bluuebunny/crossref_metadata_2025 huggingface dataset:
Activity of Gemcitabine and Continuous Infusion Fluorouracil in Advanced Pancreatic Cancer
Authors: Rauch D.P. , Maurer C.A. , Aebi S. , Pampallona S. , Friess H. , Ludwig C.U. , Büchler M.W. , Borner M.M.
Published: April 2003

Background/Objectives: Gemcitabine has been shown to improve survival and quality of life parameters compared to fluorouracil alone in advanced pancreatic cancer [J Clin Oncol 1997;15:2403–2413]. However, fluorouracil was given as a weekly bolus in that study and other administration schedules might be more effective. The objective of this trial was to determine the activity and toxicity of gemcitabine in combination with continuous infusion (CI) fluorouracil in advanced pancreatic cancer. Patients and Methods: Chemotherapy-naïve patients with measurable advanced adenocarcinoma of the pancreas were treated with gemcitabine 1,000 mg/m2 intravenously weekly × 3 followed by 1 week of rest every 4 weeks and 200 mg/m2/day CI fluorouracil until disease progression or limiting toxicity. Results: Twenty-five patients were evaluable for response and toxicity. Objective partial responses were documented in 5 patients (20%; 95% confidence interval 6.8–40.7%) and disease stabilization or minor responses in 13 patients (52%; 31.3–72.2%). Toxicity was mild with grade 2/3 leucopenia in 26%, stomatitis in 15%, nausea in 6%, diarrhea in 3%, and hand-foot syndrome in 2% of the treatment cycles. In 3 patients a catheter thrombus occurred and in 1 patient the treatment had to be stopped due to asthenia. The performance status improved in 39% of the patients and 65% benefitted in terms of a decrease in pain intensity or consumption of analgesics. Conclusion: This phase II trial confirms a significant antitumor activity and a beneficial clinical effect of gemcitabine plus CI fluorouracil in advanced pancreatic cancer. The combination is well tolerated and it will have to be shown whether oral fluoropyrimidines can increase the practicability of this treatment without impairing efficacy.
Thrombospondin-1 and -2 in Node-Negative Breast Cancer: Correlation with Angiogenic Factors, p53, Cathepsin D, Hormone Receptors and Prognosis
Authors: Gasparini Giampietro , Toi Masakazu , Biganzoli Elia , Dittadi Ruggero , Fanelli Massimo , Morabito Alessandro , Boracchi Patrizia , Gion Massimo
Published: April 2003

Objective: Thrombospondins (TSPs) are a multigene family of five secreted glycoproteins involved in the regulation of cell proliferation, adhesion and migration.Two members of the TSP family, namely TSP-1 and TSP-2, are also naturally occurring inhibitors of angiogenesis. The aim of the present study was to determine the prognostic significance of the determination of TSP-1 and -2 and their correlation with the angiogenic peptides vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP), as well as with other biological and clinicopathological features investigated. Methods: We evaluated a series of 168 women with node-negative breast cancer with a median follow-up period of 66 months, not treated with adjuvant therapy. The cytosolic levels of TSP-1 and -2 were determined in the primary tumour by a commercially available immunometric assay. Results: We found that 166 tested tumours had measurable levels of TSP-1 and -2 protein (median value 5.978, range 0.579–31.410 ng/mg of protein). On the basis of Spearman’s rank correlation coefficient, a weak inverse association of TSP-1 and -2 with tumour size and cathepsin D was found. Moreover, principal component analysis on ranks evidenced a poor association between TSP-1 and -2, VEGF and TP. The results of the clinical outcome were analysed by both univariate and multivariate [for relapse-free survival (RFS) only]) Cox regression models. TSP-1 and -2 were not significant prognostic factors in univariate analysis for either RFS (p = 0.427) or overall survival (p = 0.069). To investigate the ‘angiogenic balance hypothesis’, bivariate analyses were performed to investigate the interactions of TSP-1 and -2 with VEGF, TP or p53, but none were included in the selected models. Finally, in multivariate analysis for RFS a baseline model, previously defined in a larger case series and inclusive of VEGF, TP and their interaction was adopted. It was highly significant (p = 0.002, Harrell c statistic value of 0.703); but when TSP-1 and -2 were added, their contribution was negligible (p = 0.731, Harrell c statistic value of 0.705). Conclusions: The results of this study suggest that TSP-1 and -2 do not provide additional prognostic contribution to the joint effects of VEGF and TP. In the series of node-negative breast cancer patients investigated, determination of the angiogenic peptides VEGF and TP gave significant prognostic information. On the contrary, TSP-1 and -2, potential naturally occurring negative regulators of angiogenesis, lacked of prognostic value.
Treatment of Advanced Stage Hodgkin’s Disease
Authors: Tesch H. , Sieber M. , Diehl V.
Published: April 2003

