北山 丈二

Gastrointestinal stromal tumors (GIST) in patients under 18 years of age are classified as pediatric GIST. Pediatric GIST are extremely rare, and there are no reports of laparoscopic-endoscopic cooperative surgery for these lesions. We report the use of non-exposed endoscopic wall-inversion surgery as a laparoscopic-endoscopic cooperative surgery-related procedure for the treatment of a pediatric GIST. The case involved a 17-year-old male patient who presented with anemia and was found to have a bleeding gastric tumor. The tumor was resected transorally using the non-exposed endoscopic wall-inversion surgery technique. No gene mutation of c-Kit or Platelet-Derived Growth Factor Receptor α (PDGFRα) was found, and the final pathological diagnosis was epithelial-type GIST due to a succinate dehydrogenase abnormality. Follow-up included a CT scan every 4 months. No recurrence has occurred to date.

OBJECTIVE: Mucin1 (MUC1), a member of the mucin family, is a glycoprotein which is often expressed in malignant cells. However, the expression and function of MUC1 in human duodenal adenocarcinoma (DAC) has not yet been characterized because of its low frequency. Here, we examined the functional roles of core protein (MUC1-C) in DAC. MATERIALS AND METHODS: Using a human duodenal cancer cell line, HuTu80, proliferation, migration, invasion, ALDH activity was assessed by cell counting kit-8, scratch wound healing, matrigel invasion, and ALDEFUOR assays, respectively. The function of MUC1 protein was evaluated with knockdown using specific siRNA as well as anti-MUC1-C peptide, GO203. MUC1 expression in human DAC was evaluated immunohistochemically in surgically resected tumors. RESULTS: The positive expression of MUC1 in HuTu80 was confirmed by RT-PCR and flow cytometry. In vitro cell growth was inhibited by the addition of 50-100 μM GO203 as well as treatment with siRNA for MUC1-C. Silencing of MUC1-C also significantly reduced migration, invasion, ALDH activity. Local injection of GO-203 (14 mg/kg) significantly suppressed the growth of subcutaneous HuTu80 tumors in nude mice. Immunohistochemically, MUC1 was strongly detected in seven DAC cases, but not in 11 others. The outcome of patients with high MUC1 expression was significantly worse than those without MUC1 expression. CONCLUSIONS: These results suggest that MUC1 is functionally associated with the malignant potential of DAC and could be a novel therapeutic target for this rare tumor.

INTRODUCTION: Immune thrombocytopenic purpura is an acquired thrombocytopenia. Preoperative management of thrombocytopenia is important in patients with gastric cancer. Partial splenic embolization can be effective for patients with thrombocytopenia, but could lead to ischemic necrosis of the remnant stomach when performing subtotal gastrectomy with splenectomy. PRESENTATION OF CASE: The patient is an 84-year old woman evaluated for anemia. Endoscopy revealed an advanced gastric cancer with bleeding. The patient also had immune thrombocytopenic purpura with a platelet count <50,000/μL. Administration of platelets did not increase the platelet count. Partial splenic embolization was performed followed by administration of high-dose immunoglobulin. The platelet count was over 50,000/μL preoperatively. The patient underwent combined subtotal gastrectomy and splenectomy, followed by an uneventful course. DISCUSSION: Patients with immune thrombocytopenic purpura and advanced gastric cancer can have anemia. Partial splenic embolization has been used to treat patients with refractory immune thrombocytopenic purpura as an alternative to splenectomy. Preoperative partial splenic embolization and high-dose immunoglobulin therapy resulted an increased platelet count in this patient. Elderly patients with gastric cancer have a high risk of postoperative complications. Patients with gastric cancer undergoing total gastrectomy have an impaired postoperative quality of life compared to those who undergo subtotal gastrectomy. We performed a subtotal gastrectomy and splenectomy as a function-preserving operation, completed safely by maintaining blood flow to the remnant stomach. CONCLUSION: Partial splenic embolization is effective for patients with immune thrombocytopenic purpura and gastric cancer. Combined subtotal gastrectomy and splenectomy is achieved by preserving blood flow to the remnant stomach.

INTRODUCTION: Gastric hyperplastic polyps are common stomach lesion and these polyps are generally benign. However, they can undergo malignant transformation. Most reported cases of malignant transformation of gastric hyperplastic polyps have been to well or moderately differentiated adenocarcinoma, and those transformed into poorly differentiated adenocarcinoma are extremely rare. No case has been reported that has changed to diffuse type adenocarcinoma with lymphatic invasion. PRESENTATION OF CASE: A 48-year-old woman presented with worsening anemia. A polyp was seen in the gastric cardia seven years prior to presentation. Helicobacter pylori infection was also found at that time. She underwent upper gastrointestinal endoscopy and biopsy of the polyp revealed signet ring cell carcinoma. Total gastrectomy was performed due to concern about possible invasion into the submucosal layer and there was no evidence of distant metastases. Histologic examination revealed both poorly differentiated adenocarcinoma and signet ring cell carcinoma surrounded by hyperplastic epithelium at the head of the polyp. Lymphatic invasion was also found, and malignant cells were limited to the mucosa. DISCUSSION: Gastric hyperplastic polyps are commonly associated with chronic gastritis which is related to Helicobacter pylori infections. Gastric hyperplastic polyps are generally benign and rarely undergo malignant transformation to adenocarcinoma with differentiated histology. The gastric hyperplastic polyp in this patient transformed to poorly differentiated adenocarcinoma with lymphatic invasion. CONCLUSION: Even small polyps may become poorly differentiated adenocarcinoma with invasion, so close follow-up or endoscopic resection are recommended as well as eradication of Helico Pylori infection when appropriate.

