bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Significance of mdm2 and p53 Expression in Bladder Cancer
Authors: Shiina Hiroaki , Igawa Mikio , Shigeno Kazushi , Yamasaki Youji , Urakami Shinji , Yoneda Tatsuaki , Wada Yukihiro , Honda Satoshi , Nagasaki Makoto
Published: April 2003

Background: Clinical significance of immunohistochemically detectable level of p53 protein has been reported, but with some limitation as a prognosticator of bladder cancer patients. Whether or not simultaneous evaluation of mdm2 and p53 expression in bladder cancer exceed the prognostic significance of conventional histological findings, cell proliferation markers and apoptotic parameters remains unclear. Materials and Methods: The paraffin-embedded materials taken from 84 patients with transitional cell carcinoma of the bladder who were treated with total cystectomy were used in this study. Immunostainings of p53 protein, mdm2 protein and Ki67 antigen were performed using monoclonal antibodies (clone DO7, clone 1B10 and clone MIB1, respectively). In addition, the apoptotic cells were determined using a terminal deoxynucleotidyl transferase (TdT) mediated dUTP biotin nick end labeling (TUNEL) technique. The results were quantitatively evaluated using a CAS 200 Image Analyzer (Cell Analysis System, Elmhurst, Ill., USA) and were compared with histological findings and clinical course. Results: The mean values of mdm2 expression, p53 immunoreactivity, Ki67 expression and apoptotic index were 19.2, 20.5, 22.4 and 0.96%, respectively. Histological grade and pT category were significantly positively correlated with 53 immunoractivity (p < 0.05 and p < 0.05, respectively), Ki67 expression (p < 0.005 and p < 0.0001, respectively) and apoptotic index (p < 0.01 and p < 0.0001, respectively), while both were not correlated with mdm2 expression. Using univariate analysis, the prognostic relevance for both survival and disease progression was noted in histological grade, pT category, p53 expression, Ki67 index and apoptotic index, whereas it was not in mdm2 expression. However, when analyzing the simultaneous evaluation of mdm2 and p53 expression (mdm2-p53 category), the relationship of the mdm2-p53 category with Ki67 expression and apoptotic index showed a statistical significance and a borderline significance (p = 0.0085 and p = 0.0652, respectiely). In addition, the patients with both mdm2(–) and p53(–) showed a signifiant better prognosis as compared with either counterpart of mdm2-p53 category (p < 0.05 for both). Multivariate analysis revealed only pT category and mdm2-p53 category as independent factors for both disease progression and survival. Conclusions: Clinical significance of simultaneous evaluation of mdm2 and p53 immunostaining proved to be superior over that of cell proliferation and/or apoptotic markers when elucidating the biological characteristics of bladder cancer.
Prognosis for Pedunculated Hepatocellular Carcinoma
Authors: Horie Yutaka , Shigoku Azusa , Tanaka Hisao , Tomie Yasushi , Maeda Naoto , Hoshino Ushio , Koda Masahiko , Shiota Goshi , Yamamoto Tetsuo , Kato Seiichi , Murawaki Yoshikazu , Suou Takeaki , Kawasaki Hironaka
Published: April 2003

We retrospectively compared the outcome of 13 patients at our institution and that of 163 reported cases of pedunculated hepatocellular carcinoma (HCC) with that of conventional HCC subdivided by tumor diameter (group A: less than 2 cm; group B: 2–5 cm, group C: more than 5 cm). The survival of patients with pedunculated HCC in the 163 reported cases was no different from that of group B, but less favorable than in group A (p < 0.01) and more favorable than in group C (p < 0.01). Among the 163 patients with pedunculated HCC, the 113 cases of surgically treated patients had higher survival than the 21 patients treated with transcatheter arterial embolization (n = 16) or transcatheter arterial infusion chemotherapy (n = 5) (p < 0.01) and than 29 conservatively treated patients (p < 0.001). A total of 70 patients out of 163 (42%) died within 1 year after diagnosis. Additionally, almost all cases of pedunculated HCC showed histologically moderately or poorly differentiated characteristics according to Edmondson and Stainer’s classification or the WHO classification. These results suggest that pedunculated HCC has not a favorable prognosis if appropriate surgical resection has not been performed very early within a few months because of its rapid progressive nature.
Malignant Seeding of the Lumpectomy Cavity upon Breast-Conserving Surgery
Authors: Motomura Kazuyoshi , Koyama Hiroki , Noguchi Shinzaburo , Inaji Hideo , Kasugai Tsutomu , Nagumo Sachiko
Published: April 2003

One of the etiologic factors involved in local recurrence after breast-conserving surgery may be malignant seeding of the wound during the lumpectomy procedure. A total of 340 patients with stage I and II breast cancer were entered into the study. Of these, 270 patients received breast-conserving surgery (BCS group), and the other 70 patients underwent mastectomy (control group). After resection, lavage cytology was performed at the surgical wound. There were 55 patients (20.4%) who showed positive lavage cytology in the BCS group. In the control group, there were only 3 patients (4.3%) with positive cytology. Positivity was significantly higher in the former group (p = 0.00064). Patients with evidence of cutting across cancer lesions showed significantly higher positive rates in lavage cytology (p < 0.00001). Positivity in lavage cytology was significantly higher in patients with positive surgical margins evaluated by frozen sections (p = 0.0017), touch cytology (p < 0.0001) and formalin-fixed, paraffin-embedded sections (lateral or medial margin; p = 0.0036, anterior and posterior margin: p = 0.0210). The positivity was also significantly higher in patients with an extensive intraductal component (p < 0.0001), and less than or equal to 50 (p = 0.0061) years of age. Multivariate analysis revealed that the highest relative risk factor for positive cytology was evidence of cutting across cancer lesions (relative risk = 8.166; p < 0.00001).
Outpatient Treatment of Neutropenic Fever with Oral Antibiotics and Granulocyte Colony-Stimulating Factor
Authors: Papadimitris Constantinos , Dimopoulos Meletios A. , Kostis Evangelos , Papadimitriou Christos , Anagnostopoulos Athanassios , Alexopoulos George , Papamichael Christos , Gika Dimitra , Mitsibounas Dimitrios , Stamatelopoulos Stamatios
Published: April 2003

