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Primary gastric melanoma is a rare clinical finding. It presents with upper gastrointestinal symptoms like abdominal pain, weight loss and melaena. It is often difficult to differentiate a primary gastric melanoma from primary cutaneous melanoma with gastric metastasis. Upper gastrointestinal endoscopy and biopsy of the lesion for histopathology and immunohistochemistry help to reach a definite diagnosis. We report a case of primary gastric melanoma with metastases to the liver and bone. The patient was treated with palliative radiotherapy, palliative chemotherapy and a bone-stabilising agent.

A man in his 80s who had a history of diabetes mellitus and aortic valve replacement was referred to our hospital for treatment of early gastric cancer and underwent endoscopic submucosal dissection (ESD). Three days after ESD, the patient presented with low back pain and fever (38.7°). We initially considered adverse events associated with gastric ESD such as delayed perforation. Moreover, thromboembolism and infectious endocarditis were suspected because of his medical history. However, there were no remarkable findings suggestive of these diseases. Finally, based on the results of blood cultures and MRI, the diagnosis of pyogenic spondylitis (PS) was made. We administered antibiotics for 12 weeks, and the patient improved without neurological impairments. This case indicates that bacteraemia and subsequent PS can occur following gastric ESD. Physicians should not overlook the patient’s physical signs related to various adverse events after ESD.

The objective was to evaluate the association between octogenarian age and the rate of postoperative morbidity and mortality and 5-year survival in older adults at the National Institute of Neoplastic Diseases (INEN) during the period 2000-2013. We developed an observational, retrospective, analytical, paired cohort study. It includes patients with gastric adenocarcinoma as diagnosis, treated by R0 D2 gastrectomy at INEN during the period 2000 to 2013. One group included all octogenarian patients who met the inclusion criteria (92) and the other group made up of non-octogenarian patients, aged between 50 to 70 years because it is the age peak for this pathology (276). In a 1:3 ratio, paired according to sex, tumor stage, and type of gastrectomy, which are the main factors that could influence survival in this population. Octogenarians had lower albumin level (p < 0.002), lower preoperative hemoglobin (p= III and postoperative complication grade >= 3 by Clavien Dindo scale were predictors of survival. In conclusion, octogenarians have a higher rate of postoperative morbidity, mainly for respiratory causes. Postoperative mortality and overall survival rates do not differ between octogenarians and non-octogenarians with stomach cancer treated by R0 D2 gastrectomy. El objetivo de la presente investigación es evaluar la asociación entre la edad octogenaria y la tasa de morbimortalidad posoperatoria y supervivencia a los 5 años en adultos mayores tratados mediante gastrectomía R0 D2 en el Instituto Nacional de Enfermedades Neoplásicas (INEN) durante el periodo 2000-2013. Se realizó un estudio observacional, retrospectivo, analítico de cohorte pareado, que incluye pacientes con diagnóstico de adenocarcinoma gástrico tratados mediante gastrectomía R0 D2 en el INEN durante los años 2000 a 2013. Un grupo compuesto por todos los pacientes octogenarios que cumplieron los criterios de inclusión (92) y otro grupo compuesto por pacientes no octogenarios, con edades entre 50 a 70 años por ser el pico de presentación para esta patología (276). En una proporción 1:3, pareados según sexo, estadio tumoral y tipo de gastrectomía, los cuales constituyen los principales factores que podrían influir en la sobrevida de esta población. Los octogenarios presentaron menor albúmina (p

Afferent loop syndrome (ALS) is an uncommon complication of gastrojejunostomy. It may be acute or chronic depending on whether symptoms manifest within 7 days of surgery. Rarely acute ALS may give rise to acute pancreatitis. It may present early in the postoperative course and, if diagnosed late, may result in organ failure within 48h. We report a middle-aged woman with carcinoma of the stomach managed by subtotal gastrectomy with Billroth II gastrojejunostomy and Braun jejunojejunostomy. The patient developed vomiting and abdominal pain in the first postoperative day with acute renal shutdown and about 500ml drain output of dirty fluid. On investigation, a diagnosis of acute pancreatitis due to afferent loop syndrome was made, and the patient was resuscitated in the intensive care unit. However, she showed early signs of organ failure and succumbed to her condition within 6 days of surgery. Since the complication is rare following gastrojejunostomy and often mimics ALS, an early diagnosis becomes difficult. If delay in management happens, premature organ failure may lead to high morbidity and mortality.

A 64-year-old woman presented with diffuse abdominal pain, postprandial bloating and 5 kg of unintentional weight loss in the last 3 months. She had a previous medical history of nephrectomy due to recurrent pyelonephritis and hypothyroidism. Physical examination revealed only mild tenderness in

The microbiome is hypothesized to have a significant impact on cancer development. In gastric cancer (GC), Helicobacter pylori is an established class I carcinogen. However, additional organisms in the intratumoral microbiome play an important role in GC pathogenesis and progression. In this study, we characterize the full spectrum of the microbes present within GC and identify distinctions among molecular subtypes.A microbiome bioinformatics pipeline that is generalizable across multiple next-generation sequencing platforms was developed. Microbial profiles for alpha diversity and enrichment were generated for 2 large, demographically distinct cohorts: (1) internal Memorial Sloan Kettering Cancer Center (MSKCC) and (2) The Cancer Genome Atlas (TCGA) cohorts. A total of 520 GC samples were compared with select tumor-adjacent nonmalignant samples. Microbiome differences among the GC molecular subtypes were identified.Compared with nonmalignant samples, GC had significantly decreased microbial diversity in both MSKCC and TCGA cohorts ( P0.05). Helicobacter , Lactobacillus , Streptococcus , Prevotella , and Bacteroides were significantly more enriched in GC samples when compared with nonmalignant tissue ( P0.05). Microsatellite instability-high GC had distinct microbial enrichment compared with other GC molecular subtypes.Distinct patterns of microbial diversity and species enrichment were identified in patients with GC. Given the varied spectrum of disease progression and treatment response of GC, understanding unique microbial signatures will provide the landscape to explore key microbial targets for therapy.

Background Detailed understanding of pre-, early and late neoplastic states in gastric cancer helps develop better models of risk of progression to gastric cancers (GCs) and medical treatment to intercept such progression. Methods We built a Boolean implication network of gastric cancer and deployed machine learning algorithms to develop predictive models of known pre-neoplastic states, e.g., atrophic gastritis, intestinal metaplasia (IM) and low- to high-grade intestinal neoplasia (L/HGIN), and GC. Our approach exploits the presence of asymmetric Boolean implication relationships that are likely to be invariant across almost all gastric cancer datasets. Invariant asymmetric Boolean implication relationships can decipher fundamental time-series underlying the biological data. Pursuing this method, we developed a healthy mucosa → GC continuum model based on this approach. Results Our model performed better against publicly available models for distinguishing healthy versus GC samples. Although not trained on IM and L/HGIN datasets, the model could identify the risk of progression to GC via the metaplasia → dysplasia → neoplasia cascade in patient samples. The model could rank all publicly available mouse models for their ability to best recapitulate the gene expression patterns during human GC initiation and progression. Conclusions A Boolean implication network enabled the identification of hitherto undefined continuum states during GC initiation. The developed model could now serve as a starting point for rationalizing candidate therapeutic targets to intercept GC progression.

