[A Case of Gastric Cancer with Extensive Lymph Node Metastasis Causing Stenosis Symptoms in the Primary pCR after Preoperative Chemotherapy].

A 65‒year‒old man was found with a circumferential type 2 tumor in the gastric antrum by upper gastrointestinal endoscopy, and biopsy revealed poorly a differentiated adenocarcinoma and HER2‒negative results. According to imaging examinations and laparoscopy, he was diagnosed with an advanced gastric cancer, classified as cT4a(SE)N3M0 and cStage Ⅲ. He underwent neoadjuvant chemotherapy(SOX regimen)because of the bulky N finding. After 2 courses of the treatment, marked reductions in the primary gastric lesion and metastatic lymph nodes were observed, although stenosis appeared at the gastric tumor site. The W‒ED tube was used to depressurize the stomach and to manage his nutrition, and the patient's surgery was conducted under good general conditions. We performed a distal gastrectomy(D2 dissection)and cholecystectomy. Histopathological examination showed no viable tumor cells in the primary gastric lesion(Grade 3). Two metastases were found in the dissected lymph nodes, although only a few cancer cells persisted. We report a case of gastric cancer in which pCR was obtained in the primary lesion, although stenosis appeared after the neoadjuvant chemotherapy.

The therapeutic strategy for advanced gastric cancer with pyloric stenosis and liver metastasis; successfully treated by gastro-jejunal bypass and chemotherapy first, followed by curative R0 resection.

BACKGROUND: The indication of surgical resection for liver metastasis from gastric cancer (GC) is still limited and controversial because of its more aggressive oncological characteristics than liver metastasis from colorectal cancer. Pyloric stenosis causes an inadequate oral intake and malnutrition in GC patients. We herein report a case of GC with these two factors that was successfully treated by the combination of gastro-jejunal bypass and chemotherapy, followed by curative R0 resection. CASE PRESENTATION: A 60-year-old man was diagnosed with type 2 GC with liver metastasis and pyloric stenosis, which was confirmed as the HER2-positive type. He underwent gastrojejunostomy and received capecitabine and cisplatin (XP) + trastuzumab chemotherapy. After three courses of the XP + trastuzumab regimen, shrinkage of the primary lesion and liver metastasis was confirmed and his nutritional parameters markedly improved with a stable oral intake after bypass surgery. He underwent curative R0 resection by distal gastrectomy with D2 lymphadenectomy and partial hepatectomy. Histologically, viable tumor cells were observed in less than one-third of the primary lesion, and only scar tissue without viable cancer cells was noted in the resected liver specimen. His postoperative course was uneventful, and recurrence has not been detected in the 30 months after surgery without adjuvant chemotherapy. CONCLUSION: The present case report describes a successful strategy for advanced GC with pyloric stenosis and liver metastasis.

[Preoperative Esophageal Decompression and Enteral Nutrition Using a W-ED Tube in Patients with Esophagogastric Junction Cancer-A Case Report].

The patient was a 67-year-old male diagnosed with adenocarcinoma of the esophagogastric junction. The esophagus was markedly dilated due to severe stenosis, and aspiration pneumonia was observed. Therefore, he was treated with a W- ED tube for simultaneous esophageal decompression and enteral nutrition. Two weeks of W-ED tube placement improved esophageal dilatation and pneumonia while maintaining nutritional status; thus, he underwent proximal gastrectomy, lower esophagectomy and combined resection of distal pancreas, spleen and left crus of diaphragm with jejunal interposition reconstruction. His postoperative course was uneventful, and he was discharged 16 days after surgery without any postoperative infectious complications such as pneumonia, anastomotic leakage, pancreatic fistula and enterocolitis. In the preoperative management for patients with esophagogastric junction cancer with severe stenosis, simultaneous esophageal decompression and enteral nutrition using a W-ED tube is very useful because it can improve aspiration pneumonia, reduce the risk of anastomotic leakage by improving esophageal edema, and prevent disuse atrophy of small intestinal villi.

