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Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis

  • Chengkai Zhang , Wenjianlong Zhou , Dainan Zhang , Shunchang Ma , Xi Wang , Wang Jia , Xiudong Guan EMAIL logo and Ke Qian EMAIL logo
Published/Copyright: February 14, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

More clinical evidence is needed regarding the relative priority of treatments for brain metastases (BMs) from EGFR/ALK-negative/unselected non-small cell lung cancer (NSCLC). PubMed, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov databases were searched. Overall survival (OS), central nervous system progression-free survival (CNS-PFS), and objective response rate (ORR) were selected for Bayesian network meta-analyses. We included 25 eligible randomized control trials (RCTs) involving 3,054 patients, investigating nine kinds of treatments for newly diagnosed BMs and seven kinds of treatments for previously treated BMs. For newly diagnosed BMs, adding chemotherapy, EGFR-TKIs, and other innovative systemic agents (temozolomide, nitroglycerin, endostar, enzastaurin, and veliparib) to radiotherapy did not significantly prolong OS than radiotherapy alone; whereas radiotherapy + nitroglycerin showed significantly better CNS-PFS and ORR. Surgery could significantly prolong OS (hazard ratios [HR]: 0.52, 95% credible intervals: 0.41–0.67) and CNS-PFS (HR: 0.32, 95% confidence interval: 0.18–0.59) compared with radiotherapy alone. For previously treated BMs, pembrolizumab + chemotherapy, nivolumab + ipilimumab, and cemiplimab significantly prolonged OS than chemotherapy alone. Pembrolizumab + chemotherapy also showed better CNS-PFS and ORR than chemotherapy. In summary, immune checkpoint inhibitor (ICI)-based therapies, especially ICI-combined therapies, showed promising efficacies for previously treated BMs from EGFR/ALK-negative/unselected NSCLC. The value of surgery should also be emphasized. The result should be further confirmed by RCTs.

Keywords: Bayesian network meta-analysis; non-small cell lung cancer; brain metastasis; immunotherapy; radiotherapy

1 Introduction

Lung cancer is the leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) represents approximately 85% of lung cancer cases [1]. Around 25–30% of NSCLC patients develop brain metastases (BMs) [2]; moreover, NSCLC is the most common primary cancer that metastasizes to the brain [2]. The prognosis of NSCLC patients with BMs is dismal, with a median survival time of only approximately 1 month in the absence of treatment [3,4]. Several strategies have been employed to treat BMs from NSCLC, including surgery, targeted therapy, immune checkpoint therapy, chemotherapy, radiotherapy, and their combination [3,5]. Each of these treatments has both advantages and drawbacks, and their relative efficacies are not fully understood.

In recent years, targeted therapies for NSCLC and BMs have rapidly developed. For instance, the epidermal growth factor receptor (EGFR) plays an essential role in lung cancer and depends on its expression status among the population. The mutations in EGFR and its polymorphisms are associated with the onset of carcinogenesis, the prediction of the metastases, and the response to tyrosine kinase inhibitors (TKIs) [6,7]. EGFR mutations are detected in 15–35% of NSCLC, with a higher percentage observed in the Asian population than in Europeans [8–10]. For patients with EGFR mutations and BMs, previous studies have shown that third-generation EGFR–TKIs and EGFR–TKIs combined with chemotherapy or radiotherapy have favorable efficacy [11,12]. Anaplastic lymphoma kinase (ALK) rearrangement, which occurs in 2–7% NSCLC, is also a classic target [13]. ALK inhibitors (especially the second and third-generation inhibitors) have shown promising efficacy for NSCLC with BMs [14].

However, there are still a significant number of patients with negative EGFR/ALK NSCLC BMs. In addition, limited to socioeconomic factors, genomic tests cannot cover all the patients, which means the genomic status of many patients remains unknown. Therefore, treatments with broader indications (including surgery, radiotherapy, immune checkpoint therapy, chemotherapy, and other innovative therapies) are more suitable for such patients [15]. Surgery is recommended for BMs that are large, have significant perilesional edema, and result in neurological deficits. It can provide immediate relief from symptomatic mass effects and help to confirm the diagnosis [10]. Radiotherapy, which mainly consists of whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS), is considered the cornerstone of the treatment for BMs [10,16]. WBRT has previously been the standard treatment for BMs. However, considering the neurocognitive toxicity, the value of WBRT has been challenged, and SRS has gradually become popular [10,17,18]. As an alternative to surgical resection, SRS is a high precise localized irradiation given in one fraction. It can achieve a dose to the tumor with a low risk of damage to the surrounding normal brain [16]. SRS is recommended for BMs of a limited number (up to 4) and limited size (up to 3 cm) [18–20]. Immune checkpoint inhibitors (ICIs) represent a major breakthrough for treating metastatic NSCLC and have shown preliminarily promising outcomes in patients with BMs from NSCLC [10]. Nevertheless, previous studies generally analyzed single-arm treatments or compared pairwise treatments and could not generate clear hierarchies of treatment approaches. Consequently, we performed a systematic literature review and Bayesian network meta-analysis (NMA) to analyze the comparative efficacy of all types of therapy available for these patients.

2 Methods

2.1 Data sources and search strategy

This research was performed following the guidelines provided by the PRISMA (preferred reporting items for systematic reviews and meta-analyses) report [21] (PRISMA Checklist). We searched the PubMed, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov databases from inception until April 10, 2022, without language restrictions, for randomized control trials (RCTs). The search took into account both medical subject headings and text words, using the main search terms “NSCLC,” “brain metastasis,” and terms specific to the different treatments. The detailed search strategy for the databases is presented in Table S1. The reference lists of the relevant articles were checked for additional articles. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42021227078).

