Specific induction of metallothionein synthesis by mitochondrial oxidative stress.

Metallothionein (MT), a sulfhydryl-rich protein, may be increased by administration of a variety of agents, including metals, cytokines and oxidative stress agents. Mitochondria are a major source of reactive oxygen species, but antioxidant systems against mitochondrial free radicals are not fully understood. In this study, we examined the induction of MT synthesis by administration of mitochondrial-specific reactive oxygen generators such as antimycin A (AA), an electron transfer inhibitor, and 2,4-dinitrophenol (DNP), an uncoupling agent. Subcutaneous administration of AA to mice significantly increased the hepatic MT concentration in a dose- and time-dependent manner. AA slightly elevated glutathione peroxidase (GSHPx) activity, but the rate of increase in GSHPx (1.3-fold) was smaller than that in MT (11.8-fold). Other antioxidants such as catalase, manganese-superoxide dismutase (Mn-SOD), copper/zinc-superoxide dismutase (Cu/Zn-SOD) and GSHPx were not activated by AA treatment. Moreover, administration of DNP induced the synthesis of MT in the liver. Although DNP slightly elevated Mn-SOD activity, the rate of increase in Mn-SOD (1.3-fold) was smaller than that in MT (3.7-fold). Other antioxidants such as catalase, Cu/Zn-SOD and GSHPx were not activated by DNP treatment. These data suggest that MT plays a major role in protection against oxidative stress induced in mitochondria.

A case report of cribriform carcinoma of the pancreas with long time survival.

A 62-year-old man had complained of left abdominal pain and tenderness and a body weight loss. Abdominal ultrasonography and computed tomography revealed homogeneous tumor with clear margin, and an irregular shape (3.5 x 2.0 cm) in the body of the pancreas. Endoscopic retrograde cholangiopancreatography showed a shadow defect in the main pancreatic duct adjacent to the tumor, which suggested intraductal tumor spread. Distal pancreatectomy with splenectomy and left paraaortic lymph node dissection was performed. Microscopically, the tumor showed microtubular carcinoma, which was characterized by a cribriform pattern, medullary growth, and little interstitium. The tumor was encapsulated by a relatively thick fibrous capsule. The patient was discharged uneventfully, and he is alive 33 months after operation without a distinct sign of recurrence. In conclusion, cribriform carcinoma of the pancreas has specific characteristics, such as good prognosis, expansive growth with little invasion, intraductal growth and spread without mucin production and histological marked cribriform pattern. This type of carcinoma should be classified as a new disease entity of carcinoma of the pancreas.

Significance of K-ras mutation and CEA level in pancreatic juice in the diagnosis of pancreatic cancer.

The early diagnosis of pancreatic carcinoma is essential for increasing patient survival rates. In this study, 52 patients with suspected pancreatic diseases were examined to investigate the value of K-ras codon 12 point mutation, levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9), and cytology of pancreatic juice in the diagnosis of pancreatic carcinoma. Pancreatic juice was taken without secretin stimulation. K-ras mutation was detected by enriched polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). K-ras mutation in pancreatic juice was more frequent in carcinoma than in benign diseases (P = 0.0448). The positive predictive value of K-ras mutation for the diagnosis of neoplastic disease was 83%. The CEA level in pancreatic juice in carcinoma was significantly greater than that in benign disease (P< 0.0001). When the cutoff level of CEA was set at 50 ng/ml, its accuracy for the diagnosis of carcinoma was 85%. A multivariate analysis showed that K-ras mutation and CEA level in pancreatic juice, as well as serum CA19-9 level and age of the patient were independent variables for the diagnosis of carcinoma, and the accuracy of diagnosis by this analysis was increased to 90%. In conclusion, both K-ras mutation and CEA level in pancreatic juice may be valuable for the diagnosis of carcinoma. Better discrimination was possible with a multivariate analysis.

Significance of thymidine phosphorylase/platelet-derived endothelial cell growth factor in carcinoma of the papilla of Vater.