[A Case of Gastric Carcinoma with Lymphoid Stroma That Was Difficult to Diagnose Preoperatively].

A 71-year-old man was referred to our hospital because of a gastric submucosal tumor. Gastrointestinal stromal tumor (GIST)was diagnosed in the antrum of the stomach and local resection was undergone. At this time, upper gastrointestinal endoscopy found the gastric submucosal tumor with a size of about 5 mm on the posterior wall of the fundus, but it was followed up. The lesion had grown to a size of about 10 mm by endoscopy 2 years later, and a biopsy was performed. Gastric mucosa associated lymphoid tissue(MALT)lymphoma was diagnosed by pathological examination, and Helicobacter pylori eradication therapy was performed. Endoscopy after treatment further increased the size of the lesion to about 20 mm, and ulceration was also observed. A biopsy was performed again, and a diagnosis of poorly differentiated adenocarcinoma was made, and laparoscopic proximal gastrectomy was undergone. It was the diagnosis of gastric carcinoma with lymphoid stroma(GCLS), pT3N0M0, pStage ⅡA in the postoperative pathological examination. GCLS is a rare disease with a frequency of about 1 to 4% of all gastric cancers, and preoperative diagnosis is difficult. From the morphology and histology, the differential diagnosis from submucosal tumors and lymphomas becomes problems.

[A Surgical Case Report of Gastric Cancer Patient with Severe COPD Successfully Controlled by Preoperative Pulmonary Rehabilitation].

A 72-year-old man with a history of chronic obstructive pulmonary disease(COPD)was diagnosed with type 3 gastric cancer at the posterior wall of the gastric body. Although there was no distant metastasis in preoperative imaging tests, pulmonary function test revealed severe obstructive ventilatory impairment, suggesting that the patient had high risks of perioperative pulmonary complications. After treatment for COPD and preoperative pulmonary rehabilitation under hospitalization for 2 weeks, laparoscopic distal gastrectomy plus D2 lymphadenectomy plus Roux-en-Y reconstruction was performed. The patient showed stable respiratory condition postoperatively, and was discharged from hospital on postoperative day 12 without serious postoperative complications. It was suggested that preoperative pulmonary rehabilitation reduced postoperative pulmonary complications and allowed safe surgery in patients with severe COPD.

Publisher Correction: miR-3140 suppresses tumor cell growth by targeting BRD4 via its coding sequence and downregulates the BRD4-NUT fusion oncoprotein.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

miR-3140 suppresses tumor cell growth by targeting BRD4 via its coding sequence and downregulates the BRD4-NUT fusion oncoprotein.

Bromodomain Containing 4 (BRD4) mediates transcriptional elongation of the oncogene MYC by binding to acetylated histones. BRD4 has been shown to play a critical role in tumorigenesis in several cancers, and the BRD4-NUT fusion gene is a driver of NUT midline carcinoma (NMC), a rare but highly lethal cancer. microRNAs (miRNAs) are endogenous small non-coding RNAs that suppress target gene expression by binding to complementary mRNA sequences. Here, we show that miR-3140, which was identified as a novel tumor suppressive miRNA by function-based screening of a library containing 1090 miRNA mimics, directly suppressed BRD4 by binding to its coding sequence (CDS). miR-3140 concurrently downregulated BRD3 by bind to its CDS as well as CDK2 and EGFR by binding to their 3' untranslated regions. miR-3140 inhibited tumor cell growth in vitro in various cancer cell lines, including EGFR tyrosine kinase inhibitor-resistant cells. Interestingly, we found that miR-3140 downregulated the BRD4-NUT fusion protein and suppressed in vitro tumor cell growth in a NMC cell line, Ty-82 cells. Furthermore, administration of miR-3140 suppressed in vivo tumor growth in a xenograft mouse model. Our results suggest that miR-3140 is a candidate for the development of miRNA-based cancer therapeutics.

[Efficacy of Palliative Radiotherapy for Unresectable Advanced Gastric Cancer with Bleeding].

