Management of type 1 gastric neuroendocrine tumors: an 11-year retrospective single-center study.

BACKGROUND: Type 1 gastric neuroendocrine tumors (NETs) are relatively rare to the extent that some physicians have little experience in diagnosing and treating them. The purpose of this study was to increase the understanding of the disease by analyzing and summarizing the management and prognoses of patients with type 1 gastric NETs at our center. METHODS: The data of 229 patients (59.4% female) with type 1 gastric NETs who were treated at our center during 2011-2022 were retrospectively analyzed. RESULTS: The average patient age was 50.5 ± 10.8 years. Multiple tumors affected 72.5% of the patients; 66.4% of the tumors were < 1 cm, 69.4% were NET G1, and 2.2% were stage III-IV. A total of 76.9% of the patients had received endoscopic management, 60.7% had received traditional Chinese medicine treatment, 10.5% received somatostatin analogues treatment, and 6.6% underwent surgical resection. Seventy patients (41.2%) experienced the first recurrence after a median follow-up of 31 months (range: 2-122 months), and the median recurrence-free time was 43 months. The 1-, 2-, and 3-year cumulative recurrence-free survival rates were 71.8%, 56.8%, and 50.3%, respectively. During a median follow-up of 39 months (range: 2-132 months), one patient had bilateral pulmonary metastasis, and no disease-related deaths were observed. CONCLUSION: Type 1 gastric NETs have a high recurrence rate and a long disease course, underscoring the importance of long-term and comprehensive management.

A Prospective and Retrospective Clinical Controlled Observation of Chinese Herbal Decoction (SMLJ01) for Type 1 Gastric Neuroendocrine Tumors.

INTRODUCTION: Type 1 gastric neuroendocrine tumors (g-NETs) have a good prognosis but a high recurrence rate. AIM: To observe the clinical efficacy of the treatment of type 1 g-NETs with the Chinese herbal decoction SMLJ01. MATERIALS AND METHODS: A prospective and retrospective, clinical, controlled observation was conducted in 4 Chinese centers from 2012 to 2019. Patients with type 1 g-NETs were nonrandomly divided into treatment and control groups after endoscopic treatment based on herbal treatment administered according to their wishes. The treatment group received oral SMLJ01, with follow-up every 6 to 12 months, while the control group received follow-up alone. Patient follow-up (via telephone) from 2012 to 2017 was mainly retrospective. All patients after 2017 were followed prospectively. The recurrence times and rates were compared after treatment for at least 6 months. Symptom improvements were evaluated in the treatment group. The follow-up ended on October 31, 2019. RESULTS: During a median follow-up of 22 months (range: 2-86 months), the survival rate was 100%, and no metastases occurred. Twenty-one of the 82 treated patients (25.6%) had recurrence after a median of 22 months, and 22 of the 54 control patients (40.7%) had recurrence after a median of 8 months (P = .063). The Kaplan-Meier curve analysis showed that the patients in the treatment group had a significantly longer median recurrence-free survival (RFS) time than those in the control group (P = .001). The risk of recurrence in the treatment group was 0.38 relative to that in the control group (95% CI: 0.20-0.70). The symptom score of the patients after taking Chinese medicine was 19.5 (10.3, 28.0), which was significantly lower than before treatment (31.5 (19.3, 38.0)). The difference was statistically significant (P < .01). CONCLUSION: SMLJ01, with the effects of soothing the liver, strengthening the spleen, increasing acid and harmonizing the stomach, may help reduce the recurrence rate, relieve symptoms and prolong the recurrence time in patients with type 1 g-NETs and is worthy of evaluation with further randomized research with large sample sizes and longer follow-up periods.

hnRNPK promotes gastric tumorigenesis through regulating CD44E alternative splicing.

