In this study, we aimed to investigate the effects of curcumin on cell activities of gastric cancer (GC), and the connection between curcumin and P53, as well as, PI3K signaling. This study was ...conducted with two cell lines SGC‐7901 and BGC‐823, both were exposed to curcumin at the concentrations of 0, 10, 20, and 40 μm. MTT assay, flow cytometry (FCM) assay, transmission electron microscopy (TEM) were used to study the underlying mechanisms of curcumin in respective of proliferation, apoptosis, and autophagy. Western blot assay was also employed to detect impacts of curcumin on tophosphatidylinositol‐3 kinase (PI3K) and P53 signaling pathways‐related proteins. MTT assay displayed that curcumin inhibited GC cell proliferation. FCM results indicated that curcumin induced the apoptosis of GC cells. TEM revealed that curcumin induced autophagy in GC cells. Western blot results showed that curcumin activated P53 signaling pathway and inhibited PI3K signaling pathway. Curcumin may inhibit proliferation and induce the autophagy and apoptosis in GC cells. Additionally, curcumin activated the P53 signaling pathway by up‐regulating P53 and P21, which also inhibited PI3K pathway through down‐regulating PI3K, p‐Akt, and p‐mTOR.
Curcumin may inhibit proliferation and induce the autophagy and apoptosis in GC cells. Additionally, curcumin activated the P53 signaling pathway by up‐regulating P53 and P21, which also inhibited PI3K pathway through down‐regulating PI3K, p‐Akt, and p‐mTOR.
Clinicopathological and molecular features of responders to nivolumab for advanced gastric cancer (AGC) are not well understood.
Patients (pts) with AGC who were treated with nivolumab after two or ...more chemotherapy regimens in a single institution from September 2017 to May 2018 were enrolled in this study. PD-L1 expression in tumor cells (TC) and mismatch repair (MMR) were analyzed by immunohistochemistry. Epstein-Barr virus (EBV) was detected by in situ hybridization. Cancer genome alterations were evaluated by a next-generation sequencing-based panel. High tumor mutation burden (TMB) was defined as more than 10 mutations/megabase.
A total of 80 pts were analyzed in this study. Tumor response was evaluated in 72 pts with measurable lesions and 14 pts (19%) had an objective response. Overall response rate (ORR) was significantly higher in pts with ECOGPS 0 in those with PS 1 or 2, MMR-deficient (MMR-D) in those with MMR-proficient (MMR-P), PD-L1+ in TC in those with PD-L1- in TC and PIK3CA mutation in those with PIK3CA wild-type. ORR was 31% in pts with at least one of the following factors; MMR-D, high TMB, EBV+ and PD-L1+ in TC vs. 0% in those without these factors. Progression-free survival was significantly longer in pts with PS 0 than in those with PS 1 or 2, MMR-D than in those with MMR-P, and PD-L1+ in TC than in those with PD-L1- in TC.
Some features were associated with favorable response to nivolumab for AGC. Combining these features might be useful to predict efficacy.
Surgery plays a critical role in the management of all stages of gastric cancer.
For patients with early gastric cancer and low risk of lymph node metastasis, endoscopic therapy or surgery alone is ...potentially curative. Novel techniques, such as sentinel lymph node biopsy, may allow for greater use of stomach-sparing procedures that could improve quality of life without compromising oncologic outcomes; however, experience with these techniques is rare outside of East Asia, and studies of long-term outcomes are still ongoing. Patients with later-stage localized gastric cancer benefit from more extensive lymphadenectomy and multimodality therapy, as they are at risk for nodal and distant metastases. There have been recent advances in chemotherapy that have led to improved survival, but the optimal sequencing of multimodality therapy is still being investigated. Better systemic therapy may also increase the role of surgery for patients with oligometastatic disease. There are ongoing studies examining the efficacy of peritoneal-directed therapies in both patients with low-volume peritoneal disease and patients at high risk of peritoneal recurrence.
The management of gastric cancer continues to evolve. Surgeons should be aware of novel surgical approaches currently under investigation as well as how surgery fits into the contemporary multidisciplinary approach to this disease.