The expression of thymidine phosphorylase (TP) in carcinoma of the papilla of Vater was studied to clarify its significance in tumor progression and in determining prognosis. Fifty-nine cases of surgically resected carcinoma of the papilla of Vater were studied. Immunohistochemical staining was performed to evaluate the expression of TP, microvessel count and p53 overexpression. TP expression was demonstrated in tumor cells in 62.7% (37/59) of the cases. A higher frequency of regional lymph node metastasis was found in TP-positive tumors than in TP-negative tumors (P = 0.006). TP-positive tumors were more advanced than TP-negative tumors with regard to clinical stage (P = 0.035). TP-positive tumors had significantly higher microvessel density (27.6 +/- 10.1) than TP-negative tumors (20.4 +/- 10.0, P = 0.01). Moreover, TP expression was significantly correlated with a poor prognosis (P = 0. 02). These suggest that in carcinoma of the papilla of Vater, TP production by tumor cells is correlated with tumor progression through its regulatory effect on neovascularization.

Giant solid cystic tumor of the pancreas with a fibrous septum caused by extracapsular growth in middle-aged woman: report of a case.

We report herein the case of a 57-year-old female who was admitted to our hospital for treatment of rectal carcinoma and incidentally found to have a giant cystic tumor, 20 cm in diameter, in the body and tail of the pancreas. Several imaging procedures, including ultrasonography, computed tomography, and magnetic resonance imaging, showed that this tumor was round and hypovascular, and had a septum with protuberant lesions. The capsule was 3-4 mm thick with partial calcification. A preoperative diagnosis of a solid cystic tumor (SCT) of the pancreas was made, even though these tumors are rarely found in females in their fifties. Moreover, few reports of SCT with a septum have been described. Distal pancreatectomy and splenectomy were performed, and the tumor was found to be filled with massive necrotic tissue. Microscopically, the tumor was confirmed to be a SCT with a fibrous septum. We present this case due to the atypical findings, including the age of the patient and the existence of a septum caused by extracapsular growth.

Bilateral inguinal hernia repaired by laparoscopic technique: a rare complication of femorofemoral bypass.

Femorofemoral bypass is an established procedure for limb salvage and disabling claudication. However, surgical exposure of the femoral artery may result in damage leading to development of an inguinal hernia. Herein we report the first case of laparoscopic repair of bilateral inguinal hernias that developed after femorofemoral bypass.

p53 and p21/Waf1 protein expression and K-ras codon 12 mutation in carcinoma of the papilla of Vater.

OBJECTIVE: There have been few studies on the molecular biological characteristics of carcinoma of the papilla of Vater. In this study, p53 and p21/Waf1 expression and K-ras codon 12 mutation in carcinoma of the papilla of Vater were investigated. METHODS: Thirty-seven cases of carcinoma of the papilla of Vater were studied. Macroscopically, the carcinoma was ulcerative in 15 cases and nonulcerative in 22 cases. Histologically, nine were intestinal type, 27 were pancreaticobiliary type, and one was undifferentiated. Formalin-fixed, paraffin-embedded sections were immunohistochemically stained for p53 and p21. K-ras codon 12 mutation was detected with the two-step polymerase chain reaction-restriction fragment length polymorphism method, followed by direct sequencing. RESULTS: p53 overexpression was found in 17 of 37 cases (46%) and was more frequent in the ulcerative type than in the nonulcerative type (67% vs 32%, p < 0.05). p21/Waf1 protein expression was found in 15 of 37 cases (41%), and was not correlated with that of p53. K-ras codon 12 mutation was found in 14 of 37 cases (38%), and was more frequently detected in the intestinal type than in the pancreaticobiliary type (66% vs 30%, p < 0.05). On direct sequencing, the mutations were mainly GGT to GAT (9/14) and GGT to GTT (4/14). The type of mutation did not correlate with the histological type. CONCLUSIONS: In carcinoma of the papilla of Vater, p53 overexpression may play a role in tumor ulceration. p21/Waf1 expression is induced via a p53-independent pathway. Carcinomas of the intestinal and pancreaticobiliary types may develop via different mechanisms, and K-ras mutation is mainly associated with the intestinal type.

