SIRT1 Promotes Chemoradiotherapy Resistance in Esophageal Squamous Cell Carcinoma.

INTRODUCTION: Identifying accurate biomarkers for predicting response to chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC) is a critical challenge. The protein SIRT1, recognized for its implications in longevity, has been associated with tumor promotion in ESCC. However, data regarding its correlation with CRT sensitivity remain unreported. Therefore, in this study, we aimed to investigate the relationship between SIRT1 expression and CRT sensitivity and concurrently assess the effect of SIRT1 knockdown on CRT sensitivity in ESCC. METHODS: This study included 73 patients who underwent radical esophagectomy after CRT. SIRT1 expression in pre-treatment endoscopic biopsies was assessed through immunostaining, followed by a comparative analysis of CRT effects on surgical specimens. Small interfering RNA was used to attenuate SIRT1 expression in TE5 and TE10 cells, which were then subjected to cisplatin treatment at varying doses and concentrations and irradiation with X-rays, respectively. RESULTS: High SIRT1 tissue expression was significantly associated with CRT resistance. Multivariate analysis identified high SIRT1 expression as an independent biomarker for poor CRT response. In TE-5 and TE-10 cells, SIRT1 knockdown significantly decreased cell viability and increased sensitivity to cisplatin and radiation treatment compared to that of the negative control. CONCLUSION: Our study results demonstrate the potential of SIRT1 as a predictive biomarker for CRT response in ESCC, highlighting the heightened sensitivity to CRT upon the transcriptional inactivation of SIRT1. Targeting SIRT1 emerges as a promising strategy for enhancing the efficacy of CRT for ESCC.

CT-derived skeletal muscle change before immunotherapy predicts survival of advanced gastric cancer: associations with inflammatory markers and liver lipid metabolism.

BACKGROUND: Skeletal muscle (SM) is a key factor in cancer treatment. However, it is unclear whether pretreatment SM change affects the outcome of immune checkpoint inhibitors (ICIs) therapy in gastric cancer (GC). METHODS: Advanced GCs treated with ICIs were retrospectively investigated. SM evaluated by psoas muscle area at the third lumbar vertebra was measured on CT acquired within 1 month from the start of ICIs therapy (CT-1), and on CT acquired 2.8 ± 0.84 months before CT-1. Monthly change rate of SM (MCR-SM) was defined as the change rate of SMs between those two CTs divided by the period between those CTs (month). Monthly change rate of body weight (MCR-BW) during the same period was also calculated. They were compared with disease-specific survival (DSS) and progression-free survival (PFS). MCR-SM was compared with pretreatment markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP), and liver-to-spleen CT attenuation ratio (LSR) as a marker of liver lipid metabolism. RESULTS: This study enrolled eighty-three GC patients. MCR-SM significantly correlated with DSS and PFS (P < 0.0001, 0.001, respectively), whereas MCR-BW did not. Kaplan-Meier analyses demonstrated that higher MCR-SM (MCR-SM ≥ -0.7185%) significantly associated with better DSS and PFS (P = 0.0002, 0.03, respectively). Patients with positive MCR-SM showed significantly lower NLR, MLR, and CRP than those with negative (P = 0.01, 0.006, 0.003, respectively). MCR-SM showed a significant positive correlation with LSR (P = 0.007, R = 0.30). CONCLUSIONS: Pretreatment SM loss, associated with high systemic inflammation and hepatic fat accumulation, related to poor outcome of ICIs therapy in GC.

[Chemotherapy Strategy in a Case of MSI-High Patients with Gastric Cancer-Case Report].

A 73-year-old woman was referred to our hospital with a chief complaint of black stools and abdominal distention. She was diagnosed with advanced gastric cancer with pyloric stenosis and multiple lymph node metastasis(cT4aN3M0, cStage Ⅲ)and was administered preoperative chemotherapy after laparoscopy and gastric jejunal bypass surgery. The surgical diagnosis was sT4aN3M0P0CY0. After surgery, 2 courses of DS therapy were administered. However, a new liver metastatic lesion was found, and XELOX therapy was selected as the second-line of treatment. Subsequently, enlarged hepatic hilar lymph nodes were found; microsatellite instability testing confirmed MSI-High cancer. Nivolumab was selected as the third- line therapy. After 15 courses, a new liver metastatic lesion appeared. Although Ram+nab-PTX therapy was chosen as the fourth-line therapy, the patient developed myelosuppression after 3 courses. Two years and 4 months after the initial treatment, the patient was considered to have achieved CR. Because drug-induced liver injury had occurred, the Ram therapy was discontinued. The patient has remained in CR for 1 year without receiving any anticancer drugs. This case suggests that for MSI-high patients with gastric cancer, the consideration of treatment strategy should be based on the molecular biological background.

