Synthesis of new tricyclic thiolactams as potent antitumor agent for pancreatic cancer.

We synthesized the novel tricyclic thiolactams 2a-d, 3d-k, having a benzyl or substituted benzyl substituent on the nitrogen of indole subunit, and their preferential cytotoxicity under both nutrient-deprived medium (NDM) and Dulbecco's modified Eagle's medium (DMEM) was evaluated against a human pancreatic cancer cell line PANC-1. Among the tested compounds, the 4'-hydroxy derivative 3d showed the most potent cytotoxicity in NDM (PC50 1.68µM) although the moderate preferential cytotoxicity (PC50 1.68µM in NDM vs PC50 20µM in DMEM). The 3'-hydroxy derivative 3e exhibited the most preferential cytotoxicity (PC50 1.96µM in NDM vs less than 50% inhibition at 30µM in DMEM). The benzyl 2a and halogenated benzyl derivatives 2b,c showed no cytotoxicity in NDM. In addition, the indole (10, PC50 173.7µM), lactone (11, PC50 131.7µM), and lactam (12, PC50 44.8µM) derivatives showed week or moderate cytotoxicity in NDM. These results indicated that the hydroxy group on the benzyl substituent and tricyclic thiolactam ring were essential for the cytotoxicity in NDM against PANC-1 cell line. Moreover, 3'-hydroxy derivative 3e compound exhibited antitumor activity against the pancreatic ductal adenocarcinoma (PDAC) xenograft model in vivo.

Efficacy of non-stented pancreaticojejunostomy demonstrated in the hard pancreas.

BACKGROUND/AIMS: The aim of this study was to compare hard and soft pancreas for short-term complications of pancreaticoduodenectomy performed with a duct-to-mucosa anastomosis of pancreaticojejunostomy without a stenting tube. METHODOLOGY: We investigated 156 patients with pancreaticojejunostomy who were classified into two groups of hard pancreas (group A: 79) and soft pancreas (group B: 77). Outcomes, including complications and operative procedures, are reported. RESULTS: There were no differences between groups A and B for median age, gender, performance status. Biliary drainage ratio and disease classification of Groups A and B were statistically different. In preoperative status, there were no differences in Body Mass Index, total bilirubin, albumin, hemoglobin, creatinine, and PFD. Group B had lower HbA1C levels than group A. In operative procedures, there were no differences in operative times and blood loss, but group B had longer postoperative hospital days than group A. On operative results, there were no differences in mortality, delayed gastric emptying, biliary fistula, hemorrhage, cholangitis, lymph leakage, and others. There were significant differences between groups A and B in morbidity (12.7% vs. 35.1%), pancreatic fistula (0% vs. 9.1%), intra-abdominal abscess (1.3% vs. 9.1%). CONCLUSION: Efficacy of pancreaticojejunostomy without a stenting tube for hard pancreas was demonstrated.

Adjuvant chemotherapy using gemcitabine for resected distal bile duct and ampullary cancers.

BACKGROUND/AIMS: This retrospective study aimed to evaluate adjuvant chemotherapy using gemcitabine for resected distal bile duct and ampullary cancers. METHODOLOGY: Thirty-seven patients who had curative surgery for distal bile duct and ampullary cancers were classified into two groups: A, 19, surgery alone, and B, 18, surgery plus gemcitabine adjuvant chemotherapy between 2004 and 2010. Outcomes, including backgrounds, overall survival (OS), disease free survival (DFS), and adverse events are reported. RESULTS: There were no differences in characteristics between patients of groups A and B for age, gender, location of tumor, UICC stage, UICC pT factor, UICC pN factor, curability, and operative procedures. For all stages, except stage II, there was no difference between groups A and B for OS and DFS. For stage II however, groups A and B showed significant differences in median survival times for OS and DFS. Grade 3 or 4 adverse events included 5.6% with leucopenia. CONCLUSIONS: Adjuvant chemotherapy using gemcitabine showed the potential of contributing to prolonged OS and DFS in stage II resected distal bile duct and ampullary cancers. However, a large cohort will be needed to confirm the overall efficacy in all stages of resected BTC's.