Three generations of hereditary chronic pancreatitis.

The patient was a 22 year-old male. Hereditary chronic pancreatitis was suspected as a diagnosis since his mother's uncle had been operated on for chronic pancreatitis 14 years previously at the age of 64 years and his mother had been operated on for chronic pancreatitis with calculi 5 years previously at the age of 40 years. Surgery was needed, since: 1) he had experienced abdominal pain for 8 years; 2) endoscopic retrograde cholangiopancreatography (ERCP) revealed a marked irregular dilatation in the main pancreatic duct and a marked irregular dilatation and protein plugs in the ductule of the tail of the pancreas; and, 3) pancreatic functional diagnostic (PFD) test examination showed a 75% decrease in exocrine function. If a surgical procedure had not been performed, the patient would likely have experienced calculi formation in the pancreas and a further decrease in exocrine function. Since the patient was very young and had many protein plugs in the dilated ductule of the tail of the pancreas, we decided to perform a spleen-preserving Puestow's procedure with removal of the tail of the pancreas. Clinical and pathological findings of hereditary pancreatitis are reviewed.

Significance of K-ras codon 12 point mutation in pancreatic juice in the diagnosis of carcinoma of the pancreas.

The significance of K-ras codon 12 point mutation in pancreatic juice in the diagnosis of carcinoma of the pancreas is still unclear. The aim of this study was to evaluate the significance of K-ras codon 12 point mutation in pancreatic juice in the diagnosis of carcinoma of the pancreas. All of the 78 reports written from 1988 to 1996 on K-ras point mutation of carcinoma, mucin-producing tumors, and hyperplastic epithelia of the pancreas in both surgical or autopsy specimens and pancreatic juice are reviewed. As results, in surgical or autopsy specimens, K-ras mutation was found in 81% of ordinary duct cell carcinoma and in 53% of mucin-producing tumor of the pancreas; this mutation was also found in hyperplastic epithelia in chronic pancreatitis (7%) and in autopsy cases without pancreatic diseases. In pancreatic juice, K-ras mutation was found in 72% of ordinary pancreatic carcinoma and in 53% of mucin-producing tumor, respectively. In conclusion, most previous reports have indicated that K-ras mutation in pancreatic juice is useful for a diagnosis of pancreatic carcinoma. However, since K-ras gene mutation was also detected in non-tumorous lesions, the diagnosis of pancreatic carcinomas is not necessarily correct if it is based solely on the detection of K-ras mutation in pancreatic juice. Future studies should focus on analyzing the amino acid sequence of K-ras mutation or the combination of this mutation with other parameters such as tumor markers in pancreatic juice, to enhance its specificity and accuracy.

Enteral administration of glutamine in purulent peritonitis.

The intestinal hypomotility associated with purulent peritonitis is generally regarded as a contraindication to enteral nutrition. However, enteral nutrition may be feasible in suppurative peritonitis if administered with great caution, i.e., assuring the appropriate amount, delivery speed, and osmolality of the enteral formulation. Glutamine (Gln) increases muscle protein synthesis and decreases muscle protein degradation in sepsis, regardless of the route of administration. Therefore, administering small amounts of supplemental Gln via the enteral route to peritonitis patients may be beneficial. Two purulent peritonitis patients received L-Gln through a jejunostomy tube. The average amount of supplemental Gln was 16 g/d. Systemic inflammatory responses, i.e., high temperature and a high serum C-reactive protein level, persisted throughout the treatment period. Femoral arterial and venous blood samples were drawn simultaneously for determination of amino acid levels before and after 7 d of Gln supplementation. Enterally administered Gln was well-tolerated by both patients. There was an increase in plasma Gln levels after Gln supplementation. Moreover, the release of Gln, alanine, and phenylalanine from the lower extremities was lower after as compared to before Gln supplementation. Enteral administration of Gln may be feasible even in purulent peritonitis.

