bluuebunny/crossref_metadata_2025 huggingface dataset:
Colon Cancers and Peritoneal Mesothelioma Occurring 29 Years after Abdominal Radiation for Testicular Seminoma
Authors: Tassile D. , Roth A.D. , Kurt A.M. , Rohner A. , Morel Ph.
Published: April 2003

Secondary malignancies represent an increasing problem for long survivors of primary malignancies treated by chemo- and/or radiotherapy. The occurrence of secondary myelodysplasia and leukaemias after treatment for Hodgkin’s disease is well established. Secondary solid tumors are mostly observed following radiation therapy. We report the case of a patient who presented 3 abdominal solid malignancies within 3 years, 29 years after abdominal radiotherapy for a testicular seminoma, namely 2 colon cancers and a peritoneal mesothelioma. Both types of cancer are independently reported in the literature to be more frequent in patients with a history of abdominal radiation than in the general population. To our knowledge there is no other reported case with 3, nearly simultaneously occurring separate solid tumors, which could all be related to former abdominal irradiation. Such a radiotherapy-related long-term side effect should be taken into account when considering adjuvant radiotherapy in patients with low-risk stage I testicular seminoma.
Curcumin Inhibits SK-Hep-1 Hepatocellular Carcinoma Cell Invasion in vitro and Suppresses Matrix Metalloproteinase-9 Secretion
Authors: Lin Liang-In , Ke Yuh-Fen , Ko Ya-Chen , Lin Jen-Kun
Published: April 2003

Curcumin (diferuloylmethane), widely used as a spice and coloring agent in food, possesses potent antioxidant, anti-inflammatory and anticarcinogenic properties. Recently, curcumin was further demonstrated to have an antimetastatic effect in mice. In this study, we attempted to clarify the possible mechanisms of this latter effect of curcumin. A highly invasive SK-Hep-1 cell line of human hepatocellular carcinoma (HCC) was selected for this study. An in vitro assay, without or with Matrigel matrix, was used to quantitate cellular migration and invasion. Gelatin-based zymography was adapted to assay the secretion of matrix metalloproteinase (MMP). We found that curcumin, at 10 µM, inhibited 17.4 and 70.6% of cellular migration and invasion of SK-Hep-1, respectively. Compared with a less invasive human HCC cell line, Huh-7, SK-Hep-1 showed a much higher MMP-9 secretion. Further, and parallel with its anti-invasion activity, curcumin inhibited MMP-9 secretion in SK-Hep-1 in a dose-dependent fashion. We conclude that curcumin has a significant anti-invasion activity in SK-Hep-1 cells, and that this effect is associated with its inhibitory action on MMP-9 secretion.
Expression of nm23-H1 Gene and Sialyl Lewis X Antigen in Breast Cancer
Authors: Yamaguchi Akio , Ding Kefeng , Maehara Masanori , Goi Takanori , Nakagawara Gizo
Published: April 2003

The nm23 gene has been proposed as a candidate tumor metastasis suppressor in some human cancers. Sialyl Lewis X (sLex) has been demonstrated to play an important role in the adhesion of human cancer cells to human vascular endothelium, inducing metastasis. Little information has been reported about the correlation between the expression of nm23 and sialylated carbohydrate antigens. In the present study, 102 surgically resected primary breast cancer tissues were sectioned and stained with antibody against nm23-H1 and sLex. Of the 102 cases, 39 (38.2%) cases with a reduced expression of nm23-H1 were observed, and the numbers of sLex-positive cases were 61 (59.8%), respectively. The reduced expression of nm23-H1 and the positive expression of sLex were significantly associated with lymph node involvement. Among the 100 patients who underwent curative surgery, the disease-free survival rate was significantly correlated to both the nm23-H1 and sLex expressions. No interrelated expressions were found between nm23-H1 and sLex. In multivariate analysis using Cox regression model, combination assay of nm23-H1 and sLex expression emerged as independent significant prognostic factors. These results suggest that nm23-H1 gene and sLex may be involved in different steps of the metastatic process in human breast cancer, and immunohistochemical detection of the combination of sLex and nm23-H1 may be a biologic marker of prognostic significance.
Amplification of the c-met, c-erbB-2 and Epidermal Growth Factor Receptor Gene in Human Gastric Cancers: Correlation to Clinical Features
Authors: Tsugawa Kouichiro , Yonemura Yutaka , Hirono Yasuo , Fushida Sachio , Kaji Masahide , Miwa Kouichi , Miyazaki Itsuo , Yamamoto Hiroshi
Published: April 2003

We examined amplification of the c-met, c-erbB-2, and epidermal growth factor receptor (EGFR) gene in the patients with primary gastric cancer, and compared the data with clinical features in order to clarify the relationship between oncogenic abnormality and clinical features. Oncogene amplifications were examined by slot blot hybridization using DNAs extracted from formalin-fixed and paraffin-embedded tissues of primary gastric cancers. Seven of the seventy cancers (10.0%) had c-met gene amplification, nine (12.9%) had c-erbB-2 gene amplification, and six (8.6%) had EGFR gene amplification, respectively. Eighteen cases (25.7%) exhibited one or multiple oncogene amplification, and two cases (2.9%) exhibited simultaneous amplification of the three genes. The cases with c-met gene amplification tend to show invasive character and were related to peritoneal dissemination. The cases with c-erbB-2 gene amplification were related to lymph node metastasis. The cases with EGFR gene amplification had large tumors and were in highly advanced stage. The survival rate in patients with oncogene amplification was significantly lower than that in patients without amplification. Our data indicated that these genes were related to growth and metastasis of gastric cancer. Furthermore, this study about the three genes suggested that the type of activated gene might decide on the type of metastasis and clinical features.
Clonal Composition of Malignant Fibrous Histiocytoma: Analysis by PCR-Based Assay of the Human Androgen Receptor Gene (HUMARA)
Authors: Fujita Masaki Q. , Hashida Noriyasu , Shin Masaru , Nakanishi Hirofumi , Yoshihara Wataru , Aozasa Katsuyuki
Published: April 2003