PURPOSE In patients with resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma, surgery plus perioperative platinum-based chemotherapy is the standard of care. Perioperative chemotherapy remains debatable for gastric/GEJ adenocarcinoma with deficient mismatch repair (dMMR)/microsatellite instability–high (MSI-H). PATIENTS AND METHODS NEONIPIGA (ClinicalTrials.gov identifier: NCT04006262 ) phase II study evaluated neoadjuvant nivolumab 240 mg once every two weeks ×6 and ipilimumab 1 mg/kg once every six weeks ×2, followed by surgery and adjuvant nivolumab 480 mg once every four weeks (nine injections) in patients with locally advanced resectable dMMR/MSI-H, clinical (c) tumor (T)2-T4 node (N)x metastasis (M)0 gastric/GEJ adenocarcinoma. The primary end point was a pathological complete response (pCR) rate. RESULTS Between October 2019 and June 2021, 32 patients with dMMR/MSI-H gastric/GEJ adenocarcinoma were enrolled. The median age was 65.5 years (range, 40-80). Clinical stages were cT2-T3N0 (n = 9), cT2-T3N1 (n = 22), and cT3N1M1 (n = 1, wrongly included). With a median follow-up of 14.9 months (95% CI, 10.6 to 17.6), 32 patients received neoadjuvant immunotherapy (27 patients completed all cycles). Neoadjuvant therapy-related grade 3/4 adverse events occurred in six patients (19%). Twenty-nine patients underwent surgery; three did not have surgery and had complete endoscopic response with tumor-free biopsies and a normal computed tomography scan (two refused surgery and one had metastasis at inclusion). The rate of surgical morbidity (Clavien-Dindo classification) was 55% (one postoperative death occurred). All 29 patients had an R0 resection, and 17 (58.6%; 90% CI, 41.8 to 74.1) had pCR (pathological T0N0). Becker tumor regression grades 1a, 1b, 2, and 3 were observed in 17 patients, three (including two pathological T0N1), two, and seven patients, respectively. Of the 29 patients with surgery, 23 received adjuvant nivolumab. At database lock, no patient had relapse and one died without relapse. CONCLUSION Nivolumab and ipilimumab-based neoadjuvant therapy is feasible and associated with no unexpected toxicity and a high pCR rate in patients with dMMR/MSI-H resectable gastric/GEJ adenocarcinoma.

It is unclear whether obesity confers increased risk of non-cardia gastric adenocarcinoma and its precursor, gastric intestinal metaplasia. Here, we examined whether various dimensions of adiposity independently predispose to the development of non-cardia gastric intestinal metaplasia.We compared data from 409 non-cardia gastric intestinal metaplasia cases and 1748 controls without any gastric intestinal metaplasia from a cross-sectional study at the VA Medical Center in Houston, Texas. Participants completed standardized questionnaires, underwent anthropometric measurements, and underwent a study endoscopy with gastric mapping biopsies. Non-cardia gastric intestinal metaplasia cases included participants with intestinal metaplasia on any non-cardia gastric biopsy. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression models.Increasing body mass index (BMI) was not associated with risk of non-cardia gastric intestinal metaplasia (per unit BMI adjusted OR, 0.98; 95% CI, 0.96-1.00). Similarly, we found no associations with increase in waist circumference (per 10-cm increase adjusted OR, 0.94; 95% CI, 0.87-1.03) and waist-to-hip ratio (WHR) (per unit WHR adjusted OR, 2.34; 95% CI, 0.37-14.7). However, there was a significant inverse association with gastric intestinal metaplasia and increasing hip circumference, reflecting gluteofemoral obesity (per 10-cm increase adjusted OR, 0.89; 95% CI, 0.80-0.98). The inverse association was observed for both extensive and focal gastric intestinal metaplasia.The independent dimensions of adiposity (BMI, waist circumference) are not associated with increased risk of non-cardia gastric intestinal metaplasia. The inverse association between gluteofemoral obesity and risk of gastric intestinal metaplasia warrants additional study.

To determine the expression and function of glutamate-cysteine ligase catalytic (GCLC) and glutamate-cysteine ligase catalytic modifier (GCLM) in gastric adenocarcinoma.Bioinformatics was used to analyze the expression of GCLC and GCLM. We download and analyzed the expression of gastric adenocarcinoma patients from TCGA database. Moreover, the method of immunochemistry was used to verify the expression of GCLC and GCLM in gastric adenocarcinoma.At first, the expression of GCLC and GCLM in gastric adenocarcinoma tissues were both significantly higher compared with normal tissues analyzed via TCGA database. Then, gastric adenocarcinoma tissues were collected and performed with immunochemistry. The gastric adenocarcinoma with positive staining for GCLC and GCLM was 77% and 80%, respectively, which was significantly higher compared with adjacent normal tissues (9% and 11%, respectively).The disordered expression of GCLC and GCLM in gastric adenocarcinoma suggested that these factors may induce tumorigenesis and may be a novel target for diagnosis and treatment of gastric adenocarcinoma.

Everolimus was designed as a mammalian target of rapamycin (mTOR) inhibitor. It has been proven as a targeted drug for gastric cancer (GC) therapy. However, long-term treatment with everolimus may cause severe side effects for recipients. Decreasing the dosage and attenuating the associated risks are feasible to promote clinical translation of everolimus. This study aimed to identify the underlying mechanisms of responses to everolimus and develop novel regimens for GC treatment. Our findings proved that there was a significant dose-dependent relationship of everolimus-induced GC cell apoptosis and glycolysis inhibition. Then, we found that a member of glucose transporter (GLUT12) family, GLUT12, was actively upregulated to counteract the anticancer effects of everolimus. GLUT12 might be overexpressed in GC. High expression of GLUT12 might be correlated with tumor progression and short survival time of GC patients. Bioinformatic analysis suggested that GLUT12 might be involved in regulating cancer development and metabolism. The experiments proved that GLUT12 significantly promoted GC growth, glycolysis and impaired the anticancer effects of everolimus. Androgen receptor (AR) is a classical oncogenic factor in many types of cancer. Everolimus elevated GLUT12 expression in an AR-dependent manner. Inhibition of AR activity abrogated the promotive effects on GLUT12 expression. Both

Background Gastric cancer is worldwide the fourth more common cancer type by incidence, and the third by mortality. We analyzed three missense variants of TAS2R38 gene: rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I296V). These variants and their combination in haplotypes (proline, alanine and valine/tasters or alanine, valine and isoleucine/nontasters) and diplotypes are responsible for individual differences in bitter perception. The single-nucleotide polymorphisms and the related phenotypes are known to be associated with susceptibility to Gram-negative bacterial infections, such as Helicobacter pylori, and with risk of various cancer types. An association between intermediate tasters (as defined by TAS2R38 diplotypes) and increased risk of gastric cancer was reported in a Korean population. Methods We analyzed 2616 individuals of Latin American origin, representing the whole spectrum of lesions from gastritis to gastric cancer. Results Comparing cancer cases vs. noncancers we observed a decrease in risk associated with heterozygous carriers of rs10246939 (P = 0.006) and rs1726866 (P = 0.003) when compared with homozygotes of the more common allele. Also, the analysis of diplotypes/phenotypes reflected the same association, with super-tasters showing a borderline increased risk of developing gastric cancer compared to medium-tasters [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.04-2.56; P = 0.033]. Also, nontasters showed an increased risk when compared to medium-tasters although not reaching statistical significance (OR = 1.58; 95% CI, 0.80-2.87; P = 0.203). We also tested the interactions between the TAS2R38 genotypes and H. pylori cagA status in a subset of samples and found no interaction. Conclusion In conclusion, our results suggest only a modest contribution of TAS2R38 gene genetic variability in gastric cancer etiology.

Accumulating evidence has unfolded the significance of extracellular vesicles (EVs) in diseases and cancers. Here, we attempted to discuss the role of cancer-associated fibroblasts (CAFs)-derived EVs containing miR-199a-5p in gastric tumorigenesis. Upregulated miR-199a-5p was first identified in cancer cells. Then, we selected CAFs for isolation of EVs which were co-cultured with AGS cells. We observed successful delivery of miR-199a-5p via CAF-derived EVs. Besides, miR-199a-5p promoted malignant properties of AGS cells. Moreover, miR-199a-5p downregulated FKBP5, leading to upregulated phosphorylation level of AKT1, which promoted the malignant phenotypes of AGS cells by activating mammalian target of rapamycin complex 1(mTORC1). Exosomal miR-199a-5p from CAFs promoted gastric tumorigenesis

Three distinct gastric carcinoid (GC) tumour types have been described based on differing biological behaviour and prognoses. Type I GC tumours account for the vast majority (70%–80%), are associated with chronic atrophic gastritis and have a low metastatic potential. Type II carcinoid tumours are the least common (5%–10%), are related to Zollinger-Ellison syndrome and occur in relation to multiple neoplasia type I. Sporadic type III tumours (15%–25%) are the most aggressive type, are unrelated to gastrin over secretion and carry the worst prognosis. In this case report, we present a patient with longstanding gastroesophageal reflux disease (GERD) who presented with epigastric abdominal pain and tarry stools and was found to have a large gastric polyp on endoscopy. Despite current literature recommending surgical resection for larger GC tumours, endoscopic resection was successfully used to excise the tumour with pathology demonstrating complete resection with negative margins.

