Targeting Stem Cells and Dysplastic Features With Dual MEK/ERK and STAT3 Suppression in Gastric Carcinogenesis.

BACKGROUNDS & AIMS: Precancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these precancerous lesions are currently lacking. To address this, we aimed to identify key signaling pathways that are upregulated during metaplasia progression and critical for stem cell survival and function in dysplasia. METHODS: To assess the response to chemotherapeutic drugs, we used metaplastic and dysplastic organoids derived from Mist1-Kras mice and 20 human precancerous organoid lines established from patients with gastric cancer. Phospho-antibody array analysis and single-cell RNA-sequencing were performed to identify target cell populations and signaling pathways affected by pyrvinium, a putative anticancer drug. Pyrvinium was administered to Mist1-Kras mice to evaluate drug effectiveness in vivo. RESULTS: Although pyrvinium treatment resulted in growth arrest in metaplastic organoids, it induced cell death in dysplastic organoids. Pyrvinium treatment significantly downregulated phosphorylation of ERK and signal transducer and activator of transcription 3 (STAT3) as well as STAT3-target genes. Single-cell RNA-sequencing data analyses revealed that pyrvinium specifically targeted CD133+/CD166+ stem cell populations, as well as proliferating cells in dysplastic organoids. Pyrvinium inhibited metaplasia progression and facilitated the restoration of normal oxyntic glands in Mist1-Kras mice. Furthermore, pyrvinium exhibited suppressive effects on the growth and survival of human organoids with dysplastic features, through simultaneous blocking of the MEK/ERK and STAT3 signaling pathways. CONCLUSIONS: Through its dual blockade of MEK/ERK and STAT3 signaling pathways, pyrvinium can effectively induce growth arrest in metaplasia and cell death in dysplasia. Therefore, our findings suggest that pyrvinium is a promising chemotherapeutic agent for reprogramming the precancerous milieu to prevent gastric cancer development.

RNA expression of 6 genes from metastatic mucosal gastric cancer serves as the global prognostic marker for gastric cancer with functional validation.

BACKGROUND: Molecular analysis of advanced tumors can increase tumor heterogeneity and selection bias. We developed a robust prognostic signature for gastric cancer by comparing RNA expression between very rare early gastric cancers invading only mucosal layer (mEGCs) with lymph node metastasis (Npos) and those without metastasis (Nneg). METHODS: Out of 1003 mEGCs, all Npos were matched to Nneg using propensity scores. Machine learning approach comparing Npos and Nneg was used to develop prognostic signature. The function and robustness of prognostic signature was validated using cell lines and external datasets. RESULTS: Extensive machine learning with cross-validation identified the prognostic classifier consisting of four overexpressed genes (HDAC5, NPM1, DTX3, and PPP3R1) and two downregulated genes (MED12 and TP53), and enabled us to develop the risk score predicting poor prognosis. Cell lines engineered to high-risk score showed increased invasion, migration, and resistance to 5-FU and Oxaliplatin but maintained sensitivity to an HDAC inhibitor. Mouse models after tail vein injection of cell lines with high-risk score revealed increased metastasis. In three external cohorts, our risk score was identified as the independent prognostic factor for overall and recurrence-free survival. CONCLUSION: The risk score from the 6-gene classifier can successfully predict the prognosis of gastric cancer.

Distribution of Perigastric Station 4d Lymph Nodes in Vascularized Gastroepiploic Lymph Node Transfer: An Anatomic Study and Case Series.

