Technique and surgical outcomes of mesenterization and intra-operative neural monitoring to reduce recurrent laryngeal nerve paralysis after thoracoscopic esophagectomy: A cohort study.

BACKGROUND: Because the thoracic esophageal carcinoma has a high metastatic rate to the upper mediastinal lymph nodes, especially along the recurrent laryngeal nerves (RLN), it is crucial to perform a complete lymphadenectomy along the RLN without complications. Although intraoperative neural monitoring (IONM) during thyroid surgery has gained widespread acceptance as a useful tool for visual nerve identification, utilization of IONM during esophageal surgery has not become common. Here, we describe our procedures, focusing on a lymphadenectomy along the RLN utilizing the IONM. METHODS: Eighty-seven patients who underwent prone esophagectomy between December 2009 and September 2017 were included in this study. We divided patients into two groups: neural monitoring group (Nm, n = 31) and conventional method group without IONM (Cm, n = 56). We first dissect around the esophagus, preserving the membranous structure; mesoesophagus, which contains tracheoesophageal artery; RLN; and lymph nodes (mesenterization). In Nm group, we next identify the location of the RLN, which runs in the mesoesophagus using IONM before visual contact. Next, we perform lymphadenectomy around the RLN, preserving the nerve itself. Early surgical outcomes were retrospectively compared between two groups. RESULTS: In all 31 cases in the Nm group, we detected the location of the RLN before the visual contact. The sensitivity and specificity of the IONM to detect the RLN paralysis were 67% and 96%, respectively. Postoperative RLN paralysis was observed in 3 cases in the Nm group (9.7%), which was lower than that in the Cm group (32.1%, p = 0.03). Clavien-Dindo grade 2 and over aspiration were seen in 2 (Nm, 6.5%) and 16 (Cm, 28.6%) cases (p = 0.01), respectively. The postoperative hospital stay was shorter in the Nm group (22 days, median) than in the Cm group (39 days, median, p = 0.0002). The number of dissected mediastinal lymph nodes was similar in both groups (25 vs. 20, median, p = 0.12). CONCLUSIONS: The combination of IONM and the concept of the mesoesophagus have substantial advantages in allowing accurate and safe mediastinal lymphadenectomy during prone esophagectomy.

Laparoscopic appendectomy during the third trimester: Case presentation and literature review.

Acute appendicitis is the most common general surgical problem encountered during pregnancy. Laparoscopic appendectomy (LA) is widely accepted as a minimally invasive procedure for acute appendicitis. However, LA during the third trimester is associated with problems, including technical difficulty, risk of preterm delivery, and fetal loss. We successfully managed three cases of LA during the third trimester between 2011 and 2016. None of the cases required conversion to an open procedure, and none of the patients had postoperative complications and/or fetal loss. We reviewed the literature using the PubMED database from 2007 to 2016 to acquire further evidence and identified 6 reports and 17 cases. The conversion rate was 11.8% (2 cases), the complication rate was 6.67% (1 case), and the preterm delivery rate was 20% (3 cases); no fetal loss was observed. Our study and literature review highlights the role of LA as a potentially feasible treatment approach for appendicitis during the third trimester.

Clinical factors that affect the outcomes after anatomical versus non-anatomical resection for hepatocellular carcinoma.

PURPOSE: For hepatocellular carcinoma (HCC), the superiority of anatomical resection (AR) over non-anatomical resection (NR) is still controversial. In this study, we assessed the potential benefits of AR for HCC. METHODS: We enrolled 173 consecutive patients with HCC who underwent hepatectomy in our hospital from August 2003 to May 2013 and compared the outcomes for the AR group (n = 125) with those for the NR group (n = 48). RESULTS: The median observational period was 790 days. The 1- and 2-year overall survival (OS) rates were 92.1 and 85.8 %, respectively; the 1- and 2-year disease-free survival (DFS) rates were 78.2 and 63.0 %, respectively. The AR and NR groups did not significantly differ in the OS or DFS. However, the 2-year DFS was significantly better for the AR group than the NR group among HCV patients (68.2 vs. 32.2 %; P = 0.004) and patients with alpha-fetoprotein (AFP) within the normal range (<20 ng/ml; 76.7 vs. 60.9 %; P = 0.031), total bilirubin <0.8 mg/dl (70.8 vs. 47.0 %; P = 0.034), and tumors 2-5 cm in diameter (82.0 vs. 62.5 %; P = 0.025). CONCLUSIONS: If a patient is HCV-negative, has low AFP, low total bilirubin, or a tumor diameter of 2-5 cm, AR is recommended.

