bluuebunny/crossref_metadata_2025 huggingface dataset:
Putative Role of Dihydropyrimidine Dehydrogenase in the Toxic Side Effect of 5-Fluorouracil in Colorectal Cancer Patients
Authors: Katona Csilla , Kralovánszky Judit , Rosta András , Pandi Erzsébet , Fónyad Gábor , Tóth Katalin , Jeney András
Published: April 2003

Dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme in the catabolism of 5-fluorouracil (5-FU). It has been reported from various laboratories that the plasma concentration of 5-FU was influenced by DPD activities in various normal human organs (e.g. liver or lymphocytes). Since the congenital deficiency in DPD caused severe, in some cases lethal, FU-related toxicity, it was decided to collect data about the DPD activity in colorectal cancer patients in order to investigate the possible correlation between the enzyme activity and appearance of the side effects of 5-FU. Assuming that DPD activity in lymphocytes represents the 5-FU catabolic capacity of the organism, DPD activity was determined in the lymphocytes of 48 patients with colorectal cancer after surgery during the therapeutic course with 5-FU and folinic acid. On the basis of the enzyme activity, patients were divided into three categories: low (DPD <5.03 pmol/min/106 lymphocytes); medium (DPD = 5.04–13.25 pmol/min/106 lymphocytes), and high (DPD > 13.26 pmol/min/106 lymphocytes) activity groups. By evaluating the toxic side effects during the 5-FU + folinic acid treatment, the following results were obtained. In the low DPD activity group, 9 of 11 patients had 5-FU-related side effects (mucositis, diarrhea, myelotoxicity, angina pectoris, hypertension). In 3 patients, no change of the therapy was needed, in 3 patients symptoms could be reversed by dose reduction of 5-FU while in 3 patients interruption of 5-FU therapy was needed. In the medium DPD activity group, mild toxicity (diarrhea, transitory hypertension) occurred in 5 of 29 and in the high activity group (diarrhea) in 1 of 8 patients, respectively. In these last two groups, no dose reduction of 5-FU was necessary. The present study furnished further evidence for the possible correlation between the 5-FU side effects and DPD function. Consequently, it is recommended to measure DPD activity prior to 5-FU based chemotherapy, which might be helpful in avoiding drug-related toxicity by adjusting the dose of 5-FU individually.
Residual Disease and Presence of Human Papillomavirus after Conization
Authors: Kanamori Yasunobu , Kigawa Junzo , Minagawa Yukihisa , Irie Takashi , Oishi Testuro , Itamochi Hiroaki , Cheng Xiusi , Terakawa Naoki
Published: April 2003

The objective of this study was to evaluate the incidence of residual disease and the presence of human papillomavirus (HPV) after conization. Data on 53 patients with carcinoma in situ or microinvasive carcinoma who underwent hysterectomy less than 2 months after conization were examined. Seven of 53 patients (13%) had positive margins. In 4 of these 7 patients (57%), residual disease was found in the postconization hysterectomy specimen. Two of 46 patients (4%) with negative margins also had residual disease. HPV DNA was detected by PCR in 27 of 53 conization specimens and in 2 postconization hysterectomy specimens. Of 2 patients, 1 did not have residual disease. Residual disease could be present even with a negative conization margin, and HPV DNA may be found in a histologically normal cervix after conization.
Endoluminal Radiotherapy for Rectal Tumors
Authors: Tanum Gunnar , Wiig Johan , Andersen OveKjell
Published: April 2003

The present study was performed to evaluate local tumor control and side effects of endoluminal radiotherapy given to patients with rectal tumors. Twelve patients with adenocarcinoma and 10 patients with villous/adenovillous adenomas were treated with curative intent from 1989 to 1995. The majority of patients were of advanced age and in poor medical condition, and had previously been found unable to undergo radical surgery or colostomy. Three patients had tumor remains following radiotherapy, they successfully received local surgery (n = 2) or an iridium implant (n = 1) as second-line treatment. Two patients (adenomas) later experienced a local relapse. No serious side effects were observed. We conclude that endoluminal radiotherapy is an efficacious option for patients with malignant or premalignant tumors in the lower rectum who are in poor medical condition.
Sequential Administration of Doxorubicin and Paclitaxel Followed by Cyclophosphamide, Methotrexate and 5-Fluorouracil Combination (CMF) in Women with Metastatic Breast Cancer
Authors: Papadimitriou Christos A. , Dimopoulos Meletios A. , Ampela Constantina , Louvrou-Fertaki Androniki , Anagnostopoulos Athanasios , Athanassiades Peter , Stamatelopoulos Stamatios , Keramopoulos Antonios
Published: April 2003

Although the combination of paclitaxel with doxorubicin has yielded high response rates in metastatic breast cancer, severe cardiotoxic events have been reported in several patients. The rationale for our study was to evaluate the activity of paclitaxel/doxorubicin combination in patients with this disease but to avoid excessive cardiotoxicity. Therefore, we administered 4 cycles of doxorubicin/paclitaxel followed by 6 cycles of standard cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen. Study medication consisted of doxorubicin 60 mg/m2 as a 15-min intravenous infusion followed by paclitaxel 175 mg/m2 as a 3-hour infusion. CMF regimen consisted of cyclophosphamide 600 mg/m2 as 1-hour intravenous infusion followed by methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 bolus injection. The main toxicity of doxorubicin/paclitaxel treatment phase was neutropenia (WHO grade 3/4, 58%), but we observed only one cardiac adverse event. Toxicities of the CMF treatment phase were not significant. Of 24 patients evaluable for response, 2 (8%) had complete responses and 11 (46%) achieved partial response. Ten additional patients (42%) had stable disease. The median time to progression was 12 months and the median overall survival was 18.5 months. The sequential administration of doxorubicin and paclitaxel followed by CMF appeared active and well tolerated in patients with metastatic breast cancer.
Mitomycin C, Vinorelbine, Carboplatin plus Granulocyte-Macrophage Colony-Stimulating Factor for Treatment of Advanced Non-Small Cell Lung Carcinoma
Authors: Hejna M. , Kornek G.V. , Raderer M. , Marosi L. , Schneeweiss B. , Greul R. , Weinländer G. , Valencak J. , Huber H. , Scheithauer W.
Published: April 2003