Prognostic Impact of Hepatic Steatosis Evaluated by CT on Immunotherapy for Gastric Cancer: Associations with Sarcopenia, Systemic Inflammation, and Hormones.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are expected to improve the prognosis of gastric cancer (GC). Also, hepatic steatosis has been reported to be associated with cancer cachexia and is expected to be a cancer biomarker. The purpose of this study was to evaluate prognostic impact of hepatic steatosis in ICI therapy for GC. METHODS: Unresectable or recurrent GC treated with ICIs was investigated. Using unenhanced CT, the liver-to-spleen CT attenuation ratio (LSR) was calculated as a parameter of hepatic steatosis. LSR was compared with the presence of sarcopenia and inflammatory markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR). These parameters were also compared with disease-specific survival (DSS) and progression-free survival (PFS). Associations of LSR with insulin-like growth factor 1 (IGF-1) and growth hormone were also evaluated. RESULTS: A total of 70 patients were investigated. LSR of sarcopenia patients was significantly lower than that of non-sarcopenic ones (p = 0.02). LSR showed significant negative correlations with NLR, PLR, and MLR (p = 0.003, 0.03, 0.01, respectively). Lower LSR was significantly associated with a higher level of serum IGF-1 (p = 0.03). In univariate analysis, LSR was significantly correlated with DSS and PFS (both p < 0.0001), and multivariate analysis demonstrated that LSR was the independent prognostic factor for both DSS and PFS (both p = 0.01). ROC analysis demonstrated that LSR >1.263 was a good predictive marker for favorable DSS (>5.3 months) with an AUC of 0.80. CONCLUSION: Hepatic steatosis can be a promising prognostic biomarker for ICI therapy of GC, associated with sarcopenia and the elevation of inflammatory markers. Our data suggested that GC with steatohepatitis might be less responsive to ICI therapy.

ypTNM staging is a potentially useful prognostic stratification tool in patients with advanced gastric cancer after preoperative chemotherapy.

PURPOSE: Although the usefulness of the ypStage in neoadjuvant chemotherapy for advanced gastric cancer (GC) has been reported, whether or not the ypStage is applicable to all GC patients who receive preoperative chemotherapy, including conversion surgery cases, is unclear. Therefore, this retrospective study evaluated the value of the ypTNM staging system in all advanced GC patients who received chemotherapy prior to gastrectomy. METHODS: A total of 66 patients who underwent chemotherapy prior to gastrectomy for advanced GC at Chiba University Hospital from January 2008 to December 2020 were enrolled in the current study. The prognostic impact of the ypStage on the overall survival (OS) and relapse-free survival (RFS) were examined via univariate and multivariate analyses. RESULTS: The 5-year OS rates for ypStage I, II, III, and IV were 87.5%, 64.7%, 52.9%, and 28.6%, respectively, while the 5-year RFS rates were 81.3%, 57.4%, 44.4%, and 28.6%, respectively. The univariate analysis revealed that the ypStage was significantly correlated with the OS (p = 0.037) and the ypT status and ypStage showed a significant correlation with the RFS (p = 0.043 and p = 0.021, respectively). The multivariate analysis demonstrated that only the ypStage was an independent prognostic factor for the OS and RFS (p = 0.024 and p = 0.018, respectively). CONCLUSION: The ypTNM stage may be a useful tool for the risk stratification of all advanced GC patients treated with chemotherapy followed by gastrectomy, including not only neoadjuvant but also conversion surgery cases.

[A Case of Primary Duodenal Adenocarcinoma in the Third Portion Treated with Partial Duodenectomy and Adjuvant Chemotherapy].

