[Systemic therapy of breast cancer: practice guideline]. / Az emlõrák szisztémás kezelése: szakmai útmutatás.

The article presents the practice guideline of systemic treatment of breast cancer and recommendations of the 3rd Hungarian Breast Cancer Consensus Conference. It reflects the recent international guidelines (ESMO, NCCN, ABC2, St Gallen's) irrespectively of the current financial opportunities. Here we follow the early - locally advanced - locally relapsed - metastatic breast cancer line for didactic considerations and we discuss the different subgroups of breast cancer based on hormone receptor and HER2 receptor status. Diagnosis and treatment options of rare clinical entities are summarised at the end of the paper.

Inflammatory breast cancer-comparing the effectivity of preoperative docetaxel-epirubicine protocol to conventional antracycline-containing chemotherapy to achieve clinical benefit and complete pathological response.

Our retrospective analysis compared the effectiveness of conventional antracycline-containing protocols (A+) and docetaxel/epirubicine (TE) as primary systemic chemotherapies (PSCT) for inflammatory breast cancer (IBC). Seventy IBC patients received either A + (n = 48) or TE (n = 22) as PSCT. The objective clinical response and clinical benefit rate of treated patients were 54.3% (A+: 54,2% vs. TE: 54,5%; p = 0,28) and 92.8% (A+: 91,7% vs. TE: 95,5%; p = 0,57), respectively. The clinical complete response rate (cCR) was 23.2% (A+: 27,1% vs. TE:4,5%; χ (2) = 4,79; p = 0,03) with 7.14% (A+: 10,4% vs. TE:0%; χ (2) = 2,47; p = 0,12) of pathological complete responses (pCR). The median progression free (PFS)/local progression free (LPFS)/overall survival (OS) was 2.0/5.4/4.0 years, respectively. Patients achieving cCR had a tendency for better survival parameters than patients with less than cCR. Response rates or survival data were not statistically different in the two chemotherapy (CT) treatment groups. The survival was not influenced by the number of CT cycles in either protocols. In this set of patients, the clinical efficacy of the two alternative primary systemic chemotherapies (A + and TE) is equivalent in the treatment of inflammatory breast cancer (IBC), despite of the significant difference in favour of A + noticed in CRs. Six cycles of CT could be enough for patients achieving CR, however sequential pre- and/or postoperative CT with non cross-resistant drugs should be considered for non-responders.

Epidermal growth factor receptor (EGFR) high gene copy number and activating mutations in lung adenocarcinomas are not consistently accompanied by positivity for EGFR protein by standard immunohistochemistry.

The purpose of this study was to investigate whether detectable protein biomarker overexpression is a prerequisite for the presence of increased gene copy number or activating mutations and responsiveness to the epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib in patients with lung adenocarcinomas. EGFR status was prospectively analyzed in tumor biopsy samples by three methods: protein expression (n = 117) by standardized immunohistochemistry (IHC), gene copy number (n = 97) by fluorescent in situ hybridization (FISH), and mutation analysis by sequencing (n = 126). Fifty-nine percent of the samples were positive by IHC, 40% were positive by FISH, and 13.5% contained activating kinase domain mutations. Thirty-four percent of the FISH-positive and 27% of the mutant samples were also IHC-negative. All EGFR mutant patients had major clinical responses (five complete response and five partial response) to gefitinib or erlotinib treatment, although three of these tumors were IHC-negative and four were FISH-negative. In a retrospective analysis of samples from nine patients with excellent therapeutic responses (three complete response, five partial response, one stable disease) to erlotinib or gefitinib, mutations were identified in eight cases, but IHC was negative in four of these tumors. These results indicate that molecular diagnostic methods appear to be most important for the identification of lung adenocarcinoma patients who may benefit from EGFR inhibitor treatments.

Molecular targeted therapy: a strategy of disillusions or optimism?

