Rate of True-Positive Findings of COVID-19 Typical Appearance at Chest CT per RSNA Consensus Guidelines in an Increasingly Vaccinated Population.

Background RSNA consensus guidelines for COVID-19-related chest CT are widely used but, to the knowledge of the authors, their rate of true-positive findings for COVID-19 pneumonia in vaccinated patients has not been assessed. Purpose To assess the rate of true-positive findings of typical appearance for COVID-19 at chest CT by using RSNA guidelines in fully vaccinated patients with polymerase chain reaction (PCR)-confirmed COVID-19 infection compared with unvaccinated patients. Materials and Methods Included were patients with COVID-19 who had typical appearance on chest CT images and one PCR test for COVID-19 with a positive result or two tests with negative results within 7 days of undergoing chest CT between January 2021 and January 2022 at a quaternary academic medical center. True-positive findings were defined as chest CT images interpreted as COVID-19 typical appearance and PCR-confirmed COVID-19 infection within 7 days. Logistic regression models were constructed to quantify the association between PCR results and vaccination status, vaccination status and COVID-19 variants, and vaccination status and number of months. Results Included were 652 patients (median age, 59 years; IQR, 48-72 years; 371 men [57%]) with CT scans classified as typical appearance. Of those patients, 483 (74%) were unvaccinated and 169 (26%) were fully vaccinated. The overall rate of true-positive findings on CT images rated as typical appearance was lower in vaccinated versus unvaccinated patients (70 of 169 [41%; 95% CI: 34, 49] vs 352 of 483 [73%; 95% CI: 69, 77]; odds ratio [OR], 3.8 [95% CI: 2.6, 5.5]; P < .001). Unvaccinated patients were more likely to have true-positive findings on CT images compared with fully vaccinated patients during the peaks of COVID-19 variants Alpha (OR, 16; 95% CI: 6, 42; P < .001) and Delta (OR, 8; 95% CI: 4, 16; P < .001), but no statistical differences were found during the peak of the Omicron variant (OR, 1.7; 95% CI: 0.3, 11; P = .56). Conclusion Fully vaccinated patients with confirmed COVID-19 breakthrough infections had lower rates of true-positive findings of COVID-19 typical appearance at chest CT. © RSNA, 2022 Supplemental material is available for this article.

Diagnostic accuracy of general dermatologists and supportive oncodermatologists for biopsied cutaneous immune-related adverse events.

PURPOSE: Supportive oncodermatology has been shown to improve several aspects of care for patients with cancer, but research showing improved diagnostic accuracy as a benefit of supportive oncodermatology is largely lacking. We thus aimed to evaluate different dermatologist groups' diagnostic accuracy for heterogenous cutaneous toxicities, using cutaneous immune-related adverse events (cirAEs) from immune checkpoint inhibitors (ICIs) as a test model. METHODS: Billing/requisition codes were used to identify patients who initiated programmed death-1/ligand-1 (PD-1/PD-L1) ICIs between 2010 and 2019 at Dana-Farber Cancer Institute/Brigham and Women's Hospital/Massachusetts General Hospital and underwent a subsequent skin biopsy. For each biopsied cirAE, pre-biopsy clinical diagnoses and post-biopsy clinico-pathologic diagnoses were retrospectively obtained from the medical record. Each biopsy-ordering dermatology provider was categorized as a general dermatologist or supportive oncodermatologist on the basis of providing clinical care within a cancer-center or attending on a hospital/clinic service dedicated to anti-cancer drug-related skin toxicities. RESULTS: Of 4,183 patients who initiated anti-PD-1/PD-L1 therapy between 2010 and 2019, 101 (2.4%) patients collectively had 104 biopsied cirAEs. In more than one-third of all reviewed biopsied cirAEs (n = 39, 37.5%), histopathology results frequently led to revision of the pre-biopsy clinical diagnosis. The rate of initial cirAE misclassification amongst supportive oncodermatologists was significantly lower than that amongst general dermatologists (18/66, 27.3% vs. 21/38, 55.3%; Fischer's-exact-test p = 0.006). CONCLUSION: Experienced supportive oncodermatologists may benefit patient care through increased diagnostic accuracy for skin toxicities from ICIs. Collectively, these results underscore that both skin biopsy from any dermatology provider and oncodermatology referral (where available) are valuable resources that should be integrated into supportive cancer care.

Patterns of Cutaneous and Noncutaneous Immune-Related Adverse Events Among Patients With Advanced Cancer.

