bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Analysis of a Functional G Protein β3 Subunit Gene Polymorphism (C825T) in Mood Disorders
Authors: Lin Chien-Nan , Tsai Shih-Jen , Hong Chen-Jee
Published: April 2003

The guanine nucleotide-binding proteins (G proteins), heterotrimers consisting of α, β and γ subunits, convey signals initiated by the activation of many neurotransmitter receptors. Evidence for involvement of the G proteins in mood disorders relies on the effects of mood stabilizers and antidepressants on G protein function. In addition, abnormalities in the expression of G proteins have been demonstrated in mood disorder patients. Therefore, we tested the hypothesis that a functional polymorphism (C825T) in the G protein β3 gene subunit (GNB3) confers susceptibility to mood disorders. A population-based association study was utilized, and GNB3 was genotyped for 144 mood disorder patients and 153 normal controls. The results reveal that it is not likely that the C825T polymorphism in the GNB3 gene subunit is involved in mood disorder pathogenesis. Further studies of the associations between other G protein subunits and mood disorder are needed to fully elaborate the involvement of this protein in mood disorders.
Predictive Value of Amino Acids in the Treatment of Major Depression with Fluvoxamine
Authors: Mauri Massimo C. , Boscati Luigi , Volonteri Lucia S. , Scalvini Marta E. , Steinhilber Clara P.C. , Laini Valerio , Zamberlan Federica
Published: April 2003

Sixteen outpatients (mean age ± SD 50.18 ± 11.55 years; 11 females and 5 males) affected by major depression without melancholia (DSM-IV) were included in the study. The control group consisted of 11 healthy volunteers (mean age ± SD 39.90 ± 13.39 years; 2 females and 9 males). Patients were treated with fluvoxamine (FVX) 100–300 mg daily. Clinical assessment was performed using the Hamilton Rating Scales for Anxiety and Depression (HRS-A; HRS-D) and the Clinical Global Impression Scale (CGI) at basal time (T₀), after 4 weeks and after 8 weeks (T8). Plasma and platelet amino acid levels were determined at T₀ in all the subjects and also at T8 in depressed patients. A significant clinical improvement was observed in depressed patients according to the HRS-A (p = 0.004), HRS-D (p = 0.008) and CGI (p = 0.002). A negative correlation (r = –0.53, p = 0.049) was found between platelet levels of valine and HRS-D improvement rate. Patients showed significantly higher tyrosine/large neutral amino acids (LNAAs) and lower tryptophan/LNAAs, ratios which could represent an index of good response to a serotonergic drug like FVX.
Changes in Vesicular Monoamine Transporter (VMAT2) and Synaptophysin in Rat Substantia nigra and Prefrontal Cortex Induced by Psychotropic Drugs
Authors: Zucker Michal , Weizman Abraham , Harel Daniela , Rehavi Moshe
Published: April 2003

We investigated the regulatory effect of the dopaminergic agent L-dopa, the mood stabilizer lithium and the nonselective monoamine oxidase inhibitor phenelzine on brain vesicular monoamine transporter (VMAT2) expression. Rats were treated chronically (21 days) with the three psychoactive drugs. VMAT2 gene expression at the protein level was assessed in the prefrontal cortex and striatum by autoradiography with high-affinity [3H]dihydrotetrabenazine ([3H]TBZOH) binding and at the mRNA level in the substantia nigra pars compacta by in situ hybridization. In addition, the effect of various treatments on the synaptophysin mRNA level was determined in the substantia nigra by in situ hybridization. Chronic administration of L-dopa resulted in a significant decrease (28%, p < 0.05) in the density of [3H]TBZOH binding in the prefrontal cortex but had no effect on VMAT2 and synaptophysin mRNA levels in the substantia nigra. Lithium treatment increased [3H]TBZOH-specific binding in the prefrontal cortex (23%, p < 0.05) but had no effect on VMAT2 and synaptophysin mRNA levels. Phenelzine did not modulate VMAT2 gene expression but reduced the synaptophysin mRNA level (19%, p < 0.05). The modulatory activities of these drugs, although relatively weak, may be relevant to the drug-induced synaptic and neuronal plasticity as well as to the molecular and cellular pathophysiology of monoamine-related neuropsychiatric disorders.
Increase in Amino Acids in the Pons after Sleep Deprivation: A Pilot Study Using Proton Magnetic Resonance Spectroscopy
Authors: Murck Harald , Struttmann Tobias , Czisch Michael , Wetter Thomas , Steiger Axel , Auer Dorothee P.
Published: April 2003

Total sleep deprivation (TSD) is an efficient method to relieve depression. An involvement of GABAergic and glutamatergic neurotransmission in the pathophysiology of depression and the mechanism of action of TSD has been suggested. To directly assess the content of GABA, glutamate (Glu) and glutamine (Gln) before and after TSD, we estimated their concentrations in four brain regions in six healthy subjects using proton magnetic resonance spectroscopy. The unresolved estimate of GABA, Glu and Gln, as well as GABA and Gln were increased in the pons after 24 h of TSD, the effect being prominent in three subjects. There were no significant changes in the hypothalamus, thalamus or parietooccipital cortex. These preliminary data support earlier animal data and indirect findings in humans suggesting that GABA and Gln, especially in the pontine structures, may play a key role in the mechanism of TSD.
Molecular Mechanism of a Cross-Talk between Estrogen and Growth-Factor Signaling Pathways
Authors: Kato Shigeaki , Kitamoto Takuya , Masuhiro Yoshikazu , Yanagisawa Junn
Published: April 2003

