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In this study, the precipitation of minerals onto rock surfaces was investigated to consider whether sealing of pores and cracks in rock can be accelerated. Cylindrical specimens were prepared and then kept in purified water with powders of high-strength and ultra-low-permeability concrete (HSULPC), which will be used to confine transuranic wastes in Japan. Then, the rock specimens were weighed and the surfaces of rock specimens were inspected under a microscope. It was recognized that precipitation occurred on the surface of the rock specimens. It was also shown that precipitation did not occur on rock specimens kept in water without HSULPC. The weight of all specimens stored in HSULPC increased, and the observed weight change was larger for rocks with higher porosities. It is concluded that precipitation of minerals occurs on the rock surface when the rock is kept in water with HSULPC powders. From the results obtained in this study, it is suggested that the sealing of pores and cracks in rock can be accelerated by the precipitation of calcium compounds using HSULPC. It is concluded that HSULPC is useful for underground radioactive waste disposal.

Despite recent advances in surgical techniques including staple closure and ultrasonic devices, the reported incidence of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) remains high. Therefore, we devised a new strategy in which the pancreatic stump is enveloped with the elevated jejunum (EJ) by a modified Blumgart anastomotic technique. Eighty-one patients who underwent open DP with splenectomy from January 2008 to December 2014 were enrolled. Comparisons were made between 42 patients who underwent placement of an EJ patch using the modified Blumgart method after scalpel transection and 39 patients who underwent scalpel transection alone, using unmatched and propensity score-matched analysis. After 25 patients from each group were selected by propensity score matching, the EJ patch technique was significantly associated with a lower incidence of clinically relevant POPF (P = 0.036). Multivariate analysis showed that the EJ patch was an independent predictor of a lower incidence of POPF (odds ratio, 0.16; 95 % confidence interval, 0.01–0.48; P = 0.017) as was the estimated remnant pancreatic volume. Addition of the EJ patch improves postoperative outcomes in patients who undergo open DP with splenectomy by scalpel transection and hand-sewn closure of the pancreatic remnant.

Morphological subtypes of intraductal papillary mucinous neoplasm (IPMN) have been established. Invasive IPMNs include colloid carcinoma and tubular carcinoma. Few studies have explored the association between the morphological and invasive subtypes in a large population. Clinical relevance of the morphological subtypes remains unclear. One hundred sixty-nine consecutive patients who underwent curative resection of IPMN were enrolled. The intraductal components were classified into four distinct epithelial subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. The invasive components were classified as colloid or tubular. The numbers of patients with gastric, intestinal, pancreatobiliary, and oncocytic subtypes were 123, 42, 3, and 1, respectively. Fifty-six patients had invasive cancer (tubular type, 42; colloid type, 14). The proportions of gastric type IPMN within each histological grade were 88 % among adenomas, 43 % among noninvasive carcinomas, 41 % among minimally invasive carcinomas, and 74 % among invasive carcinomas. Gastric subtype was more commonly associated with branch duct type and intestinal subtype with main duct type, and these tendencies were statistically significant (P = 0.0131). Furthermore, there was a strong correlation between gastric and tubular types and between intestinal and colloid types (P

Although several studies have reported that locally administering oncolytic viruses effectively targets malignancies, the efficacy of systemically administered oncolytic viruses is restricted. Recently, however, it was reported that systemic administration of oncolytic vesicular stomatitis virus adsorbed onto antigen-specific lymphocytes was effective against malignancies. We hypothesized that intravenously administering such virus might have significant potential in treatment of the malignant tumors. We adsorbed oncolytic herpes simplex virus-1 mutant R3616 onto lymphocytes harvested from mice with acquired antitumor immunity. We administered adsorbed R3616 to peritoneally disseminated tumors and analyzed the efficacy of this treatment. Mice administered adsorbed R3616 survived significantly longer than mice administered R3616 adsorbed onto non-specific lymphocytes, or mice administered either virus or tumor antigen-specific lymphocytes alone. In this context, herpes oncolytic virus is a promising treatment not only for primary lesions, but also for multiple metastasizing lesions. This treatment strategy may become one of the most effective methods for systemic virus delivery.

Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group (P=0.016). Angiogenesis was significantly higher in treatment group (P=0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group (P=0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.

Molecular mechanisms behind the oncogenesis of gastric cancer (GC) have yet to be identified. A novel candidate tumor-suppressor gene, which is also associated with inhibition of epidermal growth factor (EGF), was sought by means of double combination array analysis for use as a prognostic marker of GC. This consisted of expression array and single nucleotide polymorphism array analysis, along with a literature search. Cancerous and noncancerous tissues from an 82-year-old man with GC were analyzed simultaneously. The expression array and literature search identified that the suppressor of cytokine signaling 4 (SOCS4), a negative feedback regulator of EGF signaling, had significantly attenuated expression in tumor tissue. Although chromosomal deletion was not found at 14q22 where SOCS4 is located, numerous CpG sites were observed in the promoter region of the SOCS4 gene. Several GC cell lines showed reactivation of SOCS4 mRNA expression after treatment with 5-aza-2′-deoxycytidine. Using surgically resected specimens, we found that 40 of 50 (80%) tumor tissues exhibited promoter hypermethylation of the SOCS4 gene. Consequently, SOCS4 expression in tumor tissues was significantly weaker than in noncancerous counterparts (P

Pylorus-preserving pancreatoduodenectomy (PPPD) has replaced conventional pancreatoduodenectomy with a distal gastrectomy (cPD) as the most commonly performed procedure. However, there has been no evidence from prospective studies to indicate the overwhelming superiority of PPPD over cPD. A recent report revealed that resection of the pyloric ring reduced the incidence of delayed gastric emptying (DGE) in a randomized controlled trial. In 158 patients with pancreatic head cancer, the perioperative outcomes and long-term nutritional consequences were retrospectively compared among three types of pancreatoduodenectomy: cPD; PPPD; and subtotal stomach-preserving pancreatoduodenectomy (SSPPD), in which the pyloric ring and duodenum were removed and more than 90% of the stomach was preserved. The incidence of DGE was significantly higher in the PPPD group than in the cPD and SSPPD groups (27.3 vs. 5.8 and 5.4%, respectively; P = 0.0012). The serum albumin concentration and total lymphocyte count at 1 year postoperatively were significantly higher in the SSPPD group than in the PPPD group (P = 0.0303 and P = 0.0203, respectively). The patients in the SSPPD group showed longer survival times than the patients in the cPD and PPPD groups (median survival times, 21.3, 17.1, and 17.7 months, respectively), although the differences did not reach statistical significance. Our results suggest that preservation of the pyloric ring without vagal innervation has little significance, and that SSPPD with better perioperative and long-term outcomes is more suitable as a standard procedure for patients with pancreatic head cancer.

