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PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a 40% recurrence rate, lacking effective prognostic biomarkers and surveillance methods. This prospective, multicenter, observational study aimed to evaluate circulating tumor DNA (ctDNA) as a biomarker for detecting MCC recurrence. METHODS: Plasma samples, clinical data, and imaging results were collected from 319 patients. A tumor-informed ctDNA assay was used for analysis. Patients were divided into discovery (167 patients) and validation (152 patients) cohorts. Diagnostic performance, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed. RESULTS: ctDNA showed high sensitivity, 95% (discovery; 95% CI, 87 to 99) and 94% (validation; 95% CI, 85 to 98), for detecting disease at enrollment, with corresponding specificities of 90% (95% CI, 82 to 95) and 86% (95% CI, 77 to 93). A positive ctDNA during surveillance indicated increased recurrence risk, with hazard ratios (HRs) of 6.8 (discovery; 95% CI, 2.9 to 16) and 20 (validation; 95% CI, 8.3 to 50). The PPV for clinical recurrence at 1 year after a positive ctDNA test was 69% (discovery; 95% CI, 32 to 91) and 94% (validation; 95% CI, 71 to 100), respectively. The NPV at 135 days after a negative ctDNA test was 94% (discovery; 95% CI, 90 to 97) and 93% (validation; 95% CI, 89 to 97), respectively. Patients positive for ctDNA within 4 months after treatment had higher rates of recurrence, with 1-year rates of 74% versus 21% (adjusted HR, 7.4 [95% CI, 2.7 to 20]). CONCLUSION: ctDNA testing exhibited high prognostic accuracy in detecting MCC recurrence, suggesting its potential to reduce frequent surveillance imaging. ctDNA also identifies high-risk patients who need more frequent imaging and may be best suited for adjuvant therapy trials.

PurposeMany MRI sequences are sensitive to motion and its associated artifacts. The linearized geometric solution (LGS), a balanced steady-state free precession (bSSFP) off-resonance signal demodulation technique, is evaluated with respect to motion artifact resilience.Theory and methodsThe mechanism and extent of LGS motion artifact resilience is examined in simulated, flow phantom, and in vivo clinical imaging. Motion artifact correction capabilities are decoupled from susceptibility artifact correction when feasible to permit controlled analysis of motion artifact correction when comparing the LGS with standard and phase-cycle-averaged (complex sum) bSSFP imaging.ResultsSimulations reveal that the LGS demonstrates motion artifact reduction capabilities similar to standard clinical bSSFP imaging techniques, with slightly greater resilience in high SNR regions and for shorter-duration motion. Flow phantom experiments assert that the LGS reduces shorter-duration motion artifact error by ∼24%-65% relative to the complex sum, whereas reconstructions exhibit similar error reduction for constant motion. In vivo analysis demonstrates that in the internal auditory canal/orbits, the LGS was deemed to have less artifact in 24%/49% and similar artifact in 76%/51% of radiological assessments relative to the complex sum, and the LGS had less artifact in 97%/81% and similar artifact in 3%/16% of assessments relative to standard bSSFP. Only 2 of 63 assessments deemed the LGS inferior to either complex sum or standard bSSFP in terms of artifact reduction.ConclusionThe LGS provides sufficient bSSFP motion artifact resilience to permit robust elimination of susceptibility artifacts, inspiring its use in a wide variety of applications.

PurposeSpatially fractionated radiation therapy (SFRT), which delivers highly nonuniform dose distributions instead of conventionally practiced homogeneous tumor dose, has shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration, and clinical and translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance the feasibility of such trials.Methods and materialsPrimary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific expert panels. Clinical trial design criteria included eligibility, SFRT technology and technique, dose and fractionation, target- and normal-tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, expert panel consensus reviews and discussions, and public comment posting were used for consensus development.ResultsClinical trial criteria were developed for head and neck cancer and soft-tissue sarcoma. Final consensus among the 22 trial design categories each (a total of 163 criteria) was high to moderate overall. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry and physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and the degree of agreement are presented and discussed.ConclusionsThis consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft-tissue sarcoma through in-advance harmonization of the fundamental clinical trial design among SFRT experts, potential investigators, and the SFRT community.