The actions of estrogen (E2) are considered to be mediated through its nuclear E2 receptor (ER). In cancer development, growth factors are shown to act synergistically with E2. Recently, we found that the mitogen-activated protein kinase, activated by growth factors, phosphorylates human ERα and this phosphorylation potentiates the transactivation function of human ERα demonstrating a novel cross-talk between E2 and growth factor-signaling pathways. In this review, the molecular mechanism of this cross-talk is discussed.
Requirement of Estrogen Receptor Expression and Function for [12Val] K-Ras-Mediated NIH3T3 Cell Transformation
Authors: Kato Kiyoko , Sakamoto Takako , Wake Norio
Published: April 2003

We investigated the biological significance of estrogen receptors (ERs) in NIH3T3 cell transformation by the [12Val] K-Ras mutant. This mutant enhanced the steady-level and transcriptional activity of ER. Coexpression of the progesterone receptor with mutant K-Ras led to suppression of tumorigenicity and inhibition of the activation of ER. The antisense oligomers complementary to the ER suppressed proliferation and transformed phenotypes of K12V cells. These observations support the importance of ER in Ras-mediated cell transformation.
Optimizing Chemotherapy for Patients with Advanced Breast Cancer
Authors: Marty M. , Espie M. , Cottu P.H. , Cuvier C. , Lerebours F.
Published: April 2003

Chemotherapy is offered to almost all patients with metastatic breast cancer. Optimization of treatment has four major goals: (1) To improve access to chemotherapy. Orally active chemotherapy is an attractive option for those patients when access to hospital is limited by financial considerations, long journeys or patient reluctance. In the past, only alkylating agents (cyclophosphamide, chlorambucil, melphalan) could be administered orally. The activity (first- and second-line) of Xeloda® (capecitabine) with limited side effects and the development of oral vinorelbine and anthracyclines should improve access to chemotherapy and also concentrate further interest on treatment with long-term administration of cytotoxic agents. (2) To improve response rates and duration in first-line treatment. Response rates have been increased by the use of combinations of taxoids and anthracyclines and/or alkylating agents and/or fluoropyrimidines (>60–70% with complete remission in 10–15% of patients). There is increasing interest in sequential use of active agents or combinations at their optimal doses. Nevertheless, such ‘induction regimen’ fail to prolong response duration (rarely longer than 9–12 months). The use of less-toxic maintenance chemotherapy regimens increases response duration and disease-free survival. Such maintenance regimens could be used on an outpatient basis and will be further simplified by the availability of active oral agents such as the novel fluoropyrimidine Xeloda. (3) To increase cure rates. This can only be considered with first-line treatment in selected patients (long disease-free interval, minimal number of visceral sites and ability to tolerate high-dose chemotherapy). The completed studies with high-dose chemotherapy and hematopoietic stem cell support have, in fact, shown only a minimal effect on cure rates. Incorporation of very active agents such as taxoids and use of multicycle high-dose therapy may improve these results. (4) To offer alternative active regimens in second and subsequent metastatic progression. Taxoids, vinorelbine and, more recently, Xeloda all achieve a 20–40% response rate in these situations. The reintroduction of agents previously used for adjuvant or first-line therapy can also be considered.
Can an Autocrine Loop Explain Sex-Hormone-Dependent Tumor Growth?
Authors: Sato Bunzo
Published: April 2003

Sex hormones and their related compounds have been known to regulate the target cell growth positively or negatively in the receptor-dependent manner. The molecular mechanism of these complicated events, especially sex hormone-dependent growth enhancement, has been studied extensively. In MCF-7 cells, estrogen-induced autocrine loop has been demonstrated to play the important role for estrogen-dependent growth. Androgen has been also found to promote the growth of SC-3 cell through the induction of an autocrine growth factor (FGF 8). The blockade of FGF 8 activity resulted in a complete inhibition of androgen-dependent growth of SC-3 cells, suggesting that FGF 8 acts as an essential component of androgen-dependent growth. However, the constitutional expression of FGF 8 failed to convert SC-3 cells from an androgen-dependent to an androgen-independent phenotype. These observations would suggest that sex hormone-induced autocrine loop is an obligatory but not sufficient component for the growth of sex hormone-dependent tumor.
Redox Regulation of the Nuclear Receptor
Authors: Tanaka Hirotoshi , Makino Yuichi , Okamoto Kensaku , Iida Takahisa , Yoshikawa Noritada , Miura Takanori
Published: April 2003

Redox regulation is currently considered a mode of signal transduction for coordinated regulation of a variety of cellular processes. Transcriptional regulation of gene expression is also influenced by the cellular redox state, for example, through the oxidoreductive modification of transcription factors. The nuclear receptors act as ligand-dependent transcription factors and are considered to be one of the key regulators of essential biological processes. Using a glucocorticoid receptor as a model, we show that redox regulation of receptor function is one of the dynamic cellular responses to environmental stimuli.
Topotecan and Gemcitabine in Platinum/Paclitaxel-Resistant Ovarian Cancer
Authors: Greggi Stefano , Salerno M. Giovanna , D’Agostino Giuseppe , Ferrandina Gabriella , Lorusso Domenica , Manzione Luigi , Mancuso Salvatore , Scambia Giovanni
Published: April 2003

24 patients were enrolled into a phase I–II study conducted to determine the maximum tolerated doses of topotecan-gemcitabine in sequential combination and the response rate in platinum/paclitaxel resistant ovarian cancer patients. A total of 83 courses are evaluable, with a median number of three cycles administered per patients (range 2–7). Topotecan was administered on days 1–5 by 30 min i.v. infusion immediately after gemcitabine given by 30 min i.v. on days 1 and 3; cycles were repeated every 28 days. The starting doses were topotecan 0.7 mg/m2 and gemcitabine 200 mg/m2. Following dose levels were 08/400; 0.9/600; 0.9/800 for topotecan and gemcitabine, respectively. The maximum tolerated dose (MTD) was reached at dose level 3, the dose-limiting toxicity being represented by febrile neutropenia and thrombocytopenia. After the MTD was reached, granulocyte-colony-stimulating factor was administered in 27% of cycles. Mild and manageable was non hematological toxicity. All patients are so far evaluable for response. Among them 2 complete responses (8.3%; 95% CI: 2.6–19), 1 partial response (4.2%; 95% CI: 3.8–12), 9 no change (37.5%; 95% CI: 18–56.8) and 12 progressions (50%; 95% CI: 30–70) have been registered. Based on these data, there is no evidence that combining topotecan and gemcitabine is better than using either of the two drugs used separately
Docetaxel in Patients with Anthracycline-Resistant Advanced Breast Cancer
Authors: Vici Patrizia , Belli Franca , Di Lauro Luigi , Amodio Antonella , Conti Francesca , Foggi Paolo , Gionfra Tommaso , Morelli Maria Francesca , Botti Claudio , Ferraironi Alessandro , Lopez Massimo
Published: April 2003