Importance: Cutaneous immune-related adverse events (cirAEs) are some of the earliest toxic reactions to emerge following immune-checkpoint inhibitor (ICI) initiation. As an early indicator of robust inflammatory response, cirAEs may be associated with patterns of immune-mediated toxic effects, but associations between these events and noncutaneous immune-related adverse events (irAEs) remain underexplored. Objectives: To characterize patterns of cirAEs and irAEs across care settings and examine associations between the features of first cirAE, overall irAE risk, and risk of specific irAE subtypes. Design, Setting, and Participants: A retrospective cohort study was conducted at a single academic medical center. The cohort included 358 patients with cancer who initiated anti-programmed death 1/ligand 1 and/or anticytotoxic-T-lymphocyte-4 ICI therapy between January 1, 2016, and March 8, 2019, and developed 1 or more cirAEs, identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and confirmed via manual medical record review. All relevant information documented before March 31, 2020, was included. Exposures: Anti-programmed death 1/ligand 1 and/or anticytotoxic-T-lymphocyte-4 therapy. Main Outcomes and Measures: Associations between specific cirAE morphologic classes and patterns of irAEs (occurrence, timeline, organ class, and specific toxic effects). Given the potential that shared underlying factors are associated with the risk of both noncutaneous and cutaneous toxic effects, the presence of observed positive associations between certain cirAE and irAE subtypes was hypothesized. Results: Of the 358 patients, 213 were men (59.5%); median age was 65 years (interquartile range, 55-73 years). Nearly half of the patients (177 [49.4%]) with cirAE also developed a noncutaneous irAE. Most patients (128 [72.3%]) experienced their first cirAE before developing any irAE. Several cirAE morphologic classes were found to be associated with overall, organ-based, and specific irAEs. More specifically, mucositis was found to be associated with overall irAE risk (odds ratio [OR], 5.28; 95% CI, 1.11-24.26; P = .04), gastrointestinal irAEs (OR, 5.70; 95% CI, 1.11-29.40; P = .04), and the specific diagnosis of gastroenterocolitis (OR, 6.80; 95% CI, 1.24-37.39; P = .03). In addition, psoriasis was associated with an increased risk of endocrine irAEs (OR, 4.54; 95% CI, 1.21-17.04; P = .03). Conclusions and Relevance: In this cohort study, these findings underscore the risk of multisystem toxic effects in patients experiencing cirAEs and highlight potential opportunities for dermatologists in the management of noncutaneous toxic effects.

Retro-2 protects cells from ricin toxicity by inhibiting ASNA1-mediated ER targeting and insertion of tail-anchored proteins.

The small molecule Retro-2 prevents ricin toxicity through a poorly-defined mechanism of action (MOA), which involves halting retrograde vesicle transport to the endoplasmic reticulum (ER). CRISPRi genetic interaction analysis revealed Retro-2 activity resembles disruption of the transmembrane domain recognition complex (TRC) pathway, which mediates post-translational ER-targeting and insertion of tail-anchored (TA) proteins, including SNAREs required for retrograde transport. Cell-based and in vitro assays show that Retro-2 blocks delivery of newly-synthesized TA-proteins to the ER-targeting factor ASNA1 (TRC40). An ASNA1 point mutant identified using CRISPR-mediated mutagenesis abolishes both the cytoprotective effect of Retro-2 against ricin and its inhibitory effect on ASNA1-mediated ER-targeting. Together, our work explains how Retro-2 prevents retrograde trafficking of toxins by inhibiting TA-protein targeting, describes a general CRISPR strategy for predicting the MOA of small molecules, and paves the way for drugging the TRC pathway to treat broad classes of viruses known to be inhibited by Retro-2.

CRISPR screening using an expanded toolkit of autophagy reporters identifies TMEM41B as a novel autophagy factor.

The power of forward genetics in yeast is the foundation on which the field of autophagy research firmly stands. Complementary work on autophagy in higher eukaryotes has revealed both the deep conservation of this process, as well as novel mechanisms by which autophagy is regulated in the context of development, immunity, and neuronal homeostasis. The recent emergence of new clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-based technologies has begun facilitating efforts to define novel autophagy factors and pathways by forward genetic screening in mammalian cells. Here, we set out to develop an expanded toolkit of autophagy reporters amenable to CRISPR/Cas9 screening. Genome-wide screening of our reporters in mammalian cells recovered virtually all known autophagy-related (ATG) factors as well as previously uncharacterized factors, including vacuolar protein sorting 37 homolog A (VPS37A), transmembrane protein 251 (TMEM251), amyotrophic lateral sclerosis 2 (ALS2), and TMEM41B. To validate this data set, we used quantitative microscopy and biochemical analyses to show that 1 novel hit, TMEM41B, is required for phagophore maturation. TMEM41B is an integral endoplasmic reticulum (ER) membrane protein distantly related to the established autophagy factor vacuole membrane protein 1 (VMP1), and our data show that these two factors play related, albeit not fully overlapping, roles in autophagosome biogenesis. In sum, our work uncovers new ATG factors, reveals a malleable network of autophagy receptor genetic interactions, and provides a valuable resource (http://crispr.deniclab.com) for further mining of novel autophagy mechanisms.