Spontaneously complete regression of pseudolymphoma of the remnant pancreas after pancreaticoduodenectomy.

BACKGROUND: Pancreatic pseudolymphoma is extremely rare. METHOD: We present multiple pseudolymphomas in the head and body of the pancreas. The hypoechoic lesions observed by endoscopic ultrasound were enhanced in late-phase angio-computed tomography and homogeneously hypointensive in T1-weighted magnetic resonance imaging (MRI). (18)F-fluorodeoxyglucose positron emission tomography showed strong accumulation in the lesions. The lesions were suspected to be non-functioning islet cell carcinoma. The intraoperative pathological diagnosis for the specimen obtained by a pylorus-preserving pancreaticoduodenectomy was non-neoplastic lymphoid cells. The remnant lesion in the pancreatic body was preserved. RESULTS: Macroscopically, the mass was well-circumscribed gray-white colored lesion. The pathological diagnosis was pancreatic pseudolymphoma. The lesion in the remnant pancreas spontaneously disappeared within one year after the operation. CONCLUSION: The differential diagnosis of pancreatic pseudolymphoma from malignant tumor is very difficult, however, the image findings demonstrated here may be informative. The spontaneous disappearance of pancreatic pseudolymphoma was firstly observed in the present case.

Comparison of clinicopathological characteristics of curatively resected pancreatic head and body/tail ductal cancers.

Few studies exist comparing the clinicopathological features between resectable pancreatic head (Ph) and body/tail ductal cancer (Pbt). Eighty consecutive patients with resectable tumors (Ph-56, Pbt-24) were analyzed. Tumor size was the only significant difference in clinicopathological factors between Ph and Pbt (Ph

Continuous infusion of 5-fluorouracil with versus without low-dose, consecutive administration of cisplatin in advanced colorectal cancer. A prospective randomized phase II study.

Recently, the treatment of advanced gastric cancer by continuous infusion of 5-fluorouracil (5-FU) with low-dose cisplatin (CDDP) has improved efficacy without severe toxicities. The possible effectiveness of 5-FU+low-dose CDDP for colorectal cancer (CRC) is intriguing. One hundred fifty-five patients with far-advanced CRC including at least one measurable lesion were enrolled in a prospective randomized clinical trial funded by the Japanese Foundation for Multidisciplinary Treatment of Cancer. These patients were assigned to the two arms to assess the value of low-dose CDDP when added to a continuous intravenous infusion of 5-FU at a dose of 300 mg/m(2)/24 hrs in a one-week cycle consisting of 5 days of treatment and 2 days of rest for at least 12 weeks. CD-DP was given intravenously at a dose of 3 mg/m(2) on days 1-5 and days 8-12, and then at a dose of 7 mg/m(2) twice a week. Three patients were excluded from the trial. The response rate in the 5-FU+low-dose CDDP arm (n=75) was significantly higher than that in the 5-FU arm (n=77) (25.3% vs. 11.7%; P = 0.037). There was no significant difference in the median overall survival time between the 5-FU+low-dose CDDP arm and the 5-FU arm (479 and 491 days, respectively). Grades 3/4 toxicities occurred infrequently in both arms. The quality of life was almost the same between the arms. Low-dose CDDP improved the response rate while keeping toxicities within clinically acceptable limits. However, this combined treatment did not confer a survival advantage over treatment with continuous infusion of 5-FU alone for patients with far-advanced CRC; that might be attributable to the short CDDP administration setting of 12 weeks.

Moderate neutropenia with S-1 plus low-dose cisplatin may predict a more favourable prognosis in advanced gastric cancer.

