Opitz, Isabelle

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T.C. Mineo et al. / European Journal of Cardio-thoracic Surgery 38 (2010) 245—253252Appendix A. Conference discussionDr T. Treasure (London, United Kingdom): There is a matter we need to beclear about, the difference between a prognostic feature and a predictivefeature. A feature may be prognostic in the sense of determining a differentialnatural history in the disease itself. Patients with good prognostic features willlive longer whether you operate on them or not. On the other hand, R0 versusR1 may be predictive of better outcome. I would make that distinction. So Iwould put it to you that interesting though the results are, and important inavoiding unavailing surgery in patients who are going to die quite soonwhatever you do, that you have done an analysis of prognostic factors, whichare prognostic irrespective of whether you operate or not. It isn’t that youshouldn’t use that information but you should be very clear in your own mindexactly what you have found. I admire the study, it’s very thorough, and themore we know about this disease, the better we’re going to be able to treat it.Dr Pompeo: Your comments are very important, and, of course, theyunderline the main limit of this study. I perfectly agree with yourconsiderations. Maybe these factors might better be considered as predictiverather than prognostic factors because the main limit of this study is itsretrospective nature. The hope is that in the future these kinds ofEditorial coMay cyclooxygenase-2 (COX-2), p21 andtherapeutic strategy of patients withKeywords: Malignant pleural mesothelioma; COX-2; p21; p27Mineo and colleagues from the Department of ThoracicSurgery of the University of Rome retrospectively investi-gated the immunohistochemical expression of cyclooxygen-ase-2 (COX-2), p21 and p27 in a cohort of 77 consecutivemesothelioma patients [1]. The triple-combination of highCOX-2 and low p21 and p27 expression was found to be theonly independent prognosticator for shorter overall survivalfor mesothelioma patients in the whole panel of factorsanalysed (beside stage, histology or therapy).This kind of research — analysis of different markers forthe prognosis of several tumours — recently came under somecriticism, finding ‘another marker amongst thousands’. In myopinion, it is still important research to be performed,especially in the context of mesothelioma research.Heterogeneous results concerning the outcome of patientswith sarcomatoid histology or involved mediastinal lymphnodes after induction chemotherapy followed by surgerycannot be only explained by different patient groups [2—4].There must be differences in the biological features ofmesothelioma patients that are responsible for thesediffering survival outcomes! Therefore, investigation ofmarkers and correlation with clinical outcome may providenew knowledge regarding the biology of this aggressivetumour. Furthermore, subgroups of patients benefitting fromaggressive treatment regimens can be defined.COX-2 is an inducible enzyme, which catalyses theconversion of arachidonic acid to prostaglandins in responseto pro-inflammatory or mitogenic signals; it is overexpressedprognosticators can help to avoid aggressive surgery in patients in whom itis unnecessary.Dr M. Alam (Dublin, Ireland): I have just one quick question. You identifieda high level of concentration of COX-2. Do you see a role for highly selectiveCOX-2 inhibitors in the future management or treatment of mesothelioma?Dr Pompeo: Yes. I think one important result is the association between allthese factors. There has already been more than one study emphasizing thepossible interdependence of all 3 of these factors in revealing the negative orpositive effect on the natural history of solid tumours, and I think we willcontinue to assess all these factors together.Dr W. Weder (Zurich, Switzerland): I have one question. From the studyyou have done now and the data, how does this influence your next steps?Dr Pompeo: It’s difficult to answer. One thing might be to assess expressionof these factors before surgery and to see in which patients COX-2 is very highand the contrary for the other factors, and then avoid extrapleuralpneumonectomy in patients with a predictable poor result, but I think themost important thing is to consider this as a first step to better understandpathophysiologic mechanisms of mesothelioma progression and continue to tryto find some new therapeutic agents that will be able to help us with thisdisease.mmentp27 expression affect prognosis andmalignant pleural mesothelioma?in many solid tumours; and in vitro experiments, by usingspecific COX-2 inhibitors, have shown that COX-2 may be apotential target for novel cancer therapies [5]. Therefore,this marker is a very promising one as it can be used not onlyfor prognostic reasons but also as a therapeutic target. Asmentioned in the discussion, several authors have alreadyconfirmed the role of COX-2 as a prognosticator in malignantpleural mesothelioma (MPM) [6,7]. The two cyclin-depen-dent kinase-inhibitors, p21 and p27, are cell-cycle regulatorsthat are implicated in the regulation of the molecularmechanism of cell division. High expression of p27 wascorrelated to prolonged