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Volum 12 Numarul 1, 2006

3 Editorial

This first issue for 2006 of our Journal, heralds an updated series of those diagnostic and therapeutic guidelines that have been published several years ago. This initiative of the National Cancer Commission on behalf of the Ministry of Health is supported by the Physicians’ College of Romania and the Society of Radiotherapy & Oncology, as well. The first two guides to be published are for breast and cervix cancers and they are to be followed by those for colon & rectum, lung, endometrium and testicular cancers. They are the result of a joint effort performed by specialists from the Bucharest and Cluj Cancer Institutes. Any suggestion from your part is welcome and should be sent on the RSRO address.

The first paper in the Review section, signed by Iulia Diaconu et al, deals with the basic principles of immunohistochemistry, a method that has revolutionized the field of pathology and implicitly that of oncology. The possibilities of IHC testing at the Cancer Institute “Ion Kiricuta” are presented and exemplified by a few diagnostic algorithms. The main advantages of this new tool is more precision in establishing the histological origin of tumors, the visualization of some histological prognostic factors (Bcl 2, Ki 67, p53, Her2/neu) and some infectious agents (HPV, CMV) or identification of molecular targets (hormonal receptors, c-erbB-2, c-Kit, CD 20, etc), all of which a real must today for a correct diagnosis. The problem of diagnosis and treatment is approached also by Alexandru Irimie et al, for thyroid carcinomas, based on the analysis of the cases registered in Cancer Institute Cluj, into a period of 30 years.

An original study is presented by Ovidiu Vereşezan, who tries to establish the predictive value of Comet and Micronuclei assays, for the severe radioinduced complications risk. These tests are simple, quick to perform and non-expensive methods, well suited for the study of the cellular radiosensitivity. Irinel Popescu et al. publish some preliminary data of a more complex genomic project which is actually running at Clinical Institute Fundeni, a real premiere for Romania. The database of the study includes various clinical and therapeutic aspects that are correlated with the determination of the molecular profile of pancreatic cancer. This first published report deals with the surgical experience of the group led by professor I. Popescu and is illustrative for the multitude of the problems related to the therapeutic approach of the pancreatic cancer. It is worth to underline the necessity to work together the organ specialist and different oncologists (medical, radiotherapy, molecular biologist, etc.). Another surgical group, led by Mircea Cazacu from the IVth Surgical Clinic in Cluj, presents their experience with a natural extract from Viscum Album, as immunostimulant for the postoperative colorectal cancer: they claim a positive influence with a possible decrease of complications and improved survival. Patriciu Achimas Cadariu et al., again a surgical group, is addressing a biological problem, by evaluating the prognostic significance of angiogenesis, in ovarian cancer but in the experience of the Cancer Institute Cluj, the results did not proved to be superior to the already known clinical and morphological prognostic cancer.

The excellent results of high-dose methotrexate in childhood nonHodgkin’s lymphomas is discussed by Rodica Cosnarovici et al. who reports an increased rate of complete remissions and overall survival. Another clinical paper, by Doina Piciu et al., analyzes in a retrospective study, the diagnostic and treatment methods in parathyroid tumors as it was done in the center from Cluj. The clinical section is closing with the presentation of a rare case of severe neuropathy due to a small dose of vincristine in a patient with Hodgkin disease, signed by VasileŢibre.

The content of this issue is varied with many different and valuable experiences but a common trait is a growing interest from the part of the clinicians for the integration of the recent advances in biology, in the clinical practice. These are good prognostic & predictive signs for the future of Romanian oncology but in the same time, there are a lot of others problems that should be tackled if we want to improve our journal and our professionalism, that are discussed by Maria Retegan-Turdean.

As final remark, we have the pleasure to make the first announcement and call for papers form the part of the acting president of our Society, Rodica Anghel, for the 16th SRRO Congress that will take place on the 13th-15th October in Bucharest. The main themes of the congress are the gastrointestinal cancers and the present status of the oncological research in Romania. We would like to be joined in this important event by all the professional societies that are interested in cancer care and research and this is a formal invitation for them. We expect to have many participants, an interesting scientific program, many collegial disputes and finally a very pleasant and rewarding experience.

