Incidence of In Situ and Invasive Cutaneous Melanomas During the COVID-19 Pandemic in the US.

This cohort study provides detailed annual rates and percentage changes of melanoma incidence before vs during the COVID-19 pandemic.

Cutaneous immune-related adverse events from immune checkpoint inhibitor therapy: Moving beyond "maculopapular rash".

Uncoupling toxicity from therapeutic effect lies at the foundation of the current state of the field of cutaneous immune-related adverse events to immune checkpoint inhibitor therapy. This will be achieved through understanding the drivers of toxicity, tumor response, and resistance via large, well-powered population-level studies, institutional cohort data, and cellular-level data. Increasing diagnostic specificity through the application of consensus disease definitions has the power to improve clinical care and each approach to research. Cutaneous immune-related adverse events are associated with increased survival, and their treatment must invoke the maintenance of a delicate balance between immunosuppression, anti-tumor effect of immune checkpoint inhibitor therapy, and quality of life. The multidisciplinary care of cancer patients with adverse events is critical to optimizing clinical and translational research outcomes and, as such, dermatologists are vital to moving the study of cutaneous adverse events forward.

DNA repair and immune checkpoint blockade response.

Immune checkpoint blockade (ICB) has shown immense promise for treating patients with various cancer types, but its effectiveness relies on our ability to identify likely responders. Here, we examined the association between mutations in 25 core DNA repair genes and ICB outcomes in 6619 patients across 9 cancer types with advanced disease and MSK-IMPACT tumor sequencing. Notably, we observed that mutations in 7 of the DNA repair genes (ATM, ATR, POLE, ERCC4, NBN, RAD50, PARP1) were significantly associated with improved overall survival in ICB-treated patients (p < 0.05 for all) and had significant interaction with treatment (pinteraction <0.05 for all). Similarly, DNA repair mutations were enriched in other cancer types not previously assessed and primary tumors of unknown origins, suggesting that mutations could serve as a biomarker independent of cancer type. Although our cohort was enriched in certain cancer types, such as melanoma and non-small cell lung cancer, and clinically matched samples were not assessed, our study provides a robust approach in characterizing clinically-adoptable biomarkers that can select for potential ICB responders.

Pan-Cancer Survival Classification With Clinicopathological and Targeted Gene Expression Features.

Prognostication for patients with cancer is important for clinical planning and management, but remains challenging given the large number of factors that can influence outcomes. As such, there is a need to identify features that can robustly predict patient outcomes. We evaluated 8608 patient tumor samples across 16 cancer types from The Cancer Genome Atlas and generated distinct survival classifiers for each using clinical and histopathological data accessible to standard oncology workflows. For cancers that had poor model performance, we deployed a random-forest-embedded sequential forward selection approach that began with an initial subset of the 15 most predictive clinicopathological features before sequentially appending the next most informative gene as an additional feature. With classifiers derived from clinical and histopathological features alone, we observed cancer-type-dependent model performance and an area under the receiver operating curve (AUROC) range of 0.65 to 0.91 across all 16 cancer types for 1- and 3-year survival prediction, with some classifiers consistently outperforming those for others. As such, for cancers that had poor model performance, we posited that the addition of more complex biomolecular features could enhance our ability to prognose patients where clinicopathological features were insufficient. With the inclusion of gene expression data, model performance for 3 select cancers (glioblastoma, stomach/gastric adenocarcinoma, ovarian serous carcinoma) markedly increased from initial AUROC scores of 0.66, 0.69, and 0.67 to 0.76, 0.77, and 0.77, respectively. As a whole, this study provides a thorough examination of the relative contributions of clinical, pathological, and gene expression data in predicting overall survival and reveals cancer types for which clinical features are already strong predictors and those where additional biomolecular information is needed.

Pan-cancer Transcriptomic Predictors of Perineural Invasion Improve Occult Histopathologic Detection.

