CD49d and CD49e induce cell adhesion-mediated drug resistance through the nuclear factor-κB pathway in Burkitt lymphoma.

Burkitt lymphoma (BL) is a highly aggressive form of non-Hodgkin's B-cell lymphoma. Currently, multi-agent chemotherapy regimens are being used to significantly improve cure rates and achieve complete remissions in BL patients. However, drug resistance can often occur within 6 months in BL patients, contributing to poor prognosis. Mounting evidence suggests that cell adhesion-mediated drug resistance (CAM-DR), caused by the interaction between the bone marrow microenvironment and tumour cells may play an important role in drug resistance to chemotherapy. However, the molecular mechanism underlying CAM-DR in BL has not been identified yet. In this study, we investigated the molecular mechanism responsible for CAM-DR in BL cells. We also examined the therapeutic targets of CAM-DR in BL cells and found CD49d and CD49e to be the important adhesion molecules involved. However, CD49a, CD49b, CD11a, CD29, CD18, and CD61 were not found to be associated with CAM-DR in BL cells. Furthermore, we clarified that CD49d- and CD49e-mediated CAM-DR could be attributed to an increase in the expression of B cell leukemia-xL (Bcl-xL) and survivin proteins, and a decrease in the expression of Bcl-2 associated X (Bax), Bcl-2 interacting mediator (Bim) and p53 upregulated modulator of apoptosis (PUMA) proteins via nuclear factor kappaB (NF-κB) activation. In addition, bortezomib was found to overcome CAM-DR in BL cells by inhibiting NF-κB. Thus, bortezomib may have potential clinical applications in the treatment of CD49d- and CD49e-mediated CAM-DR in BL patients.

Impact of intraperitoneal chemotherapy after gastrectomy with positive cytological findings in peritoneal washings.

BACKGROUND: There is no standard treatment available for gastric cancer patients whose sole 'non-curative factor' is positivecytological findings in peritoneal washings (CFPW). The aim of this study was to examine the safety, pharmacokinetics and efficacy for free intraperitoneal cancer cells of intraperitoneal chemotherapy with paclitaxel after gastrectomy with en bloc D2 lymph node dissection in cases of gastric cancer with positive CFPW. METHODS: Ten patients with gastric cancer who underwent gastrectomy and systemic lymphadenectomy with D2 dissection, without any other non-curative factors besides positive CFPW, were treated with early postoperative intraperitoneal paclitaxel. Intra-chemotherapeutic toxicity and operative complications were measured using NCI-CTC version 3.0. Intraperitoneal and plasma paclitaxel concentrations were measured using a high-performance liquid chromatographic assay. RESULTS: Grade 3/4 toxic effects included anemia (20%) and neutropenia (10%) that required no treatment. Operative complications were, for example, superficial surgical site infections (10%) that were treated with antibiotics. No viable cancer cells were observed in the intra-abdominal fluid 24 h after intraperitoneal administration of paclitaxel. The intraperitoneal/plasma area under the drug concentration-time curve ratio was 2,003.3:1. CONCLUSION: Intraperitoneal chemotherapy with paclitaxel is a safe and effective treatment modality for free intraperitoneal cancer cells.

Prospective randomized trial of short-term neoadjuvant chemotherapy for advanced gastric cancer.

BACKGROUND: We performed short-term neoadjuvant chemotherapy (s-NAC) to examine whether anticancer drugs can change the proliferative ability of cancer cells in gastric cancer patients. METHODS: Chemotherapy was performed for 72 h before gastrectomy in 63 gastric cancer patients. Patients were classed into four groups: Group F, 16 cases who received a single administration of 5-fluorouracil (5-FU); Group C, 15 cases who received a single administration of cis-diamminedichloroplatinum (CDDP; cisplatin); Group FC, 16 cases who received both 5-FU+CDDP; and a Control group, 16 cases who did not receive chemotherapy. We reviewed neoadjuvant biopsy tissue and gastric cancer tissue delivered by operation in these cases. The TUNEL method and immunohistochemistry with an anti-MIB-1 antibody were used to evaluate cellular apoptosis and proliferative ability, respectively. The apoptotic index (AI) and an MIB-1 index (MI) were also calculated. RESULTS: There were no differences in AI or MI in biopsy tissue between the groups. The AI of gastric cancer tissue in Group FC was significantly higher than in the other groups (P < 0.01). The MI of Group FC was significantly lower than in the other groups (P < 0.05). In addition, after s-NAC operation there was a significant inhibition of proliferative potency and an induction of apoptosis in Group FC. CONCLUSION: Combination of CDDP and 5-FU reduced proliferative potency and increased cellular apoptosis in gastric cancer cells.

