bluuebunny/crossref_metadata_2025 huggingface dataset:
Biologic Fixation of the Electrode Cable of Cochlea Implants
Authors: Hüttenbrink Karl-Bernd , Zahnert Thomas , Vogel Uwe , Hofmann Gert
Published: April 2003

Objectives: To verify the necessity for special surgical techniques or clips for fixation of the electrode cable of a cochlea implant against dislocation, and to test the stability of postoperative biologic cicatrization as the sole and solid anchoring of the cable. Material: Temporal bone experiments with a simulated connective tissue sheath around conventional (Med El Combi 40+) and prototype (profiled surface) electrode cables. Results and Conclusions: The electrode cable is anchored securely in a sheath of scar tissue, since unphysiologic loads are needed for pulling it out of its anchorage. The drag during one extraction trial with a profiled cable even resulted in the rupture of the cable. These results confirm our confidence in this biologic fixation of the electrode cable inside its postoperative cicatric tissue sheath. More than 80 cochlea implantations with the electrode simply imbedded in a drop of fibrin glue in the posterior tympanotomy never demonstrated a shift of the electrodes in the last 8 years. Therefore, special fixation of the electrode cable with clips or surgical techniques is not necessary.
In Search of Connexin 26 Mutations in Archival Temporal Bones from Individuals with Congenital Deafness
Authors: Tropitzsch Anke S. , Merchant Saumil N. , Kristiansen Arthur G. , McKenna Michael J.
Published: April 2003

Mutations in the connexin 26 gene have been found to be associated with approximately half of all cases of congenital nonsyndromic sensorineural hearing loss, and represent the single most common cause of genetic sensorineural hearing loss. Seven sets of temporal bones from individuals with congenital sensorineural hearing loss or hearing loss with onset in early childhood were examined for the presence of connexin 26 mutations with the hope of being able to characterize the histopathology of this common disorder. DNA was extracted from temporal bone specimens and analyzed by allele-specific polymerase chain reaction using previously published primer sets and also by direct sequencing. The allele-specific primers resulted in what was initially thought to be mutations in three specimens. However, this could not be confirmed by direct sequencing, which failed to reveal evidence of connexin 26 mutations in any specimens, including those which seemed to be positive by the allele-specific method. Potential problems associated with the molecular analysis of archival human temporal bones are reviewed.
Zenker-Divertikel: Mikroendoskopische Schwellenspaltung mit dem CO2-Laser
Authors: Zbären P. , Schär P. , Häusler R.
Published: April 2003

Fragestellung: Ziel dieser Untersuchung war es, die Resultate, die Komplikationen sowie die Vorteile der mikroendoskopischen Schwellendurchtrennung mit dem CO2-Laser beim Zenker-Divertikel zu analysieren und mit Angaben aus der Literatur zu vergleichen. Patienten und Methode: Es handelt sich um eine retrospektive Analyse von 63 Patienten mit Zenker-Divertikel, bei welchen eine mikroendoskopische Durchtrennunng des Musculus cricopharyngeus mit dem CO2-Laser durchgeführt wurde. Ergebnisse: 2 der 63 Patienten hatten Komplikationen (postoperative Blutung und makroskopisch sichtbare Eröffnung des Mediastinums). Die durchschnittliche Hospitalisationsdauer war 6,9 Tage. 58 der 63 Patienten waren mit dem Resultat zufrieden, 4 Patienten waren ziemlich zufrieden und 1 Patient erklärte sich unzufrieden. Schlussfolgerungen: Die mikroendoskopische Durchtrennung des M. cricopharyngeus mit dem CO2-Laser beim Zenker-Divertikel ist eine wenig invasive, präzise und sichere Behandlungsmethode. Die meisten Patienten sind mit den Resultaten sehr zufrieden; die Hospitalisationsdauer ist kürzer als bei der klassischen transzervikalen Behandlungsmethode.
The Sigmoid Venous Sinus in Temporal Bone Surgery: Anatomic Variations with Case Presentations
Authors: Zaytoun George , Hamdan Abdul-Latif
Published: April 2003

Objective: The sigmoid venous sinus is a vital structure the otologic surgeon has to deal with while operating on the temporal bone. Anatomic variations and/or abnormal locations of the sigmoid venous sinus may be the source of troublesome bleeding and may constitute a mechanical barrier to the proper visualization of the surgical field. The definition of its ‘normal’ anatomic locations and the description of deviations from the normal may often be difficult. Material and Methods: In this paper, the authors give a detailed description of the ‘normal’ location of the sigmoid venous sinus, its most commonly described variations and anomalous presentations. Two illustrative case reports are presented and discussed. Conclusion: Preoperative radiological evaluation with surgical emphasis on the pneumatization of the temporal bone may give clues to the location of the sigmoid venous sinus in the mastoid.
The Effects of Diazepam on Sleep Spindles: A Qualitative and Quantitative Analysis
Authors: Suetsugi Masatomo , Mizuki Yasushi , Ushijima Itsuko , Kobayashi Takayoshi , Watanabe Yoshifumi
Published: April 2003

The effects of 2.5 or 5 mg diazepam (DIZ) on the sleep spindles were studied in 12 healthy male subjects. Polygraphic recordings and the state anxiety scale of the State Trait Anxiety Inventory (STAI) were made for 6 consecutive nights. An inert placebo was given on the first 3 nights and on the sixth night, and DIZ was administered on the fourth and fifth nights. DIZ produced increases in the amount of the slow and fast spindles in a dose-dependent manner. DIZ dose-dependently lowered the frequency of the fast spindles and elevated that of the slow spindles. Furthermore, the influence of DIZ on fast spindles was greater than that on slow spindles. DIZ decreased the state anxiety of the subjects in a dose-dependent manner. These results suggest that measuring the amount and the frequency of fast spindles could be a useful tool in predicting the anxiolytic effects of benzodiazepines.
Polymorphism of the 5`-Upstream Region of the Human SNAP-25 Gene:An Association Analysis with Schizophrenia
Authors: Tachikawa Hirokazu , Harada Shoji , Kawanishi Yoichi , Okubo Takehito , Suzuki Toshihito
Published: April 2003

