Early drug development in solid tumours: analysis of National Cancer Institute-sponsored phase 1 trials.

BACKGROUND: The low expectation of clinical benefit from phase 1 cancer therapeutics trials might negatively affect patient and physician participation, study reimbursement, and slow the progress of oncology research. Advances in cancer drug development, meanwhile, might have favourably improved treatment responses; however, little comprehensive data exist describing the response and toxicity associated with phase 1 trials across solid tumours. The aim of the study is to evaluate the trend of toxicity and response in phase 1 trials for solid tumours over time. METHODS: We analysed patient-level data from the Cancer Therapy Evaluation Program of the National Cancer Institute-sponsored investigator-initiated phase 1 trials for solid tumours, from Jan 1, 2000, to May 31, 2019. We assessed risks of treatment-related death (grade 5 toxicity ratings possibly, probably, or definitely attributable to treatment), all on-treatment deaths (deaths during protocol treatment regardless of attribution), grade 3-4 toxicity, and proportion of overall response (complete response and partial response) and complete response rate in the study periods of 2000-05, 2006-12, and 2013-2019, and evaluated their trends over time. We also analysed cancer type-specific and investigational agent-specific response, and analysed the trend of response in each cancer type over time. Univariate associations of overall response rates with patients' baseline characteristics (age, sex, performance status, BMI, albumin concentration, and haemoglobin concentration), enrolment period, investigational agents, and trial design were assessed using risk ratio based on the modified Poisson regression model. FINDINGS: We analysed 465 protocols that enrolled 13 847 patients using 261 agents. 144 (31%) trials used a monotherapy and 321 (69%) used combination therapies. The overall treatment-related death rate was 0·7% (95% CI 0·5-0·8) across all periods. Risks of treatment-related deaths did not change over time (p=0·52). All on-treatment death risk during the study period was 8·0% (95% CI 7·6-8·5). The most common grade 3-4 adverse events were haematological; grade 3-4 neutropenia occurred in 2336 (16·9%) of 13 847 patients, lymphopenia in 1230 (8·9%), anaemia in 894 (6·5%), and thrombocytopenia in 979 (7·1%). The overall response rate for all trials during the study period was 12·2% (95% CI 11·5-12·8; 1133 of 9325 patients) and complete response rate was 2·7% (2·4-3·0; 249 of 9325). Overall response increased from 9·6% (95% CI 8·7-10·6) in 2000-05 to 18·0% (15·7-20·5) in 2013-19, and complete response rates from 2·5% (2·0-3·0) to 4·3% (3·2-5·7). Overall response rates for combination therapy were substantially higher than for monotherapy (15·8% [15·0-16·8] vs 3·5% [2·8-4·2]). The overall response by class of agents differed across diseases. Anti-angiogenesis agents were associated with higher overall response rate for bladder, colon, kidney and ovarian cancer. DNA repair inhibitors were associated with higher overall response rate in ovarian and pancreatic cancer. The rates of overall response over time differed markedly by disease; there were notable improvements in bladder, breast, and kidney cancer and melanoma, but no change in the low response of pancreatic and colon cancer. INTERPRETATION: During the past 20 years, the response rate in phase 1 trials nearly doubled without an increase in the treatment-related death rate. However, there is significant heterogeneity in overall response by various factors such as cancer type, investigational agent, and trial design. Therefore, informed decision making is crucial for patients before participating in phase 1 trials. This study provides updated encouraging outcomes of modern phase 1 trials in solid tumours. FUNDING: National Cancer Institute.

Scalable Strategies to Increase Efficiency and Augment Public Health Activities During Epidemic Peaks.

