Extent of Lymphadenectomy for Surgical Management of Right-Sided Colon Cancer: The Randomized Phase III RELARC Trial.

PURPOSE: Complete mesocolic excision (CME) is being increasingly used for the treatment of right-sided colon cancer, although there is still no strong evidence that CME provides better long-term oncological outcomes than D2 dissection. The controversy is mainly regarding the survival benefit from extended lymph node dissection emphasized by CME. METHODS: This multicenter, open-label, randomized controlled trial (ClinicalTrials.gov identifier: NCT02619942) was performed across 17 hospitals in China. Patients diagnosed with stage T2-T4aNanyM0 or TanyN + M0 right-sided colon cancer were randomly assigned (1:1) to undergo either CME or D2 dissection during laparoscopic right colectomy. The primary outcome was the 3-year disease-free survival (DFS), and the main secondary outcome was the 3-year overall survival (OS). RESULTS: Between January 11, 2016, and December 26, 2019, 1,072 patients were randomly assigned (536 patients to CME and 536 patients to D2 dissection). In total, 995 patients (median age 61 years, 59% male) were included in the primary analysis (CME [n = 495] v D2 dissection [n = 500]). No significant differences were found between the groups in 3-year DFS (hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.02]; P = .06; 86.1% in the CME group v 81.9% in the D2 group) or in 3-year OS (HR, 0.70 [95% CI, 0.43 to 1.16]; P = .17; 94.7% in the CME group v 92.6% in the D2 group). CONCLUSION: This trial failed to find evidence of superior DFS outcome for CME compared with standard D2 lymph node dissection in primary surgical excision of right-sided colon cancer. Standard D2 dissection should be the routine procedure for these patients. CME should only be considered in patients with obvious mesocolic lymph node involvement.

A case of malignant gastric glomus tumor and literature review: A case report.

RATIONALE: Malignant gastric glomus tumor (GGT) is an extremely rare malignant tumor of mesenchymal origin, it affects the patient's health and even threatens life. Malignant GGT with vascular invasion is even more rarely reported in the available literature without a prognostic study. So, in this case, we report a malignant GGT with vascular invasion and performed a 5-year postoperative follow-up. To the best of our knowledge, we report the first case of malignant GGT with vascular invasion without recurrence 5 years after surgery. This provides examples and lessons for the treatment of malignant GGT with vascular invasion. PATIENT CONCERNS: A 49-year-old male was admitted to the hospital with gallbladder stones found on health check. After completing abdominal CT and ultrasound gastroscopy, a mass in the gastric antrum was found. DIAGNOSES: The diagnosis of malignant GGT was confirmed by combination of postoperative pathology with positive immunohistochemistry for SMA, vimentin, synaptophysin, H-caldesmon, and calponin, mitosis > 10/50 HPF and moderate-to-severe nuclear atypia. INTERVENTIONS: On the 6th day of hospitalization, the patient underwent laparoscopic distal gastrectomy and cholecystectomy. OUTCOMES: The patient was discharged successfully 1 week after surgery and was followed up for 5 years without recurrence. CONCLUSION: Malignant GGT can be asymptomatic. For malignant GGT without distant metastasis, despite the presence of vascular invasion, negative margin surgery can still be the standard surgical radical treatment.

Gut microbiota and therapy for obesity and type 2 diabetes.

There has been a major increase in Type 2 diabetes and obesity in many countries, and this will lead to a global public health crisis, which not only impacts on the quality of life of individuals well but also places a substantial burden on healthcare systems and economies. Obesity is linked to not only to type 2 diabetes but also cardiovascular diseases, musculoskeletal disorders, and certain cancers, also resulting in increased medical costs and diminished quality of life. A number of studies have linked changes in gut in obesity development. Dysbiosis, a deleterious change in gut microbiota composition, leads to altered intestinal permeability, associated with obesity and Type 2 diabetes. Many factors affect the homeostasis of gut microbiota, including diet, genetics, circadian rhythms, medication, probiotics, and antibiotics. In addition, bariatric surgery induces changes in gut microbiota that contributes to the metabolic benefits observed post-surgery. Current obesity management strategies encompass dietary interventions, exercise, pharmacotherapy, and bariatric surgery, with emerging treatments including microbiota-altering approaches showing promising efficacy. While pharmacotherapy has demonstrated significant advancements in recent years, bariatric surgery remains one of the most effective treatments for sustainable weight loss. However, access to this is generally limited to those living with severe obesity. This underscores the need for non-surgical interventions, particularly for adolescents and mildly obese patients. In this comprehensive review, we assess longitudinal alterations in gut microbiota composition and functionality resulting from the two currently most effective anti-obesity treatments: pharmacotherapy and bariatric surgery. Additionally, we highlight the functions of gut microbiota, focusing on specific bacteria, their metabolites, and strategies for modulating gut microbiota to prevent and treat obesity. This review aims to provide insights into the evolving landscape of obesity management and the potential of microbiota-based approaches in addressing this pressing global health challenge.

