[A Case of Advanced Gastric Cancer Treated with Conversion Surgery followed by Nivolumab Combination Chemotherapy].

The use of nivolumab as first-line therapy for unresectable advanced gastric cancer has now become a standard practice, and its efficacy has been established. This is the first report of a patient with advanced gastric cancer who underwent conversion surgery after first-line nivolumab combination chemotherapy. The patient was a 58-year-old woman. Her medical history included hypertension and dyslipidemia. She had advanced gastric cancer with extensive lymph node metastasis in the left supraclavicular fossa and around the abdominal aorta. After confirming the HER2-negative status and the PD-L1 CPS score to be ≥5, nivolumab was administered in combination with chemotherapy. After the treatment, she underwent a total gastrectomy with D2 dissection, combined splenectomy and pancreatic tail resection for adhesions, and para-aortic lymph node sampling as a conversion surgery. There was no obvious cancerous remnant in the resected specimen, and the pathological response was Grade 3. The patient was alive and recurrence-free at 4 months postoperatively.

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.

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.

[Successful Treatment of Gastric Cancer with Conversion Surgery after Nivolumab Treatment-A Case Report].

Immunocheckpoint inhibitors including anti-PD-1 antibody have shown certain therapeutic effects on various cancer types. They have also attracted great attention as novel cancer treatment options in addition to surgical resection, chemotherapy, and radiation therapy. Herein, we report a case of gastric cancer that was successfully treated with conversion surgery after nivolumab treatment. The patient was 68 years old and male. Upper gastrointestinal endoscopy revealed a type 3 tumor in the antrum, and he was referred to our department for further examination. The gastric cancer was diagnosed as cT4aN2M0, cStage ⅢA, and he was administered SOX as the first-line and nab-PTX/RAM as the second-line treatment, which was also a PD. As the third-line treatment, nivolumab showed remarkable reduction of the tumor after initiation, and after 14 courses, conversion surgery was performed. The patient remains alive without recurrence.

[Development of TP53-Targeted Treatment in Esophageal Squamous Cell Carcinoma Using Cancer Genomic Profiling Test].

Recently, the interest in cancer genomic medicine has increased, owing to the powerful and cost-effective technology of next-generation sequencing(NGS), which allows rapid identification of a large number of gene mutations. TP53 mutations are frequently found in solid cancers, especially in esophageal squamous cell carcinoma(ESCC), wherein the frequency of TP53 mutation is considered to be 90% or more. However, there is no clinical targeted therapy as yet utilizing TP53. Here, we aimed to characterize TP53 mutations associated with ESCC, in order to assess its feasibility as a therapeutic target. We extracted DNA and RNA from specimens of ESCC patients and analyzed them using NGS, which revealed different TP53 mutations. Based on previous reports, it is considered that different TP53 mutations lead to different functions of the protein, and subsequently account for varied prognosis in squamous cell carcinoma of the head and neck. We also performed cell viability assay using ESCC cell lines with different TP53 mutations and 2 kinds of p53-targeted drug and found differences in the growth inhibition of the cell lines. Although individual treatment can be determined depending on the type of TP53 mutation, it would be necessary to further examine the interaction of TP53 with other genes to determine its therapeutic efficacy as a target.

[A Case of Gallbladder Jejunal Anastomosis and Duodenal Jejunal Anastomosis to Maintain QOL for an Elderly Patient with Pancreatic Cancer].

An 87-year-oldwoman was admittedto our hospital with abdominal pain andfever. Computedtomography showeda 25 mm tumor mass in the pancreatic headandshowedd ilatation of the pancreatic duct andcommon bile duct. She was diagnosed with obstructive cholangitis due to pancreatic head cancer. An endoscopic naso-biliary drainage(EUS)tube was inserted, and an endoscopic ultrasound(ENBD)examination was performed. At this time, duodenal perforation occurred, and an emergency operation was performed. During the laparotomy, perforation was found in the anterior wall of the duodenum. The contamination in the abdominal cavity and the degree of tissue damage in the duodenum were mild. Gall bladder jejunal andd uodenal jejunal anastomoses were performedfor biliary bypass andto close the perforation andbypass the gastrointestinal tract, respectively. She hadno postoperative complications andwas discharged 13 days postoperatively. Oral intake was possible after discharge, andthe patient returnedhome without complications. She died 5 months postoperatively. In this case, we performedbile duct andgastrointestinal bypass surgery prophylactically. Although this surgery will not be effective for all patients, we thought that it wouldbe useful for predicting the patient's future condition and for increasing the procedural options, even in case of emergency surgery.

[Long-Term Survival of a Rectal Cancer Patient with Virchow Lymph Node Metastasis, Liver Metastasis, and Para-Aortic Lymph Node Metastasis].

