bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Management of Stage I–II High-Grade Primary Gastric Lymphomas
Authors: Ferreri Andrés J.M. , Cordio Stefano , Paro Serena , Ponzoni Maurilio , Freschi Massimo , Veglia Fabrizio , Villa Eugenio
Published: April 2003

The best treatment for primary gastric lymphomas (PGL) has not yet been defined. Eighty-three patients with stage I/II PGL are documented, focusing on prognostic factors, treatment-related morbidity and mortality, and therapeutic outcome. Chemotherapy improved survival in comparison to local treatments, i.e. gastrectomy (n = 15) or gastrectomy and radiotherapy (n = 5). Patients treated with primary chemotherapy and/or radiotherapy (n = 21), with gastrectomy and chemotherapy (n = 26) or with gastrectomy and chemotherapy and radiotherapy (n = 16) showed a similar survival rate. Conservative treatment obtained a 5-year actuarial survival of 82% with a stomach preservation rate of 100%. Two treatment failures and 19 relapses (24%) were observed. Sixty patients (72%) are alive (59 no evidence of disease) at a median follow-up of 58 months. Ten-year actuarial survival is 64%. Local control was influenced by stage, tumor size, depth of infiltration, LDH ratio, and therapeutic modality, while age, stage, LDH ratio, and the use of chemotherapy had independent prognostic value. Because of its efficacy and safety, conservative strategy should be considered as first-line treatment for high-grade PGL. Gastrectomy should be indicated only for urgent cases, in which surgery followed by chemotherapy appears the best choice, followed by radiotherapy in patients with stage II2 disease.
A Randomized Controlled Comparative Study of Oral Medroxyprogesterone Acetate 1,200 and 600 mg in Patients with Advanced or Recurrent Breast Cancer
Authors: Koyama Hiroki , Tominaga Takeshi , Asaishi Kazuaki , Abe Rikiya , Iino Yuichi , Enomoto Kohji , Miura Shigeto , Nomura Yasuo , Nakazato Hiroaki , Abe Osahiko
Published: April 2003

A randomized controlled comparative study of oral medroxyprogesterone acetate (MPA) 1,200 mg (arm I) and 600 mg (arm II) was conducted in 80 patients with advanced or recurrent breast cancer. There were no significant differences between arm I and arm II in terms of response rate, duration of response and survival, or in terms of incidence and severity of adverse reactions. The lowest serum MPA concentration in responders tended to be higher than that in nonresponders. In the cohort of this study, the lowest concentration in partial response was 17.4 ng/ml, suggesting that this level may be the required minimum serum concentration.
Tumor-Associated Macrophage Infiltration in Pulmonary Adenocarcinoma: Association with Angiogenesis and Poor Prognosis
Authors: Takanami Iwao , Takeuchi Ken , Kodaira Susumu
Published: April 2003

The relation between tumor-associated macrophage (TAM) density and the density of microvessels was investigated in specimens from 113 patients with pulmonary adenocarcinoma, as was the influence of TAM density on prognosis. The rank correlation test revealed a significant relation between TAM density and microvessel density (y = 14.418 + 0.863x, r = 0.454, p > 0.0001). A significant difference in patient survival rate was detected between tumors with a TAM density defined as high and those with a TAM density defined as low (p < 0.01). Multivariate analysis also showed that TAM density was significantly related to survival (p < 0.05). These data indicate that TAM infiltration may contribute to tumor angiogenesis, and that TAM density is a useful prognostic marker in pulmonary adenocarcinoma.
Neoangiogenesis and Relationship to Nuclear p53 Accumulation and Vascular Endothelial Growth Factor Expression in Advanced Gastric Carcinoma
Authors: Saito Hiroaki , Tujitani Shunichi , Ikeguchi Masahide , Maeta Michio , Kaibara Nobuaki
Published: April 2003

Recent studies have shown that tumor suppressor genes, particularly p53, may play a crucial regulatory role in the control of angiogenesis. Accordingly, we analyzed the correlation between p53 accumulation and the expression of vascular endothelial growth factor (VEGF) and microvessel counts in a series of human gastric adenocarcinomas by immunohistochemical staining. p53 expression was absent in 35 cases (29.7%), weak in 34 cases (28.8%), moderate in 35 cases (29.7%), and strong in 14 cases (11.8%). The prognosis of patients with both absent and weak expression of p53 was significantly better than that of patients with both moderate and strong expression of p53. VEGF expression was significantly associated with increased p53 expression. Moreover, increasing expression of p53 significantly correlated with an increase in microvessel counts. Nuclear p53 accumulation may correlate with tumor angiogenesis through VEGF upregulation in gastric carcinomas.
Infusions of Fluorouracil and Leucovorin: Effects of the Timing and Semi-Intermittency of Drug Delivery
Authors: Falcone Alfredo , Allegrini Giacomo , Antonuzzo Andrea , Brunetti Isa , Pfanner Elisabetta , Lencioni Monica , Masi Gianluca , Danesi Romano , Del Tacca Mario , Conte Pierfranco
Published: April 2003

