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Background: Systemic inflammation has been reported to be associated with cancer progression and metastasis. Systemic inflammation score (SIS), calculated from preoperative serum albumin level and lymphocyte-to-monocyte ratio, has been shown to be a novel prognostic factor for several types of tumors. This study aimed to evaluate the prognostic value of the SIS in patients with pT2–4 resectable gastric cancer (GC). Methods: Total 97 patients with pT2–4 GC who underwent curative surgery from 322 cases between 2009 and 2015 in Fukushima Medical University Hospital were included. We performed univariate and multivariate analyses to evaluate the usefulness of preoperative SIS and other prognostic factors for relapse-free survival (RFS) and overall survival (OS). Results: The higher SIS score was associated with undifferentiated cancer and recurrence. Univariate analysis of RFS identified deeper tumor invasion and higher SIS were significant risk factors and multivariate analysis revealed that both of them were independent prognostic factors for RFS. As for OS, age, tumor invasion, SIS and LNR were significantly correlated with RFS. In multivariate analysis, tumor invasion, SIS and LNR were independent prognostic factors for OS. Conclusions: SIS was an independent prognostic factor for RFS and OS in pT2–4 resectable gastric cancer patients who underwent curative gastrectomy. [ABSTRACT FROM AUTHOR]

Deficient mismatch repair (dMMR)/microsatellite instability (MSI) colorectal cancer (CRC) has high immunogenicity and better prognosis compared with proficient MMR (pMMR)/microsatellite stable (MSS) CRC. Although the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered to contribute to the high number of CD8+ TILs, its role in dMMR/MSI CRC is largely unknown. In this study, to examine the role of the cGAS-STING pathway on the recruitment of CD8+ TILs in dMMR/MSI CRC, we used public datasets and clinical tissue samples in our cohorts to evaluate the expression of cGAS, STING, and CD8+ TILs in pMMR/MSS and dMMR/MSI CRCs. According to the analysis of public datasets, the expression of cGAS-STING, CD8 effector gene signature, and CXCL10-CCL5, chemoattractants for CD8+ TILs which regulated by the cGAS-STING pathway, was significantly upregulated in dMMR/MSI CRC, and the expression of cGAS-STING was significantly associated with the expression of CD8 effector gene signature. Immunohistochemistry staining of the clinical tissue samples (n = 283) revealed that cGAS-STING was highly expressed in tumor cells of dMMR CRC, and higher expression of cGAS-STING in tumor cells was significantly associated with the increased number of CD8+ TILs. Moreover, we demonstrated that the downregulation of MMR gene in human CRC cell lines enhanced the activation of the cGAS-STING pathway. Taken together, for the first time, we found that dMMR/MSI CRC has maintained a high level of cGAS-STING expression in tumor cells, which might contribute to abundant CD8+ TILs and immune-active TME. [ABSTRACT FROM AUTHOR]

Background: Circulating tumor cells (CTCs) are known to be a systemic process of malignant progression of cancer cells and there is a possibility that analysis for CTCs as a liquid biopsy become predictive or prognostic tools for cancer patients. Methods: In the present study with the novel CTCs detection system (Celsee system®), we performed quantitative and qualitative analysis of CTCs in patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemotherapy (NAC) with 5FU + CDDP regimen. CTCs are defined as having both DAPI positive and CD45 negative. Vimentin-positive CTCs were defined as mesenchymal-type CTCs (M-CTCs), while epithelial-type CTCs (E-CTCs) were only positive for pan-cytokeratin. Results: At the baseline, there are detectable amounts of CTCs in all patients (n = 30) at all stages, and there were no significant differences of total CTCs, E-CTCs, or M-CTCs numbers between stages. Of importance, among total CTCs, M-CTCs are more dominant than E-CTCs in number. Also, there was no significant change of detectable amounts and phenotype of CTCs before and after NAC (n = 24). Of note, early recurrent group indicated that there was an elevated total CTCs number before NAC and an increased M-CTCs after NAC in comparison to those in non-recurrent group. Conclusions: Quantitative and qualitative analysis of CTCs may provide useful complementary predictive and prognostic information in ESCC. [ABSTRACT FROM AUTHOR]