  1. Ethical approval: The conducted research is not related to either human or animal use.

2.2 Study selection

Two investigators, Zhang C.K. and Zhou W.J.L., independently assessed the eligibility of studies based on the title, abstracts, and full texts, resolving disagreements by obtaining a consensus with Guan X.D. We included published and unpublished trials that met the following criteria:

  • Population: Adult (≥18 years) histologically or cytologically diagnosed NSCLC patients with one or more BMs; EGFR/ALK status was negative or unselected. There was no restriction on PD-L1 expression. Eligible participants had a Karnofsky Performance Status ≥60 and stable systemic disease with adequate hematologic, renal, and hepatic function.

  • Interventions and comparisons: Two or more different arms of treatment for brain metastasis originating from NSCLC. ICIs were classified as anti-CTLA4 or anti-PD-(L)1 checkpoint inhibitors. Target therapy, such as EGFR-TKIs, was also included in our analyses if the participants were unselected for EGFR/ALK status. Chemotherapy referred to traditional NSCLC chemotherapy (platinum-based chemotherapy or other NSCLC chemotherapies recommended by NCCN guidelines). Other innovative medicines, such as temozolomide (TMZ, which is commonly used for glioma chemotherapy), were listed separately. Radiotherapy was defined as either WBRT, SRS, three-dimensional conformal radiation therapy (3D-CRT), or any of their combination.

  • Outcomes: Central nervous system progression-free survival (CNS-PFS) or overall survival (OS) times were reported. Some of the included trials also reported the CNS objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).

  • Study design: RCTs were included. The follow-up period was required to be no shorter than 1 year. Since neurosurgical resection is an invasive and personalized treatment, it is impracticable to perform RCTs in terms of surgery. Therefore, retrospective trials comparing surgery or not were included in another separate meta-analysis.

  • We excluded studies not adhering to the inclusion criteria. The other exclusion criteria were as follows:

  • Studies only recruited patients NSCLC with EGFR-mutation or ALK-rearrangement.

  • Trials comparing treatments that have not been approved by the US Food and Drug Administration.

  • Reviews, animal experiments, basic research, case reports, and meta-analyses.

2.3 Data extraction and quality assessment

Two authors, Zhang C.K. and Zhou W.J.L., independently extracted data from the eligible studies and assessed the risk of bias in the individual studies. Disagreements were resolved by consensus or referral to a third reviewer, Guan X.D. The extracted items included study details (name of the first author, country, registration number, and phase of the study), participant details (number of participants, age, and gender), intervention and comparison in each arm, and survival outcomes (hazard ratios [HRs] and 95% confidence interval [CI], including the OS rate, PFS rate, and ORR).

The quality and risk of bias were assessed for each trial using the Cochrane Collaboration risk of bias tool [22], random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other sources of bias were examined. The quality of each study was categorized as high, low, or unclear.

2.4 Statistical analyses

The risk of bias in the RCTs was assessed by Review Manager (RevMan, 5.3, The Cochrane Collaboration, London, UK). The Bayesian NMA was performed using the JAGS program and GEMTC package in R software (version 4.0.2, R Foundation, Vienna, Austria). HRs of CNS-PFS and OS rates were analyzed on a natural log scale and pooled as HRs and 95% credible intervals (CrIs). For studies that did not directly provide HRs, we extracted and estimated the HRs and corresponding standard error from a high-quality Kaplan–Meier curve with the methods described by Tierney [23]. The ORR was pooled with the risk ratio (RR) and corresponding 95% CrI. The simulation was performed using the Markov chain Monte Carlo technique with three different chains, and each of them produced 10,000 interactions with 100,000 burn-in samples and ten thinning rates. Fixed-effect models were used, since in most cases, the treatment of interest was evaluated in only one trial. We assessed statistical inconsistencies by the edge-splitting method to compare direct and indirect evidence. Statistical significance was considered when P < 0.05. Statistical heterogeneity was estimated by the I2 statistic, which indicates what proportion of variability in outcomes was due to heterogeneity rather than chance. An I2 > 50% was regarded as significant heterogeneity, while I2 < 25% indicated a small level of heterogeneity. To assess the robustness and reliability of the results, we also performed a sensitivity analysis in the absence of low-quality trials.

3 Results

3.1 Study selection and characteristics

The procedures of the screening and the reasons for exclusion are shown in Figure 1. A total of 2,099 studies met the search criteria. After title and abstract screening, 47 trials were retrieved, and the full text was reviewed. Ultimately, 25 trials [24–48] were included in this NMA. Another five trials were included in a traditional meta-analysis comparing surgery or not. As shown in Table 1, a total of 3,054 participants were enrolled in the selected RCTs. Most participants were male and over 55 years of age. The demographic and clinical characteristics kept a balance between the intervention and control groups in each RCT. The trial publication dates ranged from 2005 to 2022. The bias assessment is presented in Figure S1, with two trials assessed as having a high risk of bias [26,27] and 23 trials assessed as having a low risk of bias [24,25,28–48].

Figure 1 Flowchart of study selection. A total of 25 randomized controlled trials that met the inclusion criteria were included in the NMA.
Figure 1

Flowchart of study selection. A total of 25 randomized controlled trials that met the inclusion criteria were included in the NMA.