A 69-year-old man was referred for vomiting. CT and upper gastrointestinal endoscopy revealed a circumferential stenotic lesion in the third portion of the duodenum, and partial duodenectomy and lymph node dissection were performed for the diagnosis of duodenal adenocarcinoma. The histopathological diagnosis was pT3, pN0, pStage ⅡA(UICC 8th)well differentiated tubular adenocarcinoma. The patient was treated with FOLFOX as adjuvant chemotherapy and is alive 2 years and 4 months postoperatively without recurrence. Primary duodenal adenocarcinoma in the third portion is rare, and further case experience is required for selection of the operation and adjuvant therapy.

An anti-alcoholism drug, disulfiram and copper complex improves radio-resistance of tumor-initiating cells in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a malignant cancer with a poor prognosis. Chemoradiotherapy is one of the most important strategies for patients with locally advanced unresectable ESCC; however, its therapeutic effect is unsatisfactory. Tumor-initiating cells (TICs) have been reported to be resistant to conventional chemotherapy and radiotherapy so far. Therefore, we aimed to develop a treatment strategy targeting TICs in ESCC to improve radiosensitivity. METHODS: First, we validated aldehyde dehydrogenase 1 (ALDH1) as a TIC marker and investigated its ability to mediate resistance in human ESCC cell lines using flow cytometry, Western blotting, and functional analyses. Then, we focused on disulfiram (DSF), an aldehyde dehydrogenase inhibitor, used to treat alcohol use disorder. We investigated the effect of DSF and copper (II) D-gluconate (Cu) on the radiosensitivity of ESCC in xenograft mouse models. RESULTS: ALDH1-positive cells showed an upregulation of SOX2 and Nanog, exhibiting much stronger tumor-initiating properties than ALDH1-negative cells. Furthermore, inhibition of ALDH1 attenuated the tumor-initiating properties of ESCC cell lines. Our results also showed that ALDH1-positive cells were resistant to chemotherapy and radiotherapy, and the inhibition of ALDH1 led to the mitigation of therapeutic resistance. Our in vitro and in vivo studies revealed that the DSF/Cu complex could radiosensitize ALDH1-positive ESCC cells and downregulate the phosphoinositide 3-kinase/Akt pathway. CONCLUSION: ALDH1 inhibition by the DSF/Cu complex enhances the radiosensitivity of TICs in ESCC. The drug repositioning approach using disulfiram is a potential treatment option to overcome radioresistance in patients with locally advanced ESCC.

Gut microbiome can predict chemoradiotherapy efficacy in patients with esophageal squamous cell carcinoma.

PURPOSE: The gut microbiome plays an important role in cancer pathogenesis and therapy. Some studies have reported that specific bacteria in tumor tissues may contribute to the prognosis and treatment of esophageal squamous cell carcinoma (ESCC). However, there is limited evidence that the gut microbiome is associated with ESCC. This study assessed the utility of the gut microbiome as a predictive marker of the therapeutic effect in patients with ESCC undergoing chemo-radiotherapy (CRT). PATIENTS AND METHODS: Fecal samples were collected from 51 patients with ESCC who had never undergone treatment between April 2021 and May 2022 in the Department of Frontier Surgery, Chiba University. The gut microbiome was analyzed using 16S metagenomics sequencing. The association between the gut microbiome composition and stage according to the TNM classification (American Joint Committee on Cancer 7.0) and CRT response according to the RECIST criteria was evaluated. RESULTS: The relative abundance of Fusobacteriaceae was enriched in cStage III-IVb group. Among the 27 patients who received CRT, the relative abundance of Lactobacillaceae was enriched in those with a partial and complete response. Lactobacillaceae also did not correlate with any clinical data, but the high Lactobacillales group had a higher LMR (P = 0.032) and lower PLR (P = 0.045) than in the low Lactobacillales group. CONCLUSIONS: In conclusion, we found that the relative abundance of Lactobacillaceae was enriched in patients with a partial or complete response among CRT those with ESCC, thus suggesting that the relative abundance of Lactobacillaceae can predict the effect of CRT.

HIF-1α stimulates the progression of oesophageal squamous cell carcinoma by activating the Wnt/ß-catenin signalling pathway.