BACKGROUND: The high prevalence of alternative splicing among genes implies the importance of genomic complexity in regulating normal physiological processes and diseases such as gastric cancer (GC). The standard form of stem cell marker CD44 (CD44S) and its alternatives with additional exons are reported to play important roles in multiple types of tumors, but the regulation mechanism of CD44 alternative splicing is not fully understood. METHODS: Here the expression of hnRNPK was analyzed among the Cancer Genome Atlas (TCGA) cohort of GC. The function of hnRNPK in GC cells was analyzed and its downstream targeted gene was identified by chromatin immunoprecipitation and dual luciferase report assay. Finally, effect of hnRNPK and its downstream splicing regulator on CD44 alternative splicing was investigated. RESULTS: The expression of hnRNPK was significantly increased in GC and its upregulation was associated with tumor stage and metastasis. Loss-of-function studies found that hnRNPK could promote GC cell proliferation, migration, and invasion. The upregulation of hnRNPK activates the expression of the splicing regulator SRSF1 by binding to the first motif upstream the start codon (- 65 to - 77 site), thereby increasing splicing activity and expression of an oncogenic CD44 isoform, CD44E (has additional variant exons 8 to 10, CD44v8-v10). CONCLUSION: These findings revealed the importance of the hnRNPK-SRSF1-CD44E axis in promoting gastric tumorigenesis.

Screening key long non-coding RNAs in early-stage colon adenocarcinoma by RNA-sequencing.

AIM: We aim to identify the key long noncoding RNAs (lncRNAs) in early-stage colon adenocarcinoma (COAD). PATIENTS & METHODS: Compared with colonic intraepithelial neoplasia, differentially expressed lncRNAs (DElncRNAs) in early-stage COAD were obtained by RNA-sequencing. Our previous work has obtained the differentially expressed mRNAs and miRNAs (DEmRNAs and DEmiRNAs) in early-stage COAD. DEmiRNA-DElncRNA-DEmRNA interaction analysis and functional annotation were performed. Validation of expression and receiver-operating characteristic analyses were performed based on The Cancer Genome Atlas. RESULTS: Seventy-nine significantly DElncRNAs in early-stage COAD were obtained. MiR-153-3p-TUG1-DAPK1/ARNT2/KLK3/PLD1/SMAD2 and miR-153-3p-SNHG17-COL11A1/IGFBP3/KLF6 interactions were associated with early-stage COAD. Five DElncRNAs (ELFN1-AS1, LINC01234, SNHG17, UCA1 and LOC101929549) involved in early-stage COAD with potential diagnostic value. CONCLUSION: LncRNAs involve in early-stage COAD by interaction with COAD-regulated genes and miRNAs.

Safety and efficacy of total parenteral nutrition versus total enteral nutrition for patients with severe acute pancreatitis: a meta-analysis.

Objective This study was performed to systematically compare the safety and efficacy of total enteral nutrition (TEN) and total parenteral nutrition (TPN) for patients with severe acute pancreatitis (SAP). Methods The PubMed database was searched up to January 2017, and nine studies were retrieved. These studies were selected according to specific eligibility criteria. The methodological quality of each trial was assessed, and the study design, interventions, participant characteristics, and final results were then analyzed by Review Manager 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Results Nine relevant randomized controlled trials involving 500 patients (244 patients in the TEN group and 256 patients in the TPN group) were included in the meta-analysis. Pooled analysis showed a significantly lower mortality rate in the TEN than TPN group [odds ratio (OR), 0.31; 95% confidence interval (CI), 0.18-0.54]. The duration of hospitalization was significantly shorter in the TEN than TPN group (mean difference, -0.59; 95% CI, -2.56-1.38). Compared with TPN, TEN had a lower risk of pancreatic infection and related complications (OR, 0.41; 95% CI, 0.22-0.77), organ failure (OR, 0.17; 95% CI, 0.06-0.52), and surgical intervention (OR, 0.17; 95% CI, 0.05-0.62). Conclusions This meta-analysis indicates that TEN is safer and more effective than TPN for patients with SAP. When both TEN and TPN have a role in the management of SAP, TEN is the preferred option.

Hsa-miR-202-3p, up-regulated in type 1 gastric neuroendocrine neoplasms, may target DUSP1.