Bleeding and obstruction negativelyimpact qualityof life for patients with unresectable advanced gastric cancer. There are several choices against bleeding and obstruction such as surgery, endoscopic therapy, radiotherapy and interventional radiology. We report on an 85-year-old woman with StageIV gastric cancer with tumor bleeding. Radiation therapyof 30 Gyin 10 fractions was performed. Anyadverse events were not confirmed. Bleeding or obstruction did not occur for 7 months after radiation therapy. Palliative radiation therapy to gastric cancer can be a reasonable option for patients with unsuitable general conditions for surgical intervention.

[A Case of Laparoscopic Cholecystectomy(TANKO)for Gallbladder Cancer with Torsion].

Gallbladder torsion is comparatively rare. Gallbladder cancer is found in 1.5% of cases of acute cholecystitis. We report a case of laparoscopic cholecystectomy(TANKO)for gallbladder cancer with torsion. CASE: A 54-year-old woman with epigastric pain underwent enhanced computed tomography. Gallbladder torsion and a tumor at the gallbladder neck were suspected, and ascites was observed. She was diagnosed with gallbladder torsion, and surgery was performed the same day. Intraoperative findings: The gallbladder was movable, minimally attached to the liver bed, rotated 360°around the cystic duct and cystic artery, and appeared necrotic. The torsion was relieved and laparoscopic cholecystectomy(TANKO)was performed. We accidentally perforated the gallbladder and bile leaked out. COURSE: The patient did well postoperatively. Pathological diagnosis revealed gallbladder cancer. DISCUSSION: Gallbladder cancer with torsion has been reported in 14 cases, not including ours. Among these, none were performed using laparoscopic cholecystectomy(TANKO). We believe that laparoscopic cholecystectomy is appropriate for such cases, but the approach must be carefully considered because of the risk of perforation.

miR-509-5p and miR-1243 increase the sensitivity to gemcitabine by inhibiting epithelial-mesenchymal transition in pancreatic cancer.

The epithelial-mesenchymal transition (EMT) contributes to various processes in cancer progression, such as metastasis and drug resistance. Since we have already established a cell-based reporter system for identifying EMT-suppressive microRNAs (miRNAs) in the pancreatic cancer cell line Panc1, we performed a function-based screening assay by combining this reporter system and a miRNA library composed of 1,090 miRNAs. As a result, we identified miR-509-5p and miR-1243 as EMT-suppressive miRNAs, although the mechanisms for EMT-suppression induced by these miRNAs have yet to be clarified. Herein, we demonstrated that overexpression of miR-509-5p and miR-1243 increased the expression of E-cadherin through the suppression of EMT-related gene expression and that drug sensitivity increased with a combination of each of these miRNAs and gemcitabine. Moreover, miR-509-5p was associated with worse overall survival in patients with pancreatic cancer and was identified as an independently selected predictor of mortality. Our findings suggest that miR-509-5p and miR-1243 might be novel chemotherapeutic targets and serve as biomarkers in pancreatic cancer.

Genome-wide screening of DNA methylation associated with lymph node metastasis in esophageal squamous cell carcinoma.

Lymph node metastasis (LNM) of esophageal squamous cell carcinoma (ESCC) is well-known to be an early event associated with poor prognosis in patients with ESCC. Recently, tumor-specific aberrant DNA methylation of CpG islands around the promoter regions of tumor-related genes has been investigated as a possible biomarker for use in early diagnosis and prediction of prognosis. However, there are few DNA methylation markers able to predict the presence of LNM in ESCC. To identify DNA methylation markers associated with LNM of ESCC, we performed a genome-wide screening of DNA methylation status in a discovery cohort of 67 primary ESCC tissues and their paired normal esophageal tissues using the Illumina Infinium HumanMethylation450 BeadChip. In this screening, we focused on differentially methylated regions (DMRs) that were associated with LNM of ESCC, as prime candidates for DNA methylation markers. We extracted three genes, HOXB2, SLC15A3, and SEPT9, as candidates predicting LNM of ESCC, using pyrosequencing and several statistical analyses in the discovery cohort. We confirmed that HOXB2 and SEPT9 were highly methylated in LNM-positive tumors in 59 ESCC validation samples. These results suggested that HOXB2 and SEPT9 may be useful epigenetic biomarkers for the prediction of the presence of LNM in ESCC.

