尿吡啶酚、尿脱氧吡啶酚、尿氨基末端肽在转移性骨肿瘤临床随访价值的应用研究

[目的]探讨尿吡啶酚（uPvd）、尿脱氧吡啶酚（uDpd）、尿氨基末端肽（uNTx）在肿瘤骨转移患者随访中的应用价值。[方法]晚期肿瘤骨转移患者46例，分别按肿瘤内科治疗原则选用化疗、双膦酸盐治疗、姑息治疗。治疗开始前测定基线uPyd、uDpd、uNTX水平，以后于第1、3个月及以后每3个月检测。记录骨相关不良事件（SItE）。[结果]在1年随访期间，骨转移患者uPyd、uDpd、uNTx水平在含双膦酸盐治疗后1个月有明显下降（P〈0．01）。SRE发生时uNTx测定水平与SRE发生前最近一次uNTx测定水平比较有统计学差异（P〈0．01），Lg（uNTx／Cr）从2．24±0．12升至2.31±0．13。[结论]uPyd、uDpd、uNTx水平能及时反映抗骨转移治疗特别是双膦酸盐治疗的效果；uNTx水平在SRE发生时有升高趋势，能提示骨病变的进展。     

uNTX、sICTP及sBALP表达在恶性肿瘤骨转移中的临床意义

目的探讨尿Ⅰ型胶原交联氨基末端肽（uNTX）、血清Ⅰ型胶原羧基末端肽（sICTP）及骨碱性磷酸酶（sBALP）表达在恶性肿瘤骨转移患者中的临床意义。方法对32例恶性肿瘤骨转移患者,在治疗前后分别采用酶联免疫吸附法（ELISA）、小麦菌凝集素沉淀法,测定uNTX、sICTP及sBALP水平。随访骨相关事件（SREs）及生存状况。结果患者基线uNTX/Cr、sICTP及sBALP水平明显高于正常,其浓度与骨转移负荷呈正相关性,与疼痛强度无显著相关性。治疗3个月时uNTX/Cr、sICTP及sBALP水平明显降低,而放射性核素全身骨显像（ECT）尚无明显改变;32例患者中24例基线uNTX/Cr水平高于正常水平,治疗后降至正常水平的15例患者骨相关事件发生率为53%,而治疗后仍维持在较高水平的9例患者为89%（P=0.039）;32例患者中27例基线sICTP水平高于正常,治疗后16例降至正常,11例仍维持在较高水平,两者骨相关事件发生率为50%和91%（P=0.032）;26例基线sBALP水平高于正常值,治疗后16例降至正常水平,10例仍维持在较高水平,两者骨相关事件发生率为50%和90%（P=0.038）。uNTX/Cr、sICTP及sBALP水平与肿瘤患者生存率无明显相关性。结论骨代谢标记物uNTX、sICTP及sBALP对恶性肿瘤骨转移的诊断、疗效的监测及骨相关事件的预测具有一定的价值。     

骨代谢标记物在实体瘤骨转移诊治中的临床意义

目的探讨血清骨源性碱性磷酸酶(BALP)及尿Ⅰ型胶原交联氨基末端肽(uNTx)的表达在实体瘤骨转移诊治中的临床意义。方法对500例恶性肿瘤骨转移患者在治疗前采用酶联免疫吸附法(ELISA)测定uNTx、BALP水平。定期复查(2月1次),行近期疗效评价。结果伴骨转移的患者基线uNTx、BALP水平明显升高(P<0.05),其浓度与骨转移负荷呈正相关(P<0.05),但与骨癌痛无明显相关性。血清BALP、uNTx水平与对骨转移后生存率的影响无统计学意义(P>0.05)。结论骨代谢标记物对于骨转移的诊断有一定的价值,对治疗的反应敏感性优于影像学检查。     

UNTX水平检测在监测肺癌骨转移中的价值

目的 检测与分析肺癌骨转移瘤患者尿I型胶原交联氨基末端肽（uNTX）水平,评价其与骨转移病情发展和疗效的关系。方法 研究对象为正常组33例;肺癌组31例;肺癌骨转移组30例。分别测定3组uNTX水平,同时进行尿脱氧吡啶酚及血清AKP活性和Ca2＋浓度的测定,肺癌骨转移组进行了治疗前后uNTX水平对比。结果 肺癌骨转移组uNTX水平明显高于其他两组,其治疗前后uNTX水平也有显著性差异。结论 肺癌骨转移时uNTX水平会发生异常,uNTX水平与骨转移的发生呈正相关,uNTX敏感度高于尿脱氧吡啶酚及血清AKP活性和Ca^2＋浓度,在预测肺癌骨转移瘤和监测病变进程中有重要临床价值。     