Cytotoxic drugs were designed to kill tumor cells, whereas agents of molecular targeted therapy inhibit various molecular functions of the tumor cell. Consequently, their toxicity profiles also differ. Molecular targeted agents, except for monoclonal antibodies, are enumerated here in three classes: compounds active extracellularly, extra/intracellularly, and intracellularly. Although no major breakthrough has occurred in the drug treatment of neoplastic diseases yet, such compounds as trastuzumab, cetuximab, bevacizumab, gefitinib, erlotinib, imatinib, and bortezomib have shown considerable clinical promise. Major obstacles to the further development of molecular targeted compounds are described. The use of different endpoints, positron emission tomography for evaluation, and predictive genetic markers are recommended. Combination therapy with cytotoxic drugs and studies in an adjuvant setting are also recommended. It is concluded that cautious optimism about the future of molecular targeted therapy is reasonable.

[Clinical studies with imatinib in 2004]. / Klinikai vizsgálatok imatinibbel 2004-ben.

The successful period of targeted molecular therapy of malignancies started with the beneficial clinical application of trastuzumab and imatinib. Imatinib is a targeted molecule capable to inhibit tyrosine kinase active in the production of abl-bcr protein responsible for the translocation of 9 and 22 chromosome in chronic myeloid leukemia. Simultaneously the drug may be active against C-kit PDGFRalpha and beta, COL 1a1 and FIPI-LI gene mutations as well. Consequently, imatinib exerts a therapeutic effect upon chronic myeloid leukemia, gastrointestinal stroma tumor, dermatofibrosarcoma protuberans and hypereosinophilic syndroma. Besides, several studies are ongoing in other solid tumours characterized by those mutations, which might be blocked through imatinib treatment. Studies are in progress determining the place of imatinib in the "complex therapy". Resistance developed against the drug may be overcome by new molecules, such as SU 11248 or everolimus. It can be stated that imatinib--a drug which is applied orally and has a highly tolerable toxicity profile--signifies a new perspective for a successful targeted molecular therapy.

[Effect of imatinib treatment of gastrointestinal stromal tumors]. / Az imatinibkezelés hatása gastrointestinalis stroma eredetú daganatokban.

INTRODUCTION: Advanced malignant gastrointestinal stromal tumours are practically resistant to further radio- or chemotherapy. These tumours are characterized by the presence of C-KIT (a transmembrane tyrosin kinase) mutation which can be specified by CD117 expression. Imatinib (2-fenilaminopirimidine) is a selective inhibitor of the mutated C-KIT. AIM: The purpose of our study was to determine the potential antitumour effect of imatinib in patients with gastrointestinal stroma tumour patients. MATERIALS AND METHODS: An open, non-randomized trial was performed involving 38 patients each of which had received/metastatic disease associated with CD117 positivity. Consecutively daily doses of 400-600 mg imatinib was administered orally to the patients. The evaluation was carried out on 37 patients in a form of an interim analysis. RESULTS: After a 3-18 months observation period 1 complete, 19 partial remissions and 10 static diseases could be registered (78%), in association of only grade 1-2 toxicity. CONCLUSIONS: The imatinib treatment improved the quality of life of the patients with gastrointestinal stroma tumour and their life expectancy became considerably prolonged. Further follow-up of the patients as well as design of a prospective, randomized trial on a larger patient material is urgently needed.

[Perspectives for the hormonal therapy of breast cancer]. / Az emlôrák endokrin kezelésének kutatási távlatai.

The role of estrogens, including its sources, tissue distribution, metabolism, and mechanism of action, is discussed in this review. The ER alpha and beta are functioning separately, and there is a physiological balance between their activity. Whenever this balance is over thrown due to endogenous or exogenous carcinogenic factors, malignancy develops. Risk factors of breast cancer are listed and evaluated individually. It should be stressed however, that their carcinogenic effect sums up. The knowledge of established risk factors rises the possibility of chemoprevention, which might be highly desirable in case of gene carriers. Special emphasis is attached to the SERM molecules which act as antiestrogens. Their antitumour effect is largely used in the treatment of hormone sensitive advanced breast cancer patients, and their efficacy has been proved in adjuvant therapy as well. Their preventive use might also be justified, especially in gene carriers. Aromatase inhibitors form a special class among the SERM molecules. In Hungary, anastrozole, letrozole and exemestane are widely applied for the therapy of breast cancer patients, while raloxifene has only been introduced recently, mainly in order to prevent osteoporosis. The therapeutic value of fulvestrant is unknown yet and its antitumour effect has to be explored. The therapeutic significance of these molecules lies in the fact that they might be effective after the development of tamoxifen resistance. There are several explanations for this phenomenon offering new targets for the further development of a succesful antitumour chemotherapy.

