Association between proton-pump inhibitors and the risk of gastric cancer: a systematic review and meta-analysis.

BACKGROUND: Proton pump inhibitors (PPIs) may be associated with gastric cancer, but studies in recent years have proven still inconsistent results. We conducted a systematic review and meta-analysis to investigate the association between PPI use and gastric cancer. METHODS: Pubmed, EMBASE, and Cochrane library were searched for studies published up to 15th February 2022. Studies on the association between PPI and the risk of gastric cancer, pooled the odds ratios (ORs) using a random-effects model. The subgroup analysis for study design, site of gastric cancer, and the duration of PPI use was performed. Heterogeneity was assessed using the I2 and Cochran's Q statistics. RESULTS: Sixteen cohorts and case-control studies were included. PPI use was significantly associated with gastric cancer (OR: 1.75, 95% CI: 1.28-2.40). The subgroup analysis found a significant risk increase in non-cardia gastric cancer (OR: 2.14, 95%CI: 1.50-3.07). There was no duration-dependent effect of PPI use and gastric cancer risk (< 1 year: OR: 2.56, 95% CI: 1.41-4.64, I2 = 98%; 1-3 years: OR: 1.47, 95% CI: 1.26-1.71, I2 = 41%; > 3 years: OR: 1.58, 95% CI: 1.16-2.14, I2 = 74%). CONCLUSIONS: PPIs were significantly associated with an increased risk of gastric cancer. However, this association does not confirm causation. Several well-design studies are needed to confirm the findings in the future.

Phenotype, genotype, and clinical outcome of Taiwanese with congenital nephrotic syndrome.

BACKGROUND/PURPOSE: Congenital nephrotic syndrome (CNS) is one of the important causes of end-stage kidney disease in children. Studies on the genotype, phenotype, and clinical outcome in infants with CNS caused by genetic mutations are scarce. METHODS: We analyzed the genetic background, clinical manifestations, treatment response, and prognosis of pediatric patients with CNS in Taiwan. RESULTS: Fifteen infants with CNS were enrolled, and 11 patients of median age 21 (interquartile range 3∼44) days caused by genetic mutations from 10 unrelated families were included in the study. Of the eleven patients, 9 had extra-renal manifestations including microcephaly, facial dysmorphism, and skeletal anomalies. More than two-thirds of the patients had disease onset before 1 month of age. Diffuse meningeal sclerosis was the most common histological characteristic. Whole exome sequencing followed by direct Sanger sequence revealed mutations in OSGEP (R247Q), WT1 (R366H and R467Q), LAMB2 (Q1209∗ and c. 5432-5451 19 bp deletion), NUP93 (D302V), and LAGE3 (c.188+1G > A). Three of the variants were novel. Corticosteroids and/or immunosuppressants were administered in 2 patients, but both were refractory to treatment. During the mean 3.5 years of follow-up, all but two died of uremia and sepsis. The two survivors reached end-stage kidney disease and required peritoneal dialysis, and one of them underwent uneventful renal transplantation. CONCLUSIONS: The majority of patients with CNS in Taiwan were caused by OSGEP followed by WT1 mutation. R247Q is the hotspot mutation of OSGEP in Taiwan. CNS patients in Taiwan suffer from significant morbidity and mortality.

Efficacy and safety of belimumab therapy in systemic lupus erythematosus: A systematic review and meta-analysis.

BACKGROUND: Belimumab is the first biological agent approved for the treatment of systemic lupus erythematosus (SLE). The efficacy and safety of belimumab for SLE patients are not clear. Therefore, this meta-analysis is integrating the efficacy and safety of belimumab for patients with SLE. METHODS: PubMed, EMBASE, and Cochrane Library were searched for randomized clinical trials (RCTs) that studied the efficacy and safety of belimumab plus standard therapy before November 1, 2021. Data were pooled using the random-effects model and are expressed as risk ratios (RRs) or mean difference (MD) and corresponding 95% confidence intervals (CIs). Heterogeneity was assessed and quantified using I2. RESULTS: Seven RCTs with 3,009 participants were included in this meta-analysis. Belimumab showed significantly decreased at least a 4-point improvement in Safety of Estrogen in Lupus National Assessment (SELENA)-Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score than placebo (RR, 1.32; 95% CI, 1.21-1.44; p < 0.001). However, belimumab significantly reduced the prednisone dose by 50% or more than placebo (RR, 1.59; 95% CI, 1.17-2.15; p = 0.003) and belimumab significantly increased the 36 Physical Component Summary (PCS) score (MD, 1.60; 95% CI, 0.30-2.90; p = 0.02). Regarding adverse events, there was no significant difference between the belimumab group and the control group. CONCLUSION: The results suggest that belimumab plus standard therapy is more effective than placebo plus standard therapy in SLE patients.

