Lack of Clinically Significant Relationships of Age or Body Mass Index with Merkel Cell Carcinoma Immunotherapy Outcomes.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a high risk of metastasis. The development of anti-PD-1/PD-L1 immunotherapy has improved outcomes for advanced MCC, yet about 50% of such patients do not achieve durable responses. This study analyzed the effects of age and body mass index (BMI) on immunotherapy response in 183 advanced MCC patients from a single-center longitudinal database. Using Fine-Gray or Cox regression models, treatment response, progression-free survival (PFS), MCC-specific survival, and overall survival (OS) were evaluated. Age showed a significant non-linear relationship with treatment response (p = 0.04), with patients much older or younger than 70 years less likely to respond. However, age was not significantly associated with PFS (p = 0.21), MCC-specific survival (p = 0.72), or OS (p = 0.36). Similarly, BMI was not significantly correlated with treatment response (p = 0.41), PFS (p = 0.52), MCC-specific survival (p = 0.78), or OS (p = 0.71). Unlike previous studies suggesting that obesity and advanced age improve outcomes in other cancers, these associations were not observed in MCC. These findings suggest that age and BMI should not influence eligibility for immunotherapy in MCC patients, emphasizing the importance of unbiased patient selection for this treatment.

GWO+RuleFit: rule-based explainable machine-learning combined with heuristics to predict mid-treatment FDG PET response to chemoradiation for locally advanced non-small cell lung cancer.

OBJECTIVE: Vital rules learned from FDG-PET radiomics of tumor subregional response can provide clinical decision support for precise treatment adaptation. We combined a rule-based machine learning (ML) model (RuleFit) with a heuristic algorithm (Gray Wolf Optimizer, GWO) for mid-chemoradiation FDG-PET response prediction in patients with locally advanced non-small cell lung cancer. Approach: Tumors subregions were identified using K-means clustering. GWO+RuleFit consists of three main parts: (i) a random forest is constructed based on conventional features or radiomic features extracted from tumor regions or subregions in FDG-PET images, from which the initial rules are generated; (ii) GWO is used for iterative rule selection; (iii) the selected rules are fit to a linear model to make predictions about the target variable. Two target variables were considered: a binary response measure (∆SUVmean⩾20% decline) for classification and a continuous response measure (∆SUVmean) for regression. GWO+RuleFit was benchmarked against common ML algorithms and RuleFit, with leave-one-out cross-validated performance evaluated by the area under the receiver operating characteristic curve (AUC) in classification and root-mean-square error (RMSE) in regression. Main results: GWO+RuleFit selected 15 rules from the radiomic feature dataset of 23 patients. For treatment response classification, GWO+RuleFit attained numerically better cross-validated performance than RuleFit across tumor regions and sets of features (AUC:0.58-0.86 vs. 0.52-0.78, p=0.170-0.925). GWO+Rulefit also had the best or second-best performance numerically compared to all other algorithms for all conditions. For treatment response regression prediction, GWO+RuleFit (RMSE:0.162-0.192) performed better numerically for low-dimensional models (p=0.097-0.614) and significantly better for high-dimensional models across all tumor regions except one (RMSE:0.189-0.219, p<0.004). Significance: The GWO+RuleFit selected rules were interpretable, highlighting distinct radiomic phenotypes that modulated treatment response. GWO+Rulefit achieved parsimonious models while maintaining utility for treatment response prediction, which can aid clinical decisions for patient risk stratification, treatment selection, and biologically driven adaptation. Clinical trial: NCT02773238.

An alternating-intervention pilot trial on the impact of an informational handout on patient-reported outcomes and follow-up after lung cancer screening.

