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Background The aim of the study was to explore the treatment outcomes and prognostic factors for patients with previously irradiated but unresectable recurrent head and neck squamous cell carcinoma (rHNSCC) treated by stereotactic body radiotherapy (SBRT) plus cetuximab at a single institute in Taiwan. Methods From February 2016 to March 2019, 74 patients with previously irradiated but unresectable rHNSCC were treated with SBRT plus cetuximab. All patients received irradiation to the gross tumor and/or nodal area with 40-50 Gy in five fractions, with each fraction interval ≥ 2 days over a 2-week period by using the CyberKnife M6 machine. An18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scan was performed before treatment for treatment target delineation (n = 74) and 2 months later for response evaluation (n = 60). The median follow-up time was 9 months (range 1-36 months). Results The treatment response rate was complete response: 25.0%, partial response: 41.7%, stable disease: 11.7%, and progressive disease: 21.7% based on the criteria of the Response Evaluation Criteria in Solid Tumors (n = 72) and complete metabolic response: 21.7%, partial metabolic response: 51.7%, stable metabolic disease: 13.3%, and progressive metabolic disease: 13.3% based on PET-CT (n = 60), respectively. The 1-/2-year overall survival (OS) and progression-free survival (PFS) rates were 42.8%/22.0% and 40.5%/19.0%, respectively. In the logistic regression model, a re-irradiation interval > 12 months was observed to be the only significant prognostic factor for a favorable treatment response. In the Cox proportional hazards model, a re-irradiation interval > 12 months and gross tumor volume (GTV) ≦ 50 ml were favorable prognostic factors of OS and PFS. Conclusion SBRT plus cetuximab provides a promising salvage strategy for those patients with previously irradiated but unresectable rHNSCC, especially those with a re-irradiation interval > 12 months or GTV ≦ 50 ml.

Purpose Emergency endotracheal intubations outside the operating room (OR) are associated with high complications. We compare the outcome of emergency endotracheal intubation in the general ward, the intensive care unit (ICU) and the emergency department (ED). Materials and methods We retrospectively analyzed adult patients requiring emergency endotracheal intubation that called for anesthesiologists at our tertiary care institution from January 1, 2015 to December 31, 2016. We evaluated the outcomes, including aspiration, hemodynamic collapse, pneumothorax, emergency tracheostomy, and survival to hospital discharge in the general ward, ICU, and ED. Results There were 416 non-OR emergency endotracheal intubation calls for the anesthesiologist. Among these areas, the ED had the highest proportion of difficult endotracheal (DET) intubation (n = 144 [80.4%]), followed by the general ward (n = 85 [66.4%]), and then the ICU (n = 65 [59.6%]). The incidence of hemodynamic collapse was higher in the general ward (n = 44 [34.4%]) than the ICU (n = 18 [16.5%]) or the ED (n = 16 [9.0%]). We reported the survival rate of the general ward (55.5%), which was lower than the ICU (63.3%) and the ED (80.4%). Among these locations, the ED had the highest rate of neurologically intact (91%) to hospital discharge, compared to the ICU (56.6%) and the general ward (55%). As for the ED, although there was no difference in survival between non-preventive and preventive intubations, preventive intubations was associated with high neurological intact with hospital discharge. Conclusion Emergency and DET intubation in the general ward and ICU resulted in a higher incidence of hemodynamic collapse and mortality than those performed in the ED. Early calls for the anesthesiologist for DET intubation without medications in the ED resulted in a higher rate of neurologically intact survival to hospital discharge.

Heathcare Workers (HCWs) recognize their responsibility to support the bereaved loved ones of our patients, but we also must attend to our own professional and personal grief in the COVID-19 pandemic. COVID-19 grief is occurring in the setting of incomplete grief, disenfranchised grief, fractured US governmental leadership, and evidence of great mistrust, systemic racism, and social injustice. In the intensity and pervasiveness of COVID-19, HCW fears for themselves, their colleagues, and their own loved ones are often in conflict with professional commitments. Even at the dawn of promising national and global vaccination programs, significant HCW morbidity and mortality in COVID-19 has already become clear, will continue to grow, and these effects likely will last far into the future. Given the risks of complicated grief for HCWs in the setting of COVID-19 deaths, individual HCWs must put every effort into their own preparation for these deaths as well as into their own healthy grieving. Equally importantly, our healthcare systems have a primary responsibility both to prepare HCWs and to support them in their anticipatory and realized grief. Special attention must be paid to our HCW trainees, who may have not yet developed personal or professional grief management strategies and are coming into healthcare practice during a time of great disruption to both teaching and clinical care.

This study evaluated the safety, effectiveness, and feasibility of indocyanine green (ICG) tracing in guiding lymph-node (LN) dissection during laparoscopic D2 radical gastrectomy in patients with advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NAC). We retrospectively analyzed data on 313 patients with clinical stage of cT1-4N0-3M0 who underwent laparoscopic radical gastrectomy after NAC between February 2010 and October 2020 from two hospitals in China. Grouped according to whether ICG was injected. For the ICG group (n = 102) and non-ICG group (n = 211), 1:1 propensity matching analysis was used. After matching, there was no significant difference in the general clinical pathological data between the two groups (ICG vs. non-ICG: 94 vs. 94). The average number of total LN dissections was significantly higher in the ICG group and lower LN non-compliance rate than in the non-ICG group. Subgroup analysis showed that among patients with LN and tumor did not shrink after NAC, the number of LN dissections was significantly more and LN non-compliance rate was lower in the ICG group than in the non-ICG group. Intraoperative blood loss was significantly lesser in the ICG group than in the non-ICG group, while the recovery and complications of the two groups were similar. For patients with poor NAC outcomes, ICG tracing can increase the number of LN dissections during laparoscopic radical gastrectomy, reduce the rate of LN non-compliance, and reduce intraoperative bleeding. Patients with AGC should routinely undergo ICG-guided laparoscopic radical gastrectomy.

Body composition profiles influence the prognosis of several types of cancer; however, the role of body composition in patients with locally advanced gastric cancer (LAGC) after neoadjuvant treatment (NT) has not been well characterized.A total of 213 patients with LAGC who underwent gastrectomy after NT at a high-volume institution from southern China were comprehensively evaluated for primary analysis. Additionally, 170 and 77 patients from Western China and Italy, respectively, were reviewed for external validation. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and the subcutaneous as well as the visceral adiposity index were assessed from clinically acquired CT scans at diagnosis and preoperatively.Overall, none of the body composition parameters significantly changed after NT. The pre-NT skeletal muscle radiodensity (SMD) and change in SMI (ΔSMI) were both significantly lower in the patients with poor response (tumor regression50%; mean SMD: 43.5 vs 46.5, P = 0.003; mean ΔSMI: -1.0 vs 2.2, P 0.001), and the cutoff values were calculated according to the Youden index as 43.7 and 1.2, respectively. Based on these 2 parameters, a novel model, the Skeletal Muscle Score (SMS), was proposed to predict the pathological response (AUC = 0.764 alone and = 0.822 in combination with the radiological response). Moreover, patients with an SMI loss1.2 had a significantly prolonged drainage tube removal time (mean: 10.0 vs 8.2, P = 0.003) and postoperative hospital stay (mean: 11.1 vs 9.8, P = 0.048), as well as a significantly higher rate of postoperative complications (30.9% vs 16.7%, P = 0.015). In the multivariate analysis, SMI loss1.2 independently predicted poor overall survival (HR: 1.677, 95% CI 1.040-2.704, P = 0.034) and recurrence-free survival (HR: 1.924, 95% CI 1.165-3.175, P = 0.011). ΔSMI was also significantly associated with pathological response, surgical outcomes, and survival in the 2 external cohorts (P all 0.05).For LAGC, the pre-NT SMD and ΔSMI could accurately predict the pathological response after NT. An SMI loss1.2 is closely associated with poorer outcomes and may indicate the need more supportive treatment.

Background: Depression is common in the oncology patient population. Little data exist on the impact of depression on health care utilization. Objectives: We evaluated the prevalence of depression and the relationship between depression and health care utilization in patients with cancer. Design: This cross-sectional study utilized patient-reported outcome data from predominately Medicare beneficiaries with cancer. We examined the emergency department visits and inpatient admissions within 3 months from survey. The relationship between depression and hospital visits was assessed using generalized linear models. Results: Of 1038 patients included in the study, 13% had moderate to severe depression. In adjusted models, patients with moderate or severe depression trended toward increased risk of hospitalizations compared with patients without depression (risk ratio: 1.25, 95% confidence interval: 0.97-1.62). Conclusions: Clinically significant depression is not uncommon in cancer patients. Further research is needed evaluating the relationship between depression, health care utilization, and early psychiatric intervention in oncology.

