Public Support for Tobacco Endgame Policies: A Systematic Review and Meta-analysis.

INTRODUCTIONS: An increasing number of countries are adopting the tobacco endgame goal. High levels of public support can accelerate momentum towards implementing tobacco endgame policies. We aimed to conduct a systematic review of public support for tobacco endgame policies and to examine the geographical distribution of studies, support among key populations (adolescents and young adults, people who smoke), and the association between survey design and support. METHODS: We searched Embase, PubMed, Scopus, Web of Science, and Google Scholar for studies published from 2013 onwards. Google was used to search the grey literature. The reference lists of included articles were hand-searched. Studies were included if they reported the proportions of people supporting one or more endgame policies. Risk of bias was assessed using the JBI checklist for prevalence studies. RESULTS: Forty-seven articles were included. Aotearoa/New Zealand and the United States were the countries with the most studies (n=11, respectively). Three-level meta-analyses showed the highest support for mandating a very low nicotine content in tobacco products (76%, 95% CI 61-87%). Meta-regressions were performed to assess the associations of population subgroup and survey design with support levels. The level of support was lower among people who smoke compared to the general population (ß range: -1.59 to -0.51). Support for some policies was lower when neutral or don't know response options were included. CONCLUSIONS: Public support for most tobacco endgame policies was high. IMPLICATIONS: Assessing public support can assist with progressing tobacco endgame policies. Policies that are widely supported by the public may be more politically feasible to implement. Qualitative studies and trial studies can further inform communication and implementation strategies for tobacco endgame policies.

Decrease in household secondhand smoking among Korean adolescents associated with smoke-free policies: grade-period-cohort and interrupted time series analyses.

OBJECTIVES: Smoke-free areas have expanded and related campaigns have been implemented since 1995 in Korea. As a result, household secondhand smoke (SHS) exposure has decreased over the past 15 years. We assessed the cohort effect, the effect of a 2008 campaign on household SHS exposure, and the impact of a complete smoking ban in public places along with increased penalties, as implemented in December 2011. METHODS: Nationally representative cross-sectional 15-wave survey data of Korean adolescents were used. The 810,516 participants were classified into 6 grade groups, 15 period groups, and 20 middle school admission cohorts. An age-period-cohort analysis, conducted with the intrinsic estimator method, was used to assess the cohort effect of household SHS exposure, and interrupted-time series analyses were conducted to evaluate the effects of the smoke-free policy and the campaign. RESULTS: For cohorts who entered middle school from 2002 to 2008, the risk of household SHS exposure decreased among both boys and girls. Immediately after implementation of the smoke-free policy, the prevalence of household SHS exposure by period decreased significantly for boys (coefficient, -8.96; p<0.05) and non-significantly for girls (coefficient, -6.99; p=0.07). After the campaign, there was a significant decrease in household SHS exposure by cohort among boys, both immediately and post-intervention (coefficient, -4.84; p=0.03; coefficient, -1.22; p=0.02, respectively). CONCLUSIONS: A school-admission-cohort effect was found on household SHS exposure among adolescents, which was associated with the smoke-free policy and the campaign. Anti-smoking interventions should be implemented consistently and simultaneously.

Corrigendum: Modeling the future of tobacco control: Using SimSmoke to explore the feasibility of the tobacco endgame in Korea.

[This corrects the article DOI: 10.18332/tid/174127.].

Modeling the future of tobacco control: Using SimSmoke to explore the feasibility of the tobacco endgame in Korea.