Background: Although immunotherapy with immune checkpoint inhibitors (ICIs) has become a standard therapeutic strategy in colorectal cancer (CRC) exhibiting microsatellite instability-high, limited patients benefit from this new approach. To increase the efficacy of ICIs in CRC patients, it is crucial to control the function of immunosuppressive cells in the tumor microenvironment. M2-tumor-associated macrophages (TAMs) are key immunosuppressive cells and promote tumor growth, angiogenesis, and epithelial-mesenchymal transition. In the present study, we focused on the VEGF signaling pathway in M2-TAMs to control their inhibitory function. Methods: We evaluated the population of M2-TAMs, the VEGF receptor 2 (VEGFR2) expression on M2-TAMs, and the correlation between HIF-1α-positive cells and VEGFR2 expression levels on M2-TAMs in CRC using the analysis of The Cancer Genome Atlas colorectal adenocarcinoma dataset (n = 592), the flow cytometry of freshly resected surgical specimens of CRC (n = 20), and the immunofluorescence staining of formalin-fixed paraffin-embedded whole tissue samples of CRC (n = 20). Furthermore, we performed a functional assay of M2 macrophages through the VEGF/VEGFR2 signaling pathway in vitro. Results: The population of M2-TAMs and their VEGFR2 expression significantly increased in the tumor compared to the normal mucosa in the CRC patients. HIF1-α-positive cells significantly correlated with the VEGFR2 expression level of M2-TAMs. M2 macrophages induced by cytokines in vitro produced TGF-β1 through the VEGF/VEGFR2 signaling pathway. Conclusions: Our results suggest that anti-VEGFR2 therapy may have therapeutic potential to control the immune inhibitory functions of M2-TAMs in CRC, resulting in enhanced efficacy of immunotherapy with ICIs. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus-positive gastric cancer [EBV (+) GC] is a distinct GC subtype with unique genetic and epigenetic aberrations. Here, we examined resected GC samples and publicly available microarray data and The Cancer Genome Atlas (TCGA) database to identify the mechanism underlying overexpression of PD-L1 in EBV (+) GC. We found that high levels of PD-L1 overexpression in EBV (+) GC were caused by focal amplification of CD274. By contrast, relatively high expression of PD-L1 in tumor tissue and infiltrating immune cells correlated with CD8 lymphocyte infiltration and IFN-γ expression via IRF3 activation. Since we reported previously that PD-L1 expression is associated both with the presence of CD8 T cells in the tumor microenvironment and with IFN-γ expression in GC, we examined a database to see whether IFN-γ-associated overexpression of PD-L1 plays a significant role in EBV (+) GC. Immunohistochemical staining showed that expression of the IRF3 signature in clinical GC samples was higher in EBV (+) than in EBV (−) cases. The data presented herein reveal a unique dual mechanism underlying PD-L1 overexpression in EBV (+) GC: high focal amplification of CD274 or IFN-γ-mediated signaling via activation of IRF3. [ABSTRACT FROM AUTHOR]

Background: AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene that is frequently mutated in gastric cancer (GC). Although ARID1A mutations are not a druggable target for conventional treatments, novel therapeutic strategies based on a synthetic lethal approach are effective for ARID1A-deficient cancers. The histone methyltransferase EZH2 acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer, although its role in GC remains unknown. Methods: The selective sensitivity of the EZH2 inhibitors for ARID1A-deficient GC cells was evaluated using cell viability and colony formation assays. The expression of PI3K/AKT signaling genes were investigated using TCGA's cBioPortal database to determine whether the homeostasis between ARID1A and EZH2 is related to cell proliferation and survival via the PI3K/AKT signaling pathway. We also evaluated the phosphorylation of PI3K/AKT signaling proteins in ARID1A knock downed ARID1A-WT GC cells. Results: EZH2 inhibitors decreased the viability of ARID1A-deficient cells in a dose-dependent manner and demonstrated the selective sensitivity to ARID1A-deficient cells in vitro experiment system. Bioinformatics approach revealed that the PI3K/AKT signaling was tended to be activated in ARID1A-deficient GC enhancing cell viability and, furthermore, down-regulation of EZH2 in ARID1A-deficient GC was related to normalization of PI3K/AKT signaling pathway. The cell experiment revealed that phosphorylated AKT was upregulated in ARID1A-deficent GC cells. Conclusions: The present findings provide a rationale for the selective sensitivity of EZH2 inhibitors against ARID1A-deficient GC and suggest the potential efficacy of targeted therapy using EZH2 inhibitors in this patient population. [ABSTRACT FROM AUTHOR]

