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Esophageal bronchogenic cysts are rare, and since a limited number of cases has been reported, the treatment plan for asymptomatic patients is difficult. A 55-year-old man without any symptoms visited our hospital for further examination of an esophageal mass detected on simple computed tomography. Upper endoscopy showed the protruding, submucosal mass covered by normal mucosa, and endoscopic sonography confirmed hypoechoic lesions originating from the muscularis propria. The patient was diagnosed as having an esophageal duplication cyst and underwent thoracoscopic resection. Pathological findings were consistent with an esophageal bronchogenic cyst. The patient was discharged without any problems on the 6th postoperative day. Upper endoscopy was performed 6 months after surgery, and no evidence of esophageal diverticula or narrowing was present. In conclusion, early thoracoscopic resection of esophageal bronchogenic cysts, before appearance of the symptom, can be a considerable treatment option because it is less invasive and may be advantageous for obtaining a definitive diagnosis in patients who are candidates for safe surgical resection.

Background: The prognosis of patients with recurrent gastric cancer is extremely poor despite chemotherapy being clinically recommended as the first therapeutic strategy. Recent clinical trials have established the clinical utility of nivolumab in the third-line treatment of such patients. Remarkably, immune-related adverse events (irAE) have been focused as a promising predictor for tumor response to nivolumab. This report aims to present a long-term survivor of recurrent gastric cancer who was followed up without any treatments after the nivolumab discontinuation because of irAE.Case presentation: A 65-year-old male with stage III gastric cancer (cT4aN1M0) underwent distal gastrectomy and a partial resection of the transverse colon with D2 lymph node dissection after neoadjuvant chemotherapy. Owing to the final pathological stage IIIB (ypT4bN1M0), the patient received adjuvant chemotherapy. Nevertheless, during adjuvant chemotherapy 1-year post-surgery, computed tomography (CT) revealed lymph node swelling in station no. 9. Thus, upon diagnosis with lymph node recurrence, the patient was treated with two courses of capecitabine + oxaliplatin and three courses of ramucirumab + paclitaxel as the first- and second-line regimens, respectively. Based on these regimens, the patient had a progressive disease to chemotherapy. Consequently, we administered nivolumab 3 mg/kg intravenously every 2 weeks and 240 mg/kg intravenously every 2 weeks after September 2018 as the third-line regimen. After four courses of nivolumab, CT revealed a significant shrinkage of the metastatic lymph node, with a 45.6% reduction. We confirmed a partial response during 11 courses of nivolumab. Since the occurrence of grade 4 diabetes mellitus after 12 courses of nivolumab, the patient was followed up without any treatment after the nivolumab discontinuation. Currently, the patient remains a partial response for 15 months since the nivolumab discontinuation and is alive for 31 months after disease recurrence.Conclusions: Acute irAE during nivolumab chemotherapy could be one of the crucial clinical factors to predict tumor suppression in patients with advanced gastric cancer.

Cancer is a leading cause of death worldwide, and the incidence continues to increase. Despite major research aimed at discovering and developing novel and effective anticancer drugs, oncology drug development is a lengthy and costly process, with high attrition rates. Drug repositioning (DR, also referred to as drug repurposing), the process of finding new uses for approved noncancer drugs, has been gaining popularity in the past decade. DR has become a powerful alternative strategy for discovering and developing novel anticancer drug candidates from the existing approved drug space. Indeed, the availability of several large established libraries of clinical drugs and rapid advances in disease biology, genomics/transcriptomics/proteomics and bioinformatics has accelerated the pace of activity‐based, literature‐based and in silico DR, thereby improving safety and reducing costs. However, DR still faces financial obstacles in clinical trials, which could limit its practical use in the clinic. Here, we provide a brief review of DR in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan., We provide a brief review of drug repositioning (DR) in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan.

