Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In Asia, adjuvant chemotherapy after gastrectomy with D2 or more extensive lymph-node dissection is standard treatment for people with pathological stage III gastric or gastro-oesophageal junction (GEJ) cancer. We aimed to assess the efficacy and safety of adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy administered in this setting. METHODS: ATTRACTION-5 was a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial conducted at 96 hospitals in Japan, South Korea, Taiwan, and China. Eligible patients were aged between 20 years and 80 years with histologically confirmed pathological stage IIIA-C gastric or GEJ adenocarcinoma after gastrectomy with D2 or more extensive lymph-node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and available tumour tissue for PD-L1 expression analysis. Patients were randomly assigned (1:1) to receive either nivolumab plus chemotherapy or placebo plus chemotherapy via an interactive web-response system with block sizes of four. Investigational treatment, either nivolumab 360 mg or placebo, was administered intravenously for 30 min once every 3 weeks. Adjuvant chemotherapy was administered as either tegafur-gimeracil-oteracil (S-1) at an initial dose of 40 mg/m2 per dose orally twice per day for 28 consecutive days, followed by 14 days off per cycle, or capecitabine plus oxaliplatin consisting of an initial dose of intravenous oxaliplatin 130 mg/m2 for 2 h every 21 days and capecitabine 1000 mg/m2 per dose orally twice per day for 14 consecutive days, followed by 7 days off treatment. The primary endpoint was relapse-free survival by central assessment. The intention-to-treat population, consisting of all randomly assigned patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of trial drug, was used for analysis of safety endpoints. This trial is registered with ClinicalTrials.gov (NCT03006705) and is closed. FINDINGS: Between Feb 1, 2017, and Aug 15, 2019, 755 patients were randomly assigned to receive either adjuvant nivolumab plus chemotherapy (n=377) or adjuvant placebo plus chemotherapy (n=378). 267 (71%) of 377 patients in the nivolumab group and 263 (70%) of 378 patients in the placebo group were male; 110 (29%) of 377 patients in the nivolumab group and 115 (31%) of 378 patients in the placebo group were female. 745 patients received assigned treatment (371 in the nivolumab plus chemotherapy group; 374 in the placebo plus chemotherapy group), which was the safety population. Median time from first dose to data cutoff was 49·1 months (IQR 43·1-56·7). 3-year relapse-free survival was 68·4% (95% CI 63·0-73·2) in the nivolumab plus chemotherapy group and 65·3% (59·9-70·2) in the placebo plus chemotherapy group; the hazard ratio for relapse-free survival was 0·90 (95·72% CI 0·69-1·18; p=0·44). Treatment-related adverse events occurred in 366 (99%) of 371 patients in the nivolumab plus chemotherapy group and 364 (98%) of 374 patients in the placebo plus chemotherapy group. Discontinuation due to adverse events was more frequent in the nivolumab plus chemotherapy group (34 [9%] of 371 patients) than the placebo plus chemotherapy group (13 [4%] of 374 patients). The most common treatment-related adverse events were decreased appetite, nausea, diarrhoea, neutrophil count decreased, and peripheral sensory neuropathy. INTERPRETATION: The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer. FUNDING: Ono Pharmaceutical and Bristol Myers Squibb.

Redefining aberrant P53 expression of gastric cancer and its distinct clinical significance among molecular-histologic subtypes.

BACKGROUND: Numerous studies have demonstrated a correlation between p53 overexpression and diminished survival in gastric cancer patients. However, conflicting findings exist, and we hypothesize that these discrepancies arise from the cancer's complexity and heterogeneity, coupled with a lack of consensus on aberrant p53 expression. METHODS: We enrolled a cohort of 187 patients with surgically resected gastric cancer. Patient categorization was based on Epstein-Barr virus (EBV), microsatellite instability (MSI), and Lauren classification (intestinal, diffuse and mixed). Utilizing an incremental algorithm, we evaluated p53 immunohistochemical (IHC) patterns in all 187 cases, while next-generation sequencing was successfully performed on 152 cases to identify TP53 mutations (mutTP53). RESULTS: MutTP53 was identified in 32 % of the 152 cases, comprising 36 missense, 5 nonsense, and 7 frameshift alterations. Missense mutations predominantly correlated with p53 overexpression, while nonsense and frameshifting alterations related to null expression. Trial calculations indicated that null expression and a p53 IHC cutoff at >40 % offered the best prediction of mutTP53 (kappa coefficient, 0.427), with the highest agreement (0.524) observed in diffuse type and the lowest (0.269) in intestinal type. Null expression and a p53 IHC cutoff at >10 %, but not mutTP53 per se, provided the optimal prediction of survival outcome (p = 0.043), particularly in diffuse type (p = 0.044). Multivariate analysis showed that aberrant p53 IHC expression was not an independent prognostic factor. CONCLUSIONS: P53 IHC patterns are predictive biomarkers for mutTP53 and gastric cancer outcomes, where a prerequisite involves a nuanced approach considering cutoff values and molecular-histologic subtyping.