Esophageal cancer after distal gastrectomy.

The effect of gastrectomy on the subsequent development of esophageal cancer was investigated. Duodenogastroesophageal reflux is thought to be common in patients after distal gastrectomy, but whether this contributes to the development of esophageal cancer in such patients is controversial. We retrospectively evaluated 153 patients who underwent subtotal esophagectomy for thoracic esophageal cancer between January 2002 and July 2005. They were divided into two groups, according to whether or not they had previously undergone a gastrectomy: group 1, comprising 14 patients who had undergone gastrectomy and group 2, comprising 139 patients who had not. Clinical profiles of the patients were obtained from the medical records and the whole resected esophagus was histopathologically examined. The interval between gastrectomy and esophagectomy in group 1 was significantly shorter in the patients who had undergone gastrectomy for gastric cancer (10.5 +/- 4.2 years) than in those who had undergone gastrectomy for a peptic ulcer (28.9 +/- 3.0 years). The interval was also somehow shorter in the patients for whom anastomosis had been performed by Billroth I (21.3 +/- 5.6 years) compared with Billroth II (29.7 +/- 3.2 years), although the difference did not reach its statistical significance (P = 0.11). Moreover, the proportion of lower third tumors in patients after gastrectomy was significantly higher compared with that of the patients with intact stomach. These findings suggest that a history of gastrectomy is associated with more lower-third squamous cell esophageal carcinoma.

Massive bleeding from multiple jejunal diverticula associated with an angiodysplasia: report of a case.

We report herein the case of a 70-year-old woman who presented with massive bleeding from multiple jejunal diverticula. She was initially admitted to our hospital with massive melena. An upper gastrointestinal endoscopic examination revealed no bleeding site. Colonoscopy revealed clotted and red blood throughout the colon, and a small diverticulum in the ascending colon which was thought to be the source of bleeding. Following admission, she was treated conservatively at first, but melena continued and the anemia did not improve despite blood transfusions. A laparotomy was performed and multiple jejunal diverticula, distributed from 10 to 40 cm distal to the ligament of Treitz, were found. A segment of the jejunum containing all diverticula was resected. The most distal diverticulum contained a clot of blood, but no ulceration was observed. A histological examination revealed many dilated blood vessels in the mucosa and submucosa of this diverticulum, which were compatible with the findings of angiodysplasia. Based on these findings, we believe that angiodysplasia was the cause of bleeding from the jejunal diverticula in this case.

Complete regression of recurrent esophageal carcinoma with reduced expression of glutathione S-transferase-pi by treatment with continuous infusion of 5-fluorouracil and low-dose cisplatin infusion.

The mortality rate of recurrent esophageal carcinoma remains high because of its resistance to chemotherapy and radiation therapy. We present a patient with recurrent esophageal carcinoma, which dramatically disappeared after treatment with the combination of continuous infusion of 5-fluorouracil and low-dose cis-Diamminedichloroplatinum-II (cisplatin) infusion (FP therapy). Furthermore, we immunohistologically found that glutathione S-transferases (GST)-pi, a marker of resistance to cisplatin, was faintly expressed both in the endoscopical biopsy specimens of recurrent tumor and in the resected specimens of esophageal carcinoma and metastatic lymph nodes. FP therapy was suggested to be effective for recurrent esophageal carcinoma. Immunostaining for GST-pi might be a prospective marker for the sensitivity of esophageal carcinoma to FP therapy, particularly cisplatin.

Infantile myofibromatosis of the triceps detected by prenatal sonography.

A routine prenatal sonographic examination at 36 weeks' menstrual age revealed a solid and slightly inhomogeneous soft-tissue tumor on a fetus's left upper arm. The mass in the left triceps brachii muscle measured 8 x 7 x 5 cm at birth. Because of progressive flexion contracture of the left elbow joint, at 2 months of age the infant underwent radical resection of the tumor, sparing some muscle fibers. Light microscopic and immunohistochemical studies revealed myofibromatosis. Neither tumor nor functional disorder of the arm was evident 3 years after surgery.