Background/aim Kinesin family member 15 (KIF15) participates in the transport of macromolecules in essential cellular processes. In this study we evaluated the clinical relevance of KIF15 expression in hepatocellular carcinoma (HCC). Materials and methods Association between KIF15 expression and clinical outcomes in HCC patients was analyzed using three independent cohorts. Localization of KIF15 expression was assessed by immunohistochemical analysis. Co-culture experiments were performed using healthy donor peripheral blood mononuclear cells (PBMC) and HCC cell lines. Results Immunohistochemical analysis showed that KIF15 was mainly expressed in inflammatory monocytes around cancer cells. Multivariate analysis indicated high KIF15 expression was an independent poor prognostic factor for survival. HCC cells with high expression of minichromosome maintenance protein 2 (MCM2) were located close to KIF15-expressing inflammatory monocytes. The proliferation ability of HCC cells was increased by co-culture with PBMC. Conclusion High KIF15 expression in inflammatory monocytes in tumor tissues may serve as a prognostic marker for poor outcome in HCC.

Alternative splicing, regulated by DEAD‐Box Helicase (DDX) families, plays an important role in cancer. However, the relationship between the DDX family and cancer has not been fully elucidated. In the present study, we identified a candidate oncogene DDX56 on Ch.7p by a bioinformatics approach using The Cancer Genome Atlas (TCGA) dataset of colorectal cancer (CRC). DDX56 expression was measured by RT‐qPCR and immunochemical staining in 108 CRC patients. Clinicopathological and survival analyses were carried out using three CRC datasets. Biological roles of DDX56 were explored by gene set enrichment analysis (GSEA), and cell proliferation in vitro and in vivo, cell cycle assays, and using DDX56‐knockdown or overexpressed CRC cells. RNA sequencing was carried out to elucidate the effect of DDX56 on mRNA splicing. We found that DDX56 expression was positively correlated with the amplification of DDX56 and was upregulated in CRC cells. High DDX56 expression was associated with lymphatic invasion and distant metastasis and was an independent poor prognostic factor. In vitro analysis, in vivo analysis and GSEA showed that DDX56 promoted proliferation ability through regulating the cell cycle. DDX56 knockdown reduced intron retention and tumor suppressor WEE1 expression, which functions as a G2‐M DNA damage checkpoint. We have identified DDX56 as a novel oncogene and prognostic biomarker of CRC that promotes alternative splicing of WEE1.

Recent developments in molecular-targeted therapies have improved the clinical outcome of cancer patients; however, the issue of adverse effects due to treatments has often gone unconsidered. We herein report the results of a clinical trial of dual genomic analyses for healthy longevity in a postoperative cancer patient. We performed dual genomic analyses for a representative 79-year-old rectal cancer patient who relapsed with liver metastasis. First, we determined single-nucleotide polymorphisms according to the constitution and disease risk in the genomic DNA from the patient’s saliva by referring to the data of 10,000 Japanese patients obtained from Yahoo Japan Corporation. Second, we conducted whole-exome sequencing to detect druggable mutations in the primary tumour. Forty of 59 determinable characters related to the constitution were consistent with the clinical phenotype. Several diseases classified as ‘high risk’ diseases actually occurred during the patient’s clinical course. Of the 129 significant mutations, we identified somatic mutations in BRAF, PIK3CA, and SMAD4 as targets. The dual genomic examination will improve the follow-up observation system to support primary care doctors in the social community for taking care of postoperative cancer patients.

Background Perforated diverticulitis with purulent peritonitis (Hinchey III diverticulitis) has traditionally been treated with a Hartmann’s procedure in order to avoid the considerable postoperative morbidity and mortality associated with one-stage resection and primary anastomosis. Although there have been reports regarding laparoscopic lavage as the initial treatment of perforated Hinchey III diverticulitis, a formal treatment strategy has not been established yet. We performed a three-stage surgery, including laparoscopic lavage and drainage with diverting ileostomy (first stage), laparoscopic sigmoidectomy (second stage), and ileostomy closure (third stage) in a morbidly obese patient with Hinchey III diverticulitis. Case presentation A 31-year-old man who presented with abdominal pain was diagnosed with perforated diverticulitis and sent to our hospital for evaluation. He had morbid obesity (body mass index (BMI) 50 kg/m2), acute renal failure, and uncontrolled diabetes. We performed an emergency operation including laparoscopic lavage and drainage with a diverting ileostomy for this case of Hinchey III diverticulitis. Fifteen months after the first-stage surgery, we performed laparoscopic sigmoidectomy as the second stage. Finally, 5 months later, we performed ileostomy closure. The patient recovered without significant complications. Conclusion Three-stage surgery including early laparoscopic lavage and proximal diversion for morbidly obese, comorbid patients with Hinchey III diverticulitis may be indicated in the acute phase to avoid perioperative complications and permanent colostomy creation.