Retrospective study of gemcitabine plus S-1 versus gemcitabine alone in cases with unresectable advanced pancreatic cancer.

BACKGROUND/AIMS: The aim of this study was to compare gemcitabine plus S-1 (GS) combination chemotherapy to gemcitabine (GEM) monotherapy in cases with unresectable advanced pancreatic cancer. METHODS: We retrospectively reviewed 107 consecutive patients with unresectable advanced pancreatic cancer who received GEM monotherapy or GS combination chemotherapy between 2004 and 2010. In 73 patients, GEM (1000 mg/m2) was administered intravenously on days 1, 8 and 15, repeated every four weeks. The GS regimen received by 34 patients consisted of intravenous GEM (1000 mg/m2) on days 1 and 8, combined with oral S-1 (40 mg/m2) twice daily on days 1-14, repeated every four weeks. RESULTS: Response rates in the GEM and GS groups (6.8% versus 32.4%) varied significantly, as did disease control rates (28.8% versus 61.8%, respectively). There was a significant difference in median overall survival (206 versus 258 days) and median progression-free survival (86 versus 123 days) between the GEM and GS groups. Grade 3/4 toxicities in both groups were neutropenia (16.4% in GEM, 17.6% in GS), thrombocytopenia (1.3%, 2.9%), anorexia (1.3%, 0%), and diarrhea (1.3%, 0%). CONCLUSIONS: Retrospectively, GS combination therapy is feasible more effective than GEM monotherapy, and therefore should be considered in cases with unresectable advanced pancreatic cancer.

Pancreaticoduodenectomy can be safely performed in the elderly.

BACKGROUND: Although pancreaticoduodenectomy has been recognized in the past for its severe complications, improvements in operative methods and perioperative management have made it a safe procedure. Therefore, pancreaticoduodenectomy can be performed in elderly patients, and our experience and outcomes are described in this report. METHODS: We retrospectively investigated 142 patients in whom pancreaticoduodenectomy was performed without stenting tubes during pancreaticojejunostomy. The patients were classified into two groups: (A) those older and (B) younger than 75 years. The outcomes, including preoperative characteristics, intraoperative characteristics, postoperative complications and mortality, are herein reported. Continuous variables were compared using Student's t test and the Chi-square test. RESULTS: There were no differences between groups A and B in terms of sex, operative time, amount of blood loss, performance status, soft pancreas rate, disease distribution and operative procedure. Comorbidities in groups A and B were statistically different. Regarding the preoperative status, the elderly patients exhibited lower serum albumin and hemoglobin levels than the younger patients. There were no differences in mortality (0 vs. 0 %), morbidity (24.3 vs. 29.5 %, p = 0.362), postoperative hospital days or major complications such as pancreatic fistula development, delayed gastric emptying, intra-abdominal abscess development, biliary fistula formation and postpancreatectomy hemorrhage. CONCLUSIONS: Pancreaticoduodenectomy can be safely performed in elderly as well as younger patients.

[A case of bile duct cancer with positive surgical margin obtaining long-term survival after S-1 monotherapy].

We report a case of bile duct cancer with a positive surgical margin obtaining long-term survival after S-1 monotherapy. A 79-year-old male with fever and liver dysfunction was admitted to our hospital. After a series of examinations he was diagnosed as hilar cholangiocarcinoma, which was treated with bile duct resection and biliary reconstruction for adhesion and pulmonary dysfunction of tuberculosis. Histopathological findings revealed that both surgical margins of the bile duct were positive. After operation, the patient received S-1 oral monotherapy(100mg/day for 28 days, followed by 14 days of rest)for 3 years. The patient has been alive for 5 years without recurrence.

[Effectiveness of adjuvant chemotherapy using gemcitabine for resected pancreatic cancer].