AT-rich interactive domain 1A (ARID1A), which is a tumor suppressor gene, is frequently mutated in Epstein-Barr virus-positive gastric cancer [EBV (+) GC]. While most ARID1A mutations in GC are truncating mutations, leading to loss of ARID1A protein expression, epigenetic modifications appear to contribute to ARID1A deficiency in EBV (+) GC harboring wild-type ARID1A. Based on the significant role of epigenetic modifications in EBV (+) GC that contributes to ARID1A deficiency, the methylation status of ARID1A was evaluated in EBV-infected cells and GC patients using a publicly available microarray and the Cancer Genome Atlas (TCGA) database. EBV-encoded miRNAs that potentially target ARID1A were identified as an additional epigenetic modulator by computational prediction. In vitro experiments were conducted to evaluate how EBV-encoded miRNAs affected ARID1A mRNA and protein levels. In clinical GC samples, the expression of predicted miRNAs and ARID1A and the mutation status of ARID1A was evaluated. As results, ARID1A was not hypermethylated in EBV (+) GC samples or EBV-infected GC cells. EBV infection did not alter ARID1A mRNA levels, suggesting that ARID1A protein deficiency was caused by post-transcriptional gene silencing in ARID1A -WT EBV (+) GC. Overexpression of miR-BART11-3p and miR-BART12, which were identified as miRNAs that potentially bind ARID1A , suppressed ARID1A protein expression in MKN7 and NCI-N87 cells. Highly expressed miR-BART11-3p and miR-BART12 were correlated with decreased ARID1A levels in GC tumors which did not harbor ARID1A mutations. The present findings revealed that ARID1A expression was epigenetically regulated by miR-BART11-3p and miR-BART12 in EBV (+) GC. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) patients with PD-L1-negative tumor occasionally have a favorable response to anti-PD-1 mAb. The aim of the present study was to investigate the regulatory mechanism and immunosuppressive role of PD-L2 in GC. Methods: We used immunohistochemistry to evaluate the expression of PD-L2 in primary tumors from 194 patients with GC. The mechanism of PD-L2 expression was assessed in TCGA stomach adenocarcinoma tissue dataset and in vitro assay using GC cell lines. The immunosuppressive role of PD-L2 was evaluated by cytotoxicity of CTL clone against PD-L2 expressing GC cells. Results: PD-L2 was expressed on tumor cells (TCs) of 28.4% patients and PD-L2 expression on TCs was significantly associated with tumor progression. TCGA dataset revealed that IFN-γ and, to a lesser extent, IL-4 signature significantly correlated with PD-L2 expression. In vitro assay showed that IFN-γ and, also to a lesser extent, IL-4 can upregulate PD-L2 expression on GC cells. Anti-PD-L2 mAb significantly enhanced the cytotoxicity of CTL clone against GC cell lines expressing PD-L2. Conclusions: PD-L2 is expressed on GC cells and PD-1/PD-L2 interaction are functionally involved in anti-tumor CTL activities. PD-L2 expression should be considered when determining the optimal immunotherapy for GC. [ABSTRACT FROM AUTHOR]

Background: Gastric hamartomatous inverted polyp (GHIP) is a pathological condition where enlarged gastric glands with cystic dilatation grow in the submucosa. It is difficult to excise the tissue due to its location. In addition, even if the tissue is taken correctly, making an accurate diagnosis is difficult due to foveolar epithelium in the tissue, which can be misdiagnosed as gastric mucosal epithelium. Thus, an accurate diagnosis of GHIP is rarely established from a biopsy alone preoperatively. We here report a case of GHIP with a central dimple, which was diagnosed and treated using a modified combination of laparoscopic and endoscopic approaches to neoplasia with a non-exposure technique (modified CLEAN-NET). Case presentation: A 60-year-old man with a submucosal tumor (SMT) in the stomach was referred to our hospital by a primary care doctor. On examination, a gastrointestinal stromal tumor was suspected. Modified CLEAN-NET was performed for diagnostic and therapeutic purposes. The histopathological examination of the resected specimen showed an enlarged gland duct in the submucosal layer. This finding, along with immunostaining results, led to the diagnosis of GHIP. The postoperative course was uneventful without any symptoms. Conclusions: GHIP should be considered among the differential diagnoses of SMT of the stomach. Modified CLEAN-NET may be beneficial in the removal of SMTs such as GHIP with a central dimple because it can avoid stomach deformation of the stomach and tumor dissemination. [ABSTRACT FROM AUTHOR]

Adjuvant chemotherapy is considered for patients with stage II colorectal cancer (CRC) characterized by poor prognostic clinicopathological features; however, current stratification algorithms remain inadequate for identifying high-risk patients. To develop prognostic assays, we conducted a step-wise screening and validation strategy using nine cohorts of stage II patients based on multiple platforms, including microarray, RNA-sequencing (RNA-seq) and immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) tissues. Four microarray datasets (total n = 458) were used as the discovery set to screen for single genes associated with postoperative recurrence. Prognostic values of candidate genes were evaluated in three independent microarray/RNA-seq validation cohorts (n = 89, n = 93 and n = 183, respectively), and then IHC for KRT17 was conducted in two independent FFPE series (n = 110 and n = 44, respectively). We found that high levels of KRT17 transcript expression were significantly associated with poor relapse-free survival (RFS) not only in the discovery set, but also in three validation cohorts, and its prognostic impact was independent of conventional factors by multivariate analyses. Positive staining of KRT17 protein was significantly associated with poor RFS in two independent FFPE cohorts. KRT17 protein expression had independent prognostic impact on RFS in a multivariate model adjusted for conventional variables, including high-risk clinicopathological features. In conclusion, using nine independent cohorts consisting of 997 stage II patients, we identified and validated the expression of KRT17 transcript and KRT17 protein as a robust prognostic biomarker that can discriminate postoperative stage II patients who are at high probability of disease recurrence, providing additional prognostic stratification beyond the currently available high-risk factors. [ABSTRACT FROM AUTHOR]

