Recent Strategies for Treating Stage IV Gastric Cancer: Roles of Palliative Gastrectomy, Chemotherapy, and Radiotherapy.

Recently, many strategies have been reported for the effective treatment of gastric cancer. However, the strategy for treating stage IV gastric cancer remains controversial. Conducting a prospective phase III study in stage IV cancer patients is difficult because of heterogeneous performance status, age, and degree of cancer metastasis or extension. Due to poor prognosis, the variance in physical status, and severe symptoms, it is important to determine the optimal strategy for treating each individual stage IV patient. In the past decade, many reports have addressed topics related to stage IV gastric cancer: the 7th Union for International Cancer Control (UICC) TNM staging system has altered its stage IV classification; new chemotherapy regimens have been developed through the randomized ECF for advanced and locally advanced esophagogastric cancer (REAL)-II, S-1 plus cisplatin versus S-1 in RCT in the treatment for stomach cancer (SPIRITS), trastuzumab for gastric cancer (ToGA), ramucirumab monotherapy for previously-treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD), and ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously-treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW) trials; and the survival efficacy of palliative gastrectomy has been denied by the reductive gastrectomy for advanced tumor in three Asian countries (REGATTA) trial. Current strategies for treating stage IV patients can be roughly divided into the following five categories: palliative gastrectomy, chemotherapy, radiotherapy, gastric stent, or bypass. In this article, we review recent publications and guidelines along with above categories in the light of individual symptoms and prognosis.

Small bowel obstruction caused by endometriosis in a postmenopausal woman.

We report a rare case of small bowel obstruction (SBO) caused by endometriosis in a postmenopausal woman. A 54-year-old postmenopausal woman presented with severe abdominal pain and vomiting. Before menopause, she sometimes had abdominal pain associated with menses. Axial multi-dimensional CT images revealed a SBO with small nodules near the terminal ileum. The obstruction was diagnosed as being caused by small bowel endometriosis. Curved planar reconstruction images showed a complicated obstruction of the small intestine 15 cm from the terminal ileum. Based on the stenotic lesion, a SILS procedure was performed. The patient's SBO diagnosis was histologically confirmed as being caused by small bowel endometriosis. SILS was deemed to be a safe, feasible procedure for treating this bowel obstruction. Curved planar reconstruction images were useful in preoperative imaging and diagnosis of SBO, especially as they were able to highlight the constricting legion.

Pathological complete response and long-term survival in a very elderly patient after neoadjuvant chemotherapy for locally advanced, unresectable gastric cancer.

We address the pathological complete response and long-term survival of elderly patients after neoadjuvant chemotherapy in locally advanced, unresectable gastric cancer. An 83-year-old man was hospitalized for upper abdominal pain. Gastrointestinal endoscopy showed a large tumor spanning from the gastric angle to the antrum, and extending to the duodenum. Histological analysis of the biopsy specimen revealed a poorly differentiated adenocarcinoma. Computed tomography images showed thickening of the gastric wall and invasion of the body and head of the pancreas, but did not show distant metastases. The patient was diagnosed with unresectable gastric cancer, and was treated with neoadjuvant chemotherapy using S-1 (80 mg/m(2)) and paclitaxel (60 mg/m(2)). After the third course of chemotherapy, gastrointestinal endoscopy and abdominal computed tomography revealed a remarkable reduction in tumor size. This reduction allowed distal gastrectomy to be conducted. Histological examination of the specimen revealed no cancer cells in the primary lesion or lymph nodes. The patient was treated with adjuvant chemotherapy of oral tegafur-uracil (300 mg/day) for one year after surgery. He lived for five years after surgery without recurrence. Neoadjuvant chemotherapy using S-1 and paclitaxel is a potent strategy for improving survival in very elderly patients with unresectable gastric cancer.

Profile of microRNAs associated with aging in rat liver.