The systemic inflammatory response caused by host-tumor interactions is currently recognized as a hallmark feature of cancer. No study has confirmed which systemic inflammatory factors can accurately predict the progression and long-term prognosis of gastric cancer (GC). Through the analysis of receiver operating characteristic curve (ROC), in the discovery cohort, a variety of indicators composed of usual inflammatory factors were compared. Fibrinogen-albumin ratio (FAR), which can accurately predict the long-term survival of GC patients was selected and was further verified in the test cohort and the external validation cohort. The ROC curve analysis showed that the area under curve (AUC) value of FAR on the overall survival (OS) of GC patients was higher than that of other combined markers (P < 0.01). Patients in the high FAR group showed more advanced pathological stages, larger tumor diameters, and more poorly differentiated pathological type than those in the low FAR group (P < 0.05). Logistic regression analysis elucidated that, FAR was an independent risk factor for LN metastasis and tumor invasion of GC. High FAR was an independent risk factor for poor prognosis of GC patients. The relationship between FAR and pathological stage of GC and long-term prognosis of patients was verified in the test cohort and the external validation cohort with the same FAR cutoff value. The results are consistent with those of the discovery cohort. As a new developed inflammation-related marker, FAR can independently and effectively predict the tumor burden and long-term prognosis of patients with advanced GC.

PURPOSE To investigate the effect of dynamic changes in systemic inflammatory markers (SIM) on long-term prognosis of patients with gastric cancer (GC). METHODS A retrospective analysis was performed on the data of 2180 patients with GC who underwent radical gastrectomy in the Fujian medical university Union Hospital from January 2009 to December 2014. Changes in SIM between preoperatively and 1-6 months and 12 months postoperatively were reported. RESULTS In multivariate analysis, higher preoperative systemic inflammation score (pre-SIS) was independent predictor of poor prognosis (p

The application of splenic hilar lymph node (no. 10 LN) dissection (no. 10 LND) for proximal gastric cancer (PGC) remains controversial. This study aimed to investigate the clinical relevance of no. 10 LND from the perspective of long-term survival. The main study population included 995 previously untreated patients who underwent laparoscopic radical total gastrectomy between January 2008 and December 2014. Of these 995 patients, 564 underwent no. 10 LND (no. 10D+ group) and the remaining 431 patients did not (no. 10D– group). Propensity score-matching was applied to reduce the effects of confounding factors. The study end points were overall survival (OS) and disease-free survival (DFS). Additionally, 39 patients who received neoadjuvant chemotherapy during the same period also were included as a separate population for analysis. The metastasis rate for no. 10 LN was 10.5 % (59/564). No significant differences were observed in intra- and postoperative complications nor in mortality between the no. 10D+ and no. 10D– groups (all P > 0.05). After 1:1 matching, the two groups were comparable in clinicopathologic characteristics. The no. 10D+ group had significantly better survival than the no. 10D– group (5-year OS: 63.3 % vs 52.2 %, P = 0.003; 5-year DFS: 60.4 % vs 48.1 %, P = 0.013). For the patients who received neoadjuvant chemotherapy, the 5-year OS rates in the no. 10D+ and no. 10D– groups were respectively 50.6 % and 31.3 % (P = 0.150) and the 5-year DFS rates were respectively 51.5 % and 31.3 % (P = 0.123). Patients with untreated PGC may achieve the benefit of long-term survival from no. 10 LND. For patients with PGC who undergo neoadjuvant chemotherapy, no. 10 LND may not bring survival benefits. However, further validation with a large-sample study is needed.

Background: Compared with other histologic types, signet ring cell gastric carcinoma (SRC) has unique oncological characteristics, and its implication on the prognosis of gastric cancer patients remains unclear. The purpose of this study was to evaluate the prognostic impact of body mass index (BMI) on SRC patients. Methods: A retrospective analysis was performed using the clinical records of 3342 patients with SRC or tubular adenocarcinoma who underwent radical gastrectomy between 2000 and 2014. Patients were divided into three groups according to histologic subtype: SRC, well-to-moderately differentiated adenocarcinoma (WMD), and poorly differentiated adenocarcinoma (PD). We compared the survival of SRC patients with that of tubular adenocarcinoma patients according to BMI. Results: The 5-year survival of SRC was significantly worse than that of WMD (P 0.05) and better than that of PD (P

Background: Carcinoembryonic antigen (CEA) is one of the important indexes for the diagnosis and prognosis of gastrointestinal cancer. Systemic inflammatory response (SIR) is closely related to the occurrence and development of gastrointestinal cancer. Methods: A total of 803 patients who underwent radical gastrectomy in Qinghai University Affiliated Hospital from January 2012 to December 2016 were included as training set. Multivariable Cox proportional hazard regression was used to identify associations with outcome of gastric cancer (GC). CNLR was established by combining CEA and the neutrophils to lymphocytes ratio (NLR, a typical parameter in SIR) to generate a novel prognostic score system and its prognostic value was externally validated. Results: Multivariate analysis showed that CEA and NLR were independent prognostic factors for GC patients (both p < 0.05). A higher CNLR was significantly associated with older age, male sex, larger tumor size, vascular invasion and advanced stages (all p < 0.05). Patients with higher CNLR had poor prognosis than those with lower CNLR (p < 0.05). Multivariate analysis showed that CNLR was an independent prognostic factor (p < 0.05). Incorporation of the CNLR into a prognostic model including age and TNM stage generated a nomogram, which predicted accurately 3- and 5-year survival for GC patients. And similar results were obtained in the external validation set. Conclusions: The CNLR prognostic scoring system established by combining CEA and NLR is an independent prognostic factor for GC, which can be incorporated into the traditional TNM staging to improve the prediction of long-term survival outcomes.

The poor prognosis of gastric cancer (GC) results largely from metastasis and chemotherapy resistance. Toward novel therapeutic strategies that target or evade these phenomena, we evaluated the function of the transcriptional regulator transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) in GC cells, including stem-like cells. In this study, the correlation of expression of TBL1XR1 and clinical features and GC patients' outcomes was evaluated. Knockdown or exogenous expression of TBL1XR1 was combined with in vitro (2D and 3D cultures) and in vivo (mouse lung and lymphatic metastasis models) assays to evaluate the function of TBL1XR1. TBL1XR1's downstream signaling was delineated by phospho-kinase array and knockdown of candidate mediators. Analysis of clinical data showed that TBL1XR1 overexpression was correlated with worse prognosis. Functional assays showed that TBL1XR1 promoted stemness, epithelial-mesenchymal transition (EMT), and lung and lymphatic metastasis in GC cells. TBL1XR1 activated ERK1/2-Sox2 signaling and was dependent on signaling via PI3K/AKT, in GC stem-like cells distinguished by CD44 expression. Moreover, inhibition of these signaling proteins reversed chemoresistance in in vitro and in vivo models. Taken together, our results indicate that TBL1XR1 promotes stemness and metastasis in GC, making it a potential prognostic indicator. The PI3K/AKT-TBL1XR1-ERK1/2-Sox2 axis may represent a target for the treatment of GC.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late detection and highly metastatic characteristics. PDAC cells vary in their tumorigenic capabilities with the presence of a subset of PDAC cells known as pancreatic cancer stem cells (CSCs), which are more resistant to currently used therapeutics. Here, we describe the role of CSCs and tumour stroma in developing therapeutic strategies for PDAC and suggest that developmental plasticity could be considered a hallmark of cancers. We provide an overview of the molecular targets in PDAC treatments, including targeted therapies of cellular processes such as proliferation, evasion of growth suppressors, activating metastasis, and metabolic effects. Since PDAC is an inflammation-driven cancer, we also revisit therapeutic strategies targeting inflammation and immunotherapy. Lastly, we suggest that targeting epigenetic mechanisms opens therapeutic routes for heterogeneous cancer cell populations, including CSCs.