Monoclonal Antibodies for First-Line Treatment Metastatic Colorectal Cancer.

BACKGROUND: In addition to discontinuing treatment at disease progression, cumulative toxicity limitations and genetic mutations play important roles in chemotherapy choice in metastatic colorectal cancer (mCRC). However, in recent years, targeted therapies, such as immune checkpoint inhibitors or monoclonal antibodies (MoAbs), have been used with chemotherapy to improve clinical outcomes in patients with mCRC. AREAS OF UNCERTAINTY: Approximately 15% of patients with CRC would be eligible for further targeted therapy with immune checkpoint inhibitors based on genetic testing, but most patients with CRC would not qualify, especially Kirsten rat sarcoma wild-type. Therefore, adding MoAb is only an option for most patients until disease progression or unacceptable toxicity occurs. However, the results are not consistent with the combination of MoAb and different chemotherapy bases. In addition, most results from combining MoAb with different chemotherapy bases are not consistent. DATA SOURCES: This meta-analysis includes published of the PubMed and Embase databases, limited to English literature, and patients were treated with MoAb combination. Randomized control trials conducted published up to May 2021 were considered for inclusion. THERAPEUTIC ADVANCES: Fluoropyrimidine-based chemotherapy has been the backbone of palliative therapy for mCRC, with demonstrated benefits. This article will review the efficacy and safety of randomized control trials comparing different MoAb with fluoropyrimidine-based chemotherapy as first-line therapy for patients with mCRC, particularly in Kirsten rat sarcoma wild-type. CONCLUSION: This meta-analysis revealed that MoAb plus chemotherapy has better progression-free survival and objective response rate than chemotherapy alone. However, treatment-related serious adverse events (grade ≥ 3) should be considered, particularly severe rash, diarrhea, and hypertension.

Efficacy and immunogenicity of insulin biosimilar compared to their reference products: a systematic review and meta-analysis.

BACKGROUND: To ascertain the efficacy, safety, and immunogenicity from existing evidence via conducting a meta-analysis of randomized controlled trials between biosimilar and originator insulins. METHODS: The PubMed, Cochrane Library, EMBASE, and ClinicalTrails.gov were searched to identify head-to-head randomized controlled trials (RCTs) that directly compare the efficacy and safety of biosimilar insulin and its originator. Efficacy was assessed by change of HbA1C, fasting plasma glucose (laboratory or self-monitoring of blood glucose (SMBG)), and change all mean of 7 points- or 8 points- SMBG. Safety was assessed by change in proportion hypoglycemia and serious hypoglycemia. The occurrence of anti-insulin antibodies (AIAs) was also evaluated. RESULTS: Fourteen RCTs with 6188 patients from different countries were included. Data were pooled using a random-effects model and were expressed as the mean difference (MD), odds ratio (OR), and 95% confidence interval (CI). In efficacy, Insulin biosimilar products showed similar in change of HbA1C at weeks 26 and 52, the MD were 0.03 (95% CI - 0.02 to 0.07, p = 0.28), and 0.05 (95% CI - 0.05 to 0.15, p = 0.36), respectively. The proportion of HbA1C less than 7% at endpoint, the OR were 1.04 (95% CI 0.89 to 1.20, p = 0.64). The change of fasting plasma glucose (laboratory or SMBG) mmol/L in 24-52 weeks and change all mean of 7 points-/8 points- SMBG mmol/L in 24-52 weeks, the MD were 0.02 (95% CI - 0.20 to 0.24, p = 0.87) and - 0.34 (95% CI - 1.35 to 0.67, p = 0.51), respectively. In occurrence of hypoglycemia (≥ 1 events) and severe hypoglycemia, the OR were 0.96 (95% CI 0.85 to 1.09, p = 0.52) and 1.06 (95% CI 0.85 to 1.31, p = 0.62). The AIA was 1.02 (95% CI 0.90 to 1.16, p = 0.76). Analysis stratified by type of diabetes and duration of insulin. There was no significant difference between the biosimilar and their reference group in a different type of diabetes and different duration of insulin. CONCLUSIONS: Insulin biosimilar showed comparable characteristics with the reference drug in terms of efficacy, safety, immunogenicity, through comprehensive and specific conventional meta-analysis.

Effectiveness of glutamine in the management of oral mucositis in cancer patients: a meta-analysis of randomized controlled trials.