Background: Several articles have recently reported that certain colon microbiota can improve the efficacy of cancer immunotherapy. To develop new treatment strategies, including immunotherapy for colorectal cancer (CRC), we evaluated the correlations between subpopulations of tumor-infiltrating immune cells (TIICs) and intestinal microbiota in CRC. Methods: Fresh surgically resected specimens, formalin-fixed paraffin-embedded whole tissue samples, and stool samples were collected. TIICs including Tregs, Th17 cells and tumor-associated macrophages (TAMs) in the surgically resected specimens were analyzed using flow cytometry. FOXp3, CD8, CD163, and phosphorylated-STAT1-positive TIICs in the whole tissue samples were analyzed using IHC, and intestinal microbiota in the stool samples was analyzed using 16S metagenome sequencing. TIICs subpopulations in the normal mucosa and tumor samples were evaluated, and the correlations between the TIIC subpopulations and intestinal microbiota were analyzed. Results: FOXp3lowCD45RA+ Tregs were significantly reduced (p = 0.02), FOXp3lowCD45RA− Tregs were significantly increased (p = 0.006), and M1 TAMs were significantly reduced in the tumor samples (p = 0.03). Bacteroides (phylum Bacteroidetes) and Faecalibacterium (phylum Firmicutes) were increased in the patients with high numbers of Tregs and clearly high distribution of FOXp3highCD45RA− Tregs, which are the effector Tregs. Faecalibacterium, Ruminococcaceae, Eubacterium (phylum Firmicutes), and Bacteroides were increased in patients with a high distribution of M1 TAMs. Conclusions: The findings of the present study indicate that immune responses to tumors are suppressed in the tumor microenvironment of CRC depending on the increment of Tregs and the reduction of M1 TAMs and that intestinal microbiota might be involved in immunosuppression. [ABSTRACT FROM AUTHOR]

A small subset of patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS)-colorectal cancer (CRC) benefit from immunotherapy with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade. Therefore, the aim of the current study was to evaluate the immune status of patients with pMMR/microsatellite instability-low (MSI-L)/MSS-CRC and deficient MMR (dMMR)/MSI-high (MSI-H)-CRC in order to identify responders to anti-PD-1/PD-L1 inhibitors. The current study used a dataset downloaded from The Cancer Genome Atlas (TCGA) as well as 219 clinical tissue samples to investigate the infiltrating grade of cluster of differentiation (CD) 4 and CD8 tumor infiltrating lymphocytes (TILs), the expression levels of PD-L1 and PD-L2, the interferon-γ (IFN-γ) and CD8 T effector gene signatures, and the phosphorylated signal transducer and activator of transcription 1 (p-STAT1) status in patients with pMMR/MSI-L/MSS-CRC and dMMR/MSI-H-CRC. Analysis of TCGA dataset revealed that the mRNA expression levels of PD-L1 and PD-L2, the IFN-γ gene signature and the CD8 T effector gene signature were significantly upregulated in MSI-H tumors compared with MSI-L/MSS tumors. Additionally, a subpopulation of patients with upregulation of the IFN-γ and CD8 T effector gene signatures was observed in those with MSI-L/MSS-CRC. Immunohistochemical staining of the clinical samples revealed a subpopulation of patients with pMMR-CRC that were positive for PD-L1 and p-STAT1, and whom had levels of elevated CD8(+) and CD4(+) TILs infiltration similar to those observed in patients with dMMR-CRC. The results obtained in the current study suggested that a subpopulation of patients with MSI-L/MSS-CRC and pMMR-CRC with upregulated IFN-γ and CD8 T effector gene signatures may benefit from immunotherapy with antibodies against PD-1 and PD-L1. [ABSTRACT FROM AUTHOR]

The expression of fucosyltransferase 8, an enzyme responsible for core fucosylation encoded by FUT8, influences tumor biology and correlates with patient prognosis in several solid cancers. We hypothesized that p53 alteration modifies prognostic associations of FUT8 expression in colorectal cancer (CRC), since FUT8 has recently been identified as a direct transcriptional target of wild-type p53. Utilizing multiple datasets of microarray and RNA sequence of CRC, FUT8 mRNA was found to be highly expressed in wild-type p53 tumors (n = 382) compared to those of mutant p53 (n = 437). Prognostic values of FUT8 expression in conjunction with the p53 status for disease-free survival (DFS) were analyzed using two independent cohorts of stage II and III CRC after curative surgery, including the immunohistochemistry (IHC) cohort (n = 123) and the microarray cohort (n = 357). In both cohorts, neither FUT8 expression nor the p53 status was associated with DFS. Strikingly, positive expression of FUT8 protein was significantly associated with better DFS only in tumors with negative p53, while it had no prognostic impact in tumors with positive p53 in the IHC cohort. Although not statistically significant, a similar prognostic trend was observed in the microarray cohort when patients were stratified by the p53 status. Our results suggest that the prognostic values of FUT8 expression on DFS may be modified by the p53 status, and the expression of FUT8 protein can be a prognostic biomarker for patients with stage II and III CRC. [ABSTRACT FROM AUTHOR]