Characteristics in primary signet-ring cell carcinoma of the colorectum, from clinicopathological observations.

BACKGROUND: The biological behavior of signet-ring cell carcinomas in colorectum tends to be worse than that of mucinous carcinomas. However, in previous studies, clinicopathological features of this disease have been somewhat ill-defined because various histological criteria of this disease were adopted. METHODS: We selected 11 cases of signet-ring cell carcinomas and 29 cases of mucinous carcinomas among 1595 consecutive colorectal carcinomas on defined criteria and compared clinicopathological and molecular biological features between these two types of carcinomas. RESULTS: Clinical staging of signet-ring cell carcinomas were far advanced and their prognosis tended to be worse than that of mucinous carcinomas. Furthermore, the incidence of K-ras mutations in signet-ring cell and mucinous carcinomas showed no difference between these two types of carcinomas. However, the incidence of K-ras mutation in these diseases was slightly lower than that in 30 ordinary colorectal carcinomas examined as a comparison. CONCLUSIONS: These results suggest that the carcinogenesis of signet-ring cell and mucinous carcinomas are different from that of ordinary colorectal carcinomas and that there may exist other genes related to malignancy of signet-ring cell carcinomas.

Heterogeneity of DNA ploidy pattern in carcinoma of the gallbladder: primary and metastatic sites.

There are few detailed reports on the heterogeneity of the nuclear DNA ploidy pattern in carcinoma of the gallbladder. We studied twelve autopsied cases who died of extended gallbladder carcinoma. Multiple samples were taken from the primary site (Pri), from direct invasion of the liver (Hinf), from hematogenous metastasis to the liver (H), from lymphatic metastasis (LN) and from peritoneal dissemination (P). The DNA ploidy pattern was investigated by image cytometry. Heterogeneity of the DNA ploidy pattern in Pri, Hinf, H, LN and P was found in 7/11, 2/10, 5/10, 2/6 and 3/6 cases, respectively. Aneuploidy was more frequently found in Hinf than at the Pri. The DNA index of Hinf was significantly higher than that of Pri. Several stemlines, with different quantities of DNA, were found in Pri. Most of these stemlines were also observed in other sites. These facts may suggest that polyclonal cancer cells rather than one cancer cell or monoclonal cancer cells of a Pri metastasize or infiltrate, and that various polyclonal cancer cells proliferate to different degrees under different circumstances.

Acute acalculous cholecystitis with a decrease in CD4/CD8 ratio.

Acute acalculous cholecystitis (AAC) usually occurs in the elderly and in those with severe pre-existing pathological conditions. However, there have recently been reports of AAC in relatively young immunosuppressed patients, such as those with acquired immunodeficiency syndrome (AIDS). We report here a 27-year-old woman with AAC who received an emergent cholecystectomy. Although anti-human immunodeficiency virus antibody (anti-HIV) was not detected, a decrease in the CD4/CD8 ratio in sera was found. This rare case of AAC in a patient with decreased CD4/CD8 ratio who showed no other related diseases suggests that surgeons should keep in mind the possible presence of immunosuppression in this condition.

Appleby operation for carcinoma of the body and tail of the pancreas.

