Rikkunshito increases peripheral incretin-hormone levels in humans and rats.

BACKGROUND: It was reported that rikkunshito (TJ-43) improved the cisplatin-induced decreases in the active form of ghrelin in plasma; however, other effects on gastrointestinal hormones have not been investigated. AIM: To investigate the effects of TJ-43 on peripheral levels of incretin hormones, including gastric inhibitory polypeptide (GIP) and glucagon-like polypeptide-1 (GLP-1), in humans and rats. METHODS: Patients were divided into two groups, namely patients who received TJ-43 immediately following surgery [TJ-43(+) group] and those who received TJ-43 on postoperative day 21 [TJ-43(-) group], and the plasma levels of active GIP and active GLP-1 were assessed. In animal experiments, rats were treated with TJ-43 [rat (r)TJ-43(+) group] or without [rTJ-43(-) group] by gavage for 4 wk, and the plasma active GIP and active GLP-1 levels were measured. The expression of incretin hormones in the gastrointestinal tract and insulin in the pancreas were investigated by immunohistochemistry. Furthermore, the cyclic adenosine monophosphate activities were assessed in pancreatic tissues from rats treated with or without TJ-43 in vivo, and the blood glucose levels and plasma insulin levels were measured in rats treated with or without TJ-43 in oral glucose tolerance tests. RESULTS: In humans, the active incretin hormone levels increased, and values were significantly greater in the TJ-43(+) group compared those in the TJ-43(-) group. In rats, the plasma active incretin levels significantly increased in the rTJ-43(+) group compared with those in the rTJ-43(-) group. GIP and GLP-1 expressions were enhanced by TJ-43 treatment. Moreover, plasma insulin levels increased and blood glucose levels were blunted in the rTJ-43(+) group. CONCLUSION: The results show that TJ-43 may be beneficial for patients who undergo pancreatic surgery.

Rikkunshito increases appetite by enhancing gastrointestinal and incretin hormone levels in patients who underwent pylorus-preserving pancreaticoduodenectomy: A retrospective study.

BACKGROUND: Rikkunshito (TJ-43) relieves gastrointestinal disturbance by increases in the levels of acylated ghrelin. AIM: To investigate the effects of TJ-43 in patients undergoing pancreatic surgery. METHODS: Forty-one patients undergoing pylorus-preserving pancreaticoduodenectomy (PpPD) were divided into two groups; patients took daily doses of TJ-43 after surgery or after postoperative day (POD) 21. The plasma levels of acylated and desacylated ghrelin, cholecystokinin (CCK), peptide YY (PYY), gastric inhibitory peptide (GIP), and active glucagon-like peptide (GLP)-1 were evaluated. Oral calorie intake was assessed at POD 21 in both groups. The primary endpoint of this study was the total food intake after PpPD. RESULTS: The levels of acylated ghrelin were significantly greater in patients treated with TJ-43 than those in patients without TJ-43 administration at POD 21, and oral intake was significantly increased in patients treated with TJ-43. The CCK and PYY levels were significantly greater in patients treated with TJ-43 than those in patients without TJ-43 treatment. Furthermore, the GIP and active GLP-1 levels increased and values at POD 21 were significantly greater in patients treated with TJ-43 than those in patients without TJ-43 administration. Insulin secretion tended to increase in patients treated with TJ-43. CONCLUSION: TJ-43 may have advantages for oral food intake in patients in the early phase after pancreatic surgery. Further investigation is needed to clarify the effects of TJ-43 on incretin hormones.

Prognostic value of preoperative psoas muscle index as a measure of nutritional status in patients with esophageal cancer receiving neoadjuvant therapy.