Table 1

Characteristics of included trials

Author/Year Study number (Phase) Country No. of patients (I/C) Males% (I/C) Age† (I/C) Previous treatment for BMs Intervention arm Control arm
Lim et al. [24] 2015 NCT01301560 (III) Korea 49/49 71%/73% 58 (33–77)/57 (29–85) No SRS + Chem Chem
Zhu et al. [34] 2018 NA China 31/31 55%/58% NA 24/31 in I and 19/31 in C received Chem; 11/31 in I and 9/31 in C received targeted therapy 3D-CRT (18–36 Gy) + TMZ CRT(18–36 Gy)
GlaxoSmithKline [28] 2006 NCT00390806(Ⅲ) Multiple 236/236 64.4%/66.9% 59.4 ± 8.56/57.8 ± 8.65 Received chemotherapy WBRT(30 Gy/10fra) + Chem WBRT(30 Gy/10fra)
Sperduto et al. [25] 2013 NCT00096265(Ⅲ) US and Canada 40/44 NA 63(NA)/64(NA) No WBRT(37.5 Gy/15fra) + SRS(15–24 Gy, size depended) + TMZ WBRT(37.5 Gy/15fra) + SRS(15–24 Gy, size depended)
　 　 　 41/44 NA 61(NA)/64(NA) No WBRT(37.5 Gy/15fra) + SRS(15–24 Gy, size depended) + Erlotinib WBRT(37.5 Gy/15fra) + SRS(15–24 Gy, size depended)
He et al. [27] 2017 NCT02284490(Ⅱ) China 32/28 34.4%/39.3% 59(52–73)/58.5(45–77) No WBRT(30 Gy/10fra) + Chem WBRT(30 Gy/10fra) + TMZ
Hassler et al. [26] 2013 NCT00266812(Ⅱ) Austrian 22/13 59%/61.5% 69(36–85)/64(54–78) No WBRT(40 Gy/20fra or 30 Gy/10fra) + TMZ WBRT(40 Gy/20fra or 30 Gy/10fra)
Guerrieri [30] 2004 NA(Ⅲ) Australia 21/21 71%/71% 60(42–77)/63(39–78) No WBRT(20 Gy/5fra) + Chem WBRT(20 Gy/5fra)
Chua et al. [29] 2010 NCT00076856(Ⅱ) China 47/48 64%/67% 59(38–78)/62(43–79) No WBRT(30 Gy/10fra,over 2 week) + TMZ WBRT
Chabot et al. [31] 2017 NCT01657799(II) Multiple 102/102 65%/55% 62(39–81)/60(41–86) No WBRT(30 Gy/10fra) + Veli WBRT(30 Gy/10fra)
Lee et al. [35] 2014 NCT00554775(II) Britain 40/40 37.5%/52.5% 61.3(48–75)/62.2(41–73) No WBRT(20 Gy/5fra) + Erlotinib WBRT(20 Gy/5fra)
Grønberg et al. [37] 2012 NCT00415363(II) Multiple 39/41 NA NA No WBRT(20 Gy/5fra or 30 Gy/10fra) + Enza WBRT(20 Gy/5fra or 30 Gy/10fra)
Jiang et al. [33] 2014 NCT01410370(II) China 40/40 NA NA No WBRT(30 Gy/10fra,2 week) + Endo WBRT(30 Gy/10fra, 2 week)
Zhao et al. [32] 2016 NA(II) China 40/40 52.5%/55% 67(57–75)/64(59–75) No WBRT(30 Gy/10fra,2 week) or 3D-CRT + Endo WBRT(30 Gy/10fra, 2 week) or 3D-CRT
Yang et al. [36] 2020 NCT01887795(III) China 106/114 59.4%/60.5% 55.5(26–70)/56(27–70) No WBRT(40 Gy/20fra) + Erlotinib WBRT(40 Gy/20fra)
Pesce et al. [38] 2012 NCT00238251(III) Switzerland 16/43 56.3%/62.8% 57(46–82)/63(45–79) 9/59 received Chem WBRT(30 Gy/10fra) + Gefitinib WBRT(30 Gy/10fra)
Wang et al. [40] 2015 NA(II) China 37/36 67.6%/63.9% 61(NA)/62(NA) No 3D-CRT(50 Gy) + Gefitinib CRT(50 Gy) + Chem
Arrieta et al. [39] 2022 NCT04338867(II) Mexico 46/50 54.3%/45.7% 61.4 ± 10.2/57.9 ± 12.8 No WBRT(30 Gy/10fra) + Nitro WBRT(30 Gy/10fra)
Gadgeel et al. [41] 2019 NCT02008227(Ⅲ) Multiple 61/62 55.7%/53.2% 59.0(39–79)/62.5(39–83) Previously treated and asymptomatic Atez Chem
Sezer et al. [48] 2021 NCT03088540(III) Multiple 34/34 NA NA Previously treated and stable Cemi Chem
Borghaei et al. [42] 2015 NCT01673867(III) Multiple 43/42 NA NA Previously treated, 74% had radiotherapy Nivo Chem
Wu et al. [43] 2019 NCT02613507(III) China 45/27 NA NA Previously treated and stable Nivo Chem
Paz-Ares et al. [44] 2021 NCT03215706(III) Multiple 64/58 NA NA Previously treated and stable Nivo + Ipil Chem
Hellmann et al. [45] 2019 NCT02477826(III) Multiple 64/51 NA NA Previously treated and stable Nivo + Ipil Chem
Mansfield et al. [46] 2021 NCT01295827 Multiple 199/94 49.7%/56.4% 59.0(31–88)/60.0(31–81) Previously treated and stable Pemb Chem
NCT01905657
NCT02142738
NCT02220894
Powell et al. [47] 2019 NCT02039674 Multiple 105/66 NA NA Previously treated and stable Pemb + Chem Chem
NCT02578680
NCT02775435

†Patients’ age was described as median age (range) or average age ± SD.