Hodgkin’s disease remains one of the few malignant diseases which can be cured by modern chemotherapy in most cases even in advanced stages. Adriamycin-containing chemotherapy regimens are considered as the standard therapy which induce long-term remission in about 60–70% of patients. The ABVD scheme, developed by Bonadonna and colleagues in Milan, has a favorable toxicity profile and causes less myelotoxicity, acute leukemia or sterility relative to many previous treatment programs containing alkylating agents. However, 20– 30 % of patients eventually relapse and are then frequently treated with high-dose programs including stem cell transplantation. There are two major goals in advanced Hodgkin’s disease: (1) to improve the cure rate and (2) to reduce acute and long-term toxicities. The recent definition of prognostic factors identified patients who are at a high risk of treatment failure as well as those in whom less toxic approaches can be applied. The optimal approach or program has not yet been defined, although new chemotherapy regimens such as BEACOPP and Stanford V with increased tumor response rates have been identified. These new drug combinations are currently analyzed and compared with ABVD in several international trials. While the addition of radiotherapy improved disease control in some trials a survival benefit was not identified and the role of radiotherapy remains controversial. High dose programs remain experimental in advanced stage Hodgkin’s disease and should be restricted to prospective clinical trials.
Phase II Trial of Systemic Recombinant Interleukin-2 in the Treatment of Refractory Nasopharyngeal Carcinoma
Authors: Chi Kwan-Hwa , Myers Jeffrey N. , Chow Kuan C. , Chan Wing K. , Tsang Yuk-Wah , Chao Yee , Yen Sang H. , Lotze Michael T.
Published: April 2003

Background: Interleukin-2 (IL-2) is a cytokine produced by activated T cells, which has shown powerful immunostimulatory and antineoplastic properties. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with abundant lymphocyte infiltration histologically. The activity of IL-2 in the treatment of NPC patients is currently unknown. A phase II study was, therefore, initiated to evaluate the efficacy, toxicity and immunological consequences of intravenous bolus IL-2 in patients with recurrent/metastatic NPC. Methods: Between November 1996 and April 1997, 14 patients with recurrent/metastatic NPC were entered into the study. Recombinant IL-2 (Proleukin, Chiron) was injected by intravenous bolus every 8 h at 72,000 IU/kg for a maximum of 15 doses. After 7 days, patients were retreated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5–6 weeks later went on to receive another course (two cycles) of therapy. All patients received prophylactic antibiotics and antipyretic medicine. Response and toxicities were evaluated. Serial plasma level of TNF-α, IL-6, soluble IL-2 receptor, IL-10 and soluble CD8 were determined. Results: Fourteen patients received a total of 34 cycles of therapy. No response was observed. Fifty percent had stable disease, 50% had progressive disease after a median of two cycles of therapy. There was one treatment-related death from acute myocardial infarction. Body weight increase (>5%) occurred in 80% of cycles, and hypotension (BP <80 mm Hg systolic) occurred in 53%. Serum creatinine increase (>2 mg%) occurred in 24% of cycles, and SGOT/SGPT increase (>3×) in 10% of cycles. Symptoms of somnolence, general malaise, nausea and vomiting, pruritus, xerostomia, desquamation were generally mild to moderate but rapidly reversible. Conclusion: The single modality of intravenous bolus IL-2 at the dose level of 72,000 IU/kg is clinically ineffective in NPC patients. Potential mechanisms of the ineffectiveness of IL-2 therapy on NPC patients are discussed.
Overexpression of Vascular Endothelial Growth Factor C Is Related to Lymphogenous Metastasis in Early Gastric Carcinoma
Authors: Kabashima Akira , Maehara Yoshihiko , Kakeji Yoshihiro , Sugimachi Keizo
Published: April 2003

Vascular endothelial growth factor C (VEGF-C) is considered to be potentially lymphangiogenic and can selectively induce hyperplasia of the lymphatic vasculature. In this study, we clarified the clinicopathological features of early gastric carcinoma (EGC) that has metastasized to the lymph nodes, as well as the correlation between lymphogenous metastases in EGC and the expression of VEGF-C and VEGF. We selected 35 cases of lymph node metastasis-positive [n(+)] EGC and 70 cases of lymph node metastasis-negative [n(–)] EGC for the present study. The expression of VEGF and VEGF-C was investigated with immunohistochemical staining using monoclonal antibodies against VEGF and VEGF-C. Clinicopathologically, there were significant differences in median size (4.1 ± 2.4 vs. 2.4 ± 1.7 cm), lymphatic invasion (54 vs. 4%) and venous invasion (23 vs. 3%) between n(+) EGC and n(–) EGC. Immunohistochemically, the incidence of positive expression of VEGF-C in lymphatic invasion-positive EGC (36%) was significantly higher than that in lymphatic invasion-negative EGC (14%). The incidence of positive expression of VEGF-C in n(+) or venous invasion-positive EGC tended to be higher than that in n(–) or venous invasion-negative EGC. In conclusion, lymphatic invasion was significantly increased in VEGF-C-positive EGC.
A Comparison of DNA Copy Number Changes Detected by Comparative Genomic Hybridization in Malignancies of the Liver, Biliary Tract and Pancreas
Authors: Shiraishi Kei , Okita Kiwamu , Kusano Noriyoshi , Harada Tomohiko , Kondoh Satoshi , Okita Satoshi , Ryozawa Shomei , Ohmura Ryosuke , Noguchi Takayoshi , Iida Yozo , Akiyama Tetsuji , Oga Atsunori , Fukumoto Yohei , Furuya Tomoko , Kawauchi Shigeto , Sasaki Kohsuke
Published: April 2003

