The treatment of patients with non-small cell lung cancer carrying uncommon EGFR mutations, HER2 mutations, or brain metastases: a systematic review of pre-clinical and clinical findings for dacomitinib.

Background: Accumulating evidence has shown that dacomitinib has potential activities for patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations, human epidermal growth factor receptor 2 (HER2) mutations, or central nervous system (CNS) metastases. Methods: This study aimed to give a systematic review on its potential applications in the above settings by searching MEDLINE/PubMed, Embase, Cochrane Library, American Society of Clinical Oncology.org, European Society for Medical Oncology.org, and ClinicalTrials.gov. Results: The literature search yielded 649 publications in total. According to our findings, dacomitinib exhibited promising efficacy in patients with major uncommon EGFR mutations (including G719X, S768I, and L861Q). Both EGFR exon 20 insertional mutation (Ex20ins) and HER2 Ex20ins demonstrated significant internal heterogeneity in response to dacomitinib, among which specific subtypes (including EGFR D770delinsGY, A763_Y764insFQEA, and HER2 M774delinsWLV) were highly sensitive. Other uncommon EGFR mutations including 18del and L747P have also been shown responsive to dacomitinib. Interestingly, limited studies suggested dacomitinib application on certain first or third generation tyrosine kinase inhibitors (TKIs)' resistant secondary mutations. Last but not least, both pre-clinical and clinical data indicated that dacomitinib has an encouraging intracranial tumor control ability, regardless of uncommon mutations. Conclusions: Dacomitinib demonstrated good disease control on patients with NSCLC harboring major uncommon EGFR mutations and specific EGFR or HER2 mutation subtypes, and selective clinical application of dacomitinib is considerable in this setting, especially for those with intracranial metastases.

Sarcopenic obesity by the ESPEN/EASO criteria for predicting mortality in advanced non-small cell lung cancer.

BACKGROUND: The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) recently released the first international consensus on the diagnostic criteria for sarcopenic obesity (SO), which recommended skeletal muscle mass adjusted for body weight (SMM/W) to determine low muscle mass. SMM adjusted for body mass index (SMM/BMI) appeared to be better associated with physical performance than SMM/W. Thus, we modified the ESPEN/EASO criteria by using SMM/BMI. We aimed (1) to evaluate the agreement of the ESPEN/EASO-defined SO (SOESPEN) and the modified ESPEN/EASO-defined SO (SOESPEN-M) with other commonly used SO definitions, and (2) to compare different SO definitions for predicting mortality in a prospective cohort with advanced non-small cell lung cancer (NSCLC). METHODS: This prospective study included patients with advanced NSCLC. We defined SO according to five different diagnostic criteria: SOESPEN, SOESPEN-M, Asian Working Group for Sarcopenia (AWGS)-determined sarcopenia with BMI-determined obesity (SOAWGS), computed tomography-derived sarcopenia with BMI-determined obesity (SOCT), and fat mass to fat-free mass ratio >0.8 (SOFM). The outcome was all-cause mortality. RESULTS: Of the 639 participants (mean age 58.6 years, 229 women) we studied, 488 (76.4%) died during the median follow-up period of 25 months. SMM/BMI was significantly lower in the death group than in the survivor group (men: p = 0.001, women: p < 0.001), but SMM/W was not. Only 3 (0.47%) participants met all five SO diagnostic criteria. SOESPEN showed an excellent agreement with SOESPEN-M (Cohen's kappa = 0.896), a moderate agreement with SOAWGS (Cohen's kappa = 0.415), but poor agreements with SOCT and SOFM (Cohen's kappa = 0.078 and 0.092, respectively). After full adjustment for potential confounders, SOESPEN (HR 1.54, 95% CI 1.26-1.89), SOESPEN-M (HR 1.56, 95% CI 1.26-1.92), and SOAWGS (HR 1.43, 95% CI 1.14-1.78) were significantly associated with mortality. However, SOCT (HR 1.17, 95% CI 0.87-1.58) and SOFM (HR 1.15, 95% CI 0.90-1.46) showed no significant association with mortality. CONCLUSIONS: SOESPEN showed an excellent agreement with SOESPEN-M, a moderate agreement with SOAWGS, but poor agreements with SOCT and SOFM. SOESPEN, SOESPEN-M, and SOAWGS were independent prognostic factors for mortality in our study population, but SOCT and SOFM were not. Although SMM/BMI was better associated with survival than SMM/W, SOESPEN-M did not show an advantage in predicting survival over SOESPEN.

