Distinct time trends in colorectal cancer incidence in countries with SDI levels from 1990 to 2019: an age-period-cohort analysis for the Global Burden of Disease 2019 study.

Introduction: The burden of colorectal cancer (CRC) plays a pivotal role in the global cancer epidemic. Our study reported the incidence trends in CRC and the associated effects of age, period, and birth cohort in 204 countries and territories over the past 30 years. Methods: The incidence data of CRC were extracted from the Global Burden of Disease Study (GBD) 2019. We performed the age-period-cohort (APC) model to estimate the overall annual percentage change (net drift) in the incidence rate, the annual percentage change by age group (local drift), and the relative risk (period and cohort effects) of the period and cohort in CRC during 1990-2019. This approach allows examining and distinguishing age, period, and cohort effects in incidence and potentially distinguishing colorectal cancer gaps in prevention and screening. Results: In 2019, the incidence of CRC was 2.17 (95% UI 2.00-2.34) million, of which China, the United States of America, and Japan had the highest incidence population, accounting for 45.9% of the global population. The age-standardized incidence rate (ASIR) was 26.7 (95% UI 28.9-24.6) per 100,000 people, of which 30 countries had an incidence rate greater than 40.0 per 100,000 people. From 1990 to 2019, the middle SDI region had the largest increase in incidence rate, with a net drift of 2.33% (95% CI 2.2-2.46%, p < 0.001). Globally, the incidence population was concentrated in the age group of 50-69 years, and the age group of 30-34 years had the largest increase in incidence rate (local drift 1.19% (95% CI 1.01-1.37%)). At the same time, the sex and age distributions of CRC incidence had significant heterogeneity across regions and countries. In the past 30 years, the incidence rate in 31 countries has been well controlled (net drift <0), and most of them were concentrated in high-and high-middle-SDI regions, such as Australia, Czechia, and Belgium, and the relative risk of incidence generally improved over time and consecutive young birth cohorts. CRC incidence showed an unfavorable trend (net drift ≥1%) in 89 countries, of which 27 countries were more significant (net drift >2%), mostly concentrated in the middle SDI region, such as China, Mexico, and Brazil, and the risk of period and birth cohort was unfavorable. Conclusion: Globally, the incidence of CRC has shown an overall upward trend over the past 30 years, with the exception of some countries with higher SDI values. Significant age-period-cohort differences were observed in the risk of incidence in CRC worldwide. Effective prevention and control policies need to take into account the age-period-cohort effect characteristics of different regions.

Multi-step validation of a deep learning-based system with visual explanations for optical diagnosis of polyps with advanced features.

Artificial intelligence (AI) has been found to assist in optical differentiation of hyperplastic and adenomatous colorectal polyps. We investigated whether AI can improve the accuracy of endoscopists' optical diagnosis of polyps with advanced features. We introduced our AI system distinguishing polyps with advanced features with more than 0.870 of accuracy in the internal and external validation datasets. All 19 endoscopists with different levels showed significantly lower diagnostic accuracy (0.410-0.580) than the AI. Prospective randomized controlled study involving 120 endoscopists into optical diagnosis of polyps with advanced features with or without AI demonstration identified that AI improved endoscopists' proportion of polyps with advanced features correctly sent for histological examination (0.960 versus 0.840, p < 0.001), and the proportion of polyps without advanced features resected and discarded (0.490 versus 0.380, p = 0.007). We thus developed an AI technique that significantly increases the accuracy of colorectal polyps with advanced features.

