The effects of the herbal medicine Daikenchuto (TJ-100) after esophageal cancer resection, open-label, randomized controlled trial.

BACKGROUND: Daikenchuto (TJ-100), a traditional Japanese herbal medicine, is widely used in Japan. Its effects on gastrointestinal motility and microcirculation and its anti-inflammatory effect are known. The purpose of this prospective randomized controlled trial was to investigate the effect of TJ-100 after esophagectomy in esophageal cancer patients. METHODS: Forty patients for whom subtotal esophageal resection for esophageal cancer was planned at our institute from March 2011 to August 2013 were enrolled and divided into two groups at the point of determination of the operation schedule after informed consent was obtained: a TJ-100 (15 g/day)-treated group (n = 20) and a control group (n = 20). The primary efficacy end-points were maintenance of the nutrition condition and the recovery of gastrointestinal function. The secondary efficacy end-points were the serum C-reactive protein (CRP) level and adrenomedullin level during the postoperative course, the incidence of postoperative complications, and the length of hospital stay after surgery. RESULTS: We examined 39 patients because one patient in the TJ-100 group was judged as having unresectable cancer after surgery. The mean age of the TJ-100 group patients was significantly older than that of the control group patients.The rate of body weight decrease at postoperative day 21 was significantly suppressed in the TJ-100 group (3.6% vs. the control group: 7.0%, p = 0.014), but the serum albumin level was not significantly different between the groups. The recovery of gastrointestinal function regarding flatus, defecation, and oral intake showed no significant between-group differences, but postoperative bowel symptoms tended to be rare in the TJ-100 group. There was no significant between-group difference in the length of hospital stay after surgery. The serum CRP level at postoperative day 3 was 4.9 mg/dl in the TJ-100 group and 6.9 mg/dl in the control group, showing a tendency of a suppressed serum CRP level in the TJ-100 group (p = 0.126). The rate of increase in adrenomedullin tended to be high postoperatively, but there was no significant difference between the two groups. CONCLUSIONS: TJ-100 treatment after esophageal cancer resection has the effects of prompting the recovery of gastrointestinal motility and minimizing body weight loss, and it might suppress the excess inflammatory reaction related to surgery.

CXCR4 Expression is Associated with Poor Prognosis in Patients with Esophageal Squamous Cell Carcinoma.

BACKGROUND: Chemokines and their receptors are known to play important roles in the tumorigenesis of many malignancies. The chemokine CXCL12 and its receptors CXCR4 and CXCR7 were suggested to be involved in cancer invasion and metastasis. The aim of this retrospective study was to evaluate the prognostic impact of the expressions of CXCL12, CXCR4 and CXCR7 in patients with esophageal squamous cell carcinoma (ESCC). METHODS: We used immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction (RT-PCR) to evaluate the expressions of CXCL12, CXCR4, and CXCR7 in ESCC patients' tumor biopsy specimens obtained during preoperative endoscopy or surgery. These results were compared with the patients' clinicopathological parameters and survival. RESULTS: IHC was conducted for 172 patients. High expression of CXCR4 in the cytoplasm and nuclei and that of CXCR7 were associated with poor cause-specific survival (CSS) (P= .002 and .010, respectively). The specimens from 52 of the 172 patients were examined by RT-PCR and quantitative real-time PCR. The expression levels of messenger RNA (mRNA) of CXCR4 and CXCR7 were significantly increased in the tumors compared with normal esophageal mucosae (P < .0001). The expression level of mRNA of CXCR4 was associated with poor recurrence-free survival and CSS (P = .012 and .038, respectively). CONCLUSIONS: CXCR4 expression is associated with poor prognosis in patients with ESCC.

[Pathological complete response in a case of advanced esophageal cancer invading aorta treated by preoperative chemotherapy with docetaxel and cisplatin plus 5-FU].

The patient was a 64-year-old man, diagnosed as cStage IVa esophageal cancer invading the aorta with lymph node metastasis. He received combination chemotherapy with docetaxel/cisplatin/5-FU(DFP therapy). After one course, CT and endoscopic examination showed remarkable reduction of the primary lesion and lymph node metastasis. We performed subtotal esophagectomy and gastric tube reconstruction by the retroposterior mediastinum route. The pathological specimen evidenced fibrosis and infiltration of inflammatory cells on almost all layers, but showed no viable malignant cells in the middle thoracic esophagus. Therefore, the pathological effect was judged as Grade 3(pCR). This case suggested that DFP combination chemotherapy may prove to be a useful treatment for advanced esophageal cancer with invasion to other organs.