BACKGROUND: Vascularized gastroepiploic lymph node transfer (VGLNT) is a well-accepted surgical treatment for restoring physiological function in chronic lymphedema. However, the inclusion of substantial lymph nodes (LNs) in the flap remains uncertain. This study aimed to identify the anatomical basis for reliable flap harvest for VGLNT. PATIENTS AND METHODS: The anatomy of perigastric station 4d LNs was studied in healthy cadavers (n = 15) and patients with early gastric cancer (EGC) (n = 27). The omentum was divided into three segments: proximal, middle, and distal from the origin of the right gastroepiploic vessels. The flap dimension, number, location, size of LNs, and caliber of the vessels were reviewed. Eight patients underwent VGLNT for upper/lower limb lymphedema. RESULTS: The mean numbers of LNs in the proximal, middle, and distal segment were 2.5, 1.4, 0.5 in the cadavers, and 4.9, 2.7, 0.7 in the gastrectomy specimens, respectively. The proximal third included a significantly greater number of LNs than the distal third in the cadaveric (p = 0.024) and ECG (p = 0.016) specimens. A total of 95% of the LNs were located within proximal two-thirds of the flap from the vessel origin both in the cadavers (21.0 × 5.0 cm) and in the gastrectomy specimens (20 × 3.5 cm). In VGLNT, the transferred flap was 25.5 ± 6.9 × 4.1 + 0.7 cm in dimension, containing a mean number of 6.5 ± 1.9 LNs. At postoperative 6 months, the volumetric difference was significantly reduced by 22.8 ± 9.2% (p < 0.001). CONCLUSIONS: This study provides a distinct distribution pattern of station 4d LNs. Inclusion of the proximal two-thirds of the flap, which carries majority of the LNs, is recommended for VGLNT.

Long-Term Outcome of Proximal Gastrectomy for Upper-Third Advanced Gastric and Siewert Type II Esophagogastric Junction Cancer Compared With Total Gastrectomy: A Propensity Score-Matched Analysis.

BACKGROUND: This study aimed to investigate the oncologic long-term safety of proximal gastrectomy for upper-third advanced gastric cancer (AGC) and Siewert type II esophagogastric junction (EGJ) cancer. METHODS: The study enrolled patients who underwent proximal gastrectomy (PG) or total gastrectomy (TG) with standard lymph node (LN) dissection for pathologically proven upper-third AGC and EGJ cancers between January 2007 and December 2018. Propensity score-matching with a 1:1 ratio was performed to reduce the influence of confounding variables such as age, sex, tumor size, T stage, N stage, and tumor-node-metastasis (TNM) stage. Kaplan-Meier survival analysis was performed to analyze oncologic outcome. The prognostic factors of recurrence-free survival (RFS) were analyzed using the Cox proportional hazard analysis. RESULTS: Of the 713 enrolled patients in this study, 60 received PG and 653 received TG. Propensity score-matching yielded 60 patients for each group. The overall survival rates were 61.7 % in the PG group and 68.3 % in the TG group (p = 0.676). The RFS was 86.7 % in the PG group and 83.3 % in the TG group (p = 0.634). The PG group showed eight recurrences (1 anastomosis site, 1 paraaortic LN, 1 liver, 1 spleen, 1 lung, 1 splenic hilar LN, and 2 remnant stomachs). In the multivariate analysis, the operation method was not identified as a prognostic factor of tumor recurrence. CONCLUSION: The patients who underwent PG had a long-term oncologic outcome similar to that for the patients who underwent TG for upper-third AGC and EGJ cancer.

Predictive Value of KLASS-02-QC Assessment Score on KLASS-02 Surgical Outcomes: Validation of Surgeon Quality Control and Standardization for D2 Lymphadenectomy.

OBJECTIVE: The aim of this study was to audit the 22 items and assessed each item's predictive value on surgical outcomes. BACKGROUND: The KLASS-02 trial revealed that the oncologic outcomes of laparoscopic distal gastrectomy are not inferior to open distal gastrectomy in patients with advanced gastric cancer. The surgeons participating in this trial were chosen based on the assessment scores from the KLASS-02-QC trial, which used 22 items for standardization of D2 lymphadenectomy and quality control. METHODS: We reviewed proficiency scores (PSs) for 22 items for 20 surgeons who participated in KLASS-02. The surgeons were divided into 2 groups according to PS, and the perioperative outcomes of 924 patients enrolled in KLASS-02 were compared between groups. Each item's predictive value for perioperative outcome was then assessed using multivariable regression models. RESULTS: Of the total 924 patients, 529 were operated on by high-score surgeons (high PS) and 395 were operated on by low-score surgeons (low-PS). High-PS group had less intraoperative blood loss, longer operation times, and fewer complications, major complications, reoperations, and shorter first flatus and hospital stay than low-PS group ( P =0.006, P <0.001, P <0.001, P <0.001, P =0.042, P =0.013, and P <0.001, respectively). Some items used in KLASS-02-QC predicted perioperative outcomes, such as intraoperative blood loss, major complications, reoperation, and hospital stay. CONCLUSIONS: Although this study only analyzed data associated with qualified surgeons, the 22 items effectively assessed the surgeons based on PS. A high score was associated with longer operation times, but better perioperative outcomes.

