Genomic testing among patients with newly diagnosed advanced non-small cell lung cancer in the United States: A contemporary clinical practice patterns study.

OBJECTIVES: According to 2018 United States and international lung cancer and pathology guidelines, testing of EGFR, ALK, ROS1 and BRAF genes is a minimum requirement to identify targeted therapy options in patients with advanced non-small cell lung cancer (aNSCLC). We describe real-world use and clinical features of next-generation sequencing (NGS) and other non-NGS testing technologies in these patients. MATERIALS AND METHODS: Patients were from the Flatiron Health electronic health record-derived de-identified database and were newly diagnosed with non-squamous aNSCLC between 1 January 2018 and 30 June 2019. We describe occurrence and patterns of NGS- (including comprehensive genomic profiling [CGP]) and non-NGS-based genomic testing before the start of first-line therapy, unsuccessful genotyping (<4 genes tested) and incidence of potentially missed targeted therapy options (<4 genes tested with no positive results). RESULTS: Among 3050 patients, 2356 received any type of genomic testing (NGS: 1406 [59.7%]). Unsuccessful genotyping occurred in 13.2% and 52.2% of NGS- and non-NGS-tested patients, respectively. Among NGS-tested patients, 10.0% had a potentially missed targeted therapy option (CGP: 2.9%), compared with 40.2% in the non-NGS tested group. While all four guideline-recommended genes were tested in ≥ 92% of patients who had NGS testing, when only non-NGS testing was used, although EGFR and ALK had similarly high testing proportions, BRAF and ROS1 (56.1% and 83.7%, respectively) were examined less often. CONCLUSIONS: Our findings suggest that in aNSCLC clinical practice, NGS testing may help to avoid potentially missed targeted therapy options and improve testing uptake for recently approved biomarkers. Results therefore support the use of guideline-recommended broad-panel NGS testing in clinical practice.

Clinico-Genomic Characterization of Patients with Metastatic Urothelial Carcinoma in Real-World Practice Identifies a Novel Bladder Immune Performance Index (BIPI).

PURPOSE: This retrospective analysis of the largest available clinico-genomic database used de-identified patient-level electronic health record-derived real-world data (RWD) combined with FoundationOne comprehensive genomic profiling (CGP) to characterize patients with metastatic urothelial carcinoma (mUC) treated in the real-world setting, detect potential biomarkers, and develop a bladder immune performance index (BIPI). EXPERIMENTAL DESIGN: Patients with mUC who started front-line single-agent immune checkpoint inhibitors (ICI) and an unmatched group treated with front-line platinum-based chemotherapy between January 1, 2011, and September 30, 2019, were selected. Clinical and genomic data were correlated with overall survival (OS). A novel BIPI predicting outcome with ICIs was developed using machine learning methods and validated using data from a phase II trial (NCT02951767). RESULTS: In ICI-treated patients (n = 118), high tumor mutational burden (≥10 mutations/megabase) was associated with improved OS (HR, 0.58; 95% CI, 0.35-0.95; P = 0.03). In chemotherapy-treated patients (n = 268), those with high APOBEC mutational signature had worse OS (HR, 1.43; 95% CI, 1.06-1.94; P = 0.02). Neither FGFR3 mutations nor DNA damage-repair pathway alterations were associated with OS. A novel BIPI combining clinical and genomic variables (nonmetastatic at initial diagnosis, normal or above normal albumin level at baseline, prior surgery for organ-confined disease, high tumor mutational burden) identified ICI-treated patients with longest OS and was validated in an independent dataset. CONCLUSIONS: Contemporary RWD including FoundationOne CGP can be used to characterize outcomes in real-world patients according to biomarkers beyond PD-L1. A validated, novel clinico-genomic BIPI demonstrated satisfactory prognostic performance for OS in patients with mUC receiving front-line ICI therapy.

Association between olfactory dysfunction and COVID-19 severity: A prospective study in a highly complex hospital in Peru.