A combination of fluorouracil and leucovorin (5-FU/LV) with oxaliplatin (FOLFOX) is an established first-line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. A strategy to stop FOLFOX, deliver 5-FU/LV as a maintenance therapy and reintroduce FOLFOX was found to be equivalent in terms of efficacy while neurotoxicity was substantially reduced. The aim of this study was to evaluate feasibility of a stop-and-go strategy with S-1, an oral fluoropyrimidine derivative, as a maintenance therapy administered between modified FOLFOX6 (mFOLFOX6) as a first-line treatment of mCRC.Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 followed by maintenance therapy with oral S-1. Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or upon tumor progression. The primary endpoint was duration of disease control (DDC).Twenty-one of the 30 patients who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in 15 patients. Median DDC and progression-free survival were 9.3 and 7.9 months, respectively. The response rates and disease control rates were 40.0 and 86.6% for the initial mFOLFOX6, 23.8 and 57.1% for S-1 maintenance therapy and 20.0 and 73.3% for mFOLFOX6 reintroduction, respectively. Twenty-eight patients (93.3%) had peripheral neuropathy, but grade 3 neurotoxicity was observed in only 1 patient (3.3%).The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible as a first-line treatment for Japanese mCRC patients. Further prospective randomized control study is warranted.

Resection of hepatocellular carcinoma (HCC) located in the right liver often requires hepatic mobilization. However, exposure of the HCC may be restricted when using the conventional abdominal approach (AA). In such cases, a thoracoabdominal approach (TA) can provide a good operating field. Although several studies have reported on the TA for hepatectomy for HCC, none have been published since 2003. Accordingly, this issue seemed to have been resolved, based on the advantages of this approach. However, surgical instruments are constantly improving and hepatectomy may be possible without the TA. Data were retrospectively collected from 284 consecutive patients who underwent primary hepatectomy for HCC located in the right liver between January 1991 and December 2009. We compared the perioperative outcomes between patients who underwent the TA (n = 111) and those who underwent the AA (n = 173). Patient characteristics of both groups were comparable. The morbidity rate (Clavien grade ≥ 1) was significantly greater with the TA than with the AA (64.2 vs. 49.2%, p = 0.01), as was operative time (median = 370 vs. 315 min, p = 0.001) and hospital stay (median = 25 vs. 21 days, p = 0.005). There were no differences in hospital mortality or overall or disease-free survival. The TA provides no additional benefits over the AA in terms of safety and postoperative outcomes. We recommend that the TA should be used in exceptional circumstances because it resulted in a higher morbidity rate and longer operative time and postoperative hospitalization compared with the AA.

The negative impact of anastomotic leakage on cancer-specific survival and recurrence patterns has been recognized in colorectal cancer. In pancreatic cancer, pancreatic fistula (PF) is a serious morbidity, but its negative effect on long-term outcome remains to be elucidated. The aim of this study was to determine the impact of PF on pancreatic cancer recurrence. The medical records of 184 patients with curative pancreatectomy for pancreatic cancer were reviewed. PF was scored on the basis of the International Study Group of Pancreatic Fistula classification. Overall and disease-free survivals and recurrence patterns were analyzed. Grade A PF was excluded because the negative effects can be negligible. PF occurred in 51 of the 184 patients (27.7%). The mortality related to PF was 0.5% (1 of 184). PF was an independent risk factor for peritoneal recurrence (hazard ratio 3.974; 95% confidence interval 1.345–11.737; P = 0.013). According to the analysis of disease-free survival in patients with peritoneal recurrence, time to recurrence was shorter and the survival rate was worse in patients with PF than in those without PF (5.6 vs. 8.2 months; 6-month survival, 40 vs. 71%; 1-year survival, 7 vs. 19%; P = 0.053). PF was an independent prognostic factor after multivariate analysis (hazard ratio 3.257; 95% confidence interval 1.201–8.828; P = 0.020). PF was statistically significantly related to peritoneal recurrence, and patients with PF developed peritoneal recurrence earlier than those without PF. With regard to the development of peritoneal recurrence, PF may be considered to be a negative prognostic factor.

The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Cancer (QLQ-C30) and the site-specific module for gastric cancer (QLQ-STO22) have seldom been used to measure the postoperative health-related quality of life (HRQOL) in Japanese gastric cancer patients. The aim of this study was to evaluate the HRQOL after gastrectomy using these instruments and to compare various aspects of HRQOL among surgical procedures. A total of 98 patients who underwent gastrectomy and had no recurrence were evaluated. Among them, we compared the differences between major surgical procedures consisting of open total gastrectomy (TG, n = 8), open distal gastrectomy (DG, n = 24), and laparoscopy-assisted distal gastrectomy (LADG, n = 44). Questionnaires were completed at baseline and at 1, 3, 6 and 12 months postoperatively. The worst scores for most of the items were observed at 1 month after surgery and usually improved thereafter. Scores after TG were the worst of all surgical procedures across all dimensions throughout the period. Scores after LADG were generally superior to those after DG at 1 and 3 months postoperatively but not at 12 months. EORTC QLQ-C30 and STO22 detected differences in several aspects of HRQOL among patients treated by the three surgical procedures. The laparoscopic approach resulted in superior short-term outcomes, whereas TG continued to affect the HRQOL in several items 12 months after surgery.

In 2005, we initiated a clinical trial that examined the efficacy of the oncolytic virus HF10 to treat pancreatic cancer. Pancreatic cancer continues to have a high mortality rate, despite multimodal treatments for patients, and new therapeutic methods are greatly needed. The current mainstream methods for cancer treatment include biological therapeutics such as trastuzumab (Herceptin) for breast cancer or erlotinib (Tarceva) for non-small cell lung cancer. Oncolytic virus therapy is a new and promising treatment strategy for cancer. Oncolytic viruses are novel biological therapeutics for advanced cancer that appear to have a wide spectrum of anticancer activity with minimal human toxicity. To examine the efficacy of oncolytic virus therapy for pancreatic cancer, we initiated pilot studies by injecting six patients with non-resectable pancreatic cancer with three doses of HF10. All patients were monitored for 30 days for local and systemic adverse effects and were not administered any other therapeutics during this period. There were no adverse side-effects, and we observed some therapeutic potential based on tumor marker levels, survival, pathological findings and diagnostic radiography. The tumors were classified as stable disease in three patients, partial response in one patient and progressive disease in two patients.

Laparoscopic surgery requires fundamental skills peculiar to endoscopic procedures such as eye–hand coordination. Acquisition of such skills prior to performing actual surgery is highly desirable for favorable outcome. Virtual-reality simulators have been developed for both surgical training and assessment of performance. The aim of the current study is to show construct validity of a novel simulator, LapVR (Immersion Medical, San Jose, CA, USA), for Japanese surgeons and surgical residents. Forty-four subjects were divided into the following three groups according to their experience in laparoscopic surgery: 14 residents (RE) with no experience in laparoscopic surgery, 14 junior surgeons (JR) with little experience, and 16 experienced surgeons (EX). All subjects executed “essential task 1” programmed in the LapVR, which consists of six tasks, resulting in automatic measurement of 100 parameters indicating various aspects of laparoscopic skills. Time required for each task tended to be inversely correlated with experience in laparoscopic surgery. For the peg transfer skill, statistically significant differences were observed between EX and RE in three parameters, including total time and average time taken to complete the procedure and path length for the nondominant hand. For the cutting skill, similar differences were observed between EX and RE in total time, number of unsuccessful cutting attempts, and path length for the nondominant hand. According to the programmed comprehensive evaluation, performance in terms of successful completion of the task and actual experience of the participants in laparoscopic surgery correlated significantly for the peg transfer (P = 0.007) and cutting skills (P = 0.026). The peg transfer and cutting skills could best distinguish between EX and RE. This study is the first to provide evidence that LapVR has construct validity to discriminate between novice and experienced laparoscopic surgeons.