Abbreviations: BMs, brain metastases; I, intervention group; C, control group; SRS, stereotactic radiotherapy; WBRT, whole-brain radiotherapy; fra, fraction; 3D-CRT, three-dimensional conformal radiation therapy; TMZ, temozolomide; Chem, chemotherapy; Veli, veliparib; Enza, enzastaurin; Nitro, nitroglycerin; Endo, endostatin; Atez, atezolizumab; Cemi, cemiplimab; Nivo, nivolumab; Ipil, ipilimumab; and Pemb, pembrolizumab.

NA, not available.

Seventeen studies compared radiotherapy with radiotherapy plus systemic therapies [24–40]. Such systemic therapies include traditional chemotherapy for NSCLC, EGFR-TKIs (Gefitinib or Erlotinib), and six kinds of innovative therapies (TMZ, Endostar [Endo], Enzastaurin [Enza], Nitroglycerin [Nitro], and Veliparib [Veli]). Since ALK inhibitors were only applied to patients with ALK-positive NSCLC [14], relevant studies were not included in the current study about EGFR/ALK negative or unselected patients. These studies mainly recruited patients with newly diagnosed BMs, and the BMs have not previously received local treatment (neither surgery nor radiotherapy). Only three studies recruited some patients who had previously received systemic chemotherapy or targeted therapy [28,34,38]. In each included trial, the intervention and control groups applied the same radiation technique and dose, except for Lim’s study [24], which compared SRS + chemotherapy with chemotherapy alone. According to the current guideline, WBRT was recommended at a standard dose (30 Gy in ten fractions) or a lower dose (20 Gy in five fractions) for patients with newly diagnosed BMs [18]. For trials included in our analyses, eight trials performed WBRT of 30 Gy in ten fractions [27–39]; two trials performed WBRT of 20 Gy in five fractions [30,35]; and one trial performed WBRT of either 30 Gy in ten fractions or 20 Gy in five fractions [37]. In addition, several trials applied WBRT at a higher dose. Yang’s trial performed WBRT of 40 Gy in 20 fractions [36]. Hassler’s trial performed WBRT of either 30 Gy in ten fractions or 40 Gy in 20 fractions [26]. Two trials performed 3D-CRT of 18–36 Gy [34] or 50 Gy [40]. One trial performed both WBRT (37.5 Gy in 15 fractions) and size-dependent SRS (lesions <2 cm, 2.1–3.0 cm, and 3.1–4.0 cm received 24, 18, and 15 Gy, respectively) [25]. Only one trial performed SRS with an unclear dose [24]. Trials on Nitro, Veli, Enza, and Endo performed concurrent systemic therapy with radiotherapy [31–33,37,39]. Trials on EGFR-TKI, TMZ, and traditional chemotherapy performed systemic therapy both during and after radiotherapy [25–30,34–36,38,40]. One trial started chemotherapy within 3 weeks after SRS [24].

Eight studies compared ICI-based therapies with chemotherapy, including Pembrolizumab (Pemb), Atezolizumab (Atez), Cemiplimab (Cemi), Nivolumab (Nivo), and Ipilimumab (Ipil). These eight studies recruited patients with previously treated (radiation therapy and/or surgery for BMs) and clinically stable BMs [41–48].

In addition, five retrospective studies [49–53] compared surgery (n = 269) with radiotherapy alone (n = 431) for patients who have opportunities for surgery (Table S2). Seven hundred previously untreated resectable BMs from NSCLC were included in analyses.

Considering the heterogeneity of the study design and treatment history, we divided the analyses into three parts: (1) NMA about radiotherapy or systemic therapy for previously untreated patients; (2) NMA about ICIs or chemotherapies for previously treated patients; and (3) traditional meta-analysis comparing surgery with radiotherapy alone for patients who had opportunities of surgery.

3.2 OS

The NMA results for the OS outcome are displayed in Figure 2. Sixteen radiotherapy-related trials about nine regimens reported OS for previously untreated BMs (Figure 2a). Unfortunately, none of such regimens showed a significant survival benefit over radiotherapy alone (Figure 2b). Radiotherapy + endostatin (HR: 0.78, 95% CrI: 0.43–1.4), radiotherapy + nitroglycerin (HR: 0.86, 95% CrI: 0.52–1.4), and chemotherapy alone (HR: 0.79, 95% CrI: 0.49–1.3) showed slightly beneficial trends on OS without statistical significance. Radiotherapy combined with EGFR-TKIs, or other innovative medicines (TMZ, Veli, or Enza) had similar or even worse effects than radiotherapy alone in terms of OS.