The preventive surgical site infection bundle in patients with colorectal perforation.

BACKGROUND: Incisional surgical site infection (SSI) is one of the most frequent complications that occur after colorectal surgery. Surgery for colorectal perforation carries an especially high risk of incisional SSI because fecal ascites contaminates the incision intraoperatively, and in patients who underwent stoma creation, the incision is located near the infective origin and is subject to infection postoperatively. Although effectiveness of the preventive SSI bundle of elective colorectal surgery has been reported, no study has focused exclusively on emergency surgery for colorectal perforation. METHODS: Patients with colorectal perforation who underwent emergency surgery and stoma creation from 2010 to 2015 at our center were consecutively enrolled in the study. In March 2013, we developed the preventive incisional SSI bundle for patients with colorectal perforation undergoing stoma creation. The effectiveness of the bundle in these patients was determined and the rates of incisional SSI between before and after March 2013 were compared. RESULTS: We enrolled 108 patients with colorectal perforation who underwent emergency operation during the study period. Thirteen patients were excluded because they died within 30 days after surgery, and 23 patients without stoma were excluded; thus, 72 patients were analyzed. There were 47 patients in the pre-implementation group and 25 patients in the post-implementation group. The rate of incisional SSI was significantly lower after implementation of preventive incisional SSI bundle (43% vs. 20%, p = 0.049). Postoperative hospital stay was significantly shorter after implementation of the bundle (27 vs. 18 days respectively; p = 0.008). CONCLUSIONS: The preventive incisional SSI bundle was effective in preventing incisional SSI in patients with colorectal perforation undergoing emergency surgery with stoma creation.

Prediction of mortality in patients with colorectal perforation based on routinely available parameters: a retrospective study.

INTRODUCTION: Even after surgery and intensive postoperative management, the mortality rate associated with colorectal perforation is high. Identification of mortality markers using routinely available preoperative parameters is important. METHODS: We enrolled consecutive patients with colorectal perforation who underwent operations from January 2010 to January 2015. We divided them into a mortality and survivor group and compared clinical characteristics between the two groups. Additionally, we compared the mortality rate between different etiologies: malignant versus benign and diverticular versus nondiverticular. We used the χ (2) and Mann-Whitney U tests and a logistic regression model to identify factors associated with mortality. RESULTS: We enrolled 108 patients, and 52 (48 %) were male. The mean age at surgery was 71 ± 13 years. The postoperative mortality rate was 12 % (13 patients). Multivariate logistic regression analysis showed that a high patient age (odds ratio [OR], 1.09; 95 % confidence interval [CI], 1.020-1.181) and low preoperative systolic blood pressure (OR, 0.98; 95 % CI, 0.953-0.999) were independent risk factors for mortality in patients with colorectal perforation. In the subgroup analysis, there was no significant difference between the malignant and benign group (11.8 % vs. 23.9 %, respectively; p = 0.970), while the diverticular group had a significantly lower mortality rate than the nondiverticular group (2.6 % vs. 17.1 %, respectively; p = 0.027). CONCLUSIONS: Older patients and patients with low preoperative blood pressure had a high risk of mortality associated with colorectal perforation. For such patients, operations and postoperative management should be performed carefully.

Comparison between anatomical subsegmentectomy and nonanatomical partial resection for hepatocellular carcinoma located within a single subsegment: a single-center retrospective analysis.

BACKGROUND/AIMS: For hepatocellular carcinoma (HCC) within a single subsegment, the superiority of anatomical subsegmentectomy over non-anatomical partial resection is still controversial. In this study, we assessed the potential benefit of subsegmentectomy. METHODOLOGY: We selected 44 patients with a single HCC lesion within one subsegment who had undergone anatomical subsegmentectomy or non-anatomical partial resection from among 173 patients who underwent hepatectomy in our hospital from August 2003 to May 2013. We compared the results following anatomical subsegmentectomy (Group A; n = 16) and non-anatomical partial resection (Group N; n = 28). RESULTS: One- and two-year survival rates were 92.5% and 89.3%, respectively; 1- and 2-year recurrence-free survival (RFS) rates were 88.9% and 69.1%, respectively. There was no significant difference in overall survival or RFS between the groups. However, among HBV-positive patients, RFS was significantly better for Group A than Group N (p = 0.008). CONCLUSIONS: For HBV-positive HCC within a single subsegment, we recommend subsegmentectomy.