Malignant fibrous histiocytoma (MFH), the most common soft-tissue sarcoma, consists mainly of two different cell populations: histiocytelike and fibroblastlike cells. It has been suggested to contain a large amount of reactive histiocytes and fibroblasts hard to distinguish from the tumor cells. In this study, the clonality of MFH was determined by analyzing the patterns of X chromosome inactivation at the human androgen receptor gene (HUMARA) using DNA samples from archival snap-frozen and paraffin-embedded tissues. All the eleven informative female heterozygotes without severe inflammation showed the monoclonal pattern; 8 storiform-pleomorphic (6 distinct, 2 relative monoclonal pattern) and 3 myxoid (3 distinct monoclonal pattern) subtype. Although normal tissue DNA, amplifiable by the polymerase chain reaction, valid for the assay was not available in these cases, statistically at least 5 cases are monoclonal (p = 0.037 <0.05), even when markedly skewed lyonization were to primarily exist in the normal tissue at the highest rate as ever reported (33%). Experiments using the mixture of monoclonal and polyclonal DNA at varying ratios have suggested that a distinct monoclonal pattern is obtained only when the monoclonal component exceeds 80%. Our study demonstrates that most cells that are present in MFH are monoclonal in origin which may be the population of tumor cells.
Immunohistochemical Analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 Expression in Pancreatic Cancers
Authors: Miyamoto Yoshiharu , Hosotani Ryo , Wada Michihiko , Lee Jeon-Uk , Koshiba Takatomo , Fujimoto Koji , Tsuji Shouichirou , Nakajima Sanae , Doi Ryuichiro , Kato Masayuki , Shimada Yuta , Imamura Masayuki
Published: April 2003

Expression of several members of the Bcl-2 family proteins was investigated by means of both immunohistochemical analysis in 30 invasive ductal adenocarcinomas and 23 intraductal papillary-mucinous tumors (IPMTs) and immunoblot analysis in 6 cancer tissues and 7 pancreatic cancer cell lines. We found that Bcl-2 was expressed in 23%, Bax in 53%, Bcl-X in 90%, and Mcl-1 in 90% of the invasive ductal adenocarcinomas. In intraductal papillary-mucinous adenocarcinomas, the expression rate of Bax was 44% and those of Bcl-XL and Mcl-1 were 88%; these values were higher than those for intraductal papillary-mucinous adenomas. Immunoblot analysis identified Bcl-XL as the predominant form of the Bcl-X protein in both pancreatic cancer tissues and cell lines, and demonstrated that both Bcl-XL and Mcl-1 protein levels were uniformly high in all cell lines. These results suggest that an imbalance between antiapoptosis proteins (such as Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic proteins (such as Bax and Bcl-Xs) is involved in the distinctive biologic features of adenocarcinomas of the pancreas. Furthermore, predominantly high expressions of Bcl-XL and Mcl-1 in intraductal papillary-mucinous adenocarcinomas might be involved in the carcinogenesis in IPMT of the pancreas.
Human Small Cell Lung Cancer Cells Produce Brain Natriuretic Peptide
Authors: Ohsaki Yoshinobu , Gross Andrew J. , Le Phuong Tram , Oie Herbert , Johnson BruceE.
Published: April 2003

The tumoral production of brain natriuretic peptide (BNP) was studied using 9 small cell lung cancer (SCLC) cell lines which were established from patients with small cell lung cancer. BNP cDNA fragment was generated from 20 µg total RNA which was prepared from the human right cardiac atrium by reverse transcription-based polymerase chain reaction. Expression of BNP mRNA was detected in 30 µg total cellular RNA from these cell lines by RNase protection assays in 5 of 9 SCLC cell lines. Radioimmunoassays using 125I-radiolabeled human BNP(1–32) and antihuman BNP(1–32) antibody detected immunoreactivity in cell pellets from SCLC cell lines which had detectable BNP mRNA. BNP immunoreactivity in the cell pellets corresponds with the data from BNP mRNA analyses. We conclude that SCLC cells have detectable BNP mRNA by RNase protection assay and BNP immunoreactivity in the cells.
Flow Cytometry and Squamous Cell Carcinoma of the Maxillary Sinus: A Possible Prognostic Indicator for Multimodality Intervention
Authors: Halvorson David J. , Day Scott , Christian Jr. Don R. , Porubsky Edward S.
Published: April 2003

Malignant tumors of the paranasal sinuses constitute less than 1% of all malignancies. Unfortunately, few prognostic factors have been identified regarding the efficacy of interventional therapy. Patients with carcinoma of the maxillary sinus frequently present with an advanced stage of disease and multimodality therapy is often proposed. Although some tumors appear to be more sensitive to preoperative chemotherapy and radiation therapy, a method of predicting and evaluating tumor behavior has not been recognized. Introduced as a means of identifying cell populations with abnormalities in total DNA content, flow-cytometric DNA analysis provides a quick and reliable means of tumor characterization for many malignancies. Although nuclear DNA content has been implicated as a prognostic factor in an increasing number of tumor types, current data on the role of DNA content in head and neck carcinoma is conflicting and incomplete. To evaluate the role of flow-cytometric DNA analysis in predicting therapeutic alternatives, 22 patients with squamous cell carcinoma of the maxillary sinus were reviewed. Patient outcome and histopathologic grade were retrospectively compared with flow-cytometric evaluations of paraffin-embedded formalin-fixed tumor specimens. Four of sixteen tumors (25%) were found to be aneuploid and were also associated with an increased survival rate (p < 0.01). This initial data emphasizes the possible usefulness of DNA measurement for characterization of squamous cell carcinoma of the maxillary sinus and stresses the need for further evaluation.
A Phase I Study of Paclitaxel and Epirubicin, without and with Filgrastim, for the Treatment of Platinum-Resistant Advanced Ovarian Cancer
Authors: Lauria Rossella , Ferrari Ettore , Tramontana Sergio , Morabito Alessandro , Perrone Francesco , Maffeo Antonio , Fiorentino Roberto , Casella Gennaro , Iodice Francesco , Ricchi Paolo , Carlomagno Chiara , Varriale Elisa , De Placido Giuseppe , De Placido Sabino , Bianco Angelo Raffaele , Pignata Sandro
Published: April 2003