Preclinical and clinical studies have demonstrated that the circadian modulation of 5-FU delivery may reduce toxicities and improve antitumor activity. However, the relative importance of the timing of 5-FU delivery has not been clinically addressed. The aims of this study were to determine the toxicities, the maximum tolerable doses and the activity of a regimen with 5-fluorouracil (5-FU) and leucovorin (LV) administered as a 14-day continuous infusion according to a flat or three different chronomodulated rhythms in patients with metastatic gastrointestinal carcinomas. A total of 113 patients entered the study and their characteristics were comparable among the four groups. Toxicities included mainly stomatitis and diarrhea, and a reduced toxicity was observed in all the three chronogroups that allowed the delivery of higher dose intensities. Response rates were not significantly different among the four groups. These results suggest that a reduction in 5-FU+LV toxicity and an increase in 5-FU dose intensity can be obtained by a nonsinusoidally circadian modulated infusion. However, the reduction in toxicity observed seems to be dependent mainly on the quasi-intermittency and not on the timing of 5-FU+LV delivery.
Phase II Study of Irinotecan and Cisplatin as First-Line Chemotherapy in Advanced or Recurrent Cervical Cancer
Authors: Sugiyama Toru , Yakushiji Michiaki , Noda Kiichiro , Ikeda Masanori , Kudoh Ryouichi , Yajima Akira , Tomoda Yutaka , Terashima Yoshiteru , Takeuchi Shoshichi , Hiura Masamichi , Saji Fumitaka , Takahashi Takeshi , Umesaki Naohiko , Sato Shinji , Hatae Masanori , Ohashi Yasuo
Published: April 2003

Irinotecan (CPT-11) and cisplatin are singly active against cervical cancer. We evaluated the efficacy and toxicity of CPT-11 plus cisplatin as first-line chemotherapy in patients with advanced or recurrent cervical cancer. Twenty-nine chemotherapy-naive patients with advanced or recurrent cervical cancer were treated with CPT-11 (60 mg/m2) on days 1, 8, and 15 by intravenous infusion over 90 min, followed by cisplatin (60 mg/m2 i.v.) on day 1 over 90 min. The patients’ median age was 57 years (range 35–75). Nineteen patients (66%) had advanced primary disease. Six patients with recurrent disease (21%) had been treated with prior radiotherapy. The remaining 4 patients (14%) had residual or recurrent disease after radical surgery. The histologic diagnoses were squamous cell carcinoma in 25 patients (87%), adenocarcinoma in 3, and adenosquamous cell carcinoma in 1. All eligible patients were included in the toxicity and response analysis based on the intent to treat. Two patients (7%) achieved a complete response and 15 (52%) a partial response (overall response rate: 59%, 95% confidence interval; 41–74%). Stable disease was recorded in 6 patients (21%) and progressive disease in 3 patients (10%). In 3 patients, image-guided evaluation of response was judged to be unfeasible at the time of independent extramural review (10%). The median time to response was 32 days (range 16–62 days). The median survival was 27.7+ months (range, 6.4–52.8+ months). Two dose-limiting side effects were observed: grade 3 (28%) or 4 (45%) neutropenia and grade 3 (7%) or 4 (7%) diarrhea. Other severe toxicities included anemia (45%), thrombocytopenia (3%), nausea/vomiting (31%), and alopecia (7%). The combination of CPT-11 with cisplatin is an active regimen for treatment of advanced or recurrent cervical cancer albeit with a significant degree of myelosuppression.
p53 Gene Mutation, Microsatellite Instability and Adjuvant Chemotherapy: Impact on Survival of 388 Patients with Dukes’ C Colon Carcinoma
Authors: Elsaleh Hany , Powell Brenda , Soontrapornchai Prinya , Joseph David , Goria Fabrizio , Spry Nigel , Iacopetta Barry
Published: April 2003

Two common genetic alterations in colon carcinoma, p53 mutation and microsatellite instability (MSI), were investigated to determine their prognostic importance for cancer-specific survival and response to adjuvant chemotherapy in patients with Dukes’ C colon cancer. The p53 tumour suppressor gene encodes for a nuclear phosphoprotein involved in cellular response to DNA damage, while MSI is a characteristic feature of tumours with defective DNA mismatch repair. The cellular response mechanisms to DNA-damaging agents in tumours with mutant p53 or MSI may as a consequence differ, and this might translate into different outcomes following adjuvant chemotherapy. A consecutive series of 388 Dukes’ C colon carcinomas with 5-year median follow-up was analysed for p53 mutation and for MSI (in proximal/transverse carcinomas only) using polymerase chain reaction single-strand conformation polymorphism. The incidence of p53 mutation was 28% in all carcinomas while that of MSI in proximal/transverse carcinomas was 19%. One hundred and thirty-three patients (34%) received adjuvant chemotherapy (5-fluorouracil/levamisole) with curative intent. The presence of p53 mutation did not predict for survival in either the treated or untreated groups. The presence of MSI in the proximal/transverse colon carcinoma group was associated with significantly better 5-year survival: 58 versus 32% (p = 0.015, log rank test). This was largely due to better survival observed in the MSI subgroup that received adjuvant chemotherapy (p = 0.017, log rank test). Further work in prospective, randomised clinical trials investigating the effects of adjuvant therapy should consider incorporating MSI status in order to determine whether this is an independent predictive factor for survival and/or response to adjuvant chemotherapy.
High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation: The Lymphoma Experience and Its Potential Relevance to Solid Tumors
Authors: Armitage James O.
Published: April 2003

Lymphomas, which are frequently subdivided into Hodgkin’s disease and non-Hodgkin’s lymphoma, represent one of the more curable cancers that present as a solid tumor. Unfortunately, most patients cannot be cured with conventional chemotherapy, therefore new techniques have been developed including high-dose chemotherapy and autotransplantation. Non-Hodgkin’s lymphoma was one of the first illnesses to be tested using the new methods and initial encouraging results in relapsed lymphoma led to the testing of high-dose chemotherapy with autotransplantation as a primary therapy for patients with lymphomas. Encouraging results have been obtained in several randomized trials. Studies of the treatment of lymphoma have identified several principles related to the application of autotransplantation, which may be relevant to other solid tumors. Autotransplantation is likely to be of benefit only when using active chemotherapeutic agents that can be escalated in dose and when myelosuppression is the dose-limiting toxicity. Chemotherapy-responsive tumors are obvious targets for autotransplantation, whereas chemotherapy-resistant tumors are unlikely to benefit. Other factors that should be taken into account when selecting patients for high-dose chemotherapy regimens include the extent of disease, preceding therapy and the performance status of the patient.
Low-Grade Fibromyxoid Sarcoma
Authors: van den Bossche M.R.P. , van Mieghem H.
Published: April 2003