Background/aim The clinical benefit of conversion surgery (CS) after chemotherapy remains unclear for stage IV gastric cancer (GC) patients. This study aimed to investigate the prognostic factors used to determine whether CS is a promising therapeutic strategy. Patients and methods We retrospectively analyzed data from 156 patients diagnosed with unresectable stage IV GC who underwent chemotherapy as the initial treatment, including 40 patients who had R0 resection in CS. Results The median survival time of the CS patients was significant longer than that of patients who underwent chemotherapy alone. A multivariate analysis identified only pN3 as an independent prognostic factor in CS patients. Among the differentiated tumor type patients, carbohydrate antigen 19-9 (CA19-9) levels were significantly higher in pN3 patients than in pN0-2 patients before chemotherapy. Among undifferentiated tumor type patients, pN3 patients had a significantly lower tumor size ratio (before chemotherapy/before surgery) than pN0-2 patients. Conclusion Although it is clinically difficult to diagnose lymph node metastasis using preoperative examinations, CA19-9 levels and tumor size ratios may be preoperative indicators for predicting pN3, which is associated with a poor prognosis in CS.

Background/aim To determine the prognostic utility of trastuzumab-based chemotherapy based on human epidermal growth factor receptor 2 (HER2) expression in patients with para-aortic lymph node (PAN) metastasis from gastric cancer. Patients and methods A total of 41 patients with clinical PAN metastasis from gastric cancer who underwent chemotherapy were retrospectively enrolled. Results Eighteen (43.9%) patients had HER2-positive tumors and consequently, received trastuzumab-based chemotherapy. A total of 11 patients underwent surgery. HER2 status was significantly correlated with the number of distant metastatic sites, the presence or absence of trastuzumab-based chemotherapy, and the presence or absence of gastrectomy. HER2-positive patients had significantly better prognosis than HER2-negative patients. Multivariate analysis identified age and trastuzumab-based chemotherapy based on HER2 status as an independent prognostic factor. Conclusion Assessing HER2 expression and subsequent trastuzumab-based chemotherapy can be an effective method for determining the prognosis of patients with PAN metastasis from gastric cancer.

Background Anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell lymphoma, which is a rare type of non-Hodgkin lymphoma. ALCL rarely presents in the gastrointestinal tract, and the esophageal involvement in of ALCL is extremely rare. Case presentation An 11-year-old boy who complained of abdominal pain and cough was diagnosed with ALK-positive ALCL on the basis of systemic lymphadenopathy findings and immunohistochemistry results of pleural effusion. Although remission was observed after chemotherapy at 5 months after diagnosis, dysphagia persisted, and esophagoscopy revealed a severe stricture in the middle thoracic esophagus. At 9 months after diagnosis, allogeneic bone marrow transplantation was performed to ensure that complete remission was maintained; however, dysphagia and saliva retention did not improve. Approximately 10 months after diagnosis, esophagoscopy revealed a blind end in the middle thoracic esophagus, similar to that in congenital esophageal atresia. Subsequently, we performed minimally invasive subtotal esophagectomy under thoracoscopy and laparoscopy and gastric conduit reconstruction via the retrosternal route more than 2 years after allogeneic bone marrow transplantation. The final pathological diagnosis was esophageal atresia with esophagitis, with no malignancy. During postoperative evaluation, the patient required swallowing training for a few months, although no major complications were noted. Oral intake was possible, and complete remission was maintained at 14 month post-surgery. Conclusions Oncologists must consider the possibility of acquired esophageal cicatricial atresia as a complication during chemotherapy for ALCL. If esophageal obstruction or esophageal atresia occur and if remission is maintained, esophagectomy and esophageal reconstruction are useful treatment options for maintaining oral intake.