INTRODUCTION: Olfactory dysfunction has been included among the early symptoms of coronavirus disease (COVID-19). Evidence suggests that a relationship exists between the duration of olfaction disorders and the probability of developing severe COVID-19. Given the scope of the COVID-19 pandemic, this study aimed to determine the frequency of smell alteration and its association with the severity of COVID-19 in a referral hospital in Peru, which is one of the most affected countries in the Latin American region. MATERIALS AND METHODS: This study was an observational, prospective cohort study that included patients with COVID-19 who were treated at the Hospital Nacional Edgardo Rebagliati Martins from August to November 2020. To assess the association, the chi-square test of independence or Fisher's exact test was performed. The outcome variable was COVID-19 severity, and the exposure variable was olfactory dysfunction. The first data collection was in the emergency department and the follow-up was via telephone. RESULTS: A total of 179 patients were included. The mean age was 61.6 ± 15.5 years, and 129 patients (72.1%) were male. Olfactory dysfunction was observed in 43 patients (24%). An inverse association was found between age and olfactory dysfunction (P = .002). No significant association was found between COVID-19 severity level and olfactory alteration (P = .056). However, a direct association was found between COVID-19 severity and age (P = .003), cough (P < .001), and respiratory distress (P = .003). CONCLUSION: This study did not find any association between the severity of COVID-19 and olfactory dysfunction. It showed a low incidence rate of smell alteration compared with studies from other regions. Moreover, smell alteration was associated with younger age.

Gallbladder endometrioma associated with obstructive jaundice and a serous ovarian cystic adenoma.

The occurrence of pelvic endometriosis is not uncommon, but endometriosis of the gallbladder is extremely rare. To our knowledge, only one such case has previously been described in the literature. This report concerns another patient with gallbladder endometriosis, which formed two distinct lesions at the fundus of the organ. The clinicopathological findings and pathogenesis are discussed. Endometriosis should be considered in the differential diagnosis of a fertile woman with a painful mass, particularly if the mass is associated in size and tenderness with menstrual variability.

A family of structural and functional models for the active site of a unique dioxygenase: Acireductone dioxygenase (ARD).

We report the synthesis and biomimetic activity of a family of model complexes with relevance to acireductone dioxygenase (ARD), an enzyme that displays dual function based on metal identity found in the methionine salvage pathway (MSP). Three complexes with related structural motifs were synthesized and characterized derived from phenolate, and pyridine N4O Schiff-base ligands. They display pseudo-octahedral Ni(II)-N4O ligand coordination with water at the sixth site, in close alignment to the structure in the resting state of ARD. The three featured complexes exhibit carbon­carbon bond cleavage activation of lithium acetylacetonate, which was used as a model enzyme substrate. Computationally derived mechanistic routes for the observed reactivity consistent with experimental conditions are herein proposed. The mechanism suggests the possibility of Ni(II)-substrate interactions, followed by oxygen insertion. These results constitute only the third functional model system of ARD, in an attempt to further advance biomimetic contributions to the ongoing debate of ARD's unique metal mediated, regioselective oxidative cleavage.

Predicting Chronic Spontaneous Urticaria Symptom Return After Omalizumab Treatment Discontinuation: Exploratory Analysis.

BACKGROUND: Omalizumab is highly effective in controlling chronic spontaneous urticaria (CSU) symptoms; however, patients can experience symptom return on treatment discontinuation. Pivotal clinical trials have identified 2 categories of patients who experience symptom return: rapid and slow. OBJECTIVE: The objective of this study was to identify potential predictors of the speed of symptom return after stopping omalizumab treatment. METHODS: Phase III randomized controlled trial (RCT) data from ASTERIA I (n = 319; 6 × 4 weekly injections of omalizumab 75, 150, 300 mg or placebo; NCT01287117) and ASTERIA II (n = 323; 3 × 4 weekly injections of omalizumab 75, 150, 300 mg, or placebo; NCT01292473) were pooled to identify predictors of symptom return after stopping omalizumab treatment (16-week follow-up). The least absolute shrinkage and selection operator regularization regression model was used to select predictive variables, and relapse probability was represented using heatmap visualizations. Model accuracy was tested using data from the GLACIAL phase III RCT (n = 336; 6 × 4 weekly injections of omalizumab 300 mg or placebo; NCT0126493). RESULTS: Of 746 variables assessed, 2 were selected by the model as predictors of symptom return: baseline urticaria activity score over 7 days (UAS7) and early area above the curve (AAC; determined by plotting the UAS7 scores across time points). Results suggest that high baseline UAS7 and low UAS7 AAC (slow decrease of symptoms) indicate a higher probability of rapid symptom return than low baseline UAS7 and high UAS7 AAC. CONCLUSIONS: These results suggest that the probability of rapid symptom return in patients with CSU who discontinue treatment with omalizumab can be estimated based on baseline UAS7 and early treatment response.