Tumors arising from the liver, biliary tract and pancreas, which originate in the foregut and are in close anatomical proximity to each other, sometimes show similar histological features. No studies have focused on genetic similarities and differences between tumors of these organs. To elucidate the similarities and differences in DNA copy number alterations between tumors of these organs, we applied comparative genomic hybridization (CGH) to cancers of the liver (31 cases), biliary tract (42 cases) and pancreas (27 cases). Some alterations were common to tumors of all three organs, and some were preferential in certain types of tumor. Gains of 1q and 8q and losses of 8p and 17p were common to all tumors. In contrast, 13q14 and 16q losses were detected exclusively in hepatocellular carcinomas (HCCs; p < 0.01). The incidence of 17q21 gain and 5q loss was higher in biliary tract cancers than in the other two types (p < 0.05). Pancreatic cancers exhibited higher incidence of 5q14-q23 gain and 19p loss than tumors of other organs (p < 0.01). Gains of 7p, 7q, 12p and 20q and losses of 3p, 6q, 9p and 18q were frequent in both biliary tract and pancreatic cancers but rare in HCCs (p < 0.05). The present results suggest that although genes located at 1q, 8p, 8q and 17p are frequently involved in HCC, biliary tract and pancreatic cancer, at least some of the genes implicated in carcinogenesis are different between these three types. It is also suggested that CGH analysis is useful as a potential adjunct for the diagnosis and management of these tumors of organs that are anatomically close to one another.
Clinical Significance of Human Erythrocyte Glucose Transporter 1 Expression at the Deepest Invasive Site of Advanced Colorectal Carcinoma
Authors: Furudoi Akira , Tanaka Shinji , Haruma Ken , Yoshihara Masaharu , Sumii Koji , Kajiyama Goro , Shimamoto Fumio
Published: April 2003

Objective: Malignant cells exhibit increased glucose uptake and utilization in vitro and in vivo. This process is thought to be mediated by the glucose transporter (Glut) family. The aim of this study was to elucidate the clinical significance of Glut1 expression at the site of deepest invasion as a predictor of the invasive/metastatic potential and prognosis of advanced colorectal carcinoma (CRC). Methods: One hundred and fifty-two patients who had undergone surgical resection for advanced CRC were entered in this study. Histologic subclassifications at the deepest invasive site included well-differentiated (W), moderately to well-differentiated (Mw), moderately to poorly differentiated (Mp), poorly differentiated (Por) and mucinous (Muc) adenocarcinomas. Glut1 expression was examined immunohistochemically with a labeled streptavidin-biotin kit using anti-Glut1 polyclonal antibody MYM. As a marker of cell proliferation, Ki-67 expression was also examined. All immunoreactivity was analyzed at the deepest invasive site, central portion and superficial part. The immunohistochemical expression of Glut1 was defined as positive if distinct staining of the membrane or cytoplasm was observed in at least 30% of tumor cells. Results: Glut1 expression was detected in 56 of 152 lesions (36.8%) at the deepest invasive site. The incidence of Glut1 expression at the deepest invasive site correlated significantly with histologic grade (W/Mw grade, 28% vs. Mp/Por/Muc grade, 48%), depth of invasion (invasion of muscularis propria/invasion of subserosa or subadventitia, 29% vs. invasion of serosa or adventitia/invasion of adjacent structures, 52%), lymphatic invasion (absence of lymphatic invasion, 19% vs. presence of lymphatic invasion, 40%), lymph node metastasis (absence of lymph node metastasis, 25% vs. presence of lymph node metastasis, 41%) and Duke’s stage (Duke’s <D, 32% vs. Duke’s D, 51%). In the central portion and superficial part, there were no significant differences between Glut1, Ki-67 expression and clinicopathological findings. Glut1 expression at the deepest invasive site correlated significantly with the Ki-67 labeling index. In cases of curative surgery, patients with Glut1-positive lesions at the deepest invasive site showed a significantly poorer prognosis than those with Glut1-negative lesions. Multivariate analysis with logistic regression for 5-year survival in patients who had undergone curative surgery showed that lymph node metastasis and Glut1 expression were significant risk factors. Conclusion: These results indicate that Glut1 expression at the deepest site of tumor invasion can be a useful predictor of a high malignant potential and poor prognosis in advanced CRC.
Micrometastatic p53-Positive Cells in the Lymph Nodes of Early Stage Epithelial Ovarian Cancer: Prognostic Significance
Authors: Suzuki Mitsuaki , Ohwada Michitaka , Saga Yasushi , Kohno Takahiro , Takei Yuji , Sato Ikuo
Published: April 2003

We used immunohistochemical staining of p53 protein to detect micrometastasis in regional lymph nodes that were judged tumor-free by conventional histopathological methods in 58 patients with stage I or II (pT1 or 2, N0) epithelial ovarian cancer. Overexpression of p53 protein in the primary lesions of ovarian cancer was observed in 31 patients (53%), and p53 protein-positive cells were detected in the regional lymph nodes (micrometastasis-positive) in 19 of 31 patients with p53 protein overexpression (61%). In patients with micrometastasis, the prognosis was significantly poorer than that in those without micrometastasis (p < 0.05). Detection of micrometastasis of the regional lymph nodes of ovarian cancer by immunohistochemical staining of p53 protein may be useful in predicting the prognosis of patients with stage I or II epithelial ovarian cancer.
Dose-Dense Sequential Adjuvant Chemotherapy with Epirubicin, Paclitaxel and CMF in High-Risk Breast Cancer
Authors: Fountzilas G. , Papadimitriou C. , Aravantinos G. , Nicolaides C. , Stathopoulos G. , Bafaloukos D. , Kalofonos H. , Ekonomopoulos T. , Skarlos D. , Pavlidis N. , Dimopoulos A.M.
Published: April 2003