PURPOSE Subset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR-amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to date. PATIENTS AND METHODS A total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments–approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB). RESULTS Sixty patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR-amplified GEA received EGFRi. CONCLUSION Patients with EGFR-amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

Primary retroperitoneal neuroendocrine tumours (NETs) are extremely rare, and many a times, these are metastatic lesions with known or unknown primary location, most commonly arising from the stomach, duodenum, small intestine and rectum. NETs arising from the duodenum are more commonly seen in the first part of the duodenum followed by the second part. The incidence is increasing because of easy accessibility to endoscopies and cross-sectional imaging. In NETs, lymph node (LN) metastasis occurs commonly when the tumour size is more than 2 cm. In contrast, LN metastasis occurs even with subcentimetric lesions, especially the ampullary variant of NETs. A patient presented to us with mild abdominal pain and found to have retroduodenal mass. On evaluation found to be a metastatic LN deposit of NET with the primary arising from the first part and supra-ampullary part of duodenum.

Gastric cancer is among the most common gastrointestinal malignancies. Recent studies have suggested that bone morphogenetic protein-2 (BMP2) is related to the development and progression of various cancers. Meanwhile, evidence suggests that BMP2 might lead to epigenetic changes in gastric cancer. Thus, we investigated whether BMP2 plays a role in the development of gastric cancer via epigenetic regulation. Cell viability, colony formation, and cell cycle assays were performed to assess the effect of recombinant human BMP2 (rhBMP2) in gastric cancer cells. LDN-193189 and Noggins were used as antagonists of the canonical BMP-SMAD signaling pathway. The protein levels were determined using a western blot analysis. Lentiviral vectors with EZH2 shRNA or EZH2 overexpression were used to mediate the role of EZH2 and the relationship between BMP2 and EZH2 in gastric cancer. We found that rhBMP2 inhibits cell proliferation by arresting the cell cycle in HGC-27 and SNU-216 gastric cancer cells. Neither LDN-193189 nor Noggins, antagonists of the canonical BMP-SMAD signaling pathway, can reverse the effect of rhBMP2 on gastric cancer. Molecularly, rhBMP2 downregulates the expression of EZH2 and H3K27me3, leading to increases in P16 and P21 and decreases in CDK2, CDK4, and CDK6. Altogether, in this study, we demonstrate that BMP2 serves as a tumor suppressor in gastric cancer cells by downregulating EZH2 and H3K27me3 through the non-SMAD BMP pathway, suggesting that BMP2 might be a new therapeutic target for gastric cancer treatment.bAbbreviations:/bBMP: bone morphogenetic protein; TGF-β: transforming growth factor-beta; EZH2: enhancer of zeste homolog 2; H3K27me3: trimethylation histone H3 lysine 27; HRECs: human retinal endothelial cells; PcG: polycomb group; PRC: polycomb repressive complexes.

Cilj: Cilj ovog istraživanja bio je analizirati patohistološke osobitosti adenokarcinoma želuca i kratkoročne kliničke ishode u bolesnika operiranih u razdoblju od 1. siječnja 2018. do 1. kolovoza 2020. godine. Materijali i metode: U istraživanje su uključeni bolesnici operirani zbog adenokarcinoma želuca u razdoblju od 1. siječnja 2018. do 1. kolovoza 2020. Iz arhive povijesti bolesti i patohistoloških nalaza su prikupljeni sljedeći podatci: dob, spol, lokalizacija tumora, TNM stadij, gradus, histološki tip, status limfnih čvorova, dužina hospitalizacije, tip operacije. Rezultati: Od ukupnog broja bolesnika muških je bilo 36,65%, a ženskih 19,35%. Stariji od 63 godine čine 75% ukupnog broja bolesnika. Najzastupljeniji patološki stadij je IIIA (20%), a srednja vrijednost udaljenosti tumora od ruba je 5,00 cm. Medijan odstranjenih limfnih čvorova je 6,50. Srednja vrijednost pozitivnih limfnih čvorova je 3,00. Srednja vrijednost pozitivnih limfnih čvorova kod tumora visokog gradusa je 9,86, a kod tumora niskog gradusa 2,32. Međutim, ne postoji statistički značajna povezanost, P=0,276. Najčešći tip operacije je bila subtotalna gastrektomija. Komplikacije su utvrđene u 29,09%, a potreba za revizijom je utvrđena u 9,09% bolesnika. Neposredno nakon operacije nije umro niti jedan promatrani bolesnik. Srednja vrijednost duljine hospitalizacije u bolesnika s komplikacijama je bila za 9 dana duža u odnosu na bolesnike u kojih komplikacija nije bilo. Zaključci: Demografske i patohistološke odrednice adenokarcinoma želuca ne odstupaju od ostalih istraživanja. Duljina resekcijskih rubova je u skladu sa smjernicama. Prosječan broj odstranjenih limfnih čvorova je manji od preporučenog. Histološki gradus je povezan s većim brojem pozitivnih limfnih čvorova, ali povezanost nije statistički značajna., Objective: The aim of this study was to analyse the pathohistological features of gastric adenocarcinoma and short-term clinical outcomes in patients operated in the period from 1 January 2018 to 1 August 2020.Materials and methods: This retrospective study included patients operated on for gastric adenocarcinoma in the period from 1 January 2018 to 1 August 2020. The following data were collected from the archive of disease history and path histological findin-gs: age, sex, tumour localization, TNM stage, grade, histological type, lymph node status, length of hospitalization, type of surgery.Results: Of the total number of patients, 36 (65%) were male, and 19 (35%) were female. People over 63 make up 75% of the total number of patients. The most common pathological stage is IIIA (20%), and the mean distance of the tumour from the edge is 5.00 cm. The median number of removed lymph nodes is 6.50. The mean value of positive lymph nodes is 3.00. The mean value of positive lymph nodes in high-grade tumours was 9.86, and in low-grade tumours 2.32. However, there is no statistically significant association, P=0.276. The most common type of surgery was subtotal gastrectomy. Complications were found in 29.09%, and the need for revision was found in 9.09% patients. Not a single observed patient died immediately after the operation. The mean length of hospitalization in patients with complications was 9 days longer than in patients without complications.Conclusions: Demographic and pathohistological determinants of gastric adenocarcinoma do not differ from other studies. The length of the resection margins is in accordance with the guidelines. The average number of removed lymph nodes is less than recommended. Histological grade is associated with a higher number of positive lymph nodes, but the association is not statistically significant.

HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification.This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing.Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%] of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients; all grade 1-2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths.These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies.Zymeworks.

High-grade (grade 3) neuroendocrine neoplasms (G3 NENs) have poor survival outcomes. From a clinical standpoint, G3 NENs are usually grouped regardless of primary site and treated similarly. Little is known regarding the underlying genomics of these rare tumors, especially when compared across different primary sites. We performed whole transcriptome (n = 46), whole exome (n = 40), and gene copy number (n = 43) sequencing on G3 NEN formalin-fixed, paraffin-embedded samples from diverse organs (in total, 17 were lung, 16 were gastroenteropancreatic, and 13 other). G3 NENs despite arising from diverse primary sites did not have gene expression profiles that were easily segregated by organ of origin. Across all G3 NENs, TP53, APC, RB1, and CDKN2A were significantly mutated. The CDK4/6 cell cycling pathway was mutated in 95% of cases, with upregulation of oncogenes within this pathway. G3 NENs had high tumor mutation burden (mean 7.09 mutations/MB), with 20% having >10 mutations/MB. Two somatic copy number alterations were significantly associated with worse prognosis across tissue types: focal deletion 22q13.31 (HR, 7.82; P = 0.034) and arm amplification 19q (HR, 4.82; P = 0.032). This study is among the most diverse genomic study of high-grade neuroendocrine neoplasms. We uncovered genomic features previously unrecognized for this rapidly fatal and rare cancer type that could have potential prognostic and therapeutic implications.

