Startseite Medizin The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
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The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis

  • Jianping Liu ORCID logo , Weijian Zhou , Wei Zhang , Congwang Chang , Peng Zhang und Guanghua Fu EMAIL logo
Veröffentlicht/Copyright: 26. März 2025
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Aus der Zeitschrift Open Medicine Band 20 Heft 1

Abstract

Introduction

We sought to determine the efficacy and safety of Bacillus Calmette-Guérin (BCG) combined with mitomycin C (MMC) compared with BCG monotherapy in intravesical therapies for non-muscle-invasive bladder cancer (NMIBC).

Methods

We followed the recommended PRISMA guidelines for systematic reviews. Systematic literatures were performed on PubMed, EMBASE, Cochrane Library, CNKI, CBM, VIP, Wan Fang, and Clinical Trials.gov. Randomized controlled trials (RCTs) comparing BCG combined with MMC and BCG monotherapy in intravesical therapies for non-muscle-invasive bladder cancer patients were searched until August 1, 2023.

Results

This meta-analysis included 11 RCTs with a total of 1,349 subjects. Compared with BCG monotherapy, BCG combined with MMC was associated with lower disease recurrence rate (relative risk [RR] 0.66, 95% confidence interval [CI]: 0.56–0.77, P < 0.00001), disease progression rate (RR 0.61, 95% CI: 0.44–0.84, P = 0.003), and disease-specific mortality (RR 0.46, 95% CI: 0.26–0.78, P = 0.004). However, there was a higher incidence of systemic adverse reactions (RR 1.57, 95% CI: 1.22–2.02, P = 0.0004). There was no significant difference in the incidence of local adverse reactions (RR 1.07, 95% CI: 0.95–1.20, P = 0.26) and all-cause mortality (RR 0.80, 95% CI: 0.62–1.03, P = 0.08) between the two groups.

Conclusions

BCG combined with MMC was associated with a decreased risk of bladder cancer recurrence and disease progression compared with BCG monotherapy. However, there was no significant difference in the incidence of local adverse events and all-cause mortality between the two groups. Due to the limitations of the number and quality of the included studies, more high-quality RCTs are needed to further explore the efficacy and safety of combined therapies.

Keywords: urinary bladder neoplasms; non-muscle-invasive bladder cancer; intravesical therapies; Bacillus Calmette-Guérin; mitomycin C

1 Introduction

Bladder cancer is one of the most common malignancies of the genitourinary system, with the tenth highest incidence of all cancers worldwide, the sixth highest incidence of male malignancies, and the ninth highest mortality rate. According to cancer statistics in 2021, there were 573,000 new cases of bladder cancer worldwide in 2020, with 213,000 deaths, and the incidence of bladder cancer in men was generally higher than that in women. It is more common in men than in women, with respective incidence and mortality rates of 9.5 and 3.3 per 100,000 among men. Southern Europe has the highest incidence of bladder cancer in the world [1].

Non-muscle-invasive bladder cancer (NMIBC) accounts for about 75% of patients initially diagnosed with bladder cancer, including Ta, T1, and carcinoma in situ (Tis), among which Ta accounted for about 70%, T1 for about 20%, and Tis for about 10% [2]. NMIBC patients were divided into a low-risk group, an intermediate-risk group, a high-risk group, and a very high-risk group [3]. The low-risk group met the following conditions: a primary, single, Ta/T1 LG/G1 tumor <3 cm in diameter without CIS in a patient aged ≤70 years and a primary Ta LG/G1 tumor without CIS with at most ONE additional clinical risk factors (age >70 years, multiple papillary tumors, and tumor diameter ≥3 cm). The high-risk group met the following conditions: all T1 HG/G3 without CIS or all CIS patients, except those included in the very high-risk group. The very high-risk group met the following conditions: Ta HG/G3 and CIS with all three risk factors, T1 G2 and CIS with at least two risk factors, T1 HG/G3 and CIS with at least one risk factor, and T1 HG/G3 no CIS with all three risk factors. The intermediate risk group was the patients without CIS who were not included in either the low-, high-, or very high-risk groups [4].

Transurethral resection of bladder tumor (TURBT) is the standard treatment for NMIBC patients. However, due to the high recurrence and possible progression of the disease, postoperative adjuvant therapy is indispensable. The current guidelines recommend immediate intravesical infusion chemotherapy within 24 h after TURBT, as well as follow-up chemotherapy or immunotherapy based on pathological results. The standard treatment regimen for low-risk patients who need only one immediate perfusion and cannot be perfused immediately is still controversial. In patients with intermediate- and high-risk tumors, intravesical BCG after TURBT is more effective than TURB alone or TURB and intravesical chemotherapy [4]. However, some studies have shown better efficacy in combination therapy and should be given more attention.