Functional genomics screening identifies aspartyl-tRNA synthetase as a novel prognostic marker and a therapeutic target for gastric cancers.

Efficient molecular targeting therapies for most gastric cancers (GCs) are currently lacking, despite GC being one of the most frequent and often devastating malignancies worldwide. Thus, identification of novel therapeutic targets for GC is in high demand. Recent advancements of high-throughput nucleic acid synthesis methods combined with next-generation sequencing (NGS) platforms have made it feasible to conduct functional genomics screening using large-scale pooled lentiviral libraries aimed at discovering novel cancer therapeutic targets. In this study, we performed NGS-based functional genomics screening for human GC cell lines using an originally constructed 6,399 shRNA library targeting all 2,096 human metabolism genes. Our screening identified aspartyl-tRNA synthetase (DARS) as a possible candidate for a therapeutic target for GC. In-house tissue microarrays containing 346 cases of GC combined with public datasets showed that patients with high expression levels of DARS protein exhibited more advanced clinicopathologic parameters and a worse prognosis, specifically among diffuse-type GC patients. Both in vitro and in vivo experiments concretely evidenced that DARS inhibition achieved robust growth suppression of GC cells. Moreover, RNA sequencing of GC cell lines under shRNA-mediated DARS knockdown suggested that DARS inhibition exerts its effect through the inactivation of multiple p-ERK pathways. This MAPK-related growth suppression by DARS inhibition would also be applicable to other cancers; thus, it is warranted to investigate the expression and clinical significance of DARS in a wide spectrum of malignancies. Taken together, NGS-based high-throughput pooled lentiviral screening showed DARS as a novel prognostic marker and a promising therapeutic target for GC. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Research Progress on Gene Editing Based on Nano-Drug Delivery Vectors for Tumor Therapy.

Malignant tumors pose a serious threat to human health and have high fatality rates. Conventional clinical anti-tumor treatment is mainly based on traditional surgery, chemotherapy, radiotherapy, and interventional therapy, and even though these treatment methods are constantly updated, a satisfactory efficacy is yet to be obtained. Therefore, research on novel cancer treatments is being actively pursued. We review the classification of gene therapies of malignant tumors and their advantages, as well as the development of gene editing techniques. We further reveal the nano-drug delivery carrier effect in improving the efficiency of gene editing. Finally, we summarize the progress in recent years of gene editing techniques based on nano-drug delivery carriers in the treatment of various malignant tumors, and analyze the prospects of the technique and its restricting factors.

DEK modulates both expression and alternative splicing of cancer­related genes.

DEK is known to be a potential proto­oncogene and is highly expressed in gastric cancer (GC); thus, DEK is considered to contribute to the malignant progression of GC. DEK is an RNA­binding protein involved in transcription, DNA repair, and selection of splicing sites during mRNA processing; however, its precise function remains elusive due to the lack of clarification of the overall profiles of gene transcription and post­transcriptional splicing that are regulated by DEK. We performed our original whole­genomic RNA­Seq data to analyze the global transcription and alternative splicing profiles in a human GC cell line by comparing DEK siRNA­treated and control conditions, dissecting both differential gene expression and potential alternative splicing events regulated by DEK. The siRNA­mediated knockdown of DEK in a GC cell line led to significant changes in gene expression of multiple cancer­related genes including both oncogenes and tumor suppressors. Moreover, it was revealed that DEK regulated a number of alternative splicing in genes which were significantly enriched in various cancer­related pathways including apoptosis and cell cycle processes. This study clarified for the first time that DEK has a regulatory effect on the alternative splicing, as well as on the expression, of numerous cancer­related genes, which is consistent with the role of DEK as a possible oncogene. Our results further expand the importance and feasibility of DEK as a clinical therapeutic target for human malignancies including GC.