OBJECTIVE: Scalable strategies to reduce the time burden and increase contact tracing efficiency are crucial during early waves and peaks of infectious transmission. DESIGN: We enrolled a cohort of SARS-CoV-2-positive seed cases into a peer recruitment study testing social network methodology and a novel electronic platform to increase contact tracing efficiency. SETTING: Index cases were recruited from an academic medical center and requested to recruit their local social contacts for enrollment and SARS-CoV-2 testing. PARTICIPANTS: A total of 509 adult participants enrolled over 19 months (384 seed cases and 125 social peers). INTERVENTION: Participants completed a survey and were then eligible to recruit their social contacts with unique "coupons" for enrollment. Peer participants were eligible for SARS-CoV-2 and respiratory pathogen screening. MAIN OUTCOME MEASURES: The main outcome measures were the percentage of tests administered through the study that identified new SARS-CoV-2 cases, the feasibility of deploying the platform and the peer recruitment strategy, the perceived acceptability of the platform and the peer recruitment strategy, and the scalability of both during pandemic peaks. RESULTS: After development and deployment, few human resources were needed to maintain the platform and enroll participants, regardless of peaks. Platform acceptability was high. Percent positivity tracked with other testing programs in the area. CONCLUSIONS: An electronic platform may be a suitable tool to augment public health contact tracing activities by allowing participants to select an online platform for contact tracing rather than sitting for an interview.

A Multidimensional Bioinformatic Platform for the Study of Human Response to Surgery.

OBJECTIVE: To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing. BACKGROUND: Elective surgery is an opportunity to understand both the systemic and focal responses accompanying controlled and well-characterized injury to the human body. The overarching goal of this ongoing project is to define stereotypical responses to surgical injury, with the translational purpose of identifying targetable pathways involved in healing and resilience, and variations indicative of aberrant peri-operative outcomes. METHODS: Clinical data from the electronic medical record combined with large-scale biological data sets derived from blood, urine, fecal matter, and tissue samples are collected prospectively through the peri-operative period on patients undergoing 14 surgeries chosen to represent a range of injury locations and intensities. Specimens are subjected to genomic, transcriptomic, proteomic, and metabolomic assays to describe their genetic, metabolic, immunologic, and microbiome profiles, providing a multidimensional landscape of the human response to injury. RESULTS: The highly multiplexed data generated includes changes in over 28,000 mRNA transcripts, 100 plasma metabolites, 200 urine metabolites, and 400 proteins over the longitudinal course of surgery and recovery. In our initial pilot dataset, we demonstrate the feasibility of collecting high quality multi-omic data at pre- and postoperative time points and are already seeing evidence of physiologic perturbation between timepoints. CONCLUSIONS: This repository allows for longitudinal, state-of-the-art geno-mic, transcriptomic, proteomic, metabolomic, immunologic, and clinical data collection and provides a rich and stable infrastructure on which to fuel further biomedical discovery.

Integration of proteomics with CT-based qualitative and radiomic features in high-grade serous ovarian cancer patients: an exploratory analysis.

OBJECTIVES: To investigate the association between CT imaging traits and texture metrics with proteomic data in patients with high-grade serous ovarian cancer (HGSOC). METHODS: This retrospective, hypothesis-generating study included 20 patients with HGSOC prior to primary cytoreductive surgery. Two readers independently assessed the contrast-enhanced computed tomography (CT) images and extracted 33 imaging traits, with a third reader adjudicating in the event of a disagreement. In addition, all sites of suspected HGSOC were manually segmented texture features which were computed from each tumor site. Three texture features that represented intra- and inter-site tumor heterogeneity were used for analysis. An integrated analysis of transcriptomic and proteomic data identified proteins with conserved expression between primary tumor sites and metastasis. Correlations between protein abundance and various CT imaging traits and texture features were assessed using the Kendall tau rank correlation coefficient and the Mann-Whitney U test, whereas the area under the receiver operating characteristic curve (AUC) was reported as a metric of the strength and the direction of the association. P values < 0.05 were considered significant. RESULTS: Four proteins were associated with CT-based imaging traits, with the strongest correlation observed between the CRIP2 protein and disease in the mesentery (p < 0.001, AUC = 0.05). The abundance of three proteins was associated with texture features that represented intra-and inter-site tumor heterogeneity, with the strongest negative correlation between the CKB protein and cluster dissimilarity (p = 0.047, τ = 0.326). CONCLUSION: This study provides the first insights into the potential associations between standard-of-care CT imaging traits and texture measures of intra- and inter-site heterogeneity, and the abundance of several proteins. KEY POINTS: • CT-based texture features of intra- and inter-site tumor heterogeneity correlate with the abundance of several proteins in patients with HGSOC. • CT imaging traits correlate with protein abundance in patients with HGSOC.

Deep Learning-Based Risk Model for Best Management of Closed Groin Incisions After Vascular Surgery.