INTRODUCTION: Lung cancer screening (LCS) can reduce lung cancer mortality; however, poor understanding of results may impact patient experience and follow-up. We sought to determine whether an informational handout accompanying LCS results can improve patient-reported outcomes and adherence to follow-up. STUDY DESIGN: This was a prospective alternating intervention pilot trial of a handout to accompany LCS results delivery. SETTING/PARTICIPANTS: Patients undergoing LCS in a multisite program over a 6-month period received a mailing containing either: 1) a standardized form letter of LCS results (control) or 2) the LCS results letter and the handout (intervention). INTERVENTION: A two-sided informational handout on commonly asked questions after LCS created through iterative mixed-methods evaluation with both LCS patients and providers. OUTCOME MEASURES: The primary outcomes of 1)patient understanding of LCS results, 2)correct identification of next steps in screening, and 3)patient distress were measured through survey. Adherence to recommended follow-up after LCS was determined through chart review. Outcomes were compared between the intervention and control group using generalized estimating equations. RESULTS: 389 patients were eligible and enrolled with survey responses from 230 participants (59% response rate). We found no differences in understanding of results, identification of next steps in follow-up or distress but did find higher levels of knowledge and understanding on questions assessing individual components of LCS in the intervention group. Follow-up adherence was overall similar between the two arms, though was higher in the intervention group among those with positive findings (p = 0.007). CONCLUSIONS: There were no differences in self-reported outcomes between the groups or overall follow-up adherence. Those receiving the intervention did report greater understanding and knowledge of key LCS components, and those with positive results had a higher rate of follow-up. This may represent a feasible component of a multi-level intervention to address knowledge and follow-up for LCS. TRIAL REGISTRATION: ClinicalTrials.gov NCT05265897.

Estimating infants' language exposure: A comparison of random and volume sampling from daylong recordings collected in a bilingual community.

In North America, the characteristics of a child's language environment predict language outcomes. For example, differences in bilingual language exposure, exposure to electronic media, and exposure to child-directed speech (CDS) relate to children's language growth. Recently, these predictors have been studied through the use of daylong recordings, followed by manual annotation of audio samples selected from these recordings. Using a dataset of daylong recordings collected from bilingually raised infants in the United States as an example, we ask whether two of the most commonly used sampling methods, random sampling and sampling based on high adult speech, differ from each other with regard to estimating the frequencies of specific language behaviors. Daylong recordings from 37 Spanish-English speaking families with infants between 4 and 22 months of age were analyzed. From each child's recording, samples were extracted in two ways (at random/based on high adult speech) and then annotated for Language (Spanish/English/Mixed), CDS, Electronic Media, Social Context, Turn-Taking, and Infant Babbling. Correlation and agreement analyses were performed, in addition to paired sample t-tests, to assess how the choice of one or the other sampling method may affect the estimates. For most behaviors studied, correlation and agreement between the two sampling methods was high (Pearson r values between 0.79 and 0.99 for 16 of 17 measures; Intraclass Correlation Coefficient values between 0.78 and 0.99 for 13 of 17 measures). However, interesting between-sample differences also emerged: the degree of language mixing, the amount of CDS, and the number of conversational turns were all significantly higher when sampling was performed based on high adult speech compared to random sampling. By contrast, the presence of electronic media and one-on-one social contexts was higher when sampling was performed at random. We discuss advantages of choosing one sampling technique over the other, depending on the research question and variables at hand.

Repeatability of 18F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials.

BACKGROUND: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients that have bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases. METHODS: For this study, nine patients with 38 bone lesions were imaged with 18F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified by the most commonly used PET parameter, the maximum tumor voxel normalized by dose and body weight (SUVmax) and also by the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals for SUVmax and SULpeak were used to determine the limits of 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-FDG before and after standard-of-care therapy for response assessment. RESULTS: The mean relative difference of SUVmax and SULpeak in 38 bone tumors of the first cohort were 4.3% and 6.7%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and - 16.3% for SUVmax, and 21.2% and - 17.5% for SULpeak. 18F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification using SULpeak for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria for SULpeak changed the status of 3 patients compared to the standard Positron Emission Tomography Response Criteria in Solid Tumors of ± 30% SULpeak. CONCLUSION: In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18F-FDG SUVmax, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18F-FDG imaging in clinical trials investigating bone lesions in these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response.

Diagnostic Performance of Point-of-Care Apparent Diffusion Coefficient Measures to Reduce Biopsy in Breast Lesions at MRI: Clinical Validation.

