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Abstract Background Incorporating image guidance into ion beam therapy is critical for minimizing beam range uncertainties and realizing the modality's potential. One promising avenue for image guidance is to capture transmission ion radiographs (iRads) before and/or during treatment. iRad image quality is typically maximized using a single‐event imaging system, which involves tracking individual ions, albeit the approach is generally not suited to clinical beam settings. An alternative faster and clinically compatible method is integrated mode imaging, where individual pencil beam data is acquired, rather than single ion data. To evaluate the usefulness of transmission ion imaging for image guidance, it is crucial to evaluate the image quality of integrated mode iRad systems. Purpose We report extensive image quality metrics of integrated mode carbon ion radiographs (cRads) and compare them with proton radiographs (pRads). Methods iRads were obtained at the Marburg Ion Beam Therapy Center using a plastic volumetric scintillator equipped with CCD cameras. The detector captures orthogonal views of the 3D energy deposition in the scintillator from individual pencil beams. Four phantoms were scanned using a field of view and a beam spacing of 1 mm. First, 9 tissue‐substitute inserts were used to evaluate water equivalent thickness (WET) accuracy. Radiographs of those inserts were reconstructed for beam spacings ranging from 1 to 7 mm to evaluate the impact of spacing on quantitative accuracy. For spatial resolution, custom 3D printed line pair (lp) modules ranging from 0.5 to 10 lp/cm were scanned. To evaluate low contrast detectability, a custom 3D printed low contrast module consisting of 20 holes with depths ranging from 1 to 8 mm and diameters from 1 to 10 mm was scanned. iRads of an anthropomorphic head phantom were also obtained. Results Spatial resolution and low contrast detection are systematically improved for cRads compared to pRads. Image resolution was 3.7 lp/cm for cRads and 1.7 lp/cm for pRads in the center of the field of view. Spatial resolution was found to vary with the object's location in the field of view. While pRads could mostly resolve low contrast holes of 10 mm in diameter, cRads could resolve holes of up in 4 mm diameter. WET accuracy is similar for both ion species, with a root mean squared error of approximately 1 mm. WET accuracy was stable (maximum of 0.1 mm increase) across beam spacings, although important under‐sampling artifacts were observed for iRads reconstructed using large beam spacings, especially for cRads. iRads of the anthropomorphic head phantom showed improved apparent contrast using cRads, especially to identify bony structures. Conclusions This work is the first investigation of image quality metrics such as spatial resolution and low contrast detectability for integrated mode cRads, with a full comparison with pRads. Enhanced image quality is obtained with cRads compared to pRads, although pRads still maintain high WET accuracy and deliver image quality within acceptable bounds.

AbstractBackgroundExternal‐beam radiation (EBRT) is a noninvasive therapeutic alternative to transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The objective of this study was to conduct a systematic review and meta‐analysis of prospective randomized clinical trials to assess the clinical efficacy of EBRT versus TACE for HCC as either a definitive monotherapy or as a bridge to transplantation/surgery.MethodsA systematic review and meta‐analysis were performed to include prospective randomized trials comparing EBRT versus TACE. Data was analyzed with random and fixed‐effects models. The inconsistency index (I2) was chosen to assess heterogeneity. Three publications were included with a total of 142 patients. Outcomes included local control (LC), overall survival (OS), progression‐free survival (PFS), and occurrences of grade ≥3 toxicity. Comparisons are reported as hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs).ResultsThere were three randomized trials that met inclusion criteria. The EBRT was delivered in three to 15 fractions with a total dose between 30 and 75 gray(Gy). EBRT was associated with significantly improved LC (HR, 0.16; 95% CI, 0.08–0.34; I2 = 0%) and PFS (HR, 0.37; 95% CI, 0.23–0.60; I2, 0%) compared with TACE. There was no significant difference between EBRT and TACE in OS (RR, 0.79; 95% CI, 0.51–1.22; I2 = 0%) or grade ≥3 toxicity (RR, 0.86; 95% CI, 0.31–2.37; I2 = 57%). None of the analyses had statistically significant heterogeneity.ConclusionsCompared with TACE, EBRT yields superior LC and PFS without providing a survival benefit in early and intermediate stage HCC. Additional larger prospective randomized controlled trials should be conducted to further investigate differences in clinical outcomes amongst patients with more advanced disease.