Background: The Japanese Gastric Cancer Treatment Guidelines recommend S-1 and S-1 plus docetaxel as postoperative chemotherapy for pathological stage II and III gastric cancer (GC). There is currently no strategy for using chemotherapy to treat high-risk recurrent pathological stage II/III. Previous studies reported that the several nutritional, immunological, and inflammatory markers examined the association with clinical outcomes after surgery for GC. Methods: Ninety patients with GC (stage II, n = 48; stage III, n = 42) for whom gastrectomy was performed at our institution between November 2009 and September 2018 were examined. Nutritional, immunological, and inflammatory markers were calculated from blood samples within 1 week before surgery. Results: The prognostic nutritional index (PNI) status correlated with the pathological stage and disease recurrence after surgery (p = 0.015 and p < 0.0001, respectively). Thirty-three patients had disease recurrence after gastrectomy (stage II, n = 11; stage III, n = 22). The PNI was significantly lower in the recurrent group than in the non-recurrent group (p = 0.0003). The PNI correlated with overall survival and recurrence-free survival after gastrectomy (p = 0.0021 and p = 0.0001, respectively). A multivariate analysis identified the PNI as an independent prognostic factor (p = 0.006). Conclusion: The PNI may be useful for predicting the outcomes of patients with pathological stage II/III GC and may contribute to the selection of an appropriate adjuvant chemotherapy regimen.

Background Synovial sarcoma (SS) of the esophagus is extremely rare. Because of the microscopic features of SS, the monophasic type can easily be misdiagnosed as other spindle cell tumors. Here, we present the first case of a primary SS of the esophagus in the presence of SS18-SSX2 fusion transcripts. Case presentation A 47-year-old Japanese woman was initially diagnosed with thyroid papillary carcinoma in the left lobe and leiomyoma of the cervical esophagus and subsequently underwent left thyroid lobectomy and enucleation of the esophageal tumor. Four years after the first surgery, the esophageal tumor recurred. Endoscopic biopsy of the tumor revealed atypical cell proliferation with spindle cell features and mitoses. Immunohistochemistry showed focal positivity for bcl-2 and HHF35. Furthermore, the presence of SS18-SSX2 fusion transcripts was confirmed by reverse transcription-polymerase chain reaction analysis, using a paraffin-embedded tumor specimen. Therefore, the tumor was diagnosed as monophasic SS of the cervical esophagus. We re-evaluated the surgical specimen enucleated 3 years previously, which was initially diagnosed as leiomyoma, and the diagnosis of SS was confirmed. The patient underwent cervical esophagectomy with isolated jejunal interposition reconstruction. Three years after the second surgery, SS recurred in the distal anastomotic site between the jejunum and the esophagus, and the patient underwent thoracoscopic esophagectomy with gastric conduit reconstruction. The pathological grade of the lesion worsened with every recurrence. Conclusions Monophasic SS can be difficult to discriminate from other spindle cell tumors based on microscopy alone, and molecular analysis could be useful for confirming the precise diagnosis of monophasic SS.

Using a circular stapler to create an anastomosis for esophagogastrostomy after esophagectomy is well accepted; however, it remains uncertain if the greater curvature (GC) or lesser curvature (LC) of the gastric conduit is better for the anastomosis. We conducted this prospective study to compare the integrity of esophagogastrostomy between the esophagus and the GC or LC side of the gastric conduit. The subjects of this study were 70 patients who underwent esophagectomy and were randomized to a “GC” group and an “LC” group (n = 35 each). The primary and secondary end points were anastomotic leakage (AL) and anastomotic stricture (AS), respectively. The overall AL rate was 22.1%, without a significant difference between the groups. Stump leakage developed in eight of nine patients in the GC group, whereas leakage developed at the esophagogastric anastomosis in five of six patients in the LC group. The rate of stump leakage was significantly higher than that of esophagogastric AL in the GC group. The overall AS rate was 4.4%, with a significant difference between the groups (0% in the GC group vs. 9.1% in the LC group). AL rates were comparable in the two groups, but the sites of leakage were significantly different.