Described is a low-grade fibromyxoid sarcoma (LGFMS) of the abdominal wall muscles in a 38-year-old black woman. There was no evidence of metastatic disease. A 5.2-kg LGFMS – the largest case ever reported – was resected. One year after surgery, the patient is alive without any sign of local recurrence or distant metastasis. Follow-up comprises abdominal and thoracic CT scans at 6-month intervals.
A Phase II Study of Gemcitabine and 5-Fluorouracil in Metastatic Pancreatic Cancer: An Eastern Cooperative Oncology Group Study (E3296)
Authors: Berlin Jordan D. , Adak Sudeshna , Vaughn David J. , Flinker David , Blaszkowsky Lawrence , Harris Jules E. , Al Bowen Benson III A.B.
Published: April 2003

Gemcitabine has recently been compared favorably to 5-fluorouracil (5-FU) as the standard chemotherapy for advanced pancreas cancer. Based on phase I data that combining gemcitabine with 5-FU is safe and has evidence for clinical activity, a phase II trial was conducted by the Eastern Cooperative Oncology Group (ECOG). Patients with metastatic disease, good performance status and organ function were eligible and enrolled after providing informed consent. Patients were given gemcitabine (1,000 mg/m2) followed by 5-FU (600 mg/m2) weekly for 3 weeks of every 4. Of 37 patients enrolled over a 3-month period, 36 were eligible. Partial responses were seen in 5 patients (14%). Median survival was 4.4 months with a 1-year survival rate of 8.6%. A randomized trial of the combination of 5-FU and gemcitabine versus gemcitabine alone is currently accruing patients in ECOG.
Alteration of a p53 Gene Status Affects Outcome of Patients with Recurrent Ovarian Cancer
Authors: Irie Takashi , Kigawa Junzo , Minagawa Yukihisa , Oishi Tetsuro , Takahashi Masakuni , Shimada Muneaki , Kamazawa Shunji , Sato Shinya , Terakawa Naoki
Published: April 2003

The aim of this longitudinal study was to examine whether and how the p53 gene is altered in patients with recurrent ovarian cancer and to determine the significance of p53 mutation in recurrent tumors. The primary and recurrent tumors were examined in 15 patients who had recurrent epithelial ovarian cancer, and whose primary tumor contained a wild-type p53 gene. The interval between cytoreductive surgery and the appearance of recurrence ranged from 5.2 to 63.6 months (mean 23.4 months). Mutations in the p53 gene were screened by polymerase chain reaction single strand conformation polymorphism analysis and determined by cycle sequencing. Mutation of the p53 gene in the recurrent tumor was found in 7 of the 15 patients (46.7%). Estimated 3- and 5-year survival rates were 57.1 and 0%, respectively, for patients with p53 gene mutation detected in the recurrence tumor, and 75.0% and 37.5% for patients without the mutation (p = 0.0155). The interval between cytoreductive surgery and the appearance of recurrence did not differ between those groups (549.7 ± 102.2 vs. 832.9 ± 283.8 days). Mean survival time after recurrence was significantly better in the patients without mutation (438.6 ± 56.4 vs. 873.0 ± 157.5 days, p = 0.0125). The present study suggests that p53 gene mutation frequently occurs in recurrent ovarian cancer and that alteration of p53 gene status affects salvage chemotherapy. This phenomenon affects the prognosis of recurrent disease and may predict outcome.
ets-1 Expression in Extrahepatic Bile Duct Carcinoma and Cholangiocellular Carcinoma
Authors: Ito Yasuhiro , Miyoshi Eiji , Takeda Tsutomu , Sakon Masato , Tsujimoto Masahiko , Yokosaki Yasuyuki , Monden Morito , Matsuura Nariaki
Published: April 2003

ets-1 is a transcription factor known to induce the expression of various genes important for carcinoma progression. However, its clinical significance does not seem to be uniform for all carcinomas. In this study, we investigated the ets-1 expression in 41 extrahepatic bile duct carcinomas (BDC) and 19 cholangiocellular carcinomas (CCC). Epithelial cells of normal ducts only occasionally expressed ets-1, whereas cells of reactive ducts and dysplastic ducts were often positive for this protein. On the other hand, 61.0% of BDC and 21.6% of CCC were classified as ets-1-positive, because more than 5% of the carcinoma cells expressed ets-1. The expression of ets-1 showed inverse relationships with the Ki-67-labeling index and vascular and perineural invasion of BDC, whereas no such relationships could be established in CCC. Furthermore, the well-differentiated BCD more frequently expressed ets-1. These results suggest that ets-1 works as a transcription factor in malignant transformation and progression in early phases of BDC.
Prognosis and Surgical Treatment of Gastric Cancer Invading the Pancreas
Authors: Maehara Yoshihiko , Oiwa Hisao , Tomisaki Shinichi , Sakaguchi Yoshihisa , Watanabe Akihiro , Anai Hideaki , Sugimachi Keizo
Published: April 2003