Prognosis of esophageal squamous cell carcinoma in patients positive for human epidermal growth factor receptor family can be improved by initial chemotherapy with docetaxel, fluorouracil, and cisplatin.

BACKGROUND: The human epidermal growth factor receptor (HER) family, Ki-67 and p53 are important biomarkers for several malignancies. However, few studies have examined the role of these in prognosis and therapeutic sensitivity of esophageal squamous cell carcinoma (ESCC). The efficacy of triple-drug combination therapy with docetaxel, fluorouracil and cisplatin has recently been expected for ESCC. METHODS: Subjects comprised 142 patients with ESCC who underwent operation (OP group, n = 54), neoadjuvant chemotherapy with docetaxel, fluorouracil, and cisplatin (DFP therapy) followed by operation (NAC group, n = 37) or initial systemic DFP therapy (CT group, n = 51) between January 2004 and December 2010. Immunohistochemical expressions of epidermal growth factor receptor (EGFR), HER2, HER3, Ki-67, and p53 were evaluated and compared with prognosis and sensitivity to DFP therapy. RESULTS: Positive correlations existed between EGFR, HER2, and HER3 expressions. In the OP group, EGFR was independently associated with postoperative recurrence in multivariate analysis (P = .036). In the NAC group, EGFR correlated with pathological response to DFP therapy (P = .004). In the CT group, EGFR, HER2, and HER3 correlated with clinical response to DFP therapy and EGFR was independently associated with favorable prognosis in multivariate analysis (P = .022). CONCLUSION: EGFR represents a predictor of postoperative recurrence and sensitivity to triple-drug combination therapy including a taxane. EGFR-positive patients may show improved prognosis with taxane combination chemotherapy and molecular targeted therapy for HER family members.

Sentinel lymph node biopsy using intraoperative indocyanine green fluorescence imaging navigated with preoperative CT lymphography for superficial esophageal cancer.

BACKGROUND: The sentinel lymph node (SLN) concept has been gaining attention for gastrointestinal neoplasms but remains controversial for esophageal cancer. This study evaluated the feasibility of SLN identification using intraoperative indocyanine green (ICG) fluorescence imaging (IGFI) navigated by preoperative computed tomographic lymphography (CTLG) to treat superficial esophageal cancer. METHODS: Subjects comprised 20 patients clinically diagnosed with superficial esophageal cancer. Five minutes after endoscopic submucosal injection of iopamidol around the primary lesion using a four-quadrant injection pattern with a 23-gauge endoscopic injection sclerotherapy needle, three-dimensional multidetector computed tomography was performed to identify SLNs and lymphatic routes. ICG solution was injected intraoperatively around the tumor. Fluorescence imaging was obtained by infrared ray electronic endoscopy. Thoracoscope-assisted standard radical esophagectomy with lymphadenectomy was performed to confirm fluorescent lymph nodes detected by CTLG. RESULTS: Lymphatic vessels and SLNs were identified preoperatively using CTLG in all cases. Intraoperative detection rates were 100% using CTLG and 95% using IGFI. Lymph node metastases were found in four cases, including one false-negative case with SLNs occupied by bulky metastatic tumor that were not enhanced with both methods. The other 19 cases, including three cases of metastatic lymph nodes, were accurately identified by both procedures. CONCLUSIONS: Preoperative CTLG visualized the correct number and site of SLNs in surrounding anatomy during routine computed tomography to evaluate distant metastases. Referring to CTLG, SLNs were identified using IGFI, resulting in successful SLN navigation and saving time and cost. This method appears clinically applicable as a less-invasive method for treating superficial esophageal cancer.

[A case of a patient with stage IVa esophageal cancer surviving over 4 years by combination chemotherapy with docetaxel,5 -FU and cisplatin, without operation].

A male patient in his 50s was found to have lower thoracic advanced esophageal squamous cell carcinoma by upper gastrointestinal endoscopy with the chief complaint of dysphagia in July 2006. CT revealed supraclavicular lymph node metastasis, and he was diagnosed as clinical stage IVa. He underwent two courses of combination chemotherapy with docetaxel, 5-FU and cisplatin(DFP therapy: docetaxel at 25mg/m / / 2 on day 1, 5-FU at 370 mg/m2 on days 1-5, and cisplatin at 7 mg/m2 on days 1-5 were repeated weekly for 4 weeks). The primary tumor disappeared and the lymph node was reduced as observed by upper gastrointestinal endoscopy and CT. After 2 courses of DFP therapy, PET-CT revealed that the primary tumor and lymph node had no new accumulation. Because he refused both operation and chemoradiotherapy, the patient underwent oral chemotherapy. In January 2010, PET-CT and upper gastrointestinal endoscopy revealed that the primary tumor relapsed. DFP therapy was performed and was effective once again. He has survived for over 4 years and 4 months without operation.