β-CTX、BAP、uNTx联合检测对于诊断肺癌骨转移的价值

目的探讨血清β-Ⅰ型胶原羧基端肽(β-CTX)、骨碱性磷酸酶(BAP)、尿Ⅰ型胶原交联氨基末端肽(uNTx)诊断肺癌骨转移的价值。方法选取64例肺癌骨转移患者(转移组)、60例肺癌未发生骨转移的患者(对照组);检测2组的血清β-CTX、BAP、uNTx水平;分析三项指标单独及联合应用时诊断肺癌骨转移的临床价值。结果转移组患者的β-CTX、BAP、uNTx水平均高于对照组,差异具有统计学意义(P<0.05);≥2个转移部位患者的β-CTX、BAP、uNTx水平均高于1个转移部位的患者,差异具有统计学意义(P<0.05)。β-CTX诊断肺癌骨转移的灵敏度为49.21%、特异度为76.42%、AUC值为0.675;BAP诊断肺癌骨转移的灵敏度为57.88%、特异度为79.85%、AUC值为0.738;uNTx诊断肺癌骨转移的灵敏度为68.33%、特异度为81.30%、AUC值为0.758;β-CTX、BAP、uNTx联合应用诊断肺癌骨转移的灵敏度为91.27%、特异度为80.55%、AUC值为0.889。结论β-CTX、BAP、uNTx联合应用诊断肺癌骨转移能显著提高诊断的灵敏度。     

骨代谢生化指标在恶性肿瘤骨转移诊断中的价值

目的：探讨溶骨性骨代谢生化指标尿Ⅰ型胶原交联氨基末端肽（NTx）、血Ⅰ型胶原交联羧基末端肽（ICTP）定量检测诊断恶性肿瘤骨转移的价值。方法：用ELISA方法测定77例恶性肿瘤患者尿NTx和血ICTP水平。结果：骨转移组患者尿NTx和血ICTP均明显高于无骨转移组以及正常值范围（P〈0．01）。骨转移患者尿NTx与血ICTP成正相关（r=0．880，P〈0．01）。尿NTx诊断恶性肿瘤骨转移的灵敏度、特异度和准确度分别为82．5％、83．8％和83．2％（P〈0．05）。血ICTP的灵敏度、特异度和准确度分别为87．5％、73．0％和80．6％（P〈0．05）。骨转移患者尿NTx与血ICTP水平与骨转移范围成正相关（r=0．453、0．475，P〈0．01），与骨痛程度无显著相关（r=0．010、0．083，P〉0．05）。结论：NTx和血ICTP对恶性肿瘤患者骨转移的诊断有重要的参考意义，可协助及时诊断恶性肿瘤骨转移。     

骨标志物在乳腺癌骨转移诊断与疗效观察中的作用

目的 探讨I型胶原交联羧基氨基端肽(β-Cross Laps)和总骨1型前胶原氨基端延长肽(P1NP)在乳腺癌骨转移诊断与疗效观察中的临床价值。方法 运用电化学发光法对β-Cross Laps、P1NP、CA15-3进行定量检测。57例乳腺癌骨转移患者按转移灶多少分为2组,分别为骨显像轻度异常组(Ⅰ组)36例与骨显像明显异常组(Ⅱ组)21例。结果 骨转移组β-Cross Laps、P1NP两种血清标志物较无骨转移组与对照组明显升高,差异具有统计学意义(P＜0.01),且治疗后两种指标明显低于治疗前水平(P＜0.05),随转移灶增加两种标志物水平也有升高趋势,差异具有统计学意义(P＜0.01)。而各组间及治疗前后CA15-3无显著变化(P＞0.05)。骨标志物β-Cross Laps、P1NP对乳腺癌骨转移的诊断灵敏度分别达到71.25%与64.05%,特异性分别达到88.00%与81.99%,均高于骨显像所显示结果的50.32%和61.17%。结论 血清骨标志物β-Cross Laps、P1NP水平可以反映乳腺癌骨转移患者病情变化,并可以运用于疗效监测,有较好的临床应用价值。     