Dose-dense sequential chemotherapy appears to be a promising approach in the management of patients with operable breast cancer. We evaluated the tolerability of such a novel chemotherapeutic regimen in high-risk patients. From February 1995 until September 1997, 49 women with histologically confirmed breast cancer and ≧10 involved axillary nodes were treated postoperatively with three cycles of epirubicin (110 mg/m2) followed by three cycles of paclitaxel (250 mg/m2 in a 3-hour infusion) followed by three cycles of ‘intensified’ CMF (cyclophosphamide 840 mg/m2, methotrexate 57 mg/m2, fluorouracil 840 mg/m2; E-T-CMF). All cycles were repeated every 2 weeks with G-CSF support. Ovarian ablation with monthly injections of triptorelin for 1 year was performed in premenopausal patients and tamoxifen was prescribed for 5 years to all women with positive receptor status after the completion of chemotherapy. A total of 456 cycles of chemotherapy were administered, 363 (80%) of them at full dose. Forty-seven (96%) patients received all 9 cycles of chemotherapy. Relative dose intensity of epirubicin was 0.98, of paclitaxel 0.97, of cyclophosphamide 0.99, of methotrexate 0.98 and of fluorouracil 0.99. Grade 3–4 toxicities included anemia (8%), leukopenia (8%), peripheral neuropathy (6%), neutropenia (4%), thrombocytopenia (4%), stomatitis (2%), diarrhea (2%), fatigue (2%) and hypersensitivity reaction (2%). Febrile neutropenia occurred in 2 patients. Alopecia was universal. After a median follow-up of 3 years, 11 women (22%) relapsed and 4 (8%) died. The 3-year actuarial disease-free survival rate was 72% and the 3-year overall survival rate 90%. The E-T-CMF regimen is well tolerated, as adjuvant treatment, in patients with operable breast cancer with promising activity and deserves further evaluation in phase III studies.
T-Cell-Rich B-Cell Lymphoma
Authors: Tsirigotis Panagiotis , Economopoulos Theofanis , Rontogianni Dimitra , Dervenoulas John , Papageorgiou Efstathios , Bollas Georgios , Mantzios Georgios , Kalantzis Dimitris , Koumarianou Anna , Raptis Sotirios
Published: April 2003

Objectives: Clinical features, response to treatment and survival of T-cell-rich B-cell lymphoma (TCRBCL) patients were compared to those of a similar group of patients with diffuse large B-cell lymphoma (DLBCL). Methods: Between 1992 and 1999, 10 patients with a diagnosis of TCRBCL were treated in our department. Over the same 7-year period, a group of 65 patients with DLBCL were diagnosed in the same department. Both groups of patients were treated with the same anthracycline-based chemotherapy. Results: A significantly higher percentage of patients with TCRBCL presented with B-symptoms, elevated LDH, bone marrow infiltration and disseminated extranodal involvement compared to patients with DLBCL. TCRBCL patients responded poorly to combination chemotherapy, since only 3 of them achieved complete remission (33%) compared to 48 (75%) patients with DLBCL. All patients with TCRBCL who achieved complete response relapsed within the first 2 years while 65% of patients with DLBCL survive disease free for a median follow-up period of 4 years. The median overall survival for DLBCL patients has not been reached yet, while it was 18 months for TCRBCL patients. Conclusions: Although the number of patients in our study is small, it seems that patients with TCRBCL present with advanced disease, respond poorly to chemotherapy and display a short disease-free and overall survival compared to patients with DLBCL.
Effectiveness of Trastuzumab (HerceptinTM) in a Patient with Locally Recurrent Breast Cancer after Cardiac Failure Caused by Severe Cytotoxic Pretreatment
Authors: Gerber Bernd , Krause Annette , Markmann Susanne , Reimer Toralf , Fietkau Rainer , Müller Heiner
Published: April 2003

In HER2-positive breast cancer patients, the humanized anti-HER-2 monoclonal antibody trastuzumab (HerceptinTM) may improve overall survival. No reports exist regarding the application of trastuzumab in patients with cytotoxically induced cardiac failure and decreased left ventricular ejection fraction or about locally recurrent and advanced disease. In this case report, trastuzumab resulted in a complete and long-lasting response of recurrent and locally advanced breast cancer and was well tolerated in a severely cytotoxically pretreated patient with cardiac failure. We encourage other oncologists to offer trastuzumab also to severely cytotoxically pretreated patients with conditions after cardiac insufficiency or with locally advanced breast cancer.
STn and Prognosis in Breast Cancer
Authors: Leivonen Marja , Nordling Stig , Lundin Johan , von Boguslawski Kristina , Haglund Caj
Published: April 2003

Sialyl-Tn (STn) is a carbohydrate antigen formed by the premature 2–6 sialylation of N-acetylgalactosamine. It belongs to a family of antigens widely expressed in carcinomas but only to a limited degree in normal tissue. The expression of STn has been associated with prognosis in different tumors. In this immunohistochemical study of 218 patients with invasive stage I–III breast cancer, STn was expressed in 39% of the tumors. High expression of STn correlated with estrogen and progesterone hormone receptor negativity (p = 0.0002 and p = 0.0003, respectively), and marginally with large tumor size (p = 0.04), high S-phase fraction (p = 0.04) and aneuploidy (p = 0.04), but not significantly with node status, grade or age. The patients had a median follow-up of 17 years. The breast-cancer-specific survival rate of patients with STn-negative cancers was higher than that of patients with cancers that expressed STn during the first 5 years of the follow-up (p = 0.013), but the difference between the groups decreased during the long-term follow-up. STn expression seems to be a marker for short-term, but not for long-term breast cancer outcome prediction.
Successful Treatment of Bronchiolitis obliterans Organizing Pneumonia with Low-Dose Methotrexate in a Patient with Hodgkin’s Disease
Authors: Egerer G. , Witzens M. , Spaeth A. , Breitbart A. , Möller P. , Goldschmidt H. , Ho A.D.
Published: April 2003

