Citations

Purpose: We previously analyzed the 2006 appropriateness criteria for cardiac computed tomography (CT) and found 42% of our patients were not classifiable, suggesting the criteria were difficult to apply clinically. These criteria were revised in 2010. The purpose of our study is to compare the new 2010 appropriate use criteria to the original 2006 criteria to determine if the 2010 criteria were more applicable. Materials and Methods: In a previous study we applied the 2006 appropriateness criteria to 251 patients that underwent cardiac CT from June 1 to December 31, 2007. Each patient was assigned an indication from the 2006 appropriate use criteria by two observers, classifying patients as appropriate, inappropriate, uncertain, or nonclassifiable. A third observer settled disagreements. This process was applied to the same 251 patients using the 2010 criteria. The data from the previous study using the 2006 criteria was compared to the data obtained using the 2010 criteria to determine changes in the number of nonclassifiable, appropriate, inappropriate, and uncertain exams. These results were then analyzed using Bowker's test of symmetry. Observer agreement was calculated using the kappa statistic. Results: 115 patients (46%) were not classifiable using the 2006 criteria. When the 2010 criteria were applied, the number of not classifiable patients decreased to 40 (16%), with the plurality, 41 (16%), of the not classifiable patients moving to inappropriate. In 2006, 69 (27%) were classified as appropriate, 25 (10%) were uncertain, 42 (17%) inappropriate. In 2010, the appropriate increased to 84 (33%), uncertain increased to 40 (16%), and inappropriate increased to 87 (35%). Bowker's test of symmetry demonstrated a statistically significant change with a p<0.001. Agreement between the two observers assigning patients to classification groups also improved with a kappa of 0.55 using the 2010 criteria compared to kappa of 0.31 in 2006. Conclusion: The number of not classifiable patients decreased using the 2010 criteria and the interobserver agreement improved, suggesting they are more applicable and complete than the 2006 criteria. This decrease in not classifiable patients came primarily from an increase in the number of inappropriate indications.

The Impact of Ordering Provider Specialty on Appropriateness Classification In prior studies, our laboratory applied the ACCF/ASNC AUC for SPECT MPI to several cohorts of patients in Mayo Clinic Rochester. The purpose of this study was to re-examine our data to test the hypothesis that the specialty of the ordering provider affected the appropriateness. We compared the ordering providers specialty with appropriateness determined in prior studies. The study group consisted of 281 patients who underwent stress SPECT MPI studies in May 2005 and 282 patients in October 2006 (before any quality improvement initiatives were begun at Mayo). Appropriateness categories were assigned by 2 experienced nurses from the CV Research Studies Unit not affiliated with the nuclear laboratory. Patients who were studied for pre-operative evaluation (n = 20) or post myocardial infarction (n = 7) were excluded because they comprised less than 5 percent of the patients. Pre-operative testing in our institution is done primarily by stress echocardiography. The final study group consisted of 526 patients. Excluding the 64 unclassified patients, AUE categories were appropriate (75 %), uncertain (13 %), inappropriate (12%). Results by ordering provider are shown in the figure, where CV = Cardiovascular MDs, ED = Emergency Department MDs, IM = General and Internal Medicine MDs, RN = Registered Nurses, and SP = other Specialty MDs. There was no significant association (p = 0.19); Chi-square analysis between appropriateness and specialty groups. In a clinical practice where pre-operative testing using SPECT is infrequent, the rate of inappropriate studies was similar for all ordering providers. Quality improvement efforts in similar practices will likely require a broad focus on all ordering physicians/nurses.

Background: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. Methods: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18–90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. Results: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC–; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P <.001) and FPC group assignment (odds ratio, 1.57; P <.001; relative to PGV+/FPC–) were independent predictors of harboring a pancreatic cyst. Conclusions: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC– risk groups by surveillance protocols.