Patients with advanced gastric cancer experience rapid disease progression with limited survival, high mortality, and a lack of surgical options. Thus, radiochemotherapy or a combination of chemotherapeutics with targeted therapy is the mainstay of treatment. In comparison to the treatment of other malignant tumors, in gastric cancer, the development of molecularly targeted drugs has been relatively slow. Currently, there are two major classes of molecularly targeted drug regimens that have achieved a certain efficacy in clinical practice: anti-vascular endothelial growth factor (anti-VEGF) therapy and anti-epidermal growth factor receptor (anti-EGFR) therapy. Trastuzumab has been approved as the standard of care for first-line treatment in advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer. Ramucirumab in combination with paclitaxel is the recommended regimen for second-line treatment, and apatinib is recommended as third-line treatment. This review summarizes the current status of targeted therapies in the treatment of gastric cancer and gives a perspective on the future.

Although palliative radiotherapy for gastric cancer may improve some symptoms, it may also have a negative impact due to its toxicity. We investigated whether symptoms improved after radiotherapy with adjustment for the Palliative Prognostic Index (PPI) considering that patients with limited survival tend to experience deterioration of symptoms.This study was an exploratory analysis of the Japanese Radiation Oncology Study Group study (JROSG 17-3). We assessed six symptom scores (nausea, anorexia, fatigue, shortness of breath, pain at the irradiated area and distress) at registration and 2, 4 and 8 weeks thereafter. We tested whether symptoms linearly improved after adjusting for the baseline PPI. Shared parameter models were used to adjust for potential bias in missing data.The present study analysed all 55 patients enrolled in JROSG 17-3. With time from registration as the only explanatory variable in the model, a significant linear decrease was observed in shortness of breath, pain and distress (slopes, -0.26, -0.22 and -0.19, respectively). Given that the interaction terms (i.e. PPI × time) were not significantly associated with symptom scores in any of the six symptoms, only PPI was included as the main effect in the final multivariable models. After adjusting for the PPI, shortness of breath, pain and distress significantly improved (slope, -0.25, -0.19 and -0.17; P0.001, 0.002 and 0.047, respectively). An improvement in fatigue and distress was observed only in patients treated with a biologically effective dose ≤14.4 Gy.Shortness of breath, pain and distress improved after radiotherapy. Moreover, a higher PPI was significantly associated with higher symptom scores at all time points, including baseline. In contrast, PPI did not seem to influence the improvement of these symptoms. Regardless of the expected survival, patients receiving radiotherapy for gastric cancer can expect an improvement in shortness of breath, pain and distress over 8 weeks. Multiple-fraction radiotherapy might hamper the improvement in fatigue and distress by its toxicity or treatment burden.

Summary Aim of the study Nomograms have been proposed to assess prognosis following curative surgery for gastric cancer. The objective of the current study was to evaluate the performance of the Gastric Cancer Collaborative Group nomograms developed in 2014 by Kim et al., using a cohort of patients from a 10-year single institution experience in gastric cancer management. Patients and methods We retrospectively reviewed patients who underwent curative-intent surgery for histologically confirmed gastric cancer at First Surgical Clinic of Padua University Hospital (Italy) from January 2010 to May 2020. Univariable and multivariable Cox proportional hazard models were employed to assess the effect of the variables of interest on mortality and recurrence. Multivariable analysis was performed by considering the variables included in the Gastric Cancer Collaborative Group nomograms in order to validate them. The performance of the nomograms was evaluated using Harrell's C-index and calibration plots. Results Overall, 168 patients were included, with a median follow-up of 20.1 months. On multivariable analysis, tumor location, lymph node ratio, and pathological T stage were associated with recurrence; age, tumor location, lymph node ratio, and pT stage were associated with OS (overall survival). The nomograms had good discriminatory capability to classify both OS (C-index: 0.75) and DFS (disease-free survival) (C-index 0.72). The corrected C-Index for DFS based on the AJCC staging system revealed better prediction (C-Index 0.75), while the corrected C-Index for OS had worse discrimination ability compared with the current nomogram (C-Index 0.72). Conclusions The Gastric Cancer Collaborative Group nomograms demonstrated good performances in terms of prediction of both OS and DFS on external validation. The two nomograms are easy to apply, and variables included are widely available to most facilities.

Several randomized controlled trials have evaluated the efficacy of neoadjuvant chemotherapy in the management of resectable gastric cancer. Most patients in these studies had node-positive disease or more advanced T stage. The benefit of neoadjuvant therapy in patients with early-stage gastric cancer remains unclear.We queried the National Cancer Data Base to identify patients presenting with clinical stage IB gastric adenocarcinoma between 2006 and 2015. Multivariable logistic regression was used to identify factors associated with receipt of neoadjuvant therapy. Patients undergoing neoadjuvant therapy were 1:1 propensity matched for age, year of diagnosis, Charlson index, insurance, tumor location, tumor grade, surgical approach, lymph nodes examined, and receipt of adjuvant therapy. Log rank testing was used to evaluate differences in overall survival between matched cohorts.A total of 1,258 patients met the inclusion criteria; 402 (32%) received neoadjuvant therapy. On multivariable logistic regression, increasing age (odds ratio 0.52, 95% confidence interval 0.34-0.80) was associated with reduced adjusted odds of undergoing neoadjuvant therapy, whereas proximal tumor location (odds ratio 3.67, 95% confidence interval 2.71-4.99) and poorly differentiated histology (odds ratio 1.78, 95% confidence interval 1.00-3.16) were associated with an increased adjusted odds of undergoing neoadjuvant therapy. A total of 271 patients undergoing neoadjuvant therapy were successfully matched to 271 patients undergoing upfront resection. There was no statistically significant difference in 5-year overall survival (58.8% vs 50.3%, P = .512) between matched cohorts.Neoadjuvant therapy does not appear to be associated with an overall survival benefit in patients with stage IB stage gastric cancer.

The purpose of this study is to explore the effect of nursing intervention based on the chronic disease trajectory model in nutritional support for patients with gastric cancer. A total of 106 patients with gastric cancer hospitalized at our surgical oncology from January to October 2018 were randomly divided into the intervention group and the control group, with 53 patients in each. The control group was treated with routine nursing methods, and the other group was given a new nursing method based on the chronic disease trajectory model. We collected the data of postoperative complications, the six-month nutritional status and the negative emotion scores from the two groups. At discharge and the first-, second-, third- and sixth-month follow-up, the measured values of albumin and prealbumin in the intervention group were significantly higher than the control group. At discharge and six months after follow-up, the SAS and SDS scores in the intervention group were lower than the control group. The nursing intervention based on the chronic disease trajectory model can improve the nutritional status and negative emotions of patients with gastric cancer and decrease the incidence of postoperative complications.

White light imaging (WLI) is the most common endoscopic technique used for screening of gastrointestinal diseases. However, despite the advent of a new processor that offers sufficient clear illumination and other advanced developments in endoscopic instrumentation, WLI alone is inadequate for detecting all gastrointestinal diseases with abnormalities in mucosal discoloration and morphological changes to the mucosal surface. The recent development of image-enhanced endoscopy (IEE) has dramatically improved the detection of gastrointestinal diseases. Texture and colour enhancement imaging (TXI) is a new type of IEE that enhances brightness, surface irregularities, such as elevations or depressions, and subtle colour changes. TXI with two modes, namely modes 1 and 2, can selectively enhance brightness in dark areas of an endoscopic image and subtle tissue differences such as slight morphological or colour changes while simultaneously preventing over-enhancement. Several clinical studies have investigated the efficacy of TXI for detecting and visualizing gastrointestinal diseases, including oesophageal squamous cell carcinoma (ESCC), Barret's epithelium, gastric cancer, gastric mucosal atrophy and intestinal metaplasia. Although TXI is often more useful for detecting and visualizing gastrointestinal diseases than WLI, it remains unclear whether TXI outperforms other IEEs, such as narrow-band imaging (NBI), in similar functions, and whether the performance of TXI modes 1 and 2 are comparable. Therefore, large-scale prospective studies are needed to compare the efficacy of TXI to WLI and other IEEs for endoscopic evaluation of patients undergoing screening endoscopy. Here, we review the characteristics and efficacy of TXI for the detection and visualization of gastrointestinal diseases.Key MessagesTXI mode 1 can improve the visibility of gastrointestinal diseases and qualitative diagnosis, especially for diseases associated with colour changes.The enhancement of texture and brightness with TXI mode 2 enables the detection of diseases, and is ideal for use in the first screening of gastrointestinal tract.