Clinical utility of circulating cell-free Epstein-Barr virus DNA in patients with gastric cancer.

Recent comprehensive molecular subtyping of gastric cancer (GC) identified Epstein-Barr virus (EBV)-positive tumors as a subtype with distinct salient molecular and clinical features. In this study, we aimed to determine the potential utility of circulating cell-free EBV DNA as a biomarker for the detection and/or monitoring of therapeutic response in patients with EBV-associated gastric carcinoma (EBVaGC). The EBV genes-to-ribonuclease P RNA component H1 ratios (EBV ratios) in the GC tumors and plasma samples were determined by quantitative real-time polymerase chain reaction in 153 patients with GC, including 14 patients with EBVaGC diagnosed by the conventional method. Circulating cell-free EBV DNA was detected in 14 patients with GC: the sensitivity and specificity of detection were 71.4% (10/14) and 97.1% (135/139), respectively. Plasma EBV ratios were significantly correlated with the size of EBVaGC tumors, and the plasma EBV DNA detected before surgery in EBVaGC cases disappeared after surgery. Patients with EBVaGC may have a better prognosis, but circulating cell-free EBV DNA had no or little impact on prognosis. In addition, repeated assessment of the plasma EBV ratio in EBVaGC showed a decrease and increase in plasma EBV DNA after treatment and during tumor progression/recurrence, respectively. These results suggest the potential utility of circulating cell-free DNA to reveal EBV DNA for the identification of the EBVaGC subtype and/or for real-time monitoring of tumor progression as well as treatment response in patients with EBVaGC.

[A Case of Esophago-Gastric Junctional Carcinoma with Intramural Invasion and Cervical Lymph Node Metastasis].

The patient was a 66-year-old man who was diagnosed with a type 3 lesion in the esophago-gastric junction and a type 1 lesion in the upper esophagus. Both the lesions were diagnosed as adenocarcinoma. Chest and abdominal computed tomography examinations pointed out No. 106recL lymph node metastasis. He was diagnosed with Stage III esophago-gastric cancer( T2N3M0)and treated by a laparoscopic subtotal esophagectomy with 2-field lymph node dissection. The histological diagnosis was type 3 adenocarcinoma in the esophago-gastric junction with intramural metastasis and massive lymph node metastasis(No. 1, No. 2, No. 101L, No. 106recL). A vertical connection of venous invasion in the submucosal layer was also observed from the primary lesion to the cervical esophagus via intramural invasion. Treatment based on esophageal cancer is necessary in advanced esophago-gastric cancers with intramural metastasis or massive venous invasion.

[A Case of Gemcitabine and Nab-Paclitaxel Therapy for Multiple Metastatic Pancreatic Cancer].

Pancreatic cancer is one of the leading causes of cancer-related death in Japan. Nab-paclitaxel(nab-PTX)and gemcitabine( GEM)combination chemotherapysignificantlyimproved overall survival in a phase III trial(MPACT). This combination chemotherapyhas become one of the first-line treatments for patients with metastatic pancreatic cancer since December 2014. We report a case of a patient who underwent this chemotherapyfor recurrence of pancreatic head cancer. A 64-yearold man, who underwent curative resection of pancreatic cancer 2 years ago, relapsed with multiple lung metastases and a para-aortic nodal metastasis. The patient was treated with combination chemotherapyof nab-PTX 125mg/m2 plus GEM 1,000mg/m2. He died from carcinomatous pleurisy1 9 months after starting the chemotherapy. The patient skipped scheduled chemotherapyonly3 times due to Grade 3 neutropenia during his clinical course over 19 months. The combination regimen of nab-paclitaxel and gemcitabine is thought to be a well-tolerated and standard treatment for metastatic pancreatic cancer.