Expression of manganese superoxide dismutase in esophageal and gastric cancers.

The tumor-killing activity of radiotherapy and chemotherapy for cancer is closely associated with the production of active oxygen, and the relation between therapeutic resistance and active oxygen scavengers produced by the tumor itself is gaining more attention. It is considered that manganese superoxide dismutase (MnSOD) protects host cells from oxidative stress, in synergy with other antioxidant enzymes. In this study, we used a quantitative polymerase chain reaction assay to measure MnSOD mRNA in resected specimens from patients with esophageal and gastric cancers. In both esophageal and gastric cancers, the level of MnSOD mRNA was significantly elevated in cancer tissue compared to non-cancer tissue (P < 0.01). In gastric cancer tissue, the MnSOD mRNA level was significantly higher than in esophageal cancer tissue (P < 0.01). The significance of MnSOD in cancer tissue was investigated further by measuring MnSOD content in resected specimens using an enzyme-linked immunosorbent assay, and by examining its location by an immunohistochemical method. Upregulation of MnSOD in cancer tissue most likely serves as a protective mechanism against anti-cancer therapies known to produce superoxide radicals as a key component of their tumor-killing activity.

[Effect of glucagon and insulin administration on the inhibition of rat liver regeneration by acute ethanol treatment after partial hepatectomy].

We studied the effects of glucagon and insulin (GI) administration on the inhibition of liver regeneration by acute ethanol treatment after partial hepatectomy (PH) in rats. When ethanol was given 1 hour before PH at 3 gm/kg body wt., [3H] thymidine incorporation into the hepatic DNA 24 hr after PH was significantly inhibited, but it was completely reversed by GI treatment. Although hepatic ornithine decarboxylase (ODC) activity in the ethanol-treated group 4 hr after PH was significantly inhibited, it was completely reversed by GI treatment. The putrescine (PUT) level in the liver 4 hr after PH was decreased by ethanol, but it was increased by GI treatment. At 12 hr after PH, ODC activity was not inhibited and PUT level in the liver was not decreased by ethanol. The levels of spermidine and spermine in the liver 4 hr after PH were unaffected either by ethanol or by GI treatment. Spermidine/spermine-N1 acetyltransferase activity in the liver 4 hr after PH was showed a tendency to increase by ethanol but it was decreased by GI treatment. Difluoromethylornithine, a specific inhibitor of ODC, decreased the level of PUT in the liver, and inhibited [3H] thymidine incorporation. The intraperitotneal administration of PUT significantly increased [3H] thymidine incorporation. The increase in ODC mRNA caused by pH was inhibited by ethanol, but it was completely reversed by GI treatment. SAT mRNA was affected neither by ethanol ner GI treatment. These results suggested that GI treatment was effective on the inhibition of liver regeneration by acute ethanol treatment, and activation of liver regeneration by GI treatment is closely related with ODC induction at the level of transcription.

An unusual presentation of congenital infantile myofibromatosis arising from the interspinous ligament.

The authors describe an extremely rare presentation of congenital infantile myofibromatosis. A full-term newborn boy presented with a thumb-sized subcutaneous mass on the mid-spinal line between the 2nd and 3rd lumbar spinous processes. A solid tumor arising from the interspinous ligament was resected. Microscopic and immunohistochemical studies revealed myofibromatosis.

Effect of vitamin E deficiency on inhibition of liver regeneration by long-term administration of alcohol.

The effects of vitamin E (VE) deficiency on liver regeneration suppressed by long-term administration of alcohol were studied. Male rats were divided into two groups: the alcohol group and the control group. In addition, each group was subdivided into two groups according to the presence or not of VE. Altogether, four groups were provided: a group maintained on the VE-deficient alcohol diet (group EA), a group maintained on the VE-deficient control diet (group EC), a group maintained on the ordinary alcohol diet (group A), and a group maintained on the ordinary control diet (group C). After pair-feeding for 6 weeks, partial hepatectomy was performed to determine the omithine decarboxylase (ODC) activity, polyamine levels, lipid peroxide levels, and DNA synthesis, DNA synthesis at 24 hr after partial hepatectomy was suppressed significantly in the alcohol administration group, regardless of the presence or not of VE DNA synthesis at 48 hr after partial hepatectomy tended to show low values in group EA, compared with group A. As for the hepatic ODC activity, group EA showed the lowest value at 4 hr after partial hepatectomy. Of polyamines, the putrescine level in group EA at 4 hr after partial hepatectomy was significantly low, compared with the other three groups. The levels of spermidine and spermine decreased by long-term administration of alcohol, but the effect of VE deficiency was not found. The lipid peroxide level increased significantly in the VE-deficient diet administration group, but the effect of alcohol administration was not found. These results suggested that the decrease in putrescine after ODC suppression by VE deficiency in addition to the decrease in spermidine and spermine caused by long-term alcohol administration were concerned with suppression of DNA synthesis later.