Recent studies have suggested that synaptic abnormalities may be part of the pathophysiology of schizophrenia. SNAP-25 (synaptosomal-associated protein of 25 kD) is one of the synaptic proteins responsible for presynaptic neurotransmission, axonal elongation and synaptogenesis. Genetic variation in the 5′-upstream region of the SNAP-25 gene was analyzed in 87 unrelated schizophrenic patients and 100 healthy controls. A novel polymorphic (TAAA)n tandem repeat was identified in the 5′-upstream region. There were no significant differences between the patient and the control groups in the distribution of repeat numbers of alleles or genotypes. In addition, no associations were found between the polymorphism for subtypes, longitudinal courses or positive family history of the patients. Our results suggest that polymorphisms in the 5′-upstream region of the SNAP-25 gene have no association with schizophrenia.
Impulsive Traits and 5-HT2A Receptor Promoter Polymorphism in Alcohol Dependents: Possible Association but No Influence of Personality Disorders
Authors: Preuss U.W. , Koller G. , Bondy B. , Bahlmann M. , Soyka M.
Published: April 2003

Objective: Impulsive behavior in alcoholics puts them at serious risk of severer course of disease and has been related to the serotonergic neurotransmission dysfunction. The aim of this study is to investigate the association between impulsive aggression in alcohol dependents with regard to the G-1438A polymorphism in the promoter region of the 5-HT2A receptor gene. Furthermore, we investigated the statistical interaction between 5-HT2A alleles, antisocial personality disorder (APD) and impulsive aggression in alcohol dependents. Alcohol dependents were investigated because these personality disorders and impulsive behavior are very frequent in alcohol dependence anf of clinical relevance. Methods: One hundred and thirty-five patients of German descent meeting DSM-IV criteria of alcohol dependence were recruited. Blood samples were taken from alcohol dependents to determine 5-HT2A promoter polymorphisms using PCR (polymerase chain reaction) of lymphocyte DNA. Impulsive aggression was assessed using a German version of the Barratt Impulsiveness Scale which was translated and backtranslated. Alcohol dependents were subdivided into low- or high-impulsivity groups using a median split of the Barratt score. APD and borderline personality disorder (BPD) were assessed using the SCID-II interview. Results: The low-impulsivity group was slightly older and showed a later age at alcoholism onset than the highly impulsive group. Alcohol dependents with high impulsive traits showed a significant association with 5-HT2A 1438 A alleles. After excluding alcohol dependents with APD or BPD from the analysis, this association remained significant. Furthermore, no association between APD, BPD and 5-HT2A alleles was noted. Conclusions: Inpatient alcohol dependents showed a significant association between 5-HT2A A alleles and impulsive traits, independent of the presence of APD or BPD. No association was noted between personality disorders and the polymorphism. This is the first report about an association of 5-HT2A promoter polymorphism and impulsive behavior in alcohol dependents. This finding may refer only to impulsive traits and may be independent of personality disorders in this sample. These results have to be confirmed in larger samples and in healthy control subjects to determine whether this association is of general validity.
Polymorphisms in the Promoter and Coding Regions of the Synapsin III Gene
Authors: Imai Koubun , Harada Shoji , Kawanishi Yoichi , Tachikawa Hirokazu , Okubo Takehito , Suzuki Toshihito
Published: April 2003

The human synapsin III gene, located on chromosome 22q12–13, has previously been reported to indicate a susceptibility for schizophrenia. Noval rare variants (Thr136Thr in exon 3, Pro468Ser, Glu525Gln and Pro534Leu in exon 12, and 1769 G/C in the untranslated region of exon 13) were found in addition to the polymorphic variant (–196 G/A in the promoter region). No significant differences in genotypic or allelic frequencies of the –196 G/A polymorphism were found between 87 unrelated schizophrenic patients and 100 healthy controls, even when the patients were diagnostically subdivided into subtypes and course specifiers. Furthermore, allelic frequencies of the GATG repeat in intron 1 were not significantly different between the patients and the controls. These results suggest that synapsin III gene polymorphisms are not associated with schizophrenia.
Pharmacological Characterization of the Serotonin Transporter in Young and Elderly Subjects
Authors: Marazziti Donatella , Baroni Stefano , Rossi Alessandra , Masala Irene , Giannaccini Gino , Gori Veronica , Lucacchini Antonio , Cassano Giovanni B.
Published: April 2003

The potency of some tricyclics (imipramine and clomipramine) and selective 5-HT reuptake inhibitors (fluoxetine, paroxetine, and citalopram) in displacing the [3H]paroxetine binding to platelet membranes was measured in young and elderly subjects of both sexes. The results showed that the most potent compound in all subjects was paroxetine, followed by clomipramine, citalopram, fluoxetine, and imipramine, with no differences between male and female subjects. All drugs, except paroxetine and clomipramine, showed significantly lower pKi values in the elderly subjects of both sexes. These findings would suggest that although the pharmacological profile of the 5-HT transporter is not modified qualitatively by age, quantitative changes in its affinity do perhaps occur which would justify more careful studies on this topic in order to get optimal dosages of drugs acting at this level.
Dopamine D2 Receptor and N-Methyl-D-Aspartate Receptor 2B Subunit Genetic Variants and Intelligence
Authors: Tsai Shih-Jen , Yu Younger W.-Y. , Lin Ching-Hua , Chen Tai-Jui , Chen Sheau-Ping , Hong Chen-Jee
Published: April 2003