INTRODUCTION: We used a simulation model to assess the feasibility of reaching the tobacco endgame target (reducing the smoking prevalence to below 5% by 2050) and explored potential implementation strategies. METHODS: The impact of strengthened tobacco-control policies on smoking prevalence was analyzed using Korea SimSmoke, a discrete-time Markov process. We considered the effects of various scenarios from 2023 and predictions were conducted until 2050. To confirm the stability of the results, deterministic and probabilistic sensitivity analyses were carried out by increasing and decreasing parameter estimates. RESULTS: The implementation of tobacco-control policies in accordance with the WHO MPOWER (Μonitor tobacco use and prevention policies; Protect people from tobacco smoke; Offer help to quit tobacco smoking; Warn of the dangers of tobacco; Enforce bans on tobacco advertising, promotion, and sponsorship; Raise taxes on tobacco) measures were insufficient to achieve the tobacco endgame objective of 5% by 2050. The overall predicted smoking prevalence in 2050 is 4.7% if all policies are fully implemented in accordance with the FCTC guidelines together with a complete ban on the sale of cigarettes to people born after 2003 and annual 10% increases in price. Sensitivity analyses using the varying policy effect assumptions demonstrated the robustness of the simulation results. CONCLUSIONS: For a substantive reduction in smoking prevalence, it is essential to strongly implement the MPOWER strategy. Beyond this foundational step, the eradication of smoking requires a paradigm shift in the perception of conventional tobacco-control policies, including a tobacco-free generation strategy and radical increases in the price of tobacco products.

Association between tobacco industry advertising expenses and tobacco advertising exposure among Korean adolescents.

INTRODUCTION: Monitoring the activities and impacts of tobacco industries is vital for tobacco control. Based on tobacco industry financial statements and a nationally representative survey of Korean adolescents, we examined the association between tobacco industry commercial advertising expenses and advertising exposure among Korean adolescents. METHODS: The commercial advertising expenses of three major tobacco industries in Korea (KT&G, Philip Morris Korea, and British and American Tobacco Korea) were identified in a repository (Data Analysis Retrieval and Transfer System) established by the Korean Financial Supervisory Service. The yearly advertising expenses were merged with data from the Korean Youth Risk Behavior Survey (2015-2018 and 2021, total N=309 190). We used logistic regression analyses to analyse the associations between tobacco industry advertising expenses and adolescent tobacco advertisement exposure. RESULTS: In 2021, the total advertising expenses of the three companies exceeded US$260 million, and the proportion of Korean adolescents exposed to tobacco advertisements ranged from 65.9% to 78.7% during 2015-2018 and 2021. Higher advertising expense sizes were associated with the risk of exposure to tobacco advertisements in both girls and boys, with OR of 1.009 (95% CI (1): 1.008 to 1.010) and 1.010 (95% CI: 1.009 to 1.011), respectively. CONCLUSION: Tobacco industry advertising expenses are associated with tobacco marketing exposure among adolescents. We used financial data to identify the reach of tobacco advertising among Korean adolescents. It is essential to increase tobacco industry surveillance using various data sources and to regulate tobacco advertising more strongly.

Trends in adolescent secondhand smoke exposure at home over 15 years in Korea: Inequality by parental education level.

INTRODUCTION: Low parental education level and parental smoking are major risk factors for household secondhand smoke (SHS) exposure among adolescents. We investigated the trend in household SHS exposure according to sex, school, and parental education level to determine whether the decline in household SHS exposure over time depends on parental education level. METHODS: We used cross-sectional Korea Youth Risk Behavior datasets (2006-2020; 806829 subjects were eligible). We applied binary logistic regression to assess household SHS exposure trends and evaluated the interaction between period and parental education level. RESULTS: Household SHS exposure over 15 years has declined. The difference (0.121) was the smallest for male middle school students with low-educated parents. The slope for the estimated probability of household SHS exposure among students with high-educated parents was steeper than that for those with low-educated parents, except for female high school students (difference=0.141). Students with low-educated parents were at higher risk of household SHS exposure (male middle school students, adjusted odds ratio, AOR=1.52; 95% CI: 1.47-1.56; male high school students, AOR=1.42; 95% CI: 1.38-1.47; female middle school students, AOR=1.62; 95% CI: 1.58-1.67; female high school students, AOR=1.62; 95% CI: 1.57-1.67). The interaction between parental education level and period was significant. We also found a significant interaction between parental education level and parental smoking (other × present interaction, AOR=0.64; 95% CI: 0.60-0.67; low-low × present interaction, AOR=0.89; 95% CI: 0.83-0.95). CONCLUSIONS: Changes in parental education level over time mainly contributed to changes in adolescents' household SHS exposure. Adolescents with low-educated parents were at higher risk of household SHS exposure, with a slower decline. These gaps must be considered when creating and implementing interventions. Campaigns and community programs to prevent household SHS need to be emphasized among vulnerable adolescents.

