The Key Role of Tumor Budding in Predicting the Status of Lymph Node Involvement in Early Gastric Cancer Patients: A Clinical Multicenter Validation in China.

BACKGROUND: Accurate preoperative prediction of lymph node (LN) involvement is essential for the management of early gastric cancer (EGC). Our objective was to formulate a potent nomogram for predicting LN involvement in EGC by leveraging an innovative predictor of tumor budding. METHODS: We assembled a cohort of EGC patients who underwent radical surgery at two tertiary cancer centers. Tumor budding was stratified by using an optimal cutoff value and integrated with other clinicopathological variables to ascertain the risk factors associated with LN involvement. A nomogram was developed and its predictive performance was assessed by using receiver operating characteristic (ROC) curves and calibration plots. In addition, we conducted decision curve analysis to evaluate its clinical utility. Finally, an external validation was conducted by using an independent cohort. RESULTS: Finally, 307 eligible patients (215 in the primary cohort and 92 in the validation cohort) were included. Tumor budding, categorized by a count of two, exhibited a robust association with LN involvement (OR 14.12, p = 0.012). Other significant risk factors include lymphovascular invasion, depth of tumor invasion, ulceration, and tumor differentiation. Notably, the nomogram demonstrated exceptional discriminative power (area under the ROC curve, 0.872 in the primary cohort and 0.885 in the validation cohort) and precise predictive capabilities. Furthermore, the nomogram showed notable clinical applicability through decision curve analysis, particularly in endoscopic curability C-2, by mitigating the risk of overtreatment. CONCLUSIONS: Tumor budding is a robust predictor of LN involvement in EGC. The incorporation of tumor budding into a nomogram is an effective strategy, thereby informing and enhancing clinical decision-making.

Development and Validation of a Prognostic Model for Postoperative Anastomotic Recurrence in Siewert II or III Adenocarcinomas Without Neoadjuvant Therapy in an East Asian Population.

PURPOSE: Anastomotic recurrence leads to poor prognosis in patients with Siewert II or III adenocarcinoma who undergo radical gastrectomy and do not receive neoadjuvant therapy. We aimed to establish a prognostic model to evaluate the risk of postoperative anastomotic recurrence in patients with Siewert II or III adenocarcinoma who did not receive neoadjuvant therapy. METHODS: We included 366 patients with Siewert II or III adenocarcinoma who were treated with radical gastrectomy without neoadjuvant therapy at Fujian Provincial Hospital (FPH) between 2012 and 2018 as the development cohort. Cox regression was used to verify prognostic factors for anastomotic recurrence, and a nomogram was established. The nomogram was externally validated using a combined cohort of two external centers. Patients were classified into high- or low-risk groups according to the diagnostic threshold and nomogram scores, and recurrence-related survival analysis was analyzed. RESULTS: The average age was 64.6 years, and 285 patients were male. All surgeries were successfully performed (185 open vs 181 laparoscopic). The 3-year anastomotic recurrence rate was significantly lower in the low-risk group (3.5% vs 18.8%, P < 0.001). The predictive performance was verified in the external validation cohort. This model better stratified patient survival than the American Joint Committee on Cancer (AJCC) TNM staging system. CONCLUSIONS: This novel nomogram with surgical margin, postoperative tumor node metastasis (pTNM) stage, and neural invasion as prognostic factors has a significant predictive performance for the risk of anastomotic recurrence after radical gastrectomy in patients with Siewert II or III adenocarcinoma.

Discovery of CDK signature and CDK5 as potential biomarkers for predicting prognosis and immunotherapeutic response in gastric cancer peritoneal metastases.

Gastric cancer peritoneal metastases (GCPM) are a leading cause of death in gastric cancer patients. In this study, we focused on the expression of cyclin-dependent protein kinases (CDK), essential regulators of transcription, metabolism, and cell differentiation, in GCPM. Utilizing the GSE62254 cohort, we established a CDK signature (CDKS) model comprising ten CDK gene family members. Analysis of both the GSE62254 and TCGA cohorts revealed that patients with low CDKS had a worse prognosis compared to those with high CDKS. Furthermore, patients with high CDKS demonstrated positive responses from immunotherapy, as observed in the KIM cohort. We investigated the association between CDKS and the tumor microenvironment, including immune escape mechanisms. Immunohistochemistry analysis revealed a positive correlation between CDK5 and PD-L1 expression in gastric cancer. Furthermore, we found that CDK5 knockdown led to the inhibition of PD-L1 expression in gastric cancer cells. Our findings highlight the potential of CDKS as a prognostic biomarker and an indicator of immunotherapy response in gastric cancer patients. Moreover, our study suggests that targeting CDK5 could provide a new pathway for exploring immunotherapeutic research.

