Bidirectional associations between periodontal disease and systemic diseases: a nationwide population-based study in Korea.

To evaluate the associations of periodontal disease (PD) with systemic diseases, including diabetes mellitus (DM) and cardiovascular disease (CVD), as well as the reciprocal association. The CVD included the cases of coronary heart disease and heart failure. A prospective study was conducted from 2007 to 2019 using linked data from three databases in Korea. Three separate study groups were formed to individually determine the risks of PD (n = 10,533), DM (n = 14,523) and CVD (n = 14,315). All diseases were confirmed based on physicians' diagnoses using medical records and self-reports. Cox proportional hazard regression was applied with 95% confidence intervals (CIs) to obtain hazard ratios (HRs). PD was significantly associated with an elevated risk of DM (HR [95% CI]: 1.22 [1.07-1.39]) after full adjustment for age, sex, lifestyle factors, body mass index, dental behaviour and CVD. PD was also found to increase the risk of CVD (1.27 [1.03-1.57]), whereas CVD increased the risk of PD (1.20 [1.09-1.32]) after full adjustment for other covariates including DM. This study found a bidirectional association between PD and CVD, as well as a positive association of PD with DM.

A time-dependent subdistribution hazard model for major dental treatment events in cancer patients: a nationwide cohort study.

BACKGROUND: Dental care in cancer patients tends to be less prioritized. However, limited research has focused on major dental treatment events in cancer patients after the diagnosis. This study aimed to examine dental treatment delays in cancer patients compared to the general population using a national claims database in South Korea. METHOD: The Korea National Health Insurance Service-National Sample Cohort version 2.0, collected from 2002 to 2015, was analyzed. Treatment events were considered for stomatitis, tooth loss, dental caries/pulp disease, and gingivitis/periodontal disease. For each considered event, time-dependent hazard ratios and associated 95% confidence intervals were calculated by applying a subdistribution hazard model with time-varying covariates. Mortality was treated as a competing event. Subgroup analyses were conducted by type of cancer. RESULTS: The time-dependent subdistribution hazard ratios (SHRs) of stomatitis treatment were greater than 1 in cancer patients in all time intervals, 2.04 within 30 days after cancer diagnosis, and gradually decreased to 1.15 after 5 years. The SHR for tooth loss was less than 0.70 within 3 months after cancer diagnosis and increased to 1 after 5 years. The trends in SHRs of treatment events for other dental diseases were similar to those observed for tooth loss. Subgroup analyses by cancer type suggested that probability of all dental treatment event occurrence was higher in head and neck cancer patients, particularly in the early phase after cancer diagnosis. CONCLUSION: Apart from treatments that are associated with cancer therapy, dental treatments in cancer patients are generally delayed and cancer patients tend to refrain from dental treatments. Consideration should be given to seeking more active and effective means for oral health promotion in cancer patients.

Effect of Preoperative Androgen Stimulation on Penile Size and Postoperative Complication Rate in Patients with Hypospadias: A Systematic Review and Meta-Analysis.

PURPOSE: To systematically review and evaluate the beneficial effects of preoperative androgen stimulation (PAS) on penile length, glans width, and postoperative complications in patients with hypospadias using meta-analysis. MATERIALS AND METHODS: A comprehensive search of the published literature between 1980 and 2022 was done on PubMed, Embase, Google Scholar, Scopus, Web of Science, and Proquest. Studies of patients with 5-alpha reductase deficiency, differentiation sex disorder, or micro-penis without hypospadias were excluded. The full-text screening, quality assessment, and data acquisition were done independently by two reviewers. Meta-analysis was done to quantify the penile growth and postoperative complications. RESULTS: The initial literature search yielded 2,389 records, wherein 32 studies were eligible for the systematic review and meta-analysis. Preoperative testosterone stimulation increased the penile length and glans width by 9.34 mm (95% CI: 6.71-11.97) and 3.26 mm (95% CI: 2.50-4.02), respectively. A longer penis at the baseline led to greater length gain following treatment (1 mm longer at the baseline was likely to gain 0.5 mm more). However, the increase in penile length was not associated with the severity of hypospadias. While the treatment did not affect the overall complication rate, the postoperative fistula risk was lower in those receiving PAS (RR=0.52, 95% CI: 0.30-0.91, p=0.02). CONCLUSIONS: The beneficial effects of PAS on increasing the penile length and glans width were again confirmed. More gain of penile length was expected in the larger penis at baseline. There are no reported increased postoperative complications in association with PAS.