To evaluate whether insertion of self-biodegradable stent into the pylorus to prevent delayed-gastric emptying after pylorus-preserving gastrectomy is feasible and safe through porcine experiment.Self-biodegradable dumbbell-shaped pyloric stents were designed from absorbable suture materials: poly(glycolide-co-caprolactone) (PGCL) or poly-p-dioxanone (PPDO). After gastrotomy on ten pigs, each stent was inserted: two shams, four PGCL stents, and four PPDO stents. Body weight (Bwt), body temperature (BT), complete blood cell (CBC) count, and plain X-ray were evaluated. On postoperative day (POD) 13, euthanasia was performed for histologic evaluation.Operation was successfully performed in all ten pigs. Without tagging suture, both stents migrated before POD 3. The migration was delayed up to POD 13, when the tagging sutures (-t) were applied between stent and stomach wall. Self-degradation of PGCL started from POD 3, and stents were completely excreted from the abdomen by POD 8. Although PPDO were also weakened as self-degradation progressed, its shape was maintained in gastrointestinal tract for 13 days. Unexpected sudden death occurred in the pig with PPDO-t2 on POD 10, which is more likely due to acute volvulus rather than stent-related complication. There was no significant difference between three groups in terms of Bwt, BT, CBC, and histology (sham vs. PGCL vs. PPDO, all p 0.05).The concept of biodegradable stents made of absorbent suture material seems feasible in porcine experiment. Among them, PGCL which has shown rapid absorption, appears to be a more suitable material for transient pyloric absorbable stent when considering safety aspect.

BACKGROUND AND OBJECTIVE: EBV-associated gastric cancer (EBVaGC) is a distinct subtype of GC, and EBV plays an important role in tumor progress. The standard method to identify EBV-positive tumor is determined by in situ hybridization for EBV-encoded EBERs in tumor tissues. The present study aims to detect the serological expression of EBV-related antibodies and ET-1 axis to provide a noninvasive method for diagnosis of EBVaGC. METHODS: The content of EBV-related antibodies and ET-1 axis in preoperative peripheral blood of GC was performed by Chemiluminescence and ELISA assay. The EBV DNA copy number was measured by qRT-PCR. RESULTS: The results showed that the levels of anti-EBV early antigen (EA) IgG, viral capsid antigen (VCA) IgA, nuclear antigen (NA) IgG, and EBV DNA copy number were significantly higher in EBVaGC. The ET-1 axis level was much lower in EBVaGC than EBVnGC. CONCLUSIONS: The combined detection of specific anti-EBV antibodies and ET-1 axis might provide new molecular markers for the identification of EBVaGC.

PURPOSE High pathologic complete response (pCR) rates and comparably good survival data were seen in a phase II trial combining perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy with trastuzumab for resectable, esophagogastric adenocarcinoma (EGA). The current trial evaluates the addition of trastuzumab and pertuzumab to FLOT as perioperative treatment for human epidermal growth factor receptor 2–positive resectable EGA. METHODS In this multicenter, randomized phase II/III trial, patients with human epidermal growth factor receptor 2–positive, resectable EGA (≥ clinical tumor 2 or clinical nodal–positive) were assigned to four pre- and postoperative cycles of either FLOT alone (arm A) or combined with trastuzumab and pertuzumab, followed by nine cycles of trastuzumab/pertuzumab (arm B). The primary end point for the phase II part was the rate of pCR. RESULTS The trial was closed prematurely, without transition into phase III, after results of the JACOB trial were reported. Eighty-one patients were randomly assigned (A: 41/B: 40) during the phase II part. The pCR rate was significantly improved with the trastuzumab/pertuzumab treatment (A: 12%/B: 35%; P = .02). Similarly, the rate of pathologic lymph node negativity was higher with trastuzumab/pertuzumab (A: 39%/B: 68%), whereas the R0 resection rate (A: 90%/B: 93%) and surgical morbidity (A: 43%/B: 44%) were comparable. Moreover, the inhouse mortality was equal in both arms (overall 2.5%). The median disease-free survival was 26 months in arm A and not yet reached in arm B (hazard ratio, 0.58; P = .14). After a median follow-up of 22 months, the median overall survival was not yet reached (hazard ratio, 0.56; P = .24). Disease-free survival and overall survival rates at 24 months were 54% (95% CI, 38 to 71) and 77% (95% CI, 63 to 90) in arm A and 70% (95% CI, 55 to 85) and 84% (95% CI, 72 to 96) in arm B, respectively. More ≥ grade 3 adverse events were reported with trastuzumab/pertuzumab, especially diarrhea (A: 5%/B: 41%) and leukopenia (A: 13%/B: 23%). CONCLUSION The addition of trastuzumab/pertuzumab to perioperative FLOT significantly improved pCR and nodal negativity rates at the price of higher rates of diarrhea and leukopenia.

Objective. This study is aimed at screening out effective active compounds of Qizhen capsule (QZC) and exploring the underlying mechanisms against gastric cancer (GACA) by combining both bioinformatic analysis and experimental approaches. Weighted gene coexpression network analysis (WGCNA), network pharmacology, molecular docking simulation, survival analysis, and data-based differential gene and protein expression analysis were employed to predict QZC’s potential targets and explore the underlying mechanisms. Subsequently, multiple experiments, including cell viability, apoptosis, and protein expression analyses, were conducted to validate the bioinformatics-predicted therapeutic targets. The results indicated that luteolin, rutin, quercetin, and kaempferol were vital active compounds, and TP53, MAPK1, and AKT1 were key targets. Molecular docking simulation showed that the four abovementioned active compounds had high binding affinities to the three main targets. Enrichment analysis showed that vital active compounds exerted therapeutic effects on GACA through regulating the TP53 pathway, MAPK pathway, and PI3K/AKT pathway. Furthermore, data-based gene expression analysis revealed that TP53 and JUN genes were not only differentially expressed between normal and GACA tissues but also correlated with clinical stages. In parallel, in vitro experimental results suggested that QZC exerted therapeutic effects on GACA by decreasing IC50 values, downregulating AKT expression, upregulating TP53 and MAPK expression, and increasing apoptosis of SGC-7901 cells. This study highlights the potential candidate biomarkers, therapeutic targets, and basic mechanisms of QZC in treating GACA, providing a foundation for new drug development, target mining, and related animal studies in GACA.

Endoscopic submucosal dissection (ESD) is an established technique for the treatment of early gastrointestinal neoplasia. Generally, multi-day (M-D) admission is required for patients undergoing ESD due to potential complications.To evaluate the feasibility of a same-day (S-D) discharge strategy for ESD of the esophagus or stomach.The data of patients who underwent esophageal or gastric ESD were retrospectively collected from January 2018 to December 2021 at Peking University Cancer Hospital. The propensity score matching (PSM) method was applied to balance the unevenly distributed patient baseline characteristics between the S-D and M-D groups. Intraoperative and postoperative parameters were compared between the matched groups.Among the 479 patients reviewed, 470 patients, including 91 in the S-D group and 379 in the M-D group, fulfilled the inclusion and exclusion criteria. Following PSM, 78 patients in each group were paired using the 1:1 nearest available score match algorithm. No significant difference was found between groups with respect to intraoperative and postprocedural major adverse events (AEs). Tumor size, complete resection rate, and procedural duration were comparable between the groups. The S-D group demonstrated a significantly shorter length of hospital stay (The S-D discharge strategy may be feasible and effective for esophagogastric ESD, and the procedural-related AEs can be managed successfully.

The encoding product of Chordin-like 2 (CHRDL2) is a member of the chordin family of proteins, which has been shown to be aberrantly expressed in several types of solid tumors. The regulatory underlying mechanisms of CHRDL2, however, remain poorly understood in gastric cancer (GC). In the present study, we determined that CHRDL2 was abnormally upregulated in human gastric cancer tissues compared with adjacent normal tissues. We also showed that CHRDL2 was positively associated with T stage, the pathological stage, distant metastasis, and poor patient prognosis. Furthermore, the serum level of CHRDL2 was obviously higher in GC patients than normal people, and is positively correlated with later TNM stage, deeper T stage, later N stage and poorer differentiation. Moreover, we verified that overexpressing CHRDL2 promoted the proliferation and cell cycle transition of GC cells both in vitro and in vivo, whereas the opposite results were observed in CHRDL2-depleted cells. In addition, the phosphorylation levels of Yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ) and the total levels MST2 were decreased in CHRDL2 overexpressing cells. Consistent with previous findings, we observed the converse results in CHRDL2-silenced GC cells. Additionally, knockdown of YAP and overexpression of STK3 (MST2) could reverse the effects of CHRDL2 overexpression-induced proliferation of GC cells in vitro. Taken together, CHRDL2 plays a key role by activating the YAP/TAZ pathway in gastric cancer. Therefore, CHRDL2 could serve as a potential therapeutic tool for the treatment of gastric cancer.