Figure 2 Pooled result of OS for different treatments for BMs from EGFR/ALK-negative/unselected NSCLC. (a) Network diagram and (b) forest plot of OS for different treatments compared with radiotherapy alone in newly diagnosed BMs. (c) Network diagrams and (d) forest plot of OS for different treatments compared with chemotherapy alone in previously treated BMs. (e) Forest plot of OS comparing surgery with radiotherapy alone. Each node in the network diagram represents one treatment, and the numbers represent direct head-to-head comparisons. Abbreviations: RT, radiotherapy; TMZ, temozolomide; Chem, chemotherapy; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitors; Enza, enzastaurin; Nitro, nitroglycerin; Veli, veliparib; Endo, endostatin; Atez, atezolizumab; Cemi, cemiplimab; Nivo, nivolumab; Ipil, ipilimumab; and Pemb, pembrolizumab.
Figure 2

Pooled result of OS for different treatments for BMs from EGFR/ALK-negative/unselected NSCLC. (a) Network diagram and (b) forest plot of OS for different treatments compared with radiotherapy alone in newly diagnosed BMs. (c) Network diagrams and (d) forest plot of OS for different treatments compared with chemotherapy alone in previously treated BMs. (e) Forest plot of OS comparing surgery with radiotherapy alone. Each node in the network diagram represents one treatment, and the numbers represent direct head-to-head comparisons. Abbreviations: RT, radiotherapy; TMZ, temozolomide; Chem, chemotherapy; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitors; Enza, enzastaurin; Nitro, nitroglycerin; Veli, veliparib; Endo, endostatin; Atez, atezolizumab; Cemi, cemiplimab; Nivo, nivolumab; Ipil, ipilimumab; and Pemb, pembrolizumab.

Eight studies compared six kinds of ICI-based treatments with chemotherapy for previously treated BMs reported OS (Figure 2c). Pembrolizumab + chemotherapy (HR: 0.48, 95% CrI: 0.32–0.71), nivolumab + ipilimumab (HR: 0.50, 95% CrI: 0.37–0.69), and cemiplimab (HR: 0.17, 95% CrI: 0.039–0.76) significantly prolonged OS than chemotherapy (all P < 0.05) (Figure 2d). Atezolizumab monotherapy (HR: 0.74, 95% CrI: 0.49–1.1) and pembrolizumab monotherapy (HR: 0.83, 95% CrI: 0.62–1.1) also showed beneficial trend than chemotherapy in terms of OS (all P > 0.05). Nivolumab monotherapy had similar effect than chemotherapy on OS (HR: 0.95, 95% CrI: 0.63–1.4). The derived HR for treatments compared with each other are demonstrated in Figure S2.

Five trials compared OS for patients who performed surgery or not (Figure 2e). Surgical resection of BMs from NSCLC was associated with a significantly favorable OS than radiotherapy alone (HR: 0.52, 95% CrI: 0.41–0.67, common effect model).

3.3 CNS-PFS

As shown in Figure 3a, nine studies reported CNS-PFS in terms of eight kinds of radiotherapy-associated treatments for previously untreated BMs: radiotherapy alone, radiotherapy + EGFR-TKI, radiotherapy + chemotherapy, chemotherapy alone, and radiotherapy combined with other innovative systemic agents (TMZ, Nitro, Enza, or Veli). Only radiotherapy + nitroglycerin showed significant benefit over radiotherapy in terms of CNS-PFS (HR: 0.49, 95% CrI: 0.25–0.95) (Figure 3b). Nevertheless, compared with radiotherapy alone, radiotherapy + EGFR-TKIs, radiotherapy + chemotherapy, and radiotherapy combined with other innovative medicines (TMZ, Enza, or Veli) did not derive significant survival benefits for CNS-PFS (all P > 0.05) (Figure 2b).

Figure 3 Pooled result of CNS-PFS for different treatments for BMs from EGFR/ALK-negative/unselected NSCLC. (a) Network diagram and (b) forest plot of CNS-PFS for different treatments compared with radiotherapy alone in newly diagnosed BMs. (c) Network diagrams and (d) forest plot of CNS-PFS for different treatments compared with chemotherapy alone in previously treated BMs. (e) Forest plot of CNS-PFS comparing surgery with radiotherapy alone. Each node in the network diagram represents one treatment, and the numbers represent direct head-to-head comparisons. Abbreviations: RT, radiotherapy; TMZ, temozolomide; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitors; Enza, enzastaurin; Nitro, nitroglycerin; Veli, veliparib; Chem, chemotherapy; Pemb, pembrolizumab; and Atez, atezolizumab.
Figure 3

Pooled result of CNS-PFS for different treatments for BMs from EGFR/ALK-negative/unselected NSCLC. (a) Network diagram and (b) forest plot of CNS-PFS for different treatments compared with radiotherapy alone in newly diagnosed BMs. (c) Network diagrams and (d) forest plot of CNS-PFS for different treatments compared with chemotherapy alone in previously treated BMs. (e) Forest plot of CNS-PFS comparing surgery with radiotherapy alone. Each node in the network diagram represents one treatment, and the numbers represent direct head-to-head comparisons. Abbreviations: RT, radiotherapy; TMZ, temozolomide; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitors; Enza, enzastaurin; Nitro, nitroglycerin; Veli, veliparib; Chem, chemotherapy; Pemb, pembrolizumab; and Atez, atezolizumab.

Regarding ICIs for previously treated BMs, three trials about four treatments reported CNS-PFS and were included in analyses (Figure 3c). Atezolizumab (HR: 0.38, 95% CrI: 0.16–0.90), pembrolizumab + chemotherapy (HR: 0.44, 95% CrI: 0.31–0.62) showed statistically significant benefits than chemotherapy alone on CNS-PFS (Figure 3d). Pembrolizumab monotherapy showed a similar effect with chemotherapy on CNS-PFS (HR: 0.96, 95% CrI: 0.73–1.3).

