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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.

This study evaluated the efficacy of fibrin glue for preventing post-endoscopic submucosal dissection (ESD) bleeding in high-risk patients for bleeding (expected iatrogenic ulcer size ≥ 40 mm or receiving antithrombotic therapy).A multicenter, open-label, randomized controlled trial was performed at four tertiary-medical centers in 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).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, 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) of the fibrin glue group and 7.3% (9/122) in the control group (p=0.301).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.

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 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.

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

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.

Background To investigate the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal outcomes in patients with type 2 diabetes. Methods MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify randomized controlled trials (RCTs) of DPP-4 inhibitors from inception to September 2017. We selected eligible RCTs comparing DPP-4 inhibitors with placebo or other antidiabetic agents and reporting at least one renal outcome. A meta-analysis was conducted to calculate standardized mean differences, weighted mean differences (WMDs), relative risks (RRs), and 95% confidence intervals (CIs) for each renal outcome. Results We included 23 RCTs with 19 publications involving 41,359 patients. Overall changes in urine albumin-to-creatinine ratio were comparable between DPP-4 inhibitors and controls (P=0.150). However, DPP-4 inhibitors were associated with significantly lower risk of incident microalbuminuria (RR, 0.89; 95% CI, 0.80 to 0.98; P=0.022) and macroalbuminuria (RR, 0.77; 95% CI, 0.61 to 0.97; P=0.027), as well as higher rates of regression of albuminuria (RR, 1.22; 95% CI, 1.10 to 1.35; P

Purpose Dexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary malignancy development, and elucidate risk factors for secondary malignancies in dexrazoxane-treated pediatric patients. Materials and methods Data was collected from 15 hospitals in Korea. Patients who received any anthracyclines, and completed treatment without stem cell transplantation were included. For efficacy evaluation, the incidence of cardiac events and cardiac event-free survival rates were compared. Data about risk factors of secondary malignancies were collected. Results Data of total 1,453 cases were analyzed; dexrazoxane with every anthracyclines group (D group, 1,035 patients) and no dexrazoxane group (non-D group, 418 patients). Incidence of the reported cardiac events was not statistically different between two groups; however, the cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in D group (91.2% vs. 80.1%, p=0.04). The 6-year cumulative incidence of secondary malignancy was not different between both groups after considering follow-up duration difference (non-D, 0.52%±0.37%; D, 0.60%±0.28%; p=0.55). The most influential risk factor for secondary malignancy was the duration of anthracycline administration according to multivariate analysis. Conclusion Dexrazoxane had an efficacy in lowering cardiac event-free survival rates in patients with higher cumulative anthracyclines. As a result of multivariate analysis for assessing risk factors of secondary malignancy, the occurrence of secondary malignancy was not related to dexrazoxane administration.