Activated neutrophils release neutrophil extracellular traps (NETs), which can capture and destroy microbes. Recent studies suggest that NETs are involved in various disease processes, such as autoimmune disease, thrombosis, and tumor metastases. Here, we show a detailed in vitro technique to detect NET activity during the trapping of free tumor cells, which grow after attachment to NETs. First, we collected low density neutrophils (LDN) from postoperative peritoneal lavage fluid from patients who underwent laparotomies. Short-term culturing of LDN resulted in massive NET formation that was visualized with green fluorescent nuclear and chromosome counterstain. After co-incubation of human gastric cancer cell lines MKN45, OCUM-1, and NUGC-4 with the NETs, many tumor cells were trapped by the NETs. Subsequently, the attachment was completely abrogated by the degradation of NETs with DNase I. Time-lapse video revealed that tumor cells trapped by the NETs did not die but instead grew vigorously in a continuous culture. These methods may be applied to the detection of adhesive interactions between NETs and various types of cells and materials.

Purpose Intraperitoneal paclitaxel plus systemic chemotherapy demonstrated promising clinical effects in patients with gastric cancer with peritoneal metastasis. We aimed to verify its superiority over standard systemic chemotherapy in overall survival. Patients and Methods This randomized phase III trial enrolled patients with gastric cancer with peritoneal metastasis who had received no or short-term (< 2 months) chemotherapy. Patients were randomly assigned at a two-to-one ratio to receive intraperitoneal and intravenous paclitaxel plus S-1 (IP; intraperitoneal paclitaxel 20 mg/m2 and intravenous paclitaxel 50 mg/m2 on days 1 and 8 plus S-1 80 mg/m2 per day on days 1 to 14 for a 3-week cycle) or S-1 plus cisplatin (SP; S-1 80 mg/m2 per day on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 for a 5-week cycle), stratified by center, previous chemotherapy, and extent of peritoneal metastasis. The primary end point was overall survival. Secondary end points were response rate, 3-year overall survival rate, and safety. Results We enrolled 183 patients and performed efficacy analyses in 164 eligible patients. Baseline characteristics were balanced between the arms, except that patients in the IP arm had significantly more ascites. The median survival times for the IP and SP arms were 17.7 and 15.2 months, respectively (hazard ratio, 0.72; 95% CI, 0.49 to 1.04; stratified log-rank P = .080). In the sensitivity analysis adjusted for baseline ascites, the hazard ratio was 0.59 (95% CI, 0.39 to 0.87; P = .008). The 3-year overall survival rate was 21.9% (95% CI, 14.9% to 29.9%) in the IP arm and 6.0% (95% CI, 1.6% to 14.9%) in the SP arm. Both regimens were well tolerated. Conclusion This trial failed to show statistical superiority of intraperitoneal paclitaxel plus systemic chemotherapy. However, the exploratory analyses suggested possible clinical benefits of intraperitoneal paclitaxel for gastric cancer.

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Despite recent advances in chemotherapy, outcomes of patients with peritoneal metastases (PM) from gastric cancer are still very poor and standard treatment has not been established. Although oral S-1 appears to be effective for patients with PM, the effects of systemic chemotherapy are limited. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) yield fewer benefits in patients with PM from gastric cancer than in patients with PM from other malignancies. In comparison, repeated intraperitoneal chemotherapy (RIPEC) with taxanes using an implantable peritoneal access port has a pharmacokinetic advantage for the control of peritoneal lesions and in combination with systemic chemotherapy can result in surprisingly long-term survival in patients with PM from gastric cancer. Herein, we review the results of recent clinical studies specifically targeting PM from gastric cancer and discuss future prospects for an intraperitoneal approach to the ideal treatment of patients with gastric cancer with peritoneal involvement.

Many types of immune cells appear in peritoneal cavity after abdominal surgery. In patients who underwent laparotomy due to gastric cancer, peritoneal lavages were obtained before and after surgical procedure. Cells were recovered from intermediate layer after Ficoll-Hypaque centrifugation and analyzed for phenotypes and functions, especially focused on low density neutrophils (LDN). The number of CD66b (+) LDN with mature phenotype was markedly elevated in postoperative as compared with preoperative lavages. Short term culture of the purified LDN produced many threadlike structures positive for SYTOX, nucleic acid staining, as well as histone and myeloperoxidase, suggesting the NETs formation. Human gastric cancer cells, MKN45, OCUM-1 and NUGC-4, were selectively attached on the NETs, which was totally abolished by the pretreatment of DNAse I. Intraperitoneal (IP) co-transfer of the LDN with MKN45 in nude mice strongly augments the metastasis formation on peritoneum, which was strongly suppressed by the following IP administration of DNAse I. Many NETs-like structures were detected on the surface of human omental tissue resected by gastrectomy. NETs on peritoneal surface can assist the clustering and growth of free tumor cells disseminated in abdomen. Disruption of the NETs by DNAse might be useful to prevent the peritoneal recurrence after abdominal surgery.

INTRODUCTION: Black adrenal adenoma (BAA) is a rare, benign adrenal lesion with a black or brown appearance. This is the first report of this lesion in a patient with a synchronous esophageal cancer and highlights the importance of considering a false positive finding on a Positron Emission Tomography (PET) scan, which might otherwise preclude resection. PRESENTATION OF CASE: A 73-year-old male was diagnosed with mid-esophagus carcinoma. Computed tomography scan revealed an enlarged left adrenal gland. Plasma adrenocorticotropic hormones levels were normal. To characterize the adrenal lesion, a PET scan was obtained which showed high uptake of 18F-fluoro-2-deoxy-d-glucose (FDG), consistent with a metastasis, suggesting T3N2M1, clinical stage IV esophageal cancer. After two courses of neo-adjuvant therapy, sub-total esophagectomy and left adrenalectomy were performed. The adrenal tumor was soft, and black in color, diagnosed as a BAA on histology. The pathologic stage of the esophageal cancer was T3N0M0, Stage II. Six months after surgery, he is alive without recurrence. DISCUSSION: High FDG uptake by an adrenal lesion on PET scan, as in this patient, usually suggests a metastatic lesion. Although rare, patients with esophageal cancer and adrenal metastases have been reported to have long-term survival, so it is important to characterize an adrenal lesion when found. CONCLUSION: Most adrenal lesions with high FDG uptake are malignant, but BAA is also positive on PET scan. Although rare, BAA should be considered in patients with solitary adrenal lesions with high uptake on PET scan, even in the presence of a malignancy.