Only two trials reported CNS-PFS in terms of surgery (Figure 3e). Surgical resection of BMs from NSCLC still showed better CNS-PFS than radiotherapy alone (HR: 0.32, 95% CrI: 0.18–0.95, common effect model).

3.4 ORR

Eleven radiotherapy-related trials about eight kinds of treatments reported ORR (Figure 4a). Radiotherapy + nitroglycerin showed a significant benefit over radiotherapy alone on ORR (RR: 1.8, 95% CrI: 1.1–3.0). Adding chemotherapy or other innovative medicines (TMZ, Endo, Veli, or Enza) to radiotherapy did not show significant benefit over radiotherapy alone (all P > 0.05). Patients treated with chemotherapy alone had the lowest ORR (versus radiotherapy RR: 0.71, 95% CrI: 0.43–1.2) (Figure 4b).

Figure 4 Pooled result of ORR for different treatments for BMs from EGFR/ALK-negative/unselected NSCLC. (a) Network diagram and (b) forest plot of ORR for different treatments compared with radiotherapy alone in newly diagnosed BMs. (c) Network diagrams and (d) forest plot of ORR for different treatments compared with chemotherapy alone in previously treated BMs. (e) Forest plot of ORR comparing surgery with radiotherapy alone. Each node in the network diagram represents one treatment, and the numbers represent direct head-to-head comparisons. Abbreviations: RT, radiotherapy; TMZ, temozolomide; Chem, chemotherapy; Endo, endostatin; Enza, enzastaurin; Nitro, nitroglycerin; Veli, veliparib; and Pemb, pembrolizumab.
Figure 4

Pooled result of ORR for different treatments for BMs from EGFR/ALK-negative/unselected NSCLC. (a) Network diagram and (b) forest plot of ORR for different treatments compared with radiotherapy alone in newly diagnosed BMs. (c) Network diagrams and (d) forest plot of ORR for different treatments compared with chemotherapy alone in previously treated BMs. (e) Forest plot of ORR comparing surgery with radiotherapy alone. Each node in the network diagram represents one treatment, and the numbers represent direct head-to-head comparisons. Abbreviations: RT, radiotherapy; TMZ, temozolomide; Chem, chemotherapy; Endo, endostatin; Enza, enzastaurin; Nitro, nitroglycerin; Veli, veliparib; and Pemb, pembrolizumab.

Only two trials about ICIs for previously treated BMs reported ORR (Figure 4c). Pembrolizumab + chemotherapy showed significantly better ORR than chemotherapy (RR: 2.0, 95% CrI: 1.2–3.7), while pembrolizumab monotherapy did not (RR: 1.5, 95% CrI: 0.92–2.5) (Figure 4d).

Three trials about surgery reported ORR (Figure 4e). Surgery showed a favorable trend of ORR for BMs from NSCLC but did not reach a statistical difference (RR: 1.04, 95% CrI: 0.89–1.21, common effect model).

3.5 Heterogeneity, consistency, and sensitivity analysis

There was low global heterogeneity for the comparison of radiotherapy-associated regiments (I2 = 0% for OS, I2 = 0% for CNS-PFS, and I2 = 8% for ORR) and low to moderate heterogeneity for the comparison of ICIs (I2 = 22% for OS, I2 = 33% for CNS-PFS, and I2 = 25% for ORR). Furthermore, local heterogeneities were also acceptable between paired treatments (Table S3). In terms of inconsistency, there was no significant difference between direct and indirect comparisons of the OS, CNS-PFS, and ORR (Figure S3). During the sensitivity analysis, one study with unclear random sequence generation [27] and another study with imbalanced patients’ initial baseline [26] were excluded. The results showed the same ranks compared with those of the original NMA (Figure S4). The sensitivity analyses showed that the overall results remained robust.

4 Discussion

Currently, there is a wide range of alternative treatments available for brain-metastatic NSCLC with negative or unselected EGFR/ALK status. Nevertheless, direct comparisons of such treatments are limited. Our study analyzed the relative efficacy of each treatment for previously treated and untreated BMs. It showed that several ICIs were associated with longer OS and CNS-PFS than chemotherapy in patients with previously treated BMs. Except for nitroglycerin, the addition of EGFR-TKIs, chemotherapy, and other non-ICI systemic innovative medicines to RT did not improve OS, CNS-PFS, and OS. Surgery of BMs was associated with better OS, CNS-PFS, rather than ORR. The reasons for these findings are presented as follows.

Currently, ICIs have been the standard first-line treatments for metastatic NSCLC without sensitizing EGFR or ALK or other druggable mutations [54]. However, the intracranial efficacies of ICIs remained uncertain. The exact mechanism of ICIs for brain tumors was also unclear. First, it may be related to modified immune cell activity rather than direct action in the brain. By immune cell trafficking and T-cell priming in the extracranial immune system, ICIs could produce an effective immune response in the CNS [55,56]. Moreover, due to the infiltration of lymphocytes in BMs [57] and the relatively stable PD-L1 expression level between primary tumors and BMs [58], it can be hypothesized that PD-(L)1 inhibitors might provide similar effects inside and outside the brain [59].

