Ameliorating Effects of Electroacupuncture on Dysmotility, Inflammation, and Pain Mediated via the Autonomic Mechanism in a Rat Model of Postoperative Ileus.

BACKGROUND/AIMS: Postoperative ileus increases healthcare costs and reduces the postoperative quality of life (QOL). The aim of this study is to investigate effects and mechanisms of electroacupuncture (EA) at ST36 and PC6 on gastrointestinal motility in rat model of postoperative ileus. METHODS: Laparotomy was performed in 24 rats (control [n = 8], sham-EA [n = 8], and EA [n = 8]) for the implantation of electrodes in the stomach and mid-jejunum for recording of gastric and small intestinal slow waves. Electrodes were placed in the chest skin for electrocardiogram (ECG). Intestinal manipulation (IM) was performed in Sham-EA and EA rats after surgical procedures. Small intestinal transit (SIT), gastric emptying (GE), postoperative pain, and plasma TNF-α were evaluated in all rats. RESULTS: (1) Compared with sham-EA, EA accelerated both SIT (P < 0.05) and GE (P < 0.05) and improved regularity of small intestinal slow waves. (2) Compared with the control rats (no IM), IM suppressed vagal activity and increased sympathovagal ratio assessed by the spectral analysis of heart rate variability from ECG, which were significantly prevented by EA. (3) EA significantly reduced pain score at 120 minutes (P < 0.05, vs 15 minutes) after the surgery, which was not seen with sham-EA. (4) Plasma TNF-α was increased by IM (P = 0.02) but suppressed by EA (P = 0.04) but not sham-EA. CONCLUSION: The postoperative ileus induced by IM, EA at ST36 and PC6 exerts a prokinetic effect on SIT and GE, a regulatory effect on small intestinal slow waves and an analgesic effect on postoperative pain possibly mediated via the autonomic-cytokine mechanisms.

Intraoperative Vagus Nerve Stimulation Accelerates Postoperative Recovery in Rats.

INTRODUCTION: Postoperative ileus (POI) is a heavy burden for healthcare industries and reduces the postoperative quality of life. The aim of this study was to investigate the effects and mechanisms of the intraoperative vagus nerve stimulation (iVNS) on gastrointestinal motility in a rodent model of POI. METHODS: For control group (control, n = 8), electrodes were placed on the chest wall for recording the electrocardiogram and on the stomach and small intestine for measuring gastric slow waves (GSWs) and small intestinal slow waves (SSWs). For sham group (sham, n = 8) and iVNS group (VNS, n = 8), after the same surgery as the control, intestinal manipulation (IM) was performed to induce POI. iVNS was performed during the surgery for the iVNS group. Small intestinal transit (SIT), gastric emptying (GE), postoperative pain, and plasma TNF-α were evaluated after operation. RESULTS: IM delayed GE that was normalized by iVNS (P < 0.05). iVNS reduced plasma TNF-α increased by IM (P = 0.04). iVNS prevents the injury of ileum mucosa induced by IM (P < 0.05). iVNS reduced the postoperative pain (P < 0.05). iVNS prevented the IM-induced decrease in vagal activity (sham 0-30 min vs. 150-180 min, P = 0.03, VNS 0-30 min vs. 150-180 min, P = 0.58) and increase in sympathovagal balance (sham 0-30 min vs. 150-180 min, P = 0.04, VNS 0-30 min vs. 150-180 min, P = 0.72). CONCLUSIONS: iVNS accelerates postoperative recovery by improving GE, reducing postoperative pain, and preventing the injury of ileum mucosa mediated via the autonomic mechanisms.

Prognosis Prediction for Postoperative Esophageal Cancer Patients Using Onodera's Prognostic Nutritional Index.