Esophageal carcinosarcoma is a rare neoplasm. Esophagectomy with lymph node dissection has often been performed, although the efficacy of chemotherapy or radiotherapy is not yet confirmed. Four cases of esophageal carcinosarcoma who underwent chemoradiotherapy are presented. Complete response of the primary tumor was observed in one case; tumor size decreased in three cases. Two patients have been observed to be disease free, another patient died of metastatic disease, and the other had recurrence. Six cases of carcinosarcoma treated with chemoradiotherapy were retrieved from the literature and analyzed with the four cases in the current study. Reduction of the tumor was observed in seven of the ten cases. Disease progression or local recurrence was observed in three cases, and another two cases died of metastatic disease. Although chemoradiotherapy seems to be capable of local control, whether it is beneficial in terms of prolonging survival of patients with this disease remains unknown.

Insertion of drainage tubes at gastric cancer surgery could be useful for the prediction and management of postoperative complications. However, drains should be removed as soon as they are deemed unnecessary for various reasons. Amylase concentration of the drainage fluid following total gastrectomy for gastric cancer has been reported to be a useful risk factor for surgical complications. Between January 2002 and December 2008, the authors measured amylase concentration of the drainage fluid on the first postoperative day for 372 patients who underwent gastrectomy with lymphadenectomy for gastric cancer at the Department of Surgery II, Nagoya University. Univariate and multivariate analyses were performed to evaluate the significance of various covariates as risk factors for the pancreas-related complications. Postoperative complications developed in 111 patients, of which 27 were pancreas-related. Amylase concentration was significantly higher in patients who underwent splenectomy, pancreaticosplenectomy, total/proximal gastrectomies, and extended lymphadenectomy and in those who eventually developed intra-abdominal abscess. Amylase concentration ≥1,000 IU/l on the first postoperative day, along with the body mass index, was an independent risk factor for pancreas-related intra-abdominal abscess. With a negative predictive value of 97.7%, pancreas-related complications are highly unlikely to be observed when amylase concentration is less than 1,000 IU/l, and early removal of the drainage tube could be recommended for these patients.

Wound healing consists of sequential steps of tissue repair, and cell migration is particularly important. In order to analyze the potential function of growth arrest and DNA damage inducible protein 34 (GADD34) in tissue repair, we performed in vitro and in vivo wound healing experiments. In an in vitro scratch assay, GADD34 knockout (KO) mouse embryonic fibroblasts (MEFs) had higher migration rates than did wild type (WT) MEFs. Furthermore, the rate of wound closure was faster in GADD34 KO MEFs than in WT MEFs. Using in vivo punch biopsy assays, GADD34 KO mice had accelerated wound healing compared to WT mice. WT mice expressed higher amounts of myosin IIA in migrating macrophages and myofibroblasts than did GADD34 KO mice. These results indicate that GADD34 negatively regulates cell migration in wound healing via expression of myosin IIA.

Background: This multicentre randomised phase III trial was designed to determine whether adjuvant chemotherapy with gemcitabine improves the outcomes of patients with resected pancreatic cancer. Methods: Eligibility criteria included macroscopically curative resection of invasive ductal carcinoma of the pancreas and no earlier radiation or chemotherapy. Patients were randomly assigned at a 1 : 1 ratio to either the gemcitabine group or the surgery-only group. Patients assigned to the gemcitabine group received gemcitabine at a dose of 1000 mg m−2 over 30 min on days 1, 8 and 15, every 4 weeks for 3 cycles. Results: Between April 2002 and March 2005, 119 patients were enrolled in this study. Among them, 118 were eligible and analysable (58 in the gemcitabine group and 60 in the surgery-only group). Both groups were well balanced in terms of baseline characteristics. Although heamatological toxicity was frequently observed in the gemcitabine group, most toxicities were transient, and grade 3 or 4 non-heamatological toxicity was rare. Patients in the gemcitabine group showed significantly longer disease-free survival (DFS) than those in the surgery-only group (median DFS, 11.4versus 5.0 months; hazard ratio=0.60 (95% confidence interval (CI): 0.40–0.89); P=0.01), although overall survival did not differ significantly between the gemcitabine and surgery-only groups (median overall survival, 22.3 versus 18.4 months; hazard ratio=0.77 (95% CI: 0.51–1.14); P=0.19). Conclusion: The current results suggest that adjuvant gemcitabine contributes to prolonged DFS in patients undergoing macroscopically curative resection of pancreatic cancer.

To examine the efficacy of ultrasound-mediated gene therapy in the treatment of hepatic cancer, we performed cationic liposome-mediated interferon-beta (IFNbeta) gene therapy combined with sonoporation, using metastatic hepatic tumors of murine colon cancer. The combination of liposome/DNA treatment and ultrasound gave higher transgene IFNbeta expression in Colon26 colon adenocarcinoma cells than that with microbubble/DNA in combination with ultrasound and that with liposome/DNA alone. Cationic liposome-mediated IFNbeta gene therapy combined with ultrasound showed an antitumor effect in vitro and combination use of the anticancer drug cis-diamminedichloroplatinum (CDDP) showed a synergistic effect with the IFNbeta gene therapy. The survival of mice with metastatic hepatic tumor of Colon26 cells was significantly prolonged by cationic liposome-mediated IFNbeta gene therapy alone, and sonoporation had a synergistic effect on prolongation of survival and inhibition of tumor growth rate in these mice. Combination use of CDDP with IFNbeta gene therapy also showed a synergistic effect on prolongation of survival and inhibition of tumor growth rate. In conclusion, ultrasound-mediated gene therapy for the treatment of hepatic cancers may be effective in a clinical setting.

We present our experience in the treatment of nonfunctioning neuroendocrine pancreatic tumors (NFNPTs) to define the clinical and pathological characteristics and to suggest proper management.The records of 17 patients with NFNPTs operated on between 1998 and 2008 were retrospectively reviewed, and all tumors were classified clinicopathologically as benign, uncertain, and malignant, based on the World Health Organization (WHO) classification of neuroendocrine tumors.There were four benign, six uncertain, and seven malignant NFNPTs. The most frequent symptoms were abdominal pain (five patients) and obstructive jaundice (one patient). Most of these symptomatic patients had malignant tumors. Mean tumor size of benign, uncertain, and malignant tumors were 1.0 +/- 0.3, 3.2 +/- 1.6, and 5.3 +/- 2.4 cm, respectively. Metastatic lesions of malignant tumors were lymph node (six patients), liver (four patients), and adrenal gland (one patient). Six of seven patients with malignant tumors underwent curative rejection. There were recurrences in four of six patients with curatively rejected malignant tumors. Two patients underwent more rejection, three patients received systemic chemotherapy, and two patients underwent radiofrequency ablation and transcatheter arterial chemoembolization for liver metastases. Survival of patients with malignant tumors was significantly shorter than that of patients with benign and uncertain tumors. However, three patients with malignant tumors had long survival of more than 3 years, even with metastases or recurrences.Aggressive surgical resection should be performed in patients with resectable NFNPTs, even with metastases. Even when a tumor was unresectable or there were recurrences, long-time palliation could be achieved by a multidisciplinary approach.