Objective:. Laboratory diagnosis of neurosyphilis (NS) remains a great challenge. This study was the aimed to identify miRNA candidates as biomarkers to distinguish between NS, non-neurosyphilis, and healthy controls (HCs). Methods:. We analyzed miRNA expression profiles in peripheral blood mononuclear cells (PBMCs) from six patients with NS, eight patients with secondary syphilis (SS), and five HCs using microarray technology. The differentially expressed miRNAs were validated in 33 NS samples, 31 SS samples, and 30 HC samples using TaqMan miRNA real-time qPCR (qRT-PCR). Results:. Thirty-nine miRNAs were differentially expressed in SS and NS patients compared with HCs. Thirteen miRNAs were randomly selected to validate their expression levels in the same samples used in microarray assay by qRT-PCR. All miRNAs were upregulated in SS and NS samples compared with HC. qRT-PCR analysis of the expression of the 13 miRNAs in a second cohort (76 samples) showed that the average expression levels of nine miRNAs were higher in SS than in NS (SS: 0.185, NS: 0.136, P=3.8E-10), while the expressions of the other four miRNAs were lower in SS than in NS (SS: 0.000757, NS: 0.000873, P=0.022). ROC curve analysis of the 13 miRNAs showed the area under the curve value to be 1.00 for distinguishing SS patients from HCs, 1.00 for distinguishing NS patients from HCs, 1.00 for distinguishing SS and NS patients from HCs, and 0.968 for distinguishing NS from SS patients. Conclusion:. The present study is the first one that identified differentially expressed miRNAs in PBMCs from patients with NS. Our results suggest that the 13 candidate miRNAs in PBMCs may be novel noninvasive biomarkers for NS diagnosis.

The effect of POC1 centriolar protein A (POC1A) on gastric cancer (GC) has not been clearly defined. In this study, POC1A expression and clinical information in patients with GC were analyzed. Multiple databases were used to investigate the genes that were co-expressed with POC1A and genes whose changes co-occurred with genetic alternations of POC1A. Moreover, the TISIDB and TIMER databases were used to analyze immune infiltration. The GSE54129 GC dataset and LASSO regression model (tumor vs. normal) were employed, and 6 significant differentially expressed genes (LAMP5, CEBPB, ARMC9, PAOX, VMP1, POC1A) were identified. POC1A was selected for its high expression in adjacent tissues, which was confirmed with IHC. High POC1A expression was related to better overall and recurrence-free survival. GO and KEGG analyses demonstrated that POC1A may regulate the cell cycle, DNA replication and cell growth. Furthermore, POC1A was found to be correlated with immune infiltration levels in GC according to the TISIDB and TIMER databases. These findings indicate that POC1A acts as a tumor suppressor in GC by regulating the cell cycle and cell growth. In addition, POC1A preferentially regulates the immune infiltration of GC via several immune genes. However, the specific mechanism requires further study.

Background The relationship between sarcopenia and the prognoses of patients with gastric neuroendocrine neoplasms (g-NENs) is unclear. This study was designed to explore the effects of sarcopenia on short-term and long-term outcomes of patients with g-NENs after radical gastrectomy. Methods This study retrospectively collected data from 138 patients with g-NENs after radical gastrectomy. The skeletal muscle index (SMI) diagnostic threshold for sarcopenia was determined using X-tile software. Cox regression analyses were performed to determine the independent risk factors for 3-year overall survival (OS) and 3-year recurrence-free survival (RFS). Results In this study, 59 patients (42.8%) were diagnosed with sarcopenia. Among patients in the sarcopenia group and nonsarcopenia group, the incidences of total postoperative complications were 33.9 and 30.4%, incidences of serious postoperative complications were 0 and 3.7%, incidences of postoperative surgical complications were 13.6 and 15.2%, and incidences of postoperative systemic complications were 20.3 and 15.2%, respectively (all p > 0.05). The 3-year OS and RFS rates were significantly worse in the sarcopenia group than in the nonsarcopenia group (OS: 42.37% vs 65.82%, p = 0.004; RFS: 52.54% vs 68.35%, p = 0.036). The multivariate analysis revealed a relation between sarcopenia and the long-term prognoses of patients with g-NENs. A stratified analysis based on the pathological type revealed that the Kaplan-Meier curve was only significantly different in patients with gastric mixed adenoneuroendocrine carcinoma (gMANEC) (OS: 40.00% vs 71.79%, p = 0.007; RFS: 51.43% vs 74.36%, p = 0.026); furthermore, the multivariate analysis identified sarcopenia as an independent risk factor for patients with gMANEC (p Conclusions Sarcopenia is not related to the short-term prognoses of patients with g-NENs. Sarcopenia is an independent risk factor for patients with gMANEC after radical surgery.

Background The benefits of neoadjuvant therapy for patients with locally advanced gastric cancer (GC) are increasingly recognized. The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual first proposed ypTNM staging, but its accuracy is controversial. This study aims to develop a modified ypTNM staging. Patients and Methods Clinicopathological data of 1,791 patients who underwent curative-intent gastrectomy after neoadjuvant therapy in the Surveillance, Epidemiology, and End Results database, as the development cohort, were retrospectively analyzed. Modified ypTNM staging was established based on overall survival (OS). We compared the prognostic performance of the AJCC 8th edition ypTNM staging and the modified staging for patients after neoadjuvant therapy. Results In the development cohort, the 5-year OS for AJCC stages I, II, and III was 58.8%, 39.1%, and 21.6%, respectively, compared with 69.9%, 54.4%, 34.4%, 24.1%, and 13.6% for modified ypTNM stages IA, IB, II, IIIA, and IIIB. The modified staging had better discriminatory ability (C-index: 0.620 vs. 0.589, p < .001), predictive homogeneity (likelihood ratio chi-square: 140.71 vs. 218.66, p < .001), predictive accuracy (mean difference in Bayesian information criterion: 64.94; net reclassification index: 35.54%; integrated discrimination improvement index: 0.032; all p < .001), and model stability (time-dependent receiver operating characteristics curves) over AJCC. Decision curve analysis showed that the modified staging achieved a better net benefit than AJCC. In external validation (n = 266), the modified ypTNM staging had superior prognostic predictive power (all p < .05). Conclusion We have developed and validated a modified ypTNM staging through multicenter data that is superior to the AJCC 8th edition ypTNM staging, allowing more accurate assessment of the prognosis of patients with GC after neoadjuvant therapy. Implications for Practice The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual first proposed ypTNM staging, but its accuracy is controversial. Based on multi-institutional data, this study developed a modified ypTNM staging, which is superior to the AJCC 8th edition ypTNM staging, allowing more accurate assessment of the prognosis of patients with gastric cancer after neoadjuvant therapy.

Background Toward identifying new strategies to target gastric cancer stem-like cells (CSCs), we evaluated the function of the tumour suppressor CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) in gastric CSC maintenance. Methods We examined the expression of CDK5RAP3 and CD44 in gastric cancer patients. The function and mechanisms of CDK5RAP3 were checked in human and mouse gastric cancer cell lines and in mouse xenograft. Results We show that CDK5RAP3 is weakly expressed in gastric CSCs and is negatively correlated with the gastric CSC marker CD44. CDK5RAP3 overexpression decreased expression of CSC markers, spheroid formation, invasion and migration, and reversed chemoresistance in gastric CSCs in vitro and vivo. CDK5RAP3 expression was found to be regulated by extracellular-related kinase (ERK) signalling. ERK inhibitors decreased spheroid formation, migration and invasion, and the expression of epithelial-to-mesenchymal transition (EMT)-related proteins in both GA cells and organoids derived from a genetically engineered mouse model of GA. Finally, CDK5RAP3 expression was associated with reduced lymph-node metastasis and better prognosis, even in the presence of high expression of the EMT transcription factor Snail, among patients with CD44-positive GA. Conclusions Our results demonstrate that CDK5RAP3 is suppressed by ERK signalling and negatively regulates the self-renewal and EMT of gastric CSCs.

Background BATF2, also known as SARI, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Methods We obtained GC tissues and corresponding normal tissues from 8 patients and identified BATF2 as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine BATF2 levels in normal and GC tissues. The prognostic value of BATF2 was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of BATF2 in GC growth and metastasis were evaluated in vitro and in vivo. Results BATF2 expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that BATF2 was an independent prognostic factor and effective predictor in patients with GC. Low BATF2 expression was remarkably associated with peritoneal recurrence after curative gastrectomy. Moreover, elevated BATF2 expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, BATF2 binds to p53 and enhances its protein stability, thereby inhibiting the phosphorylation of ERK. Tissue microarray results indicated that the prognostic value of BATF2 was dependent on ERK activity. In addition, the N6-methyladenosine (m6A) modification of BATF2 mRNA by METTL3 repressed its expression in GC. Conclusions Collectively, our findings indicate the pivotal role of BATF2 in GC and highlight the regulatory function of the METTL3/BATF2/p53/ERK axis in modulating GC progression, which provides potential prognostic and therapeutic targets for GC treatment.