Recent progress in the development of anticancer agents.

Cancer chemotherapy started with the discovery of the cytostatic effect of N-mustard and its derivatives more than five decades ago. This observation opened the way for the synthesis of various alkylating agents, antimetabolites and antimitotics expliciting antitumour activity against several human malignancies. The considerable toxicity of these drugs however, limited their application and only hormone-active products were relatively well tolerated. Besides, the majority of human malignant tumours proved to be chemoresistant. Consequently, there was still an urgent need for finding less toxic compounds possessing broader antitumour spectrum. Therefore, it became obvious that better understanding of the cellular metabolism - due to revolution in molecular biology - yielded new targets for cancer chemotherapeutic agents. Key enzymes active in signal transduction pathways could be blocked by new substances. Cell cycle control could be influenced by apoptosis inducers. Mitotic division could be inhibited by antitubulin agents. Multidrug resistance (MDR) could be modified by revertants. New concepts also emerged: a) chemoprevention, which is based on the principle, that since carcinogenesis is a genetically determined, progressive multistep process it can timely be reconverted into the direction of normal cellular metabolism by redifferentiating agents; b) antimetastatic therapy: originally performed postoperatively as an adjuvant therapy nowadays before surgical intervention, in order to block vascular dissemination of tumor cells (neoadjuvant therapy); c) antiangiogenic therapy: substances capable to hinder the vessel production essential for the development of metastasis; d) antitelomerase molecules inhibiting the immortal division capacity of DNA in malignant cells. All these new research approaches necessitate to review the existing drugs which are in clinical use or are investigational agents against human malignancies.

Molecular Events as Targets of Anticancer Drug Therapy.

The aim of this review is to introduce some molecular targets for cancer chemotherapy, with comments on their mode of action, preclinical and clinical results. The representatives of the following groups are covered: phosphorylation inhibitors, protein kinase modulators, receptor antagonists, immunomodulators, differentiating agents, multidrug resistance modulation, telomerase inhibitors, and bioreductive agents.

Clinica del edema encefalico. / Clinical manifestations of encephalic edema

El edema encefalico se presenta en numerosos y variados cuadros clinicos tanto sistemicos como localizados del sistema nervioso central, los que se enumeran. Se senalan las manifestaciones clinicas del edema encefalico. Estas son inespecificas y sugieren la existencia de una disfuncion cerebral difusa. Entre ellas destacan las alteraciones de conciencia, las convulsiones y los sintomas y signos de hipertension intracraneana. Entre los procedimientos preconizados en el estudio del edema encefalico deben mencionarse la monitorizacion de la impedancia cerebral; el estudio de la compleance cerebral; las determinaciones de la presion intracraneana; el registro del electroencefalograma; la puncion lumbar y el analisis del liquido cefalo-raquideo y la tomografia axial computarizada. Se enumeran y discuten los principales cuadros clinicos en los cuales existe edema encefalico, destacando las hiponatremias; el desequilibrio osmotico postdialisis; la recuperacion del paro cardiaco; las meningitis purulentas; la encefalopatia hepatica; los traumatismos encefalo-craneanos; la encefalopatia hipertensiva y la eclampsia; la quetoacidosis-diabetica; la altura, etc

Tratamiento del edema encefalico. / Treatment of encephalic edema

Se analizan las indicaciones, ventajas y limitaciones de los diversos elementos actualmente disponibles en el tratamiento del edema encefalico que reconoce variadas causas y acompana diversas patologias. Entre ellas destacan los corticoides; los barbituricos, los diureticos osmoticos y no osmoticos, ninguno de los cuales garantiza resultados invariablemente satisfactorios