BackgroundSpinal cord dose limits are critically important for the safe practice of spine stereotactic body radiotherapy (SBRT). However, the effect of inherent spinal cord motion on cord dose in SBRT is unknown.ObjectiveTo assess the effects of cord motion on spinal cord dose in SBRT.MethodsDynamic balanced fast field echo (BFFE) magnetic resonance imaging (MRI) was obtained in 21 spine metastasis patients treated with SBRT. Planning computed tomography (CT), conventional static T2-weighted MRI, BFFE MRI, and dose planning data were coregistered. Spinal cord from the dynamic BFFE images (corddyn) was compared with the T2-weighted MRI (cordstat) to analyze motion of corddyn beyond the cordstat (Dice coefficient, Jaccard index), and beyond cordstat with added planning organ at risk volume (PRV) margins. Cord dose was compared between cordstat, and corddyn (Wilcoxon signed-rank test).ResultsDice coefficient (0.70-0.95, median 0.87) and Jaccard index (0.54-0.90, median 0.77) demonstrated motion of corddyn beyond cordstat. In 62% of the patients (13/21), the dose to corddyn exceeded that of cordstat by 0.6% to 13.8% (median 4.3%). The corddyn spatially excursed outside the 1-mm PRV margin of cordstat in 9 patients (43%); among these dose to corddyn exceeded dose to cordstat >+ 1-mm PRV margin in 78% of the patients (7/9). Corddyn did not excurse outside the 1.5-mm or 2-mm PRV cord cordstat margin.ConclusionSpinal cord motion may contribute to increases in radiation dose to the cord from SBRT for spine metastasis. A PRV margin of at least 1.5 to 2 mm surrounding the cord should be strongly considered to account for inherent spinal cord motion.

Purpose: Fathers play a critical but underresearched role in their children's cognitive and linguistic development. Focusing on two-parent families with a mother and a father, the present longitudinal study explores the amount of paternal input infants hear during the first 2 years of life, how this input changes over time, and how it relates to child volubility. We devote special attention to parentese, a near-universal style of infant-directed speech, distinguished by its higher pitch, slower tempo, and exaggerated intonation. Method: We examined the daylong recordings of the same 23 infants at ages 6, 10, 14, 18, and 24 months, given English-speaking families. The infants were recorded in the presence of their parents (mother-father dyads), who were predominantly White and ranged from mid to high socioeconomic status (SES). We analyzed the effects of parent gender and child age on adult word counts and parentese, as well as the effects of maternal and paternal word counts and parentese on child vocalizations. Results: On average, the infants were exposed to 46.8% fewer words and 51.9% less parentese from fathers than from mothers, even though paternal parentese grew at a 2.8-times faster rate as the infants aged. An asymmetry emerged where maternal word counts and paternal parentese predicted child vocalizations, but paternal word counts and maternal parentese did not. Conclusions: While infants may hear less input from their fathers than their mothers in predominantly White, mid-to-high SES, English-speaking households, paternal parentese still plays a unique role in their linguistic development. Future research on sources of variability in child language outcomes should thus control for parental differences since parents' language can differ substantially and differentially predict child language.