Pancreatic carcinoma causes more than 20,000 deaths every year in Japan. The role of (neo-) adjuvant chemotherapy for pancreatic carcinoma is still controversial.At the 34th Annual Meeting of the Japanese Society of Pancreatic Surgery in 2007, questionnaires were distributed regarding the use of (neo-) adjuvant chemo(radio)therapy for pancreatic carcinoma between 2001 and 2005.Sixty of the 146 member institutions responded to the questionnaires. There were a total of 1,846 cases of resected pancreatic carcinoma between 2001 and 2005. The study population had a greater proportion of males, and a mean age of 65.3 years (range 34-90 years). The lesion was located in the head of the pancreas in 1,204 cases (71.7%), in the body in 353 cases (21.0%), and in the tail in 111 cases (6.6%). Overall survival rates were 67.3% at 1 year, 36.0% at 2 years, and 23.9% at 3 years, respectively. Adjuvant chemotherapy (usually involving gemcitabine) was used in 66.0% of cases. The use of adjuvant chemotherapy was found to improve the overall survival rate. Interestingly, adjuvant chemotherapy only improved survival in late-stage (UICC stages IIB, III, and IV) but not early stage (IA, IB, and IIA) patients. Survival was treatment duration-dependent, with patients who received more than 12 months of therapy having a 3-year survival rate of 51.2%.This high volume retrospective data indicated the promising effect of gemcitabine-based adjuvant chemotherapy and the rational duration of adjuvant chemotherapy should be determined in the future prospective studies.

Linitis plastica-type gastric carcinoma remains a disease with poor prognosis despite an aggressive surgical approach. Although a prominent pattern of disease failure is peritoneal carcinomatosis, some patients experience rapid disease progression without signs of the peritoneal disease. Clinicopathologic data from 178 patients with linitis plastica-type gastric cancer operated on between 1991 and 2000 were analyzed. Survival stratified by curability of surgery, pN stage, and patterns of failure were evaluated by using the Kaplan-Meier method, and χ2 test was used to evaluate correlation between the number of metastatic lymph nodes in terms of pN categories and the incidence of various patterns of metastasis and recurrence. Cox regression hazard model was used to identify independent prognostic factors. R0 resection was performed only among 82 patients (46% of those who underwent laparotomy). Node metastasis was frequent with only 22 patients classified as pN0. Peritoneal carcinomatosis was observed in 131 patients and was the commonest pattern of recurrence. Bone metastasis, found in 13 patients, was associated with poor outcome, and its incidence was significantly correlated with the number of metastatic nodes. pT4 status and pN3 status were identified as significant independent prognostic determinants. Treatment strategy for the linitis plastica should in general combine surgery with aggressive treatment directed toward peritoneal disease. However, patients with >16 metastatic nodes more often are associated with bone metastasis than those with modest nodal involvement and suffer from poor prognosis.

Alteration in transforming growth factor-beta signalling pathway is one of the main causes of pancreatic cancer. The human runt-related transcription factor 3 gene (RUNX3) is an important component of this pathway. RUNX3 locus 1p36 is commonly deleted in a variety of human cancers, including pancreatic cancer. Therefore, we examined genetic and epigenetic alterations of RUNX3 in human pancreatic cancer. Thirty-two patients with pancreatic cancer were investigated in this study. We examined the methylation status of RUNX3 promoter region, loss of heterozygosity (LOH) at 1p36, and conducted a mutation analysis. The results were compared with clinicopathological data. Promoter hypermethylation was detected in 20 (62.5%) of 32 pancreatic cancer tissues, confirmed by sequence of bisulphite-treated DNA. Loss of heterozygosity was detected in 11 (34.3%) of 32 pancreatic cancers. In comparison with clinicopathological data, hypermethylation showed a relation with a worse prognosis (P=0.0143). Hypermethylation and LOH appear to be common mechanisms for inactivation of RUNX3 in pancreatic cancer. Therefore, RUNX3 may be an important tumour suppressor gene related to pancreatic cancer.

Objective Objective of this study was to detect the expression of neuroepithelial transforming gene-1 (NET-1) and proliferating cell nuclear antigen (PCNA) in hepatocellular carcinoma (HCC) and adjacent tissues, and to investigate the relation of the expression of NET-1 in HCC tissue with cancer proliferation, metastasis and clinic stages. Methods The expression of NET-1 mRNA was detected by reverse transcription-polymerase chain reaction method in 34 human HCC tissues, and it was matched with 34 paracarcinoma tissues. The expression of PCNA in HCC was analyzed by immunohistochemistry. Meanwhile, the relation of the expression with clinic pathological features of HCC was evaluated, and the correlation between the expression of NET-1 and PCNA in HCC was investigated. Results Expression of NET-1 was significantly higher in HCC than that in matched paracarcinoma tissues. The expression of NET-1 was significantly higher in TMN III–IV HCC tissues when compared with TMN I–II HCC tissues (P < 0.05). The expression level of NET-1 in HCC tissues was related to intrahepatic metastasis and portal vein infiltration. The expression of NET-1 in HCC tissues was positively correlated with PCNA. Conclusions The expression of NET-1 may relate to proliferation, metastasis and clinic stages of HCC. The expression of NET-1 in HCC tissues may positively correlate to the TMN stages.

Abdominal lymphangioma is usually diagnosed within the first 2 years of life and is extremely rare in adults. The most common location of abdominal lymphangioma is the mesentery, but there are sporadic reports of its development in the gallbladder. A 66-year-old woman was found to have a cystic lesion near the gallbladder. Preoperative studies, including endoscopic ultrasonography, computed tomography, and magnetic resonance imaging, showed a tumor with multilocular cystic structure, originating in the gallbladder fossa. The patient underwent exploratory laparotomy, and the mass was resected en bloc with the gallbladder, as there was no evidence of malignancy on intraoperative ultrasonography. Macroscopically, the tumor was a multilocular cystic mass, 6 x 3 x 2 cm in size, with a rough, sponge-like appearance. Histologically, the cystic tumor was diagnosed as a lymphangioma, originating in the gallbladder. To our knowledge, only three other cases of a cystic lymphangioma originating in the gallbladder have been reported in the medical literature of the world.

Pancreatic cancer still has a poor prognosis, even if aggressive therapy is pursued. Currently, new modalities of oncolytic virus therapy are being tested against this cancer. The combination of one of two representative mutant herpes simplex viruses (R3616: gamma(1)34.5 inactivated, hrR3: UL39 inactivated) with a standard anti-pancreatic cancer chemotherapy drug (gemcitabine), was investigated in this study.The intracellular concentration of ribonucleotide reductase was estimated by Western blotting. The effect of gemcitabine on viral replication and the total cytotoxic effect of the combination therapy were investigated on pancreatic cancer cell lines. We compared the results of two oncolytic viruses, R3616 and hrR3. A mouse model of pancreatic cancer with peritoneal dissemination was used to evaluate the in vivo effect of the combination therapy.Although the replication of both viruses was inhibited by gemcitabine, the combination caused more tumor cell cytotoxicity than did virus alone in vitro. The results with R3616 were more striking. Although the difference was not statistically significant, R3616 with gemcitabine had a greater effect than did R3616 alone, while hrR3 with gemcitabine had a weaker effect than did hrR3 alone in vivo experiments.The combination of oncolytic virus with gemcitabine is a promising new strategy against advanced pancreatic cancer. Each virus has different functional characteristics, and can affect the results of the combination of viruses and chemotherapy drugs. The results indicate that there is a complicated interaction among viruses, cells, and chemotherapy drugs and that the best combination of oncolytic virus and chemotherapeutic agents should be studied more extensively before embarking on a clinical trial.