Abstract: Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor, and it is urgently needed to develop novel therapeutic strategies including immunotherapy. In this study, we investigated the upregulation of the programmed death ligand 1 (PD‐L1) due to epithelial‐mesenchymal transition (EMT) in ESCC using an in vitro treatment system with the EMT inducer, glycogen synthase kinase (GSK)‐3 inhibitor, and we also analyzed the correlation of EMT and PD‐L1 expression in the clinical tumor samples of both tissue microarray (TMA) samples (n = 177) and whole tissue samples (n = 21). As a result, the inhibition of GSK‐3β induces EMT phenotype with upregulated vimentin and downregulated E‐cadherin as well as increased Snail and Zinc finger E box‐binding homeobox (ZEB)‐1 gene expression. Simultaneously, we showed that EMT‐converted ESCC indicated the upregulation of PD‐L1 at both protein (total and surface) and mRNA levels. Of importance, we showed that EMT‐converted tumor cells have a capability to induce T‐cell apoptosis to a greater extent in comparison to original epithelial type tumor cells. Furthermore, the immunohistochemical stains of ESCC showed that PD‐L1 expression on tumor cells was positively correlated with EMT status in TMA samples (P = .0004) and whole tissue samples (P = .0029). In conclusion, our in vitro and in vivo study clearly demonstrated that PD‐L1 expression was upregulated in mesenchymal type tumors of ESCC. These findings provide a strong rationale for the clinical use of anti‐PD‐1/anti‐PD‐L1 monoclonal antibodies for advanced ESCC patients. [ABSTRACT FROM AUTHOR]

Homeobox A (HOXA) cluster genes, members of the HOX family, perform an important role in normal organ development. It has previously been reported that HOXA gene expression in various types of cancer is associated with poor patient outcomes. However, the role of HOXA genes, as well as their expression, in colorectal cancers (CRC) remains unknown. Therefore, the present study investigated HOXA gene expression in patients with CRC and revealed that HOXA9 expression was significantly increased in tumor tissues compared with non‑tumor tissues. Additionally, the functional role of HOXA9 was assessed by knocking down the HOXA9 gene in CRC cells and by evaluating cell growth. Regarding gene expression, cases with positive HOXA9 expression (as detected by immunohistochemical staining) were significantly associated with higher TNM stage and positive lymph node metastasis, although no association was observed between increased HOXA9 levels and the rate of overall survival in the present cohort. Regarding the functional role, HOXA9 expression was demonstrated to be upregulated in patients with CRC and was associated with lymph node metastasis. [ABSTRACT FROM AUTHOR]

Enhancement of antibody-dependent cellular cytotoxicity (ADCC) with some modalities may be a promising approach to enhance the efficacy of therapeutic monoclonal antibodies (mAbs). It has previously been demonstrated that the removal of fucose from antibody oligosaccharides (defucosylation) leads to augmentation of ADCC activity. To establish clinically relevant evidence of this procedure, the present study evaluated trastuzumab- and cetuximab-mediated ADCC by comparing defucosylated mAbs with conventional mAbs using peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 20 patients with gastrointestinal tract cancer and 10 healthy volunteers. ADCCs were measured using PBMCs as effector cells and two gastric cancer cell lines as target cells. ADCCs were significantly enhanced with defucosylated mAbs compared with conventional mAbs using PBMC from the healthy donors and patients with cancer. The results confirmed that the cetuximab- and trastuzumab-mediated ADCCs in advanced disease were impaired in comparison to those in early disease or healthy individuals. However, when the defucosylated mAbs were used instead of the conventional mAbs, the ADCC activities in the advanced cases were almost comparable with those in early disease or healthy individuals. Furthermore, the expression of ADCC associated molecules were modified toward immunosuppressive status with a mitogen-activated protein kinase inhibitor in vitro, the conventional cetuximab- and trastuzumab-mediated ADCC was downregulated, and the defucosylated mAbs overcome the downregulation of ADCC. In conclusion, defucosylated therapeutic mAbs may enhance ADCC activities in patients with cancer, which may lead to more effective anti-cancer treatments. [ABSTRACT FROM AUTHOR]