Giant purulent mesenteric cyst.

Infected intra-abdominal cystic lymphangiomas are very rare. We report a case of a purulent mesenteric cyst, histologically a cystic lymphangioma, w which developed in a 1-year-old girl who presented with marked abdominal distension and high fever. Magnetic resonance imaging revealed that the huge cystic lesion occupied the entire peritoneal cavity. It originated from the mesocolon. It was removed completely, and contained sticky pus at the base where the right fallopian tube penetrated it, which indicated the focus of infection. This may be the first report of a purulent mesenteric cyst in which the route of infection was suspected.

Calcification in carcinoma of the stomach: report of a case.

By upper gastrointestinal series, a 57 years-old woman was pointed out to have scattered calcifications along the greater curvature of the stomach. On computerized tomography, the calcifications distributed in the irregularly thickened gastric wall. With a diagnosis of calcified mucinous adenocarcinoma showing Borrmann type III, total gastrectomy with splenectomy was carried out. The characteristics of this lesion were briefly presented with a review of the literature.

Effect of combined alanine and glutamine administration on the inhibition of liver regeneration caused by long-term administration of alcohol.

We studied the effect of administration of a mixture of alanine and glutamine on the inhibition of liver regeneration caused by alcohol in rats undergoing partial hepatectomy 6 weeks after the start of alcohol administration. DNA synthesis was inhibited 24 hr after partial hepatectomy in rats given alcohol, but treatment with alanine and glutamine partially prevented this inhibition. To identify the mechanism of this effect, polyamine metabolism was studied. Administration of alcohol or alanine plus glutamine had no effect on the activity of ornithine decarboxylase, a rate-limiting enzyme of polyamine metabolism. In the liver, of the three polyamines, only the spermine concentration changed significantly. It decreased during long-term administration of alcohol, and this decrease was prevented by treatment with alanine and glutamine. The level of N(1)-acetylspermidine, the acetylated product of spermidine, was increased by alcohol, and its elevation was significantly less when alanine and glutamine were given. Hepatic spermidine/spermine N(1)-acetyltransferase, the key enzyme of polyamine acetylation, was induced by long-term administration of alcohol, and this induction was suppressed by alanine plus glutamine. The results suggest that treatment with alanine and glutamine can help to prevent the inhibition of liver regeneration caused by alcohol by maintaining the spermine level and suppressing the acetylation of spermidine.

[Blood leukotriene B4 response to endotoxin in fish oil fed rats].

Six-week-old male Wistar rats were given a low fat diet containing 15% cod liver oil (FO; n = 30) or 15% safflower oil (SO; n = 30) for 6 weeks. In the polymorphonuclear leukocytes, arachidonic acid (AA) was significantly lower in the FO group than in the SO group (p < 0.001), and eicosapentaenoic acid (EPA) in the FO group was present in large amounts showing the EPA/AA ratio of 1.76. When lipopolysaccharide (LPS; 10mg/kg) was intraperitoneally injected, white blood cell counts in the blood significantly decreased in both groups (p < 0.001) compared to the controls 2 hours later, and at 4 hours, the counts in the SO group (2,033 +/- 151/mm3) were lower than in the FO group (3,189 +/- 624/mm3), (p < 0.01). In both groups, leukotriene B4 (LTB4) in the whole blood increased at 4 hours following LPS-administration compared to the controls (1,219 +/- 167.3pg/ml in the SO group and 600.0 +/- 109.0pg/ml in the FO group, p < 0.001). It should be noted that the level of LTB4 in the SO group was significantly higher than in the FO group (p < 0.001). Changes of the metabolites including decreased LTB4 production in the arachidonic cascade related to the increase of EPA may play a role in the inhibition of the decrease in white blood cell counts.