Summary Background Linezolid improves the treatment outcomes of multidrug-resistant tuberculosis substantially. We investigated whether use of linezolid instead of ethambutol increases the proportion of sputum culture conversion at 8 weeks of treatment in patients with pulmonary tuberculosis. Methods We did a phase 2, multicentre, randomised, open-label trial for patients with pulmonary tuberculosis at the three affiliated hospitals to Seoul National University and National Medical Center (Seoul–Seongnam, South Korea). Patients, aged 20–80 years, with a positive sputum for pulmonary tuberculosis, but without resistance to rifampicin, and current treatment administered for 7 days or fewer, were randomly assigned at a 1:1:1 ratio into three groups. The control group received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The second group used linezolid (600 mg/day) for 2 weeks and the third group for 4 weeks instead of ethambutol for 2 months. We used a minimisation method to randomise, and stratified according to institution, cavitation on chest radiographs, and diabetes. The primary endpoint was the proportion of patients with negative culture conversion of sputum in liquid media after 8 weeks of treatment. The results of this trial were analysed primarily in the modified intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01994460. Findings Between Feb 19, 2014, and Jan 13, 2017, a total of 429 patients were enrolled and 428 were randomly assigned into either the control group (142 patients), the linezolid 2 weeks group (143 patients), or the linezolid 4 weeks group (143 patients). Among them, 401 were eligible for primary efficacy analyses. In the modified intention-to-treat analyses, negative cultures in liquid media at 8 weeks of treatment were observed in 103 (76·9%) of 134 control patients, 111 (82·2%) of 135 in the linezolid 2 weeks group, and 100 (75·8%) of 132 in the linezolid 4 weeks groups. The difference from the control group was 5.4% (95% CI −4·3 to 15·0, p=0·28) for the linezolid 2 weeks group and −1·1% (−11·3 to 9·1, p=0·83) for the linezolid 4 weeks group. Numbers of patients who experienced at least one adverse event were similar across the groups (86 [62·8%] of 137 in control, 79 [57·2%] of 138 in the linezolid 2 weeks group, and 75 [62·0%] of 121 in the linezolid 4 weeks group). Resistance to linezolid was not identified in any patient. Interpretation Higher rates of culture conversion at 8 weeks of treatment with short-term use of linezolid were not observed. However, safety analyses and the resistance profile suggested the potential role of linezolid in shortening of treatment for drug-susceptible tuberculosis. Funding Ministry of Health and Welfare, South Korea.

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.

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.

We aimed to evaluate the comparative efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose co-transporter 2 inhibitors (SGLT2i), or thiazolidinedione (TZD) as an adjunctive treatment in patients with poorly controlled type 2 diabetes mellitus (T2DM) on insulin therapy. We searched Medline, Embase, the Cochrane Library, and ClinicalTrials.gov through April 2016. Bayesian network meta-analyses were performed with covariate adjustment. The primary outcome was the change in glycated hemoglobin A1c (HbA1c) from baseline. Fifty randomized controlled trials covering 15,494 patients were included. GLP-1RA showed the greatest HbA1c-lowering effect compared to the control (−0.84%; 95% credible interval, −1.00% to −0.69%), followed by TZD (−0.73%; −0.93 to −0.52%), SGLT2i (−0.66%; −0.84% to −0.48%), and DPP4i (−0.54%; −0.68% to −0.39%). SGLT2i showed the greatest fasting plasma glucose reduction. GLP-1RA and SGLT2i showed greater body weight reduction, whereas TZD increased body weight. TZD was ranked the highest in terms of insulin dose reduction. The risk of hypoglycemia was increased with TZD or GLP-1RA. The study provides the best available evidence on the comparative efficacy and safety of non-insulin anti-diabetic agents on top of pre-existing insulin therapy for inadequately controlled T2DM patients.

Sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors have complementary mode of action. For the meta-analysis comparing the efficacy and safety between SGLT2 inhibitor plus DPP4 inhibitor (SGLT2i/DPP4i) and placebo plus DPP4 inhibitor (PCB/DPP4i) in patients with type 2 diabetes mellitus (T2DM), we selected randomized controlled trials from electronic databases by predefined criteria. The primary outcome of interest was the change in glycated hemoglobin A1c (HbA1c) from baseline. Of 605 potentially relevant studies, 7 eligible RCTs comprising 2,082 patients were included.SGLT2i/DPP4i showed a greater reduction in HbA1c (weighted mean difference −0.6%, 95% CI −0.7 to −0.5%), fasting plasma glucose, 2 h postprandial plasma glucose, and body weight compared to PCB/DPP4i. The risk of hypoglycemia increased in SGLT2i/DPP4i compared to that in PCB/DPP4i only when insulin or sulfonylureas were included as a background therapy. The risk of urinary tract infection was not increased in SGLT2i/DPP4i; however, the risk of genital infection increased upon adding SGLT2 inhibitors to pre-existing DPP4 inhibitors. In conclusion, compared to PCB/DPP4i, SGLT2i/DPP4i achieved better glycemic control and greater weight reduction without increasing the risk of hypoglycemia and urinary tract infection in patients with inadequately controlled T2DM.