A Randomized Controlled Trial of Fibrin Glue to Prevent Bleeding After Gastric Endoscopic Submucosal Dissection.

INTRODUCTION: This study evaluated the efficacy of fibrin glue for preventing postendoscopic submucosal dissection (ESD) bleeding in high-risk patients for bleeding (expected iatrogenic ulcer size ≥40 mm or receiving antithrombotic therapy). METHODS: A multicenter, open-label, randomized controlled trial was performed at 4 tertiary medical centers in South Korea between July 1, 2020, and June 22, 2022. Patients with gastric neoplasm and a high risk of post-ESD bleeding were enrolled and allocated at 1:1 to a control group (standard ESD) or a fibrin glue group (fibrin glue applied to iatrogenic ulcers after standard ESD). The primary outcome was overall bleeding events within 4 weeks. The secondary outcomes were acute bleeding (within 48 hours post-ESD) and delayed bleeding (48 hours to 4 weeks post-ESD). RESULTS: In total, 254 patients were randomized, and 247 patients were included in the modified intention-to-treat population (125 patients in the fibrin glue group and 122 patients in the control group). Overall bleeding events occurred in 12.0% (15/125) of the fibrin glue group and 13.1% (16/122) of the control group ( P = 0.791). Acute bleeding events were significantly less common in the fibrin glue group than in the control group (1/125 vs 7/122, P = 0.034). Delayed bleeding events occurred in 11.2% (14/125) in the fibrin glue group and 7.3% (9/122) in the control group ( P = 0.301). DISCUSSION: This trial failed to show a preventive effect of fibrin glue on overall post-ESD bleeding in high-risk patients. However, the secondary outcomes suggest a potential sealing effect of fibrin glue during the acute period.

9 months of delamanid, linezolid, levofloxacin, and pyrazinamide versus conventional therapy for treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis (MDR-END): a multicentre, randomised, open-label phase 2/3 non-inferiority trial in South Korea.

BACKGROUND: With the introduction of new anti-tuberculosis drugs, all-oral regimens with shorter treatment durations for multidrug-resistant tuberculosis have been anticipated. We aimed to investigate whether a new all-oral regimen was non-inferior to the conventional regimen including second-line anti-tuberculosis drugs for 20-24 months in the treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis. METHODS: In this multicentre, randomised, open-label phase 2/3 non-inferiority trial, we enrolled men and women aged 19-85 years with multidrug-resistant tuberculosis confirmed by phenotypic or genotypic drug susceptibility tests or rifampicin-resistant tuberculosis by genotypic tests at 12 participating hospitals throughout South Korea. Participants with fluoroquinolone-resistant multidrug-resistant tuberculosis were excluded. Participants were randomly assigned (1:1) to two groups using a block randomisation, stratified by the presence of diabetes and cavitation on baseline chest radiographs. The investigational group received delamanid, linezolid, levofloxacin, and pyrazinamide for 9 months, and the control group received a conventional 20-24-month regimen, according to the 2014 WHO guidelines. The primary outcome was the treatment success rate at 24 months after treatment initiation in the modified intention-to-treat population and the per-protocol population. Participants who were "cured" and "treatment completed" were defined as treatment success following the 2014 WHO guidelines. Non-inferiority was confirmed if the lower limit of a 97·5% one-sided CI of the difference between the groups was greater than -10%. Safety data were collected for 24 months in participants who received a predefined regimen at least once. This study is registered with ClinicalTrials.gov, NCT02619994. FINDINGS: Between March 4, 2016, and Sept 14, 2019, 214 participants were enrolled, 168 (78·5%) of whom were included in the modified intention-to-treat population. At 24 months after treatment initiation, 60 (70·6%) of 85 participants in the control group had treatment success, as did 54 (75·0%) of 72 participants in the shorter-regimen group (between-group difference 4·4% [97·5% one-sided CI -9·5% to ∞]), satisfying the predefined non-inferiority margin. No difference in safety outcomes was identified between the control group and the shorter-regimen group. INTERPRETATION: 9-month treatment with oral delamanid, linezolid, levofloxacin, and pyrazinamide could represent a new treatment option for participants with fluoroquinolone-sensitive multidrug-resistant tuberculosis. FUNDING: Korea Disease Control and Prevention Agency, South Korea.