INTRODUCTION: Gastric leiomyomas are benign mesenchymal tumors, comprising about 2.5% of gastric neoplasms, which can be difficult to differentiate from gastrointestinal stromal tumors which have malignant potential. Granular cell tumors in the abdominal wall are also rare. Since mesenchymal tumors are difficult to diagnose by imaging, further studies are needed to establish the diagnosis. PRESENTATION OF CASE: A 60-year-old asymptomatic woman underwent routine upper endoscopy and was found to have a gastric submucosal lesion. Computed tomography scan also showed an abdominal wall mass. The appearance of both lesions on imaging studies were similar, but it was unclear if the two lesions had the same origin. Endoscopic ultrasound-guided fine needle aspiration biopsy of the gastric lesion was insufficient to establish the diagnosis. Laparoscopic-endoscopic cooperative resection of the gastric lesion and ultrasound-guided core-needle biopsy of the abdominal wall mass enabled pathological diagnosis of both lesions. DISCUSSION: Diagnostic imaging findings of these two lesions were similar. Histologic and immunohistochemical studies are essential to establish a definitive diagnosis. Laparoscopic-endoscopic cooperative surgery may be an effective minimally invasive approach, allowing both pathological diagnosis and complete resection of a gastric submucosal tumor, especially when endoscopic-ultrasound guided fine needle aspiration or biopsy fails to make the diagnosis. CONCLUSION: Laparoscopic-endoscopic cooperative surgery can be an effective minimally invasive approach to resect some lesions. This is first report of the patient with a synchronous gastric leiomyoma and an intramuscular granular cell tumor in the abdominal wall.

BACKGROUND: Computed tomographic colonography (CTC) is reported to be feasible for screening of colorectal polyps; however, its efficacy in preoperative workup remains unknown. This study was done to define our CTC methodology and assess CTC's potential for preoperative examination in patients with colon cancer. METHODS: A total of 86 colon cancer patients underwent CTC prior to laparoscopic colectomy in our department from February 2014 to November 2015. The location of primary colon cancer determined by CTC was compared with that confirmed during the surgery. CTC was performed just after preoperative colonoscopy; for a small colon cancer, we performed clipping during colonoscopy to enhance CTC detectability. We classified wall deformities and compared them with the pathological T stage. RESULTS: CTC accurately located all 87 primary colon cancers prior to surgery. No patient experienced complications associated with CTC. The deformity classification correlated significantly with the pathological T stage (p < 0.001, Kruskal-Wallis nonparametric tests). CTC provided reconstructed images depicting the feeding artery of the primary colon cancer; feeding artery information obtained by CTC facilitated precise lymph node dissection. CONCLUSION: CTC appears to be a feasible and useful preoperative examination modality for colon cancer treatment.

BACKGROUND: The outcome of gastric cancer patients with peritoneal metastasis remains poor. We treated these patients with intraperitoneal and intravenous paclitaxel plus oral S-1 (tegafur/gimeracil/oteracil), followed by gastrectomy in responders. We evaluated the clinical significance of peritoneal lavage carcinoembryonic antigen (CEA) messenger RNA (mRNA) levels as a biomarker for indication of conversion gastrectomy. METHODS: The peritoneal lavage of 68 patients who received the above regimen as induction chemotherapy was repeatedly collected via intraperitoneal access ports. Gastrectomy was considered when improvement of peritoneal metastasis was confirmed by a second laparoscopic examination with negative peritoneal cytology. CEA and porphobilinogen deaminase mRNAs were chronologically quantified using the transcription reverse-transcription concerted reaction method. The CEA mRNA index (CmRI) was calculated as CEA mRNA/porphobilinogen deaminase mRNA × 10,000. RESULTS: Thirty-nine patients underwent gastrectomy and 29 patients did not (median survival time, 27.8 vs. 10.7 months, respectively; P < 0.001). In gastrectomy-positive patients, the outcome largely differed according to CmRI values immediately prior to surgery. Patients with a preoperative CmRI value <100 (n = 20) were associated with a significantly longer survival than those with a preoperative CmRI value >100 (n = 19) (41.8 vs. 20.1 months, respectively; P < 0.001). A preoperative CmRI value <100 was confirmed as an independent predictor of survival for gastrectomy-positive patients in the multivariate analysis. CONCLUSIONS: The CmRI reflects the response of peritoneal metastases to induction intraperitoneal chemotherapy. It may be a useful biomarker for indicating gastrectomy in gastric cancer patients with peritoneal metastasis.