In recent years, several cancer patients who developed neutropenic fever were effectively treated on an outpatient basis with either intravenous or oral antibiotics. This approach is associated with reduced cost and improved patient convenience. However, the appropriate antibiotic regimen and the role of growth factors have not been established yet. In order to address these issues we performed a nonrandomized phase II study to assess the feasibility and efficacy of an oral antibiotic regimen in combination with granulocyte colony-stimulating factor (G-CSF) for the outpatient treatment of cancer patients with low-risk neutropenic fever. In 50 patients with solid tumors or lymphoma, 60 episodes of neutropenic fever were treated with the combination of oral ofloxacin 400 mg twice a day, oral amoxicillin 1 g 3 times a day and G-CSF 5 μg/kg/day subcutaneously. Patients receiving G-CSF prophylaxis were eligible for our study. Oral antibiotics were administered for at least 5 days and G-CSF was continued until resolution of neutropenia. Our patients were ambulatory, hemodynamically stable, and without significant comorbidity. Our combination was successful in 57 episodes (95%) with a median time for fever resolution of 3 days (range: 1–5 days). There was no significant toxicity associated with the antibiotic regimen with the exception of one case of reversible renal impairment. The role of G-CSF in the success of our antibiotic treatment is highly questionable since one half of our patients developed fever while on G-CSF prophylaxis. The combination of oral ofloxacin and amoxicillin with G-CSF is highly effective for the outpatient treatment of cancer patients who develop uncomplicated febrile neutropenia. The relative contribution of G-CSF needs clarification with a prospective randomized study.
Cooccurrence of Reduced Expression of α-Catenin and Overexpression of p53 Is a Predictor of Lymph Node Metastasis in Early Gastric Cancer
Authors: Xiangming Che , Hokita Shuichi , Natsugoe Shoji , Tanabe Gen , Baba Masamichi , Takao Sonshin , Kuroshima Kazunao , Aikou Takashi
Published: April 2003

Background and Objectives: Even though the pathological background contributes to lymph node metastasis, the biological characteristics of tumors have also gained wide attention. In this study, the expression of the cadherin-catenin complex and p53 was studied in early gastric cancer. Their correlation with lymph node metastasis and the predictability of lymph node metastases, by combining these factors, were also discussed. Methods: One hundred and one specimens obtained from surgery were studied by immunohistochemistry using monoclonal anti-E-cadherin, anti-α-catenin and anti-p53 antibodies. Results: Expression of E-cadherin and α-catenin was reduced in 50.5 and 64.4%, respectively. p53 protein staining was positive in 29.7%. There was a significant correlation between E-cadherin and α-catenin expression, but no correlation was found between p53 expression and E-cadherin or α-catenin expression. A reduction in α-catenin expression and p53 overexpression correlated to lymph node metastases, respectively. Multivariate analysis showed that cooccurrence of reduced expression of α-catenin and overexpression of p53 was an independent factor indicating lymph node metastases. Conclusion: A study of both α-catenin and p53 expression may be helpful to predict lymph node metastases in early gastric cancer.
Thymidylate Synthase: A Target for Combination Therapy and Determinant of Chemotherapeutic Response in Colorectal Cancer
Authors: van Triest B. , Peters G.J.
Published: April 2003

In this review, we describe the role of thymidylate synthase (TS) as a determinant of chemotherapeutic response. TS is an essential enzyme for the de novo synthesis of thymidylate and subsequent DNA synthesis. TS has been used as a target for cancer chemotherapy in the development of fluoropyrimidines such as 5-fluorouracil (5FU) and 5-fluorodeoxyuridine and novel folate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), LY231514, AG337 (Thymitaq) and GW1843U89. All these antifolates have different transport mechanisms and various polyglutamylation and accumulation patterns which are all important for drug sensitivity. An update of clinical studies with TS inhibitors (antifolate-based TS inhibitors and 5FU combination studies) will be given and new perspectives for clinical development will be discussed. The prognostic or predictive value of TS (in vitro, in vivo and in patients) will be reviewed, focusing on colorectal cancer.
MIB-1 Immunoreactivity Correlates with Blood Vessel Density and Survival in Disseminated Malignant Melanoma
Authors: Vlaykova Tatyana , Talve Lauri , Hahka-Kemppinen Marjo , Hernberg Micaela , Muhonen Timo , Franssila Kaarle , Collan Yrjö , Pyrhönen Seppo
Published: April 2003

The purpose of our current work was to evaluate the prognostic significance of tumor cell proliferation in advanced metastatic melanomas and to investigate a possible correlation between the proliferation index and blood vessel density in metastatic tissue. Sixty patients with disseminated malignant melanoma treated with four-drug chemotherapy combined with interferon-α were included in this study. Proliferative activity and vascularity in metastatic tissues were examined by immunohistochemistry with anti-Ki-67 (MIB-1) and anti-CD31 antibody, respectively. A significant relationship between MIB-1 index and blood vessel number was detected (rho = 0.323, p = 0.013). In survival analysis, the overall survival and disease-free survival were significantly longer (58 and 38 vs. 38 and 17 months) for patients with low MIB-1 immunoreactivity (p = 0.012 and p = 0.023, respectively). Likewise, the low MIB-1 labeling index was associated with the prolonged survival calculated from the initiation of the chemoimmunotherapy (12 vs. 7 months, p = 0.032). In multivariate Cox’s proportional hazard analysis, MIB-1 positivity was an independent prognostic factor both for overall survival and for survival after beginning of the chemoimmunotherapy (p = 0.016 and p = 0.029).
Combined Treatment of Metastatic Osteosarcoma of the Spine
Authors: Bauernhofer T. , Stöger H. , Kasparek A.K. , Ploner F. , Kuss I. , Pieber T.R. , Kotz R. , Samonigg H.
Published: April 2003