Background: The therapeutic potential of chemotherapy in the treatment of recurrent or metastatic non-small cell lung carcinoma (NSCLC) seems modest. Thus, the search for novel agents and combination regimens with a superior therapeutic index has a high priority. The present combination regimen consisting of mitomycin C, vinorelbine, carboplatin and granulocyte-macrophage colony-stimulating factor (GM-CSF) was chosen because of the known activity of these agents in NSCLC and their potential drug synergism without (nonhematologic) cross-toxicity. To prevent/counteract neutropenia that was assumed to represent the dose-limiting toxicity, the hematopoietic growth factor GM-CSF was routinely adminstered. The objective of our trial was to determine the antitumor efficacy and tolerance of this combination regimen in patients with advanced NSCLC. Patients and Methods: Forty consecutive patients with nonresectable, measurable NSCLC (stage IIIB, 7; stage IV, 33) were treated with an intravenous combination chemotherapy regimen consisting of mitomycin C 8 mg/m2 on day 1, vinorelbine 40 mg/m2 on days 1 and 21, and carboplatin 250 mg/m2 on days 1 and 21; GM-CSF 5 µg/kg was administered subcutaneously on days 2–8 and 22–28. Treatment cycles were repeated every 6 weeks. All patients are evaluable in terms of toxicity and response assessment. A total of 123 courses was administered. Results: Objective tumor response was notes in 16 patients (40%; 95% confidence interval 24.9–56.7%), including 3 (7.5%) complete and 13 partial responses. There was no change in 12 (31.5%) patients, and 12 had progressive disease. Median duration of response was 6 (range 3–15) months, the median time to progression for all patients was 6.2 (range 1–17.5) months, and the projected median survival time was 8.7 (range 1–23.3) months; the 1-year survival rate was 27.5%. Myelosuppression was the most frequently encountered adverse reaction; WHO grade 3 or 4 granulocytopenia and/or thrombocytopenia occurred in 42.5 and 12.5%, respectively. Other toxicities were generally mild to moderate, and always fully reversible. Conclusion: With a 40% major response rate and disease stabilization in one additional third of our patients, this drug combination seems to have significant activity against advanced metastatic NSCLC. Due to its subjective tolerance and ease of administration, further investigation of this regimen in the palliative-intent care setting seems warranted.
C-myc and c-fos in Human Osteosarcoma: Prognostic Value of mRNA and Protein Expression
Authors: Gamberi Gabriella , Benassi M. Serena , Bohling Tom , Ragazzini Paola , Molendini Lara , Sollazzo M. Rosa , Pompetti Franca , Merli Mara , Magagnoli Giovanna , Balladelli Alba , Picci Piero
Published: April 2003

The c-myc and c-fos proto-oncogenes have several putative functions, including regulation of cell growth. In many neoplasms c-myc overexpression has been linked to poor prognosis. In order to study the role of c-myc and c-fos expression on the tumorigenesis, and the metastatic spread of osteosarcoma, frozen and paraffin-embedded tissue 38 primary osteosarcoma and 10 lung metastases were analyzed. The mRNA analysis was performed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. The protein expression was studied by Western blot analysis and immunohistochemistry. C-myc and c-fos were found overexpressed in a high percentage of the relapsed tumors and of the metastases, and overexpression of both oncogenes in the same tumor was strongly correlated to the development of metastases (p < 0.05), as 6 of the 7 primary tumors overexpressing both the oncogenes gave metastases. In conclusion, both c-myc and c-fos are involved in the growth and spread of osteosarcoma and a synchronous overexpression of both oncogenes is highly significant for a metastatic potential of a primary tumor.
Enhancement of Interleukin-2-Induced Lymphokine-Activated Killer Activity by Interleukin 7 against Autologous Human Renal Cell Carcinoma
Authors: Kondo Masahiko , Nonomura Norio , Miki Tsuneharu , Kojima Yasuyuki , Yokoyama Masayoshi , Nakano Etsuji , Okuyama Akihiko
Published: April 2003

Adjuvant immunotherapy with interferons and/or interleukin 2 (IL-2) is widely used for advanced kidney cancer. However, the results are not satisfactory so far. The purpose of this study is to evaluate the inducible activity of lymphokine-activated killer (LAK) cells against autologous human renal cell carcinoma. The effect of interleukin 7 (IL-7) on IL-2-induced LAK activity was assessed by the autologous assay system which we have established. Peripheral blood lymphocytes from patients with renal cell carcinoma were stimulated with IL-2 and/or IL-7, and tested for antitumor activity against autologous renal cell carcinoma. In all 10 cases tested, IL-7 alone induced LAK activity. Moreover, IL-2-induced LAK activity was augmented by the concomitant addition of IL-7. Flow cytometry revealed an increase in IL-2-receptor-positive lymphocytes following incubation with IL-7. These results suggest that combination therapy using IL-2 and IL-7 may be a useful treatment for patients with advanced renal cell carcinoma.
The Role of Chemotherapy in the Treatment of Adult Soft Tissue Sarcomas
Authors: O’Byrne K. , Steward W.P.
Published: April 2003