Peripheral Blood Inflammatory Markers as A Reliable Predictor of Gastric Mucosal Metaplasia Change in the Middle-aged Population.

Purpose: The study aims to evaluate the efficacy of peripheral blood inflammatory markers as clinical predictors for gastric intestinal metaplasia (IM), a known precursor to gastric cancer. This research investigates the potential of these markers to serve as reliable indicators for detecting gastric IM. Methods: A retrospective cohort study was conducted on 59,143 individuals who underwent checkups at the Taoyuan Chang Gung Memorial Hospital Health Clinic Center from 2010 to 2014. Of these, 11,355 subjects who received gastroscopic biopsies were recruited. After omitting cases with incomplete blood data, the sample was narrowed to 10,380 participants. After exclusion and propensity score matching, subjects in the group with IM and control patients without IM were balanced and included in the study. These subjects were stratified by gender and age, and predictors such as the Systemic Inflammation Response Index (SIRI), Systemic Immune Inflammation Index (SII), and Monocyte-to-Lymphocyte Ratio (MLR) were evaluated. Multivariate logistic regression models were employed to analyze the presence or absence of IM accurately. Results: Out of the 10,380 subjects, 2,088 (20.1%) were diagnosed with IM, while 8,292 (79.9%) did not have IM. In our analysis, inflammation indices were found to have a limited impact on younger patients. For middle-aged and elderly individuals, SII showed statistical significance for predicting IM in males (p=0.0019), while SIRI and MLR were significant for females (SIRI p=0.0001, MLR p=0.0009). Additionally, the Area Under the Curve (AUC) value indicated that inflammation indices were more influential in females (55.1%) than males. Conclusions: The study results reveal that peripheral blood inflammatory markers could be useful in predicting gastric mucosal metaplasia changes, particularly in middle-aged and elderly populations. Although the markers' predictive power varies with gender, they represent a significant step forward in the non-invasive detection of gastric IM. This could aid in the early identification and management of precancerous conditions.

Artificial Intelligence Model for a Distinction between Early-Stage Gastric Cancer Invasive Depth T1a and T1b.

Background: Endoscopic submucosal dissection (ESD) is a widely accepted treatment for patients with mucosa (T1a) disease without lymph node metastasis. However, the inconsistency of inspection quality of tumor staging under the standard tool combining endoscopic ultrasound (EUS) with computed tomography (CT) scanning makes it restrictive. Methods: We conducted a study using data augmentation and artificial intelligence (AI) to address the early gastric cancer (EGC) staging problem. The proposed AI model simplifies early cancer treatment by eliminating the need for ultrasound or other staging methods. We developed an AI model utilizing data augmentation and the You-Only-Look-Once (YOLO) approach. We collected a white-light image dataset of 351 stage T1a and 542 T1b images to build, test, and validate the model. An external white-light images dataset that consists of 47 T1a and 9 T1b images was then collected to validate our AI model. The result of the external dataset validation indicated that our model also applies to other peer health institutes. Results: The results of k-fold cross-validation using the original dataset demonstrated that the proposed model had a sensitivity of 85.08% and an average specificity of 87.17%. Additionally, the k-fold cross-validation model had an average accuracy rate of 86.18%; the external data set demonstrated similar validation results with a sensitivity of 82.98%, a specificity of 77.78%, and an overall accuracy of 82.14%. Conclusions: Our findings suggest that the AI model can effectively replace EUS and CT in early GC staging, with an average validation accuracy rate of 86.18% for the original dataset from Linkou Cheng Gun Memorial Hospital and 82.14% for the external validation dataset from Kaohsiung Cheng Gun Memorial Hospital. Moreover, our AI model's accuracy rate outperformed the average EUS and CT rates in previous literature (around 70%).