Assessing Global, Regional, and National Time Trends and Associated Risk Factors of the Mortality in Ischemic Heart Disease Through Global Burden of Disease 2019 Study: Population-Based Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of death among noncommunicable diseases worldwide, but data on current epidemiological patterns and associated risk factors are lacking. OBJECTIVE: This study assessed the global, regional, and national trends in IHD mortality and attributable risks since 1990. METHODS: Mortality data were obtained from the Global Burden of Disease 2019 Study. We used an age-period-cohort model to calculate longitudinal age curves (expected longitudinal age-specific rate), net drift (overall annual percentage change), and local drift (annual percentage change in each age group) from 15 to >95 years of age and estimate cohort and period effects between 1990 and 2019. Deaths from IHD attributable to each risk factor were estimated on the basis of risk exposure, relative risks, and theoretical minimum risk exposure level. RESULTS: IHD is the leading cause of death in noncommunicable disease-related mortality (118.1/598.8, 19.7%). However, the age-standardized mortality rate for IHD decreased by 30.8% (95% CI -34.83% to -27.17%) over the past 30 years, and its net drift ranged from -2.89% (95% CI -3.07% to -2.71%) in high sociodemographic index (SDI) region to -0.24% (95% CI -0.32% to -0.16%) in low-middle-SDI region. The greatest decrease in IHD mortality occurred in the Republic of Korea (high SDI) with net drift -6.06% (95% CI -6.23% to -5.88%), followed by 5 high-SDI nations (Denmark, Norway, Estonia, the Netherlands, and Ireland) and 2 high-middle-SDI nations (Israel and Bahrain) with net drift less than -5.00%. Globally, age groups of >60 years continued to have the largest proportion of IHD-related mortality, with slightly higher mortality in male than female group. For period and birth cohort effects, the trend of rate ratios for IHD mortality declined across successive period groups from 2000 to 2004 and birth cohort groups from 1985 to 2000, with noticeable improvements in high-SDI regions. In low-SDI regions, IHD mortality significantly declined in female group but fluctuated in male group across successive periods; sex differences were greater in those born after 1945 in middle- and low-middle-SDI regions and after 1970 in low-SDI regions. Metabolic risks were the leading cause of mortality from IHD worldwide in 2019. Moreover, smoking, particulate matter pollution, and dietary risks were also important risk factors, increasingly occurring at a younger age. Diets low in whole grains and legumes were prominent dietary risks in both male and female groups, and smoking and high-sodium diet mainly affect male group. CONCLUSIONS: IHD, a major concern, needs focused health care attention, especially for older male individuals and those in low-SDI regions. Metabolic risks should be prioritized for prevention, and behavioral and environmental risks should attract more attention to decrease IHD mortality.

Nickel-Catalyzed Enantioselective Synthesis of Dienyl Sulfoxide.

Sulfoxides are widely used in the pharmaceutical industry and as ligands in asymmetric catalysis. However, the efficient asymmetric synthesis of this structural motif remains limited. In this study, we disclosed a Ni-catalyzed enantioconvergent reaction that utilizes both racemic allenyl carbonates and ß-sulfinyl esters. Our method employs cheap and more sustainable Ni(II) as a precatalyst and successfully overcomes the challenging poisoning effect and instability of sulfenate generated in situ. This enables the synthesis of a series of dienyl sulfoxides with enantioselectivity of up to 98 % ee. The product exhibits tremendous potential in various applications, including diastereoselective Diels-Alder reactions, coordination with transition metals, and incorporation into medicinal compounds, among others. Using a combination of experimental and computational methods, we have uncovered an interesting associated outersphere mechanism that contrasts with conventional mechanisms commonly observed in asymmetric transition metal catalysis.

Personalized radiomics signature to screen for KIT-11 mutation genotypes among patients with gastrointestinal stromal tumors: a retrospective multicenter study.

OBJECTIVES: Gastrointestinal stromal tumors (GISTs) carrying different KIT exon 11 (KIT-11) mutations exhibit varying prognoses and responses to Imatinib. Herein, we aimed to determine whether computed tomography (CT) radiomics can accurately stratify KIT-11 mutation genotypes to benefit Imatinib therapy and GISTs monitoring. METHODS: Overall, 1143 GISTs from 3 independent centers were separated into a training cohort (TC) or validation cohort (VC). In addition, the KIT-11 mutation genotype was classified into 4 categories: no KIT-11 mutation (K11-NM), point mutations or duplications (K11-PM/D), KIT-11 557/558 deletions (K11-557/558D), and KIT-11 deletion without codons 557/558 involvement (K11-D). Subsequently, radiomic signatures (RS) were generated based on the arterial phase of contrast CT, which were then developed as KIT-11 mutation predictors using 1408 quantitative image features and LASSO regression analysis, with further evaluation of its predictive capability. RESULTS: The TC AUCs for K11-NM, K11-PM/D, K11-557/558D, and K11-D ranged from 0.848 (95% CI 0.812-0.884), 0.759 (95% CI 0.722-0.797), 0.956 (95% CI 0.938-0.974), and 0.876 (95% CI 0.844-0.908), whereas the VC AUCs ranged from 0.723 (95% CI 0.660-0.786), 0.688 (95% CI 0.643-0.732), 0.870 (95% CI 0.824-0.918), and 0.830 (95% CI 0.780-0.878). Macro-weighted AUCs for the KIT-11 mutant genotype ranged from 0.838 (95% CI 0.820-0.855) in the TC to 0.758 (95% CI 0.758-0.784) in VC. TC had an overall accuracy of 0.694 (95%CI 0.660-0.729) for RS-based predictions of the KIT-11 mutant genotype, whereas VC had an accuracy of 0.637 (95%CI 0.595-0.679). CONCLUSIONS: CT radiomics signature exhibited good predictive performance in estimating the KIT-11 mutation genotype, especially in prediction of K11-557/558D genotype. RS-based classification of K11-NM, K11-557/558D, and K11-D patients may be an indication for choice of Imatinib therapy.

