Digital Spatial Profiling Identifies Distinct Molecular Signatures of Vascular Lesions in Pulmonary Arterial Hypertension.

RATIONALE: Idiopathic Pulmonary Arterial Hypertension (IPAH) is characterized by extensive pulmonary vascular remodeling due to plexiform and obliterative lesions, media hypertrophy, inflammatory cell infiltration, and alterations of the adventitia. OBJECTIVE: Test the hypothesis that microscopic IPAH vascular lesions express unique molecular profiles, which collectively are different from control pulmonary arteries. METHODS: We used digital spatial transcriptomics to profile the genome-wide differential transcriptomic signature of key pathological lesions (plexiform, obliterative, intima+media hypertrophy, and adventitia) in IPAH lungs (n= 11) and compared these data to the intima+media and adventitia of control pulmonary artery (n=5). RESULTS: We detected 8273 transcripts in the IPAH lesions and control lung pulmonary arteries. Plexiform lesions and IPAH adventitia exhibited the greatest number of differentially expressed genes when compared with intima-media hypertrophy and obliterative lesions. Plexiform lesions in IPAH showed enrichment for (i) genes associated with TGFß-signaling and (ii) mutated genes affecting the extracellular matrix and endothelial-mesenchymal transformation. Plexiform lesions and IPAH adventitia showed upregulation of genes involved in immune and interferon signaling, coagulation, and complement pathways. Cellular deconvolution indicated variability in the number of vascular and inflammatory cells between IPAH lesions, which underlies the differential transcript profiling. CONCLUSIONS: IPAH lesions express unique molecular transcript profiles enriched for pathways involving pathogenetic pathways, including genetic disease drivers, innate and acquired immunity, hypoxia sensing, and angiogenesis signaling. These data provide a rich molecular-structural framework in IPAH vascular lesions that inform novel biomarkers and therapeutic targets in this highly morbid disease.

The tumor microenvironment of benign and malignant salivary gland tumors.

BACKGROUND: Treatment of salivary gland tumors (SGTs) remains challenging. Little is known about the immune landscape of SGTs. We aimed to characterize the tumor microenvironment in benign and malignant SGTs. METHODS: Eleven benign and nine malignant tumors were collected from patients undergoing curative intent surgery. Specimens were analyzed using mass cytometry by time-of-flight. Immune cell populations were manually gated, and T cells were clustered using the FlowSOM algorithm. Population frequencies were compared between high-grade and low-grade malignancies, corrected for multiple hypothesis testing. RESULTS: There were trends towards increased CD4+ and CD8+ T cells among malignant tumors. High-grade malignancies exhibited trends towards higher frequencies of CD8+ PD-1+ CD39+ CD103+ exhausted T cells, CD4+ FoxP3+ TCF-1+ CD127- Tregs, and CD69+ CD25- CD4+ T cells compared to low-grade malignancies. CONCLUSION: SGTs exhibit significant immunologic diversity. High-grade malignancies tended to have greater infiltration of exhausted CD8+ T cells and Tregs, which may guide future studies for immunotherapy strategies.

Gut Microbiome and Metabolic and Immune Indices in Males with or without Evidence of Metabolic Dysregulation.

Background: The contributions of the gut microbiota to obesity and metabolic disease represent a potentially modifiable factor that may explain variation in risk between individuals. This study aimed to explore relationships among microbial composition and imputed functional attributes, a range of soluble metabolic and immune indices, and gene expression markers in males with or without evidence of metabolic dysregulation (MetDys). Methods: This case-control study included healthy males (n=15; 41.9±11.7 years; body mass index [BMI], 22.9±1.2 kg/m2) and males with evidence of MetDys (n=14; 46.6±10.0 years; BMI, 35.1±3.3 kg/m2) who provided blood and faecal samples for assessment of a range of metabolic and immune markers and microbial composition using 16S rRNA gene sequencing. Metagenomic functions were imputed from microbial sequence data for analysis. Results: In addition to elevated values in a range of traditional metabolic, adipokine and inflammatory indices in the MetDys group, 23 immunomodulatory genes were significantly altered in the MetDys group. Overall microbial diversity did not differ between groups; however, a trend for a higher relative abundance of the Bacteroidetes (P=0.06) and a lower relative abundance of the Verrucomicrobia (P=0.09) phyla was noted in the MetDys group. Using both family- and genera-level classifications, a partial least square discriminant analysis revealed unique microbial signatures between the groups. Conclusion: These findings confirm the need for ongoing investigations in human clinical cohorts to further resolve the relationships between the gut microbiota and metabolic and immune markers and risk for metabolic disease.

Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing.

Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.

Ablative margin quantification using deformable versus rigid image registration in colorectal liver metastasis thermal ablation: a retrospective single-center study.

PURPOSE: To investigate the correlation of minimal ablative margin (MAM) quantification using biomechanical deformable (DIR) versus intensity-based rigid image registration (RIR) with local outcomes following colorectal liver metastasis (CLM) thermal ablation. METHODS: This retrospective single-institution study included consecutive patients undergoing thermal ablation between May 2016 and October 2021. Patients who did not have intraprocedural pre- and post-ablation contrast-enhanced CT images for MAM quantification or follow-up period less than 1 year without residual tumor or local tumor progression (LTP) were excluded. DIR and RIR methods were used to quantify the MAM. The registration accuracy was compared using Dice similarity coefficient (DSC). Area under the receiver operating characteristic curve (AUC) was used to test MAM in predicting local tumor outcomes. RESULTS: A total of 72 patients (mean age 57; 44 men) with 139 tumors (mean diameter 1.5 cm ± 0.8 (SD)) were included. During a median follow-up of 29.4 months, there was one residual unablated tumor and the LTP rate was 17% (24/138). The ranges of DSC were 0.96-0.98 and 0.67-0.98 for DIR and RIR, respectively (p < 0.001). When using DIR, 27 (19%) tumors were partially or totally registered outside the liver, compared to 46 (33%) with RIR. Using DIR versus RIR, the corresponding median MAM was 4.7 mm versus 4.0 mm, respectively (p = 0.5). The AUC in predicting residual tumor and 1-year LTP for DIR versus RIR was 0.89 versus 0.72, respectively (p < 0.001). CONCLUSION: Ablative margin quantified on intra-procedural CT imaging using DIR method outperformed RIR for predicting local outcomes of CLM thermal ablation. CLINICAL RELEVANCE STATEMENT: The study supports the role of biomechanical deformable image registration as the preferred image registration method over rigid image registration for quantifying minimal ablative margins using intraprocedural contrast-enhanced CT images. KEY POINTS: • Accurate and reproducible image registration is a prerequisite for clinical application of image-based ablation confirmation methods. • When compared to intensity-based rigid image registration, biomechanical deformable image registration for minimal ablative margin quantification was more accurate for liver registration using intraprocedural contrast-enhanced CT images. • Biomechanical deformable image registration outperformed intensity-based rigid image registration for predicting local tumor outcomes following colorectal liver metastasis thermal ablation.

Differences in Telemedicine Use Between People With and Without an Intellectual or Other Developmental Disability During the COVID-19 Pandemic.

Telemedicine utilization of people with an Intellectual or Other Developmental Disability (IDD) during the COVID-19 Pandemic is not well known. This study compares telemedicine utilization of those with and without IDD prior to the pandemic to after it began. Using the Utah All Payers Claims Database from 2019 to 2021, the study identified telemedicine utilization of adults aged 18 to 62 years old in 2019. Propensity score matching was used to minimize observed confounders of subjects with and without IDD in 2019. Negative binomial regression was used to identify factors that were associated with telemedicine utilization. The final number of subjects in the analysis was 18 204 (IDD: n = 6068, non-IDD: n = 12 136 based on 1:2 propensity score matching). The average (SD) age of the subjects was 31 (11.3) years old in 2019. Forty percent of the subjects were female, about 70% of subjects were covered by Medicaid in 2019. Average (SD) number of telemedicine use in 2020 (IDD: 1.96 (5.97), non-IDD: 1.18 (4.90); P < .01) and 2021 (IDD: 2.24 (6.78) vs 1.37 (5.13); P < .01) were higher for the IDD group than the non-IDD group. The regression results showed that the subjects with IDD had 56% more telemedicine encounters than those in the non-IDD group (Incidence Rate Ratio (IRR) = 1.56, P < .01). The growth of telemedicine during the COVID-19 pandemic has the potential to reduce persistent healthcare disparities in individuals with IDD. However, quality of telemedicine should be considered when it is provided to improve health of subjects with IDD.