Adult soft tissue sarcomas are relatively rare tumours which are curable with radical surgery. Approximately 50% of patients will develop inoperable disease or metastases for which chemotherapy may be appropriate. Only two cytotoxic agents – doxorubicin and ifosfamide – have activity in >20% of patients. For both these agents there is evidence of a dose-response relationship. There is currently no good evidence that combination chemotherapy confers a clinical benefit compared with single agents. Outside a clinical trial, standard first-line therapy should be with single agent doxorubicin at a dose intensity ≥70 mg2 every 3 weeks. Approximately 25% of patients may be expected to respond to this regimen. There is the suggestion that responses may occur to ifosfamide in patients who progress on doxorubicin. The role of chemotherapy in the adjuvant setting remains uncertain. Several trials have suggested a modest relapse-free and overall survival benefit for the use of post-operative chemotherapy and a recent overview of 14 randomised trials confirms a small though significant benefit. These benefits have to be weighed against the toxicity of chemotherapy. The importance of treating all patients with soft tissue sarcomas in clinical trials is stressed. There is an urgent need to define new active agents to treat this disease.
Effect of Adjuvant Tamoxifen Therapy on Thyroid Function in Postmenopausal Women with Breast Cancer
Authors: Zidan Jamal , Rubenstein Wolf
Published: April 2003

Serum thyroid-stimulating hormone (TSH), free thyroxine (FT4) and total tri-iodothyronine (TT3) concentrations were measured in 45 postmenopausal breast cancer patients before adjuvant treatment with tamoxifen and at 3- and 6-month intervals. A significant increase in TSH (p = 0.002) at the end of 3 months and a subsequent decrease at the end of 6 months was noted. There were no significant changes in TT3 and FT4. We concluded that tamoxifen therapy in postmenopausal women may result in a reversible increase in TSH after 3 months.
Infrequent Presence of Anti-c-Myc Antibodies and Absence of c-Myc Oncoprotein in Sera from Lung Cancer Patients
Authors: Yamamoto Akiyoshi , Shimizu Eiji , Takeuchi Eiji , Houchi Hitoshi , Doi Hiroyuki , Bando Hiroyasu , Ogura Takeshi , Sone Saburo
Published: April 2003

To clarify the host immune response and explore a new serological marker of lung cancer, we examined serum c-Myc antigens and auto-antibodies against c-Myc in 68 lung cancer patients and 30 healthy volunteers using bacterially synthesized glutathione S-transferase c-Myc fusion proteins and immunoblotting. The detection rate of anti-c-Myc antibodies was 13.2% (9/68) in lung cancer patients and 3.3% (1/30) in healthy volunteers. These anti-c-Myc antibodies were directed toward exon 2 alone (4/68), exon 3 alone (1/68), and both exon 2 and exon 3 (4/68) of c-Myc. Circulating c-Myc antigen was not detected in any individuals with lung cancer and normal controls. Age, sex, performance status, histology, stage, smoking history, and prior treatment of the patients with and without anti-c-Myc antibodies were not significantly different. The low incidence of anti-c-Myc antibodies and c-Myc antigens in peripheral blood suggests that these examinations are not useful in the serological diagnosis of lung cancer.
Ovarian Cancer: Loss of Heterozygosity Frequently Occurs in the ATM Gene, but Structural Alterations Do Not Occur in This Gene
Authors: Koike Michiaki , Takeuchi Seisho , Park Susan , Hatta Yoshihiro , Yokota Jun , Tsuruoka Nobuyoshi , Koeffler H. Phillip
Published: April 2003

Ataxia-telangiectasia is a multisystem recessive disease characterized clinically by cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, sensitivity to radiomimetic agents and an increased predisposition to cancer. This pleiotropic disorder is caused by mutations in the ATM gene, which is located at the human chromosomal region 11q23. Loss of heterozygosity (LOH) at 11q22–q23 is a frequent event in ovarian cancer, suggesting the presence of a tumor suppressor gene in this region. We have found that LOH in the ATM gene occurred in 44% of informative cases in a series of 22 primary ovarian tumors. LOH of this region occurred at the same frequency during the advanced stages (III–IV; 3/9, 33%) as in the early stages (I–II; 4/13, 31%) of ovarian cancer. To investigate the role of ATM in ovarian cancer, we used a PCR-based single-strand conformation polymorphism assay for mutation detection of the entire coding sequence of the ATM gene (65 exons) in 22 ovarian tumors. No somatic alterations of the ATM gene were found in these ovarian cancer samples including those with LOH present in the ATM gene. Our study has identified a region (11q23) which probably contains a frequently altered tumor suppressor gene in ovarian cancer, and this gene does not appear to involve the coding sequences of the ATM gene.
Detection of Loss of Heterozygosityat Microsatellite Loci in Esophageal Squamous-Cell Carcinoma
Authors: Ikeguchi Maahide , Unate Hitoshi , Maeta Michio , Kaibara Nobuaki
Published: April 2003

Microsatellite alterations at 3 genetic loci (chromosomes 2p, 3p and 17p) were analyzed in 25 tumors (20 primary tumors and 5 metastatic lymph nodes) from 20 patients after surgical treatment for esophageal cancer. DNA samples from tumors were compared with control DNA from lymphocytes obtained from the peripheral blood of the individual patients. Microsatellite alterations [microsatellite instability (MSI) and loss of heterozygosity (LOH)] were detected in 15% of 20 primary tumors with marker D2S123 (chromosome 2p), 55% with marker D3S1067 (chromosome 3p) and 50% with marker TP53 (chromosome 17p). The 3-year disease-free survival rate of the 10 patients who had tumors without alterations or with an alteration at only 1 of 3 microsatellite loci was 75% and it was better than that of the 10 patients who had tumors with alterations at 2 or 3 microsatellite loci (48%, p = 0.049). This finding suggests that esophageal cancer with alterations at multiple microsatellite loci might have strong malignant potential. However, MSI was only detected in one of 20 patients, which suggests that MSI might not play an important role in the development of this cancer. Three of 5 metastatic lymph nodes showed no LOH even though primary tumors of these patients exhibited LOH with 1 or 2 markers, and 1 metastatic lymph node had LOH that was detected with D3S1067 even though the primary tumor of this patient had no LOH with all markers. Thus, clonal heterogeneity might exist in esophageal squamous-cell carcinomas.
Phase II Study of Cisplatin and Dacarbazine for Metastatic Colorectal Carcinoma Resistant to 5-Fluorouracil
Authors: İçli Fikri , Arıcan Ali , Çay Filiz , Akbulut Hakan , Dinçol Dilek , Karaoguz Handan , Demirkazık Ahmet
Published: April 2003