Recent studies suggest that small non­coding microRNAs (miRNAs or miRs) play an important role in the regulation of genes involved in various cellular and developmental processes. However, the expression of miRNAs during the aging process remains largely unknown. The aim of the present study was to analyze miRNA expression profiles in rat livers during the aging process. The livers of male Wistar rats at different stages of development (fetal, aged 3 days, and 1, 2, 4, 8 and 36 weeks of age) were used. Total RNA was extracted from the livers. We analyzed the expression levels of 679 rat miRNA probes. In addition, immunohistochemical staining for proliferating cell nuclear antigen (PCNA) was performed. Several up- and downregulated miRNAs were identified in the rat livers at 7 different fetal developmental stages and at 36 weeks of age. We observed the upregulation of miR­29a, miR­29c, miR­195 and miR­497, whereas miR­301a, miR­148b-3p, miR­7a, miR­93, miR­106b, miR­185, miR­450a, miR­539 and miR­301b were downregulated in the aging rat livers. The number of PCNA-positive hepatocytes was decreased with age. In conclusion, our findings suggest that these up- and downregulated miRNAs play an important role in aging by regulating cell cycles that are involved in liver senescence. Further investigation is required to reveal additional target genes of the miRNAs expressed in the liver and the roles of miRNAs in the developmental process of aging in the liver.

Current innovations in endoscopic therapy for the management of colorectal cancer: from endoscopic submucosal dissection to endoscopic full-thickness resection.

Endoscopic submucosal dissection (ESD) is accepted as a minimally invasive treatment for colorectal cancer. However, due to technical difficulties and an increased rate of complications, ESD is not widely used in the colorectum. In some cases, endoscopic treatment alone is insufficient for disease control, and laparoscopic surgery is required. The combination of laparoscopic surgery and endoscopic resection represents a new frontier in cancer treatment. Recent developments in advanced polypectomy and minimally invasive surgical techniques will enable surgeons and endoscopists to challenge current practice in colorectal cancer treatment. Endoscopic full-thickness resection (EFTR) of the colon offers the potential to decrease the postoperative morbidity and mortality associated with segmental colectomy while enhancing the diagnostic yield compared to current endoscopic techniques. However, closure is necessary after EFTR and natural transluminal endoscopic surgery (NOTES). Innovative methods and new devices for EFTR and suturing are being developed and may potentially change traditional paradigms to achieve minimally invasive surgery for colorectal cancer. The present paper aims to discuss the complementary role of ESD and the future development of EFTR. We focus on the possibility of achieving EFTR using the ESD method and closing devices.

Molecular mechanisms of [18F]fluorodeoxyglucose accumulation in liver cancer.

To elucidate the molecular mechanisms underlying the insufficient sensitivity in the detection of hepatocellular carcinoma (HCC) by [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), the characteristics of glucose metabolism-related protein expression in HCC were examined in liver metastasis from colorectal cancer (Meta). Thirty-four patients (14 Meta and 20 HCC) who underwent FDG-PET and hepatectomy were studied. The relationships between the maximum standardized uptake value (SUV) in tumors and the mRNA expression of glucose metabolism-related proteins [hexokinase (HK), glucose transporter 1 (GLUT1), and glucose-6-phosphatase (G6Pase)] and proliferating cell nuclear antigen (PCNA) were examined in snap-frozen specimens with quantitative PCR. Tumor detection rates were lower in HCC (15/20) compared to Meta (13/14) patients. HK and GLUT1 expression was lower and G6Pase expression was higher in HCC compared to Meta. In particular, GLUT1 overexpression was 92-fold in Meta and 11-fold in HCC compared to the surrounding liver. The SUV correlated with GLUT1 and PCNA expression in HCC, but not Meta patients. Of note, four cases of poorly differentiated (P/D) HCC compared to moderately differentiated (M/D) HCC produced completely different results for FDG uptake (SUV, 14.4 vs. 4.0) and mRNA expression (G6Pase expression, 0.007 vs. 1.5). Variations in the expression of glucose metabolism-related enzymes between HCC and Meta patients are attributed to origin or degree of differentiation. Low FDG uptake in M/D HCC reflected low GLUT1 and high G6Pase expression, while high FDG accumulation in P/D HCC could reflect increased GLUT1 and decreased G6Pase expression. These results may explain why M/D HCC is not detected as sensitively by FDG-PET.

