Effect of inactivated vaccine boosters against severe and critical COVID-19 during the Omicron BA.5 wave: A retrospective analysis of hospitalized patients in China.

Few real-world analyses of the ability of vaccines to protect against severe COVID-19 have been published. In this real-world study, we compared the prevalence of severe or critical COVID-19 between patients at our hospital who were not vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or who had been vaccinated partial, full, or booster course with the CoronaVac, containing inactivated virus propagated in Vero cells. Data from electronic health records were retrospectively analyzed for 4090 inpatients with COVID-19 who were treated at West China Hospital, Chengdu between December 6, 2022 and February 14, 2023. Clinicodemographic characteristics and COVID-19 severity were compared among patients who had been vaccinated 0, 1, 2 or more times with inactivated vaccine CoronaVac. To evaluate vaccine effectiveness over time, we plotted Kaplan-Meier curves with the percentage of patients with the outcome of severe or critical COVID-19 from the time of their last vaccine dose according to vaccination status. Ordinal logistic regression was used to assess associations between vaccination status and COVID-19 severity. Cox regression was used to identify risk factors for severe or critical COVID-19. Among the 4090 patients, 171 had been vaccinated partial and 423 twice with the full CoronaVac regimens, while 905 had been vaccinated three times (boosted). The prevalence of severe or critical COVID-19 among patients was 11 percentage points lower among those vaccinated (40%) at least twice than among those unvaccinated (51%) (p＜0.001), while it was 10% points lower among those who had received a booster (41%) than among those unvaccinated (51%) (p＜0.001). Protection against severe or critical COVID-19 due to vaccination was significantly weakened by being older than 65 years, being male, or having diabetes, chronic heart disease, autoimmune disease, or chronic lung disease. Completing a full course of immunization with inactivated vaccine CoronaVac against SARS-CoV-2 can reduce the risk of severe or critical COVID-19 due to the Omicron BA.5 subvariant.

Exploration of immunotherapy in advanced pulmonary lymphoepithelioma-like carcinoma.

Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and histologically distinctive subtype of nonsmall cell lung cancer (NSCLC). High expression of programmed death ligand 1 (PD-L1) and scarcity of druggable driver mutations raise the potential of immunotherapy for advanced PELEC. However, evidence on the clinical impact of immune-checkpoint inhibitors (ICIs) remained limited and unconvincing. The present study retrospectively enrolled advanced PLELC patients who received ICIs either as up-front or salvage therapy in SYSUCC between March 15, 2017 and March 15, 2022. The comparative efficacy of chemoimmunotherapy vs chemotherapy in the first-line setting and chemoimmunotherapy vs ICIs monotherapy in the ≥2 line setting was investigated. A total of 96 patients were finally enrolled; 49 PLELC patients received immunotherapy plus platinum-based chemotherapy, while 45 patients received platinum-based chemotherapy as first-line treatment. Patients with chemoimmunotherapy significantly obtain more survival benefits than those receiving chemotherapy (median progression-free survival [PFS]: 15.6 vs 8.6 months, P = .0015). Additionally, patients with chemoimmunotherapy obtained more PFS benefits than those with ICIs monotherapy in the ≥2 line of therapy (median PFS: 21.7 months vs 7.8 months, P = .094). A significant correlation was observed between prognostic nutritional index (PNI) and favorable treatment outcomes in patients receiving first-line chemoimmunotherapy (median PFS: 17.8 months vs 7.6 months, P < .0001). Likewise, patients in the monocyte-to-lymphocyte ratio (MLR)-high group had significantly shorter PFS than the MLR-low group (median PFS: 11.2 months vs not reached, P = .0009). Our study elucidated the superior efficacy of ICIs therapy, especially chemoimmunotherapy in advanced PLELC, which may provide new insight into the role of immunotherapy in advanced PLELC.

Role of antiangiogenic agents in first-line treatment for advanced NSCLC in the era of immunotherapy.

