Oncology

Association between Helicobacter pylori infection and pancreatic cancer.

Raderer M. Wrba F. Kornek G. Maca T. Koller DY. Weinlaender G. Hejna M. Scheithauer W.
Department of Internal Medicine I, Vienna University Medical School, Austria.
PURPOSE: In order to determine whether infection with Helicobacter pylori might be associated with pancreatic adenocarcinoma, we performed a study to compare the H. pylori seroprevalence rate between patients with pancreatic carcinoma and matched control subjects. PATIENTS AND METHODS: Blood samples from 92 patients with histologically confirmed diagnosis of pancreatic adenocarcinoma admitted to our hospital between January 1994 and July 1995 were analyzed for the presence of IgG antibodies against H. pylori by a commercially available enzyme-linked immunosorbent assay. Thirty patients with gastric cancer, 35 patients with colorectal cancer, and 27 healthy volunteers served as controls. In addition to these serological analyses, tumor specimens from 20 patients with pancreatic adenocarcinoma were microscopically investigated for the presence of H. pylori. RESULTS: 65% of pancreatic cancer patients and 69% of those with gastric cancer were found to be seropositive, while only 45% of the other controls tested positive. Statistical analysis revealed no difference in seropositivity between the cohort of patients suffering from pancreatic and gastric cancer. The rate of seropositivity was more prominent, however, in pancreatic cancer patients when compared with those suffering from colorectal cancer combined with normal controls (p = 0.035), with an odds ratio of 2.1 (1.1-4.1). Microscopic evaluation of human pancreatic cancer specimens showed no evidence for the presence of H. pylori. CONCLUSION: Our data suggest an association between H. pylori infection and pancreatic cancer. Despite demonstration of a positive relationship and its physiological plausibility, larger prospective studies are needed to confirm our preliminary findings and to assess H. pylori as a potential carcinogenic risk factor.

Plasmacytoma of the gastrointestinal tract in Korea: higher incidence than in Japan and Epstein-Barr virus association.

Tomita Y. Ohsawa M. Hashimoto M. Qiu K. Yang WI. Park CI. Aozasa K.
Department of Pathology, Osaka University Medical School, Japan.
As a result of a systematic review of non-Hodgkin's lymphoma of the gastrointestinal tract (GI) at the Yonsei University, Seoul, Korea and the Osaka University, Osaka, Japan, we found an extramedullary plasmacytoma in 5 of a total of 78 cases (6.4%) in Korea and 1 of 136 cases (0.7%) in Osaka, which represents an approximately 9-fold difference in frequency. The presence of the Epstein-Barr virus (EBV) genome was examined in paraffin-embedded specimens from the 5 cases with GI plasmacytoma from Korea together with 17 patients collected by a nationwide study in Japan. There were no clinical findings suggestive of the presence of immunodeficiency in these Korean and Japanese patients. There were no prominent differences in the age distribution or sex ratio between the patients of the two countries. Histologically, the proliferation of mature plasma cells was almost monomorphous with occasional bi- or multinucleated forms. The immunohistochemistry revealed a restricted cytoplasmic expression of immunoglobulin light chain, kappa type in 8 cases and lambda type in 14. A polymerase chain reaction of preserved DNA from 4 Korean and 16 Japanese patients found that only 2, both Korean, were positive for EBV of subtype A. The difference in the frequency of EBV positivity between Korean and Japanese cases was significant (p < 0.05). In situ hybridization revealed positive signals in the nucleus of the tumor cells. IHC revealed that the tumor cells in these two cases were positive for latent membrane protein-1 and EB nuclear antigen-2, showing latent infection of EBV. These findings suggest a close association of EBV and Korean GI plasmacytoma, and might partly explain the remarkable number of cases in this country.

Clinical pilot study of intrahepatic arterial chemotherapy with methotrexate, 5-fluorouracil, cisplatin and subcutaneous interferon-alpha-2b for patients with locally advanced hepatocellular carcinoma.