BACKGROUND: The aim was to evaluate the adjuvant chemotherapy using gemcitabine (GEM) for resected pancreatic cancer. METHODS: We investigated 69 patients who had undergone curative operations for pancreatic cancer. They were classified into two groups of patients using GEM (group A: 37) and patients with surgery alone (group B: 32) between 2009 and 1998. Outcomes, including disease-free survival (DFS), median survival time (MST), and adverse events were reported retrospectively. Patients assigned to the gemcitabine group received GEM at a dose of 800 mg/m² on days 1, 8 and 15, every 4 weeks for 5 cycles. RESULTS: DFS and MST did not differ significantly between group A and group B (DFS; group A: 10. 4 vs group B 8. 0 months, MST; group A: 21. 7 vs group B 16. 3 months). The estimated overall survival rates at 3 and 5 years were 40% and 25. 7%, respectively, in group A, and 12. 9% and 12. 9% in group B. Grade 3 or 4 toxicity revealed 8.1%with leucopenia, 2. 7% with thrombocytopenia, and 2. 7% with nausea. RESULTS: Adjuvant chemotherapy using gemcitabine for resected pancreatic cancer contributes to prolonged DFS, MST, and estimated overall survival.

Pancreaticoduodenectomies with a duct-to-mucosa pancreaticojejunostomy anastomosis with and without a stenting tube showed no differences in long-term follow-up.

BACKGROUND/PURPOSE: The aim of this study was to evaluate the long-term complications of pancreaticoduodenectomy with a duct-to-mucosa pancreaticojejunostomy anastomosis without a stenting tube. METHODS: Patients were followed for at least 3 years after pancreaticoduodenectomy. They were classified into two groups: duct-to-mucosa pancreaticojejunostomy anastomosis with a stenting tube (group A: 24) and without a stenting tube (group B: 21). Outcomes, including complications and dilatation of the pancreatic duct, were reported retrospectively. RESULTS: The following complication rates were found for group A: morbidity 29.1%, cholangitis 12.5%, nonalcoholic steatohepatitis 4.2%, liver abscess 4.2%, intrahepatic stones 4.2%, abnormal glucose tolerance (progression of diabetes) 20.8%, and dilatation of the pancreatic duct 20.8%. In group B, the rates for morbidity (14.3%) and abnormal glucose tolerance (19%), and dilatation of the pancreatic duct (4.8%) were lower than those in group A, but all results lacked statistical significance. CONCLUSIONS: Pancreaticoduodenectomy with a duct-to-mucosa anastomosis of pancreaticojejunostomy with or without a stenting tube showed no difference in long-term follow-up.

Pancreatic schwannoma: a case report and literature review with special reference to imaging features.

CONTEXT: We report the imaging features of pancreatic schwannomas, a rare benign type of pancreatic tumor. CASE REPORT: A 66-year-old woman was admitted to our hospital with a pancreatic tumor indicated in medical examinations. Computed tomography (CT), magnetic resonance imaging (MRI) and endoscopic ultrasonography (EUS) revealed a solid and cystic tumor, 3 cm in diameter, within the body of the pancreas. Contrast-enhanced CT, MRI and ultrasonography showed partial enhancement in the solid component. Endoscopic retrograde cholangiopancreatography (ERCP) and angiography showed no abnormal findings. A distal pancreatectomy together with a splenectomy and lymph node dissection were performed with a tentative diagnosis of mucinous cystic neoplasm of the pancreas. The cut surface of the resected pancreas showed a well-demarcated, pale yellow, solid tumor within the pancreas parenchyma. Histopathological examination of the tumor revealed proliferation of the spindle cells showing interlacing and palisading patterns. Immunohistochemically, these spindle cells were positive for S-100 protein and vimentin, and negative for alpha-smooth muscle actin, CD34, and cytokeratin. Thus the tumor was diagnosed as a pancreatic schwannoma. CONCLUSION: CT and US can detect pancreatic schwannomas as solid and cystic masses, and MRI shows a relatively characteristic feature. Imaging procedures such as CT, MRI and US are able to differentiate a pancreatic tumor, such as a pancreatic schwannoma.

[A case of pathologic complete response of primary esophageal carcinoma treated with 5-FU/CDDP as neoadjuvant chemotherapy].

