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.
Background
Although primary (PGC) and remnant gastric cancers (RGC) both originate from the same gastrointestinal organ, they have very distinct clinicopathological behaviors. We hypothesized that ...there would be distinct differences in DNA methylation patterns that would occur during carcinogenesis of RGC and PGC, and that the differences in methylation patterns may help identify the primary factor contributing to chronic inflammation in patients with RGC.
Methods
We investigated the genome-wide DNA methylation patterns of PGC and RGC tissues from 48 patients using the Infinium HumanMethylation450 Beadchip assay. The results were validated by quantitative methylation-specific PCR (qMSP) in separate, independent cohorts.
Results
We found that in our training cohort of 48 patients, the most variable genes from the gastric cancer tissues identified by the Infinium HumanMethylation450 Beadchip clustered the resultant heatmap into high and low methylation groups. On multivariate analysis, PGCs contributed significantly to the high methylation group (
p
= 0.004, OR 12.33), which suggested that the promoter methylation status in PGC is higher than that in RGC. Supporting this conclusion was the finding that in a separate qMSP analysis in a test cohort, the EPB41L3 gene, chosen because of its high β value on microarray analysis in the gastric cancer tissues, had significantly higher DNA promoter methylation in cancer tissues in the validation PGC tissues than in RGC.
Conclusions
This study demonstrated that promoter methylation status in PGC is higher than in RGC. This result may reflect the effects of the absence of
Helicobacter pylori
on the reduced DNA methylation in the remnant stomach.
Children born to women who experience stress during pregnancy have an increased risk of atherosclerosis in later life, but few animal models have explored mechanisms. To study this phenomenon, ...timed-bred ApoE knockout mice were determined pregnant with ultrasound and randomly assigned on
to either a control (no stress) or prenatal stress (PS) group using 2 h of restraint for five consecutive days. PS significantly increased plasma corticosterone levels in pregnant mice. The litters from PS mice showed increased neonatal mortality within the first week of life. Body weights (at euthanasia) of adult offspring at 25 wk from the PS group were significantly increased compared with weights of controls. Adult offspring from these pregnancies were serially imaged with ultrasound to measure plaque thickness and were compared with plaque macroscopic and microscopic pathology. PS groups had increased plaque thickness determined by ultrasound, gross, histological evaluation and increased aortic root and valve macrophage infiltration at 25 wk. Five-week-old mice from PS group had significant decrease in mean arterial pressure, yet blood pressure normalized by 10 wk. As prenatal stress induced increased atherosclerosis, and telomeres are susceptible to stress, aortas from 10-wk-old mice were compared for telomere lengths and were found to be significantly shorter in PS mice compared with control mice. These studies support future investigation of how stress impacts telomere shortening in animal models and human aortas. This model could be further used to investigate the role of prenatal stress, telomere biology, and atherosclerosis pathogenesis in adults.
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.
Background Postoperative pyoderma gangrenosum (PPG) is a rare inflammatory skin disease of unknown etiology characterized by blistering and ulcerative lesions in postoperative wounds. Untreated ...pyoderma gangrenosum (PG) is potentially life-threatening; therefore, immediate and appropriate treatment is essential. Although PPG and surgical site infection (SSI) present similar clinical findings, they should be differentiated because of their conflicting treatment modalities.Case presentation An 82-year-old man with comorbidities of pulmonary tuberculosis, chronic obstructive pulmonary disease, and diabetes underwent laparoscopic gastrectomy for gastric cancer. On postoperative day 6, fever exceeding 39°C, port wound redness, and pain was observed. Laboratory tests revealed severe inflammatory reactions: white blood cell, 42,800/μL and C-reactive protein, 30.2 mg/mL. The patient was diagnosed with SSI and treatment with antibiotics and drainage was started; however, his general and wound conditions also worsened. Therefore, he was diagnosed with PG because painful skin findings were exacerbated by external stimuli and no significant bacteria were detected in the culture test. Treatment with oral prednisolone was started, which significantly improved his skin and inflammatory conditions.Conclusion We managed a rare case of PPG that occurred in a port wound after laparoscopic gastrectomy. If atypical clinical findings of postoperative SSI are observed, general surgeons should recognize and consider PPG as a differential diagnosis.