PURPOSE: Preoperative nutritional status may impact surgical outcome and prognosis. We evaluated the predictive value of Onodera's prognostic nutritional index (O's-PNI) of surgical outcome following esophagectomy in esophageal cancer patients. PATIENTS AND METHODS: In total, 144 patients undergoing esophagectomy for esophageal cancer from April 2010 to May 2015 were evaluated, retrospectively. Eighty-four patients were enrolled in this study. O's-PNIs were calculated before surgery, discharge, and 1, 2, and 6 mo after discharge. The relationship between O's-PNI and occurrence of complications as classified by the Clavien-Dindo (C-D) classification, length of hospital stay, and survival time was investigated. RESULTS: The mean O's-PNI for patients with complications of more than Grade 2 by the C-D classification was 37.4, which was significantly lower than that for Grades 0 or 1 (40.5, P = 0.0094). A negative correlation was obtained between O's-PNI and hospital stay length (P = 0.0006), whereas a positive correlation was obtained for O's-PNI at 6 mo postsurgery and overall survival (P = 0.0171, P = 0.0201). CONCLUSION: O's-PNI may represent a useful indicator of the occurrence of complications and length of hospital stay, and may influence overall survival at 6 mo postsurgery. Nutritional management during the perioperative period could therefore contribute to satisfactory outcomes following esophagectomy in esophageal cancer patients.

Fluctuation in Plasma 5-Fluorouracil Concentration During Continuous 5-Fluorouracil Infusion for Colorectal Cancer.

BACKGROUND/AIM: It is generally believed that the plasma concentration of 5-fluorouracil (5-FU) is constant when 5-FU is continually administered for chemotherapy. The aim of the present study was to verify whether this is true. PATIENTS AND METHODS: Nine patients with colorectal cancer were enrolled in this study. All patients received chemotherapy; four patients received FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) and five received FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin). 5-FU was administered continuously (2400 mg/m(2)) for 46 h. Serum was collected at 12 points after the start of administration. The concentration of 5-FU was evaluated using a new immunoassay method and gas chromatography-mass spectrometric (GC/MS) method. RESULTS: The concentrations of 5-FU fluctuated dramatically over time, with greater than 3-fold changes in each individual, and the pattern was not constant. CONCLUSION: Because the serum concentration of 5-FU fluctuates and displays various patterns, the dosage should not be based on body surface area. A new individualized method for determining the 5-FU dosage should be developed.

Clinical outcome of lower esophageal sphincter- and vagus-nerve-preserving partial cardiectomy for early gastric cancer of the subcardia.

BACKGROUND: No definitive operative method has been established for the treatment of early subcardial gastric cancer. Our newly developed technique involves local resection of the subcardia while preserving the lower esophageal sphincter and vagus nerve. A new fornix is constructed to accept the transposed esophagus. METHODS: Thirty patients underwent this procedure between July 2003 and December 2010. Continuous gastric pH monitoring was performed immediately after surgery, and esophageal manometry was undertaken 1 month later. Serum total protein, albumin, total cholesterol, cholinesterase, and body mass index (BMI) were recorded every 3 months. Pre- and postoperative oral intake were compared, reflux symptoms were recorded, and reflux esophagitis was assessed by endoscopy after 1 year. RESULTS: Twenty-five patients (86 %) reported no symptoms of reflux, and 27 (92.8 %) patients could eat 70 % or more of what they had eaten before surgery. Lower esophageal pressures were found to be >10 mmHg in 66.7 % of patients, and the fraction of time that pH <4 was <5 % of the 24-h monitoring period in 70 %. Serum parameters and BMI were unchanged. CONCLUSIONS: This surgical technique is a useful means of preserving postoperative quality of life after local gastrectomy by preventing reflux and maintaining nutritional status.

Octreotide acetate-steroid combination therapy for malignant gastrointestinal obstruction.

AIM: The Aim of this study was to investigate improvements in symptoms caused by gastrointestinal obstruction following administration of octreotide acetate (Sandostatin®) injection through steroid and opioid administration. PATIENTS AND METHODS: Patients (n=37) hospitalized with malignant gastrointestinal obstruction were enrolled in the present study. Twenty seven of them were investigated for gastrointestinal symptoms using the Japanese version of the Support Team Assessment Schedule (STAS-J). RESULTS: Octreotide acetate was administered intravenously to all 27 patients. Out of them, 17 showed a marked response, four a good response, and six no response. The overall response rate was 77.8%. Octreotide acetate with a steroid was administered to 19 patients; 13 showed a marked response, four a good response, and two no response at all. Multiple logistic regression analysis showed that that steroid administration improved the efficacy of octreotide acetate after adjusting for infusion dose (p=0.03). CONCLUSION: Intravenous administration of octreotide acetate with steroid can effectively improve gastrointestinal symptoms due to malignant gastrointestinal obstruction without adverse events.

