Olgotrelvir as a Single-Agent Treatment of Nonhospitalized Patients with Covid-19.

BACKGROUND: Olgotrelvir is an oral antiviral with dual mechanisms of action targeting severe acute respiratory syndrome coronavirus 2 main protease (i.e., Mpro) and human cathepsin L. It has potential to serve as a single-agent treatment of coronavirus disease 2019 (Covid-19). METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of olgotrelvir in 1212 nonhospitalized adult participants with mild to moderate Covid-19, irrespective of risk factors, who were randomly assigned to receive orally either 600 mg of olgotrelvir or placebo twice daily for 5 days. The primary and key secondary end points were time to sustained recovery of a panel of 11 Covid-19-related symptoms and the viral ribonucleic acid (RNA) load. The safety end point was incidence of treatment-emergent adverse events. RESULTS: The baseline characteristics of 1212 participants were similar in the two groups. In the modified intention-to-treat population (567 patients in the placebo group and 558 in the olgotrelvir group), the median time to symptom recovery was 205 hours in the olgotrelvir group versus 264 hours in the placebo group (hazard ratio, 1.29; 95% confidence interval [CI], 1.13 to 1.46; P<0.001). The least squares mean (95% CI) changes of viral RNA load from baseline were -2.20 (-2.59 to -1.81) log10 copies/ml in olgotrelvir-treated participants and -1.40 (-1.79 to -1.01) in participants receiving placebo at day 4. Skin rash (3.3%) and nausea (1.5%) were more frequent in the olgotrelvir group than in the placebo group; there were no treatment-related serious adverse events, and no deaths were reported. CONCLUSIONS: Olgotrelvir as a single-agent treatment significantly improved symptom recovery. Adverse effects were not dose limiting. (Funded by Sorrento Therapeutics, a parent company of ACEA Therapeutics; ClinicalTrials.gov number, NCT05716425.).

Metagenomic next-generation sequencing for the detection of pathogenic microorganisms in patients with pulmonary infection.

OBJECTIVE: To explore the clinical value of metagenomic next-generation sequencing (mNGS) in diagnosing pulmonary infectious diseases. METHODS: A retrospective analysis was performed on 82 patients with pulmonary infection who were admitted to the Eighth Affiliated Hospital of Guangxi Medical University & Guigang City People's Hospital from January 2020 to December 2021. The pathogens were detected by mNGS and conventional methods (culture and PCR). Then, the type and number of detected pathogens, as well as the specificity and sensitivity, were compared between the two methods. In addition, the positive rates of bacteria, fungi, tubercle bacillus, and mixed infection in bronchoalveolar lavage fluid, sputum, pleural effusion, and blood detected by mNGS, and the advantage in required test time were evaluated. RESULTS: More types and numbers of pathogens were detected by mNGS with a higher sensitivity but a lower specificity, as compared to the conventional detection methods (all P<0.05). The positive rates and integrity rates of bacteria, fungi, and tubercle bacillus detected by mNGS were higher than those by conventional methods (all P<0.05). Moreover, there was no difference in the overall sensitivity of mNGS among different sample types, but the sensitivities of mNGS in bronchoalveolar lavage fluid and sputum samples were significantly higher than those of conventional methods (both P<0.05). The average test time for mNGS was shorter than that of conventional methods. CONCLUSION: mNGS can detect more types and numbers of pathogenic microorganisms, improve the detection sensitivity, and reduce the detection time in patients with pulmonary infection.

Serum cortisol levels and adrenal gland size in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To determine the clinical significance of serum Cortisol (Cor) levels and adrenal gland size in patients with chronic obstructive pulmonary disease (COPD). METHODS: We assigned 80 patients with COPD admitted to our hospital to an observation group, and 80 healthy individuals to a control group. Serum Cor, C-reactive protein (CRP) level, and adrenal gland size were measured. Patients with COPD were divided into several subgroups according to BODE (BMI, Obstruction, Dyspnea, Exercise capacity) indexes and forced expiratory volume in the first second (FEV1), and Cor levels and adrenal gland size were compared between subgroups. The Pearson Correlation was used to analyze correlations of adrenal gland size and Cor levels with partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), FEV1, forced vital capacity (FVC), and FEV1/FVC. After 30 days' follow-up, the patients were allocated into good-prognosis group and poor-prognosis group. The clinical value of Cor levels in predicting prognosis was estimated by the receiver operating characteristic (ROC) curve. RESULTS: Increased serum CRP levels were found in the observation group, while Cor levels and adrenal gland diameter were decreased (P<0.05 for each comparison). In the observation group, an increase in BODE index or decrease in FEV1 led to decreased Cor levels and adrenal gland diameter, as well as increased CRP levels (P<0.05, each comparison). Correlation analysis showed that adrenal gland diameter and Cor levels were positively correlated with PaO2, FEV1, FVC, and FEV1/FVC, but negatively correlated with PaCO2. The ROC curve indicated that Cor levels were valuable in predicting the prognosis (AUC>0.7, P<0.05). CONCLUSION: Cor levels and adrenal gland size are closely associated with the severity of COPD, and Cor levels are predictive of prognosis.

