Thyroid hormone activated upper gastrointestinal motility without mediating gastrointestinal hormones in conscious dogs.

This study was conducted to clarify the relationship between thyroid function and gastrointestinal motility. We established an experimental configuration in which the feedback of thyroid function was completely removed using conscious dogs. With hypothyroidism, time of phase I of interdigestive migrating contractions (IMC) was longer, time of phase II and phase III was significantly shortened, and both the continuous time of strong tetanic contraction at antrum and 10-h frequency of phase III counted from the first IMC after meal significantly decreased. Whereas, hyperthyroidism caused the opposite events to those with hypothyroidism. Furthermore, We found giant migrating contractions (GMC) occurred from the upper gastrointestinal tract when we administrated high dose of thyroid hormone. One GMC occurred from anal sides propagated to cardiac, and this propagation was similar to the emesis-like interdigestive motor activity, the other GMC occurred from oral sides propagated to anal sides and this was similar to the diarrhea-like interdigestive motor activity. We examined the relationship between thyroid function and gastrointestinal hormones including of ghrelin, GLP-1, and cholecystokinin (CCK). However, we could not find significant differences under different thyroid hormone status. This is the first report that thyroid hormone activated upper gastrointestinal motility without mediating gastrointestinal hormones.

A prospective pilot study of an elemental nutritional supplement for prevention of oral mucositis during S-1 adjuvant chemotherapy for gastric cancer.

PURPOSES: Oral mucositis is one of the most common reasons for discontinuation of S-1 adjuvant chemotherapy after radical gastrectomy. Some studies suggest that nutritional support with amino acids may improve oral mucositis. We conducted a prospective, randomized clinical trial of patients who underwent adjuvant chemotherapy for gastric cancer to examine whether an oral elemental diet prevents chemotherapy associated oral mucositis and body weight loss. METHODS: Patients were randomly assigned to a group consuming Elental® (the treatment group, n = 11) or a control diet group (n = 11). Patients in the treatment group consumed one pack of Elental® per day during adjuvant chemotherapy. The primary endpoint was the presence and grade of oral mucositis. Secondary endpoints included adherence to Elental® based on the doses recorded in a diary, changes in nutrition parameters, and frequency and severity of adverse events. RESULTS: The incidence of oral mucositis was significantly lower in the treatment group (9.1%) than in the control group (27.3%). The median body weight loss in the treatment group was significantly smaller than that in the control group (P = .015). According to Kaplan-Meier estimates the treatment group was significantly associated with high cumulative S-1 continuation rates (log-rank P = .047). CONCLUSION: We conclude that the amino-acid-rich elemental diet Elental® may be useful as a countermeasure for S-1 adjuvant chemotherapy-induced mucositis.

Comparison of the Physiological Effect of Billroth-I and Roux-en-Y Reconstruction Following Laparoscopic Distal Gastrectomy.

BACKGROUND: Laparoscopic distal gastrectomy (LDG) is a widely used minimally invasive surgery. Following LDG, Billroth-I (B-I) provides physiological reconstruction by preserving the duodenal passage but results in a high incidence of reflux esophagitis that decreases postoperative quality of life. Because of this, Roux-en-Y (R-Y) reconstruction is often considered the first choice after LDG. However, very few studies have investigated differences in physiological function between B-I and R-Y after LDG. We hypothesized that B-I would outperform R-Y in clinical and physiological outcomes, including nutrition parameters. METHODS: We compared hemoglobin, ferritin, serum iron, Vitamin B12, 25(OH)-Vitamin D (V-D), body weight, and gastric emptying after LDG in patients with either B-I or R-Y reconstruction. RESULTS: The levels of hemoglobin in the B-I group were significantly higher than that in the R-Y group at all time points later than 6 months postsurgery. The ferritin levels were significantly higher in the B-I group at all time points later than 9 months postsurgery. The concentration of serum V-D in the B-I group was significantly higher than that in the R-Y group at 1 year 6 months, 1 year 9 months, and 2 years after surgery. Gastric emptying in the R-Y group was significantly slower than in the B-I group. CONCLUSIONS: Our data indicate that B-I leads to less postsurgical iron deficiency anemia and V-D deficiency compared with R-Y reconstruction. Furthermore, gastric emptying was preserved in B-I reconstruction compared with R-Y reconstruction. In conclusion, after LDG, B-I reconstruction seems to cause fewer nutritional complications than R-Y reconstruction.

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.

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.

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.

Low Expression of FBXO45 Is Associated with Gastric Cancer Progression and Poor Prognosis.

