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Brain tumors are the most common cause of cancer-related deaths among the pediatric population. Among these, pediatric glioblastomas (GBMs) comprise 2.9% of all central nervous system tumors and have a poor prognosis. The purpose of this study is to determine whether the imaging findings can be a prognostic factor for survival in children with GBMs.The imaging studies and clinical data from 64 pediatric patients with pathology-proven GBMs were evaluated. Contrast enhancement patterns were classified into focal, ring-like, and diffuse, based on preoperative postcontrast T1-weighted magnetic resonance images. We used the Kaplan-Meier method and Cox proportional hazard regression to evaluate the prognostic value of imaging findings.Patients with ring-enhanced GBMs who underwent gross total resection or subtotal resection were found to have a significantly shorter progression-free survival (P = 0.03) comparing with other enhancing and nonenhancing glioblastomas.In this study, we analyzed survival factors in children with pediatric glioblastomas. In the group of patients who underwent gross total resection or subtotal resection, those patients with focal-enhanced GBMs had significantly longer progression-free survival (P = 0.03) than did those with other types of enhancing GBMs (diffuse and ring-like).

Delayed terminal duct lobular unit (TDLU) involution is associated with elevated mammographic breast density (MD). Both are independent breast cancer risk factors among women with benign breast disease (BBD). Prior digital analyses of normal breast tissues revealed that epithelial nuclear density (END) and TDLU involution are inversely correlated. Accordingly, we examined associations of END, TDLU involution, and MD in BBD clinical biopsies. This study included digitized images of 262 representative image-guided hematoxylin and eosin–stained biopsies from 224 women diagnosed with BBD, enrolled within the cross-sectional BREAST-Stamp project that were visually assessed for TDLU involution (TDLU count/100 mm2, median TDLU span and median acini count per TDLU). A digital algorithm estimated nuclei count per unit epithelial area, or END. Single X-ray absorptiometry of prebiopsy ipsilateral craniocaudal digital mammograms measured global and localized MD surrounding the biopsy region. Adjusted ordinal logistic regression models assessed relationships between tertiles of TDLU and END measures. Analysis of covariance examined mean differences in MD across END tertiles. TDLU measures were positively associated with increasing END tertiles [TDLU count/100 mm2, ORT3vsT1: 3.42, 95% confidence interval (CI), 1.87–6.28; acini count/TDLUT3vsT1, OR: 2.40, 95% CI, 1.39–4.15]. END was significantly associated with localized, but not, global MD. Relationships were most apparent among patients with nonproliferative BBD. These findings suggest that quantitative END reflects different but complementary information to the histologic information captured by visual TDLU and radiologic MD measures and merits continued evaluation in assessing cellularity of breast parenchyma to understand the etiology of BBD.

Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities

Legends for supplementary figures and tables.

Supplementary Table 1

Supplementary Table 2B

Supplementary Figure 1. Average Percent Dense Area by Age Supplementary Figure 2. Average Percent Dense Volume by Age.

Supplementary Figure 2

Supplementary Table 1. Spearman partial rank-order correlations for TDLU measures among pre- and postmenopausal women Supplementary Table 2. Spearman partial rank-order correlations between global and peri-lesional volumetric mammographic density measures among pre- and postmenopausal women with benign breast disease Supplementary Tables 3 to 5: Association between TDLU and mammographic density measures (percent, absolute and nondense) among postmenopausal women with benign breast disease

Supplementary Table 3

Supplementary Figure 1

Supplementary Table 1. Age- and BMI-adjusted linear regression results for the association between participant characteristics and standardized volume and area mammographic density measures. Supplementary Table 2. Spearman's rank correlation coefficients for volume and area density measures, unadjusted and adjusted for age and body mass index.

Supplementary Table from Pilot Phase II Trial of Neoadjuvant Immunotherapy in Locoregionally Advanced, Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck

Purpose:In oropharyngeal squamous cell carcinoma (OPC), high CD8+ tumor-infiltrating lymphocyte (CD8+TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab + tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8+TIL density, safety, and efficacy in patients with OPC.Patients and Methods:Patients with newly diagnosed stage II–IVA OPC or locoregionally recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab + tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8+TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes.Results:Of 28 eligible patients (14/arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8+TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P = 0.97; 95% CI: −1.07–2.28). In each group, 6 patients (43%, 95% CI: 17.66–71.14) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8+TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8+TIL change in patients with a MPR was seen (P = 0.059; 95% CI: −0.33–3.46). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence.Conclusions:Durvalumab + tremelimumab did not increase CD8+TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC.

