Brizel D M, Schroeder T, Scher R L, Walenta S, Clough R W, Dewhirst M W, Mueller-Klieser W
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Int J Radiat Oncol Biol Phys. 2001 Oct 1;51(2):349-53. doi: 10.1016/s0360-3016(01)01630-3.
Hypoxia shifts the balance of cellular energy production toward glycolysis with lactate generation as a by-product. Quantitative bioluminescence imaging allows for the quantitation of lactate concentrations in individual tumors. We assessed the relationship between pretreatment tumor lactate concentrations and subsequent development of metastatic disease in patients with newly diagnosed head-and-neck cancer.
At the time of biopsy of the primary site, a separate specimen was taken and flash-frozen for subsequent quantitation of lactate concentration using a luciferase bioluminescence technique. The two-dimensional spatial distribution of the bioluminescence intensity within the tissue section was registered directly using a microscope and an imaging photon counting system. Photon intensity was converted to distributions of volume-related tissue concentrations (micromol per gram wet weight). Treatment consisted of either surgery and postoperative radiotherapy or primary radiotherapy, based on presenting disease stage and institutional treatment policies. The subsequent development of metastatic disease constituted the primary clinical endpoint.
Biopsies obtained from 40 patients were evaluable in 34. The larynx was the most frequent primary site (n = 25). Other sites included oropharynx (n = 5), hypopharynx (n = 3), and oral cavity (n = 1). Most patients (74%) presented with an advanced stage T3 or T4 primary tumor. Nodal involvement was present in 19 (54%) patients. The median tumor lactate concentration was 7.1 micromol/g. Tumors were classified as having either low or high lactate concentrations according to whether these values were below or above the median. The median follow-up time for surviving patients is 27 months. Two-year actuarial survival was 90% for patients with low-lactate-concentration tumor vs. 35% for patients with high-lactate-concentration primaries (<0.0001). Two-year metastasis-free survival was adversely influenced by high tumor lactate concentrations (90% vs. 25%, p < 0.0001). The median lactate concentration for tumors that subsequently metastasized was 12.9 micromol/g vs. 4.8 micromol/g for patients who remained continuously free of disease (p < 0.005). Lactate concentration was not correlated with presenting T stage or N stage.
Elevated tumor lactate concentrations are associated with the subsequent development of nodal or distant metastases in head-and-neck cancer patients. This more aggressive malignant phenotype is probably associated with hypoxia-mediated radioresistance and the upregulation of metastasis-associated genes.
缺氧会使细胞能量产生的平衡转向糖酵解，并产生乳酸作为副产品。定量生物发光成像可对单个肿瘤中的乳酸浓度进行定量分析。我们评估了新诊断的头颈癌患者治疗前肿瘤乳酸浓度与随后转移性疾病发生之间的关系。
在对原发部位进行活检时，取一个单独的样本并速冻，以便随后使用荧光素酶生物发光技术对乳酸浓度进行定量分析。使用显微镜和成像光子计数系统直接记录组织切片内生物发光强度的二维空间分布。光子强度被转换为与体积相关的组织浓度分布（每克湿重微摩尔数）。根据疾病分期和机构治疗策略，治疗包括手术加术后放疗或单纯放疗。转移性疾病的后续发生构成主要临床终点。
从40例患者获取的活检样本中，34例可进行评估。喉部是最常见的原发部位（n = 25）。其他部位包括口咽（n = 5）、下咽（n = 3）和口腔（n = 1）。大多数患者（74%）表现为晚期T3或T4原发肿瘤。19例（54%）患者有淋巴结受累。肿瘤乳酸浓度中位数为7.1微摩尔/克。根据这些值是低于还是高于中位数，将肿瘤分为乳酸浓度低或高两类。存活患者的中位随访时间为27个月。乳酸浓度低的肿瘤患者两年精算生存率为90%，而乳酸浓度高的原发肿瘤患者为35%（<0.0001）。肿瘤乳酸浓度高对两年无转移生存率有不利影响（90%对25%，p < 0.0001）。随后发生转移的肿瘤的乳酸浓度中位数为12.9微摩尔/克，而持续无病患者为4.8微摩尔/克（p < 0.005）。乳酸浓度与初始T分期或N分期无关。
头颈癌患者肿瘤乳酸浓度升高与随后淋巴结或远处转移的发生相关。这种更具侵袭性的恶性表型可能与缺氧介导的放射抗性以及转移相关基因的上调有关。
