Experience of Endoscopic Jejunojejunostomy for Anastomotic Obstruction After Subtotal Gastrectomy Using Magnetic Compression Anastomosis.

Magnetic compression anastomosis (MCA) was developed as a low-invasive treatment for gastro-enteric or entero-enteric obstruction. A 72-year-old man underwent subtotal gastrectomy with Billroth II reconstruction for early gastric cancer. After the operation, he suffered from repeated aspiration pneumonia due to anastomotic obstruction caused by jejunal kinking at the efferent loop of anastomosis. We therefore performed jejunojejunostomy via the MCA technique, as his situation was not improved despite conservative therapy and he had a high reoperative risk. We prepared two flat plate-shaped neodymium magnets (15 × 3 mm) each with a small hole, and a nylon thread was passed through each hole. Each magnet was then delivered endoscopically to the anal side of the jejunal kinking, subsequently to the anastomosis, using biopsy forceps. The two magnets immediately became attracted towards each other transmurally. Oozing hemorrhage with clot at the mated magnets was observed 10 days after starting the compression. After retrieving the magnets, we confirmed the completion of jejunojejunostomy and then successfully achieved hemostasis of the anastomotic hemorrhage using argon plasma coagulation. The widely patent anastomosis was confirmed endoscopically 1 month after canalization; and he has been asymptomatic and able to eat a normal diet ever since. Endoscopic MCA is an effective, low-invasive treatment for anastomotic obstruction after subtotal gastrectomy. A standardized, safer procedure should be established for general use in the clinical setting.

Prophylactic Biliary Stenting Before Cholecystectomy in Patients With Gallstones and Common Bile Duct Stones.

BACKGROUND: The usefulness of prophylactic biliary stenting for patients with common bile duct stones (CBDS) and gallstones (GS) to prevent recurrent biliary events after endoscopic sphincterotomy (EST) and CBDS extraction before elective cholecystectomy remains controversial. The aim of this study was to evaluate the risk of recurrent CBDS around the perioperative period and clarify its risk factors. METHODS: The clinical data of all patients who received prophylactic biliary stenting after EST for CBDS and later underwent cholecystectomy for GS followed by stent extraction in our institution were retrospectively reviewed. The numbers of residual CBDS at the end first and second endoscopic retrograde cholangiography (ERC) studies were compared. Univariate and multivariate analyses were performed using a logistic regression model to determine risk factors for recurrent CBDS in the perioperative period. RESULTS: Forty-two consecutive patients received prophylactic biliary stenting and subsequent cholecystectomy for GS. Three of these patients were excluded from this study because the number of residual stones was not confirmed. The median maximum CBDS diameter at second ERC was 0 mm (range, 0 - 10 mm); six patients had multiple CBDS (≥ 5). The number of CBDS at second ERC was increased in comparison to that at the first ERC in 15 patients (38.4%), and was unchanged or decreased in 24 patients. The median minimum cystic duct diameter was 4 mm (range, 1 - 8 mm). The median interval between first ERC and operation was 26 days (range, 2 - 131 days). The median interval between operation and second ERC was 41 days (range, 26 - 96 days). Laparoscopic cholecystectomy (LC) was performed in 38 patients, one of whom was converted from LC to open cholecystectomy. Postoperative complications (transient bacteremia) occurred in one patient. The cystic duct diameter was an independent risk factor for an increased number of CBDS at second ERC in the multivariate analysis (odds ratio 0.611 (95% confidence interval (0.398 - 0.939)), P = 0.03). CONCLUSION: Recurrent CBDS around the perioperative period of cholecystectomy is not a rare complication after EST and the removal of CBDS with concomitant GS. Prophylactic biliary stenting is considered useful for preventing CBDS-associated complications, especially for patients in whom the cystic duct diameter is larger (≥ 5 mm).

[Impact of Preoperative Comorbidities on Long-Term Prognosis in Elderly Patients with Gastric and Colorectal Cancer].

BACKGROUND: There has been an increase in the number of elderly cancer patients with preoperative comorbidities, which decrease the safety of surgical therapy. Assessment of comorbidities is useful for prediction of the outcome of treatment in these patients. PATIENTS AND METHODS: The Charlson comorbidity index(CCI)was determined in 83 elderly patients undergo- ing surgery for gastric and colorectal cancer. Relationships of CCI with prognosis were examined in pathological R0/R1 and R2 cases. RESULTS: In the R0/R1 group, CCI was significantly associated with overall survival in univariate(p=0.027)and multivariate( p=0.031)analyses. Mortality from other diseases within a year after surgery for patients with CCIB4 was significantly higher than that for those with CCIC3(11.0% vs 1.4%, p=0.028). CONCLUSION: CCI is an independent prognostic factor after surgery for elderly patients with gastric and colorectal cancer.