The dopaminergic and glutamate systems have been implicated in cognitive function. We tested the associations between the dopamine D2 receptor (DRD2) and N-methyl-D-aspartate receptor 2B subunit (GRIN2B) gene variants and intelligence quotient (IQ). Subjects with the DRD2 A1/A1 genotype had a significantly higher mean performance IQ than A2/A2 carriers, while no significant differences in IQ scores were determined for the three GRIN2B genotype groups. These results suggest that genetic variants of the DRD2 gene may play a role in cognitive function. Considering the major role played by the dopaminergic system in general cognitive function, genetic variants of the dopamine receptors and those involved in metabolism and modulation of reuptake should be tested to improve gene-based prediction of general cognitive function.
Association for Serotonin Transporter Gene Variable Number Tandem Repeat Polymorphism and Schizophrenic Disorders
Authors: Tsai Shih-Jen , Ouyang Wen-Chen , Hong Chen-Jee
Published: April 2003

In contrast with two previous western reports, a recent study on a Chinese population found an association for allele 12 of the variable number tandem repeat (VNTR) in the second intron of the serotonin transporter (5-HTT) gene and schizophrenic disorders. We have replicated this finding for a Chinese population in Taiwan (114 schizophrenic patients and 127 controls), demonstrating a modest but significant statistical association for the 5-HTT-VNTR allele 12 and schizophrenic patients (one-sided p = 0.043). This positive finding further supports the proposition that the 5-HTT-VNTR allele 12 is a risk factor for schizophrenic disorders in Chinese populations, although the effect is weak.
Estrogen Dependency in Uterine Endometrial Cancers
Authors: Fujimoto Jiro , Hirose Reiko , Sakaguchi Hideki , Tamaya Teruhiko
Published: April 2003

Estrogen dependency in uterine endometrial cancers involves complicated tumor biology. A transformed phenotype of uterine endometrial cancers is supported by estrogen-dependent oncogene (c-Ha-ras, c-fos and c-jun) expressions. The relative overexpression of estrogen receptor exon 5 splicing variant and the damaged expression of progesterone receptor A, which belong to a lack of estrogen dependency, are related to metastatic potential. The estrogen-related metastatic processes, detachment, invasion and angiogenesis in some uterine endometrial cancers can be inhibited by progestins.
Fluoropyrimidines: A Critical Evaluation
Authors: Brito Rogelio A. , Medgyesy Diana , Zukowski Thomas H. , Royce Melanie E , Ravandi-Kashani Farhad , Hoff Paulo M. , Pazdur Richard
Published: April 2003

After nearly four decades of clinical experience with the fluoropyrimidines, 5-fluorouracil (5-FU) remains an integral part of chemotherapy for colorectal cancer. A range of 5-FU treatment regimens with or without biochemical modulation are currently used and toxicity appears to be schedule dependent. The use of oral 5-FU was abandoned because of erratic absorption caused by varying levels of dihydropyrimidine dehydrogenase (DPD) found in the gastrointestinal tract. This effect may be overcome by administering agents that are converted to 5-FU or by inhibiting or inactivating DPD. Xeloda® (capecitabine) was designed as an orally administered, selectively tumoractivatedTM cytotoxic agent which achieves higher levels of 5-FU in the primary tumor than in plasma or other tissues. The United States Food and Drug Administration (FDA) has approved Xeloda for use in patients with metastatic breast cancer resistant to paclitaxel and in whom further anthracycline therapy is contraindicated. Xeloda is also registered in Canada, Switzerland, Thailand and Argentina. In phase II clinical trials in colorectal cancer, Xeloda produced response rates of 21–24% and median time to disease progression of 127–230 days. Other oral agents in development for the treatment of colorectal cancer include tegafur/uracil plus oral leucovorin, S-1 and eniluracil plus oral 5-FU.
Rational Design of New TumoractivatedTM Cytotoxic Agents
Authors: Verweij Jaap
Published: April 2003

5-Fluorouracil (5-FU) plays an important role in the treatment of several tumor types, particularly colorectal cancer and breast cancer. Xeloda® (capecitabine; 5′-deoxy-5-fluoro-N-[(pentyloxy)carbonyl-cytidine]) is a new rationally designed fluoropyrimidine carbamate. It is administrated orally and after absorption it is first metabolized to 5′-deoxy-5-fluorocytidine (5′-DFCR) by carboxylesterase from the liver and then converted to 5′-deoxy-5-fluorouridine (5′-DFUR) by cytidine deaminase from the liver and tumor tissues. Finally, thymidine phosphorylase (TP) converts 5′-DFUR to 5-FU. TP is more active in tumor tissues than in normal tissue. This tissue localization pattern results in preferential metabolism and generates higher levels of 5-FU in malignant tissue, thus enhancing efficacy but minimizing side effects. The tumor tissue selectivity was confirmed in a study of 19 patients with colorectal cancer. After Xeloda administration, concentrations of 5-FU were 2.5 times higher in the primary tumor compared with adjacent healthy tissue. Xeloda was highly active in human tumor xenografts. It was more active than 5-FU, 5′-DFUR and tegafur plus uracil (UFT) and had a better therapeutic index. Xeloda also demonstrated synergistic or additive activity when used in combination with cyclophosphamide, methotrexate, doxorubicin, paclitaxel and docetaxel. This may be in part a result of up-regulation of TP by the cytotoxic agents. Phase I and II clinical trials have shown that Xeloda is active across a range of tumor types, and phase III studies are ongoing.
Potential of Xeloda® in Colorectal Cancer and Other Solid Tumors
Authors: Cassidy Jim
Published: April 2003