Phase II Trial of Combined Durvalumab Plus Tremelimumab with Proton Therapy for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

PURPOSE: This phase II study investigated whether durvalumab/tremelimumab with proton therapy improves the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in heavily treated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) patients. MATERIALS AND METHODS: Patients who previously received more than one chemotherapy, including at least one platinum-based regimen, and who had at least two measurable lesions were enrolled. Patients received 1,500 mg durvalumab intravenously combined with 75 mg tremelimumab intravenously every 4 weeks for four cycles followed by 1,500 mg durvalumab every 4 weeks. After one cycle of the durvalumab/tremelimumab treatment, proton therapy was given with a total dose of 25 Gy in 5 Gy daily fractions to one of the measurable lesions. We also assessed the ORR in the target lesion outside the radiation field to evaluate the abscopal effect. RESULTS: Thirty-one patients were enrolled between March 2018 and July 2020. With 8.6 months of follow-up, the ORR was 22.6% (7/31), including one complete response and six partial responses. The median OS was 8.4 months (95% confidence interval [CI], 2.5 to 14.3) and the median PFS was 2.4 months (95% CI, 0.6 to 4.2). Among the 23 evaluable patients who completed proton therapy, the ORR was 30.4% (7/23). The median OS was 11.1 months (95% CI, 6.5 to 15.8), and the median PFS was 3.7 months (95% CI, 1.6 to 5.7). Grade 3 or higher adverse events were observed in six patients (19.4%) as follows: anemia (n=1), constipation (n=1), electrolyte imbalances (n=2), hyperglycemia (n=1), and pneumonia (n=1). CONCLUSION: The combination of durvalumab/tremelimuab with proton therapy was tolerated well and had encouraging anti-tumor efficacy in non-irradiated tumor lesions of heavily treated HNSCC patients.

Tobacco consumption, sales, and output as monitoring indicators in the era of the tobacco endgame: a Korean example.

OBJECTIVES: The consumption, sales, and output of tobacco products each suggest different areas of intervention for tobacco control. In the era of the tobacco endgame, as increasingly stronger supply-side measures are implemented, multifaceted indicators that assess both supply and/or demand are required. We aimed to estimate the consumption of cigarette and heated tobacco products (HTPs) and sought agreement between the various indicators. METHODS: The annual cigarette and HTP consumption in 2014-2020 was calculated using the frequency and intensity of cigarette use from representative surveys of adults and adolescents by sex and age. Sales and output data were acquired from governmental sources. Spearman correlation coefficients and Bland-Altman plots were used to compare the indicators. RESULTS: Tobacco output, cigarette sales, and cigarette consumption were greatest in 2014. The HTP consumption calculated for 2020 was 292.28 million packs. Cigarette consumption and sales correlated significantly, as did tobacco output and tobacco sales. A Bland-Altman plot comparing the difference between cigarette consumption and sales showed that this difference was largest in 2014, immediately before cigarette prices increased. With the exception of a single year, all cigarette consumption values were within the limits of agreement for cigarette sales and tobacco output. CONCLUSIONS: Our analyses showed agreement between demand-side (tobacco consumption) and supply-side (sales and output) indicators. We recommend using all indicators to monitor the impacts of tobacco control on both demand and supply sides. The systematic use of various indicators is critical to achieve the end of the tobacco epidemic.

Neoadjuvant chemotherapy with gemcitabine and cisplatin followed by selective bladder preservation chemoradiotherapy in muscle-invasive urothelial carcinoma of bladder.