Objective: To better determine docetaxel activity in patients with well-defined anthracycline-resistant breast cancer. Methods: From October 1996, we carried out a phase II trial in 69 heavily pretreated patients with advanced breast cancer with docetaxel 100 mg/m2 by a 1-hour infusion on day 1, with cycles repeated every 3 weeks. Patients were classified as having primary anthracycline resistance (n = 32), secondary anthracycline resistance (n = 7), anthracycline pretreatment (n = 22) or no anthracycline pretreatment (n = 8). Results: Among 68 evaluable patients, we observed 6 (9%) complete responses and 27 (40%) partial responses, for an overall response rate of 49% (95% confidence interval 37–61%); the disease remained stable in 17 patients (25%). Responses according to the above subgroups were as follows: primary anthracycline resistance 41%, secondary anthracycline resistance 43%, anthracycline pretreatment 64% and no anthracycline pretreatment 43%. The median time to response, median time to progression and median overall survival were 2, 7 and 10 months, respectively. Myelosuppression was the dose-limiting toxicity, with grade 4 neutropenia occurring in 47% of the patients and neutropenic fever in 12%. G-CSF was added in the case of grade 4 febrile neutropenia; a 25% reduction in the dose of docetaxel was required in 4 patients. Other side effects were mild. Conclusions: The results of the present trial confirm the high activity of docetaxel in heavily pretreated patients with advanced breast cancer, including those with strictly defined anthracycline resistance.
Thymidine Labeling Index Analysis in Early Breast Cancer Patients Randomized to Receive Perioperative Chemotherapy
Authors: Pronzato Paolo , Queirolo Paola , Vecchio Stefania , Lionetto Rita , Del Mastro Lucia , Venturini Marco , Gardin Giovanni , Alama Angela , Sertoli Mario R.
Published: April 2003

Objective: To identify through a substudy of a larger, multicenter study of adjuvant treatment in primary operable breast cancer patients any possible correlation between cellular proliferation rate, measured by thymidine labeling index (TLI), and perioperative chemotherapy (periCT). Methods: TLI was measured in slices of early breast carcinoma patients. The main trial was designed to randomize patients after primary surgery to receive one cycle of periCT consisting of cyclophosphamide, epidoxorubicin and 5-fluorouracil, or no periCT. Results: Of 600 patients randomized into the main study, 197 were eligible for inclusion in this substudy. Characteristics of patients were quite similar to those of the entire population entered into the main study. The TLI cutoff value in our series was 0.7% expressed as the median percentage ratio of thymidine-labeled cells undergoing DNA synthesis in the tumor cell population of specimens from the 197 patients. No differences were observed in terms of relapse-free survival (RFS) and overall survival (OS) after grouping the patients by TLI value (low and high) and by treatment. Among node-negative patients, a significant improvement in terms of OS (p = 0.02), but not RFS (p = 0.06), was seen in patients with a high-TLI value who underwent periCT versus controls. Conclusions: TLI may be a useful tool for the identification of node-negative patients with high-TLI values who may benefit from periCT.
Irinotecan and Mitomycin C in 5-Fluorouracil-Refractory Colorectal Cancer Patients
Authors: Comella Pasquale , Biglietto Maria , Casaretti Rossana , De Lucia Luigi , Avallone Antonio , Maiorino Luigi , Di Lullo Liberato , De Cataldis Giuseppe , Rivellini Flavia , Comella Giuseppe
Published: April 2003

Purpose: To define the maximum tolerated dose (MTD) of irinotecan (CPT-11) given on days 1 and 8 with mitomycin C (MMC) given on day 1 in a monthly cycle, and to assess the toxicity and activity of this regimen in patients with previously treated colorectal carcinoma. Methods: Fifty-two patients, all pretreated with adjuvant 5-fluorouracil (20 patients) and/or one (35 patients) or two (8 patients) lines of chemotherapy, were entered in this study. Escalating doses of CPT-11 (starting from 150 mg/m2) were administered on days 1 and 8, with escalating doses of MMC (starting from 8 mg/m2) given on day 1, recycling every 28 days. At least 3 patients were treated at each dose level. Escalation proceeded unless 2 out of 3 or 4 out of 6 patients experienced a dose-limiting toxicity (DLT) after the first cycle. Results: Twelve patients were entered in the phase I study, and 4 consecutive dose levels were tested. At the last dose level (CPT-11 200 mg/m2 plus MMC 10 mg/m2) 4 of 6 patients experienced a DLT (i.e., grade 4 neutropenia in 2 patients and grade 3 diarrhea in 2 patients). Therefore, this dose level was considered as the MTD. Forty patients were treated at the previous dose level (CPT-11, 175 mg/m2 plus MMC 10 mg/m2). One complete, 4 partial, 3 minor responses and 11 cases of stable disease were registered, giving a response rate of 12% [95% confidence interval (CI), 4–27%] and an overall control of tumor growth in 47% (95% CI, 31–64%) of patients. The median time to treatment failure was 6 months (range 1–19+). The median survival time was 14.5 months, and the 1-year and 2-year probability of survival were 56 and 43%. Neutropenia and diarrhea affected 62 and 58% of patients, grade 3 or 4 being registered in 26 and 23% of them, respectively. One episode of neutropenic fever was reported. Other acute toxicities were usually mild and manageable. Conclusions: CPT-11 175 mg/m2 on days 1 and 8 associated with MMC 10 mg/m2 on day 1, every 4 weeks, is a safe and moderately active regimen in heavily pretreated patients with advanced colorectal carcinoma. The role of MMC in this combination is doubtful, and further attempts with other new agents should be made to improve the outcome in these patients.
Adjuvant Chemotherapy with High-Dose Cyclophosphamide, Etoposide and Cisplatin Intensification without Progenitor Cell Support in Breast Cancer Patients with Ten or More Involved Nodes: 5-Year Results of a Pilot Trial
Authors: Ballestrero Alberto , Rubagotti Alessandra , Stura Paola , Ferrando Fabio , Amoroso Domenico , Rinaldini Michela , Sismondi Piero , Genta Franco , Mesiti Mario , Brema Fulvio , Patrone Franco , Boccardo Francesco
Published: April 2003