Long-term survival after resection of pancreatic cancer: a single-center retrospective analysis.

AIM: To retrospectively analyze factors affecting the long-term survival of patients with pancreatic cancer who underwent pancreatic resection. METHODS: From January 2000 to December 2011, 195 patients underwent pancreatic resection in our hospital. The prognostic factors after pancreatic resection were analyzed in all 195 patients. After excluding the censored cases within an observational period, the clinicopathological characteristics of 20 patients who survived ≥ 5 (n = 20) and < 5 (n = 76) years were compared. For this comparison, we analyzed the patients who underwent surgery before June 2008 and were observed for more than 5 years. For statistical analyses, the log-rank test was used to compare the cumulative survival rates, and the χ (2) and Mann-Whitney tests were used to compare the two groups. The Cox-Hazard model was used for a multivariate analysis, and P values less than 0.05 were considered significant. A multivariate analysis was conducted on the factors that were significant in the univariate analysis. RESULTS: The median survival for all patients was 27.1 months, and the 5-year actuarial survival rate was 34.5%. The median observational period was 595 d. With the univariate analysis, the UICC stage was significantly associated with survival time, and the CA19-9 ≤ 200 U/mL, DUPAN-2 ≤ 180 U/mL, tumor size ≤ 20 mm, R0 resection, absence of lymph node metastasis, absence of extrapancreatic neural invasion, and absence of portal invasion were favorable prognostic factors. The multivariate analysis showed that tumor size ≤ 20 mm (HR = 0.40; 95%CI: 0.17-0.83, P = 0.012) and negative surgical margins (R0 resection) (HR = 0.48; 95%CI: 0.30-0.77, P = 0.003) were independent favorable prognostic factors. Among the 96 patients, 20 patients survived for 5 years or more, and 76 patients died within 5 years after operation. Comparison of the 20 5-year survivors with the 76 non-survivors showed that lower concentrations of DUPAN-2 (79.5 vs 312.5 U/mL, P = 0.032), tumor size ≤ 20 mm (35% vs 8%, P = 0.008), R0 resection (95% vs 61%, P = 0.004), and absence of lymph node metastases (60% vs 18%, P = 0.036) were significantly associated with the 5-year survival. CONCLUSION: Negative surgical margins and a tumor size ≤ 20 mm were independent favorable prognostic factors. Histologically curative resection and early tumor detection are important factors in achieving long-term survival.

[Long-term survival following resection of a leiomyosarcoma originating from the inferior vena cava].

We describe the case of a 46-year-old woman in which a large intra-abdominal tumor was detected using computed tomography. It was a low-density, homogeneous, 7 cm tumor, adjacent to the inferior vena cava (IVC). The tumor, along with a portion of the anterior wall of the IVC, was surgically resected. The tumor originated from the IVC wall, and histopathological examination revealed a diagnosis of leiomyosarcoma. The patient is alive without recurrence 10 years after surgery. Although this disease is rare and typically has a poor prognosis, complete resection with long-term survival is achievable.

[A case of mixed adenoneuroendocrine carcinoma of the transverse colon].

A 7 1-year-old man presented to our hospital with constipation and abdominal pain. Computed tomography of the abdomen and colonoscopy revealed advanced cancer of the transverse colon. The biopsy specimen indicated a highly differentiated adenocarcinoma. The patient underwent extended right hemicolectomy with regional lymph node dissection. Pathological examination showed a neuroendocrine carcinoma (NEC) with concurrent adenocarcinoma of the transverse colon and regional lymph node metastases of the NEC and adenocarcinoma. The histopathological examination confirmed a diagnosis of mixed adenoneuroendocrine carcinoma (MANEC) in accordance with the 2010 WHO Classification of Tumors of the Digestive System. Liver and lung metastases were identified 8 months after the surgery. We administered chemotherapy including 5-fluorouracil, Leucovorin, and oxaliplatin (mFOLFOX) plus bevacizumab, with limited therapeutic effect, as the disease progressed despite treatment. The patient chose best supportive care 13 months after the surgery. Several studies have reported that most patients with adenoendocrine cell carcinoma, including MANEC, experience relapse within 1 year after surgery, and few patients remain disease-free for long periods after surgery. The optimal strategy for the management of MANEC is variable owing to its rarity; only 2 cases of MANEC in the colon, including the present case, have been reported in Japan. It is thus important to gather more evidence on this disease and its management.