Sylvester’s study has shown that many chemotherapy drugs, such as mitomycin C (MMC), epirubicin, and pirarubicin, have shown good efficacy, and the 5-year recurrence rate has been reduced by 14% compared with TURBT alone [5]. Since Morales A first used Bacillus Calmette-Guérin (BCG) in bladder instillation and put forward a 6-week induced instillation therapy in 1976 [6], a large number of studies have shown that BCG is superior to any other single drug in preventing disease recurrence, but the side effects caused by BCG infusion are also significantly more than those caused by chemotherapy [7].

Although BCG showed a good therapeutic effect, some patients still experience recurrence or progression after BCG treatment, so more attention and research are needed [8]. Radical cystectomy is the gold standard treatment option for BCG failure, while other available conservative treatments are thought to be oncologically poor [4]. For patients with poor overall health, conservative management is recommended to mitigate the potential complications of major surgical procedures. Nonetheless, there remains a lack of standardized treatment protocols for intravesical therapy [9].

Rajala’s study showed that BCG combined with MMC had stronger anti-tumor activity against bladder cancer cells than the BCG group, and there may be a synergistic effect between the two groups [10]. Therefore, BCG combined with MMC may be a potential choice to enhance the efficacy without increasing or even reducing the incidence of adverse reactions. Given the discrepancy between clinical practice and guidelines and uncertainty regarding optimal treatment strategies, we conducted a meta-analysis on the benefits and harms of intravesical therapies about BCG combined with MMC or BCG alone for NMIBC.

2 Materials and methods

This study carries on the analysis report according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) system review and meta-analysis [11].

2.1 Study search and selection

Through a systematic literature search of PubMed, EMBASE, Cochrane Library, CNKI, CBM, VIP, Wan Fang, and Clinical Trials.gov, we found the related randomized controlled trials (RCTs) of BCG combined with MMC intravesical instillation in the treatment of NMIBC patients compared with BCG alone. The search time limit is from the establishment of the database to August 1, 2023. Each database is searched systematically according to the established retrieval strategy, and the search results are imported into the document management software EndNote. Titles and abstracts were examined by two independent reviewers according to the eligibility criteria. If there are differences in the results of the two researchers during the screening process, discuss or invite the third researcher to help solve the problem.

2.2 Eligibility criteria

Studies were included if they met the following criteria: (1) participants: all patients were pathologically diagnosed as NMIBC for the first time; (2) intervention: intravesical instillation of BCG combined with MMC; (3) control: intravesical instillation of BCG alone; (4) outcomes: at least one of the following, disease recurrence, disease progression, adverse reactions, disease-specific mortality, all-cause death; and (5) only RCTs were included. Studies were excluded if they met the following criteria: (1) the repeatedly published literature; (2) the studies compared the differences between BCG and MMC combination therapy with other agents; and (3) literature review, animal experiments, case reports, meta-analysis, etc.

2.3 Quality assessment and data extraction

Two researchers evaluated the quality of each original study with The Cochrane Collaboration Risk of Bias Tool, which included the following six items: (1) the generation of random sequences; (2) Allocation concealment; (3) whether to implement a blind method for participants and researchers; (4) whether to implement the blind method for outcome evaluation; (5) whether to selectively report research results; and (6) other sources of bias. The evaluation results are low risk, uncertain risk, and high risk. Two researchers independently evaluated the quality of the original research, and if there were inconsistencies in the evaluation process, they resolved their differences through discussion and finally reached an agreement.

Two researchers independently extracted the following data information: name of the first author, country, year of publication, type of study, sample size of the test group and the control group, average age, sex ratio, tumor stage, grade and risk stratification, follow-up time, dose, course of treatment and times of administration of BCG and MMC in the test group, dose and course of treatment of BCG in the control group, etc. The outcomes include recurrence rate, progression rate, adverse reactions (divided into local adverse reactions and systemic adverse reactions), all-cause mortality, and disease-specific mortality.

2.4 Statistical analysis

The meta-analysis of the original research data was carried out by using Revman5.4 software and Stata16.0 software. The main results of the study were tumor recurrence and disease progression after treatment during the follow-up period of each original study, and the secondary results were adverse reactions (local adverse reactions include hematuria, bladder irritation, chemical cystitis, systemic adverse reactions include fever, flu-like symptoms, etc.), all-cause mortality and disease-specific mortality.

The data types extracted in this study are binary variables, using relative risk (RR) and its 95% confidence interval (CI) to combine statistics. The forest Chi-square test and the size of I 2 were used to evaluate the heterogeneity among the included results. The size of heterogeneity is determined according to the value of I 2. When P ≥ 0.1 and I 2 < 50%, the heterogeneity among the studies is low, then the fixed effect model (FEM) is used for combined statistical analysis. When P < 0.1, I 2 > 50%, it indicates that the heterogeneity among the studies is large and then sensitivity analysis and subgroup analysis are used to find the source of heterogeneity and eliminate heterogeneity as far as possible. After excluding the influence caused by obvious clinical heterogeneity, the random effect model is selected for combined statistical analysis. The test level set by meta-analysis was α = 0.05 (P < 0.05), which indicated that the difference of combined statistical effect was statistically significant. Publication bias was detected by funnel chart, Egger regression analysis, and Begg rank correlation method.