Twenty-six patients with metastatic colorectal cancer were given cisplatin (CDDP) and dacarbazine (DTIC). Patients who relapsed while receiving adjuvant 5-fluorouracil (FU) or had 5-FU-resistant metastatic disease were included. Median age was 52 years and the male-to-female ratio was 1. Performance status (ECOG) was 3 in 5 patients and 0–2 in the remainder. CDDP (20 mg/m2/day i.v.) and DTIC were given (250 mg/m2/day i.v.) on days 1–5. The treatment was repeated every 3 weeks until disease progression. Total response rate was 19.2% (95% confidence interval: 4.5–34.3%) with one clinical complete response (3.8%) and 4 partial responses (15.4%). Median response duration was 5 months. Median survival for the whole group and for responders was 6 and 8 months, respectively. In conclusion, CDDP + DTIC combination has modest activity in patients with colorectal cancer resistant to 5-FU treatment.
Prognostic Value of Immunohistochemical Expression of Beta-1 Integrin in Pancreatic Carcinoma
Authors: Böttger Thomas C. , Maschek Hans , Lobo Martina , Gottwohl Rainer G. , Brenner Walburgis , Junginger Theo
Published: April 2003

Background: Prognostically relevant factors based on the histological assessment of the resected pancreas are known. However, the knowledge of additional factors associated with the prognosis is helpful in planning the therapy for an individual patient. β1 Integrin expression is known to have a prognostic influence in some malignant tumors. No data are, however, available on the prognostic value of β1 integrins in pancreatic carcinoma. Method: We investigated paraffin-embedded specimens of 19 patients undergoing surgical treatment for periampullary carcinoma and of 42 patients for ductal pancreatic carcinoma by immunohistochemistry to assess the expression pattern and the prognostic impact of β1 integrins. Neither histomorphological parameters nor the survival time of the patients were known at the time of the investigation. Results: No correlation was established between histomorphological parameters and β1 integrin expression in periampullary or ductal pancreatic carcinoma, respectively. Patients with periampullary carcinoma and β1 integrin overexpression had a significantly poorer prognosis than patients without overexpression of β1 integrins (median survival: 18.3 vs. 58.4 months). In ductal pancreatic carcinoma β1 integrin expression had no influence on prognosis. Conclusion: β1 Integrins exert an influence on prognosis in periampullary carcinoma but not in ductal pancreatic carcinoma. However, further investigations in larger patient samples are required to confirm these results.
Recurrences and Relation to Tumor Growth Potential and Local Immune Response in Node-Negative Advanced Gastric Cancer
Authors: Maehara Yoshihiko , Kabashima Akira , Tokunaga Eriko , Hasuda Shota , Oki Eiji , Kakeji Yoshihiro , Baba Hideo , Sugimachi Keizo
Published: April 2003

Biological characteristics and the prognosis for subjects with node-negative advanced gastric cancer have been given little attention in related literature. We analyzed data on 112 patients with serosally invasive gastric cancer who were lymph node metastasis-negative; all had been surgically treated in the Department of Surgery II, Kyushu University Hospital, between 1970 and 1992. Recurrences and relation to the growth potential of the tumor and local immune response were examined. Thirty patients died with a recurrence of the gastric cancer, and in these patients, the tumor was larger, the whole stomach was more frequently involved and infiltrative growth was more common, compared to findings in patients who were recurrence-free. Peritoneal recurrence was evident in half the number of patients and the 5-year survival rate was 74.5%. Tumor growth potential was evaluated, based on the level of proliferating cell nuclear antigen (PCNA) of the primary tumor and on dendritic cell infiltration into the tumor, determined as a level of local immune function of the host. Higher growth potential and lower immune levels were more frequent in patients with recurrences. Multivariate analysis revealed that tumor size and PCNA labeling index were significant prognostic factors for node-negative gastric cancers. In a subset of advanced gastric cancers, there was no apparent distinct lymph node metastasis and the prognosis was better. However, cancer cells with a higher growth potential and a lower immune response in the host can biologically amplify and mainly infiltrate the gastric wall, extend to the serosa and disseminate transserosally into the peritoneum.
Protective Effect of Transferrin C3 in Lung Cancer?
Authors: Beckman L.E. , van Landeghem G.F. , Sikström C. , Lundgren R. , Beckman L.
Published: April 2003

In a previous study of lung cancer patients and controls from the Stockholm area in central Sweden, we found a significantly decreased frequency of the transferrin (TF) variant C3 in small cell and squamous epithelial lung cancer but not in adenocarcinoma, suggesting a protective effect of TF C3 in small cell and squamous lung cancer. In an attempt to replicate this association we studied TF types in lung cancer patients and controls from two additional Swedish subpopulations, viz. northern Sweden and southwestern Sweden. We were able to confirm the significantly decreased frequency of TF C3, especially in small cell lung cancer, in northern Sweden but not in southwestern Sweden. Thus the eventual protective effect of TF C3 in small cell lung cancer is an open question. We hypothesize that the association between TF C alleles and lung cancer may be secondary and dependent on linkage disequilibrium with allelic variants of newly discovered tumor-associated genes known to map to the same position (3q21) as TF, e.g. NCK and H-RYK.
Metallothionein Expression Correlates with the Pathological Response of Patients with Esophageal Cancer Undergoing Preoperative Chemoradiation Therapy
Authors: Yamamoto Makoto , Tsujinaka Toshimasa , Shiozaki Hitoshi , Doki Yuichiro , Tamura Shigeyuki , Inoue Masatoshi , Hirao Motohiro , Monden Morito
Published: April 2003