Surgical Therapy for a Solitary Form of Hepatic Epithelioid Hemangioendothelioma: A Long-Term Survival Case.

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare neoplasm of vascular origin. The clinical presentation of HEHE is variable, and the therapeutic criteria are still unclear since its natural history is unpredictable. A 53-year-old woman was admitted to our hospital because she had a 2.5-cm diameter nodule in the segment V of the liver. She had undergone segmental hepatectomy for solitary HEHE in segment VII 10 years before. There had been no recurrence for the 10 years after the first operation. The tumor was diagnosed as a new lesion of HEHE by percutaneous needle liver biopsy, and thereafter repeated hepatectomy was performed. HEHE seems to be resistant to chemotherapy and radiotherapy. Either surgical resection or orthotopic liver transplantation is generally recommended as a curative treatment for this disease. However, HEHE tends to be detected in multiple lesions, and localized disease is rare. Therefore, the chance of resection is very low. Some reports do not recommend local resection because of early aggressive tumor spread even after curative resection. We herein demonstrate a rare case of HEHE in a patient who underwent repeated hepatectomy for a solitary lesion and who survived for 17 years. It is concluded that surgical resection is one of the most effective treatments for a solitary form of HEHE.

Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: final results of a randomized multi-institutional trial.

PURPOSE: Although the outcome of surgery for locally advanced pancreatic cancer remains poor, it is improving, with 5-year survival up to about 10% in Japan. The preliminary results of our multi-institutional randomized controlled trial revealed better survival after surgery than after radiochemotherapy. We report the final results of this study after 5 years of follow-up. METHODS: Patients with preoperative findings of pancreatic cancer invading the pancreatic capsule without involvement of the superior mesenteric or common hepatic arteries, or distant metastasis, were included in this randomized controlled trial, with their consent. If the laparotomy findings were consistent with these criteria, the patient was randomized to a surgery group or a radiochemotherapy group (5-fluorouracil 200 mg/m2/day and 5040 Gy radiotherapy). We compared the mean survival time, 3-and 5-year survival rates, and hazard ratio. RESULTS: The surgery and radiochemotherapy groups comprised 20 and 22 patients, respectively. Patients were followed up for 5 years or longer, or until an event occurred to preclude this. The surgery group had significantly better survival than the radiochemotherapy group (P<0.03). Surgery increased the survival time and 3-year survival rate by an average of 11.8 months and 20%, respectively, and it halved the instantaneous mortality (hazard) rate. CONCLUSION: Locally invasive pancreatic cancer without distant metastases or major arterial invasion is treated most effectively by surgical resection.

Prognostic implication of para-aortic lymph node metastasis in resectable pancreatic cancer.

BACKGROUND: The survival curve of patients who undergo surgical resection of pancreatic cancer displays a steep decline within 1 year and a relatively slow decline thereafter. The patients with a short survival time may have identifiable clinicopathologic factors that lead to rapid relapse. STUDY DESIGN: We analyzed clinicopathologic factors in 133 patients who underwent margin-negative pancreatoduodenectomy with extended radical lymphadenectomy for invasive ductal carcinoma of the pancreas to detect factors that could be responsible for the short survival. RESULTS: Tumor size, invasion of the anterior pancreatic capsule, retroperitoneal invasion, portal venous invasion, major arterial invasion, and metastasis to the para-aortic lymph nodes were variables associated with survival time in univariate analysis. Metastasis to the para-aortic lymph nodes was the single independent factor with a significant association with mortality in multivariate analysis. Some 84% of the patients who had positive para-aortic lymph nodes died within 1 year, versus 46% of the patients with negative nodes. CONCLUSIONS: Although tumors that involve the para-aortic lymph nodes may technically be resectable, the expected postoperative survival time for most patients is less than 1 year. If para-aortic nodal metastasis is detected, alternative treatment strategies should be considered.

Bcl-XL antisense oligonucleotides coupled with antennapedia enhances radiation-induced apoptosis in pancreatic cancer.

