Background
Metabolomics is useful for analyzing the nutrients necessary for cancer progression, as the proliferation is regulated by available nutrients. We studied the metabolomic profile of gastric ...cancer (GC) tissue to elucidate the associations between metabolism and recurrence.
Methods
Cancer and adjacent non-cancerous tissues were obtained in a pair-wise manner from 140 patients with GC who underwent gastrectomy. Frozen tissues were homogenized and analyzed by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Metabolites were further assessed based on the presence or absence of recurrence.
Results
Ninety-three metabolites were quantified. In cancer tissues, the lactate level was significantly higher and the adenylate energy charge was lower than in non-cancerous tissues. The Asp, β-Ala, GDP, and Gly levels were significantly lower in patients with recurrence than in those without. Based on ROC analyses to determine the cut-off values of the four metabolites, patients were categorized into groups at high risk and low risk of peritoneal recurrence. Logistic regression and Cox proportional hazard analyses identified β-Ala as an independent predictor of peritoneal recurrence (hazard ratio HR 5.21 95% confidence interval 1.07–35.89,
p
= 0.029) and an independent prognostic factor for the overall survival (HR 3.44 95% CI 1.65–7.14,
p
< 0.001).
Conclusions
The metabolomic profiles of cancer tissues differed from those of non-cancerous tissues. In addition, four metabolites were significantly associated with recurrence in GC. β-Ala was both a significant predictor of peritoneal recurrence and a prognostic factor.
There is no consensus on the efficacy of perioperative immunonutrition in patients with upper gastrointestinal (GI) cancer surgery. We clarified the impact of perioperative immunonutrition on ...postoperative outcomes in patients with upper GI cancers. We searched MEDLINE (PubMed), MEDLINE (OVID), EMBASE, Cochrane Central Register of Controlled Trials, Web of Science Core Selection, and Emcare from 1981-2022 using search terms related to immunonutrition and upper GI cancer. We included randomized controlled trials. Intervention was defined as immunonutritional therapy, including arginine, n-3 omega fatty acids, or glutamine during the perioperative period. The control was defined as standard nutritional therapy. The primary outcomes were infectious complications, defined as events with a Clavien-Dindo classification grade ≥ II that occurred within 30 days after surgery. After screening, 23 studies were included in the qualitative synthesis and in the quantitative synthesis. The meta-analysis showed that immunonutrition reduced infectious complications (relative risk ratio: 0.72; 95% confidence interval: 0.57-0.92; certainty of evidence: Moderate) compared with standard nutritional therapy. In conclusion, nutritional intervention with perioperative immunonutrition in patients with upper GI cancers significantly reduced infectious complications. The effect of immunonutrition for upper GI cancers in reducing the risk of infectious complications was about 30%.
We investigated the impact of the difference in fat distribution between men and women on long-term prognosis after gastrectomy in patients with advanced gastric cancer. Patients with advanced ...gastric cancer deeper than p-T2 who underwent gastrectomy between April 2008 and June 2018 were included. Visceral fat mass index (VFI) and subcutaneous fat mass index (SFI) were calculated by dividing the cross-sectional area at the umbilical level by the height squared. The medians of VFI and SFI by sex were defined as cut-off values, below which values were defined as low VFI and low SFI. Of the 485 patients, 323 (66.6%) were men and 162 (33.4%) were women. Men with a low VFI had a significantly worse overall survival (OS) (
= 0.004) and women with a low SFI had a significantly worse OS (
= 0.007). Patients with a low VFI and low SFI had the worst prognosis. Multivariate analysis showed that a low VFI was an independent poor prognostic factor in men, while a low SFI was an independent poor prognostic factor in women. In conclusion, a low visceral fat mass in men and a low subcutaneous fat mass in women were independent poor prognostic factors after radical gastrectomy for advanced gastric cancer.
This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) ...positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018-March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score CPS ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% 20/24) were PD-L1 positive than those with MSI-low/stable tumors (60.8% 216/355; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% 16/24) vs those with MSI-low/stable tumors (24.8% 88/355; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.