BACKGROUND: Reduced surgical site infection (SSI) rates have been reported with use of closed incision negative pressure therapy (ciNPT) in high-risk patients. METHODS: A deep learning-based, risk-based prediction model was developed from a large national database of 72,435 patients who received infrainguinal vascular surgeries involving upper thigh/groin incisions. Patient demographics, histories, laboratory values, and other variables were inputs to the multilayered, adaptive model. The model was then retrospectively applied to a prospectively tracked single hospital data set of 370 similar patients undergoing vascular surgery, with ciNPT or control dressings applied over the closed incision at the surgeon's discretion. Objective predictive risk scores were generated for each patient and used to categorize patients as "high" or "low" predicted risk for SSI. RESULTS: Actual institutional cohort SSI rates were 10/148 (6.8%) and 28/134 (20.9%) for high-risk ciNPT versus control, respectively (P < 0.001), and 3/31 (9.7%) and 5/57 (8.8%) for low-risk ciNPT versus control, respectively (P = 0.99). Application of the model to the institutional cohort suggested that 205/370 (55.4%) patients were matched with their appropriate intervention over closed surgical incision (high risk with ciNPT or low risk with control), and 165/370 (44.6%) were inappropriately matched. With the model applied to the cohort, the predicted SSI rate with perfect utilization would be 27/370 (7.3%), versus 12.4% actual rate, with estimated cost savings of $231-$458 per patient. CONCLUSIONS: Compared with a subjective practice strategy, an objective risk-based strategy using prediction software may be associated with superior results in optimizing SSI rates and costs after vascular surgery.

Radiogenomics of High-Grade Serous Ovarian Cancer: Multireader Multi-Institutional Study from the Cancer Genome Atlas Ovarian Cancer Imaging Research Group.

Purpose To evaluate interradiologist agreement on assessments of computed tomography (CT) imaging features of high-grade serous ovarian cancer (HGSOC), to assess their associations with time-to-disease progression (TTP) and HGSOC transcriptomic profiles (Classification of Ovarian Cancer [CLOVAR]), and to develop an imaging-based risk score system to predict TTP and CLOVAR profiles. Materials and Methods This study was a multireader, multi-institutional, institutional review board-approved, HIPAA-compliant retrospective analysis of 92 patients with HGSOC (median age, 61 years) with abdominopelvic CT before primary cytoreductive surgery available through the Cancer Imaging Archive. Eight radiologists from the Cancer Genome Atlas Ovarian Cancer Imaging Research Group developed and independently recorded the following CT features: characteristics of primary ovarian mass(es), presence of definable mesenteric implants and infiltration, presence of other implants, presence and distribution of peritoneal spread, presence and size of pleural effusions and ascites, lymphadenopathy, and distant metastases. Interobserver agreement for CT features was assessed, as were univariate and multivariate associations with TTP and CLOVAR mesenchymal profile (worst prognosis). Results Interobserver agreement for some features was strong (eg, α = .78 for pleural effusion and ascites) but was lower for others (eg, α = .08 for intraparenchymal splenic metastases). Presence of peritoneal disease in the right upper quadrant (P = .0003), supradiaphragmatic lymphadenopathy (P = .0004), more peritoneal disease sites (P = .0006), and nonvisualization of a discrete ovarian mass (P = .0037) were associated with shorter TTP. More peritoneal disease sites (P = .0025) and presence of pouch of Douglas implants (P = .0045) were associated with CLOVAR mesenchymal profile. Combinations of imaging features contained predictive signal for TTP (concordance index = 0.658; P = .0006) and CLOVAR profile (mean squared deviation = 1.776; P = .0043). Conclusion These results provide some evidence of the clinical and biologic validity of these image features. Interobserver agreement is strong for some features, but could be improved for others. © RSNA, 2017 Online supplemental material is available for this article.

Using computer-extracted image phenotypes from tumors on breast magnetic resonance imaging to predict breast cancer pathologic stage.