Nomogram based on quantitative dynamic contrast-enhanced magnetic resonance imaging, apparent diffusion coefficient, and clinicopathological features for early prediction of pathologic complete response in breast cancer patients receiving neoadjuvant chemotherapy.

Background: The aim of this study was to develop two nomograms for predicting pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) for breast cancer based on quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), apparent diffusion coefficient (ADC), and clinicopathological characteristics at two time-points: before and after two cycles of NACT, respectively. Methods: 3.0 T MRI scans were performed before and after 2 cycles of NACT in 215 patients. A total of 74 female patients with stage II-III breast cancer were included. According to univariate and multivariate logistic regression analysis, nomogram model 1 and nomogram model 2 were developed based on the independent predictors for pCR before and after 2 cycles of NACT, respectively. Nomogram performance was assessed with the area under the receiver operating characteristic curve (AUC) and calibration slope. Results: The independent predictors of pCR were different at the two time points. Both nomograms were found to effectively predict pCR: nomogram model 2 based on Ki67, ΔKtrans%, and ΔADC% after 2 cycles of NACT showed better predictive discrimination [AUC =0.900 (0.829, 0.970) vs. 0.833 (0.736, 0.930)] and calibration ability (mean absolute error of the agreement: 0.017 vs. 0.051) compared to nomogram model 1 based on pre-NACT HER2, Ki67, and Ktrans. Conclusions: Nomograms based on quantitative DCE-MRI parameters, ADC, and clinicopathological characteristics can predict pCR in breast cancer and facilitate individualized decision-making for NACT.

Intraoperative Diagnosis of Serosal Invasion in Gastric Cancer by Magnifying Endoscopy with Narrow-Band Imaging for Intraoperative Measurement Decision.

Purpose: To establish a precise diagnostic method for serosal invasion in gastric cancer (GC) during surgery using therapeutic measures, and facilitate quick decision-making. Methods: A total of 19 GC patients treated in the department of gastrointestinal surgery of Fujian Provincial Hospital between April 2019 and December 2020 were enrolled. An electronic gastroscopy with a magnifying endoscope with narrow-band imaging was used to photograph the serosal surface of the GC lesion site and the normal gastric wall around the lesion during surgery. The endoscopic diagnosis was confirmed on the basis of the microvascular phenotype of the serosal surface and validated by comparison with the pathological diagnosis. Results: Under the specific endoscopy, serosal invasion, including subserosal tissue invasion and serosal layer invasion, was diagnosed by observing the capillary morphology change, and capillary diameter and density increase. According to the pathological diagnosis, the accuracy of serosal invasion diagnosis was 94.7%, the sensitivity was 100%, the specificity was 75%, the positive predictive value was 93.8%, and the negative predictive value was 100%. To further distinguish the subserosal tissue invasion and serosal layer invasion, the magnifying endoscope with narrow-band imaging possessed a 78.9% accuracy by distinguishing irregular changes in microvessels. Conclusions: Magnifying endoscope with narrow-band imaging is less time-consuming than pathological diagnosis. Intraoperative diagnosis using microvascular observation can accurately detect serosal invasion. It is of value for the intraoperative diagnosis in GC patients.

Optimal postoperative surveillance strategies for cancer survivors with gastric neuroendocrine carcinoma based on individual risk: a multicenter real-world cohort study.

BACKGROUND: The best follow-up strategy for cancer survivors after treatment should balance the effectiveness and cost of disease detection while detecting recurrence as early as possible. Due to the low incidence of gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma [G-(MA)NEC], high-level evidence-based follow-up strategies is limited. Currently, there is a lack of consensus among clinical practice guidelines regarding the appropriate follow-up strategies for patients with resectable G-(MA)NEC. MATERIALS AND METHODS: The study included patients diagnosed with G-(MA)NEC from 21 centers in China. The random forest survival model simulated the monthly probability of recurrence to establish an optimal surveillance schedule maximizing the power of detecting recurrence at each follow-up. The power and cost-effectiveness were compared with the National Comprehensive Cancer Network, European Neuroendocrine Tumor Society, and European Society for Medical Oncology Guidelines. RESULTS: A total of 801 patients with G-(MA)NEC were included. The patients were stratified into four distinct risk groups utilizing the modified TNM staging system. The study cohort comprised 106 (13.2%), 120 (15.0%), 379 (47.3%), and 196 cases (24.5%) for modified groups IIA, IIB, IIIA, and IIIB, respectively. Based on the monthly probability of disease recurrence, the authors established four distinct follow-up strategies for each risk group. The total number of follow-ups 5 years after surgery in the four groups was 12, 12, 13, and 13 times, respectively. The risk-based follow-up strategies demonstrated improved detection efficiency compared to existing clinical guidelines. Further Markov decision-analytic models verified that the risk-based follow-up strategies were better and more cost-effective than the control strategy recommended by the guidelines. CONCLUSIONS: This study developed four different monitoring strategies based on individualized risks for patients with G-(MA)NEC, which may improve the detection power at each visit and were more economical, effective. Even though our results are limited by the biases related to the retrospective study design, we believe that, in the absence of a randomized clinical trial, our findings should be considered when recommending follow-up strategies for G-(MA)NEC.