Dysplastic Stem Cell Plasticity Functions as a Driving Force for Neoplastic Transformation of Precancerous Gastric Mucosa.

BACKGROUND & AIMS: Dysplasia carries a high risk of cancer development; however, the cellular mechanisms for dysplasia evolution to cancer are obscure. We have previously identified 2 putative dysplastic stem cell (DSC) populations, CD44v6neg/CD133+/CD166+ (double positive [DP]) and CD44v6+/CD133+/CD166+ (triple positive [TP]), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of noncancerous Trop2+/CD133+/CD166+ DSCs initially developed in the transition from precancerous metaplasia to dysplasia in the stomach. METHODS: Dysplastic organoids established from active Kras-induced mouse stomachs were used for transcriptome analysis, in vitro differentiation, and in vivo tumorigenicity assessments of DSCs. Cell heterogeneity and genetic alterations during clonal evolution of DSCs were examined by next-generation sequencing. Tissue microarrays were used to identify DSCs in human dysplasia. We additionally evaluated the effect of casein kinase 1 alpha (CK1α) regulation on the DSC activities using both mouse and human dysplastic organoids. RESULTS: We identified a high similarity of molecular profiles between DP- and TP-DSCs, but more dynamic activities of DP-DSCs in differentiation and survival for maintaining dysplastic cell lineages through Wnt ligand-independent CK1α/ß-catenin signaling. Xenograft studies demonstrated that the DP-DSCs clonally evolve toward multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Last, growth and survival of both mouse and human dysplastic organoids were controlled by targeting CK1α. CONCLUSIONS: These findings indicate that the DSCs are de novo gastric cancer-initiating cells responsible for neoplastic transformation and a promising target for intervention in early induction of gastric cancer.

Standard follow-up after curative surgery for advanced gastric cancer: secondary analysis of a multicentre randomized clinical trial (KLASS-02).

BACKGROUND: The benefit of regular follow-up after curative resection for gastric cancer is controversial as there is no evidence that it will improve survival. This study assessed whether regular follow-up leads to improved survival in patients after surgery for gastric cancer. METHODS: A secondary analysis was undertaken of patients who participated in an RCT of laparoscopic versus open distal gastrectomy for advanced gastric cancer between November 2011 and April 2015. Depending on whether patients were compliant with the initial trial follow-up protocol or not, they were analysed as having had either regular or irregular follow-up. Clinicopathological characteristics, recurrence patterns, detection, treatments, and survival were compared between the groups. RESULTS: The regular and irregular follow-up groups comprised 712 and 263 patients respectively. Disease recurrence within 36 months was more common in the regular group than in the irregular group (17.0 versus 11.4 per cent; P = 0.041). Recurrence patterns did not differ between the groups. The 3-year recurrence-free survival rate was worse in the regular than in the irregular group (81.2 versus 86.5 per cent; P = 0.031). However, the 5-year overall survival rate was comparable (84.5 versus 87.5 per cent respectively; P = 0.160). Multivariable analysis revealed that type of follow-up was not an independent factor affecting 5-year overall survival. CONCLUSION: Regular follow-up after radical gastrectomy was not associated with improved overall survival.

Cross-phenotype association analysis of gastric cancer: in-silico functional annotation based on the disease-gene network.