START-GAP2/DLC2 is localized in focal adhesions via its N-terminal region.

START-GAP2, also termed as DLC2, is a START domain-containing RhoGAP and a negative regulator of RhoA and Cdc42. Although it was reported as a tumor suppresser gene product, the molecular basis for function of START-GAP2 remains to be clarified. Here, we demonstrate that START-GAP2 is localized in focal adhesions through a "FAT (focal adhesion targeting)" region in the N-terminal half. START-GAP2 competes with START-GAP1/DLC1, another START domain-containing RhoGAP, in focal adhesion targeting. Moreover, the C-terminus of tensin2, one of focal adhesion components and reported to bind START-GAP1, also directly interacts with START-GAP2. These results suggest that START-GAP2 and START-GAP1 share the same molecular mechanism in targeting to focal adhesions.

Gene expression changes in a chemoresistant model with human esophageal cancer xenografts using cDNA microarray.

BACKGROUND: 5-Fluorouracil (5-FU) and cisplatin combined chemotherapy (FP) is commonly used for esophageal cancer. Acquired resistance needs to be overcome to improve the chemotherapeutic effect. MATERIALS AND METHODS: The FP-resistant xenograft model using severe combined immunodeficient (SCID) mice was established as an acquired resistance model. RNA was extracted pretreatment, at the onset of the anticancer effect, during the most effective, and regrowth period in the FP administration group and during the mid-progressive period and the far advanced period in the control group. A microarray was applied to explore gene expression changes. RESULTS: The data set containing up-regulated genes in the regrowth period was uploaded into Ingenuity Pathway Analysis. The expression change profiles suggested that activation of not only 5-FU- and cisplatin-specific genes, but also the Phosphoinositide 3-kinase (PI3K)/AKT signal were associated with FP resistance. CONCLUSION: A xenograft model using SCID mice with esophageal cancer cells would monitor gene changes during treatment and regrowth.

[Complete response in a case of advanced esophageal cancer treated with docetaxel/5-FU/CDDPand S-1/docetaxel as neoadjuvant chemotherapy].

A 64-year-old woman with advanced esophageal cancer underwent chemotherapy with docetaxel/5-FU/CDDP (DFP). Adverse reactions were severe nausea and general fatigue, so the patient decided to discontinue DFP therapy. The treatment was changed to S-1/docetaxel. Adverse reactions were not so severe, so she could receive 1 course of the medication completely. After the treatment, the primary lesion showed a partial response, so we performed surgery. In the resected specimen, no malignant cell could be seen microscopically. Though the advanced esophageal cancer was regarded as a systemic disease, the appropriate combination of chemotherapy and surgery proved effective.

START-GAP3/DLC3 is a GAP for RhoA and Cdc42 and is localized in focal adhesions regulating cell morphology.

In the human genome there are three genes encoding RhoGAPs that contain the START (steroidogenic acute regulatory protein (StAR)-related lipid transfer)-domain. START-GAP3/DLC3 is a tumor suppressor gene similar to two other human START-GAPs known as DLC1 or DLC2. Although expression of START-GAP3/DLC3 inhibits the proliferation of cancer cells, its molecular function is not well understood. In this study we carried out biochemical characterization of START-GAP3/DLC3, and explored the effects of its expression on cell morphology and intracellular localization. We found that START-GAP3/DLC3 serves as a stimulator of PLCdelta1 and as a GAP for both RhoA and Cdc42 in vitro. Moreover, we found that the GAP activity is responsible for morphological changes. The intracellular localization of endogenous START-GAP3/DLC3 was explored by immunocytochemistry and was revealed in focal adhesions. These results indicate that START-GAP3/DLC3 has characteristics similar to other START-GAPs and the START-GAP family seems to share common characteristics.

Current status of sentinel lymph node navigation surgery in breast and gastrointestinal tract.