Paper-based photoelectrochemical immunoassay for ultrasensitive screening of carcinoembryonic antigen on hollow CdS/CdMoO4-functionalized photoanode.

Lab-based testing systems utilizing photoelectrochemical (PEC) biosensing methodologies for the ultrasensitive carcinoembryonic antigen (CEA) have been developed, although the majority have shown complicated operating procedures and dependence on precise apparatus. Herein, a portable photoelectrochemical split diagnostic platform based on a hollow CdS/CdMoO4 (h-CdS@CdMoO4) shell-shell structured photoanode system was developed for ultrasensitive detection of CEA. Using a small LED flashlight as the excitation light source and a digital multimeter (DMM) as the signal readout device, real-time CEA on a paper-based printed screen electrode developed in-house was quickly detected. The composite h-CdS@CdMoO4 featured a special hollow shell-shell heterojunction structure that optimizes photon usage in the bulk phase on the one hand, and facilitates directed separation of the electrons and holes therein on the other. A split-sandwich immunoassay and detection antibodies for modified glucose oxidase were introduced into the paper-based photoanode test system, and the signals were displayed with a DMM to realize a point-of-care test for CEA. Under optimized conditions, the constructed portable PEC sensing system was sensitive to the target CEA from 0.02 to 50.0 ng mL-1 with a detection limit of 11.3 pg mL-1. Interferent experiments and stability test evaluations demonstrate the specificity and robustness of the constructed paper-based portable PEC sensor. The portable, paper-based PEC immunoassay system developed offers a fresh way of exploring affordable, approachable sensors to satisfy both the relevant community medical testing demands and hospital objectives for quick testing.

Ultrasensitive photoelectrochemical biosensing platform based target-triggered biocatalytic precipitation reactions on a flower-like Bi2O2S super-structured photoanode.

Herein, we reported a novel photoelectrochemical immunoassay method based on a target-triggered on/off signal of the ultra-structured Bi2O2S (BOS) photoanode system for the sensitive testing of carcinoembryonic antigens (CEAs) in serum samples. Well-defined three-dimensional sheet-like self-assembled flower-like Bi2O2S superstructures were obtained using a time-controlled hydrothermal method. Such well-shaped multifaceted surfaces were considered to be good laser cavity mirror surfaces for multifaceted reflection and refraction of excitation light in the material. An elegant enzyme biocatalytic strategy was introduced into the constructed detection model to sensitively detect CEAs. The substrate 4-chloro-1-naphthol (4-CN) was oxidized to 4-chloro-hexadienone (4-CD) under the formation of target-triggered immune complexes against mAb1 and peroxidase-modified mAb2. Subsequently, 4-CD produced by the biocatalytic precipitation reaction was transferred to the photoanodes of Bi2O2S nanoflowers (BOS NFs) to burst their photoelectric signals, thus achieving the quantification of CEAs. Through optimization of the conditions of the immunization protocol, a good negative photocurrent response to the target CEA was found in the wide range of 0.02-50 ng mL-1 with a detection limit of 11.2 pg mL-1. Impressively, the reported biocatalytic PEC sensing strategy on superstructures is comparable, or superior, to the gold standard ELISA kit in terms of sensitivity and the target response range. This study presents a target-mediated PEC immunoassay for biocatalytic precipitation based on a self-assembled superstructure of Bi2O2S, providing a fresh scheme for the analysis of disease-related markers.

Low FNDC5/Irisin expression is associated with aggressive phenotypes in gastric cancer.