Aims/Introduction The combination of dipeptidyl peptidase-4 (DPP4) inhibitors and α-glucosidase inhibitors (AGIs) might provide an additive or synergistic glucose-lowering effect, as they have a complementary mode of action. In the present study, we examined the efficacy and safety of the addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI. Materials and Methods We carried out an electronic search of MEDLINE, EMBASE, the Cochrane Library and Clinicaltrials.gov through October 2016. Randomized controlled trials written in English that compared DPP4 inhibitors plus AGI (DPP4i/AGI) and placebo plus AGI (PCB/AGI) in patients with type 2 diabetes were selected. Data on the study characteristics, efficacy and safety outcomes were extracted, and the risk of potential biases was assessed. The efficacy and safety of DPP4i/AGI and PCB/AGI were compared. Results Of 756 potentially relevant published articles and 40 registered trials, five studies including 845 patients randomized to DPP4i/AGI and 832 patients randomized to PCB/AGI were included for meta-analysis. Compared with PCB/AGI, DPP4i/AGI showed a greater reduction in glycated hemoglobin (weighted mean difference −1.2%, 95% confidence interval −1.6 to −0.8), fasting plasma glucose and 2-h postprandial plasma glucose levels, with no increase in bodyweight. The risks of hypoglycemia and gastrointestinal adverse events were similar between DPP4i/AGI and PCB/AGI. Conclusions The addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI achieved better glycemic control without further increasing the risk of weight gain and hypoglycemia.

Background: The presence of a telomerase reverse transcriptase (TERT) promoter mutation has been suggested as a potential prognostic marker for thyroid cancer, and a synergistic association with the BRAFV600E mutation has been demonstrated. The aim of this study was to verify the role of this genetic duet in papillary thyroid cancer (PTC). Methods: Studies of the association of BRAFV600E and TERT promoter mutations with clinicopathologic features, recurrence, or PTC-related mortality were included from PubMed and Embase databases (inception to September 2016). Results: Thirteen eligible studies incorporating 4347 patients with PTC were included, and 283 (median 8.3%) of these patients had coexistent BRAFV600E and TERT promoter mutations. The coexistence of the two mutations was far more strongly associated with high-risk clinicopathologic features than either mutation alone was, including advanced TNM stage (vs. BRAFV600E: odds ratio [OR] = 4.19 [confidence interval (CI) 3.07–5.71]; vs. TERT: OR = 4.66 [C...

Background: Gastrointestinal stromal tumours (GISTs) with high-risk features have poor prognosis even if adjuvant treatment is given. Neoadjuvant imatinib may increase the cure rate by shrinking large GISTs and preserve organ function. Methods: We conducted an Asian multinational phase II study for patients with gastric GISTs ≥10 cm. Patients received neoadjuvant imatinib (400 mg/day) for 6–9 months. The primary end point was R0 resection rate. Results: A total of 56 patients were enroled in this study. In the full analysis set of 53 patients, neoadjuvant imatinib for ≥6 months was completed in 46 patients. Grade 3–4 neutropenia and rash occurred in 8% and 9%, respectively, but there were no treatment-related deaths. The response rate by RECIST was 62% (95% CI, 48–75%). The R0 resection rate was 91% (48/53) (95% CI, 79–97%). Preservation of at least half of the stomach was achieved in 42 of 48 patients with R0 resection. At the median follow-up time of 32 months, 2-year overall and progression-free survival rates were 98% and 89%, respectively. Conclusions: Neoadjuvant imatinib treatment for 6–9 months is a promising treatment for large gastric GISTs, allowing a high R0 resection rate with acceptable toxicity.