Background: Mammographic density (MD), the area of non–fatty-appearing tissue divided by total breast area, is a strong breast cancer risk factor. Most MD analyses have used visual categorizations or computer-assisted quantification, which ignore breast thickness. We explored MD volume and area, using a volumetric approach previously validated as predictive of breast cancer risk, in relation to risk factors among women undergoing breast biopsy.Methods: Among 413 primarily white women, ages 40 to 65 years, undergoing diagnostic breast biopsies between 2007 and 2010 at an academic facility in Vermont, MD volume (cm3) was quantified in craniocaudal views of the breast contralateral to the biopsy target using a density phantom, whereas MD area (cm2) was measured on the same digital mammograms using thresholding software. Risk factor associations with continuous MD measurements were evaluated using linear regression.Results: Percent MD volume and area were correlated (r = 0.81) and strongly and inversely associated with age, body mass index (BMI), and menopause. Both measures were inversely associated with smoking and positively associated with breast biopsy history. Absolute MD measures were correlated (r = 0.46) and inversely related to age and menopause. Whereas absolute dense area was inversely associated with BMI, absolute dense volume was positively associated.Conclusions: Volume and area MD measures exhibit some overlap in risk factor associations, but divergence as well, particularly for BMI.Impact: Findings suggest that volume and area density measures differ in subsets of women; notably, among obese women, absolute density was higher with volumetric methods, suggesting that breast cancer risk assessments may vary for these techniques. Cancer Epidemiol Biomarkers Prev; 23(11); 2338–48. ©2014 AACR.

Supplementary Figure from Pilot Phase II Trial of Neoadjuvant Immunotherapy in Locoregionally Advanced, Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck

Supplementary Figure 1. Spearman's rank correlation coefficients (rs) for volume and area density measures, stratified by age.

Purpose:In locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), surgery followed by radiotherapy is standard but can be cosmetically and functionally devastating, and many patients will have recurrence.Patients and Methods:Newly diagnosed or recurrent stage III–IVA CSCC-HN patients amenable to curative-intent surgery received two cycles of neoadjuvant PD-1 inhibition. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included pathologic response [pathologic complete response (pCR) or major pathologic response (MPR; ≤10% viable tumor)], safety, DSS, DFS, and OS. Exploratory endpoints included immune biomarkers of response.Results:Of 20 patients enrolled, 7 had recurrent disease. While only 6 patients [30%; 95% confidence interval (CI), 11.9–54.3] had partial responses by RECIST, 15 patients (75%; 95% CI, 50.9–91.3) had a pCR (n = 11) or MPR (n = 4). No SAEs ocurred during or after the neoadjuvant treatment. At a median follow-up of 22.6 months (95% CI, 21.7–26.1), one patient progressed and died, one died without disease, and two developed recurrence. The 12-month DSS, DFS, and OS rates were 95% (95% CI, 85.9–100), 89.5% (95% CI, 76.7–100), and 95% (95% CI, 85.9–100), respectively. Gene expression studies revealed an inflamed tumor microenvironment in patients with pCR or MPR, and CyTOF analyses demonstrated a memory CD8+ T-cell cluster enriched in patients with pCR.Conclusions:Neoadjuvant immunotherapy in locoregionally advanced, resectable CSCC-HN is safe and induces a high pathologic response rate. Pathologic responses were associated with an inflamed tumor microenvironment.