For over four decades, 5-fluorouracil (5-FU) has been the mainstay of therapy for colorectal cancer and a major cytotoxic agent for treating gastrointestinal tumors and a variety of others, including breast and head and neck cancers. Xeloda® (capecitabine) is a new drug that is administered orally and has been rationally designed to generate 5-FU selectively within solid tumors. Theoretically, it has two major advantages, which should translate into an improved therapeutic index: firstly, enhanced drug concentration at the cancer site and therefore greater anti-tumor activity and secondly, reduced drug levels in non-tumor tissues, with a consequent reduction in systemic toxicity. After promising preclinical studies, phase I clinical trials of Xeloda have been performed with a variety of schedules, both with and without the oral biomodulator leucovorin. Anti-tumor activity has been observed with all regimens tested. In the setting of colorectal cancer, a randomized phase II study substantiated the phase I reports of activity and established the most promising regimen for phase III clinical trials. Patients in the phase II trial were randomly selected to receive either continuous Xeloda, intermittent Xeloda or intermittent Xeloda plus leucovorin. There were complete or partial responses in 21% of patients in the continuous arm, 24% in the intermittent arm, and 23% in the arm with intermittent Xeloda plus leucovorin. In addition, 51–63% of patients in each arm achieved stable disease. Therapy was well tolerated in all three arms. The intermittent regimen of Xeloda alone was associated with a longer time to disease progression and offered a one-week rest period to the patient. It was therefore selected for subsequent studies. Two randomized phase III trials of Xeloda versus the ’Mayo’ regimen in patients with advanced colorectal cancer have completed recruitment. They are designed to demonstrate at least equivalent efficacy, with important secondary endpoints of comparisons of toxicity, medical care utilization, and quality of life. No formal results are yet available from these studies. The same regimen of Xeloda is now being evaluated in a large scale adjuvant study, which is expected to recruit approximately 1,700 Dukes’ C colonic cancer patients (X-ACT study). The modest toxicity of Xeloda (particularly its low incidence of neutropenia) makes it a suitable candidate for novel combination therapies involving other agents that are active in colorectal cancer, including camptothecin and its analogues, oxaliplatin and radiotherapy. Further studies of Xeloda can be expected with other diseases known to be responsive to fluoropyrimidines, together with diseases traditionally thought to be resistant.
Inhibitory Effect of Telomere-Mimic Phosphorothioate Oligodeoxy Nucleotides (S-ODNS) on Human Tumor Cell Lines
Authors: Saeki Toshiaki , Takashima Shigemitsu , Tachibana Mari , Koga Masakazu , Hiyama Eiso , Salomon David S. , Holland James F. , Ohnuma Takao
Published: April 2003

To clarify the inhibitory effect of telomere-mimic oligonucleotides on human cancer cell lines, we synthesized 18-mers (18T; n = 3), 24-mers (24T; n = 4) and 30-mers (30T; n = 5) of telomere-mimic phosphorothioate oligodeoxy nucleotides [5′-d(TTA GGG)n-3′] and examined their effects on the proliferation of human tumor cells by XTT assay. After 7 days of continuous exposure to 24T and 30T at concentrations ranging from 0.1 to 10 µM, concentration-dependent cell growth inhibition was observed in MCF-7 clone E3, ZR-75-1, MDA-MB 231, Colo 201 and WiDr. All of these cell lines highly expressed telomerase using the telomeric repeat amplification protocol. None of these tumor cell lines were affected by 18T. In MCF-7, ZR-75-1 and Colo 201 cell lines, a more than 50% growth inhibition was obtained by 3 µM of 24T and 30T whereas, in MDA-MB 231 and WiDr cell lines, cell growth inhibition was less than 50%. 30T was more effective than 24T. Estrogen-dependent growth of both MCF-7 and ZR-75-1 was inhibited by 3 µM of 24T and 30T, however, in the absence of estrogen, no growth inhibition was seen. The MCF-10A cell line, which was developed from normal human breast tissue and expressed telomerase only weakly, was inhibited by 10 µM of 18T. In conclusion, these observations indicate that S-ODNs inhibit tumor growth in cell lines expressing telomerase in a concentration-dependent manner and that cell growth inhibition is dependent on the length of S-ODNs. In addition, the short-length S-ODNs may inhibit growth of cells weakly expressing telomerase, but not of cells with high telomerase expression.
17-Beta-Hydroxysteroid Dehydrogenase in Human Breast and Endometrial Carcinoma
Authors: Sasano Hironobu , Suzuki Takashi , Takeyama Junji , Utsunomiya Hiroki , Ito Kiyoshi , Ariga Naohiro , Moriya Takuya
Published: April 2003