Urabe T. Kaneko S. Matsushita E. Unoura M. Kobayashi K.
First Department of Internal Medicine, Faculty of Medicine, Kanazawa University, Japan. urabe@med.kanazawa-u.ac.jp
To evaluate the efficacy of methotrexate (MTX)-5-fluorouracil (5-FU), cisplatin (CDDP), and interferon-alpha-2b(IFN alpha-2b) combination therapy, we conducted a clinical pilot study in patients with locally advanced hepatocellular carcinoma (HCC). Sixteen patients, who had received no prior treatment for the HCC, with portal tumor thrombosis in the main trunk or in the major branch were enrolled in the study. IFN alpha-2b (3 x 10(6) units) was injected subcutaneously 3 times per week. After a bolus administration of MTX (30 mg/m2), CDDP (75 mg/m2) and thereafter 5-FU (750 mg/m2) were given weekly by intrahepatic arterial infusion. In 15 eligible patients, there were 1 complete response (CR) and 6 partial responses (PR) with a response rate of 46.7%. Median survival of the 15 patients was 7 months, and the 2-year survival rate of CR and PR patients was 57.1%. There was severe transient hematologic toxicity. More than grade 2 nausea/vomiting was noted in > 50%. In conclusion, the IFN alpha-2b combination chemotherapy demonstrated good response in patients with locally advanced HCC. This treatment should be tried in a controlled study.

A pilot study on intensive weekly 24-hour intra-arterial infusion with 5-fluorouracil and folinic acid for colorectal liver metastases.

Lorenz M. Staib-Sebler E. Gog C. Petrowsky H. Kohne CH. Encke A.
Department of General Surgery, University Hospital, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
PURPOSE: A pilot study was performed to evaluate the tolerance and efficacy of a hepatic arterial infusion (HAI) of 5-fluorouracil (5-FU) and folinic acid (FA) in patients with unresectable liver metastases from colorectal carcinoma. PATIENTS AND METHODS: In 11 patients, 135 applications of high-dose HAI of 5-FU/FA were administered. All patients had been intra-arterially pretreated, and 2 of them had received an additional intravenous therapy. The chemotherapy regimen consisted of a weekly HAI of FA 500 mg/m2 over 1 h, immediately followed by HAI of 5-FU over 24 h. Four patients received a 5-FU starting dose of 2,000 mg/m2 and 7 patients of 2,400 mg/m2. One course consisted of 12 weekly applications interrupted by 1 week after 6 applications and 4 weeks after 12 applications. RESULTS: The applied regimen caused only mild side effects. Nausea and vomiting were the most frequently side effects with 36 episodes out of 135 applications (WHO grade > or = 3: 2 episodes). Diarrhea was a minor problem occurring with 8 episodes (WHO grade > or = 3: 1 episode). There was no evidence of myelosuppression, hand-foot syndrome, neurotoxicity, and biliary sclerosis. A partial remission was observed in 3 patients, and a disease stabilization in 2 patients while the disease progressed in 6 patients under high-dose HAI of 5-FU/FA. CONCLUSION: The present pilot study demonstrates that the weekly high-dose HAI of 5-FU/FA is well tolerated and associated with very mild toxicity. Because of the encouraging response rate in patients, whose disease progressed under the conventional intra-arterial therapy either with 5-FU/FA or 5-fluorodeoxyuridine, this regimen seems to be an effective second-line treatment and should be evaluated in nonpretreated patients in a phase II study.

Prognostic value of HLA-DR expression and dendritic cell infiltration in gastric cancer.

Ishigami S. Aikou T. Natsugoe S. Hokita S. Iwashige H. Tokushige M. Sonoda S.
First Department of Surgery, Kagoshima University School of Medicine, Japan.
We attempted to correlate the expression of human leukocyte antigen DR (HLA-DR) and tumor infiltration by S-100-protein-positive dendritic cells with clinicopathologic features in 165 patients with gastric cancer. The expression of HLA-DR was correlated with the histologic type. Infiltration of dendritic cells correlated negatively with distant lymph node metastases, clinical stage, and peritoneal invasion. There was no correlation between the expression of HLA-DR and infiltration by dendritic cells. In patients with resectable gastric cancer, the grade of infiltrating dendritic cells may be a suitable predictor of prognosis.