Abstract Background Since 2009, inflammatory bowel disease (IBD) specialists have utilized “IBD LIVE,” a weekly live video conference with a global audience, to discuss the multidisciplinary management of their most challenging cases. While most cases presented were confirmed IBD, a substantial number were diseases that mimic IBD. We have categorized all IBD LIVE cases and identified “IBD-mimics” with consequent clinical management implications. Methods Cases have been recorded/archived since May 2018; we reviewed all 371 cases from May 2018–February 2023. IBD-mimics were analyzed/categorized according to their diagnostic and therapeutic workup. Results Confirmed IBD cases made up 82.5% (306/371; 193 Crohn’s disease, 107 ulcerative colitis, and 6 IBD-unclassified). Sixty-five (17.5%) cases were found to be mimics, most commonly medication-induced (n = 8) or vasculitis (n = 7). The evaluations that ultimately resulted in correct diagnosis included additional endoscopic biopsies (n = 13, 21%), surgical exploration/pathology (n = 10, 16.5%), biopsies from outside the GI tract (n = 10, 16.5%), genetic/laboratory testing (n = 8, 13%), extensive review of patient history (n = 8, 13%), imaging (n = 5, 8%), balloon enteroscopy (n = 5, 8%), and capsule endoscopy (n = 2, 3%). Twenty-five patients (25/65, 38%) were treated with biologics for presumed IBD, 5 of whom subsequently experienced adverse events requiring discontinuation of the biologic. Many patients were prescribed steroids, azathioprine, mercaptopurine, or methotrexate, and 3 were trialed on tofacitinib. Conclusions The diverse presentation of IBD and IBD-mimics necessitates periodic consideration of the differential diagnosis, and reassessment of treatment in presumed IBD patients without appropriate clinical response. The substantial differences and often conflicting treatment approaches to IBD versus IBD-mimics directly impact the quality and cost of patient care.

BACKGROUND Diagnosis of PMM2-CDG, the most common congenital disorder of glycosylation (CDG), relies on measuring carbohydrate-deficient transferrin (CDT) and genetic testing. CDT tests have false negatives and may normalize with age. Site-specific changes in protein N-glycosylation have not been reported in sera in PMM2-CDG. METHODS Using multistep mass spectrometry–based N-glycoproteomics, we analyzed sera from 72 individuals to discover and validate glycopeptide alterations. We performed comprehensive tandem mass tag–based discovery experiments in well-characterized patients and controls. Next, we developed a method for rapid profiling of additional samples. Finally, targeted mass spectrometry was used for validation in an independent set of samples in a blinded fashion. RESULTS Of the 3,342 N-glycopeptides identified, patients exhibited decrease in complex-type N-glycans and increase in truncated, mannose-rich, and hybrid species. We identified a glycopeptide from complement C4 carrying the glycan Man 5 GlcNAc 2 , which was not detected in controls, in 5 patients with normal CDT results, including 1 after liver transplant and 2 with a known genetic variant associated with mild disease, indicating greater sensitivity than CDT. It was detected by targeted analysis in 2 individuals with variants of uncertain significance in PMM2 . CONCLUSION Complement C4–derived Man 5 GlcNAc 2 glycopeptide could be a biomarker for accurate diagnosis and therapeutic monitoring of patients with PMM2-CDG and other CDGs. FUNDING U54NS115198 (Frontiers in Congenital Disorders of Glycosylation: NINDS; NCATS; Eunice Kennedy Shriver NICHD; Rare Disorders Consortium Disease Network); K08NS118119 (NINDS); Minnesota Partnership for Biotechnology and Medical Genomics; Rocket Fund; R01DK099551 (NIDDK); Mayo Clinic DERIVE Office; Mayo Clinic Center for Biomedical Discovery; IA/CRC/20/1/600002 (Center for Rare Disease Diagnosis, Research and Training; DBT/Wellcome Trust India Alliance)

AbstractBackgroundUndifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence‐based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi‐institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative.MethodsData were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event‐free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively.ResultsSeventy‐eight patients were identified with a median age of 9.9 years [interquartile range [IQR): 7–12]. Twenty‐seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6 cm [IQR: 0.0–4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04–0.6]. At a median follow‐up of 4 years [IQR: 2–8], the EFS was 70.0% [95% CI: 60%–82%] and OS was 83% [95% CI: 75%–93%].ConclusionComplete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

AbstractObjectiveTo develop a convolutional neural network‐based computer vision model to recognize and track 2 mastoidectomy surgical instruments—the drill and the suction‐irrigator—from intraoperative video recordings of mastoidectomies.Study DesignTechnological development and model validation.SettingAcademic center.MethodsTen 1‐minute videos of mastoidectomies done for cochlear implantation by varying levels of resident surgeons were collected. For each video, containing 900 frames, an open‐access computer vision annotation tool was used to annotate the drill and suction‐irrigator class images with bounding boxes. A mastoidectomy instrument tracking module, which extracts the center coordinates of bounding boxes, was developed using a feature pyramid network and layered with DETECTRON, an open‐access faster—region‐based convolutional neural network. Eight videos were used to train the model, and 2 videos were used for testing. Outcome measures included Intersection over Union (IoU) ratio, accuracy, and average precision.ResultsFor an IoU of 0.5, the mean average precision for the drill was 99% and 86% for the suction‐irrigator. The model proved capable of generating maps of drill and suction‐irrigator stroke direction and distance for the entirety of each video.ConclusionsThis computer vision model can identify and track the drill and suction‐irrigator from videos of intraoperative mastoidectomies performed by residents with excellent precision. It can now be employed to retrospectively study objective mastoidectomy measures of expert and resident surgeons, such as drill and suction‐irrigator stroke concentration, economy of motion, speed, and coordination, setting the stage for characterization of objective expectations for safe and efficient mastoidectomies.

Abstract Background: Neuropilin 2 (NRP2) is a co-receptor that enhances signaling of growth factor and cytokine receptors and is expressed in tumor and microenvironment (TME) cells in melanoma and other tumors. Neuropilin 2 expression in tumor cells is associated with more aggressive tumors. Expression in tumor associated macrophages enhances efferocytosis and immunologically silent tumor cell death. Methods: Whole excisional lymph node biopsies were obtained from 10 treatment naïve patients with metastatic cutaneous melanoma who subsequently received anti-PD1 treatment. A single 5mm formalin-fixed paraffin embedded tissue section was used to assess a panel of 39 analytes by cyclic multiplex immunofluorescence (MxIF). Fields of view (~1mm2, n=288) were selected from pathologist-annotated regions of the tumor core, tumor-immune interface and adjacent lymphoid tissue. Pixel-based single cell segmentation and a supervised classifier approach was applied to resolve 12 distinct tumor, stromal and immune cell phenotypes and functional states (NRP2 positive or negative) in 1.5 million cells. Results: Tumor recurrence was observed in 6 patients (relapsed), whereas 4 patients were recurrence-free (non-relapsed) during follow up. Among the different cell types, NRP2 expression was more frequent in macrophages (44%), tumor cells (40%), dendritic cells (40%), followed by Tregs (31%) and T helper cells (29%), and less frequent in neutrophils (24%), cytotoxic T cells (23%) and B cells (15%). In colocalization permutation analysis, NRP2 expressing macrophages clustered away from tumor cells in non-relapsed patients while a random spatial distribution of NRP2 expressing macrophages with respect to tumor cells was observed in relapsed patients. In comparing the odds of tumor cell interactions with NRP2-expressing macrophages to those with NRP2 non-expressing macrophages, we found in the tumor:stromal interface (10% tumor cells) that cells from both non-relapsed and relapsed patients were more likely to interact with NRP2 non-expressing macrophages (OR = 0.73, 95% CI = [0.71, 0.75] and OR = 0.56, 95% CI = [0.55, 0.58] for non-relapsed and relapsed patients, respectively). However, in the tumor core (90% tumor cells), tumor cells from relapsed patients had significantly higher odds of interacting with NRP2 expressing macrophages, (OR = 1.15, 95% CI = [1.12, 1.18]), and this was not seen for non-relapsed patients (OR = 0.68, 95% CI = [0.66, 0.71]). In FOVs dominated by tumor cells (75% tumor), tumor cells from relapsed patients had 4.97 times the odds of expressing NRP2 compared to tumor cells from non-relapsed patients (95% CI = [2.23, 11.09], p = 0.0001). Conclusions: These spatial analytics suggest complex interactions among NRP2 expression in tumor and TME of melanoma determining risk for relapse with anti-PD1 treatment. Citation Format: Anastasios Dimou, Raymond M. Moore, Caitlin Ward, Alexey Leontovich, Ruifeng Guo, Chen Wang, Shankar Suman, Betty Dicke, Jill M. Schimke, Noah A. Stueven, Chathu A. Atherton, Wendy Nevala, Svetomir N. Markovic. Spatial analysis of neuropilin 2 expression in the microenvironment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2905.