BACKGROUND: The objective of this study was to demonstrate that computer-extracted image phenotypes (CEIPs) of biopsy-proven breast cancer on magnetic resonance imaging (MRI) can accurately predict pathologic stage. METHODS: The authors used a data set of deidentified breast MRIs organized by the National Cancer Institute in The Cancer Imaging Archive. In total, 91 biopsy-proven breast cancers were analyzed from patients who had information available on pathologic stage (stage I, n = 22; stage II, n = 58; stage III, n = 11) and surgically verified lymph node status (negative lymph nodes, n = 46; ≥ 1 positive lymph node, n = 44; no lymph nodes examined, n = 1). Tumors were characterized according to 1) radiologist-measured size and 2) CEIP. Then, models were built that combined 2 CEIPs to predict tumor pathologic stage and lymph node involvement, and the models were evaluated in a leave-1-out, cross-validation analysis with the area under the receiver operating characteristic curve (AUC) as the value of interest. RESULTS: Tumor size was the most powerful predictor of pathologic stage, but CEIPs that captured biologic behavior also emerged as predictive (eg, stage I and II vs stage III demonstrated an AUC of 0.83). No size measure was successful in the prediction of positive lymph nodes, but adding a CEIP that described tumor "homogeneity" significantly improved discrimination (AUC = 0.62; P = .003) compared with chance. CONCLUSIONS: The current results indicate that MRI phenotypes have promise for predicting breast cancer pathologic stage and lymph node status. Cancer 2016;122:748-757. © 2015 American Cancer Society.

MR Imaging Radiomics Signatures for Predicting the Risk of Breast Cancer Recurrence as Given by Research Versions of MammaPrint, Oncotype DX, and PAM50 Gene Assays.

Purpose To investigate relationships between computer-extracted breast magnetic resonance (MR) imaging phenotypes with multigene assays of MammaPrint, Oncotype DX, and PAM50 to assess the role of radiomics in evaluating the risk of breast cancer recurrence. Materials and Methods Analysis was conducted on an institutional review board-approved retrospective data set of 84 deidentified, multi-institutional breast MR examinations from the National Cancer Institute Cancer Imaging Archive, along with clinical, histopathologic, and genomic data from The Cancer Genome Atlas. The data set of biopsy-proven invasive breast cancers included 74 (88%) ductal, eight (10%) lobular, and two (2%) mixed cancers. Of these, 73 (87%) were estrogen receptor positive, 67 (80%) were progesterone receptor positive, and 19 (23%) were human epidermal growth factor receptor 2 positive. For each case, computerized radiomics of the MR images yielded computer-extracted tumor phenotypes of size, shape, margin morphology, enhancement texture, and kinetic assessment. Regression and receiver operating characteristic analysis were conducted to assess the predictive ability of the MR radiomics features relative to the multigene assay classifications. Results Multiple linear regression analyses demonstrated significant associations (R2 = 0.25-0.32, r = 0.5-0.56, P < .0001) between radiomics signatures and multigene assay recurrence scores. Important radiomics features included tumor size and enhancement texture, which indicated tumor heterogeneity. Use of radiomics in the task of distinguishing between good and poor prognosis yielded area under the receiver operating characteristic curve values of 0.88 (standard error, 0.05), 0.76 (standard error, 0.06), 0.68 (standard error, 0.08), and 0.55 (standard error, 0.09) for MammaPrint, Oncotype DX, PAM50 risk of relapse based on subtype, and PAM50 risk of relapse based on subtype and proliferation, respectively, with all but the latter showing statistical difference from chance. Conclusion Quantitative breast MR imaging radiomics shows promise for image-based phenotyping in assessing the risk of breast cancer recurrence. © RSNA, 2016 Online supplemental material is available for this article.

Metrology Standards for Quantitative Imaging Biomarkers.

Although investigators in the imaging community have been active in developing and evaluating quantitative imaging biomarkers (QIBs), the development and implementation of QIBs have been hampered by the inconsistent or incorrect use of terminology or methods for technical performance and statistical concepts. Technical performance is an assessment of how a test performs in reference objects or subjects under controlled conditions. In this article, some of the relevant statistical concepts are reviewed, methods that can be used for evaluating and comparing QIBs are described, and some of the technical performance issues related to imaging biomarkers are discussed. More consistent and correct use of terminology and study design principles will improve clinical research, advance regulatory science, and foster better care for patients who undergo imaging studies.

Radiogenomics of clear cell renal cell carcinoma: preliminary findings of The Cancer Genome Atlas-Renal Cell Carcinoma (TCGA-RCC) Imaging Research Group.