The aim of the study was to determine the maximum tolerated dose (MTD) of epirubicin combined with a fixed dose of paclitaxel, without and with support of filgrastim, in patients with platinum resistant or refractory ovarian cancer. Paclitaxel (150 mg/m2) and epirubicin (starting dose 90 mg/m2, 15 mg/m2 escalation per level) were given on day 1, every 28 days for 4–6 cycles. Filgrastim (F) (5 µg/kg/die) was given in case of grade 4 leukopenia (levels without support) or from day 4 up to leukocyte count >10,000/mm3 after nadir (levels with support). Cohorts of 3 patients were enrolled at each level and further 3 patients were planned if 1 or 2 unacceptable toxic events (UTE) were registered. MTD was determined first without and then with filgrastim. Four levels were studied (90, 90+F, 105+F, 120+F) with 4, 6, 5 and 4 patients enrolled, respectively. UTE (grade 4 neutropenia) were observed in 3 patients at level 1. Thus, 90 mg/m2 was the MTD for epirubicin without filgrastim. MTD of epirubicin with filgrastim was not reached at 120 mg/m2. Hematological toxicity was mild. Grade 3 mucositis was reported in 1 patient. Among the 14 patients with measurable or evaluable disease, 3 objective responses were observed (1 complete and 2 partial) for an overall response rate of 21.4%. The combination of paclitaxel 150 mg/m2 and epirubicin at 120 mg/m2 with filgrastim is a feasible therapy. Grade 4 leukopenia is the dose limiting toxicity using epirubicin at 90 mg/m2 without filgrastim.
Phase I Study of Cisplatin, Ifosfamide and Irinotecan with rhG-CSF Support in Advanced Non-Small Cell Lung Cancer
Authors: Fujita Akihisa , Takabatake Hirotsugu , Tagaki Shigeru , Sekine Kyuhichiro
Published: April 2003

A phase I study was conducted in advanced non-small cell lung cancer to determine the maximum tolerated dose (MTD) of irinotecan combined with a fixed schedule of cisplatin and ifosfamide with rhG-CSF support. In addition, efficacy including survival time was evaluated at 2 years after the completion of patient registration. Cisplatin (20 mg/m2) and ifosfamide (1.5 g/m2) were administered at fixed doses on days 1–4, and irinotecan was given on days 1, 8 and 15 starting at 40 mg/m2, which was increased in 10 mg/m2 increments. This regimen was repeated every 4 weeks. rhG-CSF was administered subcutaneously at a dose of 50 µg/m2 on days 5–18 except on the day of irinotecan treatment. Forty-five patients were registered and 35 had received no prior chemotherapy. MTD or irinotecan was defined according to toxicity and the dose during three courses was increased up to 70 mg/m2. The dose 60 mg/m2 was recommended for phase II study. The dose-limiting factor was thrombocytopenia. The overall response rate was 57.8% and the median survival time was 492 days. In chemotherapy-naive patients, the response rate was 65.7% (95% CI; 50–81.4%), median response duration 161 days, median survival time 513 days, 1-year survival rate 62.4%, and 2-year survival rate 27.3%.
Platinum-Based Chemotherapy of Primary Extragonadal Germ Cell Tumours: The Hellenic Cooperative Oncology Group Experience
Authors: Pectasides D. , Aravantinos G. , Visvikis A. , Bakoyiannis Ch. , Halikia A. , Kalofonos Ch. , Kosmidis P. , Skarlos D. , Fountzilas G.
Published: April 2003

Extragonadal germ cell tumours (EGCT) are uncommon, most frequently arise in the mediastinum and retroperitoneum and have variable responses to platinum-based chemotherapy. A retrospective analysis was performed on 38 patients with EGCT treated with cisplatin-based (CDDP) or carboplatin-based (CBDCA) chemotherapy between 1984 and 1998. Twenty-four patients had nonseminomatous germ cell tumours (NSGCT) and 14 seminoma. Twenty-two tumours arose in the mediastinum (13 nonseminomas, 9 seminomas) and 16 in the retroperitoneum (11 NSGCT, 5 seminomas). Initial surgery included complete resection in 1 patient, biopsy in 27 patients and debulking surgery in 10 patients. Complete response rates with chemotherapy ± surgery were as follows: mediastinum 14 of 21 (66.66%) patients (8 of 12–75% NSGCT, 6 of 9–66.66% seminomas) and retroperitoneum 14 of 16 (87.5%) patients (9 of 11–81.81% NSGCT, 5 of 5–100% seminomas). One patient who underwent complete resection of a mediastinal malignant teratoma combined, received PVB chemotherapy on an adjuvant basis and remains alive and disease-free. Three additional seminoma patients who achieved partial response after chemotherapy remain alive and disease-free following mediastinal radiotherapy. All 14 patients with extragonadal seminomas remain alive with no evidence of disease at a median follow-up of 49 months (range 7–164), giving an overall survival of 100%. Nine of 13 (69.23%) patients with mediastinal NSGCT are long-term disease-free at a median follow-up of 43.5 months (range 7–152). Nine of 11 (81.81%) patients with retroperitoneal NSGCT remain alive and disease-free at a median follow-up of 56 months (range 14–110). Complete surgical resection of residual mass was undertaken in 10 patients (3 seminomas, 7 nonseminomas). The histology revealed necrosis/fibrosis in 6 patients (3 seminomas, 3 NSGCT) and viable cancer in 4 patients. Patients who had viable malignant cells in the resected specimens received two more courses of VelP chemotherapy. None of our patients had relapsed at the time of this analysis. None of our 6 patients who underrwent testicular biopsy (1 patient) or orchiectomy (5 patients) due to suspicious ultrasound of the testis were found to have testicular tumour or fibrotic scar. In conclusion, this retrospective analysis showed significant responses in patients with either mediastinal or retroperitoneal NSGCT treated with CDDP- or CBDCA-based chemotherapy ± surgery. All patients with extragonadal seminomas remain alive with no evidence of disease, regardless of the site at presentation.
Phase I Study of High-Dose Epirubicin in Platinum-Pretreated Patients with Ovarian Carcinoma
Authors: Vermorken J.B. , ten Bokkel Huinink W.W. , Kobierska A. , van der Burg M.E.L. , Forni M. , Piccart M.J. , van der Putten E.
Published: April 2003