Background The Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group multicenter A6702 trial identified an optimal apparent diffusion coefficient (ADC) cutoff to potentially reduce biopsies by 21% without affecting sensitivity. Whether this performance can be achieved in clinical settings has not yet been established. Purpose To validate the performance of point-of-care ADC measurements with the A6702 trial ADC cutoff for reducing unnecessary biopsies in lesions detected at breast MRI. Materials and Methods Consecutive breast MRI examinations performed from May 2015 to January 2019 at a single medical center and showing biopsy-confirmed Breast Imaging Reporting and Data System category 4 or 5 lesions, without ipsilateral cancer, were identified. Point-of-care lesion ADC measurements collected at clinical interpretation were retrospectively evaluated. MRI examinations included axial T2-weighted, diffusion-weighted, and dynamic contrast-enhanced sequences. Sensitivity and biopsy reduction rates were calculated by applying the A6702 optimal (ADC, 1.53 × 10-3 mm2/sec) and alternate conservative (1.68 × 10-3 mm2/sec) cutoffs. Lesion pathologic outcomes were the reference standard. To assess reproducibility, one radiologist repeated ADC measurements, and agreement was summarized using the intraclass correlation coefficient. Results A total of 240 lesions in 201 women (mean age, 49 years ± 13 [SD]) with pathologic outcomes (63 malignant and 177 benign) were included. Applying the optimal ADC cutoff produced an overall biopsy reduction rate of 15.8% (38 of 240 lesions [95% CI: 11.2, 20.9]), with a sensitivity of 92.1% (58 of 63 lesions [95% CI: 82.4, 97.4]; sensitivity was 97.2% [35 of 36 lesions] [95% CI: 82.7, 99.6] for invasive cancers). Results were similar for screening versus diagnostic examinations (P = .92 and .40, respectively). Sensitivity was higher for masses than for nonmass enhancements (NMEs) (100% vs 85.3%; P = .009). Applying the conservative ADC cutoff achieved a sensitivity of 95.2% (60 of 63 lesions [95% CI: 86.7, 99.0]), with a biopsy reduction rate of 10.4% (25 of 240 lesions [95% CI: 6.7, 14.5]). Repeated single-reader measurements showed good agreement with clinical ADCs (intraclass correlation coefficient, 0.72 [95% CI: 0.58, 0.81]). Conclusion This study validated the clinical use of ADC cutoffs to reduce MRI-prompted biopsies by up to 16%, with a suggested tradeoff of lowered sensitivity for in situ and microinvasive disease manifesting as NME. Clinical trial registration no. NCT02022579 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Honda and Iima in this issue.

Practice Patterns of Spatially Fractionated Radiation Therapy: A Clinical Practice Survey.

Purpose: Spatially fractionated radiation therapy (SFRT) is increasingly used for bulky advanced tumors, but specifics of clinical SFRT practice remain elusive. This study aimed to determine practice patterns of GRID and Lattice radiation therapy (LRT)-based SFRT. Methods and Materials: A survey was designed to identify radiation oncologists' practice patterns of patient selection for SFRT, dosing/planning, dosimetric parameter use, SFRT platforms/techniques, combinations of SFRT with conventional external beam radiation therapy (cERT) and multimodality therapies, and physicists' technical implementation, delivery, and quality procedures. Data were summarized using descriptive statistics. Group comparisons were analyzed with permutation tests. Results: The majority of practicing radiation oncologists (United States, 100%; global, 72.7%) considered SFRT an accepted standard-of-care radiation therapy option for bulky/advanced tumors. Treatment of metastases/recurrences and nonmetastatic primary tumors, predominantly head and neck, lung cancer and sarcoma, was commonly practiced. In palliative SFRT, regimens of 15 to 18 Gy/1 fraction predominated (51.3%), and in curative-intent treatment of nonmetastatic tumors, 15 Gy/1 fraction (28.0%) and fractionated SFRT (24.0%) were most common. SFRT was combined with cERT commonly but not always in palliative (78.6%) and curative-intent (85.7%) treatment. SFRT-cERT time sequencing and cERT dose adjustments were variable. In curative-intent treatment, concurrent chemotherapy and immunotherapy were found acceptable by 54.5% and 28.6%, respectively. Use of SFRT dosimetric parameters was highly variable and differed between GRID and LRT. SFRT heterogeneity dosimetric parameters were more commonly used (P = .008) and more commonly thought to influence local control (peak dose, P = .008) in LRT than in GRID therapy. Conclusions: SFRT has already evolved as a clinical practice pattern for advanced/bulky tumors. Major treatment approaches are consistent and follow the literature, but SFRT-cERT combination/sequencing and clinical utilization of dosimetric parameters are variable. These areas may benefit from targeted education and standardization, and knowledge gaps may be filled by incorporating identified inconsistencies into future clinical research.