Prognostic Factors and the Role of Adjuvant Chemotherapy in Pathological Node-Negative T3 Gastric Cancer.

The role of adjuvant chemotherapy in pathological T3N0M0 (pT3N0M0) gastric cancer (GC) remains unclear. The aim of this study was to analyze the prognostic factors of patients with pT3N0M0 GC and to clarify which ones could benefit from adjuvant chemotherapy. A total of 137 patients with pT3N0M0 GC were recruited between 1994 and 2020. Clinicopathological factors and adjuvant chemotherapy regimens were retrospectively collected. Prognostic factors of disease-free survival (DFS) and cancer-specific survival (CSS) were determined using univariate and multivariate analyses. The chemotherapy group was younger (p = 0.012), had had more lymph nodes retrieved (p = 0.042) and had higher percentages of vascular invasion (p = 0.021) or perineural invasion (p = 0.030) than the non-chemotherapy group. There were no significant differences in DFS (p = 0.222) and CSS (p = 0.126) between patients treated with or without adjuvant chemotherapy. Stump cancer, tumor size and perineural invasion were associated with higher rates of recurrence. Tumor size was an independent prognostic factor for DFS (hazard ratio, 4.55; confidence interval, 1.59-12.99; p = 0.005) and CSS (hazard ratio, 3.97; confidence interval, 1.38-11.43; p = 0.011). Tumor size independently influenced survival outcomes in pT3N0M0 patients who underwent radical surgery with and without adjuvant chemotherapy.

Risk factors of recurrent secondary hyperparathyroidism after adequate primary surgical treatment.

Background: Secondary hyperparathyroidism (SHPT) is a common condition in patients with end-stage renal disease (ESRD) who are on dialysis. Parathyroidectomy is a treatment for patients when medical therapy has failed. Recurrence may occur and is indicated for further surgery in the era of improved quality of care for ESRD patients. Methods: We identified, 1060 patients undergoing parathyroidectomy from January, 2011 to June, 2020. After excluding patients without regular check-up at our institute, primary hyperparathyroidism, or malignancy, 504 patients were enrolled. Sixty-two patients (12.3%, 62/504) were then excluded due to persistent SHPT even after the first parathyroidectomy. We aimed to identify risk factors for recurrent SHPT after the first surgery. Results: During the study period, 20% of patients who underwent parathyroidectomy at our institute (in, 2019) was due to recurrence after a previous parathyroidectomy. There were 442 patients eligible for analysis of recurrence after excluding patients with the persistent disease (n = 62). While 44 patients (9.95%) had recurrence, 398 patients did not. Significant risk factors for recurrent SHPT within 5 years after the first parathyroidectomy, including dialysis start time to first operation time < 3 years (p = 0.046), postoperative PTH >106.5 pg/mL (p < 0.001), and postoperative phosphorus> 5.9 mg/dL (p = 0.016), were identified by multivariate analysis. Conclusions: The starting time of dialysis to first operation time < 3 years in the patients with dialysis, postoperative PTH> 106.5 pg/mL, and postoperative phosphorus> 5.9 mg/dL tended to have a higher risk for recurrent SHPT within 5 years after primary treatment.

Gastroesophageal Reflux Disease Symptoms after Laparoscopic Sleeve Gastrectomy: A Retrospective Study.

(1) Background: Laparoscopic sleeve gastrectomy (LSG) is widely performed in bariatric surgery. However, the prevalence and risk factors of gastroesophageal reflux disease (GERD) symptoms after LSG remain unclear to date. This study aimed to identify risk factors of GERD after LSG. (2) Methods: We conducted a retrospective study at Linkou Chang Gung Memorial Hospital and reviewed 296 patients who underwent LSG from 2016 to 2019. A total of 143 patients who underwent preoperative esophagogastroduodenoscopy and completed the 12-month postoperative follow-up were enrolled. Patients' demographic data, comorbidities, and postoperative weight loss results were recorded for analysis. The GerdQ questionnaire was used to assess GERD after LSG. (3) Results: There were eight surgical complications (5.6%) among the 143 studied patients (median age, 36 years; 56 (39.2%) men; median body weight 105.5 kg; median body mass index [BMI], 38.5 kg/m2). Twenty-three patients (16.1%) developed de novo GERD symptoms. GERD was significantly associated with older age (p = 0.022) and lower BMI (<35 kg/m2, p = 0.028). In multiple logistic regression analysis, age and BMI were significantly associated with GERD. (4) Conclusions: LSG is a safe and effective weight loss surgery. In our study, it led to 16.1% of de novo GERD symptoms, which were significantly related to older age and lower BMI (<35 kg/m2).