Background: In vitro data demonstrated a dose-response relationship for doxorubicin in ovarian cancer (OC) cell lines. However, this dose-response question for doxorubicin was never carefully addressed in OC patients. These data and the more favorable toxicity profile of the anthracycline analogue epirubicin prompted us to study high-dose epirubicin (HDE) in relapsed OC patients. Patients and Methods: This phase I study included 19 OC patients with measurable or evaluable disease and no more than one prior (cisplatin-containing) chemotherapy regimen. Dose escalation was not allowed in individual patients. Epirubicin was administered by rapid intravenous infusion (<5 min) once every 3 weeks and studied at the following dose levels: 120, 135, 150, 180 and 200 mg/m2 (at least 3 patients per dose level). None of the patients received hematopoietic growth factors. We defined the maximum tolerated dose (MTD) as the dose at which we observed WHO grade 4 hematologic toxicity in ≥50% and/or WHO grade 3 nonhematologic toxicity in ≥30% of the patients. Results: The MTD was 200 mg/m2, with DLT being both hematologic (leukopenia and/or thrombocytopenia) and nonhematologic (mucositis). Objective responses were observed in 6 patients (response rate 32%), 3 of them occurring in 10 patients with primary platinum resistance. Conclusions: HDE is tolerable and has activity in second-line after cisplatin-based chemotherapy in OC patients. The recommended dose for phase II trials in such patients is 150 mg/m2, with escalation to 180 mg/m2 if toxicity permits.
Genetic Aberrations Detected by Comparative Genomic Hybridization in Biliary Tract Cancers
Authors: Shiraishi Kei , Kusano Noriyoshi , Okita Satoshi , Oga Atsunori , Okita Kiwamu , Sasaki Kohsuke
Published: April 2003

In order to elucidate cytogenetic changes characteristic of biliary tract cancer, we examined the genetic imbalances in 18 biliary tract cancers using comparative genomic hybridization (CGH). The most common sites of increases in copy number, in order of frequency, were 17q (33% of the cases), 5p (28%), 3q (22%), 7p (22%), 8q (22%), and 12p (22%), whereas copy number decreases of 6q (28%), 18q (28%), 4q (22%), 5q (22%), and 9p (22%) were frequent. The average number of chromosomal aberrations was significantly greater in stage IV than in stage III tumors (7.9 vs. 2.2/tumor, p < 0.05). The frequent aberrations detected in this study may be related to the development and/or progression of biliary tract cancers. This is the first report on CGH of biliary tract cancers.
Enhanced Expression of Thymidylate Synthase May Be of Prognostic Importance in Advanced Cervical Cancer
Authors: Suzuki Mitsuaki , Tsukagoshi Shizuka , Saga Yasushi , Ohwada Michitaka , Sato Ikuo
Published: April 2003

The enhanced expression of thymidylate synthase (TS) has been associated with a poor prognosis in patients with several types of epithelial tumors. To determine the association between TS expression and the prognosis of patients with advanced cervical cancer after radiation therapy, we immunohistochemically assayed TS levels in paraffin-embedded tissue sections from 66 patients with stage IIIb cervical cancer using a polyclonal antibody to recombinant human TS. In the 30 patients with high TS expression, the cumulative 5- and 8-year survival rates were 36.8% (95% CI: 17.4–56.2) and 31.6% (95% CI: 12.4–50.7), respectively. In contrast, the 36 patients with low TS expression showed a significantly (p < 0.001) better prognosis, with cumulative 5- and 8-year survival rates of 87.2% (95% CI: 75.5–99.0) and 69.2% (95% CI: 50.7–87.7), respectively. These results suggest that TS expression may be useful in determining the prognosis of patients with advanced cervical cancer.
Prognostic Significance of CEA, CA 19-9 and CA 72-4 Preoperative Serum Levels in Gastric Carcinoma
Authors: Marrelli Daniele , Roviello Franco , De Stefano Alfonso , Farnetani Maurizio , Garosi Lorenzo , Messano Angelo , Pinto Enrico
Published: April 2003