AIMS: The effects of haematological adverse events on the prognosis of patients with gastric cancer were investigated. MATERIALS AND METHODS: We retrospectively analysed the association between haematological adverse events and prognosis in 23 patients with far advanced or recurrent gastric cancer treated with a JFMC27-9902 regimen consisting of an oral fluorouracil derivative S-1 plus low-dose cisplatin. RESULTS: The patients who suffered grade 2-3 neutropenia (n = 10; median survival time [MST] 679 days) were found to have significantly more favourable prognoses than patients who developed grade 0-1 (n = 10; MST 271 days) or grade 4 neutropenia (n = 3; MST 408 days) (P = 0.0039 and 0.0112, respectively), although no significant differences were found among the clinicopathological factors of any grade groups. With respect to anaemia or thrombocytopenia, there were no significant differences among the MSTs of the groups stratified by toxicity grade. Multivariate survival analysis revealed that grade 2-3 neutropenia is an independent predictor of a more favourable prognosis (hazard ratio = 38.693, P = 0.0004). CONCLUSIONS: These results suggest that S-1 plus low-dose cisplatin against gastric cancer may contribute to long survival when it induces moderate neutropenia.

Transplatin, a cisplatin trans-isomer, may enhance the anticancer effect of 5-fluorouracil.

Transplatin (TDDP), a trans-isomer of cisplatin (CDDP), is well known to have faint cytotoxicity because its geometric structure allows less adduct formation with DNA than does CDDP. However, TDDP might have the potential to enhance the anticancer effect of 5-fluorouracil (5-FU) as well as CDDP. In this study, five gastric cancer cell lines were used. Cells were treated with 5-FU, TDDP, TDDP+5-FU, CDDP, and CDDP+5-FU, for 72 hrs. Synergistic effects between TDDP and 5-FU were observed in OCUM-2MD3, OCUM-2M, and OCUM-11, though they were not observed in MKN-45 or MKN-28. The cell lines in which synergistic effects were observed between TDDP and 5-FU were the same ones in which synergistic effects are shown between CDDP and 5-FU. The cell lines without synergism between 5-FU +TDDP/CDDP had lower thymidylate synthase (TS) activities than those with synergism, suggesting TS might be attributable to the synergistic mechanism. TDDP alone, compared to CDDP alone, gave rather low cytotoxicity for these cell lines. In conclusion, TDDP might be a clinically useful modulator of 5-FU.

Complete regression of low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in the gastric stump after eradication of Helicobacter pylori.

Recent studies have suggested that Helicobacter pylori (H. pylori)-associated gastritis may play an important role in the pathogenesis of primary gastric lymphoma. Recently, triple therapy using proton pump inhibitor, amoxicillin, and clarithromycin, has been established for the eradication therapy of H. pylori infection, and is also recommended for the treatment of the superficial type of low-grade gastric MALT (mucosa-associated lymphoid tissue ) lymphoma. MALT lymphoma of the gastric stump is rare, and total resection or chemotherapy for MALT lymphoma of the gastric stump has been previously reported. Therefore, there is no evidence that eradication therapy is effective for low-grade MALT lymphoma of the gastric stump. Our case illustrates the remarkable efficacy of eradication of H. pylori for low-grade MALT lymphoma of the gastric stump without other modalities such as surgery and systemic chemotherapy.

Evaluation of serum KL-6, a mucin-like glycoprotein, as a tumor marker for breast cancer.

The utility of serum KL-6 as a tumor marker for breast cancer was evaluated in this study. The sera from 146 patients with breast cancer, 13 with benign breast disease, and 108 healthy individuals were measured for KL-6 titer using a sandwich enzyme immunoassay method. Carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA15-3) titers were also tested in the same sera from the patients. The mean KL-6 titer of patients with primary breast cancer was 673 units/ml, which was significantly higher than that of benign and healthy individuals (P = 0.037 and P < 0.0001, respectively). The titer of patients with relapsed breast cancer was 1964 units/ml, which was also higher than that of primary cancer (P = 0.013). KL-6 titer was related to tumor stage, distant metastasis, and relapse site (P = 0.0053, P < 0.0001, and P = 0.0251, respectively). Using the cutoff value of 467 units/ml, the sensitivity of KL-6 was 31% for primary breast cancer (16% for stage I and 29% for stage II) and 73% for relapsed breast cancer (50% for local relapse and 89% for distant relapse). The specificity was 92%. The sensitivity of KL-6 was higher than that of CA15-3 and CEA. Combination of the three markers, followed by KL-6 and CEA, raised the sensitivity for primary breast cancer. Single use of KL-6 demonstrated a higher sensitivity than in each combination for relapsed breast cancer. In conclusion, serum KL-6 may be helpful for clinical use as a tumor marker for breast cancer, and it may play an important role, especially in the surveillance of disease relapse.