OBJECTIVE: The aim of this meta-analysis was to evaluate the effectiveness of glutamine for preventing or treating moderate-to-severe oral mucositis induced by chemotherapy or radiation therapy in patients with cancer. METHODS: PubMed, Cochrane Library, and Embase were searched for eligible randomized controlled trials (RCTs) up to June 2020. The outcomes analyzed were oral mucositis (at all levels of severity). Data were pooled using the random-effects model and are expressed as risk ratios (RRs) and corresponding 95% confidence intervals (CIs). Heterogeneity was assessed and quantified using I2. RESULTS: Sixteen RCTs were included in this review. In this meta-analysis, compared with placebo, glutamine significantly reduced the incidence of grade 3 and 4 oral mucositis induced by chemotherapy or radiation therapy (RR, 0.53; 95% CI, 0.32-0.88). In subgroup analysis, oral glutamine administration (RR, 0.56; 95% CI, 0.34-0.92) and a medium or low daily dose of glutamine (RR, 0.58; 95% CI, 0.44-0.77; RR, 0.53; 95% CI, 0.28-0.94; respectively) decreased risk. Glutamine caused a borderline significant reduction in the risk of grade 3 and 4 oral mucositis induced by radiotherapy (RR, 0.75; 95% CI, 0.58-0.99) and especially in its prevention (RR, 0.51; 95% CI, 0.28-0.94). CONCLUSIONS: Glutamine significantly reduces the risk of oral mucositis during chemotherapy or radiation therapy. Furthermore, large prospective trials are required to support these findings.

Radiofrequency ablation versus surgical resection for the treatment of solitary hepatocellular carcinoma 2 cm or smaller: A cohort study in Taiwan.

BACKGROUND/PURPOSE: Radiofrequency ablation (RFA) is increasingly being used instead of surgical resection for the treatment of hepatocellular carcinoma (HCC) tumor measuring ≦2 cm. However, the long-term outcomes of RFA, especially in comparison to surgical resection, are still debated. We compared the outcomes of surgical resection and RFA in patients with a solitary HCC tumor measuring ≦2 cm from a 10-year cohort study. METHODS: From Jan 2006 to Dec 2016, 156 patients with a resectable HCC measuring ≦2 cm who underwent surgical resection (n = 83) or RFA (n = 73) at the Buddhist Tzu Chi Medical Foundation were enrolled. Patient characteristics, overall survival (OS), and recurrence-free survival (RFS) were retrospectively examined, and comparisons were made between the two groups and through subgroup analyses. RESULTS: The 1-year, 3-year, 5-year, and 7-year OS outcomes were comparable between the surgical resection group and the RFA group (P = 0.193), but the surgical resection group had significantly higher 1-year, 3-year, 5-year, 7-year, and 10-year RFS than the RFA group (P = 0.018). Multivariate analysis revealed that patients with lower age, Child-Turcotte-Pugh score, or albumin-bilirubin score before treatment had better OS, and patients with an HCV infection or receiving RFA treatment had higher HCC recurrence rates. CONCLUSION: The liver reserve determined the long-term OS of patients with an HCC tumor ≦ 2 cm, and surgical resection offered better RFS than RFA (ClinicalTrials.gov number, NCT04525833.).

Hypnotics and Risk of Cancer: A Meta-Analysis of Observational Studies.

Background and objectives: The association between hypnotic drugs and risk of cancer remains controversial. Therefore, we performed a meta-analysis to investigate this association. Materials and Methods: Pubmed and Embase were searched systematically to identify publications up to April 2020. The Newcastle-Ottawa scale for observational studies was used to assess the quality of studies. All included studies were evaluated by two reviewers independently; any discrepancies were resolved through discussion. Results: Twenty-eight studies including 22 case-control studies and 6 cohort studies with 340,614 hypnotics users and 1,828,057 non-users were included in the final analyses. Hypnotics (benzodiazepines and Z-drugs) use was significantly associated with an increased risk of cancer (odds ratio [OR] or relative risk [RR] 1.17; 95% confidence interval 1.09-1.26) in a random-effects meta-analysis of all studies. Subgroup meta-analysis by anxiolytics/sedatives effect (anxiolytics benzodiazepines vs. sedatives group (include sedatives benzodiazepines and Z-drugs)) revealed that a significant association in sedatives group (pooled OR/RR 1.26, 95% CI, 1.10-1.45), whereas no significant relationship was observed in anxiolytics benzodiazepines (pooled OR/RR 1.09, 95% CI, 0.95-1.26). Moreover, a significant dose-response relationship was observed between the use of hypnotics and the risk of cancer. Conclusions: This meta-analysis revealed association between use of hypnotics drugs and risk of cancer. However, the use of lower dose hypnotics and shorter duration exposed to hypnotics seemed to be not associated with an increased risk of cancer. Moreover, the use of anxiolytics effect benzodiazepines seemed to be lower risk than sedatives benzodiazepines. A high heterogeneity was observed among identified studies, and results were inconsistent in some subgroups. Randomized control trials are needed to confirm the findings in the future.