A proposal for T1 subclassification in hepatocellular carcinoma: reappraisal of the AJCC 8th edition.

BACKGROUND: In the 8th edition of American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC), tumor size is not considered in T1 stage. The present study aimed to find out the optimal cutoff for tumor size to further stratify patients with T1 HCC. METHODS: Operated HCC patients were identified from the Chang Gung Research Database (CGRD), and the patients with T1bN0M0 tumors were further divided into two groups based on the tumor size. The resulting subgroups were denoted as T1b (≤ cutoff) and T1c (> cutoff). The survivals were compared between T1a/b and T1c as well as T1c and T2. RESULTS: From 2002 to 2018, a total of 2893 patients who underwent surgery for T1N0M0 HCC were identified from the CGRD. After excluding cases who died within 30 days of surgery, Kaplan-Meier survival analysis discovered that T1 tumors > 65 mm (T1c) had survivals similar to those of T2N0M0 tumors. Cox regression multivariate analysis further demonstrated that tumor size > 6.5 cm was an independent poor prognostic indicator for T1 HCC. Sensitivity tests also confirmed that tumors lager than 6.5 cm were significantly more likely to develop both tumor recurrence and liver-specific death after surgery. CONCLUSIONS: Our study demonstrated that tumor size would significantly impact the survival outcome of T1 HCC after surgery. Due to significantly worse survival, we proposed a subclassification within T1 HCC, T1c: solitary tumor > 6.5 cm without vascular invasion, to further stratify those patients at risk. Further studies are mandatory to validate our findings.

A flexible three-dimensional heterophase computed tomography hepatocellular carcinoma detection algorithm for generalizable and practical screening.

Hepatocellular carcinoma (HCC) can be potentially discovered from abdominal computed tomography (CT) studies under varied clinical scenarios (e.g., fully dynamic contrast-enhanced [DCE] studies, noncontrast [NC] plus venous phase [VP] abdominal studies, or NC-only studies). Each scenario presents its own clinical challenges that could benefit from computer-aided detection (CADe) tools. We investigate whether a single CADe model can be made flexible enough to handle different contrast protocols and whether this flexibility imparts performance gains. We developed a flexible three-dimensional deep algorithm, called heterophase volumetric detection (HPVD), that can accept any combination of contrast-phase inputs with adjustable sensitivity depending on the clinical purpose. We trained HPVD on 771 DCE CT scans to detect HCCs and evaluated it on 164 positives and 206 controls. We compared performance against six clinical readers, including two radiologists, two hepatopancreaticobiliary surgeons, and two hepatologists. The area under the curve of the localization receiver operating characteristic for NC-only, NC plus VP, and full DCE CT yielded 0.71 (95% confidence interval [CI], 0.64-0.77), 0.81 (95% CI, 0.75-0.87), and 0.89 (95% CI, 0.84-0.93), respectively. At a high-sensitivity operating point of 80% on DCE CT, HPVD achieved 97% specificity, which is comparable to measured physician performance. We also demonstrated performance improvements over more typical and less flexible nonheterophase detectors. Conclusion: A single deep-learning algorithm can be effectively applied to diverse HCC detection clinical scenarios, indicating that HPVD could serve as a useful clinical aid for at-risk and opportunistic HCC surveillance.

Prognostic Significance of Perineural Invasion in Patients with Stage II/III Gastric Cancer Undergoing Radical Surgery.