Intratumoral metabolism and synthesis of estrogens are considered to play very important roles in the pathogenesis and development of various sex steroid-dependent neoplasms including breast and endometrial carcinoma. 17β-Hydroxysteroid dehydrogenase (17β-HSD) isozymes catalyze the interconversion of estradiol (E2) and estrone (E1), and thereby serve to modulate the tissue levels of bioactive E2. 17β-HSD type 1 primarily catalyzes the reduction of E1 to E2, whereas 17β-HSD type 2 primarily catalyzes the oxidation of E2 to E1. In the human breast and its disorders, 17β-HSD type 1 is expressed in proliferative diseases without atypia, atypical ductal hyperplasia, ductal carcinoma in situ and invasive ductal carcinoma. 17β-HSD type 2 is not detected in any of the lesions. In addition, 17β-HSD type 1 coexpression is significantly correlated with estrogen receptor status in invasive ductal carcinoma cases. These results indicate that breast carcinoma can effectively convert E1, produced as a result of in situ aromatization, to E2, a biologically potent estrogen, and exerts estrogenic actions on tumor cells through the estrogen receptor. On the other hand, in the human endometrium, 17β-HSD type 2 is expressed, but not 17β-HSD type 1. 17β-HSD type 2 is expressed in the secretory phase but not in any proliferative phase in the endometrial mucosa. The enzyme is expressed in 75% of endometrial hyperplasias and 37% of carcinoma cases. In endometrial carcinoma cases, a significant inverse correlation has been detected between17β-HSD type 2 immunoreactivity and age (p < 0.02). These results indicate that oxidation of E2 to E1 is dominant in endometrial carcinoma, 17β-HSD types 1 and 2 play an important role in the regulation of in situ estrogen production in breast and endometrial carcinoma.
Gonadotropins Stimulate Growth of MCF-7 Human Breast Cancer Cells by Promoting Intracellular Conversion of Adrenal Androgens to Estrogens
Authors: Tanaka Yuji , Kuwabara Koichiro , Okazaki Tomoki , Fujita Toshiro , Oizumi Iwao , Kaiho Shin-ichi , Ogata Etsuro
Published: April 2003

Estrogen receptor (ER)-positive breast cancers initially respond well to estrogen ablation treatment but finally acquire refractoriness, the phenomenon that is a major clinical problem. Because some breast cancers synthesize estradiol (E2) and E2 synthesis is regulated by gonadotropins in normal ovaries, and because circulating gonadotropins are elevated in postmenopausal women and during estrogen ablation treatment, we hypothesized that gonadotropins might modulate estrogen synthesis/metabolism in breast cancer tissue as well. To test this possibility, MCF-7 cells were treated with dehydroepiandrosterone (DHEA) or human chorionic gonadotropin (hCG; ∼LH), each alone or in combination. Cell growth (3-day treatment) was assayed by the MTT method and estrogen synthesis (24-hour treatment) was measured using the ERE-luciferase reporter system. First, MCF-7 cell growth was stimulated by DHEA in a concentration-dependent manner with a maximal effect at 10–4M. Although hCG alone did not have a significant proliferative effect, hCG significantly and dose dependently stimulated MCF-7 cell growth in the presence of a submaximal concentration of DHEA (10–7 M). This stimulatory effect of DHEA and hCG was blocked by a pure antiestrogen ICI182,780 and an aromatase inhibitor, arimidex. Using MCF-7 cells transfected with the ERE-luciferase reporter system, hCG treatment was shown to increase ERE-mediated transcription. These results indicate that MCF-7 cells intrinsically converted DHEA into E2 upon hCG stimulation, then grew their own cells DHEA- and hCG-dependently. We conclude that gonadotropins can act on breast cancer cells and accelerate conversion of DHEA into estrogens, thereby stimulating growth of estrogen-dependent tumor cells. This phenomenon, at least in part, could explain: (1) an increased tissue concentration of E2 in postmenopausal breast cancer; (2) acquisition of hormone refractoriness during estrogen ablation treatment, and (3) the effectiveness of GnRH antagonist/superagonist in some postmenopausal breast cancer patients.
The Novel Isoform of the Progesterone Receptor cDNA in the Human Testis and Detection ofIts mRNA in the Human Uterine Endometrium
Authors: Hirata Shuji , Shoda Tomoko , Kato Junzo , Hoshi Kazuhiko
Published: April 2003

A novel isoform (termed isoform S) of the progesterone receptor (PR) cDNA (PR isoform S cDNA) which consists of a previously unidentified 5’ sequence and exons 4–8 of the intracellular PR gene has been cloned from the human testicular cDNA library. The 5′ sequence of the message was confirmed to be derived from a novel exon (termed exon S) by genomic cloning. The expression level of the PR isoform S mRNA was higher in the spermatozoon than in the uterine endometrium with a lower expression level of the PR isoforms B and A mRNAs in the spermatozoon than in the endometrium. These results implied that the PR isoform S which was possibly translated from the PR isoform S mRNA in the spermatozoon might be related to the cell surface membrane PR. Moreover, the PR isoform S in the uterine endometium might play some physiological and/or pathogenic roles.
Vaccination for Malignant Melanoma: Recent Developments
Authors: Jäger Dirk , Jäger Elke , Knuth Alexander
Published: April 2003

The identification of tumor-associated antigens recognized by cellular or humoral effectors of the immune system has opened new perspectives for cancer immunotherapy. Different categories of cancer-associated antigens have been described as targets for CD8+ T cells in vitro and in vivo: (1) ‘cancer-testis’ (CT) antigens expressed in different tumors and normal testis; (2) melanocyte differentiation antigens; (3) point mutations of normal genes; (4) antigens that are overexpressed in malignant tissues, and (5) viral antigens. Clinical trials with antigenic peptides have been initiated to induce specific immunological responses in vivo. Immunological and clinical parameters for the assessment of peptide-specific reactions have been defined: DTH, CD8+ T cell, autoimmune and tumor regression responses. Preliminary results show that tumor-associated peptides alone elicit specific DTH and CD8+ T cell responses associated with tumor regression after intradermal vaccination. Granulocyte macrophage colony-stimulating factor has been shown to enhance peptide-specific immune reactions by amplification of dermal antigen-presenting dendritic cells. Complete tumor regressions have been observed after the induction of CD8+ T cell responses by peptide immunization. Based on these results, active immunotherapy with tumor-associated antigens may be a promising approach for patients in adjuvant treatment situations, who are at high risk for tumor recurrence. Recently, a strategy utilizing spontaneous antibody responses to tumor-associated antigens (SEREX) has led to the identification of a new CT antigen, NY-ESO-1. NY-ESO-1-specific spontaneous humoral and cellular immune responses were found in approximately 50% of patients with NY-ESO-1-positive tumors. Clinical studies have been initiated to evaluate the immunological effects of immunization with NY-ESO-1 peptides in cancer patients with detectable or absent immunity against NY-ESO-1.
Loss of Imprinting of Long QT Intronic Transcript 1 in Colorectal Cancer
Authors: Tanaka Kiwamu , Shiota Goshi , Meguro Makiko , Mitsuya Kohzoh , Oshimura Mitsuo , Kawasaki Hironaka
Published: April 2003