The clinicopathologic characteristics of gastric cancer invading the pancreas have not been determined. Gastrectomy was performed in 282 patients with gastric cancer invading adjacent organs at the Department of Surgery II, Kyushu University Hospital, between 1970 and 1987, and patient data were retrospectively analyzed using univariate and multivariate analyses. Of these patients, 150 (53.2%) had tumors invading the pancreas and 132 had tumors invading adjacent organs other than the pancreas. In both groups, the undifferentiated tissue type with infiltrative growth, lymphatic involvement and lymph node metastasis was common. In cases of pancreas invasion, the extent of lymph node metastasis was more severe, vascular involvement was more frequent and the rate of concomitant liver metastasis was higher. The survival time of the patients with pancreas invasion was shorter compared to patients with cancer invading other organs, and pancreas involvement was one of the independent factors predicting a poor prognosis. With respect to surgical treatment of gastric cancer invading the pancreas, the prognosis was better for cases treated with curative surgery and pancreas resection. Of 39 patients treated with partial resection of the pancreas, the tumor had invaded only the capsule of the pancreas in 18 and the pancreas in the other 21. Pancreas-invasive gastric cancer cells are likely to advance via lymphatic and vascular routes and survival time is shorter, but curative resection can improve the survival rate, and perioperative treatment should be appropriately designed.
Diffuse Mode of Tumor Cell Invasion and Expression of Mutant p53 Protein But Not of p21 Protein Are Correlated with Treatment Failure in Oral Carcinomas and Their Metastatic Foci
Authors: Osaki Tokio , Kimura Tsuyoshi , Tatemoto Yukihiro , Dapeng Lu , Yoneda Kazunori , Yamamoto Tetsuya
Published: April 2003

Lack of control of metastatic foci is the most prevalent cause of death in patients with oral carcinomas, and it is important for tumor control to identify the factors that predispose patients to death. In the present study, we examined 225 patients with oral squamous cell carcinoma and investigated the immunohistopathological characteristics of 43 tumors that led to death, comparing them with those of the non-lethal tumors. In the 43 patients, lack of control of the primary site, lymph node and distant metastatic tumors were noted in 20, 18 and 16 patients, respectively. The mode of tumor cell invasion was closely correlated with death. The diffuse invasion modes of grades 4C and 4D were observed in 15 (34.9%) of the 43 tumors with a poor outcome and in 35 (19.2%) of the 182 controlled tumors (p < 0.02). The expression of p53 was highly correlated with death. Of the tumors with poor prognosis, p53 protein was expressed in 32 tumors (76.2%). However, p53 protein expression was observed in 52.7% of the tumors with good prognosis (p < 0.02). In contrast, the expression of p21 protein in the well-controlled tumors (30.4%) was almost equal to that of the 43 lethal tumors (26.2%). Compared with the ratios of local recurrence, metastases and their treatment failures in the p53-negative grade 1 and 2 tumors, those in the mutant p53-positive grade 3, 4C and 4D tumors were mostly high. These results indicate that measuring p53 protein expression and evaluating the mode of tumor cell invasion are important for oral carcinoma therapy because the expression of mutant p53 protein and the diffuse modes of tumor cell invasion indicate a predisposition toward a poor prognosis.
Expression and Prognostic Role of Cyclin-Dependent Kinase 1 (cdc2) in Hepatocellular Carcinoma
Authors: Ito Yasuhiro , Takeda Tsutomu , Sakon Masato , Monden Morito , Tsujimoto Masahiko , Matsuura Nariaki
Published: April 2003

The expression of cyclin-dependent kinase 1 (cdc2), cyclin A and cyclin B1 was immunohistochemically studied in 101 hepatocellular carcinomas (HCC). cdc2 overexpression was directly related to advanced stage, portal invasion, intrahepatic metastasis, poor differentiation, high α-fetoprotein level, large size, high Ki-67 labeling index and poor prognosis. Cyclin A and B1 overexpression showed similar tendency to that of cdc2, but they were not recognized as independent prognostic factors by multivariate analysis. These findings suggest that cdc2 plays the most crucial role of the G2/M modulators in cell cycle progression and cell proliferation of HCC and significantly predicts the recurrence of this carcinoma.
Different Expression of Sialyl Tn Antigen between Polypoid and Nonpolypoid Growth Types of Advanced Colorectal Carcinoma
Authors: Nakagoe Tohru , Nanashima Atsushi , Sawai Terumitsu , Tuji Takashi , Yamaguchi Eiichiro , Jibiki Masaaki , Yamaguchi Hiroyuki , Yasutake Toru , Ayabe Hiroyoshi , Matuo Tatsuki , Tagawa Yutaka
Published: April 2003

Colorectal tumors can be classified based on their growth pattern into the polypoid growth type (PG-type) and nonpolypoid growth type (NPG-type). We examined sialyl Tn antigen expression in advanced colorectal carcinomas that were classified as PG-type and NPG-type cancers in order to ascertain whether or not such expression correlates with other biologically and clinically important differences. A total of 94 advanced colorectal carcinomas were examined for sialyl Tn antigen expression, which was immunohistochemically detected by the monoclonal antibody TKH2. Univariate and multivariate analyses using logistic regression models were performed. Forty carcinomas (42.6%) were negative and 54 (57.5%) were positive for sialyl Tn antigen. Eighteen carcinomas (19.2%) were of PG type and 76 (80.8%) of NPG type. NPG-type cancers had a higher proportion of positive lymph node metastasis than PG-type cancers. Furthermore, sialyl Tn antigen was less often detected in NPG-type cancers (39 of 76; 51.3%) than in PG-type cancers (15 of 18; 83.3%; p = 0.0167). Multivariate analysis showed that two variables, lymph node metastasis and sialyl Tn antigen expression in carcinoma, were independently related to tumor growth patterns, that is NPG type and PG type. These data suggest that the difference in sialyl Tn antigen expression between two kinds of tumor growth patterns of advanced colorectal carcinomas, PG type and NPG type, may reflect different biological behaviors during tumor progression.
An Analysis of Serum Interleukin-6 Levels to Predict Benefits of Medroxyprogesterone Acetate in Advanced or Recurrent Breast Cancer
Authors: Nishimura Reiki , Nagao Kazuharu , Miyayama Haruhiko , Matsuda Masakazu , Baba Kenichirou , Matsuoka Yukio , Yamashita Hiroya , Fukuda Makoto , Mizumoto Takao , Hamamoto Rieko
Published: April 2003