Objectives: The purpose of this study was to evaluate the clinical efficacy and tolerability of high-dose (HD) chemotherapy with growth factor support in primary breast cancer with extensive nodal involvement. Patients and Methods: Fifty-three patients with ten or more involved nodes were recruited and were given three cycles of standard-dose fluorouracil, epidoxorubicin and cyclophosphamide followed by one single course of high-dose CEP (cyclophosphamide, etoposide and cisplatin). No autologous progenitor support was used. Results: Five-year actuarial disease-free and overall survival were 40 and 60%, respectively. High-dose CEP required a median of 22 days of hospitalization and was associated with grade G3–G4 nausea and vomiting in two thirds of the cases. Hematological toxicity was comparable to that of high-dose therapies delivered with autologous progenitor support. No therapy-related mortality was observed. Conclusions: The efficacy of treatment was comparable to the best results of conventional therapy, with only a trend for improved survival. High-dose CEP was feasible with acceptable toxicity. Although this regimen does not require stem cell harvesting and storage, it requires clinical support comparable to autotransplantation procedures and side effects are not so manageable to recommend its use outside specialized units.
Vinorelbine-Based Regimens as Salvage Treatment in Patients with Advanced Non-Small Cell Lung Cancer: Two Parallel Multicenter Phase II Trials
Authors: Agelaki Sophia , Bania Helen , Kouroussis Charalambos , Blazoyiannakis George , Souglakos John , Tsiafaki Xanthi , Harpidou Adriani , Kalbakis Kostas , Rapti Ageliki , Androulakis Nikos , Sarra Evi , Georgoulias Vassilis , Papadakis Emmanuel
Published: April 2003

Two parallel phase II trials were conducted in order to evaluate the efficacy and toxicity of vinorelbine-ifosfamide (VNB-IFX) and vinorelbine-carboplatin (VNB-C) combinations as salvage treatment in patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods: Patients failing platinum-based front-line chemotherapy were enrolled in the VNB-IFX trial while patients failing non-platinum-containing chemotherapy were treated with VNB-C. Twenty-nine patients were treated with VNB-IFX [median age: 59 years; performance status, PS (WHO) 0–1: 72% and disease stage IV: 79%] and 37 with VNB-C [median age: 61 years; PS (WHO) 0–1: 51% and stage IV: 84%]. Patients received vinorelbine 25 mg/m2 i.v. on days 1 and 8 and ifosfamide 1.6 g/m2 i.v. on days 8–10 with uroprotective mesna, in cycles of 28 days. G-CSF (5 µg/kg/day s.c.) was administered prophylactically on days 11–16 or until hematological recovery. The VNB-C regimen consisted of carboplatin 300 mg/m2 on day 1 and vinorelbine 30 mg/m2 on days 1 and 8 every 28 days. Results: Twenty-six patients were evaluable for response in the VNB-IFX trial and 29 in the VNB-C. Overall response rates (intent-to-treat analysis) were 3% (1 patient; duration of response: 3 months) for the VNB-IFX and 16% (median duration of response: 7.5 months) for the VNB-C combination. The median time to progression and survival for patients receiving VNB-IFX were 4.5 and 6 months (1-year survival: 19%), respectively; the corresponding values for VNB-C were 9.0 and 8.5 months (1-year survival: 38%). The median survival of patients achieving stable disease was 10 (VNB-IFX) and 14.5 (VNB-C) months. Grade 3–4 neutropenia occurred in 4 (13%) of the patients treated with VNB-IFX; all cases were complicated with fever. Grade 3–4 neutropenia was documented in 13 (35%) patients in the VNB-C trial; 6 (16%) developed neutropenic fever. There were no treatment-related deaths. Non-hematologic toxicity for the VNB-IFX and VNB-C regimens was mild with grade 2–3 peripheral neurotoxicity occurring in 3 (10%) and 7 (19%) patients, and grade 2–3 asthenia in 11 (38%) and 18 (48%) patients, respectively. Conclusion:  Both combinations were associated with a tolerable toxicity profile. VNB-C demonstrated notable activity in patients previously treated with a taxane-based regimen, whilst VNB-IFX failed to produce a significant response rate in patients treated with platinum-containing chemotherapy. Stabilization of disease was associated with a favorable survival in both studies.
Imbalance between Neutral Endopeptidase 24.11 and Endothelin-1 Expression in Human Endometrial Carcinoma
Authors: Suzuki Takahiro , Kikkawa Fumitaka , Ino Kazuhiko , Nagasaka Tetsuro , Tamakoshi Koji , Mizutani Shigehiko
Published: April 2003