Loss of imprinting (LOI) of the insulin-like growth factor 2 (IGF2) and H19 genes on human chromosome 11 has been found not only in childhood tumors but also in common adult cancers including colorectal cancer. Recently, a transcript called LIT1 (long QT intronic transcript 1) has been identified within the KvLQT1 locus on chromosome 11. LIT1 is expressed preferentially from the paternal allele and is transcribed in most human tissues. LOI of LIT1 was found in a considerable number of Beckwith-Wiedemann syndrome (BWS) patients, suggesting that it is associated with the etiology of BWS. Since LOI of IGF2 was observed in association with overexpression of IGF2 in colorectal cancer in our previous study, we examined the status of genomic imprinting of LIT1 and H19 in comparison with IGF2 in colorectal cancer. We examined 44 surgically dissected colorectal cancer tissues. Ten of them represented informative cases for LIT1. None of these patients exhibited loss of heterozygosity (LOH) of LIT1, and LOI of LIT1 was observed in 4 of the 10 (40%) informative patients, but not in non-cancerous tissues. Neither LOH nor LOI of H19 was observed. LOI of IGF2 was observed in 4 of 18 (22%) informative patients. These results suggest that LOI of LIT1 is frequently observed in colorectal cancer and may be a useful marker for diagnosis of colorectal cancer.
Role of the Basement Membrane in Tumor Cell Dormancy and Cytotoxic Resistance
Authors: Pogány Gábor , Timár Ferenc , Oláh Júlia , Harisi Revekka , Polony Gábor , Paku Sándor , Bocsi József , Jeney András , Laurie Gordon W.
Published: April 2003

Objectives and Methods: Tumor dormancy and resistance to cytotoxic agents are key limiting events in the treatment of malignant diseases. To determine whether both are influenced by the extracellular milieu in which tumors reside, HT1080 human fibrosarcoma, MCF-7 breast carcinoma and OSCORT osteosarcoma cell proliferation, viability, apoptosis and cytoreductive-treatment-induced death were investigated in the presence or absence of extracellular matrix (ECM). Results: ECM-adherent, but not plastic-adherent HT1080 cells formed a multicellular network accompanied by reduced proliferation and lowered DNA synthetic capacity. The number of cells in S-phase was dramatically reduced. Viable cells entered a state of dormancy reminiscent of that observed in the step of metastasis after extravasation, i.e. prior to the initiation of progressive growth. Such ECM-induced dormancy could be reversed by plating cells on plastic, but only after a 48-hour lag period. No difference was indicated in clonogenicity of HT1080 cells originated from plastic or ECM gel. However, the cells released from ECM gel showed significantly reduced migration ability. The resistance of anchored cells against cytotoxic damage was increased by ECM gel. Examination of cytoreductive treatment revealed that ECM adherence at the time of injury is partially protective, a property which was also moderately apparent when injured cells were transferred to the basement membrane. Conclusions: Taken together, these results suggest that the ECM plays a key role in tumor dormancy and cytotoxic resistance, both explorable at the molecular level using our in vitro model system.
Late Recurrence of a Primitive Neuro-Ectodermal Tumor
Authors: Rao Ravi D. , Robins H. Ian , Mehta Minesh P.
Published: April 2003

Late recurrences after therapy are rare in primitive neuro-ectodermal tumor (PNET). Most recurrences occur within the first 2 years after therapy, although a small number of recurrences may occur up to 5 years after therapy. We present a rare case of a recurrence of PNET in a 31-year-old woman 17 years after her initial presentation. The potential biological implications of this late recurrence as well as responses to subsequent therapy, including temozolomide, are discussed.
Evaluation of a Standardized Protocol of Intracavitary Recombinant Interferon Alpha-2b in the Palliative Treatment of Malignant Peritoneal Effusions
Authors: Sartori Sergio , Nielsen Ingrid , Tassinari Davide , Trevisani Lucio , Abbasciano Vincenzo , Malacarne Paolo
Published: April 2003