The prognostic significance of perineural invasion in patients with gastric cancer (GC) is controversial. This study aimed to determine the prognostic value of perineural invasion in patients with stage II/III GC undergoing radical surgery. A total of 1913 patients with stage II/III GC who underwent curative resection between 1994 and 2015 were recruited. Clinicopathological factors, tumor recurrence patterns, disease-free survival, and cancer-specific survival were compared in terms of perineural invasion. The prognostic factors of disease-free survival and cancer-specific survival were determined using univariate and multivariate analyses. Perineural invasion was found in 57.1% of the patients. Age of <65 years, female sex, large tumor size, upper tumor location, total gastrectomy, advanced tumor invasion depth and nodal involvement, greater metastatic to examined lymph node ratio, undifferentiated tumor, and presence of lymphatic or vascular invasion were significantly associated with perineural invasion. The patients with perineural invasion had higher locoregional/peritoneal recurrence rates than those without. Perineural invasion was independently associated with disease-free survival and cancer-specific survival. In conclusion, perineural invasion positivity is associated with aggressive tumor behaviors and higher locoregional/peritoneal recurrence rates in patients with stage II/III GC undergoing curative surgery. It is an independent unfavorable prognostic factor of disease recurrence and cancer-specific survival.

Quercetin exerts anti-inflammatory effects via inhibiting tumor necrosis factor-α-induced matrix metalloproteinase-9 expression in normal human gastric epithelial cells.

BACKGROUND: Gastric injury is the most common digestive system disease worldwide and involves inflammation, which can lead to gastric ulcer or gastric cancer (GC). Matrix metallopeptidase-9 [MMP-9 (gelatinase-B)] plays an important role in inflammation and GC progression. Quercetin and quercetin-rich diets represent potential food supplements and a source of medications for treating gastric injury given their anti-inflammatory activities. However, the effects and mechanisms of action of quercetin on human chronic gastritis and whether quercetin can relieve symptoms remain unclear. AIM: To assess whether tumor necrosis factor-α (TNF-α)-induced MMP-9 expression mediates the anti-inflammatory effects of quercetin in normal human gastric mucosal epithelial cells. METHODS: The normal human gastric mucosa epithelial cell line GES-1 was used to establish a normal human gastric epithelial cell model of TNF-α-induced MMP-9 protein overexpression to evaluate the anti-inflammatory effects of quercetin. The cell counting Kit-8 assay was used to evaluate the effects of varying quercetin doses on cell viability in the normal GES-1 cell line. Cell migration was measured using Transwell assay. The expression of proto-oncogene tyrosine-protein kinase Src (c-Src), phospho (p)-c-Src, extracellular-signal-regulated kinase 2 (ERK2), p-ERK1/2, c-Fos, p-c-Fos, nuclear factor kappa B (NF-κB/p65), and p-p65 and the effects of their inhibitors were examined using Western blot analysis and measurement of luciferase activity. p65 expression was detected by immunofluorescence. MMP-9 mRNA and protein levels were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and gelatin zymography, respectively. RESULTS: qRT-PCR and gelatin zymography showed that TNF-α induced MMP-9 mRNA and protein expression in a dose- and time-dependent manner. These effects were reduced by the pretreatment of GES-1 cells with quercetin or a TNF-α antagonist (TNFR inhibitor) in a dose- and time-dependent manner. Quercetin and TNF-α antagonists decreased the TNF-α-induced phosphorylation of c-Src, ERK1/2, c-Fos, and p65 in a dose- and time-dependent manner. Quercetin, TNF-α antagonist, PP1, U0126, and tanshinone IIA (TSIIA) reduced TNF-α-induced c-Fos phosphorylation and AP-1-Luciferase (Luc) activity in a dose- and time-dependent manner. Pretreatment with quercetin, TNF-α antagonist, PP1, U0126, or Bay 11-7082 reduced TNF-α-induced p65 phosphorylation and translocation and p65-Luc activity in a dose- and time-dependent manner. TNF-α significantly increased GES-1 cell migration, and these results were reduced by pretreatment with quercetin or a TNF-α antagonist. CONCLUSION: Quercetin significantly downregulates TNF-α-induced MMP-9 expression in GES-1 cells via the TNFR-c-Src-ERK1/2 and c-Fos or NF-κB pathways.

Hepatectomy or/with Metastatectomy for Recurrent Intrahepatic Cholangiocarcinoma: Of Promise for Selected Patients.