This book, Gastric Cancer - An Update, is a collection of reviewed and relevant research chapters, offering a comprehensive overview of recent developments in the field of gastric cancer. The book is ...comprised of single chapters authored by various researchers and it is edited by experts active in this field of study. All chapters are complete in itself but united under a common research topic. This publication aims at providing a thorough overview of the latest research efforts by international authors on gastric cancer, and opening new possible research paths for further novel developments.
Agenesis of the left hepatic lobe is an exceedingly rare morphological anomaly. Moreover, agenesis of the left hepatic lobe accompanied by esophagogastric cancer is even rarer, with no reports to ...date. Agenesis of the hepatic lobe is commonly related to some anatomical variations of the gastrohepatic system. A 76-year-old man was referred to our hospital for surgery for esophagogastric cancer with short Barrett's esophagus. Multiple preoperative imaging modalities revealed agenesis of the left hepatic lobe accompanied by esophagogastric cancer. Robotic proximal gastrectomy and transhiatal lower esophagectomy were performed. Intraoperative findings showed agenesis of the left hepatic lobe. The patient's postoperative course was favorable. Today, 16 months after surgery, the patient is alive without recurrence of esophagogastric cancer. We report a case of agenesis of the left hepatic lobe in a patient undergoing robotic proximal gastrectomy and transhiatal lower esophagectomy for esophagogastric cancer. Preoperative comprehension of various visceral anomalies reduces the risk of surgical complications.
Abstract
Children born to women who experience stress during pregnancy have an increased risk of cancer in later life, but no previous animal studies have tested such a link. We questioned whether ...prenatal stress (PS) in A/J mice affected the development of lung tumors after postnatal response to tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Timed-bred A/J mice were randomly assigned on gestation day 12.5 to PS by restraint for 5 consecutive days or control (no restraint). Adult offspring of control and stressed pregnancies were all treated with three NNK injections (50 mg/kg every other day) and euthanized 16 weeks later to examine their lungs. Compared with controls, PS dams exhibited significantly increased levels of plasma corticosterone, increased adrenal weights and decreased fetus weights without fetal loss. Prenatally stressed litters had a significantly higher neonatal death rate within first week of life, and surviving male and female offspring developed lung epithelial proliferations with increase multiplicity, increased area and aggressive morphology. PS also induced more advanced atypical adenomatous hyperplasia lesions. We found no difference in lung NNK-derived methyl DNA adducts, but PS did significantly enhance CD3+ T cell and Foxp3+ T cell tumor infiltration. PS significantly increases multiplicity, area of NNK-induced lung tumors and advanced morphology. PS did not affect production of NNK-derived methyl DNA adducts but did increase lymphocytic infiltration of lung tumors. To our knowledge, this is the first animal model of PS with evaluation of cancer development in offspring.
PS significantly increases offspring NNK-induced lung tumor area, multiplicity, with more CD3+ and Foxp3+ T-cell infiltration compared with control mice. To our knowledge, this is the first animal model of PS with evaluation of carcinogenesis in offspring.
Fatty acid synthase (FAS) is overexpressed in lung cancer, and we have investigated the potential use of FAS inhibitors for chemoprevention of lung cancer.
Expression of FAS was evaluated in ...preinvasive human lung lesions (bronchial squamous dysplasia and atypical adenomatous hyperplasia) and in murine models of lung tumorigenesis 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone-induced and urethane-induced lung tumors in A/J mice. Then, the ability of pharmacologic inhibitors of FAS to prevent development of the murine tumors was investigated. Finally, the effect of the FAS inhibitor treatment of levels of phosphorylated Akt in the murine tumors was evaluated by immunohistochemistry.
Immunohistochemical studies show that human bronchial dysplasia and atypical adenomatous hyperplasia express high levels of FAS compared with normal lung tissues, suggesting that FAS might be a target for intervention in lung carcinogenesis. FAS is also expressed at high levels in chemically induced murine lung tumors, and the numbers and sizes of those murine tumors are significantly reduced by treating carcinogen-exposed mice with pharmacologic inhibitors of FAS, C75 and C93. C93 treatment is associated with reduced levels of phosphorylated Akt in tumor tissues, suggesting that inhibition of this signal transduction pathway might be involved in the chemopreventative activity of this compound.
We conclude that increased levels of FAS are common in human preinvasive neoplasia of the lung. Based on studies in mouse models, it seems that inhibiting FAS is an effective strategy in preventing and retarding growth of lung tumors that have high expression of this enzyme.
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