Expression of intercellular adhesion molecule-1 in invasive breast cancer reflects low growth potential, negative lymph node involvement, and good prognosis.

To understand the role of intercellular adhesion molecule-1 (ICAM-1) in tumor progression in the host, we examined ICAM-1 expression in breast cancer by immunohistochemistry. This study included 274 female patients with invasive breast cancer, with a median follow-up of 98 months. The molecule was identified in formalin-fixed, paraffin-embedded primary tumors, and the relationship to clinicopathological factors and prognosis was analyzed. ICAM-1 expression occurred in 50.3% of patients. ICAM-1 expression had negative correlation to tumor size (P = 0.003), lymph node metastasis (P < 0.0001), tumor infiltration (P = 0.003), nuclear pleomorphism (P = 0.004), and nuclear grade (P = 0.042). Patients with ICAM-1-positive tumors had better relapse-free and overall survival than those with negative tumors (P < 0.0001 and P = 0.0003, respectively). These results suggest that expression of ICAM-1 on cancer cells might have a role as a suppressor of tumor progression under the host immune surveillance system.

Clinical significance of serum soluble intercellular adhesion molecule 1 in gastric cancer.

We studied the correlation between serum soluble intercellular molecule 1 (sICAM-1) and clinicopathological features in patients with gastric cancer. The impact of sICAM-1 on prognosis was also evaluated. The sera from 224 patients with gastric cancer, 44 healthy individuals, and 35 patients with benign gastrointestinal diseases (4 patients with submucosal stomach tumors, 6 patients with gastric ulcers, 1 patient with Crohn disease, 2 patients with ulcerative colitis, 7 patients with gall stones, 5 patients with chronic pancreatitis, and 10 patients with liver cirrhosis) were measured for sICAM-1 titer using a sandwich enzyme immunoassay method. There was no correlation between the serum titer of sICAM-1 and the age or gender of healthy controls. Among patients with benign gastrointestinal diseases, the patients with liver cirrhosis had a significantly higher mean serum sICAM-1 titer than that of healthy controls (P < 0.0001). The mean serum sICAM-1 titer of all patients with gastric cancer was not significantly different from that of healthy controls. However, among the patients with stage IV and recurrent disease, the serum sICAM-1 titer of those with hematogenous metastasis was significantly higher than that of patients without hematogenous metastasis (P = 0.001). The patients with a high serum sICAM-1 titer of more than 304 ng/ml (mean of healthy controls plus SD) showed a significantly worse prognosis than patients with a low serum sICAM-1 titer (P = 0.010). Nevertheless, serum sICAM-1 titer was not an independent predictor of prognosis by multivariate analysis. In conclusion, serum sICAM-1 cannot be used as a tumor marker for early diagnosis. However, sICAM-1 in sera may still be worthwhile to measure for monitoring hematogenous metastasis.

Association between hsp60 messenger-RNA levels and Cisplatin resistance in human head and neck-cancer cell-lines.

Development of resistance to cisplatin (cDDP) is a major obstacle in the cure of many cancers. Recently, a cDNA from cDDP-resistant human ovarian carcinoma cells was identified as the mitochondrial hsp60 chaperonin. The aim of this study was to determine the changes in expression of hsp60 during selection for cDDP resistance in two head and neck cancer cell lines, UMSCC5 and UMSCC10b and whether the emergence of resistance could be correlated with the level of hsp60 expression. We have selected cDDP-resistant variants of two squamous cell carcinoma cell lines, the UMSCC5 and UMSCC10b with levels of resistance varying from 1.5 to 6-fold. Concomitant with the emergence of resistance, the basal level of hsp60 increased 2 to 3-fold. In addition, less cDDP resistance as well as lower hsp60 levels were detected in cDDP resistant variants of the UMSCC10b cell line when selected in the presence of tamoxifen, suggesting a correlation between the intrinsic level of hsp60 expression and cDDP resistance. Using linear regression analysis both UMSCC5 and UMSCC10b cell lines demonstrated a high degree of correlation with coefficients of 0.91 and 0.90, respectively. In conclusion, the expression of hsp60 was closely related to the development of cDDP resistance and could be used as a marker for the emergence of cDDP resistance.