Effect of Probiotics on the Glucose Levels of Pregnant Women: A Meta-Analysis of Randomized Controlled Trials.

Background: Gestational diabetes mellitus (GDM) is a condition, in which women develop high blood sugar levels during pregnancy without having diabetes. Evidence on the effects of probiotics on the blood glucose levels of women with GDM is inconsistent. Objective: The present study aimed to investigate the effects of probiotics on the blood glucose levels of pregnant women. Methods: Online databases, such as PubMed, Cochrane, and Excerpta Medica Database (EMBASE) were searched for randomized controlled trials (RCTs) published before July 2018. Trials had to meet the inclusion criteria of our study. Methodological quality and risk bias were independently assessed by two reviewers. Data were pooled using a random effects model and were expressed as the mean difference (MD) and 95% confidence interval (CI). Heterogeneity was evaluated and quantified as I². Results: In total, 12 RCTs were included in this study. Studies have shown that the use of probiotics significantly reduced the fasting blood glucose (FBG) level (MD: -0.10 mmol/L; 95% CI: -0.19, -0.02), insulin concentration (MD: -2.24 µIU/mL; 95% CI: -3.69, -0.79), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score (MD: -0.47; 95% CI: -0.74, -0.21), and Homeostasis model of assessment-estimated ß cell function (HOMA-B) score (MD: -20.23; 95% CI: -31.98, -8.49) of pregnant women. In a subgroup analysis, whether the blood glucose-lowering effect of probiotics influenced the diagnosis of pregnant women with GDM was assessed. The results showed that probiotics had significantly reduced the fasting blood glucose (FBG) level (MD: -0.10 mmol/L; 95% CI: -0.17, -0.04) and HOMA-IR score (MD: -0.37; 95% CI: -0.72, -0.02) of pregnant women who were not diagnosed with GDM. Conclusion: Probiotics reduce the blood glucose level of pregnant women, especially without GDM diagnosis. However, further research using RCTs must be conducted to validate the results of the present study.

S-Adenosylmethionine (SAMe) as an adjuvant therapy for patients with depression: An updated systematic review and meta-analysis.

BACKGROUND: Major depressive disorder (MDD) is an intractable disease requiring long-term treatment. S-adenosyl-L-methionine (SAMe), a natural substance, has antidepressant effects, but the exact effect remains unclear. This study examines the evidence concerning the efficacy of SAMe as a monotherapy or in combination with antidepressants. METHODS: The PubMed, EMBASE, and Cochrane electronic databases were searched for meta-analyses of randomized controlled clinical trials (RCTs) until June 30, 2023. We performed a systematic review and meta-analysis of the enrolled trials that met the inclusion criteria, with the aim to compare the effects of SAMe to those of a placebo or active agents, or SAMe combined with other antidepressants in the treatment of MDD. RESULTS: Fourteen trials, with a total of 1522 subjects, were included in this review. The daily dose of SAMe varied from 200 to 3200 mg and the study duration ranged between 2 and 12 weeks. The results of SAMe versus placebo as a monotherapy, SAMe versus imipramine or escitalopram as a monotherapy, and SAMe versus placebo as an adjunctive therapy, showed no significant difference in depression with SAMe compared to the comparison treatment. CONCLUSIONS: SAMe may provide relief of depression symptoms similar to imipramine or escitalopram. However, the results of the comparisons should be interpreted with caution due to the small number of studies and the large range of SAMe doses that were used in the included trials. Therefore, we recommend that patients discuss treatment options with their doctor before taking SAMe.

Efficacy of PD-1/PD-L1 inhibitors in advanced hepatocellular carcinoma: A systematic review and meta-analysis.