Introduction: Intrahepatic cholangiocarcinoma (ICC) has devastating outcomes owing to its advanced stage at diagnosis and high recurrence after hepatectomy. There is no preferred treatment for recurrent ICC. We retrospectively reviewed our patients who underwent repeated operations for recurrent ICCs based on their different indications to appraise the outcomes. Methods: In all, 160 out of 216 patients with ICC (71.4%) experienced recurrence after curative resection from 1977 to 2014. The patterns of recurrence were categorized according to the locations and numbers of recurrent tumors. Results: Patients with merely intrahepatic recurrence (n = 38) had superior overall survival (OS) compared with those with beyond intrahepatic recurrence (p < 0.0001). Twenty-seven out of 160 patients (16.8%) underwent repeat hepatectomy or/with metastatectomy for recurrence and had superior OS when compared to the remaining 133 patients who received nonoperative treatment/palliation (85.6 months versus 20.9 months, p < 0.001). Furthermore, patients suitable for repeat hepatectomy in the intrahepatic recurrent group (n = 12) had superior post-recurrence overall survival (PROS) than the remaining 26 patients receiving nonoperative treatment (61.6 months versus 14.7 months, p < 0.05). Conclusion: Liver is the most commonly involved site of recurrent ICC. However, merely intrahepatic recurrence may have a favorable prognosis compared to recurrence involving other sites. Aggressive hepatectomy may provide a survival benefit in selected patients.

Outcomes of Conversion Surgery for Metastatic Gastric Cancer Compared with In-Front Surgery Plus Palliative Chemotherapy or In-Front Surgery Alone.

The survival benefits of conversion surgery in patients with metastatic gastric cancer (mGC) remain unclear. Thus, this study aimed to determine the outcomes of conversion surgery compared to in-front surgery plus palliative chemotherapy (PCT) or in-front surgery alone for mGC. We recruited 182 consecutive patients with mGC who underwent gastrectomy, including conversion surgery, in-front surgery plus PCT, and in-front surgery alone at Linkou Chang Gung Memorial Hospital from 2011 to 2019. The tumor was staged according to the 8th edition of the American Joint Committee on Cancer. Patient demographics and clinicopathological factors were assessed. Overall survival (OS) was evaluated using the Kaplan−Meier curve and compared among groups. Conversion surgery showed a significantly longer median OS than in-front surgery plus PCT or in-front surgery alone (23.4 vs. 13.7 vs. 5.6 months; log rank p < 0.0001). The median OS of patients with downstaging (pathological stage I−III) was longer than that of patients without downstaging (stage IV) (30.9 vs. 18.0 months; p = 0.016). Our study shows that conversion surgery is associated with survival benefits compared to in-front surgery plus PCT or in-front surgery alone in patients with mGC. Patients who underwent conversion surgery with downstaging had a better prognosis than those without downstaging.

Prediction of Gastric Gastrointestinal Stromal Tumors before Operation: A Retrospective Analysis of Gastric Subepithelial Tumors.

Gastrointestinal stromal tumors (GISTs), leiomyomas, and schwannomas are the most common gastric subepithelial tumors (GSETs) with similar endoscopic findings. Preoperative prediction of GSETs is difficult. This study analyzed and predicted GSET diagnosis through a retrospective review of 395 patients who underwent surgical resection of GISTs, leiomyomas, and schwannomas measuring 2-10 cm. GSETs were divided by size (group 2-5, >2 and ≤5 cm; group 5-10, >5 and ≤10 cm) for analysis. Demographics, clinical symptoms, and images were analyzed. A recursive partitioning analysis (RPA) was used to identify optimal classifications for specific GSET diagnoses. GIST patients were relatively older than other patients. Both groups had higher proportions of UGI bleeding, lower hemoglobin (Hb) levels, and a higher ratio of necrosis on their computed tomography (CT) scans. The RPA tree showed that (a) age ≤ 55, Hb ≥ 10.7, and CT necrosis; (b) age ≤ 55 and Hb < 10.7; (c) age >55 and Hb < 12.9; and (d) age >55 and CT hetero-/homogeneity can predict high GIST risk in group 2-5. Positive or negative CT necrosis, with age >55, can predict high GIST risk in group 5-10. GIST patients were older and presented with low Hb levels and tumor necrosis. In RPA, the accuracy reached 85% and 89% in groups 2-5 and 5-10, respectively.

Molecular mechanism of therapeutic approaches for human gastric cancer stem cells.