BACKGROUND: A gene or variant has pleiotropic effects, and genetic variant identification across multiple phenotypes can provide a comprehensive understanding of biological pathways shared among different diseases or phenotypes. Discovery of genetic loci associated with multiple diseases can simultaneously support general interventions. Several meta-analyses have shown genetic associations with gastric cancer (GC); however, no study has identified associations with other phenotypes using this approach. METHODS: Here, we applied disease network analysis and gene-based analysis (GBA) to examine genetic variants linked to GC and simultaneously associated with other phenotypes. We conducted a single-nucleotide polymorphism (SNP) level meta-analysis and GBA through a systematic genome-wide association study (GWAS) linked to GC, to integrate published results for the SNP variants and group them into major GC-associated genes. We then performed disease network and expression quantitative trait loci (eQTL) analyses to evaluate cross-phenotype associations and expression levels of GC-related genes. RESULTS: Seven genes (MTX1, GBAP1, MUC1, TRIM46, THBS3, PSCA, and ABO) were associated with GC as well as blood urea nitrogen (BUN), glomerular filtration rate (GFR), and uric acid (UA). In addition, 17 SNPs regulated the expression of genes located on 1q22, 24 SNPs regulated the expression of PSCA on 8q24.3, and rs7849820 regulated the expression of ABO on 9q34.2. Furthermore, rs1057941 and rs2294008 had the highest posterior causal probabilities of being a causal candidate SNP in 1q22, and 8q24.3, respectively. CONCLUSIONS: These findings identified seven GC-associated genes exhibiting a cross-association with GFR, BUN, and UA.

Comparison of perioperative outcomes between bipolar sealing, ultrasonic shears and a hybrid device during laparoscopic gastrectomy for early gastric cancer: a prospective, multicenter, randomized study.

BACKGROUND: Although EBDs are essential for minimally invasive surgery, well-established prospective randomized studies comparing EBDs are scarce. This study aimed to compare the intraoperative inflammatory response and short-term surgical outcomes among different energy-based devices (EBDs) in laparoscopic distal gastrectomy (LDG). METHODS: Patients with clinical stage I gastric cancer scheduled for LDG at two different medical centers were prospectively randomized into three groups: ultrasonic shears (US), advanced bipolar (BP) and ultrasonic-bipolar hybrid (HB). The C-reactive protein (CRP) level, operation time, intraoperative blood loss (IBL), laboratory tests, cytokines (interleukin (IL)-6 and IL-10), hospital stay, and complication rate were analyzed. A novel semiquantitative measurement method using indocyanine green (ICG) and a near-infrared camera measured the amount of lymphatic leakage. RESULTS: The primary endpoint, the CRP level, was significantly lower in the BP (n = 60) group than in the US (n = 57) or HB (n = 57) group [9.03 ± 5.55 vs. 11.12 ± 5.02 vs. 12.67 ± 6.14, p = 0.001, on postoperative day (POD) 2 and 7.48 vs. 9.62 vs. 9.48, p = 0.026, on POD 4]. IBL was significantly lower in BP than in US or HB (26.3 ± 25.3 vs. 43.7 ± 42.0 vs. 34.9 ± 37.0, p = 0.032). Jackson-Pratt drainage triglycerides were significantly lower in BP than in US (53.6 ± 33.7 vs. 84.2 ± 59.0, p = 0.11; HB: 71.3 ± 51.4). ICG fluorescence intensity, operation time, laboratory results, cytokines, hospital stay, and complication rate were not significantly different among the 3 groups. CONCLUSION: BP showed a lower postoperative CRP level and less IBL than US and HB, suggesting less collateral thermal damage and better sealing function. Surgeons may consider this when selecting EBDs for laparoscopic surgery.

Feasibility and safety of inserting transient biodegradable stents in the pylorus during pylorus-preserving gastrectomy for gastric cancer: a preliminary study in a porcine for proof of concept.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Long-term outcomes of a phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumors of the stomach.

BACKGROUND: Neoadjuvant treatment is recommended for large GISTs due to their friability and risk of extensive operations; however, studies on the indications and long-term results of this approach are lacking. METHODS: Patients with large (≥ 10 cm) gastric GISTs were enrolled from multiple centers in Korea and Japan after a pathologic confirmation of c-KIT ( +) GISTs. Imatinib (400 mg/d) was given for 6-9 months preoperatively, and R0 resection was intended. Postoperative imatinib was given for at least 12 months and recommended for 3 years. RESULTS: A total of 56 patients were enrolled in this study, with 53 patients receiving imatinib treatment at least once and 48 patients undergoing R0 resection. The 5-year overall survival and progression-free survival rates were 94.3% and 61.6%, respectively. Even patients with stable disease by RECIST criteria responded well to preoperative imatinib treatment and could undergo R0 resection, with most being evaluated as partial response by CHOI criteria. The optimal reduction in tumor size was achieved with preoperative imatinib treatment for 24 weeks or more. No resumption of imatinib treatment was identified as an independent prognostic factor for recurrence after R0 resection. No additional size criteria for a higher risk of recurrence were identified in this cohort with a size of 10 cm or more. CONCLUSIONS: Neoadjuvant imatinib treatment is an effective treatment option for gastric GISTs 10 cm or larger. Postoperative imatinib treatment is recommended even after R0 resection to minimize recurrence.