F1 alpha: a novel mucin antigen associated with gastric carcinogenesis.

Yamashita Y. Chung YS. Sawada T. Horie R. Saito T. Murayama K. Kannagi R. Sowa M.
First Department of Surgery, Osaka City University Medical School, Japan.
In a previous study, we obtained a novel monoclonal antibody (F1 alpha-75) directed against a synthetic mucin antigen termed F1 alpha, and demonstrated that this antigen was expressed in a high percentage (80.2%; 89/111) of gastric carcinomas. In the present study, we compared the expression of F1 alpha with that of sialyl-Tn antigen, a mucin antigen similar to F1 alpha, in 54 human early gastric carcinomas, intestinal metaplasia and adenomatous polyps of the stomach to determine how differences in the expression of these antigens correlated with gastric carcinogenesis. The rate of expression of F1 alpha in early gastric carcinoma tissues, 81.5%, was higher than that of sialyl-Tn antigen, 57.4%. No correlation was found between the rate of expression and histological type, depth of cancerous invasion or lymph node metastasis. Sialyl-Tn antigen was extensively expressed in 77.5% of specimens of complete intestinal metaplasia and in 78.6% of those of incomplete intestinal metaplasia; however, the expression of F1 alpha in those specimens was rare and sporadic, with rates of only 25.0 and 27.7%, respectively. In adenomatous polyps, the rate of expression of F1 alpha is 6.25% and that of sialyl-Tn antigen is 43.8%. Our findings indicate that F1 alpha is a more specific antigen for gastric cancer than sialyl-Tn antigen, and that F1 alpha is an antigen associated with carcinogenesis of the stomach.

Molecular genetics and clinical-pathology features of hereditary nonpolyposis colorectal carcinoma (Lynch syndrome): historical journey from pedigree anecdote to molecular genetic confirmation.

Year 1998
Lynch HT. Smyrk T. Lynch JF.
Creighton University School of Medicine, Omaha, Nebr. 68178, USA. htlynch@creighton.edu
Hereditary nonpolyposis colorectal cancer (HNPCC), also termed Lynch syndrome, was originally called cancer family syndrome. Historically, in 1913 Aldred Warthin, a pathologist, published a family, now known as Family G, which had features of HNPCC. It was first delineated as a hereditary cancer syndrome in the mid-1960s by Lynch. There was an apparent autosomal dominant mode of inheritance of colorectal cancer and certain integral cancers, the most prominent of which was endometrial carcinoma. Prior to the discovery in 1993 and 1994 of genes (hMSH2, hMLH1, hPMS1, hPMS2) known as mis-match repair genes or mutator genes, the diagnosis of HNPCC rested exclusively upon evaluation of clinical findings in concert with a well-documented and extended pedigree. Thus, this disorder has evolved from a medical curiosity into a clinical syndrome wherein molecular biologists provided proof of its hereditary status. These discoveries should aid in elucidating its pathogenesis and carcinogenesis and in the next decade we likely will learn more about chemoprevention and surgical prophylaxis of HNPCC.

Diagnosing and staging of pancreatic carcinoma-what is necessary?

Year 1998
Bottger TC. Boddin J. Duber C. Heintz A. Kuchle R. Junginger T.
Department of Surgery, Johannes Gutenberg University, Mainz, Germany.
The aim of the present prospective observational study was to diagnose and stage pancreatic carcinoma with a minimum of diagnostic procedures. Our experiences in 307 patients with a histologically confirmed pancreatic carcinoma show that for diagnosing pancreatic carcinoma sonography and computed tomography are sufficient in 95% of the cases. The combination of both has a sensitivity equal to that of endoscopic retrograde cholangiopancreatography (ERCP; 96.8 vs. 98.7%; n.s., chi2 test). ERCP is only indicated in cases with negative sonography and computed tomography, and suspicion of pancreatic cancer. For tumor staging, the routine performance of angiography cannot be recommended in view of the fact that although it provides greater sensitivity for the evaluation of an infiltration of the portal vein (80% for angiography vs. 22% for sonography or computed tomography), it is associated with a lower positive predictive value (56.4 vs. 68 and 72%) which results in a lower accuracy. Despite recent advantages in diagnostic technology, less than 50% of unresectable tumors were identified preoperatively at a 10% false-positive rate. The major reason for unresectability is infiltration into the mesenteric axis, which cannot be identified laparoscopically. Laparoscopy or percutaneous biopsy is recommended only in the presence of a tumor with suspicion of distant metastasis detected by radiological imaging and requiring histological confirmation. In conclusion, sonography and computed tomography as the only diagnostic images are sufficient for diagnosing and staging of pancreatic carcinoma in more than 95% of the patients. Only a small number of patients needs further diagnostic procedures.

Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil: pharmacokinetic studies.

Year 1998
Jacquet P. Averbach A. Stephens AD. Stuart OA. Chang D. Sugarbaker PH.
The Washington Cancer Institute, Washington Hospital Center, Washington, DC 20010, USA.
PURPOSE: The purpose of this study was to report the pharmacokinetics of heated intraoperative intraperitoneal mitomycin C (MMC) and to analyze the impact of heat, extent of peritoneal resections, and effect of intraoperative hyperthermic chemotherapy on the pharmacological properties of the peritoneal plasma barrier. METHODS: Sixty patients with peritoneal carcinomatosis were included in a phase I/II study combining cytoreductive surgery with 2 h of heated intraperitoneal mitomycin C in an intraoperative lavage technique and one cycle of early postoperative 5-fluorouracil (5-FU) given on postoperative days 1-5. Three pharmacokinetic analyses were performed: (1) pharmacokinetics of heated intraoperative intraperitoneal MMC was determined for 18 patients by sampling peritoneal fluid, plasma, and urine during the 2-h procedure; (2) impact of peritoneal resections on MMC pharmacokinetics was assessed by comparing a group of patients who underwent < or = 1 peritonectomy procedure (minimal surgery) to a group of patients who underwent > or = 2 peritonectomy procedures (extensive surgery), and (3) effects of heated intraoperative intraperitoneal chemotherapy on the pharmacokinetics of early postoperative intraperitoneal 5-FU by comparing a group of patients treated with heated intraoperative intraperitoneal MMC to a control group who did not receive heated intraoperative intraperitoneal chemotherapy. RESULTS: The mean dose of heated intraoperative intraperitoneal MMC per patient was 22.5+/-7.1 mg (12.9+/-3.8 mg/m2). Drug absorption from perfusate was 14.3+/-2.7 mg. The mean aeras under the curve (AUC) for perfusate and plasma were, respectively, 340+/-138 and 15+/-4 microg/ml x min. The mean AUC peritoneal fluid/plasma ratio was 23.5+/-5.8. Patients who underwent extensive peritoneal resections exhibited a significantly (p = 0.037; Wilcoxon rank test) increased peak plasma concentration of MMC, a significantly (p = 0.029) increased AUC of plasma concentrations and a significantly (p = 0.034) decreased peritoneal fluid/plasma AUC ratio. Pharmacokinetic studies of early postoperative intraperitoneal 5-FU showed no significant difference in plasma AUC, perfusate AUC and AUC ratio between patients who received and those who did not receive heated intraoperative intraperitoneal MMC. CONCLUSIONS: Heated intraoperative intraperitoneal chemotherapy achieves high peritoneal concentrations of MMC with limited systemic absorption. Systemic drug absorption during heated intraoperative intraperitoneal chemotherapy is increased when extensive peritoneal resections are performed, but such slight increases are unlikely to change the risk of systemic drug toxicities. Heated intraoperative intraperitoneal chemotherapy does not alter the pharmacokinetics of early postoperative intraperitoneal 5-FU.

Cyclin D1 overexpression and prognosis in colorectal adenocarcinoma.