Eicosapentaenoic acid modifies cytokine activity and inhibits cell proliferation in an oesophageal cancer cell line.

BACKGROUND/AIM: The present study investigated the effect of eicosapentaenoic acid (EPA) on nuclear factor-kappa B (NF-κB) activation, inflammatory interleukin-6 (IL-6) production, and cell proliferation in a human oesophageal carcinoma cell line (TE-1). MATERIALS AND METHODS: Lipopolysaccharide (LPS)-induced IL-6 production in TE-1 cells in the presence or absence of EPA was determined using enzyme-linked immunosorbent assay (ELISA). The proliferation of TE-1 cells was determined by the WST-1 assay. TE-1 cells were stained with Hoechst 33342 and propidium iodide to observe apoptosis. Immunohistochemical staining of NF-κB in TE-1 cells was performed. RESULTS: LPS increased IL-6 production in TE-1 cells, and EPA treatment prevented this effect. EPA treatment inhibited NF-κB activation and induced apoptosis of TE-1 cells. CONCLUSION: EPA inhibits NF-κB activation and IL-6 production in oesophageal cancer cells, their inducing apoptosis. These effects of EPA may be of benefit in improving the outcome of cancer surgery.

Evaluation of electrical activity after vagus nerve-preserving distal gastrectomy using multichannel electrogastrography.

BACKGROUND: Multichannel electrogastrography (M-EGG) can be used to evaluate gastrointestinal motility. The myoelectric activity of the remnant stomach after surgery has not been measured by M-EGG. This study examined whether myoelectric activity varied with surgical technique and compared vagus nerve-preserving distal gastrectomy (VP-DG) with standard distal gastrectomy without vagus nerve preservation (DG). Furthermore, we examined the relationship between the M-EGG findings and patients' postoperative symptoms. METHODS: Twenty-six patients who underwent VP-DG, 20 who underwent DG, and 12 healthy volunteers as controls were examined with M-EGG. The Gastrointestinal Symptom Rating Scale (GSRS) was used to assess postoperative symptoms. RESULTS: Longer periods of normal gastric function (normogastria, 2.0-4.0 cycle min(-1)) were detected in channel 1 in the VP-DG group than in the DG group in either the fasted or fed state (P<0.05). The percentage of slow wave coupling (%SWC) in the fed state correlated negatively with GSRS scores (reflux, r=-0.59, P=0.02; abdominal pain, r=-0.51, P=0.04, indigestion, r=-0.59, P=0.02 and total score, r=-0.75, P=0.02). CONCLUSIONS: Slow waves can be recorded non-invasively using M-EGG in the remnant stomach following gastrectomy. The VP-DG group showed better preserved gastric myoelectric activity than the DG group, and the %SWC showed a significant negative correlation with scores of GSRS (reflux, abdominal pain, indigestion and total score) in the VP-DG group.

Current status of multichannel electrogastrography and examples of its use.

Electrogastrography (EGG) is a non-invasive diagnostic motility for recording gastric myoelectrical activity. Gastric myoelectrical activity was first recorded in 1922. Advances in recording equipment enabled widespread use of cutaneous EGG after 1985. Later, introduction of multichannel EGG (M-EGG) enabled measurement of electrical activity transmission. At present, M-EGG findings are used as objective indicators of gastric motility disorders caused by various diseases. EGG measures two categories of gastric electrical activity: electrical response activity, or spike potentials; and electrical control activity, or slow waves. The appearance of abnormal rhythmic electrical activity is indicative of abnormalities in gastric motility. The normal frequency range of gastric electrical activity (normogastria) is around 3 cycles per?min. Multiple EGG parameters assist in the assessment of gastric myoelectrical activity, and significant correlations between EGG and other gastric motility tests have been demonstrated in many studies. In Japan, however, EGG remains in the exploratory stage, and its clinical use is limited. There are large variations in procedures and systems used in previous studies, thus there is a need for standardization of EGG procedures and technical terminology. Here, we outline the current status of EGG and report the M-EGG procedures used in our department in addition to our M-EGG findings.