YAP-Driven Malignant Reprogramming of Epithelial Stem Cells at Single Cell Resolution.

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ cell tracing approaches with spatiotemporally controlled oncogene activation and tumor suppressor inhibition to unveil the processes underlying oral epithelial progenitor cell reprogramming into cancer stem cells (CSCs) at single cell resolution. This revealed the rapid emergence of a distinct stem-like cell state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal (pEMT) invasive gene programs. Interestingly, CSCs harbor limited cell autonomous invasive capacity, but instead recruit myeloid cells to remodel the basement membrane and ultimately initiate tumor invasion. CSC transcriptional programs are conserved in human carcinomas and associated with poor patient survival. These findings illuminate the process of cancer initiation at single cell resolution, thus identifying candidate targets for early cancer detection and prevention.

Participation in genetic screening: testing different outreach methods across a diverse hospital system based patient population.

Introduction: Genomics has the potential to transform medicine by identifying genetic risk factors that predispose people to certain illnesses. Use of genetic screening is rapidly expanding and shifting towards screening all patients regardless of known risk factors, but research is limited on the success of broad population-level outreach for genetic testing and the effectiveness of different outreach methods across diverse populations. In this study, we tested the effectiveness of Digital Only (emailing and texting) and Brochure Plus Digital (mailed brochure, emailing, and texting) outreach to encourage a diverse patient population to participate in a large hospital system's whole genome sequencing program. Methods: Disproportionate stratified sampling was used to create a study population more demographically diverse than the eligible population and response rates were analyzed overall and by demographics to understand the effectiveness of different outreach strategies. Results: 7.5% of all eligible patients enrolled in the program. While approximately 70% of patients invited to complete genetic testing identified in their EHR as being Hispanic, Black or African America, Asian, or another non-White race, these patients generally enrolled at lower rates than the overall population. Other underrepresented groups had higher enrollment rates including people with Medicaid coverage (8.7%) and those residing in rural areas (10.6%). We found no significant difference in enrollment rates between our Digital-Only and our Brochure Plus Digital outreach approaches in the overall population, but enrollment rates were significantly higher for Asian patients and patients who resided in rural areas in the Brochure Plus Digital group. Across both outreach approaches, links provided in emails were most commonly used for enrollment. Discussion: Our study reveals expected enrollment rates for proactive outreach by a hospital system for genetic testing in a diverse population. As more hospital systems are adopting population-scale genetic testing, these findings can inform future outreach efforts to recruit patients for genetic testing including those patients traditionally underrepresented in genomics.

Assessing the impact of recovery housing on healthcare utilization in Portland, Oregon.

Introduction: Central City Concern (CCC) operates several recovery housing sites in the Portland, Oregon metropolitan region, including the Blackburn Center (Blackburn) and the Richard L. Harris Building (Harris). This retrospective, observational study was designed to assess recovery housing's impact on inpatient detoxification readmission rates and healthcare utilization patterns. Methods: Our study population consisted of individuals discharged from CCC's Hooper Detox Stabilization Center from June 2019 to September 2020. A total of 75 clients housed at Blackburn, 63 clients housed at Harris, and 57 clients discharged as unhoused were included in the study sample. Using logistic regression for each of the two recovery housing groups relative to the unhoused group, we examined differences in readmissions to inpatient detoxification after their qualifying discharge. We then used Difference-In-Difference model to compare the per member per year (PMPY) use of different domains of health care before and after their qualifying discharge. Results: Compared to clients discharged as unhoused, Blackburn and Harris residents had lower risk of readmissions to inpatient detoxification treatment at 90- and 180-days post-discharge. Additionally, while the mean number of PMPY emergency department visits increased for clients discharged as unhoused in the post period, the average number of emergency department visits decreased for clients who obtained recovery housing at Blackburn (DiD=-3.65 PMPY, p-value=0.02) and at Harris (DiD=-3.87 PMPY, p-value=0.01). Conclusion: Findings highlight the impact and importance of recovery housing for individuals managing a substance use disorder and the value of healthcare system and public sector investment housing like Blackburn and Harris.