Long-term survival of carcinomas in the body and tail of the pancreas after surgery is still rare. One of the major reasons for unresectability is cancerous invasion to major vessels, such as the common hepatic and splenic arteries. Resection of the involved arteries can increase resectability and thus might increase post-operative survival. The aim of this study was to clarify the importance of the Appleby operation for carcinoma of the body and tail of the pancreas. A Case Report was carried out with a 54 year-old man, had suffered back pain and loss of body weight for six months. Imaging procedures such as US, CT or angiography showed a carcinoma in the body of the pancreas, about 3 cm in size, and both the common hepatic and splenic arteries were invaded by the tumor. The Appleby operation was used for this patient, since firstly there was no invasion to the head of the pancreas, secondly neither the proper hepatic artery nor the SMA was involved, thirdly the root of the CA was free of carcinoma, and finally because clear pulsation of the proper hepatic artery could be felt one or two minutes after occlusion of the CHA, which indicated that resection of the CHA would not lead to hepatic ischemia. The postoperative course was uneventful. His appetite recovered well and his body weight increased to the level before the disease. The patient was relieved from back pain and has returned to work 18 months after the operation, although he had a local recurrence eight months after the operation. In addition, eleven cases with carcinoma of the body and tail of the pancreas were used for a literature review. The average survival time after the Appleby operation is 6.6 months, and four patients are still alive. One patient has survived 13 years after the operation. It was concluded that although the prognosis after Appleby procedure is still not satisfactory that this operation can at least offer patients a better quality of life.

Renal cell carcinoma of the spindle cell type with metastasis to the pancreas: a case report.

We report a case of renal cell carcinoma in a 49-year-old man with multiple metastases, including some to the pancreas which were initially diagnosed as primary pancreatic carcinoma. The first clinical manifestation was jaundice caused by a large metastatic lymph node. Computed tomography showed tumors in the body and tall of the pancreas as well as in the left kidney. Angiography showed that all of the lesions were hypervascular. The patient was finally diagnosed as having renal cell carcinoma. Cholecystectomy and choledochojejunostomy were performed. Intraoperative biopsy of the lymph nodes along the common hepatic artery showed spindle cell carcinoma which was compatible with renal cell carcinoma. Since renal cell carcinoma with pancreatic metastasis is rare, special attention should be paid to its differentiation from primary pancreatic carcinoma in patients with tumors in both the pancreas and kidneys.

Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein.

BACKGROUND: The significance of preserving the spleen has recently been shown. However, there are few reports of spleen-preserving distal pancreatectomy for lesions of the body and tail of the pancreas, and this procedure is not generally performed. The aim of this study was to clarify the technique and indications for spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein for benign lesions of the distal pancreas. METHODS: Four patients (two each with an endocrine tumor and a cystic lesion) underwent the procedure. We also performed the spleen-preserving Puestow's procedure with removal of the tail of the pancreas in a 22-year-old male patient with familial chronic pancreatitis. An important technique is to remove the splenic vein from the pancreas from the body of the pancreas toward the spleen and to remove the splenic artery from the pancreas in the other direction. The splenic vein is identified behind the pancreas and within the thin connective tissue membrane, which is cut longitudinally above the splenic vein. It is important to remove the splenic vein from the pancreas from the body of the pancreas toward the spleen, because it is very difficult to remove it in the other direction. There are many branches from the splenic vein on both sides; these branches should be carefully ligated and cut. The pancreas is removed from the splenic artery from the spleen toward the head of the pancreas. This procedure is much easier than removal of the pancreas from the vein. RESULTS: The postoperative course was uneventful in four of the five patients. A pancreatic fistula remained in one patient for several weeks. The mean and standard deviation of the operative blood loss, the duration of the operation, and the postoperative hospital stay in the four uneventful cases, excluding the one in which Puestow's procedure was performed, were 600 +/- 479 ml, 290 +/- 48 minutes, and 40 +/- 21 days, respectively. No severe complications occurred in any of the five patients. CONCLUSIONS: Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein is easy and safe and should be performed for benign lesions of the distal pancreas.

A new method of duodenum-preserving subtotal resection of the head of the pancreas based on the surgical anatomy.