Sentinel lymph node biopsy (SLNB) has been developed as a new diagnostic and therapeutic modality in melanoma and breast cancer surgery. The purpose of the SLNB include preventing the operative morbidity and improving the pathologic stage by focusing on fewer lymph nodes using immunocytochemic and molecular technology has almost achieved in breast cancer surgery. The prognostic meaning of immunocytochemically detected micrometastases is also evaluating in the SLN and bone marrow aspirates of women with early-stage breast cancer. SLNB using available techniques have suggested that the lymphatic drainage of the gastrointestinal tract is much more complicated than other sites, skip metastasis being rather frequent because of an aberrant lymphatic drainage outside of the basin exist. At the moment, the available data does not justify reduced extent of lymphadenectomy, but provides strong evidence for an improvement in tumor staging on the basis of SLNB. Two large scale prospective multi-center trials concerning feasibility of gamma-probe and dye detection for gastric cancer are ongoing in Japan. Recent studies have shown favorable results for identification of SLN in esophageal cancer. CT lymphography with endoscopic mucosal injection of iopamidol was applicable for SLN navigation of superficial esophageal cancer. The aim of surgical treatment is complete resection of the tumor-infiltrated organ including the regional lymph nodes. Accurate detection of SLN can achieve a selection of a more sophisticated tailor made approach. The patient can make a individualized choice from a broader spectrum of therapeutic options including endoscopic, laparoscopic or laparoscopy-assisted surgery, modified radical surgery, and typical radical surgery with lymph node dissection. Ultrastaging by detecting micrometastasis at the molecular level and the choice of an adequate treatment improve the postoperative quality of life and survival. However these issues require further investigation.

[An elderly case of advanced cervical esophageal cancer successfully treated with UFT after chemoradiotherapy with docetaxel/5-FU/CDDP].

An 80-year-old woman with advanced cervical esophageal cancer underwent chemoradiotherapy with docetaxel/5-FU/CDDP (DFP). The tumor reduced in size after the treatment,but severe pancytopenia and scar stenosis of cervical esophagus appeared. In consideration of her age,the treatment was changed to the administration of UFT alone on an outpatient basis. Ten months after the medication, a follow-up CT scan showed multiple lung metastases and mediastinal lymph node metastases. The patient was treated with DFP therapy again, and all tumors reduced in size, but severe general fatigue and pancytopenia appeared during this therapy. Given the difficulty of continuing this therapy, the treatment was changed to UFT alone on an outpatient basis. The followup CT scan showed a reduction in the size of all tumors even 8 months after discharge. UFT alone appears to be safe and effective as maintenance therapy after DFP therapy, especially for elderly patients.

A case of early relapsed multiple lung metastases after esophagectomy successfully treated with S-1/cisplatin therapy after docetaxel/5-fluorouracil/cisplatin therapy.

A 55-year-old-male patient underwent subtotal esophagectomy for esophageal cancer (pT1b, N0, M0, stage II) in April 2005. The patient received postoperative chemotherapy (docetaxel 40 mg/body, 5-fluorouracil 750 mg/body, cisplatin 10mg/body: administered every 4 weeks) for 3 months. Six months postoperatively, routine follow up CT demonstrated multiple metastatic tumors in the bilateral lungs. Under the diagnosis of multiple lung metastases, the patient was hospitalized and received intensive chemotherapy with docetaxel 40 mg/week (day 1), 5-fluorouracil 500 mg/day (days 1-5), cisplatin 10 mg/day (days 1-5). After two weeks administration, the patient eagerly hoped for outpatient treatment. The treatment was changed to outpatient chemotherapy with S-1 100 mg/day (continuous administration for 3 weeks followed by rest for 1 week) and cisplatin 20 mg/every week. The treatment enabled the patient to keep working. Follow up CT showed disappearance of all tumors two months after TS-1/cisplatin chemotherapy. There were no obvious signs of recurrence 5 months after chemotherapy. The S-1/cisplatin therapy in the outpatient was thought to be one of the effective treatments in maintaining quality of life for the patient.

[A case of rectal cancer treated by preoperative chemoradiation].