Treatment of advanced or recurrent breast cancer with medroxyprogesterone acetate (MPA) shows high response rates and the accessory effects of appetite stimulation, improvement in performance status (PS) and bone marrow protection. In recent years, interleukin-6 (IL-6) has been reported to cause cachexia. In this study, to clarify the significance of IL-6 in advanced or recurrent breast cancer, the relationship between the IL-6 level and clinical findings or effect of MPA was investigated. Sixty-five patients with recurrent or advanced breast cancer participated in a prospective study. The age of patients ranged from 28 to 79 years with an average age of 51.3 years. IL-6 level was investigated in these patients dosed with 800 mg/day of MPA and in 17 postoperative nonrecurrent patients. Serum MPA level was measured by high-performance liquid chromatography and IL-6 level was measured prior to MPA administration, 4 weeks (in 59 cases) and 12 weeks (in 32 patients) after MPA administration by ELISA. Serum IL-6 level was significantly higher in recurrent cases, especially in those with visceral metastasis. Further, in patients for whom MPA therapy was effective, the IL-6 level prior to the treatment was clearly low. The IL-6 level was significantly increased after 4 weeks. However, response to MPA was significantly higher and PS was improved in those cases demonstrating less increased IL-6 levels after 4 weeks. In addition, the effect of MPA was significantly related to a higher serum concentration of MPA-positive ER, and longer disease-free interval, although there was no significant predictive factor for the clinical effect of MPA therapy in multivariate analysis. In conclusion, MPA therapy was effective in cases demonstrating a low IL-6 level and less increased IL-6 levels after 4 weeks. PS was improved in those cases in which the degree of IL-6 increase was suppressed by MPA, and many such cases showed low IL-6 levels prior to MPA therapy. Furthermore, PS was improved even in nonresponders to MPA. Therefore, it is suggested that MPA therapy might be useful in treating recurrent breast cancer, and its benefits might be mediated by IL-6.
Oxaliplatin-Induced Fever and Release of IL-6
Authors: Ulrich-Pur Herbert , Fiebiger W.C.C. , Schüll B. , Kornek Gabriela V. , Scheithauer Werner , Raderer Markus
Published: April 2003

Background: Oxaliplatin is a novel cytotoxic agent with documented activity in colorectal cancer. Side effects are generally moderate, and include peripheral neuropathy along with mild bone marrow suppression and gastrointestinal side effects. To our knowledge, induction of febrile episodes by this agents has not been described in the literature. Case Report: We present the case of a 74-year-old male patient admitted to our institution for palliative treatment of metastatic colorectal carcinoma. Due to progression during treatment with 5-fluorouracil and leucovorin, chemotherapy consisting of oxaliplatin 85 mg/m2 on days 1 + 15 plus mitomycin C 8 mg/m2 on day 1 repeated every 28 days was initiated. The first cycle of this combination was tolerated without side effects, but the patient experienced fever up to 39°C starting 2 h after oxaliplatin administration on day 15 of the second cycle, which persisted for 3 days. Fever again recurred at the same interval following administration of oxaliplatin on day 1 of the next cycle. Blood samples taken at regular intervals disclosed an increase in IL-6 serum levels parallel to the body temperature curve, with the peak corresponding to the highest temperature, while C-reactive protein values remained unchanged. In spite of intensive premedication with steroids, antipyretics and clarithromycin, fever promptly recurred during the third cycle of treatment. Conclusion: Our data suggest a clear- cut correlation between fever, the release of IL-6 and oxaliplatin administration. Whether IL-6 release is directly triggered by the application of oxaliplatin or is a bystander phenomenon, however, remains unclear at the moment.
A Unique Case of Eccrine Porocarcinoma with Pulmonary Lymphangitis and Pericardial Involvement: Biological Characterization and Clinical Aggressiveness
Authors: Biondi Edoardo , Ranieri Girolamo , Nicolò Antonio , Gasparini Giampietro
Published: April 2003

A unique case of eccrine porocarcinoma with pulmonary lymphangitis and pericardial involvement is reported. The clinical course was aggressive, leading to the death of the patient a few months after diagnosis. Certain pathologial markers of clinical aggressiveness were retrospectively investigated: p53 and Ki-67 expression were determined by means of immunohistochemistry. Angiogenesis was assessed by determination of intratumor microvessel density at the vascular ‘hot spot’ with the anti-CD34 monoclonal antibody and quantitative analysis using computerized image analyzer. Both primary tumor and metastatic lymph node presented immunostaining for p53 and Ki-67, with a higher degree of vascularization in the secondary lesions compared to the primary tumor. Our findings suggest a correlation between tumor vascularization and clinicopathological parameters of aggressiveness in malignant eccrine porocarcinoma. Taking into account the disappointing results of current treatments for metastatic eccrine porocarcinoma, the assay of microvessel density may be helpful in selecting the patients of high risk for recurrence or death who may benefit of anti-angiogenic therapies.
Analysis of Genomic Imprinting of Insulin-Like Growth Factor 2 in Colorectal Cancer
Authors: Takano Yuji , Shiota Goshi , Kawasaki Hironaka
Published: April 2003