BACKGROUND/AIMS: Duodenum-preserving resection of the head of the pancreas has been performed for benign and, sometimes, malignant diseases of the pancreas. We propose a new procedure of duodenum-preserving subtotal pancreatectomy of the pancreas according to the precise anatomy of the pancreatoduodenal region, especially of the pancreaticoduodenal arteries which provide blood to the duodenum. MATERIAL AND METHODS: After a complete Kocher's maneuver is performed, the pancreas is cut above the portal vein and removed from the third portion of the duodenum, followed by the removal of the posterior surface of the pancreas head from a connective tissue membrane. The main pancreatic duct is identified at its junction with the terminal portion of the bile duct from the posterior surface of the head of the pancreas and is cut at the junction. The pancreas is cut in the line of the ASPD. This line is almost the same as the left side of the common bile duct. The ASPD and the common bile duct should be preserved in this procedure. RESULTS: The reason for leaving part of the pancreas between the duodenum and the anterior superior pancreaticoduodenal artery and the common bile duct is that the artery toward the papilla of Vater runs along the right side of the common bile duct and would be difficult to be preserved with the removal of this part of the pancreas. The most important technique of this procedure is in keeping the connective tissue membrane of the posterior surface of the pancreas intact so as to preserve pancreaticoduodenal arteries and veins, because all the pancreaticoduodenal arteries and veins are situated on this membrane. Complete Kocher's maneuver should cause no problem in this procedure. CONCLUSIONS: Benign lesions as well as low-grade malignancy of the head of the pancreas may possibly be the indication of this procedure.

Clinicopathological characteristics and surgical procedures for carcinoma of the papilla of Vater.

BACKGROUND/AIMS: In the present study, clinicopathological characteristics of carcinoma of the papilla of Vater and suitable operative procedures for treatment were investigated. MATERIAL AND METHODS: Sixty cases (40 male and 20 female) of resected carcinoma of the papilla of Vater were studied clinicopathologically. RESULTS: Among the patients, a polypoid type without ulceration and an ulcer-formation type, with regard to the gross appearance, were found in 37 cases and 23 cases, respectively. Submucosal invasion, invasion to the sphincter Oddi, pancreatic parenchymal invasion and lymph node involvement were found more frequently in the ulcer-formation type than in the polypoid type without ulceration. Postoperative survival curves revealed that the prognosis was poor when either lymph node involvement, invasion to pancreatic parenchyma or ulcer formation was found. Local resection was performed in seven cases, in all of whom carcinoma was found histologically in the cut surface of the tumor. This is easily explained by the fact that mucosal spread or interstitial infiltration was frequently found even in cases with carcinoma at a relatively early stage. CONCLUSIONS: Local resection for carcinoma of the papilla of Vater is inadequate as a curative resection, and pylorus-preserving pancreatoduodenectomy should be the treatment of choice for carcinoma of the papilla of Vater. However, since there were no differences between the postoperative survival curves of patients who underwent pancreatoduodenectomy or local resection, local resection may still be suitable for patients with other major diseases or a poor condition.

Different clinicopathologic findings in two histologic types of carcinoma of papilla of Vater.

The aim of this study was to investigate the differences between the clinicopathological findings in two histologic types of carcinoma of the papilla of Vater. We histologically classified carcinoma of the papilla into two types: 1) an intestinal type that resembles tubular adenocarcinoma of the stomach or colon, and 2) a pancreaticobiliary type that is characterized by papillary projections with scant fibrous cores. We examined 53 cases of resected carcinoma of the papilla. The intestinal-type carcinomas were similar to the intestinal mucosa in that they had lysozyme-containing, Paneth or argyrophil cells, as demonstrated by the immunohistochemically positive stainings for the anti-lysozyme antibody. Although both the sizes of the two types of carcinomas and the age distributions of cases with the two types of carcinoma were almost the same, the prognosis of the cases with the intestinal type was much better than that of the cases with the pancreaticobiliary type. Histological lymph node metastasis was found significantly more often in the pancreaticobiliary type. This result was supported by the fact that small carcinomas of the intestinal type showed little or no invasion into the surrounding interstitium, as opposed to the pancreaticobiliary type, which had a strong infiltrative tendency. The pathogenesis of carcinoma of the papilla of Vater should be further evaluated, taking into consideration the existence of these two histologic types.