Gastric cancer (GC) is a primary cause of cancer-related mortality worldwide, and even after therapeutic gastrectomy, survival rates remain poor. The presence of gastric cancer stem cells (GCSCs) is thought to be the major reason for resistance to anticancer treatment (chemotherapy or radiotherapy), and for the development of tumor recurrence, epithelial-mesenchymal transition, and metastases. Additionally, GCSCs have the capacity for self-renewal, differentiation, and tumor initiation. They also synthesize antiapoptotic factors, demonstrate higher performance of drug efflux pumps, and display cell plasticity abilities. Moreover, the tumor microenvironment (TME; tumor niche) that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor. However, the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential. In this review, we provide up-to-date information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development. This information will support improved diagnosis, novel therapeutic approaches, and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy. To date, most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents. However, when used in combination with adjuvant therapy, treatment can improve. By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC, the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy, radiotherapy, or other adjuvant treatment.

Dedifferentiation-like tubular and solid carcinoma of the stomach shows phenotypic divergence and association with deficient SWI/SNF complex.

Gastric carcinoma showing an abrupt transition from a tubular to solid pattern is an unusual phenomenon reminiscent of dedifferentiation. The phenotypic and molecular characteristics of this transition are still unclear. We retrospectively collected 41 gastric carcinomas exhibiting dedifferentiation-like tubular to solid transition and applied an array of immunohistochemical stains, including neuroendocrine and hepatocytic markers, to delineate their lineage. The status of Epstein-Barr virus (EBV) infections, mismatch repair proteins, SWI/SNF complex proteins and p53 expression levels were examined. The clinicopathologic differences were assessed by statistical analysis. Except for 10 cases with neuroendocrine differentiation and 2 EBV-associated carcinomas, we identified 8 hepatoid carcinomas and 21 solid adenocarcinomas with loss of CDX2 and/or hep-par1 expression in solid part (12/29). A subset of solid adenocarcinoma was associated with MSI (8) and mutant p53 expression was frequent in non-MSI cases (10/13). We found hepatoid carcinomas usually harbored SMARCA2 loss (5/8), MSI-associated cases commonly had ARID1A loss (6/8), and non-MSI solid adenocarcinomas frequently showed SMARCA2/A4 loss (7/13) with a high rate of concurrent ARID1A loss (4/7). Spatial correlation between solid transition and loss of SWI/SNF complex subunits were seen in 63% of tumors (12/19). Dedifferentiation-like tubular and solid carcinoma was associated with a propensity to inferior survival outcomes (p = 0.034), especially hepatoid carcinoma and in the non-MSI/EBV intestinal subgroup. In conclusion, gastric cancer exhibiting dedifferentiation-like tubular to solid transition is a phenotypically divergent group that shares common alterations in the SWI/SNF complex.

The Severity of Postoperative Pancreatic Fistula Predicts 30-Day Unplanned Hospital Visit and Readmission after Pancreaticoduodenectomy: A Single-Center Retrospective Cohort Study.

BACKGROUND: Unplanned hospital visits (UHV) and readmissions after pancreaticoduodenectomy (PD) impact patients' postoperative recovery and are associated with increased financial burden and morbidity. The aim of this study is to identify predictive factors related to these events and target the potentially preventable UHV and readmissions. METHODS: We enrolled 518 patients in this study. Characteristics were compared between patients with or without UHV and readmissions. RESULTS: The unplanned visit and readmission rate was 23.4% and 15.8%, respectively. Postoperative pancreatic fistula (POPF) grade B or C, the presence of postoperative biliary drainage, and reoperation were found to be predictive factors for UHV, whereas POPF grade B or C and the presence of postoperative biliary drainage were independently associated with hospital readmission. The most common reason for readmission was an infection, followed by failure to thrive. The overall mortality rate in the readmission group was 4.9%. CONCLUSIONS: UHV and readmissions remain common among patients undergoing PD. Patients with grade B or C POPF assessed during index hospitalization harbor an approximately two-fold increased risk of subsequent unplanned visits or readmissions compared to those with no POPF or biochemical leak. Proper preventive strategies should be adopted for high-risk patients in this population to maintain the continuum of healthcare and improve quality.

Serum microRNA panels predict bariatric surgery outcomes.

