Akiharu Kimura

Nesfatin-1 Suppresses Gastric Contractions and Inhibits Interdigestive Migrating Contractions in Conscious Dogs

AbstractBackgroundNesfatin-1 is a novel 82-amino acid anorectic peptide. Acute injection of nesfatin-1 into the third brain ventricle reduces food consumption during the dark phase in rats. Nesfatin-1 is also expressed in gastric X/A-like cells in the peripheral tissues. Nesfatin-1 has been reported to reduce gastric and duodenal motility and to delay gastric emptying.AimIn the present study, we investigated the effects of nesfatin-1 on gastrointestinal motility in conscious dogs.MethodsForce transducers were implanted onto the serosal surfaces of the gastric bodies, gastric antra, duodena, and jejuna of healthy beagle dogs, and gastrointestinal motility was monitored. We evaluated the effects of nesfatin-1 on gastrointestinal motility and on the circulating levels of nesfatin-1 in the fasted and fed states.ResultsThe intravenous administration of nesfatin-1 reduced gastric contractions and inhibited cyclical interdigestive migrating contractions in the fasted state. In the fasted state, circulating levels of nesfatin-1 tended to increase during late phase I. In addition, the kinetics of the circulating levels of nesfatin-1 were opposite to those of ghrelin during the fasted state.ConclusionsNesfatin-1 regulates gastrointestinal motility, and, in particular, it inhibits gastric contractions in the fasted state. Interdigestive migrating contractions may be regulated by interactions between nesfatin-1, ghrelin, and motilin.

Nuclear heat shock protein 110 expression is associated with poor prognosis and chemotherapy resistance in gastric cancer

Heat shock protein (HSP) expression is induced by the exposure to stress, such as fever, oxidative stress, chemical exposure, and irradiation. In cancer, HSP promotes the survival of malignant cells by inhibiting the induction of apoptosis. In colorectal cancer, a loss-of-function mutation of HSP110 (HSP110ΔE9) has been identified. HSP110ΔE9 inhibits the nuclear translocation of wild-type HSP110, which is important for its chaperone activity and anti-apoptotic effects. The patients carrying HSP110ΔE9 mutation exhibit high sensitivity to anticancer agents, such as oxaliplatin and 5-fluorouracil. There is still insufficient information about HSP110 localization, the clinicopathological significance of HSP110 expression, and its association with chemotherapy resistance in gastric cancer. Here, we found that high nuclear expression of HSP110 in gastric cancer tissues is associated with cancer progression, poor prognosis, and recurrence after adjuvant chemotherapy. In vitro results showed that HSP110 suppression increases the sensitivity to 5-fluorouracil and cisplatin of human gastric cancer cell lines. Our results suggest that nuclear HSP110 may be a new drug sensitivity marker for gastric cancer and a potential molecular therapeutic target for the treatment of gastric cancer patients with acquired anticancer drug resistance.

High STMN1 level is associated with chemo-resistance and poor prognosis in gastric cancer patients

Background:Stathmin1 (STMN1) is a cytosolic phosphoprotein that regulates cellular microtubule dynamics and is known to have oncogenic activity. Despite several reports, its roles in gastric cancer (GC) remain unclear owing to a lack of analyses of highly metastatic cases. This study aimed to investigate STMN1 as a prognostic and predictive indicator of response to paclitaxel therapy in patients with GC, including inoperable cases.Methods:Immunohistochemical analysis of STMN1 was performed on both operable (n=95) and inoperable GC (n=61) samples. The roles of STMN1 in cancer cell proliferation and sensitivity to a microtubule-targeting drug, paclitaxel, were confirmed by knockdown experiments using GC cell lines.Results:Multivariate and Kaplan–Meier analyses demonstrated that high STMN1 was predictive of poor prognosis in both the groups. In the operable cohort, STMN1 expression correlated with cancer curability, recurrence, and resistance to adjuvant therapy. A correlation with paclitaxel resistance was observed in inoperable cases. Knockdown of STMN1 in GC cell lines inhibited proliferation and sensitised the cells to paclitaxel by enhancing apoptosis.Conclusions:STMN1 is a possible biomarker for paclitaxel sensitivity and poor prognosis in GC and could be a novel therapeutic target in metastatic GC.

A multicenter long‐term study of imatinib treatment for Japanese patients with unresectable or recurrent gastrointestinal stromal tumors

This multicenter study, which was conducted in northern Kanto, Japan, aimed to assess the efficacy of imatinib mesylate against advanced or recurrent gastrointestinal stromal tumors (GIST).

Heat shock-induced HIKESHI protects cell viability via nuclear translocation of heat shock protein 70

Heat shock proteins (HSPs), particularly HSP70, help restore normal cellular function following damage caused by stressors. HSP expression in tumor tissues indicates cancer progression, and while the development of HSP inhibitors is progressing, these substances are not widely used to treat cancer. HIKESHI (C11orf73) does not control the intracellular movement of HSP70 at normal temperatures; however, it does regulate the function and movements of HSP70 during heat shock. In this study, we examined the intracellular movement of HSP70 during heat shock to investigate the significance of HIKESHI expression in gastric cancer (GC) and determine if HIKESHI inhibition has cytotoxic effects. We examined HIKESHI using GC cell lines and immunostaining in 207 GC tissue samples. HIKESHI expression in GC tissues was associated with the progression of lymphatic invasion. Suppressing HIKESHI using siRNA did not affect cell viability at normal temperatures. However, suppressing HIKESHI during heat shock inhibited HSP70 nuclear transport and suppressed cell viability. Our results suggest that HIKESHI is a marker of cancer progression and that the combination of HIKESHI inhibition and hyperthermia is a therapeutic tool for refractory GC.