OBJECTIVES: It has been reported that preoperative nutritional status in some gastrointestinal cancers has a significant effect on postoperative prognosis. However, there are few reports on esophageal cancer, especially for esophageal cancer patients who have undergone neoadjuvant therapy and surgery. Psoas muscle index (PMI) is widely known as an index for assessing preoperative nutritional status, and has recently been reported for its prognostic value in many malignancies. The aim of this study was to investigate and evaluate the clinical results in our hospital using the PMI method. METHODS: We retrospectively investigated esophageal cancer in patients (clinical stage II or III) who underwent neoadjuvant therapy and surgical treatment (R0 cases) from January 2008 to December 2015. Applicable 63 cases were entered accordingly. In our hospital, nutritional supplements are used for nutritional management during preoperative adjuvant therapy, and these are administered to patients who have difficulty ingesting nutrition by feeding tube or total parenteral nutrition. The target value for nutritional supplement administration was 36 kcal/kg. Taking into account that chemotherapy for esophageal cancer was being performed using Harris-Benedict's basal energy expenditure (25 kcal/kg), we multiplied by 1.44 (active factor; 1.2, stress factor; 1.2) and set 36 kcal/kg as a guide. PMI was evaluated before neoadjuvant therapy and before surgery. We defined sarcopenia by PMI of the third lumbar vertebra (L3) by a computed tomography (CT) examination using 3-dimensional image analysis software, <6.36 for men and <3.92 for women, and investigated the effect of each on prognosis. RESULTS: The prevalence of sarcopenia decreased from 74.6% (47 of 63) to 69.84% (44 of 63) during the pretherapeutic to preoperative period (P = 0.691), suggesting improved nutritional status. Regarding PMI divided by cutoff value for each sex (the cutoff value was the PMI mean value -2 SD [6.36 cm2 m2 for men and 3.92 cm2/m2 for women] of healthy individuals <50 y of age, which was reported as a standard for low skeletal muscle mass in Japanese individuals), there was an improvement observed in the preoperative compared to pretherapeutic period, but it was not obtained as a significant difference (pretherapeutic PMI; 0.87 ± 0.06 [mean ± SD], preoperative PMI; 0.89 ± 0.06 [mean ± SD], P = 0.18). In overall survival (OS) and disease-free survival (DFS), there was no significant difference in the short-term results with and without sarcopenia in the pretherapeutic group (both OS and DFS, P = 0.17). There was a significant difference with and without sarcopenia in the preoperative group in terms of OS and DFS (OS, P = 0.045; DFS, P = 0.043), which was short term due to nutritional intervention during preoperative adjuvant therapy. It was suggested that the results would be improved. CONCLUSIONS: Improving nutritional status before surgery was shown to improve short-term prognosis in patients with esophageal cancer. It is hence suggested that it is important to maintain or improve nutritional status by intervention from the time of neoadjuvant therapy.

Nephrotic syndrome due to preeclampsia before 20 weeks of gestation: a case report.

BACKGROUND: Preeclampsia (PE) refers to the development of hypertension and new-onset proteinuria or progressive organ damage (especially kidney) in a previously normotensive pregnant women after 20 weeks of gestation. Thus, new-onset nephrotic syndrome due to PE before 20 weeks of gestation seems to be rare, making its diagnosis difficult in this time period. CASE PRESENTATION: A 28-year-old woman presented with a new-onset nephrotic syndrome at 16 weeks of gestation. A high dose of oral glucocorticoids (prednisolone, 40 mg) was initiated for presumed glomerulonephritis since she presented with severe nephrotic syndrome before 20 weeks of gestation, however, the treatment was not effective. At 21 weeks of gestation, we confirmed that the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio was very high (sFlt-1, 13,400 pg/mL; PlGF, 21.9 pg/mL; serum sFlt-1/PlGF ratio 611.9). Therefore, we diagnosed nephrotic syndrome due to PE, and oral glucocorticoids were discontinued. After she underwent a cesarean section at 24 weeks & 3 days, we performed a kidney biopsy. Focal segmental sclerotic lesions with epithelial cell hyperplasia and foam cells in the tubular poles were seen on light microscopy. On immunofluorescence tests, C4d staining showed linear peripheral patterns in the glomeruli. Electron microscopy revealed diffuse subendothelial edema with focal foot process effacement. The histological diagnosis was severe glomerular endotheliosis with focal segmental glomerulosclerosis. Furthermore, the histology of placenta was consistent with PE. Eight months after delivery, her proteinuria disappeared completely. CONCLUSIONS: We not only confirmed an abnormal serum sFlt-1/PlGF ratio but also presented the histology compatible with pure PE in the kidney and placenta in a case of nephrotic syndrome before 20 weeks of gestation. The serum sFlt-1/PlGF ratio may be useful in determining the treatment strategy for atypical cases of pregnant women with nephrotic syndrome, particularly before 20 weeks of gestation.

Influence of magnesium and parathyroid hormone on cisplatin-induced nephrotoxicity in esophageal squamous cell carcinoma.