  1. Ethical approval: An ethics statement is not applicable because this study is based exclusively on published literature.

3 Results

3.1 Study selection and characteristics

Through preliminary retrieval, a set of 710 articles was obtained, and 192 duplicated studies were first removed. Finally, 11 RCTs including 1,349 patients [12,13,14,15,16,17,18,19,20,21,22] were selected using the strategy shown in Figure 1. The characteristics of the included studies are summarized in Table 1. The sample size of each study ranged from 41 to 407, the average age of the subjects was 54–73 years old, and the average follow-up time ranged from 1 to 7.1 years. In three studies, only induced perfusion was performed without maintenance perfusion, and maintenance perfusion therapy was performed in the other eight studies. All eleven studies compared the outcome index of disease recurrence, six studies compared the outcome index of disease progression, eight studies compared local adverse reactions, and five studies compared systemic adverse reactions.

Figure 1 Flow diagram of studies’ selection process.
Figure 1

Flow diagram of studies’ selection process.

Table 1

Characteristics of included trials

Study and year Country Period Simple size (M/F) Mean age stage Follow-up Treatment schedules (intervention) Treatment schedules (control)
Di Stasi et al., 2006 [12] Italy 1994–2002 212 (173/39) 66 T1, Tis 88 (63–110) m BCG 81 mg/w, BCG 81 mg/w, MMC 40 mg/w (3 cycles) + MMC 40 mg/m, MMC 40 mg/m, BCG 81 mg/m (3 cycles) BCG 81 mg/w, 6 w + BCG 81 mg/m, 10 m
Oosterlinck et al., 2011 [13] Belgium 2001–2005 96 (86/9)1 68 Ta, T1, Tis 4.7 y MMC 40 mg/w, 6 w + BCG 5 × 108 CFU/w, 6 w + (MMC 40 mg/w, 1 w + BCG5 × 108 CFU/w, 2 w) every 6 m until 3 y BCG 5 × 108 CFU/w, 9 w + (BCG5 × 108 CFU/w, 3 w) every 6 m until 3 y
Gülpinar et al., 2012 [14] Turkey 2004–2006 51 (41/10) 58 Ta, T1, Tis 41.3 (8–64) m MMC 40 mg/w, 1 w + BCG 5 × 108 CFU/w, 6 w BCG 5 × 108 CFU/w, 6 w
Solsona et al., 2015 [15] Spain 1993–1994 407 (366/41) 65 Ta, T1, Tis 7.1 y MMC 30 mg once + BCG 81 mg/w, 9 w BCG 81 mg/w, 9 w
Chen et al., 2016 [16] China 56 2 y MMC 40 mg once + BCG 100 mg/w, 12 w BCG 100 mg/w, 12 w
Fang et al., 2007 [17] China 2000–2005 74 (63/11) 62 Ta, T1 6–36 m MMC 40 mg/w, 6 w + BCG 120 mg, 6 w BCG 120 mg/m, 24 m BCG 120 mg/w, 8 w
BCG 120 mg/m, 24 m
Gong et al., 2014 [18] China 2008–2010 95 (79/16) 59 Ta, T1 3 y alternating MMC 40 mg/w, BCG 80 mg/w, 8 w + MMC 40 mg/2 w, BCG 80 mg/2 w, 3 m + MMC 40 mg/m, BCG 80 mg/m, 2 y BCG 80 mg/w, 8 w + BCG 80 mg/2 w, 3 m + BCG 80 mg/m, 2 y
He et al., 2013 [19] China 2005–2009 79 (62/17) 61 Ta, T1 21.2 ± 9.6 m MMC 40 mg/w, 3 w + BCG 1 × 106 CFU/w, 6 w + BCG 1 × 106 CFU/m, 12 m + BCG1 × 106 CFU/3 m, 9 m BCG 1 × 106 CFU/w, 6 w + BCG 1 × 106 CFU/m, 12 m + BCG1 × 106 CFU/3 m, 9 m
Liu and Liu, 2007 [20] China 2000–2003 110 (84/26) 55 Ta, T1 35 (12–70) m MMC 20 mg/w, 3 w + BCG 150 mg, 6 w BCG 150 mg, 6 w + BCG 150 mg/w, 3 w at 3, 6, 12, 18, 24, 30, 36 m
BCG 150 mg/w, 3 w at 3, 6, 12, 18, 24, 30, 36 m
Abd El Kader, 2010 [21] Egypt 2004–2008 128 (86/42) 54 Ta, T1 26 (6–45) m MMC 40 mg/w, 1 w + BCG/w, 6 w BCG/w, 6 w
Gao, 2018 [22] China 2014–2016 41 (21/20) 68 1 y alternating BCG 120 mg/w, MMC 40 mg/w, 8 w + BCG 120 mg/m, MMC 40 mg/m, 10 m BCG 120 mg/w, 8 w + BCG 120 mg/m, 10 m

Abbreviations: BCG: Bacillus Calmette-Guérin; MMC: mitomycin C; CFU: colony-forming units; M: male; F: female; w: week; m: months; y: year.

