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      Relevance of micrometastases detected by reverse transcriptase-polymerase chain reaction for melanoma recurrence: systematic review and meta-analysis

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          Abstract

          CONTEXT: Cutaneous melanoma presents significant morbidity and mortality. Nowadays, about 90% of them are diagnosed by clinical examination and most are localized melanomas. Sentinel node biopsy has brought about a new and interesting approach towards localized cutaneous melanoma. The meaning of micrometastases in sentinel nodes diagnosed by the reverse transcriptase-polymerase chain reaction is not well established. OBJECTIVE: To define the real value of micrometastases diagnosed by the reverse transcriptase-polymerase chain reaction in relation to melanoma recurrence. METHODS: Systematic literature review and meta-analysis. The Cochrane Library, Medline, Embase and Lilacs were the databases searched. We used the following key words: sentinel node and melanoma; sentinel node and reverse transcriptase-polymerase chain reaction; melanoma and reverse transcriptase-polymerase chain reaction. Cohort studies enrolling localized cutaneous melanoma patients who underwent sentinel node biopsy were selected. Sentinel node evaluations included hematoxylin and eosin, immunohistochemistry and reverse transcriptase-polymerase chain reaction. RESULTS: Out of the 1,542 studies evaluated, four were eligible. The four studies, when combined, were statistically homogeneous. The sample totaled 450 patients grouped as follows: 163 with a sentinel node negative to hematoxylin eosin and immunohistochemistry and positive to the reverse transcriptase-polymerase chain reaction; 192 with a sentinel node negative to hematoxylin eosin, immunohistochemistry and the reverse transcriptase-polymerase chain reaction and 95 patients with a sentinel node positive to hematoxylin eosin and/or immunohistochemistry. We analyzed the first two groups. The meta-analysis for the random model showed an increased effect from a positive reverse transcriptase-polymerase chain reaction on the recurrence rate. A similar result occurred in the meta-analysis for the fixed effect model. CONCLUSION: Patients with a positive reverse transcriptase-polymerase chain reaction had a greater recurrence rate than those with a negative reverse transcriptase-polymerase chain reaction. This suggests an important role for the reverse transcriptase-polymerase chain reaction in sentinel node examinations. In view of the small sample, a clinical trial could better evaluate this question.

          Translated abstract

          CONTEXTO: O melanoma cutâneo apresenta importante morbidade e mortalidade. A incidência de melanoma cutâneo vem aumentando em todo o mundo nos últimos 50 anos. Atualmente, cerca de 90% dos casos são diagnosticados pelo exame clínico e, na maioria das vezes, ainda na forma de melanoma localizado. A biópsia de linfonodo sentinela trouxe uma nova e interessante abordagem para o melanoma cutâneo localizado. OBJETIVO: Definir o real valor de micrometástases diagnosticadas em linfonodo sentinela através da técnica de transcriptase reversa associada à reação de polimerização em cadeia (reverse transcriptase-polymerase chain reaction, PCR) na recorrência do melanoma cutâneo. MÉTODOS: Realizamos uma revisão sistemática da literatura com metanálise. Cochrane Library, Medline, Embase e Lilacs foram os bancos de dados pesquisados. Foram usadas as seguintes palavras-chave: sentinel node and melanoma, sentinel node and reverse transcriptase-polymerase chain reaction, melanoma and reverse transcriptase-polymerase chain reaction. Fez-se seleção de estudos prognósticos coorte, abrangendo pacientes portadores de melanoma cutâneo submetidos a biópsia de linfonodo sentinela. O exame do linfonodo sentinela incluiu análise histopatológica por hematoxilina e eosina, imunohistoquímica e reação de polimerase em cadeia. Foi realizada metanálise através do software RevMan (Review Manager 4.1-c; Cochrane Collaboration) com avaliação de odds ratio e risco relativo, utilizando modelo de efeito fixo e randômico. RESULTADOS: Entre 1.542 estudos identificados, quatro foram elegíveis para a revisão sistemática. Os quatro estudos combinados foram estatisticamente homogêneos (c2 = 2,66, p = 0,44 para odds ratio e c2 = 3,17, p = 0,37 para risco relativo). A casuística totalizou 450 pacientes. Esses pacientes foram distribuídos em três grupos: 163 com linfonodo sentinela negativo para hematoxilina-eosina e imunohistoquímica, sendo a reação de polimerase em cadeia positiva; 192 com linfonodo sentinela negativo para hematoxilina-eosina, imunohistoquímica e a reação de polimerase em cadeia e 95 com linfonodo sentinela positivo para hematoxilina-eosina e ou imunohistoquímica. Apenas os dois primeiros grupos foram objetos de nossa análise. A metanálise utilizando modelo de efeito randômico mostrou aumento de recorrência para o grupo com a reação de polimerase em cadeia positiva (odds ratio = 3,0 [1.16, 7.78] e risco relativo = 2.55 [1.06, 6.12]). Resultado similar foi encontrado na metanálise utilizando modelo de efeito fixo (odds ratio = 3,64 [1.51, 8.76] e risco relativo = 3.16 [1.39, 7.19]). CONCLUSÃO: Pacientes com reação de polimerase em cadeia positiva tiveram uma taxa de recorrência maior que aqueles com reação de polimerase em cadeia negativa. Esse resultado sugere um importante papel da reação de polimerase em cadeia no exame do linfonodo sentinela. Considerando-se a pequena casuística, um estudo clínico prospectivo poderia avaliar melhor esta questão.

