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Volum 13 Numarul 1, 2007

3 EDITORIAL

5 Lung Cancer: Diagnostic and Treatment Guideline

T.E.Ciuleanu, M.Dediu, Petronela Rusu, Al.Grigorescu, L. Miron, Şt.Curescu

19 The CellScan Technology: A Complex Tool in Cancer Research From theEarly Detection of Cancer to the Treatment Follow-up

Eva Fischer Fodor1 , Olga Soriţău1 , Doris Pelau1 , Piroska Virág1 , Yael S. Schiffenbauer2

1„Prof. I. Kiricuta“ Cancer Institute Cluj-Napoca, Radiobiology Laboratory; 2Medis El Technologies, Lod, Israel

The present paper examines the employments of the CellScan technique in cancer research, in order to improve the methods concerning diagnosis and treatment of malignant diseases. The CellScan is a laser scanning static cytometer, enabling repetitive spectroscopic measurements in intact living cells. Early detection of cancer is of decisive importance to the patient’s quality of life and survival, prognosis and treatment options. This is possible based on the transformations which occur in the cytoplasm of circulating lymphocytes stimulated by tumoral antigens. The detection of fluorescence changes due by this phenomenon is possible with the CellScan system. It was also demonstrated the potential of CellScan technology to detect the in vitro effects of the chemotherapy on tumor cells, making this method a valuable tool for chemosensitivity tests. The specificity and the sensitivity of CellScan are greater than those of other methods. The simplicity, rapidity and non-invasive character of this method make the system a new perspective in clinical studies and also in basic research.

Keywords: Cancer detection, Chemosensitivity, Lymphocytes, CellScan, Fluorescence

Radioterapie & Oncologie Medicală, 2007, 1:19-24

25 Photodynamic Therapy: Mechanisms and Applications in Cancer

Maria Perde-Schrepler1, Gabriela Cherecheş1, Simina Dreve2

1 „Prof. I.Kiricuta” Cancer Institute Cluj-Napoca; 2Izotopic and Molecular Technologies Research Institute Cluj-Napoca

Photodynamic therapy (PDT) is an emerging treatment modality in cancer management. Most modern cancer treatments are not discriminating between normal and malignant cells, affecting both. An ideal cancer treatment would have sufficient selectivity to kill only tumor cells, sparing normal ones. Photodynamic therapy might provide such an option. It is based on the killing of tumor cells by light-activated photosensitive compounds called photosensitisers (PS). PDT is currently used as a treatment modality in a few selected centers and for a limited number of cancer types and localizations. Still, PDT is gaining slowly acceptance as an alternative to conventional cancer therapies. This paper tries to summarize the advantages and disadvantages of this treatment method, its mechanisms and current clinical applications.

Key Words: Photodynamic therapy, Photosensitizers, Light, Apoptosis, Cancer.

Radioterapie & Oncologie Medicală, 2007, 1:25-30

31 Volume Effect and Normal Tissue Complication Probability. Radiobiological Principles

Daniela Martin1, V. Cernea1,2, N. Ghilezan1

1„Prof. I. Kiricuta” Cancer Institute, Cluj-Napoca;

2 University of Medicine and Pharmacy „Iuliu Hatieganu” Cluj-Napoca

The goal of radiotherapy is to deliver sufficient dose to the tumor providing a high probability of cure and, in the meantime, to produce minimal damage to the normal tissues, leaving them architecturally intact and functionally competent. The new era of modern treatment techniques (3D, IMRT) led the physicians, researchers and radiobiologists to evaluating and modeling complex dose distribution plans, particularly in terms of predicting normal tissue complications.This paper will review the following as they relate to normal tissue damage and response to radiotherapy: 1) The concept of tolerance in relation to tissue structure and the differences between damage and morbidity; 2) The influence of field size on radiation damage in small tissue volumes and inward migration of the surviving clonogenic cells; 3) Experimental models (lung, spinal cord, large bowel) for defining the relationship between treatment volume and normal tissue response; 4) Theoretical models to estimate NTCP for partial volume irradiations and inhomogeneous dose distributions.

Key words: Volume effect, Normal tissue, Complication probability.