3.2 Risk of bias in included studies

The results of quality assessment using the Cochrane Collaboration’s recommended tool. The quality assessment indicated that as a whole, risk of the selection bias, detection bias, and attrition bias were low in all the included studies (Figure 2).

Figure 2 Assessment of risk of bias.
Figure 2

Assessment of risk of bias.

3.3 Primary outcomes

Recurrence of the disease was reported in all 11 studies. There was no heterogeneity among the studies (I 2 = 17%, P = 0.28). Therefore, the FEM was used for meta-analysis. The results showed that intravesical instillation of BCG combined with MMC could significantly reduce the recurrence rate of disease compared with that of BCG alone (RR 0.66, 95% CI: 0.56–0.77, P < 0.00001, Figure 3a).

Figure 3 Forest plot of primary outcomes: (a) recurrence rate and (b) progression rate.
Figure 3

Forest plot of primary outcomes: (a) recurrence rate and (b) progression rate.

Six studies compared the progress of the disease. There was no heterogeneity among the studies (I 2 = 36%, P = 0.16). The FEM was used for Meta-analysis. The results showed that compared with BCG perfusion alone, the combined group could significantly reduce the rate of disease progression (RR 0.61, 95% CI: 0.44–0.84, P = 0.003, Figure 3b).

3.4 Secondary outcomes

Eight studies compared the incidence of local adverse reactions in patients with intravesical instillation. The heterogeneity among these studies was low (I 2 = 37%, P = 0.13), so the FEM was used for meta-analysis. The results showed that there was no significant difference between BCG combined with MMC and BCG alone in terms of local adverse reactions of bladder instillation (RR 1.07, 95% CI: 0.95–1.20, P = 0.26, Figure 4a).

Figure 4 Forest plot of Secondary outcomes: (a) local adverse reactions; (b) systemic adverse reactions; (c) disease-specific mortality; and (d) all-cause mortality.
Figure 4

Forest plot of Secondary outcomes: (a) local adverse reactions; (b) systemic adverse reactions; (c) disease-specific mortality; and (d) all-cause mortality.

Five studies compared the incidence of systemic adverse reactions, and heterogeneity tests showed that the heterogeneity among the studies was low (I 2 = 38%, P = 0.17), so the FEM was used for meta-analysis. The results showed that in terms of the incidence of systemic adverse reactions, BCG combined with MMC had a higher incidence of systemic adverse reactions than intravesical instillation of BCG alone (RR 1.57, 95% CI: 1.22–2.02, P = 0.0004, Figure 4b).

Only three studies reported disease-specific mortality and all-cause mortality. For disease-specific mortality, the heterogeneity among the studies was low (I 2 = 0%, P = 0.57). The results showed that BCG combined with MMC had lower disease-specific mortality (RR 0.46, 95% CI: 0.26–0.78, P = 0.004, Figure 4c) than intravesical instillation of BCG alone. In terms of all-cause mortality, the heterogeneity test of the combined analysis showed that the heterogeneity among the studies was low (I 2 = 0%, P = 0.47). The results showed that there was no significant difference between the combined treatment group and BCG alone (RR 0.80, 95% CI: 0.62–1.03, P = 0.08, Figure 4d).

3.5 Subgroup analysis

Each study paid more attention to the outcome indicators of disease recurrence, progression, and adverse reactions. Combined with the original study, we only made a subgroup analysis of the main outcome index of disease recurrence and were divided into subgroups according to when induced perfusion was performed and maintenance perfusion was performed. Due to the limited number of original studies on other outcome indicators such as disease progression, adverse reactions, and disease-specific death, there are no further subgroups. Three studies only performed induced perfusion, while the other eight studies performed maintenance perfusion on the basis of induced perfusion. The results of subgroup analysis showed that when only induced perfusion was performed, there was no significant difference in disease recurrence between the combined group and the BCG alone group (RR 0.78, 95% CI: 0.52–1.19 P = 0.25). When maintenance perfusion was performed, BCG combined with the MMC perfusion group could significantly reduce the disease recurrence rate (RR 0.63, 95% CI: 0.54–0.75, P < 0.00001, Figure 5).

