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Journal Issue: Vol.6, No.1 - January 2007

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Editorial

Editorial

Austral - Asian Journal of Cancer(AJC) from the modest of beginning has become a reputed international journal covering articles from well-known international authors. The editorial board is confident that in the coming years, AJC will serve as a platform for exhibiting and sharing of various interesting articles amongst the clinicians and scientists. In this edition we have included articles covering a wide range of topics from clinical and molecular aspects of cancer to chemotherapeutic trials. Neuroblastoma is one of the common solid childhood tumors. Genetic alteration play an important role in the development and progression of the diseases. The article 'The Enigmatic Role of p16CDKN2/INK4a in Neuroblastoma: An Enigma of Expressive Proportions', deals with the role of p16 and other cyclin dependent kinase inhibitors in the development of neuroblastoma. Liquid chromotography/mass spectometic assey is a novel test to assess various drug interactions for many anticancer agents. The article 'Analysis of Potential Drug - Drug Interactions for Anti-cancer Agents in Human Liver Microsomes by High Throughput Liquid Chromatography/ Mass Spectrometry Assay', deals with this specific and reproducible method to determine inhibition of multiple CYP enzymes in a single array. This technique is also a useful tool for screening anticancer compounds for clinically relevant drug interactions. Dermatofibroma (DF) and Dermatofibrosarcoma Protuberans (DFSP) are rare tumor of dermis. The differential diagnosis in most of the cases are straight forward by routine H/E sections. In doubtful cases immunohistochemistry is also useful. In the article 'Dermatofibrosarcoma Protuberans and Dermatofibroma: Dermal Dendrocytomas: An Ultra-structural Study', the authors have analyzed the ultra-structural characteristics of Dermatofibrosarcoma Protuberans and Dermatofibroma has come out with valuable information to differentiate both. Uterine Leiomyomas are benign tumors of the uterus. Often patients are asymptomatic. In spite of this, the uterine leiomyomas can cause significant morbidity. In the article 'Uterine Leiomyoma: Updates in Cytogenetics and Molecular Analysis', the authors have analyzed the cytogenetics and molecular aspects of uterine leiomyoma in detail. Non-dysgerminomatous ovarian tumors are relatively rare tumors seen in adolescents and young women. Conservative surgery is the standard treatment for most of the patients. In the article 'Non-dysgerminomatous Ovarian Tumors: Clinical Characteristics, Treatment and Outcome', the authors have done a retrospective analysis of clinical characteristics, treatment outcome and prognostic factors of non- dysgerminomatous ovarian tumors from their institution. Metastatic colorectal carcinoma carries a poor prognosis. However, recent advancements in chemotherapeutic drugs have improved the median survival of these patients. Many newer chemotherapeutic drugs have shown to improve the survival in these patients. In the article 'Comparison of 5-Flourouracil and Leucovorin, Versus 5-Flourouracil, Leucovorin and Oxaliplatin, in Metastatic Colorectal Malignancy', the authors have compared 5-Flourouracil and Leucovorin, Versus 5- Flourouracil, Leucovorin and Oxaliplatin, in metastatic colorectal cancer and has concluded that addition of oxaliplatin improves the overall survival as well as response rate of metastatic colorectal carcinoma. Inflammatory bowel disease carries a significant morbidity. Many a times, correct diagnosis is difficult. In the article 'Twin Studies in Inflammatory Bowel Disease. A Review', the authors have analyzed in depth, the pathogenesis of IBD and has concluded that genetic and environmental factors should also be evaluated in the aetiology of inflammatory bowel diseases (IBD). We hope all of you will like the vast range of contents in this issue. Readers comments and suggestions for further improvements are always welcome. We take this opportunity to wish all our readers a prosperous and happy New Year. Editors.