Abstract Spread to regional lymph nodes is the most common site of metastasis from melanoma and almost all solid tumors. Lymphatic metastases begin in the first lymph nodes draining from the primary tumor, i.e., the sentinel lymph nodes (SLN), preceded by the development of the premetastatic niche (PMN) initiated by primary cutaneous melanoma. Melanoma mediators are known to play a critical role in developing the PMN through the immune subversion in SLN. The DCs are a vital component of LN immunity that directly relates to eliciting T-cell functions. Our multiplex immunofluorescence (MxIF) analysis of SLNs indicates significantly decreased levels of DCs and cytotoxic-T cells in both core and interface areas of tumors in recurred patients treated with immunotherapy compared to non-recurred melanoma patients. The goal of this study is to determine whether the lymphatic extracellular vesicles (L-EVs) of melanoma patients regulate DC tolerization in SLN in order to stimulate the development of PMN. To identify whether L-EVs stimulate DC suppression, we extracted L-EVs from the lymphatic fluid of patients with melanoma downstream of primary cutaneous melanomas, compared it with controls (non-malignant post-operative fluid collected from the lymph node dissection field, and evaluated their effect on DC maturation by challenging these L-EVs in monocytic (CD14+) and hematopoietic stem cells (CD34+) cells. We found that L-EVs derived from melanoma patients suppress differentiation of CD11c+HLA-DR+ DCs and their maturation (defined by CD83 and CD86) compared to control L-EVs in CD14+ based DC maturation assay. We also found a reduction of conventional type 1 DC (cDC1) in CD34+-based DC maturation assay those challenged with patients’ L-EVs compared to control. To understand the mechanism of DC suppression in patients' L-EVs, we also conducted a total RNA sequencing analysis of subsets of DCs from maturation experiments to evaluate differently regulated transcriptomic profiles. The gene ontology analysis indicates that patient-derived L-EVs interfere with tRNA processing, oncostatin M & IL-10 signaling, and other immunoregulatory pathways to alter the hematopoietic cell lineage pathways in the DC maturation. Furthermore, the proteomic analysis of L-EVs also indicated several differentially regulated cargo-identified proteins in patient L-EVs, which are associated with immunomodulation, including regulation of DC function compared to control L-EVs. In conclusion, our study revealed that the patient's L-EVs carry differential proteomic cargoes secreted by cutaneous melanoma, which may be involved in regulating DC differentiation and maturation to diminish their functions and support the developing PMN in SLN. Citation Format: Shankar Suman, Wendy K. Nevala, James W. Jakub, Ray Guo, Alexey A. Leontovich, Raymond M. Moore, Chathu L. Atherton, Liyi Geng, Jeffrey E. Johnson, Sarah A. McLaughlin, Svetomir N. Markovic. Melanoma-derived lymphatic extracellular vesicles suppress dendritic cell differentiation and maturation in the sentinel lymph node [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1503.