Abstract Introduction We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks. Methods Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment. Results In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; grade ≥ 3: 147 [26.8%]). Gastrointestinal and hepatic TRAEs, including diarrhea (171 [31.1%]), nausea (80 [14.6%]), elevated alanine aminotransferase (ALT; 68 [12.4%]), and elevated aspartate aminotransferase (AST; 67 [12.2%]) were the most common (≥10%). Dose interruption and dose reduction of sotorasib resulted in the resolution of >90% of diarrhea events; median time to resolution were 18.0 days and 22.0 days, respectively. Similar trends were observed for elevated ALT and AST events. Patients who stopped immunotherapy <3 months before initiating sotorasib had a higher incidence of treatment-related hepatotoxicity (80/240 [33.3%]) than those who stopped immunotherapy ≥3 months before initiating sotorasib (26/188 [13.8%]). Treatment-related pneumonitis/interstitial lung disease (ILD) and corrected QT (QTc) prolongation were observed in 9 (1.6%) and 4 (0.7%) patients, respectively. Two (0.4%) patients died with TRAEs, 1 with ILD whose ultimate cause of death was disease progression, and the other with an unknown cause. Conclusions Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose modification.

Objective To analyze the use of electrical field imaging (EFI) in the detection of extracochlear electrodes in cochlear implants (CI) Study Design Retrospective cohort study Setting Tertiary academic medical center Methods EFI patterns from 6 recipients with extracochlear electrodes were compared with 10 recipients with all intracochlear electrodes to identify differences in EFI patterns between these two groups. For the extracochlear group, EFI patterns were analyzed using two methods: visual inspection and calculation of the average impedance difference (AID) between specific EFI curves. These results were then compared with information from CT and plain film imaging, surgical notes, and audiology tests to confirm the placement of the electrodes in each recipient. Results An average AID of 0.06 kΩ was calculated from the EFI patterns for recipients with complete electrode insertion, whereas an average AID of 0.15 kΩ was calculated from the EFI curves measured for the extracochlear electrodes. Visual analysis of the EFI impedance curves for extracochlear electrodes showed a distinct separation from those measured for intracochlear electrodes. Based on AID analysis and visual inspection the EFI, patterns were in close agreement with the number of extracochlear electrodes detected based on either imaging, intraoperative surgical note, or audiological findings. Conclusion EFI is a noninvasive, inexpensive, and time-efficient measurement that can be used to detect extracochlear electrodes and monitor electrode migration from the cochlea.

AbstractBackgroundThe residual approach has found wide application in researching cognitive resilience, a phenomenon conceptually understood as cognitive performance being better‐than‐typical for an individual, despite apparent AD pathology. The standard residual approach extracts information about an individual’s resilience from the residuals of a linear model predicting cognition. This approach is subject to several limiting assumptions. Here, we explore the implications of these assumptions and propose an alternative predictive modeling approach which circumvents them.MethodsOur alternative approach relies on training a machine learning model on a sample of participants who follow a “typical” clinical progression (Fig. 1A). Residuals are then extracted for a heterogeneous dataset that potentially includes resilient participants by comparing observed cognitive outcomes to those predicted by the “typical” model (Fig. 1B). Additionally, our estimate can be refined by effectively estimating and removing model error from the extracted residual by leveraging a second predictive model (Fig. 1C). Using simulated data, we explore the assumptions made by the standard approach and the consequences of their violation. We then contrast this against our approach.ResultsOur simulations demonstrated that the standard residual approach only extracted accurate resilience estimates if the predictors used in the model explained cognition sufficiently well, while being unrelated to resilience itself. That is, as the predictors explain more of the resilience, the residuals became increasingly determined by model error (Fig. 2). We found that residuals achieved with our approach are more precise and provide individualized estimates that are unaffected by the aforementioned trade‐off (Fig. 3).ConclusionsOur approach holds several advantages over the standard approach: The definition of resilience can be freely adjusted and enforced via different definitions of “typical”, it allows for incorporating complex, non‐linear models without removing relevant information from the residual, the error component of the residual can be estimated through cross‐validation, and all predictors that potentially explain cognition can be included into the model without losing resilience information from the residual. Our approach can be used to measure any phenomenon that can be operationalized as a deviation from a typical outcome and, thus, is also applicable for researching resistance to pathology.