Kinesin family member 4A (KIF4A) is a member of the kinesin 4 subfamily of kinesin-related proteins and serves an important role in cell division. The expression levels of KIF4A have been investigated in numerous types of cancer, including cervical, lung, oral, and breast cancer, and are established to be associated with poor patient prognosis. However, the role of KIF4A, as well as its expression in colorectal cancer (CRC), remains to be elucidated. Therefore, the current study investigated KIF4A expression levels in patients with CRC and demonstrated that its levels were increased in tumor tissues compared with non-tumor tissues. To investigate the functional role of KIF4A, KIF4A was knocked down in CRC cells and cell viability was evaluated. CRC cells with KIF4A knockdown exhibited lower cell proliferation compared with control cells. In addition, KIF4A expression levels, as determined by immunohistochemistry, were compared with the expression of Ki-67, but no significant associations were observed in the patients with CRC. Therefore, KIF4A was found to be upregulated in patients with CRC and downregulation of KIF4A reduced cell proliferation in CRC cells. These results suggest that KIF4A may be a potential therapeutic target, which may improve the outcomes of patients with CRC. [ABSTRACT FROM AUTHOR]

Solute carrier (SLC) drug transporters exchange various molecules without energy from adenosine triphosphate hydrolysis, indicating an association with anticancer drug resistance. However, the expression and role of SLC transporters in malignant tumors has not yet been fully elucidated. Therefore, in the current study, the expression of SLC37A family genes was evaluated in patients with colorectal cancer (CRC), and it was revealed that SLC family 37 member 1 (SLC37A1) expression was significantly increased in tumorous tissues compared with that in non-tumorous tissues. The cases with upregulated expression of SLC37A1 by immunohistochemical staining were significantly associated with positive venous invasion and liver metastasis. Furthermore, upregulated SLC37A1 expression was associated with poor overall survival time in the present cohort. These results indicated that SLC37A1 is involved in the hematogenous metastasis of CRC. To investigate whether SLC37A1 is associated with hematogenous metastasis and glycolipid metabolism, SLC37A1 was knocked down in colon cancer cells, and the expression of sialyl Lewis A and sialyl Lewis X was observed to be decreased. In summary, upregulation of SLC37A1 was observed in patients with CRC, and was associated with poor patient outcomes and survival. To the best of our knowledge, the present study is the first to propose a key role of SLC37A1 in CRC, and additional studies are warranted to reveal the functional role of SLC37A1 in CRC development. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy has become a promising treatment strategy for cancer. Immune checkpoint blockade with anti-CTLA4 mAb and anti-PD-1 mAb has demonstrated clear evidence of objective responses including improved overall survival and tumor shrinkage, driving renewed enthusiasm for cancer immunotherapy in multiple cancer types including esophageal squamous cell carcinoma (ESCC). There are several clinical trials using anti-PD1 mAb for ESCC in early phases and the results are currently promising. Results and Conclusions: In this review, recent advances in cancer immunotherapy for ESCC are discussed with particular focus on immune checkpoint inhibitors and cancer vaccine. [ABSTRACT FROM AUTHOR]

Among advanced gastric cancer cases, peritoneal dissemination is a life-threatening mode of metastasis, and any strategy to control peritoneal metastasis will significantly improve treatment outcomes. Since intraperitoneal administration of anticancer drugs can induce an extremely high concentration of drugs in the peritoneal cavity, intraperitoneal chemotherapy would appear to be a reasonable and promising strategy to control the peritoneal dissemination. However, it has been reported in the past that intraperitoneal administration of mitomycin C or cisplatin resulted in no significant clinical effects against peritoneal metastasis of gastric cancer. In contrast, intraperitoneal paclitaxel is expected to remain inside the peritoneal cavity due to its large molecular weight and fat solubility, leading to a high concentration of the drug in the peritoneal cavity. In fact, promising results in several phase II clinical trials using intraperitoneal paclitaxel have been reported, including a median survival time of 16.2-24.6 months and a 1-year overall survival rate of 69-78 %. Thereafter, a phase III randomized control study (PHOENIX-GC trial) with intraperitoneal paclitaxel plus systemic S-1 and intravenous paclitaxel in comparison to systemic S-1 plus cisplatin was conducted in Japan. Moreover, a phase II clinical trial of combination chemotherapy of intraperitoneal paclitaxel with systemic capecitabine plus oxaliplatin is currently ongoing in Singapore. In this review, based on clinical experience from Singapore and Japan, the clinical significance of intraperitoneal chemotherapy for gastric cancer with peritoneal disease is discussed. [ABSTRACT FROM AUTHOR]