BACKGROUND: Patients with esophageal cancer and a history of gastrectomy or concurrent gastric cancer undergo not only esophagectomy but also total gastrectomy. The goal of this study is to evaluate the postoperative quality of life (QOL) and dysfunction of these patients using two postoperative questionnaires. MATERIALS AND METHODS: From 1999 to 2015, 41 patients underwent concurrent esophagectomy and total gastrectomy. A jejunal pedicle with the subcutaneous supercharge technique was used for reconstruction. Patients were divided into two groups, including those undergoing concurrent esophagostomy and gastrectomy (Group 1), and those undergoing esophagectomy alone (Group 2, history of previous gastrectomy). Patients were analyzed by time interval, including patients within three years of surgery (Group A) and those more than three years after surgery (Group B). RESULTS: Eighteen patients completed the questionnaires. The mean DAUGS20 score was 26.4 ± 13.2. The DAUGS20 scores of groups 1 (N = 7) and 2 (N = 11) were 25.4 ± 12.5 and 27 ± 15.4 (p = 0.58), respectively. Global health status scored by the EORTC QLQC-30 were 71.4 ± 18.5 in group 1 and 67.4 ± 22.8 in group 2 (p = 0.85). DAUGS20 scores of group A (N = 10) and B (N = 8) were 28.1 ± 12.4 and 23.3 ± 14.4 (p = 0.35). No significant differences were found between groups A and B regarding the QLQ-C30 scores. CONCLUSION: DAUGS20 and QLQ-C30 scores showed no significant differences between groups 1 and 2 or groups A and B. These results suggest that postoperative QOL and dysfunction may be influenced more by current status than by surgical history and postoperative interval. Previous reports describe a DAUGS 20 score after gastrectomy of 27.8 and after esophagectomy of 36.1. The DAUGS20 score of these 18 patients is lower than DAUGS20 scores for patients undergoing either operation alone. Reconstruction using a subcutaneously placed jejunal segment seems to be reasonable.

Intraperitoneal administration of chemotherapeutics is expected for the treatment of peritoneally disseminated gastric cancer because of poor migration of the drugs from the systemic circulation to the peritoneal cavity. In this study, for intraperitoneal delivery of cisplatin (CDDP), we developed a hyaluronan (HA)-based hybrid system in which CDDP-loaded HA nanogels were either physically encapsulated in or chemically conjugated to injectable HA hydrogels. Physical encapsulation enabled sustained release of HA nanogels from the HA hydrogel matrix for over a week. This was a longer release period than that of encapsulated free CDDP, which released 80% of the drug in 2 days. The longer release was attributed to delayed diffusion of HA nanogels from the hydrogel matrix network. The release profile could be tuned by modifying the chemical conjugation of HA nanogels to the HA hydrogel matrix, as well as the type of chelating ligands used to load CDDP to the nanogel. Furthermore, intraperitoneally administered hybrid had significant antitumor activity in a mouse model of peritoneally disseminated gastric cancer, especially for nodules smaller than 1.0 mm.

Background: Repeated intraperitoneal (IP) administration of paclitaxel (PTX) with concurrent systemic chemotherapy is clinically effective for the treatment of peritoneal metastases (PM) from gastric cancer. However, it is unclear how biochemical modifications may affect the pharmacokinetics and bioavailability of IP administered PTX. Methods: In a xenograft PM model using human gastric cancer cells, MKN45, fluorescein-conjugated PTX (OG-PTX) was given IP and the intra-tumor distribution of PTX examined with fluorescein microscopy. Results: After IP injection, PTX was seen to directly infiltrate up to several hundred micrometers from the surface of the PM. Co-injection with 5 % non-animal stabilized hyaluronic acid increased PTX infiltration and suppressed the development of PM more efficiently than PTX alone. PTX solubilized with amphiphilic polymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) and n-butyl methacrylate (BMA) efficiently formed a micellar formation 50-100 nm in diameter. IP injection of the nanomicellar PTX (PTX-30W) also showed significantly enhanced tumor infiltration and further inhibition of the growth of PM compared with PTX solubilized with Cremophor-ethanol (PTX-Cre). Finally, IP administration of NK105, another nanomicellar PTX, inhibited the growth of subcutaneous tumors as well as PM, compared with conventional PTX-Cre in the same murine model. Conclusions: PTX administered IP directly infiltrates PM and are thus a useful strategy for the treatment of PM. Drug modification with nanotechnology may further enhance penetration of PM resulting in improved clinical efficacy.

Lysophosphatidic acid (LysoPA) has been proposed to be involved in the pathogenesis of various cancers. Moreover, glycero-lysophospholipids (glycero-LysoPLs) other than LysoPA are now emerging as novel lipid mediators. Therefore, we aimed to elucidate the possible involvement of glycero-LysoPLs in the pathogenesis of gastric cancer by measuring glycero-LysoPLs, autotaxin (ATX), and phosphatidylserine-specific phospholipase A1 (PS-PLA1) in ascites obtained from patients with gastric cancer and those with cirrhosis (as a control). We observed that after adjustments according to the albumin levels, the lysophosphatidylserine (LysoPS) and lysophosphatidylglycerol (LysoPG) levels were significantly higher, while the LysoPA and ATX levels were lower, in the ascites from patients with gastric cancer. We also found that multiple regression analyses revealed that ATX was selected as a significant explanatory factor for all the detectable LysoPA species only in the cirrhosis group and that a significant positive correlation was observed between LysoPS and PS-PLA1 only in the gastric cancer group. In conclusion, the LysoPA levels might be determined largely by LysoPC and LysoPI (possible precursors) and the PS-PLA1-mediated pathway might be involved in the production of LysoPS in gastric cancer. Glycero-LysoPLs other than LysoPA might also be involved in the pathogenesis of cancer directly or through being converted into LysoPA.

Gastric cancer is a common malignancy and remains potentially lethal. The prognosis of patients with stage IV gastric cancer is thought to be poor, but new molecular targeted therapy may benefit patients with advanced gastric cancer. Currently, conversion surgery after chemotherapy with a trastuzumab-containing regimen is reported to be effective in these patients. We present 3 patients with human epidermal growth factor receptor 2 (HER2)–positive advanced gastric cancer who underwent conversion surgery after receiving a trastuzumab-containing chemotherapy regimen. Interestingly, the primary lesion acquired resistance to the trastuzumab-containing regimen, although the metastatic lesions maintained a complete response. The reason why the primary lesions became resistant to trastuzumab remains unclear. More studies are needed to clarify the mechanism of resistance. Conversion surgery, made possible by the use of molecular-targeted therapy, may improve the prognosis of patients with stage IV gastric cancer, particularly if metastatic lesions show a complete response to therapy.