PURPOSE: To investigate associations between imaging features and mutational status of clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: This multi-institutional, multi-reader study included 103 patients (77 men; median age 59 years, range 34-79) with ccRCC examined with CT in 81 patients, MRI in 19, and both CT and MRI in three; images were downloaded from The Cancer Imaging Archive, an NCI-funded project for genome-mapping and analyses. Imaging features [size (mm), margin (well-defined or ill-defined), composition (solid or cystic), necrosis (for solid tumors: 0%, 1%-33%, 34%-66% or >66%), growth pattern (endophytic, <50% exophytic, or ≥50% exophytic), and calcification (present, absent, or indeterminate)] were reviewed independently by three readers blinded to mutational data. The association of imaging features with mutational status (VHL, BAP1, PBRM1, SETD2, KDM5C, and MUC4) was assessed. RESULTS: Median tumor size was 49 mm (range 14-162 mm), 73 (71%) tumors had well-defined margins, 98 (95%) tumors were solid, 95 (92%) showed presence of necrosis, 46 (45%) had ≥50% exophytic component, and 18 (19.8%) had calcification. VHL (n = 52) and PBRM1 (n = 24) were the most common mutations. BAP1 mutation was associated with ill-defined margin and presence of calcification (p = 0.02 and 0.002, respectively, Pearson's χ (2) test); MUC4 mutation was associated with an exophytic growth pattern (p = 0.002, Mann-Whitney U test). CONCLUSIONS: BAP1 mutation was associated with ill-defined tumor margins and presence of calcification; MUC4 mutation was associated with exophytic growth. Given the known prognostic implications of BAP1 and MUC4 mutations, these results support using radiogenomics to aid in prognostication and management.

Two-stage adaptive cutoff design for building and validating a prognostic biomarker signature.

Cancer biomarkers are frequently evaluated using archived specimens collected from previously conducted therapeutic trials. Routine collection and banking of high quality specimens is an expensive and time-consuming process. Therefore, care should be taken to preserve these precious resources. Here, we propose a novel two-stage adaptive cutoff design that affords the possibility to stop the biomarker study early if an evaluation of the model performance is unsatisfactory at an early stage, thereby allowing one to preserve the remaining specimens for future research. In addition, our design integrates important elements necessary to meet statistical rigor and practical demands for developing and validating a prognostic biomarker signature, including maintaining strict separation between the datasets used to build and evaluate the model and producing a locked-down signature to facilitate future validation. We conduct simulation studies to evaluate the operating characteristics of the proposed design. We show that under the null hypothesis when the model performance is deemed undesirable, the proposed design maintains type I error at the nominal level, has high probabilities of terminating the study early, and results in substantial savings in specimens. Under the alternative hypothesis, power is generally high when the total sample size and the targeted degree of improvement in prediction accuracy are reasonably large. We illustrate the use of the procedure with a dataset in patients with diffuse large-B-cell lymphoma. The practical aspects of the proposed designs are discussed. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

New Approach to Equitable Intervention Planning to Improve Engagement and Outcomes in a Digital Health Program: Simulation Study.

BACKGROUND: Digital health programs provide individualized support to patients with chronic diseases and their effectiveness is measured by the extent to which patients achieve target individual clinical outcomes and the program's ability to sustain patient engagement. However, patient dropout and inequitable intervention delivery strategies, which may unintentionally penalize certain patient subgroups, represent challenges to maximizing effectiveness. Therefore, methodologies that optimize the balance between success factors (achievement of target clinical outcomes and sustained engagement) equitably would be desirable, particularly when there are resource constraints. OBJECTIVE: Our objectives were to propose a model for digital health program resource management that accounts jointly for the interaction between individual clinical outcomes and patient engagement, ensures equitable allocation as well as allows for capacity planning, and conducts extensive simulations using publicly available data on type 2 diabetes, a chronic disease. METHODS: We propose a restless multiarmed bandit (RMAB) model to plan interventions that jointly optimize long-term engagement and individual clinical outcomes (in this case measured as the achievement of target healthy glucose levels). To mitigate the tendency of RMAB to achieve good aggregate performance by exacerbating disparities between groups, we propose new equitable objectives for RMAB and apply bilevel optimization algorithms to solve them. We formulated a model for the joint evolution of patient engagement and individual clinical outcome trajectory to capture the key dynamics of interest in digital chronic disease management programs. RESULTS: In simulation exercises, our optimized intervention policies lead to up to 10% more patients reaching healthy glucose levels after 12 months, with a 10% reduction in dropout compared to standard-of-care baselines. Further, our new equitable policies reduce the mean absolute difference of engagement and health outcomes across 6 demographic groups by up to 85% compared to the state-of-the-art. CONCLUSIONS: Planning digital health interventions with individual clinical outcome objectives and long-term engagement dynamics as considerations can be both feasible and effective. We propose using an RMAB sequential decision-making framework, which may offer additional capabilities in capacity planning as well. The integration of an equitable RMAB algorithm further enhances the potential for reaching equitable solutions. This approach provides program designers with the flexibility to switch between different priorities and balance trade-offs across various objectives according to their preferences.