Therapy guided by chemotherapy sensitivity and resistance assays may lead to rational treatment decisions. Paclitaxel, one of several new drugs for gastric carcinoma, has not been extensively evaluated by in vitro chemosensitivity tests.Chemosensitivity testing by histoculture drug response assay (HDRA) was performed with fresh specimens of primary tumor from 113 patients with gastric carcinoma. The test was performed in medium containing paclitaxel at three different concentrations for the initial 45 samples. Correlations between the results of chemosensitivity testing, determined at the optimal concentration, and the patients' clinicopathologic factors and outcome were then assessed for all patients.By analyzing the initial 45 samples, 10 microg/ml was considered the optimal concentration of paclitaxel for this test. HDRA was successfully performed for 100 of 113 samples and chemosensitivity, calculated as the percentage of optical density of a tumor treated with anticancer drugs in relation to the optical density of the tumor cultured in the medium only, was distributed widely at this concentration. No significant correlation was observed between chemosensitivity and age, sex, clinical stage, histopathologic type, and outcome of patients with gastric carcinoma.A histoculture drug response assay can now be performed to predict the chemosensitivity of paclitaxel at the concentration found in the current study. The accuracy of the assay to actually predict survival needs to be validated by a prospective clinical trial involving patients who have received paclitaxel in the postoperative adjuvant setting.

Some of our patients showed a recurrence of adhesive small bowel obstruction (ASBO) with nonoperative management. The aim of this study was to evaluate the parameters predicting the recurrence of ASBO in patients managed with a long tube. Of 234 patients with ASBO admitted from April 1998 to September 2002, a total of 91 who recovered with nonoperative management after long tube placement were enrolled in this retrospective clinical study. We divided them into two groups for follow-up: the recurrence group and the no-recurrence group. We compared baseline characteristics, the number of previous ASBO admissions, the number of abdominal operations, the interval from the onset of symptoms to long-tube insertion, the duration of long-tube placement, the type of the contrasted intestine through the long tube, the location of the long-tube tip, and the drainage volume through the long tube between the two groups. We then examined the cumulative recurrence rate. A significant difference was found in the number of previous ASBO admissions, the duration of long-tube placement (77 hours vs. 43 hours), the contrasted intestine through the long tube, and the location of the long-tube tip. By multivariate analysis, the duration of long-tube placement was an independent parameter predicting the recurrence of ASBO. These results suggest that the duration of long-tube placement might serve as a parameter for predicting recurrence of ASBO in patients managed with a long tube.

To determine the incidence and importance of functioning tumors among incidentally discovered adrenal masses in the era of laparoscopic surgery. We defined adrenal incidentaloma as a tumor detected during abdominal imaging for adrenal-unrelated reasons, and we reviewed 197 consecutive patients with adrenal incidentaloma diagnosed since we started laparoscopic adrenalectomy. Incidentaloma was discovered initially in 91 (46%) patients and pheochromocytoma was detected as an incidentaloma in 21 (39%) of 54 patients. One patient, a 21-year-old woman taking mesalamine for ulcerative colitis, had a remarkably elevated urinary normetanephrine level, which resulted in the initial misdiagnosis of a 10-cm right adrenal incidentaloma as a pheochromocytoma. Laparoscopic right adrenalectomy resulted in a pathological diagnosis of ganglioneuroma. A series of urinary normetanephrine measurements were taken in parallel with the mesalamine doses. We found that other patients medicated with mesalamine, without adrenal tumors, had elevated urinary normetanephrine levels, confirming that mesalamine metabolites interfere with urinary normetanephrine measurements. It is essential to diagnose the functional potential of adrenal incidentaloma preoperatively, and not to perform laparoscopic adrenalectomy for adrenal incidentaloma without careful evaluation first.

Failure of a pancreatic-enteric anastomosis very frequently leads to morbidity and mortality after pancreaticoduodenectomy. Pancreaticojejunostomy or pancreaticogastrostomy is often used after pancreaticoduodenectomy. The many reports on pancreaticogastrostomy support the low rates of anastomotic leakage and mortality compared with pancreaticojejunostomy.Between January 1995 and December 2004, 155 pancreaticojejunostomies and 58 pancreaticogastrostomies were performed after pancreatic resection in the Second Department of Surgery of Nagoya University Hospital. Postoperative morbidity and mortality were analyzed.The incidence of pancreatic fistula was similar for the pancreaticojejunostomy (12.2%) and pancreaticogastrostomy (20.7%) groups and the mortality rate was 0% in both groups.This restrospective clinical study suggested no significant difference in the incidence rate of pancreatic fistula and mortality between pancreaticojejunostomy and pancreaticogastrostomy.

Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Although the survival of patients with IBC has been greatly improved by the use of combined treatment modalities, women with IBC still have lower survival rates. We have summarized a single-center experience involving IBC patients. Our objectives are to clarify molecular alterations of HER- 2/neu and p53 in IBC and to investigate the prognostic factors. Between January 1990 and December 2000, 57 patients with IBC were referred to the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The incidence of IBC among primary breast cancers was 1.0% (57/5,757) in our hospital. Forty-six patients meeting Haagensen's criteria for inflammatory breast carcinoma were evaluated. All patients had biopsy-proven carcinomas but no distant metastases at referral. The median age at diagnosis for IBC was 51.8 (range, 28 to 70). All patients underwent a mastectomy. Chemotherapy was performed pre-or postoperatively. Three-year and 5-year survival rates were 56.5%, and 40.7%, respectively. Expressions of HER- 2/neu and the p53 protein were determined retrospectively by immunohistochemical (IHC) staining of thin paraffin-embedded sections of primary tumors. Of 46 patients, 23 (50.0%) with tumors testing positive for HER-2/neu fared somewhat worse than those with negative tumors, but the differences were not significant for either overall survival (OS) or disease-free survival (DFS). Of 46 patients, 19 (41.3%) whose tumors were positive for p53 fared somewhat better than patients with negative tumors, with no significant differences in either OS or DFS. Patients presenting with less than ten pathologically involved axillary lymph nodes showed significantly better OS and DFS. Overexpression of HER-2/neu and the p53 protein were not significant prognostic factors in inflammatory breast cancer. However, the increased incidence of HER-2/neu and the poor outcome of IBC may be of clinical interest, suggesting the need for clinical trials of antibody therapy targeted to HER- 2/neu. Moreover, a high prevalence of p53 may be useful in determining the specific use of chemotherapy.

Many patients with advanced esophageal cancer have a stent inserted in the esophagus, but very little else can be done. We devised a new method of delivering thermotherapy using an implant heating system (IHS) with a metallic stent. To our knowledge, there are no other reports of thermotherapy using metallic stents. We report our clinical results of treating patients with this new technique.A metallic stent was placed in the esophagus and heated for thermotherapy. This was combined with simultaneous chemotherapy in 13 patients and radio-chemotherapy in 5 patients. Each thermotherapy session consisted of heating the stent to 50 degrees C for 10 min. These 18 patients received a collective 52 sessions of thermotherapy. The tumor was excised after this treatment in 5 of these 18 patients.We evaluated 17 of the 18 patients, after the exclusion of 1 patient who underwent radio-chemotherapy before placement of the stent. There was 1 complete response (CR) and 12 partial responses (PR), accounting for 76%. The patient with a CR had no residual cancer cells detected by pathologic examination after surgical resection. Thermotherapy proved effective in 8 (89%) of 9 patients who received this treatment at least three times. It was effective in all (100%) patients who underwent concomitant radio-chemotherapy.Our results show that thermotherapy using a stent can improve the effectiveness of combination therapy, suppress local tumor growth, and enhance quality of life over a long period.