We report on a 28-year-old male with a single metastasis of an osteosarcoma in the twelfth thoracic vertebra occurring 9 years after initial diagnosis of the primary tumour in the left distal femur and neoadjuvant treatment according to a modified T-10 protocol. After pre-operative second-line combination chemotherapy with doxorubicin, carboplatin and etoposide leading to regression of the primarily inoperable metastasis wide resection of the tumour employing total spondylectomy was done. The duration of response had been 65 months since the end of subsequent postoperative chemotherapy with the same regimen.
Effect of Granisetron on Performance Status during High-Dose Interferon Therapy
Authors: Drapkin Robert , Barolo Jennifer L. , Blower Peter R.
Published: April 2003

Two case reports demonstrating the new complete amelioration of the toxicity of alpha-2b recombinant interferon using granisetron i.v. or p.o.
CDKN2 Mutation Is Infrequent in German Hepatocellular Carcinoma
Authors: Volkmann Martin , Stilgenbauer Franziska , Hofmann Walter J. , Otto Gerd , Schiff Jan H. , Fiehn Walter
Published: April 2003

For hepatocellular carcinoma, only scarce and controversial data on CDKN2 alterations are available. A high rate of mutations in a Chinese study contrasts with a low rate found in Japanese tumors and a CDKN2 germline mutation in 4/26 Swiss tumors examined. We analyzed 23 hepatocellular carcinomas from German patients for homozygous deletions of CDKN2 by coamplification with the human tyrosine hydroxylase (TH) gene and for CDKN2 mutations by PCR-single strand conformation polymorphism analysis and direct DNA sequencing. Our results indicate the lack of homozygous deletions. In one tumor, DNA sequencing showed a GCG-ACG (alanine-threonine) substitution at codon 148, a polymorphism in exon 2 of CDKN2. We conclude that the alteration of CDKN2 by deletion or mutation appears not to be a frequent event in hepatocarcinogenesis in German patients.
Scintigraphic Imaging of Sarcomatous Tumors with [111In-DTPA-Phe-1]-Octreotide
Authors: Giannakenas C. , Kalofonos H.P. , Apostolopoulos D. , Petsas T. , Kalogeropoulou C. , Tzorakelefterakis E. , Skopa C.D. , Vassilakos P.J.
Published: April 2003

The objective of the present study was to investigate the efficacy of 111In-DTPA-octreotide (OC) for in vivo scintigraphic imaging of these relatively uncommon tumors. Thirteen patients (9 males, 4 females, mean age 59 years) with known sarcomatous lesions were studied. All patients had known lesions as demonstrated by previous investigation with other modalities, e.g. CAT, MRI. Following intravenous injection of 10 μg of OC labeled with 2.8–4.2 mCi 111In, planar imaging was done at 6 ± 1 and 22 ± 2 h, respectively. Histologic verification was obtained in all cases, either from fine needle aspiration or from surgically removed tissue. Positive imaging was observed in 12/13 cases (92.3%). One scan was false-negative (7.7%). Occult lesions were demonstrated in two patients. The histologic typing and the scintigraphy results were: fibrosarcoma (1+/1), embryonic rhabdomyosarcoma (1+/1), leiomyosarcomas (3+/3), liposarcomas (2+/2), uterine sarcomas (2+/2), HIV (–) Kaposi sarcoma (1+/1), osteosarcoma (1+/1), chondrosarcoma (1–/1) and neurogenous sarcoma (1+/1). OC appears to have properties that lead to a new indication for its use. Other possible applications relate to the therapeutic use of octreotide either unlabeled or labeled with a beta-emitting radionuclide, as well as its use in radioimmunoguided surgery. Regarding the latter, our preliminary results are encouraging.
Second Malignancies following Pure Seminoma
Authors: Rüther U. , Dieckmann K.-P. , Bussar-Maatz R. , Eisenberger F.
Published: April 2003

Purpose: Second malignancies in patients with pure testicular seminoma were studied in order to look for adverse late effects of treatment and to study the significance of second malignancies during follow-up. Patients, Methods: In a multicentric investigation, 839 consecutive patients with pure testicular seminoma were observed for a median follow-up of 3.9 years. Thirty-seven patients had been excluded from the study because they already had had either a contralateral testicular germ cell tumor or another malignancy. 758 patients received radiotherapy, 76 underwent chemotherapy, 5 had surveillance only. The expected rate of second cancers was calculated according to the data of the cancer registry of Saarland, Germany. Results: Twenty-two second cancers (13 contralateral testicular tumors, 9 extratesticular malignancies) were recorded. The overall risk of having a second cancer was RR = 4.8 (95% CI 3.0–7.3). The risk of having a subsequent testicular tumor is RR = 44.8 (95% Cl 23.9–76.7). 1.1% of the patients developed a nontesticular second tumor. The risk of having a nontesticular second cancer is RR = 2.1 (95% CI 1.0–4.0). A significantly increased risk was observed for renal cell cancer as well (RR = 12.5; 95% Cl: 1.5–45.1). Increased RR without reaching statistical significance were found for rectal cancer (RR = 5.0; 95% Cl: 0.1–27.9) and non-Hodgkin lymphoma (RR = 6.7; 95% CI 0.2–37.1). None of the second cancers were directly located within the radiation field; 5 neoplasms arose at the border of the radiation field. Conclusions: This study confirmed the increased risk of having a second testicular germ cell cancer. There is also a small but definitely increased overall risk of having a nontesticular second cancer. Treatment-unrelated factors – possibly genetic predisposition – must be considered for a substantial number of these second tumors, since in the present study the follow-up was rather short and most of the second cancers were located outside of the radiation fields. In particular, the association of renal cancer with testicular cancer appears to be a more than chance occurrence. Second cancer is a real hazard following treatment of testicular cancers and should always be considered during follow-up.
Expression of Tumor Suppressor Gene p16INK4 Products in Primary Gastric Cancer
Authors: Tsujie Masaki , Yamamoto Hirofumi , Tomita Naohiro , Sugita Yurika , Ohue Masayuki , Sakita Isao , Tamaki Yasuhiro , Sekimoto Mitsugu , Doki Yuichiro , Inoue Masatoshi , Matsuura Nariaki , Monden Takushi , Shiozaki Hitoshi , Monden Morito
Published: April 2003