Adenomyomatosis of the gallbladder: a clinical survey of 30 surgically treated patients.

Thirty patients with adenomyomatosis of the gallbladder (AMG) were operated on between January 1983 and June 1990. They were made up 3.3% of patients who underwent cholecystectomy during the same interval. Of the 30 patients, ages ranged from 22 to 77 years (mean 52.3 years) and the male-to-female ratio was 8:7. Among the macroscopic types, 10 cases of generalized, 12 of segmental (S) and 8 of fundal (F) were noted, and the size of the affected portion in type S (0.8 +/- 0.2 cm, mean +/- SD) was significantly thinner than in other two types (p less than 0.05). Although the main symptom was abdominal pain, the majority of patients with type F had no complaints. Twenty patients (27%) were accompanied by gallstones including cholesterol stones in 60% of cases, and all six cases showing microbes in the bile had gallstones. Only six patients were diagnosed as AMG by preoperative imaging techniques. Other diagnoses comprised 15 of chronic cholecystitis and 3 of suspected gallbladder carcinoma. To identify the expanded Rokitansky-Aschoff sinuses, endoscopic retrograde cholangiography and/or ultrasonography of the abdomen were most useful. No preponderant coexistent lesion other than gallstones was noted. Levels of carcinoembryonic antigen in gallbladder bile in cases of AMG (2.5 +/- 1.5 ng/ml, mean +/- SD) were significantly lower than in gallbladder carcinoma (p less than 0.01). All the patients were easily treated with cholecystectomy, and 24 patients who have been followed up after surgery are doing well.(ABSTRACT TRUNCATED AT 250 WORDS)

Reappeared pancreatic cyst after surgical treatment of cystic lesions of the pancreas.

An extremely high incidence of reappearing cyst of the pancreas (24.1%; 7 out of 29 patients) was noted in the present survey. However, reappearance could have been avoided in the majority of cases with the use of thorough pre- and peri-operative assessments of the extent of cystic lesion of the pancreas. The recurrence rate after surgical treatment for pseudocysts (13.6%; 3 out of 22 patients) was similar compared with usual recurrence rate of approximately 10 percent. If the reappearing cyst is a retention cyst or a pseudocyst, a minimally aggressive procedure should initially be considered to aid its resolution. A part of this study was reported at the 51st meeting of the Japanese Society for Clinical Surgery on November 2, 1989 at Kobe, Japan.

Induction and degradation of Zn-, Cu- and Cd-thionein in Chang liver cells.

Human liver cells (Chang liver) were exposed to 5 micrograms Zn, 2.5 micrograms Cu or 1 microgram Cd/ml in cultured medium. These exogeneous heavy metals were accumulated by the cells and induced de novo synthesis of metallothionein after a 3-h incubation period. The production of Zn-, Cu- or Cd-thionein started in the cells with accumulation of 1 nmol Zn, 0.3 nmol Cu and 0.1 nmol Cd/mg cytosol protein and subsequently the amounts of metal-binding thioneins increased in agreement with the relative amount of metal accumulated in the cytosol over a 24-h period. When cells containing Zn- or Cu-thionein were placed in metal free medium, 70% or 25% of the zinc or copper bound to each original metallothionein was released after 3 h; bound metals decreased to 85% and 65% respectively after 24 h. The disappearance of metal from metallothionein correlated with increases of metal in the medium. On the other hand, 35S-counts incorporated into Zn- and Cu-thionein decreased only to 40% and 15% of the levels in the original metallothionein after 3 h; 35S-counts decreased to 65% and 45%, respectively, after 24 h, indicating that metals bound to metallothionein decreased more quickly than 35S-counts. These results suggest that metals were released from metallothionein and were excreted into the medium. However, 35S- and 109Cd-counts in Cd-thionein changed very little, if at all, in the cells even after a 24-h incubation period. Our data strongly suggest that Zn- and Cu-thionein are degraded in the cells, but that Cd-thionein remains longer than either Zn- or Cu-thionein. When cells containing Zn-thionein were incubated in metal-free medium, Zn-thionein was digested in the cells and peptide fragments ranging about 200-400 daltons were excreted from the cells.