We have shown that activation of the receptor tyrosine kinase (RTK)-RAS pathway in gastric adenocarcinoma (GA) promotes acquisition of cancer stem-like cell (CSC) phenotypes including metastasis and chemotherapy resistance. Here, we evaluated the prognostic value of the CSC marker CD44 and the RTK-RAS activation marker phosphorylated MEK (p-MEK) in patients with resectable GA. CD44 and p-MEK were measured in tumors from GA patients who underwent curative-intent gastrectomy at Fujian Medical University Union Hospital (FMUUH, n = 134) and Memorial Sloan Kettering Cancer Center (MSKCC, n = 56). Overall survival (OS) was estimated by the Kaplan-Meier method, and multivariate analysis was performed by Cox proportional hazards regression modeling. Despite multiple significant differences in clinicopathologic characteristics between the FMUUH and MSKCC cohorts, high CD44 and high p-MEK expression were both independent negative prognostic factors for OS on univariate analysis in both cohorts (p

Background In clinical practice, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are the most common markers measured before and after surgery for gastric cancer (GC). However, which pre- or post-operative combined tumour markers (CEA and CA19-9) have more prognostic value remains unclear. Methods Consecutive patients undergoing a resection for GC at the Fujian Medical University Union Hospital were included as a discovery database between January 2011 and December 2014. The prognostic impact of pre- and post-operative tumour markers was evaluated using Kaplan–Meier log-rank survival analysis and multivariable Cox regression analysis. The results were then externally validated. Results A total of 735 and 400 patients were identified in the discovery cohort and in the validation cohort, respectively. Overall survival rates decreased in a stepwise manner in association with the number of pre- and post-operative positive tumour markers (both P P Conclusion Pre-operative tumour markers have a better discriminatory ability for post-operative survival in GC patients than post-operative tumour markers, and the normalisation of tumour markers after surgery was associated with better survival.

Background: There are controverted whether the long-term use of proton pump inhibitors (PPI) will increase the risk of gastric cancer. We performed a meta-analysis to assess the risk of gastric cancer in PPI users compared with non-PPI users. Methods: The main inclusion criteria were original studies reporting the incidence of gastric cancer in PPI users compared with non-PPI users. Key outcomes were the risk ratios (RR) for gastric cancer in association with PPI users or non-PPI users. Results: We analyzed data from 8 studies, comprising more than 927,684 patients. The risk of gastric cancer in PPI users was significantly higher than in non-PPI users [RR= 2.10, 95% CI (1.17-3.97)]. The risk of gastric cancer was similar between the 2 groups when the duration was ≤1 year [RR= 2.18, 95% CI (0.66-7.11)]. While the risk of gastric cancer for PPI users was higher than in non-PPI users when the duration was between 1-3 years, ≥1 year, ≥3 years and ≥5 years. The risk of non-cardiac gastric cancer for PPI users was higher than for non-PPI users [RR= 2.66, 95% CI (1.66 -4.27)], and the risk of non-cardiac gastric cancer for PPI users was higher than for non-PPI users when the duration ≥1 year [RR= 1.99, 95% CI (1.03-3.83)], but the risk for cardiac gastric cancer was similar between the 2 groups [RR= 1.86, 95% CI (0.71-4.89)]. Conclusions: We found the long-term use of PPI (duration ≥1 year) was significantly associated with a higher risk of non-cardiac gastric cancer.

Purpose: To evaluate whether the European Neuroendocrine Tumor Society (ENETS) system or the 8th American Joint Committee on Cancer (AJCC) staging manual are suitable for gastric neuroendocrine carcinomas and/or mixed adenoneuroendocrine carcinomas (G-NECs/MANECs). Methods: Patients in a multicentric series with G-NEC/MANEC who underwent curative-intent surgical resection for a primary tumor were included. An optimal staging system was proposed base on analysis of the T and N status and validated by the SEER database. Results: Compared with the ENETS system, the survival curves of the T category and N category in the 8th AJCC system were better separated and distributed in a more balanced way, but the survival curves of T2 vs. T3, N0 vs. N1, and N3a vs. N3b overlapped. For the T category, the 8th AJCC T category was modified by combining T2 and T3, which was consistent with the T category in the 6th AJCC manual for GC. For the N category, the optimal cut-off values of metastatic lymph nodes using X-tile were also similar to those of the N category in the 6th AJCC system. The Kaplan-Meier plots of the 6th AJCC system showed statistically significant differences between individual substages. Compared with the other 2 classifications, the 6th AJCC system also showed superior prognostic stratification. Similar results were obtained in both multicentric and SEER validation sets. Conclusions: Compared to the 8th AJCC and ENETS systems, the 6th AJCC staging system for GC is more suitable for G-NEC/MANEC and can be adopted in clinical practice.

Objective: To evaluate the prognostic significance of the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging classification for gastric cancer. Methods: Prospective databases were reviewed to identify patients who underwent radical gastrectomy at two specialized eastern centers. The prognostic value of the eighth edition TNM classification was estimated and compared with that of the seventh edition. Additional external validation was performed using a dataset from a Western population. Results: Significant differences in 5-year overall survival (OS) rates were observed for each TNM stage when using the eighth edition system, and smaller Akaike information criteria (AIC) values and a higher c-statistic were observed relative to those of the seventh edition. However, the OS rates in each subgroup of stage III patients based on the eighth edition were significantly different. Patients with the same pN stage, namely, the pT4a and pT4b groups, showed similar 5-year OS (P>0.05). Based on the survival data, we propose a simplified staging system. In the improved TNM (iTNM) staging system, the subgroups of a given TNM stage do not show statistically significant differences in OS. The iTNM staging exhibits superior prognostic stratification, with lower AIC values and a higher c-statistic than the eighth edition TNM classification. Similar results were obtained with the external validation dataset from the IMIGASTRIC database. Conclusion: The prognostic prediction of the eighth edition of the AJCC TNM classification is superior to that of the seventh edition. However, it remains associated with some stage migration. The iTNM staging system permits simplification and slightly better prognostic prediction.

Background: Several meta-analyses have tried to defi ne the role of minimally invasive approaches. However, further evidence to get a wider spread of these methods is necessary. Current studies describe minimally invasive surgery as a possible alternative to open surgery but deserving further clarifi cation. However, despite the increasing interest, the difficulty of planning prospective studies of adequate size accounts for the low level of evidence, which is mostly based on retrospective experiences. A multi-institutional prospective study allows the collection of an impressive amount of data to investigate various aspects of minimally invasive procedures with the opportunity of developing several subgroup analyses. A prospective data collection with high methodological quality on minimally invasive and open gastrectomies can clarify the role of diff erent procedures with the aim to develop specifi c guidelines. Methods and analysis: a multi-institutional prospective database will be established including information on surgical, clinical and oncological features of patients treated for gastric cancer with robotic, laparoscopic or open approaches and subsequent follow-up. The study has been shared by the members of the International study group on Minimally Invasive surgery for GASTRIc Cancer (IMIGASTRIC) The database is designed to be an international electronic submission system and a HIPPA protected real time data repository from high volume gastric cancer centers. Ethics: This study is conducted in compliance with ethical principles originating from the Helsinki Declaration, within the guidelines of Good Clinical Practice and relevant laws/regulations. Trial registration number: NCT02751086

The present study was designed to evaluate the dynamic survival and recurrence of remnant gastric cancer (RGC) after radical resection and to provide a reference for the development of personalized follow‐up strategies. A total of 298 patients were analyzed for their 3‐year conditional overall survival (COS3), 3‐year conditional disease‐specific survival (CDSS3), corresponding recurrence and pattern changes, and associated risk factors. The 5‐year overall survival (OS) and the 5‐year disease‐specific survival (DSS) of the entire cohort were 41.2% and 45.8%, respectively. The COS3 and CDDS3 of RGC patients who survived for 5 years were 84.0% and 89.8%, respectively. The conditional survival in patients with unfavorable prognostic characteristics showed greater growth over time than in those with favorable prognostic characteristics (eg, COS3, ≥T3: 46.4%‐83.0%, Δ36.6% vs ≤T2: 82.4%‐85.7%, Δ3.3%; P 0.05). Time‐dependent logistic regression analysis showed that the AJCC stage independently affected recurrence within 2 years after surgery (P, Patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow‐up model for RGC patients of different stages.

To examine the associations of the Age-Adjusted Charlson Comorbidity Index (ACCI) and preoperative systemic inflammation with survival in gastric cancer (GC) patients who underwent radical gastrectomy.Data from patients with GC who underwent radical gastrectomy between January 2009 and December 2014 in Fujian Medical University Union Hospital were retrospectively analyzed. Univariate and multivariate Cox regression analyses were performed to identify the prognostic factors. The relationship between the ACCI and systemic inflammation of the patients was explored, and the prognostic value of a new scoring system based on the ACCI and systemic inflammation (ANLR) was evaluated.A total of 2257 patients with GC were included. The ACCI and neutrophil to lymphocyte ratio (NLR) were independent prognostic factors for overall survival (both P 0.001) by multivariate analysis. A higher ACCI was an independent predictor of the increase in preoperative NLR (P 0.001). Based on the preoperative ACCI and NLR, we established a novel marker, ANLR. Multivariate analysis showed that the ANLR was a significant independent predictor of 5-year OS (P 0.001). The Harrell's C-statistics (C-index) of a model combining the ANLR and pTNM was 0.744 (95% CI: 0.728-0.760), which was significantly higher than the pTNM stage (0.717, 95% CI: 0.702-0.731; P 0.001).The ACCI of patients with gastric cancer was associated with preoperative systemic inflammation. The ACCI combined with the NLR, which are commonly collected biomarkers, could enhance prognostication for GC patients.