Implementation of minimally invasive gastrectomy (MIG) for malignancy is increasing. However, risk factors for conversion to open surgery during laparoscopic and robotic gastrectomy are poorly understood. This study aimed to determine the risk factors for, and impact of, conversion during oncologic resection.The National Cancer Database (NCDB) was used to identify patients with clinical stage I-III gastric cancer from 2010 to 2017. Chi-squared test and t-test were used to compare the robotic versus laparoscopic groups. Propensity score weighted multivariable logistic regression was used to evaluate factors associated with conversion to open surgery.Of 6990 patients identified, 5702 (81.6%) underwent a laparoscopic resection and 1288 (18.4%) underwent robotic-assisted resection. Conversion rates were 14.7% and 7.8% for laparoscopic and robotic gastrectomy, respectively. The robotic approach was associated with lower likelihood of conversion compared to laparoscopic approach (odds ratio [OR] = 0.470, P0.001). Other factors predictive of conversion included tumor size5 cm compared to2 cm (OR 1.714, P = 0.010), total gastrectomy compared to partial gastrectomy (OR 2.019, P0.001), antrum/pylorus (OR 2.345, P0.001), and body (OR 2.152, P0.001) tumors compared to cardia tumors. Compared to those treated with laparoscopic and robotic gastrectomy, patients who underwent conversion experienced significantly longer hospital length of stay and higher rates of positive surgical margins.Laparoscopic gastrectomy was associated with a higher conversion rate compared to robotic gastrectomy. Conversion to open surgery was associated with a significantly longer length of stay and higher rates of positive margins. Identification of risk factors for conversion can aid in appropriate modality selection.

Gastric cancer is the fourth most common cause of cancer-linked deaths in the world. Gastric tumor cells have biological characteristics such as rapid proliferation, high invasiveness, and drug resistance, which result in recurrence and poor survival. Helicobacter pylori (H. pylori) has been proposed as a first‐class carcinogen for gastric cancer according to the 1994 world health organization (WHO) classification. One of the important mechanisms by which H. pylori affects the gastric environment and promotes carcinogenesis is triggering inflammation. H. pylori induces an inflammatory response and a plethora of different signal transduction processes, leading to gastric mucosal disturbance, chronic gastritis, and a multi-step complex pathway that initiates carcinogenesis. It seems undeniable that the interaction between various cell types, including immune cells, gastric epithelium, glands, and stem cells, is vital for the progression and development of carcinogenesis concerning H. pylori. The interactions of H. pylori with surrounding cells play a key role in cancer progression. In this review, we discuss the interplay between H. pylori and tumor-supportive cells, including mesenchymal stem cells (MSCs), cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid derived-suppressor cells (MDSCs) in gastric cancer. It is hoped that clarifying the specific mechanisms for ‘cross-talk’ between H. pylori and these cells will provide promising strategies for developing new treatments.

Gastric cancer is a leading cause of tumor-associated death worldwide. Metastasis and chemoresistance are crucial barriers for gastric cancer treatment. The Forkhead Box M1 (FOXM1) transcription factor has been reported as a promising treatment target for various types of tumors, but its effects on gastric cancer progression are not fully understood. In the present study, we found that FOXM1 expression levels were significantly up-regulated in human gastric cancer cell lines and tissues, and its expression was much higher in patients with metastasis. We then found that suppressing FOXM1 with its inhibitor thiostrepton (THIO) significantly reduced the proliferation of gastric cancer cells, while induced G0/G1 and apoptosis. Moreover, reactive oxygen species (ROS) production, mitochondrial impair and autophagy were remarkably provoked in gastric cancer cells treated with THIO, which were required for the regulation of apoptotic cell death. Furthermore, THIO exposure considerably suppressed the migration, invasion and angiogenesis in gastric cancer cells. The inhibitory effects of THIO on tumor growth and metastasis were confirmed in an established gastric cancer xenograft mouse model without detectable toxicity. Intriguingly, our in vitro studies showed that the anti-cancer effects of THIO on gastric cancer were almost abolished upon FOXM1 over-expression, indicating the necessity of FOXM1 suppression in THIO-inhibited tumor growth. In addition, higher FOXM1 expression was detected in gastric cancer cells with chemoresistance. Both in vitro and in vivo studies illustrated that THIO strongly promoted the drug-resistant gastric cancer cells to chemotherapies, proved by the considerably decreased cell proliferation and epithelial-mesenchymal transition (EMT) process. Together, these findings revealed that FOXM1 was a promising therapeutic target for gastric cancer treatment, and THIO exerted potential as an therapeutic agent for the disease.

Gastric cancer with gastric outlet obstruction (GOO) is generally found at an advanced stage and with an unfavorable prognosis. This study was performed to examine the prevalence of radiologically occult peritoneal carcinomatosis in GOO and determine the optimal treatment strategy.This single-center study was a retrospective review of the clinical data of 186 patients with locally advanced gastric cancer at the distal stomach who underwent surgery from 2008 to 2016. These patients were divided into two groups according to the presence or absence of GOO due to cancer progression: With GOO (n=71) and without GOO (n=115).The incidence of peritoneal carcinomatosis [with macroscopic peritoneal deposits (P1)/positive peritoneal cytology (CY1)] detected at laparotomy/laparoscopy was significantly higher in the group with GOO than in the group without (32.4% vs. 9.6%, p0.01). The R0 resection rate was lower in the group with GOO (62.0% vs. 87.0%, p0.01). The 5-year overall survival rate was also lower in the group with GOO (43.9% vs. 68.5%, p0.01). However, in the subset of patients who underwent R0 surgery, the 5-year rates were similar for the two groups (67.4% vs. 73.1%, p=0.91). The multivariable analysis showed that a type 3 tumor appearance (odds ratio=3.66) and presence of GOO (odds ratio=2.87) were predictors of peritoneal carcinomatosis.The prevalence of radiologically occult peritoneal carcinomatosis in gastric cancer with GOO exceeded 30%. Staging laparoscopy (gastrojejunal bypass, if needed) should be performed to determine the optimal treatment plan.

The mesentery of the jejunum (MJ) of the Roux limb is conventionally divided when Roux-en-Y reconstruction is performed after total gastrectomy for gastric cancer (GC). However, the impact of dividing or preserving the MJ on anastomotic leakage (AL) at the esophagojejunostomy (EJS) site after minimally invasive total gastrectomy for GC is unclear.This retrospective cohort study enrolled 226 patients with GC who underwent EJS after laparoscopic or robotic total gastrectomy, including preservation of the MJ (n = 87) and division of the MJ (n = 137). The prevalence of anastomotic complications at the EJS and short-term outcomes were compared between groups using propensity score (PS) matching.After PS matching, 69 patients were selected for the preserving and dividing MJ groups. There were no significant intergroup differences in patient backgrounds, including oncological stage, body mass index, and gender ratio. After PS matching, overall and severe complications after surgery were compared between the preserving and dividing MJ groups (21.7% vs. 27.5%, p = 0.554 and 8.7% vs. 13.8%, p = 0.137, respectively). However, the rate of AL at the EJS was significantly lower in the preserving than that in the dividing MJ group (1.4% vs. 13.0%, p = 0.017). In addition, the median postoperative hospital stay was significantly shorter in the preserving than that in the dividing MJ group (13.0 days vs. 16.0 days, p = 0.005).Preserving the MJ significantly reduced AL at the EJS after minimally invasive total gastrectomy for GC.

