Efficacy and potential resistance mechanisms of afatinib in advanced non-small cell lung cancer patients with EGFR G719X/L861Q/S768I.

BACKGROUND: Afatinib is the only currently approved EGFR-tyrosine kinase inhibitors for advanced non-small cell lung cancer (NSCLC) patients with EGFR G719X/L861Q/S768I. However, there are limited real-world data concerning the benefits and resistance mechanisms of afatinib in patients with these nonclassical mutations. To fill this gap, the present study was conducted. METHODS: All NSCLC patients treated with afatinib were screened, and patients with EGFR G719X/L861Q/S768I were enrolled into the analysis. Either tumor tissue or blood specimens were detected by the commercial next-generation sequencing (NGS) panels or amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR) to figure out the mutation genotype. RESULTS: A total of 106 advanced NSCLC patients with EGFR G719X/L861Q/S768I received afatinib treatment. The benefits of afatinib exhibited heterogeneity in different mutation genotypes. Notably, at baseline, NGS testing was performed in 59 patients, and TP53 was the most frequently coexisting mutation. Patients with TP53 mutations obtained fewer survival benefits than those with TP53 wild-type. A total of 68 patients ultimately experienced progression, and 27 patients received NGS testing to clarify the potential resistance mechanisms. EGFR-T790M, CDK4 amplification, FGFR1 amplification, PIK3CA, MET amplification, RET fusions, HER2, and BRAF mutations were identified in three (11.1%), three (11.1%), three (11.1%), three (11.1%), three (11.1%), one (3.7%), one (3.7%), and one (3.7%) of the cases, respectively. Five patients underwent ARMS-PCR testing for detecting EGFR-T790M mutation, and only one patient was T790M-positive. CONCLUSIONS: The present study elucidated the differential benefits of afatinib within different mutation genotypes and first revealed the spectrum of potential resistance mechanisms in patients with EGFR G719X/L861Q/S768I. The results of this study may provide practical clinical information that can guide optimal treatment in this setting.

Incidence and influencing factors related to social isolation among HIV/AIDS patients: Protocol for a systematic review and meta-analysis.

BACKGROUND: People living with HIV (PLWH) are susceptible to social isolation as a result of stigma and discrimination, which not only diminishes adherence to antiretroviral therapy but also heightens the risks of hospital readmission, depression, and mortality. However, there is currently no systematic review addressing the occurrence and impact of social isolation in individuals with HIV. Therefore, this study undertook a comprehensive systematic review and meta-analysis of existing literature to examine the prevalence and influencing factors associated with social isolation among PLWH. METHODS AND ANALYSIS: PubMed, EMBASE, CINAHL, Cochrane Library, Web of Science, Google Scholar, China Science and Technology Journal Database, The China National Knowledge Infrastructure, WanFang Data and Chinese Biomedicine Literature Database will be searched from the establishment of the database to the latest search date. Literature screening, data extraction and literature quality assessment will be done independently by two researchers and results will be cross-referenced. Data analysis will be performed using stata15.1 software. Risk of publication bias will be assessed using Begg's and Egger's methods. Heterogeneity between studies will then be assessed using the I2 index and its 95% CI and Q statistics. Sources of heterogeneity will be accounted for by subgroup and sensitivity analyses. RESULTS: The results may reveal the prevalence of social isolation among PLWH and provide data support for understanding its etiology and prevention. CONCLUSION: By systematically reviewing the existing literature on social isolation among PLWH, this study aims to provide a comprehensive understanding of the prevalence of social isolation within this population, elucidate the detrimental effects it poses for people affected by HIV, and effectively inform targeted interventions for high-risk groups. Furthermore, these findings offer valuable insights to support evidence-based decision-making in public health policy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42024499044.

Omadacycline for the Treatment of Severe Chlamydia psittaci Pneumonia Complicated with Multiple Organ Failure: A Case Report.

Psittacosis is a rare zoonotic disease caused by Chlamydia psittaci infection, and tetracyclines are the preferred treatment. Omadacycline is a novel tetracycline that has a strong in vitro antibacterial activity against atypical pathogens, including C. psittaci; however, clinical data for its usage are lacking. We report a patient with severe C. psittaci-induced pneumonia presenting with a high fever, muscle aches, severe hepatic and renal insufficiency, and acute respiratory failure requiring tracheal intubation and mechanical ventilation. The condition was diagnosed using metagenomic next-generation sequencing. The patient was discharged after treatment with omadacycline. The findings of this study suggest that metagenomic next-generation sequencing is valuable for the rapid and accurate diagnosis of psittacosis. With its good safety profile and no requirement for dose adjustment in special populations, omadacycline is a new option for the treatment of severe C. psittaci pneumonia. However, additional case reports are needed to support this conclusion.