PURPOSE: To assess the safety and efficacy of gemcitabine and cisplatin as neoadjuvant chemotherapy followed by selective bladder preservation chemoradiotherapy in muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: Patients with clinical T2-T4aN0M0 MIBC eligible for radical cystectomy and cisplatin-based chemotherapy were treated with gemcitabine 1,000 mg/m² on days 1, 8 and 15, and cisplatin 70 mg/m² on day 1 every 28 days for 3 cycles. After clinical re-staging with computed tomography scans and cystoscopy, patients with clinical complete response (CR) were eligible to proceed without cystectomy and receive bladder preservation chemoradiotherapy involving weekly cisplatin 10 mg/m² and up to 70.2 Gy of radiation. The primary endpoint of the present prospective phase II study was metastasis-free survival (MFS). RESULTS: Between Oct 2017 and Nov 2019, a total of 138 MIBC patients were enrolled and treated with neoadjuvant gemcitabine/cisplatin. Neoadjuvant chemotherapy was well-tolerated, with fatigue, nausea, and pruritus being the most commonly observed adverse events. After completion of planned neoadjuvant chemotherapy, 54 patients with a clinical CR and 10 patients who did not have CR but refused surgery received bladder preservation chemoradiotherapy. With a median follow-up duration of 34 months (95% confidence interval [CI], 32%-36%), the 3-year MFS rate in 64 chemoradiotherapy patients was calculated to be 70% (95% CI, 58%-82%). CONCLUSIONS: Neoadjuvant chemotherapy followed by selective bladder preservation chemoradiotherapy based on the clinical CR was feasible and efficacious in the treatment of MIBC.

HER2 Aberrations as a Novel Marker in Advanced Biliary Tract Cancer.

HER2 aberrations have been reported as a novel biomarker in HER2-directed therapy or as a prognostic marker in various tumor types. However, in advanced biliary tract cancer (BTC), there have been few studies regarding HER2 aberrations as a biomarker. We analyzed 121 advanced BTC patients who had been treated with Gemcitabine/Cisplatin (GP) as a 1st line therapy between November 2019 and April 2021. Next-generation sequencing (NGS), namely, HER2 aberrations was performed in all patients. The TruSight™ Oncology 500 assay from Illumina was used for the NGS panel. Among 121 patients with advanced BTC, HER2 aberrations were observed in 18 patients (14.9%). For subtypes of HER2 aberrations, point mutation was observed in 5 patients (27.8%), gene amplification in 11 patients (61.1%), and both point mutation and gene amplification in 2 patients (11.1%). The frequency of HER2 aberrations was significantly different according to the primary tumor (p = 0.009). In gallbladder cancer, HER2 aberrations were observed at a relatively high frequency (36.4%). The tumor response to GP did not differ between patients with and without HER2 aberrations (33.3%, vs. 26.2%, respectively, p = 0.571). The median progression-free survival (PFS) to GP was 4.7 months (95% CI, 4.0 to 5.5 months) in patients with HER2 aberrations and 7.0 months (95% CI, 5.2 to 8.8 months) without HER2 aberrations (p = 0.776). The median overall survival (OS) was not reached and not reached in patients with and without HER2 aberrations (p = 0.739), respectively. The univariate analysis for PFS to GP and OS showed that HER2 aberrations were not an independent factor for survival. This study showed that the HER2 aberrations were observed in 14.9% of advanced BTC and were not an independent biomarker for survival.

The prevalence of homologous recombination deficiency (HRD) in various solid tumors and the role of HRD as a single biomarker to immune checkpoint inhibitors.