A 67-year-old female was diagnosed with Stage Ⅳ rectal cancer with paraaortic lymph node metastasis. The patient underwent Hartmann's operation with D3 lymph node and paraaortic lymph node dissection. Postoperative chemotherapy with FOLFIRI was then administered for 1 year. However, liver metastasis developed, for which partial hepatectomy was performed. Postoperative chemotherapy with S-1(20 courses)was then administered. Three years and 11 months following the first operation, lymph node metastases developed and resection of lymph nodes(No. 12p, No. 16b1int)was performed. Postoperative chemotherapy with capecitabine(Cape)(8 courses)was then administered. Five years and 7 months following the first operation, Virchow lymph node metastasis developed. Despite chemotherapy with Cape and bevacizumab (Bmab), Virchow lymph node swelling recurred, and resection was performed. Nine years and 4 months following the first operation, lymph node metastases developed, and resection of lymph nodes(Virchow, No. 16b1int)was performed. Postoperative chemotherapy with S-1(8 courses)was then administered. At present, 11 years and 4 months after the first operation, the patient, whose chemotherapy has been discontinued, is alive without recurrence.

[Pulmonary Metastasis Resection Twice after Curative Resection of Esophageal Cancer-A Long-Term Survival Case].

The prognosis of patients with esophageal cancer recurrence is poor, and surgical treatment is rarely performed. Here, we report on a patient with long-term survival who underwent pulmonary metastasis resection twice after curative resection of esophageal cancer. A 62-year-old male underwent curative resection of esophageal cancer after preoperative chemoradiotherapy. The histopathological diagnosis was poorly differentiated squamous cell carcinoma(pT2N1M0, fStage Ⅱ). Five months after the operation, right lung metastasis(right-S2)was detected. Accordingly, pulmonary metastasis resection was performed. Fourteen months after the initial operation, left lung metastases(left-S3/S6)were detected. The patient underwent resection again for the pulmonary metastases. The patient died of pneumonia without recurrence 8 years 3 months after the initial operation. In selected cases, surgical resection seems effective for treating distant esophageal cancer metastasis, suggesting that surgery should be an option in cases of accumulation of numerous distant metastases in esophageal cancer.

[A Case of Colon Metastasis from Invasive Lobular Carcinoma of the Breast].

The patient was a 48-year-old woman. She consulted our hospital with a chief complaint of vomiting. Colonoscopy showed stenosis and edematous mucosa, and biopsy was performed. Histological examination demonstrated the lesion to be colonic metastasis of breast cancer, invasive lobular carcinoma. Although colorectal metastasis of breast cancer has a poor prognosis and chemotherapy is considered as the main treatment modality, hormone therapy is also a treatment option depending on the condition.

[A Case of HER2 Positive Locally Advanced Breast Cancer Successfully Treated with a Combination Therapy of Eribulin, Trastuzumab and Pertuzumab].

The patient was an 82-year-oldwoman. She consultedour hospital with a chief complaint of left breast mass. MRI showed enhancedtumor with skin andextensive pectoral muscle invasion, so it was unresectable. Immunohistopathological analysis revealeda HER2-positive lesion. We administerederibulin, trastuzumab andpertuzumab, after which the tumor became resectable. Histological examination revealedremarkable response. Combination therapy of eribulin, trastuzumab andpertuzumab was well toleratedandconsid eredto be effective.

[A Comparison of the Treatment Methods for Obstructive Colorectal Cancer].

PURPOSE: Emergency surgery for obstructive colorectal cancer is considered to be associated with a high degree of risk, and surgery may after decompression is considered to be safer. In cases of obstructive colorectal cancer, decompression can be achieved with surgery, an ileus tube, or a stent, depending on the disease condition. We herein compare the treatment methods for obstructive colorectal cancer. METHODS: Forty-two patients with obstructive colorectal cancer underwent emergency treatment between January 2012 and December 2016. RESULTS: Among the patients with obstructive colorectal cancer, 18 receiveda stent, 10 receiveda nasal ileus tube, 6 receiveda transanal ileus tube, 5 underwent stoma construction, and 3 underwent emergency surgery without decompression. The stent group showed the highest laparoscopic operation rate. There was no significant difference in the overall survival of the treatment groups. One patient in the stent group developed duplicated cancer. CONCLUSION: Stent placement can be considered to be a viable option in the emergency treatment for obstructive colorectal cancer because laparoscopic surgery anda preoperative examination can be performed.

The Antitumor Effects of Metformin on Gastric Cancer In Vitro and on Peritoneal Metastasis.

BACKGROUND/AIM: Gastric cancer (GC) with peritoneal metastasis remains difficult to treat. The anti-diabetic drug metformin exerts various antitumor effects via the 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway and nuclear factor-kappa B (NF-ĸB). Therefore, we evaluated the antitumor effects of metformin for GC in vitro and on peritoneal metastasis. MATERIALS AND METHODS: The human GC cell lines MKN1, MKN45, KATO-III and SNU-1 were used. The antiproliferative effect was evaluated in vitro with 0.5 mM or 25 mM glucose and in vivo using tumor xenograft peritoneal models of metastasis. The protein expression of AMPK, liver kinase B1 (LKB1) and NF-ĸB in tumors was examined by western blotting. RESULTS: Metformin inhibited cell proliferation in all GC lines and sensitivity was increased under low-glucose conditions in vitro. Metformin also suppressed peritoneal metastasis. In tumors, metformin reduced the numbers of proliferating cells and NF-ĸB expression, but a similar trend was not noted for AMPK. CONCLUSION: Metformin may be a useful drug for the treatment of GC with peritoneal metastasis.