Repeatability of 18F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials.

BACKGROUND: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients with bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases.In this study, nine patients with 38 bone lesions were imaged with 18F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified as the maximum tumor voxel normalized by dose and body weight (SUVmax) and the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals of SUVmax and SULpeak were used to determine limits of 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-FDG before and after standard-of-care therapy for response assessment. RESULTS: The mean relative difference of SUVmax in 38 bone tumors of the first cohort was 4.3%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and -16.3%, respectively. The 18F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria changed the status of 3 patients compared to standard the standard Positron Emission Tomography Response Criteria in Solid Tumors of ±30% SULpeak. CONCLUSIONS: In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18F-FDG uptake, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18F-FDG imaging in clinical trials investigating bone lesions from these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response.

Postoperative Radiation Therapy Is Indicated for "Low-Risk" Pathologic Stage I Merkel Cell Carcinoma of the Head and Neck Region but Not for Other Locations.

Purpose: The role of postoperative radiation therapy (PORT) in early stage Merkel cell carcinoma (MCC) is controversial. We analyzed the role of PORT in preventing local recurrences (LR) among patients with low-risk, pathologic stage I MCC based on the location of the primary tumors: head/neck (HN) versus non-HN sites. Methods and Materials: One hundred forty-seven patients with MCC were identified that had "low risk" disease (pathologic T1 primary tumor, negative microscopic margins, negative pathologic node status, no immunosuppression or prior systemic therapy). LR was defined as tumor recurrence within 2 cm of the primary surgical bed, and its frequency was estimated with the cumulative incidence method. Results: Seventy-nine patients received PORT (30 HN, 49 non-HN) with a median dose of 50 Gy (range, 8-64 Gy) and 68 patients were treated with surgery alone (30 HN, 38 non-HN). Overall, PORT was associated with a decreased risk of LR (5-year rate: 0% vs 9.5%; P = .004) with 6 LRs observed in the surgery alone group. Although the addition of PORT significantly reduced LR rates among patients with HN MCC (0% vs. 21%; P = .034), no LRs were observed in patients with non-HN MCC managed with surgery alone. There was no significant difference in MCC-specific survival comparing HN versus non-HN groups, with or without PORT. Conclusions: For low-risk, pathologic stage I MCC of the extremities and trunk, excellent local control rates were achieved with surgery, and PORT is not indicated. However, PORT was associated with a significant reduction in LRs among low-risk MCC of the HN.

Limited Axial Interpretation of Coronary CT Angiography in the Emergency Department Setting.

PURPOSE: Incorporating coronary CT angiographic (CCTA) imaging into emergency department (ED) workflows has been limited by the need for 24/7 real-time postprocessing. The aim of this study was to determine whether interpretation of transaxial CCTA images alone (limited axial interpretation [LI]) is noninferior to interpretation of combined transaxial and multiplanar reformation images (full interpretation [FI]) in assessing patients with acute chest pain in the ED. METHODS: CCTA examinations from 74 patients were evaluated by two radiologists, one without dedicated CCTA training and one with basic CCTA experience. Each examination was evaluated three times in separate sessions, once by LI and twice by FI, in random order. Nineteen coronary artery segments were rated as having significant stenoses (≥50%) or not. Interreader agreement was assessed using Cohen's κ statistic. The primary analysis was whether the accuracy of LI for detecting significant stenosis was noninferior to that of FI at the patient level (margin = -10%). Secondary analyses included similar analyses of sensitivity and specificity, at both the patient and vessel levels. RESULTS: Interreader agreement for significant stenosis was good for both LI and FI (κ = 0.72 vs 0.70, P = .74). Average accuracy for significant stenosis at the patient level was 90.5% for LI and 91.9% for FI, with a difference of -1.4%. The accuracy of LI was noninferior to FI, because the confidence interval did not include the noninferiority margin. Noninferiority was also found for patient-level sensitivity and for accuracy, sensitivity, and specificity at the vessel level. CONCLUSIONS: LI of the coronary arteries using transaxial CCTA images may be sufficient for the detection of significant coronary artery disease in the ED setting.