Magnesium (Mg) supplementation has previously been demonstrated to confer protective effects against nephrotoxicity induced by cisplatin. Parathyroid hormone (PTH) regulates Mg homeostasis. The aim of present study was to determine the protective effects of Mg supplementation against cisplatin-induced nephrotoxicity and its association with PTH levels in patients with esophageal squamous cell carcinoma (ESCC). A total of 55 patients with primary ESCC who received chemotherapy with high-dose cisplatin were examined. Mg was administered intravenously, and serum concentrations of PTH, parathyroid hormone-related protein (PTH-rP), creatinine and Mg were prospectively measured. Of the 55 patients, 37 received Mg supplementation. Post-chemotherapeutic creatinine concentrations were significantly increased in patients without Mg supplementation (P=0.01), with grade 1 and 2 increases of 22.2 and 5.6%, respectively, whereas these increases were suppressed by Mg supplementation (change in creatinine, P=0.21), with grade 1 and 2 increases of 8.1 and 0%, respectively. In addition, PTH and PTH-rP concentrations were high in 8 (14.5%) and 6 (10.9%) of all 55 patients, respectively. Alterations in creatinine concentrations (post-/pre-chemotherapy) due to chemotherapy were higher in patients with high levels of PTH regardless of Mg supplementation (P<0.01). Pre-therapeutic creatinine concentrations did not correlate with the alterations in creatinine concentrations due to chemotherapy. Intravenous Mg supplementation therefore conferred protective effects against cisplatin-induced nephrotoxicity in patients with ESCC. Furthermore, increases in PTH or PTH-rP may have influenced the extent of nephrotoxicity.

Significance of GSTP1 for predicting the prognosis and chemotherapeutic efficacy in esophageal squamous cell carcinoma.

Glutathione S-transferases (GSTs) have been reported to be activated in several types of cancers, including esophageal squamous cell carcinoma (ESCC). The aim of the present study was to investigate whether GSTP1 protein expression is a useful predictor of the clinical outcome or drug resistance in ESCC. Immunohistochemistry was conducted with 75 ESCC resected specimens using a monoclonal antibody against GSTP1. The patients were divided into two groups according to the degree of GSTP1 staining, and the relationship between the GSTP1 level and the clinicopathological features was examined. Seventy-five patients were divided into low (grade 1, n=36) and high (grade 2, n=39) GSTP1 expression groups. The overall survival was significantly worse in the grade 2 patients than in the grade 1 patients (5­year survival rate, 78.5 vs. 51.2%; p=0.027). Cox proportional hazard analysis revealed that macroscopic type 3 or 4 disease (p=0.001), lymph node metastasis (p=0.010), and high GSTP1 expression (p=0.029) were independent predictors of a poor prognosis. With regard to the subgroup analysis among the 31 patients undergoing adjuvant chemotherapy, the grade 2 patients had a worse prognosis than did the grade 1 patients (5­year survival rate, 45.0 vs. 81.8%; p=0.081). This tendency was not observed in the subgroup without adjuvant chemotherapy (5­year survival rate, 51.7 vs. 59.9%; p=0.979). In conclusion, the GSTP1 expression is a good predictor of prognosis, and it may be closely related to the chemotherapeutic efficacy of 5-FU plus cisplatin in ESCC patients.

Case involving long-term survival after esophageal cancer with liver and lung metastases treated by multidisciplinary therapy: report of a case.

A 57-year-old male with lower esophageal cancer underwent subtotal esophagectomy with lymphadenectomy. The histopathological diagnosis was poorly differentiated squamous cell carcinoma, pT2N1M0 pStageIIB. After one course of postoperative adjuvant chemotherapy involving low-dose CDDP/5FU, a PET-CT scan obtained 12 months after surgery revealed a solitary liver metastasis in the S2 area. The patient then underwent five courses of docetaxel chemotherapy (80 mg/body, tri-weekly), and a partial response was observed. We also performed radiofrequency ablation (RFA), after which a complete response was observed. Twenty months after surgery, we detected local liver recurrence in the same position and performed additional RFA. Twenty-four months after surgery, a solitary lung metastasis was detected in the left S2 area and the patient was administered five additional courses of docetaxel therapy. Subsequently, PET-CT revealed growth of lung and liver tumors without recurrence in other areas. Twenty-nine months after surgery, we partially excised metastatic liver and lung tumors, and no subsequent recurrence has since been detected. The prognoses of patients who suffer from esophageal cancer organ recurrence are known to be extremely poor, and optimal therapeutic strategies for treating these patients have not been established. This long-term survival case suggests that multidisciplinary therapy for the treatment of liver and lung recurrence after esophagectomy is effective.

Circulating tumor cells and aberrant methylation as tumor markers in patients with esophageal cancer.