FGFR2 gene amplification, and resulting FGFR2 protein overexpression, is rare in gastric cancer patients, and development of an accurate and widely available method for mass screening to identify ...patients who may respond to treatment with fibroblast growth factor receptor (FGFR) inhibitors is important. We first screened 312 gastric cancer patients with known copy number variations by FGFR2b immunohistochemistry using FPR2-D, an isoform-specific antibody. Next, we performed immunohistochemistry on tissue microarrays from 1574 gastric cancer patients. Selected cases were analyzed for FGFR2 amplification by FISH. In addition, FGFR2b overexpression was studied in 88 matched primary and metastatic gastric cancers. In the first cohort, FGFR2b immunohistochemistry results correlated very well with those of copy number variation (r=0.79) and FISH (r=1.0). In total, FGFR2b overexpression was identified in 73 of 1974 gastric cancers (4%). The concordance between immunohistochemistry and FISH was extremely high; all 2+ and 3+ cases identified by immunohistochemistry were FGFR2 amplified. In the matched primary and metastatic gastric cancer pairs, the positivity and percentage of positive tumor cells were significantly higher in metastatic gastric cancers than in primary gastric cancers (8% vs 3% and 75% vs 47%, respectively; P<0.001). FGFR2b overexpression was significantly more frequent in gastric cancers with diffuse subtype (P=0.01) and higher N stage (P=0.006). FGFR2b overexpression with H-score ≥150 were independent prognostic factors for overall survival with hazard ratio of 1.836 (95% confidence interval, 1.034–3.261; P=0.038). FGFR2b positivity in immunohistochemistry was strongly correlated with FGFR2 amplification. Given the low frequency of FGFR2 amplification in gastric cancers, FGFRb2 immunohistochemistry is an accurate screening tool to detect FGFR2 amplification, and both primary and metastatic gastric cancer tissues should be tested to select gastric cancer patients for treatment with FGFR2 inhibitors.
Highlights • G3 GEP NECs are more heterogeneous than expected according to WHO classification. • 6 studies investigating large series of G3 GEP-NECs have been published. • Tumor morphology and Ki-67 ...emerged as potential prognostic factors. • This has important prognostic and therapeutic implications.
Abstract Aim To evaluate the clinical significance of intratumoral HER2 heterogeneity in gastric cancer (GC). Methods A total of 322 GC tissues were evaluated by HER2 immunohistochemistry (IHC), of ...which 73 with IHC 2+ or 3+ were subjected to fluorescence in situ hybridisation (FISH). Also, 3–5 distinct spots in each case showing different HER2 staining intensities were evaluated individually by comparing IHC staining intensity with gene copy number (GCN). Minimum, average and maximum FISH scores were generated for each case. Results Intratumoral heterogeneity of HER2 overexpression and gene amplification were 54 and 30 of 73 cases with IHC 2+ or 3+, respectively. These cases were characterised by diffuse or mixed Lauren type, HER2 IHC 2+, and low-level amplification. Kaplan–Meier survival analysis revealed that the heterogeneous overexpression was significantly associated with longer disease-free survival times than the homogeneous, and the high average GCN was most associated with poor outcome. Also, there was a strong correlation between the IHC and FISH results for each spot. Quantitative polymerase chain reaction (PCR) analysis of the cancer tissues and the cell-free plasma showed that HER2 gene copy by quantitative PCR on tissue correlated well with those by FISH, but plasma HER2 level was not. Conclusions Considering the high incidence of intratumoral HER2 heterogeneity in GC, accurate HER2 assessment would require larger tissues and more detailed guidelines. The guidelines should include the recommendation that FISH-scoring areas be selected with reference to a corresponding IHC slide. Also, the definition of HER2-positive tumours should be reassessed considering the intratumoral heterogeneity.
GEP-NENs are rare malignancies with increasing incidence. Their molecular characteristics are still undefined. We explored the underlying biology of GEP-NENs and the differences between ...gastrointestinal (GI) and pancreatic (PNEN), high-grade (HG), and low-grade (LG) tumors.
GEP-NENs were analyzed using next-generation sequencing (NGS; MiSeq on 47 genes, NextSeq on 592 genes), IHC, and
hybridization. Tumor mutational burden (TMB) was calculated on the basis of somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci.