[Impact of Muscle Mass Reduction on Postoperative Adjuvant Chemotherapy and Long-Term Prognosis in Patients with Gastric Cancer].

BACKGROUND: Measuring the area of the psoas muscle on computed tomography is useful for the evaluation of skeletal muscle mass. The skeletal muscle is thought to be involved in weight loss after gastric surgery, and weight loss causes a decrease in compliance with chemotherapy continuity. PATIENTS AND METHODS: The psoas muscle index(PMI)was determined in 33 patients undergoing surgery for Stage Ⅱ-ⅢB gastric cancer. The rate of change in PMIwas calculated, and patients were classified into maintained and reduced muscle groups using a cutoff of -0.23 month-1. Relationships between the rate of PMIchanges and prognosis and chemotherapy continuity were examined. RESULTS: The rate of PMIchanges was significantly associated with recurrence-free survival in univariate(maintained vs reduced muscle: p=0.002)and multivariate(p= 0.0018)analyses. A reduction in the muscle mass was associated with dropout from adjuvant chemotherapy and was a predictor of a poor prognosis. CONCLUSION: The rate of PMIchanges is related to the period of adjuvant chemotherapy and is an independent prognostic factor after surgery for StageⅡ-ⅢB gastric cancer.

Docetaxel and cyclophosphamide as neoadjuvant chemotherapy in HER2-negative primary breast cancer.

BACKGROUND: Docetaxel plus cyclophosphamide (TC) has recently been established as a standard adjuvant chemotherapy regimen for HER2-negative (HER2-) operable breast cancer. However, the efficacy and tolerability of TC as neoadjuvant chemotherapy (NAC) remain unclear. We, therefore, conducted a prospective study to evaluate the efficacy of TC NAC in HER2- primary breast cancer. METHODS: Patients who were diagnosed with HER2-, N0-N1, invasive breast cancer between July 2011 and February 2014 and had tumors measuring 1-7 cm were eligible. The subtypes were classified using a core-needle or vacuum-assisted breast biopsy. The efficacy and safety of NAC comprising TC (75 mg/m2 docetaxel and 600 mg/m2 cyclophosphamide, four cycles every 3 weeks) were investigated in a prospective study in patients with HER2- breast cancer. RESULTS: Fifty-two patients were enrolled. Of these, 94.2 % (49/52) completed four cycles of TC. The overall pCR rate was 16.3 % (8/49). The pCR rates for patients with luminal A-like breast cancer [estrogen receptor-positive (ER+), Ki67 index of <20 %, and HER2-], luminal B-like breast cancer (ER+, Ki67 index of >20 %, and HER2-), and triple-negative breast cancer [ER-negative (ER-) and HER2-] were 0 % (0/12), 4.3 % (1/23), and 50.0 % (7/14), respectively. Almost all pCRs occurred in triple-negative breast cancer patients. CONCLUSIONS: The pCR rate of TC NAC was not very high despite the high completion rate. TC NAC was effective against the triple-negative subtype, resulting in a higher pCR rate. Therefore, our results indicated that TC NAC showed limited efficacy in luminal subtype breast cancer with the exception of the triple-negative subtype.

Docetaxel, cyclophosphamide, and trastuzumab as neoadjuvant chemotherapy for HER2-positive primary breast cancer.

BACKGROUND: The standard primary systemic therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancer is anthracyclines and/or taxanes combined with trastuzumab, which demonstrates a high pathological complete response (pCR). A pCR is a predictive marker of prognosis. However, results slightly differ, depending on the hormone receptor status. The efficacy and tolerability of docetaxel, cyclophosphamide, and trastuzumab (HER-TC) as neoadjuvant chemotherapy (NAC) remain unclear. We performed a prospective multicenter study of HER-TC NAC for HER2+ primary breast cancer. METHODS: Eligible patients had a clinical diagnosis of HER2+ invasive breast cancer greater than 1 cm but less than 7 cm and a tumor stage of N0 or N1. T hey were diagnosed between July 2011 and February 2014. For NAC, four cycles of HER-TC (6 mg/kg loading dose, 8 mg/kg, 75, and 600 mg/m2) were administered intravenously every 3 weeks. We investigated the pCR of the primary breast tumors. A pCR was defined as no histological evidence of invasive carcinoma or the appearance of only ductal carcinoma in situ. RESULTS: We enrolled 42 patients. The completion rate for four cycles of HER-TC was 97.6 % (41/42 patients). The overall pCR rate was 43.9 % (18/41 patients). The pCR rate for patients with the luminal HER2 subtype [estrogen receptor (ER)-positive+, HER2+] and the HER2-enriched subtype (ER-, HER2+) was 40.0 % (8/20 patients) and 47.6 % (10/21 patients), respectively. A pCR was achieved with nearly the same probability for each subtype. CONCLUSIONS: Four cycles of HER-TC may be a NAC option for HER2-positive breast cancer.