Figure 5 Forest plot and meta-analysis of recurrence rate between BCG combined with MMC and BCG alone: subgroup analysis based on induced perfusion and maintenance perfusion.
Figure 5

Forest plot and meta-analysis of recurrence rate between BCG combined with MMC and BCG alone: subgroup analysis based on induced perfusion and maintenance perfusion.

3.6 Publication bias

In this study, the funnel chart of the main outcome indicator of disease recurrence was drawn by Revman5.4 software as follows. At the same time, the publication bias was quantitatively tested by Egger regression analysis and the Begg rank correlation method in Stata16.0 software. The results of the Egger regression analysis showed that the quantitative results of the Begg rank correlation method showed that the publication bias was 0.276 > 0.05. The results of the Egger regression analysis showed that the publication bias was 0.344 > 0.05 (Figure 6). The tests of both methods suggested that there was no significant publication bias in the included study.

Figure 6 Publication bias: Funnel plot and Begg’s test and Egger’s test of the eleven studies involving the outcomes of recurrence rate.
Figure 6

Publication bias: Funnel plot and Begg’s test and Egger’s test of the eleven studies involving the outcomes of recurrence rate.

4 Discussion

This meta-analysis aimed to evaluate the results of BCG combined with MMC compared with BCG alone in tumor recurrence, disease progression, adverse reactions, all-cause mortality, and disease-specific mortality in patients with NMIBC. Compared with BCG intravesical instillation alone, BCG combined with MMC had more advantages in disease recurrence, progression, and disease-specific mortality but had a higher incidence of systemic adverse reactions, and there was no significant difference in all-cause mortality and local adverse reactions between the two groups. When we conducted a subgroup analysis of whether or not to maintain perfusion, we found that there was no significant difference in disease recurrence between the two groups if only induced perfusion was used.

Since Morales first proposed BCG for bladder instillation and 6 weeks induction instillation in 1976 [6], BCG was not widely accepted not until 1980; an RCT study of the Southwest Cancer Group (SWOG) in the United States showed that BCG for bladder cancer patients after standard surgery had clear benefits in reducing the recurrence rate and increasing the median recurrence-free survival time [23]. The current guidelines recommend TURBT combined with intravesical drug instillation as the gold standard treatment for NMIBC patients, which mainly includes immunomodulator and chemotherapy drugs, but the choice of postoperative infusion drugs should be individualized according to the risk stratification of NMIBC patients [4].

Although BCG is currently the standard infusion drug for medium- and high-risk NMIBC patients, some patients still relapse or progress to MIBC. Bourlotos’s study showed that bladder instillation of BCG may cause dysuria, we hypothesized that BPH surgery before BCG instillation might improve tolerance in patients with concomitant BPH [24]. de Jong et al. identified three distinct BCG response subtypes (BRS1, BRS2, and BRS3), and the findings confirmed the prognostic relevance of molecular subtypes in high-risk NMIBC (HR-NMIBC) patients. The results showed that patients with BRS3 tumors had reduced relapse-free and progression-free survival compared with patients with BRS1/2 tumors and that BRS3 tumors were more frequently associated with Treg macrophages and B cells associated with immunosuppression, findings associated with poor clinical outcomes after BCG therapy. Thus, the identification of BRS3 tumors may be a critical step in the implementation of a more aggressive treatment regimen, such as early RC [25]. Witjes’s study demonstrated that Bladder EpiCheck holds clinical significance, exhibits a high negative predictive value, reduces the risk of false positive results on subsequent endoscopy, and avoids temporary interruption of therapy. Its use in clinical routine could reduce the number of follow-up cystoscopies, and thus associated patient and financial burdens [26]. Poli et al. analyzed the expression levels of CK20, NLRP3, NLRP4, NLRP9, and NAIP in urine sediments from patients before TURBT, 3 weeks after surgery, at the beginning of the BCG induction cycle and then before each instillation event. They found that higher levels of NLRP4 and NLRP9 were associated with an increased risk of recurrence. If larger cohort studies are conducted to confirm these results, assessing the expression levels of NLRP 4 and NLRP 9 would be useful in predicting BCG failure, playing a key role in the decision-making process of early radical surgical intervention [27].