PURPOSE: Homologous recombination deficiency (HRD) is related to tumorigenesis. Currently, the possibility of HRD as a prognostic biomarker to immune checkpoint inhibitors is unknown. We aimed to investigate whether HRD has potential as a biomarker for immunotherapy. METHODS: The status of homologous recombination deficiency (HRD) was assessed with the next-generation sequencing (NGS) TruSight™ Oncology 500 assay in 501 patients with advanced solid tumor including gastrointestinal (GI), genitourinary (GU), or rare cancer. RESULTS: among the 501 patients, HRD was observed as follows: 74.7% (347/501) patients; GU cancer (92.0%, 23 of 25), colorectal cancer (CRC) (86.1%, 130 of 151), hepatocellular carcinoma (HCC) (83.3%, 10 of 12), pancreatic cancer (PC) (76.2%, 32 of 42), biliary tract cancer (BTC) (75.0%, 36 of 48), sarcoma (65.0%, 39 of 60), melanoma (52.4%, 11 of 21), other GI cancers (50.0%, 11 of 22), and rare cancer (50.0%, 2 of 4). Sixty-five of the 501 patients had received immune checkpoint inhibitors (ICIs) during the course of the disease. Tumor types of 65 patients treated with ICIs are as follows: melanoma (95.2%, 20 of 21), HCC (33.3%, 4 of 12), rare cancer (25.0%, 1 of 4), GC (12.2%, 14 of 116), BTC (10.4%, 5 of 48), and sarcoma (5.0%, 3 of 60). The most frequently reported mutations were BRCA2 (n = 90), ARID1A (n = 77), ATM (n = 71), BARD1 (n = 67). Patients without HRD exhibited an objective response rate (ORR) of 33.3% (4 of 12), and patients with HRD exhibited an ORR of 34.0% (18 of 53). There was no significant difference in ORR between patients with and without HRD (P = 0.967). Progression-free survival (PFS) was 6.5 months (95% CI 0.000-16.175) in patients without HRD and 4.1 months (95% CI 2.062-6.138) in patients with HRD, revealing no statistical significance (P = 0.441). CONCLUSION: Herein, we reported the status of HRD using a cancer-panel for various solid tumor patients in routine clinical practice and demonstrated that HRD as a single biomarker was not sufficient to predict efficacy of ICIs in solid tumor patients.

Tumor Mutational Burden as a Biomarker for Advanced Biliary Tract Cancer.

Background: High tumor mutational burden (TMB-H) has been reported as a predictive marker to immunotherapy or prognostic marker in various tumor types. However, there has been little study of the role of TMB-H in advanced biliary tract cancer (BTC). Methods: We analyzed 119 advanced BTC patients who received Gemcitabine/Cisplatin (GP) as a first-line treatment between November 2019 and April 2021. Next-generation sequencing (NGS), including TMB analysis, as a routine clinical practice was performed in 119 patients. The TruSightTM Oncology 500 assay from Illumina was used as a cancer panel. Results: Among 119 patients, 18 (18.5%) had a tumor with high TMB (≥ 10 Muts/Mb). There were no significant differences between the status of TMB and clinical outcomes with GP, including objective response rate (ORR) (P = .126), disease control rate (DCR) (p = .454), and median progression-free survival (PFS) (p = .599). The median overall survival (OS) was not different between patients with TMB-H and no TMB-H (p = .430). In subgroup analysis of 32 patients receiving immune checkpoint inhibitor (ICIs), there were significant differences in ORR (p = .034) and median PFS (p = .025) with ICIs between patients with and without TMB-H. Conclusions: This study revealed that TMB-H in advanced BTCs did not have a prognostic or role in the standard first-line treatment. However, TMB-H might be a predictive biomarker for response to ICIs in advanced BTC.

Fat-to-muscle Ratio: A New Indicator for Coronary Artery Disease in Healthy Adults.

Background: Coronary artery disease (CAD) is an important issue in public health. Previous studies have shown that the ratio of fat to muscle mass is a significant predictor of metabolic disease, and it is known to be associated with atherosclerosis. In this study, we evaluated the association between the fat-to-muscle ratio (FMR) and CAD in healthy adults. Methods: A total of 617 participants without diabetes mellitus, hypertension, known CAD, or stroke who visited the Health Promotion Center from 2009 to 2018 were included in this study. Computed tomography imaging and bioelectrical impedance analysis were used to ascertain the coronary artery calcium (CAC) score, degree of CAD, and FMR. Results: Univariate logistic regression analysis showed that old age, male sex, smoking history, creatinine, aspartate aminotransferase, gamma-glutamyl transferase, uric acid, total cholesterol, and low-density lipoprotein cholesterol were significantly associated with CAC. After adjusting for potential confounding covariates, the presence of CAC was independently associated with FMR (OR, 1.014; 95% CI, 1.002-1.026; p = 0.019. The association was maintained even after adjusting for body mass index and waist circumference (odds ratio, 1.019; 95% confidence interval, 1.004 -1.034; P = 0.012). Conclusion: In this study, a high FMR was significantly associated with CAC. A large-scale prospective study on the association with FMR and cardiovascular diseases is necessary to confirm this relationship.