To test the hypothesis that plasminogen activator inhibitor-1 (PAI-1) may serve as a candidate marker for the malignancy of colorectal cancer (CRC), we performed a quantitative RT-PCR for PAI-1 gene and evaluated the possible relationship between PAI-1 gene expression levels and clinicopathological findings in CRC. A significant increase in PAI-1 expression scores was observed in lymph node metastasis-positive CRCs (2.19 +/- 0.43) compared to negative ones (0.35 +/- 0.42) (P = 0.0037) as well as in distant metastasis-positive CRCs (3.50 +/- 1.18) compared to negative ones (0.99 +/- 0.30). The PAI-1 expression score markedly increased with the tumour stage (P = 0.0063; ANOVA test). Moreover, multivariate analysis revealed the PAI-1 expression score to be a strong and independent prognostic factor for CRC (P = 0.0432). These results suggested that PAI-1 might serve as a new parameter for the prediction of prognoses in CRC.

We examined whether sonoporation enhanced by a contrast agent (BR14) was effective in gene therapy for hepatocelluar carcinoma (HCC). Human hepatic cancer cells (SK-Hep1) and plasmid cDNAs expressing green fluorescent protein (GFP), interferonbeta (IFNbeta), and LacZ were used. In vitro, SK-Hep1 cell suspensions with DNA and BR14 were sonoporated. Expressions of every plasmid cDNA and the antitumor effect of IFNbeta were analyzed. In vivo, GFP and IFNbeta genes with BR14 were directly injected into subcutaneous tumors using SK-Hep1 in nude mice, and transcutaneous sonoporation of the tumors was performed. GFP gene transfections and tumor diameters after IFNbeta gene transfection were examined. In vitro, no SK-Hep1 cells were transfected without sonication, whereas transfections were successful after sonication with BR14. Antitumor effect of IFNbeta gene transfection by ultrasound (US) and with BR14 was revealed. In vivo, the SK-Hep1 cells expressed GFP, and the IFNbeta gene transfection by US with BR14 reduced tumor size significantly. In conclusion, gene therapy with sonoporation enhanced by a contrast agent may become a new treatment option for HCC.

Calciphylaxis is a relatively rare but life-threatening complication in uremic patients. Clinical findings and prognosis were evaluated in six patients who developed calciphylaxis from a group of 1499 patients who underwent parathyroidectomy (PTx) for advanced renal hyperparathyroidism (HPT) in our department from July 1972 to July 2003. The frequency of calciphylaxis was 0.40% (6/1499). Two patients were women and four were men. The mean age was 50.5 years, and the mean duration of hemodialysis (HD) treatment was 14.0 years. In five of six patients, calciphylaxis was classified as distal type; in one case, as proximal type. In three patients, calciphylaxis was diagnosed at the time for PTx. In two patients, calciphylaxis was identified after PTx, although the serum parathyroid hormone (PTH) level was within the appropriate range for dialysis patients. In two patients, calciphylaxis improved after PTx, but two patients required leg and toe amputations after PTx. In one patient with the proximal type of calciphylaxis, the condition occurred when a high PTH level recurred after the initial PTx. The patient died as a result of a serious infection due to uncontrollable skin ulcers. Calciphylaxis is a rare complication in patients who require PTx for renal HPT. Especially the proximal type has a poor prognosis. High levels of the Ca x P product and/or PTH are risk factors. Therefore, this syndrome should be kept in mind and attention should be paid to reduce risk factors. It is important that PTx being performed at the right time in patients with advanced renal HPT refractory to medical treatment.

Recently, the loss of CDH13 (T-cadherin, H-cadherin) gene expression accompanied by CDH13 promoter methylation was identified in colon cancers. We examined CDH13 methylation in oesophageal and gastric carcinomas. Five of 37 oesophageal cancers (14%) and 23 of 66 gastric cancers (35%) demonstrated abnormal methylation of the CDH13 promoter. Abnormal methylation was frequently found in gastric cancers of patients at all clinical stages just as in E-cadherin, another of the cadherin family, suggesting that these cancers could be methylated at an early stage. These results suggested that CDH13 might play a variety of roles depending on the tissue type.

Background. We previously reported that water extract of Mekabu, a kind of seaweed, induced apoptosis in a human breast cancer cell line. In the present study we investigated intracellular signaling in apoptosis, with a focus on caspases. Methods. Mekabu extract, obtained with ultrapure water, was used to induce apoptosis in a human breast cancer cell line, MDA-MB231, and DNA fractionation was investigated by flow cytometry and electrophoresis. In addition, using the caspase detection kit Caspa Tag, activation of caspases 3, 6, 8, and 9 was observed under a fluorescence microscope. Furthermore, using antibodies to caspases 3, 8, 9, and Bid, we conducted a protein analysis by Western blotting to determine the activation of these substances. Results. Obvious ladder formation demonstrating DNA fractionation was seen, confirming that Mekabu extract induced apoptosis. In the fluorescence microscope observations, activation of caspases 3, 6, and 8, but not caspase 9, was seen. Activated caspases 3 and 8 were detected in the Western blotting analysis, but no proteins of activated caspase 9 or Bid were detected. Conclusion. Mekabu extract activates caspases 3, 6, and 8 and contributes to intracellular signaling to induce apoptosis in a human breast cancer cell line. This signaling is not via the mitochondria.

The mechanisms underlying progression of peritoneal metastasis by gastric cancer after micrometastasis formation remain unclear. In the present study, we investigated metastasis to the abdominal wall peritoneum, one of the major features of peritoneal spread, using a human gastric cancer cell line (GCIY-EGFP) tagged with the green fluorescence protein gene (GFP). This model allows sensitive, specific and sequential observation of metastasis development from the initial deposits to peritoneal carcinomatosis at the end stage. In the initial phase, GCIY-EGFP cells could form micrometastasis selectively on the omentum and mesenterium in a milky spot-dependent manner, but not on abdominal wall peritoneum lacking milky spots until the late stages. In vitro analysis using primary mesothelial cells revealed addition of TNF-alpha to decrease their stress fibers, leading to morphological change followed by exposure of the submesothelial extracellular matrix (ECM) in intercellular gaps. Such TNF-alpha pretreatment was found to enhance attachment of tumor cells to the mesothelial monolayer. When tumor cells were injected into the peritoneal cavity of TNF-alpha pretreated mice, they could metastasize to the abdominal wall peritoneum from the very early stages, resulting in accelerated accumulation of ascites than in TNF-alpha non-pretreatment controls. RT-PCR analysis revealed that tumor cells express cytokines and chemokines, including TNF-alpha. Furthermore, TNF-alpha treatment results in up-regulation of expression of monocyte chemoattractant protein-1 (MCP-1) and IL-8 by mesothelial cells and of TNF-alpha itself by inflammatory leukocytes in the peritoneal cavity. These results suggest that metastasis to the abdominal wall peritoneum occurs as a second step from the first omental metastasis in a milky spot-independent manner and that TNF-alpha derived from tumor cells, mesothelial cells and inflammatory leukocytes in the peritoneal cavity may be involved in the progression of peritoneal metastasis.