Immunohistochemical staining for metallothionein (MT) and p53 was performed on biopsy specimens of 30 patients with esophageal squamous cell carcinoma who had received curative resection following preoperative chemoradiation. The pathologic response to chemoradiation was a partial response in 19 cases and no change was observed in 11 cases. In 16 cases with MT-positive tumor, 10 (62.5%) showed no change. In 14 cases with MT-negative tumor, 13 (92.8%) showed partial response. In 8 patients with negative staining for p53 and MT, 7 were responders, whereas in 9 patients with positive staining for p53 and MT, 6 were nonresponders. The pathologic response was significantly associated with the prognosis (p = 0.0167). The survival rate of the responders was significantly better than that of the nonresponders. These findings suggest that MT might be a prognostic marker, and consequently we can select the patients who will benefit from preoperative chemoradiation.
So-Called Carcinosarcoma of the Esophagus: A Clinicopathologic, Immunohistochemical and DNA Flow-Cytometric Analysis of 6 Cases
Authors: Natsugoe Shoji , Matsushita Yoshifumi , Chuman Yutaka , Kijima Fumio , Haraguchi Yusei , Shimada Mario , Yoshinaka Heiji , Baba Masamichi , Mueller James , Aikou Takashi
Published: April 2003

Six cases of carcinosarcoma of the esophagus were studied clinicopathologically, immunohistochemically and with DNA flow cytometry. Transitional areas with morphology intermediate between carcinoma and sarcoma were found microscopically in all cases. Immunohistochemically, the carcinomatous areas contained keratin-positive cell components in all cases while vimentin-positive cells were found in sarcomatous areas in 5 cases. By DNA flow analysis of microdissection, the sarcomatous components of the tumors showed an aneuploid pattern with one exception, in contrast the carcinomatous components were diploid in all cases. In these few cases, PCNA, S-phase fraction and the mitotic rate were extremely high, apparently indicating a correlation with malignant behavior. Accordingly, examination by immunohistochemistry and DNA ploidy is useful for the analysis of biological properties in the so-called carcinosarcoma of the esophagus.
Management of Non-Epithelial Ovarian Tumours
Authors: Bridgewater John A. , Rustin Gordon J.S.
Published: April 2003

Ovarian tumours of non-epithelial origin are less common than those of epithelial origin but must be distinguished from these as their natural history and management differ. As these tumours are rare, histological review by an expert in the field is essential. There have been no randomised trials to outline the management of these tumours and therefore this paper represents a review of descriptive data. Non-epithelial ovarian tumours, which represent approximately 50% of all ovarian tumours and approximately 25% of malignant ovarian tumours, are outlined. Lymphomas and metastatic tumours should be treated the same as when found in other sites and will not be discussed further.
Induction Chemotherapy followed by Concurrent Chemotherapy and High-Dose Radiotherapy for Locally Advanced Squamous Cell Carcinoma of the Cervical Oesophagus
Authors: Stuschke Martin , Stahl Michael , Wilke Hansjochen , Walz Martin K. , Oldenburg Anne R. , Stüben Georg , Jahnke Klaus , Seeber Siegfried , Sack Horst
Published: April 2003

The efficacy and toxicity of combined radiochemotherapy for locally advanced squamous cell carcinomas of the cervical oesophagus was evaluated retrospectively. Induction chemotherapy consisted of three courses of 5-fluorouracil (5-FU), leucovorin, etoposide and cisplatin (FLEP) or two courses weekly six times of 5-FU and leucovorin combined with biweekly cisplatin. This induction regimen was followed by high-dose external beam radiotherapy up to 60–66 Gy and concurrent chemotherapy with cisplatin and etoposide. Median follow-up of the recruited 17 patients was 37 months (13–73 months). Long-term survival was 24% at 2 and 3 years. The probabilities of locoregional tumour recurrences and distant metastases as sites of first relapse were 67 and 39% at 2 years. Acute and late toxicity of this schedule was moderate. The protocol offers a definitive chance of long-term survival for patients with locally advanced carcinomas of the cervical oesophagus, but local in-field recurrences remain the predominant risk after treatment. Intensification of the regimen seems possible because no dose-limiting late toxicities were observed.
Efficacy of Continuous Hyperthermic Peritoneal Perfusion for the Prophylaxis and Treatment of Peritoneal Metastasis of Advanced Gastric Cancer: Evaluation by Multivariate Regression Analysis
Authors: Hirose Kazuo , Katayama Kanji , Iida Atsushi , Yamaguchi Akio , Nakagawara Gizo , Umeda Syun-ichi , Kusaka Yukinori
Published: April 2003

Thirty-two patients with advanced gastric cancer underwent continuous hyperthermic peritoneal perfusion (CHPP) combined with surgery: to prevent peritoneal recurrence in 15 patients without peritoneal metastasis (prophylactic CHPP) and to treat 17 patients with peritoneal metastases (therapeutic CHPP). The postoperative outcome was compared with that of control patients treated with surgery alone. Peritoneal recurrence was less frequent (26%) and the 5-year survival rate was significantly higher (39%) in the patients with prophylactic CHPP than in 40 control patients (42 and 17%, respectively). The patients with therapeutic CHPP showed significantly better median survival than did 20 control patients (11 vs. 6 months). Cox multivariate regression analysis revealed that CHPP was an independent prognostic factor in the prophylactic study (hazard ratio = 0.3965), and that the independent prognostic factor in the therapeutic study was not CHPP but complete resection of the peritoneal metastasis. Thus, CHPP has no marked benefit for established peritoneal metastasis. CHPP for the prevention of peritoneal recurrence may have a beneficial effect on long-term survival, but a prospective randomized trial is needed to clarify its prognostic value.
IL-6, M-CSF and IAP Cytokines in Ovarian Cancer: Simultaneous Assessment of Serum Levels
Authors: Foti E. , Ferrandina G. , Martucci R. , Romanini M.E. , Benedetti Panici P. , Testa U. , Mancuso S. , Scambia G.
Published: April 2003