BackgroundPeritoneal dissemination (PD) frequently occurs in gastric cancer (GC) and is incurable. In this study, we aimed to identify novel PD-associated genes and clarify their clinical and biological significance in GC.Materials and methodsWe identified LOXL1 as a PD-associated candidate gene by in silico analysis of GC datasets (highly disseminated peritoneal GC cell line and two freely available GC datasets, GSE15459 and TCGA). Next, we evaluated the clinical significance of LOXL1 expression using RT-qPCR and immunohistochemistry staining (IHC) in a validation cohort (Kyushu cohort). Moreover, we performed gene expression analysis, including gene set enrichment analysis (GSEA) with GSE15459 and TCGA datasets. Finally, we performed a series of in vitro experiments using GC cells.ResultsIn silico analysis showed that LOXL1 was overexpressed in tumor tissues of GC patients with PD and in highly disseminated peritoneal GC cells, relative to that in the control GC patients and cells, respectively. High expression of LOXL1 was a poor prognostic factor in the TCGA dataset. Next, IHC showed that LOXL1 was highly expressed in GC cells. High LOXL1 mRNA expression was associated with poorly differentiated histological type, lymph node metastasis, and was an independent poor prognostic factor in the Kyushu validation cohort. Moreover, LOXL1 expression was positively correlated with the EMT (epithelial-mesenchymal transition) gene set in GSEA. Finally, LOXL1-overexpressing GC cells changed their morphology to a spindle-like form. LOXL1 overexpression reduced CDH1 expression; increased the expression of VIM, CDH2, SNAI2, and PLS3; and promoted the migration capacity of GC cells.ConclusionsLOXL1 is associated with PD in GC, possibly through the induction of EMT.

Background: There is growing evidence that patients with metastatic breast cancer whose disease progresses from a new metastasis (NM) have a worse prognosis than that of patients whose disease progresses from a pre-existing metastasis. The aim of this pilot study is to identify a blood biomarker predicting NM in breast cancer. Methods: The expression of epithelial (cytokeratin 18/19) or mesenchymal (plastin-3, vimentin, and N-cadherin) markers in the peripheral blood (PB) of recurrent breast cancer patients undergoing chemotherapy with eribulin or S-1 was measured over the course of treatment by RT-qPCR. The clinical significance of preoperative N-cadherin expression in the PB or tumor tissues of breast cancer patients undergoing curative surgery was assessed by RT-qPCR or using public datasets. Finally, N-cadherin expression in specific PB cell types was assessed by RT-qPCR. Results: The expression levels of the mesenchymal markers N-cadherin and vimentin were high in the NM cases, whereas that of the epithelial marker cytokeratin 18 was high in the pre-existing metastasis cases. High preoperative N-cadherin expression in PB or tumor tissues was significantly associated with poor recurrence-free survival. N-cadherin was expressed mainly in polymorphonuclear leukocytes in PB. Conclusion: N-cadherin mRNA levels in blood may serve as a novel prognostic biomarker predicting NM, including recurrence, in breast cancer patients.

BACKGROUND/AIM Certain chromosomal arms are clonally amplified in colorectal cancer (CRC) and may contain novel driver genes. The aim of this study was to identify a novel driver gene for colorectal cancer carcinogenesis on long arm of chromosome 7 and the clarify its biological function. MATERIALS AND METHODS We identified ArfGAP with GTPase domain, ankyrin repeat and PH domain 3 (AGAP3) as a putative driver gene using the CRC dataset in The Cancer Genome Atlas (TCGA). Biological functions of AGAP3 and CRMP5-associated GTPase (CRAG), a splicing variant of AGAP3, were explored by overexpression. AGAP3/CRAG expression in our cohort was examined by quantitative reverse transcription polymerase chain reaction. Clinical significance of AGAP3/CRAG expression in TCGA dataset, Gene Expression Omnibus datasets and our clinical cohort was evaluated. RESULTS AGAP3 expression was significantly increased in CRC and colorectal adenoma compared to normal tissue. CRAG overexpression up-regulated c-Jun expression, and significantly increased cell proliferation and colony formation capability. AGAP3 expression did not have a concordant association with patient prognosis among datasets. CONCLUSION CRAG may contribute to development of CRC via activator protein 1 activation.