Real-World Data from a Refractory Triple-Negative Breast Cancer Cohort Selected Using a Clinical Data Warehouse Approach.

PURPOSE: Triple-negative breast cancer (TNBC) is well known for its aggressive course and poor prognosis. In this study, we sought to investigate clinical, demographic, and pathologic characteristics and treatment outcomes of patients with refractory, metastatic TNBC selected by a clinical data warehouse (CDW) approach. PATIENTS AND METHODS: Data were extracted from the real-time breast cancer registry integrated into the Data Analytics and Research Window for Integrated Knowledge C (DARWIN-C), the CDW of Samsung Medical Center. Between January 1997 and December 2019, a TNBC cohort was searched for in the breast cancer registry, which includes records from more than 40,000 patients. Among them, cases of pathologically confirmed metastatic TNBC (mTNBC) were selected as the cohort group (n = 451). The extracted data from the registry via the CDW platform included clinical, pathological, laboratory, and chemotherapy information. Refractory TNBC was defined as confirmed distant metastasis within one year after adjuvant treatment. RESULTS: This study comprised a total of 451 patients with mTNBC, including 69 patients with de novo mTNBC, 131 patients in the nonrefractory TNBC group with confirmed stage IV disease after one year of adjuvant treatment, and 251 patients with refractory mTNBC, whose disease recurred as stage IV within one year after completing adjuvant treatment. The refractory mTNBC cohort was composed of patients with disease that recurred at stage IV after surgery (refractory mTNBC after surgery) (n = 207) and patients in whom metastasis was confirmed during neoadjuvant chemotherapy (unresectable TNBC due to progression during neoadjuvant chemotherapy) (n = 44). Patients in the refractory mTNBC group were younger than those in the nonrefractory group (median age 46 vs. 51 years; p < 0.001). Considering the pathological findings, the refractory group had a greater proportion of cases with Ki-67 ≥ 3+ than did the nonrefractory group (71% vs. 47%; p = 0.004). During a median 8.4 years of follow-up, the overall survival was 24.8 months in the nonrefractory mTNBC group and 14.3 months in the refractory mTNBC group (p < 0.001), and the median progression-free survival periods were 6.2 months and 4.2 months, respectively (p < 0.001). The median disease-free survival period was 30.1 months in the nonrefractory mTNBC group and only 7.6 months in the refractory mTNBC group. Factors related to metastatic sites affecting overall survival were liver metastasis at diagnosis (p < 0.001) and leptomeningeal involvement (p = 0.001). CONCLUSIONS: We revealed that patients with refractory mTNBC had a much poorer prognosis among all mTNBC cases and described the characteristics of this patient group.

When to apply immune checkpoint inhibitor in patients with refractory advanced gastric cancer.

Background: Immune checkpoint inhibitors (ICIs) show clinical benefit in patients with refractory advanced gastric cancer (GC). The ICIs in routine clinical practice have been used in various treatment lines. Therefore, we investigated the timing for application of ICI in patients with refractory advanced GC. Methods: We analyzed 187 patients with refractory advanced or recurrent GC who received ICIS as a 3rd- or 4th-line treatment between September 2015 and October 2020. Clinical outcomes of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were evaluated. Results: Among 187 patients, 105 received ICIs as a 3rd-line treatment and 82 as a 4th line. The ORR for ICIs was 10.5% (11/105) in 3rd line and 8.5% (7/82) in 4th line. The DCR for ICIs was 36.2% (38/105) in 3rd-line treatment and 31.7% (26/82) in 4th line. There was no significant difference for ORR (P = 0.819) or DCR (P = 0.870). The median PFS and OS to ICIs was 1.4 months (95% CI, 1.1 to 1.8 months) and 4.4 months (95% CI, 1.6 to 7.2 months) in 3rd line and 1.8 months (95% CI, 1.4 to 2.3 months) and 2.8 months (95% CI, 2.2 to 3.4 months) in 4th line. The median PFS and OS to ICIs was not different between 3rd line and 4th line (P = 0.495 and P=0.208, respectively). There were also no significant difference for PFS and OS between PD-L1-positive tumors (CPS≥1) and PD-L1-negative tumors (P = 0.910 and P=0.931, respectively). Conclusions: ICIs showed similar clinical benefits in the 3rd-line and 4th-line settings. ICIs might be a reasonable approach for patients with refractory GC in the setting of 3rd-line or 4th-line treatment options.