Treatment shortening of drug-sensitive pulmonary tuberculosis using high-dose rifampicin for 3 months after culture conversion (Hi-DoRi-3): a study protocol for an open-label randomized clinical trial.

BACKGROUND: The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted. METHODS: This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited. DISCUSSION: This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB. TRIAL REGISTRATION: ClinicalTrials.gov NCT04485156 . Registered on July 24, 2020.

An approach to exploring patterns of imbalance and potential missingness in reports of the randomized baseline values for primary outcomes measurable at baseline in randomized controlled trials for meta-analyses.

BACKGROUND: This study evaluated the adequacy of randomization in randomized controlled trials by investigating baseline differences in the primary outcome when a meta-analysis employed an outcome whose baseline level was measurable. METHODS: We retrieved Cochrane reviews published during one year. We calculated the proportion of studies that reported randomized baseline values for the primary outcome. The standardized mean difference (SMD) was used to assess baseline imbalance and heterogeneity. We explored ranking-ordered forest plots using a normal cumulative probability curve as a guideline representing well-performed randomized trials. When skewness was suggested, a funnel plot was drawn to assess whether there was a significant linear trend. RESULTS: In 10 of 18 meta-analyses, more than 25% of trials did not report randomized baseline values of the primary outcomes. Three meta-analyses indicated baseline imbalance (P < 0.1) and three showed substantial heterogeneity (I2 > 60%). Four meta-analyses with forest plots suggesting a skewed SMD distribution also showed a linear trend on their standard errors on the funnel plot. CONCLUSIONS: If the primary outcome is measured at baseline, it is essential to explore the full scope of baseline imbalance among the trials. This could help understand patterns of bias, including missingness, for designing adjustment.

Korean Guidelines for Pharmacoeconomic Evaluations: Updates in the Third Version.

The first version of the pharmacoeconomic (PE) guidelines was published in South Korea in 2006. Despite its first revision in 2011, there were still ambiguities in its interpretation. Moreover, methodologies for estimating effectiveness and costs have also evolved since then. Under these circumstances, the Health Insurance Review and Assessment Service published the third version in January 2021. This article reviews the revision process and major changes made in the new edition of the PE guidelines. The revision was processed through reviews of the previous 50 PE submissions, international guidelines, academic literature, and surveys and advisory meetings to obtain stakeholders' opinions. The analysis perspective has changed from a limited societal perspective to a healthcare system perspective. In addition to the drug with the highest market share, drugs used in clinical trials can be selected as comparators under certain conditions. The discount rate decreased from 5% to 4.5%. Furthermore, the revised guidelines provide more detailed and specific instructions for items including non-inferiority margin, extrapolation, utility elicitation, and uncertainty. Treatment switch and co-dependent technology guidelines are newly included; the budget impact analysis guideline is deleted. Through this revision, transparency and consistency of decision-making is expected to improve.

The age-standardized incidence, mortality, and case fatality rates of COVID-19 in 79 countries: a cross-sectional comparison and their correlations with associated factors.

OBJECTIVES: During the coronavirus disease 2019 (COVID-19) pandemic, crude incidence and mortality rates have been widely reported; however, age-standardized rates are more suitable for comparisons. In this study, we estimated and compared the age-standardized incidence, mortality, and case fatality rates (CFRs) among countries and investigated the relationship between these rates and factors associated with healthcare resources: gross domestic product per capita, number of hospital beds per population, and number of doctors per population. METHODS: The incidence, mortality, and CFRs of 79 countries were age-standardized using the World Health Organization standard population. The rates for persons 60 years or older were also calculated. The relationships among the rates were analysed using trend lines and coefficients of determination (R2). Pearson correlation coefficients between the rates and the healthcare resource-related factors were calculated. RESULTS: The countries with the highest age-standardized incidence, mortality, and CFRs were Czechia (14,253 cases/100,000), Mexico (182 deaths/100,000), and Mexico (6.7%), respectively. The R2 between the incidence and mortality rates was 0.852 for all ages and 0.945 for those 60 years or older. The healthcare resources-related factors were associated positively with incidence rates and negatively with CFRs, with weaker correlations among the elderly. CONCLUSIONS: Compared to age-standardized rates, crude rates showed greater variation among countries. Medical resources may be important in preventing COVID-19-related deaths; however, considering the small variation in fatality among the elderly, preventive measures such as vaccination are more important, especially for the elderly population, to minimize the mortality rates.