Case Report: Chlamydia psittaci pneumonia complicated by Guillain-Barré syndrome detected using metagenomic next-generation sequencing.

Psittacosis and Guillain-Barré syndrome are both rare clinical diseases with low incidence, and their combination has rarely been reported. Here, we report a case of Chlamydia psittaci pneumonia combined with Guillain-Barré syndrome. The patient initially presented with high fever, difficulty breathing, and fatigue. Chest computerised tomography indicated large consolidation opacities in both lungs. Metagenomic next-generation sequencing clearly identified the pathogen as C. psittaci. The patient's fever subsided after targeted antibiotic treatment, but difficulty breathing and fatigue worsened, and the patient developed symmetric limb numbness and weakness. Lumbar puncture, electrophysiological examination, and clinical characteristics were suggestive of Guillain-Barré syndrome, and the symptoms improved after treatment with human immunoglobulin. The results of this study suggest that metagenomic next-generation sequencing is useful for the rapid diagnosis of pulmonary infectious agents. Psittacosis is closely associated with the development of Guillain-Barré syndrome; however, more cases are needed to support this conclusion, and early targeted antibiotic treatment, immunotherapy, and basic supportive treatment are essential for improving outcomes.

The Predictive Values of Advanced Non-Small Cell Lung Cancer Patients Harboring Uncommon EGFR Mutations-The Mutation Patterns, Use of Different Generations of EGFR-TKIs, and Concurrent Genetic Alterations.

INTRODUCTION: Epidermal growth factor receptor (EGFR) 19del and L858R mutation are known as "common mutations" in non-small cell lung cancer (NSCLC) and predict sensitivities to EGFR tyrosine kinase inhibitors (TKIs), whereas 20ins and T790M mutations confer drug-resistance to EGFR-TKIs. The role of the remaining uncommon EGFR mutations remains elusive. METHODS: We retrospectively screened a group of NSCLC patients with uncommon EGFR mutations other than 20ins and T790M. The mutation patterns, use of different generations of EGFR-TKIs, and concurrent genetic alterations were analyzed. Meanwhile, a cohort of patients with single 19del or L858R were included for comparison. RESULTS: A total of 180/1,300 (13.8%) patients were identified. There were 102 patients with advanced or recurrent NSCLC that received first-line therapy of gefitinib/erlotinib/icotinib and afatinib and were eligible for analysis. The therapeutic outcomes among patients with common mutations (EGFRcm, n = 97), uncommon mutation plus common mutations (EGFRum+EGFRcm, n = 52), complex uncommon mutations (complex EGFRum, n = 22), and single uncommon mutations (single EGFRum, n = 28) were significantly different (ORRs: 76.3%, 61.5%, 54.5%, and 50.0%, respectively, p = 0.023; and mPFS: 13.3, 14.7, 8.1, and 6.0 months, respectively, p = 0.004). Afatinib showed superior efficacy over gefitinib/erlotinib/icotinib in EGFRcm (ORR: 81.0% vs. 75.0%, p = 0.773; mPFS: 19.1 vs. 12.0m, p = 0.036), EGFRum+EGFRcm (ORR: 100% vs. 54.5%, p = 0.017; mPFS: NE vs. 13.6m, p = 0.032), and single EGFRum (ORR: 78.6% vs. 21.4%, p = 0.007; mPFS: 10.1 vs. 3.0m, p = 0.025) groups. Comprehensive genomic profiling by Next Generation Sequencing encompassing multiple cancer-related genes was performed on 51/102 patients; the mPFS of patients without co-mutation (n = 16) and with co-mutations of tumor-suppressor genes (n = 31) and driver oncogenes (n = 4) were 31.1, 9.2, and 12.4 months, respectively (p = 0.046). TP53 mutation was the most common co-alteration and showed significantly shorter mPFS than TP53 wild-type patients (7.0 vs. 31.1m, p < 0.001). Multivariate analysis revealed that concurrent 19del/L858R and tumor-suppressor gene alterations independently predicted better and worse prognosis in patients with uncommon mutations, respectively. CONCLUSIONS: Uncommon EGFR mutations constitute a highly heterogeneous subgroup of NSCLC that confer different sensitivities to EGFR-TKIs with regard to the mutation patterns. Afatinib may be a better choice for most uncommon EGFR mutations. Concurrent 19del/L858R and tumor-suppressor gene alterations, especially TP53, can be established as prognostic biomarkers.