To assess whether a pH-balanced vaginal gel containing lactic acid is more effective than a placebo (lactate-free gel) in improving dyspareunia and sexual function among breast cancer survivors who were premenopausal at diagnosis and had dyspareunia after adjuvant chemotherapy.In a single-center, double-blind, randomized trial, a pH-balanced gel or placebo was administered three times per week at bedtime as well as during sexual intercourse for 8 weeks. The primary outcome was the improvement of dyspareunia measured by pain score of the Female Sexual Function Index after the treatment. Secondary outcomes included the total and individual domains of Female Sexual Function Index score, sexual dysfunction (a total Female Sexual Function Index score less than 25.0), vaginal pH, vaginal maturation index, and adverse events related to the intervention. A sample size of 47 per group was planned to achieve 80% power to detect a 19% difference in the primary outcome.From October 2009 and March 2013, 167 women were screened and 136 were randomized: 69 to a pH-balanced gel and 67 to placebo. Baseline characteristics were similar in both groups. Although there was no difference between the two groups, both experienced a significant improvement of dyspareunia. The increase in median pain score from baseline was 1.2 in both groups (median [interquartile range] from 2.8 [2.0-4.0] to 4.0 [2.8-4.8] in the pH-balanced group and from 3.2 [2.0-4.0] to 4.4 [3.2-4.8] in the placebo group; all P.01). Overall Female Sexual Function Index score and the frequency of sexual dysfunction also did not differ between the two groups although there was a significant improvement. On the other hand, vaginal pH and vaginal maturation index were slightly but significantly improved only in the pH-balanced group. There were no severe adverse events in either group.The pH-balanced vaginal gel is not superior to the placebo in improving dyspareunia and overall sexual function.ClinicalTrials.gov, https://www.clinicaltrials.gov, NCT00981305.

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.

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. Electronic supplementary material The online version of this article (10.1186/s12874-019-0727-7) contains supplementary material, which is available to authorized users.

We aimed to meta-analytically compare the incidence of acute adverse reactions (AARs) to nonionic iodinated contrast media (ICM) according to the type of ICM in patients who underwent radiologic examinations with administration of ICM via intravascular route.A systematic literature search identified studies evaluating the incidence of AARs to 7 nonionic ICM (iobitridol, iohexol, iomeprol, iopamidol, iopromide, ioversol, and iodixanol) with extractable outcomes. These outcomes were pooled using a random-effects model, and the effect of ICM type on the incidence of overall and severe AARs was evaluated using meta-regression analysis.Thirty studies with 1,360,488 exposures to ICM were included. The pooled incidences of overall and severe AARs to nonionic ICM were 1.03% (95% confidence interval [CI], 0.81%-1.30%; I = 0.99) and 0.0141% (95% CI, 0.0108%-0.0183%; I = 0.56), respectively. Iomeprol had the highest overall AAR incidence (1.74%; 95% CI, 0.79%-3.76%; I = 0.99), followed by iohexol (1.21%; 95% CI, 0.67%-2.17%; I = 0.99), iopamidol (1.10%; 95% CI, 0.60%-2.03%; I = 0.99), ioversol (0.88%; 95% CI, 0.43%-1.83%; I = 0.96), iodixanol (0.85%; 95% CI, 0.36%-1.95%; I = 0.99), iopromide (0.82%; 95% CI, 0.43%-1.55%; I = 0.99), and iobitridol (0.77%; 95% CI, 0.36%-1.62%; I = 0.99). Multivariable meta-regression analysis revealed that study design (P = 0.0014) and premedication (P = 0.0230) were statistically significant determinants affecting the incidence of overall AARs. Iodinated contrast media type did not affect the incidence of overall and severe AARs (P = 0.1453 and 0.4265, each).The varying pooled incidences of overall and severe AARs to specific types of nonionic ICM do not remain as significant after adjusting confounders. Our results may support nonrestriction of certain types of nonionic ICM in the context of AAR avoidance.

