential treatment effect claims were not supported. Oncology subgroup analyses should be interpreted with caution, and improvements to the quality of subgroup analyses are needed.

Previous studies have shown that the zinc-responsive MRI probe, GdL1, can distinguish healthy versus malignant prostate tissues based upon differences in zinc content and secretion. In this study, mice were fed chow containing low, normal, or high zinc content for 3 weeks before imaging glucose stimulated zinc secretion (GSZS) by MRI. The distribution of zinc in prostate tissue in these three groups was imaged by synchrotron radiation X-ray fluorescence (SR-XRF). A zinc deficiency caused systemic and organ-level dysregulation, weight loss, and altered zinc bioavailability. Zinc efflux from the prostate increased in parallel to dietary zinc in healthy mice but not in TRAMP mice, consistent with a lowered capacity to store dietary zinc in malignant cells. This differential zinc efflux suggests that a dietary supplement of zinc prior to a GSZS study may enhance image contrast between healthy and malignant prostate tissue, thereby improving the accuracy of prostate cancer detection in man., Competing Interests: Competing interestsPATENTS: A) 10,207,013 B2*2/2019 Inventors: Christian Preihs, Jing Yi, V.C.J., Yunkou Wu, Khaled Nasr, A.D.S., S.C. B) 11,097,017 B2*8/2021 Inventors: Christian Preihs, Jing Yi, V.C.J., Yunkou Wu, Khaled Nasr, A.D.S., S.C. C) 11,713,305 B2*8/2023 Inventors: A.F.M., S.C., V.C.J., A.D.S. These patents pertain to the Gd-based zinc probe used in this manuscript. All three have been licensed by VitalQuan, LLC. INDIVIDUAL CONFLICT OF INTEREST: A.D.S. is a scientific C-Founder of VitalQuan, LLC and holds founders stock. The remaining authors declare no competing interests., (© The Author(s) 2024.)

Background: Although most patients with cancer are treated with local therapy (LT), the proportion of late-phase clinical trials investigating local therapeutic interventions is unknown. The purpose of this study was to determine the proportion, characteristics, and trends of phase 3 cancer clinical trials assessing the therapeutic value of LT over time., Methods: This was a cross-sectional analysis of interventional randomized controlled trials in oncology published from 2002 through 2020 and registered on ClinicalTrials.gov. Trends and characteristics of LT trials were compared to all other trials., Results: Of 1877 trials screened, 794 trials enrolling 584,347 patients met inclusion criteria. A total of 27 trials (3%) included a primary randomization assessing LT compared with 767 trials (97%) investigating systemic therapy or supportive care. Annual increase in the number of LT trials (slope [m] = 0.28; 95% confidence interval [CI], 0.15-0.39; p < .001) was outpaced by the increase of trials testing systemic therapy or supportive care (m = 7.57; 95% CI, 6.03-9.11; p < .001). LT trials were more often sponsored by cooperative groups (22 of 27 [81%] vs. 211 of 767 [28%]; p < .001) and less often sponsored by industry (5 of 27 [19%] vs. 609 of 767 [79%]; p < .001). LT trials were more likely to use overall survival as primary end point compared to other trials (13 of 27 [48%] vs. 199 of 767 [26%]; p = .01)., Conclusions: In contemporary late-phase oncology research, LT trials are increasingly under-represented, under-funded, and evaluate more challenging end points compared to other modalities. These findings strongly argue for greater resource allocation and funding mechanisms for LT clinical trials., Plain Language Summary: Most people who have cancer receive treatments directed at the site of their cancer, such as surgery or radiation. We do not know, however, how many trials test surgery or radiation compared to drug treatments (that go all over the body). We reviewed trials testing the most researched strategies (phase 3) completed between 2002 and 2020. Only 27 trials tested local treatments like surgery or radiation compared to 767 trials testing other treatments. Our study has important implications for funding research and understanding cancer research priorities., (© 2023 American Cancer Society.)