Evaluation of 5-FU plasma concentration by 13C breath test in patients treated with oral 5-FU analogs.

BACKGROUND/AIM: The objective of this study was to investigate the influence of digestive gastrointestinal absorption function on the pharmacokinetics of the orally-administered anticancer drug, Tegafur-gimestat-otastat potassium (TS-1), by measuring the plasma 5-fluorouracil (5-FU) concentration using stable isotope breath tests. PATIENTS AND METHODS: Twenty-nine patients with progressive/recurrent digestive organ cancer were enrolled for this pharmacokinetic study, and blood samples were obtained from each patient. The area under-the-time-concentration curve between 0 and 480 min (AUC0-480 min), time-of-drug concentration peak (T(max)), maximum drug concentration (C(max)) and the half-life period (t(1/2)) of 5-FU were investigated. Simultaneously, a continuous (13)C-acetate breath test was performed for each patient. The parameters measured with the breath test were the area under the (13)CO(2) excretion rate curve between 0-4 h (AUC(0-4h)), peak (13)CO(2) value and elimination rate constant (K(el)) value. RESULTS: The AUC(0-8h) and C(max) of 5-FU were significantly correlated with K(el) (p=0.012 and p=0.024, respectively), and the 5-FU C(max) value was significantly correlated with the peak value of (13)CO(2) (p=0.037). Multivariate regression analysis also found the C(max) of 5-FU to be associated with K(el) (p=0.0118). The C(max) and AUC(0-8h) of 5-FU were also significantly correlated (p<0.0001). CONCLUSION: The results of this study suggest that gastrointestinal absorption is closely-related to plasma 5-FU concentration after oral administration of TS-1.

An immunoassay method for the pharmacokinetics of 5-fluorouracil in patients with gastric cancer administered adjuvant chemotherapy.

Conventional gas chromatography-mass spectrometry (GC-MS) was compared with a new immunoassay method for measuring plasma (5-FU) concentrations in adjuvant chemotherapy with TS-1 for patients with gastric cancer. TS-1 was administered orally to patients after gastrectomy. Blood samples for pharmacokinetic analysis were collected on the seventh day of treatment. The mean area under the time concentration curve (AUC)(0-8), half-life (t(1/2)), and maximum drug concentration (C(max)) obtained by the two methods were as follows: GC-MS, 847.9 µg/ml/hr, 2.76 h, and 186.6 ng/ml; and immunoassay, 1311.2 µg/ml/hr, 3.5 h, and 259.8 ng/ml. Significant correlations were observed for AUC(0-8) (p=0.0001), C(max) (p=0.0007), and changes in the 5-FU concentration in blood over time (p=0.018) for the two methods. Compared with the conventional GC-MS method, the new immunoassay method provides similar results, but is simpler and results can be obtained earlier. This method will be useful for monitoring the 5-FU concentration in serum from patients with gastric cancer receiving TS-1.

A combined therapy with docetaxel and nedaplatin for relapsed and metastatic esophageal carcinoma.

We performed combined chemotherapy using docetaxel and nedaplatin with and without radiation therapy as a second-line treatment for relapsed or metastatic esophageal carcinoma. Eighteen patients were enrolled from April 2003 to June 2010; 10 cases were metastatic and 8 cases were recurrent. Nedaplatin (30 mg/m(2)) and Docetaxel (30 mg/m(2)/day) were administered on days 1, 8 and 15. Nine cases undertook the combined-chemotherapy only, with a response rate of 22.2% (2/9). The other nine cases received combined chemo-radiotherapy, with a response rate of 55.5% (5/9). The median survival time of all patients was 273 days, the median survival time for patients treated with combined chemotherapy was 331 days, while for patients treated with combined chemoradiotherapy was 244 days. The two-year survival rate overall was 11.1% (1/9). The adverse event of leukocytopenia greater than grade 3 was observed in three cases of combined chemoradiotherapy cases only. Docetaxel and Nedaplatin combination chemotherapy is well tolerated and useful as second-line chemotherapy for patients with relapsed or metastatic esophageal cancer.