Profile

Profile: Dr. Silvia Regina Rogatto

Dr Silvia Regina Rogatto Dr. Silvia Regina Rogatto, M.Sc, Ph.D an expert in the field of human genetics and cancer research is currently Associate Professor in the Department of Urology, Director of the NeoGenae Laboratory, Research Center, Experimental Laboratories of the Faculty of Medicine, Sao Paulo State University, UNESP, Botucatu, and Coordinator of the NeoGene: a multidisciplinary group for human neoplasia research, National Directory of Research Groups, The National Council for Scientific and Technological Development (CNPq)/ Ministry of Science and Technology (MCT), Brazil. Dr. Rogatto graduated in Biology in 1982 at the University of Sao Paulo, USP, Ribeiro Preto, where she also obtained her master in 1986 and doctoral in 1990. In 1998, she began her one-year post-doctoral training in the Princess Margaret hospital, Ontario Cancer Institute, University of Toronto, Canada, after having undertaken a fellowship from The State of Sao Paulo Research Foundation (FAPESP). Dr. Rogatto is an active member of the Brazilian Society of Genetics, in which she served as President of the Sao Paulo State Branch from 1994 to1996 and as member of the National Board from 2000 to 2002. She has participated in the organization and as guest speaker in several scientific and /or technological meetings. In addition to her research and academic responsibilities, Dr. Rogatto currently serves as member of the Advisory Committee of the Sao Paulo State Oncocenter Foundation (FOSP), of the Foundation for the Development of the Sao Paulo State University (FUNDUNESP), of the Scientific Advisory Committee for Health Sciences of The State of Sao Paulo Research Foundation (FAPESP) and of the post-graduation program in genetics as a Coordinator 2000-2003), Bio-sciences Institute, Sao Paulo State University, UNESP. Furthermore, she has contributed as reviewer for national granting agencies, external reviewer for several peer-reviewed publications and as member of editorial board of the Oral Diseases and the Applied Cancer Research. Dr. Rogatto received several national research awards and honors. She was a visiting professor in the M.D. Anderson Cancer Center, Department of Cell Biology, Houston, Texas, USA in 1989 at the Instituto de Investigaciones Biomedicas, SIC, Madrid, Spain (1992), in the University of Manitoba, Winnepeg, Manitoba, Canada (2004), and in Ontario Cancer Institute, Princess Margaret Hospital, Department of Laboratory Medicine and Patho-biology, University of Toronto, Canada in 2000, 2001 and 2004. Dr. Rogatto has devoted her professional career to the undergraduate teaching of human and medical genetics and to the training students at post-graduating levels in the Department of General Biology, State University of Londrina, UEL, Londrina, PR from 1987 to 1993, in the Department of Genetics, Biosciences Institute from 1994 to 2002 and actually in the Department of Urology, Faculty of Medicine, Sao Paulo State University, UNESP. She maintains active national and international collaborations practices and a close and rewarding relationship with colleagues and former students. Dr. Rogatto's research interests include classical and molecular cytogenetics and molecular biology of benign and malignant human solid tumors, especially breast fibroadenomas, uterine leiomyomas and carcinomas of the prostate, breast, and the head and neck. Dr. Rogatto and her husband Flavio have been married since 19 years. They have two nice daughters, Lidia and Alice.


Manuscript

p16(CDKN2/INK4a) in Neuroblastoma:An Enigma of Expressive Proportions

Dr Mitchell B Diccianni

  1. Dr Mitchell B Diccianni
    PhD
    University of California at San Diego, Department of Pediatric Hematology/Oncology

Neuroblastoma is one of most common solid tumors of young children and has a wide spectrum of clinical and biological features. Most patients with localized disease (stage 1 and 2) and stage 4s survive the disease while patients with advanced disease (stage 3 and 4) have a poor prognosis. A number of molecular alterations have been associated with a poor prognosis in neuroblastoma, including amplification of N-myc proto-oncogene and deletion of a portion of the short arm of chromosome 1. Though the exact mechanism by which these alterations influence outcome remains elusive, they are known to act through cell cycle deregulation. Cyclin dependent kinase inhibitors such as p16, p18 and p27 also regulate the cell cycle. Deletions, mutations, promoter hypermethylation or translational inactivation of these genes being very common in most cancers, with p16 appearing to be almost universally inactivated in many cancer types. However, neuroblastoma is a notable exception. In contrast to inactivation, the p16 gene is paradoxically highly expressed in many advanced neuroblastoma and associated with a poor outcome. In this review, I will offer an overview of the status of the CDKI p16 in neuroblastoma, and offer some insights into the role p16 and two other CDKIs, p18 and p27, may play in this disease.