Objectives: Neutral endopeptidase 24.11 (NEP)/CD10 is a cell-surface peptidase that degrades various bioactive peptides including endothelin-1 (ET-1). This enzyme is known to play a role in maintaining ET-1-regulated vascular homeostasis in the normal human endometrium. The purpose of the present study was to investigate the expression and localization of NEP and ET-1 in neoplastic endometria, and also to clarify the correlation of their expression with the tumor grade of endometrial carcinoma. Methods: Immunohistochemical analysis for NEP and ET-1 expression was performed on paraffin-embedded tissue sections of 7 normal endometria (after menopause), 5 atypical endometrial hyperplasias (AEH), and 32 endometrial endometrioid adenocarcinomas. Results: In normal endometrium and AEH, NEP immunoreactivity was detected in stromal cells, but not in glandular cells. In contrast, ET-1 immunoreactivity was detected in both glandular and stromal cells. In the stromal cells of grade 1 endometrial adenocarcinoma, NEP was detected at high or moderate quantities. However, significantly decreased NEP immunoreactivity was observed in the stromal cells of grade 2 and 3 adenocarcinomas. However, NEP was not immunostained in adenocarcinoma cells except for the lesions of squamous differentiation. ET-1 immunoreactivity was weakly detected in the stromal cells of grade 1 adenocarcinoma, but the intensity of ET-1 staining increased with advancing tumor grade. The ratio of the staining scores of stromal ET-1 to stromal NEP was positively correlated with the tumor grade. Conclusions: These findings demonstrate that NEP expression in the stromal cells of endometrial adenocarcinoma is downregulated, while stromal ET-1 is upregulated, with increasing tumor grade. The present findings also suggest that NEP may play a role in the regulation of neoplastic transformation, tumor progression, and differentiation in endometrial neoplasms, possibly by degrading certain peptide growth factors such as ET-1.
Involvement of CTGF, a Hypertrophic Chondrocyte-Specific Gene Product, in Tumor Angiogenesis
Authors: Shimo Tsuyoshi , Nakanishi Tohru , Nishida Takashi , Asano Masahiro , Sasaki Akira , Kanyama Manabu , Kuboki Takuo , Matsumura Tomohiro , Takigawa Masaharu
Published: April 2003

Connective tissue growth factor (CTGF) is a potent secreted signaling factor which functions in multiple stages of angiogenesis. In the present study, we examined the role of CTGF in tumor angiogenesis and made the following observations: (1) Histological analysis of human breast cancer (MDA231) cell and human fibrosarcoma (HT1080) cell xenografts in BALB/c nude mice showed a high level of neovascularization. Human squamous cell carcinoma (A431) xenografts induced only a low level of neovascularization. (2) CTGF mRNA was strongly expressed in MDA231 and in HT1080 cells in vivo and in vitro, but not in A431 cells. (3) CTGF protein was markedly produced in MDA231 cells and HT1080 cells and secreted into culture medium, and its production was greater during phases of growth rather than confluency. (4) Production of CTGF in bovine aorta endothelial cells was induced by CTGF, VEGF, bFGF and TGF-β. (5) Neovascularization induced by HT1080 cells or MDA231 cells on chicken chorioallantoic membrane was suppressed in the presence of neutralizing CTGF-specific polyclonal antibody. These results suggest that CTGF regulates progression in tumor angiogenesis and the release or secretion of CTGF from tumor cells is essential for the angiogenesis.
Clinicopathological Study of Early Adenocarcinoma of the Gastric Cardia: Comparison with Early Adenocarcinoma of the Distal Stomach and Esophagus
Authors: Tajima Yusuke , Nakanishi Yukihiro , Yoshino Takayuki , Kokawa Atsushi , Kusano Mitsuo , Shimoda Tadakazu
Published: April 2003

To clarify the clinicopathological characteristics of adenocarcinoma of the gastric cardia (AGC), including its association with Barrett’s esophagus and intestinal metaplasia, 49 surgically resected early AGCs (EAGCs) were examined clinicopathologically, histopathologically, histochemically, and immunohistochemically. The clinicopathological characteristics of the patients with EAGC were compared with those of 293 patients with early adenocarcinoma of the distal stomach (EADS) and 7 patients with early adenocarcinoma of the esophagus (EAE). Histochemical staining with paradoxical concanavalin A (ConA) and immunohistochemical staining with monoclonal antibodies 45M1, Ccp58, and 56C6 were performed to investigate the differentiation phenotype of the tumor. ConA and 45M1 were used for markers of the gastric phenotype, and Ccp58 and 56C6 were used for markers of the intestinal phenotype. EAGC was associated with a higher mean age (p < 0.0001), a higher male-to-female ratio (p < 0.05), a higher incidence of elevated-type tumors (p < 0.0001), a higher incidence of differentiated-type tumors (p < 0.0001), and greater depth of invasion (p < 0.05) compared with EADS. EAE was associated with a higher incidence of elevated-type tumors (p < 0.001), a higher incidence of differentiated-type tumors (p < 0.05), and larger tumor size (p < 0.05) compared with EADS. The prevalence of Barrett’s esophagus in patients with EAGC was significantly lower than in patients with EAE (10.2%, 5/49 patients vs. 100%, 7/7; p < 0.0001). The prevalence of intestinal (Barrett’s) metaplasia in surrounding non-neoplastic mucosa in patients with EAGC was significantly lower than in patients with EADS or EAE (36.7%, 18/49 patients vs. 72.0%, 211/293 and 85.7%, 6/7; p < 0.0001 and p < 0.05, respectively). EAGC was associated with a higher incidence of tumors that reacted positively for gastric phenotype markers alone than EADS (32.7%, 16/49 cases vs. 17.1%, 50/293; p < 0.05) and a lower incidence of tumors that reacted positively for both gastric and intestinal markers than EADS or EAE (40.8%, 20/49 cases vs. 59.7%, 175/293 and 85.7%, 6/7; p < 0.05, respectively). Our findings indicate that AGC forms a specific category different from both adenocarcinoma of the distal stomach and esophagus in terms of association with Barrett’s esophagus or intestinal metaplasia, and the differentiation phenotype of the tumor.
Renal Vein and Vena cava Involvement Does Not Affect Prognosis in Patients with Renal Cell Carcinoma
Authors: Ficarra Vincenzo , Righetti Rita , D’Amico Antonio , Rubilotta Emanuele , Novella Giovanni , Malossini Gianni , Mobilio Gaetano
Published: April 2003