Viorica Magdalena Nagy

5 SRRO’s Journal ………. S.O.S.!

Maria Retegan Turdean

7 Cervical Cancer: Diagnostic and Treatment Guideline

16 Breast Cancer: Diagnostic and Treatment Guideline

27 Theoretical and Practical Concepts of Immunohistochemistry

Iulia Diaconu1, Liliana Resiga1, N. Ghilezan2, C.D.Olinici3

„Prof. I. Kiricuta” Cancer Institute: 1Dept. of Pathology, 2Dept. of Radiotherapy;

3„Iuliu Haţieganu” U.M.Ph. Cluj-Napoca, Dept. of Pathology

Immunohistochemistry (IHC) is the application in histology of immunologic principles. There is probably no other method that has so revolutionized the field during the past 50 years as the immunohistochemical technique. To fully exploit this technique, the pathologists must not only be acquainted with the distribution of various antigens in different tumors and tissues but also have sufficient knowledge of the methodology to avoid pitfalls in interpretation. The standard immunostaining use Krenacs-Miller-Rhodes score. The algorithm illustrates how IHC may provide supplementary information to enhance the haematoxylin and eosin impression of a tumor. The following article summarizes the usually theoretical and practical principles of IHC.

Key words: IHC, Antigen, Antibody, Standard.

Radioterapie & Oncologie Medicală, 2006, 1:27-32

33 Diagnostic and Treatment Algorithms in MedullaryThyroid Carcinoma

Al. Irimie1,2, C. Lisencu2, Doina Piciu2,3, P. Achimaş-Cadariu1,2

1„Iuliu Haþieganu“ U.M.Ph. Cluj-Napoca, Dept. of Surgical Oncology;
Cancer Institute „Prof. I. Kiricuta“ Cluj-Napoca: 2Surgical Dept., 3Dept. of Nuclear Medicine

Medullary thyroid carcinoma occurs in familial form in 25-30% of cases and requires rigorous familial screening for its detection in subclinical stages. The impossibility of performing routine screening, with clinical examination doubled by imaging investigations and cytogenetic study, justifies the need for improving patient diagnosis, treatment and follow-up. The present study (1648 patients) aimed to create a diagnostic and therapeutic algorithm for familial medullary thyroid carcinoma that allowed the early detection of the disease. The efficiency of the therapy was evaluated regularly every 3 and 6 months, as well as annually; the follow-up interval ranged from one to 18 years. The tenedency to level diagnostic and therapeutic attitudes, which exists in all neoplastic localizations, also led to the creation and implementation of certain protocols – „guidelines” that allowed a selective, potentially flawless approach to medullary thyroid carcinoma.

Key words: Medullary thyroid carcinoma, Diagnostic algorithm, Therapeutic algorithm.

Radioterapie & Oncologie Medicală, 2006, 1:33-38

39 In vitro Evaluation of Radiation-induced DNA Damage Using Comet Assay and Micronucleus Assay

  1. Vereşezan, Ioana Brie, Maria Perde, Piroska Virag, Eva Fischer-Fodor

Cancer Institute „Prof. Dr. I. Chiricuţă”, Cluj-Napoca, Tumoral Biology Dept.

Introduction: Since normal tissues reactions are limiting for radiotherapy, much effort has been devoted to establish predictive tests that can detect patients at risk for severe complications. Material and Method: Lymphocytes from 12 healthy volunteer donors and 15 patients with cervix carcinoma, respectively tumor cells from 18 patients with cervix carcinoma were gamma-irradiated with 2 and 4 Gy in vitro and analyzed using the alkaline comet assay. Lymphocytes from 13 healthy volunteer donors and 16 patients with cervix carcinoma were also in vitro gamma-irradiated and analyzed using the Micronucleus Assay. Results: Three biological parameters were evaluated: the background level, the magnitude of induction by irradiation and the repair of the radio induced lesions. Conclusions: DNA damage assays like Comet Assay and Micronucleus Assay are moderns, simples, quick and non-expensive methods for the study of cellular radio sensitivity.

Key words: Comet assay, Micronucleus assay, Lymphocytes, Cellular radio sensitivity.

Radioterapie & Oncologie Medicală, 2006, 1:39-42

43 Prognossis Factors in Pancreatic Cancer. Preliminary Analysis on 34 Patients

  1. Popescu1, C. Stroescu1, V. Herlea2, A. Dragnea1, Olivia Sgarbură3, M. Ionescu1

Fundeni Clinical Institute: 1General Surgery & Liver Transplant Center, 2Dept. of Pathology; 3„Carol Davila“ UMPh Bucureşti, Dept. of Medical Psychology

Pancreatic cancer has a poor prognosis and represents the third cause of mortality among digestive malignances. This study is a prospective non-randomized analysis, of a group of 34 pancreatic resections for ductal adenocarcinoma. The patients were enrolled in a genomic study as result of a public-private partnership between IC Fundeni and Rntech, from March 2003 till October 2005. We performed an analysis of various clinical aspects: location and diameter of the tumor, staging, grading, lymph nodes metastases, the type of therapy (surgical and adjuvant), the morbidity after surgery and the long term survival. The distribution of tumors: 28 cephalic, 4 in the body and tail, and 2 cases with entire pancreas involvement. The global resectability was 24,7%. The postoperative morbidity was recorded for19 patients (56%) with 21% rate of pancreatic leakage. No postoperative mortality was registered for this group. The mean overall survival was 8 months with 11 months for cephalic pancreatic neoplasm and 6 months in the body and tail localization. The following parameters emerge as independent prognostic factors in this study: the diameter and the stage of the tumor, lymph nodes metastases, the elevated levels of serum CA 19-9, the localization in the tail or in the body of the pancreas. The results of genomic investigation will be analyzed in a future study.