A method for assessing robustness of the results of a star-shaped network meta-analysis under the unidentifiable consistency assumption.

BACKGROUND: In a star-shaped network, pairwise comparisons link treatments with a reference treatment (often placebo or standard care), but not with each other. Thus, comparisons between non-reference treatments rely on indirect evidence, and are based on the unidentifiable consistency assumption, limiting the reliability of the results. We suggest a method of performing a sensitivity analysis through data imputation to assess the robustness of results with an unknown degree of inconsistency. METHODS: The method involves imputation of data for randomized controlled trials comparing non-reference treatments, to produce a complete network. The imputed data simulate a situation that would allow mixed treatment comparison, with a statistically acceptable extent of inconsistency. By comparing the agreement between the results obtained from the original star-shaped network meta-analysis and the results after incorporating the imputed data, the robustness of the results of the original star-shaped network meta-analysis can be quantified and assessed. To illustrate this method, we applied it to two real datasets and some simulated datasets. RESULTS: Applying the method to the star-shaped network formed by discarding all comparisons between non-reference treatments from a real complete network, 33% of the results from the analysis incorporating imputed data under acceptable inconsistency indicated that the treatment ranking would be different from the ranking obtained from the star-shaped network. Through a simulation study, we demonstrated the sensitivity of the results after data imputation for a star-shaped network with different levels of within- and between-study variability. An extended usability of the method was also demonstrated by another example where some head-to-head comparisons were incorporated. CONCLUSIONS: Our method will serve as a practical technique to assess the reliability of results from a star-shaped network meta-analysis under the unverifiable consistency assumption.

Pleural recurrence after transthoracic needle lung biopsy in stage I lung cancer: a systematic review and individual patient-level meta-analysis.

INTRODUCTION: Conflicting results exist regarding whether preoperative transthoracic biopsy increases the risk of pleural recurrence in early lung cancer. We conducted a systematic, patient-level meta-analysis to evaluate the risk of pleural recurrence in stage I lung cancer after percutaneous transthoracic lung biopsy. METHODS: A systematic search of OVID-MEDLINE, Embase and the Cochrane Database of Systematic Reviews was performed through October 2018. Eligible studies were original articles on the risk of pleural recurrence in stage I lung cancer after transthoracic biopsy. We contacted the corresponding authors of eligible studies to obtain individual patient-level data. We used the Fine-Gray model for time to recurrence and lung cancer-specific survival and a Cox proportional hazards model for overall survival. RESULTS: We analysed 2394 individual patient data from 6 out of 10 eligible studies. Compared with other diagnostic procedures, transthoracic biopsy was associated with a higher risk for ipsilateral pleural recurrence, which manifested solely (subdistribution HR (sHR), 2.58; 95% CI 1.15 to 5.78) and concomitantly with other metastases (sHR 1.99; 95% CI 1.14 to 3.48). In the analysis of secondary outcomes considering a significant interaction between diagnostic procedures and age groups, reductions of time to recurrence (sHR, 2.01; 95% CI 1.11 to 3.64), lung cancer-specific survival (sHR 2.53; 95% CI 1.06 to 6.05) and overall survival (HR 2.08; 95% CI 1.12 to 3.87) were observed in patients younger than 55 years, whereas such associations were not observed in other age groups. DISCUSSION: Preoperative transthoracic lung biopsy was associated with increased pleural recurrence in stage I lung cancer and reduced survival in patients younger than 55 years.

Comparative Renal Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-Glucose Cotransporter 2 Inhibitors on Individual Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis.

BACKGROUND: To compare the renal effects of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors on individual outcomes in patients with type 2 diabetes. METHODS: We searched electronic databases (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) from inception to June 2019 to identity eligible randomized controlled trials of DPP-4 inhibitors or SGLT2 inhibitors that reported at least one kidney outcome in patients with type 2 diabetes. Outcomes of interest were microalbuminuria, macroalbuminuria, worsening nephropathy, and end-stage kidney disease (ESKD). We performed an arm-based network meta-analysis using Bayesian methods and calculated absolute risks and rank probabilities of each treatment for the outcomes. RESULTS: Seventeen studies with 87,263 patients were included. SGLT2 inhibitors significantly lowered the risks of individual kidney outcomes, including microalbuminuria (odds ratio [OR], 0.64; 95% credible interval [CrI], 0.41 to 0.93), macroalbuminuria (OR, 0.48; 95% CrI, 0.24 to 0.72), worsening nephropathy (OR, 0.65; 95% CrI, 0.44 to 0.91), and ESKD (OR, 0.65; 95% CrI, 0.46 to 0.98) as compared with placebo. However, DPP-4 inhibitors did not lower the risks. SGLT2 inhibitors were considerably associated with higher absolute risk reductions in all kidney outcomes than DPP-4 inhibitors, although the benefits were statistically insignificant. The rank probabilities showed that SGLT2 inhibitors were better treatments for lowering the risk of albuminuria and ESKD than placebo or DPP-4 inhibitors. CONCLUSION: SGLT2 inhibitors were superior to DPP-4 inhibitors in reducing the risk of albuminuria and ESKD in patients with type 2 diabetes.