乳腺癌骨转移患者血液OSC、OPG、NTX及与尿液NTX水平相关性探讨

目的:探讨乳腺癌骨转移患者血液骨钙素（OSC）、骨保护素（OPG）、I型胶原吡啶交联氨基末端肽（NTX）及与尿液NTX水平的相关性。方法:通过对比40例乳腺癌骨转移患者（实验组）和40例健康女性（对照组）血液OSC、OPG、NTX 和尿液 NTX水平，比较实验组治疗前和对照组的血液OSC、OPG、NTX和尿液NTX水平的差异。评估血液OSC与血液NTX水平相关性，血液OPG与血液NTX水平相关性，血液和尿液NTX水平相关性。结果:实验组中血液OSC、OPG和NTX水平比对照组要高，两组的OSC差异具有统计学意义（P＜0.001），两组的OPG差异具有统计学意义（P＜0.003），两组的NTX差异具有统计学意义（P＜0.001）。相关性统计结果显示血液中的NTX的升高和血液中的OSC及OPG水平具有关性，血液NTX和OSC之间的r=0.768(P＜0.001)，血液NTX和OPG之间的r=0.685(P＜0.001)，差异均具有统计学意义；血液NTX和尿液NTX之间也具有相关性r=0.638(P＜0.005)，差异具有统计学意义。结论:乳腺癌骨转移的患者血液OSC、OPG、NTX及与尿液NTX水平之间具有一定关系，且有一定的临床意义。     

乳腺癌骨转移患者骨代谢指标PICP、β-CTx与治疗效果的关系

目的 探讨骨代谢指标Ⅰ型胶原羧基端前肽(carboxyl-terminal propeptide of type 1 procollagen,PICP)、β胶原降解产物(beta collagen degradation products,β-CTx)与乳腺癌骨转移患者治疗反应的关系.方法 测定56例乳腺癌骨转移患者治疗前后骨代谢指标PICP和β-CTx,比较治疗前后骨代谢指标与治疗效果的关系,并进行随访.结果 56例乳腺癌骨转移患者中,临床获益组36例,治疗3月后PICP和β-CTx明显下降(P=0.016,P=0.001);病情进展组20例,治疗3月后PICP和β-CTx有所升高(P=0.008,P=0.042).临床获益组中20例患者骨代谢指标先于影像学检查提示临床治疗有效.结论 PICP和β-CTx可作为乳腺癌骨转移患者评价疗效的辅助指标.     

血清I型胶原吡啶交联终肽(ICTP)与核素骨扫描联合诊断鼻咽癌骨转移的临床价值

目的:评价血清Ⅰ型胶原吡啶交联终肽(ICTP)与核素骨扫描联合检测在鼻咽癌骨转移诊断中的临床价值。方法:对127例首次确诊的鼻咽癌患者同时进行放疗前、放疗后3、6、12月的血清Ⅰ型胶原吡啶交联终肽(ICTP)检测和骨核素扫描(SPECT)。结果:SPECT与ICTP平行试验联合敏感性高于SPECT和ICTP单独的敏感性。SPECT与ICTP系列试验联合特异性高于SPECT和ICTP单独的特异性。结论:SPECT和ICTF联合检测在诊断鼻咽癌早期骨转移方面优于SPECT或ICTP单独检测。     

Tartrate-resistant acid phosphatase 5b activity is a useful bone marker for monitoring bone metastases in breast cancer patients after treatment.

Metabolic markers of bone metabolism may be useful for the diagnosis and monitoring of bone metastasis in breast cancer patients. Serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity is a novel bone resorption marker. The treatment response of serum TRACP5b activity, bone alkaline phosphatase (BAP) activity, and concentrations of NH(2)-terminal telopeptide of type 1 collagen (NTX) in 68 breast cancer patients with bone metastasis were determined. These patients were treated and followed up as clinically indicated. Fifty-four healthy women were recruited as control. Serum TRACP5b activity, BAP activity, and NTX level of breast cancer patients with bone metastasis were significantly higher than those of normal controls. In normal subjects, serum TRACP5b activity and NTX level are significantly correlated (P < 0.0001). Neither was correlated with BAP activity. In breast cancer patients with bone metastasis, all marker pairs correlated to each other significantly (P < 0.0001). Biomarkers were examined repeatedly in 38 patients who were evaluable for treatment response. Based on clinical criteria, 20 patients were responders and 18 were nonresponders. In the 20 responders, serum TRACP5b activity and NTX level decreased significantly (P < 0.0001 and 0.0107, respectively) after treatment. In the 18 nonresponders, only NTX level showed significant increase (P = 0.0342) after treatment; TRACP5b and BAP were unchanged. By means of multiple logistic regression with stepwise selection, we determined that TRACP5b activity has a higher probability than NTX level to indicate treatment response as a function of percent change after treatment (18 times versus 12 times). Our data support the use of either TRACP5b activity or NTX level to follow up breast cancer patients with bone metastasis after treatment instead of the prevailing BAP activity.     

Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy

PURPOSE: Denosumab, a fully human monoclonal antibody to RANKL, suppresses bone resorption. This study evaluated the effects of denosumab in i.v. bisphosphonate (IV BP)-na?ve patients with breast cancer-related bone metastases. EXPERIMENTAL DESIGN: Eligible women (n = 255), stratified by type of antineoplastic therapy, were randomized to 1 of 5 blinded denosumab cohorts or an open-label IV BP cohort. Denosumab was administered s.c. every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg) through 21 weeks. Final efficacy results for up to 25 weeks are reported, including percentage change from baseline in urine N-telopeptide corrected for creatinine (uNTx/Cr) and incidence of skeletal-related events (SRE). Safety results are reported through the end of follow-up (up to 57 weeks). RESULTS: At week 13 and 25, the median percent changes in uNTx/creatinine (Cr) among patients with measurable uNTx were -73% and -75% for the pooled denosumab groups and -79% and -71% for the IV BP group. Among patients with > or =1 postbaseline measurement of uNTx at week 25, 52% (109 of 208) of denosumab-treated patients and 46% (19 of 41) of IV BP-treated patients achieved >65% uNTx/Cr reduction. On-study SREs occurred in 12% (26 of 211) of denosumab-treated patients and 16% (7 of 43) of IV BP-treated patients. Overall rates of adverse events were 95% in denosumab and IV BP groups. No denosumab-related serious or fatal adverse events occurred. CONCLUSIONS: In IV BP-na?ve breast cancer patients with bone metastases, denosumab suppresses bone turnover and seems to reduce SRE risk similarly to IV BPs, with a safety profile consistent with an advanced cancer population receiving systemic therapy.     

Evaluation of bone metabolic markers in breast cancer with bone metastasis

PURPOSE: In the present study, four bone metabolic markers were examined to clarify them meaning and clinical value in the detection of bone metastasis (BM) from breast cancer. METHODS: we examined serum carboxyterminal telopeptide of type I collagen (ICTP), tartrate resistant acid phosphatase (TRACP), total alkaline phosphatase (ALP) and urinary type I collagen cross-linked N-telopeptides (NTx) as potential markers. These bone markers were evaluated simultaneously in 156 breast cancer patients; 114 patients without metastasis (group A), 23 patients with BM (group B) and 19 patients with metastasis at sites other than bone (group C). RESULTS: The mean values of ICTP and TRACP in group B were significantly greater than those in group A. Group B consisted of the patients with varying degrees of BM and variation in their treatments. The patients in group B were divided into BM (+) and BM (++) according to hot spots in bone scan. ICTP and TRACP were elevated in BM (++) patients compared to BM (+) patients (p<0.05). The values of ICTP and TRACP of the twelve patients without treatment in group B were significantly higher than those in group A. In the treated patients of group B, the mean values of ICTP and TRACP were lower in responders and cases of stable disease than those with progression. NTx and ALP were inferior to ICTP and TRACP for clinical evaluation of BM. CONCLUSIONS: We confirmed that ICTP and TRACP might be useful markers for screening and monitoring BM in breast cancer.     

Increased Dickkopf-1 expression in breast cancer bone metastases

The aim of this study was to determine whether Dickkopf-1 (Dkk-1) expression in breast cancer was associated with bone metastases. We first analysed Dkk-1 expression by human breast cancer cell lines that induce osteolytic or osteoblastic lesions in animals. Dickkopf-1 levels were then measured in the bone marrow aspirates of hind limbs from eight NMRI mice inoculated with breast cancer cells that induced bone metastases and 11 age-matched non-inoculated control animals. Finally, Dkk-1 was measured in the serum of 17 women with breast cancer in complete remission, 19 women with breast cancer and bone metastases, 16 women with breast cancer and metastases at non-bone sites and 16 healthy women. Only breast cancer cells that induce osteolytic lesions in animals produced Dkk-1. There was a six-fold increase in Dkk-1 levels in the bone marrow from animals inoculated with MDA-B02 cells when compared with that of control non-inoculated animals (P=0.003). Median Dkk-1 levels in the serum of patients with breast cancer and bone metastases were significantly higher than levels of patients in complete remission (P=0.016), patients with breast cancer having metastases at non-bone sites (P<0.0001) and healthy women (P=0.047), although there was a large overlap in individual levels between the different groups. In conclusion, Dkk-1 is secreted by osteolytic human breast cancer cells lines and increased circulating levels are associated with the presence of bone metastases in patients with breast cancer. Measurements of circulating Dkk-1 levels may be useful for the clinical investigation of patients with breast cancer and bone metastases.     