Objectives: The prognostic value of tumor extension into the renal vein or vena cava is still a controversial issue. The aim of this study is to report our experience with radical surgery in patients with renal cell carcinoma (RCC) extending into the renal vein or subdiaphragmatic vena cava. Methods: We evaluated 142 patients with RCC involving the renal vein or inferior subdiaphragmatic vena cava. RCC had extended into the renal vein in 118 patients and into the inferior vena cava in the remaining 24. Radical nephrectomy was performed in all cases with renal vein invasion. Radical nephrectomy with cavotomy and tumor thrombus removal was carried out in all cases with inferior subdiaphragmatic vena caval invasion. Cause-specific survival was calculated by means of the Kaplan-Meier method. The log rank test was used for survival comparisons and univariate analysis. Results: The 5- and 10-year cause-specific survival rates were 51.5 and 39%, respectively, in the group of patients with tumor extension into the renal vein and 33.4% in those with inferior vena caval involvement. In 52 patients (44%), RCC extended only into the renal vein. In the remaining 66 patients, renal vein invasion was associated with other adverse prognostic factors. Life expectancy was lower for patients with other concurrent adverse prognostic factors than for those affected by renal vein involvement alone (p < 0.0001). In the latter group, survival expectancy was similar to those with stage T2N0M0 tumor. In 7 cases (29%), inferior vena caval invasion was not associated with other adverse prognostic factors. In the remaining 15 patients (71%), vena caval involvement was associated with other adverse prognostic factors. Concurrence of other adverse prognostic factors with vena caval invasion significantly decreased the disease-specific survival expectancy in comparison with the patients in whom vena caval involvement was the main prognostic factor (p = 0.008). In these patients, disease-specific survival was similar to those with stage T2N0M0 tumor. Conclusion: Renal vein or inferior subdiaphragmatic vena caval involvement does not significantly affect prognosis in patients with RCC.
Functionally Active Duplications of the CYP2D6 Gene Are More Prevalent among Larynx and Lung Cancer Patients
Authors: Agúndez José A.G. , Gallardo Lourdes , Ledesma María C. , Lozano Luis , Rodriguez-Lescure Alvaro , Pontes José C. , Iglesias-Moreno María C. , Poch Joaquin , Ladero José M. , Benítez Julio
Published: April 2003

The cytochrome P450 CYP2D6 is a polymorphic drug-metabolizing enzyme that is involved in the metabolism of several drugs and xenobiotics. Several independent studies indicate that the CYP2D6 metabolic status is a secondary factor in the risk of developing lung cancer, with individuals with high activity being at increased risk. The occurrence of functionally active duplications of the CYP2D6 gene is a phenomenon that affects 3–8% of Caucasians and up to 30% in some ethnic groups. These duplications cause ultrarapid metabolism of CYP2D6 substrates. In order to establish whether the highest CYP2D6 enzyme activity is associated with an increased risk of cancer, we analyzed the frequency of CYP2D6 gene duplications and enzyme-inactivating mutations in 199 Caucasian patients with lung or larynx cancer and in 335 healthy controls. A significantly increased frequency of carriers of the CYP2D6 gene duplication were found among lung and larynx cancer patients (13%), as compared with healthy controls (6.9%; p < 0.02). The frequency of the mutated active CYP2D6*9 allele was increased in lung cancer patients (p < 0.01) but not in larynx cancer patients. Global findings indicate that over 20% patients with lung or larynx cancer show CYP2D6 genotypes leading to ultrarapid metabolism or to the expression of an enzyme with altered kinetics (p < 0.01 vs. healthy controls). This may influence the metabolism of CYP2D6 substrates, including antineoplastic drugs and opioid derivatives used for pain relief in cancer patients. These patients would require higher doses than those considered as standard. We conclude that dosages for CYP2D6 substrates should be adapted to lung and larynx cancer patients.
Clinicopathological Significance of Cathepsin D Expression in Gastric Adenocarcinoma
Authors: Ikeguchi Masahide , Fukuda Kenji , Oka Shin-ichi , Yamaguchi Ken-ichi , Hisamitsu Kazunori , Tsujitani Shun-ichi , Sakatani Takashi , Ueda Tsuyoshi , Kaibara Nobuaki
Published: April 2003