Introduction: Diffusion weighted MRI (DWI) has emerged as a promising adjunct to reduce unnecessary biopsies prompted by breast MRI through use of apparent diffusion coefficient (ADC) measures. The purpose of this study was to investigate the effects of different lesion ADC measurement approaches and ADC cutoffs on the diagnostic performance of breast DWI in a high-risk MRI screening cohort to identify the optimal approach for clinical incorporation. Methods: Consecutive screening breast MRI examinations (August 2014–Dec 2018) that prompted a biopsy for a suspicious breast lesion (BI-RADS 4 or 5) were retrospectively evaluated. On DWI, ADC (b=0/100/600/800s/mm2) measures were calculated with three different techniques for defining lesion region-of-interest (ROI; single slice('2D'), whole volume('3D') and lowest ADC region('hotspot')). An optimal data-derived ADC cutoff for each technique was retrospectively identified to reduce benign biopsies while avoiding any false negatives, inherently producing cutoffs with 100% sensitivity in this particular cohort. Further, diagnostic performance of these measures was validated using two prespecified ADC cutoffs: 1.53x10-3mm2/s from the ECOG-ACRIN A6702 trial and 1.30x10-3mm2/s from the international EUSOBI group. Diagnostic performance was compared between ADC maps generated with 2(0/800s/mm2) and 4(0/100/600/800s/mm2) b-values. Benign biopsy reduction rate was calculated (number of benign lesions with ADC >cutoff)/(total number of benign lesions). Results: 137 suspicious lesions (in 121 women, median age 44 years [range, 20-75yrs]) were detected on contrast-enhanced screening breast MRI and recommended for biopsy. Of those, 30(21.9%) were malignant and 107(78.1%) were benign. Hotspot ADC measures were significantly lower (p<0.001) than ADCs from both 2D and 3D ROI techniques. Applying the optimal data-derived ADC cutoffs resulted in comparable reduction in benign biopsies across ROI techniques (range:16.8% -17.8%). Applying the prespecified A6702 and EUSOBI cutoffs resulted in benign biopsy reduction rates of 11.2-19.6%(with 90.0-100% sensitivity) and 36.4-51.4%(with 70.0-83.3% sensitivity), respectively, across ROI techniques. ADC measures and benign biopsy reduction rates were similar when calculated with only 2 b-values (0,800 s/mm2) versus all 4 b-values. Discussion: Our findings demonstrate that with appropriate ADC thresholds, comparable reduction in benign biopsies can be achieved using lesion ADC measurements computed from a variety of approaches. Choice of ADC cutoff depends on ROI approach and preferred performance tradeoffs (biopsy reduction vs sensitivity). [ABSTRACT FROM AUTHOR]

Background Patients with mycosis fungoides (MF)/Sézary Syndrome (SS) can experience impacted health-related quality of life (HRQoL). Objectives To validate the CTCL-S, a novel subscale of the Functional Assessment of Cancer Therapy–General (FACT-G), in patients with MF/SS. Methods Qualitative interviews were conducted with expert clinicians and patients with MF/SS. Thematic analysis identified the most common concerns, and 19 items were selected. Patients with MF/SS were recruited from a single centre. FACT-G, CTCL-S (collectively 'FACT-CTCL'), Skindex-29 and Visual Analogue Scale–Pruritis (VAS-itch) were administered. A subset repeated FACT-CTCL and VAS-itch after ≈2 weeks. Patient demographics and clinical characteristics were obtained via review of the electronic medical records. Psychometric properties were assessed. Internal consistency was estimated using Cronbach's α. Convergent and discriminant validity were assessed by comparing CTCL-S with disease stage, age, VAS-itch, FACT-G and Skindex-29. Exploratory factor analysis (EFA) was used to preliminarily assess CTCL-S dimensionality. Test–retest repeatability was summarized using intraclass correlation coefficient (ICC), within-subject standard deviation and within-subject coefficient of variation. Results Seventy-two patients completed the initial survey, and 35 repeated the FACT-CTCL and VAS-itch after ≈2 weeks. Two-thirds were men; most were White (78%). The majority (85%) had MF, 15% had SS and 75% early (stage IA–IIA) and 25% advanced (≥ stage IIB) disease. Preliminary EFA found a single predominant factor, supporting a hypothesis of unidimensionality of the CTCL-S. Internal consistency of the CTCL-S was high, with α = 0.95 [95% confidence interval (CI) 0.93–0.96]. There was no significant change in CTCL-S average test–retest scores [ICC 0.93 (P = 0.63)]. CTCL-S was significantly lower in advanced vs. early-stage disease [median (interquartile range) 34 (26–48) vs. 59 (44–68), P < 0.001] and strongly correlated with VAS-itch [Spearman's r (rs) –0.70, 95% CI –0.81 to –0.55], FACT-G (rs 0.77, 95% CI 0.65–0.85) and Skindex-29 (rs –0.90, 95% CI –0.94 to –0.84), supporting convergent validity. CTCL-S scores had little correlation with age (rs 0.19, 95% CI –0.05 to 0.41, P = 0.12), supporting discriminant validity. Conclusions The FACT-CTCL is a disease-specific instrument for assessing HRQoL with high reproducibility and good performance in a cohort of patients with MF/SS. [ABSTRACT FROM AUTHOR]