Although the incidence of port-site metastasis after laparoscopic surgery for colorectal cancer has markedly decreased since laparoscopic colectomy was first reported in 1991, it still has not reached zero. In colorectal cancer, the safety of laparoscopic surgery, including the low incidence of port-site metastasis, has been proven in large, randomized trials. In gastric cancer, reports of port-site metastasis are extremely rare, but we should await the results of ongoing trials. This brief review summarizes the current knowledge regarding port-site metastasis after laparoscopic surgery for colorectal and gastric cancer.

BACKGROUND: Despite recent progress in systemic chemotherapy, the prognosis of gastric cancer patients with peritoneal metastasis (P1) or positive peritoneal cytology findings (CY1) is still poor. We developed a regimen combining intraperitoneal (IP) paclitaxel (PTX) with S-1 and PTX, which can produce notable efficacy with regard to peritoneal lesions. Surgery after response to combination chemotherapy is a promising option for P1 or CY1 gastric cancer. A retrospective study was performed to evaluate the safety and efficacy. METHODS: This study enrolled 100 primary P1 or CY1 gastric cancer patients treated with IP PTX plus S-1 and PTX at the University of Tokyo Hospital between 2005 and 2011. Radical gastrectomy was performed when peritoneal cytology findings became negative, and the disappearance or obvious shrinkage of peritoneal metastasis was confirmed by laparoscopy. The same chemotherapy regimen was restarted after surgery and repeated with appropriate dose reduction. RESULTS: Gastrectomy was performed in 64 (P1 56, P0CY1 8) of 100 (P1 90, P0CY1 10) patients. R0 resection was achieved in 44 patients (69%). The median survival time was 30.5 months [95% confidence interval (CI) 23.6-37.7 months] from the initiation of intraperitoneal chemotherapy and 34.6 months (95% CI 26.8-39.4 months) from the diagnosis of gastric cancer. Postoperative complications included anastomotic leakage and pancreatic fistula, each in two patients, which were cured conservatively. There were no treatment-related deaths. The median survival time of the 36 patients who did not undergo surgery was 14.3 months (95% CI 10.0-17.8 months). CONCLUSIONS: Surgery after response to intraperitoneal and systemic chemotherapy is safe and may prolong the survival of P1 and CY1 gastric cancer patients.

INTRODUCTION: Carbohydrate antigen (CA) 19-9 is a widely used tumor marker in colorectal cancer (CRC). However, its prognostic impact in patients with stage IV CRC who have undergone curative resection is not clear. We evaluated the prognostic power of preoperative serum CA 19-9 in these patients. PATIENTS AND METHODS: We performed a retrospective review of 173 patients with stage IV CRC who had undergone curative resection at our institution. Patients were categorized into normal and high CA 19-9 groups, and relapse-free survival and overall survival were compared using Kaplan-Meier curves. Multivariate analyses were performed using a Cox proportional hazard model. RESULTS: The preoperative serum CA 19-9 level was elevated in 80 patients (46%). The 3-year relapse-free survival of the high CA 19-9 group was significantly worse than that of the normal CA 19-9 group (18% vs. 28%, respectively; P = .026). The 3-year overall survival of the high CA 19-9 group was significantly lower than that of the normal CA 19-9 group (75% vs. 82%; P = .047). Multivariate analyses indicated that elevated preoperative serum CA 19-9 level was an independent prognostic factor for poor relapse-free survival and overall survival, with a hazard ratio of 1.46 (95% confidence interval, 1.03-2.06; P = .035) and 1.90 (95% confidence interval, 1.10-3.29; P = .023), respectively. CONCLUSION: The preoperative serum CA 19-9 level is a good predictive marker of tumor recurrence and prognosis in patients with stage IV CRC who have undergone curative resection.

Peritoneal metastasis of gastric cancer remains a refractory disease, and the standard treatment strategy is still unclear. Intraperitoneally administered paclitaxel(PTX)remains in the intraperitoneal(IP)cavity for a long time and directly infiltrates peritoneal metastatic nodules, thereby producing antitumor effects. We designed an IP chemotherapy regimen of S-1 combined with weekly intravenous(IV)and IP PTXadministration. In our phase I study, the recommended dose of IP PTXwas determined to be 20mg/m2. In our phase II study for patients with P1(macroscopic peritoneal metastasis-positive)or CY1 (cytology-positive)gastric cancer, the 1-year overall survival(OS)rate was 78%and the median survival time(MST)was 23.6 months. In another phase II study of patients with P1 gastric cancer, the 1-year OS rate was 77%and the MST was 17.1 months. A phase III PHOENIX-GC trial comparing IP chemotherapy to S-1 plus cisplatin has recently been completed. Phase II studies of the IP administration of docetaxel have also shown favorable results. Recently, the results of several clinical studies investigating the effects of S-1 combined with weekly IV and IP PTXadministration for peritoneal metastasis of pancreatic cancer have been published.

Gastrointestinal (GI) cancer, including gastric and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer have a familial history, and several causative genes have been identified. Gene carriers with these hereditary GI syndromes often harbor several kinds of cancer at an early age, and genetic testing and specific surveillance may save their lives through early detection. Gastroenterologists and GI surgeons should be familiar with these syndromes, even though they are not always associated with a high penetrance of GI cancer. In this review, we provide an overview and discuss the diagnosis, genetic testing, and management of four major hereditary GI cancers: familial adenomatous polyposis, Lynch syndrome, hereditary diffuse gastric cancer, and Li-Fraumeni syndrome.