Monitoring the HER2 copy number status in circulating tumor DNA by droplet digital PCR in patients with gastric cancer.

BACKGROUND: We previously demonstrated the potential of circulating tumor DNA (ctDNA) for the amplification of detecting HER2 in patients with gastric cancer (GC). In the present study, we focused on the clinical courses of patients who developed recurrence with GC, and investigated the potential clinical utility of the ddPCR-based HER2 copy number (CN) as a marker for the temporal and/or spatial heterogeneities of GC during treatment progress. METHOD: We enrolled 30 healthy volunteers and 60 patients with GC who underwent surgery, including 17 patients who developed recurrence. Using ribonuclease P RNA component H1 (RPPH1) as a reference gene, plasma HER2 to RPPH1 ratios (the HER2 ratio) were determined using ddPCR. RESULTS: The preoperative plasma HER2 ratio correlated with the tumor HER2 status (p < 0.001), and sensitivity and specificity were 0.733 and 0.933, respectively. Analyses of plasma samples during the postoperative follow-up periods revealed that high plasma HER2 ratios were detected at the time of recurrence in 7 of 13 cases, which were diagnosed as being HER2 negative at the time of surgery. These results were supported by continuously increasing HER2 ratios thereafter with the progression of recurrent cancer. CONCLUSION: The plasma HER2 ratio determined by ddPCR is a repeatable and noninvasive approach for real-time evaluations of the HER2 status to monitor the effects of treatments for patients with HER2-positive GC and enable treatment options for patients with HER2-negative GC but positive conversion of the HER2 status after recurrence.

Tumor exosome-mediated promotion of adhesion to mesothelial cells in gastric cancer cells.

BACKGROUND: Peritoneal metastasis consists of a highly complex series of steps, and the details of the underlying molecular mechanism remain largely unclear. In this study, the effects of tumor-derived exosomes (TEX) on the progression of gastric cancers were investigated in peritoneal metastasis. RESULTS: TEX were internalized in both mesothelial and gastric cancer cells in a cellular origin non-specific manner. Internalization of TEX into mesothelial cells promoted significant adhesion between mesothelial and gastric cancer cells, and TEX internalization into gastric cancer cells significantly promoted migratory ability, while internalization of mesothelial cell-derived exosomes did not. Expression of adhesion-related molecules, such as fibronectin 1 (FN1) and laminin gamma 1 (LAMC1), were increased in mesothelial cells after internalization of TEX from gastric cancer cell line and malignant pleural effusion. METHODS: TEX were extracted from cell-conditioned medium by ultracentrifugation. The effects of TEX on the malignant potential of gastric cancer were investigated in adhesion, invasion, and proliferation assays. PCR array as well as western blotting were performed to determine the underlying molecular mechanisms. The molecular changes in mesothelial cell after internalization of TEX derived from malignant pleural effusion were also confirmed. CONCLUSIONS: TEX may play a critical role in the development of peritoneal metastasis of gastric cancer, which may be partially due to inducing increased expression of adhesion molecules in mesothelial cells.

Plasma level of metastasis-associated lung adenocarcinoma transcript 1 is associated with liver damage and predicts development of hepatocellular carcinoma.

