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Background RSNA COVID-19 chest CT consensus guidelines are widely used, but their true positive rate for COVID-19 pneumonia has not been assessed among vaccinated patients. Purpose To assess true positive rate of RSNA typical chest CT findings of COVID-19 among fully vaccinated subjects with PCR-confirmed COVID-19 infection compared with unvaccinated subjects. Materials and Methods Patients with COVID Typical chest CT findings and one positive or two negative PCR tests for COVID-19 within 7 days of their chest CT between January 2021 - January 2022 at a quaternary academic medical center were included. True positives were defined as chest CTs interpreted as COVID Typical 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 months. Results 652 subjects (median age 59, [IQR, 48-72]); 371 [57%] men) with CT scans classified as COVID Typical were included. 483 (74%) were unvaccinated and 169 (26%) were fully vaccinated. The overall true positive rate of COVID Typical CTs was lower among vaccinated versus unvaccinated (70/169 [41%; 95% CI: 34, 49%] vs 352/483 [73%; 69, 77%]; OR (95% CI): 3.8 (2.6, 5.5); P.001). Unvaccinated subjects were more likely to have true positive CTs compared with fully vaccinated subjects during the peaks of COVID-19 variants Alpha (OR, 16 [95% CI: 6.1, 42]

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 2010–2019 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 2010–2019, 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%; Fisher’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.

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 usingInternational 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.

BACKGROUND Cutaneous immune-related adverse events (cirAEs) are a common side-effect of immune checkpoint inhibitors (ICIs). However, prior work examining these toxicities in detail has considered only the fraction of events evaluated by dermatologists. Associations between dermatology referral, cirAE treatment and survival outcomes remain underexplored across care settings. OBJECTIVES To comprehensively categorize cirAE patterns among all patients treated with immunotherapy at our institution, and to evaluate: (i) the effect of dermatology referral on cirAE treatment and (ii) the impact of cirAE treatment on survival. METHODS This was a retrospective cohort analysis of patients with cancer who initiated ICI therapy between 1 January 2016 and 8 March 2019 and developed one or more cirAEs, as screened for using International Classification of Diseases 10th revision codes and confirmed via manual chart review (n = 358). All relevant information documented prior to 31 March 2020 was included. RESULTS CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred (odds ratio 6·08, P

Immune checkpoint inhibitors (ICIs) have improved survival for multiple malignancies in adults and children.1,2 However, their benefits are tempered by a range of serious immune-related adverse events (irAEs). 1,2 Among these, cutaneous irAEs (cirAEs) represent one of the most common subtypes, impacting approximately one-third of adult patients receiving ICIs.1,3 The patterns and significance of cirAEs in children remain unclear, largely because these reactions have not been evaluated in detail.

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.

e14523 Background: Cutaneous immune-related adverse events (cirAE) may disrupt immune-checkpoint inhibitor (ICI) therapy. Current guidelines recommend systemic corticosteroids (SCS) for moderate to severe cirAE, but SCS-associated complications and their impact on survival remain poorly understood. We therefore investigated the impact of SCS exposures on infectious complications and survival outcomes among patients with cirAE. Methods: We retrospectively reviewed the medical records of patients who initiated anti-programmed death-1/ligand-1 (PD-1/PDL-1) and/or anti-cytotoxic-T-lymphocyte-4 (CTLA-4) ICI therapy between 1/1/16-3/8/19 with confirmed cirAE, obtaining oncologic history, clinical features, SCS exposures, infection rates, and survival outcomes. SCS exposures were categorized by indication (cirAE, other immune-related adverse event, other medical reason) and dosage in prednisone equivalents (low, ≤7.5mg/day for ≥2 months; moderate, > 7.5mg/day for ≥2 months; high, ≥1mg/kg/day for ≥1 week). Infection rates were compared among patients treated with SCS for initial cirAE and those with no SCS exposures for any indication. Cox proportional hazards (CPH) models adjusted for age, sex, and covariates with P

SummarySelective autophagy comprises cytoplasm-to-lysosome trafficking routes that transport cargos using double-membrane vesicles (autophagosomes). Cargos are detected by receptor proteins, which typically also bind to lipid-conjugated LC3 proteins on autophagosome membranes. We dissected lysosomal delivery of four SQSTM1-like receptors by genome-wide CRISPR screening looking for novel autophagy-related (ATG) factors and trafficking routes. We uncovered new mammalian ATG factors including TMEM41B, an endoplasmic reticulum membrane protein required for autophagosome membrane expansion and/or closure. Furthermore, we found that certain receptors remain robustly targeted to the lysosome even in the absence of ATG7 or other LC3 conjugation factors. Lastly, we identified a unique genetic fingerprint behind receptor flux in ATG7KO cells, which includes factors implicated in nucleating autophagosome formation and vesicle trafficking factors. 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.