The prognostic value of preoperative serum levels of CEA, CA 19-9 and CA 72-4 tumor markers was investigated in 153 patients resected for gastric cancer. The positivity rates for CEA, CA 19-9 and CA 72-4 were 20.9, 34.6 and 28.1%, respectively. Multiple logistic regression analysis for positive levels of tumor markers indicates that CEA positivity is significantly related to the depth of invasion (p < 0.005) and the presence of distant metastasis (p < 0.05), CA 19-9 positivity is related to nodal involvement (p < 0.05) and the depth of invasion (p < 0.05), whereas CA 72-4 positivity is influenced by tumor size (p < 0.005) and noncurative surgery (p < 0.05). Positive levels of each tumor marker were associated with a worse prognosis if compared with negative cases using univariate analysis. Multivariate analysis of curatively resected cases identified depth in gastric wall (p < 0.0001), nodal status (p < 0.0005), and tumor location in the upper third (p < 0.05) as significant prognostic variables; CEA, CA 19-9 and CA 72-4 serum positivity did not reach statistical significance. However, when the positivity of the three markers was associated, a p value < 0.05 was observed. The analysis of survival curves stratified by tumor stage revealed that marker positivity significantly affects survival in stages I, II and IV (p < 0.05). The combined assay of CEA, CA 19-9 and CA 72-4 preoperative serum levels provides additional prognostic information in patients resected for gastric cancer; patients with preoperative positivity for one of these tumor markers should be considered at high risk of recurrence even in early stages of gastric carcinoma.
Cytogenetic Aberrations Detected by Flow Cytometry and Fluorescence in situ Hybridization in Colorectal Cancers: Two Cytogenetic Pathways in Colorectal Carcinogenesis
Authors: Sato Toshihiko , Oga Atsunori , Ikeda Eiichi , Todoroki Takeshi , Furuya Tomoko , Sasaki Kohsuke
Published: April 2003

We measured DNA content by flow cytometry and determined the number of chromosomes 7, 17 and 18 by fluorescence in situ hybridization using DNA probes in 38 sporadic colorectal adenocarcinomas including 14 early cancers. Based on DNA ploidy and the copy number of chromosome 18, colorectal cancers were divided into two groups. In early cancers (mucosal and submucosal adenocarcinomas), monosomy 18 with DNA hypotriploidy was detected exclusively in 6 sessile tumors without adenoma portions. Seven of the remaining 8 tumors in which adenoma portions coexisted manifested disomy 18 and DNA diploidy or near diploidy. These tumors were considered to occur along the adenoma-carcinoma sequence. In contrast, monosomy 18 was accompanied by DNA diploidy or near diploidy in advanced cancers penetrating the muscularis propria. In advanced cancers, DNA hypertriploidy was linked with disomy 18 and chromosomes 7 and 17 were trisomic or tetrasomic. Observations indicate at least two different cytogenetic pathways in colorectal carcinogenesis. According to these findings, two thirds of advanced cancers were estimated to originate from adenoma, and the others were not.
Administration in a Hypotonic Solution Is Preferable to Dose Escalation in Intraperitoneal Cisplatin Chemotherapy for Peritoneal Carcinomatosis in Rats
Authors: Tsujitani S. , Oka A. , Kondo A. , Katano K. , Oka S. , Saito H. , Ikeguchi M. , Maeta M. , Kaibara N.
Published: April 2003

An animal model of intraperitoneal (i.p.) cisplatin chemotherapy using hypotonic solutions of sodium chloride has been developed as a treatment for peritoneal carcinomatosis. The concentrations of platinum in the plasma and in the i.p. fluid of Donryu rats were measured after i.p. injection of hypotonic (103 or 154 mosm/l) and isotonic (308 mosm/l) solutions that contained an equal amount of cisplatin. The maximum concentration (Cmax) and the area under the curve of concentration versus time (AUC) of platinum in the plasma increased proportionately with increases in the dose of cisplatin and they were significantly higher in rats given cisplatin in hypotonic solutions than in those given the drug in isotonic solution. The Cmax and AUC of total platinum were similar for the solution of 103 mosm/l with 2.5 mg/kg cisplatin and the isotonic solution with 5.0 mg/kg cisplatin. The Cmax and AUC of free platinum in the plasma did not increase with increases in the dose of cisplatin in isotonic solution but did increase after hypotonic injection. However, the solutions of lower osmolarity gave a decreased AUC of platinum in the i.p. fluid. Hypotonic conditions continued for 30 min at most after i.p. injection of hypotonic solutions. When the same dose of cisplatin was given to rats with tumors derived from AH100B carcinoma cells, the amount of platinum taken by i.p. solid tumors from the solution of 103 mosm/l was about twice that from the isotonic solution and was much the same as that taken up from the isotonic solution with twice the amount of cisplatin. These results indicate that hypotonic i.p. cisplatin chemotherapy might be preferable to escalation of the dose of i.p. cisplatin in the treatment of peritoneal carcinomatosis.
Hypermethylation of the p16 Gene in Sporadic T3N0M0 Stage Colorectal Cancers: Association with DNA Replication Error and Shorter Survival
Authors: Liang Jin-Tung , Chang King-Jen , Chen Jeng-Chang , Lee Chun-Chung , Cheng Yung-Ming , Hsu Hey-Chi , Wu Ming-Shiang , Wang Shih-Ming , Lin Jaw-Town , Cheng Ann-Lii
Published: April 2003