UNLABELLED: Objectives The aim of this study was to evaluate the safety and efficacy of intravenous and intraperitoneal paclitaxel (PTX) combined with S-1 for treatment of gemcitabine-refractory pancreatic cancer with malignant ascites. Methods After the feasibility of this regimen was first confirmed in an interim analysis in 10 patients, a total of 35 patients were enrolled between April 2011 and December 2014. PTX was administered intravenously (50 mg/m(2)) and intraperitoneally (20 mg/m(2)) on days 1 and 8, and 80 mg/m(2) S-1 was administered on days 1-14 every 3 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), the objective tumor response, efficacy against malignant ascites, and safety. Result In all 35 patients, the median OS and PFS were 4.8 (95 % confidence interval [CI], 2.1-5.3) months and 2.8 (95 % CI, 0.9-4.1) months, respectively. The 26 patients who were evaluable for efficacy achieved a response rate of 8 % and a disease control rate of 69 %. Malignant ascites had disappeared or decreased in 18 (69 %) patients, including complete resolution in 4 (15 %), and a negative change in cytological status was achieved in 8 (31 %) patients. The major grade 3/4 adverse events included neutropenia (34 %), anemia (31 %), nausea (9 %), and catheter-related infections (6 %). Conclusion Combination chemotherapy consisting of intravenous and intraperitoneal PTX with S-1 showed acceptable toxicity and favorable efficacy in pancreatic cancer patients with malignant ascites. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000005306).

Aberrant activation of Wnt/β-catenin signaling is a major driving force in colon cancer. Wnt/β-catenin signaling induces the expression of the transcription factor c-Myc, leading to cell proliferation and tumorigenesis. c-Myc regulates multiple biological processes through its ability to directly modulate gene expression. Here, we identify a direct target of c-Myc, termed MYU, and show that MYU is upregulated in most colon cancers and required for the tumorigenicity of colon cancer cells. Furthermore, we demonstrate that MYU associates with the RNA binding protein hnRNP-K to stabilize CDK6 expression and thereby promotes the G1-S transition of the cell cycle. These results suggest that the MYU/hnRNP-K/CDK6 pathway functions downstream of Wnt/c-Myc signaling and plays a critical role in the proliferation and tumorigenicity of colon cancer cells.

BACKGROUND: We present a case of asynchronously occurring adenocarcinomas 29 and 36 years after ureterosigmoidostomy for bladder cancer, respectively, at both anastomosis sites. CASE PRESENTATION: A colonoscopy that was performed on a 69-year-old man because of bloody stool and an elevated carcinoembryonic antigen (CEA) level revealed a polypoid lesion at the right ureterosigmoid anastomosis site 29 years after the patient's ureterosigmoidostomy. Endoscopic resection was performed, and the lesion was diagnosed as adenocarcinoma. Seven years later (36 years after ureterosigmoidostomy), an elevated lesion was detected at the left ureterosigmoid anastomosis site by colonoscopy performed after detection of high CEA levels. Biopsy revealed an adenocarcinoma that was immunohistologically positive for CDX2; sigmoidectomy and ureterectomy were subsequently performed. The pathological diagnosis of the second tumor was adenocarcinoma arising in the ureterosigmoid anastomosis site and invading the left ureter. CONCLUSIONS: Diligent long-term follow-up of patients who underwent ureterosigmoidostomy is essential.

BACKGROUND: CD133 is a transmembrane protein that is proposed to be a stem cell marker of colorectal cancer (CRC); however, the correlation between CD133 expression and survival of CRC patients with liver metastasis has not been fully examined. METHODS: CD133 expression was evaluated immunohistochemically, both in primary tumors and synchronous liver metastases of 88 consecutive CRC patients, as well as recurrent lesions in the remnant liver of 27 of these 88 patients. The relationship between CD133 expression and clinicopathological characteristics, recurrence-free survival, and overall survival (OS) was analyzed. RESULTS: CD133 expression in liver metastases (mCD133) was detected in 50 of 88 patients (56.8 %), and had significant correlation with CD133 expression in primary lesions (pCD133) (p < 0.001). CD133 expression in liver recurrent lesions (recCD133) also had a significant correlation with mCD133 (p < 0.001). mCD133+ patients had significantly longer disease-free survival (p = 0.043) and OS (p = 0.014) than mCD133- patients. In addition, mCD133+ patients had a significantly lower rate of extrahepatic recurrence (p < 0.001). CONCLUSIONS: Patients without CD133 expression in liver metastasis had significantly shorter survival, perhaps because mCD133- patients had a significantly higher rate of extrahepatic recurrence.

Colon cancers in male and female patients are suggested to be oncologically different. The aim of this study is to elucidate the prognostic impact of lymph node dissection (LND) in male and female colon cancer patients. A total of 5941 stage I-III colon cancer patients who were curatively operated on during the period from 1997 to 2007 were retrospectively studied. Cancer-specific survival (CSS) was individually compared between for male and female patients treated with D3, D2, and D1 LND. Background differences of the patients were matched using propensity scores. D3, D2, and D1 LND were performed in 3756 (63 %), 1707 (29 %), and 478 (8 %), respectively, and more extensive LND was indicated for younger patients and more advanced disease. D2 LND was significantly associated with decreased cancer-specific mortality compared to D1 LND in male patients (HR 0.54, 95 % CI 0.32-0.89, p = 0.04), but not in female patients. D3 LND did not correlate to an improved prognosis compared to D2 LND both in male and female patients. D2 LND was associated with an improved CSS in male, but not female colon cancer patients, compared to D1 LND. This suggested that colon cancer in male and female patients might be oncologically different, and that the prognostic impact of the extent of surgical intervention for colon cancer might therefore be different between sexes.