Background: FNDC5 belongs to the family of proteins called fibronectin type III domain-containing which carry out a variety of functions. The expression of FNDC5 is associated with the occurrence and development of tumors. However, the role of FNDC5 in gastric cancer remains relatively unknown. Methods: In the research, the expression of FNDC5 and its value for the prognosis of gastric cancer patients were observed with the TCGA database and GEO datasets of gastric cancer patients. The role of FNDC5 in the regulation of gastric cancer cells proliferation, invasion, and migration was determined. WGCNA and Enrichment analysis was performed on genes co-expressed with FNDC5 to identify potential FNDC5-related signaling pathways. Meanwhile, the LASSO Cox regression analysis based on FNDC5-related genes develops a risk score to predict the survival of gastric cancer patients. Results: The expression of FNDC5 was decreased in gastric cancer tissues compared to normal gastric tissues. However, survival analysis indicated that lower FNDC5 mRNA levels were associated with better overall survival and disease-free survival in gastric cancer patients. Meanwhile, a significant negative correlation was found between FNDC5 and the abundance of CD4+ memory T cells in gastric cancer. In vitro overexpression of FNDC5 inhibits the migration and invasion of gastric cancer cells, without affecting proliferation. Finally, A two-gene risk score module based on FNDC5 co-expressed gene was built to predict the overall clinical ending of patients. Conclusion: FNDC5 is low expressed in gastric cancer and low FNDC5 predicts a better prognosis. The better prognosis of low FNDC5 expression may be attributed to the increased number of CD4+ memory activated T-cell infiltration in tumors, but the exact mechanism of the effect needs to be further explored. Overexpressing FNDC5 inhibits the invasion and migration of gastric cancer but does not affect proliferation. At last, we constructed a clinical risk score model composed of two FNDC5-related genes, and this model may help lay the foundation for further in-depth research on the individualized treatment of gastric cancer patients.

Flexible and High-Throughput Photothermal Biosensors for Rapid Screening of Acute Myocardial Infarction Using Thermochromic Paper-Based Image Analysis.

Herein, we developed a flexible, low-cost thermosensitive fiber paper for the visual display in photothermal biosensing systems for early acute myocardial infarction. The thermal signal visualization device was encapsulated with rewritable thermal fibers, which exhibited excellent stability and reversibility. The mechanism of color change in thermal paper was based on a temperature-driven reversible transformation of the structure of the dye molecule (crystalline violet lactone, CVL). It exhibits a gradation from blue to colorless at higher temperatures and gradually returns to blue when the temperature drops. Immobilization and cascade enzymatic reactions of target molecules occurred in an integrated 3D-printed detection device, a photothermal conversion process occurred under near-infrared light excitation, and the colorimetric change values of the encapsulated thermal paper were recorded and evaluated for possible pathogenicity using a smartphone. It was worth noting that the effect of the thermogenic ring-opening behavior of CVL on the macroscopic phenomenon of color change was obtained by density functional theory calculations. Under optimized conditions, the naked-eye-recognizable range of the thermal paper-based photothermal immunoassay sensor was 0.2-20 ng mL-1, This work creatively presents theoretical studies of promising thermal paper-based photothermal biosensors and provides new insights for the development of low-cost, instrument-free portable photothermal biosensors.

Construction and efficacy evaluation of an early warning scoring system for septic shock in patients with digestive tract perforation: A retrospective cohort study.

Objective: To establish an early warning scoring system for septic shock in patients with digestive tract perforation (DTP) and evaluate its diagnostic efficacy. Methods: Patients with surgically confirmed or clinically diagnosed DTP admitted to the Department of Intensive Care Medicine of Fujian Provincial Hospital from June 2012 to October 2021 were retrospectively analyzed. General demographic characteristics, perforation-related information, vital signs, common laboratory indicators, and common ICU scores (Glasgow Coma Scale score, Acute Physiology and Chronic Health Evaluation-II score,Sequential Organ Failure Assessment score) were collected. The patients were divided into shock group and non-shock group according to whether the patients had septic shock during hospitalization. The risk factors of septic shock were screened by basic statistical analysis and multivariate Logistic regression analysis. The receiver operating characteristic curve was drawn to determine the cut-off value of the continuous indicators and discretized with reference to clinic, and the corresponding score was set according to the ß regression coefficient of each variable. Results: A total of 176 patients with DTP were included. The average age of the patients was 64.13 ± 14.67 years old, and 74.40% were males. The incidence of septic shock was 30.11% (53/176). Multivariate Logistic regression analysis showed that the highest heart rate≥105 beats/min, Glasgow Coma Scale score≤14 points, lactic acid≥5.75 mmol/L, procalcitonin≥41.47 ug/L, C-reactive protein≥222.5 mg/L were independent risk factors for septic shock in patients with DTP. The total score of clinical diagnostic scoring system of septic shock in patients with DTP was 6 points, including the highest heart rate≥105 beats/min (1 point), lactic acid≥5.75 mmol/L (two points), procalcitonin≥41.47 ug/L (one point), C-reactive protein≥222.5 mg/L (1 point), and Glasgow Coma Scale score≤14 points (1 point). The area under ROC curve (AUC) of this scoring system was 0.789 and the 95% confidence interval was 0.717-0.860 (P < 0.001); when the optimal cut-off value was 2.5, the sensitivity and specificity were 54.70 and 87.80%, respectively. Conclusion: This new score system has its certain clinical value and has important guiding significance for clinicians to judge the prognosis of patients with DTP in time.