Hypermethylation in the promoter region of the p16 gene was suspected to be involved in the tumorigenesis of colorectal cancers, although its clinical and biological significance remains obscure. In this study, we collected 84 T3N0M0 stage primary colorectal cancers that were curatively resected. The clinicopathologic data were reviewed. p16 hypermethylation was determined by a methylation-specific polymerase chain reaction (PCR). p53 overexpression was detected by immunocytochemistry (ICC). The point mutations in the 12 and 13 codons of the K-ras gene were screened by restriction enzyme analysis. Loss of heterozygosity (LOH) of the DCC (Deleted in Colorectal cancer) gene was examined by PCR using primers of the DCC (18q21) microsatellite marker. The DNA replication error (RER) was examined using 7 microsatellite markers at distinct chromosomal loci. p16 hypermethylation, regarded as an indication of p16 inactivation, was evident in 24 (28.6%) of the tumors. No correlation was found between p16 hypermethylation and various clinicopathologic factors, includinig age, sex, tumor location, tumor size, growth pattern, tumor differentiation, mucin production, vascular and/or lymphatic invasion, lymphocyte infiltration of the tumor, and serum level of carcinoembryonic antigen. There was no association between p16 hypermethylation of K-ras gene mutation, p53 overexpression and LOH of the DCC gene. However, p16 hypermethylation was significantly associated with DNA RER (p = 0.01). Survival analysis revealed a significant survival disadvantage of p16-hypermethylated versus non-p16-hypermethylated tumors (p = 0.0001). These findings indicate that p16 hypermethylation plays a role in the carcinogenesis of a subset of colorectal cancers; and the presence of p16 hypermethylation predicts shorter survival in T3N0M0 stage colorectal cancers.
An Early Phase II Study of Oral S-1, a Newly Developed 5-Fluorouracil Derivative for Advanced and Recurrent Gastrointestinal Cancers
Authors: Sugimachi Keizo , Maehara Yoshihiko , Horikoshi Noboru , Shimada Yosuhiro , Sakata Yuh , Mitachi Yasushi , Taguchi Tetsuo
Published: April 2003

5-Fluorouracil (5-FU) or a 5-FU derivative 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) has been widely prescribed for patients with gastrointestinal cancer. However, the phosphorylation of 5-FU in the digestive tract causes gastrointestinal toxicities. 5-FU is also rapidly degraded to α-fluoro-β-alanine after contact with dihydropyrimidine dehydrogenase (DPDase) which is mainly present in the liver. Therefore, to overcome these metabolic events, S-1, an antitumor agent was developed, based on the biochemical modulation of FT by 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo), in a molar ratio of 1:0.4:1. The antineoplastic effect of S-1, was examined in Japanese patients with advanced gastric (G) or colorectal (C) cancer in a multicenter early phase II study involving 24 centers throughout Japan. The patients were prescribed a minimum of 2 courses of S-1 orally, with each course consisting of 75 or 50 mg (in terms of FT) twice a day for 28 days followed by withdrawal for 2 weeks. Thirty-one patients with G and 31 C were entered into this study. The clinical response and extent of toxicity were evaluated in G 28 and C 30 cases, respectively. Nine (32.1%) G patients and 14 (46.7%) C patients had been treated previously with other anticancer drugs. In G patients, there was a 53.6% (15/28) and in C patients a 16.7% (5/30) response rate (90% confidence interval G 38.4–68.1% and C 8.4–30.5%) with 15 (53.6%) (G) and 5 (16.7%) (C) partial responses (PR), and these responses persisted for 79 days (G) and 120 days (C) (median value). In particular, the response rate for the primary lesion was 27.8% (5/18) (G) and 33.3% (1/3) (C). No change (NC) in the disease was observed in 4 (14.3%) (G) and 13 (43.3%) (C) patients, and in 6 (21.4%) (G) and 7 (23.3%) (C) the disease progressed (PD). At the time of analysis, the median survival was 298 days (G) and 358 days (C). Major adverse effects consisted of gastrointestinal symptoms and myelosuppression while toxicities of grade 3 or more occurred in 35.7% (10/28) (G) and 33.3% (10/30) (C). Based on these data, S-1 is considered to have positive effects in patients with advanced gastrointestinal cancer.
Safety and Cost of Hyperhydration for the Prevention of Hemorrhagic Cystitis in Bone Marrow Transplant Recipients
Authors: Ballen Karen K. , Becker Pamela , Levebvre Kristine , Emmons Robert , Lee Kerry , Levy William , Stewart F. Marc , Quesenberry Peter , Lowry Philip
Published: April 2003

Hemorrhagic cystitis is a major cause of morbidity after bone marrow transplantation. Traditional methods of prevention have included mesna (2-mercaptoethane sodium sulfonate) and bladder irrigation. We report the use of hyperhydration as an alternative to these prophylactic measures. One hundred consecutive patients who underwent autologous or allogeneic bone marrow transplantation received high dose cyclophosphamide with hyperhydration using 5% dextrose normal saline at the rate of 250 ml/h and furosemide to maintain a urine output of >150 ml/h. Seventy-one of these patients also received high dose cyclophosphamide as mobilization chemotherapy. There were no episodes of hemorrhagic cystitis following mobilization chemotherapy. The incidence of hemorrhagic cystitis after transplant conditioning was 7% with 2 patients developing clinically significant hemorrhagic cystitis; one was a severe episode. The cost of hyperhydration was US$ 20 per course as opposed to US$ 1,500 per course for mesna, based on acquisition costs at our institution. We conclude that hyperhydration is a safe, inexpensive means of preventing hemorrhagic cystitis associated with high dose cyclophosphamide in bone marrow transplant recipients.
First-Line Chemotherapy with Vinorelbine and Paclitaxel as Simultaneous Infusion in Advanced Breast Cancer
Authors: Vici Patrizia , Amodio Antonella , Di Lauro Luigi , Conti Francesca , Gionfra Tommaso , Belli Franca , Lopez Massimo
Published: April 2003

Based on preclinical data showing a synergistic activity of simultaneous administration of vinorelbine and paclitaxel, we carried out a phase II trial in previously untreated advanced breast cancer patients. Treatment consisted of vinorelbine 25 mg/m2 and paclitaxel 150 mg/m2, both drugs given by intravenous infusion over 3 h on day 1, with cycles repeated every 3 weeks. Granulocyte colony-stimulating factor, 300 μg subcutaneously, was given on days 7–12 to the first 10 patients. From October 1995 to January 1997, 43 patients with advanced breast cancer entered the study, and 41 were evaluable for response. We obtained 2 complete responses (5%) and 18 partial responses (44%), for an overall response rate of 49% (95% CI 34–64%). Median time to response, time to progression and survival were 2, 7 and 22 months, respectively. Myelosuppression was the dose-limiting toxicity, with G4 neutropenia in 21% and neutropenic fever in 7% of the patients. Other toxicities were mild. Simultaneous infusion of vinorelbine and paclitaxel is a well-tolerated and active regimen in metastatic breast cancer, with overall results similar to those reported with more toxic regimens; furthermore, it may be a good option in patients with anthracycline contraindications.
Expression of the Cell Adhesion Molecules ICAM-1, VCAM-1 and NCAM in Uveal Melanoma: A Clinicopathological Study
Authors: Anastassiou Gerasimos , Schilling Harald , Stang Andreas , Djakovic Stana , Heiligenhaus Arnd , Bornfeld Norbert
Published: April 2003