[18F]Fluorodeoxyglucose accumulation as a biological marker of hypoxic status but not glucose transport ability in gastric cancer.

BACKGROUND: The use of [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for detection of gastric cancer is often debated because FDG uptake varies for each patient. The purpose of this study was to clarify the molecular mechanisms involved in FDG uptake. MATERIAL AND METHODS: Fifty patients with gastric cancer who underwent FDG-PET and gastrectomy were studied. Snap-frozen tumor specimens were collected and examined by real-time PCR for relationships between maximum standardized uptake value (SUV) and mRNA expression of the following genes: glucose transporter 1 (GLUT1), hexokinase 2 (HK2), hypoxia-inducible factor 1α (HIF1α), and proliferating cell nuclear antigen (PCNA). RESULTS: Tumor size was the only clinicopathological parameter that significantly correlated with SUV. Transcripts for the genes evaluated were about three-fold higher in malignant specimens than in normal mucosa, although only HIF1α was significantly correlated with SUV. When divided into intestinal and non-intestinal tumors, there was a significant correlation between SUV and tumor size in intestinal tumors. Interestingly, the weak association between SUV and HIF1α expression in intestinal tumors was substantially stronger in non-intestinal tumors. No correlation was found between SUV and mRNA expression of other genes in intestinal or non-intestinal tumors. CONCLUSION: SUV was correlated with HIF1α, but not PCNA, HK2, or GLUT1 expression. FDG accumulation could therefore represent tissue hypoxia rather than glucose transport activity for aggressive cancer growth.

Rectal perforations and fistulae secondary to a glycerin enema: closure by over-the-scope-clip.

Rectal perforations due to glycerin enemas (GE) typically occur when the patient is in a seated or lordotic standing position. Once the perforation occurs and peritonitis results, death is usually inevitable. We describe two cases of rectal perforation and fistula caused by a GE. An 88-year-old woman presented with a large rectal perforation and a fistula just after receiving a GE. Her case was further complicated by an abscess in the right rectal wall. The second patient was a 78-year-old woman who suffered from a rectovesical fistula after a GE. In both cases, we performed direct endoscopic abscess lavage with a saline solution and closed the fistula using an over-the-scope-clip (OTSC) procedure. These procedures resulted in dramatic improvement in both patients. Direct endoscopic lavage and OTSC closure are very useful for pararectal abscess lavage and fistula closure, respectively, in elderly patients who are in poor general condition. Our two cases are the first reports of the successful endoscopic closure of fistulae using double OTSCs after endoscopic lavage of the debris and an abscess of the rectum secondary to a GE.

Effectiveness of CO2-insufflated endoscopic submucosal dissection with the duodenal balloon occlusion method for early esophageal or gastric cancer: a randomized case control prospective study.

BACKGROUND: Endoscopic submucosal dissection (ESD) has typically been performed using air insufflation. Recently, however, insufflation of CO2 has been increasingly used to avoid complications. This prospective study was designed to compare the CO2 concentration, intestinal volume, and acid-base balance using the duodenal balloon procedure. METHODS: From June 2010 to February 2011, we enrolled 44 patients with esophageal or gastric cancer and randomly allocated them into two groups. We compared 22 patients undergoing CO2-insufflated ESD with a balloon placed into the duodenal bulb (duodenal balloon group) and 22 patients undergoing regular CO2-insufflated ESD (regular group). Three-dimensional computed tomography was performed before and after the procedure to measure intestinal volume. CO2 concentrations were measured every 10 minutes. The visual analogue system (VAS) scores for postoperative symptoms were recorded, and pH was measured immediately after the procedure. This was a prospective case control study randomized by the sealed envelope method. RESULTS: Intestinal CO2 gas volume before and after ESD was lower in the duodenal balloon group than in the regular group (P = 0.00027). The end-tidal CO2 level was significantly lower in the duodenal balloon group than in the regular group (P = 0.0001). No significant differences in blood ΔpH were found between the two groups. The VAS score for the occurrence of nausea due to abdominal distension after ESD indicated a significant difference (P = 0.031). CONCLUSIONS: ESD using the duodenal balloon occlusion method is effective for reduction of post-ESD intestinal CO2 gas volume, resulting in a lower total amount of CO2 insufflation during ESD and reducing harmful influences on the human body to some extent.