Supplementary Tables

Tectal gliomas (TGs) are rare tumors that involve critical locations in the brainstem, including the superior and inferior colliculi and the Sylvian aqueduct. The rarity of these tumors and the lack of large clinical studies have hindered adequate understanding of this disease. We sought to determine the association between imaging characteristics of TG and progression-free survival (PFS).In this retrospective cohort study, impact of imaging characteristics (contrast enhancement, calcifications, cystic changes, presence of hydrocephalus) on survival was analyzed for 39 patients with TG. We used the Kaplan-Meier survival analysis method for determining the association between imaging characteristics and PFS. Progression-free survival was measured from time of diagnosis to radiographic or pathological disease progression during observation period. Progression was defined as more than 25% increase of the lesion in size, per response assessment in neuro-oncology, together with clinical deterioration and/or a need for intervention. Progression-free survival differences by various imaging characteristics were assessed using the log-rank test and univariable Cox proportional hazard regression. Because most of the studies in the current literature tend to overrepresent pediatric patients, we aimed to determine the association between TG tumors' imaging characteristics and PFS in both adult and pediatric patients. All statistical analyses were performed using STATA version 16.1 (Stata Corp, College Station, Tex).Of the 39 patients, radiographic tumor progression was observed in 15 cases (38.5%). Median PFS for 39 patients during observation was 21.8 years. Tectal gliomas that showed contrast enhancement initially or developed contrast enhancement during surveillance on magnetic resonance imaging had significantly lower PFS than those without (hazard ratio, 3.55; 95% confidence interval, 1.09-11.58; log-rank P value, 0.02).Analysis of this patient population showed that contrast-enhancing TGs should not be categorically defined as benign lesions. This subgroup of patients should be followed closely for signs of progression.

Background Elevated mammographic breast density is a strong breast cancer risk factor with poorly understood etiology. Increased deposition of collagen, one of the main fibrous proteins present in breast stroma, has been associated with increased mammographic density. Collagen fiber architecture has been linked to poor outcomes in breast cancer. However, relationships of quantitative collagen fiber features assessed in diagnostic biopsies with mammographic density and lesion severity are not well-established. Methods Clinically indicated breast biopsies from 65 in situ or invasive breast cancer cases and 73 frequency matched-controls with a benign biopsy result were used to measure collagen fiber features (length, straightness, width, alignment, orientation and density (fibers/µm2)) using second harmonic generation microscopy in up to three regions of interest (ROIs) per biopsy: normal, benign breast disease, and cancer. Local and global mammographic density volumes were quantified in the ipsilateral breast in pre-biopsy full-field digital mammograms. Associations of fibrillar collagen features with mammographic density and severity of biopsy diagnosis were evaluated using generalized estimating equation models with an independent correlation structure to account for multiple ROIs within each biopsy section. Results Collagen fiber density was positively associated with the proportion of stroma on the biopsy slide (p p = 0.035) and within a 2 mm perilesional ring (p = 0.02), but not with global mammographic density measures. As severity of the breast biopsy diagnosis increased at the ROI level, collagen fibers tended to be less dense, shorter, straighter, thinner, and more aligned with one another (p Conclusions Collagen fiber density was positively associated with local, but not global, mammographic density, suggesting that collagen microarchitecture may not translate into macroscopic mammographic features. However, collagen fiber features may be markers of cancer risk and/or progression among women referred for biopsy based on abnormal breast imaging.

Open spina bifida or myelomeningocele (MMC) is a congenital defect that results from failure of caudal neurulation. We present a case series of patients who were treated with postnatal surgical correction for MMC, evaluating the possible preoperative and intraoperative risk factors associated with neurologic outcomes.A retrospective chart review of patients who underwent postnatal surgical correction for MMCs over 11 years at our institution was performed. MMCs were classified based on their morphologic configuration into 3 types. Type I includes defects without a sac and there is cerebrospinal fluid (CSF) leak. Type II includes where there is a sac ≤4 cm, with or without CSF leak. Type III includes defects with a sac that are greater than 4 cm.Fifty patients were included. The median age of gestation at surgery was 37.4 weeks. There were 30 females (60%). All mothers received adequate folate supplementation. All patients underwent surgical correction in the first 48 hours. Lower extremity motor function at the last clinical follow-up was normal in 34 patients (68%). CSF leak, infection, and mortality were 8%, 2%, and 0%, respectively. Twenty-one patients (42%) underwent ventriculoperitoneal shunt for hydrocephalus.Despite there being no statistically significant associations with a timely closure, all cases were treated within the first 48 hours and this could influence the low complication rate. Individuals of Hispanic background who received appropriate folate supplementation still had high rates of MMC and we posit that this may be caused in part by a genetic/molecular predisposition.