[A case of chemo-radiation therapy with high degree of efficacy for esophageal cancer with liver metastasis].

A 78-year-old man underwent a radical resection for esophageal cancer (Stage III) and cardiac gastric cancer (Stage IA) at another hospital 2 years ago. After the operation, he was followed at that hospital. In 2008, abdominal CT scan and FDG-PET/CT revealed a liver tumor. He was referred to our hospital and was diagnosed as esophageal cancer with liver metastasis. He received chemo-radiation therapy (CRT). The regimen was docetaxel hydrate (30 mg/m2, day 1, 8, 29 and 36) and S-1 (60 mg/m2, day 1-14 and day 29-45) with radiation (45 Gy) for liver metastasis. He finished the CRT without any hematotoxicity, liver disorder and non-hematotoxic adverse event (grade 3). Abdominal CT was done 2 months after the end of CRT and revealed that the tumor lesion disappeared completely. The patient is alive for 11 months after the CRT without any evidence of recurrence. The tumor disappeared completely for the last 11 months. We conclude that CRT is safe and very effective for esophageal cancer with liver metastasis.

[A resected case of postoperative liver metastasis of a gastrointestinal stromal tumor showing complete response after imatinib treatment].

A 71-year-old man visited the hospital complaining of nausea in December 2002. Following a diagnosis of a gastrointestinal stromal tumor (GIST), partial resection of the stomach was performed in January 2003. The tumor was immunohistochemically positive for c-kit and CD34. The tumor size was 6.5 x 5.0 x 4.5 cm with a mitotic index of 25 out of 50 in the high-power field. The pathological diagnosis indicated a high-risk GIST. Treatment with imatinib at a dose of 400 mg/day was started because of liver metastasis of the GIST in January 2004. The liver metastasis was gradually reduced and exhibited cystic change. We considered that there was a complete response without accumulation by FDG-PET in June 2007. An hepatic segmentectomy was performed and imatinib was discontinued in July 2007. Most intratumorale in the specimen underwent hyaline degeneration after pathological examination, but there were viable cells in a portion of the tumor border. Imatinib treatment was resumed because of recurrence in the remnant stomach four months postoperatively owing to imatinib withdrawal. In making a diagnosis at the cell level by FDG-PET, it was difficult to determine the effectiveness of imatinib, and therefore, it is suggested that imatinib treatment must be continued after surgical resection.

[Results of hepatic arterial infusion chemotherapy with 5-FU and leucovorin for unresectable liver metastases from colorectal cancer].

PURPOSE: Hepaticarterial infusional(HAI)5-FU chemotherapy, which involves the use of interventional radiology technique, has matured technically in Japan in the 1990's. The antitumor effect of 5-FU is enhanced by combination with leucovorin. This study was performed to evaluate the efficacy and toxicity of HAI 5-FU and leucovorin chemotherapy for patients with unresectable liver metastases from colorectal cancer. METHODS: Treatment was given to 20 patients with unresectable liver metastases from colorectal cancer. The chemotherapy regimen consisted of weekly HAI of 5-FU(1,000 mg/body)and leucovorin(250 mg/body)over five hours. The survival and response rates to the therapy were assessed according to RECIST. Hematologic and non-hematologic toxicity was assessed according to CTCAE v3.0. RESULTS: Combined HAI 5-FU and leucovorin therapy was carried out an average of 27 times. The response rate for liver tumors was 75%, and the median survival time was 22 months. The applied regimen caused only mild adverse events. There was no evidence of myelosuppression except for platelet decrease(grade 3)in a patient with chronic renal failure. CONCLUSION: This HAI approach using 5-FU and leucovorin was effective and the therapy for unresectable liver metastases from colorectal cancer was tolerated well. Therefore the HAI approach should be reconsidered as an effective therapy against this disease in Japan.