Background Application of indocyanine green (ICG) fluorescence imaging is effective in guiding laparoscopic radical lymphadenectomy for gastric cancer. However, the optimal approach for indocyanine green injection is controversial. Therefore, the objective of this study was aimed to compare the efficacy and ICG injection between the preoperative submucosal and intraoperative subserosal approaches for lymph node (LN) tracing during laparoscopic gastrectomy. Method This randomized controlled trial (ClinicalTrials.gov, NCT04219332) included 266 patients with potentially resectable gastric cancer (cT1–T4a, N0/+, M0) enrolled from a tertiary teaching center between December 2019 and October 2020. The primary endpoint was total number of retrieved LNs. Results In total, 259 patients (n = 130 and n = 129 in the submucosal and subserosal groups, respectively) were included in the per-protocol analysis. There are no significant differences in total number of retrieved LNs between the two groups (49.8 vs. 49.2, P = 0.713). The rate of LN noncompliance in the submucosal group was comparable to that in the subserosal group (32.3% vs. 33.3%, P = 0.860). No significant difference was found between the submucosal and subserosal groups in terms of the incidence (17.7% vs. 16.3%; P = 0.762) or severity of postoperative complications. The mean fluorescence cost in the submucosal group was higher than that in the subserosal group ($335.3 vs. $182.4; P < 0.001). The overall treatment satisfaction score was lower in the submucosal group than in the subserosal group (70.5 vs. 76.1%, P = 0.048). Conclusion ICG administered by subserosal injection was comparable to that administered by submucosal injection for lymph node tracing in gastric cancer. However, the former approach imposed a lower economic and mental burden on patients undergoing laparoscopic D2 lymphadenectomy. Trial registration ClinicalTrials.gov, NCT04219332.

Simple Summary Even after the implementation of intensity-modulated radiotherapy (IMRT), nasopharyngeal cancer (NPC) survivors may continue to exhibit several physical symptoms that negatively affect long-term quality of life (QoL). An NPC patient cohort study (n = 682) was conducted to examine the potential mediating effect of QoL (evaluated at multiple treatment-related time points) on the cancer stage–mortality association. Patients with advanced NPC exhibited low global health QoL and high QoL-HN35 symptom pre-IMRT, 3 months post-IMRT, and 2 years post-IMRT. Global health QoL and QoL-HN35 symptom scores 2 years after IMRT explained 49.4% and 39.4% of the excessive effect of advanced NPC on mortality risk. Our findings indicate that global health QoL and QoL-HN35 symptom 2 years after IMRT are key mediators of the relationship between advanced NPC and high mortality. These findings emphasize the significance of QoL-HN35 symptom and global health QoL-associated medical support and care for patients with NPC who received IMRT. Abstract Background: Quality of life (QoL) attained before, during, or after treatments is recognized as a vital factor associated with therapeutic benefits in cancer patients. This nasopharyngeal cancer (NPC) patient longitudinal study assessed the relationship among QoL, cancer stage, and long-term mortality in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). Patients and Methods: The European Organization for Research and Treatment of Cancer (EORTC) core QoL questionnaire (QLQ-C30) and the head and neck cancer-specific QoL questionnaire module (QLQ-HN35) were employed to evaluate four-dimensional QoL outcomes at five time points: pre- (n = 682), during (around 40 Gy) (n = 675), 3 months (n = 640), 1 year (n = 578) and 2 years post-IMRT (n = 505), respectively, for 682 newly diagnosed NPC patients treated between 2003 and 2017 at a single institute. The median followed-up time was 7.5 years, ranging from 0.3 to 16.1 years. Generalized estimating equations, multivariable proportional hazards models, and Baron and Kenny’s method were used to assess the investigated effects. Results: Advanced AJCC stage (III–IV) patients revealed a 2.26-fold (95% CI—1.56 to 3.27) higher covariate-adjusted mortality risk than early-stage (I–II) patients. Compared with during IMRT, advanced-stage patients had a significantly low global health QoL and a significantly high QoL-HN35 symptom by a large magnitude at pre-, 3 months, and 2 years post-IMRT. QoL scales at pre-IMRT, 1 year, and 2 years post-IMRT were significantly associated with mortality. The effect changes of mortality risk explained by global health QoL, QoL-C30, and QoL-HN35 symptom were 5.8–9.8% at pre-IMRT but at 2 years post-IMRT were 39.4–49.4% by global health QoL and QoL-HN35 symptoms. Conclusions: We concluded advanced cancer stage correlates with a long-term high mortality in NPC patients treated with IMRT and the association is partially intermediated by QoL at pre-IMRT and 2 years post-IMRT. Therefore, QoL-HN35 symptom and global health QoL-dependent medical support and care should be focused and tailored at 2 years post-IMRT.

Pancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide due to delayed diagnosis and limited treatments. More than 90% of all pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). Extensive communication between tumour cells and other cell types in the tumour microenvironment have been identified which regulate cancer hallmarks during pancreatic tumorigenesis via secretory factors and extracellular vesicles (EVs). The EV-capsuled factors not only facilitate tumour growth locally, but also enter circulation and reach distant organs to construct a pre-metastatic niche. In this review, we delineate the key factors in pancreatic ductal adenocarcinoma derived EVs that mediate different tumour processes. Also, we highlight the factors that are related to the crosstalk with cancer stem cells/cancer-initiating cells (CSC/CIC), the subpopulation of cancer cells that can efficiently metastasize and resist currently used chemotherapies. Lastly, we discuss the potential of EV-capsuled factors in early diagnosis and antitumour therapeutic strategies.

This cross-sectional study examines the characteristics and presence of research waste, defined as unpublished data, inadequate reporting, or avoidable design limitations, among randomized clinical trials in gastric cancer., Key Points Question Is there research waste (ie, unpublished data, inadequate reporting, or avoidable design limitations) in randomized clinical trials (RCTs) of gastric cancer? Findings This cross-sectional study included 137 RCTs, of which 119 had 1 or more features of research waste. Additionally, 35 RCTs were referenced in guidelines, and 18 had their prospective data reused. Meaning This study found a research waste burden in gastric cancer RCTs during the past 20 years, which may provide evidence for the development of rational RCTs and reduction of waste in the future., Importance The results of numerous large randomized clinical trials (RCTs) have changed clinical practice in gastric cancer (GC). However, research waste (ie, unpublished data, inadequate reporting, or avoidable design limitations) is still a major challenge for evidence-based medicine. Objectives To determine the characteristics of GC RCTs in the past 20 years and the presence of research waste and to explore potential targets for improvement. Design, Setting, and Participants In this cross-sectional study of GC RCTs, ClinicalTrials.gov was searched for phase 3 or 4 RCTs registered from January 2000 to December 2019 using the keyword gastric cancer. Independent investigators undertook assessments and resolved discrepancies via consensus. Data were analyzed from August through December 2020. Main Outcomes and Measures The primary outcomes were descriptions of the characteristics of GC RCTs and the proportion of studies with signs of research waste. Research waste was defined as unpublished data, inadequate reporting, or avoidable design limitations. Publication status was determined by searching PubMed and Scopus databases. The adequacy of reporting was evaluated using the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline checklist. Avoidable design limitations were determined based on existing bias or lack of cited systematic literature reviews. In the analyses of research waste, 125 RCTs that ended after June 2016 without publication were excluded. Results A total of 262 GC RCTs were included. The number of RCTs increased from 25 trials in 2000 to 2004 to 97 trials in 2015 to 2019, with a greater increase among RCTs of targeted therapy or immunotherapy, which increased from 0 trials in 2000 to 2004 to 36 trials in 2015 to 2019. The proportion of RCTs that were multicenter was higher in non-Asian regions than in Asian regions (50 of 71 RCTs [70.4%] vs 96 of 191 RCTs [50.3%]; P = .004). The analysis of research waste included 137 RCTs, of which 81 (59.1%) were published. Among published RCTs, 65 (80.2%) were judged to be adequately reported and 63 (77.8%) had avoidable design defects. Additionally, 119 RCTs (86.9%) had 1 or more features of research waste. Study settings that included blinding (odds ratio [OR], 0.56; 95% CI, 0.33-0.93; P = .03), a greater number of participants (ie, ≥200 participants; OR, 0.07; 95% CI, 0.01-0.51; P = .01), and external funding support (OR, 0.22; 95% CI, 0.08-0.60; P = .004) were associated with lower odds of research waste. Additionally, 35 RCTs (49.3%) were referenced in guidelines, and 18 RCTs (22.2%) had their prospective data reused. Conclusions and Relevance To our knowledge, this study is the first to describe the characteristics of GC RCTs in the past 20 years, and it found a research waste burden, which may provide evidence for the development of rational RCTs and reduction of waste in the future.