Background/aim Circulating microRNAs (miRs) in blood have been highlighted as diagnostic, prognostic and predictive biomarkers for "Precision medicine". This study aimed to explore the possibility of using circulating precursor miRs (pre-miRs) as clinical biomarkers of recurrence in breast cancer. Materials and methods We performed miR microarray analyses of circulating miRs in blood from patients with or without recurrence of breast cancer and identified miR-488-5p as a recurrence-related miR. Then, the expression levels of pre-miR-488 or miR-488-5p were measured by RT-qPCR and the clinicopathological and prognostic significance of circulating pre-miR-488 was assessed in the blood of breast cancer patients. Results A positive correlation was noted between pre-miR-488 and miR-488-5p expression in blood. In 330 cases of surgically-treated breast cancer, high expression of circulating pre-miR-488 was an independent poor prognostic factor for recurrence-free survival. Conclusion Circulating pre-miR-488 expression could be a novel prognostic biomarker for predicting recurrence in breast cancer patients.

A Darwinian evolutionary shift occurs early in the neutral evolution of advanced colorectal carcinoma (CRC), and copy number aberrations (CNA) are essential in the transition from adenoma to carcinoma. In light of this primary evolution, we investigated the evolutionary principles of the genome that foster postoperative recurrence of CRC. CNA and neoantigens (NAG) were compared between early primary tumors with recurrence (CRCR) and early primary tumors without recurrence (precancerous and early; PCRC). We compared CNA, single nucleotide variance (SNV), RNA sequences, and T-cell receptor (TCR) repertoire between 9 primary and 10 metastatic sites from 10 CRCR cases. We found that NAG in primary sites were fewer in CRCR than in PCRC, while the arm level CNA were significantly higher in primary sites in CRCR than in PCRC. Further, a comparison of genomic aberrations of primary and metastatic conditions revealed no significant differences in CNA. The driver mutations in recurrence were the trunk of the evolutionary phylogenic tree from primary sites to recurrence sites. Notably, PD-1 and TIM3, T cell exhaustion-related molecules of the tumor immune response, were abundantly expressed in metastatic sites compared to primary sites along with the increased number of CD8 expressing cells. The postoperative recurrence-free survival period was only significantly associated with the NAG levels and TCR repertoire diversity in metastatic sites. Therefore, CNA with diminished NAG and diverse TCR repertoire in pre-metastatic sites may determine postoperative recurrence of CRC., Author summary We found that copy number aberrations (CNAs) may be the most important selective pressure promoting cancer evolution from early-to-advanced tumors in primary sites. The diminished neoantigens (NAG) in cancer cells and the diverse TCR repertoire in cytotoxic T cells were crucial for the onset of postoperative recurrence during genomic neutral evolution, along with clonal CNA and several driver SNVs from primary to recurrent sites. Therefore, cancer metastasis could be prevented by activating CTL at the premetastatic sites before priming of the metastatic process.

Highlights • Usefulness and safety of combined vascular and biliary fluorescent ICG imaging during laparoscopic cholecystectomy was reported. • Aberrant bile ducts are rare anatomical variation and clinically important because of the susceptibility to injury during cholecystectomy. • We encountered a case of laparoscopic cholecystectomy with an aberrant bile duct detected by intraoperative fluorescent cholangiography concomitant with angiography., Introduction Laparoscopic cholecystectomy is the standard surgical treatment for patients with benign gallbladder disease. However, bile duct injury continues to be reported as a surgical complication. Intraoperative cholangiography is recommended to reduce the risk of bile duct injury during laparoscopic cholecystectomy. Intraoperative cholangiography using indocyanine green, which is excreted into bile and shows fluorescence under infrared light, has recently been reported as useful in preventing bile duct injury during laparoscopic cholecystectomy. We report here a case of laparoscopic cholecystectomy with an aberrant bile duct detected by intraoperative fluorescent cholangiography concomitant with angiography. Presentation of case An 82-year-old woman was diagnosed with cholecystolithiasis and underwent laparoscopic cholecystectomy. An aberrant bile duct branching from the right side of the common hepatic duct was detected by intraoperative indocyanine green fluorescent cholangiography. Furthermore, we were able to confirm the cystic artery by reinjecting indocyanine green during the procedure. Laparoscopic cholecystectomy was performed safely without injuring the aberrant bile duct, despite no recognition of the abnormality on preoperative computed tomography or magnetic resonance imaging. Discussion and conclusions Aberrant bile ducts are rare anatomical variation and clinically important because of the susceptibility to injury during cholecystectomy. Our case reported for the first time that fluorescence cholangiography concomitant with angiography was useful for identifying an aberrant bile duct and the cystic artery during laparoscopic cholecystectomy.

