Treatment for Hematological Malignancy - Research Proposal Example

Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome. Marco Ladetto, Sonia Vallet, Andreas Trojan, Maria Dell'Aquila, Luigia Monitillo, Rosalba Rosato, Loredana Santo, Daniela Drandi, Alessandra Bertola, Patrizia Falco, Federica Cavallo, Irene Ricca, Federica De Marco, Barbara Mantoan, Beata Bode-Lesniewska, Gloria Pagliano, Roberto Francese, Alberto Rocci, Monica Astolfi, Mara Compagno, Sara Mariani, Laura Godio, Lydia Marino, Marina Ruggeri, Paola Omed, Antonio Palumbo, and Mario Bocc Blood, 15 June 2005, Vol. 105, No. 12, pp. 4784-4791. Prepublished online as a Blood First Edition Paper on February 24, 2005; DOI 10.1182/blood-2004-11-4201. Summary Prostaglandins are an important member of the group of mediators involved in inflammatory processes and angiogenesis. Due to the latter characteristic, they have been found to play role in not only in the initiation but also in the progression of a variety of solid tumors. One of the key enzymes of the pathways resulting in the production of prostaglandins is Cyclooxygenase-2 (COX-2) specifically in the tissue, which is being insulted, and either on the way to transform to or has been transformed to a malignant tissue. Among these cancers, some common ones are: lung, head and neck, ovarian, uterine cervix, colorectum, and breast. Even in the presence of high level of convincing data supporting the role of COX-2 in the progression of cancer, no definitive evidence is available which provides any clue to the relationship between COX-2 and haematological cancers. Myeloma (MM) is very well described as the deregulation of the cytokine network accompanied by secretion of inflammatory cytokines. A study was carried out to look for the COX-2 deregulation in the pathogenesis of MM. For this purpose, a sample of 142 specimen form 132 patients with plasma cell dyscrasias were taken and further tested for the expression of the proteins by Western Blot (WB) method. These patients were at different stages of the diseases as far as the advancement or severity was concerned. These specimen samples were taken after the informed consent from the patients were obtained. Clinical features of all the patients were documented. Apart from WB, real time Polymerase Chain Reaction (PCR) were also carried out for some specimen. Along with these, COX-2 immunochemistry as well as separation of plasma cells was also performed. For statistical inferences, descriptive, univariate and multivariate analyses were done by using Cox model. Apart from the validation and assessment of MM samples and correlation between COX-2 expression and clinical parameters, the prognostic value of COX-2 expression in MM was also determined. It was found that median overall survival (OS) follow up for the study participants was 48 months and the relationship between COX-2 positive and negative was (28 months vs 52 months) and it was significantly different. While Progression Free survival (PFS) was estimated as 18 months for positive and 36 months for negative patients and it was also significantly different. COX-2 was found to be related to MM as a prognostic factor and it opened the venue for treatment options for MM as well as for more research work in the same and related areas to further explore any other associations. Significant contribution of the study The research work presented in this article is the first scientific report on the relationship between Cyclooxygenase-2 (COX-2) and Multiple Myeloma (MM). This is indeed an important finding, which adds to the available evidence on two facets: 1) apart from solid tumor, COX-2 has got a relationship with haematological malignancies especially with multiple myeloma where it showed statistically significant association with short progression free period in COX-2 positive patients as compared to COX-2 negative patients (18 vs 36 months; P < .001) and at the same time poor overall survival in COX-2 positive patients than in COX-2 negative patients (28 vs 52 months; P < .05); 2) multiple myeloma has got an additional explanation for the disease progression which will have a considerable impact on the treatment choice of the disease by focusing on this pathway. In this research study COX-2 has been shown to be an important prognostic factor in the disease process specifically related to plasma cell lineage. The presence of COX-2 in patients with plasma cell dyscrasias provides a hint for the course of the disease. At premalignant stage of monoclonal gammopathy of undetermined significance (MGUS) progressed to multiple myeloma and the COX-2 negative patients eveloved from mGUS to multiple myeloma developed COX-2 positive status afterwards. the patients with multiple myeloma in relapse phase and who were cOX-2 positive they also went to remission. Data convincing The authors have provided the description on the methodology and results in fairly impressive way. The selection of the patients, various types of patients, and their characteristics has been described in a simple way, which gives almost full understanding of the processes used. Various laboratory procedures and mechanisms, which helped in performing different tests as well as maintaining the quality, have been discussed comprehensively. The authors could provide descriptive statistics, univariate and multivariate analyses with discussion on the results and methodology of study. These all steps helped in keeping the quality of the data high. The case definitions for progression free survival 9pfS) and Overall Survival (OS) have been mentioned clearly. In addition to these impressive attributes of the study there have been some flaws, which may not strongly oppose the authenticity of the data but if these are tried to be avoided or minimized will be helpful in improving the validity of the study. These weaknesses are: samples from all the participants were not utilized for various laboratory tests; at the same time no legitimate reason was shared for using some specimen or excluding others even these reason were obvious. For survival analysis, a portion of the participants included and other participants were excluded. There is not detail how and why the specific group was included and the reasons for the exclusion criteria have not been shared. Track record of author in the area The first author of the study, Ladetto Marco, has been a very busy scientist in the area of cancers especially haematological cancers. The author has got more than six publications on the related topics in the peer-reviewed journals over the last tow years. Som eof the publications are provided here: Ladetto M, Magni M, Pagliano G, De Marco F, Drandi D, Ricca I, Astolfi M, Matteucci P, Guidetti A, Mantoan B, Bodoni CL, Zanni M, Boccadoro M, Gianni AM, Tarella C. Rituximab induces effective clearance of minimal residual disease in molecular relapses of mantle cell lymphoma. Biol Blood Marrow Transplant. 2006 Dec;12(12):1270-6. Ladetto M, Mantoan B, De Marco F, Drandi D, Aguzzi C, Astolfi M, Vallet S, Ricca I, Dell' Aquila M, Pagliano G, Monitillo L, Pollio B, Santo L, Cristiano C, Rocci A, Francese R, Bodoni CL, Borchiellini A, Schinco P, Boccadoro M, Tarella C. Cells carrying nonlymphoma-associated bcl-2/IgH rearrangements (NLABR) are phenotypically related to follicular lymphoma and can establish as long-term persisting clonal populations. Exp Hematol. 2006 Dec;34(12):1680-6. Ladetto M, Vallet S, Trojan A, Dell'Aquila M, Monitillo L, Rosato R, Santo L, Drandi D, Bertola A, Falco P, Cavallo F, Ricca I, De Marco F, Mantoan B, Bode-Lesniewska B, Pagliano G, Francese R, Rocci A, Astolfi M, Compagno M, Mariani S, Godio L, Marino L, Ruggeri M, Omede P, Palumbo A, Boccadoro M. Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome. Blood. 2005 Jun 15;105(12):4784-91. Epub 2005 Feb 24. Ladetto M, Compagno M, Ricca I, Pagano M, Rocci A, Astolfi M, Drandi D, di Celle PF, Dell'Aquila M, Mantoan B, Vallet S, Pagliano G, De Marco F, Francese R, Santo L, Cuttica A, Marinone C, Boccadoro M, Tarella C. Telomere length correlates with histopathogenesis according to the germinal center in mature B-cell lymphoproliferative disorders. Blood. 2004 Jun 15;103(12):4644-9. Epub 2004 Feb 26. Ladetto M, Mantoan B, Ricca I, Astolfi M, Drandi D, Compagno M, Vallet S, dell'Aquila M, Alfarano A, Rossatto P, Rocci A, Vitolo U, Corradini P, Boccadoro M, Tarella C. Recurrence of Bcl-2/IgH polymerase chain reaction positivity following a prolonged molecular remission can be unrelated to the original follicular lymphoma clone. Exp Hematol. 2003 Sep;31(9):784-8. Verification of data by other groups Prince et al carried out a study with an objective to assess the tolerability of the combination of thalidomide and celecoxib and the research findings were published as 'Multicenter Phase II Trial of Thalidomide and Celecoxib for Patients with Relapsed and Refractory Multiple Myeloma'. Through this study the authors wanted to explore the role of synergistic effect of the two drugs. To support their research work they referred to the information provided in the article 'Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome' by. Aggressive disease in Multiple Myeloma (MM) has significant association with oncogenic RAS expression. To further explore the area, a research study was carried out by Hoang et al to test a role for cox-2 in mutant RAS-containing MM cells. For the development of the proposal to carry out the said project Hoang and the colleagues utilized the evidence contained in the research article by Ladetto et al, entitled 'Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome'. This article by Hoang is entitled 'Oncogenic RAS mutations in myeloma cells selectively induce cox-2 expression, which participates in enhanced adhesion to fibronectin and chemoresistance'. Experiments needed in future As this study was carried out on the participants with different characteristics like: age, their clinical presentation, and the treatment strategies used for managing the disease, so the results may not support this relationship very strongly. Therefore, on the same line a large sample size study with random allocation should be repeated. The relationship found between COX-2 and MM suggests some relationship between COX-2 and haematological malignancies other than MM. So it would be a logical approach if a research work is carried out to look for this relationship. The only finding of association between COX-2 and MM may not be helpful in explaining the real role of COX-2 so that a therapeutic strategy developed; rather an independent study is needed to explore the role of specific and non-specific inhibitors. As the course of MM after it has been established is not hopeful so a couple of pharmacological agents are available which may target the causative factors and interfere with the progression of the disease. In the same regard, with the information of the association between COX-2 and MM, further drugs may be tested through clinical trials and at the same time a combination of various drugs can also be assessed to get the maximum benefits. Read More