Background: The laparoscopic approach in gastric cancer surgery is being increasingly adopted worldwide. However, studies focusing specifically on laparoscopic gastrectomy with D2 lymphadenectomy are still lacking in the literature. This retrospective study aimed to compare the short-term and long-term outcomes of laparoscopic versus open gastrectomy with D2 lymphadenectomy for gastric cancer. Methods: The protocol-based, international IMIGASTRIC (International study group on Minimally Invasive surgery for Gastric Cancer) registry was queried to retrieve data on patients undergoing laparoscopic or open gastrectomy with D2 lymphadenectomy for gastric cancer with curative intent from January 2000 to December 2014. Eleven predefined, demographical, clinical, and pathological variables were used to conduct a 1:1 propensity score matching (PSM) analysis to investigate intraoperative and recovery outcomes, complications, pathological findings, and survival data between the two groups. Predictive factors of long-term survival were also assessed. Results: A total of 3033 patients from 14 participating institutions were selected from the IMIGASTRIC database. After 1:1 PSM, a total of 1248 patients, 624 in the laparoscopic group and 624 in the open group, were matched and included in the final analysis. The total operative time (median 180 versus 240 min, p &lt, 0.0001) and the length of the postoperative hospital stay (median 10 versus 14.8 days, p &lt, 0.0001) were longer in the open group than in the laparoscopic group. The conversion to open rate was 1.9%. The proportion of patients with in-hospital complications was higher in the open group (21.3% versus 15.1%, p = 0.004). The median number of harvested lymph nodes was higher in the laparoscopic approach (median 32 versus 28, p &lt, 0.0001), and the proportion of positive resection margins was higher (p = 0.021) in the open group (5.9%) than in the laparoscopic group (3.2%). There was no significant difference between the groups in five-year overall survival rates (77.4% laparoscopic versus 75.2% open, p = 0.229). Conclusion: The adoption of the laparoscopic approach for gastric resection with D2 lymphadenectomy shortened the length of hospital stay and reduced postoperative complications with respect to the open approach. The five-year overall survival rate after laparoscopy was comparable to that for patients who underwent open D2 resection. The types of surgical approaches are not independent predictive factors for five-year overall survival.

The value of indocyanine green (ICG) fluorescence imaging in tracing metastatic lymph nodes (LNs) has rarely been reported. We aimed to evaluate the clinical implications of fluorescence imaging-guided lymphadenectomy and the sensitivity of fluorescent lymphography to detect metastatic LN stations in gastric cancer (GC).This analysis pooled data from two randomized controlled trials (FUGES-012 and FUGES-019 studies) on laparoscopic ICG tracer-guided lymphadenectomy for GC between November 2018 and October 2020. Patients who received ICG injection using either the intraoperative subserosal or preoperative submucosal approaches 1 day before surgery and underwent fluorescence imaging-guided lymphadenectomy were defined as the ICG group. Patients who underwent conventional lymphadenectomy without ICG injection and intraoperative imaging were defined as the non-ICG group.Among 514 enrolled patients, the ICG and non-ICG groups included 385 and 129, respectively. A significantly higher mean number of LNs was retrieved in the ICG group than in the non-ICG group (49.9 vs. 42.0, P 0.001). The ICG group showed a lower LN noncompliance rate than that in the non-ICG group (31.9% vs. 57.4%, P 0.001). The sensitivity of fluorescence imaging for detecting all metastatic LN stations was 86.8%. The negative predictive value was 92.2% for nonfluorescent stations. For detecting all metastatic stations, subgroup analysis revealed 97.7%, 91.7%, 86.2%, and 84.3% sensitivities for pT1, pT2, pT3, and pT4a tumors, respectively. Regardless of gastrectomy type, the diagnostic accuracy for detecting all metastatic stations in the D1+ and D2 stations for cT1-cT2 disease reached 100%.ICG fluorescence imaging, using either the subserosal or submucosal approaches, assisted in the thorough dissection of potentially metastatic LNs, as recommended for individualized laparoscopic lymphadenectomy for GC.

BackgroundLHPP, a histidine phosphatase, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. MethodsWe obtained GC tissues and corresponding normal tissues from 8 patients and identified LHPP as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine LHPP levels in normal and GC tissues. The prognostic value of LHPP was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of LHPP in GC growth and metastasis were evaluated in vitro and in vivo. ResultsThe results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that LHPP was an independent prognostic factor and effective predictor in patients with GC. The low expression of LHPP was significantly related to the poor prognosis and chemotherapy sensitivity of gastric cancer patients. Moreover, elevated LHPP expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, the m6A modification of LHPP mRNA by METTL14 represses its expression; LHPP inhibits the phosphorylation of GSK3b through acetylation, and mediates HIF1A to inhibit glycolysis, proliferation, invasion and metastasis of gastric cancer cells. ConclusionLHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. Thus, LHPP is a potential predictive biomarker and therapeutic target for GC.

ObjectiveTo validate the prognostic value of tumor regression grading (TRG) and to explore the associated factors of TRG for advanced gastric cancer (AGC) with neoadjuvant chemotherapy (NACT) plus surgery.MethodsTwo hundred forty-nine AGC patients treated with NACT followed by gastrectomy at the Mayo Clinic, USA and the Fujian Medical University Union Hospital, China between January 2000 and December 2016 were enrolled in this study. Cox regression was used to identify covariates associated with overall survival (OS) and recurrence-free survival (RFS). Logistic regression was used to reveal factors predicting tumor regression grading.ResultsFor patients with TRG 0-1, the 3- and 5-year OS rates were 85.2% and 74.5%, respectively, when compared to 56.1% and 44.1% in patients with TRG 2 and 28.2% and 23.0% in patients with TRG 3, respectively (pvs 19.5 months, respectively; p=0.01). Subgroup analyses by histological subtype indicated that the oxaliplatin-based regimen improved the OS in nonsignet ring cell carcinoma compared to the nonoxaliplatin-based regimen (53.7 months vs 19.5 months, respectively; p=0.011). However, similar findings were not observed in RFS.ConclusionTRG was an independent factor of AGC treated with neoadjuvant chemotherapy plus surgery. Oxaliplatin-based neoadjuvant chemotherapy regimens improve tumor response and may have an overall survival benefit for patients with nonsignet ring cell carcinoma.

The triad of noise-generated, drug-induced, and age-related hearing loss is the major cause of acquired sensorineural hearing loss (ASNHL) in modern society. Although these three forms of hearing loss display similar underlying mechanisms, detailed studies have revealed the presence of sex differences in the auditory system both in human and animal models of ASNHL. However, the sexual dimorphism of hearing varies among noise-induced hearing loss (NIHL), ototoxicity, and age-related hearing loss (ARHL). Importantly, estrogen may play an essential role in modulating the pathophysiological mechanisms in the cochlea and several reports have shown that the effects of hormone replacement therapy on hearing loss are complex. This review will summarize the clinical features of sex differences in ASNHL, compare the animal investigations of cochlear sexual dimorphism in response to the three insults, and address how estrogen affects the auditory organ at molecular levels.