This study aimed to investigate the association of malnutrition, defined by the Global Leadership Initiative on Malnutrition (GLIM) according to preoperative chronic inflammation with long-term ...prognosis after gastrectomy in patients with advanced gastric cancer. We included patients with primary stage I-III gastric cancer who underwent gastrectomy between April 2008 and June 2018. Patients were categorized as normal, moderate malnutrition, and severe malnutrition. Preoperative chronic inflammation was defined as a C-reactive protein level of >0.5 mg/dL. The primary endpoint was overall survival (OS), compared between the inflammation and non-inflammation groups. Among the 457 patients, 74 (16.2%) and 383 (83.8%) were included in the inflammation and non-inflammation groups, respectively. The prevalence of malnutrition was similar in both groups (
= 0.208). Multivariate analyses for OS showed that moderate malnutrition (hazard ratios: 1.749, 95% concordance interval: 1.037-2.949,
= 0.036) and severe malnutrition (hazard ratios: 1.971, 95% CI: 1.130-3.439,
= 0.017) were poor prognostic factors in the non-inflammation group, but malnutrition was not a prognostic factor in the inflammation group. In conclusion, preoperative malnutrition was a poor prognostic factor in patients without inflammation, but it was not a prognostic factor in patients with inflammation.
Background
Adjuvant chemotherapy with XELOX (capecitabine plus oxaliplatin) has been shown to be beneficial following resection of gastric cancer in South Korean, Chinese, and Taiwanese patients. ...This phase II study (J-CLASSIC-PII) was undertaken to evaluate the feasibility of XELOX in Japanese patients with resected gastric cancer.
Methods
Patients with stage II or III gastric cancer who underwent curative D2 gastrectomy received adjuvant XELOX (eight 3-week cycles of oral capecitabine, 1000 mg/m
2
twice daily on days 1–14, plus intravenous oxaliplatin 130 mg/m
2
on day 1). The primary endpoint was dose intensity. Secondary endpoints were safety, proportion of patients completing treatment, and 1-year disease-free survival (DFS) rate.
Results
One hundred patients were enrolled, 76 of whom completed the study as planned. The mean dose intensity was 67.2 % (95 % CI, 61.9–72.5 %) for capecitabine and 73.4 % (95 % CI, 68.4–78.4 %) for oxaliplatin, which were higher than the predefined age-adjusted threshold values of 63.4 % and 69.4 %, respectively, and the study therefore met its primary endpoint. The 1-year DFS rate was 86 % (95 % CI, 77–91 %). No new safety signals were identified.
Conclusions
The feasibility of adjuvant XELOX in Japanese patients with resected gastric cancer is similar to that observed in South Korean, Chinese, and Taiwanese patients in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study. Based on findings from this study and the CLASSIC study, the XELOX regimen can be considered an adjuvant treatment option for Japanese gastric cancer patients who have undergone curative resection.
Esophageal basaloid squamous cell carcinoma (EBSCC) is a poorly differentiated variant of esophageal squamous cell carcinoma (ESCC). We aimed to investigate the clinicopathological and molecular ...biological characteristics of EBSCC and enrolled 58 patients with EBSCCs. Clinicopathological factors including age, sex, tumor size and location, gross tumor type (superficial, protrusive, ulcerative, and unclassifiable), lymphovascular invasion, infiltrative growth, intramural invasion, TNM stage, and dominant histological type were examined. EBSCCs were classified into four types (solid, cribri, microcystic, and tubular) according to the dominant histology. Next-generation sequencing (NGS) of a cancer hotspot panel was performed in 19 cases. NGS identified
TP53
as the most frequently mutated gene, and copy number variation analysis revealed the most frequent loss of heterozygosity (LOH) at the ataxia telangiectasia mutated (
ATM
) and retinoblastoma 1 (
RB1
) loci. Target sequencing for
TP53
was performed for the remaining 39 cases. We also performed LOH analysis for
TP53
,
ATM
, and
RB1
and immunohistochemical staining for p53, ATM, and Rb in all cases. The rates of
TP53
mutations and LOH and p53 aberrant expression were high (79.3%, 63.2%, and 72.4%, respectively); however, the frequencies were similar to those reported for ESCC. LOH rates of the
RB1
and
ATM
loci were also high (55.3% and 67.2%, respectively). Overall survival rate was 66.5%, and recurrence-free survival rate was 55.0%. Only conventional clinicopathological factors had a prognostic impact in EBSCC; the microcystic type had the poorest prognosis. Our findings could be useful in developing novel treatment strategies for EBSCC.