Recent studies have shown that the cyclin-dependent kinase (CDK) inhibitor p27Kip1 represents an indicator for patients’ outcome in several human malignancies including gastric cancer. However, the clinicopathologic value of another class of CDK inhibitor, p16INK4, has not been determined. In a retrospective study, we examined the expression of p16INK4 by immunohistochemical assay of 80 samples of primary gastric cancers and their adjacent nonneoplastic mucosas. Less than 10% of non-tumor gastric mucosal cells were p16INK4 positive, whereas the expression of p16INK4 in gastric cancer cells varied widely from 0 to 100% (mean, 24.5%). The expression of p16INK4 was not seen in 11.3% (9/80) of the cancer cases, but in 65% (52/80) this protein was even overexpressed when compared with the nonneoplastic mucosa. A clinicopathologic survey indicated that a low or no expression of p16INK4 was associated with poorly differentiated carcinoma (p = 0.0133), but the level of expression did not correlate with other parameters including patients’ prognosis or with the expression of the pRb protein. In an effort to explore the underlying mechanism for the p16INK4-negative cases, a prospective study was also performed on 20 cases of gastric cancer to compare the level of the p16INK4 protein with the methylation status of the p16INK4 promoter. Gastric cancer tissues with methylation expressed significantly lower levels of the p16INK4 protein (p = 0.0013) and two of them lacked p16INK4 expression altogether, whereas all the cancer tissues without methylation expressed it. These findings suggest that the p16INK4 protein may be associated with differentiation of gastric cancer tissues and that methylation of the p16INK4 promoter may, in part, account for the loss of p16INK4 expression.
Thrombocytes Are the Major Source for Soluble Vascular Endothelial Growth Factor in Peripheral Blood
Authors: Gunsilius Eberhard , Petzer Andreas , Stockhammer Günther , Nussbaumer Walter , Schumacher Petra , Clausen Johannes , Gastl Günther
Published: April 2003

Serum levels of vascular endothelial growth factor (VEGF-S) have been reported to correlate with tumor stage and prognosis in various human malignancies. The source of soluble VEGF in peripheral blood remains obscure. We therefore measured the concentration of immunoreactive VEGF in 241 serum samples and 61 plasma samples (VEGF-P) from 20 subjects undergoing myeloablative chemotherapy and from 3 normal platelet donors. A significant correlation between the peripheral blood platelet count (PC) and VEGF-S (r = 0.86) but not VEGF-P was found. VEGF-S levels were 58.43 ± 42.50 pg/ml (mean ± SD) in patients with a PC < 50 × 109/l, 203.29 ± 176.56 pg/ml for a PC of 50–150 × 109/l, and 457.42 ± 475.41 pg/ml for a PC > 150 × 109/l. Interestingly, VEGF-P levels were substantially lower than the corresponding VEGF-S values, namely below the detection limit in most cases. Supernatants from platelet-rich plasma contained no VEGF, but after in vitro lysis of the platelets very high VEGF levels were found. The VEGF content per 109 platelets was calculated at 2.51 ± 2.39 pg and was dependent on the mean platelet volume. In summary, VEGF release from platelets during blood clotting was found to be the main source of VEGF in serum samples. Cancer patients in clinical remission have negligible amounts of soluble VEGF in peripheral blood, and myeloablative chemotherapy causes a significant drop in VEGF-S levels corresponding to the decrease in PC. Thus, studies addressing the diagnostic and prognostic value of VEGF-S in cancer patients must be interpreted with caution. Our data provide the basis for predicting VEGF-S in relation to PC in vivo, and for reevaluating former studies of VEGF-S in patients with malignant or nonmalignant disease.
A Retrospective Study of First Indicators of Breast Cancer Recurrence
Authors: Pivot X. , Asmar L. , Hortobagyi G.N. , Theriault R. , Pastorini F. , Buzdar A.
Published: April 2003