Next Generation Sequencing Reveals a Synchronous Trilateral Lung Adenocarcinoma Case with Distinct Driver Alterations of EGFR 19 Deletion or EGFR 20 Insertion or EZR-ROS1 Fusion.

OBJECTIVE: Synchronous multiple primary lung cancer (SMPLC) has a reported occurrence from 0.5% to 2% in lung cancer, and the surgical treatment and prognosis were quite diverse. With the discovery of driver mutations in lung adenocarcinoma (ADC), next-generation sequencing (NGS) would provide an explicit answer to the key question, whether individual tumors represent intrapulmonary metastases or independent tumors. Here, we reported a 64-year-old female diagnosed with a synchronous trilateral early-stage ADC with distinct driver alterations. MATERIALS AND METHODS: NGS test targeting 31 cancer-relevant genes and amplification RNA sequencing (if gene fusion was found on DNA level) were performed on the surgical tumor tissue. RESULTS: A 64-year-old Chinese female never smoker was found with one nodule in the right upper lobe and two nodules in the right middle lobe through chest computed tomography. The lesions were resected through video-assisted thoracic surgery and diagnosed with stage IA ADC, T1N0M0, in the postoperative pathology. NGS detected three independent driver mutations in three primary sites, respectively, EGFR 19del, EGFR 20ins and ROS1 fusion. CONCLUSION: This is the first report of a synchronous trilateral early-stage ADC with distinct driver alterations. All individual tumors were independent identified by NGS methodology, which had provided a clear answer to the key question of SMPLC in this case and should be used as a routine genetic test to explore fully pathological diagnosis and more comprehensive oncogenesis information in the early-stage ADC clinical prevention.

Co-Occurring Alterations of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib.

Background: Human epidermal growth factor receptor 2 (ERBB2, HER-2) exon 20 insertion (ERBB2ex20ins) remains a refractory oncogenic driver in lung cancer. So far there is limited data showing the co-occurring mutation background of ERBB2ex20ins in Chinese lung cancer and its relationship with response to afatinib. Patients and Methods: A total of 112 Chinese patients with ERBB2ex20ins identified by next-generation sequencing from 17 hospitals were enrolled. The clinical outcomes of 18 patients receiving afatinib treatment were collected. Results: Among the 112 patients, insertion-site subtypes comprised of A775ins (71%; 79/112), G776indel (17%; 19/112), and P780ins (12%; 14/112). There were 66.1% (74/112) of patients carrying TP53 co-mutation and FOXA1 was the most prevalent co-amplified gene (5.5%, 3/55). The co-occurring genomic feature was similar among three insertional-site subtypes and had an overall strong concordance with the western population from the MSKCC cohort (R 2 = 0.74, P < 0.01). For the prognosis, patients with co-occurring mutation in cell-cycle pathway especially TP53 showed shorter OS than patients without [median OS: 14.5 m (95% CI:12.7-16.3 m) vs. 30.3 m (95% CI: not reached), p = 0.04], while the OS was comparable among three subtypes. For the response to afatinib, ERBB2ex20ins as a subclonal variant was an independent factor relating to shorter PFS [median PFS: 1.2 m (95% CI: 0.8-1.6 m) vs. 4.3 m (95% CI: 3.3-5.3 m), p < 0.05]. Conclusion: Our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, emphasizing the more valuable role of the co-mutation patterns than insertion-site subtypes in predicting prognosis of this group of patients. Moreover, the clonality status of ERBB2ex20ins was identified as a potential indicator for response to afatinib.