The aim of this study was to clarify the clinical implications of a unique carbohydrate determinant, MECA-79, in gastric cancer specimens and cells. Immunohistochemical analysis showed that 62 of 225 (27.6%) cases were defined as positive for MECA-79. MECA-79 expression was correlated with depth of invasion, venous invasion, TNM stage, and distant metastasis. In survival analyses, patients with MECA-79 expression had worse prognosis by the log-rank test. Multivariate analysis of the Cox proportional hazard model showed that MECA-79 expression was an independent factor of a worse cancer-specific survival. Among 11 gastric cancer cells, MECA-79 was observed in only MKN7 cells, which also expressed GlcNAc6ST-2 transcript. A knockdown of GlcNAc6ST-2 in MKN7 cells showed a markedly reduced expression of MECA-79, suggesting that GlcNAc-sulfation of MECA-79 is mainly synthesized by GlcNAc6ST-2. Furthermore, real-time RT-PCR analysis revealed that GlcNAc6ST-2 was significantly increased in cancer tissues compared with paired normal mucosa. In conclusion, the expression of MECA-79 could be a useful marker for the prognosis of gastric cancer. Our results might also provide novel perspectives on the biology of MECA-79 and GlcNAc6ST-2 in cancer progression and metastasis. ( Cancer Sci 2011; 102: 1088-1094) [ABSTRACT FROM AUTHOR]

Simple Summary: There is a clinical need for predictive biomarkers that can identify patients with rectal cancer who do not respond to preoperative neoadjuvant chemoradiotherapy. In this study, we assembled multiple independent microarray datasets of biopsy specimens obtained from patients with rectal cancer before neoadjuvant treatment, including 237 non-responders and 152 responders. These datasets were utilized as the discovery cohorts or the validation cohorts, to develop and validate gene expression signatures predictive of treatment response. Using an in silico meta-analysis approach, here we tested not only our 4-gene signature built in this study but also nine different single-gene and multi-gene predictive signatures that were previously reported in the literature. Nevertheless, in the validation cohorts, none of the tested signatures were consistently differentially expressed between tumor specimens from non-responders and responders, and the meta-analyses revealed that those signatures had limited predictive values in clinical practice. Background: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is widely used for patients with locally advanced rectal cancer. However, response to nCRT varies substantially among patients, highlighting the need for predictive biomarkers that can distinguish non-responsive from responsive patients before nCRT. This study aimed to build novel multi-gene assays for predicting nCRT response, and to validate our signature and previously-reported signatures in multiple independent cohorts. Methods: Three microarray datasets of pre-therapeutic biopsies containing a total of 61 non-responders and 53 responders were used as the discovery cohorts to screen for genes that were consistently associated with nCRT response. The predictive values of signatures were tested in a meta-analysis using six independent datasets as the validation cohorts, consisted of a total of 176 non-responders and 99 responders. Results: We identified four genes, including BRCA1, GPR110, TNIK, and WDR4 in the discovery cohorts. Although our 4-gene signature and nine published signatures were evaluated, they were unable to predict nCRT response in the validation cohorts. Conclusions: Although this is one of the largest studies addressing the validity of gene expression-based classifiers using pre-treatment biopsies from patients with rectal cancer, our findings do not support their clinically meaningful values to be predictive of nCRT response. [ABSTRACT FROM AUTHOR]

The inhibitory action of prostaglandin D2 (PGD2) and its effect on the cell cycle were examined in cell lines SW480 and LS174T of human colon cancer. The growth of the cell lines were assessed 24h and 48h after the addition of 1.0μg/ml and 10.0μg/ml PGD2. The growth of SW480 cells and 24h and 48h after the addition of 10.0μ/ml, while that of LS174T was inhibited by both doses after 24h and 48h. S-Phase DNA synthesis in the SW480 cells was significantly blocked 24h after the addition of 10.0μg/ml PGD2. The cell cycle of LS174T cells was arrested at the G0+G1 phase 24h after the addition of 1.0μg/ml and 10.0μg/ml PGD2. The correlation between hepatic metastasis and PGD2 concentration in human cancer tissue was examined. The mean value of PGD2 concentrations in the primary cancer tissue was significantly lower in the hepatic metastasis group than that in the group without hepatic metastasis. These findings suggest that measuring the PGD2 in cancer tissue may be useful for detecting and predicting the hepatic metastasis from human colorectal cancer. [ABSTRACT FROM AUTHOR]

To clarify the biologic characteristics of hereditary nonpolyposis colorectal cancer (HNPCC), an investigation was made of the association of this cancer with mutations of the TP53 (alias p53) and K- ras genes, and with DNA ploidy. Samples from 19 patients with HNPCC and from 56 patients with sporadic colorectal cancer were analyzed by polymerase chain reaction-single strand conformation polymorphism and flow cytometric analyses. Mutations of the p53 gene were found in 7 (32%) of 22 samples from HNPCC patients, and K- ras mutations were found in 8 (44%) of 18 samples from HNPCC patients. Aneuploidy was noted in 8 (44%) of 18 samples. Each incidence in HNPCC was similar to the corresponding incidence in the sporadic colorectal cancers. The results of this investigation indicate that HNPCC shows no difference from sporadic colorectal cancer in terms of p53 and K- ras alterations, or DNA ploidy. [ABSTRACT FROM AUTHOR]