BackgroundThe development and progression of cancers are frequently promoted by immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) mediated by ...various immune checkpoint molecules. Recently, the immune checkpoint inhibitor anti-PD-1 neutralizing antibody has become available for the first-line treatment of gastric cancer (GC) in Japan. However, there is no correlation between PD-1 or PD-L1 expression in Tregs or GC tissues and clinical responses to anti-PD-1 antibody. MDSCs are immature myeloid cells thought to suppress immune cell action, but the functional cell surface markers that define MDSCs correlated with cancer progression have not yet been clarified well. In this study, we identified a new subset of potential diagnostic and therapeutic targets for MDSCs in GC patients.MethodsA total of 71 patients with GC who visited Juntendo University Hospital were included in the study. The study protocol was approved by the ethical committee of Juntendo University and written informed consent was obtained from all participants prior to enrolment. Flow cytometry was performed on fresh peripheral blood, using flow cytometer/cell sorter. For identification of circulating MDSCs, various fluorochrome-labeled antibodies to CD11b, CD14, CD33, HLA-DR, CD66b, PD-1 and PD-L1, and for T cell activation, antibodies to CD3, CD28, CD69, CD134 and CD137 were used.ResultsA significantly higher number of circulating monocytic-MDSCs and granulocytic-MDSCs (G-MDSCs) with CCR2 was detected in advanced GC patients (n=29, Stage III and IV) compared to early stage of GC donors (n=42, Stage I and II). We also found that significantly higher levels of PD-1 and PD-L1 were expressed on G-MDSCs (Lin-/HLA-DR-/CD33+/CD66b++) from advanced than early-stage of GC patients. With the intent to identify the immunosuppressive function of PD-1 on G-MDSCs, isolated G-MDSCs pretreated with anti-PD-1 were mixed with CD3/CD28-activated T cells in vitro. Interestingly, both CD4 and CD8 T cell responses were ameliorated only in the pretreatment of G-MDSCs but not to T cells. We also found that immunosuppressive potential of G-MDSCs in GC patients was attenuated 3 weeks after anti-PD-1 Ab therapy.ConclusionsThe result of this pilot study, limited by the patient number, shows a clear increase in peripheral G-MDSCs expressing functional PD-1 in advanced GC patients. Although needed to be confirmed in the relationship between PD-1 on G-MDSCs and the duration of time of anti-PD-1 Ab therapy, these data suggest a novel subset of G-MDSCs expressing PD-1 found in advanced GC could be diagnostic and therapeutic targets.Ethics ApprovalPatients with gastric cancer who visited Juntendo University Hospital (Tokyo, Japan) were included in the study. The study protocol was approved by the ethical committee of Juntendo University and written informed consent was obtained from all participants prior to enrolment.
Gastrointestinal stromal tumors (GISTs) are typically characterized by activating mutations of the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha ...(PDGFRA). Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type GIST. We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases, and all pan-trk positive cases showed diffuse and strong expression of c-kit. Interestingly, all of these cases showed only trkB but not trkA/trkC expression. Cap analysis of gene expression (CAGE) analysis identified increased number of genes whose promoters were activated in pan-trk/trkB positive GISTs. Imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in any of trkB positive GISTs, despite higher mRNA expression. TrkB expression was found in duodenal GISTs and more than half of small intestinal GISTs, and this subset of cases showed poor prognosis. However, there was not clear difference in clinical outcomes according to the trkB expression status in small intestinal GISTs. These findings may provide a possible hypothesis for trkB overexpression contributing to the tumorigenesis and aggressive clinical outcome in GISTs of duodenal origin.
A 33-year-old woman with the complaint of hematochezia was transferred to our hospital. Contrast-enhanced abdominal computed tomography revealed active intestinal bleeding. After stabilization of the ...hemodynamic status, abdominal angiographic examination was performed, which revealed jejunal bleeding. We controlled the bleeding by N-butyl-2-cyanoacrylate (NBCA) and lipiodol embolization. However, rebleeding was noted 14 days later, and we performed single-incision laparoscopic surgery. Intraoperative examination revealed localized jejunal ecchymoses caused by the NBCA embolization. Partial resection of the jejunum was performed, followed by functional end-to-end anastomosis. The patient’s postoperative course was uneventful, and she was discharged 9 days post-surgery. Postoperative histopathological examination revealed an intestinal arteriovenous malformation (AVM). Single-incision laparoscopic surgery could be a feasible minimally invasive treatment option for intestinal AVMs.
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