Radioterapie & Oncologie Medicală, 2007, 1:31-37

38 Breast Magnetic Resonance

Anca Ciurea1, S.Sfrângeu1, Cristiana Ciortea1, Maria Turdeanu2, Larisa Ciule2

1University of Medicine and Pharmacy„Iuliu Haţieganu“ UMPh Cluj-Napoca, Discipline of Radiology;

2Cluj Clinical and Emergency County Hospital, Dept. of Oncology

Contrast enhanced breast magnetic resonance imaging has been shown to have verz high sensitivity in the detection of breast cancer, mainly in the detection of invasive breast carcinoma. Initial studies were dissapointing regarding the clinical usefullness of the method because of the modest specificity. Morphologic criteria, together with contrast-enhanced kinetics led to an increased specificity . Imaging findings are different due to various parameters of the MRI machines and due to physiologic influences. The purpose of this article is to review the principles of the breast MRI with main accent on the indications.

Key words: Breast cancer, Breast magnetic resonance.

Radioterapie & Oncologie Medicală, 2007, 1:38-42

43 3D Conformal Radiotherapy for Gastric Cancer

Alina-Simona Muntean1, V.Bogdan2, N. Ghilezan1

„I. Kirikuta“ Cancer Institute Cluj-Napoca,

1Dept. Radioterapy II;

2Dept. of Medical physics

Purpose: Optimization of radiation techniques to improve the therapeutic efficacy and to minimize adverse effects for operable gastric cancer through identification of the topography and causes of failures after surgery ± chemotherapy. Methods and Patients: The analysis of the literature of the local control after surgery ± chemotherapy in gastric cancer and the development of 2D and 3D irradiation techniques (patients selection, simulation, target contouring, planning, quality control, follow-up) for the available infrastructure at the Cancer Institute Cluj. Results and Discussious: The risk and the topography of failures are correlated with the lymphatic drainage characteristic to anatomical subdivisions of the stomach (upper-, middle- and antrum parts), TNM staging and treatment type, premises for individual tailoring of the irradiation technique. The advantages and disadvantages as well the difficulties and the precautions appropriate to different techniques are critically presented; the more promising is the IMRT irradiation but it is also the most demanding concerning time, infrastructure and quality control. Conclusions: The principles of defining the target volumes for the 2D and 3D irradiations are outlined as well as the specification of clinical indications and practical applications.

Key words: Gastric cancer, Conformal radiotherapy, Adjuvant radiotherapy.

Radioterapie & Oncologie Medicală, 2007, 1:43-48

49 Relationship Between Lymphocites’In vitro Radiosensitivity and Normal Tissues’ Clinical Radiosensivity in Patients with Cervical Carcinoma Treated by Radiotherapy

Ioana Brie1, Piroska Virág1, Maria Perde-Schrepler1, Olga Soriţău1, Eva Fischer-Fodor1, I.D. Postescu1, Claudia Ordean1, O. Coza1,2, N. Todor1, V. Cernea1,2, N. Ghilezan1, Viorica Nagy1,2

1 “I. Kiricuta” Cancer Institute Cluj-Napoca, Radiobiology Laboratory;

2 “Iuliu Ha]ieganu” UMPh Cluj-Napoca, Discipline of Oncology – Radiotherapy

Purpose: The aim of our study was to evaluate in vitro lymphocites’ radiosensitivity (RS) and to correlate it with the irradiated normal tissues’ clinical radiosensitivity in patients with cervix carcinoma undergoing radiotherapy (RT). Patients and methods: In our study were included so far 24 patients with advanced cervical caricoma treated by RT and Cisplatin as radiosensitizer between september 2004 – september 2006 in Cancer Institute „I. Kiricuta” Cluj. Their acute and late reactions in healthy tissues were recorded. Lymphocytes’ in vitro RS was assessed by micronuclei assay and comet assay. Some specific parameters of these assays were determined. Their measured values and dinamics allowed the assessment of some biological markers of RS (induction and repair of genomic lesions) which were correlated with the type and intensity of the side effects of RT. Results: Micronuclei assay: basal and radioinduced levels of unstable chromosomal aberrations are significantly higher in patients with late reactions in irradiated normal tissues (p<0.01). Comet assay: the develpoment and intensity of late toxicities after RT are associated with high induction and low repair of DNA lesions after in vitro irradiation of lymphocites (p=0.02). Conclusions: The parameters of intrinsic radiosensitivity that were assessed in this study do not correlate with acute normal tissues’ toxicity, but show a high correlation with late toxicities after radiotherapy in cervix carcinoma.

Key words: Radiosensitivity, Micronuclei Assay, Comet Assay, Cervix Carcinoma.