Specific Oral Microbial Differences in Proteobacteria and Bacteroidetes Are Associated with Distinct Sites When Moving from Healthy Mucosa to Oral Dysplasia-A Microbiome and Gene Profiling Study and Focused Review.

Oral potentially malignant disorders (OPMDs) are a group of conditions that carry a risk of oral squamous cell carcinoma (OSCC) development. Recent studies indicate that periodontal disease-associated pathogenic bacteria may play a role in the transition from healthy mucosa to dysplasia and to OSCC. Yet, the microbial signatures associated with the transition from healthy mucosa to dysplasia have not been established. To characterize oral microbial signatures at these different sites, we performed a 16S sequencing analysis of both oral swab and formalin-fixed, paraffin-embedded tissue (FFPE) samples. We collected oral swabs from healthy mucosa (from healthy patients), histologically normal mucosa adjacent to dysplasia, and low-grade oral dysplasia. Additionally, FFPE samples from histologically normal mucosa adjacent to OSCC, plus low grade and high-grade oral dysplasia samples were also collected. The collected data demonstrate significant differences in the alpha and beta microbial diversities of different sites in oral mucosa, dysplasia, and OSCC, as well as increased dissimilarities within these sites. We found that the Proteobacteria phyla abundance increased, concurrent with a progressive decrease in the Firmicutes phyla abundance, as well as altered levels of Enterococcus cecorum, Fusobacterium periodonticum, Prevotella melaninogenica, and Fusobacterium canifelinum when moving from healthy to diseased sites. Moreover, the swab sample analysis indicates that the oral microbiome may be altered in areas that are histologically normal, including in mucosa adjacent to dysplasia. Furthermore, trends in specific microbiome changes in oral swab samples preceded those in the tissues, signifying early detection opportunities for clinical diagnosis. In addition, we evaluated the gene expression profile of OSCC cells (HSC-3) infected with either P. gingivalis, T. denticola, F. nucelatum, or S. sanguinis and found that the three periodontopathogens enrich genetic processes related to cancer progression, including skin keratinization/cornification, while the commensal enriched processes related to RNA processing and adhesion. Finally, we reviewed the dysplasia microbiome literature and found a significant decrease in commensal bacteria, such as the Streptococci genus, and a simultaneous increase in pathogenic bacteria, mainly Bacteroidetes phyla and Fusobacterium genus. These findings suggest that features of the oral microbiome can serve as novel biomarkers for dysplasia and OSCC disease progression.

Study Protocol STEREOLAB: Stereotactic Liver Ablation Assisted with Intra-Arterial CT Hepatic Arteriography and Ablation Confirmation Software Assessment.

PURPOSE: This study aims to evaluate the technical efficacy and local tumor progression-free survival (LTPFS) of a standardized workflow for thermal ablation of colorectal liver metastases (CRLM) consisting of CT during hepatic arteriography (CTHA)-based imaging analysis, stereotactic thermal ablation, and computer-based software assessment of ablation margins. MATERIALS AND METHODS: This investigator initiated, single-center, single-arm prospective trial will enroll up to 50 patients (≤ 5 CRLM, Measuring ≤ 5 cm). Procedures will be performed in an angio-CT suite under general anesthesia. The primary objective is to estimate LTPFS with a follow-up of up to 2 years and secondary objectives are analysis of the impact of minimal ablative margins on LTPFS, adverse events, contrast media utilization and radiation exposure, overall oncological outcomes, and anesthesia/procedural time. Adverse events (AE) will be recorded by CTCAE (Common Toxicity Criteria for Adverse Events), and Bayesian optimal phase-2 design will be applied for major intraprocedural AE stop boundaries. The institutional CRLM ablation registry will be used as benchmark for comparative analysis with the historical cohort. DISCUSSION: The STEREOLAB trial will introduce a high-precision and standardized thermal ablation workflow for CRLM consisting of CT during hepatic arteriography imaging, stereotactic guidance, and ablation confirmation. Trial Registration ClinicalTrials.gov identifier: (NCT05361551).

Direct reprogramming of oral epithelial progenitor cells to cancer stem cells at single cell resolution in vivo.