Overexpression of RAB31 in gastric cancer is associated with released exosomes and increased tumor cell invasion and metastasis.

BACKGROUND: Gastric cancer (GC) is one of most common cancers worldwide. Several studies have suggested that Rab31 functions as a membrane vesicle transport regulator; however, the mechanism by which RAB31 regulates exosome secretion and promotes metastasis remains to be clarified. METHODS: We examined the expression of RAB31 protein and mRNA in GC tissue samples via immunohistochemistry and reverse transcription-polymerase chain reaction assays, respectively. We elucidated the function of RAB31 in GC cells by constructing a cell model and a pulmonary metastatic model of GC with overexpression of RAB31. Protein mass spectrometry was used to identify the exosomal protein. RESULTS: RAB31 expression increased at both the protein and mRNA levels with the development of GC. Cells overexpressing RAB31 showed an enhanced ability to migrate in both the in vitro cell model and the pulmonary metastatic model of GC. Exosome nanoparticle tracking analysis and electron microscopy revealed that the both the number and size of the exosomes secreted by GC cells were reduced when RAB31 expression was depleted. Injection of exosomes derived from RAB31 overexpressing cells promoted pulmonary metastasis in vivo. Analysis of the exosomal proteins revealed that PSMA1 was overexpressed in GC tissue in accordance with RAB31 expression. PSMA1 overexpression was highly associated with poor prognosis of GC patients. CONCLUSION: Our findings revealed a key role for RAB31 in GC metastasis through regulation of exosome secretion.

Global, regional, and national burden of chronic respiratory diseases and associated risk factors, 1990-2019: Results from the Global Burden of Disease Study 2019.

Background: The burden of chronic respiratory diseases has changed over the three decades. This study aims to describe the spatiotemporal trends of prevalence, mortality, and disability-adjusted life years (DALY) due to chronic respiratory diseases (CRDs) worldwide during 1990-2019 using data from the Global Burden of Disease Study 2019 (GBD 2019). Methods: The prevalence, mortality, and DALY attributable to CRDs and risk factors from 1990 to 2019 were estimated. We also assessed the driving factors and potentiality for improvement with decomposition and frontier analyses, respectively. Results: In 2019, 454.56 [95% uncertainty interval (UI): 417.35-499.14] million individuals worldwide had a CRD, showing a 39·8% increase compared with 1990. Deaths due to CRDs were 3.97 (95%UI: 3.58-4.30) million, and DALY in 2019 was 103.53 (95%UI: 94.79-112.27) million. Declines by average annual percent change (AAPC) were observed in age-standardized prevalence rates (ASPR) (0.64% decrease), age-standardized mortality rates (ASMR) (1.92%), and age-standardized DALY rates (ASDR) (1.72%) globally and in 5 socio-demographic index (SDI) regions. Decomposition analyses represented that the increase in overall CRDs DALY was driven by aging and population growth. However, chronic obstructive pulmonary disease (COPD) was the leading driver of increased DALY worldwide. Frontier analyses witnessed significant improvement opportunities at all levels of the development spectrum. Smoking remained a leading risk factor (RF) for mortality and DALY, although it showed a downward trend. Air pollution, a growing factor especially in relatively low SDI regions, deserves our attention. Conclusion: Our study clarified that CRDs remain the leading causes of prevalence, mortality, and DALY worldwide, with growth in absolute numbers but declines in several age-standardized estimators since 1990. The estimated contribution of risk factors to mortality and DALY demands the need for urgent measures to improve them. Systematic review registration: http://ghdx.healthdata.org/gbd-results-tool.