Objectives: This study aimed to investigate the efficacy and safety of programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in patients with advanced hepatocellular carcinoma (HCC). Materials and Methods: PubMed, EMBASE, and the Cochrane Library were searched for articles published until November 2022. Studies reporting the efficacy of PD-1/PD-L1 inhibitors in patients with advanced HCC were eligible for inclusion. The outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and ≥ Grade 3 treatment-related adverse events (TrAEs). Results: Fourteen trials with 4515 patients with HCC were included. Our results showed that treatment with PD-1/PD-L1 inhibitors was associated with better ORR and DCR than that with control (placebo or sorafenib or lenvatinib) (odds ratio [OR], 3.89; 95% confidence interval (CI), 2.55-5.95 and OR, 1.47; 95% CI, 1.11-1.95, respectively). The overall hazard ratio (HR) of PFS and OS were 0.66 (95% CI 0.56-0.78) and 0.65 (95% CI 0.55-0.77), respectively. In subgroup analysis, PD-1/PD-L1 inhibitor combination therapy had an advantage in terms of PFS (HR: 0.57 vs. 0.81) compared to that of PD-1/PD-L1 monotherapy. The incidence of grade 3-5 TrAEs was not significantly higher with PD-1/PD-L1 inhibitors than that with the control (OR, 1.12; 95% CI, 0.70-1.81). However, the combination of PD-1inhibitor with higher incidence of Grade 3-5 TrAEs (OR: 2.04, 95% CI 0.66-6.32) than the combination PD-L1 inhibitor (OR: 0.95, 95% CI 0.50-1.81). Conclusion: The combination of PD-1/PD-L1 inhibitors and targeted agents significantly improved the clinical outcomes in patients with advanced HCC. However, the incidence of Grade 3-5 TrAEs with PD-1 inhibitor combination therapy was higher than the combination PD-L1 inhibitor.

Efficacy and safety of cyclin-dependent kinase 4/6 inhibitor in patients with advanced breast cancer: A real-world experience.

BACKGROUND: Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) have been shown to improve progression-free survival (PFS) in patients with metastatic breast cancer (MBC) in randomized control trials. This study aimed to evaluate the efficacy and safety of CDK4/6i in patients with advanced breast cancer (ABC) in a clinical setting. METHODS: Consecutive patients with ABC were treated between October 2019 and March 2023 at Taipei Tzu Chi Hospital, Taiwan. Patients who had received at least one dose of CDK4/6i were included in this retrospective study. The main outcome of this study was efficacy based on the treating physicians' assessments in terms of PFS, and overall survival (OS), as well as the factors associated with patient outcome. The secondary outcome was safety. RESULTS: A total of 85 patients were included in the analysis, with a mean age of 66.8 years. After a median follow-up of 16.1 months, the median PFS was 28.4 months (95% CI: 22.5-33.6) and the median OS could not yet be estimated. The most common adverse events (AE) were fatigue (50.8%), anorexia (45.9%), and leukopenia (44.7%). In multivariable analysis, treatment with CDK4/6i with any grade AE or response to treatment effect (CR/PR) was an independent predictor for longer PFS (hazard ratio [HR] = 0.27, 95% CI: 0.11-0.68; HR = 0.21, 95% CI: 0.06-0.67; p < 0.05). CONCLUSION: CDK4/6i administered in a real-world setting exhibits a similar survival benefit with the clinical trials.

Efficacy and safety of anaplastic lymphoma kinase inhibitors for non-small cell lung cancer: A systematic review and network meta-analysis.

BACKGROUND: To assess the efficacy and safety of anaplastic lymphoma kinase inhibitors (ALKIs) for the treatment of advanced-stage ALK rearrangement-positive non-small cell lung cancer (NSCLC). METHODS: We searched PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) that included patients with ALK-positive NSCLC receiving ALKIs. The outcomes of the study included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs) of grade ≥3. RESULTS: A total of 12 RCTs consisting of 3169 patients with eight treatment options were included in this study. Our results showed that ALKIs have superior efficacy in OS, PFS, and ORR than chemotherapy or crizotinib (first-generation ALKI). Our study showed that only alectinib has a significant improvement in OS compared to chemotherapy (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.40-0.94). Alectinib appeared to have better OS than crizotinib (HR, 0.66; 95% CI, 0.45-0.95). Ensartinib has a significant PFS advantage over alectinib (HR, 0.62; 95% CI, 0.40-0.96). The surface under the ranking curve indicated that ensartinib (99.0%) was the highest rank regarding PFS. Moreover, both ensartinib and ceritinib showed significantly higher TRAEs of grade ≥3 compared with chemotherapy (risk ratios [RR], 2.74; 95% CI, 1.45-5.18; RR, 1.80; 95% CI, 1.26-2.57, respectively). CONCLUSIONS: These results indicated that alectinib could be associated with the best therapeutic efficacy and well-tolerance AEs in the treatment of ALK-positive NSCLC.