BACKGROUND: This study aimed to clarify the significance of the crosstalk between hypoxia-inducible factor-1α (HIF-1α) and the Wnt/ß-catenin pathway in oesophageal squamous cell carcinoma (ESCC). METHODS: The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, ß-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. RESULTS: The expression level of HIF-1α, ß-catenin, and TCF4/TCF7L2 in T.Tn and TE1 cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, migration/invasion and epithelial-mesenchymal transition (EMT) progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth, angiogenesis, and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and ß-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, ß-catenin and TCF4/TCF7L2 were increased in ESCC tumour tissues compared to the corresponding non-tumour tissues. High levels of HIF-1α and TCF4/TCF7L2 expression were correlated with aggressive phenotypes and poor prognosis in ESCC patients. CONCLUSIONS: HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/ß-catenin pathway.

Soluble PD-L1 Concentration Is Proportional to the Expression of PD-L1 in Tissue and Is Associated with a Poor Prognosis in Esophageal Squamous Cell Carcinoma.

INTRODUCTION: We determined the soluble programmed cell death-1 ligand-1 (sPD-L1) concentration in patients with esophageal squamous cell carcinoma (ESCC), and confirmed the PD-L1 expression in resected specimens. METHODS: Blood samples were collected from 73 patients with histologically proven ESCC. The serum levels of sPD-L1 were measured using an enzyme-linked immunosorbent assay. The correlations between the sPD-L1 concentration and the expression of PD-L1 in tumor specimens and tumor depth, lymph node metastasis, disease stage, and various laboratory data were assessed. RESULTS: sPD-L1 levels in patients with high PD-L1 expression levels in tumor tissue were significantly higher than in patients with low PD-L1 expression levels (p = 0.042). The OS of the sPD-L1-high group was significantly worse than that of the low group (p = 0.028). Similarly, patients in whom a tissue specimen was PD-L1-positive group showed significantly poorer OS. CONCLUSION: The sPD-L1 concentration was correlated with the PD-L1 expression in tissues. Patients with PD-L1-positive tissue specimens showed significantly higher sPD-L1 levels in comparison to PD-L1-negative cases. Furthermore, patients with high sPD-L1 expression levels had a significantly worse prognosis than those with low sPD-L1 expression levels, and patients with a PD-L1-positive tissue specimen had a significantly worse prognosis than patients in whom the tissue specimen showed a low PD-L1 expression level.

Metformin-Induced Heat Shock Protein Family A Member 6 Is a Promising Biomarker of Esophageal Squamous Cell Carcinoma.

INTRODUCTION: Antidiabetic drug metformin exerts various antitumor effects on different cancers. Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer and new treatment strategy is required. In this study, we performed a comprehensive gene expression analysis of ESCC cell lines treated with metformin, which provided helpful information on the antitumor effects of metformin in ESCC. Next, we selected a promising gene among them and examined its effects on ESCC properties. METHODS: We examined metformin-induced mRNA expression changes in two human ESCC cell lines by performing next-generation sequencing (NGS) and pathway analysis. Heat shock protein family A (Hsp70) member 6 (HSPA6) expression in surgical specimens obtained from 83 ESCC patients who underwent curative operations was evaluated immunohistochemically and analyzed. RESULTS: Metformin upregulated mRNA expression of the many genes, including HSPA6, a cancer immune-related gene, and inhibited mRNA expression of the other many genes. Pathway analysis indicated major canonical pathways and upstream regulators related to metformin. The result indicated HSPA6 as a promising biomarker. HSPA6 expression correlated with disease-free survival (DFS) of the patients with all stage ESCC (p = 0.021), especially with stage I/II ESCC (p < 0.001). With stage III, low HSPA6 expression was not associated with poor DFS (p = 0.918). Multivariate analysis indicated that independent low HSPA6 expression was an independent poor prognostic factor of stage I/II ESCC (p < 0.001). However, HSPA6 expression did not correlate with the clinicopathological characteristics, including age, sex, tumor depth, lymph node metastasis, tumor stage, and tumor markers of the patients with stage I/II ESCC. CONCLUSIONS: This NGS analysis detected prospective candidate genes, including HSPA6. Our results indicate that HSPA6 is a promising biomarker of the recurrence risk of stage I/II ESCC. Further studies on HSPA6 would lead to better treatment.

Comparison of estimated treatment effects between randomized controlled trials, case-matched, and cohort studies on laparoscopic versus open distal gastrectomy for advanced gastric cancer: a systematic review and meta-analysis.