The aim of this study was to simultaneously determine IL-6, M-CSF and IAP levels in 61 serum samples of previously untreated ovarian cancer patients. A direct correlation between IL-6 and M-CSF has been found in our patient population (r = +0.41, p = 0.013), while IAP serum levels failed to correlate with M-CSF (r = +0.15, p = 0.24) and IL-6 (r = +0.17, p = 0.18) levels. Since IL-6 and M-CSF have been demonstrated to be both induced in response to the same agents, it is conceivable that a mechanism of coregulation in the production of these cytokines by tumor cells and macrophages might occur. The direct correlation between IL-6 and M-CSF also suggests that tumor-derived cytokines can potentially lead to a self-maintaining cytokine network by recruiting cytokine-producing host cells and by perpetuating cytokine production.
Lack of p53-Mediated G1 Arrest in Response to an Environmental Carcinogen
Authors: Khan Qasim A. , Vousden Karen H. , Dipple Anthony
Published: April 2003

The environmental carcinogen, 5-methylchrysene, is a component of cigarette smoke. Its reactive metabolite, anti-5-methylchrysene-1,2-dihydrodiol-3,4-epoxide (5-MeCDE) mainly reacts with the N2-position of guanine residues in the DNA molecule. In this study, we demonstrate that the tumor suppressor protein p53 is stabilized in response to DNA damage by 5-MeCDE but fails to induce the cells’ protective mechanism of G1 arrest in the human breast carcinoma cell line, MCF-7. In contrast, actinomycin D treatment of these cells did lead to G1 arrest. Western analyses revealed that, though both actinomycin D and 5-MeCDE treatment stabilized p53, only trace levels of p21waf1/cip1 were seen in the latter case. This lack of p21waf1/cip1 expression in 5-MeCDE-treated cells is attributed to a stealth characteristic of this environmental carcinogen that allows it to damage DNA and still escape the p53-mediated cellular defense mechanism of G1 arrest.
Clinical Implications of Lymph Node Micrometastases in Patients with Colorectal Cancers
Authors: Nakanishi Yukihiro , Ochiai Atsushi , Yamauchi Yuko , Moriya Yoshihiro , Yoshimura Kimio , Hirohashi Setsuo
Published: April 2003

There is no unanimity about the prognostic significance of lymph node micrometastases from colorectal cancer. A case-control study of patients with recurrent and nonrecurrent colorectal cancer who were closely matched for the Dukes stage, extent of lymph node dissection, tumor size, tumor location, number of resected lymph nodes, age and gender was performed. The presence of micrometastases in a total of 1,633 lymph nodes from 44 patients (22 with and 22 without recurrence) were examined by immunohistochemistry using antibodies for cytokeratin (KL-1) and p53 (RSP53). Immunostaining with KL-1 revealed micrometastases in 15/22 patients [68%; 82/820 lymph nodes (10%)] and 15/22 patients [68%; 45/813 lymph nodes (6%)] in the recurrent and nonrecurrent groups, respectively. Immunohistochemical analysis, using RSP53, of 18 paired patients with p53-positive primary tumor revealed micrometastases in 4/9 patients [44%; (7/265 lymph nodes (2.6%)] and 4/9 patients [44%; 6/257 lymph nodes (2.3%)] with and without recurrence, respectively. Neither the micrometastatic frequencies of the patients nor the resected lymph nodes of the recurrent and nonrecurrent groups differed significantly. Micrometastases in regional lymph nodes are an interesting phenomenon, but do not influence patients’ prognoses if the involved lymph nodes are removed.
Artificial Neural Networks Applied to Survival Prediction in Breast Cancer
Authors: Lundin M. , Lundin J. , Burke H.B. , Toikkanen S. , Pylkkänen L. , Joensuu H.
Published: April 2003

In this study, we evaluated the accuracy of a neural network in predicting 5-, 10- and 15-year breast-cancer-specific survival. A series of 951 breast cancer patients was divided into a training set of 651 and a validation set of 300 patients. Eight variables were entered as input to the network: tumor size, axillary nodal status, histological type, mitotic count, nuclear pleomorphism, tubule formation, tumor necrosis and age. The area under the ROC curve (AUC) was used as a measure of accuracy of the prediction models in generating survival estimates for the patients in the independent validation set. The AUC values of the neural network models for 5-, 10- and 15-year breast-cancer-specific survival were 0.909, 0.886 and 0.883, respectively.The corresponding AUC values for logistic regression were 0.897, 0.862 and 0.858. Axillary lymph node status (N0 vs. N+) predicted 5-year survival with a specificity of 71% and a sensitivity of 77%. The sensitivity of the neural network model was 91% at this specificity level. The rate of false predictions at 5 years was 82/300 for nodal status and 40/300 for the neural network. When nodal status was excluded from the neural network model, the rate of false predictions increased only to 49/300 (AUC 0.877). An artificial neural network is very accurate in the 5-, 10- and 15-year breast-cancer-specific survival prediction. The consistently high accuracy over time and the good predictive performance of a network trained without information on nodal status demonstrate that neural networks can be important tools for cancer survival prediction.
p53 Autoantibodies in Patients with Primary Ovarian Cancer Are Associated with Higher Age, Advanced Stage and a Higher Proportion of p53-Positive Tumor Cells
Authors: Vogl F.D. , Stickeler E. , Weyermann M. , Köhler T. , Grill H.-J. , Negri G. , Kreienberg R. , Runnebaum I.B.
Published: April 2003