BACKGROUND: Pancreatic cancer is highly resistant to radiation and chemotherapy, and its resistance reflects the enhancement of apoptosis inhibitory genes, including Bcl-2 family. Antennapedia (pAnt) is capable of almost 100% internalization into cells through the lipid bilayer without any cytotoxic effect. The aim of this study was to examine the effects of the Bcl-XL antisense oligonucleotide for radiosensitivity of in vitro and in vivo pancreatic cancer using oligonucleotide conjugated with antennapedia. METHODS: In in vitro experiments, expression of Bcl-XL protein was examined in 5 pancreatic cancer cell lines. In AsPC-1 cells, internalization of the oligonucleotide was confirmed, and the effects of antennapedia-antisense (pAnt-AS) or antennapedia-scramble (pAnt-Scr) on Bcl-XL protein expression were examined. Cells were treated with pAnt-AS, pAnt-Scr or phosphorothioate antisense (S-AS) for 3 days, then the effects of irradiation on the cell survival, caspase-3 activity, and apoptotic index were evaluated. In AsPC-1 xenograft mice, pAnt-AS, pAnt-Scr, or S-AS was injected, and 5 or 10 Gy irradiation was added. Bcl-Xl protein expression was measured before irradiation. Apoptosis was evaluated at 48 hours after irradiation. On the 14th day after 10-Gy irradiation, tumor wet weight was measured, and tumor growth was estimated over 5 weeks. RESULTS: In in vitro experiments, all pancreatic cancer cell lines expressed Bcl-XL protein. pAnt-AS was internalized into AsPC-1 cells within 2 hours. pAnt-AS at 10 mumol/L reduced more than 90% of the Bcl-XL protein in AsPC-1 cells, whereas pAnt-Scr or S-AS treatment at the same concentration reduced as much as 10% of the Bcl-XL protein. Treatment with pAnt-AS followed by irradiation significantly reduced cell viability when compared with that of pAnt-Scr or S-AS. Caspase-3 activity was significantly upregulated in the pAnt-AS-treated group (P = .033). The rate of nuclear fragmentation was significantly higher in the pAnt-AS group (P = .013). In in vivo experiments, Bcl-XL protein was reduced about 40% in the pAnt-AS-treated mice. Tumor doubling time of the pAnt-AS-treated mice was elongated by 10-Gy irradiation. The tumor wet weight of mice treated with pAnt-AS and 10-Gy irradiation was significantly reduced when compared with mice treated with pAnt-Scr and 10-Gy irradiation (P = .046). The apoptosis index at 48 hours after irradiation was significantly increased in pAnt-AS-treated mice (P < .01). CONCLUSIONS: The results suggest that, when coupled with antennapedia, the antisense oligonucleotide against Bcl-XL could be a good therapeutic tool for radiosensitization of pancreatic cancer.

Primary sclerosing cholangitis in which differential diagnosis from gallbladder carcinoma was difficult.

We report a case of localized primary sclerosing cholangitis (PSC) which was difficult to distinguish from gallbladder carcinoma. A 75-year-old woman with elevated serum bilirubin was hospitalized and underwent endoscopic nasobiliary drainage (ENBD). There was no history of diseases such as gallbladder stone, pancreatitis, or ulcerative colitis. Cholangiography through the ENBD tube showed localized stenosis of the common bile duct; the gallbladder could not be seen. Angiography showed no encasement of the hepatic artery. Ultrasonography showed a tumor in the cystic duct, and the tumor had invaded the gallbladder and common bile duct. We diagnosed gallbladder carcinoma on radioimaging, and performed an S4aS5 subsegmentectomy of the liver and resection of the extrahepatic biliary tree. Pathologically, no malignant cells were detected, and fibrosis around bile ducts and infiltration of inflammatory cells into hepatic tissue were found. It is well known that PSC is sometimes difficult to differentially diagnose from cholangiocarcinoma. Our case is of high interest because ultrasonography showed findings suggestive of gallbladder carcinoma. It is therefore necessary to keep the possibility of PSC in mind for the diagnosis and treatment of such localized biliary stenosis.

A randomized multicenter trial comparing resection and radiochemotherapy for resectable locally invasive pancreatic cancer.