PURPOSE: Perineural invasion (PNI) is associated with aggressive tumor behavior, recurrence, and metastasis, and can influence the administration of adjuvant treatment. However, standard histopathologic examination has limited sensitivity in detecting PNI and does not provide insights into its mechanistic underpinnings. EXPERIMENTAL DESIGN: A multivariate Cox regression was performed to validate associations between PNI and survival in 2,029 patients across 12 cancer types. Differential expression and gene set enrichment analysis were used to learn PNI-associated programs. Machine learning models were applied to build a PNI gene expression classifier. A blinded re-review of hematoxylin and eosin (H&E) slides by a board-certified pathologist helped determine whether the classifier could improve occult histopathologic detection of PNI. RESULTS: PNI associated with both poor overall survival [HR, 1.73; 95% confidence interval (CI), 1.27-2.36; P < 0.001] and disease-free survival (HR, 1.79; 95% CI, 1.38-2.32; P < 0.001). Neural-like, prosurvival, and invasive programs were enriched in PNI-positive tumors (P adj < 0.001). Although PNI-associated features likely reflect in part the increased presence of nerves, many differentially expressed genes mapped specifically to malignant cells from single-cell atlases. A PNI gene expression classifier was derived using random forest and evaluated as a tool for occult histopathologic detection. On a blinded H&E re-review of sections initially described as PNI negative, more specimens were reannotated as PNI positive in the high classifier score cohort compared with the low-scoring cohort (P = 0.03, Fisher exact test). CONCLUSIONS: This study provides salient biological insights regarding PNI and demonstrates a role for gene expression classifiers to augment detection of histopathologic features.

The Internal Superior Laryngeal Nerve in Humans: Evidence for Pure Sensory Function.

OBJECTIVES: To determine if the internal branch of the superior laryngeal nerve (iSLN) provides direct motor innervation to the interarytenoid muscle, a laryngeal adductor critical for airway protection. We studied the iSLN-evoked motor response in the interarytenoid and other laryngeal muscles. If the iSLN is purely sensory, there will be no detectable short latency motor response upon supramaximal stimulation, indicating the absence of a direct efferent conduction path. STUDY DESIGN: Intraoperative case series. METHODS: In seven anesthetized patients undergoing laryngectomy for unilateral laryngeal carcinoma, the iSLN of the unaffected side was electrically stimulated intraoperatively with 0.1-ms pulses of progressive intensities until supramaximal stimulation was reached. Electromyographic responses were measured in the ipsilateral interarytenoid, thyroarytenoid, and cricothyroid muscles. RESULTS: None of the subjects exhibited short-latency interarytenoid motor responses to iSLN stimulation. Supramaximal electrical stimulation of the intact iSLN evoked ipsilateral motor responses with long latencies: 18.7-38.5 ms in the interarytenoid (n = 6) and 17.8-24.9 ms in the thyroarytenoid (n = 5). Supramaximal stimulation of the recurrent laryngeal nerve evoked ipsilateral motor responses with short latencies: 1.6-3.9 ms in the interarytenoid (n = 6) and 1.6-2.7 ms in the thyroarytenoid (n = 6). CONCLUSION: The iSLN provides no functional efferent motor innervation to the interarytenoid muscles. The iSLN exclusively evokes an interarytenoid motor response via afferent activation of central neural circuits that mediate the laryngeal reflex arc. These findings suggest that the role of the iSLN in vital laryngopharyngeal functions, such as normal swallowing and protection of the airway from aspiration, is purely sensory. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E207-E211, 2021.

Human norovirus targets enteroendocrine epithelial cells in the small intestine.

Human noroviruses are a major cause of diarrheal illness, but pathogenesis is poorly understood. Here, we investigate the cellular tropism of norovirus in specimens from four immunocompromised patients. Abundant norovirus antigen and RNA are detected throughout the small intestinal tract in jejunal and ileal tissue from one pediatric intestinal transplant recipient with severe gastroenteritis. Negative-sense viral RNA, a marker of active viral replication, is found predominantly in intestinal epithelial cells, with chromogranin A-positive enteroendocrine cells (EECs) identified as a permissive cell type in this patient. These findings are consistent with the detection of norovirus-positive EECs in the other three immunocompromised patients. Investigation of the signaling pathways induced in EECs that mediate communication between the gut and brain may clarify mechanisms of pathogenesis and lead to the development of in vitro model systems in which to evaluate norovirus vaccines and treatment.