Background: We previously disclosed the evolutionary principle shaping intratumor heterogeneity shifts from Darwinian to neutral evolution in primary colorectal cancer (CRC) progression. Here, we focused on the role of copy number aberrations (CNAs) in impairment of the host tumor immune response, which is characterized by the level of neoantigen (NAG) and diversity of the T-cell receptor (TCR) repertoire, and in fostering postoperative recurrence. Methods: We compared single nucleotide variants (SNVs), NAG, and CNAs between primary tumors from eight cases of early CRC with postoperative recurrence (CRCR) and from eight cases of precancerous CRC lesions without recurrence (PCRC) by whole-exome sequencing. Then, we compared tumor immune response-related factors, such as NAG, cytolytic activity (CYT), and TCR repertoire diversity, between eight primary and 12 metastatic sites from eight CRCR cases. Findings: In comparison of 10 primary CRC tumors with recurrence (CRCR) and eight precancerous tumors of CRC (PCRC), neoantigens were fewer in CRCR than in PCRC, and CNAs at the arm level were significantly more frequent in CRCR than in PCRC. SNVs and copy numbers (CNs) were inversely associated. In TCGA analysis, cytotoxic T lymphocyte-related genes CD8A, CD4G, and PD-1 in 48 primary tumors with recurrence were downregulated relative to those in 242 tumors without recurrence. In CRCR cases, the frequency of CNAs and mutated driver genes with clonality in primary sites were equal to those in recurrent sites; however, the recurrence-free period was significantly extended under low NAG level and diverse TCR repertoire in metastatic but not primary sites. Interpretation: During the evolution of CRC toward recurrence, CNAs determine the metastatic capability with diminished levels of NAG in primary tumors, and impaired NAG and diminished TCR repertoire diversity predominantly determine the recurrence-free survival period. Funding Statement: This project was supported by Japan Society for the Promotion of Science KAKENHI (16K19107, 15H05707), Grant-in-Aid for Scientific Research on Innovative Areas (15H0912), and Priority Issue on Post-K computer (hp170227, hp160219) and partially supported by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) and Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development, AMED. The Takamatsunomiya Cancer Research Funding. This research used the supercomputing resource provided by the Human Genome Center, Institute of Medical Science, University of Tokyo. Declaration of Interests: There are no conflicts of interest to declare. Ethics Approval Statement: The study design was approved by the institutional review boards and ethics committees of the hospitals to which the patients were admitted (Kyushu University Hospital Institutional Review Board: protocol number 486–01; Cancer Institute Hospital Institutional Review Board: protocol number 12–27). The study was conducted according to the principles expressed in the Declaration of Helsinki. We obtained written informed consent from all participants in this study.