To investigate the relationship between the expression of the cell adhesion molecules intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and neural cell adhesion molecule (NCAM) in uveal melanoma and the metastatic spread in the first 5 years after diagnosis, we performed a hospital-based case-control study with human tissue from 90 patients who underwent enucleation for primary uveal melanoma (iris melanoma excluded). Thirty-five patients developed metastasis within the first 5 years, and 55 patients lived metastasis-free for at least 5 years after enucleation. The paraffin-embedded and formalin-fixed globes were studied by immunohistochemistry with monoclonal antibodies for ICAM-1, VCAM-1 and NCAM. A strong ICAM-1 positivity (more than 75% of the tumor cells stained positive) was detected in 73 tumors (81%). The expression of 75% or less ICAM-1 positive cells in tumors was strongly associated with the development of metastases (odds ratio: 7.5, p = 0.001). Multiple logistic regression models showed that ICAM-1 is an independent risk factor for metastasis even after control for important prognostic markers like extraocular growth, ciliary body involvement, scleral infiltration and cell type. VCAM-1 was expressed in 24 out of 88 tumors (27.3%) and NCAM only in 14 out of 87 tumors (16%). Only spindle cells stained positive with anti-NCAM. NCAM and VCAM-1 expression was not related to metastasis. Our results show that the loss of ICAM-1 expression is associated with an increased risk of metastasis within the first 5 years after diagnosis.
The Emerging Role of Cytokines in the Treatment of Advanced Melanoma
Authors: Keilholz Ulrich , Eggermont Alexander M.M.
Published: April 2003

Cytokine-based treatment regimens have been evaluated for advanced melanoma in a number of phase I and phase II trials within the last decade. Treatment with interleukin-2 (IL-2) as a single agent has resulted in response rates of approximately 15%, if a high dose of IL-2 is administered. Combination of interferon-α (IFNα) and high dose IL-2 yields response rates ranging from 10 to 41%. Response rates exceeding 50% have been reported with chemoimmunotherapy, if the treatment regimens included at least the three agents IL-2, IFNα and cisplatin. Recent randomized trials have evaluated the impact of these drugs on the survival of patients with advanced melanoma. The current ‘state of the art’ is discussed in this review.
Erythropoietin in Radiation Oncology – A Review
Authors: Henke Michael , Guttenberger Roland
Published: April 2003

The therapeutic potential of erythropoietin gains increasing attention among radiation oncologists because the prognosis is better for patients with high blood hemoglobin levels following radiotherapy. However, there is still a debate on how hemoglobin affects radiotherapy. Further, the means to manipulate the hemoglobin level, their indication and administration need to be clarified. Available experimental and clinical data on hypoxia, anemia and on their treatment with erythropoietin have been extensively discussed at an international conference in Freiburg, Germany, in June 1999. This report gives a summary reviewing the topic.
Microsatellite Instability in Thyroid Papillary Carcinoma and Multinodular Hyperplasia
Authors: Dobosz Tadeusz , Łukienczuk Tadeusz , Sąsiadek Maria , Kuczyńska Anna , Jankowska Ewa , Blin Nikolaus
Published: April 2003

Microsatellite instability (MSI) is a molecular landmark of mutations in DNA mismatch repair genes. The impaired efficiency of DNA repair mechanisms promotes carcinogenesis as well as contributes to tumour progression. Until now, only few studies on MSI in thyroid tumours have been published. Therefore, the aim of the present study was to investigate MSI as a possible characteristic feature of thyroid tumours. The analysis of 12 thyroid papillary carcinomas and 17 multinodular hyperplasias at 13 microsatellite loci showed MSI and loss of heterozygosity (LOH) in both types of lesion, with more alterations noted in the papillary thyroid carcinomas (in 65%) than in multinodular hyperplasia (in 35%). In carcinomas, LOH occurred more frequently than MSI, while in multinodular hyperplasia the LOH/MSI ratio is almost equal.
Clinical Significance of Expression of Estrogen Receptor α and β mRNAs in Ovarian Cancers
Authors: Fujimoto Jiro , Hirose Reiko , Sakaguchi Hideki , Tamaya Teruhiko
Published: April 2003

Novel human estrogen receptor (ER)-β was identified in cDNA libraries from human testis. ER-β specifically expresses in testis, ovary, thymus, spleen, osteoblasts and fetus. ER-β might not conserve the same physiological functions as does ER-α. Therefore, the clinical significance of the expression of ER-α and ER-β mRNAs in ovarian cancers was investigated. The percentage of ER-β mRNA to ER-α mRNA ranged from 1.5 to 10% in normal ovaries. On the other hand, the ratios of ER-β mRNA to ER-α mRNA were in a wide range in ovarian cancers. There was no significant difference in the ratios among ovarian cancers classified according to histological types or clinical stages. In a 48-month survival rate, the patient prognosis in ovarian cancers with a low or high ratio of ER-β mRNA to ER-α mRNA (<1.5 or >10% of ER-β mRNA to ER-α mRNA) was significantly worse than that in ovarian cancers with a medium ratio (≧1.5 to ≦10% of ER-β mRNA to ER-α mRNA). In conclusion, the intact synchronized expression of ER-β mRNA interacting with ER-α mRNA might be damaged in some ovarian cancers, which might lead to poor patient prognosis.
Prevention of Metastasis by a Polyamine Synthesis Inhibitor in an Animal Bone Metastasis Model
Authors: Wakabayashi Hiroki , Hibasami Hiroshige , Iida Kohji , Satoh Norifumi , Yamazaki Takashi , Sonoda Jun , Hirata Hitoshi , Nakashima Kunio , Uchida Atsumasa
Published: April 2003