Background: The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials., Methods: From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy., Results: A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating the typical 5% type I error assertion probability. Application of trial-level multiplicity corrections reduced the rate of significant findings to 0.3% (six of 2345 tests). Factors associated with lower odds of the Table 1 Fallacy included industry sponsorship (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.18-0.47; multiplicity-corrected P < 0.0001), larger trial size (≥795 versus <280 patients; aOR 0.32, 95% CI 0.19-0.53; multiplicity-corrected P = 0.0008), and publication in a European versus American journal (aOR 0.06, 95% CI 0.03-0.13; multiplicity-corrected P < 0.0001)., Conclusions: This study highlights the persistence of the Table 1 Fallacy in contemporary oncology randomised controlled trials, with one of every four trials testing for baseline differences after randomisation. Significance testing is a suboptimal method for identifying unsound randomisation procedures and may encourage misleading inferences. Journal-level enforcement is a possible strategy to help mitigate this fallacy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Msaouel reported honoraria for scientific advisory board membership for Mirati Therapeutics, Bristol-Myers Squibb, and Exelixis; consulting fees from Axiom Healthcare; non-branded educational programmes supported by Exelixis and Pfizer; leadership or fiduciary roles as a Medical Steering Committee Member for the Kidney Cancer Association and a Kidney Cancer Scientific Advisory Board Member for KCCure; and research funding from Takeda, Bristol-Myers Squibb, Mirati Therapeutics, and Gateway for Cancer Research (all unrelated to this manuscript’s content). Dr. McCaw reported employment at Insitro (unrelated to this manuscript’s content). Dr. Tang reported grants from the Cancer Prevention & Research Institute of Texas (CPRIT) and the Andrew Sabin Family Foundation and being an Andrew Sabin Scholar and royalties from Wolters Kluwer and consulting fees and honoraria from Bayer, Diffusion Pharmaceuticals, and The Osler Institute Lecture Series (unrelated to this manuscript’s content). Dr. Taniguchi reports consulting fees from Phebry and Xerient and holds a patent related to radioprotection of the upper gastrointestinal tract. Dr. Rödel reported receiving research funding from German Cancer Aid (unrelated to this manuscript’s content). Dr. Fuller reported unrelated funding and salary support from: NIH NIBIB Research Education Programmes for Residents and Clinical Fellows Grant (R25EB025787-01); NIDCR Academic Industrial Partnership Grant (R01DE028290); NCI Parent Research Project Grant (R01CA258827) an NIH/NCI Cancer Centre Support Grant (CCSG); and an NSF Division of Civil, Mechanical, and Manufacturing Innovation (CMMI) grant (NSF 1933369). Dr. Fuller reported direct industry grant support, honoraria, and travel funding from Elekta AB unrelated to this project and reported direct infrastructure support from the multidisciplinary Radiation Oncology/Cancer Imaging Programme (P30CA016672-44) of the MD Anderson Cancer Centre Support (Core) Grant (P30CA016672) and the MD Anderson Programme in Image-guided Cancer Therapy. Dr. Sun reported personal fees from Boehringer Ingelheim (unrelated to this manuscript’s content). Dr. Meirson reported receiving personal fees from Purple Biotech (unrelated to this manuscript’s content). No other authors reported any conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Optimal management of cancer patients relies heavily on late-phase oncology randomized controlled trials. A comprehensive understanding of the key considerations in designing and interpreting late-phase trials is crucial for improving subsequent trial design, execution, and clinical decision-making. In this review, we explore important aspects of late-phase oncology trial design. We begin by examining the selection of primary endpoints, including the advantages and disadvantages of using surrogate endpoints. We address the challenges involved in assessing tumor progression and discuss strategies to mitigate bias. We define informative censoring bias and its impact on trial results, including illustrative examples of scenarios that may lead to informative censoring. We highlight the traditional roles of the log-rank test and hazard ratio in survival analyses, along with their limitations in the presence of nonproportional hazards as well as an introduction to alternative survival estimands, such as restricted mean survival time or MaxCombo. We emphasize the distinctions between the design and interpretation of superiority and noninferiority trials, and compare Bayesian and frequentist statistical approaches. Finally, we discuss appropriate utilization of phase II and phase III trial results in shaping clinical management recommendations and evaluate the inherent risks and benefits associated with relying on phase II data for treatment decisions., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Recently, we reported that exposure of prostate cells in vitro or the in vivo prostate to high glucose results in release of Zn 2+ ions, a process now referred to as glucose-stimulated zinc secretion (GSZS). To our knowledge, the metabolic event(s) that trigger GSZS remain largely unknown. Here, we explore several signaling pathways both in vitro using a prostate epithelial cell line and in vivo from the rat prostate., Methods: PNT1A cells grown to confluence were washed and tagged with ZIMIR to monitor zinc secretion by optical methods. The expression levels of GLUT1, GLUT4, and Akt in cells cultured in either zinc-rich or zinc-poor media and after exposure to high versus low glucose were determined. Zinc secretion from the rat prostate in vivo as detected by MRI was compared in control animals after injection of glucose, deoxyglucose, or pyruvate to initiate zinc secretion and in animals pre-treated with WZB-117 (a GLUT1 inhibitor) or S961 (a peripheral insulin receptor inhibitor)., Results: PNT1A cells exposed to high levels of glucose secrete zinc whereas cells exposed to an equivalent amount of deoxyglucose or pyruvate do not. Expression of Akt was dramatically altered by zinc supplementation of the culture media but not after exposure to glucose while GLUT1 and GLUT4 levels were less affected. Rats pre-treated with WZB-117 prior to imaging showed a reduction in GSZS from the prostate compared to controls whereas rats pre-treated with S961 showed no difference. Interestingly, in comparison to PNT1A cells, pyruvate and deoxyglucose also stimulate zinc secretion in vivo likely through indirect mechanisms., Conclusions: GSZS requires metabolism of glucose both in vitro (PNT1A cells) and in vivo (rat prostate). Pyruvate also stimulates zinc secretion in vivo but likely via an indirect pathway involving rapid production of glucose via gluconeogenesis. These combined results support the conclusion that glycolytic flux is required to trigger GSZS in vivo., (© 2023. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Purpose: The management of chordoma or chondrosarcoma involving the spine is often challenging due to adjacent critical structures and tumor radioresistance. Spine stereotactic radiosurgery (SSRS) has radiobiologic advantages compared with conventional radiotherapy, though there is limited evidence on SSRS in this population. We sought to characterize the long-term local control (LC) of patients treated with SSRS., Methods: We retrospectively reviewed patients with chordoma or chondrosarcoma treated with dose-escalated SSRS, defined as 24 Gy in 1 fraction to the gross tumor volume. Overall survival (OS) was calculated by Kaplan-Meier functions. Competing risk analysis using the cause-specific hazard function estimated LC time., Results: Fifteen patients, including 12 with chordoma and 3 with chondrosarcoma, with 22 lesions were included. SSRS intent was definitive, single-modality in 95% of cases (N = 21) and post-operative in 1 case (5%). After a median censored follow-up time of 5 years (IQR 4 to 8 years), median LC time was not reached (IQR 8 years to not reached), with LC rates of 100%, 100%, and 90% at 1 year, 2 years, and 5 years. The median OS was 8 years (IQR 3 years to not reached). Late grade 3 toxicity occurred after 23% of treatments (N = 5, fracture), all of which were managed successfully with stabilization., Conclusion: Definitive dose-escalated SSRS to 24 Gy in 1 fraction appears to be a safe and effective treatment for achieving durable local control in chordoma or chondrosarcoma involving the spine, and may hold particular importance as a low-morbidity alternative to surgery in selected cases., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The concept of using paramagnetic metal ion complexes as chemical exchange saturation transfer agents (paraCEST) for molecular imaging of various biological processes first appeared in the literature about 20 years ago. The first paraCEST agent was based on a highly shifted, inner-sphere, slowly exchanging water molecule that could be activated at a frequency far away from bulk water, a substantial advantage for selective activation of the agent alone. Many other paraCEST agent designs followed that were based on activation of exchanging -NH or -OH proton on the chelate itself. Both types of paraCEST designs are attractive for molecular imaging because the rates of water molecule or ligand proton exchange can be designed to be sensitive to a biological or physiological property such as pH, enzyme activity, or redox. Hence, the intensity or frequency of the resulting CEST signal provides a direct readout of that property. Many molecular designs have appeared in the literature over the past 20 years, mostly reported as proof-of-concept designs but, unfortunately, only a few reports have explored the limitations of paraCEST agents for imaging a biological process in vivo. As a community, we now know that the sensitivity of paraCEST agents is lower than one might anticipate based upon simple chemical exchange principles and, in general, it appears the sensitivity of paraCEST agents is even lower in vivo than in vitro. In this short review, we address some of the factors that contribute to the limited sensitivity of paraCEST agents in vivo, offer some thoughts on approaches that could lead to dramatically improved paraCEST sensitivity, and challenge the scientific community to perform more in vivo experiments designed to test these ideas., (© 2022 John Wiley & Sons, Ltd.)