Background: Although routine follow-up to detect asymptomatic recurrence after surgery for gastric cancer is recommended, the effect of such reassessment on survival has not been evaluated. Methods: Clinical records of patients developing recurrent disease after potentially curative resection between 1985 and 1996 were retrieved. Among these patients, 197 were in our follow-up program. We analyzed survival in these patients according to the presence or absence of cancer-related symptoms when recurrent disease was diagnosed. Results: Of all patients with recurrent disease, 50% were diagnosed within 1 year and 75% within 2 years of surgery. Asymptomatic recurrence, detected in 88 patients (45%), frequently represented distant metastasis. Although early detection significantly improved survival after detection of recurrent disease, disease-free survival for this subset was shorter. Thus, no significant difference in overall survival was observed. Conclusions: Early detection of asymptomatic gastric cancer recurrence did not improve overall survival of patients with recurrence after curative resection. Until development of more effective treatment for this disease, close follow-up may offer no survival benefit.

Germline mutations in the RET proto-oncogene are responsible for the development of human hereditary diseases, including multiple endocrine neoplasia (MEN) type 2A and 2B, familial medullary thyroid carcinoma (FMTC), and Hirschsprung's disease (HSCR). It has been reported that some families developed both MEN 2A/FMTC and HSCR, in which a mutation in a cysteine residue at codon 609, 618, or 620 in the RET gene was present. Here we report a novel RET mutation detected in a Japanese family with medullary thyroid carcinoma and HSCR. A germline mutation in cysteine 611 of the RET gene was identified in this family, which introduced an amino-acid change from cysteine to serine. By biological and biochemical analyses of mutant RET proteins, we previously predicted the potentiality that amino-acid substitution for cysteine 611 as well as cysteines 609, 618, and 620 would promote the development of MEN 2A/FMTC and HSCR. This clinical case substantiates our suggestion for the mechanism of the development of both the diseases.

The present study demonstrates that a clonal derivative (HF10) of HSV-1 strain HF effectively treated disseminated peritoneal neoplasm in an immunocompetent animal model and that all of survived mice acquired resistance to rechallenge with tumor cells. The survival time of mice treated with HF10 was longer than that of mice treated with hrR3, indicating that the oncolytic effect of HF10 was more potent than that of hrR3 in this animal model. HF10 induces syncytia formation in vitro, whereas hrR3 forms rounded CPE. The sequential administration of HF10 gave a long term survival of more than 90 days after tumor injection, with no signs of disease, in 8 of the 9 treated mice. The results suggest that treatment of disseminated peritoneal tumor with HF10 induces a specific antitumor immune response. Genomic structure determination showed that HF10 has a deletion of 3.9-kilobase pair (kbp) in the right end of UL and UL/IRL junction, resulting in the loss of UL 56 expression. A 2.3 kbp deletion and extensive rearrangement were also observed in the left end of the genome.

We report the rare case of an intraductal papillary mucinous tumor (IPMT) in a man younger than 30 years of age. The patient was admitted with upper abdominal pain and an elevated amylase level of 662 IU/l. Ultrasonography showed a cystic mass in the pancreatic body and endoscopic retrograde cholangiopancreatography (ERCP) revealed a dilated pancreatic duct with a filling defect communicating with the tumor. He was successfully treated by segmental resection, which seems to be the best surgical option for pancreatic body tumors since it results in long-term survival and preserves as much pancreatic parenchyma as possible. Nevertheless, it can only be done in the absence of additional nodules along the pancreatic duct. A pathological diagnosis of intraductal papillary adenocarcinoma of the noninvasive type was confirmed, and both stumps were free of tumor.

Background/Purpose. A clinical study was carried out to clarify the indications for extended resection of pancreatic cancer. Methods. From July 1981 to April 2000, 200 of 314 (63.7%) patients with pancreatic cancer underwent extended tumor resection. Portal vein resection was performed in 146 of the 200 (73%) resected cases. The postoperative survival rate was studied based on the operative and histopathological findings. Results. Operative death (within 30 days postoperatively) occurred in 11 of the 200 (5.5%) resected patients. Most of the patients who survived for 2 or 3 years were in the group with carcinoma-free surgical margins. Conclusion. The most important indication for an extended operation combined with portal vein resection for pancreatic cancer is the likelihood of obtaining surgical cancer-free margins. There is no indication for an extended resection in patients in whom the surgical margins will become cancer-positive if such a resection is employed.

To investigate whether the effects of anticancer agents are able to be predicted, the results of sensitivity tests on anticancer agents were compared with the results of preoperative chemotherapy. Biopsies were taken from 25 patients with esophageal cancer and 10 with gastric cancer, before chemotherapy, and the drug sensitivity was determined after culturing for 1 week. The chemotherapy consisted of low-dose cis-diamino-dichloroplatinum + 5-fluorouracil, and its clinical effect was determined after 3 or 5 weeks. Sensitivity was determined in 20 of the esophageal cancer patients and 8 of the gastric cancer patients, accounting for 80% of all the patients. Of the 11 patients judged to have sensitivity by the histoculture drug response assay (HDRA), 7 had a partial response, and of the 17 judged to have no sensitivity, 16 had a minor response or no change (NC). It was thus demonstrated that predictions of the effect of anticancer agents could be made with considerable accuracy using HDRA. The prognosis of the NC patients was poor, and distant metastasis, thought to be an adverse effect, soon appeared. From the viewpoint of both medical costs and patient quality of life, treatments other than preoperative chemotherapy should be selected for patients assessed to have NC. We believe that these sensitivity tests should be introduced clinically.

Background. Little information is available on the relative contribution of peptide growth factors and leukocyte-derived proteinases to the repair processes in inflammatory bowel disease (IBD). We investigated their possible roles in epithelial cell restitution and proliferation in patients with IBD. Methods. The expression of hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), transforming growth factor-β (TGF-β), and neutrophil elastase (NE) was examined in colonic mucosal tissues. The effects of organ culture supernatants of mucosal tissues on epithelial cell restitution and proliferation were analyzed in vitro using an intestinal cell line, IEC-6 cells. Results. Most organ cultures detected the presence of measurable levels of HGF, with a relative paucity of KGF and TGF-β activity. Greater levels of HGF were obtained in the mucosa involved with IBD, especially in patients with ulcerative colitis (UC). The mucosa involved with UC also showed higher amounts of NE. The supernatants from the mucosa involved with UC possessed a prominent stimulatory effect on the restitution of IEC-6 cells. By contrast, significant suppression beyond baseline levels was observed for the proliferation of IEC-6 cells when they were incubated with recombinant HGF plus the supernatants from the mucosa involved with UC. This suppression was diminished considerably by preincubation of the supernatants with the anti-NE antibody. Conclusions. HGF produced in the intestinal mucosa may be an important stimulator acting on epithelial cell restitution in patients with IBD. However, NE released in situ may impair mucosal repair through inhibiting epithelial cell proliferation in patients with UC.