Year 1998
Maeda K. Chung Y. Kang S. Ogawa M. Onoda N. Nishiguchi Y. Ikehara T. Nakata B. Okuno M. Sowa M.
First Department of Surgery, Osaka City University Medical School, Japan.
Recently, it has been reported that cyclin D1 plays a major role in oncogenesis in various cancers; however, there have been few studies on the association of cyclin D1 overexpression and prognosis of patients with malignant tumors. We evaluated the prognostic significance of cyclin D1 overexpression in colorectal adenocarcinoma. One hundred twenty-three specimens resected from patients with colorectal adenocarcinomas were investigated by staining with a monoclonal antibody against cyclin D1. As a result, both overall survival and disease-free survival were significantly poorer in the patients with tumors strongly positive for cyclin D1 than in those with cyclin-D1-negative or weakly positive tumors. The 5-year survival rate of the patients with tumors strongly positive for cyclin D1 was 53.3%, while the 5-year survival rates of patients with cyclin-D1-negative and weakly positive tumors were 96.2 and 78.8%, respectively. Moreover, multivariate analysis indicated that cyclin D1 overexpression is an independent predictor of disease recurrence in our patients. In conclusion, cyclin D1 overexpression may be useful as a predictor of disease recurrence in colorectal adenocarcinoma.

Prognostic relevance of MMP-2 (72-kD collagenase IV) in gastric cancer.

Year 1998
Allgayer H. Babic R. Beyer BC. Grutzner KU. Tarabichi A. Schildberg FW. Heiss MM.
Department of Surgery, Klinikum Grosshadern, Ludwig Maximilians University of Munich, Germany.
The association of MMP-2 (matrix metalloproteinase 2, 72-kD collagenase IV) with invasive and metastatic capacity of tumor cells has implicated a potential role in the prognosis for cancer patients. However, no larger study has been done to prove this hypothesis. The present study was therefore designed to investigate the prognostic impact of MMP-2 in a prospective series of 203 gastric cancer patients. MMP-2 expression was measured immunohistochemically and scored semiquantitatively (score 0-3) in carcinoma cells, and results were correlated with clinicopathological tumor parameters and parameters of the urokinase-type plasminogen activator (uPA) system. Survival analyses were done using the Kaplan-Meier method (log-rank statistics) and multivariate Cox analysis. Significant correlations were found for MMP-2 and Lauren's classification, M stage and proteases/inhibitors of the uPA system in the primary tumor. Kaplan-Meier analysis revealed an association of increasing MMP-2 expression with worse prognosis. This was especially seen in patients with a parallel high expression of uPA receptor. However, differences in survival probabilities between low and high MMP-2 levels were not significant. In a separate analysis of diffuse-type cancers, MMP-2 was significantly associated with disease-free (p = 0.0056) and overall survival (p = 0.0426). Multivariately, MMP-2 was not an independent parameter. Our results demonstrate that there is an association of immunohistochemical detection of MMP-2 with prognosis of cancer patients. For diffuse gastric cancers, it is a significant prognostic parameter, however, not of independent impact. The study further suggests that consideration of interrelated tumor-associated proteases like uPA receptor in combination with MMP-2 may improve its prognostic power.

Mucosal squamous cell carcinoma of the esophagus: a clinicopathologic study of 30 cases.

Year 1998
Natsugoe S. Baba M. Yoshinaka H. Kijima F. Shimada M. Shirao K. Kusano C. Fukumoto T. Mueller J. Aikou T.
First Department of Surgery, Kagoshima University School of Medicine, Japan.
A clinicopathologic study was carried out on 30 patients with mucosal esophageal cancer (MEC). The depth of cancer invasion was subdivided histologically into three categories: m1 = carcinoma in situ (intraepithelial carcinoma) or carcinoma with questionable invasion beyond the basal membrane; m2 = cancer invasion confined to the lamina propria, and m3 = cancer reaching to or infiltrating into the muscularis mucosae. Lymph node metastases and lymphatic invasion were found only in the tumors reaching or infiltrating the muscularis mucosae (m3). The maximum histologic vertical extent of the tumors was more than 1 mm in 4 of 5 patients with lymph node metastasis or lymphatic invasion. None of the patients died of recurrent esophageal disease, and 3 of the 6 patients who had a second primary tumor died of this other malignancy. It is critical to distinguish between m1, m2 and m3 tumors to plan a treatment strategy, including an endoscopic mucosal resection.