Nickel-catalysed enantioselective reaction of secondary phosphine oxides and activated vinylcyclopropanes.

Activated vinylcyclopropanes can form zwitterionic π-allylmetal species in the presence of transition metals and are widely used in organic synthesis. A nickel-catalyzed asymmetric allylation of secondary phosphine oxides with vinylcyclopropanes was described. Tertiary phosphine oxide products could be obtained with up to 91% yield and 92% ee.

Single-cell Transcriptomics Reveals Early Molecular and Immune Alterations Underlying the Serrated Neoplasia Pathway Toward Colorectal Cancer.

BACKGROUND & AIMS: Approximately one-third of colorectal cancers develop from serrated lesions (SLs), including hyperplastic polyp (HP), sessile serrated lesion (SSL), traditional serrated adenoma (TSA), and SSL with dysplasia (SSLD) through the serrated neoplasia pathway, which progresses faster than the conventional adenoma-carcinoma pathway. We sought to depict the currently unclarified molecular and immune alterations by the single-cell landscape in SLs. METHODS: We performed single-cell RNA sequencing of 16 SLs (including 4 proximal HPs, 5 SSLs, 2 SSLDs, and 5 TSAs) vs 3 normal colonic tissues. RESULTS: A total of 60,568 high-quality cells were obtained. Two distinct epithelial clusters with redox imbalance in SLs were observed, along with upregulation of tumor-promoting SerpinB6 that regulated ROS level. Epithelial clusters of SSL and TSA showed distinct molecular features: SSL-specific epithelium manifested overexpressed proliferative markers with Notch pathway activation, whereas TSA-specific epithelium showed Paneth cell metaplasia with aberrant lysozyme expression. As for immune contexture, enhanced cytotoxic activity of CD8+ T cells was observed in SLs; it was mainly attributable to increased proportion of CD103+CD8+ tissue-resident memory T cells, which might be regulated by retinoic acid metabolism. Microenvironment of SLs was generally immune-activated, whereas some immunosuppressive cells (regulatory T cells, anti-inflammatory macrophages, MDK+IgA+ plasma cells, MMP11-secreting PDGFRA+ fibroblasts) also emerged at early stage and further accumulated in SSLD. CONCLUSION: Epithelial, immune, and stromal components in the serrated pathway undergo fundamental alterations. Future molecular subtypes of SLs and potential immune therapy might be developed.

ERBB2 Mutations as Potential Predictors for Recurrence in Colorectal Serrated Polyps by Targeted Next-Generation Sequencing.

Background: Follow-up guidelines for serrated polyps (SPs) are mainly based on factors such as histology and size with limited evidence. The underlying genomic mechanism of SPs in relation to recurrence risks is utterly unknown. Methods: We applied targeted next-generation sequencing (NGS) approach on two groups of SPs [polyp-relapsed SPs (PRSPs) vs. polyp-free SPs (PFSPs)] based on the surveillance outcomes to compare differences of DNA variants in 71 colorectal cancer-associated genes. A multicenter validation cohort was established longitudinally from 2016 to 2019 to confirm the relevant results. Results: Among the 96 NGS samples, at least one mutant after filtration was detected in 90 samples (94%). Molecular profiling presented BRAF, KRAS, and APC as top 3 mutated genes. FBXW7, MSH2, and ERBB2 might be recurrence-relevant, while DMD, BRCA1, and BRCA2 might be negatively correlated with recurrence. Notably, ERBB2 mutants (R678Q and V842I) (n = 5) had higher risks of polyp recurrence than the wild types (n = 85), with a median polyp-free interval of 15 months compared to 26 months [P < 0.001; hazard ratio (HR) = 4.9; 95% confidence interval (CI) = 1.9-12.8]. Furthermore, a multicenter cohort composed by 321 SPs verified that ERBB2-mutated SPs had increased risks of polyp recurrence (P < 0.001; HR = 3.7; 95% CI = 2.3-6.0) and advanced neoplastic lesion (ANL) recurrence (P < 0.001; HR = 10.0; 95% CI = 2.7-36.9) compared with wild-type SPs, respectively. Conclusions: Our results are emphasizing that SP individuals with ERBB2 mutants are at higher risks of subsequent colorectal neoplasms. ERBB2 mutants might work as facilitated markers for prediction of high-risk SPs and might implicate a potential mechanism in the serrated pathway to colorectal carcinoma (CRC).