Gastric cancer is one of the most lethal human malignancies in the world. Although great efforts are put in developing novel therapeutic targets, the effective targeting drugs are still limited. Recent studies reveal the abnormality of Hippo/YAP axis play critical role in the oncogenic process of gastric cancer. It is of great importance to demonstrate the regulation of Hippo signaling activity and YAP protein turnover in gastric cancer. Besides, the phosphorylation cascade on YAP function, which has been thoroughly investigated, the ubiquitination of YAP is also important in Hippo signaling status. Here, We utilized the DUB (Deubiquitinase) siRNA library to identify critical DUB for Hippo signaling. We discovered OTUB1 as a critical factor to facilitate gastric cancer cell stemness and progression, which deubiquitinated and stabilized YAP protein. The clinical data analysis implicated OTUB1 was higher expressed in gastric cancer, which correlated with YAP activity and poor survival. OUTB1 interacted with YAP protein via its OTU domain (Ovarian tumor domain) and deubiquitinated YAP at several lysine sites (K90, K280, K343, K494 and K497), which subsequently inhibited YAP degradation. Our study revealed a novel deubiquitinase of Hippo/YAP axis and one possible therapeutic target for YAP-driven gastric cancer.

Sanggenon C is a flavonoid extracted from the root bark of white mulberry, which is a traditional Chinese medicine with anti-inflammatory, antioxidative, and antitumor pharmacological effects. In this study, sanggenon C was found to inhibit human gastric cancer (GC) cell proliferation and colony formation, induce GC cell cycle arrest in the G0-G1 phase, and promote GC cell apoptosis. Moreover, sanggenon C was found to decrease the level of mitochondrial membrane potential in GC cells and inhibit mitochondrial fission. Mechanistically, RNA sequencing, bioinformatics analysis, and a series of functional analyses confirmed that sanggenon C inhibited mitochondrial fission to induce apoptosis by blocking the extracellular regulated protein kinases (ERK) signaling pathway, and constitutive activation of ERK significantly abrogated these effects. Finally, sanggenon C was found to suppress the growth of tumor xenografts in nude mice without obvious side effects to the vital organs of animals. This study reveals that sanggenon C could be a novel therapeutic strategy for GC treatment.

The tumor-node-metastasis (TNM) staging system does not take the patient's physiological status into consideration, reportedly making it insufficient for predicting survival outcomes in frail cancer patients. We assessed the prognostic values of several nutrition- and inflammation-based markers in combination with pTNM stage in gastric carcinoma (GC) patients.In total, 1166 patients undergoing GC surgery were studied. The prognostic capabilities of 3 nutritional and 3 systemic inflammatory parameters were examined. We developed new staging systems by adding these markers, individually, to the pTNM stage. We then compared the prognostic capabilities of our new systems with that of pTNM stage alone. We also assessed the prognostic values of these systems by dividing our patient cohort into elderly (≥ 65 years) and non-elderly groups.Our novel staging systems had greater predictive capabilities for overall survival (OS) than pTNM alone. Most notably, survival discrimination was significantly increased for pTNM when it was combined with albumin-based nutritional indices (geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI)). Our new staging systems incorporating GNRI or PNI into pTNM had significantly better predictive capability for OS, especially non-GC mortality, than pTNM alone in elderly GC patients. In the non-elderly patients, the predictive capabilities of the new staging systems for OS differed minimally from that of pTNM.The predictive capability of pTNM stage was particularly enhanced when this parameter was combined with nutritional markers. Our new approach aids in predicting survival outcomes, especially non-GC-related death, in elderly GC patients.

Increasing evidence suggested that proton pump inhibitors (PPIs) use might affect the development of cancers, but previous conclusions remain controversial. Therefore, an umbrella review was performed to clarify the associations between PPIs and various types of cancer by summarizing the existing meta-analyses and systematic reviews.We searched PubMed, Cochrane Library, Embase, CNKI, Wanfang, and VIP database up to June 2022 for eligible meta-analyses or systematic reviews. The summary effect size, 95% CI, heterogeneity, small study effect, and 95% prediction interval were considered in the present study. A Measurement Tool to Assess Systematic Review 2 and grading of recommendation, assessment, development, and evaluation were used to assess methodological quality and evidence.The umbrella review included 21 meta-analyses containing 65 studies and 10 cancer types with 6.8 million subjects. The results showed that PPI use was significantly associated with increased risks of certain types of cancer, including gastric cancer (odds ratio [OR]: 2.07; 95% CI, 1.30 to 3.29), pancreatic cancer (OR: 1.73; 95% CI, 1.23 to 2.44), colorectal cancer (OR: 1.84; 95% CI, 1.26 to 2.67), and liver cancer (OR: 1.80; 95% CI, 1.27 to 2.54), but was not associated with esophageal cancer. In addition, PPI use was associated with decreased risk of breast cancer (OR: 0.69; 95% CI, 0.50 to 0.96).These findings suggested that clinicians should pay more attention to the occurrence of gastric cancer, pancreatic cancer, colorectal cancer, and liver cancer in patients who used PPIs, and PPI prescription should be written only when an accurate specific diagnosis has been made. Furthermore, additional PPIs to the treatment regimen may be benefit for women with a higher-than-average risk of breast cancer.

Purpose This study aimed to investigate whether MOS methylation can be useful for the prediction of metachronous recurrence after endoscopic resection of gastric neoplasms.Materials and Methods From 2012 to 2017, 294 patients were prospectively enrolled after endoscopic resection of gastric dysplasia (n=171) or early gastric cancer (n=123). When Helicobacter pylori was positive, eradication therapy was performed. Among them, 124 patients completed the study protocol (follow-up duration > 3 years or development of metachronous recurrence during the follow-up). Methylation levels of MOS were measured at baseline using quantitative MethyLight assay from the antrum.Results Median follow-up duration was 49.9 months. MOS methylation levels at baseline were not different by age, sex, and current H. pylorii infection, but they showed a weak correlation with operative link on gastritis assessment (OLGA) or operative link on gastric intestinal metaplasia assessment (OLGIM) stages (Spearman’s ρ=0.240 and 0.174, respectively; p < 0.05). During the follow-up, a total of 20 metachronous gastric neoplasms (13 adenomas and 7 adenocarcinomas) were developed. Either OLGA or OLGIM stage was not useful in predicting the risk for metachronous recurrence. In contrast, MOS methylation high group (≥ 34.82%) had a significantly increased risk for metachronous recurrence compared to MOS methylation low group (adjusted hazard ratio, 4.76; 95% confidence interval, 1.54 to 14.79; p=0.007).Conclusion MOS methylation can be a promising marker for predicting metachronous recurrence after endoscopic resection of gastric neoplasms. To confirm the usefulness of MOS methylation, validation studies are warranted in the future (ClinicalTrials No. NCT04830618).

This review aimed to give an updated overview of the occurrence, diagnosis, treatment and outcome of oesophageal and gastric cancer after bariatric and metabolic surgery (BMS).Two searches were done (one for original studies and one for systematic reviews) using an adapted form of "scoping review methodology". MEDLINE, Embase, CINAHL, Pubmed and the Cochrane Library were searched for studies on patients with either oesophageal or gastric cancer after BMS.A total of 52 unique studies were included which reported on 324 patients, which included 110 (34%) males and 136 (42%) females. In the remaining 78 patients, gender was not specified. A mean of 62.95 ± 32.75 months was the time from BMS to diagnosis of cancer. Most of the patients had a Roux-en-Y gastric bypass (RYGB) as index bariatric surgical procedure, followed by gastric banding (GB) and sleeve gastrectomy (SG) (respectively, 133 (41.0%) RYGB, 97 (30.0%) GB and 58 (18.0%) SG). Seven cases have been reported after OAGB-MGB (3 in gastric remnant, 4 in oesophagus/gastric pouch). Seventy-seven (24%) had distant metastasis (≥ M1/Mx status). The majority of tumours were adenocarcinoma (n = 208, 87.4%). In the majority of the cases, a surgical approach was preferred with either adjuvant chemo or radiotherapy. In the course of the disease, 122 of 324 patients died (37.8%).To our knowledge, this is the most up-to-date review addressing oesophageal and gastric malignancies after bariatric surgery. Future research should focus to optimise screening for oesophageal and gastric cancer after bariatric surgery.

Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a member of the Cas family. Previous studies have revealed that NEDD9 coordinates the focal adhesion kinase and Src signaling cascades that are involved in integrin-dependent adhesion and migration, invasion, cell apoptosis and life cycle, and survival, which may play a role in epithelial-mesenchymal transformation. The aim of this study was to analyze the expression of NEDD9 and E-cadherin in gastric cancer (GC) and evaluate their clinical significance.NEDD9 and E-cadherin expression was analyzed with immunohistochemistry using tissue microarray technique in 435 GC patients who underwent gastrectomy. The NEDD9 expression level was defined by the combination score, which was determined by multiplying the staining intensity score and the proportion score (≥5; NEDD9-high,5; NEDD9-low). E-cadherin loss was defined as a total loss of staining. The clinicopathologic parameters, overall survival, and disease-free survival rates were analyzed according to the NEDD9 and E-cadherin expression status.The combined NEDD9 and E-cadherin expression status correlated with lymphatic invasion (P = 0.001), vascular invasion (P = 0.020), and T stage (P = 0.001). Combined high NEDD9 expression and loss of E-cadherin expression status had a worse overall survival rate (P 0.001) and served as a poor prognostic factor (Hazard ratio 2.49, 95% CI 1.25-5, P = 0.01).Immunohistochemical staining for NEDD9 and E-cadherin may function as a candidate prognostic marker for gastric cancer in everyday practice, especially when applied in combination.

The incidence of adenocarcinoma of the esophagogastric junction (AEG) and proximal gastric cancer (PGC) is rising worldwide. Recently, the use of indocyanine green (ICG) tracer-guided surgery has been reported; however, its efficacy for total/proximal gastrectomy has not been clarified. We evaluated the feasibility and safety of ICG fluorescent marking for tumor localization in AEG/PGC treatment by laparoscopic surgery.We enrolled patients with AEG/PGC from October 2016 to March 2019 from a prospectively registered database. On the day before surgery, ICG markings were made at four locations just at the edge of the tumor by gastrointestinal fiberscope examination. Surgery was performed while viewing the fluorescence image of ICG, and the proximal portions of the esophagus and the distal portion of the stomach were resected at the edge of the area where ICG had spread.We enrolled 130 patients with AEG/PGC. Overall, 107 patients were eventually included in the study: AEG n = 64 (60%) and PGC n = 43 (40%). ICG markings were detected intraoperatively in all cases, and cancer invasion into the resection lines of the esophagus and stomach, performed based on ICG fluorescence images, was negative in all cases. The median visible range of ICG fluorescence was 22.5 mm. ICG diffusion expanded 20 mm proximal for AEG. There were no adverse events associated with endoscopic ICG injection.ICG fluorescence imaging is feasible and safe and can potentially be used as a tumor-marking agent for determining the surgical resection line for total/proximal gastrectomy in AEG and PGC treatment.

To explore the effectiveness and safety of laparoscopic transhiatal complete mesenteric resection (CME) surgery compared with those of the traditional laparoscopic transhiatal approach in the treatment of Siewert II/III adenocarcinoma of the esophagogastric junction (AEG).Ninety-nine patients with Siewert type II/III AEG were enrolled and divided into two groups: the laparoscopic CME transhiatal approach (CEM-TH, n = 61) group and traditional laparoscopic transhiatal (TH, n = 38) group. Intraoperative and postoperative clinical data of both groups were analyzed.The laparoscopic trasihiatal surgery was technically successful in all patients. The surgical time, intraoperative bleeding, and hospital stay were all significantly (P 0.05) reduced in the CME-TH group compared with those in the TH group. The levels of white blood cells on postoperative day (POD) 1 and 5, postoperative CRP on POD 3 and 5, and postoperative PCT were significantly (P 0.05) lower while lymph nodes were harvested significantly (P 0.05) more in the CME-TH group than in the TH group. Complications were not significantly (P 0.05) different between two groups. No death occurred within 90 days.The CME theory could be safely and effectively applied laparoscopically to treat patients with Siewert II/III AEG. Mesogastrium and lower mesoesophagus can be completely resected together with the tumor, lymph nodes, adipose tissue, and blood vessels as an "intact package," leading to better short-term outcomes.

Gastrointestinal stromal tumors (GISTs) with a diameter of2 cm are called small GISTs. Currently, endoscopic ultrasound (EUS) is widely used as a regular follow-up method for GISTs, which can also provide a preliminary basis for judging the malignancy potential of lesions. However, there are no studies on the accuracy of EUS to assess the malignant potential of small GISTs.To evaluate the efficacy of EUS in the diagnosis and risk assessment of small GISTs.We collected data from patients with small GISTs who were admitted to Shengjing Hospital of China Medical University between October 2014 and July 2019. The accurate diagnosis and risk classifications of patients were based on the pathological assessment according to the modified National Institute of Health criteria after endoscopic resection or laparoscopic surgery. Preoperative EUS features (marginal irregularity, cystic changes, homogeneity, ulceration, and strong echogenic foci) were retrospectively analyzed. The assessment results based on EUS features were compared with the pathological features.A total of 256 patients (69 men and 187 women) were enrolled. Pathological results included 232, 16, 7, and 1 very low-, low-, intermediate-, and high-risk cases, respectively. The most frequent tumor location was the gastric fundus (78.1%), and mitoses were calculated as5/50 high power field in 8 (3.1%) patients. Marginal irregularity, ulceration, strong echo foci, and heterogeneity were detected in 1 (0.4%), 2 (0.8%), 22 (8.6%), and 67 (65.1%) patients, respectively. However, cystic changes were not detected. Tumor size was positively correlated with the mitotic index (Small GISTs (diameters1.48 cm) with positive EUS features should receive intensive surveillance or undergo endoscopic surgery. EUS and dissection are efficient diagnostic and therapeutic approaches for small GISTs.

We present a case of early gastric cancer resembling a subepithelial lesion (GCSEL) derived from the submucosal ectopic gastric glands (SEGGs), diagnosed using endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). A 55-year-old woman was referred to our hospital for the investigation of a subepithelial lesion (SEL). Contrast computed tomography and esophagogastroduodenoscopy revealed two SELs in the greater curvature of the fundus and the posterior wall of the upper body of the stomach. EUS revealed a hypoechoic lesion in the submucosa and suggested partial invasion into the muscularis propria of the greater curvature of the fundus, and an anechoic lesion in the submucosa of the posterior wall of the upper body. The different diagnosis for the SEL in the fundus was GCSEL, neuroendocrine tumor, malignant lymphoma, and gastric adenocarcinoma of fundic gland type. EUS-FNA findings suggested adenocarcinoma. The patient underwent a laparoscopic proximal gastrectomy. Pathological findings confirmed a differentiated tubular adenocarcinoma derived from the SEGG, which partially invaded into the submucosa of the surrounding gastric wall without lymphovascular invasion or lymph node metastasis. The patient has been recurrence-free after 10 months of follow-up. EUS should be performed for SELs followed by EUS-FNA for lesions, such as GCSEL, that require early intervention.

Multimodality treatment improves survival for gastric cancer (GC). However, the effect of treatment sequence by stage remains unclear. We aim to compare outcomes between patients receiving neoadjuvant(neoadj) and adjuvant chemotherapy (adj).Nonmetastatic GC patients with clinical stage ≥ T2N0 who underwent both resection and neoadj or adj were identified using the National Cancer Database (2005-2014). Multivariable Cox regression analyses were performed on propensity score-matched (PSM) cohorts stratified by stage to compare overall survival (OS).We identified 11 984 patients; 55% stage I (SI), 76% stage II (SII) and 57% stage III (SIII) received neoadj. Unadjusted analysis showed worse survival among SI neoadj patients (hazard ratio [HR] 1.195, confidence interval [CI] 1.04-1.38) and improved survival for SII (HR 0.93 CI 0.87-0.998) and SIII (HR 0.75, CI 0.68-0.84). After PSM, SI patients with neoadj had worse OS with increased risk of death compared to Adj (HR 1.186, CI 1.004-1.402). SII patients had no difference in OS (HR 0.98, CI 0.91-1.07) and SIII patients had improved OS (HR 0.78, CI 0.69-0.90).In patients who received surgery and chemotherapy, the benefit of neoadj was limited to SIII with worse survival for SI. A clinical trial to examine the optimal sequence of chemotherapy is warranted.