Resource requirements to accelerate clinical applications of next generation sequencing and radiomics: Workshop commentary and review.

The National Institutes of Health (NIH)/U.S. Food and Drug Administration (FDA) Joint Leadership Council Next-Generation Sequencing (NGS) and Radiomics Working Group (NGS&R WG) was formed by the NIH/FDA Joint Leadership Council to promote the development and validation of innovative NGS tests, radiomic tools, and associated data analysis and interpretation enhanced by artificial intelligence (AI) and machine-learning (ML) technologies. A two-day workshop was held on September 29-30, 2021 to convene members of the scientific community to discuss how to overcome the "ground truth" gap that has frequently been acknowledged as one of the limiting factors impeding high-quality research, development, validation, and regulatory science in these fields. This report provides a summary of the resource gaps identified by the WG and attendees, highlights existing resources and the ways they can potentially be leveraged to accelerate growth in these fields, and presents opportunities to support NGS and radiomic tool development and validation using technologies such as AI and ML.

A Phase 1 Trial of Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer After Brachytherapy.

PURPOSE: NCT03253744 is a phase 1 trial with the primary objective to identify the maximum tolerated dose (MTD) of salvage stereotactic body radiation therapy (SBRT) in patients with local prostate cancer recurrence after brachytherapy. Additional objectives included biochemical control and imaging response. METHODS AND MATERIALS: This trial was initially designed to test 3 therapeutic dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions. Intensity modulation was used to deliver the prescription dose to the magnetic resonance imaging and prostate-specific membrane antigen-based positron emission tomography imaging-defined gross tumor volume while simultaneously delivering 30 Gy to an elective volume defined by the prostate gland. This phase 1 trial followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until trial completion at 2 years post-SBRT using Common Terminology Criteria for Adverse Events version 5.0. Escalation was halted if 2 dose limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT or any grade ≥3 genitourinary (GU) or grade 4 gastrointestinal toxicity thereafter. RESULTS: Between August 2018 and January 2023, 9 patients underwent salvage SBRT and were observed for a median of 22 months (Q1-Q3, 20-43 months). No grade 3 to 5 adverse events related to study treatment were observed; thus, no dose limiting toxicities occurred during the observation period. Escalation was halted by amendment given excellent biochemical control in DL1 and DL2 in the setting of a high incidence of clinically significant late grade 2 GU toxicity. Therefore, the MTD was considered 42.5 Gy in 5 fractions (DL2). One- and 2-year biochemical progression-free survival were 100% and 86%, representing a single patient in the trial cohort with biochemical failure (prostate-specific antigen [PSA] nadir + 2.0) at 20 months posttreatment. CONCLUSIONS: The MTD of salvage SBRT for the treatment of intraprostatic radiorecurrence after brachytherapy was 42.5 Gy in 5 fractions producing an 86% 2-year biochemical progression-free survival rate, with 1 poststudy failure at 20 months. The most frequent clinically significant toxicity was late grade 2 GU toxicity.

MR imaging predictors of molecular profile and survival: multi-institutional study of the TCGA glioblastoma data set.