It is not surprising that ICIs were associated with favorable efficacies. Current RCTs have confirmed that PD-(L)1 inhibitors could significantly improve OS and PFS rates among patients with metastatic NSCLC [60–63]. For NSCLC patients with BMs, the results of other concurrent studies are also consistent with our findings. The FIR study demonstrated that atezolizumab monotherapy showed clinical activity in NSCLC patients with or without BMs [64]. Thirteen patients with pretreated BMs receiving atezolizumab were enrolled, with an ORR of 23% (3/13) and a median PFS and OS interval of 4.3 months (95% CI: 1.1–16.2) and 6.8 months (95% CI: 3.2–19.5), respectively [64]. The KEYNOTE-001 clinical trial first confirmed the efficacy of pembrolizumab in NSCLC patients with or without BMs [65]. Goldberg’s non-random phase II study showed that when treating BM originating from NSCLC with PD-L1 expression ≥1% with pembrolizumab, the ORR, median OS time, and median PFS time were 29.7% (11/37), 9.9 months (95% CI: 7.5–29.8), and 1.9 months (95% CI: 1.8–3.7), respectively [59]. A cohort of 409 patients with BMs from NSCLC showed that the median OS and disease control rate reached 8.6 months (95% CI: 6.4–10.8) and 40% (164/409) after applying nivolumab [66]. Kitadai also found a PD-L1-negative NSCLC patient with BMs reached intracranial complete response after nivolumab monotherapy [67].

In addition, the choice of monotherapy or combined therapy also affects the therapeutic effect of ICIs for BMs. In our NMA, several combined therapies, including pembrolizumab + chemotherapy and nivolumab + ipilimumab derived relatively better effects. Current NCCN guideline recommends ICIs monotherapy for patients with PD-L1-expression more than 50%; whereas, ICIs in combination with chemotherapy is recommended regardless of PD-L1 expression [54]. Consistently, comparisons between different immunotherapy strategies for BMs also showed that combined ICIs with chemotherapy or dual ICIs had favorable efficacies for advanced NSCLC [57,68,69]. Similarly, an RCT also showed that nivolumab + ipilimumab derived better CNS-PFS and ORR than nivolumab monotherapy for BMs from melanoma [70].

Moreover, the included RCTs were aimed at previously treated BMs, whereas the efficacy of ICIs + radiotherapy for untreated BMs lacked evaluation. A meta-analysis of 19 prospective or retrospective studies showed that ICIs + radiotherapy could significantly prolong OS than RT alone (HR: 0.77, 95% CI:0.71–0.83) for BMs from NSCLC, and grade 3–4 neurological adverse event rates were similar (RR: 0.91, 95% CI:0.41–2.02) [71]. Recently, a retrospective study of 21 patients with BMs from EGFR/ALK-negative NSCLC also found the concurrent WBRT and ICIs prolonged CNS-PFS (HR: 0.29, 95% CI: 0.11–0.80; P = 0.016) and OS (HR 0.33, 95% CI: 0.08–1.12; P = 0.107) than WBRT alone [72].

The expression level of PD-L1 could also affect the response to ICIs. Studies have demonstrated that ICIs have better efficacy in NSCLC (with or without BM) patients whose PD-L1 expression is ≥1% [59,65,73], while responses can still occur in those with PD-L1 expression <1% or PD-L1-negative tumors [44,67,73–75]. Of the eight trials included in this study, six trials did not select patients according to PD-L1 expression [41–45,47], and ICIs still showed promising efficacies. One trial about pembrolizumab monotherapy recruited patients with PD-L1 expression of no less than 1%, but its effect was still inferior to pembrolizumab + chemotherapy [46]. Another trial about cemiplimab included patients with PD-L1 expression at least 50%, and showed relatively superior OS and CNS-PFS [48]. Therefore, we speculated that the therapeutic effect was determined by both PD-L1 expression and the properties of ICIs.

Nowadays, radiotherapy (SRS or WBRT) remains the mainstay of initial therapy for BMs [16]. Previous studies have shown the addition of WBRT to SRS or surgery alone could increase CNS-PFS and local control rate; however, the OS time did not prolong, and the neurocognitive toxicity also increased [18,76,77]. Therefore, local treatment (SRS or surgical resection) without WBRT is recommended for patients with up to four BMs and good physical performance [18]. With the development of the SRS technique, SRS was tried to treat selected patients with multiple (more than four) BMs. Several multicenter studies have found that patients treated with SRS for 5–10 BMs, or even 5–15 BMs derived comparable OS to those with 2–4 BMs [78,79]. WBRT is often considered for patients who are not suitable for SRS or surgery (e.g., innumerable metastases, innumerable metastases, poor physical performance, or other contraindications) [10], and was believed to prolong CNS-PFS [18]. Nevertheless, an RCT found that the WBRT showed no difference with optimal supportive care in terms of OS, quality of life, and dexamethasone for patients unsuitable for resection or SRS [80].

In current analyses, nitroglycerin + WBRT showed favorable effects for BMs. Nitroglycerin has just been used to assist tumor radiotherapy in recent years. It could reduce the radiation resistance by alleviating tumor hypoxia [39]. Nevertheless, the synergistic effect of nitroglycerin with chemoradiotherapy was only tested in several phase II trials of primary NSCLC [81–83] and only one trial about BM [39], and the results of primary NSCLC were controversial [81–83]. Therefore, the efficacy of nitroglycerin on BMs needs to be further evaluated.

On the other hand, there was no significant advantage of adding chemotherapy, EGFR-TKI, or other non-ICI innovative systemic agents to radiotherapy. Systematic reviews have revealed that radiotherapy + chemotherapy might improve response rates compared with radiotherapy alone; however, this approach does not improve survival outcomes and increases the incidence of adverse reactions in patients with BMs arising from lung cancer [84,85]. Meanwhile, WBRT plus systemic therapy was associated with increased risks for vomiting compared to WBRT alone [84,86–88]. For the same reasons, the CNS (Congress of Neurological Surgeons) and EANO (European Association of Neuro-Oncology) guidelines did not suggest routine use of cytotoxic chemotherapy either alone or following WBRT [16,89].