Background: Diabetes mellitus (DM) is suggested to be associated with colorectal cancer (CRC) however, the direct relationship between DM and CRC has not been proven. Objective: The aim of this study is to clarify oncological behavior of CRC with DM. Methods: This study is a retrospective cohort study. We investigated 1216 patients with curatively resected CRC. Clinicopathological factors and prognosis were compared between the patients with and without DM. Results: DM was observed in 34% of the patients. The patients with DM were significantly older, were predominantly males, had larger tumors, and died more frequently of causes other than CRC than those without DM. While overall survival (OS) was significantly inferior in the patients with DM than in those without (83% vs. 88%, p=0.01), there was no difference in cancer-specific survival (CSS) between the two groups (91% vs. 91%, p=0.6). The examination of survival at each cancer stage showed that CSS of the patients with DM tended to be superior in stage II cancer (97% vs. 93%, p=0.07) and was worse in stage IV cancer (54% vs. 70%, p=0.05). Conclusions: OS was worse in the CRC patients with DM who more often died of causes other than CRC, and thus, DM did not affect CSS as a whole. However, with the progression of CRC, DM appeared to worsen CSS. It is unclear whether this is attributed to differences in malignancy or in treatment this should be further examined.

Long-standing ulcerative colitis patients are known to be at high risk for the development of colorectal cancer. Therefore, surveillance colonoscopy has been recommended for these patients. Because colitis-associated colorectal cancer may be difficult to identify even by colonoscopy, a random biopsy method has been recommended. However, the procedure of carrying out a random biopsy is tedious and its effectiveness has also not yet been demonstrated. Instead, targeted biopsy with chromoendoscopy has gained popularity in European and Asian countries. Chromoendoscopy is generally considered to be an effective tool for ulcerative colitis surveillance and is recommended in the guidelines of the British Society of Gastroenterology and the European Crohn's and Colitis Organisation. Although image-enhanced endoscopy, such as narrow-band imaging and autofluorescence imaging, has been investigated as a potential ulcerative colitis surveillance tool, it is not routinely applied for ulcerative colitis surveillance in its present form. The appropriate intervals of surveillance colonoscopy have yet to be determined. Although the Japanese and American guidelines recommend annual or biannual colonoscopy, the British Society of Gastroenterology and the European Crohn's and Colitis Organisation stratified their guidelines according to the risks of colorectal cancer. A randomized controlled trial comparing random and targeted biopsy methods has been conducted in Japan and although the final analysis is still ongoing, the results of this study should address this issue. In the present review, we focus on the current detection methods and characterization of dysplasia/cancer and discuss the appropriate intervals of colonoscopy according to the stratified risks.

Background: Clinical studies of intraperitoneal chemotherapy with paclitaxel in patients of gastric cancer with peritoneal carcinomatosis is well tolerated and effective, and rare cases of metastasis and recurrence have experienced during the treatment. Disseminated carcinomatosis of the bone marrow is highly rare in gastric cancer and associated with a poor prognosis. Case presentation: A 59-year-old woman of gastric cancer with peritoneal carcinomatosis received five courses of chemotherapy with intraperitoneal administration of paclitaxel, and laparoscopy showed disappearance of the peritoneal carcinomatosis. She subsequently underwent total gastrectomy, and the histopathological findings showed a complete response to the chemotherapy. Postoperatively, chemotherapy with intraperitoneal administration of paclitaxel was continued for 30 months, without apparent recurrence. However, the gastric cancer recurred as disseminated carcinomatosis of the bone marrow with disseminated intravascular coagulation, and we hence changed the chemotherapy regimen to weekly irinotecan. Remission was achieved, and she did not experience any major symptoms; however, she died 6 months after the diagnosis of disseminated carcinomatosis of the bone marrow. Conclusions: Since intraperitoneal paclitaxel administration can strongly suppress peritoneal carcinomatosis of gastric cancer, careful attention should be paid not only to peritoneal recurrence but also for rare site metastases, such as bone marrow metastases.

AimThe rate of extension of proctitis in Western countries has been reported, but no data regarding long-term follow-up have been described for the Japanese population. Additionally, patients with long-standing or extensive ulcerative colitis have an increased risk for developing colorectal cancer. This study evaluated both the rate of extension of the disease and the development of neoplasia among patients with an initial diagnosis of ulcerative proctitis. MethodWe retrospectively investigated the medical charts of patients with proctitis from 1979 to 2014. The primary focus of this research was the extension of the inflammatory area. The secondary focus included risk factors for disease extension and the development of neoplasia. ResultsSixty-six patients satisfied the inclusion criteria. Proximal extension of the disease occurred in 34 patients: 19 patients had left-sided colitis and 15 had pancolitis. According to a multivariate analysis, disease extension was significantly higher in patients with disease onset before 25years of age (P-value=0.043). The cumulative rates of disease extension at 10 and 20years were 33.8% and 52.2%, respectively. Three patients were diagnosed with dysplasia during follow-up, all of whom experienced disease extension before the development of dysplasia. ConclusionThe rate of extension of ulcerative colitis in the Japanese population was comparable to that in Western countries. A younger age of disease onset was associated with disease extension. Extension of proctitis may be associated with an increased risk of colorectal cancer.

Background. Recent advances in endoscopic therapy, including conventional endoscopic resection and endoscopic submucosal dissection (ESD), have led to a large number of patients with early colorectal cancer (CRC) being cured; however, when resected specimens obtained by these procedures manifest risk factors for lymph node metastasis, additional treatments need to be considered. The aim of our study was to evaluate the outcomes of salvage surgery in CRC patients treated initially by advanced therapeutic endoscopy. Methods. We investigated 145 patients who underwent salvage surgery in our department after endoscopic therapy for CRC between April 2006 and March 2015. Demographic and pathological data, endoscopic procedures, reasons for surgery, and operative outcomes, including perioperative details and recurrence-free and disease-specific survival after surgery, were analyzed. These data were further compared with those of 59 patients with submucosal invasive CRC treated by conventional endoscopic resection/ESD alone and 133 patients treated by surgery alone. Results. Overall lymph node metastases were observed in 14 % of patients who underwent salvage surgery after therapeutic endoscopy and 16% of those who received abdominal surgery alone. In analyses of surgical cases, patients with lymph node metastases more frequently included cases with lymphatic infiltration (63 %) and ESD-treated cases (45 %) than those without metastases (21 %, P &lt; .0001 and 22%, P = .02; respectively). A logistic regression analysis identified lymphatic infiltration as an independent predictive factor for lymph node metastases (odds ratio: 8.77, 95 % confidence interval: 2.90-33.31, P &lt; .0001). Long-term outcomes were favorable in both lymphatic infiltration negative and positive cases. Moreover, survivals were comparable among the different treatment groups. Conclusion. Because of the high rate of nodal involvement, adequate lymphadenectomy need to be performed in salvage surgery after upfront endoscopic therapy.