Fifty-one-year-old male visited our hospital suffering from anal pain and subileus. Further examination revealed that advanced rectal cancer which invaded to presacral space (Ai, N 0, P 0, H 0, M(-), stage IIIa) caused such symptom. We administered neo-adjuvant chemoradiotherapy for fear of non curative resection of the rectum. The regimen was once weekly administration of intravenous CPT-11 40 mg, plus daily oral administration of UFT-E 600 mg/day and Uzel 75 mg/day for 4 weeks. In addition we underwent radiation 2.4 Gy/day and intravenous low-dose cisplatin (CDDP) 5 mg/day, 5 days/week for 3 weeks. Four weeks after the first administration, a partial response was confirmed on CT, and so we carried out an abdominoperineal resection. The postoperative course is almost uneventful without a little perineal infection. The specimen revealed that no malignant lesion remained, which changed to necrotic tissue. The side effects were not so severe. For example, diarrhea, nausea, and mucosal dysfunction were each less than grade 2, and there was much tolerate for renal, liver, and bone marrow function. This combination chemoradiotherapy is considered to be effective for locally advanced rectal cancer.

Glutamine protects the small intestinal mucosa in anticancer drug-induced rat enteritis model.

Supportive therapy during chemotherapy has become essential, but effective preventive therapies to gastrointestinal mucosal injury are few. We investigated the efficacy of glutamine in rat anticancer drug-induced enteritis model. In this study, we used twenty male SD rats. They were divided into control, 5-fluorouracil (5-FU) (orally administered at 20 mg/kg day), 5-FU+glutamine (1000 mg/kg/day) and 5-FU+glutamine+fiber and oligosaccharide (GFO(®)) (1000 mg/kg/day) groups. All groups were sacrificed on day 6 and upper jejunums were excised. The jejunal villous height was measured in specimens. IgA level in jejunal washing solution, and serum diamine oxidase activity were also measured. The jejunal villous height was recognized as shorter in the specimen from 5-FU treated rats compared with 5-FU+glutamine treated rats (p<0.001). Serum diamine oxidase activity in 5-FU+glutamine group were significantly superior to that in 5-FU group (p=0.028). IgA level in jejunal washing solution tended to be higher in 5-FU+glutamine group than that in 5-FU group (p=0.076). On the other hand, serum diamine oxidase activity and IgA level in jejunal washing solution showed no significant difference between 5-FU+GFO and 5-FU treatment group. Our results suggest that glutamine showed protective effects on mucosal injury of small intestine in rat anticancer drug-induced enteritis model.

The effect of nutritional support on the immune function in the acute postoperative period after esophageal cancer surgery: total parenteral nutrition versus enteral nutrition.

BACKGROUND: Enteral nutrition (EN) is now used more frequently than total parenteral nutrition (TPN) for nutritional support after resection for esophageal cancer. But consensus regarding which type of nutrition should be used does not exist. We studied the effect of TPN and EN on patients' nutritional status and immune function in the immediate postoperative period after esophageal cancer resection. METHODS: We enrolled 30 patients (27 men and 3 women) who underwent subtotal esophagectomy. The patients were randomly assigned to TPN or EN group. Either TPN or EN was begun on postoperative day 1. On postoperative days 1, 3, and 7, three endpoints were measured: albumin, C-reactive protein, and Th1/Th2 balance. RESULTS: All patients completed the study. Anastomotic leaks occurred in 6 patients in the TPN group and 7 patients in the EN group. Albumin, Th1/Th2 balance, and C-reactive protein did not differ between the groups. Th1/Th2 balance was not different regardless of the preoperative treatment or complications. CONCLUSIONS: No differences in immune function, nutritional state, or inflammatory response were seen between patients supported with TPN and those supported with EN. The results of our study suggest that perioperative nutritional support can be safely performed either with TPN or EN.

A New Candidate Supporting Drug, Rikkunshito, for the QOL in Advanced Esophageal Cancer Patients with Chemotherapy Using Docetaxel/5-FU/CDDP.

Purpose. Docetaxel/5-FU/CDDP (DFP) therapy is a useful treatment for advanced esophageal cancer. However, adverse reactions such as chemotherapy-induced nausea and vomiting (CINV) interfere often with continuation of the chemotherapy. We investigated the efficacy of rikkunshito (TJ-43) on CINV. Methods. Nineteen patients who were going to undergo DFP therapy were enrolled. They were assigned to the following two groups: a TJ-43-treated group and -nontreated group. The following parameters were compared between the 2 groups: (1) the frequency of symptoms occurred, (2) vomiting, nausea, and anorexia score, and (3) QOL score. Results. The incidence of symptoms was lower in the TJ-43-treated group than that in the control group. The nausea score of the TJ-43-treated group was significantly lower than that of the control group. In the QOL score, the mood score and the ADL score decreased significantly in the control group. Conclusion. We recommend TJ-43 administration in patients undergoing DFP chemotherapy.