Analysis of Potential Drug-Drug Interactions for Anti-cancer Agents in Human Liver Microsomes by High Throughput Liquid Chromatography/ Mass Spectrometry Assay

Dr Florence Raynaud, Dr J Moreno-Farre, Dr P Workman

  1. Dr Florence Raynaud
    The Institute of Cancer Research, Cancer Research UK Centre Therapeutics, Haddow Laboratory
  2. Dr J Moreno-Farre
    The Institute of Cancer Research, Cancer Research UK Centre Therapeutics, Haddow Laboratory
  3. Dr P Workman
    The Institute of Cancer Research, Cancer Research UK Centre Therapeutics, Haddow Laboratory

We have developed and validated a method for the high throughput inhibition screening of the major human cytochromes P450 (CYP) using an invitro substrate cocktail and liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis. A mixture of probe substrates comprising phenacetin (CYP1A2), coumarin (CYP2A6), tolbutamide (CYP2C9), amitriptyline (CYP2C19), chlorzoxazone (CYP2E1), bufuralol (CYP2D6) and midazolam (CYP3A4) was incubated with pooled human liver microsomes and measured by LC/MS/MS in a single incubation mixture. The assay was specific and reproducible with measured enzymatic parameters (Km and Vmax) for each substrate showing values similar to those reported in the literature. The IC50 values of each inhibitor in the cocktail were determined and agreed well with values previously reported in the literature. This assay was used to evaluate the drug-drug interaction potential of currently used anticancer drugs. Potent and specific inhibition of CYP2D6 enzyme was detected with 50μM vinblastine, whilst little or moderate inhibition of the metabolism of the specific probe substrates was found with other anticancer compounds tested. 17- Allylamino-17-demethoxygeldanamycin (17-AAG), a novel HSP90 inhibitor, showed significant inhibition of CYP2C9, CYP2C19 and CYP2D6 at 50μM. However, the inhibition constant (Ki) for 17-AAG was >10μM, suggesting that these interactions are unlikely to have any clinical relevance. The validated method described here offers an efficient, robust way to determine the CYP inhibition profile of large number of compounds and is now used to support our drug discovery process.


Dermatofibrosarcoma Protuberans and Dermatofibroma: Dermal Dendrocytomas: An Ultra-structural Study

Dr Hugo Dominguez-Malagon, Dr Ana Maria Cano-Valdez

  1. Dr Hugo Dominguez-Malagon
    MD
    Department of Pathology, Instituto Nacional de Cancerologia
  2. Dr Ana Maria Cano-Valdez
    MD
    Department of Pathology, Instituto Nacional de Cancerologia

Dermatofibroma (DF) and Dermatofibrosarcoma Protuberans (DFSP) are dermal tumors whose histogenesis has not been well defined to date. The differential diagnosis in most cases is established in routine H/E sections and may be confirmed by immunohistochemistry; however there are atypical variants of DF with less clear histological differences and non-conclusive immunohistochemical results. In such cases electron microscopy studies may be useful to establish the diagnosis. In the present paper the ultra-structural characteristics of 38 cases of DFSP and 10 cases of DF are described in detail, the objective was to identify some features potentially useful for differential diagnosis, and to identify the possible histogenesis of both neoplasms. DFSP in all cases was formed by stellate or spindled cells with long, slender, ramified cell processes joined by primitive junctions, sub-plasmalemmal densities were frequently seen in the processes. Other common finding was the presence of Multi-vesicular Buds (MVB). In contrast, DF is characterized by proliferation of capillary vessels with prominent endothelium and a perivascular population of plump spindled cells devoid of cell processes, these cells contained intra-cytoplasmic lipid droplets and rare sub-plasmalemmal densities but lacked MVB. With the ultra-structural characteristics and the constant expression of CD34 in DFSP, a probable origin in dermal dendrocytes is postulated. The histogenesis of DF remains obscure.


Uterine Leiomyoma: Updates in Cytogeneticsand Molecular Analysis

Dr Silvia Regina Rogatto, Dr Renata de Azevedo Canevari

  1. Dr Silvia Regina Rogatto
    PhD
    NeoGene Laboratory, Department of Urology, Faculty of Medicine - UNESP, 18618-000, Botucatu
  2. Dr Renata de Azevedo Canevari
    NeoGene Laboratory, Department of Urology, Faculty of Medicine - UNESP, 18618-000, Botucatu

Uterine leiomyomas are benign tumors of the uterus that arise from the smooth muscle cells of the myometrium, considered the most common neoplasms of the female genital tract. They also are often referred as myomas, uterine fibroids, fibromas or fibromyomas because of their firm, fibrous character and frequently high content of collagen fibers.