Key Points Question Are there any differences in prognoses or recurrence patterns associated with gastric neuroendocrine carcinoma, mixed adenoneuroendocrine carcinoma, or adenocarcinoma? Findings This cohort study included 3689 patients with resectable gastric adenocarcinoma, gastric neuroendocrine carcinoma, or gastric mixed adenoneuroendocrine carcinoma. Propensity score matching analysis found that, compared with gastric adenocarcinoma, gastric neuroendocrine carcinoma and gastric mixed adenoneuroendocrine carcinoma were independent risk factors associated with worse disease-free survival, postrecurrence survival, and distant recurrence outcomes. Meaning These findings suggest that 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 for patients with tumors penetrating into the subserosa or deeper layers and with lymph node metastasis., This cohort study examines differences in long-term survival and patterns of recurrence among patients with gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric 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

Objective: The aim of this study was to identify if breast reconstruction is a surgical risk factor for axillary web syndrome (AWS) in breast cancer (BC) patients. Methods: The data of 207 patients who have been diagnosed with unilateral BC and who had mastectomy and lymph node dissection were retrospectively reviewed. Information of their clinical and pathological data, whether they had immediate ­reconstruction and intraoperative radiotherapy, surgical methods, and postoperative complications during the 3 months after their surgery (AWS, lymphedema, seroma, and myofascial adhesion) were collected, and the incidence of AWS was compared between different surgical methods. ­Results: The overall incidence of AWS was 48.8% in 207 patients. Of the 22 patients who received reconstruction, 19 developed AWS, yielding an incidence of 86%. Multivariate logistic regression modeling showed that patients who underwent reconstruction had a significantly higher incidence of AWS (odds ratio, 4.74), as did patients with postoperative complication of myofascial adhesion (odds ratio, 7.07). Conclusions: BC survivors after breast reconstruction are susceptible to AWS, and there is a significant association between myofascial adhesion and AWS. Our results can stimulate further investigation and provide an evidence base for the development of educational guidance for patients who plan to undergo breast reconstruction.

BACKGROUND The incidence of proximal gastric cancer (GC) is increasing, and methods for the prediction of the long-term survival of proximal GC patients have not been well established. AIM To develop nomograms for the prediction of long-term survival among proximal GC patients. METHODS Between January 2007 and June 2013, we prospectively collected and retrospectively analyzed the medical records of 746 patients with proximal GC, who were divided into a training set (n = 560, 75%) and a validation set (n = 186, 25%). A Cox regression analysis was used to identify the preoperative and postoperative risk factors for overall survival (OS). RESULTS Among the 746 patients examined, the 3- and 5-year OS rates were 66.1% and 58.4%, respectively. In the training set, preoperative T stage (cT), N stage (cN), CA19-9, tumor size, ASA core, and 3- to 6-mo weight loss were incorporated into the preoperative nomogram to predict the OS. In addition to these variables, lymphatic vascular infiltration (LVI), postoperative tumor size, T stage, N stage, blood transfusions, and complications were incorporated into the postoperative nomogram. All calibration curves used to determine the OS probability fit well. In the training set, the preoperative nomogram achieved a C-index of 0.751 [95% confidence interval (CI): 0.732-0.770] in predicting OS and accurately stratified the patients into four prognostic subgroups (5-year OS rates: 86.8%, 73.0%, 43.72%, and 20.9%, P < 0.001). The postoperative nomogram had a C-index of 0.758 in predicting OS and accurately stratified the patients into four prognostic subgroups (5-year OS rates: 82.6%, 74.3%, 45.9%, and 18.9%, P < 0.001). CONCLUSION The nomograms accurately predicted the pre- and postoperative long-term survival of proximal GC patients.

BACKGROUND Because of the powerful abilities of self-learning and handling complex biological information, artificial neural network (ANN) models have been widely applied to disease diagnosis, imaging analysis, and prognosis prediction. However, there has been no trained preoperative ANN (preope-ANN) model to preoperatively predict the prognosis of patients with gastric cancer (GC). AIM To establish a neural network model that can predict long-term survival of GC patients before surgery to evaluate the tumor condition before the operation. METHODS The clinicopathological data of 1608 GC patients treated from January 2011 to April 2015 at the Department of Gastric Surgery, Fujian Medical University Union Hospital were analyzed retrospectively. The patients were randomly divided into a training set (70%) for establishing a preope-ANN model and a testing set (30%). The prognostic evaluation ability of the preope-ANN model was compared with that of the American Joint Commission on Cancer (8th edition) clinical TNM (cTNM) and pathological TNM (pTNM) staging through the receiver operating characteristic curve, Akaike information criterion index, Harrell's C index, and likelihood ratio chi-square. RESULTS We used the variables that were statistically significant factors for the 3-year overall survival as input-layer variables to develop a preope-ANN in the training set. The survival curves within each score of the preope-ANN had good discrimination (P < 0.05). Comparing the preope-ANN model, cTNM, and pTNM in both the training and testing sets, the preope-ANN model was superior to cTNM in predictive discrimination (C index), predictive homogeneity (likelihood ratio chi-square), and prediction accuracy (area under the curve). The prediction efficiency of the preope-ANN model is similar to that of pTNM. CONCLUSION The preope-ANN model can accurately predict the long-term survival of GC patients, and its predictive efficiency is not inferior to that of pTNM stage.

BACKGROUND Robotic surgery has been considered to be significantly better than laparoscopic surgery for complicated procedures. AIM To explore the short-term effect of robotic and laparoscopic spleen-preserving splenic hilar lymphadenectomy (SPSHL) for advanced gastric cancer (GC) by Huang’s three-step maneuver. METHODS A total of 643 patients who underwent SPSHL were recruited from April 2012 to July 2017, including 35 patients who underwent robotic SPSHL (RSPSHL) and 608 who underwent laparoscopic SPSHL (LSPSHL). One-to-four propensity score matching was used to analyze the differences in clinical data between patients who underwent robotic SPSHL and those who underwent laparoscopic SPSHL. RESULTS In all, 175 patients were matched, including 35 patients who underwent RSPSHL and 140 who underwent LSPSHL. After matching, there were no significant differences detected in the baseline characteristics between the two groups. Significant differences in total operative time, estimated blood loss (EBL), splenic hilar blood loss (SHBL), splenic hilar dissection time (SHDT), and splenic trunk dissection time were evident between these groups (P < 0.05). Furthermore, no significant differences were observed between the two groups in the overall noncompliance rate of lymph node (LN) dissection (62.9% vs 60%, P = 0.757), number of retrieved No. 10 LNs (3.1 ± 1.4 vs 3.3 ± 2.5, P = 0.650), total number of examined LNs (37.8 ± 13.1 vs 40.6 ± 13.6, P = 0.274), and postoperative complications (14.3% vs 17.9%, P = 0.616). A stratified analysis that divided the patients receiving RSPSHL into an early group (EG) and a late group (LG) revealed that the LG experienced obvious improvements in SHDT and length of stay compared with the EG (P < 0.05). Logistic regression showed that robotic surgery was a significantly protective factor against both SHBL and SHDT (P < 0.05). CONCLUSION RSPSHL is safe and feasible, especially after overcoming the early learning curve, as this procedure results in a radical curative effect equivalent to that of LSPSHL.

Background Previous studies have elucidated that on average, long-term cancer survivors have better prognoses than newly diagnosed individuals. This study aimed to devise a nomogram to predict the conditional probability of cancer-specific survival (CPCS) in gastric cancer (GC) patients after D2 lymphadenectomy. Methods Clinicopathological data for 2,596 GC patients who underwent D2 lymphadenectomy in an Eastern institution (the training cohort) were retrospectively analysed. Cancer-specific survival (CSS) was predicted using Cox regression models. A nomogram was constructed to predict CPCS at 3 and 5 years post-gastrectomy. Two external validations were performed using a cohort of 2,198 Chinese patients and a cohort of 504 Italian patients. Results In the training cohort, the 5-year CPCS was 59.2% immediately post-gastrectomy and increased to 68.8%, 79.7%, and 88.8% at 1, 2, and 3 years post-gastrectomy, respectively. Multivariate Cox regression analyses showed that age; tumour site, size and invasion depth; numbers of examined and metastatic lymph nodes; and surgical margins were independent prognostic factors of CSS (all P Conclusions: we developed a robust nomogram to predict CPCS after D2 lymphadenectomy for GC based on survival duration.

Traumatic brain injury (TBI) is a leading cause of death and disability throughout the world. However, the molecular mechanism contributing to TBI still remains unclear. Protein disulfide isomerases (PDI) are a family of redox chaperones, which catalyze formation or isomerization of disulfide bonds in proteins. PDIA3, a critical member of PDI family, is a multi-functional protein, playing critical roles in modulating inflammation, apoptosis and oxidative stress under various kinds of disease conditions. Nevertheless, its regulatory effects on TBI have far from to be known. In the present study, we attempted to explore the modulation of neuroinflammatory responses by PDIA3 and its contribution to oxidative stress and cell death after TBI in the wild type (PDIA+/+) and PDIA3 knockout (PDIA3+/+) C57BL/6 mice. Results here suggested that PDIA3 expression was markedly up-regulated in the late trauma human brain tissues, which was verified in the PDIA3+/+ mice at 24 h after TBI. PDIA−/- provided significant improvements in cognitive impairments and contusion volume induced by TBI. Apoptosis in brain samples was also alleviated in TBI mice with PDIA3 deficiency. Significantly, PDIA3−/− mitigated neuroinflammation after TBI in mice, as evidenced by the reduced expression of pro-inflammatory factors interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and IL-1β, while the enhanced anti-inflammatory regulator IL-10. These anti-inflammatory activities by PDIA3−/− were associated with the decrease in phosphorylated nuclear factor kappa B (NF-κB)/p65. PDIA3−/− mice following TBI showed attenuated oxidative stress, as proved by the restored superoxide dismutase (SOD) and glutathione (GSH) activities, and the down-regulated malondialdehyde (MDA) levels in brain samples. These effects regulated by PDIA3 were confirmed in OGDR-treated astrocytes. Collectively, these data demonstrated a detrimental role of PDIA3 in regulating TBI, providing an effective therapeutic target for TBI treatment in future.