AIM: To detect abnormal microRNA (miRNA) expression in type 1 gastric neuroendocrine neoplasms (g-NENs) and find potential target genes. METHODS: Tumour tissues from patients with type 1 g-NENs were used as experimental samples, and gastric mucosal tissues from the same patients obtained during gastroscopy review after several months were used as control samples. miRNA expression was examined with Agilent human miRNA chips and validated via RT-PCR. Three types of target gene prediction software (TargetScan, PITA, and microRNAorg) were used to predict potential target genes of the differentially expressed miRNAs, and a dual-luciferase reporter assay system was used for verification. RESULTS: Six miRNAs were significantly upregulated or downregulated in the tumours compared to the control samples. Among them, miR-202-3p was extraordinarily upregulated. RT-PCR of seven sample sets confirmed that miR-202-3p was upregulated in tumour tissues. In total, 215 target genes were predicted to be associated with miR-202-3p. Among them, dual-specificity phosphatase 1 (DUSP1) was reported to be closely related to tumour occurrence and development. The dual-luciferase reporter assay showed that miR-202-3p directly regulated DUSP1 in 293T cells. CONCLUSION: miR-202-3p is upregulated in type 1 g-NEN lesions and might play important roles in the pathogenesis of type 1 g-NENs by targeting DUSP1.

Identification of key miRNAs and genes associated with stomach adenocarcinoma from The Cancer Genome Atlas database.

Stomach adenocarcinoma (STAD) is the second leading cause of cancer death and a fuller understanding of its molecular basis is needed to develop new therapeutic targets. miRNA and mRNA data were downloaded from The Cancer Genome Atlas database, and the differentially expressed miRNAs and genes were identified. The target genes of differentially expressed miRNAs were screened by prediction tools. Furthermore, the biological function of these target genes was investigated. Several key miRNAs and their target genes were selected for validation using quantitative real-time polymerase chain reaction (qRT-PCR). The Gene Expression Omnibus (GEO) dataset was used to verify the expression of selected miRNAs and target genes. The diagnostic value of identified miRNAs and genes was accessed by receiver operating characteristic analysis. A total of 1248 differentially expressed genes were identified in STAD. Additionally, nine differentially expressed miRNAs were identified and 160 target genes of these nine miRNAs were identified via target gene detection. Interestingly, they were remarkably enriched in the calcium signaling pathway and bile secretion. qRT-PCR confirmed the expression of several key miRNAs and their target genes. The expression levels of hsa-miR-145-3p, hsa-miR-145-5p, ADAM12,ACAN,HOXC11 and MMP11 in the GEO database were compatible with the bioinformatics results. hsa-miR-139-5p, hsa-miR-145-3p and MMP11 have a potential diagnostic value for STAD. Differential expression of the mature form of miRNAs (hsa-miR-139-5p, hsa-miR-145-3p, hsa-miR-145-5p and hsa-miR-490-3p) and genes including ADAM12,ACAN,HOXC11 and MMP11 and calcium and bile secretion signaling pathways may play important roles in the development of STAD.

Increased mortality for colorectal cancer patients with preexisting diabetes mellitus: an updated meta-analysis.

BACKGROUND: Although the preexisting diabetes mellitus (DM) is known to have a high risk for death in many cancers, its impact on the mortality for the colorectal cancer (CRC) patients is still uncertain. In this study, we conducted a meta-analysis to explore an association of DM with the survival for the CRC patients. MATERIALS AND METHODS: We made a relative data search from the public available databases including Medline and Embase with a cutoff date to Jan 31, 2017. Pooled hazard ratios (HRs) were calculated using either a fixed or random effect model. Trim and fill analysis was conducted to test and adjust for publication bias. Subgroup analyses were also performed for overall survival and all-cause mortality when stratified by tumor stage, geographical region, duration of follow-up, gender and subsite of cancer. RESULTS: Twenty-one eligible cohorts including 1,025,034 patients were identified and included in this meta-analysis review. The sample size for each analysis was ranged from 207 to 771,297 patients. It is revealed that with the preexisting DM, the CRC patients had a significantly increased all-cause mortality (pooled adjusted HR: 1.23; 95% CI: 1.11, 1.37) and decreased overall survival (pooled adjusted HR: 1.25, 95% CI: 1.19-1.31). But no difference was found for adjusted cancer-specific survival for the CRC patients with the preexisting DM compared with subjects without DM. These associations almost remained consistent after trim and fill adjustment and across those outcomes when stratified by site of cancer, tumor stage, population geography, study design, duration of follow-up, data resource or gender. CONCLUSIONS: This meta-analysis review indicates that preexisting diabetes mellitus in CRC patients is severely associated with the worse overall survival but not with cancer-specific survival.