Influence of early colorectal cancer component on the positive margins after endoscopic resection: a retrospective study.

BACKGROUND: Endoscopic treatment methods for early colorectal cancer (ECRC) mainly depend on the size and morphology. It is unclear whether different endoscopic resection methods could achieve curative resection for ECRC confined in the mucosa. The study was designed to compare the rate of positive vertical margin (VM) of ECRC with advanced adenomas (AAs) including adenoma > 1 cm, villous adenoma, high-grade intraepithelial neoplasia/dysplasia stratified by different endoscopic resection methods. METHODS: Rate of positive VM for 489 ECRCs including Intramucosal (pTis) and superficial submucosal invasion (pT1) carcinomas were compared with those of 753 AAs stratified by different endoscopic resection methods using Chi-squared test. Multivariate logistic model was performed to investigate the risk factors of positive VM for different endoscopic resection methods. RESULTS: The pTis ECRC exhibited a similar rate of positive VM as that of AAs for en bloc hot snare polypectomy (HSP, 0% Vs. 0.85%, P = 0.617), endoscopic mucosal resection (EMR, 0.81% vs. 0.25%, P = 0.375) and endoscopic submucosal dissection (ESD, 1.82% Vs. 1.02%, P = 0.659). The pTis carcinoma was not found to be a risk factor for positive VM by en bloc EMR (P = 0.349) or ESD (P = 0.368). The en bloc resection achieved for pT1a carcinomas exhibited similar to positive VM achieved through ESD (2.06% Vs. 1.02%, P = 1.000) for AAs. Nonetheless, EMR resulted in higher risk of positive VM (5.41% Vs. 0.25%, P < 0.001) for pT1a carcinomas as compared to AAs. The pT1a invasion was identified as a risk factor for positive VM in polyps with en bloc EMR (odds ratio = 23.90, P = 0.005) but not ESD (OR = 2.96, P = 0.396). CONCLUSION: Collectively, the pTis carcinoma was not found to be a risk factor for positive VM resected by en bloc HSP, EMR or ESD. Additionally, ESD may be preferred over EMR for pT1a carcinomas with lower rate of positive VM.

Long- and short-term outcomes of early gastric cancer after endoscopic resection: a retrospective study from China.

Background and study aims The aim of the study was to evaluate short- and long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in China because no study has yet been conducted to confirm its effectiveness in EGC in China. Patients and methods A total of 570 EGC samples from 537 patients were collected for evaluation of en bloc, complete, and curative resection using ESD. Data from 302 patients with at least 3 years of active follow-up were collected for analysis of recurrence of EGC and occurrence of metachronous GC (MGC). Short- and long-outcomes of mixed-type and pure differentiated EGC were also compared. Results En bloc resection rates of 96.0 %, 98.7 %, and 95.2 %, complete resection rates of 91.2 %, 96.6 % and 90.8 %, and curative resection rates of 83.0 %, 96.2 % and 88.2 % were achieved in all EGCs included in the study, those with absolute indication, and those with expanded indication, respectively. As a long-term outcome, recurrence was observed in 1.3 % of patients, 3-year and 5-year recurrence rates being 0.7 % and 1.2 %, respectively. Thirteen patients (4.3 %) exhibited MGCs during follow-up, all of which were resected in a second ESD. Conclusions The effectiveness of ESD for EGC in China was confirmed, with satisfactory short- and long-term outcomes. With scheduled follow-up, the outcomes for mixed-type EGC can be similar to those for pure differentiated EGC after complete resection without development of lymphovascular invasion.

Evaluation of preoperative dry eye in people undergoing corneal refractive surgery to correct myopia.