OBJECTIVE: The weight losses after bariatric surgery are modulated by multiple factors in people with obesity. MicroRNAs (miRNAs) have been reported to show significant regulatory roles in adipose tissue. However, a serum miRNA signature to serve as a biomarker of sustained weight losses following bariatric surgery has not yet been established. METHODS: MiRNA microarray was used to identify differentially expressed miRNAs in the serum of patients with an effective response after bariatric surgery compared with those without. Excess weight loss > 55% at 6 months after surgery was defined as an effective response. RESULTS: Three miRNAs were shown to have a significantly differential expression between patients with or without an effective response following bariatric surgery. The miR-31-5p was downregulated, whereas miR-328-3p and miR-181a-5p were upregulated in the patients with effective responses compared with those without effective responses. Panels of the serum ratios of miR-328-3p/miR-31-5p or miR-181a-5p/miR-31-5p and individual BMI value exhibited good performance in preoperative prediction of treatment effectiveness. Bioinformatic analysis depicted that predicted targets of these miRNAs were involved in the regulation of the AMP-activated protein kinase signaling pathway. CONCLUSIONS: A circulating miRNA signature with clinical variables (BMI) can be a clinical biomarker to predict effectiveness following bariatric surgery.

Lymph node micrometastasis of poorly differentiated node-negative gastric cancer risks a worse-than-expected survival outcome under standard management algorithm.

BACKGROUND: Investigation of lymph node micrometastasis (mN) of gastric cancer has been focused on either T1 disease or T1-4N0 disease. Yet, it is unclear whether standard management algorithm toward poorly differentiated gastric cancer (PDGC) is more vulnerable to existence of mN, given its inherently biological aggressiveness, as compared with other histological types. PATIENTS AND METHODS: A surgical series (n = 3456) of gastric cancer categorized by histological differentiation was enrolled to analyze survival stratification. Of them, a cohort of T1-T4 N0 PDGC (n = 100) were subjected to cytokeratin immunohistochemistry, a surrogate of mN. RESULTS: Cancer-specific survival by AJCC8 staging system could be nicely differentiated in both well-/moderately differentiated and signet ring cell types, while those between stage IA versus IB (p = 0.105), and stage IB versus IIA (p = 0.141) in PDGC could not. Thirteen (13%) out of 100 node-negative PDGC cases exhibited mN, with 5, 2, 5 and 1 cases occurring in T1, T2, T3, and T4 stage, respectively, without identifiable contributing factors. Prognostic performance of AJCC8 working upon PDGC became more discriminative by incorporating mN, as hazard ratio of stage IIIC referenced to stage IA increased from 43 to 78. CONCLUSION: Defective discriminative survival of PDGC by standard staging algorithm prompted us to survey mN occurring in T1-T4N0 PDGC. The prognostic performance of AJCC8 working upon PDGC was enhanced by incorporating mN. As so, we recommend documentation of mN exclusively on node-negative PDGC that helps unveil stage migration phenomenon and switch to appropriate adjuvant therapy in need.

Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect.

Metabolic reprogramming is closely linked to the tumorigenesis and drug resistance of gastrointestinal stromal tumors (GISTs). Mapping the metabolic orbit of GISTs is a prerequisite if intervention against the metabolic vulnerability of refractory GISTs is desirable. Methods: A total of 43 patients with treatment-naïve GISTs who had undergone surgical resections were enrolled, on whom a metabolomics profile detected from surgical specimens was constructed based on the 1H-nuclear magnetic resonance (NMR) platform. The mRNA and protein levels of GLUT1, HK2, ACSS2, and FASN were assayed. Dual-tracer 18F-FDG/11C-acetate PET imaging was introduced before surgery in 15 patients. Results: 1H-NMR-based metabolomics revealed that GISTs were characterized by upregulation of glutamate, ascorbate, aspartate and glycine and downregulation of choline, creatine, glucose and glycerol. Bioinformatics analysis showed that the TCA cycle and alanine, aspartate, and glutamate metabolism were the two leading pathways. High- and nonhigh-risk (including intermediate-, low-, and very low-risk) GISTs preferentially displayed upregulation of HK2 and ACSS2, respectively, echoed by in vivo imaging that high- and nonhigh-risk GISTs preferentially exhibited higher uptake of 18F-FDG and 11C-acetate, respectively, while 18F-FDG and 11C-acetate were complementary to each other. Nuclear ACSS2 was exclusively identified in high-risk GISTs. Conclusion: We describe a metabolic landscape of GISTs that read aspartate as a de facto "oncometabolite," which was replenished via the TCA cycle and alanine, aspartate, and glutamate metabolism. Glycolysis and ACSS2-mediated acetate metabolism competed and complemented fatty acid synthesis, although glycolysis remained an aggressive phenotype.