Prediction of disease relapse in patients with breast cancer.

Among 157 breast cancer patients with median follow-up term of 120 months, we analyzed relationships of clinicopathologic factors and several prognostic factors determined histochemically with disease relapse, and we determined risk scores. Lymph-node status (p=0.0001) and microvessel count (MVC) (p=0.026) in all patients, p53 protein (p=0.0019) and MVC (p=0.001) in node-negative patients had independently significant prognostic value in predicting disease relapse. The risk scores based upon these factors had powerful predictive values for disease relapse (p=0.0001). Using these factors, we could simply and accurately identify patients with high-risk for relapse. Moreover, it might be useful for making decisions on adjuvant therapy.

mRNA levels of molecular chaperones hsp27, hsp60 and hsp70 in cisplatin resistant squamous cell carcinomas.

The relationship between cisplatin (cDDP) resistance and the expression of the molecular chaperonins hsp70, 60 and 27 was studied in two head and neck squamous cell carcinoma cell lines (UM-SCC-5 and UM-SCC-10B). The cDDP resistant variants were obtained by continuous exposure to escalating doses of cDDP. The IC(50)s of the parent and resistant variants (15th selection) of the UM-SCC-5 and UM-SCC-10b were 7.2+/-1.5 mu M and 20.1+/-1.2 mu M, and 6.5+/-0.6 mu M and 40.1+/-1.2 mu M, respectively. The emergence of cDDP resistance was closely related to the increase in basal expression of hsp60 (r=0.85 and 0.91 for UM-SCC-5 and UM-SCC-10B, respectively) resulting in a 2 to 3-fold increase in hsp60 mRNA in the cDDP resistant variants (15th selection). Expression of hsp27 was increased at higher levels of resistance in the UM-SCC-10B variants only (3 to 5-fold), and not in the UM-SCC-5 variants. In contrast to hsp60 and hsp27, the emergence of cDDP resistance did not lead to higher hsp70 mRNA levels. In addition, we determined the ability of cDDP resistant variants to induce the hsps 27, 60 and 70 in response to cDDP treatment. In the parental cell lines, hsp27 and hsp60 were all slightly increased after cDDP treatment (IC70 dose). However, only hsp60 could be induced in the resistant variants. In summary, emergence of cDDP resistance is associated with increased levels of hsp60 mRNA in the resistant variants and an inhibition of the transcriptional activity of hsp27 and hsp70.

Combined evaluation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2 expression in gastric carcinoma.

Urokinase-type plasminogen activator (UPA) is a serine protease implicated in cancer invasion and metastasis. There are at least two kinds of specific inhibitor which act on UPA: plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2). It has been reported that both UPA and PAI-1 antigen levels are associated with short survival in patients with breast cancer. In this study, we investigated the correlation between the expression of UPA, PAI-2 and prognosis in gastric carcinoma. One hundred and twenty specimens resected from patients with gastric carcinoma were investigated by staining with monoclonal antibodies against UPA and PAI-2. UPA positive rate was significantly higher in patients with liver metastases than in those without such metastases, There was no significant association between PAI-2 expression and clinicopathologic factors. However, patients with UPA-positive and PAI-2-negative tumors had more advanced cancer than other patients. According to the prognosis, the patients with UPA-positive and PAI-2-negative tumors had a significantly poorer prognosis than other patients. In conclusion, the combined evaluation of UPA and PAI-2 expression is associated with tumor progression in gastric cancer.

TGF-beta1 promotes liver metastasis of pancreatic cancer by modulating the capacity of cellular invasion.