Roux-en-Y gastric bypass has been considered the gold standard bariatric procedure for decades. The surgical technique for Roux-en-Y gastric bypass and perioperative management for patients who undergo the procedure are still being improved for better clinical outcomes, shorter hospitalization, and faster return to normal activity. In the past 15 years there have been similar improvements and further development of novel surgical weight loss procedures. As data on other surgical alternatives emerge, the data need to be compared with Roux-en-Y gastric bypass to determine noninferiority. Further long-term investigations are needed to determine superiority of one bariatric procedure over another.

PURPOSE Chronic susceptibility lesions in the brain can be either hemorrhagic (potentially dangerous) or calcific (usually not dangerous) but are difficult to discriminate on routine imaging. We proposed to develop quantitative diagnostic criteria for single-energy computed tomography (SECT), dual-energy computed tomography (DECT), and quantitative susceptibility mapping (QSM) to distinguish hemorrhage from calcium. MATERIALS AND METHODS Patients with positive susceptibility lesions on routine T2*-weighted magnetic resonance of the brain were recruited into this prospective imaging clinical trial, under institutional review board approval and with informed consent. The SECT, DECT, and QSM images were obtained, the lesions were identified, and the regions of interest were defined, with the mean values recorded. Criteria for quantitative interpretation were developed on the first 50 patients, and then applied to the next 45 patients. Contingency tables, scatter plots, and McNemar test were applied to compare classifiers. RESULTS There were 95 evaluable patients, divided into a training set of 50 patients (328 lesions) and a validation set of 45 patients (281 lesions). We found the following classifiers to best differentiate hemorrhagic from calcific lesions: less than 68 Hounsfield units for SECT, calcium level of less than 15 mg/mL (material decomposition value) for DECT, and greater than 38 ppb for QSM. There was general mutual agreement among the proposed criteria. The proposed criteria outperformed the current published criteria. CONCLUSIONS We provide the updated criteria for the classification of chronic positive susceptibility brain lesions as hemorrhagic versus calcific for each major clinically available imaging modality. These proposed criteria have greater internal consistency than the current criteria and should likely replace it as gold standard.

PURPOSE: We aim to characterize the quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters associated with advanced mandibular osteoradionecrosis (ORN) compared with the contralateral normal mandible. METHODS AND MATERIALS: Patients with a diagnosis of advanced ORN after curative-intent radiation treatment of head and neck cancer were prospectively enrolled after institutional review board approval and study-specific informed consent were obtained. Quantitative maps generated with the Tofts and extended Tofts pharmacokinetic models were used for analysis. Manual segmentation of advanced ORN 3-dimensional volume was done using anatomic sequences to create ORN volumes of interest (VOIs). Subsequently, normal mandibular VOIs were segmented on the contralateral healthy mandible of similar volume and anatomic location to create control VOIs. Finally, anatomic sequences were coregistered to DCE sequences, and contours were propagated to the respective parameter maps. RESULTS: Thirty patients were included. The median time to ORN diagnosis after completion of IMRT was 38 months (range, 6–184 months), whereas median time to ORN progression to advanced grade after initial diagnosis was 5.6 months (range, 0–128 months). There were statistically significant higher K(trans) and V(e) in ORN-VOIs compared with controls (0.23 vs 0.07 min(−)(1), and 0.34 vs 0.15; P

BACKGROUND: Decline in neurocognitive functioning (NCF) often occurs following brain tumor resection. Functional connectomics have shown how neurologic insults disrupt cerebral networks underlying NCF, though studies involving patients with brain tumors are lacking. OBJECTIVE: To investigate the impact of brain tumor resection upon the connectome and relationships with NCF outcome in the early postoperative period. METHODS: A total of 15 right-handed adults with left perisylvian glioma underwent resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological assessment before and after awake tumor resection. Graph theoretical analysis was applied to rs-fMRI connectivity matrices to calculate network properties. Network properties and NCF measures were compared across the pre- to postoperative periods with matched pairs Wilcoxon signed-rank tests. Associations between pre- to postoperative change in network and NCF measures were determined with Spearman rank-order correlations (ρ). RESULTS: A majority of the sample showed postoperative decline on 1 or more NCF measures. Significant postoperative NCF decline was found across measures of verbal memory, processing speed, executive functioning, receptive language, and a composite index. Regarding connectomic properties, betweenness centrality and assortativity were significantly smaller postoperatively, and reductions in these measures were associated with better NCF outcomes. Significant inverse associations (ρ = −.51 to −.78, all P