A comparison of automatic and manual measures of turn-taking in monolingual and bilingual contexts.

The Language ENvironment Analysis system (LENA) records children's language environment and provides an automatic estimate of adult-child conversational turn count (CTC) by automatically identifying adult and child speech in close temporal proximity. To assess the reliability of this measure, we examine correlation and agreement between LENA's CTC estimates and manual measurement of adult-child turn-taking in two corpora collected in the USA: a bilingual corpus of Spanish-English-speaking families with infants between 4 and 22 months (n = 37), and a corpus of monolingual families with English-speaking 5-year-olds (n = 56). In each corpus for each child, 100 30-second segments were extracted from daylong recordings in two ways, yielding a total of 9300 minutes of manually annotated audio. LENA's CTC estimate for the same segments was obtained through the LENA software. The two measures of CTC had low correlations for the segments from the monolingual 5-year-olds sampled in both ways, and somewhat higher correlations for the bilingual samples. LENA substantially overestimated CTC on average, relative to manual measurement, for three out of four analysis conditions, and limits of agreement were wide in all cases. Segment-level analyses demonstrated that accidental contiguity had the largest individual impact on LENA's average CTC error, affecting 12-17% of analyzed segments. Other factors significantly contributing to CTC error were speech from other children, presence of multiple adults, and presence of electronic media. These results indicate wide discrepancies between LENA's CTC estimates and manual CTCs, and call into question the comparability of LENA's CTC measure across participants, conditions, and developmental time points.

Increased risk of recurrence and disease-specific death following delayed postoperative radiation for Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is often treated with surgery and postoperative radiation therapy (PORT). The optimal time to initiate PORT (Time-to-PORT [ttPORT]) is unknown. PURPOSE: We assessed if delays in ttPORT were associated with inferior outcomes. METHODS: Competing risk regression was used to evaluate associations between ttPORT and locoregional recurrence (LRR) for patients with stage I/II MCC in a prospective registry and adjust for covariates. Distant metastasis and death were competing risks. RESULTS: The cohort included 124 patients with median ttPORT of 41 days (range: 8-125 days). Median follow-up was 55 months. 17 (14%) patients experienced a LRR, 14 (82%) of which arose outside the radiation field. LRR at 5 years was increased for ttPORT >8 weeks vs ≤ 8 weeks, 28.0% vs 9.2%, P = .006. There was an increase in the cumulative incidence of MCC-specific death with increasing ttPORT (HR = 1.14 per 1-week increase, P = .016). LIMITATIONS: The relatively low number of LRRs limited the extent of our multivariable analyses. CONCLUSIONS: Delay of PORT was associated with increased LRR, usually beyond the radiation field. This is consistent with the tendency of MCC to spread quickly via lymphatics. Initiation of PORT within 8 weeks was associated with improved locoregional control and MCC-specific survival.

Merkel cell carcinoma recurrence risk estimation is improved by integrating factors beyond cancer stage: A multivariable model and web-based calculator.

BACKGROUND: Merkel cell carcinoma (MCC) recurs in 40% of patients. In addition to stage, factors known to affect recurrence risk include: sex, immunosuppression, unknown primary status, age, site of primary tumor, and time since diagnosis. PURPOSE: Create a multivariable model and web-based calculator to predict MCC recurrence risk more accurately than stage alone. METHODS: Data from 618 patients in a prospective cohort were used in a competing risk regression model to estimate recurrence risk using stage and other factors. RESULTS: In this multivariable model, the most impactful recurrence risk factors were: American Joint Committee on Cancer stage (P < .001), immunosuppression (hazard ratio 2.05; P < .001), male sex (1.59; P = .003) and unknown primary (0.65; P = .064). Compared to stage alone, the model improved prognostic accuracy (concordance index for 2-year risk, 0.66 vs 0.70; P < .001), and modified estimated recurrence risk by up to 4-fold (18% for low-risk stage IIIA vs 78% for high-risk IIIA over 5 years). LIMITATIONS: Lack of an external data set for model validation. CONCLUSION/RELEVANCE: As demonstrated by this multivariable model, accurate recurrence risk prediction requires integration of factors beyond stage. An online calculator based on this model (at merkelcell.org/recur) integrates time since diagnosis and provides new data for optimizing surveillance for MCC patients.