A Large Real-World Study on the Effectiveness of the Combined Inhibition of EGFR and MET in EGFR-Mutant Non-Small-Cell Lung Cancer After Development of EGFR-TKI Resistance.

BACKGROUND: MET proto-oncogene amplification (amp) is an important mechanism underlying acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the optimal treatment strategy after acquiring MET-amp-mediated EGFR-TKI resistance remains controversial. Our study compared three treatment strategies for patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who were detected with MET-amp at EGFR-TKI progression using next-generation sequencing. METHODS: Of the 70 patients included in the study, 38 received EGFR-TKI + crizotinib, 10 received crizotinib monotherapy, and 22 received chemotherapy. Clinical outcomes and molecular profiles were analyzed. RESULTS: The objective response rate was 48.6% for EGFR-TKI + crizotinib group, 40.0% for crizotinib monotherapy group, and 18.2% for chemotherapy group. Patients who received EGFR-TKI + crizotinib had significantly longer progression-free survival than those who received crizotinib or chemotherapy (5.0 vs. 2.3 vs. 2.9 months, p = 0.010), but overall survival was comparable (10.0 vs. 4.1 vs. 8.5 months, p = 0.088). TP53 mutation (58.5%) and EGFR-amp (42.9%) were frequent concurrent mutations of the cohort. Progression-free survival was significantly longer for patients with either concurrent TP53 mutation (n = 17) (6.0 vs. 2.3 vs. 2.9 months, p = 0.009) or EGFR-amp (n = 13) (5.0 vs. 1.2 vs. 2.4 months, p = 0.016) in the EGFR-TKI + crizotinib group than the other two regimen. Potential acquired resistance mechanisms to EGFR-TKI + crizotinib included EGFR-T790M (n = 2), EGFR-L718Q (n = 1), EGFR-S645C (n = 1), MET-D1228H (n = 1), BRAF-V600E (n = 1), NRAS-Q61H (n = 1), KRAS-amp (n = 1), ERBB2-amp (n = 1), CDK4-amp (n = 1), and MYC-amp (n = 1). CONCLUSION: Our study provides real-world clinical evidence from a large cohort that simultaneous inhibition of EGFR and MET could be a more effective therapeutic strategy for patients with MET-amp acquired from EGFR-TKI therapy.

The clinical outcomes of late preterm infants: a multi-center survey of Zhejiang, China.

OBJECTIVE: To explore birth rate, delivery mode, medical problems, requirement of respiratory support, and acute outcomes of late preterm infants in Zhejiang province in eastern China. METHODS: Eleven tertiary hospitals were recruited. Clinical data of every nursery admission from January to December 2007 were collected and analyzed. RESULTS: During the study period, 44,362 infants were born with an overall preterm birth rate of 8.9%, and late preterm birth rate of 6.2%. Late preterm infants had higher cesarean section rate than the whole population (64.9% vs. 58.2%). One-fifth of the nursery admissions were late preterm infants, of whom, 63.8% were delivered by cesarean section. Respiratory distress (42.1%) was the most common medical problem of late preterm infants. Hyperbilirubinemia (17.6%), hypoglycemia (8.7%) and sepsis (5.9%) were also common. The first three primary diagnoses of respiratory distress included pneumonia (39.5%), transient tachypnea of newborn (TTN) (22.5%) and respiratory distress syndrome (RDS) (19.0%). Compared with term infants, late preterm infants with respiratory distress needed more respiratory support with nasal continuous positive airway pressure (nCPAP) (21.4% vs. 11.6%) or with a mechanical ventilator (15.4% vs. 11.0%), and also had higher in-hospital mortality (0.8% vs. 0.4%). CONCLUSIONS: Late preterm infants are associated with very high cesarean section rate and have more medical problems and poorer short-term outcomes than term infants in China.