overall survival of MPM patients [8,9]but, in the underlying analysis, only the triple combination ofall markers independently predicted longer overall survival.The correlation between the expression of the differentmarkers and several clinico-pathological markers wasevaluated; it would have been interesting if the authorshad provided additional information about the relationshipbetween the different markers. We have shown that p27immunostaining correlates in a cohort of 352 patients withthe expression of p21 [8]. The same was observed by Baldiand colleagues and, in addition, a negative correlationbetween COX-2 expression and both p27 and p21 was shown[7].In Table 1 of Mineo et al.’s paper, univariate analysis ofthe main clinico-pathological variables is illustrated andshows that out of 27 extrapleural pneumonectomies and44 pleurectomy/decortications performed, 65 patientsT.C. Mineo et al. / European Journal of Cardio-thoracic Surgery 38 (2010) 245—253 253present negative resection margins. In our experience, eventhe most radical procedure of extrapleural pneumonectomyis, in most of the cases, R1 resection only. For anatomicallimits, a clear and wide negative resection margin is, inprinciple, not possible.As the authors already stated in their discussion, thepatients were not uniformly treated. Some patients under-went surgery alone (biopsy-plus-pleurodesis, pleurectomy—decortication or extrapleural pneumonectomies), whereasothers experienced any type of multimodal treatment(adjuvant radiotherapy, adjuvant radio-chemotherapy, neo-adjuvant chemotherapy plus adjuvant radiotherapy). This canbeexplainedbya long retrospective observationperiodof over20 years. However, this is a problemwe are all confrontedwithin mesothelioma research. As there is no gold standard orstandard treatment for these patients and several approacheshave been investigated over the past decades, retrospectiveanalyses are generally performed with heterogeneous patientgroups. Nevertheless, the suggestion of the authors that in thepresence of the combination, COX-2, less aggressive optionsmight be preferred, has to be taken with caution, because ofthe relatively small number of patients and the fact that 8% ofthe patients did not undergo surgery except for pleurodesis.This has to be confirmed in a standardised treated patientgroup.Without any doubt, these results do justify furtherinvestigation in the direction of COX-2, p21 and p27;however, research has to be continued until these markerscan help to make strategical therapy decisions for a certainsubgroup of patients or can function as therapeutical target.Iam looking forward to forthcoming news!References[1] Mineo T, Ambrogi V, Cufari M, Pompeo E. May cyclooxygenase-2 (COX_2),p21 and p27 expression affect prognosis and therapeutic strategy ofpatients with malignant pleural mesothelioma? Eur J Cardiothorac Surg2010;37:245—52.[2] Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJ, Rosenzweig KE,Flores R, Friedberg JS, Pisters K, Monberg M, Obasaju CK, Vogelzang NJ.Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin fol-lowed by extrapleural pneumonectomy and radiation for malignant pleuralmesothelioma. J Clin Oncol 2009;27:3007—13.[3] Weder W, Stahel RA, Bernhard J, Bodis S, Vogt P, Ballabeni P, Lardinois D,Betticher D, Schmid R, Stupp R, Ris HB, Jermann M, Mingrone W, Roth AD.Spiliopoulos A on behalf of the Swiss Group for Clinical Cancer Research.Ann Oncol 2007;18:1196—202.[4] de Perrot M, Feld R, Cho BCJ, Bezjak A, Anraku M, Burkes R, Roberts H, TsaoMS, Leighl N, Keshavjee S, Johnston MR. Trimodality therapy with inductionchemotherapy followed by extrapleural pneumonectomy and adjuvanthigh-dose hemithoracic radiation for malignant pleural mesothelioma.J Clin Oncol 2009;27:1413—8.[5] O’Kane SL, Eagle GL, Greenman J, Lind MJ, Cawkwell L. COX-2 specificinhibitors enhance the cytotoxic effects of pemetrexed in mesotheliomacell lines. Lung Cancer 2010;67:160—5.[6] Edwards JG, Faux SP, Plummer SM, Abrams KR, Walker RA, Waller DA,O’Byrne KJ. Cyclooxygenase-2 expression is a novel prognostic factor inmalignant mesothelioma. Clin Cancer Res 2002;8:1857—62.[7] Baldi A, Santini D, Vasaturo F, Santini M, Vicidomini G, Di Marino MP,Esposito V, Groeger AM, Liuzzi G, Vincenzi B, Tonini G, Piccoli M, Baldi F,Scarpa S. Prognostic significance of cyclooxygenase-2 (COX-2) and expres-sion of cell cycle inhibitors p21 and p27 in human pleural malignantmesothelioma. Thorax 2004;59:428—33.[8] Schramm A, Opitz I, Thies S, Seifert B, Moch H, Weder W, Soltermann A.Prognostic significance of epithelial-mesenchymal transition in malignantpleural mesothelioma. Eur J Cardiothorac Surg 2010;37:566—72.[9] Kumar P, Kratzke RA. Molecular prognostic markers in malignant mesothe-lioma. Lung Cancer 2005;49(Suppl. 1):S53—60.Isabelle Opitz*Division of Thoracic Surgery, University Hospital Zurich,Ra¨mistrasse 100, 8091 Zurich, Switzerland*Corresponding author. Tel.: +41 44 255 88 02;fax: +41 44 255 88 05E-mail address: isabelle.schmitt-opitz@usz.chAvailable online 15 July 2010doi:10.1016/j.ejcts.2010.04.003

May cyclooxygenase-2 (COX-2), p21 and p27 expression affect prognosis and therapeutic strategy of patients with malignant pleural mesothelioma?

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