Citations

Abstract Genome wide association studies (GWAS) in 9,013 pancreatic cancer patients and 12,452 controls of European ancestry have discovered over 20 risk loci in the human genome. Here, we fine mapped one such locus on chromosome 16q23.1 in the vicinity of two Chymotrypsinogen precursor genes, CTRB1 and CTRB2. We fine-mapped this locus to rs72802365 (P=2.51x10-17, OR=1.36, 95% CI=1.31-1.40) and identified colocalization (PP=87%) with aberrant exon 5→7 CTRB2 splicing in pancreatic tissues. Imputation of a 584 bp insertion/deletion variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (P=2.83x10-16, OR=1.36, 95% CI=1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsin B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). The intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein may lead to ER stress and pancreatic inflammation, which in turn, may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles. Citation Format: Ashley Jermusyk, Jun Zhong, Naomi Gordon, Katelyn Connelly, Sumeth Perera, Ehssan Abdolalizadeh, Tongwu Zhang, Aidan O'Brien, Jason Hoskins, Irene Collins, Daina Eiser, Chen Yuan, Harvey Risch, Eric J. Jacobs, Donghui Li, Mengmeng Du, Rachael Stolzenberg-Solomon, Alison P. Klein, Jill P. Smith, Brian M. Wolpin, Stephen J. Chanock, Jianxin Shi, Gloria M. Petersen, Christopher Westlake, Laufey T. Amundadottir. An exception to the rule: A coding functional variant at a pancreatic cancer GWAS locus [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-11.

Abstract Introduction/Objective Advances in whole slide imaging have enabled the application of machine learning algorithms to anatomic pathology. In the current state, the development of accurate algorithms requires robust training data with correctly assigned diagnostic and classification labels. Increasingly, institutions have looked to their archival slides as a source of “ground truth” for algorithm development. However, the curation and use of archival data poses several challenges. Here, we share lessons learned from reviewing head and neck pathology consult cases spanning a 10- year period at Mayo Clinic Rochester. Methods Archived surgical pathology slides from 2,590 consult cases were reviewed. Clinical and demographic information was recorded for each case, including surgical date, surgical procedure, anatomic site, age, gender and diagnosis. Cases were excluded from the curated archive if there was insufficient volume or quality of tissue to render a specific diagnosis (141 cases, 5.6%). Slides with a range of tissue size and quality, from numerable laboratories were included in the curated archive. Selected cases were collated by anatomic site: ear, gnathic, larynx, nasopharynx, neck, oral cavity, oropharynx, salivary gland and sinonasal tract. Results Common diagnostic reconciliations (115 cases, 4.4%) fell within the following categories: (1) novel entities (59 cases, 2.3%), including biphenotypic sinonasal sarcoma and clear cell carcinoma; (2) novel classifications (21 cases, 0.8%), as seen in HPV-related oropharyngeal squamous cell carcinoma and polymorphous adenocarcinoma; and (3) novel grading schema (35 cases, 1.4%), as seen in keratinizing dysplasia and oropharyngeal malignancies. Conclusion Several nuances emerged in the process of reviewing slides, highlighting the need for continual amendment of any machine learning dataset over time. Curating anatomic pathology cases for machine learning algorithm development requires the recognition of emerging entities, with re-classification and re-grading as needed.

Abstract Purpose: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 × 104 to 3 × 106 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n = 2) and grade 4 gas gangrene (n = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n = 1), limb abscess (n = 1), soft-tissue infection (n = 1), respiratory insufficiency (n = 1), and rash (n = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.

Integrative single-cell analysis de-constructs the heterogeneity of human reprogramming and uncovers its stage-specific GRNs.

Tick-borne diseases, due to a diversity of bacterial pathogens, represent a significant and increasing public health threat throughout the Northern Hemisphere. A high-throughput 16S V1-V2 rRNA gene-based metagenomics assay was developed and evaluated using >13,000 residual samples from patients suspected of having tick-borne illness and >1,000 controls. Taxonomic predictions for tick-borne bacteria were exceptionally accurate, as independently validated by secondary testing. Overall, 881 specimens were positive for bacterial tick-borne agents.