Integrins in the Regulation of Mesenchymal Stem Cell Differentiation by Mechanical Signals.

Mesenchymal stem cells (MSCs) can sense and convert mechanical stimuli signals into a chemical response. Integrins are involved in the mechanotransduction from inside to outside and from outside to inside, and ultimately affect the fate of MSCs responding to different mechanical signals. Different integrins participate in different signaling pathways to regulate MSCs multi-differentiation. In this review, we summarize the latest advances in the effects of mechanical signals on the differentiation of MSCs, the importance of integrins in mechanotransduction, the relationship between integrin heterodimers and different mechanical signals, and the interaction among mechanical signals. We put forward our views on the prospect and challenges of developing mechanical biology in tissue engineering and regenerative medicine.

Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer: Five-Year Outcomes From the CLASS-01 Randomized Clinical Trial.

Importance: It is not clear whether laparoscopic and open distal gastrectomy produce similar outcomes among patients with locally advanced gastric cancer. Data from a multicenter, randomized clinical trial (Chinese Laparoscopic Gastrointestinal Surgical Study [CLASS]-01) showed that laparoscopic distal gastrectomy did not result in inferior disease-free survival at 3 years compared with open distal gastrectomy. Objective: To report 5-year overall survival data from the CLASS-01 trial of laparoscopic vs open distal gastrectomy among patients with locally advanced gastric cancer. Design, Setting, and Patients: This was a noninferiority, open-label, randomized clinical trial conducted at 14 centers in China. A total of 1056 eligible patients with clinical stage T2, T3, or T4a gastric cancer without bulky nodes or distant metastases were enrolled from September 12, 2012, to December 3, 2014. Final follow-up was on December 31, 2019. Interventions: Participants were randomized in a 1:1 ratio after stratification by site, age, cancer stage, and histologic features to undergo either laparoscopic distal gastrectomy (n = 528) or open distal gastrectomy (n = 528) with D2 lymphadenectomy. Main Outcomes and Measures: The 5-year overall survival rates were updated to compare laparoscopic distal gastrectomy with open distal gastrectomy. All analyses were performed on an intention-to-treat basis. In addition, per-protocol and as-treated analyses were performed for overall survival. Results: Data from 1039 patients (726 men [69.9%]; mean [SD] age, 56.2 [10.7] years) who received curative therapy were analyzed. At 5 years, the overall survival rates were 72.6% in the laparoscopic distal gastrectomy group and 76.3% in the open distal gastrectomy group (log-rank P = .19; hazard ratio, 1.17; 95% CI, 0.93-1.48; P = .19). After comparison for competing risk events, gastric cancer-related deaths (hazard ratio, 1.14; 95% CI, 0.87-1.49; P = .34) and deaths from other causes (hazard ratio, 1.23; 95% CI, 0.74-2.05; P = .42) did not differ significantly between groups. Overall rates of survival did not differ significantly between groups with each tumor stage. Conclusions and Relevance: This study found that laparoscopic distal gastrectomy with D2 lymphadenectomy performed by experienced surgeons in high-volume specialized institutions resulted in similar 5-year overall survival compared with open distal gastrectomy among patients with locally advanced gastric cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT01609309.

Increased Expression of PDK4 Was Displayed in Gastric Cancer and Exhibited an Association With Glucose Metabolism.

Previous studies reported that pyruvate dehydrogenase kinase 4 (PDK4) is closely related to diabetes, heart disease, and carcinomas. Nevertheless, the role of PDK4 in gastric cancer (GC) occurrence and development is yet poorly understood. Our experiments were taken to evaluate PDK4's function in GC. The Cancer Genome Atlas tumor genome map database was employed to validate the levels of PDK family in different grades and stages of GC. The survival ratio of PDK families in GC was detected by the Kaplan-Meier plotter database. The links existing in the expression of PDK family and the level of tumor-infiltrating immune cells were investigated by tumor immunity assessment resource (TIMER). PDK4-associated signal pathways in GC were analyzed by the Kyoto Encyclopedia of Genes and Genomes pathway analysis. PDK4 mRNA level in the GC cells was measured by qRT-PCR. Cell counting kit-8 and Transwell assays were separately carried out to evaluate PDK4-induced influence on GC cell proliferation, migration, and invasion. Our data suggested that GC cells highly expressed PDK4, and PDK4 expression presented a significant relation with the staging, grade, and survival rate of GC. PDK4 expression presented a positive correlation with the types of different infiltrating immune cells, comprising B cells, CD4+ T cells, and dendritic cells. Meanwhile, PDK4 expression exhibited a strong association with macrophages. Survival analysis revealed that the expression of PDK4 displayed a relationship with the prognosis of patients. Therefore, PDK4 was liable to be a biomarker for prognosis. Our results further displayed that PDK4 might modulate the glycolysis level in GC cells, and its expression was associated with GC cell proliferation, migration, and invasion. These data may provide insights into designing a new treatment strategy for GC.