[Analysis of primary site and pathology on 903 patients with neuroendocrine neoplasms].

OBJECTIVE: To explore the primary site and pathological feature of neuroendocrine neoplasm (NEN), especially the NEN of digestive system. METHODS: Clinicopathological data of NEN patients at China-Japan Friendship Hospital from January 2012 to December 2016 were retrospectively analyzed. Tumor primary sites were summarized. Association between tumor site and pathological grading in gastroenteropancreatic neuroendocrine neoplasm(GEP-NEN) was examined. RESULTS: There were a total of 903 cases of NEN. Sites of primary tumor included the digestive system in 699 cases(77.4%), the thorax(including lung, thymus and mediastinum) in 87 cases(9.6%), other sites in 60 cases (6.6%), unknown in 57 cases(6.3%). Among 699 GEP-NEN cases, the primary sites included the stomachin in 207 cases (29.6%), pancreas in 201 (28.8%), rectumin in 185 (26.5%), duodenum in 43(6.2%), jejunum and ileum in 18(2.6%), appendix in 15 (2.1%), gallbladder in 11(1.6%), esophagus in 10(1.4%), and the colon in 9 cases (1.3%). Pathologically, the tumor grading was neuroendocrine tumor (NET) G1 in 336 cases(48.1%), NET G2 in 203 cases (29.0%), neuroendocrine carcinoma (NEC) G3 in 139 cases (19.9%). All the esophagus NEN(10/10), most gallbladder NEN(9/11) and colon NEN(6/9) were poorly-differentiated NEC (G3), while all appendix NEN(15/15), most stomach NEN(147/207, 71.0%), pancreas NEN (156/201, 77.6%), rectum NEN (169/185, 91.4%), duodenum NEN (31/43, 72.1%), jejunum and ileum NEN(16/18, 88.9%) were well-differentiated NET G1 or G2. CONCLUSIONS: The most common primary site of NEN is the digestive system. The stomach, pancreas and rectum are most common primary sitesof GEP-NEN. Difference in pathological grading is quite greatin different primary sites of GEP-NEN. Most NENs fromesophagus, colon and gallbladder are poorly-differentiated NEC.

Associations of adiponectin receptor 2 (AdipoR2) gene polymorphisms and AdipoR2 protein expression levels with the risk of colorectal cancer: A case-control study.

The aim of the present study was to investigate the associations between adiponectin receptor 2 (AdipoR2) gene polymorphisms, AdipoR2 protein expression levels and the risk of colorectal cancer (CRC). From April 2012 to May 2015, 281 CRC patients (case group) admitted to the China­Japan Friendship Hospital and 325 healthy control subjects (control group) were recruited for the study. Peripheral venous blood samples were collected and the DNA was extracted. Genotyping was performed using denaturing high­performance liquid chromatography in the condition of partial degeneration. Linkage disequilibrium and haplotype were analyzed using SHEsis analysis software. AdipoR2 protein expression levels were detected by immunohistochemistry and logistic regression analysis was performed to determine the risk factors of CRC. The distribution of the TT genotype of AdipoR2 rs10773989 and the CC genotype of AdipoR2 rs1044471 was higher in the case group than in the control group (P<0.05). The AdipoR2 rs10773989 polymorphism was associated with the degree of tumor infiltration in CRC (P<0.05) and the AdipoR2 rs1044471 polymorphism was associated with the degree of differentiation and Dukes' staging in CRC (P<0.05). The CT haplotype was identified as a protective factor, while the TC haplotype was a risk factor in a healthy population. AdipoR2 protein expression was associated with the degree of differentiation, Dukes' staging, degree of tumor infiltration and lymphatic metastasis in CRC (all P<0.05). Logistic regression analysis demonstrated that the TT genotype of AdipoR2 rs10773989 and CC genotype of AdipoR2 rs1044471 were independent risk factors for CRC. The AdipoR2 rs10773989 and rs1044471 polymorphisms may be correlated with the susceptibility to CRC. In addition, the TC haplotype and AdipoR2 positive expression may increase the risk of CRC.

Screening key genes and miRNAs in early-stage colon adenocarcinoma by RNA-sequencing.