OBJECTIVE:To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes). APPROACH AND RESULTS:AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P=0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (β=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P

BackgroundHigh-risk components of brain arteriovenous malformations (BAVMs) can be targeted to reduce the risk of lesion rupture.ObjectiveTo evaluate targeted embolization of aneurysms against other means of treatment with a case-control analysis; we previously investigated this approach associated with BAVMs.MethodsRetrospective analysis of patients with BAVMs was performed, identifying patients treated with intention to occlude only an aneurysm associated with a BAVM. For each targeted aneurysm embolization (TAE) patient identified, 4 control patients were randomly selected, controlling for rupture status, age, and Spetzler-Martin plus Lawton-Young supplemental score. Analysis was performed to compare rates of adverse events (hemorrhage, new seizure, and death) between the 2 groups.ResultsThirty-two patients met inclusion criteria, and 128 control patients were identified, out of 1103 patients treated during the study period. Thirty-four adverse events occurred (15 ruptures, 15 new seizures, and 11 deaths) during the follow-up period (mean 1157 d for the TAE cohort and 1036 d for the non-TAE cohort). Statistically lower associations were noted for the TAE group for any adverse event (hazard ratio 0.28, P = .037) and the composite outcome of hemorrhage or new seizure (hazard ratio 0.20, P = .029).ConclusionFor BAVMs at high risk for surgical resection, TAE can be performed safely and effectively. Patients treated with TAE had better outcomes than matched patients undergoing other combinations of treatment. TAE can be considered for BAVMs with high operative risk prior to radiosurgery or when no other treatment options are available.

Little is known about the prognostic significance of specific characteristics of magnetic resonance imaging (MRI) measured plaque in the superficial femoral artery (SFA). Associations of MRI-measured plaque quantity, lumen area, and plaque composition in the SFA with subsequent mobility loss were studied in people with lower extremity peripheral artery disease (PAD). Participants with an ankle-brachial index (ABI) < 1.00 were identified from Chicago medical centers and underwent direct visualization of atherosclerotic plaque in the SFA using MRI. Participants were followed annually for up to 4 years. Mobility loss was defined as becoming unable to walk up and down a flight of stairs or walk one-quarter of a mile without assistance among participants without mobility impairment at baseline. Analyses adjusted for age, sex, race, comorbidities, ABI, physical activity, and other confounders. Of 308 PAD participants without baseline mobility impairment, 100 (32.5%) developed mobility loss during follow-up. Compared to the lowest mean plaque area tertile at baseline, participants in the highest (worst) plaque area tertile had a higher rate of mobility loss (hazard ratio (HR) = 2.08, 95% confidence interval (CI) = 1.14-3.79, p = 0.018). Compared to the highest mean lumen area tertile, the smallest (worst) mean lumen area tertile was associated with greater mobility loss (HR = 2.18, 95% CI = 1.20-3.96, p = 0.011). Neither lipid rich necrotic core nor calcium in the SFA were associated with mobility loss. In conclusion, greater plaque quantity and smaller lumen area in the proximal SFA, but not lipid rich necrotic core or calcium, were associated with higher mobility loss in people with PAD.

ObjectivesThe aim of this study was to describe associations of the presence of lipid-rich necrotic core (LRNC) in the proximal superficial femoral artery (SFA) with lower extremity peripheral artery disease (PAD) event rates and systemic cardiovascular event rates.BackgroundLRNC in the coronary and carotid arteries is associated with adverse outcomes but has not been studied previously in lower extremity arteries.MethodsParticipants with ankle-brachial index (ABI) values 0.15, and revascularization at 47-month follow-up (hazard ratio: 2.18; 95% confidence interval: 1.27 to 3.75; p = 0.005). The association of SFA LRNC with PAD events was maintained even when this combined outcome excluded lower extremity revascularization (hazard ratio: 2.58; 95% confidence interval: 1.25 to 5.33; p = 0.01). LRNC in the SFA was not associated with all-cause mortality, acute coronary events, or stroke.ConclusionsAmong patients with PAD, LRNC in the SFA was associated with higher rates of clinical PAD events, and this association was independent of ABI. Further study is needed to determine whether interventions that reduce SFA LRNC prevent PAD events.