PURPOSE: In actual surgical research, case-matched studies are frequently conducted as an alternative to randomized controlled trials (RCTs). However, it is still unclear what differences there are between RCTs and case-matched studies in upper gastrointestinal surgery, and clarifying them is a very important clinical issue. Thus, the purpose of this study was to investigate estimated treatment effects between RCTs, case-matched studies, and cohort studies regarding laparoscopic distal gastrectomy (LDG) for advanced gastric cancer (AGC). METHODS: We searched the PubMed, Cochrane Central Register of Controlled Trials, and Web of Science databases for studies that compared LDG versus open distal gastrectomy for AGC published from the inception of the databases until July 2021. A meta-analysis was performed using the Review Manager version 5.3 software program from the Cochrane Collaboration, and six short-term outcomes and three long-term outcomes were assessed. RESULTS: Twenty-three studies with 13698 patients were included. There was no difference in estimated treatment effects between RCTs and case-matched studies for all outcomes except for the number of retrieved lymph nodes and postoperative complications. In terms of intraoperative blood loss, postoperative hospital stay, number of retrieved lymph nodes, and recurrence, observational studies tended to overestimate the treatment effects. CONCLUSION: The estimated treatment effects of LDG for AGC in the case-matched study were almost the same as in the RCTs. However, to assess the true magnitude of the treatment effect, the design and actual implementation of the analysis must be critically evaluated.

Biased expression of mutant alleles in cancer-related genes in esophageal squamous cell carcinoma.

BACKGROUND: Recent progress of large-scale international studies has provided comprehensive catalogs of somatic mutations in cancers. Additionally, it has become evident that allelic imbalance in the abundance of somatic mutations between DNA and RNA were pervasive in various types of cancer. However, the allelic imbalance of the abundance of somatic mutations in esophageal squamous cell carcinoma (ESCC) has not been fully analyzed. METHODS: We performed exome sequencing for 25 Japanese patients with ESCC to detect a comprehensive catalog of somatic mutations in ESCC. Additionally, we performed mRNA sequencing to evaluate the allelic imbalance of the identified somatic mutations at the transcriptional level by comparing the mutant allele frequencies between RNA and DNA. RESULTS: The exome sequencing showed that TP53 and ZNF750 were significantly mutated genes. The expression levels of TP53 and ZNF750 were different depending on the mutation status. In almost all the tumors with missense mutations in TP53 and ZNF750, the mutant allele frequencies were higher in the RNA sequencing than those in the exome sequencing, indicating that the mutant alleles were preferentially expressed. By examining the allelic imbalances for all the identified missense mutations, we demonstrated that genes showing preferential expressions of the mutant alleles were involved in the pathways including cell cycle, cell death, and chromatin modification. CONCLUSIONS: The results of this study suggest that the allelic imbalance of the abundance of somatic mutations plays important roles in the initiation and progression of ESCC by modulating cancer-related biological pathways.

[Successful Endoscopic Submucosal Dissection of Early Gastric Cancer after Ulcer Healing Associated with a Malignant Cycle-A Case Report].

A 79-year-old man was detected with anemia on medical examination and underwent gastroscopy at the previous hospital. Gastroscopy revealed a 15-mm ulcerative lesion(Type 0-Ⅱc plus Ⅲ)on the greater curvature of the upper gastric body. Tumor biopsy showed well-differentiated adenocarcinoma. The patient was suspected of deep submucosal invasion due to poor stretching of the gastric wall and the ulcer depth; hence, he was transferred to our hospital for surgery. When gastroscopy was repeated, the ulcer was found to be scarred(Type 0-Ⅱc), thereby indicating the occurrence of intramucosal carcinoma; hence, endoscopic submucosal dissection was performed. The pathological finding showed 10×6 mm, tub1, pT1a, ly0, v0, pUL1, pHM0, pVM0, suggesting a curative resection. Early gastric cancer of the depressed type is known to develop a malignant cycle with repeated improvements and exacerbations of the ulcer. Diagnosing the depth of tumor invasion is particularly difficult when there is an active ulcer. For small lesions with active ulcers, repeating gastroscopy might allow for correct diagnosis and appropriate treatment.

Does thoracoscopic esophagectomy really reduce post-operative pneumonia in all cases?