This study was performed to evaluate the first indicators of breast cancer recurrence in 1,145 patients treated at the University of Texas MD Anderson Cancer Center, between July 1973 and December 1980. Twenty patients were excluded due to incomplete data, resulting in a total number of 1,125 evaluable patients. Data collection included the first metastatic site and its means of detection (symptoms, self-examination, physical examination performed by a physician, and the results of blood and radiological tests). Whether recurrence was found at the scheduled follow-up visits or between the scheduled visits was also analyzed. Symptoms were the primary indicator of relapse for 648 cases (57.6% of the study population). An additional 361 cases (32.1% of the total group) were detected by self-examination or by physician-performed physical examination. Other investigations, e.g. bone scans, liver scans, chest X-rays, and blood tests, revealed recurrent disease in only 116 patients (10.3% of the population). Among the 1,125 patients, 254 recurrences (22.6% of the study population) were detected at the scheduled follow-up surveillance and, among these, 64.6% were found by history or physical examination. The distribution of metastatic sites and first indicators of metastases remained constant over time. The scheduled follow-up visits detected a mean of 25.9% of relapses during the first 36 months, while after 36 months only 16.3% of relapses were detected by systematic monitoring. There were no statistically significant differences in disease-free overall survival rates between symptomatic and asymptomatic patients at the time the first recurrence was detected. Moreover, the disease-free and overall survival rates appeared to be the same in symptomatic and asymptomatic patients, whether or not the recurrence was detected by a scheduled follow-up examination. Two conclusions emerged from the present study. Extensive, routine laboratory investigations are not justifiable following curative treatment of primary breast cancer, and it seems reasonable and cost-effective to reduce follow-up surveillance to careful history and physical examination only. The actual method of surveillance does not significantly affect the time interval to metastasis detection and seems inefficient. Clearly, more sensitive methods are needed for earlier detection of recurrent metastatic breast cancer. In addition, early detection of metastases would be even more valuable if more effective treatment modalities of recurrent or metastatic breast cancer were available.
Phase II Study of S-1, a Novel Oral Derivative of 5-Fluorouracil, in Advanced Gastric Cancer
Authors: Koizumi Wasaburo , Kurihara Minoru , Nakano Shuji , Hasegawa Koichi
Published: April 2003

Purpose: To assess the efficacy and safety of S-1, a novel oral fluoropyrimidine derivative, we conducted a multicenter late phase II study in patients with advanced gastric cancer. Patients and Methods: Fifty-one patients who had received no previous chemotherapy were enrolled. Fifty patients were eligible for efficacy and safety analyses. The overall response was evaluated for the 43 patients who had metastatic lesions. S-1 was administered orally after breakfast and dinner for 28 days, followed by a 14-day break. The dosages were assigned according to the patients’ body surface area (BSA): BSA <1.25 m2, 40 mg; 1.25–1.5 m2, 50 mg, and BSA ≥1.5 m2, 60 mg, twice daily. Results: The overall response to treatment was evaluated as partial response in 19 of the 43 patients (44%; 95% confidence interval 30–59%). The median survival time in all patients was 207 days with 1- and 2-year survival rates of 36.0 and 14.0%, respectively. Grade 3 adverse reactions included decreased hemoglobin values in 2 patients, leukopenia, neutropenia and diarrhea in 1 patient each. No other grade 4 or unexpected adverse reactions were seen. Conclusions: S-1 is effective against advanced gastric cancer. This oral treatment is suitable for outpatients because of its mild toxicity. Further therapeutic benefits are likely to be obtained by combining S-1 with other chemotherapeutic agents.
Sequential Trimetrexate, 5-Fluorouracil and Folinic Acid Are Effective and Well Tolerated in Metastatic Colorectal Carcinoma
Authors: Szelényi H. , Hohenberger P. , Lochs H. , Haboubi N. , Berdel W.E. , Thiel E. , Kreuser E.D.
Published: April 2003

Trimetrexate (TMTX) is a new antifolate which avoids competition for cellular uptake with folinic acid (FA). A regimen of sequential TMTX, FA and 5-fluorouracil (5-FU) has shown efficacy in patients with colorectal cancer. Therefore, we treated 34 previously untreated patients with metastatic colorectal cancer with a weekly chemotherapy regimen consisting of 110 mg/m2 of TMTX intravenously, then 24 h later 200 mg/m2 of FA (i.v.) and 500 mg/m2 of 5-FU (i.v.). Thereafter, 7 doses of oral FA (15 mg) were given at 6-hourly intervals. A treatment cycle consisted of 6 weeks of treatment, then 2 weeks of rest. All patients were treated as outpatients unless complications arose. Thirty-three patients were assessable for tumor response, and all 34 patients were assessable for toxicity. Twelve patients (36%; 95% confidence interval: 25–49%) achieved a partial response. The median duration of response was 8.5 months, and median survival was 14 months. The most common toxicity was diarrhea of grade 3/4, observed in 22% of treatment cycles; this decreased to 8% with early loperamide treatment. Hematologic toxicity was mild. The sequential administration of TMTX, FA and 5-FU is an active regimen in the first-line treatment of metastatic colorectal cancer and warrants further studies.
Serum p53 Autoantibodies in the Follow-Up of Head and Neck Cancer Patients
Authors: Gottschlich S. , Maune S. , Maass J.D. , Görögh T. , Hoffmann M. , Hoffmann-Fazel A. , Meyer J. , Werner J.A. , Rudert H.
Published: April 2003

p53 autoantibodies (AAB) are a fairly new serological parameter in patients with malignancies. Although the actual mechanism of how they develop is still unclear, it seems that these AAB could be of prognostic relevance. Very few studies demonstrated the usefulness of p53 AAB in the follow-up of cancer patients. In this study, 109 patients with head and neck cancer were investigated using an ELISA for the presence of p53 AAB in their serum and were followed-up for at least 36 months. In 21 of the cancer patients, p53 serum AAB were detected. In 5/21 p53-seropositive AAB patients, a correlation with the clinical course was observed. Sixteen of the p53-positive patients did not show any significant AAB titer changes during the follow-up, and no significant correlation with the clinical course was seen. According to these results, the clinical value of p53 AAB in the follow-up of patients with head and neck cancer seems to be limited.
Genetic Aberrations Detected by Comparative Genomic Hybridization in Ovarian Clear Cell Adenocarcinomas
Authors: Suehiro Yutaka , Sakamoto Masaru , Umayahara Kenji , Iwabuchi Hiroshi , Sakamoto Hiroko , Tanaka Naotake , Takeshima Nobuhiro , Yamauchi Kazuhiro , Hasumi Katsuhiko , Akiya Tsukasa , Sakunaga Hotaka , Muroya Tetsuya , Numa Fumitaka , Kato Hiroshi , Tenjin Yoshio , Sugishita Tadashi
Published: April 2003