AIM: To investigate the incidence of preoperative dry eye and related factors in patients undergoing corneal refractive surgery to correct myopia. METHODS: A total of 141 patients with myopia who underwent corneal refractive surgery were surveyed by questionnaires, tear film break-up time (BUT) test, Schimer I test (SIt), corneal fluorescein staining (FL) test and diagnosed according to the currently recognized domestic diagnostic criteria for dry eye. Correlation analysis of factors such as age, gender, regular wearing of contact lens (CL), diopter (spherical equivalent), corneal thickness, and corneal curvature that may affect the onset of dry eye was carried out to clarify the main influencing factors. RESULTS: There were 64 patients (45.39%) diagnosed with dry eye. The male patients (20.31%) was significantly less than that of non-dry eye subjects (41.56%; χ 2=7.260, P=0.007); the proportion of patients with dry eye wearing CL (81.25%) was significantly higher than that of non-dry eye subjects (51.95%; χ 2=13.234, P<0.001); the median diopter level of dry eye patients was -6.59 (IQR: -8.87, -4.58) D, and the median diopter level of non-dry eye subjects was -5.69 (IQR: -7.15, -4.03) D. The diopter level of dry eye patients was significantly higher (Z=-2.086, P=0.019). However, the age, best corrected visual acuity, and intraocular pressure of dry eye patients were not statistically different from those of non-dry eye subjects (t=-0.257, -0.383 and 0.778, P=0.798, 0.702, and 0.438); the corneal thickness and corneal curvature (K1 and K2) were also not statistically different either (Z=-1.487, -1.036 and -1.707, P=0.137, 0.300, and 0.088). The research further analyzes the three significant factors in the single factor analysis (gender, CL wear, and diopter) in a multi-factor way: CL wear and diopter were the influencing factors of dry eye disease. Among them, CL wear increased the risk of dry eye by 2.934 times compared with no CL wear; for every 1 D increase in diopter, the risk of dry eye increased by 0.761 times. CONCLUSION: Preoperative dry eye is relatively common in patients who undergo corneal refractive surgery to correct myopia, especially in patients who have a history of CL wear and a high diopter level before surgery. Therefore, it is necessary to carry out preoperative screening and timely treatment of dry eye to obtain the best treatment outcome and postoperative satisfaction.

Neo-adjuvant radiation therapy provides a survival advantage in T3-T4 nodal positive gastric and gastroesophageal junction adenocarcinoma: a SEER database analysis.

BACKGROUND: Due to negative results in clinical trials of postoperative chemoradiation for gastric cancer, at present, there is a tendency to move chemoradiation therapy forward in gastric and gastroesophageal junction (GEJ) adenocarcinoma. Several randomized controlled trials (RCTs) are currently recruiting subjects to investigate the effect of neo-adjuvant radiotherapy (NRT) in gastric and GEJ cancer. Large retrospective studies may be beneficial in clarifying the potential benefit of NRT, providing implications for RCTs. METHODS: We retrieved the clinicopathological and treatment data of gastric and GEJ adenocarcinoma patients who underwent surgical resection and chemotherapy between 2004 and 2015 from Surveillance, Epidemiology, and End Results (SEER) database. We compared survival between NRT and non-NRT patients among four clinical subgroups (T1-2N-, T1-2N+, T3-4N-, and T3-4N+). RESULTS: Overall, 5272 patients were identified, among which 1984 patients received NRT. After adjusting confounding variables, significantly improved survival between patients with and without NRT was only observed in T3-4N+ subgroup [hazard ratio (HR) 0.79, 95% confidence interval (CI): 0.66-0.95; P = 0.01]. Besides, Kaplan-Meier plots showed significant cause-specific survival advantage of NRT in intestinal type (P <  0.001), but not in diffuse type (P = 0.11) for T3-4N+ patients. In the multivariate competing risk model, NRT still showed survival advantage only in T3-4 N+ patients (subdistribution HR: 0.77; 95% CI: 0.64-0.93; P = 0.006), but not in other subgroups. CONCLUSIONS: NRT might benefit resectable gastric and GEJ cancer patients of T3-4 stages with positive lymph nodes, particularly for intestinal-type. Nevertheless, these results should be interpreted with caution, and more data from ongoing RCTs are warranted.