Bronchiolitis obliterans organizing pneumonia (BOOP) is a rare disease, which is histopathologically defined by the presence of granulation tissue in the bronchioles, alveolar ducts and alveoli leading to plugging of the bronchiolar and alveolar lumen. BOOP is considered as a nonspecific response to many types of lung injury, including drugs, radiation, an underlying hematologic malignant neoplasm, autoimmune diseases, bacterial or virus infection, or an underlying lung disease, or occurs idiopathically. BOOP is mainly treated with corticosteroids, which induce a rapid clinical improvement. A frequent problem is relapse of disease when corticosteroid dosage is tapered off. We present the case of a 20-year-old patient with Hodgkin’s disease developing BOOP after chemotherapy (COPP/ABVD) and irradiation. Initially, she responded well to corticosteroids, but relapsed when medication was discontinued. Complete remission of BOOP was achieved by long-term treatment with low-dose methotrexate (5–20 mg/week, i.v.).
Pilot Study of Albendazole in Patients with Advanced Malignancy
Authors: Morris David L. , Jourdan Jean-Luc , Pourgholami Mohammad H.
Published: April 2003

Our preclinical studies have shown that the widely used antiparasitic drug albendazole has potent antiproliferative activity against colorectal cancer (CRC) and hepatocellular carcinoma (HCC). This trial was designed to evaluate albendazole in a small number of patients (n = 7) with either HCC or CRC and hepatic metastases refractory to other forms of therapy. Albendazole was given at 10 mg/kg/day orally in two divided doses for a period of 28 days. To follow the effect of treatment, tumor markers, carcinoembryonic antigen (CEA) or α-feto protein (AFP), were measured routinely in these patients. A range of hematological and biochemical indices were also serially measured to monitor bone marrow, kidney or liver toxicity. Albendazole therapy resulted in a decrease in CEA in 2 patients. In the remaining 5 with measurable tumor markers, serum CEA or AFP was stabilized in 3 patients, while in the other 2, after an initial stabilization (5–10 days), the markers began to increase. In the 7 patients completing the trial, albendazole was well tolerated and there were no significant changes in any hematological, kidney or liver function tests, but 3 patients were withdrawn for severe neutropenia which was probably contributory to the death of 1 patient. These data support our previous experimental results demonstrating that albendazole has antitumor effects.
Tumor Growth Patterns and Biological Characteristics of Early Gastric Carcinoma
Authors: Maehara Yoshihiko , Kakeji Yoshihiro , Oda Shinya , Baba Hideo , Sugimachi Keizo
Published: April 2003

Gastric cancer is a major malignant disease. The development of new diagnostic techniques and mass screening have led to increased detection rates of patients with early-stage gastric cancer in Japan. However, after curative resection of early gastric cancer, there are various types of recurrences, and residual occult disease and distant micrometastasis precede death. The growth and metastatic potential of cancer cells are closely related to the postoperative outcome, and patients at risk for cancer-related death after surgery have to be closely monitored to prevent tumor recurrence. The biological behavior of cancer cells should be determined in patients with early gastric cancer and with a less favorable prognosis to detect potential early recurrences in the liver. Two types of growth patterns have been found in early gastric cancer: the superficially spreading (Super) type and the penetrating (Pen) type, and the clinicopathological and biological characteristics of each type have been extensively determined. A subtype of the Pen-type gastric cancer, which is progressing expansively with complete destruction of the muscularis mucosae (Pen A type) has a less favorable prognosis due to early recurrences in the liver. These clinical cancer types are closely related to chromosomal instability in DNA aneuploidy and p53 overexpression, and vascular endothelial growth factor activation induced tumor angiogenesis, vascular invasion and hematogenous metastasis. Thus, patients with Pen-A-type cancer showing expansive tumor growth had a poorer postoperative outcome and a hematogenous-related recurrence of the cancer. Antiangiogenic approaches in a postoperative setting may prove to be effective in preventing tumor recurrence and improving the prognosis for these patients.
Assessment of Quality of Care in an Oncology Institute Using Information on Patients’ Satisfaction
Authors: Brédart A. , Razavi D. , Robertson C. , Didier F. , Scaffidi E. , Fonzo D. , Autier P. , de Haes J.C.J.M.
Published: April 2003

Objective: To evaluate the feasibility of conducting a patient satisfaction survey in the oncology hospital setting, using a multidimensional patient satisfaction questionnaire to be completed at home. Methods: Socio-demographic and clinical data were collected for 133 consecutive patients. Patients were asked to complete the European Organisation for Research and Treatment of Cancer QLQ-C30 (version 2.0) just before hospital discharge and the Comprehensive Assessment of Satisfaction with Care at home 2 weeks after discharge. Results: Respondents (73% of patients approached) were younger, hospitalized for a shorter time and presented less appetite loss, nausea and vomiting and better physical and role functioning than non-responders. The aspects of care for which patients wanted the most improvement were associated with the provision of medical information. In multivariate analyses, longer hospital stay was associated with higher satisfaction with all aspects of medical and nursing care, most probably because patients discharged early were not assured of continuity of care and lacked information regarding self-care at home. Higher global quality of life was associated with higher satisfaction with all aspects of care, suggesting the potential contribution of patient satisfaction to the patients’ well-being. Conclusions: Conducting a patient satisfaction survey in an oncology hospital setting proved feasible; however, further surveys should attempt to obtain the opinion of patients with more severe physical conditions. The assessment of the patients’ satisfaction provided indications for improvement of care in a particular hospital. Although the results of this study are specific to one hospital, the methods could be reproduced in other hospital settings, but may possibly lead to other conclusions.
Effect of the Dose and Duration of Interferon-Alpha Therapy on the Incidence of Hepatocellular Carcinoma in Noncirrhotic Patients with a Nonsustained Response to Interferon for Chronic Hepatitis C
Authors: Toyoda Hidenori , Kumada Takashi , Nakano Satoshi , Takeda Isao , Sugiyama Keiichi , Kiriyama Seiki , Sone Yasuhiro , Tanikawa Makoto , Hisanaga Yasuhiro , Hayashi Kazuhiko , Honda Takashi
Published: April 2003