Radioterapie & Oncologie Medicală, 2007, 1:49-57

58 Determination of HPV High Risk Virus (Subtypes 16/18) in Cervical Lesions

  1. Bălăcescu1, Ioana Neagoe1,2, Raluca Budiu1, Loredana Bălăcescu1, F. Nicula1

1“Prof. I. Kiricuta” Cancer Institute, Cluj-Napoca, Experimental Pathology Department;

2 University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, Discipline of Immunology

Genital HPV infection is a sexually transmitted disease that is caused by human papillomavirus (HPV). From the 200 or more types of HPV that have been discovered, about 40 could infect human cervical epithelium. Persistent infection with HPV represents the main cause for cervical cancer and for various stages of cervical intraepithelial neoplasia CIN. The most important genotypes HPV responsible for cervical cancer are subtypes 16 and 18. PCR methods are considered the “gold standard” for their analytical sensitivity to detect infectious organisms, including HPV. HPV DNA testing by RT-PCR represents a highly sensitive and reproducible method for HPV detection of cervical lesions. The clinical advantages of HPV DNA testing by RT-PCR together with cytologic and colposcopy evaluations could establish the individual risk factors and follow-up of patients with cervical pathology.

Key words: HPV cervical cancer, Real time-PCR.

Radioterapie & Oncologie Medicală, 2007, 1:58-62

63 Reactive Oxygen Species Generation in the Apop totic Response toOxaliplatin on Human HCT p53wt Colon Cancer Cells

Claudia Burz1, Maria C. Shoshan2, S. Linder2, Maria Berndtsson2, S. E. Leucuţa1

1University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca;

2Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute and Hospital, Stockholm, Sweden

The aim of this study was to determine the apoptosis induces by Oxaliplatin on human HCT p53wt colon cancer cells depending of ROS (Reactive Oxygen Species) generation. We quantified the level of apoptosis induced over 24 h by Oxaliplatin alone or in combination with different ROS scavenges, using an apoptosis-specific assay (Apoptosense TM, PEVIVA AB, Stockholm, Sweden). Total ROS levels were assessed by spectrophotometerie and flow-cytometrie. The results show that Oxaliplatin induced apoptosis in the concentration dependent manner and the apoptosis was partially prevented by the cell-permeable peroxynitrite scavenger PTIO and by PA pyridoxamine which prevents lipid peroxidation. In addition the induction of ROS during apoptosis occurred as early as 1-2 h post-treatment.The results showed the role of ROS in apoptosis induced by Oxaliplatin and suggest the implication of ROS in apoptosis induced by Oxaliplatin and also, in production of its side effects. Selective inhibition of ROS responsible by the apparition of Oxaliplatin side effects might be a way to prevent its neurotoxicity.

Key words: Apoptosis, Mithocondrie, Oxaliplatin, ROS (Reactive Oxygen Species).

Radioterapie & Oncologie Medicală, 2007, 1:63-67

68 Post-Chemotherapy Myelosuppression and the Limits of Recovery with Colony-Stimulating Factors in Acute Leukemias

Piroska Virág1, Olga Soriţău1, Ioana Brie1, Eva Fischer-Fodor1, Rodica Giurgea2 , Z. Uray1, Éva Pállinger3

1„Prof. Dr. I. Kiricuta” Cancer Institute, Cluj-Napoca, Dept. of Tumoral Biology;

2Biological Research Center, Cluj-Napoca;

3“Semmelweis” University of Medicine, Budapest, Hungary

Introduction: The purpose of this study was to evaluate the myelosuppression caused by different combinations of chemotherapeutical agents in acute leukemias and the possibility of recovery with colony stimulating factors: G-CSF (Granulocyte – Colony Stimulating Factor) and GM-CSF (Granulocyte, Monocyte – Colony Stimulating Factor). Patients and methods: The study group consisted of 20 patients with acute lymphoblastic and myeloblastic leukemias. 4 different combinations of chemotherapeutical agents were administered intravenously (i.v.), in perfusion (p.i.) and intrathecally (i.t.) to the patients, in accordance with BFM protocol from 1990. G-CSF or GM-CSF were administered as single daily subcutaneous or intravenous injections, 24 hours after completing chemotherapy. Before and after chemotherapy and after treatment with CSFs, several hematological parameters were determined: hemoglobin, hematocrit, white blood cells and granulocytes. Results and discussions: All the evaluated parameters decreased after chemotherapy with statistically significant values, white blood cells and granulocytes beeing the most affected, especially by combination with antimetabolits and short, intravenous administrations. The i.t. administration had no significant myelosuppressive effects. Both CSFs enhanced the recovery of the hematological parameters, G-CSF being more efficient on white blood cells, while GM-CSF on erythroid lineage. Conclusion: Both G-CSF and GM-CSF recovered the hematopoiesis after chemotherapy, their effects being influenced by dose, biological action and route of administration, the type of CSFs and the status of the hematopoietic system before chemotherapy.