A study of BCG maintenance perfusion therapy for Ta and T1 by Cambier showed that the 1-year recurrence rate was 25.9% (95% CI: 23.8–27.9), the 5-year recurrence rate was 41.3% (95% CI: 39.0–43.7%), and the progression rate was 9.5% 13.4% [8]. BCG-mediated tumor immunity includes three steps: (1) BCG attachment, (2) BCG cell internalization, and (3) BCG-mediated initiation of related innate and adaptive immune responses [28]. It can be seen that BCG attachment is the first and crucial step for it to exert its anti-tumor effect. The results of an in vitro study of Kavoussi showed that the chemical destruction of urinary tract epithelium induced by MMC can make BCG adhere to the bladder wall more effectively, thus improving the immune response and anti-tumor activity. Moreover, the instillation of MMC can also promote the uptake of BCG by the bladder wall and activate related immune effector cells [29]. In addition, Matsushima through an in vitro study of Tis found that MMC combined with BCG treatment can inhibit tumor growth and cell proliferation and prolong survival compared with BCG alone [30]. Intravesical instillation of BCG combined with MMC can increase the anti-tumor effect in patients with NMIBC, and it is logical whether chemotherapy and immunotherapy with two different anti-tumor mechanisms are more effective than BCG alone.

A meta-analysis study by Houghton showed that the combination of chemotherapy on the basis of maintenance therapy did not significantly reduce the recurrence rate (RR 0.92, 95% CI: 0.79–1.99, P = 0.32) or the progression rate (RR 0.88; 95% CI 0.61–1.27, P = 0.5) [31]. However, there are few original studies included in this study, and there are only two studies combined with BCG and MMC. However, a meta-analysis study by Lan showed that the recurrence rate of NMIBC patients treated with BCG combined with MMC was significantly lower than that of BCG or MMC alone (RR 0.81, 95% CI: 0.72–0.92, P < 0.001), but there was no significant difference in disease progression rate, all-cause mortality, and disease-specific mortality. At the same time, they conducted a subgroup analysis of MMC perfusion alone and BCG perfusion alone in terms of disease recurrence, and the results showed that the combined group had a lower rate of disease recurrence than BCG alone [32], which was consistent with our results. Because their control group contained both BCG and MMC, we did not further compare the results in other aspects such as disease progression and adverse reactions.

Our meta-analysis had some potential limitations. Although we have strict inclusion and exclusion criteria, like the meta-analysis of most drug trials, eleven RCTs included in this meta-analysis are different in treatment regimens, BCG and MMC doses, BCG strains, disease risk stratification, specific treatment time and follow-up time, and geographical distribution, which may be the causes of heterogeneity. For BCG strains, a study by Witjes compared the efficacy of BCG Connaught and BCG TICE and showed that BCG Connaught had a lower recurrence rate than BCG TICE when only induced perfusion, but when perfusion was maintained, the result was the opposite [33]. Because the original study is based on published results, we cannot obtain data from individual patients, and only a small number of studies have mentioned BCG strains and risk stratification of NMIBC patients in the included studies, we have not been able to conduct further subgroup analysis.

5 Conclusions

This study shows that compared with BCG alone, intravesical instillation of BCG combined with MMC can reduce the disease recurrence rate, disease progression rate, and disease-specific mortality in patients with NMIBC. However, there is a higher incidence of systemic adverse reactions. There was no significant difference in the incidence of all-cause death and local adverse reactions between the two groups. Due to the limitation of the number of studies included and the different doses, strains, and risk stratification of NMIBC patients in different studies. Multicenter, high-quality, more rigorous trial design studies are needed to further explore the effectiveness and safety of combined perfusion in the future.

  1. Funding information: All authors announced that they had not received any fund support.

  2. Author contributions: Guanghua Fu: conception and design. Jianping Liu and Weijian Zhou: acquisition of data and critical revision of the manuscript for important intellectual content. Jianping Liu, Peng Zhang, Wei Zhang, and Congwang Chang: analysis and interpretation of data. Jianping Liu: drafting of the manuscript. Guanghua Fu: supervision. All authors contributed to the article and approved the submitted version.

  3. Conflict of interest: The authors have no conflicts of interest to declare.

  4. Data availability statement: All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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Received: 2023-11-28
Revised: 2024-12-13
Accepted: 2024-12-14
Published Online: 2025-03-26