BACKGROUND: This study was designed to compare the detection rates of conventional tumor markers with two molecular diagnostic approaches on blood samples from patients with esophageal squamous cell cancer. MATERIALS AND METHODS: Preoperative blood samples were obtained from 44 esophageal cancer patients and were subjected to CEA-specific reverse transcriptase-polymerase chain reaction (RT-PCR) assay and methylation-specific polymerase chain reaction (MSP) assay for p16, E-cadherin and RARbeta genes. RESULTS: Circulating tumor cells were detected in 12 patients (27%); 14 patients (32%) had aberrant methylation in the promoter region of at least one gene (6, 4 and 4 patients, for p16, E-cadherin and RARbeta, respectively). No abnormality was detected by either assay in control plasmas. Altogether, 23 patients (53%) had a positive result in either molecular assay. There was no correlation between either assay result and those of conventional serum markers. CONCLUSION: The RT-PCR and MSP assays can serve as complementary markers for screening and monitoring esophageal cancer patients.

[Plasma methylation-specific polymerase chain reaction as a diagnostic tool for esophageal cancer patients].

This study was designed to perform methylation-specific polymerase chain reaction (MS-PCR) assay for p16, E-cadherin, and retinoic acid receptor beta genes on peripheral blood samples from patients with esophageal squamous cell cancers, and compare the results of MS PCR with conventional serum tumor markers and the CEA-specific reverse transcriptase polymerase chain reaction (RT-PCR) assay. Preoperative blood samples were obtained from 30 patients with esophageal cancer, and were subjected to MS PCR and RT-PCR assays. Eleven patients (37%) showed aberrant methylation of the promoter region of at least one gene. On the other hand, circulating tumor cells were detected in 11 patients (37%). There was no correlation between both results and conventional tumor markers. The MS-PCR and RT-PCR assays can serve as complementary diagnostic markers for screening and monitoring patients with esophageal cancers.

Comparison of serum aberrant methylation and conventional tumor markers in gastric cancer patients.

BACKGROUND/AIMS: This study was designed to compare a methylation-specific polymerase chain reaction (MSP) assay for three genes [p16, E-cadherin, and retinoic acid receptor beta (RARbeta)] and conventional serum tumor markers using blood samples from gastric cancer patients. METHODOLOGY: Preoperative blood samples obtained from 63 consecutive patients with gastric cancer were subjected to MSP and conventional serum marker assays. RESULTS: MSP assay detected hypermethylation of p16 in 17 patients (27%), E-cadherin in 15 patients (24%), and RARbeta in 11 patients (17%). Altogether, 32 patients (51%) showed hypermethylation in serum samples. By contrast, only 21 (33%) patients exhibited elevations of serum carcinoembryonic antigen or carbohydrate antigen 19-9. There was no correlation between MSP results and conventional tumor markers. CONCLUSIONS: The detection rate for MSP was higher than that of conventional tumor markers in serum of gastric cancer patients. Both assays can serve as complementary markers that allow for selection of cases requiring more intensive screening or aggressive postoperative treatment.

Long-term administration of low-dose cisplatin plus 5-fluorouracil prolongs the postoperative survival of patients with esophageal cancer.

To evaluate the efficacy of long-term postoperative adjuvant chemotherapy with low-dose cisplatin (CDDP) plus 5-fluorouracil (5-FU) (CDDP/5-FU), we retrospectively examined 167 patients with squamous cell carcinoma of the esophagus who received the treatment after curative surgery (R0 resection). We classified the patients into the following three groups according to their postoperative therapies and analyzed their outcomes: a) low-dose CDDP (10 mg body(-1) day(-1) x 5 days) plus 5-FU (250-500 mg body(-1) day(-1) x 5 days) repeated every 6 months for 3 years, with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) administered between each treatment cycle (low-dose CDDP/5-FU group, 98 patients); b) high-dose CDDP (80 mg body(-1) day(-1) x 1 day) plus 5-FU (750-1,000 mg body(-1) day(-1) x 5 days) administered once only, followed by treatment with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) for 3 years (high-dose CDDP/5-FU group, 17 patients); or c) surgery alone (surgery alone group, 52 patients). The 3-year survival rates were 83.7% in the low-dose CDDP/5-FU group, 61.4% in the high-dose CDDP/5-FU group, and 62.2% in the surgery alone group; the difference between the low-dose CDDP/5-FU group and surgery alone group was significant (log-rank, p<0.05). A significantly better outcome in the low-dose CDDP/5-FU group than in the surgery alone group was associated with pStage III disease (p<0.001), pN1 lymph node metastasis (p<0.001), and lymphatic invasion (p<0.01). We conclude that long-term postoperative treatment with low-dose CDDP/5-FU is therapeutically beneficial and prolongs survival in patients with esophageal cancer who have regional lymph node metastasis or lymphatic invasion.