Objective: An estrogen-regulated lysosomal protease, cathepsin D, has been detected in a variety of tissues. This proteinase has been described as closely associated with tumor progression and metastasis in malignant tumors. The purpose of this study was to determine the clinicopathological and prognostic significance of cathepsin D expression in gastric adenocarcinoma. Methods: In a consecutive series of 478 patients with gastric carcinoma (median follow-up period: 93 months, range: 1–285 months), cathepsin D expression in tumors was quantitatively analyzed with immunohistochemistry using a monoclonal antibody against cathepsin D (clone: 1C11). The percentage of cathepsin-D-positive cancer cells (the CD index) was calculated. In addition, the amount of cathepsin-D-positive stromal cells was evaluated; three grades (high, intermediate, and low) were used for the classification. Results: The mean CD index of 478 tumors was 12.8% (range: 0–100%, median: 8%). The mean CD index of diffuse-type gastric carcinomas (14.9%) was significantly higher than that of intestinal-type carcinomas (10.1%, p < 0.0001). Cathepsin D expression of cancer cells was significantly associated with the depth of tumor invasion in both types. The percentage of tumors with high cathepsin D expression in stromal cells was significantly higher in well-differentiated tumors (25.5%) than in moderately differentiated (12.8%) or in poorly differentiated tumors (19.1%). Cathepsin D expression of stromal cells was significantly associated with the depth of tumor invasion in the intestinal type, in contrast to the diffuse type. Highly expressed cathepsin D in cancer cells was associated with a poor prognosis in both types of carcinoma, but in stromal cells highly expressed cathepsin D was associated to a poor prognosis in the intestinal type only. Conclusion: These results indicate that cathepsin D expression in cancer cells may play an important role in tumor progression in diffuse-type gastric carcinoma, whereas in the intestinal type of carcinoma, cathepsin D expression in stromal cells may play an important role in tumor progression.
Chemotherapy-Related Hemolytic-Uremic Syndrome following Treatment of a Carcinoma of the Nasopharynx
Authors: Thurnher D. , Kletzmayr J. , Formanek M. , Quint C. , Czerny C. , Burian M. , Kornek G.
Published: April 2003

Objective: A cisplatin-containing regimen followed by radiation therapy is the recommended treatment for patients with advanced nasopharyngeal carcinoma. We report a case of a 58-year-old woman with hemolytic-uremic syndrome (HUS) who received induction chemotherapy for undifferentiated squamous cell carcinoma of the nasopharynx. Patients and Methods: During the 2nd course of chemotherapy (consisting of bleomycin, cisplatin and epirubicin), the patient developed hemolytic anemia, thrombocytopenia, and acute renal failure. After HUS had been diagnosed, the patient was transferred to the intensive care unit. Results: Twice daily therapeutic plasma exchange (TPE) with fresh-frozen plasma, hemodialysis and high-dose cortisone was performed. Two weeks after the start of plasma exchange, thrombocytes and renal function began to normalize. Low-dose cortisone was continued until the patient recovered from hemolytic anemia. Six weeks after the administration of the second course of chemotherapy, the patient had fully recovered from HUS, and radiation therapy was carried out as planned. The patient responded well to treatment, but died 9 months after the diagnosis due to liver metastases. Conclusion: We demonstrated that early TPE with fresh-frozen plasma and high-dose cortisone is a potentially successful treatment modality for the usually fatal, fulminant form of chemotherapy-induced HUS.
Genetic Alterations in the Human Tcf-4 Gene in Japanese Patients with Sporadic Gastrointestinal Cancers with Microsatellite Instability
Authors: Saeki Hiroshi , Tanaka Shinji , Tokunaga Eriko , Kawaguchi Hidetoshi , Ikeda Yoichi , Maehara Yoshihiko , Sugimachi Keizo
Published: April 2003

Disruption of the APC/β-catenin/Tcf pathway has been proposed as an important step in the development of cancer. The Tcf-4 transcription factor gene was reported to be one of the targets of microsatellite instability (MSI) in colorectal cancers in with MSI. We carried out a sequencing analysis of the Tcf-4 gene in 41 Japanese patients with gastrointestinal tumors with MSI as well as in cancer cell lines. Three of 21 (14.3%) colorectal tumors with MSI contained a mutant Tcf-4 gene encoding 1-bp deletion in an (A)9 repeat, leading to carboxyl terminal truncation of Tcf-4 protein. No Tcf-4 mutations were detected in 20 gastric tumors with MSI, or in gastric cancer cell lines. Additionally, we found a novel transcript of the Tcf-4 gene which contained a segment of 73 bp in front of the (A)9 repeat of the Tcf-4 coding sequence. Sequencing analysis revealed that the inserted fragment was 60% homologous to that of exon IXA of the Tcf-1 gene. It is of interest that this insertion resulted in truncation of Tcf-4, similar to the 1-bp deletion in the (A)9 repeat. Therefore, in part of the Japanese colorectal tumors with MSI, frameshift mutations in Tcf-4 may be of functional significance. Functional alterations in the Tcf-4 signaling network in gastrointestinal tumorigenesis require further investigations.
Features of Microsatellite Instability in Colorectal Cancer: Comparison between Colon and Rectum
Authors: Ikeda Yoichi , Oda Shinya , Abe Toru , Ohno Shinji , Maehara Yoshihiko , Sugimachi Keizo
Published: April 2003

In one third of colorectal cancer patients, tumours occur in the rectum. Unique aetiologies may underlie the increased carcinogenesis in this region of the colorectum. Microsatellite instability (MSI) was analysed in specimens obtained from 121 colorectal carcinoma patients, using five dinucleotide markers and a new fluorescent system. The incidence of microsatellite alterations in the proximal colon, the distal colon and the rectum was 44.4% (16/36), 37.2% (16/43) and 23.8% (10/42), respectively. Patterns of microsatellite alterations could be classified into two subtypes, one showing relatively small changes within 6 bases (type A) and the other exhibiting drastic changes over 8 bases (type B). All the changes observed in tumours in the rectum were type A, and no type B mutation was noted. There was a close correlation between type B mutations and high-frequency MSI (≧2 markers), MSI-H, and between type A mutations and low-frequency MSI (1 marker), MSI-L. The type B/MSI-H phenotype significantly correlated with the proximal localisation of tumours. In the rectum, there was no tumour with the type B/MSI-H phenotype. These findings suggest that cancers occurring in the colon and the rectum have a differential molecular background for carcinogenesis.
Isolated Central Nervous System Relapse of Non-Seminomatous Germ Cell Tumour of the Testis
Authors: Cohn Deborah A. , Stuart-Harris Robin
Published: April 2003