It has been said that "thoracoscopy suppresses the occurrence of pneumonia in comparison to thoracotomy", but does it reflect real clinical practice? To resolve this clinical question, we compared the results of randomized controlled trials (RCTs) and retrospective cohort studies from limited institutes (CLIs) in which a large number of high-volume centers were the main participants to those of retrospective cohort studies based on nationwide databases (CNDs) in which both high-volume centers and low-volume hospitals participated. A systematic review and meta-analysis were conducted to compare the short-term outcomes of thoracoscopic to open esophagectomy for esophageal cancer in the three above-mentioned research formats. In total, 43 studies with 21,057 patients, which included 1 RCT with 115 patients, 38 CLIs with 6,126 patients and 4 CNDs with 14,816 patients, were selected. Pneumonia was one of the most important complications. Although significant superiority in thoracoscopic esophagectomy was observed in RCTs (p = 0.005) and CLIs (p = 0.003), no such difference was seen in findings using nationwide databases (p = 0.69). In conclusion, unlike RCTs and CLIs, CNDs did not show the superiority of thoracoscopic surgery in terms of post-operative pneumonia. RCTs and CLIs were predominantly performed by high-volume hospitals, while CNDs were often performed by low-volume hospitals. In actual clinical practice including various types of hospitals, the superiority of thoracoscopic over open esophagectomy regarding the incidence of pneumonia may, therefore, decrease.

Tumor-derived exosomes influence the cell cycle and cell migration of human esophageal cancer cell lines.

Our laboratory previously reported the usefulness as biomarkers of exosomes in the plasma of esophageal squamous cell carcinoma (ESCC) patients. However, the influence of tumor-derived exosomes on the tumor itself and underlying mechanisms remain unclear. We here report changes in the phenotype and gene expression when cancer cells exist in an environment with tumor-derived exosomes. The exosomes were isolated from the culture medium of human ESCC cells (TE2, T.Tn) by ultracentrifugation; cell proliferation assay, wound-healing assay, and fluorescence imaging of the cell cycle were performed to clarify the phenotypic changes in the high concentration of tumor-derived exosomes. Gene expression changes were also assessed by mRNA microarray, and the data were analyzed by gene set enrichment analysis (GSEA). The data revealed that the proliferation of both TE2 and T.Tn was inhibited, and cell migration ability was upregulated in the exosome exposure group (P < .05). Fluorescence imaging using a fluorescent ubiquitination-based cell cycle indicator expressing ESCC cells revealed that the ratio of G1-phase cells was significantly increased in the exosome exposure group (P < .05). Findings of the GSEA clarified that high-density exposure of cancer-derived exosomes to their parent cancer cells downregulated the expression of genes related to cell proliferation and cell cycle, and upregulated the expression of genes related to actin filament length and extracellular structure organization. In conclusion, an environment of high-density tumor-derived exosomes induces changes in the gene expression and phenotype of tumor cells and may lead to tumor progression or malignant transformation.

[A Case of Primary Amelanotic Malignant Melanoma of the Esophagus, Wherein Pseudoprogression Was Suspected during Immune Checkpoint Inhibitor Treatment].

A 78-year-old man was admitted to our hospital with a diagnosis of esophageal cancer and gastric cancer. Gastroscopy showed a type 2 tumor located in the cardia from the lower esophagus, and a pathological examination showed malignant melanoma. Based on the physical examination and other imaging tests, the patient was diagnosed with primary amelanotic malignant melanoma of the esophagus, but the tumor was unresectable due to extensive lymph node metastasis. According to the guideline, immune checkpoint inhibitor(nivolumab)was used for treatment, but because the tumor progressed after 2 courses and the performance status of the patient worsened, aggressive treatment was ended. Six weeks after finishing treatment, computed tomography showed that the tumor had shrunk to some extent. The patient ultimately died from aspiration pneumonia 4 months after the first consultation. The patient was thought to have had an immune-related adverse event, with the tumor showing pseudoprogression.

[A Case of Boderline Resectable Pancreatic Cancer Curatively Resected after Chemotherapy with Gemcitabine and Nab-Paclitaxel].