Objective: We evaluated the effect of dose and duration of treatment with interferon (IFN)-α on the incidence of hepatocellular carcinoma (HCC) after IFN treatment in patients with chronic hepatitis C. Methods: A total of 291 noncirrhotic patients with chronic hepatitis C without hepatitis B virus coinfection in whom hepatitis C virus (HCV) was not eradicated by IFN-α therapy were retrospectively analyzed. The incidence of HCC after IFN therapy was compared according to the total dose or duration of treatment. Results: Patients were followed up for 6–117 months after the end of IFN treatment. The duration of IFN treatment (≦24 vs. >24 weeks) had no effect on the incidence of HCC. However, the incidence of HCC was significantly lower in patients who received >500 million units of IFN as a total dose than in patients who received ≦500 million units of IFN (p = 0.0480), and the total dose of IFN (>500 million units) was an independent factor affecting the incidence of HCC (p = 0.0405). In addition, when focusing on patients whose histology was F2 or F3 before IFN treatment, the suppressive effect of the total dose of IFN (>500 million units) was emphasized (p = 0.0049 in generalized Wilcoxon test and p = 0.0178 in multivariate analysis). Conclusions: Patients with chronic hepatitis C should receive more than 500 million units of IFN when IFN is used to decrease the incidence of subsequent HCC.
Expression of Metallothionein in Colorectal Cancers and Synchronous Liver Metastases
Authors: Hishikawa Yoshitaka , Kohno Hitoshi , Ueda Syuhei , Kimoto Takeo , Kumar Dhar Dipok , Kubota Hirofumi , Tachibana Mitsuo , Koji Takehiko , Nagasue Naofumi
Published: April 2003

The aim of this study is to clarify whether the expression of metallothionein (MT) is related with the malignant potential in primary colorectal cancer and/or synchronous liver metastasis. Immunohistochemical staining for MT was performed on the specimens of adenocarcinoma of the colon and rectum and its liver metastases in 34 patients treated with curative surgery, respectively. Expression of MT was compared with clinicopathological variables and patient survival. In patients with primary colorectal cancer, positive expression was found in 7 of 34 (20.6%) patients, but MT was not detected in any of the cases of liver metastases (0%; p = 0.0111). In the primary tumor, positive MT expression was significantly associated with a higher degree of lymph node involvement (mean ± SD: 48.4 ± 33.8 vs. 18.6 ± 24.4% in MT-positive and MT-negative tumors, respectively; p = 0.0122). The survival rate in the patients with MT-negative tumors was significantly better than that in those with MT-positive tumors as primary sites (p = 0.0198). MT expression in colorectal cancer may be a potential marker affecting lymph node metastases and may be a predictor of a poor prognosis, particularly in patients with synchronous liver metastases.
Clinical Prognostic Factors for Patients with Recurrent Head and Neck Cancer: Implications for Randomized Trials
Authors: Pivot X. , Niyikiza C. , Poissonnet G. , Dassonville O. , Bensadoun R.J. , Guardiola E. , Foa C. , Benezery K. , Demard F. , Thyss A. , Schneider M.
Published: April 2003

The purpose of our study was to determine the clinical prognostic factors for the duration of the overall survival from recurrence (OSR) in patients with recurrent head and neck squamous-cell carcinoma. We performed a retrospective analysis on 496 patients treated between 1982 and 1993 at the Antoine Lacassagne Center. The significant favorable prognostic factors for the OSR were: initial T1–2 (p = 0.008), no initial nodal involvement (p = 0.002), no initial chemotherapy exposure (p = 0.002), induction chemotherapy response (p = 0.001), duration of disease-free interval (DFI; p = 0.0001), performance status (PS) 0–1 (p = 0.004) and local-regional recurrence (p = 0.001). In the multivariate analysis, the apparent nonsignificance of all factors apart from the DFI suggested that relevant prognostic factors could be embedded in the DFI. Multivariate analysis was performed after excluding the DFI. The results indicated that local-regional recurrence, PS 0–1 and no initial chemotherapy exposure remained significant favorable prognostic factors for the OSR. The advantages of taking into account such prognostic factors are to eliminate the patient selection bias and to ensure a fairer comparative evaluation of new or already existing agents in recurrent head and neck cancer.
Expression of p57/Kip2 Protein in Hepatocellular Carcinoma
Authors: Ito Yasuhiro , Takeda Tsutomu , Sakon Masato , Tsujimoto Masahiko , Monden Morito , Matsuura Nariaki
Published: April 2003