Figure S3. Observed objective response rates (ORR) with 95% confidence intervals and 95% central ranges from the evaluation tool depending characteristics of simulated data sets in which the true ORR is 80%. (a) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 0.532) and − 30±N(0, 52), respectively. (b) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 1.222) and − 30±N(0, 52), respectively. (c) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 0.532) and − 30±N(0, 202), respectively. (d) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 1.222) and − 30±N(0, 202), respectively. (e) when the assumed distributions of baseline tumor burden size and percent change are LN(4.25, 0.532) and − 30±N(0, 52), respectively. (f) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 0.532) and − 30±N(20, 52), respectively. (g) when the assumed distributions of baseline tumor burden size and percent change are LN(4.25, 0.532) and − 30±N(20, 52), respectively. Dashed line: true ORR; Gray lines: the observed ORR and 95% confidence interval; Black lines: median and 95% central range from the tool. (PDF 329 kb)

Figure S1. Observed objective response rates (ORR) with 95% confidence intervals and 95% central ranges from the evaluation tool depending characteristics of simulated data sets in which the true ORR is 20%. (a) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 0.532) and − 30±N(0, 52), respectively. (b) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 1.222) and − 30±N(0, 52), respectively. (c) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 0.532) and − 30±N(0, 202), respectively. (d) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 1.222) and − 30±N(0, 202), respectively. (e) when the assumed distributions of baseline tumor burden size and percent change are LN(4.25, 0.532) and − 30±N(0, 52), respectively. (f) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 0.532) and − 30±N(20, 52), respectively. (g) when the assumed distributions of baseline tumor burden size and percent change are LN(4.25, 0.532) and − 30±N(20, 52), respectively. Dashed line: true ORR; Gray lines: The observed ORR and 95% confidence interval; Black lines: median and 95% central range from the tool. (PDF 334 kb)

Formulas of the LOAs on the original scale for the nth root-transformed variables. (DOCX 18 kb)

Background Despite well-known advantages, propofol remains off-label in many countries for general anesthesia in children under 3 years of age due to insufficient evidence regarding its use in this population. This study aimed to evaluate the efficacy and safety of propofol compared with other general anesthetics in children under 3 years of age undergoing surgery through a systematic review and meta-analysis of existing randomized clinical trials. Methods A comprehensive literature search was conducted of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to find all randomized clinical trials comparing propofol with another general anesthetic that included children under 3 years of age. The relative risk or arcsine-transformed risk difference for dichotomous outcomes and the weighted or standardized mean difference for continuous outcomes were estimated using a random-effects model. Results A total of 249 young children from 6 publications were included. The children who received propofol had statistically significantly lower systolic and diastolic blood pressures, but hypotension was not observed in the propofol groups. The heart rate, stroke volume index, and cardiac index were not significantly different between the propofol and control groups. The propofol groups showed slightly shorter recovery times and a lower incidence of emergence agitation than the control groups, while no difference was observed for the incidence of hypotension, desaturation, and apnea. Conclusion This systematic review and meta-analysis indicates that propofol use for general anesthesia in young healthy children undergoing surgery does not increase complications and that propofol could be at least comparable to other anesthetic agents., Graphical Abstract

Figure S2. Observed objective response rates (ORR) with 95% confidence intervals and 95% central ranges from the evaluation tool depending characteristics of simulated data sets in which the true ORR is 50%. (a) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 0.532) and − 30±N(0, 52), respectively. (b) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 1.222) and − 30±N(0, 52), respectively. (c) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 0.532) and − 30±N(0, 202), respectively. (d) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 1.222) and − 30±N(0, 202), respectively. (e) when the assumed distributions of baseline tumor burden size and percent change are LN(4.25, 0.532) and − 30±N(0, 52), respectively. (f) when the assumed distributions of baseline tumor burden size and percent change are LN(3.55, 0.532) and − 30±N(20, 52), respectively. (g) when the assumed distributions of baseline tumor burden size and percent change are LN(4.25, 0.532) and − 30±N(20, 52), respectively. Dashed line: true ORR; Gray lines: the observed ORR and 95% confidence interval; Black lines: median and 95% central range from the tool. (PDF 323 kb)

SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents. (DOC 127 kb)