BackgroundStroke etiology is undetermined in approximately one‐sixth to one‐third of patients. The presence of aortic flow reversal and plaques in the descending aorta (DAo) has been identified as a potential retrograde embolic mechanism.PurposeTo assess the relationships between aortic stiffness, wall thickness, and flow reversal in patients with cryptogenic stroke and healthy controls.Study TypeProspective.PopulationTwenty one patients with cryptogenic stroke and proven DAo plaques (69 ± 9 years, 43% female), 18 age‐matched controls (age: 65 ± 8 years, 61% female), and 14 younger controls (36 ± 9 years, 57% female).Field Strength/Sequence1.5T; 4D flow MRI and 3D dark blood T1‐weighted turbo spin echo MRI of the aorta.AssessmentNoncontrast aortic 4D flow MRI to measure 3D flow dynamics and 3D dark blood aortic wall MRI to assess wall thickness. 4D flow MRI analysis included automated quantification of aortic stiffness by pulse wave velocity (PWV) and voxelwise mapping of the flow reversal fraction (FRF).Statistical TestsAnalysis of variance (ANOVA) or Kruskal–Wallis tests, Student's unpaired t‐tests or Wilcoxon rank‐sum tests, regression analysis.ResultsAortic PWV and FRF were statistically higher in patients (8.9 ± 1.7 m/s, 18.4 ± 7.7%) than younger controls (5.3 ± 0.8 m/s, P < 0.0167; 8.5 ± 2.9%, P < 0.0167), but not age‐matched controls (8.2 ± 1.6 m/s, P = 0.22; 15.6 ± 5.8%, P = 0.22). Maximum aortic wall thickness was higher in patients (3.1 ± 0.7 mm) than younger controls (2.2 ± 0.2 mm, P < 0.0167) and age‐matched controls (2.7 ± 0.5 mm) (P < 0.0167). For all subjects, positive relationships were found between PWV and age (R2 = 0.71, P < 0.05), aortic wall thickness (R2 = 0.20, P < 0.05), and FRF (R2 = 0.47, P < 0.05). Patients demonstrated relationships between PWV and FRF in the ascending aorta (R2 = 0.32, P < 0.05) and arch (R2 = 0.24, P < 0.05).Data ConclusionThis study showed the utility of 4D flow MRI for evaluating aortic PWV and voxelwise flow reversal. Positive relationships between aortic PWV, wall thickness, and flow reversal support the hypothesis that aortic stiffness is involved in this retrograde embolic mechanism.Level of Evidence2Technical Efficacy Stage1

Magnetic resonance imaging and spectroscopy (MRI/MRS) at 7T represents an exciting advance in MR technology, with intriguing possibilities to enhance image spatial, spectral, and contrast resolution. To ensure the safe use of this technology while still harnessing its potential, clinical staff and researchers need to be cognizant of some safety concerns arising from the increased magnetic field strength and higher Larmor frequency. The higher static magnetic fields give rise to enhanced transient bioeffects and an increased risk of adverse incidents related to electrically conductive implants. Many technical challenges remain and the continuing rapid pace of development of 7T MRI/MRS is likely to present further challenges to ensuring safety of this technology in the years ahead. The recent regulatory clearance for clinical diagnostic imaging at 7T will likely increase the installed base of 7T systems, particularly in hospital environments with little prior ultrahigh‐field MR experience. Informed risk/benefit analyses will be required, particularly where implant manufacturer‐published 7T safety guidelines for implants are unavailable. On behalf of the International Society for Magnetic Resonance in Medicine, the aim of this article is to provide a reference document to assist institutions developing local institutional policies and procedures that are specific to the safe operation of 7T MRI/MRS. Details of current 7T technology and the physics underpinning its functionality are reviewed, with the aim of supporting efforts to expand the use of 7T MRI/MRS in both research and clinical environments. Current gaps in knowledge are also identified, where additional research and development are required. Level of Evidence 5 Technical Efficacy 2 J. MAGN. RESON. IMAGING 2021;53:333–346.