Objective: Several schedules with variable doses of intracavitary interferon have been proposed for the management of metastatic peritoneal effusions. This prospective pilot study evaluated the efficacy of a standardized schedule of intraperitoneal interferon α2b. Methods: In 41 cancer patients with malignant ascites a 9-french intraperitoneal catheter was placed under sonographic guidance, and ascites was drained until abdominal ultrasound showed complete absence of effusion. Interferon α2b, 6 or 9 million units (body weight ≤ or >50 kg, respectively), was then administered via the tube, which was clamped for 6 h. 6 courses were given at 4-day intervals. In comparison with pretreatment levels, the 30-day response was classified as complete (CR) = no fluid recurrence, partial (PR) = fluid recurrence <50% and no response (NR) = >50%. Responders were monitored until fluid recurrence requiring paracentesis. Results: 12 patients had CR, 15 PR, 14 NR. Global response (GR) was 65.9%. In ovarian cancer, GR was 75% and was not influenced by the quantity of the pretreatment daily fluid production. In the other cancers, a pretreatment fluid production ≤500 ml/day was associated with a significantly higher response (p < 0.05). Patients not showing response within the first 3 courses did not respond after the next courses. 60-day GR was 41.5%, 90-day GR was 26.8%. The mean time to fluid reaccumulation was 70.5 ± 75.3 versus 11.4 ± 4.4 days before treatment (p < 0.001). The survival of responders was 38–394 days (mean 131), and the average duration of response was 101 days. Conclusion: This protocol could be reasonably applied to ovarian cancer patients and to patients with other cancers having a fluid production of ≤500 ml/day, and it should be stopped if no response is observed after 3 courses of treatment.
A Novel 9-Aza-Anthrapyrazole Effective against Human Prostatic Carcinoma Xenografts
Authors: Supino Rosanna , Polizzi Donatella , Pavesi Raffaella , Pratesi Graziella , Guano Fulvio , Capranico Giovanni , Palumbo Manlio , Sissi Claudia , Richter Silvia , Beggiolin Gino , Menta Ernesto , Pezzoni Gabriella , Spinelli Silvano , Torriani Dante , Carenini Nives , Dal Bo Laura , Facchinetti Federica , Tortoreto Monica , Zunino Franco
Published: April 2003

Objectives: Systematic investigation of a novel series of intercalating agents, 9-aza-anthrapyrazoles, has led to the identification of a promising analogue, BBR 3438. This study describes the antitumour efficacy of the novel compound in human prostate carcinoma models and the molecular/cellular basis of its activity. Methods and Results: The novel 9-aza-anthrapyrazole BBR 3438 was significantly more effective than doxorubicin and losoxantrone (DuP-941) in two of the three tested prostate carcinoma models. The superior activity was more evident in PC3 tumour, since BBR 3438 produced an appreciable rate of complete tumour regressions. Under these conditions, the drug-induced antiproliferative activity paralleled delayed apoptosis. Tumour response to in vivo drug treatment was associated with an early down-regulation of Bcl-2, which was somewhat more marked for the aza compound. In fact, the 9-aza-anthrapyrazole induced DNA cleavage in vitro with isolated DNA topoisomerase II (isoform α) and DNA strand breaks in prostatic carcinoma cells. Although the molecular effects of losoxantrone and the 9-aza analogue on the enzyme target were comparable, the cytotoxic effects of BBR 3438 could be enhanced by long-term exposure as a consequence of favourable cellular accumulation and prominent DNA-binding affinity. In addition, a lower reduction potential of the 9-aza-anthrapyrazole in comparison with classical anthrapyrazoles suggests an increased ability of the drug to induce oxidative stress following free radical production, which may be a contributing factor in determining the long-term response (i.e. delayed cell death) to genotoxic damage. Conclusions: BBR 3438 exhibited a unique profile of preclinical activity with a superior efficacy against prostatic carcinoma models compared to reference compounds (doxorubicin and losoxantrone). The antitumour efficacy of BBR 3438 against prostatic carcinoma could be the result of a combination of favourable events, including enhanced intracellular accumulation and an increased DNA-binding affinity favouring the accumulation of multiple sublethal or lethal damage. In spite of its enhanced cytotoxic potency, the 9-aza compound was better tolerated in vivo than losoxantrone, thus improving the therapeutic index. The preclinical profile of efficacy against prostatic carcinoma, a tumour resistant to conventional antitumour drugs, makes the novel 9-aza-anthrapyrazole BBR 3438 a promising candidate for clinical evaluation.
Current Standards of Care in Small-Cell and Non-Small-Cell Lung Cancer
Authors: Schiller Joan H.
Published: April 2003

Lung cancer is the leading cause of cancer-related death in the United States, accounting for over 30% of cancer deaths in men and 25% in women. Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) are uniformly aggressive tumors, with rates of regional or distant metastases at diagnosis as high as 70%. Because the majority of these tumors are unresectable, patients with relatively good performance status receive platinum-based chemotherapy. Although no treatment consensus exists, currently recommended regimens for SCLC include PE (cisplatin and etoposide), CAV (cyclophosphamide, doxorubicin, and vincristine), CAE (cyclophosphamide, doxorubicin, and etoposide), and CAVE (cyclophosphamide, doxorubicin, vincristine, and etoposide). Of these, the PE regimen has been widely accepted in the United States, although CE (carboplatin and etoposide) provides better tolerability. For NSCLC, standard chemotherapy regimens have included platinum-based therapy (cisplatin and a vinca alkaloid or PE). Data from recent studies suggest that the addition of paclitaxel to platinum modestly improves tumor response and survival in NSCLC. Although SCLC and NSCLC are both responsive to first-line chemotherapy, most patients relapse and die from their disease, with 5-year survival rates of approximately 15%. Given the disappointing survival rates associated with SCLC and NSCLC, the introduction of new cytotoxic agents has been eagerly anticipated. Evidence of improved response and extended survival is mounting for various combinations of established regimens (e.g., PE) with newer drugs exhibiting novel mechanisms of action and single-agent antitumor activity, such as gemcitabine, paclitaxel, docetaxel, vinorelbine, and topotecan. This article reviews the current standards of care in SCLC and NSCLC, and introduces the potential role of newer agents given in combination with standard chemotherapy.
Feasibility of Oral Topotecan Plus Intravenous Paclitaxel in Advanced Non-Small-Cell Lung Cancer
Authors: Eckardt John R.
Published: April 2003