Safety of pylorus-preserving gastrectomy for gastric cancer combined with antral high-risk lesions: a comparison with endoscopic submucosal dissection.

BACKGROUND: Pylorus-preserving gastrectomy (PPG) is a surgical treatment option for cT1N0M0 gastric cancer located in the middle third of the stomach. However, data for the long-term post-PPG clinical outcomes related to metachronous gastric neoplasms (mGNs) in the residual stomach are currently lacking. Therefore, we aimed to evaluate the safety of PPG by focusing on mGNs. METHODS: In this single-center, retrospective study, we reviewed the data for 362 patients who underwent PPG with a 3-cm antral cuff and 139 who underwent endoscopic submucosal dissection (ESD) for middle-third gastric cancer between January 2013 and December 2015. The histopathologic features of the antrum in the ESD group, which could not be determined in the PPG group, were analyzed to investigate the risk factors for mGNs. The estimated and actual incidence of mGNs in the antrum were compared in the PPG group. RESULTS: The incidence of mGNs was 6.5% (9/139) in the ESD group. The presence of a synchronous adenoma (odds ratio [OR], 8.46; 95% confidence interval [CI], 1.55-46.34), carcinoma (OR, 15.71; 95% CI, 2.67-92.56) and moderate-to-severe intestinal metaplasia (OR, 9.77; 95% CI, 1.14-83.92) were associated with a higher risk of overall mGNs. However, when confined to the antrum, no significant association was observed between these factors and mGNs. In the ESD group, 2 of 9 mGNs (1.4%) were located at the 3-cm antral cuff. In the PPG group, both mGNs (0.6%) were located in the proximal remnant stomach. CONCLUSION: Pylorus-preserving gastrectomy was a safe therapeutic option with regard to the occurrence of metachronous adenomas or carcinomas in our series. Despite the low mGN incidence in the 3-cm antral cuff after PPG, the presence of synchronous neoplasms or moderate-to-severe intestinal metaplasia was a risk factor for mGNs in the ESD group; thus, further studies on longer antral cuffs with long-term follow-up are needed.

Feasibility and safety of pure single-incision laparoscopic total and proximal gastrectomy for early gastric cancer: propensity score-matched comparison to multiport totally laparoscopic approach.

BACKGROUND: There have been few studies regarding the feasibility and safety of pure single-incision laparoscopic total gastrectomy (SITG) or proximal gastrectomy (SIPG) for early gastric cancer (EGC). The purpose of this study was to analyze the surgical outcome of all consecutive SITG or SIPG cases compared with multiport laparoscopic total gastrectomy (MLTG) or proximal gastrectomy (MLPG) for EGC. METHODS: We analyzed all consecutive SITG or SIPG cases with double-tract reconstruction for ECG, including the initial case, between March 2013 and December 2021. SITG/SIPG was performed on patients without significant systemic comorbidities through a 3-4 cm vertical transumbilical incision. SITG/SIPG was matched to multiport laparoscopic total or proximal gastrectomy (MLTG/MLPG) cases performed in the same period using a 1:3 propensity score matching, including sex, body mass index (BMI), age and type of resection, year of operation, and institution as covariates. We compared perioperative clinicopathological characteristics and early postoperative morbidity within 1 month after surgery between the SITG/SIPG and MLTG/MLPG groups. RESULTS: In total, 21 patients with SITG and 15 patients with SIPG were compared with those with MLTG (n = 264) and MLPG (n = 220). No conversion to an open or multiport approach occurred in the SITG/SIPG group. After matching, operation time was similar between SITG/SIPG and MLTG/MLPG (223.9 ± 63.5 min vs 234.8 ± 68.7 min, P = 0.402). Length of stay was not significantly different between SITG/SIPG and MLTG/MLPG (11.9 ± 15.4 days vs 8.4 ± 5.0 days, P = 0.210). The average number of retrieved lymph nodes was not significantly different between SITG and MLTG (53.1 ± 16.3 vs 63.2 ± 27.5, P = 0.115), but it was significantly higher in SIPG than MLPG (59.6 ± 27.2 vs 46.0 ± 19.7, P = 0.040). The overall complication rate (30.6% vs 25.9%, P = 0.666) and Clavien-Dindo grade III or higher complication rates (13.9% vs 6.5%, P = 0.175) were not significantly different between the SITG/SIPG and MLTG/MLPG groups. CONCLUSION: Cautious adoption of SITG/SIPG procedures for EGC is feasible and safe.