Non-dysgerminomatous Ovarian Tumors: Clinical Characteristics, Treatment and Outcome

Dr Fatemeh Ghaemmaghami, Malihe Hasanzadeh, Azadeh Fallahi

  1. Dr Fatemeh Ghaemmaghami
    MD
    Gynaecology Oncology Department, Vali-e-Asr Hospital, Imam Khomeini Hospital Complex
  2. Malihe Hasanzadeh
  3. Azadeh Fallahi

Objective: Assessment response patients with non-dysgerminomatous ovarian germ cell tumors (NDOGCT) to chemotherapy platinum-based and to determine possible prognostic factors for relapse. Methods: We retrospectively reviewed 21 patients who had surgical resection of non-dysgerminomatous ovarian germ cell tumors (NDOGCT) and received adjuvant chemotherapy in Vali-e-Asr Hospital, Tehran, Iran during 1997-2004. The median age at presentation was 18 years with median follow up of 20 months. Results: Histologic records showed that patients had the following types of tumors: immature teratoma (n=7), mixed germ cell tumor (n=7), yolk sac tumors (n=4), and embryonal carcinoma tumors (n=3). Distribution by stage at the time of surgery was as follows; stage I (n=10), stage III (n=6), and stage IV (n=5). Initial surgery included unilateral salpingo-ophorectomy in 16 patients and cystectomy in 5 other patients. After the initial surgery, 13 patients immediately received chemotherapy and the other 8 patients received chemotherapy at a median of 5.5 months (range, 1-40 months). Post operative chemotherapy included the following: bleomycin, etoposide, and cisplatin (n=17); vincristine, actinomycin-D, and cyclophosphamide (n=2); methotrexate, etoposide, and cisplatin (n=l); and cisplatin (n=l). 31% of the patients suffered a relapse after cisplatin combination chemotherapy. The median disease free survival was 40 months and the median overall survival was 50 months. The 5 year survival rate was 39%. Conclusion: This study showed that residual disease and the interval from initial diagnosis to the start of chemotherapy were possible prognostic factors for relapse. Also our study indicates that there may be a role for aggressive cytoreductive surgery in advance NDOGCT, and need to look for feasible second-line combination chemotherapy.


Comparison of 5-Flourouracil and Leucovorin, Versus 5-Flourouracil, Leucovorin and Oxaliplatin in Metastatic Colorectal Malignancy

Dr Vinay Vyas, Shriram V Nath, Kirti M Patel, Pankaj M Shah, Shilin N Shukla, Bharat J Parikh, Asha S Anand, Shailesh S Talati, Sandip A Shah, Bhavesh Parekh, Harsha P Panchal, Apurva A Patel, Sanjay Thuruthal, Parthiv Mehta

  1. Dr Vinay Vyas
    Senior Registrar, Department of Medical Oncology, Kuwait Cancer Control Centre
  2. Shriram V Nath
  3. Kirti M Patel
  4. Pankaj M Shah
  5. Shilin N Shukla
  6. Bharat J Parikh
  7. Asha S Anand
  8. Shailesh S Talati
  9. Sandip A Shah
  10. Bhavesh Parekh
  11. Harsha P Panchal
  12. Apurva A Patel
  13. Sanjay Thuruthal
  14. Parthiv Mehta

Subjects: From March 1999 to September 2000, 32 patients were enrolled, 15 in the arm A containing 5-flourouracil & leucovorin & 17 in the arm B containing 5-FU, LCV and oxaliplatin. Results: No complete response was observed in either of the arms. Partial response was seen in 27% in arm A & 33.3% in arm B. The median duration of progression free period in partial responders in arm A is 90 days & in arm B is 150 days. In arm A median overall survival was 8 months & in arm B it is 10 months, the difference however is not statistically significant as observed by log rank test (p=0.2342). Conclusion: in the present study, the addition of oxaliplatin to standard Mayo regimen of 5-FU and LCV increases the response rate, median progression free survival & overall survival.


Twin Studies in Inflammatory Bowel Disease: A Review

Dr G Jarnerot, J Halfvarson

  1. Dr G Jarnerot
    Division of Gastroenterology, Dept of Medicine, Orebro University Hospital
  2. J Halfvarson

The cause of the inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease (CD) is still unknown. Clinically, it is generally accepted that UC and CD are two distinct diseases, although it is sometimes difficult to separate the two diagnosis and in such cases the term indeterminate colitis is often used. However, a strong association exists between UC and CD. Relatives to patients with CD have an increased risk of UC and vice versa. Geographic areas with a high incidence of one of the diseases usually have a high incidence of the other.


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