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Correlation Between Immune Lymphoid Cells and Plasmacytoid Dendritic Cells in Human Colon Cancer.

Background: Innate lymphoid cells (ILCs), so far studied mostly in mouse models, are important tissue-resident innate immune cells that play important roles in the colorectal cancer microenvironment and maintain mucosal tissue homeostasis. Plasmacytoid dendritic cells (pDCs) present complexity in various tumor types and are correlated with poor prognosis. pDCs can promote HIV-1-induced group 3 ILC (ILC3) depletion through the CD95 pathway. However, the role of ILC3s in human colon cancer and their correlation with other immune cells, especially pDCs, remain unclear. Methods: We characterized ILCs and pDCs in the tumor microenvironment of 58 colon cancer patients by flow cytometry and selected three patients for RNA sequencing. Results: ILC3s were negatively correlated, and pDCs were positively correlated, with cancer pathological stage. There was a negative correlation between the numbers of ILC3s and pDCs in tumor tissues. RNA sequencing confirmed the correlations between ILC3s and pDCs and highlighted the potential function of many ILC- and pDC-associated differentially expressed genes in the regulation of tumor immunity. pDCs can induce apoptosis of ILC3s through the CD95 pathway in the tumor-like microenvironment. Conclusions: One of the interactions between ILC3s and pDCs is via the CD95 pathway, which may help explain the role of ILC3s in colon cancer.

Short-term outcomes of complete mesocolic excision versus D2 dissection in patients undergoing laparoscopic colectomy for right colon cancer (RELARC): a randomised, controlled, phase 3, superiority trial.

BACKGROUND: Whether extended lymphadenectomy for right colon cancer leads to increased perioperative complications or improves survival is still controversial. This trial aimed to compare the efficacy and safety of complete mesocolic excision (CME) versus D2 dissection in laparoscopic right hemicolectomy for patients with right colon cancer. This article reports the early safety results from the trial. METHODS: This randomised, controlled, phase 3, superiority, trial was done at 17 hospitals in nine provinces of China. Eligible patients were aged 18-75 years with histologically confirmed primary adenocarcinoma located between the caecum and the right third of the transverse colon, without evidence of distant metastases. Central randomisation was done by means of the Clinical Information Management-Central Randomisation System via block randomisation (block size of four). Patients were randomly assigned (1:1) to CME or D2 dissection during laparoscopic right colectomy. Central lymph nodes were dissected in the CME but not in the D2 procedure. Neither investigators nor patients were masked to their group assignment but the quality control committee were masked to group assignment. The primary endpoint was 3-year disease-free survival, but the data for this endpoint are not yet mature; thus, only the secondary outcomes-intraoperative surgical complications and postoperative complications within 30 days of surgery, graded according to the Clavien-Dindo classification, mortality (death from any cause within 30 days of surgery), and central lymph node metastasis rate in the CME group only-are reported in this Article. This early analysis of safety was preplanned. The outcomes were analysed according to a modified intention-to-treat principle (excluding patients who no longer met inclusion criteria after surgery or who did not have surgery). This study is registered with ClinicalTrials.gov, NCT02619942. Study recruitment is complete, and follow-up is ongoing. FINDINGS: Between Jan 11, 2016, and Dec 26, 2019, 1072 patients were enrolled and randomly assigned. After exclusion of 77 patients, 995 patients were included in the modified intention-to-treat population (495 in the CME group and 500 in the D2 dissection group). The postoperative surgical complication rate was 20% (97 of 495 patients) in the CME group versus 22% (109 of 500 patients) in the D2 group (difference, -2·2% [95% CI -7·2 to 2·8]; p=0·39); the frequency of Clavien-Dindo grade I-II complications were similar between groups (91 [18%] vs 92 [18%], difference, -0·0% [95% CI -4·8 to 4·8]; p=1·0) but Clavien-Dindo grade III-IV complications were significantly less frequent in the CME group than in the D2 group (six [1%] vs 17 [3%], -2·2% [-4·1 to -0·3]; p=0·022); no deaths occurred in either group. Of the intraoperative complications, vascular injury was significantly more common in the CME group than in the D2 group (15 [3%] vs six [1%], difference, 1·8 [95% CI 0·04 to 3·6]; p=0·045). Metastases in the central lymph nodes were detected in 13 (3%) of 394 patients who underwent central lymph node biopsy in the CME group; no patient had isolated metastases to central lymph nodes. INTERPRETATION: Although the CME procedure might increase the risk of intraoperative vascular injury, it generally seems to be safe and feasible for experienced surgeons. FUNDING: The Capital Characteristic Clinical Project of Beijing and the Chinese Academy of Medical Sciences.