Purpose The purpose of this study was to compare the survival of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) undergoing concurrent chemoradiotherapy (CRT) alone with that of patients undergoing induction chemotherapy (IC) using docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by CRT. Materials and Methods A search of the PubMed, EMBASE, and Cochrane Library databases was performed in April 2015 and abstracts from the American Society of Clinical Oncology meetings (2008-2014) were reviewed. Summaries of the results were pooled using a fixed-effect model, and the risk of bias was evaluated using the Cochrane tool. Results A total of six relevant trials comprising 1,280 patients were identified. There was no statistically significant overall survival (OS) advantage for TPF prior to CRT (TPF/CRT) over CRT alone (hazard ratio [HR] 0.92; 95% confidence interval [CI], 0.79 to 1.09; p=0.339). Progression-free survival (PFS) was significantly longer in the TPF/CRT arms (HR, 0.82; 95% CI, 0.70 to 0.95; p=0.009). Patients with non-oropharyngeal LA-HNSCC obtained the greatest OS and PFS benefits from TPF (HR, 0.68; 95% CI, 0.47 to 0.99; p=0.043 and HR, 0.67; 95% CI, 0.48 to 0.94; p=0.022, respectively). The complete response rate was significantly increased (risk ratio [RR], 1.34; 95% CI, 1.14 to 1.56; p < 0.001), and the distant metastasis rate tended to decrease (RR, 0.65; 95% CI, 0.40 to 1.04; p=0.071) in the TPF/CRT arms. Conclusion IC with TPF followed by CRT is not superior to CRT alone for OS. However, PFS and the complete response rate were significantly improved in the TPF/CRT arms. TPF/CRT for patients with nonoropharyngeal LA-HNSCC provided clear survival advantages.

Summary Background Chemotherapy is the standard of care for incurable advanced gastric cancer. Whether the addition of gastrectomy to chemotherapy improves survival for patients with advanced gastric cancer with a single non-curable factor remains controversial. We aimed to investigate the superiority of gastrectomy followed by chemotherapy versus chemotherapy alone with respect to overall survival in these patients. Methods We did an open-label, randomised, phase 3 trial at 44 centres or hospitals in Japan, South Korea, and Singapore. Patients aged 20–75 years with advanced gastric cancer with a single non-curable factor confined to either the liver (H1), peritoneum (P1), or para-aortic lymph nodes (16a1/b2) were randomly assigned (1:1) in each country to chemotherapy alone or gastrectomy followed by chemotherapy by a minimisation method with biased-coin assignment to balance the groups according to institution, clinical nodal status, and non-curable factor. Patients, treating physicians, and individuals who assessed outcomes and analysed data were not masked to treatment assignment. Chemotherapy consisted of oral S-1 80 mg/m 2 per day on days 1–21 and cisplatin 60 mg/m 2 on day 8 of every 5-week cycle. Gastrectomy was restricted to D1 lymphadenectomy without any resection of metastatic lesions. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with UMIN-CTR, number UMIN000001012. Findings Between Feb 4, 2008, and Sept 17, 2013, 175 patients were randomly assigned to chemotherapy alone (86 patients) or gastrectomy followed by chemotherapy (89 patients). After the first interim analysis on Sept 14, 2013, the predictive probability of overall survival being significantly higher in the gastrectomy plus chemotherapy group than in the chemotherapy alone group at the final analysis was only 13·2%, so the study was closed on the basis of futility. Overall survival at 2 years for all randomly assigned patients was 31·7% (95% CI 21·7–42·2) for patients assigned to chemotherapy alone compared with 25·1% (16·2–34·9) for those assigned to gastrectomy plus chemotherapy. Median overall survival was 16·6 months (95% CI 13·7–19·8) for patients assigned to chemotherapy alone and 14·3 months (11·8–16·3) for those assigned to gastrectomy plus chemotherapy (hazard ratio 1·09, 95% CI 0·78–1·52; one-sided p=0·70). The incidence of the following grade 3 or 4 chemotherapy-associated adverse events was higher in patients assigned to gastrectomy plus chemotherapy than in those assigned to chemotherapy alone: leucopenia (14 patients [18%] vs two [3%]), anorexia (22 [29%] vs nine [12%]), nausea (11 [15%] vs four [5%]), and hyponatraemia (seven [9%] vs four [5%]). One treatment-related death occurred in a patient assigned to chemotherapy alone (sudden cardiopulmonary arrest of unknown cause during the second cycle of chemotherapy) and one occurred in a patient assigned to chemotherapy plus gastrectomy (rapid growth of peritoneal metastasis after discharge 12 days after surgery). Interpretation Since gastrectomy followed by chemotherapy did not show any survival benefit compared with chemotherapy alone in advanced gastric cancer with a single non-curable factor, gastrectomy cannot be justified for treatment of patients with these tumours. Funding The Ministry of Health, Labour and Welfare of Japan and the Korean Gastric Cancer Association.