Expression of insulin-like growth factor-2 can predict the prognosis of human colorectal cancer patients: correlation with tumor progression, proliferative activity and survival.

Year 1998
Kawamoto K. Onodera H. Kondo S. Kan S. Ikeuchi D. Maetani S. Imamura M.
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Japan.
Expression of insulin-like growth factor-2 (IGF-2) has been reported in tissue specimens and cell lines of human colorectal cancers. However, the effects of IGF-2 in colorectal cancer patients are not well known. In this study, IGF-2 staining was performed on tissue samples from 92 patients with colorectal cancer, and the relationship of IGF-2 staining to clinicopathological variables, proliferating cell nuclear antigen (PCNA) staining and patient survival was analyzed. IGF-2 staining was correlated with tumor progression, PCNA staining and patient survival. Our results suggest that IGF-2 plays an important role in tumor progression and that IGF-2 staining is useful as a prognostic factor in colorectal cancer patients.

Comparative survival analysis of p53 gene mutations and protein accumulation in colorectal cancer.

Year 1998
Caldes T. Iniesta P. Vega FJ. de Juan C. Lopez JA. Diaz-Rubio E. Fernandez C. Cerdan J. Balibrea JL. Benito M.
Servicio de Immunologia, Hospital Universitario San Carlos, Madrid, Espana.
Immunohistochemical reactivity for p53 protein is common in various human malignancies. Increased intracellular concentration of p53, which is frequently, but not systematically, related to p53 mutation, has been proposed to be associated with poor prognosis in some tumor types. In colorectal cancer, this significance is still a matter of debate. To directly investigate the relationship between prognosis and p53 alterations, we screened a series of 72 colorectal carcinomas for overexpression and mutation of the p53 gene. Mutations in exons 5-9 of the p53 gene were assayed by single-strand conformation polymorphism and direct DNA sequencing, whereas p53 protein accumulation was detected in 10-microm frozen tissue by immunostaining using 2 different monoclonal antibodies (PAb 1801 and DO7). Thirty-six tumors (50%) showed p53 overexpression. Nineteen of the 36 tumors which contained high levels of p53 protein were found to have missense point mutations. Using a multivariate survival analysis, stage, differentiation, p53 immunoreactivity and p53 mutation emerged as risk factors, but only the stage was significant. In univariate analysis, stage, differentiation and p53 immunoreactivity were significant prognostic indicators, while p53 mutation was at the borderline of significance.

Correlation between telomerase activity and DNA ploidy in gastric cancer.

Year 1998
Okusa Y. Shinomiya N. Ichikura T. Mochizuki H.
Department of Surgery I, National Defense Medical College, Tokorozawa, Saitama, Japan.
Telomerase has been reported to be activated in most immortal cells and human cancers. In the present study, we assessed the correlation between telomerase activity and cellular DNA ploidy level in gastric cancer. Telomerase activity was determined semiquantitatively using the telomeric repeat amplification protocol assay, a polymerase-chain-reaction-based assay, in surgical specimens of primary tumors obtained from 36 patients with gastric cancer. No correlation was observed between telomerase activity and the proliferating cell nuclear antigen labeling index. In contrast, a positive linear correlation was observed between telomerase activity and the DNA index (r = 0.59; p < 0.01). Tumor cells with aneuploid patterns showed higher telomerase activity than those with diploid patterns (27.6+/-5.8 vs. 5.8+/-1.1%; p < 0.01). Telomerase activity of tumors with liver metastases was significantly higher than activity of those without metastases (34.5+/-16.6 vs. 11.8+/-2.4; p < 0.05). There was a trend toward a lower survival rate in 9 patients with a telomerase activity of 20% or higher compared to 27 patients with telomerase activity lower than 20%. These results suggest that the telomerase activity of gastric cancer tissue may reflect the malignant potential of the tumor.