Autoantibodies (AAb) directed against the nuclear phosphoprotein p53 can be detected in patients with various forms of cancer. The objective was to determine the prevalence of p53 AAb at the time of diagnosis in ovarian cancer patients and to correlate the presence of p53 AAb with clinicopathological parameters. Sera of 83 patients were analyzed by an ELISA using p53 expressed from a human wild-type cDNA. p53 AAb were detectable at all stages. The overall prevalence was 46%. p53 AAb were more frequent in patients with higher age (p = 0.014), postmenopausal status (p = 0.050), or advanced tumor stage (p = 0.046). p53 AAb positivity was related to the proportion of cells positive in immunohistochemistry but not with the staining intensity. In bivariate analysis, patients with p53 AAb had a 1.96-fold risk for relapse (95% confidence interval 1.02–3.78).
Vinorelbine and Alternating Cisplatin and Ifosfamide in the Treatment of Non-Small Cell Lung Cancer
Authors: Barone Carlo , Corsi Domenico C. , Pozzo Carmelo , Cassano Alessandra , Alvaro Giuseppe , Colloca Giuseppe , Landriscina Matteo , Astone Antonio
Published: April 2003

In order to explore the activity of a combination of vinorelbine (VNL) and alternating cisplatin (CDDP) and ifosfamide (IFX) in non-small cell lung cancer (NSCLC), a phase II study was performed. Seventy chemoradiotherapy naive patients with NSCLC, stage IIIA, IIIB and IV disease, PS (ECOG) ≤2, were treated with CDDP 40 mg/m2 on days 1, 2, 3, IFX 1,800 mg/m2 on days 22, 23, 24 and VNL 30 mg/m2 on days 1, 8, 22, 29 every 6 weeks up to 6 courses. In the 67 evaluable patients, an objective response rate was observed in 47.8 ± 12% (95% CI) with complete responses in 6%; responses occurred more frequently in patients with locally advanced disease (stage IIIA/IIIB) and/or performance status 0. The median duration of survival was 12 months: 19.9 months in stage III patients who received an integrated treatment and 10 months in metastatic disease. The median time to treatment failure was 10.5 months. Toxicity was mainly hematological, even though it was not dose-limiting and easily manageable. This combination seems to be active, and the good safety profile is probably the result of the use of an alternating schedule of CDDP and IFX. Median overall survival was also encouraging in stage IV disease. The prolongation of survival obtained when surgery and/or radiotherapy is applicable needs confirmation through a larger study.
Identification of Exon-Deleted Progesterone Receptor mRNAs in Human Uterine Endometrial Cancers
Authors: Misao Ryou , Nakanishi Yoshihito , Sun Wen-Shu , Iwagaki Shigenori , Fujimoto Jiro , Tamaya Teruhiko
Published: April 2003

We demonstrated the expression of various exon-deleted progesterone receptor (PR) variant mRNAs in human uterine endometrial cancers using the reverse transcription-polymerase chain reaction-DNA sequencing analyses. In addition to PR wild-type mRNA, exon 4-deleted, exon 6-deleted, exon 3,4-deleted, exon 5,6-deleted, exon 4,5,6-deleted and exon 3,4,5,6-deleted PR variant mRNAs were identified. The exon 6-deleted and exon 5,6-deleted PR variant mRNAs lacked encoding for the steroid-binding domain. The exon 4-deleted, exon 3,4-deleted, exon 4,5,6-deleted and exon 3,4,5,6-deleted PR variant mRNAs lacked encoding for the DNA-binding domain in addition to encoding for the steroid-binding domain. While the exon 4-deleted, exon 6-deleted and exon 3,4-deleted PR variant mRNAs were observed in all samples analyzed, the exon 5,6-deleted, exon 4,5,6-deleted and/or exon 3,4,5,6-deleted PR variant mRNAs could not be detected in some cases, especially in poorly differentiated adenocarcinoma as compared with well-differentiated and moderately differentiated adenocarcinomas. The present study demonstrates the coexpression of PR exon-deleted variant mRNAs with the wild-type in uterine endometrial cancers. All translated variant proteins might possess functional diversity and might modify the progestational action of wild-type PR, and the expression of some PR variant mRNAs may be lost as endometrial cancer cells undergo dedifferentiation.
Prognostic Relevance of a Histological Grading System Using MIB-1 for Adult Soft-Tissue Sarcoma
Authors: Hasegawa Tadashi , Yokoyama Ryohei , Lee Yoon Hwan , Shimoda Tadakazu , Beppu Yasuo , Hirohashi Setsuo
Published: April 2003

Several histological grading systems have been proposed and found as strong indicators of outcome in soft-tissue sarcomas. However, a putative independent prognostic influence of recently developed biological and molecular markers remains to be established. This study investigated the prognostic relevance of a histological grading system based on the assessment of proliferative activity in adult soft-tissue sarcomas of the extremities, trunk, head, and neck. Tissue blocks from 95 of 108 patients without distant metastases or regional lymph node involvement were available. Immunohistochemical staining for MIB-1 and p53 was done on paraffin-embedded sections. All clinicopathologic and immunohistochemical variables and patient survival were assessed using univariate and multivariate analyses. Variables included histological grading based on the modified Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system using the MIB-1 score for the estimation of the proliferative potential of the tumors. Variables associated with overall survival were tumor site in the trunk, head and neck, mitosis count, necrosis, MIB-1 score, FNCLCC grade, modified FNCLCC grade using the MIB-1 score, and stage (all p values <0.05). In multivariate analysis, the modified grade proved to be the most significant predictor of shortened overall survival, in addition to tumor site in the trunk, head, and neck. Overexpression of p53 did not correlate with increased risk of tumor mortality. Using MIB-1 to replace mitosis counts in the FNCLCC system improves grading of soft-tissue sarcomas, and this in conjunction with other important factors appear to be more accurate prognostic factors for survival, and for patient selection in investigational adjuvant treatment trials.
Overexpression of the Heat Shock Protein HSP70 Family and p53 Protein and Prognosis for Patients with Gastric Cancer
Authors: Maehara Yoshihiko , Oki Eiji , Abe Toru , Tokunaga Eriko , Shibahara Kotaro , Kakeji Yoshihiro , Sugimachi Keizo
Published: April 2003