BACKGROUND & OBJECTIVE: "Anti-angiogenetic drugs plus chemotherapy" (anti-angio-chemo) and "immune checkpoint inhibitors plus chemotherapy" (ICI-chemo) are superior to traditional chemotherapy in the first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). However, in the absence of a direct comparison of ICI-chemo with anti-angio-chemo, the superior one between them has not been decided, and the benefit of adding anti-angiogenetic agents to ICI-chemo remains controversial. This study aimed to investigate the role of antiangiogenic agents for advanced NSCLC in the era of immunotherapy. METHODS: Eligible randomized controlled trials (RCTs) comparing chemotherapy versus therapeutic regimens involving ICIs or anti-angiogenetic drugs were included. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and rate of grade 3-4 toxicity assessment. R-4.3.1 was utilized to perform the analysis. RESULTS: A total of 54 studies with a sample size of 25,046 were finally enrolled. "Atezolizumab + Bevacizumab + Chemotherapy" significantly improved the ORR compared with "Atezolizumab + Chemotherapy" (Odds ratio (OR) = 2.73, 95% confidence interval (CI): 1.27-5.87). The trend also favored "Atezolizumab + Bevacizumab + Chemotherapy" in PFS and OS (hazard ratio (HR) = 0.71, 95% CI: 0.39-1.31; HR = 0.94, 95% CI: 0.77-1.16, respectively). In addition, "Pembrolizumab + Chemotherapy" and "Camrelizumab + Chemotherapy" significantly prolonged the PFS compared to "Bevacizumab + Chemotherapy" (HR = 0.65, 95% CI: 0.46-0.92; HR = 0.63, 95% CI: 0.41-0.97; respectively). Meanwhile, "Pembrolizumab + Chemotherapy" and "Sintilimab + Chemotherapy" yielded more OS benefits than "Bevacizumab + Chemotherapy" (HR = 0.69, 95% CI: 0.56-0.83; HR = 0.64, 95%CI: 0.46-0.91; respectively). Scheme between "Atezolizumab + Bevacizumab + Chemotherapy" and "Atezolizumab + Chemotherapy" made no significant difference (OR = 1.18, 95%CI: 0.56-2.42) concerning the rate of grade 3-4 toxicity. It seemed that ICI-chemo yielded more improvement in quality-adjusted life-year (QALY) than "Bevacizumab + Chemotherapy" in cost-effectiveness analysis. CONCLUSION: Our results suggest that ICI-chemo is associated with potentially longer survival, better cost-effectiveness outcomes, and comparable safety profiles than anti-angio-chemo. Also, adding bevacizumab to ICI-chemo seemed to provide additional therapeutic benefits without adding treatment burden. Our findings would supplement the current standard of care and help the design of future clinical trials for the first-line treatment of patients with advanced NSCLC.

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.

Epidermal growth factor receptor-Mutated Non-small-cell Lung Cancer with Intracranial Progressions and Stable Extracranial Diseases Benefit from Osimertinib Regardless of T790M Mutational Status.

OBJECTIVES: Osimertinib has exhibited promising central nervous system (CNS) efficacy in Epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) patients. In real-world clinical practice, patients would turn to plasma genotyping or take osimertinib blindly after CNS progression on previous tyrosine kinase inhibitors (TKIs). However, the efficacy of osimertinib in those patients according to their T790M mutational status has not been explored. MATERIALS AND METHODS: Twenty-five patients who received osimertinib due to intracranial progressions with stable extracranial diseases after early-generation EGFR-TKI treatment were collected from 1032 EGFR-mutated NSCLC. Plasma samples were analyzed for EGFR mutations using next-generation sequencing (NGS) or polymerase chain reaction (PCR). RESULTS: Among the 25 patients, 17 patients took plasma genotyping before osimertinib treatment with 8 patients EGFR T790M mutation-positive and the rest started osimertinib blindly. The median progression-free survival (PFS) was 8.0 months (95% confidence interval [CI]: 6.12-9.94) and median intracranial PFS (iPFS) was 14.4 months (95% CI: 7.27-21.59) for the total population. No statistical difference was found in PFS and iPFS among patients with different EGFR T790M mutational statuses. Intracranial disease control rate (DCR) was 100.0% for 14 patients with evaluable intracranial lesions despite different T790M mutational statuses. DCR for extracranial lesions and overall lesions were 100.0%, 66.7%, and 87.5% for patients with T790M, no T790M, and unknown T790M mutational status, respectively. CONCLUSION: For EGFR-mutated NSCLC patients with only intracranial progressions after previous TKI treatments, osimertinib is a promising treatment option regardless of T790M mutational status from plasma genotyping.

EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer.

BACKGROUND: Epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4-12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations. METHODS: Tumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80 mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib. RESULTS: EGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2 months (95% confidence interval 5.0-12.9 months; range 4.9-14.6 months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented. CONCLUSIONS: This study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.

Safety, immunogenicity and protective effectiveness of heterologous boost with a recombinant COVID-19 vaccine (Sf9 cells) in adult recipients of inactivated vaccines.

Vaccines have proven effective in protecting populations against COVID-19, including the recombinant COVID-19 vaccine (Sf9 cells), the first approved recombinant protein vaccine in China. In this positive-controlled trial with 85 adult participants (Sf9 cells group: n = 44; CoronaVac group: n = 41), we evaluated the safety, immunogenicity, and protective effectiveness of a heterologous boost with the Sf9 cells vaccine in adults who had been vaccinated with the inactivated vaccine, and found a post-booster adverse events rate of 20.45% in the Sf9 cells group and 31.71% in the CoronaVac group (p = 0.279), within 28 days after booster injection. Neither group reported any severe adverse events. Following the Sf9 cells vaccine booster, the geometric mean titer (GMT) of binding antibodies to the receptor-binding domain of prototype SARS-CoV-2 on day 28 post-booster was significantly higher than that induced by the CoronaVac vaccine booster (100,683.37 vs. 9,451.69, p < 0.001). In the Sf9 cells group, GMTs of neutralizing antibodies against pseudo SARS-CoV-2 viruses (prototype and diverse variants of concern [VOCs]) increased by 22.23-75.93 folds from baseline to day 28 post-booster, while the CoronaVac group showed increases of only 3.29-10.70 folds. Similarly, neutralizing antibodies against live SARS-CoV-2 viruses (prototype and diverse VOCs) increased by 68.18-192.67 folds on day 14 post-booster compared with the baseline level, significantly greater than the CoronaVac group (19.67-37.67 folds). A more robust Th1 cellular response was observed with the Sf9 cells booster on day 14 post-booster (mean IFN-γ+ spot-forming cells per 2 × 105 peripheral blood mononuclear cells: 26.66 vs. 13.59). Protective effectiveness against symptomatic COVID-19 was approximately twice as high in the Sf9 cells group compared to the CoronaVac group (68.18% vs. 36.59%, p = 0.004). Our study findings support the high protective effectiveness of heterologous boosting with the recombinant COVID-19 vaccine (Sf9 cells) against symptomatic COVID-19 of diverse SARS-CoV-2 variants of concern, while causing no apparent safety concerns.

Investigation of the optimal platinum-based regimen in the postoperative adjuvant chemotherapy setting for early-stage resected non-small lung cancer: a Bayesian network meta-analysis.