Genetic abnormalities were detected by comparative genomic hybridization (CGH) in 12 ovarian clear cell adenocarcinomas. DNA sequence copy number abnormalities (CNAs) occurring in more than 20% of the cancers included increased copy numbers of 8q11-q13, 8q21-q22, 8q23, 8q24-qter, 17q25-qter, 20q13-qter and 21q22-qter and reduced copy numbers of 19p. Increases in copy numbers of 8q11-q13, 8q21-q22, 8q23 and 8q24-qter occurred more frequently in disease-free patients than in recurrent/non-surviving patients (p < 0.05). However, increases in copy numbers of 17q25-qter and 20q13-qter occurred more frequently in recurrent/non-surviving patients than in disease-free patients (p < 0.05). Furthermore, increases in copy numbers of 17q25-qter and 20q13-qter occurred together (p < 0.05). Additionally, there were negative correlations between increases in copy numbers of 8q21-q22 and 17q25-qter, and between 8q21-q22 and 20q13-qter (p < 0.05). It appears that ovarian clear cell adenocarcinomas can be classified into two subtypes, one being cancer with an increase in copy numbers of 8q and the other being cancer with increases in copy numbers of 17q25-qter and 20q13-qter.
Hypnosis in the Treatment of Anticipatory Nausea and Vomiting in Patients Receiving Cancer Chemotherapy
Authors: Marchioro Giovanni , Azzarello Giuseppe , Viviani Franco , Barbato Fiorenza , Pavanetto Michela , Rosetti Francesco , Pappagallo Giovanni L. , Vinante Orazio
Published: April 2003

Aims and Background: In addition to nausea and vomiting following chemotherapy treatment, cancer patients can experience these side effects prior to a treatment session, the so-called anticipatory nausea and vomiting. As various psychological and neurophysiological aspects have been claimed to be implied in its etiopathogenesis, the present paper aims to shortly review the etiological, epidemiological and therapeutical assumptions on the topic, in particular the psychological-behavioral therapies. Patients and Methods: The present study was carried out on 16 consecutive adult cancer patients affected by chemotherapy-induced anticipatory nausea and vomiting who had received at least four treatment cycles. All of them were submitted to induction of relaxation followed by hypnosis. Results: In all subjects anticipatory nausea and vomiting disappeared, and major responses to chemotherapy-induced emesis control were recorded in almost all patients. Conclusions: The experience highlights the potential value of hypnosis in the management of anticipatory nausea and vomiting; furthermore, the susceptibility to anticipatory nausea and vomiting is discussed under the psychoanalytic point of view.
Risk-Adapted Chemotherapy of Germ Cell Tumors with Carboplatin, Etoposide and Bleomycin for Low-Risk and Cisplatin, Etoposide and Ifosfamide for High-Risk Patients
Authors: Tscherry G. , Jacky E. , Jost L.M. , Stahel R.A.
Published: April 2003

The prognosis of germ cell tumors treated with chemotherapy depends on the presence of nonseminomatous tumor, clinical parameters based on the tumor volume and site, as well as on the level of the tumor markers AFP, βHCG and LDH. We report here on the results of a risk-adapted approach to the chemotherapy of germ cell tumors. Patients with low-risk tumors, defined as seminomatous disease and/or nonseminomatous disease with a tumor mass <10 cm, less than 20 lung metastases, no liver, bone, or CNS metastases, and levels of AFP <1,000 IU/ml and βHCG <10,000 IU/l, were to receive 4 cycles of carboplatin 400 mg/m2 i.v. day 1, etoposide 120 mg/m2 i.v. days 1–3 and bleomycin 30 IU i.v. days 1, 8 and 15 during the first 3 cycles (CEB90). Patients with high-risk disease were to receive 4 cycles of ifosfamide 1,500 mg/m2 continuous infusion on days 1–4 together with mesna 1,200 mg/m2 days 1–5, cisplatin 20 mg/m2 i.v. days 1–5 and etoposide 100 mg/m2 i.v. days 1–5 (VIP). Of the 60 patients treated with this risk-adapted approach, 51 had low-risk and 9 had high-risk disease. Forty-five of 51 patiens treated with CEB90 achieved complete remission (CR), 4 achieved partial remission with marker negativity. Four patients with CR relapsed between 4 to 8 months after the start of chemotherapy. Of the 6 patients failing CEB90, 3 were treated successfully with surgery or further chemotherapy. With a median follow-up of 52 months, the estimated cause-specific 3-year survival is 93% (95% confidence interval, CI, 80–98%). Seven of 9 high-risk patients treated with VIP achieved a CR and 1 patient relapsed. All 3 patients failing VIP had successful salvage therapy. With a medium follow-up of 63 months all patients remain alive and free of disease. Forty-six patients receiving CEB90 were retrospectively classified to be in the good prognosis group according to the international germ cell consensus classification. Their estimated 3-year survival was 95% (CI 81–99%). We thus confirm that CEB90 is a well-tolerated outpatient regimen with good results in good prognosis germ cell tumors. Bleomycin at a cumulative dose of 270 U might contribute substantially to the inferior effect of carboplatin as compared to cisplatin. However, in view of the results of randomized studies favoring cisplatin over carboplatin, it is not recommended to use this regimen outside a clinical trial.
Gelatinase and Inhibitor Expression in Soft Tissue Sarcomas: Lack of Correlation with Distant Metastasis1
Authors: Maguire Patrick D. , Qi Wen-Ning , Lallemand Roger , Scully Sean P.
Published: April 2003