Hyaluronan (HA) is a promising drug carrier for cancer therapy because of its CD44 targeting ability, good biocompatibility, and biodegradability. In this study, cisplatin (CDDP)-incorporating HA nanogels were fabricated through a chelating ligand metal coordination cross-linking reaction. We conjugated chelating ligands, iminodiacetic acid or nalonic acid, to HA and used them as a precursor polymer. By mixing the ligand-conjugated HA with CDDP, cross-linking occurred via coordination of the ligands with the platinum in CDDP, resulting in the spontaneous formation of CDDP-loaded HA nanogels. The nanogels showed pH-responsive release of CDDP, because the stability of the ligand platinum complex decreases in an acidic environment. Cell viability assays for MKN45P human gastric cancer cells and Met-5A human mesothelial cells revealed that the HA nanogels selectively inhibited the growth of gastric cancer cells. In vivo experiments using a mouse model of peritoneal dissemination of gastric cancer demonstrated that HA nanogels specifically localized in peritoneal nodules after the intraperitoneal administration. Moreover, penetration assays using multicellular tumor spheroids indicated that HA nanogels had a significantly higher ability to penetrate tumors than conventional, linear HA. These results suggest that chelating-ligand conjugated HA nanogels will be useful for targeted cancer therapy.

Background: Mucinous cystadenocarcinoma is the second most common etiology of appendiceal mucocele. We report a relatively rare case of a giant appendiceal mucocele caused by mucinous cystadenocarcinoma, which occupied the entire abdomen of an adult woman. Case presentation: A 63-year-old woman presented with a chief complaint of abdominal distention. Imaging studies showed a giant cystic mass occupying her entire abdomen. Laparotomy confirmed a giant appendiceal mucocele, and the patient underwent ileocecal resection. A mucinous deposit was not found in her abdominal cavity, and the ovaries were grossly normal bilaterally. The pathological diagnosis was mucinous adenocarcinoma with a low-grade mucinous neoplasm that invaded the subserosa. Regional lymph node metastasis was not found. She has had recurrence-free survival for 5 years. Conclusions: The present case is the largest appendiceal cystadenocarcinoma ever reported. The optimal treatment of an appendiceal neoplasm requires further research based on consensus terminology of an appendiceal mucocele.

Background: The incidence of neoplasia after surgery has not been sufficiently evaluated in patients with ulcerative colitis (UC), particularly in the Japanese population, and it is not clear whether surveillance endoscopy is effective in detecting dysplasia/cancer in the remnant rectum or pouch. The aims of this study were to assess and compare postoperative development of dysplasia/cancer in patients with UC who underwent ileorectal anastomosis (IRA) or ileal pouch-anal anastomosis (IPAA) and to evaluate the effectiveness of postoperative surveillance endoscopy. Methods: One hundred twenty patients who received postoperative surveillance endoscopy were retrospectively reviewed for development of dysplasia/cancer in the remnant rectal mucosa or pouch. Results: Three hundred seventy-nine endoscopy sessions were conducted for 30 patients after IRA, while 548 pouch endoscopy sessions were conducted for 90 patients after IPAA. In the IRA group, 5 patients developed dysplasia/cancer during postoperative surveillance and in all cases, neoplasia was detected at an early stage. In the IRA group, no patient developed neoplasia within 10 years of diagnosis; the cumulative incidence of neoplasia after disease onset was 7.2, 12.0, and 23.9 % at 15, 20, and 25 years, respectively. In one case after stapled IPAA, dysplasia was found at the ileal pouch; a subsequent 9 endoscopy sessions in 8 years did not detect any dysplasia. Neoplasia was found more frequently during postoperative surveillance in the IRA group than in the IPAA group (p =.0028). The cumulative incidence of neoplasia after IRA was 3.8, 8.7, and 21.7 % at 10, 15, and 20 years, respectively, and that after IPAA was 1.6 % at 20 years. Conclusions: The cumulative incidence of neoplasia after IPAA was minimal. Those who underwent IRA had a greater risk of developing neoplasia than those who underwent IPAA, although postoperative surveillance endoscopy was able to detect dysplasia/cancer at an early stage. IRA can be the surgical procedure of choice only in selected cases in which it would be of benefit to the patient, with more careful surveillance.

Patients with hereditary hemorrhagic telangiectasia (HHT) are reportedly at a lower overall risk of malignancies, and small bowel adenocarcinoma (SBA) arising in a HHT patient is extremely rare. In this study, the case of a 37-year-old female with HHT who developed a poorly differentiated jejunal adenocarcinoma five years after ileocecal resection for multiple colonic adenomas is presented. The patient underwent curative resection of the cancer invading the ileum and the mesentery of the transverse colon, but had to overcome critical complications perioperatively, stemming from HHT-associated peripheral capillary dilatation and arteriovenous malformation, including nosebleeds and possible infusion-induced air embolism through pulmonary shunts. The patient subsequently received adjuvant chemotherapy including capecitabine and oxaliplatin for 6 months, and currently remains alive without any evidence of recurrence 12 months after the second surgery. This patient with SBA was an instructive case demonstrating the necessity of careful attention during major surgery in HHT.