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本帖最後由 goodcat1111 於 2009-4-9 00:23 編輯

作者:Laurie Barclay, MD  

  February 17, 2009 — 一項於2月18日JAMA上發表的前瞻性研究結果顯示,組織學檢驗陰性淋巴結的基因確認可能協助預測大腸直腸癌再發。
  來自賓州費城Thomas Jefferson大學的Scott A. Waldman醫師與其同事們寫到,淋巴結轉移與大腸直腸癌預後之間已被確認的關連暗示,以病理學檢驗確認淋巴結沒有癌細胞(pN0)的病患,25%的再發表示其中仍有隱性轉移。鳥糞嘌朎環化酶2C(GUCY2C)是一個大腸直腸癌細胞表現的標記,可以代表淋巴結中的隱形轉移,且是再發風險一個較好的估計,目前這項研究前瞻性地檢驗使用GUCY2C定量(反轉錄聚合酶鏈反應;RT-PCR)對於pN0大腸直腸癌患者偵測隱性轉移以及定義手術後再發疾病的風險。
  在2002年3月到2007年之間,在9個美國與加拿大中心(7個學術醫學中心與2個社區醫院),257位罹患pN0大腸直腸癌病患提供了2,570個新鮮淋巴結樣本,大小在5 mm以上,用於病理與GUCY2C訊息RNA分析。疾病再發或是死亡的平均後續追蹤時間為24個月(範圍2~63個月)。主要試驗終點是發生再發的時間,次要試驗終點是免於疾病的存活,相較於GUCY2C淋巴結表現。
  相對的,在225位GUCY2C淋巴結陽性的病患(pN0[mol+])中,47位疾病再發(20.9%,95%信賴區間為15.8-26.8%;P= 0.006)。根據多變項分析,GUCY2C淋巴結陽性是預後的獨立預測因子。pN0(mol+)的病患發生再發所需時間較短(校正後危險比值[HR]為4.66;95%信賴區間為1.11-9.29;P=0.03)。
  這項研究的限制包括後續追蹤時間較短,多變項分析中的95%信賴區間接近估計值,從個別病患取得可供分子分期鑑定的樣本數目不一,淋巴結大小小於5 mm以下者被排除在分子分析之外,以及無法確認定義風險的定量閾值。
  國家衛生研究院與Targeted Diagnostic and Therapeutics有限公司贊助這項研究。Waldman博士表示他擔任默克藥廠的有給顧問職,且是Targeted Diagnostic and Therapeutics有限公司的無報酬學術顧問團成員,該公司提供研究經費贊助,特別是贊助這項研究,有擁有販售與這項研究有關入的執照。另一位作者是Targeted Diagnostic and Therapeutics有限公司的股東。

Genetic Marker in Lymph Nodes May Predict Recurrence of Colorectal Cancer

By Laurie Barclay, MD
Medscape Medical News

February 17, 2009 — Genetic identification of a marker in histologically negative lymph nodes may help predict colorectal cancer recurrence, according to the results of a prospective study published in the February 18 issue of JAMA.

"The established relationship between lymph node metastasis and prognosis in colorectal cancer suggests that recurrence in 25% of patients with lymph nodes free of tumor cells by histopathology (pN0) reflects the presence of occult metastases," write Scott A. Waldman, MD, PhD, from Thomas Jefferson University in Philadelphia, Pennsylvania, and colleagues. "Guanylyl cyclase 2C (GUCY2C) is a marker expressed by colorectal tumors that could reveal occult metastases in lymph nodes and better estimate recurrence risk.... The current study prospectively examined the utility of GUCY2C quantitative [reverse transcriptase–polymerase chain reaction (RT-PCR)] in patients with pN0 colorectal cancer to identify occult metastases and to define the risk of developing recurrent disease after surgical treatment."

Between March 2002 and June 2007 at 9 US and Canadian centers (7 academic medical centers and 2 community hospitals), 257 patients with pN0 colorectal cancer provided 2570 fresh lymph nodes measuring 5 mm or larger for histopathology and GUCY2C messenger RNA analysis. Median follow-up for disease recurrence or death was 24 months (range, 2 – 63 months). The primary study endpoint was time to recurrence, and the secondary outcome was disease-free survival, relative to expression of GUCY2C in lymph nodes.

Of 32 patients (12.5%) with lymph nodes negative for GUCY2C (pN0 [mol?]), all but 2 were disease-free during follow-up, yielding a recurrence rate of 6.3% (95% confidence interval [CI], 0.8% – 20.8%).

In contrast, of 225 patients (87.5%) with lymph nodes positive for GUCY2C (pN0 [mol+]), 47 developed recurrent disease (20.9%; 95% CI, 15.8% – 26.8%; P = .006). Lymph nodes positive for GUCY2C was an independent marker of prognosis, based on multivariate analyses. Patients who were pN0 (mol+) had earlier time to recurrence (adjusted hazard ratio [HR], 4.66; 95% CI, 1.11 – 19.57; P =.04) and lower disease-free survival (adjusted HR, 3.27; 95% CI, 1.15 – 9.29; P = .03).

"Expression of GUCY2C in histologically negative lymph nodes appears to be independently associated with time to recurrence and disease-free survival in patients with pN0 colorectal cancer," the study authors write.

Study limitations include relatively short follow-up, broad 95% CIs around estimates in multivariate analyses, a variable number of lymph nodes available for molecular staging from individual patients, that lymph nodes smaller than 5 mm were excluded from molecular analyses, and an inability to identify the quantitative threshold defining risk.

"In future studies, it will be essential to more precisely define the quantitative relationship between marker expression and disease risk that incorporates tumor burden to optimize prognostic sensitivity and specificity," the study authors write. "Analyses of primary tumors to define mutations, gene expression and epigenetic profiles, and proteomic signatures to stratify risk, predict responses to chemotherapy, and to personalize interventions may best be applied to patients with pN0 (mol+) rather than pN0 (mol?). These considerations underscore the present and future importance of integrating molecular approaches incorporating specific markers of disease, like GUCY2C, and powerful detection methods like quantitative RT-PCR, into analytical strategies directing the management of patients with colorectal cancer."

The National Institutes of Health and the Targeted Diagnostic and Therapeutics Inc supported this study. Dr. Waldman reported being a paid consultant to Merck and the uncompensated chair of the Scientific Advisory Board of Targeted Diagnostics and Therapeutics, Inc, which provided research funding that, in part, supported this study and that has a license to commercialize inventions related to this work. Another author is a shareholder in Targeted Diagnostics and Therapeutics, Inc.

JAMA. 2009;301:745–752.


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