Tissue engineering of small intestinal tissue using collagen sponge scaffolds seeded with smooth muscle cells.

In a previously reported attempt to regenerate small intestine with autologous tissues, collagen scaffolds were used without cell seeding or with autologous mesenchymal stem cell seeding. However the regenerated intestine lacked a smooth muscle layer. To accomplish regeneration of a smooth muscle layer, this present study used collagen scaffolds seeded with the smooth muscle cells (SMC) in a canine model. Autologous SMC were isolated from stomach wall and cultured. Two types of scaffolds were fabricated: in SMC (+), cultured SMCs were mixed with collagen solution and poured into a collagen sponge; and in SMC (-), SMCs were omitted. Both scaffolds were implanted into defects of isolated ileum as a patch graft. Animals were euthanized at 4, 8, and 12 weeks; for the last time point, the ileal loop had been reanastomosed at 8 weeks. At 12 weeks, the SMC (-) group showed a luminal surface covered by a regenerated epithelial cell layer with very short villi; however only a thin smooth muscle layer was observed, representing the muscularis mucosae. In the SMC (+) group, the luminal surface was covered completely by a relatively well-developed epithelial layer with numerous villi. Implanted SMCs were seen in the lamina propria and formed a smooth muscle layer. Thus, we concluded that collagen sponge scaffolds seeded with autologous SMCs have a potential for small intestine regeneration.

[Analysis of Reg IV expression in peritoneal dissemination of gastric cancer using real-time RT-PCR].

We had performed a global analysis of the gene expression of gastric cancer cell lines established from malignant ascites to identify the novel markers for the detection of micro-metastasis in peritoneal cavity. One of the up-regulated genes is Reg IV, which is a member of the Reg gene family belonging to calcium dependent lectin (C-type lectin) gene superfamily. But the role of Reg IV in peritoneal dissemination is still unclear. We have examined the potential of Reg IV as a novel marker for the detection of peritoneal micro-metastases of gastric cancer. Reg IV expression was examined by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Mean Reg IV mRNA expression levels in surgically resected specimens (n = 41) were more than 20-times higher than those in normal mucosa from those patients. Furthermore, Reg IV mRNA expression level in the peritoneal wash was strongly higher in peritoneal metastasis compared to those without peritoneal metastasis. These results suggest that Reg IV may be involved in peritoneal dissemination of gastric cancers and Reg IV would be a potential novel marker for peritoneal dissemination of gastric cancers.

[Over expression of Reg IV in peritoneal dissemination of gastric cancer].

We previously performed a global analysis of the gene expression of gastric cancer cell lines established from peritoneal dissemination (SNU-5, SNU-16, SNU-719, KATO-III and GT3TKB) with the cDNA microarray method to identify the novel markers for the detection of micro-metastasis in peritoneal cavity. One of the up-regulated genes is Reg IV, which is a member of the Reg gene family belonging to calcium dependent lectin (C-type lectin) gene superfamily. We have examined Reg IV potential as a novel marker for the detection of peritoneal micro-metastases of gastric cancer. Reg IV expression was examined in five gastric cancer cell lines established from peritoneal dissemination and compared with myeloid leukemia cell (HL60), methothelial cell lines Met5A and the other gastric cell line established from primary tumor (SNU-1) by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Reg IV was highly overexpressed in 4 gastric cancer cell lines established from peritoneal dissemination, but weakly expressed in other cell lines. According to Reg IV mRNA expression levels in surgically resected specimens, the quantity of Reg IV correlated with wall penetration. Furthermore, Reg IV mRNA expression level in the peritoneal wash from 35 gastric cancer patients was also prone to correlation with wall penetration. These results suggest that Reg IV may be involved in peritoneal dissemination of gastric cancers and Reg IV may be a potential novel marker for peritoneal dissemination of gastric cancers.

Intratumoral administration of methotrexate bound to activated carbon particles: antitumor effectiveness against human colon carcinoma xenografts and acute toxicity in mice.