Purpose: In oropharyngeal squamous cell carcinoma (OPC), high CD8+ tumor-infiltrating lymphocyte (CD8+TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab + tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8+TIL density, safety, and efficacy in patients with OPC. Patients and Methods: Patients with newly diagnosed stage II–IVA OPC or locoregionally recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab + tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8+TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes. Results: Of 28 eligible patients (14/arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8+TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P = 0.97; 95% CI: −1.07–2.28). In each group, 6 patients (43%, 95% CI: 17.66–71.14) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8+TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8+TIL change in patients with a MPR was seen (P = 0.059; 95% CI: −0.33–3.46). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence. Conclusions: Durvalumab + tremelimumab did not increase CD8+TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC.

Background Brain metastases are manually identified during stereotactic radiosurgery (SRS) treatment planning, which is time consuming and potentially challenging. Purpose To develop and investigate deep learning (DL) methods for detecting brain metastasis with MRI to aid in treatment planning for SRS. Materials and Methods In this retrospective study, contrast material-enhanced three-dimensional T1-weighted gradient-echo MRI scans from patients who underwent gamma knife SRS from January 2011 to August 2018 were analyzed. Brain metastases were manually identified and contoured by neuroradiologists and treating radiation oncologists. DL single-shot detector (SSD) algorithms were constructed and trained to map axial MRI slices to a set of bounding box predictions encompassing metastases and associated detection confidences. Performances of different DL SSDs were compared for per-lesion metastasis-based detection sensitivity and positive predictive value (PPV) at a 50% confidence threshold. For the highest-performing model, detection performance was analyzed by using free-response receiver operating characteristic analysis. Results Two hundred sixty-six patients (mean age, 60 years ± 14 [standard deviation]; 148 women) were randomly split into 80% training and 20% testing groups (212 and 54 patients, respectively). For the testing group, sensitivity of the highest-performing (baseline) SSD was 81% (95% confidence interval [CI]: 80%, 82%; 190 of 234) and PPV was 36% (95% CI: 35%, 37%; 190 of 530). For metastases measuring at least 6 mm, sensitivity was 98% (95% CI: 97%, 99%; 130 of 132) and PPV was 36% (95% CI: 35%, 37%; 130 of 366). Other models (SSD with a ResNet50 backbone, SSD with focal loss, and RetinaNet) yielded lower sensitivities of 73% (95% CI: 72%, 74%; 171 of 234), 77% (95% CI: 76%, 78%; 180 of 234), and 79% (95% CI: 77%, 81%; 184 of 234), respectively, and lower PPVs of 29% (95% CI: 28%, 30%; 171 of 581), 26% (95% CI: 26%, 26%; 180 of 681), and 13% (95% CI: 12%, 14%; 184 of 1412). Conclusion Deep-learning single-shot detector models detected nearly all brain metastases that were 6 mm or larger with limited false-positive findings using postcontrast T1-weighted MRI. © RSNA, 2020 See also the editorial by Kikinis and Wells in this issue.

Recently, a data-driven regression analysis method was developed to utilize the resting-state (rs) blood oxygenation level-dependent signal for cerebrovascular reactivity (CVR) mapping (rs-CVR), which was previously optimized by comparing with the COTo investigate the agreement of rs-CVR and the CVR mapping with breath-hold MRI (bh-CVR) in patients with gliomas.Retrospective.Twenty-five patients (12 males, 13 females; mean age ± SD, 48 ± 13 years) with gliomas.Dynamic T2*-weighted gradient-echo echo-planar imaging during a breath-hold paradigm and during the rs on a 3-T scanner.rs-CVR with various frequency ranges and resting-state fluctuation amplitude (RSFA) were assessed. The agreement between each rs-based CVR measurement and bh-CVR was determined by voxel-wise correlation and Dice coefficient in the whole brain, gray matter, and the lesion region of interest (ROI).Voxel-wise Pearson correlation, Dice coefficient, Fisher Z-transformation, repeated-measure analysis of variance and post hoc test with Bonferroni correction, and nonparametric repeated-measure Friedman test and post hoc test with Bonferroni correction were used. Significance was set at P 0.05.Compared with bh-CVR, the highest correlations were found at the frequency bands of 0.04-0.08 Hz and 0.02-0.04 Hz for rs-CVR in both whole brain and the lesion ROI. RSFA had significantly lower correlations than did rs-CVR of 0.02-0.04 Hz and a wider frequency range (0-0.1164 Hz). Significantly higher correlations and Dice coefficient were found in normal tissues than in the lesion ROI for all three methods.The optimal frequency ranges for rs-CVR are determined by comparing with bh-CVR in patients with gliomas. The rs-CVR method outperformed the RSFA. Significantly higher correlation and Dice coefficient between rs- and bh-CVR were found in normal tissue than in the lesion.3 TECHNICAL EFFICACY STAGE: 2.