The protocol of a prospective, multicenter, randomized, controlled phase III study evaluating different cycles of oxaliplatin combined with S-1 (SOX) as neoadjuvant chemotherapy for patients with locally advanced gastric cancer: RESONANCE-II trial.

BACKGROUND: Curing locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer. METHODS: RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety. DISCUSSION: This study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer. TRIAL REGISTRATION: Registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.

A new pH/NIR responsive theranostic agent for magnetic resonance imaging guided synergistic therapy.

New nano-reagents with diagnostic imaging and therapeutic functions are very important for precision medicine against cancer. In this work, a new nanotheraontic agent for magnetic resonance imaging (MRI) guided combined photothermal therapy (PTT) and chemotherapy was constructed based on polydopamine (PDA) functionalized copper ferrite nanospheres (PDA@CFNs). The high relaxivity makes it possible for PDA@CFNs to become a promising MRI contrast agent, providing necessary and exhaustive information for tumor diagnosis. In addition, because both CFNs and PDA have strong near-infrared (NIR) absorption, PDA@CFNs exhibit excellent photothermal performance. Highly effective tumor ablation is achieved in a mouse model through PTT and pH/NIR triggered on-demand chemotherapy. These findings reveal that constructing smart pH/NIR responsive multifunctional theranostic agents is a feasible strategy for precision cancer therapy.

Discovering Biomarkers in Peritoneal Metastasis of Gastric Cancer by Metabolomics.

BACKGROUND AND OBJECTIVE: Metabolomics has recently been applied in the field of oncology. In this study, we aimed to use metabolomics to explore biomarkers in peritoneal metastasis of gastric cancer. METHODS: Peritoneal lavage fluid (PLF) of 65 gastric cancer patients and related clinical data were collected from the First Hospital of Jilin University. The metabolic components were identified by liquid chromatography-mass spectrometry (LC-MS). Total ion current (TIC) spectra, principal component analysis (PCA), and the Student's t-test were used to identify differential metabolites in PLF. A support vector machine (SVM) was used to screen the differential metabolites in PLF with a weight of 100%. Cluster analysis was used to evaluate the similarity between samples. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic ability of the metabolites. Univariate and multivariate logistic regression analyses were used to identify potential risk factors for peritoneal metastasis of gastric cancer. RESULTS: We found the differential levels of PLF metabolites by LC-MS, TIC spectra, PCA and the t-test. Cluster analysis showed the co-occurrence of metabolites in the peritoneal metastasis group (p<0.05). ROC analysis showed the diagnostic ability of metabolites (p<0.05). Univariate and multivariate logistic regression analyses showed the potential independent risk factors for peritoneal metastasis in gastric cancer patients (p<0.05). CONCLUSION: Through the statistical analysis of metabolomics, we found that TG (54:2), G3P, α-aminobutyric acid, α-CEHC, dodecanol, glutamyl alanine, 3-methylalanine, sulfite, CL (63:4), PE-NMe (40:5), TG (53:4), retinol, 3-hydroxysterol, tetradecanoic acid, MG (21:0/0:0/0:0), tridecanoic acid, myristate glycine and octacosanoic acid may be biomarkers for peritoneal metastasis of gastric cancer.