We previously developed a new formulation of methotrexate (MTX) that is adsorbed onto a suspension of activated carbon particles (MTX-CH) and reported the usefulness of local administration in murine tumors. The present study examines the effects of human colon carcinoma (LoVo) xenografts and the acute toxicity of MTX-CH compared with MTX aqueous solution (MTX-AQ) in mice. In therapeutic experiments, LoVo cells were implanted into the backs of BALB/c nude mice. When the cells had developed into tumors, we performed an intratumoral administration of a weekly dose of 30 mg/kg. The MTX concentration in the tumor was compared between the MTX-CH group and MTX-AQ group. In experiments on acute toxicity, MTX-CH and MTX-AQ were injected subcutaneously in BDF1 mice, and intoxication symptoms, changes in body weight, and date of death were recorded. In the therapeutic experiments, intratumoral administration of MTX-CH was much more effective in suppressing the tumor growth compared with MTX-AQ. In experiments of acute toxicity, the death time of the MTX-CH group was delayed to a greater extent, and the 50% lethal dose (LD(50)) values of MTX-CH were lower than those of MTX-AQ. The LD(50) values of MTX-CH are 75 times higher than the efficacious dose of 30 mg/kg. The present results suggest that intratumoral administration of MTX-CH is useful for local therapy and the therapeutic dose of MTX-CH can be safely injected subcutaneously.

[Intratumoral administration of methotrexate bound to activated carbon particles (MTX-CH) inducing antitumor effect in vivo].

Methotrexate is one of the anticancer drugs that can be safely administered subcutaneously, but locally injected MTX in aqueous solution form does not function in the administration site for very long. We developed a new dosage formulation: methotrexate bound to activated carbon particles (MTX-CH), and can report that it controlled tumor growth through its long-acting effect at the administration site. In this study, we investigated the effect of local administration of MTX-CH compared with MTX aqueous solution in tumors from transplanted human colon cancer cells (LoVo) into the back of nude mice. MTX-CH is superior to MTX aqueous solution in terms of its long-acting effect at the administration site and antitumor effect. We suggest that intratumoral injection therapy of MTX-CH is useful for patients in poor condition and with high surgical risk due to cardiac disease or old age, and patients who are diagnosed positive for cancer after endoscopic mucosal resection of early colorectal cancer.

[Analysis of effect of dextran sulfate on cancer cells].

Peritoneal recurrence is one of the critical problems that occurs after surgery for gastrointestinal cancers. Since no curative treatment has been established for peritoneal recurrence, many efforts have been made to develop an effective method for preventing such recurrence. We focused on dextran sulfate, an anti-cell-adherence agent, to prevent peritoneal metastasis. Our previous studies in vitro and in vivo clarified that dextran sulfate prevents cancer cells from adhering to plastic flasks and the abdominal wall. In this study, we investigated the effects of dextran sulfate on cancer cells from the viewpoint of the cell cycle. Changes in gene expression caused by dextran sulfate were analyzed by cDNA microarrays. Analysis by cDNA microarray revealed the decreased expression of the genes essential to the progression of G1 and S phases. Our results indicate that dextran sulfate suppresses progression of the cell cycle as well as cell adhesion, suggesting that dextran sulfate could be used as an antimetastatic agent. Anti-cell-adherence agents with such mechanisms of action could be effective drugs for treatment during and after operation to prevent peritoneal metastases induced by surgical operation.

[Endoscopic local injection of anticancer drugs bound to carbon particles for treatment of advanced rectal cancer, when surgical treatment was contraindicated].

Generally, patients with advanced rectal cancer in whom surgical treatment is contraindicated receive radiation or chemotherapy. In such patients, we have administered local injection of methotrexate and mitomycin C bound to activated carbon particles. Four patients received intratumoral injection of the dosage formulation (total dose 100-400 mg of methotrexate or 8-32 mg of mitomycin C) under colonofiberscope. After the treatment, bleeding and pain were lessened in all 4 patients. In two patients, the tumor markedly decreased in size and there was no regrowth prior to death 12-14 months after the treatment. In another patient, bleeding and pain disappeared until the patient died of pulmonary and liver metastases. The fourth patient is alive without regrowth 5 months after treatment. Side effects were not severe.

Quantitative measurement of regional blood flow in hepatic focal nodular hyperplasia. Findings on positron emission tomography.

The blood flow through normal liver parenchyma and a pathologically proven hepatic region of focal nodular hyperplasia (FNH) of the lateral lobe, was measured in a single patient in a quantitative manner using regional dynamic positron emission tomography (PET) imaging with O-15 carbon dioxide (steady state) and O-15 water (dynamic state). The steady state PET images revealed higher radioactivity concentration in the lateral lobe than in the surrounding normal liver parenchyma. Regional and total blood flow in the region of FNH, as determined by the dynamic state method, was 292.2 ml/100g/min and 330.2 ml/min, respectively. It was determined that the region of FNH in this patient had higher blood flow than that described previously for liver tumors such as hepatocellularcarcinoma and colorectal hepatic metastases.