BACKGROUND: F-Box protein 45 (FBXO45) is reported to be associated with cancer aggressiveness. We investigated the relationship between FBXO45 and clinicopathological factors in gastric cancer (GC). MATERIALS AND METHODS: We used immunohistochemistry to investigate FBXO45 expression in 104 GC samples; the prognostic value of FBXO45 was also calculated. RESULTS: FBXO45 levels in GC were higher than in normal tissues. Patients with relatively low FBXO45 expression (n=58) had increased cancer progression and poorer prognosis than those with high expression (n=46). Low FBXO45 expression was an independent negative prognostic factor in patients with GC. Using the public Kaplan-Meier plotter database, we showed that survival in patients with low expression of FBXO45 in GC was shorter than that in those with high FBXO45 expression, regardless of lymph node metastasis. CONCLUSION: A low FBXO45 expression level in GC tissues may be a powerful predictor of poor prognosis. FBXO45 might, therefore, be a promising candidate for a molecular targeted therapy in GC.

Double Endoscopic Intraluminal Operation (DEILO) for Early Gastric Cancer: Outcome of Novel Procedure for Endoscopic Submucosal Dissection.

Endoscopic submucosal dissection (ESD) has been used to treat patients with early gastric cancer (EGC). Although several endoscopic devices have been developed to ensure easy and safe ESD, this technique still requires an experienced, highly skilled endoscopist, as it is performed through a single gastroscope, thus requiring one-handed surgical techniques. To overcome these limitations, many ESD procedures with counter-traction have been developed, such as the double scope, double channel scope, clip with line, magnetic anchor, percutaneous traction and external grasping forceps methods. We devised a double endoscopic intraluminal operation (DEILO). Two endoscopes were simultaneously inserted into the stomach. One endoscope was used to lift the lesion, and the other was used to excise the lesion. The DEILO procedure was performed on 122 cases of EGC. In this article, we report the efficacy and safety of DEILO in patients with EGC.

Restoration of gastrointestinal motility ameliorates nutritional deficiencies and body weight loss of patients who undergo laparoscopy-assisted proximal gastrectomy.

BACKGROUND: Esophagogastrostomy after proximal gastrectomy (PG) is a simple and safe reconstruction, but it leads to a high incidence of reflux esophagitis and impairs postoperative quality of life. We have already reported gastric tube (GT) reconstruction after PG and performed it on more than 100 patients. No studies have reported long-term outcomes after PG-GT. The aim of this study was to investigate long-term outcomes, including nutrition indices, such as body weight, serum albumin, total protein, hemoglobin, and ferritin after PG, and observe recovery of upper gastrointestinal tract motility. METHODS: We analyzed body weight loss and laboratory findings at our outpatient clinic at 1, 6, 12, 24, 36, 48, and 60 months postoperatively. Manometric recording was carried out at 1, 2, 3, 4, and 5 years after surgery. RESULTS: The percentage change in body weight in the PG-GT group was significantly larger than that in the PG-JI and TG-RY groups at 2.5, 3, 4, and 5 years after surgery. The levels of hemoglobin and ferritin in the PG-GT and PG-JI groups were significantly higher than those in the TG-RY group at all time points except 6 months after surgery. In the fasted state, the phase III originated at the gastric tube was propagated to the duodenum 3 years after surgery. In the fed state, phasic contractions of the duodenum were in harmony with gastric tube contractions 3 years after surgery. CONCLUSIONS: PG-GT is the least invasive procedure, and restoration of gastrointestinal motilities in the gastric tube and duodenum may ameliorate body weight loss and nutritional status, including anemia, in patients after PG.

High Expression of MRE11-RAD50-NBS1 Is Associated with Poor Prognosis and Chemoresistance in Gastric Cancer.

BACKGROUND: The MRN complex of meiotic recombination 11 (MRE11), DNA repair protein Rad50 (RAD50) and Nijmegen breakage syndrome 1 (NBS1) proteins coordinate the detection and repair of DNA double-strand breaks (DSBs). DNA DSB repair-dependent chemoresistance likely has an effect on the treatment of human cancer. MATERIALS AND METHODS: We investigated the expression of MRN complex in human gastric cancer (GC) tissues using immunohistochemistry and analyzed its clinical significance and prognostic relevance. RESULTS: The expression of MRN complex was significantly associated with clinical factors including poorer prognosis and negatively associated with the expression of DNA damage marker phosphorylated H2A histone family, member X (γH2AX) in the nucleus. In the biopsy specimens, low expression of MRE11 correlated with good response to chemotherapy and surgical resection after down-staging by chemotherapy. Furthermore, the expression levels of MRE11 and RAD50 were independent predictors of surgical resection after chemotherapy. CONCLUSION: The high expression of MRN complex constituents could be a predictor for poor prognosis and chemoresistance in GC.