DIA-based proteomics analysis of serum-derived exosomal proteins as potential candidate biomarkers for intrahepatic cholestasis in pregnancy.

BACKGROUND: Data-independent acquisition (DIA) is one of the most powerful and reproducible proteomic technologies for large-scale digital qualitative and quantitative research. The aim of this study was to use proteomic methodologies for the identification of biomarkers that are over or underexpressed in women with intrahepatic cholestasis of pregnancy (ICP) compared with controls and discover a potential biomarker panel for ICP detection. METHODS: The participants included 11 ICP patients and 11 healthy pregnant women as controls. The clinical characteristic data and the laboratory biochemical data were collected at the time of recruitment. Then, a data-independent acquisition (DIA)-based proteomics approach was used to identify differentially expressed proteins (DEPs) in serum exosomes between ICP patients and controls. Finally, bioinformatics analysis was used to identify the relevant processes in which these DEPs were involved. RESULTS: The proteomics results showed that there were 162 DEPs in serum exosomes between pregnant women with ICP and healthy pregnant women, of which 106 were upregulated and 56 were downregulated in ICP. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the identified proteins were functionally related to specific cell processes including apoptosis, lipid metabolism, immune response and cell proliferation, and metabolic disorders, suggesting that these may be primary causative factors in ICP pathogenesis. Meanwhile, complement and coagulation cascades may be closely related to the development of ICP. Receiver operating characteristic curve (ROC) analysis showed that the area under the curve values of Elongation factor 1-alpha 1, Beta-2-glycoprotein I, Zinc finger protein 238, CP protein and Ficolin-3 were all approximately 0.9, indicating the promising diagnostic value of these proteins. CONCLUSIONS: This preliminary work provides a better understanding of the proteomic alterations in the serum exosomes of pregnant women with ICP.

Serum creatinine and cystatin C-based diagnostic indices for sarcopenia in advanced non-small cell lung cancer.

BACKGROUND: Sarcopenia is an important prognostic factor of lung cancer. The serum creatinine/cystatin C ratio (CCR) and the sarcopenia index (SI, serum creatinine × cystatin C-based glomerular filtration rate) are novel screening tools for sarcopenia; however, the diagnostic accuracy of the CCR and SI for detecting sarcopenia remains unknown. We aimed to explore and validate the diagnostic values of the CCR and SI for determining sarcopenia in non-small cell lung cancer (NSCLC) and to explore their prognostic values for overall survival. METHODS: We conducted a prospective cohort study of adult patients with stage IIIB or IV NSCLC. Levels of serum creatinine and cystatin C were measured to calculate the CCR and SI. Sarcopenia was defined separately using CCR, SI, and the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Participants were randomly sampled into derivation and validation sets (6:4 ratio). The cutoff values for diagnosing sarcopenia were determined based on the derivation set. Diagnostic accuracy was analysed in the validation set through receiver operating characteristic (ROC) curves. Cox regression models and survival curves were applied to evaluate the impact of different sarcopenia definitions on survival. RESULTS: We included 579 participants (women, 35.4%; mean age, 58.4 ± 8.9 years); AWGS-defined sarcopenia was found in 19.5% of men and 10.7% of women. Both CCR and SI positively correlated with computed tomography-derived and bioimpedance-derived muscle mass and handgrip strength. The optimal cutoff values for CCR and SI were 0.623 and 54.335 in men and 0.600 and 51.742 in women, with areas under the ROC curves of 0.837 [95% confidence interval (CI): 0.770-0.904] and 0.833 (95% CI: 0.765-0.901) in men (P = 0.25), and 0.808 (95% CI: 0.682-0.935) and 0.796 (95% CI: 0.668-0.924) in women (P = 0.11), respectively. The CCR achieved sensitivities and specificities of 73.0% and 93.7% in men and 85.7% and 65.7% in women, respectively; the SI achieved sensitivities and specificities of 75.7% and 86.5% in men and 92.9% and 62.9% in women, respectively. CCR-defined, SI-defined, and AWGS-defined sarcopenia were independently associated with a high mortality risk [hazard ratio (HR) = 1.75, 95% CI: 1.25-2.44; HR = 1.55, 95% CI: 1.11-2.17; and HR = 1.76, 95% CI: 1.22-2.53, respectively]. CONCLUSIONS: CCR and SI have satisfactory and comparable diagnostic accuracy and prognostic values for sarcopenia in patients with advanced NSCLC. Both may serve as surrogate biomarkers for evaluating sarcopenia in these patients. However, further external validations are required.