The cell synthesis of heat shock proteins is increased by a variety of environmental and pathophysiological stressful conditions. The 70-kD heat shock protein family (HSP70 family) which constitutively expresses hsc70 and heat-inducible hsp70 is thought to be involved in protein-protein interactions, including oncogene products. We investigated the HSP70 family expression and biological behavior of gastric cancer, and its relation to p53 overexpression. Expressions of HSP70 and p53 in 164 primary gastric tumors were determined immunohistochemically. Exploratory data were analyzed on a set of 164 primary gastric cancers, and we constructed in prognostic significance of the HSP70 expression level and the relation to p53 overexpression. Expression of HSP70 (hsc70 and hsp70) were detected in nuclei and/or cytoplasm of cancer cells. Western blotting analysis showed that hsc70 and hsp70 were both expressed in five gastric cancer cell lines. Immunohistochemically stained positive cells of HSP70 varied from 0 (very weak) to 100%, in each case. The median level of positive cell rate was 19.0%. A HSP70 expression of over 19.0% was related to the differentiated tissue type of gastric cancer, but not to other clinicopathological factors. There was no difference in survival rates in subjects with higher and lower groups of HSP70 expression. HSP70 expression was also not related to p53 overexpression in the nuclei and p53 overexpression-related poorer prognosis. Our findings show that the expression of HSP70 is not associated with tumor advance-related characteristics or with the prognosis of gastric cancer. Measurements of HSP70 expression do not appear to be a useful prognostic marker.
Vitamin D Receptor Gene BsmI Polymorphism Correlates with erbB-2/HER-2 Expression in Human Rectal Cancer
Authors: Speer G. , Dworak O. , Cseh K. , Bori Z. , Salamon D. , Török I. , Winkler G. , Vargha P. , Nagy Zs. , Takács I. , Kucsera M. , Lakatos P.
Published: April 2003

Apart from the regulation of calcium metabolism, 1,25-dihydroxyvitamin D3 plays an essential role in cell proliferation and differentiation in several tissues. The vitamin D receptor (VDR) gene shows polymorphisms in humans that appear to be clinically significant in some pathological conditions. In the present study, the BsmI polymorphism of the VDR gene was studied in 59 Caucasian patients with rectal cancer (mean follow-up: 48 months). The relationship between VDR genotypes and the expression of oncogenes as well as their influence on survival were also investigated. VDR polymorphism was examined in tumor and normal mucosa cells by PCR technique. The expression of erbB-2/HER-2, p53, ras and epidermal growth factor receptor (EGFR) was also detected by immunohistochemistry and protein blotting. The presence of the VDR B allele significantly correlated with the overexpression of the erbB-2 oncogene. There was no difference in the VDR genotype between cancer and normal mucosal cells. Coexpression of erbB-2, pan-ras, p53 and EGFR internal and external domains was significantly higher in cancer cells than in normal mucosa. There was no significant correlation between VDR genotypes and age, gender, tumor infiltration depth, number and site of lymph node metastases and lymphatic or blood vessel infiltration. The VDR genotype alone did not influence survival. Overexpression of erbB-2 and EGFR was associated with a poor prognosis. In patients expressing only one oncogene in cancer cells, the presence of the VDR B allele showed a tendency to a poor prognosis. In conclusion, VDR gene BsmI polymorphism might affect the development and prognosis of rectal cancer by influencing erbB-2 oncogene expression.
Evaluation of the Therapeutic Effect of Transcatheter Arterial Embolization for Hepatocellular Carcinoma
Authors: Okusaka Takuji , Okada Shuichi , Ueno Hideki , Ikeda Masafumi , Yoshimori Masayoshi , Shimada Kazuaki , Yamamoto Junji , Kosuge Tomoo , Yamasaki Susumu , Iwata Ryoko , Furukawa Hiroyoshi , Moriyama Noriyuki , Sakamoto Michiie , Hirohashi Setsuo
Published: April 2003

Transcatheter arterial embolization (TAE) has been widely performed for patients with hepatocellular carcinoma (HCC). However, the method of evaluating the therapeutic effect of TAE has not been established. We examined the rate of necrotic area to whole tumor (TN) by CT, the tumor regression rate (TR) and the reduction rate in serum α-fetoprotein (AFP) levels in patients with HCC who received hepatic resection within 3 months after TAE. In the evaluation of TN, the lipiodol accumulation in tumor was regarded as being necrotic. Rates of necrotic area, which were also examined pathologically (PN) in resected tumors, were compared with TN, TR and AFP reduction rates, respectively. Eighty-eight patients were enrolled in this study, and there was a significant positive correlation between TN and PN (r = 0.80, p < 0.001). Although TR significantly correlated to PN (p = 0.001), the correlation coefficient between them was low (r = 0.34). The correlation coefficients between AFP reduction rate and PN was 0.76 (p < 0.001) in 26 patients (30%) with an AFP level ≥200 ng/ml before TAE. The evaluation method using lipiodol accumulation in CT is the most useful for assessing the therapeutic effect of TAE, particularly when a sufficiently long interval exists between TAE and the evaluation, because of the highest correlation coefficient between TN and PN, and the availability of TN for all patients. The reduction rate in serum AFP levels was also useful in patients with AFP levels >200 ng/ml before treatment.