Long Noncoding RNA LINC00460 Facilitates Colorectal Cancer Progression by Negatively Regulating miR-613.

BACKGROUND: Long-noncoding RNAs (lncRNAs) could exert a crucial effect on the development of human cancers, including CRC. However, the biological function and underlying mechanism of LINCRNA00460 in the development of CRC still need deeper exploration. MATERIALS AND METHODS: The expression of LINC00460 in CRC tissues and cell lines was assessed by qRT-PCR. Cell proliferation, migration, and invasion were measured by the respective cell counting Kit-8 (CCK-8), wound healing assay and transwell invasion assay. Cell apoptosis and caspase-3 activity were detected by flow cytometry and caspase-3 activity assay. The relationship between LINC00460 and miR-613 expression was explored by Dual-luciferase reporter assay. Protein expression was measured by Western blotting. In vivo tumour growth was evaluated using a xenograft model of nude mice. RESULTS: LINC00460 was markedly up-regulated in CRC tissues and cell lines compared to their corresponding controls, which was closely correlated with clinical stage, TNM (T) classification, nodal (N) classification, metastasis (M) classification, liver metastasis and pathological differentiation, and survival rate of CRC patients. Functionally, LINC00460 knockdown decreased the proliferative, migrative and invasive abilities, and enhanced apoptosis rates and caspase-3 activity in HT29 and LOVO cells. Mechanistic studies indicated that miR-613 was targeted by LINC00460, and SphK1 was targeted and inversely regulated by miR-613 in HT29 and LOVO cells. In vivo studies, LINC00460 knockdown attenuated tumour growth. MiR-613 downregulation and SphK1 upregulation in the CRC tissues, and LINC00460 expression levels were inversely correlated with miR-613 expression and positively correlated with the SphK1 mRNA expression. Overall, LINC00460 modulated cell proliferation, migration, invasion and sphingosine kinase 1 (SphK1) expression in HT29 and LOVO cells, at least in most part, by regulating miR-613. CONCLUSION: LINC00460 functions as a competing endogenous RNA to regulate SphK1 expression by sponging miR-613 in CRC and provides a valuable therapeutic strategy for CRC patients.

Morbidity and Mortality of Laparoscopic vs Open Total Gastrectomy for Clinical Stage I Gastric Cancer: The CLASS02 Multicenter Randomized Clinical Trial.

Importance: The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains uncertain given the lack of high-level clinical evidence. Objective: To compare the safety of LTG for clinical stage I gastric cancer with that of conventional open total gastrectomy (OTG). Design, Setting, and Participants: The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) Group CLASS02 study was a prospective, multicenter, open-label, noninferiority, randomized clinical trial that compared the safety of LTG vs OTG with lymphadenectomy for patients with clinical stage I gastric cancer. From January 2017 to September 2018, a total of 227 patients were enrolled. Final follow-up was in October 2018. Interventions: Eligible patients were randomized to LTG (n = 113) or OTG (n = 114) by an interactive web response system. Main Outcomes and Measures: The primary outcome was the morbidity and mortality within 30 days following surgeries between LTG and OTG with a noninferiority margin of 10%. The secondary outcomes were recovery courses and postoperative hospital stays. Results: A total of 214 patients were analyzed for morbidity and mortality (105 patients in the LTG group and 109 patients in the OTG group). The mean (SD) age was 59.8 (9.4) years in the LTG group and 59.4 (9.2) years in the OTG group, and most were male (LTG group, 75 of 105 [71.4%]; OTG group, 80 of 109 [73.4%]). The overall morbidity and mortality rates were not significantly different between the groups (rate difference, -1.1%; 95% CI, -11.8% to 9.6%). Intraoperative complications occurred in 3 patients (2.9%) in the LTG group and 4 patients (3.7%) in the OTG group (rate difference, -0.8%; 95% CI, -6.5% to 4.9%). In addition, there was no significant difference in the overall postoperative complication rate of 18.1% in the LTG group and 17.4% in the OTG group (rate difference, 0.7%; 95% CI, -9.6% to 11.0%). One patient in the LTG group died from intra-abdominal bleeding secondary to splenic artery hemorrhage. However, there was no significant difference in mortality between the LTG group and the OTG group (rate difference, 1.0%; 95% CI, -2.5% to 5.2%), and the distribution of complication severity was similar between the 2 groups. Conclusions and Relevance: The results of the CLASS02 trial showed that the safety of LTG with lymphadenectomy by experienced surgeons for clinical stage I gastric cancer was comparable to that of OTG. Trial Registration: ClinicalTrials.gov Identifier: NCT03007550.