BACKGROUND: Though the outcome of resection for locally invasive pancreatic cancer is still poor, it has gradually improved in Japan, and the 5-year survival is now about 10%. However, the advantage of resection over radiochemotherapy has not yet been confirmed by a randomized trial. We conducted this study to compare surgical resection alone versus radiochemotherapy without resection for locally invasive pancreatic cancer using a multicenter randomized design. METHODS: Patients with pancreatic cancer who met our preoperative criteria for inclusion (pancreatic cancer invading the pancreatic capsule without involvement of the superior mesenteric artery or the common hepatic artery, or without distant metastasis) underwent laparotomy. Patients with operative findings consistent with our criteria were randomized into a radical resection group and a radiochemotherapy group (200 mg/m(2)/day of intravenous 5-fluorouracil and 5040 cGy of radiotherapy) without resection. The 2 groups were compared for mean survival, hazard ratio, 1-year survival, quality of life scores, and hematologic and blood chemical data. RESULTS: Twenty patients were assigned to the resection group and 22 to the radiochemotherapy group. There was 1 operative death. The surgical resection group had better results than the radiochemotherapy group as measured by 1-year survival (62% vs 32 %, P=.05), mean survival time (>17 vs 11 months, P < .03), and hazard ratio (0.46, P=.04). There were no differences in the quality of life score or laboratory data apart from increased diarrhea after surgical resection. CONCLUSIONS: Locally invasive pancreatic cancer without distant metastases and major arterial invasion appears to be best treated by surgical resection.

N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma.

PURPOSE: Loss of intercellular adhesion and increased cell motility promote tumor cell invasion. In the present study, E- and N-cadherin, members of the classical cadherin family, are investigated as inducers of epithelial-to-mesenchymal transition (EMT) that is thought to play a fundamental role during the early steps of invasion and metastasis of carcinomas. Cell growth factors are known to regulate cell adhesion molecules. The purpose of the study presented here was to investigate whether a gain in N-cadherin in pancreatic cancer is involved in the process of metastasis via EMT and whether its expression is affected by growth factors. EXPERIMENTAL DESIGN: We immunohistochemically examined the expression of N- and E-cadherins and vimentin, a mesenchymal marker, in pancreatic primary and metastatic tumors. Correlations among the expressions of N-cadherin, transforming growth factor (TGF)beta, and fibroblast growth factor 2 was evaluated in both tumors, and the induction of cadherin and vimentin by growth factors was examined in cultured cell lines. RESULTS: N-cadherin expression was observed in 13 of 30 primary tumors and in 8 of 15 metastatic tumors. N-cadherin expression correlated with neural invasion (P = 0.008), histological type (P = 0.043), fibroblast growth factor expression in primary tumors (P = 0.007), and TGF expression (P = 0.004) and vimentin (P = 0.01) in metastatic tumors. Vimentin, a mesenchymal marker, was observed in a few cancer cells of primary tumor but was substantially expressed in liver metastasis. TGF stimulated N-cadherin and vimentin protein expression and decreased E-cadherin expression of Panc-1 cells with morphological change. CONCLUSION: This study provided the morphological evidence of EMT in pancreatic carcinoma and revealed that overexpression of N-cadherin is involved in EMT and is affected by growth factors.

Pancreatic Cancer Registry in Japan: 20 years of experience.

The prognosis of pancreatic cancer is defined by the histology and extent of disease. Preoperative histologic diagnosis and diagnostic imaging are fundamentals in managing the disease, but it is not rare to find unexpected peritoneal dissemination or liver metastasis at the time of operation. The overall resectability rate of pancreatic cancer is 40% in Japan. Resecting the portal vein and peripancreatic plexus were performed on 40% of the patients who underwent pancreatectomy for invasive cancer in the head of the pancreas. Long-term survival was only found in patients who underwent pancreatectomy. Radical lymph node dissection, or combined resection of the large vessels, did not seem to improve survival further than the standard resection. Multidisciplinary treatments combined with surgery were performed, and various effects of postoperative chemotherapy after pancreatectomy, intraoperative- and postoperative-radiation therapy, or postoperative chemotherapy for unresectable tumor, were shown. Development of unconventional therapies and refinement of the conventional therapy should be promoted on a randomized prospective trial basis. To promote this effort, which requires the international comparisons and cooperation, JPS developed a computerized JPS registration system downloadable from the JPS website (http://www.kojin.or.jp/suizou/index.html).

Phase III trial of radiosensitizer PR-350 combined with intraoperative radiotherapy for the treatment of locally advanced pancreatic cancer.