OBJECTIVE: This study aimed to compare the efficacy and safety of different platinum adjuvant chemotherapy regimens for early-stage resected non-small-cell lung cancer (NSCLC). DESIGN: Systematic review with network meta-analysis of randomised trials. DATA SOURCES: PubMed, EMBASE, The Cochrane Library, Web of Science and Scopus Google Scholar were searched through 12 March 2021. ELIGIBILITY CRITERIA: Eligible randomised controlled trials (RCTs) comparing the postoperative platinum chemotherapy regimen with the observation-controlled group or comparing two platinum chemotherapy regimens head-to-head were included. DATA EXTRACTION AND SYNTHESIS: The primary outcome was the efficacy of adjuvant chemotherapy regimens including relapse-free survival (RFS), overall survival (OS), 2-year, 3-year, 5-year RFS rate and OS rate. The secondary outcome was the rate of grade 3-4 toxicity assessments. Cochrane Handbook (V.5) was used for the risk of bias assessment. Analyses were performed using R software V.4.3.1. RESULTS: 20 RCTs with a sample size of 5483 were enrolled in meta-analysis. The chemotherapy group had a significant RFS and OS advantage compared with the observation group (HR 0.67; 95% CI 0.56 to 0.81, p<0.0001; HR 0.80; 95% CI, 0.73 to 0.88, p<0.0001, respectively). Compared with the observation arm, only the 'cisplatin_vinorelbine' regimen had a significant RFS and OS advantage (HR 0.63; 95% CI 0.43 to 0.87; HR 0.74; 95% CI 0.63 to 0.87, respectively) while the remaining chemotherapy regimens had no significant difference of efficacy compared with the observation group. In terms of the safety of adjuvant chemotherapy, the incidence of haematological toxicities and nausea/vomiting was not significantly higher in the 'cisplatin_vinorelbine' arm than in other chemotherapy group. CONCLUSION: This study summarised the adjuvant cytotoxicity chemotherapy regimens for patients with early-stage resected NSCLC. Our analysis may provide some guiding significance for the clinicians when determining the optimal chemotherapy regimen.

LY2874455 and Abemaciclib Reverse FGF3/4/19/CCND1 Amplification Mediated Gefitinib Resistance in NSCLC.

Non-small cell lung carcinoma (NSCLC) patients who initially received tyrosine kinase inhibitor (TKI) therapy often acquired resistance via multiple complex mechanisms. The amplification of FGF3/4/19/CCND1 on chromosome 11q13 was found in many cancers with TKI resistance. However, the role of these amplifications in TKI-resistant NSCLC remains uncovered. Here, we generated the FGF3/4/19/CCND1 amplification model in the NSCLC cell lines PC-9 and HCC827. Upregulation of FGF3/4/19/CCND1 strongly promoted cell proliferation and gefitinib resistance in NSCLC cells. To find out the potential therapeutic strategies, we screened the combination of inhibitors against the FGF/FGFR signaling pathway and the CCND1/CDK4 complex and revealed that gefitinib combined with LY2874455 and abemaciclib exhibited the most effective inhibition of resistance in vitro and in vivo. Mechanistically, FGFs/CCND1 activated the MAPK pathway, which was abolished by the combination drugs. Our study provides a rationale for clinical testing of dual targeting FGFR and CCND1 with LY2874455 and abemaciclib in NSCLC patients who harbored FGF3/4/19/CCND1 amplification.

Rare EGFR E709-T710delinsX: Molecular characteristics and superior response to afatinib treatment in NSCLC patients.

OBJECTIVES: Currently, whether patients with rare epidermal growth factor receptor (EGFR) mutations could benefit from EGFR tyrosine kinase inhibitors (TKIs) demands further studies. Limited clinical data are available regarding the molecular characteristics and clinical response in non-small-cell lung cancer (NSCLC) patients harboring EGFR E709-T710delinsX mutations, a rare mutation type in exon 18 of EGFR. In this study, we aimed to explore the molecular distribution and clinical outcome of EGFR E709-T710delinsX mutated Chinese patients. METHODS: Next-generation sequencing (NGS) tests were performed in 15,078 NSCLC patients. A multicenter retrospective cohort involving 17 advanced lung cancer patients with EGFR E709-T710delinsX was collected to evaluate clinical responses to diverse therapies. In silico protein structure modeling was conducted to predict drug response. RESULTS: 5905 EGFR mutant patients (39.2%, 5905/15078) were identified, with 26 cases (0.44%, 26/5905) harbored EGFR E709-T710delinsD. Afatinib showed a better overall objective response rate (ORR) compared with the first-generation (1G) EGFR TKIs and chemotherapy with significant difference. Superior progression free survival (PFS) was also observed in patients treated with afatinib (afatinib 10.85 m vs 1G EGFR TKIs 4.0 m vs chemotherapy 2.8 m, p = 0.0007). In silico protein structure modeling predicts better binding of afatinib with EGFR E709-T710delinsD compared with other EGFR TKIs. CONCLUSIONS: This is the largest studies for EGFR E709-T710delinsX, with 26 cases with EGFR E709-T710delinsX being identified (0.44% in EGFR mutant NSCLC, 0.17% in NSCLC patients). This study also firstly revealed that afatinib might exert superior antitumor activity to the 1G EGFR TKIs and chemotherapy in EGFR E709-T710delinsX mutant patients.