New technique for safer endoscopic submucosal dissection using the duodenal balloon occlusion method.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) enables complete, collective removal of gastrointestinal (GI) malignant tumors, but requires a long operation time. Air insufflated during ESD is distributed throughout the entire GI tract, and thus causes an enlarged feeling of the abdomen. We aimed to reduce the incidence of an enlarged feeling of the abdomen by wedging a balloon in the bulbus duodeni to reduce air flow into the lower parts of the GI tract. METHODS: Sixteen patients who were approved by the institutional ethics committee and provided consent to participate in this single-center, prospective study were divided into two groups using a sealed-envelope randomization method: ESD with a balloon wedged in the bulbus duodeni (the balloon [+] group) or conventional ESD with no balloon (the balloon [-] group). Total air volume in the entire GI tract and its change before and after ESD were measured objectively by 3-D computed tomography. RESULTS: In the balloon (+) group, the mean intestinal gas volume (± standard deviation) was 274.3 ± 142.0 mL before ESD, and 352.5 ± 183.2 mL after, with a mean change of 78.1 ± 139.7 mL. The increase in intestinal gas volume was well controlled. No postoperative complications, such as an enlarged feeling of the abdomen, was reported in the balloon (+) group. CONCLUSIONS: Our new technique has several advantages, including reduction in the frequency of postoperative abdominal symptoms, and will be useful and safe for gastric ESD.

Molecular mechanism underlying the detection of colorectal cancer by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography.

BACKGROUND: Biological imaging by positron emission tomography (PET) using 18F-2-fluoro-2-deoxy-D-glucose (FDG) has been widely used clinically for the detection of primary tumors and for early prediction of response to chemotherapy. In this study, we examined the molecular mechanism underlying the detection of colorectal cancers by FDG-PET. MATERIAL AND METHODS: In all, 37 patients with colorectal cancer were examined with FDG-PET, and the maximal standardized uptake value (SUV) was calculated. Using surgical tissue samples, we examined the expression levels of hypoxia-inducible factor alpha (HIF1α), a marker of tissue hypoxia; proliferative cellular nuclear antigen (PCNA), a marker of proliferation; and glucose transporter (GLUT)1 and hexokinase (HK)2, protein of glucose uptake by using reverse transcriptase-polymerase chain reaction. RESULTS: All except two colorectal cancer lesions showed increased uptake of FDG. The mean SUV of FDG-PET was 12.0 ± 1.2 (±SEM). The mean mRNA expression levels of GLUT1 and HK2 were significantly higher in cancer tissues than in the surrounding normal mucosa. Moreover, to promote the upregulation of glucose uptake, the expressions of HIF1α and PCNA were induced to 2.6 and 3.3 times higher than that in the normal mucosa. However, the quantitative correlation analysis showed SUV was correlated with HIF1α expression but not with PCNA expression. CONCLUSION: Our molecular-based analysis suggested that FDG accumulation due to induction of glucose uptake proteins might be associated with the hypoxic environment in tumors rather than the tumor growth. Therefore, for assessing the efficacy of chemotherapy using FDG-PET, we must keep in mind that SUV does not indicate the tumor growth directly.

Surgical approach for extrahepatic metastasis of HCC in the abdominal cavity.