Type II enteropathy-associated T cell lymphoma in the duodenum: A rare case report.

INTRODUCTION: Enteropathy-associated T-cell lymphoma (EATL) is a very rare form of lymphoma in the gastrointestinal tract. The proximal jejunum and ileum are the most common sites of EATL, whereas EATL rarely arises in the duodenum, and EATL involving metastasis of the bilateral ovaries is even rarer. PATIENT CONCERNS: A 43-year-old female suffered from upper abdominal pain and weight loss for 3 months. DIAGNOSIS: Type II EATL. INTERVENTIONS: The patient was initially treated with chemotherapies, including 4 cycles of the CHOP-E and 2 cycles of the DHAP+ chidamide chemotherapy regimens. However, the patient did not respond well to chemotherapy. Surgical treatment of the duodenal obstruction, with perforation of small intestine and the duodenum, was performed successively. OUTCOMES: The patient died of septic shock only 1 day after the surgery for the second perforation. Her overall survival was 11 months from the time of initial diagnosis. CONCLUSION: This case suggests that EALT is highly invasive and its clinical course is very aggressive. Intestinal perforation, intestinal obstruction, or involvement of extraintestinal organs may occur in EALT patients. Additionally, EALT patients respond poorly to chemotherapy and have an extremely unfavorable prognosis.

Profiling of serum metabolites in advanced colon cancer using liquid chromatography-mass spectrometry.

Lymph node metastasis remains a key factor that affects the prognosis of patients with colon cancer. The aim of the present study was to identify and evaluate serum metabolites as biomarkers for the detection of tumor lymph node metastasis and the prediction of patient survival. The present study analyzed the metabolites in the serum of patients with advanced colon cancer both with and without lymph node metastasis. Blood samples from 104 patients with stage T3 colon cancer were collected and analyzed using liquid chromatography-mass spectrometry. The metabolites were structurally confirmed with data from the Human Metabolome Database. The association between the serum metabolites and the clinicopathological characteristics and survival time of patients from the present study was analyzed. Overall, 227 different metabolites were identified in the serum of patients with stage T3 colon cancer with or without lymph node metastasis. Furthermore, 17 of these metabolites may potentially distinguish those patients with lymph node metastasis from those patients without. In addition, five factors, including abscisic acid, calcitroic acid and glucosylsphingosine presence in the serum, age and sex, were identified as independent predictors for lymph node metastasis (P<0.05). Furthermore, three factors, including abscisic acid, calcitroic acid and glucosylsphingosine presence in the serum were independent predictors for patient survival (P<0.05). In conclusion, the serum levels of abscisic acid, calcitroic-acid and glucosylsphingosine may be considered as potential biomarkers to predict the occurrence of lymph node metastasis and the survival time of patients with colon cancer.

Association of serum levels of deoxyribose 1-phosphate and S-lactoylglutathione with neoadjuvant chemotherapy sensitivity in patients with gastric cancer: A metabolomics study.

The present study screened serum samples from patients with advanced-stage gastric cancer and known sensitivities to neoadjuvant chemotherapy, in order to identify metabolites that may serve as potential biomarkers for chemotherapy sensitivity. A total of 47 patients with stage III (T4b) or IV gastric cancer, including 31 in the training group and 16 in a validation group, were classified based on their responses to conversion therapy consisting of oxaliplatin, tegafur and continuous hyperthermic peritoneal perfusion with cisplatin. Serum samples were analyzed by liquid chromatography-mass spectrometry to obtain a metabolite profile of each patient. Patients who were responsive and non-responsive to neoadjuvant chemotherapy exhibited significant differences in serum levels of deoxyribose 1-phosphate, S-lactoylglutathione, lysophosphatidylcholine (16:0) and O-arachidonoyl ethanolamine. Logistic regression analysis indicated that deoxyribose 1-phosphate and S-lactoylglutathione were independently associated with chemosensitivity. Serum levels of deoxyribose 1-phosphate and S-lactoylglutathione were independently associated with the sensitivity of gastric cancer to neoadjuvant chemotherapy, therefore, serving as potential predictors of patient response.