Evaluation of the biological character of carcinomas requires understanding of cell cycle regulators. In the present study, we investigated the expression of p57 (Kip2) in 90 hepatocellular carcinomas and 66 noncancerous lesions. The average p57 labeling index in noncancerous lesions was 72.3 ± 19.7. The labeling index significantly decreased (p < 0.0001) in hepatocellular carcinoma (54.9 ± 19.7). It was significantly lower in hepatocellular carcinoma cases with high biological aggressiveness such as advanced stage (p = 0.0041), poor differentiation (p < 0.0001), larger size (p = 0.0400), portal invasion (p < 0.0001), satellite tumor (p = 0.0023), high proliferating activity (p = 0.0002) and cyclin D1 overexpression (p = 0.0416). Furthermore, cases with low p57 expression showed worse outcomes for disease-free survival in univariate analysis (p = 0.0235), although p57 expression could not be recognized as an independent prognostic factor. These findings suggest that p57 contributes to the downregulation of cell proliferation and to the progression of hepatocellular carcinoma.
Is Cisplatin Required for the Treatment of Non-Small-Cell Lung Cancer? Experience and Preliminary Results of a Phase I/II Trial with Topotecan and Vinorelbine
Authors: Stupp Roger , Bodmer Alexandre , Duvoisin Bertrand , Bauer Jean , Perey Lucien , Bakr Mohamed , Ketterer Nicolas , Leyvraz Serge
Published: April 2003

Platinum-based chemotherapy is considered standard treatment for advanced non-small-cell lung cancer (NSCLC). However, toxicity of most platinum-based regimens is substantial and requires close monitoring and supportive care. Over the past decade, paclitaxel, docetaxel, vinorelbine, gemcitabine, irinotecan, and topotecan have been introduced into the clinic. These newer agents have shown promising activity against NSCLC with a favorable toxicity profile as single agents. For patients with metastatic NSCLC, palliation is the main goal of therapy. Therefore, treatment should be easy to administer on an outpatient basis. We explored a novel combination therapy avoiding platinum. Patients with recurrent or metastatic NSCLC were treated with intravenous (i.v.) topotecan (0.5–1.0 mg/m2/day × 5) and i.v. vinorelbine (20–30 mg/m2/day on day 1 and day 5) in 21-day cycles. Dose-limiting toxicity (DLT) was defined separately with or without the addition of granulocyte colony-stimulating factor (G-CSF) support. Twenty-nine patients have been enrolled to date. At i.v. topotecan doses of 0.75–1.0 mg/m2/day and i.v. vinorelbine of 25 mg/m2/day, neutropenia was frequent but of short duration (<7 days). The DLT of i.v. topotecan (0.85 mg/m2) in the absence of G-CSF support was based on myelosuppression with neutropenic fever. With the addition of G-CSF, a DLT has not been reached. Nonhematologic toxicities included mild to moderate fatigue and constipation. An overall clinical response rate of 42% was achieved, with responses noted at all dose levels. At a short median follow-up of 15 months, the median survival for all patients is 13 months. In conclusion, the combination regimen of topotecan and vinorelbine is feasible for outpatient administration and is well tolerated with less toxicity than platinum-based regimens. Preliminary response data demonstrate good tumor activity, suggesting that this regimen could make an excellent palliative treatment for advanced NSCLC.
Biology of HER2 and Its Importance in Breast Cancer
Authors: Yarden Yosef
Published: April 2003

Human epidermal growth factor receptor-2 (HER2/erbB-2) belongs to a family of four transmembrane receptors involved in signal transduction pathways that regulate cell growth and differentiation. Overexpression/amplification of HER2 is associated with malignancy and a poor prognosis in breast cancer. HER2 acts as a networking receptor that mediates signaling to cancer cells, causing them to proliferate. HER receptors exist as monomers but dimerize on ligand binding. HER ligands are bivalent growth factor molecules whose low-affinity site binds to HER2. No HER2-specific ligand has been identified but HER2 is the preferred heterodimerization partner for other HER receptors. HER2-containing heterodimers are relatively long-lived and potent. HER3 has no inherent activity and is the major and most potent dimerization partner of HER2. HER2 overexpression biases the formation of HER2-containing heterodimers, leading to enhanced responsiveness to stromal growth factors and oncogenic transformation. Removal of HER2 from the cell surface or inhibition of its intrinsic enzymatic activity may reduce oncogenicity. Our research suggests that the antitumor efficacy of HER2-specific antibodies such as Herceptin® relates to their ability to direct HER2 to a Cbl- dependent endocytosis and degradation pathway. The reported clinical therapeutic efficacy of anti-HER2 monoclonal antibodies in breast cancer highlights the importance of understanding the biology of HER2.
Ultrasound Biomicroscopy in the Assessment of Secondary Glaucoma after Vitreoretinal Surgery and Silicone Oil Injection
Authors: Genovesi-Ebert F. , Rizzo S. , Chiellini S. , Gabbriellini G. , Laddaga F. , Nardi M.
Published: April 2003

This retrospective study was undertaken to evaluate the utility of Ultrasound Biomicroscopy (UBM) in the assessment of the anterior chamber in patients affected by silicone oil-related glaucoma after vitreoretinal surgery. UBM showed high reflectivity of angular structure, anterior chamber alterations and a fairly trophic ciliary body.
Ultrasonographic Follow-Up of Primary Choroidal Malignant Melanoma after Proton Beam Irradiation Therapy
Authors: Romani A. , Baldeschi L. , Genovesi-Ebert F. , Rizzo S. , Nardi M.
Published: April 2003

The aim of this study is to evaluate the ultrasonographic aspects of primary choroidal malignant melanoma (PCMM) after proton beam irradiation therapy and the reliability of its ultrasonographic follow-up in a series of 10 patients. All patients were examined with standardized A and B scan ultrasonography before and after treatment with proton beam irradiation therapy. The follow-up was carried out at 1, 3, 5, 8 months and then every 6 months. The mean follow-up was 20 months (range 6–34 months). The thickness of the tumors was demonstrated to be decreased and the internal reflectivity to be enhanced in 9 out of 10 cases from 8 months after treatment till the end of the follow-up period. Histopathology confirmed in 1 eye enucleated 5 months after treatment that medium-low internal reflectivity coresponded with several areas of high cellularity and cellular mitosis. The results of our study indicate the reliability of standardized A and B scan echography in the follow-up of PCMM treated with proton beam irradiation therapy.
Investigation of the ‘Fines’ Hypothesis of Primary Open-Angle Glaucoma: The Possible Role of Alpha-Crystallin
Authors: Doss Ellen W. , Ward K.A. , Koretz J.F.
Published: April 2003