Tumor-microenvironment triggered signal-to-noise boosting nanoprobes for NIR-IIb fluorescence imaging guided tumor surgery and NIR-II photothermal therapy.

High quantum yield quantum dots (QDs) with the emission in the sub-second near infrared window (NIR-IIb, 1500-1700 nm) can afford higher resolution, a deeper penetration depth and zero auto-fluorescence for bio-imaging. However, low tumor accumulation, the rapid renal clearance and potential toxicity impeding their biomedical applications. Here, we report a tumor microenvironment responsive hollowed virus-bionic MnO2 nanoshell with IR1061 loading in the cavity and QDs (PbS@CdS) anchoring on the surface for precise NIR-IIb fluorescence imaging guided tumor surgery and efficient NIR-II photothermal therapy. This QDs based nanoprobe could efficiently adhere on tumor cells to realize efficient tumor tissue accumulation. NIR-IIb fluorescence of tumor margin could be successfully delineating after extracellular weak acid triggered MnO2 biodegradation for IR1061 release with remarkable NIR-IIb signal-to-noise boosting. Then, it could facilitate complete dissection of various tumor models with the assistance of NIR-IIb fluorescence imaging. Moreover, the fascinating efficacy for micro-metastasis eradication via NIR-II photothermal effects can be achieved under NIR-IIb fluorescence imaging guidance. Specifically, in combination with negligible system toxicity, our nanoprobes showed great potential as a versatile NIR-IIb fluorescent imaging platform for precise tumor surgery and tumor therapy guidance for future clinical translation.

Liposome-Embedded Cu2-xAgxS Nanoparticle-Mediated Photothermal Immunoassay for Daily Monitoring of cTnI Protein Using a Portable Thermal Imager.

Functional photothermal nanomaterials have gained widespread attention in the field of precise cancer therapy and early disease diagnosis due to their unique photothermal conversion properties. However, the relatively narrow temperature response range and the outputable accuracy of commercial thermometers limit the accurate detection of biomarkers. Herein, we designed a liposome-embedded Cu2-xAgxS amplification-based photothermal sensor for the accurate determination of cardiac troponin I (cTnI) in health monitoring and point-of-care testing (POCT). The combinable 3D-printing detecting device monitored and visualized target signal changes in the testing system under the excitation of near-infrared (NIR) light, which was recorded and evaluated for possible pathogenicity by a smartphone. Notably, we predicted the potentially efficient thermal conversion efficiency of Cu2-xAgxS from the structure and charge density distribution, calculated by the first-principles and density functional theory (DFT), which provided a theoretical basis for the construction of novel photothermal materials, and the experimental results proved the correctness of the theoretical projections. Under optimal conditions, the photothermal immunoassay showed a dynamic linear range of 0.02-10 ng mL-1 with a detection limit of 11.2 pg mL-1. This work instructively introduces promising theoretical research and provides new insights for the development of sensitive portable photothermal biosensors.

Vehicle-Free Nanotheranostic Self-Assembled from Clinically Approved Dyes for Cancer Fluorescence Imaging and Photothermal/Photodynamic Combinational Therapy.

Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT) has attracted growing attention as a noninvasive option for cancer treatment. At present, researchers have developed various "all-in-one" nanoplatforms for cancer imaging and PTT/PDT combinational therapy. However, the complex structure, tedious preparation procedures, overuse of extra carriers and severe side effects hinder their biomedical applications. In this work, we reported a nanoplatform (designated as ICG-MB) self-assembly from two different FDA-approved dyes of indocyanine green (ICG) and methylene blue (MB) without any additional excipients for cancer fluorescence imaging and combinational PTT/PDT. ICG-MB was found to exhibit good dispersion in the aqueous phase and improve the photostability and cellular uptake of free ICG and MB, thus exhibiting enhanced photothermal conversion and singlet oxygen (1O2) generation abilities to robustly ablate cancer cells under 808 nm and 670 nm laser irradiation. After intravenous injection, ICG-MB effectively accumulated at tumor sites with a near-infrared (NIR) fluorescence signal, which helped to delineate the targeted area for NIR laser-triggered phototoxicity. As a consequence, ICG-MB displayed a combinational PTT/PDT effect to potently inhibit tumor growth without causing any system toxicities in vivo. In conclusion, this minimalist, effective and biocompatible nanotheranostic would provide a promising candidate for cancer phototherapy based on current available dyes in clinic.

Prognostic Value of mRNAsi/Corrected mRNAsi Calculated by the One-Class Logistic Regression Machine-Learning Algorithm in Glioblastoma Within Multiple Datasets.