In total, 724 GEP-NENs were examined: GI (
= 469), PNEN (
= 255), HG (
= 135), and LG (
= 335). Forty-nine percent were female, and median age was 59. Among LG tumors, the most frequently mutated genes were
(13%),
(10%), and
(10%). HG tumors showed
(51%),
(30%),
(27%), and
(23%). Immune-related biomarkers yielded a lower prevalence in LG tumors compared with HG MSI-H 0% vs. 4% (
= 0.04), PD-L1 overexpression 1% vs. 6% (
= 0.03), TMB-high 1% vs. 7% (
= 0.05). Compared with LG, HG NENs showed a higher mutation rate in
(5.4% vs. 0%,
< 0.0001),
(29.4% vs. 2.6%,
< 0.0001), and
(7% vs. 0.3%,
< 0.0001). When compared with GI, PNEN carried higher frequency of
(25.9% vs. 0.0%,
< 0.0001),
(8.6% vs. 0.8%,
= 0.005),
(20.6% vs. 2.0%,
= 0.007), and
(6.3% vs. 0.0%,
= 0.007), but lower frequency of mutations in
(1.0% vs. 13.8%,
< 0.0001).
Significant molecular differences were observed in GEP-NENs by tumor location and grade, indicating differences in carcinogenic pathways and biology.
Abstract ORAI calcium release-activated calcium modulator 1 (Orai1)- and stromal interacting molecule 1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) have been increasingly implicated in tumor ...progression; however, its role in gastric cancer (GC) is not well elucidated. We aimed to determine whether SOCE influences GC prognosis and elucidate the underlying mechanisms. Orai1 and STIM1 expressions were higher in GC tissues compared to adjacent non-tumor tissues according to RT-PCR and western blotting. Higher Orai1 and/or STIM1 expression was associated with more advanced disease, more frequent recurrence, and higher mortality rates in our study of 327 GC patients. The disease-free survival rates of Stage I-III patients and the overall survival rates of Stage IV patients were significantly worse when the tumors had high Orai1 and/or STIM1 expressions. Orai1 and/or STIM1 knockdown caused significantly reduced tumor growth and metastasis in athymic mice. Orai1 and/or STIM1 knockdown produced less proliferation, migration, and invasion of two GC cell lines. Also, Orai1 and/or STIM1 knockdown changed the markers of the cell cycle and epithelial-mesenchymal transition (EMT). These effects were reversed by metastasis-associated in colon cancer-1 (MACC1) overexpression. In summary, the composite molecules of SOCE suggest a poor prognosis for GC by promoting tumor cell proliferation, migration, and invasion by targeting MACC1.
CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level ...of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38
MAPK, a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21
CIP1/WAF1. These findings establish a function for CD44v in regulation of ROS defense and tumor growth.
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► CD44v contributes to the reduction of intracellular reactive oxygen species ► CD44v promotes GSH synthesis by interacting with glutamate-cystine transporter xCT ► Variant 8–10 region is required for CD44v-xCT interaction leading to GSH synthesis ► xCT inhibitor sulfasalazine suppresses CD44-dependent cancer cell expansion in vivo
To describe disease characteristics and treatment modalities in a group of rare patients with metastatic gastric carcinoid type 1 (GCA1).
Information on clinical, biochemical, radiological, ...histopathological findings, the extent of the disease, as well as the use of different therapeutic modalities and the long-term outcome were recorded. Patients' data were assessed at presentation, and thereafter at 6 to 12 monthly intervals both clinically and biochemically, but also endoscopically and histopathologically. Patients were evaluated for the presence of specific symptoms; the presence of autoimmune disorders and the presence of other gastrointestinal malignancies in other family members were also recorded. The evaluation of response to treatment was defined using established WHO criteria.
We studied twenty consecutive patients with a mean age of 55.1 years. The mean follow-up period was 83 mo. Twelve patients had regional lymph node metastases and 8 patients had liver metastases. The primary tumor mean diameter was 20.13 ± 10.83 mm (mean ± SD). The mean Ki-67 index was 6.8% ± 11.2%. All but one patient underwent endoscopic or surgical excision of the tumor. The disease was stable in all but 3 patients who had progressive liver disease. All patients remained alive during the follow-up period.
Metastatic GCA1 carries a good overall prognosis, being related to a tumor size of ≥ 1 cm, an elevated Ki-67 index and high serum gastrin levels.
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