Background Recently, endoscopic submucosal dissection (ESD) has been used as a less invasive treatment for superficial esophageal cancer. Additional treatment is often required after non-curative resection to prevent local recurrence and lymph node metastasis. Here, we present the outcomes of various additional treatments for patients with superficial esophageal cancer who underwent ESD. Methods Between 2006 and 2017, we performed ESD in 179 patients (210 lesions) with superficial esophageal cancer and 44 cases resulted in the non-curative resection diagnosed by the pathological examination. Among them, 29 patients received additional treatment, whereas 15 patients with no additional treatment were followed up. Additional treatment included esophagectomy (8 patients), chemoradiotherapy (15 patients), ablation using argon plasma coagulation (4 patients), and chemotherapy alone (2 patients). We examined the clinicopathological characteristics and prognosis of patients in the additional esophagectomy group (S group) and chemoradiotherapy group (CRT group). Results Twenty-three patients with pT1a-MM, pT1b, lymphatic invasion, venous invasion, and positive resection margins (both horizontal and vertical) were divided into two treatment groups. Clinicopathological characteristics of patients in the S and CRT groups were not significantly different. Pathological findings after additional esophagectomy showed one residual tumor and one lymph node metastasis. There were no recurrences in the two groups. There was no statistically significant difference in the 5-year overall survival rate between the S group (87.5%) and the CRT group (93.3%). One patient from the S group died due to respiratory pneumonia, and one patient died due to radiation pneumonia. However, five out of the 15 (33.3%) patients who were followed up with no additional treatment developed recurrence. The 5-year overall survival rate was 40.4%, which was not significantly different from that in the additional treatment group. However, the 5-year relapse-free survival rate (30%) was significantly different from that in the additional treatment group (P  > 0.05). Conclusion Additional treatment is essential after non-curative endoscopic submucosal resection for esophageal cancer. Additional esophagectomy and chemoradiotherapy were both safe and effective in this cohort. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

AT-rich interactive domain 1A (ARID1A) functions as a tumor suppressor and several therapeutic targets in ARID1A-mutated cancers are under development. Here, we investigated the prognostic value of ARID1A for gastric cancer and its association with expression of PD-L1 and p53. ARID1A expression was examined by immunohistochemistry and negative expression of ARID1A was detected in 39 (19.5%) of 200 cases in a test cohort and in 40 (18.2%) of 220 cases in a validation cohort. Negative expression of ARID1A was associated with worse overall survival in undifferentiated cases, particularly early-stage cases. Negative expression of ARID1A was detected in 11 (50%) of 22 PD-L1-positive cases and in 68 (17.1%) of 398 PD-L1-negative cases in a combined cohort. Negative expression of ARID1A was detected in 45 (22%) of 205 p53-positive cases and in 34 (15.8%) of 215 p53-negative cases in a combined cohort. In addition, expression of EZH2, a potential synthetic lethal target in ARID1A-mutated tumors, was detected in 79 ARID1A-negative cases. An ARID1A-knockdown gastric cancer cell line was subjected to microarray analysis, but no actionable targets or pathways were identified. The present results indicate that ARID1A may serve as an early-stage prognostic biomarker for undifferentiated gastric cancer. [ABSTRACT FROM AUTHOR]

Background Circulating tumor cells (CTCs) in patients with malignant tumors can be used as a prognostic marker. Recently the existence of mesenchymal CTCs have been detected by new methods. However, it has been not yet clarified how CTCs are associated with the treatment effects in esophageal cancer patients. We assessed CTCs in esophageal cancer patients and investigated the relationship between CTCs and treatment effect. Methods Seven patients who had potential of curative resection have been enrolled and peripheral blood samples (10ml) were collected before and after treatment. All patients received chemotherapy (5-FU and cisplatin) and four patients of them received as neoadjuvant therapy. Other patients received only chemotherapy and radiation therapy without operation. CTCs were analyzed using a Microfluidic Chip devise provide with the Nihon Gene Research Laboratories. This system can isolates CTCs from blood samples, based on their size and deformability differences from blood cells. Phenotypes of CTCs are determined by staining and scanning systems. A previous report revealed that this method had higher sensitivity for CTCs than conventional methods (the Cell Search system) in 61 metastatic breast cancer. Results Treatments effects were stable disease or better in all cases. Multiple CTCs were detected in all cases before treatment. Five patients had epithelial CTCs and others had only mesenchymal CTCs. Total number of CTCs after treatment whose data can be available decreased except for two cases. One patient had no CTC after treatment. Two cases have been currently analyzing. Conclusion CTCs may exist almost all patients of Stage II or more esophageal cancer. Decreasing the number of CTCs after treatment suggests some relationship between CTCs and treatment effect, and the accumulation of more cases is necessary. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]