Standard chemotherapy regimens in non-small-cell lung cancer (NSCLC) are platinum-based (cisplatin, carboplatin), with inherent, well-known antitumor activity and toxicity. However, the availability of new agents with novel mechanisms of action and activity in a range of tumor types, coupled with suboptimal activity of single-agent therapy, have prompted the investigation of multidrug regimens in the treatment of NSCLC. One potential combination regimen, in which each agent has antitumor activity in NSCLC monotherapy, is topotecan plus paclitaxel. This article will review the feasibility and tolerability of an oral formulation of topotecan (1.0–1.5 mg/m2/day × 5 days) administered with intravenous paclitaxel (175 mg/m2 as a 3-hour infusion on day 1) in advanced NSCLC patients. The maximum tolerated dose of oral topotecan will be reported, along with preliminary response and tolerability data.
Feasibility of Oral Topotecan in Previously Untreated Patients with Small-Cell Lung Cancer Ineligible for Standard Therapy
Authors: Eckardt John R.
Published: April 2003

The single-agent activity of intravenous (i.v.) topotecan has been established in small-cell lung cancer (SCLC), with overall tumor responses of 39% in previously untreated patients and 11–37% in relapsed patients. An oral formulation of topotecan has been developed that is more convenient for patients, which may lead to greater compliance and greater prescribing flexibility for use in combination with other active agents. We initiated a phase II trial to test the feasibility of oral topotecan administered at 2.0 mg/m2 on days 1–5 of a 21-day cycle in previously untreated SCLC patients. Patients received a median of 5 courses of oral topotecan. Grade 3/4 myelosuppression was common in patients treated with 2.0 mg/m2; secondary to 2 patients developing fatal sepsis, patients enrolled later in the study were treated at 1.7 mg/m2. At both doses, the majority of nonhematologic toxicity was grade 1/2 in severity, and there were no discontinuations attributed to nonhematologic toxicity. In a patient population reflective of the general SCLC population (i.e. elderly with multiple comorbidities), oral topotecan was generally well tolerated at the lower dose level, with a preliminary antitumor activity profile comparable to i.v. topotecan. Clinical studies are currently under way to compare the antitumor activity of oral topotecan with i.v. topotecan in second-line SCLC and investigate oral topotecan in combination with other active agents in SCLC.
New Combinations with Herceptin® in Metastatic Breast Cancer
Authors: Winer Eric P. , Burstein Harold J.
Published: April 2003

Preclinical data indicate that trastuzumab (Herceptin®) has the potential for synergistic or additive effects in combination with therapies including chemotherapy and hormonal agents, providing the rationale for a number of clinical trials in women with HER2-positive metastatic breast cancer. A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective (overall response rate 75%) and well tolerated, with the major side effects being typical of single-agent vinorelbine. Other combinations of trastuzumab with a variety of other chemotherapeutic and hormonal agents are also being assessed. In an effort to overcome the cardiotoxicity observed with trastuzumab plus doxorubicin in the pivotal phase III trial, combination regimens involving potentially less toxic anthracyclines such as epirubicin and liposomal formulations of doxorubicin are ongoing. In addition, trials are investigating whether trastuzumab can reverse the resistance to hormonal therapy that develops in most women with metastatic breast cancer. These and other studies will identify the regimens that produce the best outcomes with the fewest possible side effects in women with HER2-positive breast cancer.
Retrospective Analysis of the Safety of Herceptin® Immunotherapy in Metastatic Breast Cancer
Authors: Cook-Bruns Nancy
Published: April 2003

Approximately 25,000 patients have been treated to date with the humanized anti-HER2 monoclonal antibody, Herceptin®. This therapy has proved effective and well tolerated in patients with HER2-positive metastatic breast cancer; adverse events were generally infusion-related fever and chills of mild-to-moderate severity. Cardiotoxicity and infusion-related reactions emerged as the two main safety concerns with the use of Herceptin. Retrospective analysis revealed a higher incidence of heart failure when Herceptin was combined with anthracyclines than that expected with anthracyclines alone. Age, anthracycline exposure and cardiac risk factors were found to be predictors of cardiac adverse events. Patients experiencing cardiac dysfunction responded well to standard cardiac medication and the majority improved. Cardiac function should be monitored regularly and Herceptin should be discontinued if significant heart failure develops unless the benefits for an individual patient outweigh the risks. Of 25,000 patients, 74 (0.3%) were reported to have experienced a serious infusion-related reaction. The majority occurred during or shortly after the first infusion and were characterized by respiratory symptoms. Most patients were successfully treated; a total of 33 patients continued Herceptin therapy with no recurrence of infusion reactions. Although the benefit to risk ratio of Herceptin remains favorable, physicians must be vigilant and aggressive in managing cardiotoxicity and infusion-related reactions.
Progression of Visual Field Loss in Patients with Retinitis pigmentosa of Sporadic and Autosomal Recessive Types
Authors: Akeo Kiyoshi , Saga Masamichi , Hiida Yoshiki , Oguchi Yoshihisa , Okisaka Shigekuni
Published: April 2003

Purpose: We examined the natural course of patients with retinitis pigmentosa of the eight sporadic and five autosomal recessive forms over 5 years. Methods: We measured the areas of the visual fields by Goldmann perimetry using a digitizer and a computer software. Results: The visual field of V-4 isopters in 4 sporadic cases was approximately 200 cm2 during 30 years after the initial examination, but decreased down to 40 cm2 in the next 10 years. The visual field was reduced to half the normal field in 3 autosomal recessive cases early below the age of 25 years. In 4 sporadic and 2 autosomal recessive cases, the inferior temporal visual field was the widest at the onset of the disease, but exhibited the most severe loss. The superior nasal area was the narrowest initially, and showed the mildest progression. Conclusions: The visual field in retinitis pigmentosa is constricted age-dependently with severe loss of the inferior temporal visual area and mild damage to the superior nasal area.