Reoperation for secondary hyperparathyroidism (HPT) due to uremia (2HPT) may be required among patients with persistent renal failure if not all parathyroid glands are removed at the initial operation. Between March 1981 and July 2001, altogether 1,110 patients underwent total parathyroidectomy with forearm autograft for advanced 2HPT in our department. In this study, we evaluated the clinical features of patients who required reoperation and classified them into persistent HPT [the lowest intact parathyroid (PTH) level after initial operation remained higher than 60 pg/ml] and recurrent HPT (the lowest intact PTH level was normalized after surgery but reelevated became high enough to require reoperation). Removal of residual glands was indicated in 30 (2.7%) cases for persistent or recurrent HPT. All remaining glands were detected by preoperative imaging diagnoses. In 44 (4.0%) patients persistent HPT was recognized and in 15 of them (1.4% of all cases) reoperation was required. In 11 cases, the responsible glands were supernumerary ones removed from the mediastinum. In 4 cases, the glands were resected from the neck. In 15 cases (1.4%), reoperation was performed for recurrent HPT when residual glands were left either in the neck or in the thymic tongue. In all but one case, the missed glands were supernumerary. This study reveals that it is often difficult to avoid persistent HPT induced by mediastinal supernumerary glands and recurrent HPT caused by small glands left in the neck. Our findings indicate that patients with uremia should be closely followed considering the possibility that persistent or recurrent HPT may occur after parathyroidectomy.

Portal hepatofugal flow is rare after liver transplantation. We experienced a case in which hepatofugal portal flow was observed in acute rejection. A 6-year-old boy with glycogen storage disease type Ia underwent living-donor liver transplantation. On postoperative day 7, portal venous peak velocity was markedly decreased without portal thrombosis and obstruction of the hepatic vein, and hepatic arterial peak velocity increased reciprocally. Based on a diagnosis of acute rejection, made on postoperative day 8, we initiated steroid pulse therapy. Despite the employment of this therapy, continuous hepatofugal portal flow was observed in the entire liver on postoperative day 8. On day 12, as the liver disorder progressed, the Doppler waveform in the portal vein changed from continuous to pulsatile hepatofugal flow. The patient died of liver failure on day 14. The histological findings of a biopsy specimen on day 9 showed centrilobular necrosis, while total hepatocellular necrosis was seen at autopsy. Hepatofugal flow after liver transplantation is considered to be an ominous sign caused by several factors, and its appearance indicates a fatal condition.

Better diagnosis of metastatic disease has been pursued by oncologists; however, many of the tumor markers have been still controversial. Our purpose was to estimate the usefulness of soluble E-selectin and its ligand sialyl Lewis A for more accurate diagnosis as a combined tumor marker for metastases in colorectal cancer. Methods. E-selectin and sialyl Lewis A, collected from preoperative blood, were measured of its levels in 54 patients with colorectal cancer classified according to Dukes' stage. E-selectin was assayed by enzyme-linked immunosorbent assay, whereas sialyl Lewis A was quantified by enzyme immunoassay using immunoclone kit. Results. The elevation in the level of E-selectin was significantly higher in Dukes' D group than that of healthy volunteers (P < 0.001, Fisher's procedure of least significance test), Dukes' A (P = 0.01), B (P = 0.025) and C (P < 0.01). Significantly higher level of sialyl Lewis A was shown in the group of metastases than that of non-metastases (P < 0.0068, Student's t-test). Paired elevation of E-selectin and sialyl Lewis A was significantly higher in the hematogenous metastases than non-metastases (P < 0.001, Fisher exact test). Conclusions. These results suggest that E-selectin could play some role in the progress of hematogenous metastases. The elevation of E-selectin alone or both E-selectin and sialyl Lewis A may be one of the useful indexes for more precise diagnosis of hematogenous metastases of human colorectal cancer.

The repeated use of chemotherapy to treat patients with colorectal carcinoma may be limited by the fact it creates resistance cells. However, we have observed a remarkable decrease in certain types of drug resistance in patients treated with direct electric current. Experimental studies were therefore performed in animals to determine the differences in pharmacodynamics between chemotherapy with and that without electric treatment. Tumors were created in BALB/c mice by intradermal injection of 0.25 ml 4 x 10(6) Colon 26 cells/ml in the abdomen. Seven days later the mice were divided into two groups: controls and those that underwent electric treatment. Direct electric current (1,000 V, 0.2-0.8 microA) was passed between a platinum electrode inserted intradermally and the earth during and for 1 h after a single intravenous injection of 5-fluorouracil (5-FU; 12.5 mg ml(-1) kg(-1)). Peripheral blood samples were collected before and 5, 10, 20, 30, 45, and 60 min after the injection of 5-FU. Concentrations of 5-FU in the sera and tissues were measured by HPLC. The intratumoral concentrations of 5-FU in the electric treatment group were higher than those in the controls (P0.05, two-factor analysis of variance), but the serum concentrations were not statistically different between the two groups. Pharmacodynamic changes were thus observed as a result of electrostatic treatment during chemotherapy. This elevated 5-FU concentration in the tumor tissue is considered one of the reasons for the effective inhibition of 5-FU resistance in clinical cases.

Laparoscopic surgery now can be performed safely and efficiently for various types of cancer; however, reconstruction of the gastric tube may be technically demanding. We attempted to make a breakthrough by designing and employing a new technique for performing a small incisional operation with endoscopic assistance. A midline incision, 10 cm in length, was made in the upper abdomen. Some procedures were performed through the incision under direct vision, while other procedures required in the lateral extremes of the abdominal cavity, that are inaccessible by direct vision, were performed by laparoscopic-assisted surgery. Similarly, intrathoracic procedures were essentially performed through a minithoracotomy, 10–15 cm in length, made without dissection of the dorsal latissmus or anterior serratus muscles. The postoperative courses of 20 consecutive patients who underwent this procedure were generally uneventful, and significant improvements in terms of intensive care and analgesic requirements were observed.

Glial cell line derived neurotrophic factor (GDNF) signals through a multicomponent receptor complex consisting of RET receptor tyrosine kinase and a member of GDNF family receptor alpha (GFRalpha). Recently, it was shown that tyrosine 1062 in RET represents a binding site for SHC adaptor proteins and is crucial for both RAS/mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways. In the present study, we characterized how these two pathways diverge from tyrosine 1062, using human neuroblastoma and primitive neuroectodermal tumor cell lines expressing RET at high levels. In response to GDNF stimulation, SHC bound to GAB1 and GRB2 adaptor proteins as well as RET, and SHC and GAB1 were highly phosphorylated on tyrosine. The complex formation consisting of SHC, GAB1 and GRB2 was almost abolished by replacement of tyrosine 1062 in RET with phenylalanine. Tyrosine-phosphorylated GAB1 was also associated with p85 subunit of PI3-K, resulting in PI3-K and AKT activation, whereas SHC-GRB2-SOS complex was responsible for the RAS/ERK signaling pathway. These results suggested that the RAS and PI3-K pathways activated by GDNF bifurcate mainly through SHC bound to tyrosine 1062 in RET. Furthermore, using luciferase reporter-gene assays, we found that the RAS/ERK and PI3-K signaling pathways are important for activation of CREB and NF-kappaB in GDNF-treated cells, respectively. Oncogene (2000) 19, 4469 - 4475.