Isolated central nervous system (CNS) relapse of non-seminomatous germ cell tumour (NSGCT) of the testis has been reported in only 12 patients previously. We report a patient with an isolated CNS relapse of NSGCT, following a prior systemic relapse. From a review of previous cases, isolated CNS relapse appears to be more common in patients with embryonal cell histology (alone or mixed with other elements) and occurred after a median of 8.5 months following initial presentation. Long-term survival appears possible using multi-modal treatment with whole-brain radiotherapy, surgery and/or chemotherapy. However, the optimal treatment of isolated CNS relapse remains undefined.
Correlation of Beta-Catenin and Cyclin D1 Expression in Colon Cancers
Authors: Utsunomiya Takehiro , Doki Yuichiro , Takemoto Hiroyoshi , Shiozaki Hitoshi , Yano Masahiko , Sekimoto Mitsugu , Tamura Shigeyuki , Yasuda Takushi , Fujiwara Yoshiyuki , Monden Morito
Published: April 2003

Objective: Beta-catenin activates transcription by TCF/LEF and has been regarded as an oncogene in a wide range of malignant tumors. Among various molecules regulated by beta-catenin/Tcf, cyclin D1 is the most likely candidate for stimulation of the oncogenic pathway. The association between beta-catenin and cyclin D1 was investigated using clinical samples from colorectal cancers. Methods: The expression of beta-catenin and cyclin D1 was investigated by immunohistochemical analyses of samples from 70 patients with colorectal cancers. In 28 of the fresh tumor samples, beta-catenin protein was separated into soluble and insoluble fractions and quantitatively correlated with cyclin D1 protein by Western blot analysis. Results: Compared with noncancerous epithelium, beta-catenin and cyclin D1 were overexpressed (+) in 35 (50%) and 30 cases (43%), respectively. Cyclin D1 (+) was observed in 74% (26/35) of beta-catenin (+) cases, but only in 11% (4/35) of the beta-catenin (–) cases. Thus, there was a strong association between the expression of beta-catenin and that of cyclin D1 (p < 0.001). In the Western blot analysis, the amount of cyclin D1 correlated well with beta-catenin expression in the soluble fraction (p = 0.0016), but not with beta-catenin in the insoluble fraction or with E-cadherin expression. Beta-catenin (–)/cyclin D1 (–) cases displayed less tumor invasion than the remaining cases. However, there were no significant differences in lymph node metastasis or other clinicopathological findings. Conclusion: Our results indicate that beta-catenin overexpression in the cytoplasm may promote malignant transformation by triggering cyclin D1 expression in colorectal cancers.
Preliminary Results of Combined Therapy with Topotecan and Carboplatin in Advanced Non-Small-Cell Lung Cancer
Authors: Pujol J.L. , von Pawel J. , Tumolo S. , Martoni A. , Hearn S. , Fields S.Z. , Ross G.
Published: April 2003

Topotecan is a topoisomerase I inhibitor and an analogue of camptothecin with demonstrated activity in small-cell lung cancer. However, less is known about the potential role of topotecan in advanced non-small-cell lung cancer (NSCLC). Platinum-based combination therapy is currently recommended in NSCLC patients presenting with good performance status. Because topotecan demonstrates a novel mechanism of action, its investigation in platinum combinations is warranted. In phase I/II trials of topotecan given as part of a cisplatin-based regimen, significant antitumor activity has been observed, providing the rationale for conducting further studies aimed at assessing survival benefit. However, this combination exhibits sequence dependence, with increasing hematologic toxicity observed when cisplatin is administered on day 1 of a 5-day topotecan course. Cisplatin has been associated with dose-limiting nonhematologic toxicities. Carboplatin exhibits a different toxicity profile compared with cisplatin, which makes it an attractive agent to study in combination. A hypothesis can be made that carboplatin in combination with newer agents such as topotecan might compare favorably with classic cisplatin-based regimens, particularly with respect to efficacy:toxicity ratio. Therefore, a phase II study was initiated to determine the efficacy, toxicity, and safety of carboplatin-topotecan combination in advanced NSCLC. Preliminary results reported here show that topotecan with carboplatin is generally well tolerated with manageable hematologic toxicity. Indirect comparison with cisplatin-topotecan combination suggests a lower incidence of dose-limiting nonhematologic toxicity. Whether or not the carboplatin-topotecan regimen is able to offer tumor response and survival benefit comparable to those observed with cisplatin-based combinations remains to be established.
Herceptin® Alone or in Combination with Chemotherapy in the Treatment of HER2-Positive Metastatic Breast Cancer: Pivotal Trials
Authors: Baselga José
Published: April 2003

Large pivotal phase II and III clinical trials investigated the therapeutic efficacy and safety of the humanized anti-HER2 monoclonal antibody, Herceptin®, alone and in combination with standard chemotherapy, respectively, in HER2-positive metastatic breast cancer. Eligible patients were HER2 2+ and 3+ overexpressors, as determined by immunohistochemistry (IHC). Herceptin was well tolerated in both trials. Single-agent second/third-line Herceptin produced durable tumor responses. First-line Herceptin in combination with chemotherapy, in particular paclitaxel, significantly improved time to disease progression, duration of response and time to treatment failure. Combination therapy also provided a significant 25% improvement in overall survival. These clinical benefits have led to the approval of Herceptin for clinical use in the USA and elsewhere. Greater efficacy was noted in IHC 3+ patients compared with the overall population in both trials. Retrospective fluorescent in situ hybridization (FISH) testing of patient-tumor HER2 status revealed similar clinical outcomes in IHC 3+ and FISH-positive patients, consistent with the reported high concordance between IHC and FISH. Responses in the single-agent Herceptin trial were seen exclusively in FISH-positive patients. Approximately a quarter of HER2 2+ patients test FISH positive and may therefore benefit from therapy. Numerous studies are underway or planned to evaluate other Herceptin combinations and regimens in the metastatic and adjuvant settings.