© 2025 the author(s), published by De Gruyter

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

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  225. Biological properties of valve materials using RGD and EC
  226. A single oral administration of flavanols enhances short-term memory in mice along with increased brain-derived neurotrophic factor
  227. Repeat influenza incidence across two consecutive influenza seasons
  228. Letter to the Editor
  229. Role of enhanced external counterpulsation in long COVID
  230. Expression of Concern
  231. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  232. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  233. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  234. Corrigendum
  235. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  236. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  237. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  238. Retraction
  239. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  240. Retraction of: “LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through downregulating SP-A by sponging to miR-424”
  241. Retraction of: “SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways”
  242. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  243. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  244. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  245. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  246. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  247. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  248. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  249. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  250. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  251. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  252. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  253. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  254. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  255. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  256. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  257. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  258. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  259. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  260. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  261. A review of brain research on T2DM-related cognitive dysfunction
  262. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  263. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  264. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
https://doi.org/10.1515/med-2024-1134
Schlagwörter für diesen Artikel
urinary bladder neoplasms; non-muscle-invasive bladder cancer; intravesical therapies; Bacillus Calmette-Guérin; mitomycin C
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
  5. Risk factors for severe adverse drug reactions in hospitalized patients
  6. Analysis of the effect of ALA-PDT on macrophages in footpad model of mice infected with Fonsecaea monophora based on single-cell sequencing
  7. Development and validation of headspace gas chromatography with a flame ionization detector method for the determination of ethanol in the vitreous humor
  8. CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis
  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
  12. Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis
  13. Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy
  14. Association between statin administration and outcome in patients with sepsis: A retrospective study
  15. Exploration of the association between estimated glucose disposal rate and osteoarthritis in middle-aged and older adults: An analysis of NHANES data from 2011 to 2018
  16. A comparative analysis of the binary and multiclass classified chest X-ray images of pneumonia and COVID-19 with ML and DL models
  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
  126. Association of placenta weight and morphology with term low birth weight: A case–control study
  127. Investigation of the pathogenic variants induced Sjogren’s syndrome in Turkish population
  128. Nucleotide metabolic abnormalities in post-COVID-19 condition and type 2 diabetes mellitus patients and their association with endocrine dysfunction
  129. TGF-β–Smad2/3 signaling in high-altitude pulmonary hypertension in rats: Role and mechanisms via macrophage M2 polarization
  130. Ultrasound-guided unilateral versus bilateral erector spinae plane block for postoperative analgesia of patients undergoing laparoscopic cholecystectomy
  131. Profiling gut microbiome dynamics in subacute thyroiditis: Implications for pathogenesis, diagnosis, and treatment
  132. Delta neutrophil index, CRP/albumin ratio, procalcitonin, immature granulocytes, and HALP score in acute appendicitis: Best performing biomarker?
  133. Anticancer activity mechanism of novelly synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative on colon cancer cells
  134. H2valdien3 arrests the cell cycle and induces apoptosis of gastric cancer
  135. Prognostic relevance of PRSS2 and its immune correlates in papillary thyroid carcinoma
  136. Association of SGLT2 inhibition with psychiatric disorders: A Mendelian randomization study
  137. Motivational interviewing for alcohol use reduction in Thai patients
  138. Luteolin alleviates oxygen-glucose deprivation/reoxygenation-induced neuron injury by regulating NLRP3/IL-1β signaling
  139. Polyphyllin II inhibits thyroid cancer cell growth by simultaneously inhibiting glycolysis and oxidative phosphorylation
  140. Relationship between the expression of copper death promoting factor SLC31A1 in papillary thyroid carcinoma and clinicopathological indicators and prognosis
  141. CSF2 polarized neutrophils and invaded renal cancer cells in vitro influence
  142. Proton pump inhibitors-induced thrombocytopenia: A systematic literature analysis of case reports
  143. The current status and influence factors of research ability among community nurses: A sequential qualitative–quantitative study
  144. OKAIN: A comprehensive oncology knowledge base for the interpretation of clinically actionable alterations
  145. The relationship between serum CA50, CA242, and SAA levels and clinical pathological characteristics and prognosis in patients with pancreatic cancer
  146. Identification and external validation of a prognostic signature based on hypoxia–glycolysis-related genes for kidney renal clear cell carcinoma
  147. Engineered RBC-derived nanovesicles functionalized with tumor-targeting ligands: A comparative study on breast cancer targeting efficiency and biocompatibility
  148. Relationship of resting echocardiography combined with serum micronutrients to the severity of low-gradient severe aortic stenosis
  149. Effect of vibration on pain during subcutaneous heparin injection: A randomized, single-blind, placebo-controlled trial
  150. The diagnostic performance of machine learning-based FFRCT for coronary artery disease: A meta-analysis
  151. Comparing biofeedback device vs diaphragmatic breathing for bloating relief: A randomized controlled trial
  152. Serum uric acid to albumin ratio and C-reactive protein as predictive biomarkers for chronic total occlusion and coronary collateral circulation quality
  153. Multiple organ scoring systems for predicting in-hospital mortality of sepsis patients in the intensive care unit
  154. Single-cell RNA sequencing data analysis of the inner ear in gentamicin-treated mice via intraperitoneal injection
  155. Suppression of cathepsin B attenuates myocardial injury via limiting cardiomyocyte apoptosis
  156. Influence of sevoflurane combined with propofol anesthesia on the anesthesia effect and adverse reactions in children with acute appendicitis
  157. Identification of hub genes related to acute kidney injury caused by sevoflurane anesthesia and endoplasmic reticulum stress
  158. Efficacy and safety of PD-1/PD-L1 inhibitors in pancreatic ductal adenocarcinoma: a systematic review and Meta-analysis of randomized controlled trials