Geriatric Nutritional Risk Index as a prognostic marker in patients with extensive-stage disease small cell lung cancer: Results from a randomized controlled trial.

BACKGROUND: Clinical impact of the Geriatric Nutritional Risk Index (GNRI) in patients with extensive-stage disease small cell lung cancer (ED-SCLC) have not previously been reported. METHODS: This study analyzed 352 patients enrolled in a previous randomized phase III trial comparing the efficacy of irinotecan plus cisplatin with that of etoposide plus cisplatin as the first-line therapy for ED-SCLC. GNRI values were calculated using serum albumin levels and actual and ideal bodyweights. Patients with a GNRI > 98, 92-98, and <92 were grouped into no, low, and moderate/major risk groups, respectively. RESULTS: The objective response rates were 63.2%, 52.6%, and 49.2% in the no, low, and moderate/major risk groups, respectively (P = 0.024). The median progression-free survival (PFS) was shorter in patients with a lower GNRI than in those with a higher GNRI (no vs. low vs. moderate/major risk group; 6.5 vs. 5.8 vs. 5.9 months, respectively; P = 0.028). There were significant differences in median overall survival (OS) according to GNRI (no vs. low vs. moderate/major risk group; 13.2 vs. 10.3 vs. 8.4 months, respectively; P < 0.001). Multivariate analysis revealed that being in the moderate/major risk group was an independent poor prognostic factor for PFS (hazard ratio [HR]: 1.300, 95% confidence interval [CI]: 1.012-1.670; P = 0.040) and OS (HR: 1.539; 95% CI: 1.069-2.216; P = 0.020). CONCLUSIONS: This prospective study shows that a low GNRI value was associated with a poor prognosis, and it supports the relationship between systemic inflammation, nutritional status, and clinical outcomes in patients with ED-SCLC.Key points SIGNIFICANT FINDINGS OF THE STUDY: The lower GNRI group had a low response rate to chemotherapy for ED-SCLC. The HRs for PFS and OS were 1.300 and 1.539 in the patients with GNRI < 92. WHAT THIS STUDY ADDS: Low GNRI is associated with poor prognosis in ED-SCLC.

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This study was conducted to investigate the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on individual renal outcomes in patients with type 2 diabetes. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to September 2017 to identify randomized controlled trials comparing SGLT2 inhibitors with placebo or antidiabetic drugs and reporting any renal outcomes in patients with type 2 diabetes. Additionally, we identified 4 articles which were published after the predefined period to include relevant data. A meta-analysis was performed to calculate weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs) for each renal outcome. We included 48 studies involving 58,165 patients in the analysis. SGLT2 inhibitors significantly lowered urine albumin-to-creatinine ratio (UACR) (WMD, -14.64 mg/g; 95% CI, -25.15 to -4.12; P = 0.006) compared with controls. The UACR-lowering effects of SGLT2 inhibitors were greater with a higher baseline UACR. Overall changes in estimated glomerular filtration rate (eGFR) were comparable between two groups (WMD, 0.19 mL/min/1.73 m2; 95% CI, -0.44 to 0.82; P = 0.552). However, SGLT2 inhibitors significantly slowed eGFR decline in patients with a higher baseline eGFR and a longer duration of treatment. Compared with controls, SGLT2 inhibitors significantly reduced the risk of microalbuminuria (RR, 0.69; 95% CI, 0.49 to 0.97; P = 0.032), macroalbuminuria (RR, 0.49; 95% CI, 0.33 to 0.73; P < 0.001), and worsening nephropathy (RR, 0.73; 95% CI, 0.58 to 0.93; P = 0.012). In addition, the risk of end-stage renal disease was significantly lower in SGLT2 inhibitors than in controls (RR, 0.70; 95% CI, 0.57 to 0.87; P = 0.001). In conclusion, SGLT2 inhibitors had beneficial renal effects by lowering the risk of albuminuria development or progression and reducing the risk of end-stage renal disease compared with placebo or other antidiabetic drugs.