Comparison of East-Asia and West-Europe cohorts explains disparities in survival outcomes and highlights predictive biomarkers of early gastric cancer aggressiveness.

Surgical resection with lymphadenectomy and perioperative chemotherapy is the universal mainstay for curative treatment of gastric cancer (GC) patients with locoregional disease. However, GC survival remains asymmetric in West- and East-world regions. We hypothesize that this asymmetry derives from differential clinical management. Therefore, we collected chemo-naïve GC patients from Portugal and South Korea to explore specific immunophenotypic profiles related to disease aggressiveness and clinicopathological factors potentially explaining associated overall survival (OS) differences. Clinicopathological and survival data were collected from chemo-naïve surgical cohorts from Portugal (West-Europe cohort [WE-C]; n = 170) and South Korea (East-Asia cohort [EA-C]; n = 367) and correlated with immunohistochemical expression profiles of E-cadherin and CD44v6 obtained from consecutive tissue microarrays sections. Survival analysis revealed a subset of 12.4% of WE-C patients, whose tumors concomitantly express E-cadherin_abnormal and CD44v6_very high, displaying extremely poor OS, even at TNM stages I and II. These WE-C stage-I and -II patients tumors were particularly aggressive compared to all others, invading deeper into the gastric wall (P = .032) and more often permeating the vasculature (P = .018) and nerves (P = .009). A similar immunophenotypic profile was found in 11.9% of EA-C patients, but unrelated to survival. Tumours, from stage-I and -II EA-C patients, that display both biomarkers, also permeated more lymphatic vessels (P = .003), promoting lymph node (LN) metastasis (P = .019), being diagnosed on average 8 years earlier and submitted to more extensive LN dissection than WE-C. Concomitant E-cadherin_abnormal/CD44v6_very-high expression predicts aggressiveness and poor survival of stage-I and -II GC submitted to conservative lymphadenectomy.

Comprehensive Molecular Characterization of Adenocarcinoma of the Gastroesophageal Junction Between Esophageal and Gastric Adenocarcinomas.

OBJECTIVE: To investigate the molecular characteristics of AGEJ compared with EAC and gastric adenocarcinoma. SUMMARY OF BACKGROUND DATA: Classification of AGEJ based on differential molecular characteristics between EAC and gastric adenocarcinoma has been long-standing controversy but rarely conducted due to anatomical ambiguity and epidemiologic difference. METHODS: The molecular classification model with Bayesian compound covariate predictor was developed based on differential mRNA expression of EAC (N = 78) and GCFB (N = 102) from the Cancer Genome Atlas (TCGA) cohort. AGEJ/cardia (N = 48) in TCGA cohort and AGEJ/upper third GC (N = 46 pairs) in Seoul National University cohort were classified into the EAC-like or GCFB-like groups whose genomic, transcriptomic, and proteomic characteristics were compared. RESULTS: AGEJ in both cohorts was similarly classified as EAC-like (31.2%) or GCFB-like (68.8%) based on the 400-gene classifier. The GCFB-like group showed significantly activated phosphoinositide 3-kinase-AKT signaling with decreased expression of ERBB2. The EAC-like group presented significantly different alternative splicing including the skipped exon of RPS24, a significantly higher copy number amplification including ERBB2 amplification, and increased protein expression of ERBB2 and EGFR compared with GCFB-like group. High-throughput 3D drug test using independent cell lines revealed that the EAC-like group showed a significantly better response to lapatinib than the GCFB-like group (P = 0.015). CONCLUSIONS: AGEJ was the combined entity of the EAC-like and GCFB-like groups with consistently different molecular characteristics in both Seoul National University and TCGA cohorts. The EAC-like group with a high Bayesian compound covariate predictor score could be effectively targeted by dual inhibition of ERBB2 and EGFR.