Research progress in immune checkpoint inhibitors for lung cancer in China.

Immune checkpoint inhibitors (ICIs) have come to play an increasingly prominent role in the treatment of lung cancer, and some are recommended as a first-line treatment for late-stage non-small-cell lung cancer, either as a monotherapy or in combination with chemotherapy. Accordingly, the indications of Food and Drug Administration-approved ICIs have increased. In this background, China has implemented various policies to encourage and accelerate the marketing of domestic and imported innovative antitumor drugs. Eight ICIs have been approved in China. Among these, four imported programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have received approval for six indications, and one domestic PD-1 inhibitor has received approval for one indication for lung cancer in 2018. Numerous clinical trials of ICIs for lung cancer are underway in China. This review aims to summarize the recent advances and future directions of ICIs, including PD-1 inhibitors, PD-L1 inhibitors, cytotoxic T lymphocyte-associated antigen-4 inhibitors, bi-specific antibodies, and a novel inhibitor of T-cell immune-receptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains in immunotherapies for lung cancer in China.

HER2 Amplification in Advanced NSCLC Patients After Progression on EGFR-TKI and Clinical Response to EGFR-TKI Plus Pyrotinib Combination Therapy.

BACKGROUND: HER2 (or ERBB2) amplification is an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). The benefits of HER2-targeted therapy have been limited. Herein, we investigated the molecular and clinical patterns of HER2 amplification in non-small cell lung cancer (NSCLC) patients during progression on EGFR-TKIs and the potential of combining EGFR-TKI and pyrotinib to overcome resistance. METHODS: In this study, 1,637 NSCLC cases from Geneseeq after progression of EGFR-TKIs were screened and analyzed by next generation sequencing (NGS), in which 48 patients with HER2 amplification were eligible and enrolled. A total of 403 patients from Sun Yat-sen University Cancer Center (SYSUCC) were screened and five patients with concomitant EGFR mutations and HER2 amplification were retrospectively collected to assess the effect of afatinib or combination of EGFR-TKI and pyrotinib. RESULTS: In the 48 patients from the Geneseeq cohort, 27 (56.2%) patients suffered from resistance of 1st/2nd generation EGFR-TKI, and 21 (43.8%) patients from 3rd generation. As for the five patients forming the SYSUCC cohort, three patients were treated with afatinib, one achieved partial response (PR) with progression-free survival (PFS) of 6 months and two quickly developed disease progression. Two patients were treated with EGFR-TKIs plus pyrotinib, one receiving gefitinib plus pyrotinib achieved PR with PFS of 8 months and benefited from osimertinib plus pyrotinib for 3 months till data-off; one receiving osimertinib plus pyrotinib achieved SD for 4 months till data-off. The most common co-occurring alteration was TP53 (91.7%) in the mutation profile of the 48 patients from the Geneseeq cohort, and four patients had TP53 co-mutations of the five patients from the SYSUCC cohort. CONCLUSION: In this study, we detected 7% HER2 amplification present in EGFR-TKIs resistance. Patients with concomitant EGFR mutation and HER2 amplification may derive clinical benefit from therapies that target both EGFR and HER2.

An EGFR-Amplified Cervical Squamous Cell Carcinoma Patient with Pulmonary Metastasis Benefits from Afatinib: A Case Report.