BACKGROUND/AIMS: Despite recent development of therapeutic strategies for intrahepatic lesions, standard guidelines for treatment of extrahepatic metastases of hepatocellular carcinoma have not been established. METHODOLOGY: Surgical resection for intra-abdominal extrahepatic metastases of hepatocellular carcinoma was performed on 10 patients at our institution between 1992 and 2008. We retrospectively examined the clinicopathologic features and significance of a surgical approach in these patients. RESULTS: Nine of the 10 patients received treatment for primary hepatocellular carcinoma before surgery for intra-abdominal extrahepatic metastasis. A simultaneous intrahepatic lesion was detected in half of the patients when the extrahepatic metastasis was resected. Extrahepatic recurrent organs included adrenal glands, lymph nodes, abdominal wall, stomach and diaphragm. The mean survival period after resection was 36.1 months. Two patients are still alive without further recurrence. One patient died of retroperitoneal recurrence and 7 died of intrahepatic recurrence or liver failure after resection. CONCLUSIONS: With careful case selection, considering that not all extrahepatic metastases suggest systemic spread of hepatocellular carcinoma, surgical treatment for metastatic lesions in the abdominal cavity can provide a relatively good prognosis.

Frequent loss of p19INK4D expression in hepatocellular carcinoma: relationship to tumor differentiation and patient survival.

p19INK4D belongs to the family of cyclin-dependent kinase inhibitors (CdkIs) that target the cyclin-dependent kinases and inhibit their catalytic activity. The role of p19INK4D in cell cycle progression in hepatocellular carcinoma (HCC) is poorly characterized. The aim of this study was to examine the expression of p19INK4D in various liver diseases including HCC and to assess its clinical significance in HCC. We examined the expression of p19INK4D by immunohistochemistry in 81 cases of various liver diseases, including 51 HCCs. We analyzed the relationship among p19INK4D expression in HCC in combination with histopathological stage, differentiation, several histopathological factors of possible prognostic value and patient survival. Immunohistochemical analysis revealed the frequent loss of p19INK4D expression consistent with the differentiation of HCC. The loss of p19INK4D expression was shown to be associated with a poor prognosis by analyzing clinicopathological features. In conclusion, we found that loss of p19INK4D protein was frequent in HCC, especially in poorly differentiated HCC, suggesting that p19INK4D may play a role in the differentiation of HCC. Furthermore, expression of p19INK4D may be an effective predictor of clinical behavior in HCC, and therefore, a new prognostic marker for HCC.

Comparison of postoperative complications after endoscopic submucosal dissection: differences of insufflations and anesthesias.

Endoscopic submucosal dissection (ESD) has enabled the collective resection and increased the accuracy of pathological diagnosis. However, ESD requires a long operation time, which results in increased doses of analgesics/sedatives, and causes worsening of respiratory and hemodynamic statuses. To reduce postoperative complications, we have applied ESD with CO(2) insufflation and general anesthesia. This study included 50 patients who underwent ESD for early gastric cancer, 25 with air insufflation and intravenous anesthesia (Air/IV group), and the remaining 25 with CO(2) insufflation and general anesthesia (CO(2)/GA group). Postoperative enlarged feeling of the abdomen was observed only in 1 of 25 patients in the CO(2)/GA group (P = 0.0416). Postoperative severe unrest was observed in none of the patients in the CO(2)/GA group and in 4 of 25 (16%) patients in the Air/IV group (P = 0.0371). CO(2) insufflation and general anesthesia are useful in stabilizing intraoperative conditions and reducing postoperative complications.

Hepatic preconditioning using lipopolysaccharide: association with specific negative regulators of the Toll-like receptor 4 signaling pathway.