Importance: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial., Objective: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone., Design, Setting, Participants: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022., Interventions: Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression., Main Outcomes and Measures: The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing., Results: The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm., Conclusions and Relevance: In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals., Trial Registration: ClinicalTrials.gov Identifier: NCT03599765.

Advanced imaging technologies, large-scale metabolomics, and the measurement of gene transcripts or enzyme expression all enable investigations of intermediary metabolism in human patients. Complementary information about fluxes in individual metabolic pathways may be obtained by ex vivo 13 C NMR of blood or tissue biopsies. Simple molecules such as 13 C-labeled glucose are readily administered to patients prior to surgical biopsies, and 13 C-labeled glycerol is easily administered orally to outpatients. Here, we review recent progress in practical applications of 13 C NMR to study cancer biology, the response to oxidative stress, gluconeogenesis, triglyceride synthesis in patients, as well as new insights into compartmentation of metabolism in the cytosol. The technical aspects of obtaining the sample, preparing material for analysis, and acquiring the spectra are relatively simple. This approach enables convenient, valuable, and quantitative insights into intermediary metabolism in patients., (© 2022 John Wiley & Sons, Ltd.)

The role of Zn 2+ ions in proper storage of insulin in β-cell granules is well-established so when insulin is secreted from β-cells stimulated by an increase in plasma glucose, free Zn 2+ ions are also released. This local increase in Zn 2+ can be detected in the pancreas of rodents in real time by the use of a zinc-responsive MR contrast agent. This method offers the opportunity to monitor β-cell function longitudinally in live rodents. The methods used in our lab are fully described in this short report and some MR images of a rat pancreas showing clearly enhanced hot spots in the tail are presented., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The benefit of local consolidative therapy (LCT) for oligometastasis across histologies remains uncertain. EXTernal beam radiation to Eliminate Nominal metastatic Disease (EXTEND; NCT03599765) is a randomized phase 2 basket trial evaluating the effectiveness of LCT for oligometastatic solid tumors. We report here the prospective results of the single-arm "lead-in" phase intended to identify histologies most likely to accrue to histology-specific endpoints in the randomized phase., Methods and Materials: Eligible histologies included colorectal, sarcoma, lung, head and neck, ovarian, renal, melanoma, pancreatic, prostate, cervix/uterine, breast, and hepatobiliary. Patients received LCT to all sites of active metastatic disease and primary/regional disease (as applicable) plus standard-of-care systemic therapy or observation. The primary endpoint in EXTEND was progression-free survival (PFS), and the primary endpoint of the lead-phase was histology-specific accrual feasibility. Adverse events were graded by Common Terminology Criteria for Adverse Events version 4.0., Results: From August 2018 through January 2019, 50 patients were enrolled and 49 received definitive LCT. Prostate, breast, and kidney were the highest enrolling histologies and identified for independent accrual in the randomization phase. Most patients (73%) had 1 or 2 metastases, most often in lung or bone (79%), and received ablative radiation (62%). Median follow-up for censored patients was 38 months (range, 16-42 months). Median PFS was 13 months (95% confidence interval, 9-24), 3-year overall survival rate was 73% (95% confidence interval, 57%-83%), and local control rate was 98% (93 of 95 tumors). Two patients (4%) had Common Terminology Criteria for Adverse Events grade 3 toxic effects related to LCT; no patient had grade 4 or 5 toxic effects., Conclusions: The prospective lead-in phase of the EXTEND basket trial demonstrated feasible accrual, encouraging PFS, and low rates of severe toxic effects at mature follow-up. The randomized phase is ongoing with histology-based baskets that will provide histology-specific evidence for LCT in oligometastatic disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Contrast agents (CA) are administered in magnetic resonance imaging (MRI) clinical exams to measure tissue perfusion, enhance image contrast between adjacent tissues, or provide additional biochemical information in molecular MRI. The efficacy of a CA is determined by the tissue distribution of the agent and its concentration in the extracellular space of all tissues., Methods: In this work, micro-synchrotron radiation x-ray fluorescence (µ-SRXRF) was used to examine and characterize a gadolinium-based zinc-sensitive agent (GdL 2 ) currently under development for detection of