A 77-year-old man with advanced esophageal carcinoma and lymph node swelling of abdomen and mediastinum, underwent neoadjuvant chemotherapy (NAC) with 5-FU/CDDP. Adverse reactions were general fatigue and nausea of grade 3 and stomatitis of grade 2. Primary tumor and lymph node swelling revealed remarkable effectiveness after 1 course of NAC, so 2 courses of NAC were given. The esophageal carcinoma was not found by endoscopy, and a biopsy specimen revealed inflammatory granulation. Lymph node on CT examination disappeared in the abdomen and reduced in the mediastinum. Because of retention of lymph node swelling, radical resection of the esophageal carcinoma was performed. Pathologic examination of the resected specimen revealed no malignant cells in the esophagus, and 3 lymph node metastases (pStage III). He had no recurrence in 15 months after the operation. Because NAC was markedly effective for primary tumor and lymph node of esophageal carcinoma, a radical operation was performed.

Pancreaticojejunostomy of duct to mucosa anastomosis can be performed more safely without than with a stenting tube.

BACKGROUND: The aim of this study was to evaluate the safety of performing a pancreaticojejunostomy with a duct-to-mucosa anastomosis without a stenting tube. METHODS: One hundred twenty-one patients with pancreaticojejunostomy, classified into 2 groups of those with duct-to-mucosa anastomoses with stenting tubes (group A; n = 49) and without stenting tubes (group B; n = 72), were investigated. Outcomes, including complications and survival rates, are reported. RESULTS: In group A, morbidity was 32.7%, 6.7% had pancreatic fistulas, 14.3% had delayed gastric emptying, 6.1% had remnant pancreatitis, 2% had intra-abdominal abscesses, 2% had intra-abdominal bleeding, and mortality was 2%. In group B, morbidity (15.3%) and delayed gastric emptying (2.8%) showed significant differences from group A. Other results were nonsignificant. In the normal soft pancreas, pancreatic fistulas in group B (3.3%) were less frequent than in group A (12.5%). CONCLUSION: Pancreaticojejunostomy of a duct-to-mucosa anastomosis could be performed more safely without than with a stenting tube to obtain a definitive anastomosis and transection of the pancreas.

Importance of the phosphocholine linkage on sphingomyelin molecular properties and interactions with cholesterol; a study with phosphate oxygen modified sphingomyelin-analogues.

We have characterized the molecular properties and membrane behavior of synthetically modified sphingomyelin analogues, modified on the oxygen connecting the phosphocholine group to the ceramide backbone. The oxygen was replaced with an S-atom (S-PSM), an NH-group (NH-PSM) or a CH(2)-group (CH(2)-PSM). Diphenylhexatriene and Laurdan anisotropy experiments showed that an S-linkage increased and NH- and CH(2)-linkages decreased the stability of PSM-analogue bilayer membranes as compared to PSM. When the polarity of the interface was probed using Laurdan, S-PSM appeared to have a lower polarity as compared to PSM whereas NH-PSM and CH(2)-PSM had higher polarities of their respective interfaces. Fluorescence quenching-studies with cholestatrienol showed that all compounds formed SM/cholesterol-rich domains. The S-PSM/cholesterol and PSM/cholesterol domains displayed a similar thermostability, whereas NH-PSM/cholesterol and CH(2)-PSM/cholesterol domains were less thermostable. DSC on vesicles containing the PSM-analogues showed a more complex melting behavior as compared to PSM, whereas equimolar mixtures of the PSM-analogues and PSM showed almost ideal mixing with PSM for NH- and S-PSM. Our data show that the properties of the bond linking the phosphocholine head group to the 1-hydroxyl on the ceramide molecule is important for the stability of SM/SM and SM/cholesterol interactions.

[Complete response in a case of advanced esophageal and gastric double cancer treated by chemotherapy of TS-1 and low-dose cisplatin].

A 78-year-old man was admitted to our hospital complaining of dysphagea on April 8, 2005. Upper gastrointestinal endoscopic examination showed type 2 esophageal cancer in the lower thoracic area and type 3 gastric cancer in the upper body. Computed tomography showed No. 3 lymph node swelling, but no distant metastasis. Surgery was contraindicated because of many complications, so the patient was given combined chemotherapy with TS-1 and low-dose cisplatin. Chemotherapy was started on April 18. After 2 courses of chemotherapy the esophageal lesion showed a complete response, and after 5 courses the gastric lesion evidenced a complete response.