To establish expert consensus regarding the domains and topics for senior surgery residents (PGY-4) to make critical decisions and assume senior-level responsibilities, and to develop the formative American College of Surgeons Senior Resident Readiness Assessment (ACS SRRA) Program.The American College of Surgeons (ACS) education leadership team conducted a focus group with surgical experts to identify the content for an assessment tool to evaluate senior residents' readiness for their increased levels of responsibility. After the focus group, national experts were recruited to develop consensus on the topics through three rounds of surveys using Delphi methodology. The Delphi participants rated topics using Likert-type scales and their comments were incorporated into subsequent rounds. Consensus was defined as ≥ 80% agreement with internal-consistency reliability (Cronbach's alpha) ≥ 0.8. In a stepwise fashion, topics that did not achieve consensus for inclusion were removed from subsequent survey rounds.The surveys were administered via an online questionnaire.Twelve program directors and assistant program directors made up the focus group. The 39 Delphi participants represented seven different surgical subspecialties and were from diverse practice settings. The median length of experience in general surgery resident education was 20 years (IQR 14.3-30.0) with 64% of the experts being either current or past general surgery residency program directors.The response rate was 100% and Cronbach's alpha was ≥ 0.9 for each round. The Delphi participants contributed a large number of comments. Of the 201 topics that were evaluated initially, 120 topics in 25 core clinical areas were included to create the final domains of ACS SRRA.National consensus on the domain of the ACS SRRA has been achieved via the modified Delphi method among expert surgeon educators. ACS SRRA will identify clinical topics and areas in which each senior resident needs improvement and provide data to residents and residency programs to develop individualized learning plans. This would help in preparing the senior residents to assume their responsibilities and support their readiness for future fellowship training or surgical practice.

PURPOSE Given regulatory approval of immune checkpoint inhibitors in patients with mismatch repair–deficient (MMR-D) cancers agnostic to tumor type, it has become important to characterize occurrence of MMR-D and develop cost-effective screening approaches. Using a next-generation sequencing (NGS) panel (OncoPanel), we developed an algorithm to identify MMR-D frequency in tumor samples and applied it in a clinical setting with pathologist review. METHODS To predict MMR-D, we adapted methods described previously for use in NGS panels, which assess patterns of single base-pair insertion or deletion events occurring in homopolymer regions. Tumors assayed with OncoPanel between July 2013 and July 2018 were included. For tumors tested after June 2017, sequencing results were presented to pathologists in real time for clinical MMR determination, in the context of tumor mutation burden, other mutational signatures, and clinical data. RESULTS Of 20,301 tumors sequenced, 2.7% (553) were retrospectively classified as MMR-D by the algorithm. Of 4,404 samples with pathologist sign-out of MMR status, the algorithm classified 147 (3.3%) as MMR-D: in 116 cases, MMR-D was confirmed by a pathologist, five cases were overruled by the pathologist, and 26 were assessed as indeterminate. Overall, the highest frequencies of OncoPanel-inferred MMR-D were in endometrial (21%; 152/723), colorectal (9.7%; 169/1,744), and small bowel (9.3%; 9/97) cancers. When algorithm predictions were compared with historical MMR immunohistochemistry or polymerase chain reaction results in a set of 325 tumors sequenced before initiation of pathologist assessment, the overall sensitivity and specificity of the algorithm were 91.1% and 98.2%, respectively. CONCLUSION We show that targeted, tumor-only NGS can be leveraged to determine MMR signatures across tumor types, suggesting that broader biomarker screening approaches may have clinical value.