Key words: Pancreatic ductal adenocarcinoma, Pancreatic resection, Prognostic factors, Survival.

Radioterapie & Oncologie Medicală, 2006, 1:43-53

54 Inflammatory Reaction in Colo-Rectal Cancer Patients TreatedWith Viscum Album Total Extract

  1. Cazacu1, I. Domşa1, Carmen Stugren2, T. Oniu1, F. Mureşan1

1“Iuliu Haþieganu” U.M.Ph. Cluj-Napoca, IVth Surgical Clinic; 2Cancer Institute “Prof. I. Kiricuta” Cluj-Napoca

Background: Based until recently on empirical observation, the therapy with Viscum Album extracts is becoming today more and more evidence based. The purpose of this study is to assess some of the cellular and molecular mechanisms of action of the mistletoe extracts which are believed to concur to the better outcome of the surgical cancer patients. Methods: Two groups of patients undergoing surgery for colo-rectal cancer, one with and one without preoperative intravenous immunotherapy with mistletoe extract, were compared regarding the peritumoral inflammatory infiltrate, the tumoral limphocytic infiltrate and the circulating TNF-alpha. Results: The level of circulating TNF-alpha increased significantly due to immunotherapy, and remained significantly higher compared to the levels of controls in the postoperative period. While the peritumoral inflammatory infiltrate was not significantly different between the two groups, the tumoral lymphocytic infiltrate showed a trend towards a significantly higher density in mistletoe treated patients. Meanwhile, the patients receiving immunotherapy had a better postoperative outcome. Conclusions: The significant increase of the serum TNF-a and the higher infiltration of the tumor with lymphocytes could explain the beneficial effect of mistletoe extracts on the outcome of colorectal cancer patients.

Key words: Colo-rectal carcinoma, Viscum album, TNF alfa.

Radioterapie & Oncologie Medicală, 2006, 1:54-58

59 Angiogenic Biological Prognostic Factors in Ovarian Cancer

  1. Achimaş Cadariu1,2, L. Lazăr1,2, Al. Irimie1,2, Ioana Neagoe3, R. Buigă4

1U.M.Ph. “Iuliu Hatieganu” Cluj-Napoca, Dept. of Surgical Oncology; Cancer Institute Prof. I. Kiricuta” Cluj-Napoca: 2Department of Surgery, 3Department of Tumoral Biology, 4Department of Pathology

It is well known that some biological effects specific to ovarian steroids are mediated by the action of polypeptidic growth factors, some of which are angiogenic factors. PDECGF (Platlet-Derived Endothelyal Cell Growth Factor/ Thymidine Phosphorylase) is produced by the endothelial cells and by ovarian cancer cells too. Its increased expression can be associated with areas of high blood velocity in ovarian malignant tumors. The expression of this factor is higher in ovarian malignant tumors than in benign tumors or normal cells. Immunohistochemical staining of the microvascularization with CD34 antibodies allows the classification of angiogenesis into three stages according to the expected number of micro vessels present in the most vascularized tumoral area. The main objective of the study is to evaluate the association between ovarian cancer and certain biological factors, which have been proven to play a more or less important part in various forms of neoplasia. The angiogenic biological factors studied, combined with other clinical and morphological factors can predict tumoral stages and tumor grading as well as the disease-free period and global survival rates but they cannot be regarded as individual prognostic factors for any of these components of the tumoral evolution.

Key words: Ovarian cancer, Angiogenesis, Prognostic factors.

Radioterapie & Oncologie Medicală, 2006, 1:59-64

65 Therapeutic Results in Non-Hodgkin’s Lymphomas of Childhood,Advan tages and Difficulties of the High-dose Methotrexate Therapy

Rodica Cosnarovici1, Ştefania Neamţu1, Emilia Mihuţ1, N.Todor4, Dana Cernea2,
Doina Daicoviciu3, Luciana Neamţiu4, Corina Tatomir3, Gabriela Cherecheş3

Cancer Institute „Prof. I. Kiricuta” Cluj- Napoca, România; 1Dept. of Pediatric Oncology; 2Dept. of Radiotherapy; 3Dept. of Biochemistry; 4Dept. of Medical Informatics