[Pharmacokinetics of 5-FU after S-1 oral administration for adjuvant chemotherapy in gastric cancer patients].

We studied the pharmacokinetics of 5-FU after S-1 oral administration at the usual dose (80 mg/m2) for adjuvant chemotherapy in 13 advanced gastric cancer patients (Stage II, III), and at a decreased dose (60 mg/m2) for adjuvant or combined chemotherapy in 13 advanced gastric cancer patients. Pharmacokinetic parameters of 5-FU in the serum were as follows: Cmax, 159 .9 2+/-45.2 ng/mL, Tmax, 2.17+/-0.58 h;T1/2, 3.13+/-2.88 h; and AUC(0-8), 768.0+/-260.8 ng h/mL in the patients with the usual dose, and Cmax, 117.3+/-55.1 ng/mL; Tmax, 2.62+/-0.9 6 h; T1/2, 3.09+/-1.9 5 h and AUC(0-8), 565.9+/-216.8 ng h/mL in the patients with the decreased dose. No difference in AUC was observed between operative methods. Adverse events of more than grade 3 were recognized in 7 patients, and AUC of 6 patients were more than 800 ng h/mL. The plasma concentration of 5-FU was quite different between patients. The difference of Cmax and AUC was 3-4 times. It was concluded that we must pay attention to individual differences in the plasma concentration of 5-FU in postoperative gastric cancer patients when S-1 would be administered.

[A feasible study of docetaxel/nedaplatin combined chemotherapy for relapsed or refractory esophageal cancer patients as a 2nd-line chemotherapy].

As a 2nd-line treatment for relapsed or refractory esophageal cancer patients after chemoradiotherapy, we performed a combination chemotherapy of DOC/CDGP for 11 patients. Intravenous drip infusion of DOC 30 mg/m(2)and CDGP 30 mg/m(2)on days 1, 8 and 15, and 4 weeks treatment was assumed as 1 cycle. We treated 8 of 11 patients with more than 2 cycles, and 4 of 8 patients were treated with radiation therapy (RT). The effects by RECIST revealed partial response (PR) in 2 patients (50%), stable disease (SD) in 1 patient and progress disease (PD) in 1 patient without RT, and PR in 3 patients and not effective in 1 patient with RT, respectively. There was no treatment-related death nor adverse event of grade 4. The Hematological toxicities of leukopenia of grade 3 were observed in 3 patients. Non-hematological toxicites more than grade 3 were not observed. The combination chemotherapy of DOC/CDGP was concluded to be safe and effective for relapsed or refractory esophageal cancer patients as a 2nd line treatment.

[A phase I/II study of docetaxel/TS-1 with radiation for esophageal cancer patients--step 1].

The therapy 5-FU and CDDP with radiation is thought to be the standard therapy for esophageal cancer patients by now. However, the therapy is associated with a comparatively high incidence of gastrointestinal disorders and requires hospitalization. We have proposed a new regimen of Docetaxel and TS-1 with radiation for maintaining of QOL and improving outcome. Step 1 of the clinical phase I/ II study was conducted for 10 cases from May 2004 to March 2006. Treatment could be accomplished in all cases, and no treatment-related deaths or adverse events of grade 4 were observed in any case. As for hematotoxicity, one case had leucopenia of grade 3 and neutropenia of grade 2. As for non-hematotoxic adverse events, anorexia of grade 3 was recognized in one case of level 3. The response rate evaluated by RECIST was 66% (CR in 2 cases, PR in 4 cases), and the rate based on the Guide Lines for the Clinical and Pathologic Studies on Carcinoma of Esophagus by the Japanese Society for Esophageal Cancer was 70% (CR in 3 cases, PR in 4 cases). We assumed that the recommended dosage of TXT was 30 mg/m(2) and that of TS-1 was 60 mg/m(2) with radiotherapy of 60 Gy. This combination therapy may be recommended because of fewer adverse events and a higher responsive rate than the standard therapies. We intend to continue this study to step 2 and 3, and to reveal the response rate and adverse events for more esophageal cancer patients.