AbstractBackgroundThere is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial.MethodWe included 269 amyloid‐β‐positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA‐AD; 83 logopenic variant primary progressive aphasia, lvPPA‐AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS‐AD) and 68 with typical AD from 12 international cohorts, who underwent tau‐PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid‐β‐negative controls, cross‐sectional tau‐PET standardized uptake value ratios within Schaefer‐200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity‐based distance (using the 30% strongest positive region‐to‐region connections of a group‐average connectivity matrix from ADNI elderly controls) and tau‐PET covariance (group‐average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1‐4) and tau positivity probabilities were assessed accordingly.ResultTau positivity probabilities matched clinical variants, with a posterior pattern in PCA‐AD, left‐hemispheric dominant pattern in lvPPA‐AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS‐AD, and temporo‐parietal predominance in typical AD (Figure 1). In line with this, tau epicenters were highly heterogeneous across variants (Figure 1). In all variants, greater tau‐PET covariance was associated with shorter functional connectivity‐based distance (Figure 2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Figure 3).ConclusionThis multi‐center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant‐specific endpoints in clinical trials.

AbstractBackgroundThere is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial.MethodWe included 269 amyloid‐ß‐positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA‐AD; 83 logopenic variant primary progressive aphasia, lvPPA‐AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS‐AD) and 68 with typical AD from 12 international cohorts, who underwent tau‐PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid‐ß‐negative controls, cross‐sectional tau‐PET standardized uptake value ratios within Schaefer‐200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity‐based distance (using the 30% strongest positive region‐to‐region connections of a group‐average connectivity matrix from ADNI elderly controls) and tau‐PET covariance (group‐average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1‐4) and tau positivity probabilities were assessed accordingly.ResultTau positivity probabilities matched clinical variants, with a posterior pattern in PCA‐AD, left‐hemispheric dominant pattern in lvPPA‐AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS‐AD, and temporo‐parietal predominance in typical AD (Fig.1). In line with this, tau epicenters were highly heterogeneous across variants (Fig.1). In all variants, greater tau‐PET covariance was associated with shorter functional connectivity‐based distance (Fig.2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Fig.3).ConclusionThis multi‐center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant‐specific endpoints in clinical trials.

Introduction: Liver transplantation (LT) provides significant survival benefits to patients with unresectable HCC. In the United States, organ allocation policies for HCCs within the United Network for Organ Sharing criteria do not prioritize patients based on their differences in oncological characteristics. This study assessed whether transplant-associated survival benefits (TASBs) vary among patients with different tumor burden scores (TBS) measured at the time of listing. Methods: We analyzed data from adults applying for HCC MELD exception points between 2002 and 2019, with follow-up until December 2023, using the Scientific Registry of Transplant Recipients. TBS was determined based on the largest tumor diameter and number of HCCs. Patients were categorized into low (≤3), intermediate (3.1–5), and high (>5) TBS groups. TASB was measured as the difference in 5-year survival with and without LT. Results: This study included 36,634 LT candidates. High-TBS patients had higher waitlist dropout rates and marginally lower post-transplant survival, resulting in a significantly greater TASB. The 5-year TASB for the low, intermediate, and high TBS groups were 15.7, 22.1, and 25.0 months, respectively. The adjusted survival benefit expressed in 5-year survival differences was 21.9%, 34.5%, and 39.4% in the low, intermediate, and high TBS groups, respectively ( p <0.001). Conclusions: Higher TBS during listing correlates with greater LT benefits for patients with unresectable HCC within UNOS criteria. We conclude that organ allocation policies in the United States should prioritize patients with high TBS due to their increased risk of dropout and comparable post-transplant survival when compared to patients with less advanced tumors.