prostate cancer (PCa) by MRI. Prostate tissue samples were collected from control mice and mice with known PCa after an MRI exam that included injection of GdL 2 . The samples were raster scanned to investigate trends in Zn, Gd, Cu, Fe, S, P, and Ca., Results: Significant Zn and Gd co-localization was observed in both healthy and malignant tissues. In addition, a marked decrease in Zn was found in the lateral lobe of the prostate obtained from mice with PCa., Conclusion: We demonstrate here that µ-SRXRF is a useful tool for monitoring the distribution of several elements including Zn and Gd in animal models of cancer. The optimized procedures for tissue preparation, processing, data collection, and analysis are described., Competing Interests: Conflict of interest The authors state there is no conflict of interest., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Purpose: Effective treatment options for refractory depression are needed. Recent advancements permit both precise ablative radiation and functional neurologic connectome analysis using standard magnetic resonance imaging. We combined these innovations to perform stereotactic radiosurgical capsulotomy for the treatment of medically refractory major depressive disorder and study connectome response using a novel tractography-based approach., Methods and Materials: Patients with medically refractory depression were enrolled on a prospective pilot single-arm observational trial from 2020 to 2021 at a single academic tertiary referral center. Bilateral ablation of the anterior limb of the internal capsule was accomplished by mask-based linear accelerator stereotactic radiosurgery. Beck's Depression Inventory measured efficacy. Montreal Cognitive Assessment evaluated cognition., Results: Three patients were enrolled. Depression burden was improved by 88% at 12-month follow-up and by 55% at 18-month follow-up for patient 1 and 2, respectively. Patient 1 discontinued ketamine therapy, and patient 2 discontinued electroconvulsive therapy. Patient 3 reported global improvement in symptoms and function at 3 months. All 3 patients had reduction or resolution of suicidal ideation. No patient experienced cognitive decline or neurologic toxicity, and Montreal Cognitive Assessment score, as well as subjective patient-reported evaluations of concentration and attention, were superior after treatment. Tractography confirmed intended disruption of the cortico-striatal-thalamo-cortical loop with structural reorganization in the connectome. Connectome change was consistent between patients. Observed increases in caudate and putamen connectivity and decreases in thalamic connectivity may explain improved concentration, attention, and depression. The diversity and magnitude of connectome change may correlate with degree of clinical response., Conclusions: In 3 patients with refractory depression, radiosurgical capsulotomy significantly reduced the burden of depression. Functional connectome reorganization offers neurobiological evidence to support further investigations of the role of radiosurgery in depression., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Objective: To evaluate the predictors of remnant tumor regrowth and need for salvage therapy after less than gross total resection (GTR) of vestibular schwannoma (VS)., Study Design: Retrospective chart review., Setting: Tertiary neurotologic referral center., Patients: Patients who underwent VS resection between 2008 and 2019 either with GTR, near total resection (NTR), and subtotal resection (STR)., Interventions: Microsurgical resection, salvage radiosurgery., Main Outcome Measures: Regrowth free interval, salvage free interval, tumor doubling rate., Results: Three hundred eighty five cases (GTR = 236, NTR = 77, and STR = 71) from 2008 to 2019 were included. STR cohort had much larger and complex tumors with significant differences in tumor volume, ventral extension and brainstem compression (p  < 0.001). On single predictor analysis, tumor volume, ventral extension, brainstem compression as well as STR strategy was associated with significant increased risk of regrowth and need for salvage therapy. Multivariate analysis revealed STR strategy as significant predictor of regrowth (hazard ratio 3.79, p  < 0.0005). Absolute remnant volume and extent of resection (EOR) did not predict regrowth. A small proportion of cases (NTR = 4%, STR = 15%) eventually needed salvage radiosurgery with excellent ultimate local tumor control with no known recurrence to date., Conclusions: Conservative surgical strategy employing NTR or STR can be employed safely in large and complex VS. While there is increased risk of regrowth in the STR cohort, excellent local control can be achieved with appropriate use of salvage radiosurgery. No disceret radiologic or operative predictors of regrowth were identified., Competing Interests: Conflicts of Interest: A.R.: Consultant for Med-El, Advanced Bionics, Cochlear, Grace Medical, Stryker, Cook Medical; D.H.: Consultant for Med-El, Advanced Bionics, and Cochlear., (Copyright © 2022, Otology & Neurotology, Inc.)