Objective. Circular RNAs (circRNAs) have been reported to be widely involved in pathological processes of various cancers. However, little is known about their diagnostic values in early gastric cancer (EGC). This study is aimed at exploring whether circulating circRNAs in plasma could act as biomarkers for EGC diagnosis. Materials and Methods. Mass spectrometry (MS) was performed to identify the proteins that at significantly aberrantly levels in gastric cancer (GC) tissues. The target circRNA was identified by bioinformatics analysis. A receiver operating characteristic (ROC) curve was generated to evaluate the diagnostic utility. Results. MS revealed that the ribosomal protein L6 (RPL6) expression was significantly downregulated only in EGC tissues vs. nontumorous tissues; this was validated by western blotting (n=30, p=0.0094). Bioinformatics analysis predicted that there is a hsa_circ_0006848/hsa_miR-329-5p/RPL6 axis in GC progression. The hsa_circ_0006848 expression was significantly downregulated in EGC tissues (vs. nontumorous tissues, n=30, p=0.0073) and plasma samples from EGC patients (vs. paired healthy volunteers, n=30, p=0.0089). In addition, the hsa_circ_0006848 plasma level in postoperative patients was significantly higher than that of preoperative patients (n=30, p=0.047). Furthermore, the decreased hsa_circ_0006848 expression in plasma was negatively correlated with poor differentiation (p=0.037) and tumor size (p=0.046). The area under the ROC curve (AUC) of hsa_circ_0006848 in plasma was 0.733, suggesting a good diagnostic value. The plasma hsa_circ_0006848 level combined with the carcinoembryonic antigen (CEA), carbohydrate-associated antigen 19-9 (CA19-9), and carbohydrate-associated antigen 72-4 (CA72-4) level increased the AUC to 0.825. Conclusion. Our results indicated that plasma hsa_circ_0006848 may be a novel noninvasive biomarker in EGC diagnosis.

Background UFM1 has been found to be involved in the regulation of tumor development. This study aims to clarify the role and potential molecular mechanisms of UFM1 in the invasion and metastasis of gastric cancer. Methods Expression of UFM1 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was analyzed by Western blotting, immunohistochemistry, and realtime PCR. Its correlation with the clinicopathological characteristics and prognosis of gastric cancer patients was analyzed. The effects of UFM1 on the invasion and migration of gastric cancer cells were determined by the wound and trans-well assays, and the effect of UFM1 on subcutaneous tumor formation was verified in nude mice. The potential downstream targets of UFM1 and related molecular mechanisms were clarified by the human protein kinase assay and co-immunoprecipitation technique. Results Compared with the corresponding adjacent tissues, the transcription level and protein expression level of UFM1 in gastric cancer tissues were significantly downregulated (P P Conclusion UFM1 suppresses the invasion and metastasis of gastric cancer by increasing the ubiquitination of PDK1 through negatively regulating PI3K/AKT signaling.

Background Tumor-infiltrating immune cells are present in various malignant tumors, but their clinical significance in gastric cancer (GC) remains unclear. This study aimed to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Methods Using a prospective database containing 401 cases of GC, we evaluated TIL (cluster of differentiation 8 (CD8) expression) and TAM (cluster of differentiation 68 (CD68) expression) statuses via immunohistochemical staining. Results Compared with CD8+ TIL-negative cases (n = 196, 48.6%), CD8+ TIL-positive cases (n = 205, 51.1%) showed significantly better recurrence-free survival (RFS) [log-rank ppn = 217, 54.1%), CD68+ TAM-positive cases (n = 184, 45.9%) had significantly poor RFS [log-rank pp Conclusions CD8+ TIL and CD68+ TAM statuses were identified as independent prognostic factors that may be integrated into the current TNM staging system to refine risk stratification and to better predict the survival benefit from PAC in patients with GC. Trial registration The current controlled trial was registered at ClinicalTrials.gov (ID: NCT02327481) on December 30, 2014.

Summary: To identify the risk factors for intraoperative laparoscopic hemostasis during laparoscopic spleen-preserving splenic hilar lymph node dissection (LSPSD) for proximal gastric cancer (GC) and to develop and validate a model to estimate the risk of intraoperative laparoscopic hemostasis.Between January 2011 and December 2014, we prospectively collected and retrospectively analyzed the medical records of 398 patients with proximal GC who underwent LSPSD. The data were split 75/25, with one group used for model development and the other for validation testing.Of the 398 patients enrolled in this study, 174 (43.7%) required laparoscopic hemostasis treatment. A multivariate analysis determined that the risk factors for the model group were gender, preoperative N stage, and terminal branches of the splenic artery (SpA), and each factor contributed 1 point to the risk score. The intraoperative laparoscopic hemostasis rates were 11.5%, 33.6%, 58.5%, and 73.5% for the low-, intermediate-, high-, and extremely high-risk categories, respectively (p

Background Examined lymph node counts of remnant gastric cancer patients are often insufficient, and the prognostic ability of tumor-node-metastasis staging is therefore limited. This study aimed to create a simple and universally applicable prediction model for RGC patients after completion of gastrectomy. Methods A 5-year overall survival prediction model for remnant gastric cancer patients was developed using a test dataset of 148 consecutive patients. Model coefficients were obtained based on the Cox analysis of clinicopathological factors. Prognostic performance was assessed with the concordance index (C-index) and decision curve analysis. For internal validation, the bootstrap method and calibration assessment were used. The model was validated using 2 external cohorts from China (First Affiliated Hospital of Fujian Medical University, n = 46) and the United States (Mayo Clinic, n = 20). Results Depth of tumor invasion, number of metastatic lymph nodes, distant metastasis, and operative time were independent prognostic factors. Our model’s C-index (0.761) showed better discriminatory power than that of the eighth tumor-node-metastasis staging system (0.714, P = .001). The model calibration was accurate at predicting 5-year survival. Decision curve analysis showed that the model had a greater benefit, and the results were also confirmed by bootstrap internal validation. In external validation, the C-index and decision curve analysis showed good prognostic performances in patient datasets from 2 participating institutions. Moreover, we verified the reliability of the model in an analysis of patients with different examined lymph node counts (>15 or ≤15). Conclusion Utilizing clinically practical information, we developed a universally applicable prediction model for accurately determining the 5-year overall survival of remnant gastric cancer patients after completion of gastrectomy. Our predictive model outperformed tumor-node-metastasis staging in diverse international datasets regardless of examined lymph node counts.

To evaluate the effects of three nutritional scoring systems: Prognostic Nutritional Index (PNI), Controlling Nutritional Status (CONUT), and Naples Prognostic Score (NPS) on the short- or long-term prognosis of gastric cancer (GC) patients who underwent radical gastrectomy. The clinicopathological data of 2182 patients who underwent radical gastrectomy at the Fujian Medical University Union Hospital (FMUUH) from 2009 to 2014 were retrospectively analyzed. The effects of the PNI, CONUT, and NPS on the short- or long-term prognosis of GC patients were analyzed. Overall, 359 (16.5%) patients had postoperative complications. There was no significant association between the PNI, CONUT, and NPS and postoperative complications (P > 0.05); however, high CONUT and NPS were significantly associated with severe postoperative complications (P

Background: A recent study has revealed that miR-106b-5p might promote hepatocellular carcinoma (HCC) stemness maintenance and metastasis by targeting PTEN via PI3K/Akt pathway based on HCC cell lines and animal models. Its clinical relevance remains unknown. Purpose: Herein, we aimed to evaluate associations of miR-106b-5p dysregulation with various clinicopathological features of HCC patients and investigate its functions during HCC progression. Patients and methods: At first, miR-106b-5p expression in 130 pairs of HCC and adjacent normal liver tissues was detected by quantitative PCR. Chi-square test was then performed to determine clinical significance. Further investigations on its functions were performed by miRNA target prediction and validation, as well as cellular experiments. Results: miR-106b-5p levels in HCC tissues were significantly higher than those in the adjacent normal liver tissues (P