Glioblastoma (GBM) is the most common glial tumour and has extremely poor prognosis. GBM stem-like cells drive tumorigenesis and progression. However, a systematic assessment of stemness indices and their association with immunological properties in GBM is lacking. We collected 874 GBM samples from four GBM cohorts (TCGA, CGGA, GSE4412, and GSE13041) and calculated the mRNA expression-based stemness indices (mRNAsi) and corrected mRNAsi (c_mRNAsi, mRNAsi/tumour purity) with OCLR algorithm. Then, mRNAsi/c_mRNAsi were used to quantify the stemness traits that correlated significantly with prognosis. Additionally, confounding variables were identified. We used discrimination, calibration, and model improvement capability to evaluate the established models. Finally, the CIBERSORTx algorithm and ssGSEA were implemented for functional analysis. Patients with high mRNAsi/c_mRNAsi GBM showed better prognosis among the four GBM cohorts. After identifying the confounding variables, c_mRNAsi still maintained its prognostic value. Model evaluation showed that the c_mRNAsi-based model performed well. Patients with high c_mRNAsi exhibited significant immune suppression. Moreover, c_mRNAsi correlated negatively with infiltrating levels of immune-related cells. In addition, ssGSEA revealed that immune-related pathways were generally activated in patients with high c_mRNAsi. We comprehensively evaluated GBM stemness indices based on large cohorts and established a c_mRNAsi-based classifier for prognosis prediction.

Outcomes of Laparoscopic Total Gastrectomy Combined With Spleen-Preserving Hilar Lymphadenectomy for Locally Advanced Proximal Gastric Cancer: A Nonrandomized Clinical Trial.

Importance: The long-term survival of patients with laparoscopic total gastrectomy combined with spleen-preserving splenic hilar lymphadenectomy (LSTG) for advanced upper-third gastric cancer (AUTGC) and the association of splenic hilar lymph node (LN-10) metastasis with survival remain controversial. Objective: To evaluate the long-term outcomes of LSTG and the value index of LN-10 metastasis for patients with AUTGC. Design, Setting, and Participants: The Chinese Laparoscopic Gastrointestinal Surgery Study 4 (CLASS-04) was a prospective, multicenter, single-arm trial that involved 19 centers in China. A total of 251 eligible patients with clinical stage T2, T3, or T4a upper-third gastric cancer without distant metastases were enrolled from September 1, 2016, to October 31, 2017. The final follow-up was on December 31, 2020. Interventions: All patients were enrolled to undergo LSTG. Main Outcomes and Measures: The main outcomes were the 3-year overall survival (OS) and disease-free survival (DFS). Multivariate analyses were used to explore the association of LN-10 metastasis with survival. Results: Among the 251 patients, 246 (98.0%; mean [SD] age, 60.1 [9.4] years; 197 [80.1%] male) underwent LSTG and completed the study. The 3-year OS was 79.1% (95% CI, 74.0%-84.2%), and the 3-year DFS was 73.1% (95% CI, 67.4%-78.8%). In addition, the 3-year therapeutic value index of LN-10 dissection was 4.5, exceeding the indexes for the partial D2 LN group (including LNs 5, 6, 11d, and 12a). Nineteen patients (7.7%) with LN-10 metastasis had significantly worse survival than the nonmetastasis group, and multivariate analysis revealed that splenic LN-10 metastasis was an independent risk factor (OS: hazard ratio [HR], 2.38; 95% CI, 1.08-5.26; P = .03; DFS: HR, 2.28; 95% CI, 1.12-4.63; P = .02). Moreover, patients with LN-10 metastasis were more likely to have recurrence (42.1% vs 20.7%, P = .03), especially when multiple site metastasis was present (21.1% vs 4.4%, P = .01). However, patients with LN-10 metastasis who received adjuvant chemotherapy had significantly better OS and DFS than those without adjuvant chemotherapy and achieved the same oncologic effect as those without LN-10 metastasis. Conclusions and Relevance: This results of this study suggest that LSTG for AUTGC has feasible long-term outcomes. In addition, patients with LN-10 metastasis may have worse survival and may be more prone to recurrence.

Comparison of Survival and Patterns of Recurrence in Gastric Neuroendocrine Carcinoma, Mixed Adenoneuroendocrine Carcinoma, and Adenocarcinoma.