Clinical sequencing to assess tumor mutational burden as a useful biomarker to immunotherapy in various solid tumors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become established as a new therapeutic paradigm in various solid cancers. Predictive biomarkers to ICIs have not yet been fully established. Tumor mutational burden (TMB) has been considered as a useful marker to indicate patients who benefit from ICIs. METHODS: We performed next-generation sequencing, including TMB analysis, as a routine clinical practice in 501 patients with advanced gastrointestinal (GI), genitourinary (GU), or rare cancers. The TruSight™ Oncology 500 assay from Illumina was used as a cancer panel. RESULTS: In total, 11.6% (58/501) were identified with tumors with high TMB and MSI-high status was confirmed in seven out of 501 cases (1.4%). High TMB was observed in 11.6% of patients with various solid tumors, including: GU cancers (36.0%, 9/25), colorectal cancer (15.2%, 23/151), biliary tract cancer (14.6%, 7/48), melanoma (14.3%, 3/21), gastric cancer (11.2%, 13/116), hepatocellular carcinoma (8.3%, 1/12), other GI tract cancers (4.5%, 1/22), and sarcoma (1.7%, 1/60). The objective response rate (ORR) to ICIs was 75% (nine out of 12) in solid tumor patients with high TMB and 25% (30 out of 40) in those with non-high TMB. Patients with high TMB had better ORR to ICIs than those with non-high TMB (p = 0.004). Univariate analysis revealed that the status of PD-L1 expression and of TMB (high versus non-high) had significant association in response to ICIs. However, in multivariate analysis, the status of TMB (high versus non-high) was only significantly related to the response to ICIs (p = 0.036). CONCLUSION: In the present study, we analyzed the TMB using a cancer panel for various solid tumor patients in routine clinical practice and also demonstrated the usefulness of TMB to predict the efficacy for ICIs.

Prognostic Factors of Survival with Aflibercept and FOLFIRI (fluorouracil, leucovorin, irinotecan) as Second-line Therapy for Patients with Metastatic Colorectal Cancer.

Background: Aflibercept and fluorouracil, leucovorin, irinotecan (FOLFIRI) is commonly used as a second-line treatment for metastatic colorectal cancer (CRC). However, the biomarkers to guide the choice of this regimen from among treatment options remain unclear. Patients and Methods: We performed exploratory analyses to validate potential prognostic factors for patients receiving aflibercept plus FOLFIRI as a second-line systemic treatment for metastatic CRC between January 2015 and July 2019. Patient characteristics, histopathologic data, laboratory and radiologic data, and treatment outcomes were collected and reviewed. Results: Included were 52 patients: 50 (96.2%) received bevacizumab plus fluorouracil, leucovorin, oxaliplatin (FOLFOX) as prior first-line treatment. Among the 52 patients receiving aflibercept and FOLFIRI, four complete responses and 21 partial responses were observed in analyzed patients for an overall response rate of 48.1%. Median progression-free survival (PFS) was 7.0 months and overall survival (OS) was 16.8 months. Response to first-line treatment (median PFS, 8.0 versus 4.2 months), left-side location of primary tumor (7.9 versus 4.9 months), low baseline CEA level (8.0 versus 5.9 months), and no RAS/RAF mutation (9.9 versus 6.4 months) were remained significant prognostic factors for PFS in the multivariate backward stepwise Cox regression model, and the latter three factors were also significantly related to OS. Conclusions: Significant prognostic factors for PFS with aflibercept plus FOLFIRI as second-line therapy were extracted and validated in the multivariate OS model. These findings could provide useful information for selecting patients for aflibercept plus FOLFIRI as second-line therapy.

Subclinical Hypothyroidism Affects the Long-Term Outcomes of Patients Who Undergo Coronary Artery Bypass Grafting Surgery but Not Heart Valve Surgery.