Tumor initiation represents the initial step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Most studies investigating cancer-driving mechanisms in solid tumors rely on analyses of established malignant lesions, and thus cannot directly capture processes underlying the reprogramming of normal progenitor cells into cancer cells. Here, using spatiotemporally controlled oncogene expression in a genetically engineered system we demonstrate that concomitant YAP activation and HPV E6-E7 -mediated inhibition of tumor suppressive pathways is sufficient to rapidly reprogram oral epithelial progenitor cells (OEPCs) into cancer stem cells (CSCs). Single cell analyses of these nascent CSCs revealed hallmark transcriptional programs driving tumor initiation. Importantly, these CSC-enriched expression signatures distinguish normal tissue from malignant head and neck tumors and are associated with poor patient survival. Elucidating mechanisms underlying OEPC to CSC reprogramming may offer new insights to halt the conversion of premalignant cells into invasive carcinoma. HIGHLIGHTS: YAP and HPV E6-E7 reprogram oral epithelial progenitor cells into cancer stem cells. Single cell analyses reveal the transcriptional architecture of tumor initiation.CSC transcriptional programs distinguish normal tissue from carcinoma.CSC signatures are associated with poor head and neck cancer survival.

Intracellular carbon storage by microorganisms is an overlooked pathway of biomass growth.

The concept of biomass growth is central to microbial carbon (C) cycling and ecosystem nutrient turnover. Microbial biomass is usually assumed to grow by cellular replication, despite microorganisms' capacity to increase biomass by synthesizing storage compounds. Resource investment in storage allows microbes to decouple their metabolic activity from immediate resource supply, supporting more diverse microbial responses to environmental changes. Here we show that microbial C storage in the form of triacylglycerides (TAGs) and polyhydroxybutyrate (PHB) contributes significantly to the formation of new biomass, i.e. growth, under contrasting conditions of C availability and complementary nutrient supply in soil. Together these compounds can comprise a C pool 0.19 ± 0.03 to 0.46 ± 0.08 times as large as extractable soil microbial biomass and reveal up to 279 ± 72% more biomass growth than observed by a DNA-based method alone. Even under C limitation, storage represented an additional 16-96% incorporation of added C into microbial biomass. These findings encourage greater recognition of storage synthesis as a key pathway of biomass growth and an underlying mechanism for resistance and resilience of microbial communities facing environmental change.

Meeting report: The first soil viral workshop 2022.

Soil viral ecology is a growing research field; however, the state of knowledge still lags behind that of aquatic systems. Therefore, to facilitate progress, the first Soil Viral Workshop was held to encourage international scientific discussion and collaboration, suggest guidelines for future research, and establish soil viral research as a concrete research area. The workshop took place at Søminestationen, Denmark, between 15 and 17th of June 2022. The meeting was primarily held in person, but the sessions were also streamed online. The workshop was attended by 23 researchers from ten different countries and from a wide range of subfields and career stages. Eleven talks were presented, followed by discussions revolving around three major topics: viral genomics, virus-host interactions, and viruses in the soil food web. The main take-home messages and suggestions from the discussions are summarized in this report.

Evaluation of an Integrated Intervention to Address Clinical Care and Social Needs Among Patients with Type 2 Diabetes.

BACKGROUND: The Providence Diabetes Collective Impact Initiative (DCII) was designed to address the clinical challenges of type 2 diabetes and the social determinants of health (SDoH) challenges that exacerbate disease impact. OBJECTIVE: We assessed the impact of the DCII, a multifaceted intervention approach to diabetes treatment that employed both clinical and SDoH strategies, on access to medical and social services. DESIGN: The evaluation employed a cohort design and used an adjusted difference-in-difference model to compare treatment and control groups. PARTICIPANTS: Our study population consisted of 1220 people (740 treatment, 480 control), aged 18-65 years old with a pre-existing type 2 diabetes diagnosis who visited one of the seven Providence clinics (three treatment and four control) in the tri-county area of Portland, Oregon, between August 2019 and November 2020. INTERVENTIONS: The DCII threaded together clinical approaches such as outreach, standardized protocols, and diabetes self-management education and SDoH strategies including social needs screening, referral to a community resource desk, and social needs support (e.g., transportation) to create a comprehensive, multi-sector intervention. MAIN MEASURES: Outcome measures included SDoH screens, diabetes education participation, HbA1c, blood pressure, and virtual and in-person primary care utilization, as well as inpatient and emergency department hospitalization. KEY RESULTS: Compared to patients at the control clinics, patients at DCII clinics saw an increase in diabetes education (15.5%, p<0.001), were modestly more likely to receive SDoH screening (4.4%, p<0.087), and had an increase in the average number of virtual primary care visits of 0.35 per member, per year (p<0.001). No differences in HbA1c, blood pressure, or hospitalization were observed. CONCLUSIONS: DCII participation was associated with improvements in diabetes education use, SDoH screening, and some measures of care utilization.

Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes.

CD8+ T cell responses are critical for anti-tumor immunity. While extensively profiled in the tumor microenvironment, recent studies in mice identified responses in lymph nodes (LNs) as essential; however, the role of LNs in human cancer patients remains unknown. We examined CD8+ T cells in human head and neck squamous cell carcinomas, regional LNs, and blood using mass cytometry, single-cell genomics, and multiplexed ion beam imaging. We identified progenitor exhausted CD8+ T cells (Tpex) that were abundant in uninvolved LN and clonally related to terminally exhausted cells in the tumor. After anti-PD-L1 immunotherapy, Tpex in uninvolved LNs reduced in frequency but localized near dendritic cells and proliferating intermediate-exhausted CD8+ T cells (Tex-int), consistent with activation and differentiation. LN responses coincided with increased circulating Tex-int. In metastatic LNs, these response hallmarks were impaired, with immunosuppressive cellular niches. Our results identify important roles for LNs in anti-tumor immune responses in humans.

Environmental refuges from disease in host-parasite interactions under global change.

The physiological performance of organisms depends on their environmental context, resulting in performance-response curves along environmental gradients. Parasite performance-response curves are generally expected to be broader than those of their hosts due to shorter generation times and hence faster adaptation. However, certain environmental conditions may limit parasite performance more than that of the host, thereby providing an environmental refuge from disease. Thermal disease refuges have been extensively studied in response to climate warming, but other environmental factors may also provide environmental disease refuges which, in turn, respond to global change. Here, we (1) showcase laboratory and natural examples of refuges from parasites along various environmental gradients, and (2) provide hypotheses on how global environmental change may affect these refuges. We strive to synthesize knowledge on potential environmental disease refuges along different environmental gradients including salinity and nutrients, in both natural and food-production systems. Although scaling up from single host-parasite relationships along one environmental gradient to their interaction outcome in the full complexity of natural environments remains difficult, integrating host and parasite performance-response can serve to formulate testable hypotheses about the variability in parasitism outcomes and the occurrence of environmental disease refuges under current and future environmental conditions.

AAPM Task Group Report 238: 3D C-arms with volumetric imaging capability.

This report reviews the image acquisition and reconstruction characteristics of C-arm Cone Beam Computed Tomography (C-arm CBCT) systems and provides guidance on quality control of C-arm systems with this volumetric imaging capability. The concepts of 3D image reconstruction, geometric calibration, image quality, and dosimetry covered in this report are also pertinent to CBCT for Image-Guided Radiation Therapy (IGRT). However, IGRT systems introduce a number of additional considerations, such as geometric alignment of the imaging at treatment isocenter, which are beyond the scope of the charge to the task group and the report. Section 1 provides an introduction to C-arm CBCT systems and reviews a variety of clinical applications. Section 2 briefly presents nomenclature specific or unique to these systems. A short review of C-arm fluoroscopy quality control (QC) in relation to 3D C-arm imaging is given in Section 3. Section 4 discusses system calibration, including geometric calibration and uniformity calibration. A review of the unique approaches and challenges to 3D reconstruction of data sets acquired by C-arm CBCT systems is give in Section 5. Sections 6 and 7 go in greater depth to address the performance assessment of C-arm CBCT units. First, Section 6 describes testing approaches and phantoms that may be used to evaluate image quality (spatial resolution and image noise and artifacts) and identifies several factors that affect image quality. Section 7 describes both free-in-air and in-phantom approaches to evaluating radiation dose indices. The methodologies described for assessing image quality and radiation dose may be used for annual constancy assessment and comparisons among different systems to help medical physicists determine when a system is not operating as expected. Baseline measurements taken either at installation or after a full preventative maintenance service call can also provide valuable data to help determine whether the performance of the system is acceptable. Collecting image quality and radiation dose data on existing phantoms used for CT image quality and radiation dose assessment, or on newly developed phantoms, will inform the development of performance criteria and standards. Phantom images are also useful for identifying and evaluating artifacts. In particular, comparing baseline data with those from current phantom images can reveal the need for system calibration before image artifacts are detected in clinical practice. Examples of artifacts are provided in Sections 4, 5, and 6.