血清Tracp5b在乳腺癌骨转移诊断和治疗效果监测方面的临床价值

目的:探讨血清抗酒石酸酸性磷酸酶5b(tartrate-resistant acid phosphatase 5b,Tracp5b)在诊断乳腺癌骨转移以及评价乳腺癌骨转移治疗效果方面的价值.方法:采用酶联免疫吸附法(enzyme-linked immumosorbent assay,ELISA)检测30例无骨转移乳腺癌患者及22例乳腺癌骨转移患者的血清Tracp5b水平,并检测骨转移患者应用化疗或内分泌治疗同时加用双膦酸盐治疗4个月后血清Tracp5b水平,对检测结果的差异性进行比较.结果:相对于乳腺癌无骨转移组,骨转移组血清Tracp5b的水平明显升高,差异有统计学意义(P＜0.05);在化疗或内分泌治疗同时加用双膦酸盐治疗4个月后,骨转移组患者的血清Tracp5b水平明显下降,差异有统计学意义(P＜0.05).结论:血清Tracp5b在发生乳腺癌骨转移时明显升高,在治疗显效后显著下降,Tracp5b可作为诊断乳腺癌骨转移和评价乳腺癌骨转移治疗效果的血清学指标.     

The bisphosphonate incadronate for bone metastases of breast cancer

Background. Bisphosphonates are bone resorption inhibitors which are effective in the treatment of diseases of increased bone turnover, such as hypercalcemia of malignancy and osteolytic bone metastasis. The safety and efficacy of incadronate, a third-generation bisphosphonate, were evaluated in breast cancer patients with bone metastases. Methods. Fifteen breast cancer patients with bone metastasis were enrolled. Incadronate's safety, its effectiveness in relieving bone pain, and its effects on bone metabolic markers and a tumor marker were assessed in 8 patients treated with a 10-mg IV infusion once a week for 5 weeks (10 mg × 5), 3 patients treated with a single 20-mg IV infusion (20 mg × 1), and 4 patients treated with a 20-mg IV infusion once a week for 5 weeks (20 mg × 5). Pain assessment was performed only in the patients with the repeated infusion regimens. Results. All incadronate treatment regimens were administered without any serious adverse reactions. Minimal fever was noted in 6 patients, but it subsided without any treatment. Incadronate relieved bone pain in 10 of the 12 patients who received repeated infusions. Levels of bone resorption markers dropped transiently, but the decreases in the individual markers of bone resorption varied. Levels of bone formation markers did not change significantly. Levels of a tumor marker specific to breast cancer, carbohydrate antigen (CA)15-3 decreased in patients whose metastases were limited to bone. Conclusion. The third-generation bisphosphonate, incadronate, was administered safely at dosages of up to 20 mg once a week for 5 weeks. Incadronate reduced bone pain, bone resorption marker levels, and CA15-3 tumor marker levels in breast cancer patients with bone metastases. Received: November 9, 1999 / Accepted: March 6, 2000     

核素骨显像联合肿瘤标记物检测对乳腺癌骨转移的诊断价值

目的：观察核素骨显像联合肿瘤标记物对乳腺癌骨转移的诊断价值。方法选择乳腺癌患者82例,按照核素骨显像结果分为转移组43例及未转移组39例,另选取40例健康体检女性作为对照组。观察核素骨显像以及肿瘤标记物检测结果,并对其诊断价值进行考察。结果转移组血清CA125、CA15-3及CEA表达水平及阳性率显著高于未转移组及对照组,骨转移灶数目≤2患者血清CA125、CA15-3以及CEA表达水平及阳性率均显著低于骨转移灶数目＞2的患者,差异均具有统计学意义（P＜0．05）。且随着骨转移分级程度的升高,患者乳腺癌相关肿瘤标记物CA125、CA15-3及CEA表达水平及阳性率均呈升高趋势,各分级间差异有统计学意义（ P＜0．05）。结论核素骨显像联合肿瘤标记物检测可提高诊断敏感性,对于乳腺癌骨转移的诊断具有重要的参考价值。