Importance: Gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma are rare pathological types of gastric cancer, and there is a lack of multicenter studies comparing the prognosis and recurrence patterns of gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric adenocarcinoma. Objective: To compare the differences in long-term survival and patterns of recurrence among gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric adenocarcinoma. Design, Setting, and Participants: This cohort study included patients with resectable gastric neuroendocrine carcinoma and gastric mixed adenoneuroendocrine carcinoma at 23 hospitals in China from January 2006 to December 2016. In addition, patients with gastric adenocarcinoma were selected as controls. Propensity score-matched analysis was used to match pathological stage among the different pathological types, and disease-free survival (DFS), postrecurrence survival (PRS), and patterns of recurrence were examined. Data analysis was conducted from July 15, 2020, to October 21, 2020. Exposures: Curative resection for gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric adenocarcinoma. Main Outcomes and Measures: The main outcomes were DFS and patterns of recurrence. Results: A total of 3689 patients were analyzed (median [interquartile range] age, 62 [55-69] years; 2748 [74.5%] men), including 503 patients (13.6%) with gastric neuroendocrine carcinoma, 401 patients (10.9%) with gastric mixed adenoneuroendocrine carcinoma, and 2785 patients (75.5%) with gastric adenocarcinoma. After propensity score matching, 5-year DFS was 47.6% (95% CI, 42.7%-52.5%) for patients with gastric neuroendocrine carcinoma, compared with 57.6% (95% CI, 55.1%-60.1%) with gastric adenocarcinoma (P < .001) and 51.1% (95% CI, 46.0%-56.2%) for patients with gastric mixed adenoneuroendocrine carcinoma, compared with 57.8% (95% CI, 55.1%-60.5%) patients with gastric adenocarcinoma (P = .02). Multivariable analyses found that, compared with gastric adenocarcinoma, gastric neuroendocrine carcinoma (hazard ratio [HR], 1.64; 95% CI, 1.40-1.93) and gastric mixed adenoneuroendocrine carcinoma (HR, 1.25; 95% CI, 1.05-1.49) were independent risk factors associated with worse DFS. Compared with matched patients with gastric adenocarcinoma, patients with gastric neuroendocrine carcinoma were more likely to have distant recurrence (268 patients [17.2%] vs 101 patients [23.7%]; P = .002), as were patients with gastric mixed adenoneuroendocrine carcinoma (232 patients [17.3%] vs 76 patients [22.8%]; P = .02). In multivariate analysis, gastric neuroendocrine carcinoma (HR, 2.22; 95% CI, 1.66-2.98) and gastric mixed adenoneuroendocrine carcinoma (HR, 1.70; 95% CI, 1.24-2.34) were independent risk factors associated with distant recurrence. Additionally, T3 to T4 stage (odds ratio, 2.84; 95% CI, 1.57-5.14; P = .001) and lymph node metastasis (odds ratio, 2.01; 95% CI, 1.31-3.10; P = .002) were independent risk factors associated with distant recurrence of gastric neuroendocrine carcinoma and gastric mixed adenoneuroendocrine carcinoma. Conclusions and Relevance: This cohort study found that patients with gastric neuroendocrine carcinoma or gastric mixed adenoneuroendocrine carcinoma had worse prognoses and were more prone to distant recurrence than those with gastric adenocarcinoma. Thus, different follow-up and treatment strategies should be developed to improve the long-term survival of patients with gastric neuroendocrine carcinoma or gastric mixed adenoneuroendocrine carcinoma, especially patients with tumors penetrating into the subserosa or deeper layers or with lymph node metastasis.

Effectiveness and Safety of Apatinib Plus Chemotherapy as Neoadjuvant Treatment for Locally Advanced Gastric Cancer: A Nonrandomized Controlled Trial.

Importance: Apatinib is a novel treatment option for chemotherapy-refractory advanced gastric cancer (GC), but it has not been evaluated in patients with locally advanced GC. Objective: To investigate the effectiveness and safety of apatinib combined with S-1 plus oxaliplatin (SOX) as a neoadjuvant treatment for locally advanced GC. Design, Setting, and Participants: This multicenter, prospective, single-group, open-label, phase 2 nonrandomized controlled trial was conducted in 10 centers in southern China. Patients with M0 and either clinical T2 to T4 or N+ disease were enrolled between July 1, 2017, and June 30, 2019. Statistical analysis was performed from December 1, 2019, to January 31, 2020. Interventions: Eligible patients received apatinib (500 mg orally once daily on days 1 to 21 and discontinued in the last cycle) plus SOX (S-1: 40-60 mg orally twice daily on days 1 to 14; oxaliplatin: 130 mg/m2 intravenously on day 1) every 3 weeks for 2 to 5 cycles. A D2 gastrectomy was performed 2 to 4 weeks after the last cycle. Main Outcomes and Measures: The primary end point was R0 resection rate. Secondary end points were the response rate, toxic effects, and surgical outcome. Results: A total of 48 patients (mean [SD] age, 63.2 [8.2] years; 37 men [77.1%]) were enrolled in this study. Forty patients underwent surgery (38 had gastrectomy, and 2 had exploratory laparotomy), with an R0 resection rate of 75.0% (95% CI, 60.4%-86.4%). The radiologic response rate was 75.0%, and T downstaging was observed in 16 of 44 patients (36.4%). The pathological response rate was 54.2% (95% CI, 39.2%-68.6%); moreover, this rate was significantly higher in patients who achieved a radiologic response compared with those who did not (12 [80.0%] vs 1 [20.0%]; P = .03) and in those who had an Eastern Cooperative Oncology Group Performance Status score of 0 (20 [76.9%] vs 10 [45.5%]; P = .03) or had tumors located in the upper one-third of the stomach (16 [61.5%] vs 7 [31.8%]; P = .04). Patients who achieved a pathological response (vs those who did not) had significantly less blood loss (median [range]: 60 [10-200] mL vs 80 [20-300] mL; P = .04) and significantly more lymph nodes harvested (median [range]: 40 [24-67] vs 32 [19-51]; P = .04) during surgery. Postoperative complications were observed in 7 of 38 patients (18.4%). Grade 3 toxic effects occurred in 16 of 48 patients (33.3%), and no grade 4 toxic effects or preoperative deaths were observed. Conclusions and Relevance: This nonrandomized controlled trial found that apatinib combined with SOX was effective and had an acceptable safety profile as a neoadjuvant treatment for locally advanced GC. A large-scale randomized clinical trial may be needed to confirm the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT03192735.