Ablative Margins of Colorectal Liver Metastases Using Deformable CT Image Registration and Autosegmentation.

Background Confirming ablation completeness with sufficient ablative margin is critical for local tumor control following colorectal liver metastasis (CLM) ablation. An image-based confirmation method considering patient- and ablation-related biomechanical deformation is an unmet need. Purpose To evaluate a biomechanical deformable image registration (DIR) method for three-dimensional (3D) minimal ablative margin (MAM) quantification and the association with local disease progression following CT-guided CLM ablation. Materials and Methods This single-institution retrospective study included patients with CLM treated with CT-guided microwave or radiofrequency ablation from October 2015 to March 2020. A biomechanical DIR method with AI-based autosegmentation of liver, tumors, and ablation zones on CT images was applied for MAM quantification retrospectively. The per-tumor incidence of local disease progression was defined as residual tumor or local tumor progression. Factors associated with local disease progression were evaluated using the multivariable Fine-Gray subdistribution hazard model. Local disease progression sites were spatially localized with the tissue at risk for tumor progression (<5 mm) using a 3D ray-tracing method. Results Overall, 213 ablated CLMs (mean diameter, 1.4 cm) in 124 consecutive patients (mean age, 57 years ± 12 [SD]; 69 women) were evaluated, with a median follow-up interval of 25.8 months. In ablated CLMs, an MAM of 0 mm was depicted in 14.6% (31 of 213), from greater than 0 to less than 5 mm in 40.4% (86 of 213), and greater than or equal to 5 mm in 45.1% (96 of 213). The 2-year cumulative incidence of local disease progression was 72% for 0 mm and 12% for greater than 0 to less than 5 mm. No local disease progression was observed for an MAM greater than or equal to 5 mm. Among 117 tumors with an MAM less than 5 mm, 36 had local disease progression and 30 were spatially localized within the tissue at risk for tumor progression. On multivariable analysis, an MAM of 0 mm (subdistribution hazard ratio, 23.3; 95% CI: 10.8, 50.5; P < .001) was independently associated with local disease progression. Conclusion Biomechanical deformable image registration and autosegmentation on CT images enabled identification and spatial localization of colorectal liver metastases at risk for local disease progression following ablation, with a minimal ablative margin greater than or equal to 5 mm as the optimal end point. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Sofocleous in this issue.

Study Protocol COVER-ALL: Clinical Impact of a Volumetric Image Method for Confirming Tumour Coverage with Ablation on Patients with Malignant Liver Lesions.

PURPOSE: This study aims to evaluate the intra-procedural use of a novel ablation confirmation (AC) method, consisting of biomechanical deformable image registration incorporating AI-based auto-segmentation, and its impact on tumor coverage by quantitative three-dimensional minimal ablative margin (MAM) CT-generated assessment. MATERIALS AND METHODS: This single-center, randomized, phase II, intent-to-treat trial is enrolling 100 subjects with primary and secondary liver tumors (≤ 3 tumors, 1-5 cm in diameter) undergoing microwave or radiofrequency ablation with a goal of achieving ≥ 5 mm MAM. For the experimental arm, the proposed novel AC method is utilized for ablation applicator(s) placement verification and MAM assessment. For the control arm, the same variables are assessed by visual inspection and anatomical landmarks-based quantitative measurements aided by co-registration of pre- and post-ablation contrast-enhanced CT images. The primary objective is to evaluate the impact of the proposed AC method on the MAM. Secondary objectives are 2-year LTP-free survival, complication rates, quality of life, liver function, other oncological outcomes, and impact of AC method on procedure workflow. DISCUSSION: The COVER-ALL trial will provide information on the role of a biomechanical deformable image registration-based ablation confirmation method incorporating AI-based auto-segmentation for improving MAM, which might translate in improvements of liver ablation efficacy. CONCLUSION: The COVER-ALL trial aims to provide information on the role of a novel intra-procedural AC method for improving MAM, which might translate in improvements of liver ablation efficacy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04083378.