Although TMZ is recommended to be used with WBRT for patients with BMs arising from triple-negative breast cancer [89], its efficacy on BM arising from NSCLC is controversial. Several trials have yielded mixed results [90–93], while the current systematic review and meta-analysis determined that adding TMZ to radiotherapy can increase the ORR [87,94,95]. However, it is generally believed that adding TMZ cannot induce a better OS outcome [86,87,96,97]. Therefore, there is insufficient evidence to conclude that there is value in adding TMZ for the treatment of NSCLC with BM [98].

Although EGFR-TKIs were used to treat BMs from EGFR-unselected NSCLC, the effect was not ideal. Currently, with the widespread use of genetic testing technology, it is recommended to screen for EGFR-mutations in NSCLC patients with BMs and treat them with third-generation EGFR-TKIs, which have better blood–brain barrier penetrability and better efficacy [99].

Adding several other innovative systemic treatments to radiotherapy did not show survival benefits, including Veli (polyadenosine-diphosphate-ribose polymerase inhibitor), Enza (serine/threonine kinase inhibitor), and Endo (an antiangiogenic drug). This was not surprising because RCTs evaluating treatments for NSCLC (with or without metastases) have demonstrated that although Veli [100] or Endo [101] demonstrated a favorable trend in PFS and OS outcomes versus chemotherapy alone, the differences were not statistically significant; however, adding Enza to chemotherapy may induce shorter median survival times [102].

Surgical resection of BMs remains one of the mainstays of therapies for patients with BMs from NSCLC [103]. Since these metastases show radioresistance compared to SCLC, surgical resection to relieve the space-occupying effect is often the first step in treatments for these patients [10]. In the current analyses, surgery could derive better OS and CNS-PFS than radiotherapy alone for BMs from NSCLC. Consistently, previous studies also found surgery improved survival outcomes of patients with a single brain-metastatic lesion, a good karnofsky performance scale (KPS), and a limited number of extracranial metastases (primary malignancies were not filtered) [104,105].

5 Limitations

There were several limitations in this study. First, the exact techniques of RT were not compared separately. On the one hand, the indications and efficacies of WBRT and SRS have been proven by high-quality studies. On the other hand, network comparisons could not form if radiotherapy techniques were discussed separately. Therefore, our analyses mainly focused on the effect of adjuvant systemic therapy on radiotherapy. Discuss RT as a whole is feasible and consistent with previous meta-analyses on BMs [106,107], because the intervention (with adjuvant systemic therapy) and control (without adjuvant systemic therapy) groups in each trial have received radiotherapy of the same technique and dose.

There was still potential selection and publication bias. First, as mentioned above, two trials had unqualified patient inclusion processes; therefore, a sensitivity analysis was conducted, and relatively robust results were ensured. Second, there were a limited number of trials in each comparison. For this reason, we did not use funnel plots to assess publication bias or small-study effects. Third, we assumed that the patients from different trials were similar; however, patients may have had different baseline levels. For example, an unbalanced baseline can arise from the presence or absence of symptoms and the exact number and volume of BMs. All of these factors could give rise to a bias.

Moreover, limited information also restricted our analyses. We could not analyze the adverse effects and quality of life (such as KPS score and other parameters), because such information was not available or not complete. Trials on systemic therapy or radiotherapy usually did not report how many patients underwent surgery and their corresponding outcome. Therefore, we could not analyze the synergy between surgery and other treatment. Included trials about surgery did not perform subgroup analysis according to the surgery details (such as location, size, and the number of BMs), which makes it difficult for us to obtain the corresponding summary results. In addition, most trials about ICIs included in our analyses only reported OS without reporting CNS-PFS and ORR. Such data of interest need to be further explored.

6 Conclusion

ICI-based therapies, especially ICI-combined therapies, showed promising efficacies for previously treated BMs from EGFR/ALK-negative/unselected NSCLC. Adding chemotherapy, EGFR-TKIs, and some innovative agents (TMZ, Nitro, Endo, Enza, and Veli) to radiotherapy showed limited effects than radiotherapy alone for newly diagnosed BMs from EGFR/ALK-negative/unselected NSCLC. Surgery could significantly prolong OS and CNS-PFS compared with radiotherapy alone. Limited to heterogeneity and available information, the result of the current network meta-analyses should be further confirmed by RCTs.

Acknowledgment

None.

  1. Funding information: This study was supported by grants from the National Natural Science Foundation of China (No. 82071996).

  2. Author contributions: (I) Conception and design: W.J., X.D.G., and K.Q.; (II) administrative support: W.J., X.D.G., and K.Q.; (III) provision of study materials or patients: C.K.Z., and X.D.G.; (IV) collection and assembly of data: C.K.Z., D.N.Z., and S.C.M.; (V) data analysis and interpretation: W.J.L.Z. and X.W.; (VI) manuscript writing: all authors; and (VII) final approval of manuscript: all authors.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2022-01-20
Revised: 2022-08-26
Accepted: 2022-08-30
Published Online: 2023-02-14

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2022-0574
Keywords for this article
Bayesian network meta-analysis; non-small cell lung cancer; brain metastasis; immunotherapy; radiotherapy
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
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  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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