Colon adenocarcinoma is the third leading cause of cancer-related deaths across the world, developing novel and non-invasive diagnostic and prognostic biomarkers for the early-stage colon adenocarcinoma at molecular level is essential. In our study, RNA-sequencing was performed to identify the differentially expressed genes and miRNAs (DEmiRNAs) in early-stage colon adenocarcinoma compared to tissues of precancerous lesions, colonic intraepithelial neoplasia. The DEmiRNA-target interaction network was constructed and functional annotation of targets of DEmiRNAs was performed. The Cancer Genome Atlas was used to verify the expression of selected differentially expressed genes. The receiver operating characteristic analyses of selected differentially expressed genes was performed. In total, 865 differentially expressed genes, 26 DEmiRNAs, and 329 DEmiRNA-target pairs were obtained. Based on the early-stage colon adenocarcinoma network, miR-548c-5p, miR-548i, and miR-548am-5p were the top three DEmiRNAs that covered most differentially expressed genes. NTRK2, DTNA, and BTG2 were the top three differentially expressed genes regulated by most DEmiRNAs. Cancer and colorectal cancer pathways were two significantly enriched pathways in early-stage colon adenocarcinoma. The common differentially expressed genes in both the pathways were AXIN2, Smad2, Smad4, PIK3R1, and BCL2. The expression levels of eight differentially expressed genes (NTRK2, DTNA, BTG2, COL11A1, Smad2, Smad4, PIK3R1, and BCL2) in The Cancer Genome Atlas database were compatible with our RNA-sequencing. All these eight differentially expressed genes and AXIN2 had the potential diagnosis value for Colon adenocarcinoma. In conclusion, a total of ten differentially expressed genes (NTRK2, DTNA, BTG2, COLCA1, COL11A1, AXIN2, Smad2, Smad4, PIK3R1, and BCL2) and four DEmiRNAs (miR-548c-5p, miR-548i, mir-424-5p, and miR-548am-5p) may be involved in the pathogenesis of early-stage colon adenocarcinoma which may make a contribution for developing new diagnostic and therapeutic strategies for early-stage colon adenocarcinoma.

[Subtype classification and clinicopathological characteristics of gastric neuroendocrine neoplasms: an analysis of 241 cases].

OBJECTIVE: To study subtype classification of gastric neuroendocrine neoplasm (NEN) and their clinicopathological characteristics in order to provide reference for clinical practice. METHODS: Clinicopathological data of 241 gastric NEN patients (174 cases from China-Japan Friendship Hospital and 67 cases from The First Affiliated Hospital of Sun Yat-Sen University) between January 2011 and June 2016 were retrospectively summarized. According to serum gastrin, 24-hour intragastric pH monitoring and pathological grade, patients with gastric NEN were divided into 4 types: type I( (hypergastrinemia and achlorhydria, related to autoimmune chronic atrophic gastritis), type II( [hypergastrinemia and Zollinger-Ellison syndrome, related to gastrinoma or multiple endocrine neoplasia type I( (MEN-I()], type III( (sporadic disease with normal serum gastrin level), and type IIII( [poorly differentiated gastric neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC)]. Clinicopathological features, treatment and prognosis of 4 types were analyzed. RESULTS: Of 241 gastric NEN cases, there were 86 cases (35.7%) in type I(, 7 cases (2.9%) in type II(, 61 cases (25.3%) in type III( and 87 cases(36.1%) in type IIII(. Among 86 cases of type I( gastric NEN, 73 cases (84.9%) were multiple lesions,tumor size of 66 cases (76.7%) was less than 1 cm, all the 86 cases were polypoid or granular lesions. 2 cases(2.3%)presented distant metastasis, 69 cases (80.2%) had pathological grading as NET G1; most of them received endoscopic surgery treatment and follow-up; somatostatin analogs(SSA) was used in patients with multiple lesions and repeated recurrence after endoscopic treatment. Among 7 cases of type II(, 4 cases were gastrinoma, 3 cases MEN-I(; 5 cases presented distant metastasis; treatment included surgery, SSA and proton pump inhibitor (PPI) therapy. Among 61 cases of type III( gastric NEN, 49 cases(80.3%) were single lesion,tumor size of 25 cases(41.0%) was more than 2 cm, 29 cases(47.5%) had lymph node metastasis or distant metastasis; treatment included endoscopic resection, surgery or SSA therapy according to the tumor staging. Among 87 patients of type IIII( gastric NEN, 74 cases(85.0%) had single lesion,tumor size of 51 cases (58.6%) was more than 2 cm; lesions were found in gastric cardia in 35 cases (40.2%); 65 cases (74.7%) had lymph node metastasis or distant metastasis; treatment included chemotherapy, or surgery plus chemotherapy. At the end of follow-up(June 30, 2016), 58 patients were dead, including 1 case of type I(, 12 cases of type III( and 45 cases of type IIII(. The overall survival rate of all the patients was 74.2%, and was 98.8%, 100%, 79.3%, 39.2% of types I(, II(, III(, IIII( respectively. The overall survival rate between type III( and type IIII( gastric NEN was significantly different(P = 0.000). CONCLUSIONS: Subtype classification of gastric NEN is very significant for making therapeutic decisions and prognostic evaluation. Patients of type I( or type II( gastric NEN have good prognosis,while those of type III( and type IIII( have poor prognosis, and those of type IIII( have the worst prognosis.