Characterization of Immunosuppressive Myeloid Cells in Merkel Cell Carcinoma: Correlation with Resistance to PD-1 Pathway Blockade.

PURPOSE: Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Although essentially all MCCs are antigenic through viral antigens or high tumor mutation burden, MCC has a response rate of only approximately 50% to PD-(L)1 blockade suggesting barriers to T-cell responses. Prior studies of MCC immunobiology have focused on CD8 T-cell infiltration and their exhaustion status, while the role of innate immunity, particularly myeloid cells, in MCC remains underexplored. EXPERIMENTAL DESIGN: We utilized single-cell transcriptomics from 9 patients with MCC and multiplex IHC staining of 54 patients' preimmunotherapy tumors, to identify myeloid cells and evaluate association with immunotherapy response. RESULTS: Single-cell transcriptomics identified tumor-associated macrophages (TAM) as the dominant myeloid component within MCC tumors. These TAMs express an immunosuppressive gene signature characteristic of monocytic myeloid-derived suppressor cells and importantly express several targetable immune checkpoint molecules, including PD-L1 and LILRB receptors, that are not present on tumor cells. Analysis of 54 preimmunotherapy tumor samples showed that a subset of TAMs (CD163+, CD14+, S100A8+) selectively infiltrated tumors that had significant CD8 T cells. Indeed, higher TAM prevalence was associated with resistance to PD-1 blockade. While spatial interactions between TAMs and CD8 T cells were not associated with response, myeloid transcriptomic data showed evidence for cytokine signaling and expression of LILRB receptors, suggesting potential immunosuppressive mechanisms. CONCLUSIONS: This study further characterizes TAMs in MCC tumors and provides insights into their possible immunosuppressive mechanism. TAMs may reduce the likelihood of treatment response in MCC by counteracting the benefit of CD8 T-cell infiltration. See related commentary by Silk and Davar, p. 1076.

Extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy in patients with advanced melanoma and Merkel cell carcinoma.

BACKGROUND: Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in metastatic cancers remains unclear. Many patients, especially those without radiologic complete remission, develop progressive disease after ICI discontinuation. Extending DoT with ICI may potentially improve efficacy outcomes but presents major logistical and cost challenges with standard frequency dosing (SFD). Receptor occupancy data supports reduced frequency dosing (RFD) of anti-PD-1 antibodies, which may represent a more practical and economically viable option to extend DoT. METHODS: We conducted a retrospective study of patients with metastatic melanoma and Merkel cell carcinoma (MCC), who received ICI at RFD administered every 3 months, after initial disease control at SFD. We evaluated efficacy, safety, and cost-savings of the RFD approach in this cohort. RESULTS: Between 2014 and 2021, 23 patients with advanced melanoma (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT was 1.1 years at SFD and 1.2 years at RFD. The 3 year PFS after start of RFD was 73% in melanoma and 100% in MCC patients, which compare favorably to historical control rates. In the subset of 15 patients who received at least 2 years of therapy, total savings amounted to $1.1 million in drug costs and 384 h saved despite the extended DoT (median 3.4 years), as compared to the calculated cost of 2 years at SFD. CONCLUSIONS: ICI administration at RFD can allow extension of treatment duration, while preserving efficacy and reducing logistical and financial burden. RFD approach deserves further exploration in prospective clinical trials.

Evaluation of 3-dimensional stereotactic surface projection rendering of arterial spin labeling data in a clinical cohort.