Distinct Genomic Landscape of Colorectal Mucinous Carcinoma Determined via Comprehensive Genomic Profiling: Steps to a New Treatment Strategy.

Colorectal mucinous carcinoma (MC) is associated with inferior prognosis and response to treatment compared to adenocarcinoma (AC). The molecular landscapes of MC and adenocarcinoma with mucous composition (AMC) are not well-defined. We aimed to describe the genomic landscape of MC and AMC in a large colorectal cancer cohort. Tumor samples from patients with MC, AMC, or AC were analyzed using next-generation sequencing. MC had a molecular signature distinct from that of AC; genomic features were similar between AMC and MC but not between AMC and AC. HER2 amplification and TP53 and APC mutation rates were lower, whereas SMAD4, PIK3CA, ACVR2A, KMT2D, LRP1, TGFBR2, GRIN2A, BRAF V600E, PTEN, and BRCA2 mutation rates were higher in MC than in AC. The mutation frequencies in MAPK, PI3K, and TGF- pathways were higher, whereas those of cell cycle proteins and Wnt were lower in MC and AMC than in AC. The proportion of hypermutated tumors was significantly higher in MC and AMC than in AC. As MC has a distinct molecular signature from AC, immunotherapy can be potentially applied in treating MC. Similar molecular profiles of AMC and MC suggest that treatment strategies for MC, but not AC, can be used for AMC treatment.

Predictive Value of Combined Preoperative Carcinoembryonic Antigen Level and Ki-67 Index in Patients With Gastric Neuroendocrine Carcinoma After Radical Surgery.

PRÉCIS: We present a valid and reproducible nomogram that combined the TNM stage as well as the Ki-67 index and carcinoembryonic antigen levels; the nomogram may be an indispensable tool to help predict individualized risks of death and help clinicians manage patients with gastric neuroendocrine carcinoma. BACKGROUND: To analyze the long-term outcomes of patients with grade 3 GNEC who underwent curative surgery and investigated whether the combination of carcinoembryonic antigen (CEA) levels and Ki-67 index can predict the prognosis of patients with gastric neuroendocrine carcinoma (GNEC) and constructed a nomogram to predict patient survival. METHODS: In the training cohort, data were collected from 405 patients with GNEC after radical surgery at seven Chinese centers. A nomogram was constructed to predict long-term prognosis. Data for the validation cohort were collected from 305 patients. RESULTS: The 5-year overall survival (OS) was worse in the high CEA group than in the normal CEA group (40.5% vs. 55.2%, p = 0.013). The 5-year OS was significantly worse in the high Ki-67 index group than in the low Ki-67 index group (47.9% vs. 57.2%, p = 0.012). Accordingly, we divided the whole cohort into a KC(-) group (low Ki-67 index and normal CEA) and KC(+) group (high Ki-67 index and/or high CEA). The KC(+) group had a worse prognosis than the KC(-) group (64.6% vs. 46.8%, p < 0.001). KC(+) and the AJCC 8th stage were independent factors for OS. Then, we combined KC status and the AJCC 8th stage to establish a nomogram; the C-index and area under the curve (AUC) were higher for the nomogram than for the AJCC 8th stage (C-index: 0.660 vs. 0.635, p = 0.005; AUC: 0.700 vs. 0.675, p = 0.020). The calibration curve verified that the nomogram had a good predictive value, with similar findings in the validation groups. CONCLUSIONS: The nomogram based on KC status and the AJCC 8th stage predicted the prognosis of patients with GNEC well.