The predominant mode of death for most patients with soft tissue sarcomas (STS) remains distant metastasis (DM). Current clinical predictors of DM are unreliable. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) correlate with biologic aggression in other tumors. The gene expression of the gelatinase, MMP-2 and MMP-9, and their respective inhibitors, TIMP-1 and TIMP-2, in STS was evaluated. Twelve fresh-frozen surgical specimens from patients with large (>5 cm) STS were analyzed. Six patients developed DM while 6 survived disease-free (DFS) at a minimum follow-up of 13 months. Following mRNA isolation, reverse transcription-polymerase chain reaction was performed using primers for MMP-2, MMP-9, TIMP-1, and TIMP-2. Gene expression was determined by band densitometry. Ratios of MMP-9/TIMP-1 and MMP-2/ TIMP-2 gene expression as well as MMP-2 protein activation ratio (active/inactive enzyme determined by gelatin zymography) were analyzed for correlation with DM and DFS. MMP-2 gene was expressed in 12 specimens, while MMP-9 was detectable in 9. Relative levels of MMP-2 and MMP-9, MMP2/TIMP-2 ratio, and MMP-9/TIMP-1 ratio were not significantly correlated with DM. Poor DFS was significantly correlated with high MMP-9/TIMP-1 ratio (p = 0.02). Active MMP-2 protein was detected in 12 specimens, while active MMP-9 protein was detected in 2. No association was found between MMP-2 protein activation ratio and DM or DFS. While MMP-2 gene expression and protein activity occurred in these 12 specimens, gelatinase/inhibitor ratios (for both MMP-2 and MMP-9) appear to be poor predictors of DM in STS.
Clinical Investigation on Pulmonary Metastasis of Head and Neck Carcinomas
Authors: Osaki Tokio , Yoneda Kazunori , Yamamoto Tetsuya , Kimura Tsuyoshi , Matuoka Hisakazu , Sakai Hiroatsu , Ryoke Kazuo
Published: April 2003

Objective: To establish a treatment strategy for pulmonary metastases, we clinically investigated the characteristics of distant metastases from head and neck carcinomas. Methods: In 636 head and neck carcinomas, the pathophysiology of distant metastases was investigated by charts, roentgenographies, computed tomographies and scintigraphies. Results: Of the squamous cell carcinomas, oropharyngeal tumors were most highly metastatic, followed by lower gingiva, floor of the mouth, maxillary sinus, and tongue. In distant metastases, 30 (4.7%), 5 (0.8%), and 7 (1.1%) metastasized to the lungs only, lungs and other organs, and organs excluding the lungs, respectively. In pulmonary metastases, the right, left and both lungs were involved in 18, 5, and 8 patients, respectively, although details were not obtained for 4 patients. Pulmonary metastases consisted of 1, 2, and 3 or more tumors in 18, 4, and 6 patients, respectively. Diffuse cancer cell infiltration was observed in 3 patients. Of the 42 patients with distant metastases, 12 patients died of progressive pulmonary metastases, and 5 of these patients manifested only 1 pulmonary lesion throughout life. However, the metastatic pulmonary tumors were controlled surgically or conservatively in 3 patients. Conclusion: These results indicate that distant metastases from head and neck carcinomas involve the lungs most frequently and that chemoimmunotherapy and surgical removal of the metastatic tumors are recommended when indicated.
Fine Needle Aspiration May Shed Breast Cells into Peripheral Blood as Determined by RT-PCR
Authors: Hu X.C. , Chow Louis W.C.
Published: April 2003

Objective: A diagnostic test applying reverse-transcriptase chain reaction (RT-PCR) assay targeted against cytokeratin 19 (CK19), cytokeratin 20 (CK20) and the β-subunit of human chorionic gonadotropin (β-hCG) mRNAs was used to evaluate the impact of fine needle aspiration (FNA) on breast cell shedding into peripheral blood. Methods: The sensitivity of this assay was based on the different degree of admix of MCF-7 breast cancer cell line with HL-60 leukemic cell line. For blood samples of 24 cases with benign breast diseases and 20 cases with malignant ones, 5 ml of peripheral blood was drawn before and within 10 min after puncture. Total RNA was extracted from peripheral blood mononuclear (PBMN) cells; β-actin was used to assess the quality of cDNA. RT-PCR products were run in ethidium bromide gel and observed under ultraviolet. RT-PCR products for β-hCG were digested with Sty I endonuclease to confirm the specificity. Results: The sensitivity of RT-PCR assay was 1 MCF-7 cell in 105 HL-60 cells for CK19 and CK20, and 1 in 106 for β-hCG. For 24 benign cases, none of the pre- FNA samples was positive for CK20 and β-hCG, and 3 cases (12.5%) were positive for CK19. As for 20 malignant cases, 1 pre-FNA sample was positive for all three markers and 2 other samples were positive for CK19. After aspiration, 3/21 benign cases and 1/17 malignant case with pre-FNA negative signals became positive for CK19, while 3/19 malignant cases with pre-FNA negative signals were converted to a positive result for CK20 and β-hCG. Of 6 pre-FNA positive cases, all cases remained positive for the respective marker. Conclusion: FNA to breast tumor may cause hematogenous dissemination of breast cells.
Influence of Pituitary Disease on Sexual Development and Functioning
Authors: Swerdloff Ronald , Wang Christina
Published: April 2003

Pituitary disorders may have a major effect on sexual development and function. This review describes the regulation of normal reproductive hormonal function in the fetus, infant, adolescent and adult. The effects of pituitary insufficiency and pituitary adenomas on sexual development, reproductive function and sexuality in men and women are discussed.
Cognitive and Behavioural Treatment of Hypochondriasis
Authors: Bouman Theo K. , Visser Sako
Published: April 2003