We investigated the effect of TGF-beta1 on liver metastasis of pancreatic cancer using surgical specimens of pancreatic cancer and human pancreatic cancer cell lines Capan-2 and SW1990. Immunostaining of TGF-beta1 showed that TGF-beta1 positivity was significantly related to venous invasion and tumor staging, and also relatively associated with liver metastasis. Cellular invasion and protease production of MMP-2 and u-PA, and in vivo liver metastasis were significantly enhanced after treatment of cells with TGF-beta1. These findings suggest that TGF-beta1 might play an important role in enhancing liver metastasis of pancreatic cancer.

Prognostic predictive value of 18F-fluorodeoxyglucose positron emission tomography for patients with pancreatic cancer.

18Fluorine-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is a unique imaging diagnostic tool to evaluate glucose metabolism and hexokinase activity which may reflect the aggressiveness of a tumor. Thirty-seven patients with primary pancreatic cancer were evaluated with 18F-FDG-PET. Thirteen patients underwent resection for the pancreatic cancer and 24 patients had unresectable tumors. The standardized uptake values (SUV) of 18F-FDG in the primary tumors were calculated. No correlations were found between the SUV in the tumors and the metastatic status to the peritoneal/liver, TNM factors/stage, or resectability. The patients were divided into 2 groups with high and low SUV, with the cut-off value being 3.0 (median SUV value of 37 cases). No differences in the probability of survival were observed between the 2 groups in the patients with resectable tumors. However, in the patients with unresectable tumors, those in the high SUV group had a significantly shorter prognosis than those in the low SUV group. Moreover, a multivariate analysis of survival indicated that SUV is an independent prognostic factor for patients with unresectable pancreatic cancer.

Apoptosis and thymidylate synthase inductions by 5-fluorouracil in gastric cancer cells with or without p53 mutation.

We studied apoptosis and thymidylate synthase (TS) inductions by 5-fluorouracil (5-FU) in gastric cancer cells with wild-type p53 (MKN-45 and MKN-74) and with mutated p53 (MKN-28 and KATO-III). Apoptotic inductions in MKN-45 and MKN-74 were stronger than those in MKN-28 and KATO-III, suggesting that wild-type p53 may contribute to the induction of apoptosis. After continuous exposure to 0.1 microg/ml of 5-FU for 96 h, no TS induction was obtained in KATO-III, while approximately twice the amount of TS was observed compared to non-treatment cells in MKN-45, MKN-74, and MKN-28. The results of immunohistochemical staining for TS and p53 showed no relation between these two protein expressions in endoscopic biopsy specimens of 25 patients with advanced gastric cancer. These results indicated that p53 status may not play a pivotal role in regulating TS expression. We found no significantly different effects of 5-FU between intermittent (repeat of 24-h continuous infusion and 24-h drug-free) and continuous treatments in either MKN-28 or stem cells (CD34+ hematopoietic progenitor cells) when the same area under the time-concentration curve of 5-FU was administered. The TS induction in MKN-28 cells by intermittent treatment was significantly higher than that by continuous treatment; however, most TSs in both types of 5-FU treatment cells were of the inactive form, i.e., TS bound to FdUMP, a 5-FU metabolite. Therefore, neither intermittent nor continuous treatment appears to induce 5-FU resistance related to the level of increment free TS. In conclusion, our observations suggested that p53 mutation may be associated with apoptotic induction by 5-FU; however, p53 status may not strongly affect TS induction by 5-FU. Intermittent treatment can be replaced with continuous treatment without causing 5-FU resistance.

New radioimmunoassay for pancreatic cancer-associated antigen span-1 with reference to differential-diagnosis and monitoring in pancreatic-cancer.

Sera from patients with various malignant benign disorders, as well as from a large number of healthy blood donors (2197). were analyzed with a newly developed SPan-1 coated bead radioimmunoassay. Only 0.9% of the healthy patients had SPan-1 levels above the cut-off value. SPan-1 antigen levels were elevated in 89.2% of sera from pancreatic cancer patients and in 75% of T1 and T2 cancers. High diagnostic accuracy was also recognized in differentiating benign pancreatic diseases from pancreatic cancers. SPan-I levels decreased after pancreatic resection and rose again at recurrence of disease. SPan-1 could be distinguished from other tumor markers such as DU-PAN-2 and OC-125 by competition radioimmunoassays and was elevated in individuals with malignant gastrointestinal diseases who had normal levels of either or both CEA and CA 19-9 antigens. This rapid. reproducible and sensitive assay for SPan-I appears to be a useful procedure for the detection and follow-up of pancreatic cancer.