Recent studies have shown that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was overexpressed in many human solid cancers, however, its roles in plasma of hepatocellular carcinoma (HCC) patients were unclear. The aim of this study was to investigate the significance of plasma MALAT1 levels in HCC patients. Plasma samples were collected from pre-operative HCC, hepatic disease patients, and healthy controls, and tissue samples from HCC patients and colorectal cancer patients with liver metastasis. Plasma and tissue MALAT1 levels were measured. Plasma MALAT1 levels were progressively and significantly higher in HCC patients than hepatic disease patients, and higher in hepatic disease patients than healthy controls. The expression of MALAT1 in HCC tissue was slightly higher than that in paired non-cancerous liver tissue, but not significant. The expression of MALAT1 in the non-cancerous liver tissue of 20 HCC patients was significantly higher than that in normal liver tissue of 13 colorectal cancer patients. In contrast, plasma MALAT1 levels were significantly low in HCC patients with hepatitis B infection, and significantly high in patients with liver damage B or liver cirrhosis. In a receiver-operator curve analysis of HCC and hepatic disease patients, the cut-off value of plasma MALAT1 was 1.60 and the area under the curve was 0.66. Plasma MALAT1 levels were not correlated with α-fetoprotein or protein induced by vitamin K absence II, whereas sensitivity and specificity for the detection of HCC with the combination of MALAT1, α-fetoprotein, and protein induced by vitamin K absence II were 88.6% and 75%, respectively. In conclusion, the plasma MALAT1 level is associated with liver damage, and has clinical utility for predicting development of HCC.

Effects of neutropenia and histological responses in esophageal squamous cell carcinoma with neo-adjuvant chemotherapy.

BACKGROUND: Neo-adjuvant chemotherapy (NAC) followed by radical esophagectomy has been shown to prolong survival in patients with locally advanced esophageal squamous cell carcinoma (ESCC). However, neutropenia, one of the major adverse events due to NAC, influences the therapeutic course. The aim of this study is to clarify the relationship between neutropenia and therapeutic response in ESCC with NAC. METHODS: A total of 117 patients with clinical stage II/III ESCC who had undergone NAC followed by radical esophagectomy were retrospectively analyzed in terms of the relationship between neutropenia and clinicopathological features or outcomes. RESULTS: Neutropenia was the major adverse event observed in 56 % (66/117) and grade 3/4 neutropenia occurred in 29 % of patients. Grade 3/4 neutropenia correlated with a high histological response (Grade 1b-3) (p < 0.01). Correlative analysis identified grade 3/4 neutropenia and poor differentiation as independent predictors of a high histological response (odds ratio 5.13 and 3.25, p < 0.01 and p = 0.01, respectively). Survival analysis showed that patients with a high histological response had significantly longer survival than those with a low histological response (Grade 0-1a) (p = 0.03), whereas no significant differences were found for survival according to the grade of neutropenia (p = 0.45). In a subgroup analysis according to histological response, grade 3/4 neutropenia correlated with worse survival in patients with a low histological response (p = 0.05). CONCLUSION: Severe neutropenia due to NAC correlates with a high histological response in ESCC. However, severe neutropenia may also result in a worse prognosis for patients with a low histological response.

Increase in peritoneal recurrence induced by intraoperative hemorrhage in gastrectomy.

BACKGROUND: The association between intraoperative hemorrhage and the type of recurrence was examined, with a focus on peritoneal metastasis. METHODS: A total of 540 patients who underwent macroscopically curative gastrectomy for advanced gastric cancers were reviewed for various clinicopathological characteristics, such as the amount of intraoperative hemorrhage and the pattern of recurrence. Additionally, adhesion assays using gastric cancer cells and mesothelial cells were performed in the presence of blood plasma to assess its effects on cell adhesion. RESULTS: Large intraoperative hemorrhages were correlated with a higher risk of peritoneal metastasis, while small hemorrhages were not. However, there were no significant differences in the incidence of all recurrences or other types of recurrence between both groups. Multivariate analysis of all cases (T2-4) revealed that large intraoperative hemorrhages were not an independent risk factor for peritoneal recurrence (p = 0.144); however, the large hemorrhage group developed peritoneal recurrence more frequently than the small hemorrhage group in each T stage. In the adhesion assay, the ability of cancer cells and mesothelial cells to adhere to each other was enhanced by the addition of plasma to the culture medium. The addition of heparin significantly decreased the plasma-induced enhancement of cell adhesion of Kato III, but not MKN45 or MKN74. CONCLUSIONS: Advanced gastric cancer patients accompanied by a large amount of intraoperative hemorrhage are more likely to develop peritoneal recurrence, and this risk might be due, at least in part, to the increased ability of cancer cells and mesothelial cells to adhere to each other.