PURPOSE: To conduct a comprehensive analysis of radiologist-made assessments of glioblastoma (GBM) tumor size and composition by using a community-developed controlled terminology of magnetic resonance (MR) imaging visual features as they relate to genetic alterations, gene expression class, and patient survival. MATERIALS AND METHODS: Because all study patients had been previously deidentified by the Cancer Genome Atlas (TCGA), a publicly available data set that contains no linkage to patient identifiers and that is HIPAA compliant, no institutional review board approval was required. Presurgical MR images of 75 patients with GBM with genetic data in the TCGA portal were rated by three neuroradiologists for size, location, and tumor morphology by using a standardized feature set. Interrater agreements were analyzed by using the Krippendorff α statistic and intraclass correlation coefficient. Associations between survival, tumor size, and morphology were determined by using multivariate Cox regression models; associations between imaging features and genomics were studied by using the Fisher exact test. RESULTS: Interrater analysis showed significant agreement in terms of contrast material enhancement, nonenhancement, necrosis, edema, and size variables. Contrast-enhanced tumor volume and longest axis length of tumor were strongly associated with poor survival (respectively, hazard ratio: 8.84, P = .0253, and hazard ratio: 1.02, P = .00973), even after adjusting for Karnofsky performance score (P = .0208). Proneural class GBM had significantly lower levels of contrast enhancement (P = .02) than other subtypes, while mesenchymal GBM showed lower levels of nonenhanced tumor (P < .01). CONCLUSION: This analysis demonstrates a method for consistent image feature annotation capable of reproducibly characterizing brain tumors; this study shows that radiologists' estimations of macroscopic imaging features can be combined with genetic alterations and gene expression subtypes to provide deeper insight to the underlying biologic properties of GBM subsets.

Gene expression phenotypic models that predict the activity of oncogenic pathways.

High-density DNA microarrays measure expression of large numbers of genes in one assay. The ability to find underlying structure in complex gene expression data sets and rigorously test association of that structure with biological conditions is essential to developing multi-faceted views of the gene activity that defines cellular phenotype. We sought to connect features of gene expression data with biological hypotheses by integrating 'metagene' patterns from DNA microarray experiments in the characterization and prediction of oncogenic phenotypes. We applied these techniques to the analysis of regulatory pathways controlled by the genes HRAS (Harvey rat sarcoma viral oncogene homolog), MYC (myelocytomatosis viral oncogene homolog) and E2F1, E2F2 and E2F3 (encoding E2F transcription factors 1, 2 and 3, respectively). The phenotypic models accurately predict the activity of these pathways in the context of normal cell proliferation. Moreover, the metagene models trained with gene expression patterns evoked by ectopic production of Myc or Ras proteins in primary tissue culture cells properly predict the activity of in vivo tumor models that result from deregulation of the MYC or HRAS pathways. We conclude that these gene expression phenotypes have the potential to characterize the complex genetic alterations that typify the neoplastic state, whether in vitro or in vivo, in a way that truly reflects the complexity of the regulatory pathways that are affected.

Diversity, Equity, and Inclusion in Clinical Research: A Path Toward Precision Health for Everyone.

Healthcare disparities are a persistent societal problem. One of the contributing factors to this status quo is the lack of diversity and representativeness of research efforts, which result in nongeneralizable evidence that, in turn, provides suboptimal means to enable the best possible outcomes at the individual level. There are several strategies that research teams can adopt to improve the diversity, equity, and inclusion (DEI) of their efforts; these strategies span the totality of the research path, from initial design to the shepherding of clinical data through a potential regulatory process. These strategies include more intentionality and DEI-based goal-setting, more diverse research and leadership teams, better community engagement to set study goals and approaches, better tailored outreach interventions, decentralization of study procedures and incorporation of innovative technology for more flexible data collection, and self-surveillance to identify and prevent biases. Within their remit of overlooking research efforts, regulatory authorities, as stakeholders, also have the potential for a positive effect on the DEI of emerging clinical evidence. All these are implementable tools and mechanisms that can make study participation more approachable to diverse communities, and ultimately generate evidence that is more generalizable and a conduit for better outcomes. The research community has an imperative to make DEI principles key foundational aspects in study conduct in order to pursue better personalized medicine for diverse patient populations.

Meta-Analysis of the Test-Retest Repeatability of [18F]-Fluorodeoxyglucose Standardized Uptake Values: Implications for Assessment of Tumor Response.