Currently, women with metastatic or recurrent cervical cancer still have very limited treatment options. Despite the rapid advancements in targeted therapies, no targeted therapy was approved for cervical cancer, except for bevacizumab. In the present study, we reported a 52-year-old heavily pre-treated EGFR amplified patient with metastatic cervical squamous cancer who benefited from afatinib with a progression-free survival (PFS) of 5.5 months. The patient was administered with a first-line treatment of chemotherapy and bevacizumab with a PFS of 4.3 months. Subsequently the patient was treated with a second-line regimen of angiogenesis inhibitor apatinib plus chemotherapy and a third-line treatment of pembrolizumab. Genomic profiling revealed significant EGFR amplification in both primary (copy number [CN] =15.9) and metastatic lesions (CN =18). Afatinib monotherapy was then administered as the fourth-line regimen. She achieved partial response (PR) with a PFS of 5.5 months. At disease progression, the CN of EGFR was elevated to 39.9 accompanied by the emergence of PIK3CA amplification (CN =4.2). The patient was treated with everolimus and afatinib and achieved stable disease (SD) after 3 months. To the best of our knowledge, this is the first clinical evidence of an EGFR-amplified metastatic cervical cancer patient benefiting from afatinib as a single agent.

PI3K-AKT-mTOR pathway alterations in advanced NSCLC patients after progression on EGFR-TKI and clinical response to EGFR-TKI plus everolimus combination therapy.

BACKGROUND: Several mechanisms including abnormal activation of PI3K-AKT-mTOR pathway have been proved to generate acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). In this study, we investigated the genomic characteristics of PI3K pathway activated in NSCLC patients after progression on EGFR-TKIs and whether both targeting EGFR and PI3K pathway could overcome resistance. METHODS: A total of 605 NSCLC cases with a history of EGFR TKI treatment were reviewed, in which 324 patients harboring EGFR mutations were confirmed progression on at least one EGFR TKI and finally enrolled. Tumor tissues or blood samples were collected at the onset of TKI progression for next generation sequencing (NGS). Six EGFR mutant patients with co-occurring mutations in PI3K pathway were retrospectively collected to assess the effect of EGFR TKI plus everolimus, a mTOR inhibitor. RESULTS: Forty-nine (14.9%) patients resistant to EGFR TKIs have at least one genetic variation in PI3K pathway. PIK3CA, PTEN and AKT1 variations were detected in 31 (9.5%), 18 (5.5%) and 3 (0.9%) of patients, respectively. No significant differences were observed in distribution of PI3K pathway alterations among patients with different EGFR mutations (EGFR exon19 deletion mutations/EGFR L858R/uncommon EGFR mutations) and among patients resistant to different EGFR TKIs. For patients treated with everolimus and EGFR-TKI, five (5/6, 83.3%) achieved stable disease (SD) and one (1/6, 16.7%) didn't receive disease control. The median progression-free survival (PFS) was 2.1 months (95% confidence interval, 1.35-4.3 months, range, 0.9-4.4 months). The most common adverse events were dental ulcer (6/6), rash (1/6). CONCLUSIONS: Our study revealed that PI3K pathway was activated in at least 14.9% in EGFR-TKI resistant patients. EGFR-TKIs plus everolimus showed limited antitumor activity in EGFR mutant NSCLC patients with PI3K pathway aberrations.

Comparison of urine neutrophil gelatinase-associated lipocalin and interleukin-18 in prediction of acute kidney injury in adults.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) were considered as the most promising biomarkers in prediction of acute kidney injury (AKI), but the priority of them remains unclear. METHODS: Databases of PubMed, Elsevier, Cochrane library, and Web of science were searched until August 23, 2017 for studies investigated the diagnostic value of urine NGAL (uNGAL) and urine IL-18 (uIL-18) for AKI in adults. Statistical analysis and investigation of heterogeneity source were using RevMan5.3, MetaDiSc1.40, and Stata14.0. RESULTS: A total of 7 studies were included involving 2315 patients from 7 countries in this article, of whom 443 (19.1%) developed AKI. The present meta-analysis demonstrated that uNGAL was more valuable compare with uIL-18 with effect size of 1.09 (95% CI 1.03-1.15, P = .004) in specificity, but not in sensitivity with effect size of 1.12 (95% CI 0.98-1.29, P = .104). Subgroup analysis presented that research design may be a foundation affecting the diagnostic accuracy of uNGAL and uIL-18 for AKI. No substantial publication bias was found. CONCLUSIONS: uNGAL is more specific for prediction of AKI in adults as compared with uIL-18.