Purpose: To evaluate the results in childhood nonHodgkin’s lymphomas. We have take into consideration the difficulties in managing the therapy with aggressive protocols, including high dose methotrexate (HDMTX), for its safe administration. Patients-method: We have studied 64 patients, treated between 1999 and 2003, with the CHOP protocol ( 24 pts ), BFM 83 protocol ( 16 pts) and BFM 95 protocol( 24 pts ). We compared the results obtained with the clasical protocols (CHOP and BFM 83) with thoses obtained with the aggressive protocols (BFM 95). The complete remission rate, the central nervous system metastasies and the overall survival were significantly in the advantage of the BFM 95 protocol. A total of 101 infusions of HDMTX were performed. Major side effects were bone marrow suppression, mucositis, infections , gastrointestinal symptoms and higher liver enzymes. All the symptoms were transient. The severe toxicity (degree 3 and 4) was correlated with the delayed elimination of the drug. We registered no therapy related deaths. Conclusions: The therapeutic results were improved after considering in the therapy of nonHodgkin’s lymphomas the HDMTX. Mild and severe toxicity was found, but, however, the HDMTX therapy could be delivered safety, with accurate salvage therapy and efficient supportive care.

Key words: Child, NonHodgkin’s lymphomas, Methotrexate.

Radioterapie & Oncologie Medicală, 2006, 1:65-69

70 Diagnosis and Treatment of Parathyroid  TumorsExperience of Cancer Institute „Prof.I. Kiricuta“ Cluj-Napoca, Romania

Doina Piciu1, Al. Irimie2,4, Adela Bara1, Mihaela Galatâr3, Liliana Resiga3,
Cristina Goia-Moisescu1, C. Peştean1, R. Piciu5, Geta Covaci5

Cancer Institute „Prof. I. Kiricuta“ Cluj-Napoca: 1Dept. of Nuclear Medicine, 2Dept. of Surcical Oncology, 3Dept. of
4„Iuliu Haþieganu“ U.M.Ph. Cluj-Napoca; 5Synevo Laboratory Cluj-Napoca

Aim of the study: The aim of our study was to review the database of parathyroid tumors and to analyze the results of the diagnosis methods and treatments performed in the Cancer Institute “Prof.I. Kiricuta“ Cluj-Napoca. Patients and methods: We included all patients with parathyroid adenoma and carcinoma seen at our Institute, since January 1, 1970 till 2004. Diagnostic procedures were different according the moment of the diseases: clinic evaluation, serum determination of parathyroid hormone, ultrasound, computer tomography etc. Results: In these 35 years, 12 patients were registered with parathyroid tumors and a minimum follow-up of 2 years. The age at initial diagnosis (mean +/- SD) was 46.7 +/- 15.3 years. Three patients presented parathyroid carcinoma (25%). Nine patients (75%) had parathyroid adenoma, treated by complete surgical remove. One of them had relapse after 8 years. Conclusions: Parathyroid adenoma needs appropriate surgery for treatment.Parathyroid carcinoma can be an indolent disease with morbidity and mortality related to hypercalcemia. Adjuvant radiotherapy may improve local control and limit the occurrence of local relapse. Acomprehensive multidisciplinary approach with surgery, radiation therapy, and medical treatment for hypercalcemia is needed to optimize patient outcome.

Key words: Parathyroid tumors, Diagnosis, Treatment, Follow-up.

Radioterapie & Oncologie Medicală, 2006, 1:70-76

77 Severe Vincristine Neuropathy after Small Doses of Vincristine in a Patient with Hodgkin’s Lymphoma

Case Report and Review of the Literature

  1. Ţibre1, Petronela Rusu2, Carmen Cobzariu2

1„Iuliu Haþieganu“ U.M.Ph., „Ion Minea” Clinic for Neurology Cluj-Napoca; 2Cancer Institute „Prof. I. Kiricuta“ Cluj-Napoca, Dept. of Radiotherapy

In these study we present a case of severe neuropathy resembling Charcot Marie Tooth disease in a 29 year old male with Hodgkin lymphoma (HL), receiving small doses of Vincristine (4 mg, EBDV regimen), without any neurological complaint before. Severe vincristine neuropathy is difficult to predict in oncological patients without any neurological screening before. In literature there are also described association between Hodgkin lymphoma and Guillain Barre syndrome. It is also well known described asimptomatic hereditary motor sensory neuropathy (Charcot Marie Tooth disease) revealed by vincristine therapy in a patients with negative family history for inherited neuropathy.

Key words: VCR, Charcot Marie Tooth, Hodgkin Lymphoma, Neuropathy, Neurotoxicity.

Radioterapie & Oncologie Medicală, 2006, 1:77-81