Surgical management for non-functional pancreatic neuroendocrine neoplasms with synchronous liver metastasis: A consensus from the Chinese Study Group for Neuroendocrine Tumors (CSNET).

Pancreatic neuroendocrine neoplasms (p-NENs) are slowly growing tumors with frequent liver metastasis. There is a variety of approaches to treat non-functional p-NENs with synchronous liver metastasis (LM) which complicates the determination of optimal treatment. Based on updated literature review, we discussed the treatment strategy determinants for p-NEN with LM. According to the resectability of primary tumor, the WHO 2010 grade classification and the radiological type of liver metastasis, the CSNET group reached agreements on a number of issues, including the following. Prior to treatment, biopsy is required to confirm pathology. Liver biopsy is important for more accurate grading of tumor and percutaneous core needle biopsy is more available than EUS-FNA. In patients with unresectable primary, surgical resection for liver-metastatic lesions should be avoided. Curative surgery is recommended for G1/G2 p-NET with type I LM and R1 resection also seems to improve overall survival rate. Cytoreductive surgery is recommended for G1/G2 p-NET with type II LM in select patients, and should meet stated requirements. Surgical resection for G1/G2 p-NET with type III LM and p-NEC with LM should be avoided, and insufficient evidence exists to guide the surgical treatment of G3 p-NET with LM. Liver transplantation may be an option in highly select patients. In addition, the optimal time for surgical approach is still required for more evidence.

Concurrent chemoradiotherapy with or without adjuvant chemotherapy in intermediate and locoregionally advanced nasopharyngeal carcinoma.

Concurrent chemoradiotherapy (CCRT) showed a significant improvement in disease control and clinical outcome in patients with intermediate and locoregionally advanced nasopharyngeal carcinoma (NPC) (stage II, III and IVA+B). However, there has been debate about the contribution and application of additional adjuvant chemotherapy (AC) to a CCRT regime. This study aims to evaluate the additional value of AC in the treatment of intermediate and locally advanced NPC with regard to toxicity and clinical outcomes. A total of 189 patients with American Joint Committee on Cancer (AJCC) stage II to stage IVB NPC were retrospectively identified. Patient characteristics, toxicity, compliance with treatment and clinical outcomes, including response to treatment, overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), freedom from local recurrence (FLR) and freedom from distant metastasis (FDM), were analyzed. The overall response rate of CCRT and CCRT/AC groups was 97.92 % and 97.83 %, respectively (P=0.643). The 5-year OS rate was 68.2 % in the CCRT group and 75.9 % in the CCRT/AC group (P=0.53). The 5-year PFS rate was 66.7 % and 71.4 % in CCRT and CCRT/AC groups, respectively (P=0.96). This study showed no evidence of an additional value of AC in CCRT treatment in disease control and clinical outcomes in patients with locally advanced NPC in endemic regions. Moreover, three additional cycles of AC after CCRT appeared to be poorly tolerated in patients. Therefore, AC should not be routinely used for treatment, although clinical trials may be justified.