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          Technical details of intraoperative lymphatic mapping for early stage melanoma.

          The initial route of metastases in most patients with melanoma is via the lymphatics to the regional nodes. However, routine lymphadenectomy for patients with clinical stage I melanoma remains controversial because most of these patients do not have nodal metastases, are unlikely to benefit from the operation, and may suffer troublesome postoperative edema of the limbs. A new procedure was developed using vital dyes that permits intraoperative identification of the sentinel lymph node, the lymph node nearest the site of the primary melanoma, on the direct drainage pathway. The most likely site of early metastases, the sentinel node can be removed for immediate intraoperative study to identify clinically occult melanoma cells. We successfully identified the sentinel node(s) in 194 of 237 lymphatic basins and detected metastases in 40 specimens (21%) on examination of routine hematoxylin-eosin-stained slides (12%) or exclusively in immunohistochemically stained preparations (9%). Metastases were present in 47 (18%) of 259 sentinel nodes, while nonsentinel nodes were the sole site of metastasis in only two of 3079 nodes from 194 lymphadenectomy specimens that had an identifiable sentinel node, a false-negative rate of less than 1%. Thus, this technique identifies, with a high degree of accuracy, patients with early stage melanoma who have nodal metastases and are likely to benefit from radical lymphadenectomy.
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            Identifying relevant studies for systematic reviews.

            To examine the sensitivity and precision of Medline searching for randomised clinical trials. Comparison of results of Medline searches to a "gold standard" of known randomised clinical trials in ophthalmology published in 1988; systematic review (meta-analysis) of results of similar, but separate, studies from many fields of medicine. Randomised clinical trials published in 1988 in journals indexed in Medline, and those not indexed in Medline and identified by hand search, comprised the gold standard. Gold standards for the other studies combined in the meta-analysis were based on: randomised clinical trials published in any journal, whether indexed in Medline or not; those published in any journal indexed in Medline; or those published in a selected group of journals indexed in Medline. Sensitivity (proportion of the total number of known randomised clinical trials identified by the search) and precision (proportion of publications retrieved by Medline that were actually randomised clinical trials) were calculated for each study and combined to obtain weighted means. Searches producing the "best" sensitivity were used for sensitivity and precision estimates when multiple searches were performed. The sensitivity of searching for ophthalmology randomised clinical trials published in 1988 was 82%, when the gold standard was for any journal, 87% for any journal indexed in Medline, and 88% for selected journals indexed in Medline. Weighted means for sensitivity across all studies were 51%, 77%, and 63%, respectively. The weighted mean for precision was 8% (median 32.5%). Most searchers seemed not to use freetext subject terms and truncation of those terms. Although the indexing terms available for searching Medline for randomised clinical trials have improved, sensitivity still remains unsatisfactory. A mechanism is needed to "'register" known trials, preferably by retrospective tagging of Medline entries, and incorporating trials published before 1966 and in journals not indexed by Medline into the system.
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              Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

              The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.
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                Author and article information

                Journal
                spmj
                Sao Paulo Medical Journal
                Sao Paulo Med. J.
                Associação Paulista de Medicina - APM (São Paulo, SP, Brazil )
                1516-3180
                1806-9460
                2003
                : 121
                : 1
                : 24-27
                Affiliations
                [01] São Paulo orgnameUniversidade Federal de São Paulo orgdiv1Escola Paulista de Medicina Brazil
                [02] Natal orgnameUniversidade Federal do Rio Grande do Norte Brazil
                Article
                S1516-31802003000100006 S1516-3180(03)12100106
                10.1590/S1516-31802003000100006
                1c4e30b1-c6f5-4f53-b1c4-eab9812972a8

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 30 September 2002
                : 18 March 2002
                : 24 September 2002
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 26, Pages: 4
                Product

                SciELO Brazil

                Categories
                Review article

                Melanoma,Reação de polimerase em cadeia,Linfonodo,Sentinela,Reverse transcriptase,Micrometástases,Imunohistoquímica,Polymerase chain reaction,Sentinel node,Micrometastasis,Immunohistochemistry

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