BACKGROUND AND PURPOSE: To assess the feasibility of 3-dimensional stereotactic surface projection (3D-SSP) as applied to arterial spin labeling (ASL) in a clinical pilot study. METHODS: A retrospective sample of 10 consecutive patients who underwent ASL as part of a clinically indicated MR examination was collected during this pilot study. Five additional subjects with normal cerebral perfusion served as a control group. Following voxel-wise M0-correction, cerebral blood flow (CBF) quantification, and stereotactic anatomic standardization, voxel-wise CBF from an individual's ASL dataset was extracted to a set of predefined surface pixels (3D-SSP). A normal database was created from averaging the extracted CBF datasets of the control group. Patients' datasets were compared individually with the normal database by calculating a Z-score on a pixel-by-pixel basis and were displayed in 3D-SSP views for visual inspection. Independent, two-expert reader assessment, using a 3-point scale, compared standard quantitative CBF images to the 3D-SSP maps. RESULTS: Patterns and severities of regionally reduced CBF were identified, by both independent readers, in the 3D-SSP maps. Reader assessment demonstrated preference for 3D-SSP over traditionally displayed standard quantitative CBF images in three of four evaluated imaging metrics (p = .026, .031, and .013, respectively); 3D-SSP maps were never found to be inferior to the standard quantitative CBF images. CONCLUSIONS: Three-dimensional SSP maps are feasible in a clinical population and enable quantitative data extraction and localization of perfusion abnormalities by means of stereotactic coordinates in a condensed display. The proposed method is a promising approach for interpreting cerebrovascular pathophysiology.

Comparative Performance of Contrast-enhanced Mammography, Abbreviated Breast MRI, and Standard Breast MRI for Breast Cancer Screening.

Background Contrast-enhanced mammography (CEM) and abbreviated breast MRI (ABMRI) are emerging alternatives to standard MRI for supplemental breast cancer screening. Purpose To compare the diagnostic performance of CEM, ABMRI, and standard MRI. Materials and Methods This single-institution, prospective, blinded reader study included female participants referred for breast MRI from January 2018 to June 2021. CEM was performed within 14 days of standard MRI; ABMRI was produced from standard MRI images. Two readers independently interpreted each CEM and ABMRI after a washout period. Examination-level performance metrics calculated were recall rate, cancer detection, and false-positive biopsy recommendation rates per 1000 examinations and sensitivity, specificity, and positive predictive value of biopsy recommendation. Bootstrap and permutation tests were used to calculate 95% CIs and compare modalities. Results Evaluated were 492 paired CEM and ABMRI interpretations from 246 participants (median age, 51 years; IQR, 43-61 years). On 49 MRI scans with lesions recommended for biopsy, nine lesions showed malignant pathology. No differences in ABMRI and standard MRI performance were identified. Compared with standard MRI, CEM demonstrated significantly lower recall rate (14.0% vs 22.8%; difference, -8.7%; 95% CI: -14.0, -3.5), lower false-positive biopsy recommendation rate per 1000 examinations (65.0 vs 162.6; difference, -97.6; 95% CI: -146.3, -50.8), and higher specificity (87.8% vs 80.2%; difference, 7.6%; 95% CI: 2.3, 13.1). Compared with standard MRI, CEM had significantly lower cancer detection rate (22.4 vs 36.6; difference, -14.2; 95% CI: -28.5, -2.0) and sensitivity (61.1% vs 100%; difference, -38.9%; 95% CI: -66.7, -12.5). The performance differences between CEM and ABMRI were similar to those observed between CEM and standard MRI. Conclusion ABMRI had comparable performance to standard MRI and may support more efficient MRI screening. CEM had lower recall and higher specificity compared with standard MRI or ABMRI, offset by lower cancer detection rate and sensitivity compared with standard MRI. These trade-offs warrant further consideration of patient population characteristics before widespread screening with CEM. Clinical trial registration no. NCT03517813 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Chang in this issue.

Intestinal microbiota controls graft-versus-host disease independent of donor-host genetic disparity.

Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic stem cell transplantation (SCT), and severe intestinal manifestation is the major cause of early mortality. Intestinal microbiota control MHC class II (MHC-II) expression by ileal intestinal epithelial cells (IECs) that promote GVHD. Here, we demonstrated that genetically identical mice of differing vendor origins had markedly different intestinal microbiota and ileal MHC-II expression, resulting in discordant GVHD severity. We utilized cohousing and antibiotic treatment to characterize the bacterial taxa positively and negatively associated with MHC-II expression. A large proportion of bacterial MHC-II inducers were vancomycin sensitive, and peri-transplant oral vancomycin administration attenuated CD4+ T cell-mediated GVHD. We identified a similar relationship between pre-transplant microbes, HLA class II expression, and both GVHD and mortality in a large clinical SCT cohort. These data highlight therapeutically tractable mechanisms by which pre-transplant microbial taxa contribute to GVHD independently of genetic disparity.