American College of Radiology

Immunotherapy with checkpoint inhibitors targeting the PD1/PD-L1 and CTLA4 pathways has limited activity in patients with microsatellite stable (MSS) colorectal adenocarcinoma (CRC). In a prior study, the combination of cetuximab and pembrolizumab failed to improve outcomes for patients with advanced RAS wild-type (RASwt) CRC. In this post hoc secondary analysis, we show that the cetuximab and pembrolizumab-treated patients with TP53 mutant (p53mt) tumors had significantly higher progression-free survival (PFS) and a decrease in tumor burden compared to patients with TP53 wild-type (p53wt) tumors but no difference in overall survival compared to patients with p53wt tumors. The gene set enrichment analysis showed a uniform upregulation of multiple metabolic and immune gene sets, including NK-mediated immunity and IL-12 pathway, while the IL6 pathway was downregulated. There were no overlapping transcriptional alterations between the p53mt and p53wt groups with treatment that remain constant despite the therapeutic intervention. Functional overlap with treatment in both groups in the proliferative, immune, and metabolic pathways were identified. In the baseline tumor samples, the number of PD-L1+ tumor cells was significantly higher in p53mt tumors while the number of OX40-/AE1_AE3-/PD-L1- non-tumor cells, positive for either LAG3, CTLA4 or TIM3, was significantly higher in p53wt tumors. In conclusion, TP53 status was prognostic of improved PFS with cetuximab plus pembrolizumab in RASwt CRC. Future studies evaluating immune-oncology agents in patients with MSS, RASwt CRC should include TP53 as an integrated biomarker and evaluate its performance as a positive predictive biomarker (ClinicalTrials.gov NCT02713373).

The intracluster correlation coefficient (ICC) measures the correlation of observations within clusters and is a key parameter for power and sample size calculations for cluster randomized trials (CRTs). To facilitate the design of future CRTs within the National Cancer Institute Community Oncology Research Program (NCORP), all studies from the NCORP website were reviewed to identify completed CRTs. ICCs for primary and secondary outcomes (when available) were ascertained from these trials and summarized in this article as a resource for future trial development. Although ICCs are relatively small for many outcome cluster combinations, that is not always the case, so consideration should always be given to the specific outcome of interest, trial design, and type of cluster when estimating an ICC to facilitate trial development.

Prevention trials in oncology are some of the most important cancer clinical trials that can be designed, implemented, analyzed, and interpreted. They are pivotal in the goal of stopping the development of cancer before it starts. Prevention trials are unique in that they not only have some of the same requirements and challenges as treatment trials but also have challenges that may make their design more complex. This paper aims to discuss some types of prevention trials and highlight their most common design challenges, including large sample size requirements, slow accrual rates with long accrual duration, extended follow-up periods with trial adherence issues and missing data, endpoints that require extended follow-up or have a high level of confounding, and problems with optimizing study design. This article provides real study examples and suggestions for designing prevention clinical trials while mitigating the known issues they face.

To retrospectively validate the diagnostic power of attenuation values on chest and abdomen/pelvis CECTs, together and separately, compared with dual-energy X-ray absorptiometry (DEXA)-determined osteoporosis diagnoses, and to determine thresholds for accurate osteoporosis diagnosis. Subjects were identified using the electronic health record. Included patients received DEXA and CECT scans within 60days of each other. Patients were excluded if taking osteoporosis medication, undergoing dialysis, receiving hormone or cancer therapy, had a history of cancer, osseous metastases, fractures, or compressions. Minimum, mean, and maximum CECT attenuation values of L1 trabecular bone axial cross-sections were measured by a non-physician in Hounsfield units (HUs) using an elliptical region of interest (ROI) tool. DEXA diagnoses were dichotomized as positive (osteoporosis) or negative (osteopenia/normal). The area under the receiver-operator characteristic curves (AUCs) were compared to identify ideal CECT attenuation thresholds. Two hundred nineteen subjects (mean age 66 ± 0.6 [range 35-92]; 196 (89%) females and 23 (11%) males) were included for analysis. Thirty-one (14%) subjects were positive and 188 (86%) were negative for osteoporosis. Minimum, mean, and maximum combined chest and abdomen/pelvis attenuation values demonstrated AUCs of 0.75 (95% CI 0.67-0.84), 0.931 (95% CI 0.88-0.99), and 0.82 (95% CI 0.73-0.90). The optimal mean attenuation threshold for osteoporosis diagnosis was 120 HU (84% sensitive, 90% specific). There was no statistical difference in diagnostic power between mean attenuation values of chest and abdomen/pelvis CECTs. CECT mean attenuation values of either chest or abdomen/pelvis CECTs could be used as appropriate thresholds in screening for osteoporosis.

While many clinical computed tomography (CT) protocols use helical scanning, the traditional method for measuring the volume CT Dose Index (CTDIvol) requires modifying the helical protocol to perform a single axial rotation. This modification can present challenges and mismatched settings across various scanner models. This study investigates the generalizability of a helical methodology for estimating CTDIvol across a diverse range of participants, CT scanner models, and protocol parameters. A web-based platform collected axial and helical CTDIvol measurements from 24 medical physicists who submitted 569 data sets obtained using four CT protocols on scanners from seven CT manufacturers. Various parameters were tested for tube voltage (70-140 kVp), rotation time (0.25-1.50 s), beam width (8-80mm), and pitch (0.29-3.0) settings. Measurements from the two methodologies were assessed for reproducibility using three repeated exposures and then compared to each other and to the scanner-displayed CTDIvol. Agreement between the methodologies was assessed using Bland-Altman analysis, linear regression, paired t-tests, and a paired two one-sided tests (TOST) procedure with equivalence margins of 5% of the mean protocol CTDIvol. The impact of beam width and pitch on measurement accuracy was assessed using linear regression analysis and an independent t-test. This study demonstrated better measurement reproducibility with the helical method (p<0.05) and excellent concordance between helical and axial measurements (CCC>0.99), with an average difference of -0.61 mGy (limits of agreement: -4.54 and 3.32). The TOST analysis confirmed that the measurement methods were statistically equivalent within the defined equivalence margins. The number of measurements that differed from the displayed CTDIvol by more than±20% was 10 for the axial method and 22 for the helical method. We did not identify a linear correlation between measurement accuracy and beam width or pitch (R2<0.06). However, differences between axial and helical methods were significant for protocols with beam widths up to 40mm versus those greater than 40mm, as well as for protocols with pitch factors up to 1.0 compared to those greater than 1.0 (p<0.001). Utilizing the same equipment currently used for measuring CTDIvol and a simple measurement setup, the helical method offers an alternative measurement methodology that can be seamlessly implemented by medical physicists and adopted by regulatory and accrediting bodies for routine quality control of CT scanners.