A randomized, controlled trial was conducted to clarify the effect of novel radiosensitizer, PR-350, accompanied by intraoperative radiology (IOR) on locally advanced pancreatic cancer. Between July 1999 and March 2002, 48 patients were enrolled in this clinical trial and received either PR-350 or placebo. Any differences between the PR-350 group (n = 22) and control group (n = 25) were not statically significant. All patients were evaluated, and none of them showed toxicity, with the exception of 1 patient from the control group, and the PR-350 compound was considered to be safe. The efficacy of IOR with PR-350 was evaluated using CT examination. The committee responsible for evaluating efficacy reported that 47.4% of the PR-350 group showed the effective response, compared with 21.7% of the control group (P = 0.1067, Fisher analysis). At 6 months following treatment, the tumor mass reduction rate in the PR-350 group was significantly improved (P = 0.0274). By the time of the last follow-up in July 2003, 17 PR-350 patients and 24 control patients group had died of the disease. The median survival period of the PR-350 group was thus 318.5 days and that of the control group is 303.0 days. One-year survival rates of the PR-350 group and control group were 36.4% and 32.0%, respectively. Although the PR-350 group did not demonstrate significantly better survival than the control group, 4 of 22 PR-350 patients were still living more than 2 years after the end of the trial, compared with only 1 of 25 patients from the control group. The mechanism of this increased therapeutic response to radiotherapy using PR-350 must be clarified to establish more effective strategy for pancreatic cancer treatment.

Expression of pancreatic duodenal hoemobox-1 in pancreatic islet neogenesis after surgical wrapping in rats.

BACKGROUND: Surgical wrapping (SW) of the pancreas causes islet neogenesis in rodents. Pancreatic duodenal hoemobox-1 (PDX-1) is one of the transcriptional factors needed by pancreatic stem cells to develop a mature pancreas. The purpose of this study was to determine whether islet neogenesis arises from ductal cells and whether PDX-1 is involved in this process. METHODS: SW consisted of nonocclusive wrapping of the pancreas in rats. The wrapped pancreas was then harvested, insulin content was measured, and immunohistochemical analysis for insulin, cytokeratin, and PDX-1 was performed. RESULTS: The endocrine area of the wrapped pancreas significantly increased after SW. Double immunostaining identified cells positive for both insulin and cytokeratin in or along the epithelial cell lining of the ductal structures and in the centroacinar cells. PDX-1-positive cells were detected in both control islets and islets examined after SW, but these cells were observed in the exocrine area only after SW. Double staining also showed that cells positive for PDX-1 but negative for insulin were present in the exocrine area 1 day after SW and that cells positive for both PDX-1 and insulin had developed 3 days after SW. CONCLUSIONS: In the process of adult islet neogenesis after SW, cells in the acini and ductal structures developed into PDX-1-expressing cells, supposedly progenitor cells, which in turn became insulin-producing cells and thus might be the origin of small islets.

Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma.

Many cancers are resistant to Fas-mediated apoptosis despite the expression of Fas. To investigate the mechanisms by which Fas signals are attenuated, we focused on decoy receptor 3 (DcR3). DcR3 is a soluble receptor against Fas ligand belonging to the tumor necrosis factor receptor superfamily and overexpresses in some forms of cancers. Exogenous DcR3 inhibits Fas-mediated apoptosis in Fas-sensitive Jurkat cells. In our study, we examined the expression and function of DcR3 in pancreatic cancers. TaqMan RT-PCR showed that DcR3 mRNA was highly expressed in pancreatic cancer cell lines (71%) and tissues (67%). Its expression significantly correlated with cancer invasion to veins. Western blotting showed that the DcR3 protein was produced and secreted in 4 of 6 cell lines. The protein expressions were compatible with the mRNA expression. Five of 7 pancreatic cancer cell lines became sensitive to agonistic anti-Fas antibody (CH-11) to various extents, without Fas upregulation, when exposed to CH-11 for 48 hr after pretreatment with IFNgamma. Four of 7 pancreatic cancer cell lines were inhibited from growing, compared to control cells, when cocultured with membrane-bounded Fas ligand (mFasL) transfected lymphomas for 48 hr after pretreatment with IFNgamma. DcR3 reduced this growth inhibition when added exogenously. Regression analysis showed that the DcR3 expression significantly correlated with the sensitivity to mFasL, and not to CH-11. These results suggest that DcR3 is highly expressed in many pancreatic cancers and endogenous DcR3 blocks the growth inhibition signals mediated by mFasL. DcR3 can be a candidate target molecule for the therapeutic intervention.