Combination therapy containingnab -paclitaxel(nab-PTX)and gemcitabine(GEM)is widely administered for metastatic pancreatic cancer. Recently, this regimen is likely to be applied for treatment in patients with locally advanced disease or for neoadjuvant chemotherapy(NAC)in patients with borderline resectable(BR)pancreatic cancer. We report a case of BR pancreatic cancer in a patient who was eligible for comparison of the imaging findings with the microscopic findings of the resected specimen. A 72-year-old woman was admitted to our hospital with a complaint of jaundice. Enhanced CT showed a 35mm tumor at the head of the pancreas involvingthe portal vein and in contact with the superior mesenteric artery(SMA). After 4 courses of chemotherapy containinga combination of nab-PTX and GEM, the tumor reduced in size, but was still in contact with the portal vein and SMA on imaging. The level of tumor marker CA19-9 was remarkably reduced. Subtotal stomach-preservingpancreaticoduodenectomy with portal vein reconstruction was performed. Macroscopic findings of the cut surface of the resected specimen showed that a white nodule at the pancreas head involved the portal vein and was in contact with the close-cut margin from the SMA; however, microscopic findings revealed that tumor cells had disappeared in the plexus around the SMA. R0 resection was achieved. The histological treatment effect based on Evans' classification and TNM classification were GradeⅡ and pT3N1aM0(pStage ⅡB), respectively. There has been no recurrence 15 months after the surgery. Based on the abovementioned findings, chemotherapy containing a combination of nab-PTX and GEM can be an effective option of NAC for BR-A pancreatic cancer. Even if the tumor is in contact with the SMA on imaging, when the CA19- 9 level is markedly reduced, there is a possibility of achievingR0 surgery.

Antitumor effects of metformin are a result of inhibiting nuclear factor kappa B nuclear translocation in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer that has proven difficult to treat despite multidisciplinary therapy, and a new treatment strategy is demanded. Metformin is used for type 2 diabetes mellitus and its antitumor effects have been reported recently. Metformin exerts antitumor effects in various respects, such as inhibiting inflammation, tumor growth and epithelial-mesenchymal transition (EMT). However, few reports have described the efficacy of metformin on ESCC, and their findings have been controversial. We analyzed the antitumor effects of metformin and clarified its effects on anti-inflammation, growth suppression and EMT inhibition. Activation of nuclear factor kappa B (NF-κB), the major transcription factor induced by inflammation, was investigated by immunostaining. We found that localization of NF-κB in the nucleus was reduced after metformin treatment. This suggests that metformin inhibited the activation of NF-κB. Metformin inhibited tumor growth and induced apoptosis in ESCC cell lines. Associated with EMT, we examined cell motility by a wound healing assay and the epithelial marker E-cadherin expression of various ESCC cell lines by western blotting. Metformin inhibited cell motility and induced E-cadherin expression. In conclusion, metformin showed multiple antitumor effects such as growth suppression, invasion inhibition, and control of EMT by inhibiting NF-κB localization on ESCC. Further exploration of the marker of treatment efficacy and combination therapy could result in the possibility for novel treatment to use metformin on ESCC.

ZNF750 Expression Is a Potential Prognostic Biomarker in Esophageal Squamous Cell Carcinoma.

OBJECTIVE: ZNF750, a transcriptional regulator of epidermal differentiation, has been identified as a tumor suppressor in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to investigate the clinical and prognostic significance of ZNF750 expression and to evaluate the effect of ZNF750 knockdown on cell proliferation, migration, and invasion in ESCC. METHODS: A total of 124 patients with ESCC who underwent curative esophagectomy were evaluated in this study. The expression of ZNF750 in surgical specimens was immunohistochemically assessed and used in the analysis of clinicopathological features and overall survival (OS). The molecular role of ZNF750 was investigated by ZNF750 knockdown using small interfering RNA (siRNA) in ESCC cell lines. RESULTS: Low ZNF750 expression had a significant correlation with positive lymph node metastasis (p = 0.028). Furthermore, there was a significant relationship between low expression of ZNF750 in ESCC and a poor OS, and a multivariate analysis showed that low ZNF750 expression was an independent prognostic factor (p = 0.020). The cell growth, migration, and invasion were significantly increased by downregulation of ZNF750. CONCLUSIONS: The low expression of ZNF750 was significantly associated with a poor prognosis, and ZNF750 expression may, therefore, be a reliable prognostic biomarker in ESCC.