Genomic imprinting of insulin-like growth factor 2 (IGF2) has been shown to play an important role in the development of Wilms’ tumor and adult cancers including lung and esophageal cancer. Although IGF2 has been reported to be overexpressed in colorectal cancer, the status of this gene has not been fully elucidated. To clarify genomic imprinting of IGF2 in colorectal cancer, we examined loss of imprinting (LOI) and loss of heterozygosity (LOH) in surgically resected tissues by utilizing Apa1 polymorphism. Of 46 patients with colorectal cancer, 2 exhibited (2/15, 13%) LOH among 15 patients who were heterozygous for IGF2 DNA in nontumorous tissues. Four (4/12, 33%) patients showed LOI of IGF2 gene among informative patients. In these patients, the reverse transcription polymerase chain reaction and immunohistochemistry revealed that IGF2 mRNA is overexpressed in tumorous tissues, compared to nontumorous tissues. Of 15 patients in whom IGF2 was immunohistochemically more highly expressed in tumorous than in normal tissues, there were 2 with LOH and 4 with LOI. The results of the present study suggest that LOI of IGF2 plays an important role in the carcinogenesis of colorectal cancer.
Role of Fibrinogen Covalently Associated with Cell Membrane in Blood-Borne Lung Tumor Colony Formation of Murine Mammary Carcinoma Cells
Authors: Lee Soo Young , Park Lae Ok , Suk Seung-Han
Published: April 2003

The role of fibrinogen covalently associated with cell membrane in blood-borne lung tumor colony formation of murine mammary carcinoma cells in mice was studied. When mice were treated with prednisolone, their plasma fibrinogen levels profoundly increased. Hyperfibrinogenemia, induced by prednisolone treatment or plasma fibrinogen infusion of syngeneic mice, accelerated the coagulation time and significantly increased the number of lung tumor colonies of SCK tumor cells. Hypofibrinogenemia, induced by rabbit antisyngenic mouse fibrinogen immunoglobulin G or heparin infusion, markedly delayed coagulation time and prominently reduced the numbers of blood-borne lung tumor colonies of the tumor cells. SCK mammary carcinoma cells form a coating of fibrinogen on their surfaces in a medium containing fibrinogen. This coating is cross-linked in a manner characteristic of catalysis by tumor cell membrane-bound transglutaminase K. The fibrinogen coating on the surface of these tumor cells functions to protect against autologous lymphokine-activated killer cells. These results provide information on the impact of fibrin stability on blood-borne lung tumor colony formation of SCK mammary carcinoma cells.
Suppression of Invasion and MMP-9 Expression in NIH 3T3 and v-H-Ras 3T3 Fibroblasts by Lovastatin through Inhibition of Ras Isoprenylation
Authors: Wang Ing-Kae , Lin-Shiau Shoei-Yn , Lin Jen-Kun
Published: April 2003

Lovastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, was found to block the synthesis of cholesterol and to affect posttranslational modification or isoprenylation, which is essential for membrane localization and biological activity of several proteins including Ras in the signal transduction pathway. Ras activates a multitude of downstream activities with roles in cellular processing, including invasion and metastasis. We investigated the anti-invasive activity of lovastatin in NIH 3T3 and v-H-Ras-transformed NIH 3T3 (v-H-Ras 3T3) cells. Lovastatin suppressed cell invasion in vitro in a dose-dependent manner. By zymographic assay, a decrease in matrix metalloproteinase-9 (MMP-9) activity but not matrix metalloproteinase-2 (MMP-2) activity by lovastatin was detected. RT-PCR demonstrated a reduction in gene expression of MMP-9 after treatment with lovastastin. To confirm the lovastatin-induced down-regulation of MMP-9 expression, we transfected an MMP-9/luciferase reporter vector, under MMP-9 promoter control, into both NIH 3T3 and v-H-Ras 3T3. A reduction in luciferase activity was observed with lovastatin treatment. In addition, lovastatin also reduced AP-1 and NFκB binding activities. These anti-invasive features were attenuated by the presence of mevalonate. These results suggest that down-regulation of MMP-9 contributes to the anti-invasive activity of lovastatin. Furthermore, we added exogenous mevalonate, which enhances the potency of cell invasion, and Ras farnesyltransferase inhibitor (manumycin A), which inhibits the potency of cell invasion. In accordance, Western blot analysis showed that lovastatin decreased membrane localization of Ras proteins. These data indicate that the anti-invasion activity of lovastatin happens through a decrease in Ras isoprenylation and functions.
Enhanced Selective Gene Expression by Adenovirus Vector Using Cre/loxP Regulation System for Human Carcinoembryonic Antigen-Producing Carcinoma
Authors: Ueda Kentaro , Iwahashi Makoto , Nakamori Mikihito , Nakamura Masaki , Yamaue Hiroki , Tanimura Hiroshi
Published: April 2003

Selective gene targeting using the carcinoembryonic antigen (CEA) promoter is useful in gene therapy for gastrointestinal cancer. However, the expression of the CEA promoter is not sufficient. In this study, we tried to enhance CEA promoter activity using the Cre/loxP system. The double infection of CEA-producing cells such as MKN45 and LoVo with AxCEANCre and AxCALNLZ at a total multiplicity of infection (MOI) of 50 achieved 7-fold higher expression level of β-galactosidase activity than single infection of those cells with AxCEALacZ at 50 MOI. On the other hand, the double infection of CEA-nonproducing cells such as MKN1 and HeLa cells showed a very low expression of β-galactosidase activity. In the subcutaneous tumor models, the administration of AxCEANCre and AxCALNLZ into the CEA-producing tumor showed stronger expression of the LacZ gene in tumor tissue than that of AxCEALacZ. In the experiment using orthotopic models of CEA-producing gastric cancer, intraperitoneal double administration of AxCEANCre and AxCALNLZ caused evident LacZ gene expression in transplanted gastric tumors, but no LacZ gene expression in the normal stomach or liver. It was confirmed that enhanced tissue-specific gene transduction under control of CEA promoter using the Cre/loxP system was useful not only in vitro, but also in vivo, especially in orthotopic models.
Interaction between Haemochromatosis and Transferrin Receptor Genes in Hepatocellular Carcinoma
Authors: Beckman L.E. , Hägerstrand I. , Stenling R. , van Landeghem G.F. , Beckman L.
Published: April 2003