PURPOSE: Currently, guidelines for PET with 18F-fluorodeoxyglucose (FDG-PET) interpretation for assessment of therapy response in oncology primarily involve visual evaluation of FDG-PET/CT scans. However, quantitative measurements of the metabolic activity in tumors may be even more useful in evaluating response to treatment. Guidelines based on such measurements, including the European Organization for Research and Treatment of Cancer Criteria and PET Response Criteria in Solid Tumors, have been proposed. However, more rigorous analysis of response criteria based on FDG-PET measurements is needed to adopt regular use in practice. EXPERIMENTAL DESIGN: Well-defined boundaries of repeatability and reproducibility of quantitative measurements to discriminate noise from true signal changes are a needed initial step. An extension of the meta-analysis from de Langen and colleagues (2012) of the test-retest repeatability of quantitative FDG-PET measurements, including mean, maximum, and peak standardized uptake values (SUVmax, SUVmean, and SUVpeak, respectively), was performed. Data from 11 studies in the literature were used to estimate the relationship between the variance in test-retest measurements with uptake level and various study-level, patient-level, and lesion-level characteristics. RESULTS: Test-retest repeatability of percentage fluctuations for all three types of SUV measurement (max, mean, and peak) improved with higher FDG uptake levels. Repeatability in all three SUV measurements varied for different lesion locations. Worse repeatability in SUVmean was also associated with higher tumor volumes. CONCLUSIONS: On the basis of these results, recommendations regarding SUV measurements for assessing minimal detectable changes based on repeatability and reproducibility are proposed. These should be applied to differentiate between response categories for a future set of FDG-PET-based criteria that assess clinically significant changes in tumor response.

Criteria for the translation of radiomics into clinically useful tests.

Computer-extracted tumour characteristics have been incorporated into medical imaging computer-aided diagnosis (CAD) algorithms for decades. With the advent of radiomics, an extension of CAD involving high-throughput computer-extracted quantitative characterization of healthy or pathological structures and processes as captured by medical imaging, interest in such computer-extracted measurements has increased substantially. However, despite the thousands of radiomic studies, the number of settings in which radiomics has been successfully translated into a clinically useful tool or has obtained FDA clearance is comparatively small. This relative dearth might be attributable to factors such as the varying imaging and radiomic feature extraction protocols used from study to study, the numerous potential pitfalls in the analysis of radiomic data, and the lack of studies showing that acting upon a radiomic-based tool leads to a favourable benefit-risk balance for the patient. Several guidelines on specific aspects of radiomic data acquisition and analysis are already available, although a similar roadmap for the overall process of translating radiomics into tools that can be used in clinical care is needed. Herein, we provide 16 criteria for the effective execution of this process in the hopes that they will guide the development of more clinically useful radiomic tests in the future.

A Phase 1 Trial of Focal Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer.

PURPOSE: NCT03253744 was a phase 1 trial to identify the maximum tolerated dose (MTD) of image-guided, focal, salvage stereotactic body radiation therapy (SBRT) for patients with locally radiorecurrent prostate cancer. Additional objectives included biochemical control and imaging response. METHODS AND MATERIALS: The trial design included 3 dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions delivered ≥48 hours apart. The prescription dose was delivered to the magnetic resonance- and prostate-specific membrane antigen imaging-defined tumor volume. Dose escalation followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until 2 years after completion of SBRT using Common Terminology Criteria for Adverse Events, version 5.0, criteria. Escalation was halted if 2 dose-limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT and any grade 3 genitourinary (GU) or grade 4 gastrointestinal (GI) toxicity thereafter. RESULTS: Between August 2018 and May 2022, 8 patients underwent salvage focal SBRT, with a median follow-up of 35 months. No dose-limiting toxic effects were observed on DL1. Two patients were enrolled in DL2 and experienced grade 3 GU toxicities, prompting de-escalation and expansion (n = 6) at the MTD (DL1). The most common toxicities observed were grade ≥2 GU toxicities, with only a single grade 2 GI toxicity and no grade ≥3 GI toxicities. One patient experienced biochemical failure (prostate-specific antigen nadir + 2.0) at 33 months. CONCLUSIONS: The MTD for focal salvage SBRT for isolated intraprostatic radiorecurrence was 40 Gy in 5 fractions, producing a 100% 24-month biochemical progression free survival, with 1 poststudy failure at 33 months. The most frequent clinically significant toxicity was late grade ≥2 GU toxicity.