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide and the second leading cause of cancer-related deaths in developed countries, with the majority of deaths being attributed to distant metastasis. Therefore, it is necessary to identify a novel biomarker for cancer progression and metastasis, one that could also be a useful therapeutic target in CRC. Amplification of chromosome 7p is frequent in CRC, and it has been considered to harbor driver genes that promote tumorigenesis or tumor progression by the gain of function. We aimed to identify novel candidate driver genes on chromosome 7p and to clarify the clinical significance of their expression in CRC. Material and Methods: 1. We selected the candidate genes that satisfied the following criteria using CRC data from The Cancer Genome Atlas (TCGA). 1) The DNA copy number and mRNA expression are positively correlated with each other, 2) overexpressed in the tumor tissues compared to the normal tissues. 2. The mRNA expression of the candidate genes was measured in 147 surgically-resected CRC tissues and the paired normal tissues in our hospital by quantitative RT-PCR. The differences of mRNA expression between CRC tissues and normal tissues were analyzed by Mann Whitney U-test. 3. Survival analysis between high and low expression group of the candidate genes was performed by the Kaplan-Meier method. Correlation between the mRNA expression of the candidate genes and the clinicopathological factors were analyzed by Fisher’s exact test. 4. Gene Set Enrichment Analysis (GSEA) was performed in CRC data from TCGA to clarify the correlation between the candidate genes and gene sets that are associated with tumorigenesis or tumor progression. Results: The Golgi to ER traffic protein 4 (GET4) was identified as a candidate driver gene. GET4 is known to be one factor of the BCL2-associated athanogene 6 (BAG6) chaperone complex and function as a regulator for the nucleo-cytoplasmic transport of BAG6. The BAG6 complex is implicated in diverse cellular processes including apoptosis, co-chaperone, and DNA damage response. The expression of GET4 was significantly higher in CRC tissues than in normal colon tissues (p=0.03), and it correlated with depth invasion (p=0.02), and lymphatic invasion (p=0.01). The high GET4 expression group had a significantly poorer prognosis than the low expression group (p=0.02). On multivariate analysis, distant metastasis was an independent prognostic factor affecting OS (p Conclusions: GET4 could be a promising driver gene of CRC on chromosome 7p possibly through regulating the location of BAG6. GET4 may be a therapeutic target as well as a poor prognostic biomarker in CRC. Note: This abstract was not presented at the meeting. Citation Format: Kensuke Koike, Takaaki Masuda, Kuniaki Sato, Yuushi Motomura, Jyunnichi Takahashi, Dai Shimizu, Shotaro Kuramitsu, Atsushi Fujii, Akihiro Kitagawa, Miwa Noda, Yusuke tsuruda, Hajime Ootu, Yousuke Kuroda, Hidetoshi Eguchi, Takashi Nakagawa, Koushi Mimori. Clinical significance of GET4 expression in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5238.

Introduction: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with extremely poor overall survival. There is no available molecular marker in clinical application until now. SATB1(special AT-rich binding protein 1) tether genomic DNA in nucleolus and hold three-dimensional structure of genomic DNA. We evaluated SATB1 expression using clinical samples from patients of ESCC and analyzed the association with clinicopathological factors and prognosis to identify novel prognostic marker in ESCC. In addition, we investigated the function of SATB1 using ESCC cells. We focused on matrix metalloproteinase protein (MMP3), which has a SATB1 binding site in its upstream. Materials and Methods: We accumulated 71 samples of ESCC patients who underwent primary tumor resection. The relative expression levels of SATB1 were obtained by normalizing the amount of SATB1 mRNA with respect to GAPDH mRNA as an endogenous control for each sample. We divided 71 ESCC samples into 2 groups, which are SATB1 low expression group (n=35) and SATB1 high expression group (n=36) according to the median of SATB1 expression level, and performed the comparison between two groups. In order to elucidate biological significance, we generated SATB1 overexpression stable transfectants in KYSE150, and performed migration and invasion assays. Next, we knockdowned SATB1 expression of KYSE410, which are ESCC lines, using SATB1 siRNA and evaluated the capability of migration and invasion. Moreover, to validate whether SATB1 altered MMP3 genomic locus, we analyzed comparative genomic hybridization (CGH) array obtained from 54 esophageal cancer samples. We examined MMP3 expression in SATB1 overexpression cells using qRT-PCR. Result: The SATB1 high expression group showed greater tumor depth than the low expression group (P=0.003). In the overall survival curve, patients in the SATB1 high expression group had a significant poorer prognosis than those in the SATB1 low expression group (P=0.013). Multivariate analysis showed that the level of SATB1 expression was an independent prognostic predictor (OR; 1.56, 95%CI; 1.04 - 2.44, P = 0.043). SATB1 transfectants significantly increased the capability of migration and invasion compared to mock (P Conclusion: We indicated that SATB1 is novel prognostic factor in ESCC and that SATB1 promote migration and invasion of ESCC cells. SATB1 may be a promising new candidate for targeted therapies for ESCC. Citation Format: Yusuke Tsuruda, Ryunosuke Kogo, Shuhei Ito, Akihiro Kitagawa, Atsushi Fujii, Shotaro Kuramitsu, Dai Simizu, Yosuke Kuroda, Hidetoshi Eguchi, Tkaaki Masuda, Shoji Natsugoe, Masaki Mori, Koshi Mimori. SATB1 is a novel prognostic factor in esophageal cancer patients and promotes migration and invasion of esophageal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1552.