In hepatocellular carcinoma (HCC) iron has been implicated as a risk factor primarily in patients with hereditary haemochromatosis (HH) and cirrhosis. The wild-type HH (HFE) protein complexes with the transferrin receptor (TFR), and two HFE mutations (Cys282Tyr and His63Asp) have been found to increase the affinity of the TFR for transferrin resulting in an increased cellular uptake of iron. In previous studies we found an interaction between HFE and TFR genotypes in multiple myeloma and breast and colorectal carcinomas. In the present investigation we have studied HFE and TFR genotypes in 54 Swedish patients with HCC, using DNA from archival samples of paraffin wax blocks. The same HFE-TFR interaction as in the previously studied neoplastic disorders was found. Individuals carrying the HFE282Tyr allele (homo- and heterozygotes) in combination with homozygosity for the TFR Ser allele showed an increased risk for HCC (OR = 3.5; 95% confidence interval, CI = 1.3–9.3), which was further increased in HFE Tyr homozygotes and compound (Tyr/Asp) heterozygotes in combination with TFR 142Ser homozygosity (OR = 17.2; 95% CI = 1.8–168.9). The presence of liver cirrhosis could only be assessed in part of the patient material. In patients with verified liver cirrhosis the risk figures were substantially increased: for HFE 282 Tyr carriers in combination with TFR 142Ser/Ser OR = 7.2; 95% CI = 2.0–25.5 and for HFE 282Tyr homozygotes and compound heterozygotes in combination with TFR 142Ser homozygosity, OR = 62.8; 95% CI = 6.1–642.5.
CEA mRNA Identification in Peripheral Blood Is Feasible for Colorectal, But Not for Gastric or Pancreatic Cancer Staging
Authors: Piva Maria Grazia , Navaglia Filippo , Basso Daniela , Fogar Paola , Roveroni Giovanni , Gallo Nicoletta , Zambon Carlo-Federico , Pedrazzoli Sergio , Plebani Mario
Published: April 2003

Objective: It has been suggested that the molecular identification of cancer cells in the circulation may be useful in predicting the presence of micrometastasis in several cancer types. The aim of the present study was therefore to assess the feasibility of CEA mRNA identification in blood for diagnosing and staging colorectal, gastric and pancreatic cancer. Methods: We studied 16 control subjects, 69 patients with colorectal (CRC), 30 with gastric (GC), 27 with pancreatic cancer (PC) and 8 with benign diseases of the pancreatobiliary tree. At diagnosis CEA mRNA was identified in peripheral blood by means of a RT-PCR procedure. Results: The specificity of this test in control subjects was 94%, and its sensitivity in identifying CRC, GC and PC were 34, 37 and 41%, respectively. False-positive findings were recorded in 25% patients with benign diseases. No association was found between CEA mRNA and stage in patients with GC or PC. In CRC patients, positive CEA mRNA findings were correlated with local spread (χ2 = 14.6, p < 0.01), lymph node (χ2 = 18.95, p < 0.001) and distant metastasis (χ2 = 11.3, p < 0.001). In these cases, CEA mRNA, but not CEA, was entered in stepwise discriminant analysis to classify the presence of lymph node metastasis. Conclusions: The molecular detection of micrometastasis in the blood by means of CEA mRNA identification is feasible for colorectal, but not for gastric or pancreatic cancer staging. Further studies are needed in order to define the clinical utility of this marker also in follow-up protocols.
Autonomic Nervous System Responses to Personal Stressful Events in Patients with Acute Myocardial Infarction
Authors: Tsouna-Hadjis Evie D. , Mitsibounas Dimitris N. , Kallergis George E. , Sideris Dimitris A.
Published: April 2003

Background: Life events specific for each individual may influence the onset of acute myocardial infarction (AMI), and we wondered whether recall of such events elicits autonomic nervous system responses in patients. Methods: Thirty-one subjects with AMI, which occurred about 1 month previously (study group), and 22 healthy subjects were interviewed. Whenever the presence of a stressful event was found within the last 2 months before AMI onset, a key phrase of the event was isolated. Each subject was faced with 20 written key sentences (including his/her own sentence if detected) at random order, for 40 s each. At the same time the heart rate (HR) and the galvanic skin response (GSR) were continuously recorded. Pearson r correlations, χ2 and t tests were employed for comparisons between study and control group as well as within each group. Results: A recent exacerbating event was detected in 30/31 AMI patients and in 0/22 healthy subjects. For the 30 AMI patients the values of HR following the sentence of the suspected event, specific for each patient, were statistically significantly higher than the mean values of HR following the remaining 19 ‘neutral’ statements. The same significant difference appeared with regard to GSR values. The mean values of the AMI patients for the 19 neutral statements did not differ significantly from those of the healthy subjects for the 20 neutral statements, either for HR or GSR. Conclusions: Findings suggest that recall of personal stressful events elicited autonomic nervous system responses in AMI patients and, therefore, events with personal significance are related to coronary disease onset.
Do Patients with Panic Disorder Show a Memory Bias?
Authors: Neidhardt Eva , Florin Irmela
Published: April 2003