Development of a predictive model for extragastric recurrence after curative resection for early gastric cancer.

BACKGROUND: Stratification of patients who undergo curative resection for early gastric cancer (EGC) is warranted due to the heterogeneity in the risk of developing extragastric recurrence (EGR). Therefore, we aimed to stratify the need for postoperative surveillance for EGR detection in patients with EGC by developing a model for predicting EGR-free survival. METHODS: This retrospective cohort study included patients who underwent postoperative surveillance after curative resection of EGC (n = 4149). Cox proportional hazard models were used to identify predictors to build a model for predicting EGR-free survival. Bootstrap-corrected c-index and calibration plots were used for internal and external (n = 2148) validations. RESULTS: A risk-scoring system was constructed using variables significantly associated with EGR-free survival: pathologic T stage (pT1b[sm1], hazard ratio [HR] 4.928; pT1b[sm2], HR 5.235; pT1b[sm3], HR 7.748) and N stage (pN1, HR 4.056; pN2, HR 9.075; pN3, HR 30.659). Patients were dichotomized into a very-low-risk group or a low-or-greater-risk group. The 5-year EGR-free survival rates differed between the two groups (99.9 vs. 97.3%). The discriminative performance of the model was 0.851 (Uno's c-index) and 0.751 in the internal and external cohorts, respectively. The calibration slope was 0.916 and 1.131 in the internal and external cohorts, respectively. CONCLUSIONS: Our model for predicting EGR-free survival based on the pathologic T and N stages may be useful for stratifying patients who have undergone curative surgery for EGC. The results suggest that patients in the very-low-risk group may be spared from postoperative surveillance considering their extremely high EGR-free survival rate.

Glucose metabolic profiles evaluated by PET associated with molecular characteristic landscape of gastric cancer.

BACKGROUND: Although FDG-PET is widely used in cancer, its role in gastric cancer (GC) is still controversial due to variable [18F]fluorodeoxyglucose ([18F]FDG) uptake. Here, we sought to develop a genetic signature to predict high FDG-avid GC to plan individualized PET and investigate the molecular landscape of GC and its association with glucose metabolic profiles noninvasively evaluated by [18F]FDG-PET. METHODS: Based on a genetic signature, PETscore, representing [18F]FDG avidity, was developed by imaging data acquired from thirty patient-derived xenografts (PDX). The PETscore was validated by [18F]FDG-PET data and gene expression data of human GC. The PETscore was associated with genomic and transcriptomic profiles of GC using The Cancer Genome Atlas. RESULTS: Five genes, PLS1, PYY, HBQ1, SLC6A5, and NAT16, were identified for the predictive model for [18F]FDG uptake of GC. The PETscore was validated in independent PET data of human GC with qRT-PCR and RNA-sequencing. By applying PETscore on TCGA, a significant association between glucose uptake and tumor mutational burden as well as genomic alterations were identified. CONCLUSION: Our findings suggest that molecular characteristics are underlying the diverse metabolic profiles of GC. Diverse glucose metabolic profiles may apply to precise diagnostic and therapeutic approaches for GC.

Clinical significance of lipid droplets formed in the peritoneal fluid after laparoscopic surgery for gastric cancer.

BACKGROUND: Several studies have previously reported that laparoscopic surgery using an energy sealing device generates hazardous surgical smoke. However, the droplets appearing on the surface of peritoneal fluid irrigated with saline, after dissection phase of laparoscopic gastrectomy were ignored for a long time. This study aimed to investigate the composition and clinical significance of these droplet particles. METHODS: This study prospectively enrolled 15 patients with early gastric cancer (cT1NanyM0) who were scheduled for laparoscopic gastrectomy. Floating phases of peritoneal irrigation fluid containing droplets in dissected area were retrieved before and after surgical dissection. Using gas chromatography analysis, the areas under the peak were compared between the samples retrieved before and after surgical dissection. We also analyzed if the area value with significant change was related to the inflammatory response. RESULTS: In gas chromatography, the area values after laparoscopic surgical dissection were significantly increased in 10 out of 37 kinds of fatty acids, compared to those before surgical dissection. The significant increase in area value of α-linoleic and eicosadienoic acids were positively correlated with the elevated level of C-reactive protein at postoperative day 2 (Spearman's ρ = 0.843, P < 0.001; Spearman's ρ = 0.785, P = 0.001). CONCLUSIONS: The lipid droplets, generated after laparoscopic lymphadenectomy during gastric cancer surgery, contained various types of fatty acids, and some of them have been found to be associated with inflammatory response.