  159. The value of diagnostic experience in O-RADS MRI score for ovarian-adnexal lesions
  160. Health education pathway for individuals with temporary enterostomies using patient journey mapping
  161. Serum TLR8 as a potential diagnostic biomarker of coronary heart disease
  162. Intraoperative temperature management and its effect on surgical outcomes in elderly patients undergoing lichtenstein unilateral inguinal hernia repair
  163. Immunohistochemical profiling and neuroepithelial heterogeneity in immature ovarian teratomas: a retrospective digital pathology-based study
  164. Associated risk factors and prevalence of human papillomavirus infection among females visiting tertiary care hospital: a cross-sectional study from Nepal
  165. Comparative evaluation of various disc elution methods for the detection of colistin-resistant gram-negative bacteria
  166. Effect of timing of cholecystectomy on weight loss after sleeve gastrectomy in morbidly obese individuals with cholelithiasis: a retrospective cohort study
  167. Causal association between ceramide levels and central precocious puberty: a mendelian randomization study
  168. Novel predictive model for colorectal liver metastases recurrence: a radiomics and clinical data approach
  169. Relationship between resident physicians’ perceived professional value and exposure to violence
  170. Multiple sclerosis and type 1 diabetes: a Mendelian randomization study of European ancestry
  171. Rapid pathogen identification in peritoneal dialysis effluent by MALDI-TOF MS following blood culture enrichment
  172. Comparison of open and percutaneous A1 pulley release in pediatric trigger thumb: a retrospective cohort study
  173. Impact of combined diaphragm-lung ultrasound assessment on postoperative respiratory function in patients under general anesthesia recovery
  174. Development and internal validation of a nomogram for predicting short-term prognosis in ICU patients with acute pyelonephritis
  175. The association between hypoxic burden and blood pressure in patients with obstructive sleep apnea
  176. Promotion of asthenozoospermia by C9orf72 through suppression of spermatogonia activity via fructose metabolism and mitophagy
  177. Review Articles
  178. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  179. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  180. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  181. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  182. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  183. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  184. The application of augmented reality in robotic general surgery: A mini-review
  185. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  186. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  187. Plant polyphenols, terpenes, and terpenoids in oral health
  188. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  189. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  190. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  191. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  192. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  193. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  194. Giant borderline ovarian tumours – review of the literature
  195. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  196. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  197. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  198. Supplement strategies for infertility in overweight women: Evidence and legal insights
  199. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  200. A meta-analysis of the effects of DBS on cognitive function in patients with advanced PD
  201. Protective role of selenium in sepsis: Mechanisms and potential therapeutic strategies
  202. Strategies for hyperkalemia management in dialysis patients: A systematic review
  203. C-reactive protein-to-albumin ratio in peripheral artery disease
  204. Research progress on autophagy and its roles in sepsis induced organ injury
  205. Neuronutrition in autism spectrum disorders
  206. Pumilio 2 in neural development, function, and specific neurological disorders
  207. Antibiotic prescribing patterns in general dental practice- a scoping review
  208. Clinical and medico-legal reflections on non-invasive prenatal testing
  209. Smartphone use and back pain: a narrative review of postural pathologies
  210. Targeting endothelial oxidative stress in hypertension
  211. Exploring links between acne and metabolic syndrome: a narrative review
  212. Case Reports
  213. Delayed graft function after renal transplantation
  214. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  215. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  216. Giant right atrial hemangioma presenting with ascites: A case report
  217. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  218. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  219. Molecular hydrogen-rhodiola as an adjuvant therapy for ischemic stroke in internal carotid artery occlusion: A case report
  220. Coronary artery anomalies: A case of the “malignant” left coronary artery and its surgical management
  221. Combined VAT and retroperitoneoscopy for pleural empyema due to nephro-pleuric fistula in xanthogranulomatous pyelonephritis
  222. A rare case of Opalski syndrome with a suspected multiple sclerosis etiology
  223. Newly diagnosed B-cell acute lymphoblastic leukemia demonstrating localized bone marrow infiltration exclusively in the lower extremities
  224. Rapid Communication
  225. Biological properties of valve materials using RGD and EC
  226. A single oral administration of flavanols enhances short-term memory in mice along with increased brain-derived neurotrophic factor
  227. Repeat influenza incidence across two consecutive influenza seasons
  228. Letter to the Editor
  229. Role of enhanced external counterpulsation in long COVID
  230. Expression of Concern
  231. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  232. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  233. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  234. Corrigendum
  235. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  236. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  237. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  238. Retraction
  239. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  240. Retraction of: “LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through downregulating SP-A by sponging to miR-424”
  241. Retraction of: “SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways”
  242. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  243. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  244. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  245. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  246. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  247. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  248. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  249. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  250. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  251. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  252. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  253. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  254. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  255. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  256. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  257. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  258. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  259. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  260. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  261. A review of brain research on T2DM-related cognitive dysfunction
  262. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  263. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  264. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
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