Gastrojejunostomy for pyloric stenosis after acute gastric dilatation due to overeating

A 34-year-old woman presented at our hospital with abdominal distention due to overeating. Acute gastric dilatation was diagnosed. The patient was hospitalized, and nasogastric decompression was initiated. On hospitalization day 3, she developed shock, and her respiratory state deteriorated, requiring intubation and mechanical ventilation. Nasogastric decompression contributed to the improvement in her clinical condition. She was discharged 3 mo after admission. During outpatient follow-up, her dietary intake decreased, and her body weight gradually decreased by 14 kg. An upper gastrointestinal series and endoscopy revealed pyloric stenosis; therefore, we performed gastrojejunostomy 18 mo after her initial admission. The patient was discharged from the hospital with no postoperative complications. Gastric necrosis and perforation due to overeating-induced gastric dilatation are life-threatening conditions. Surgical intervention may be required if delayed pyloric stenosis occurs after conservative treatment. We report a case of pyloric stenosis due to overeating-induced gastric dilatation treated by gastrojejunostomy 18 mo after the initial presentation.

Curative Resection Following Neoadjuvant Chemotherapy for Advanced Gastric Cancer With Preservation of a Right Gastroepiploic Artery Coronary Artery Bypass Graft: A Case Report

Recently, the right gastroepiploic artery (RGEA) has been used in coronary artery bypass graft (CABG) as an alternative arterial graft. Because of the improvement of prognosis after CABG, malignant diseases are more common in older patients. However, there is a serious problem in patients with gastric cancer after CABG with RGEA graft. In these patients, an interruption of coronary blood supply through the RGEA may cause a life-threatening myocardial ischemia. Therefore, an appropriate strategy is very important to avoid risk while retaining the curability of the operation. We herein describe a 76-year-old Japanese man with advanced gastric cancer who underwent CABG using the RGEA. Abdominal computed tomography (CT) showed #6 lymph nodes (sub-pyloric lymph nodes) metastases surrounding the RGEA. We concluded that curative resection was impossible while preserving the RGEA and started combination chemotherapy using S-1 and cisplatin. After 2 courses of that, #6 lymph nodes were reduced extremely. Thereafter the patient underwent distal gastrectomy with regional lymph node dissection around the RGEA without excision of the RGEA. Histologically, there were no metastases in #6 lymph nodes. Neoadjuvant chemotherapy may be effective for preserving the RGEA graft in a patient with advanced gastric cancer after CABG.

Long-Term Imatinib Treatment for Patients with Unresectable or Recurrent Gastrointestinal Stromal Tumors

Background: Only limited data are available concerning the long-term outcomes of imatinib treatment among Japanese or Asian patients with advanced or recurrent gastrointestinal stromal tumors (GIST). Our multicenter study, which was conducted in northern Kanto, Japan, aimed to assess the efficacy of imatinib mesylate against advanced or recurrent GIST. Summary: The clinicopathological data of 234 GIST patients who were treated at one of the 11 participating hospitals from 2001 to 2011 were retrospectively reviewed (GREAT study). Imatinib was administered as a first-line therapy in cases involving unresectable disease or postoperative recurrence (41 cases). The patients treated with imatinib (n = 41) exhibited 1-, 3-, and 5-year overall survival (OS) rates of 92.3, 74.9, and 53.8% respectively. In univariate and multivariate analyses, imatinib continuation with dose reduction and achieving a complete or partial response were found to be associated with increased OS. The results of 2 large-scale, long-term trials demonstrate that the risk of tumor progression decreases with increased treatment duration. Furthermore, the interruption of imatinib treatment in responsive and controlled patients results in a high risk of disease progression. Key Messages: Long-term imatinib treatment is recommended for patients with nonprogressive disease. If patients experience significant toxicities, temporary dose reduction and treatment continuation might be useful.

Nuclear heat shock protein 110 expression is associated with poor prognosis and hyperthermo-chemotherapy resistance in gastric cancer patients with peritoneal metastasis

AIM To investigate the significance of heat shock protein 110 (HSP110) in gastric cancer (GC) patients with peritoneal metastasis undergoing hyperthermo-chemotherapy. METHODS Primary GC patients (n = 14) with peritoneal metastasis or positive peritoneal lavage cytology who underwent distal or total gastrectomy between April 2000 and December 2011 were enrolled in this study. The patients underwent postoperative intraperitoneal hyperthermo-chemotherapy using a Thermotron RF-8 heating device two weeks after surgery. We analyzed nuclear HSP110 expression in surgically resected tumors using immunohistochemistry. Additionally, the effect of HSP110 suppression on hyptherthermo-chemosensitivity was assessed in vitro in the MKN45 GC cell line using the HSP inhibitor KNK437. RESULTS HSP110 immnohistochemical staining in 14 GC patients showed that five (35.7%) samples belonged to the low expression group, and nine (64.3%) samples belonged to the high expression group. Progression-free survival was significantly shorter in the HSP110 high-expression group than in the low-expression group (P = 0.0313). However, no significant relationships were identified between HSP110 expression and the clinicopathological characteristics of patients. Furthermore, high HSP110 expression was not an independent prognostic factor in GC patients with peritoneal metastasis (P = 0.0625). HSP110 expression in MKN45 cells was suppressed by KNK437 at the hyperthermic temperature of 43 °C in vitro. Comparison of MKN45 cell proliferation in the presence and absence of KNK437 at 43 °C, revealed that proliferation was significantly decreased when HSP110 was inhibited by KNK437. Additionally, HSP110 suppression via HSP inhibitor treatment increased cellular sensitivity to hyperthermo-chemotherapy in vitro. CONCLUSION The expression of nuclear HSP110 in GC patients might be a new marker of chemosensitivity and a therapeutic target for patients who are tolerant to existing hyperthermo-chemotherapies.