Evaluation of the safety of using propofol for paediatric procedural sedation: A systematic review and meta-analysis.

Propofol is one of the most widely used drugs for paediatric procedural sedation owing to its known advantages, but some concerns remain regarding respiratory and/or cardiac complications in patients receiving propofol. Although a considerable number of randomised controlled clinical trials (RCTs) have been conducted to compare it with other sedative agents or opioids for children undergoing various procedures, propofol is still being used off-label for this indication in many countries. We performed a systematic review and meta-analysis of those RCTs to provide an overall summation of evidence that can potentially be considered for further regulatory decisions, including reimbursement policies. We searched for RCTs in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from their inception to January 31, 2018. Our meta-analysis of 30 RCTs confirmed that propofol sedation had advantages in recovery time when compared with other drugs, without excessive concerns for cardiovascular or respiratory adverse events. Its safety profile regarding coughing, nausea or vomiting, and emergence delirium was also similar to that of other drugs. The overall evidence suggests that propofol sedation for paediatric procedures should be considered more positively in the context of regulatory decisions.

Non-diagnostic Results of Percutaneous Transthoracic Needle Biopsy: A Meta-analysis.

Non-diagnostic results can affect the diagnostic performance of percutaneous transthoracic needle biopsy (PTNB) but have not been critically meta-analyzed yet. To meta-analyze the incidence and malignancy rate of non-diagnostic results, 3-by-2 table approaches rather than the conventional 2-by-2 approaches are needed to know its impact on the diagnostic performance of PTNB. A systematic literature search identified studies evaluating the diagnostic performance of PTNB with extractable outcomes. A total of 143 studies with 35,059 biopsies were included. The pooled incidence of non-diagnostic results was 6.8% (95% CI, 6.0-7.6%; I2 = 0.91). The pooled malignancy rate of non-diagnostic results was 59.3% (95% CI, 51.7-66.8%; I2 = 0.80), and was correlated with the prevalence of malignancy (correlation coefficient, 0.66; 95% CI, 0.42-0.91). Pooled percentage decrease of sensitivity and specificity due to non-diagnostic results were 4.5% (95% CI, 3.2-5.7%; I2 = 0.64) and 10.7% (95% CI, 7.7-13.7%; I2 = 0.70), respectively, and the pooled incidence of non-diagnostic results was 4.4% (95% CI, 3.2-5.8%; I2 = 0.83) in lesions ultimately diagnosed as malignancies and 10.4% (95% CI, 7.5-13.8%; I2 = 0.74) in benign disease. In conclusion, non-diagnostic results averagely occurred in 6.8% of PTNB and more than half of the results were malignancies. The non-diagnostic results decreased specificity and sensitivity by 10.7% and 4.5%, respectively, demanding efforts to minimize the non-diagnostic results in PTNB.

First-line Pembrolizumab Versus Pembrolizumab Plus Chemotherapy Versus Chemotherapy Alone in Non-small-cell Lung Cancer: A Systematic Review and Network Meta-analysis.

BACKGROUND: This study aimed to comprehensively review the available evidence regarding the efficacy of first-line pembrolizumab for advanced/metastatic non-small-cell lung cancer (NSCLC), and to compare pembrolizumab monotherapy versus pembrolizumab plus chemotherapy versus chemotherapy alone. MATERIALS AND METHODS: A search of the PubMed, EMBASE, and Cochrane Library databases was performed in July 2018, and abstracts from the American Society of Clinical Oncology meetings (2015-2018) were reviewed. Summaries of the results were pooled using a random-effect model to determine the pooled hazard ratio (HR) for progression-free survival (PFS), overall survival (OS), and their 95% confidence intervals (CIs). A network meta-analysis was used to indirectly compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy. RESULTS: A total of 4 relevant phase III trials comprising 2754 patients were identified. Pembrolizumab (with or without chemotherapy) led to significant improvements in OS and PFS, irrespective of the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS). In particular, for the subgroup with PD-L1 TPS ≥ 50%, the HR of PFS was 0.49 (95% CI, 0.32-0.76; P = .001), and that of OS was 0.57 (95% CI, 0.45-0.73; P < .001). In terms of PFS, pembrolizumab plus chemotherapy was superior to pembrolizumab monotherapy with an HR of PFS 0.52 (95% CI, 0.27-0.99; P = .048) for the subgroup with PD-L1 TPS ≥ 50%. CONCLUSIONS: For patients with NSCLC with PD-L1 TPS ≥ 50%, pembrolizumab plus chemotherapy has a better PFS than pembrolizumab monotherapy in this meta-analysis. To confirm this finding, a prospective phase III trial that directly compares the treatments is warranted.