Primary open-angle glaucoma is a disease caused by an increase in intraocular pressure due to a decreased facility of outflow of aqueous humor through the trabecular meshwork. The etiology of primary open-angle glaucoma is currently unknown, but it has been suggested that one possible mechanism may be the obstruction of flow through the trabecular meshwork by small macromolecules, analogous to the effect of ‘fines’ in column chromatography. One such candidate is α-crystallin, a lens protein which may be released into the aqueous humor from lens fiber cells at concentrations below that necessary for the formation of the native aggregate. Results of in vitro binding experiments indicate that α-crystallin and serum albumin, which is secreted at the anterior root of the iris and is believed to act as a protein escort through the trabecular meshwork in mammalian eyes, will interact at concentrations of α-crystallin up to the critical micelle concentration for α-crystallin (3.5–5 mg/ml, or 0.18–0.25 mM). There is little interaction at or above this concentration. This binding could serve the necessary function of preventing interactions between α-crystallin monomers or small aggregates and hydrophobic surfaces within the trabecular meshwork. Since, however, the interaction between the two proteins is not extremely strong, the accumulation of unbound α-crystallin monomers and/or dimers could contribute to the development of primary open-angle glaucoma.
Inflammation Measurement and Immunocharacterization of Cell Proliferation in an Experimental Model of Proliferative Vitreoretinopathy
Authors: Baudouin Ch. , Khosravi E. , Pisella P.J. , Ettaiche M. , Elena P.P.
Published: April 2003

An experimental model of proliferative vitreoretinopathy was developed in the rabbit eye by injecting a solution of human platelet-rich plasma. In this model we evaluated the progression with time of intraocular inflammation and the rate and origin of cell proliferation. A sterile solution adjusted to 107 platelets was injected into the right eye of a total of 46 pigmented and 14 albino rabbits. Animals were sequentially sacrificed at days 7, 14, 21 and 1 month after injection. Clinical evaluation of vitreoretinal proliferation, using a classification in six grades, and of anterior segment inflammation assessed by a Laser Flare Meter, were done for 1 month after injection, before histopathological analysis. Eighty percent of eyes developed tractional retinal detachment in 1 month. Histopathology showed intense cell migration and proliferation in the area of the ciliary body, as early as the seventh day, then further increasing rapidly. Infiltrates were composed of cytokeratin- and vimentin-expressing cells. Abnormal expression of vimentin was also found in ciliary and retinal epithelia and in Müller cells. Inflammation measured by the Laser Flare Meter was maximal at day 11 and then reached a plateau at significantly higher levels than controls. Albino rabbits showed significantly lower grades of proliferation, as compared to pigmented rabbits. This study thus clarified some characteristics of exper- imental vitreoretinal proliferations that proved similar to those in human diseases, such as the involvement of ciliary body and retinal pigment epithelium, the existence of inflammatory reactions preceding cell proliferation and strong changes in intermediate filaments. This may provide a simple and valuable model for antiproliferative assays and shed some light on the pathogenesis of intraocular proliferative disorders.
TGF Beta Secretion Modulates the Density-Dependent Growth of Pig Retinal Pigment Epithelium in vitro
Authors: Tezel Tongalp H. , Del Priore Lucian V.
Published: April 2003

Background: We aimed to identify the cytokine(s) responsible for the density-dependent growth regulation of pig retinal pigment epithelium (RPE) in vitro. Methods: Confluent monolayers of primary pig RPE were established on bovine corneal endothelial extracellular matrix-coated tissue culture well inserts wrapped with dialysis membranes with different molecular weight cutoffs (0.5–50 kDa). These confluent RPE monolayers were then cocultured with first passage porcine RPE plated at a density of 1 cell/mm2, so that the newly plated RPE was bathed with different molecular weight fractions of the confluent cell media. Growth rates of the newly plated RPE were determined 72 h after plating and the molecular weight fraction of the confluent cell medium that inhibits the RPE proliferation was determined. First passage pig RPE (1 cell/mm2) were cocultured with confluent monolayers of primary pig RPE on inserts in the presence of different amounts of TGF-β neutralizing antibody (0.1–100 µg/ml). Growth rates of the newly plated RPE were calculated 72 h after plating to determine the antibody concentration that would maximize the growth rate of the newly plated RPE in the presence of an adjacent confluent RPE monolayer. Results: The growth rate of the newly plated RPE decreased when RPE were bathed with the 10- to 25-kDa fractions of medium from an adjacent confluent RPE monolayer. This growth inhibition reached statistical significance with the 25- to 50-kDa fractions (p < 0.05), and was abolished by adding pan-specific neutralizing antibody against TGF-β (0.1–5 µg/ml). Blocking greater amounts of TGF-β in the medium with higher doses of antibody (>10 µg/ml) also inhibited the growth of the newly plated RPE, in the presence or absence of a neighboring confluent cell layer. Conclusion: The TGF-β family of cytokines mediates the density-dependent growth suppression of RPE in vitro. Neutralizing the effect of these cytokines by adding anti-TGF-β antibodies can result in more rapid growth of the RPE in vivo.