Objectives: 1) To analyze outcomes of cholesteatoma resection utilizing postauricular microscopic and endoscopic ear surgery (EES) approaches.2) To analyze predictors of residual and recurrent cholesteatoma., Study Design: Retrospective cohort study., Setting: Tertiary referral center., Patients: Three hundred seventy-five adult and pediatric patients with cholesteatoma (2012-2017)., Interventions: Patients underwent surgical resection of cholesteatoma with EES (n = 122) and microscopic (n = 253) approach., Main Outcome Measures: Residual cholesteatoma, recurrent cholesteatoma, second-look procedures., Results: The endoscopic cohort included significantly more pediatric cases (p = 0.0008). There was no difference in laterality, gender distribution, congenital or acquired cholesteatoma, and revision cases between the cohorts. Out of 122 EES cases, 16 (13%) developed residual disease and 9 (7%) developed recurrent disease. Of 253 microscopic cases 16 (6%) developed residual disease while 11 (4%) developed recurrent disease. Second look procedures were more commonly used in EES cohort (50 vs 18%). Single predictor analysis revealed 12 predictors for residual disease and 5 for recurrent disease. Multivariable model identified pediatric case distribution and higher disease stage to be significant predictors for both residual (p = 0.04, 0.007) and recurrent disease (p = 0.02, 0.01). EES approach was associated with a weak significance for residual disease (p = 0.049) but not recurrent disease (p = 0.34)., Conclusions: EES approach for cholesteatoma resection seems to perform similarly to microscopic approach with no difference in rates of recurrent disease. However, it is associated with a higher rate of residual disease; this may be a reflection of a greater rate of second look procedures done in this group., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2022, Otology & Neurotology, Inc.)

Purpose: This study is to investigate time-resolved 13 C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1- 13 C]pyruvate in the human brain., Methods: Time-resolved 13 C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1- 13 C]pyruvate. 13 C MRS with low flip-angle excitations and a multichannel 13 C/ 1 H dual-frequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice-wise areas under the curve (AUCs) of 13 C-metabolites were measured and kinetic analysis was performed to estimate the production rates of lactate and HCO 3 - . Linear regression analysis between brain volumes and HP signals was performed. Region-focused pyruvate metabolism was estimated using coil-wise 13 C reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45-minutes interval., Results: [1- 13 C]Lactate relative to the total 13 C signal (tC) was 0.21-0.24 in all slices. [ 13 C] HCO 3 - /tC was 0.065-0.091. Apparent conversion rate constants from pyruvate to lactate and HCO 3 - were calculated as 0.014-0.018 s -1 and 0.0043-0.0056 s -1 , respectively. Pyruvate/tC and lactate/tC were in moderate linear relationships with fractional gray matter volume within each slice. White matter presented poor linear regression fit with HP signals, and moderate correlations of the fractional cerebrospinal fluid volume with pyruvate/tC and lactate/tC were measured. Measured HP signals were comparable between two consecutive exams with HP [1- 13 C]pyruvate., Conclusions: Dynamic MRS in combination with multichannel RF coils is an affordable and reliable alternative to imaging methods in investigating cerebral metabolism using HP [1- 13 C]pyruvate., (© 2021 International Society for Magnetic Resonance in Medicine.)