Whether a Short or Long Alimentary Limb Influences Weight Loss in Gastric Bypass: a Systematic Review and Meta-Analysis.

Roux-en-Y gastric bypass, the most commonly performed procedure in bariatric surgery, still lacks a consensus on whether alimentary limb length (ALL) influences weight loss. Studies were identified by searching multiple electronic databases. Studies with enough data including body mass index (BMI) loss and percent excess weight loss (% EWL) were eligible. The statistical analysis was performed with Stata 14.0. In total, eight studies with 1714 patients were included. The meta-analysis suggested that short ALLs weakened the efficacy of Roux-en-Y gastric bypass in terms of BMI loss (standard mean deviation (SMD), - 0.33 [95% confidence intervals (CI), - 0.60, - 0.05], p = 0.021) with 3 years of follow-up and % EWL (SMD, - 0.17 [95% CI, - 0.31, - 0.04], p = 0.013) with 2 years of follow-up. The subgroup analysis demonstrated that the group with a BMI ≥ 50 kg/m2 had a significant SMD between the use of short and the standard ALLs (- 0.71 [95% CI, - 1.07, - 0.35], p = 0.000), while the subgroup with a BMI < 50 kg/m2 (SMD, - 0.29 [95% CI, - 0.78, 0.20], p = 0.247) did not. Compared with a standard ALL (130-150 cm), a short ALL (40-100 cm) may reduce the efficacy of the Roux-en-Y gastric bypass surgery, while a long ALL (170-250 cm) did not significantly improve the effects in terms of BMI loss and % EWL. In addition, a potential view of the meta-analysis indicated patients with a BMI < 50 kg/m2 might get more benefits with a short ALL, while those patients with a BMI ≥ 50 kg/m2 might benefit more from a standard ALL.

Stem cell transplantation for the treatment of patients with type 1 diabetes mellitus: A meta-analysis.

The efficacy of stem cell (SC) transplantation in patients with type 1 diabetes mellitus (T1DM) has remained to be fully elucidated. In the present study, a systematic review and meta-analysis was performed to determine the clinical outcomes. Electronic databases, including PubMed, MEDLINE, WanFang and the Cochrane Library were screened for relevant studies published until January 13, 2018. The references of retrieved papers, systematic reviews and trial registries were manually screened for additional papers. Two authors were involved in screening the titles in order to select eligible studies, extract data and assess the risk of bias. Studies were pooled using a random-effects model as well as the Begg's funnel plot and subgroup analysis was performed using Stata 14.0 software. A total of 47 studies were retrieved for detailed evaluation, of which 22 met the inclusion criteria. No substantial publication bias was identified. The meta-analysis revealed that SC therapy increased C-peptide levels when compared with placebo treatment in randomized-controlled trials [RCT; standardized mean difference (SMD), 0.93; 95% confidence interval (CI) 0.23-1.63] and self-controlled trials (SMD, 0.66; 95% CI, -0.22 to 1.54). An analysis demonstrated that SC therapy was more efficient at reducing the glycated hemoglobin level compared with the control group in RCTs (SMD, 0.56; 95% CI; 0.06-1.06; and SMD, 1.63; 95% CI, 0.92-2.34, respectively). The graphs demonstrated that SC transplantation resulted in a reduction of insulin requirement. Furthermore, subgroup analyses revealed that patient age, medical history and the SC injection dose may be sources of the heterogeneity observed. The greatest benefit of SC transplantation was seen in patients aged ≥18 years or a medical history of <3 months. In addition, the SC injection dose of ≥107 IU/kg/day was more effective than <107 IU/kg/day when the cellular composition included mesenchymal SCs and hematopoietic SCs. In conclusion, SC therapy represents an efficient option for patients with T1DM. This systematic review was registered at the International prospective register of systematic reviews (no. 42018093930).