Patterns of Lymph Node Metastasis in Patients With T1/T2 Gastroduodenal Neuroendocrine Neoplasms: Implications for Endoscopic Treatment.

Guidelines have differed in their opinion regarding the indications for endoscopic resection of gastric-neuroendocrine neoplasms (g-NENs) and duodenal-NENs (d-NENs). We examined the association between size and lymph node metastasis (LNM) to identify candidates most suitable for endoscopic resection. We identified 706 patients with T1/T2 g-NENs and 621 patients with T1/T2 d-NENs from the SEER database. The prevalence of LNM and risk factors associated with LNM were analyzed. LNM was present in 8.1% of patients with gastroduodenal neuroendocrine tumors (NETs) and 31.6% of patients with neuroendocrine carcinomas (NECs). Multivariate logistic regression indicated that tumor size >10mm, greater invasion depth, and poor differentiation were independently associated with LNM. In addition, the percentage of g-NETs invading submucosa with LNM increased with tumor size (≤10 mm,3.9%;11-20 mm,8.6%;>20 mm,16.1%). However, in contrast to the low LNM risk in patients with small g-NETs (≤10 mm), we found that LNM rate exceeded 5% even for patients with small submucosal-infiltrating d-NETs. Among patients with nodal-negative g-NETs, the cause specific survival (CSS) was similar for those who received surgical resection and endoscopic resection. Among patients with d-NETs, the CSS was better for those who received endoscopic resection. In conclusion, patients with d-NETs had a higher probability of LNM than those with g-NETs. Endoscopic resection can be utilized for curative treatment of submucosa-infiltrating g-NETs and intramucosal d-NETs when the size is 10 mm or less. These results reinforce the need to search for LNM in lesions that are larger than 10 mm.

Efficacy and safety of ultrasound-guided above-knee lateral approach for popliteal sciatic nerve block in surgeries below the knee: a randomized controlled trial.

BACKGROUND: Ultrasound guidance has become a standard method for detection of nerve structures in regional anesthesia. During ultrasound-guided blockade, to identify anatomical structures is crucial but can be challenging. In clinical practice, we find a wide difference in the visibility score of the sciatic nerve (SN) through different approaches. This study aimed to compare SNB through the anterior and above-knee lateral approach in terms of identification ease, performance efficacy, and safety. METHODS: Patients scheduled for below-knee surgery were randomized to either receive SNB using the above-knee lateral approach (Group L, n=27) or the anterior approach (Group A, n=26). The primary outcome was the visibility score of SN. Secondary outcomes included the time taken to identify the SN, nerve depth, success rate of SN identification, number of needle passes, time to elicit foot flexion, needle depth, and occurrence of SNB complications. Additionally, the sensory block onset and analgesia duration were assessed. RESULTS: We included 53 adult patients. Compared with Group A, Group L showed a higher SN visibility score [3.25 (3.17, 3.67) vs. 2.50 (1.86, 2.68), P<0.001]. The scan time was significantly shorter in Group L [8.70 (6.01) s vs. 31.54 (11.87) s, P<0.001]. The depth of the SN was 3.20 (0.56) cm in Group L and 5.53 (0.84) cm in Group A (P<0.001), and the needle insertion depth was 7.15 (0.90) cm in group L and 8.32 (1.13) cm in Group A (P<0.001). The number of needle passes was less in Group L, as well as the time to elicit foot flexion, and the time taken to perform the SN block (all P<0.001). The success rate of SN identification was non-significantly higher in Group L. There was no significant between-group difference in the onset of sensory block, as well as postoperative analgesia duration. None of the approaches involved acute systemic toxicity and hematoma occurrence. CONCLUSIONS: Based on the visibility score, the above-knee lateral approach allowed easy SN identification and safe SNB. Using the ultrasound-guided above-knee lateral approach for SNB in below-knee surgeries could be a reliable choice.

Specific epigenetic age acceleration patterns among four molecular subtypes of gastric cancer and their prognostic value.