A First-in-Human Phase I Study of GC1118, a Novel Anti-Epidermal Growth Factor Receptor Antibody, in Patients with Advanced Solid Tumors.

LESSONS LEARNED: GC1118 is a novel fully human anti-epidermal growth factor receptor (EGFR) antibody with unique binding epitopes and different ligand-binding inhibitory activity compared with cetuximab or panitumumab.GC1118 showed promising antitumor activity, especially in patients with colorectal cancer resistant to prior EGFR antibody. Skin toxicities were more common and diarrhea was less frequent compared with other anti-EGFR antibodies. BACKGROUND: GC1118 is a novel monoclonal antibody targeting epidermal growth factor receptor (EGFR) with more potent ligand inhibition than cetuximab or panitumumab. We conducted a first-in-human, phase I study of GC118 in patients with refractory solid tumors. METHODS: In the dose escalation part, GC1118 was administered on days 1, 8, 15, and 22, followed by a 2-week rest, during which dose-limiting toxicities (DLTs) were evaluated. In the expansion part, patients were enrolled into three cohorts (Cohort 1 [C1], patients with colorectal cancer [CRC] without prior anti-EGFR treatment; Cohort 2 [C2], patients with CRC with tumors resistant to anti-EGFR therapy; Cohort 3 [C3], EGFR-overexpressing gastric cancer). RESULTS: In the dose escalation part, 24 patients were treated at five dose levels: 0.3, 1.0, 3.0, 4.0, and 5.0 mg/kg. In the 5.0 mg/kg cohort, two patients experienced DLTs (skin toxicities). The maximum-tolerated dose (MTD) was 4.0 mg/kg. Common adverse events were skin toxicities. In the expansion part, 39 patients were enrolled. In Cohort 1, stable disease (SD) was observed in 58%; in Cohort 2, partial response (PR) 17% and SD 8%; in Cohort 3, PR 8% and SD 17%. CONCLUSION: GC1118 showed promising antitumor activity and was well tolerated. Infrequent diarrhea compared with other anti-EGFR antibodies might be advantageous for further development.

Development of an algorithm for evaluating the impact of measurement variability on response categorization in oncology trials.

BACKGROUND: Radiologic assessments of baseline and post-treatment tumor burden are subject to measurement variability, but the impact of this variability on the objective response rate (ORR) and progression rate in specific trials has been unpredictable on a practical level. In this study, we aimed to develop an algorithm for evaluating the quantitative impact of measurement variability on the ORR and progression rate. METHODS: First, we devised a hierarchical model for estimating the distribution of measurement variability using a clinical trial dataset of computed tomography scans. Next, a simulation method was used to calculate the probability representing the effect of measurement errors on categorical diagnoses in various scenarios using the estimated distribution. Based on the probabilities derived from the simulation, we developed an algorithm to evaluate the reliability of an ORR (or progression rate) (i.e., the variation in the assessed rate) by generating a 95% central range of ORR (or progression rate) results if a reassessment was performed. Finally, we performed validation using an external dataset. In the validation of the estimated distribution of measurement variability, the coverage level was calculated as the proportion of the 95% central ranges of hypothetical second readings that covered the actual burden sizes. In the validation of the evaluation algorithm, for 100 resampled datasets, the coverage level was calculated as the proportion of the 95% central ranges of ORR results that covered the ORR from a real second assessment. RESULTS: We built a web tool for implementing the algorithm (publicly available at http://studyanalysis2017.pythonanywhere.com/ ). In the validation of the estimated distribution and the algorithm, the coverage levels were 93 and 100%, respectively. CONCLUSIONS: The validation exercise using an external dataset demonstrated the adequacy of the statistical model and the utility of the developed algorithm. Quantification of variation in the ORR and progression rate due to potential measurement variability is essential and will help inform decisions made on the basis of trial data.