Ultrasound-guided bilateral subcostal transversus abdominis plane block in gastric cancer patients undergoing laparoscopic gastrectomy: a randomised-controlled double-blinded study.

BACKGROUND: The effectiveness of subcostal transversus abdominis plane block (TAPB) in laparoscopic gastric cancer surgery is unknown. We aimed to investigate its opioid-sparing and pain-relief effects in laparoscopic gastrectomy for gastric cancer. METHOD: One hundred and twelve patients undergoing elective laparoscopic gastrectomy were randomised to the TAPB or control group. The TAPB group received ultrasound-guided bilateral subcostal TAPB at the end of surgery, while the control group did not. We investigated fentanyl consumption administered via intravenous patient-controlled analgesia and as a rescue analgesic, the numeric rating scale (NRS) pain scores at rest and during coughing, and the opioid-related side effects at 6, 12, 24, and 48 h postoperatively. The primary outcome was cumulative fentanyl consumption at 24 h postoperatively. RESULTS: The study included 53 patients in each group. The cumulative fentanyl consumption 24 h postoperatively was significantly lower in the TAPB group than in the control group (median difference -170 mcg, P = 0.03, 95% CI -360 to -15 mcg). Subcostal TAPB also significantly reduced the resting NRS score at 48 h postoperatively (median difference -1, 95% CI -1 to 0, P = 0.01) and coughing NRS score at all time points (all median difference -1, 95% CI -2 to 0, P < 0.01, P  = 0.02, 0.01, and 0.01, respectively). However, it did not reduce the occurrence of opioid-related side effects, except the use of antiemetics during the first 6 h postoperatively (TAPB, 1.9% vs. Control, 15.1%, P = 0.03). CONCLUSION: Ultrasound-guided bilateral subcostal TAPB provides efficient postoperative analgesia with an opioid-sparing effect after laparoscopic gastrectomy.

Prediction Model for Screening Patients at Risk of Malnutrition After Gastric Cancer Surgery.

BACKGROUND: Malnutrition after gastrectomy is associated with a poor prognosis; however, no accurate model for predicting post-gastrectomy malnutrition exists. Hence, we conducted a retrospective study to develop a prediction model identifying gastric cancer patients at high risk of malnutrition after gastrectomy. METHOD: Gastric cancer patients who underwent curative gastrectomy with more than one weight measurement during a 3-year follow-up period were included. Malnutrition was defined as body mass index (BMI) < 18.5 kg/m2 according to the European Society of Clinical Nutrition and Metabolism diagnostic criteria. BMI-loss pattern was analyzed using a group-based trajectory model. A prediction model for malnutrition 6 months after gastrectomy was developed based on significant risk factors, and then validated. RESULTS: Overall, 1421 patients were examined. The BMI-loss trajectory model showed significant BMI loss at 6 months after gastrectomy. Severe BMI loss (mean 21.5%; n = 109) was significantly associated with the elderly, female sex, higher preoperative BMI, advanced cancer stage, open surgery, total gastrectomy, Roux-en-Y reconstruction, chemotherapy, and postoperative complications (all p < 0.05). Malnutrition 6 months after gastrectomy was observed in 152 (11.9%) of 1281 patients. Preoperative BMI, sex, and type of operation were included in the final prediction model as predictive factors (p < 0.05). The C-index of the developmental set and bootstrap validation of the prediction model was 0.91 (95% confidence interval 0.89-0.94) and 0.91, respectively. CONCLUSION: The prediction model for the risk of malnutrition 6 months after gastrectomy was accurately developed, with three independent risk factors: low preoperative BMI, female sex, and total or proximal gastrectomy.