Background: This study investigates the feasibility and effectiveness of time-limited treatment protocols based upon cognitive and behavioural interventions. Method: Seventeen patients with DSM-IV diagnoses of hypochondriasis were offered 12 1-hour sessions of either ‘pure’ cognitive or ‘pure’ behavioural (i.e. exposure in vivo and response prevention) treatment. Patients were used as their own controls by observing a 4-week period without interventions before and after treatment. Results: Patients in both treatment conditions improved on specific measures of hypochondriasis (Kellner’s Illness Attitude Scales) and depression. These changes took place during the active treatment period, whereas in the control periods scores remained unchanged. Furthermore, no differential treatment effectiveness could be demonstrated. Conclusions: Cognitive and behavioural interventions seem to be active ingredients in the treatment of hypochondriasis, although the contribution of nonspecific factors (e.g. patient motivation, therapist attitudes, and the therapeutic relationship) requires further study.
What Prevents Professional Drivers from Following Physicians’ Cardiologic Advice?
Authors: Emdad Reza , Belkic Karen , Theorell Töres , Cizinsky Stella
Published: April 2003

Background: There is a scarcity of published studies of the effects of cardiac counselling among professional drivers (PD). Aims of the study were: (1) to examine explanatory variables for two classical ‘driver’ risk factors – body mass index (BMI), and smoking – and to analyse the interrelations among smoking cessation, losing weight and work-related life changes; (2) to assess the effectiveness of risk factor counselling after 6 months, and (3) to gain insight into possible discrepancies between PD perception of needed changes and compliance with the physician’s advice. Methods: There were 4 groups of male PD: 13 with ischemic heart disease, 12 hypertensives, 10 borderline hypertensives and 34 normotensives. Baseline cardiovascular risk factors as well as occupational and behavioral data were assessed via questionnaire. The counselling was aimed at smoking cessation, weight loss and promoting leisure-time physical activity. Qualitative methods were used to assess PD perceptions about the work environment and health promotion. Results: Baseline smoking intensity was best predicted by the total burden of occupational stress and number of smoking years. Baseline BMI was best predicted by long work hours behind the wheel, low availability of attachment outside work and low self-reported job strain. Self-initiated smoking cessation was best predicted by few smoking years, low coffee intake and admitting fear during driving. Physical activity was significantly increased after 6 months. Losing weight was associated with: quitting or diminishing smoking and making other, work-related, life changes. None of the heavy smokers decreased their daily number of cigarettes after 6 months, although expressing the need to do so in self-generated statements. Conclusions: Exposure to occupational stressors, mainly, long work hours and the concomitant denial of job strain, in combination with low availability of social attachment outside work, could contribute to maintenance of maladaptive behavior in PD. These findings could serve as a basis for designing standardized intervention trials and suggest that modification of the work environment, with participation of the drivers, is a needed component of such trials. Particular attention should be paid to the length and scheduling of work shifts.
Combined versus Sequential Hormonal Replacement Therapy: A Double-Blind, Placebo-Controlled Study on Quality of Life-Related Outcome Measures
Authors: Bech P. , Munk-Jensen N. , Obel E.B. , Ulrich L.G. , Eiken P. , Nielsen S. Pors
Published: April 2003

Background: To compare combined and sequential hormonal replacement therapies to each other as well as placebo in patients suffering from the postmenopausal syndrome. Clinical outcomes were measured concerning both the specific postmenopausal symptoms (using the Kupperman scale) and health or well-being dimensions (using subscales of the General Health Questionnaire and specific depression and anxiety scales). Methods: A prospective randomized double-blind study over 12 months of 105 normal early postmenopausal women in the setting of a general hospital. Results: Both hormone replacement therapies were superior to placebo on the Kupperman scale (sweating, hot flushing, myalgia and vertigo). The psychic symptoms on the Kupperman scale were psychometrically invalid. However, psychic symptoms as measured by the Beck Depression Inventory and the General Health Questionnaire were significantly improved by the hormonal replacement therapies. No differences were observed when combined therapy was compared to sequential therapy. Conclusion: One-year treatment with hormonal replacement therapy is superior to placebo in measuring the somatic and psychic symptoms of the menopausal syndrome. No differences were found in this respect between combined and sequential replacement therapy.
An Open Trial of Oral Sildenafilin Antidepressant-Induced Sexual Dysfunction
Authors: Fava Maurizio , Rankin Meridith A. , Alpert Jonathan E. , Nierenberg Andrew A. , Worthington John J.
Published: April 2003

Background: Sildenafil is a selective inhibitor of cyclic GMP-specific phosphodiesterase type 5 that has been associated with greater improvement of erectile function compared to placebo among men with erectile dysfunction. The goal of our study was to evaluate its efficacy in a small sample of outpatients with antidepressant-induced sexual dysfunction. Methods: We studied the first 14 depressed outpatients (9 men and 5 women; mean age: 46.4 ± 8.4) who were consecutively treated with oral sildenafil. Twelve of the 14 patients were treated with an SSRI and 2 with mirtazapine. All patients were prescribed oral sildenafil tablets at the initial dose of 50 mg q.d. p.r.n., with the possibility of increasing the dose to 100 mg q.d. p.r.n., if clinically indicated. We administered a sexual functioning questionnaire derived from the Guided Interview Questionnaire for females and males and from the Arizona Sexual Experience Scale to all patients before and after at least 4 weeks of treatment with oral sildenafil. The mean sildenafil dose in our 14 patients was 57 ± 18 mg/day. Results: All 14 subjects completed the follow-up assessments and no subjects discontinued the drug prematurely. We observed statistically significant improvements in all domains of sexual functioning, including libido, arousal, orgasm, sexual satisfaction, and (in males only) erectile function, with a 69% rate of patients reporting themselves as much or very much improved. Oral sildenafil treatment appeared to be very well tolerated, with only 1 out of 14 (7%) patients reporting an adverse event (hot flashes). Conclusions: Our findings of statistically significant improvements in all domains of sexual functioning in a sample of 14 men and women with antidepressant-induced sexual dysfunction suggest that this agent may represent an efficacious approach to this population.