Comparison between a newly established pancreatic cystadenocarcinoma cell-line, ocup-1 and cells derived from pancreatic ductal carcinoma.

The prognosis of pancreatic cystadenocarcinoma is known to be relatively favorable, unlike poor prognosis of the majority of pancreatic cancers. However, little is known about the pathogenesis and mode of progression of this cancer. We report on a newly established pancreatic cystadenocarcinoma cell line, OCUP-1. Its characteristics were compared to those of cells derived from pancreatic ductal cell carcinoma. OCUP-1 was established by successive culture of cancer cells obtained during an operation for pancreatic cystadenocarcinoma. This cell line demonstrated mono-layered proliferation and a doubling time of 80.3 h, which was 2.1 to 5.3 times longer than that of six ductal cell carcinoma-derived cell lines. Cell cycle time agreed with the doubling time. Tumors could be produced in all nude mice by inoculating cells from the 6 different ductal cell carcinoma derived cell lines without pre-treatment. However, with OCUP-1 cell line inoculation, the nude mice had to be pre-treated with asialo-GM1 - an inhibitor of natural killer cell activity - for tumors to be produced. Although the newly established OCUP-1 cell line demonstrated low proliferative activity, its genetic characteristics (point mutation at codon 12) were similar to those of other cells derived from ductal cell carcinomas. The OCUP-1 cell line may be used to investigate the pathogenesis and progression of pancreatic cystadenocarcinomas.

Expression of the mismatch repair gene hMSH2 in sporadic colorectal cancer.

At least four genes involved in DNA mismatch repair (MMR), hMSH2, hMLH1, hPMS1 and hPMS2, have been cloned and characterized. These genes have been demonstrated to be altered in the germline of patients with hereditary non-polyposis colorectal cancer (HNPCC). HNPCC is an autosomal dominant disease characterized by a preponderance of proximal colon, young age of onset, increased multiplicity, and improved stage-specific survival. In this study, we examined the expression of hMSH2 protein in sporadic colorectal cancer (CRC). As a result, the frequency of right-sided CRC and multiple CRCs were significantly higher in the patients with hMSH2-negative CRC than in those with hMSH2-positive CRC. The rate of p53 positivity was significantly lower in the hMSH2-negative tumours than that in the hMSH2-positive tumours. The disease-free survival rate tended to be higher in the patients with hMSH2-negative CRC than in the patients with hMSH2-positive CRC. Our findings suggest that both the clinicopathological and biological features of hMSH2-negative sporadic CRC seemed to be similar to those of HNPCC. To clarify the mechanism of carcinogenesis in HNPCC and sporadic CRC, further investigations of genetic alterations caused by MMR genes will be needed.

TGF-beta1 produced by gastric cancer cells affects mesothelial cell morphology in peritoneal dissemination.

In vitro morphologic change of mesothelial cells was observed following the addition of serum-free conditioned medium (SF-CM) from peritoneal dissemination cell line OCUM-2MD3. The same morphologic change of mesothelial cells was observed following the addition of 10 ng/ml TGF-beta1, but not following the addition of b-FGF, IGF-I, VEGF or PDGF-AA. In the in vivo study, mesothelial cells of mice treated with SF-CM from OCUM-2MD3 and TGF- beta1 were separated from one another, resulting in exposure of the submesothelial connective tissue. The molecular size of the mesothelial morphology changing activity was estimated by running the SF-CM from OCUM-2MD3 through a gel filtration column TSK-gel G2000SW. The mesothelial morphology changing activity was recognized at positions equivalent of Mr 6, 500-30,000. 25 kDa TGF-beta1 was detected in the active fraction from the TSK-gel G2000SW column and the SF-CM of OCUM-2MD3 by Western blotting using a monoclonal antibody against TGF-beta1. These findings suggest that TGF-beta1 produced by gastric cancer cells changes the morphology of mesothelial cells and may thus be closely associated with peritoneal dissemination.