BACKGROUND: The aim of this study was to determine the associations between subclinical hypothyroidism (SCH) and long-term cardiovascular outcomes after coronary artery bypass grafting (CABG) or heart valve surgery (HVS). METHODS: We retrospectively reviewed and compared all-cause mortality, cardiovascular mortality, and cardiovascular events in 461 patients who underwent CABG and 104 patients who underwent HVS. RESULTS: During a mean±standard deviation follow-up duration of 7.6±3.8 years, there were 187 all-cause deaths, 97 cardiovascular deaths, 127 major adverse cardiovascular events (MACE), 11 myocardial infarctions, one unstable angina, 70 strokes, 30 hospitalizations due to heart failure, 101 atrial fibrillation, and 33 coronary revascularizations. The incidence of all-cause mortality after CABG was significantly higher in patients with SCH (n=36, 55.4%) than in euthyroid patients (n=120, 30.3%), with a hazard ratio of 1.70 (95% confidence interval, 1.10 to 2.63; P=0.018) after adjustment for age, sex, current smoking status, body mass index, underlying diseases, left ventricular dysfunction, and emergency operation. Interestingly, low total triiodothyronine (T3) levels in euthyroid patients who underwent CABG were significantly associated with increased risks of all-cause mortality, cardiovascular mortality, and MACE, but those associations were not observed in HVS patients. Both free thyroxine and thyroid-stimulating hormone levels in euthyroid patients were not related with any cardiovascular outcomes in either the CABG or HVS group. CONCLUSION: SCH or low total T3 might be associated with a poor prognosis after CABG, but not after HVS, implying that preoperative thyroid hormonal status may be important in ischemic heart disease patients.

Lotus seedpod-inspired hydrogels as an all-in-one platform for culture and delivery of stem cell spheroids.

3D culture of stem cells can improve therapeutic effects. However, there is limited research on how to deliver cultured stem cell spheroids to the desired target. Here, we developed lotus seedpod-inspired hydrogel (LoSH) containing microwells for culture and delivery of stem cell spheroids. Human adipose-derived stem cells (hADSCs) inside the square microwells (200 or 400 µm in width with various depths) spontaneously formed spheroids with high viability (94.08 ±â€¯1.56%), and fibronectins conjugated to the hydrogel successfully gripped the spheroids, similar to the funiculus gripping seeds in the lotus seedpod. The spheroids slightly bound to the LoSH surface at 37 °C were detached by the expansion of LoSH at lower temperature of 4 °C. After spheroid formation, LoSH was placed on the target substrate upside-down, expanded at 4 °C for 10 min, and removed from the target. As a result, the spheroids within the microwell were successfully transferred to the target substrate with high transfer efficiency (93.78 ±â€¯2.30%). A delivery of spheroids from LoSH to full-thickness murine skin wound with chimney model showed significant enhancement of the number of SMA-positive vessels at day 21 compared to the group received the same number of spheroids by injection. Together, our findings demonstrate LoSH as a one-step platform that can culture and deliver spheroids to a large target area, which will be useful for various biomedical applications.

Medullary thymic epithelial NF-kB-inducing kinase (NIK)/IKKα pathway shapes autoimmunity and liver and lung homeostasis in mice.

Aberrant T cell development is a pivotal risk factor for autoimmune disease; however, the underlying molecular mechanism of T cell overactivation is poorly understood. Here, we identified NF-κB-inducing kinase (NIK) and IkB kinase α (IKKα) in thymic epithelial cells (TECs) as essential regulators of T cell development. Mouse TEC-specific ablation of either NIK or IKKα resulted in severe T cell-mediated inflammation, injury, and fibrosis in the liver and lung, leading to premature death within 18 d of age. NIK or IKKα deficiency abrogated medullary TEC development, and led to breakdown of central tolerance, production of autoreactive T cells, and fatal autoimmune destruction in the liver and lung. TEC-specific ablation of NIK or IKKα also impaired thymic T cell development from the double-negative through the double-positive stages and inhibited peripheral B cell development. These results unravel a hitherto unrecognized essential role of TEC-intrinsic NIK and IKKα pathways in autoimmunity and T cell-instigated chronic liver and lung diseases.