In order to better understand the development of skeletal metastases, we developed an appropriate animal model, as the natural progression of metastases in humans cannot be studied on the cellular level. In this study, we established a new animal model which developed bone metastasis in a bone grafted subcutaneously. C57BL/6 mice, which had received a bone (femur or tibia) transplanted in the dorsal subcutis, were injected with B16 melanoma cells into the left heart ventricle. Metastasis was found in approximately 70% of the extraskeletal bones. Using this model, the antimetastatic effect of a polyamine synthesis inhibitor was investigated. Inhibitors of the polyamine biosynthetic pathway have received considerable attention for their potential use in the treatment of cancer as they are responsible for the greatly increased production of the polyamines putrescine, spermidine, and spermine. A polyamine synthesis inhibitor, methylglyoxal-bis(cyclopentylamidinohydrazone) MGBCP, was investigated for its inhibitory effects on bone metastases. MGBCP (20 mg/kg) was administered intraperitoneally every day for 4 weeks and demonstrated strong inhibitory effects on bone metastases. MGBCP inhibited angiogenesis in the transplanted bone and the growth of B16 melanoma cells, thus suggesting a preventive mechanism in bone metastasis. No remarkable adverse effects of MGBCP were observed in any animal throughout the experimental period. Our results indicate that MGBCP has a strong potential for use as an anti-metastatic drug.
Hepatic Arterial Chemotherapy for Colorectal Cancer Metastatic to the Liver
Authors: van Riel Johanna M.G.H. , van Groeningen Cees J. , Giaccone Giuseppe , Pinedo Herbert M.
Published: April 2003

In advanced colorectal cancer, liver metastases are a major problem. In patients with liver metastases as the major site of disease hepatic arterial chemotherapy is a valid alternative to systemic treatment. In this review about hepatic arterial chemotherapy we will discuss the theoretical and practical aspects, the results and complications, the selection of patients for hepatic arterial chemotherapy, and its future developments.
High Frequency of Metastatic Leydig Cell Testicular Tumours
Authors: Farkas László M. , Székely Joseph G. , Pusztai Csaba , Baki Márta
Published: April 2003

690 patients were treated for testicular tumour in the course of 18 years. The histology of 7 cases showed Leydig cell tumour. In 4 of the 7 cases, a metastatic process leading to death was observed. At the time of diagnosis, 5 patients were found to have low stage, whereas 2 of the patients had advanced lymphatic involvement. The hematogenous and lymphatic metastases proved to be resistant to chemotherapy. Contrary to the major part of the literature, retroperitoneal lymphadenectomy should be performed with this histological type for the exact pathological staging immediately following orchiectomy.
Total Tumor Cell Elimination with Minimum Damage to Normal Tissues in Musculoskeletal Sarcomas following Photodynamic Therapy with Acridine Orange
Authors: Kusuzaki Katsuyuki , Aomori Katsuhiro , Suginoshita Takehiko , Minami Ginjorou , Takeshita Hideyuki , Murata Hiroaki , Hashiguchi Shin , Ashihara Tsukasa , Hirasawa Yasusuke
Published: April 2003

Acridine orange (AO) has unique biological actions enabling tumor visualization (fluorovisualization) and a strong cytocidal effect (photodynamic therapy: AO-PDT) under illumination with blue light. Accordingly, in this study, we attempted to develop a new surgical technique for total tumor cell elimination using these photodynamic reactions with AO in a mouse osteosarcoma model. The results showed that local tumor recurrence was significantly inhibited (23%) in the group treated with curettage under fluorovisualization and AO-PDT, compared to that (80%) in the control group treated with curettage alone under ordinary light. Therefore, we concluded that the combination of curettage under fluorovisualization and AO-PDT may be useful for total tumor cell elimination with minimum damage to normal tissue in musculoskeletal sarcomas.
Oral Doxifluridine in Advanced Hepatocellular Carcinoma: A Phase II Study
Authors: Lencioni Monica , Falcone Alfredo , Allegrini Giacomo , Pfanner Elisabetta , Masi Gianluca , Brunetti Isa , Di Marsico Roberta , Fontana Eloise , Orlandini Cinzia , Stampino Corrado Gallo , Bartolozzi Carlo , Conte Pier Franco
Published: April 2003

Hepatocellular carcinoma (HCC) remains one of the most common neoplasms in the world. Doxifluridine is an oral fluoropyrimidine derivative activated to 5-fluorouracil by uridine phosphorylase which is more expressed in malignant cells. Therefore, we conducted a phase II study to evaluate the activity of oral doxifluridine in patients with advanced hepatocellular carcinoma. Twenty-five advanced hepatocellular carcinoma patients entered the study; doxifluridine was given orally at the initial daily total dose of 2,250 mg for 4 consecutive days every week. All patients are evaluable for toxicity: these included mainly grade 1–2 (WHO) diarrhea, stomatitis, nausea and vomiting; 4 patients (16%) experienced grade 3–4 diarrhea. Twenty-four patients are evaluable for response and 1 complete and 3 partial responses have been observed (response rat 17%, 95% confidence interval: 5–37). Oral doxifluridine at the dose and schedule we used, although having only modest activity in advanced HCC, may represent an alternative to other frequently used chemotherapeutic agents, because of its favorable toxicity profile and its simple route of administration.