Background: Cognitive models of panic disorder are becoming more and more influential. Therefore, research specifying cognitive processes related to panic disorder is needed. The present study investigated memory bias for panic-related material in patients with panic disorder. Methods: Memory bias for panic-related material was investigated experimentally by a memory task requiring classification of panic-related and non-panic-related words. Sixty patients with panic disorder and 60 controls with no diagnosis of a mental disorder participated in the study. Results: As expected, panic patients showed smaller differences in the time needed for classification of panic-related versus non-panic-related material than controls. Conclusions: Patients with panic disorder show a memory bias for panic-related material when conceptual implicit recall is required. In order to clarify whether this bias is involved in the maintenance of the disorder, it seems important to investigate whether the bias is still present after successful therapy.
Psychosomatic and Psychosocial Symptoms Are Associated with Low Blood Pressure in Swedish Schoolchildren
Authors: Borres Magnus P. , Tanaka Hidetaka , Thulesius Olav
Published: April 2003

Background: The relation between psychosomatic and psychosocial symptoms and blood pressure was studied in Swedish schoolchildren. Methods: Blood pressure was measured in 122 healthy Swedish schoolchildren, aged 6–16 years. Psychosomatic and psychosocial symptoms, delinquent behaviour, parental health and employment status were assessed. Results: Children with systolic blood pressure above +1 SD of mean reported significantly less symptoms (x̅ = 1.4) than children with blood pressure below –1 SD of the mean (x̅ = 2.7; p < 0.05). Children with three or more self-reported symptoms had significantly lower blood pressure than children without symptoms both in the supine (110 ± 12 vs. 120 ± 18 mm Hg; p < 0.05) and in the standing position (117 ± 17 vs. 127 ± 18 mm Hg; p < 0.05). Conclusions: We conclude that psychosomatic and psychosocial symptoms in children might be associated with low blood pressure.
Weight Gain in Depression Remitted with Antidepressants: Pharmacological or Recovery Effect?
Authors: Benazzi Franco
Published: April 2003

Background: Depression remission is often associated with weight gain. It is not clear if weight gain is caused by a pharmacological effect of antidepressants, or if instead it is an effect of recovery from depression. The aim of this study was to try to clarify this point. Methods: One hundred consecutive unipolar/bipolar remitted depressed private practice outpatients (DSM-IV diagnoses with structured interview) were interviewed with structured questions about weight changes occurring during depression and remission. Comparisons were made between remitted weight gainers and remitted nonweight gainers. Results: Seventy-two percent of patients showed weight gain when they remitted from depression, in comparison with their weight when they were depressed. No significant differences were found in age, gender, diagnoses, duration of remission, use of tricyclics, tricyclic-SSRI combination, benzodiazepines, neuroleptics, and mood stabilizers in remitted weight gainers versus nonweight gainers. SSRIs were significantly more used in remitted nonweight gainers. Significantly more weight loss and less weight gain when depressed were found in remitted weight gainers versus nonweight gainers. Conclusions: These findings suggest that weight gain in remitted depressed patients may not necessarily be a pharmacological effect of antidepressants, but may rather be an effect, at least in part, of recovery from depression.
Infants with Atopic Dermatitis: Maternal Hopelessness, Child-Rearing Attitudes and Perceived Infant Temperament
Authors: Pauli-Pott Ursula , Darui Alexander , Beckmann Dieter
Published: April 2003

Background: Atopic dermatitis (AD) is a common disease of childhood. It frequently starts in the first year of life. There is agreement on the existence of psychological influences on this disease. Although some studies in this field examine aspects of the parent-child relationship, studies concerning early infancy are very rare. The present study was conducted in order to find out whether maternal characteristics relevant to the mother-infant relationship, i.e. depressiveness/hopelessness, child-rearing attitudes and perceived infant behaviour, associated with infant AD. Methods: Two cohorts (3- to 4-month- and 10- to 12-month-old infants), each with 20 infants suffering from AD, and 20 healthy infants were recruited. AD infants were further divided into subgroups according to the diagnostic criteria: atopic family history, itching and characteristic locations of eczema. After a paediatric examination of the infant, mothers completed standardized questionnaires concerning depressiveness/hopelessness, child-rearing attitudes and perception of infant behaviour. Results: Varying with different diagnostic features of the infants’ AD, mothers of AD infants described themselves as more depressive/hopeless, as more anxious/overprotective and characterized their infant as less frequently positive and more frequently negative in its emotional behaviour compared to the control group. Conclusion: The results underline the importance of psychological support for mothers of infants with AD.
Low Plasma Prolactin Levels in Patients with Functional Dyspepsia
Authors: Jonsson Bo H. , Theorell Töres
Published: April 2003

Background: The purpose was to compare the levels and patterns of plasma cortisol and prolactin in patients with functional dyspepsia (FD) during a controlled laboratory experiment. Method: 25 patients (12 men, 13 women), aged 24–50, with recurrent FD, and 25 pair-wise gender- and age-matched community control subjects were studied at a gastroenterological laboratory in a Swedish university hospital. In an experiment, after a rest period, subjects were studied during a neutral interview and a stress interview. Before and during interventions, blood samples were drawn for later peptide analyses. The main outcome measures were the Gastrointestinal Symptom Rating Scale, heart rate, blood pressure, plasma cortisol and prolactin. Results: Mean plasma cortisol concentration correlated negatively with diarrhoea symptoms (partial correlation; p < 0.01). The level of plasma proclatin (µg/l) was significantly lower (paired t test; p < 0.01) in the patient group (mean = 3.34, CI: 2.75–3.93) compared to the control group (mean = 4.70, CI: 3.63–5.78). During the stress interview, prolactin increased significantly in both groups. When the whole sample was divided according to degree of reflux symptoms, those with high reflux symptomatology had lower prolactin (ANCOVA with covariates for group, gender, age, body mass index and smoking; p < 0.05). Conclusion: Plasma prolactin concentration was significantly lower in FD patients compared to a matched control group. A high degree of reflux symptoms was significantly associated with inhibition of the prolactin increase during a stress interview.