BACKGROUND: Preconditioning using lipopolysaccharide (LPS), a Toll-like receptor (TLR)-4 ligand, has been demonstrated to attenuate ischemia-reperfusion injury (IRI) in several organs but has not been sufficiently elucidated in the liver. We investigated the molecular mechanism of protection induced by LPS preconditioning against hepatic IRI. METHODS: BALB/c mice underwent 70% hepatic ischemia for 90 min. LPS was injected intraperitoneally 20 hr before ischemia at a range of 1 to 1000 µg/kg. Hepatic injury was evaluated based on serum alanine aminotransferase levels and histopathology. Inflammatory cytokine expression, nuclear factor-κB activation, and c-Jun N-terminal kinase phosphorylation were investigated after reperfusion. Additionally, preischemic expression of negative feedback inhibitors of the TLR4 cascade was examined. RESULTS: Only the 100 µg/kg LPS pretreatment significantly reduced serum alanine aminotransferase levels and histopathologic damage 6 hr after reperfusion; there was no difference among other LPS concentrations. In mice pretreated with LPS, intrahepatic expression of tumor necrosis factor-α and interleukin (IL)-6 as well as activation of nuclear factor-κB and c-Jun N-terminal kinase were inhibited 1 hr after reperfusion, whereas expression of IL-10, an anti-inflammatory cytokine, was induced. Suppressor of cytokine signaling (SOCS)-1, SOCS-3 and IL-1 receptor-associated kinase-M were upregulated by LPS exposure in the preischemic period. CONCLUSIONS: Hepatic LPS preconditioning elicited the upregulation of specific negative regulators in the TLR4 signaling pathway. Preischemic induction of these regulators plays an important role as immunologic preparation for the subsequent ischemia-reperfusion and produces resistance to liver injury. Preoperative modulation of the TLR4 pathway might become an alternative therapeutic strategy against hepatic IRI.

Correlation of 18F-FLT uptake with equilibrative nucleoside transporter-1 and thymidine kinase-1 expressions in gastrointestinal cancer.

PURPOSE: We examined equilibrative nucleoside transporter-1 (ENT1) and thymidine kinase-1 (TK1) messenger ribonucleic acid (mRNA) expressions in cancer tissue samples to elucidate the mechanism of 3'-deoxy-3'-F-fluorothymidine (FLT) uptake by positron emission tomography (PET) scan in gastrointestinal cancer. METHODS: A total of 21 patients with newly diagnosed gastrointestinal cancer were examined with FLT PET. Tumor lesions were identified as areas of focally increased uptake, exceeding that of surrounding normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUV) was calculated. The expressions of ENT1 and TK1 in cancer tissue samples were compared with that of FLT SUV. RESULTS: Of all gastrointestinal cancer lesions only one gastric cancer showed focally increased uptake of FLT PET. The mean (±standard deviation) FLT SUV in gastrointestinal cancer was 5.48±1.87. There was no significant correlation between FLT SUV and ENT1 (P=0.90) mRNA expression. There was a significant correlation between FLT SUV and TK1 mRNA expression (P<0.05). CONCLUSION: Results of this preliminary study indicate that TK1 activity is an important determinant of FLT uptake in gastrointestinal cancer. In this study, it was found that ENT1 activity and FLT uptake were not related.

Use of protein array technology to investigate receptor tyrosine kinases activated in hepatocellular carcinoma.

Receptor tyrosine kinases (RTKs) play a role in various processes, including cell growth, differentiation, apoptosis and carcinogenesis. RTKs are activated in various types of cancers, including breast, stomach, colon, pancreas and liver cancer and hepatocellular carcinoma (HCC). In the present study, protein array technology was used to analyze the expression status of various RTKs activated in HCC. The expression of activated RTKs was examined in the HCC cell lines, Alex, HuH7, Li-7, Hep3B, HLE and HLF; in the human normal hepatocyte cell line, hNHeps; and in human HCC and adjacent non-cancerous tissues. Of the 42 different phospho-RTKs, 15 (ErbB2, ErbB3, ErbB4, FGFR2α, FGFR3, insulin R, Mer, PDGFRß, c-Ret, ROR2, Tie, TrkA, VEGFR3, EphA1 and EphA4) were activated in some of the cancer cell lines studied. Among these, only ErbB2 was activated in all the HCC cell lines examined. Also, in vitro experiments were performed in subcutaneous HCC-bearing athymic nude mice to determine the therapeutic effects of inhibiting ErbB2 activation using the ErbB2-targeting drug trastuzumab. The results revealed that trastuzumab markedly suppressed the growth of HCC. These data suggest that ErbB2 is activated in HCC and that trastuzumab may play a role in the treatment of this disease. In addition, the use of protein array technology is proposed as a tool for detecting the expression of activated RTKs and identifying an effective RTK-based therapy.