Keywords: Hematological parameters, Post-chemotherapy myelosuppression, Colony-stimulating factors.

Radioterapie & Oncologie Medicală, 2007, 1:68-74

75 In vitro Cytoprotective Effects of BMR Extract on the Toxicity Induced by theTreatment with Doxorubicine, Hydrogen Peroxide and Radiation

Olga Soriţău1, I.D.Postescu1, Ioana Brie1, Piroska Virag1, Maria Perde-Schrepler1 , Corina Tatomir1, Mariana Paul2, V. Cernea1,3

1Prof. “I. Kiricuta” Cancer Institute Cluj-Napoca, Radiobiology Laboratory; 2Institute for Analitical Instruments Research, Cluj-Napoca; 3University of Medicine and Pharmacy “Iuliu Ha]ieganu“ UMPh Cluj-Napoca

Plant phenolics present in fruits and vegetables have received considerable attention due to their potential antioxidant activity. Grapes contain a large variety of polyphenolic antioxidants with possible application in cancer prevention and therapy. The aim of this work was to investigate the in vitro influence of a standardized hydroalcoholic extract obtained from red grapes seeds (BMR variety) on certain effects of some antitumoral agents (doxorubicine, g irradiation). Our results showed a cytoprotective activity of this photochemical preparate on normal cells (human fibroblasts Hfl1) treated with Doxorubicine, but enhancement of the drug inhibitory effect in malignant cells (HeLa). When BMR extract was given before irradiation or hydrogen peroxide administration, a small radioprotective effect -expressed by a diminished, dose-dependent DNA fragmentation- was found by comet assay.

Key words: BMR hydroalcoholic extract, Cyto-and radioprotective effects.

Radioterapie & Oncologie Medicală, 2007, 1:75-80

81 Three-Dimensional Human TumorAngiogenesis Assay – A New in VitroResearch Assay in “Prof. I. Kiricuta” Cancer Institute Cluj-Napoca

  1. Foris1, Ioana Brie2, Olga Soriţău2, V. Cernea1,2

1University of Medicine and Pharmacy “Iuliu Ha]ieganu” Cluj-Napoca; 2“Prof. I. Kiricuta” Cancer Institute Cluj-Napoca, Radiobiology Laboratory

Conventional anti-proliferative chemo- and radiotherapeutic antitumor regimens are going to be significantly changed by the new specific targeted therapies. Anti-angiogenic tumor therapies require complementary tools and techniques to assess the angiogenesis status of patients in order to define the optimal therapeutic approach and to monitor the efficacy of anti-angiogenic interventions. There is an unfilled need for improved methods to quantify an angiogenic response. This paper presents a new in vitro method to study the biology of angiogenesis in human tumor tissue, method that was first described by Gulec & Woltering and that will be used in the Radiobiology Department of the “I. Kiricuta” Cancer Institute Cluj-Napoca. This model allows quantification of the outgrowth of microvessels from a three-dimensional tissue fragment implanted in a fibrin-based matrix. Allowing the identification and quantification of both anatomic and functional characteristics of individual tumors, this new three-dimensional human tumor angiogenesis in vitro assay seems to be an ideal system to be used in angiogenesis research. It also offers the possibility to test an individual tumor against different antiangiogenic and therapeutic agents. For the first time in Cluj-Napoca, we will evaluate the angiogenic pattern of individual tumors using human tumor tissue from biopsies.

Key words: Angiogenesis, In vitro models,Tumor.

Radioterapie & Oncologie Medicală, 2007, 1:81-85

86 ASTRO 48, Philadelphia , November 2006

N.Ghilezan

88 ESTRO Basic Clinical Radiobiology Course

Ioana Brie

97 CALENDAR OF IMPORTANT MEDICAL EVENTS 2007

Viorica Magdalena Nagy

99 GUIDELINES FOR THE AUTHORS

G. Kacsó