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.

Outcomes of patients with early gastric cancer who underwent double endoscopic intraluminal surgery.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) has been used to treat patients with nonulcerated early gastric cancers of 2  cm or less, because the incidence of lymph node metastasis is negligible. However, the standard ESD procedure is long, complex, and associated with high complication rates. To overcome these limitations, we devised a double endoscopic intraluminal operation (DEILO) and assessed its efficacy and safety for superficial gastric neoplasms in a preliminary prospective study. METHODS: The DEILO procedure was performed on 101 patients with gastric cancers. Two endoscopes were simultaneously inserted into the stomach. One endoscope was used to lift the lesion, and the other was used to excise the lesion. RESULTS: The DEILO technique was performed successfully, and en bloc resection was achieved for 98 (97.0%) of 101 patients. Histologically curative resection was achieved for 85 lesions (84.2%). The mean operating time was 70 min (range 20-178 min). Perforation occurred in four patients (4.0%), all of whom were successfully treated nonsurgically. Three patients developed postoperative hemorrhage, which was controlled endoscopically. CONCLUSION: The DEILO procedure appears to shorten the operating time for ESD, with efficacy and complication rates comparable with the standard procedure.

Outcome of laparoscopic gastrectomy with D1 plus lymph node dissection in gastric cancer patients postoperatively diagnosed with locally advanced disease or lymph node metastasis.

BACKGROUND: Some laparoscopic gastrectomy (LG) patients are postoperatively diagnosed with locally advanced disease or lymph node metastasis. Few reports have reviewed the outcomes or validity of LG in such patients. METHODS: We retrospectively compared the outcomes of LG for gastric cancer patients postoperatively diagnosed with T3 (subserosal invasion) or higher or N1 (metastasis in 1-2 regional lymph nodes), or higher disease (n = 36), with open gastrectomy (OG) for c-stage I gastric cancer patients (n = 62). RESULTS: D1 plus lymph node dissection was performed in all patients in the LG group. Blood loss was significantly lower in the LG group than in the OG group (P < 0.0010). The mean postoperative hospital stay duration was significantly shorter in the LG group than in the OG group (P = 0.0016). In the LG group, lymph node metastasis occurred in 1 patient, peritoneal dissemination in 2 patients, and liver metastasis in 1 patient. The 5-year survival rate did not significantly differ between the LG and OG groups (90.00 vs. 94.52 %; P = 0.6517). CONCLUSIONS: Given the similarity in long-term outcomes between the LG and OG groups, LG is an appropriate indication for gastric cancer patients postoperatively diagnosed with locally advanced disease or lymph node metastasis.

Granular cell tumor of the esophagus with elevated preoperative serum carbohydrate antigen 19-9: a case report.

A 59-year-old Japanese man was admitted to our hospital for treatment of a submucosal tumor of the esophagus detected by upper gastrointestinal endoscopy and computed tomography (CT). Endoscopic examination revealed a submucosal tumor in the esophagus 35 cm from the incisor teeth. Biopsy of the lesions identified granular cell tumor. CT indicated a projecting and slightly enhanced homogenous mass measuring 2.0 × 1.5 cm in the esophagus below the tracheal bifurcation. Serum tumor marker studies revealed elevated carbohydrate antigen (CA) 19-9. Therefore, the tumor was considered to have malignant potential, and surgical resection was performed. The final pathologic diagnosis was a benign granular cell tumor, positive for S-100 protein. The patient was doing well with normal CA 19-9 levels and no recurrence more than 5 years after surgery. To the best of our knowledge, this is the first report of a granular cell tumor with elevated serum CA 19-9.

Schwannoma of the stomach with elevated preoperative serum carbohydrate antigen 19-9: report of a case.

We herein report a case of a gastric schwannoma with elevated preoperative serum carbohydrate antigen 19-9 (CA19-9) (155.2 U/ml, normal range 0-36.9 U/ml). A 59-year-old Japanese man was admitted to our hospital for treatment of a submucosal tumor of the stomach detected by barium meal, upper gastrointestinal endoscopy, and computed tomography. Endoscopic examination revealed a 3-cm diameter submucosal tumor in the antrum of the stomach, but biopsy of the lesion was unable to confirm the diagnosis. Positron emission tomography to evaluate the malignant potential showed a high uptake of (18)F-fluorodeoxyglucose in the tumor. Laparoscopy-assisted distal gastrectomy was therefore performed. The histopathological findings of the surgical specimen revealed a benign gastric schwannoma, positive for S-100 protein. The postoperative serum CA19-9 levels gradually decreased and normalized. To the best of our knowledge, this is the first report of a gastric schwannoma with elevated serum CA19-9.