Aims: To determine the association of the methylation age (Horvath epigenetic clock) of gastric cancer (GC) tissues with molecular subtypes and patient survival. Materials & methods: Multivariate regression models were used to determine the association of methylation age acceleration (AA) with the clinical and molecular characteristics of 333 GC patients. Results: Relative to the chromosomal instability subtype, the epigenetic AA was 49.8 (95% CI: 42.7-56.9) years for Epstein-Barr virus, 16.1 (10.6-21.6) years for microsatellite instability, and 6.05 (0.1-11.1) years for genomic stability subtype. GC patients with accelerated aging of tumor tissues had better outcomes (adjusted hazard ratio: 3.13; p = 0.03). Differentially methylated probes in patients with accelerated and decelerated methylation aging enriched in pathways including BMP signaling, HMGB1 signaling, STAT3 signaling and human embryonic stem cell pluripotency. Conclusions: Our results highlight the prognostic value of epigenetic AA in GC and suggest that epigenetic AA is also an indicator of molecular subtype in GC.

Poorly differentiated is more significant than signet ring cell component for lymph node metastasis in mixed-type early gastric cancer: a retrospective study from a large-volume hospital.

OBJECTIVE: The purpose of this study was to explore the role of different undifferentiated components in the lymph node metastasis (LNM) of early mixed gastric cancer. METHODS: A total of 1596 patients with EGC who underwent gastrectomy were divided into four types: pure differentiated (PD), pure poorly differentiated (Poorly D), pure signet ring cell carcinoma (SRC), and mixed. Mixed type was classified into four subtypes: differentiated-predominant type mixed with poorly differentiated component (MD-P), poorly differentiated-predominant type mixed with differentiated component (MP-D), differentiated-predominant type mixed with SRC component (MD-S), and poorly differentiated-predominant type mixed with SRC component (MP-S). We analyzed the clinicopathological differences between all types and the rates of LNM of patients fulfilling endoscopic submucosal dissection (ESD) criteria. RESULTS: LNM was more common in mixed (21.9%) than in PD (7.5%, P < 0.001) or SRC (11.3%, P < 0.001). When analyzed the subgroups of mixed type, LNM was more frequent in MD-P (15.4%) than in PD (7.5%, P = 0.003). LNM in MD-S (7.4%, P = 1.000) was not higher than in PD. MP-S (24.5%) showed a higher rate of LNM than SRC (11.3%, P < 0.001) rather than Poorly-D (22.7%, P = 0.681). For lesions satisfying ESD criteria, MD-S (0%, P = 1.000), and MD-P (5.9%, P = 0.12) did not have higher rates of LNM than PD (1.4%). CONCLUSION: The presence of poorly differentiated component but not SRC increases the LNM rate of mixed type. ESD is recommended for the treatment of MD-S and MD-P consistent with ESD criteria.

Personalized four-category staging for predicting prognosis in patients with small bowel Adenocarcinoma: an international development and validation study.

BACKGROUND: Log odds of positive lymph nodes (LODDS) classification showed superiority over 8th edition N staging in predicting survival of small bowel adenocarcinoma (SBA) patients. The aim of this study was to develop and validate the Tumor, LODDS, and Metastasis (TLM) staging of SBA. METHODS: Totally 1789 SBA patients from the Surveillance, Epidemiology, and End Results (SEER) database between 1988-2010, 437 patients from SEER database between 2011-2013 and 166 patients from multicenters were categorized into development, validation and test cohort, respectively. The TLM staging was developed in the development cohort using Ensemble Algorithm for Clustering Cancer Data (EACCD) method. C-index was used to assess the performance of the TLM staging in predicting cancer-specific survival (CSS) and was compared with the traditional 8th edition TNM staging. FINDINGS: Four-category TLM staging designed for the development cohort showed higher discriminatory power than TNM staging in predicting CSS in the development cohort (0.682 vs. 0.650, P < 0.001), validation cohort (0.682 vs. 0.654, P = 0.022), and test cohort (0.659 vs. 0.611, P = 0.023), respectively. TLM staging continued to show its higher predictive efficacy than the 8th TNM in TNM stage II/III patients or in patients with lymph node yield less than 8. INTERPRETATION: TLM staging showed a better prognostic performance than the 8th TNM staging especially TNM stage II/III or patients with lymph node yield less than 8 and therefore, could serve to complement the TNM staging in patients with SBA. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.