Cardiac resynchronization therapy (CRT) has been shown to reduce the risk of death and hospitalization in patients with advanced heart failure with left ventricular dysfunction. However, controversy remains regarding who would most benefit from CRT. We performed a meta-analysis, and meta-regression in an attempt to identify factors that determine the outcome after CRT. A total of 23 trials comprising 10,103 patients were selected for this meta-analysis. Our analysis revealed that CRT significantly reduced the risk of all-cause mortality and hospitalization for heart failure compared to control treatment. The odds ratio (OR) of all-cause death had a linear relationship with mean QRS duration (P=0.009). The benefit in survival was confined to patients with a QRS duration ≥145 ms (OR, 0.86; 95% CI, 0.74-0.99), while no benefit was shown among patients with a QRS duration of 130 ms (OR, 1.00; 95% CI, 0.80-1.25) or less. Hospitalization for heart failure was shown to be significantly reduced in patients with a QRS duration ≥127 ms (OR, 0.77; 95% CI, 0.60-0.98). This meta-regression analysis implies that patients with a QRS duration ≥150 ms would most benefit from CRT, and in those with a QRS duration

Retrospective cohort study of a nationwide database.The primary objective was to summarize the use of surgical methods for lumbar herniated intervertebral disc disease (HIVD) at two different time periods under the national health insurance system. The secondary objective was to perform a cost-effectiveness analysis by utilizing incremental cost-effectiveness ratio (ICER).The selection of surgical method for HIVD may or may not be consistent with cost effectiveness under national health insurance system, but this issue has rarely been analyzed.The data of all patients who underwent surgeries for HIVD in 2003 (n = 17,997) and 2008 (n = 38,264) were retrieved. The surgical methods included open discectomy (OD), fusion surgery, laminectomy, and percutaneous endoscopic lumbar discectomy (PELD). The hospitals were classified as tertiary-referral hospitals (≥300 beds), medium-sized hospitals (30-300 beds), or clinics (30 beds). ICER showed the difference in the mean total cost per 1% decrease in the reoperation probability among surgical methods. The total cost included the costs of the index surgery and the reoperation.In 2008, the number of surgeries increased by 2.13-fold. The number of hospitals increased by 34.75% (731 in 2003 and 985 in 2008). The proportion of medium-sized hospitals increased from 62.79% to 70.86%, but the proportion of surgeries performed at those hospitals increased from 61.31% to 85.08%. The probability of reoperation was highest after laminectomy (10.77%), followed by OD (10.50%), PELD (9.20%), and fusion surgery (7.56%). The ICERs indicated that PELD was a cost-effective surgical method. The proportion of OD increased from 71.21% to 84.12%, but that of PELD decreased from 16.68% to 4.57%.The choice of surgical method might not always be consistent with cost-effectiveness strategies, and a high proportion of medium-sized hospitals may be responsible for this change.4.

The presence of a telomerase reverse transcriptase (TERT) promoter mutation has been suggested as a potential prognostic marker for thyroid cancer, and a synergistic association with the BRAFStudies of the association of BRAFThirteen eligible studies incorporating 4347 patients with PTC were included, and 283 (median 8.3%) of these patients had coexistent BRAFCoexistent BRAF

SPIRIT checklist. (DOC 126 kb)