Normal values of urinary excretion and serum concentration of 5-S-cysteinyldopa and 6-hydroxy-5-methoxyindole-2-carboxylic acid, biochemical markers of melanoma progression.

The urinary excretion of the pheomelanin precursor 5-S-cysteinyldopa (5-S-CD) has been used as a tumour marker for metastatic melanoma. The eumelanin-related metabolite 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5M12C) is also excreted at high levels in some melanoma patients. In order to compare normal values, we measured urinary excretion and serum concentration of 5-S-CD and 6H5M12C in 33 Japanese normal subjects. The mean values of 5-S-CD and 6H5M12C in urine were 0.45 and 0.39 mumol/day, respectively, and those in serum 4.3 and 3.6 nmol/l. Levels of these markers in urine were much more variable than those in serum. We have adopted 1.5 mumol/day and 10 nmol/l as the upper limits for normal ranges of the urinary excretion and serum concentration, for both markers. No significant differences were found between men and women. There were no correlations among the four markers. The urinary excretion of both markers showed significant decrease in elderly subjects as compared with middle-aged subjects, while the serum concentration showed no age-dependent differences. These results suggest that the levels of 5-S-CD and 6H5M12C in serum are more reliable as tumour markers for the estimation of melanoma progression than those in urine.     

Evaluation of water soluble and lipid soluble sialic acid levels as tumor markers

Serum sialic acid and lipid-soluble sialic acid was measured in 39 cancer patients, 16 patients with Crohns disease, 13 patients with rheumatoid arthritis, 28 patients with osteoarthritis, and 40 normal patients. Sialic acid was also determined in several patients who had undergone extensive chemotherapy or radiation. Elevations of sialic acid were observed in 33 of 39 cancer patients (sensitivity = 85%). No elevations were observed in the normals (specificity = 100%). However, 11 of 13 patients with rheumatoid arthritis and 9 of 16 patients with Crohns disease had elevated sialic acid. Patients undergoing extensive chemotherapy or radiation for two months prior to sialic acid measurement frequently had normal values even though tumor was present. Four patients, who were found to have cysts instead of cancer on biopsy or pathological examination, had normal sialic acid values. Three patients with active leukemia had elevated sialic acid, but three patients whose leukemia was in remission had normal sialic acid levels. Correlations were also found between sialic acid from an enzymatic total sialic acid and the Ehrlich sialic acid, and also between total sialic acid measured by the Ehrlich method and lipid soluble sialic acid.     

血清唾液酸在恶性肿瘤中的临床应用价值

目的探讨血清唾液酸（SA）在恶性肿瘤中的临床应用价值。方法采用酶法对50名健康人、90例良性疾病及160例恶性肿瘤患者血清SA的水平进行检测,分析血清SA水平在肿瘤不同病理类型及相关治疗前后的表达变化。结果恶性肿瘤各组血清SA水平均显著高于良性疾病组及健康对照组（P〈0．01）,恶性肿瘤各组阳性率亦显著高于良性疾病组（P〈0．01）;各组织学类型恶性肿瘤组血清SA水平显著高于良性疾病组及健康对照组（P〈0．01）,但各组织学类型恶性肿瘤组之间血清SA水平差异无统计学意义（P〉0．05）;恶性肿瘤患者经相关治疗后,病情好转组血清SA水平明显下降,与治疗前相比差异有统计学意义（P〈0．01）;病情恶化组血清SA水平有上升趋势,但与治疗前相比差异无统计学意义（P〉0．05）。结论血清SA对恶性肿瘤的诊断、治疗、疗效判断、病情监测及预后判断具有一定临床应用价值。     

Use and limitations of serum total and lipid-bound sialic acid concentrations as markers for colorectal cancer

Concentrations of total serum N-acetyl-neuraminic acid (NANA) by high-performance liquid chromatography (HPLC) and lipid-bound sialic acid (LSA) by resorcinol procedure were evaluated and compared to carcinoembryonic antigen (CEA) as markers for colorectal carcinoma. Elevated concentrations of NANA were found in 32% of patients with nonmalignant disorders, 28% of patients with localized cancer, and 87% of patients with metastatic cancer. All three markers correlated with the extent of metastasis of colorectal carcinoma. Strong correlation was found between NANA and LSA measurements, whereas measurement of the sialic acid markers provide information that can not be derived from the measurement of CEA. NANA and LSA show promise as supplemental markers for staging and monitoring colorectal cancer, but they are neither sensitive nor specific enough for cancer screening.     

Serum levels of S-100 protein and 5-S-cysteinyldopa as markers of melanoma progression

Serum S-100 protein is widely used as a marker of melanoma and since 5-S-cysteinyldopa (5-S-CD) is a precursor of melanin its serum and urinary levels can reflect melanoma progression. In this study we examined the concentration changes of serum S-100 protein and 5-S-CD in 252 melanoma patients of different clinical stages. Serum samples were taken from 252 melanoma patients at 860 times, from June 1996 to July 1998. The serum S-100 protein was measured by the immunoluminometric assay, levels of 5-S-CD was determined by HPLC. The value of S-100 protein in patients with primary melanoma (0.11m mg/l) and in patients without symptoms (0.15 m mg/l) ranged around the normal level (0.01 0.12 m mg/l). There was a significant difference between the values of patients with or without symptoms. There was a similarly significant difference between the S-100 values of clinical Stage I (0.11 mg/l) and Stage III (2.91 mg/l) as well as between those of clinical Stage II (0.47 mg/l) and Stage III (2.91 mg/l), respectively. Analyzing the values of patients with symptoms we observed significant difference between the S-100 protein values of patients with primary tumor and those with solitary or multiple distant metastases. In case of 5-S-CD significant difference was found between clinical Stage I and III as well as clinical Stage II and III. Furthermore, there was a significant difference between the mean marker values of patients with primary tumor, lymph node, lung metastasis and clinical stage III.     

Evaluation of serum sialic acid, heat stable alkaline phosphatase and fucose as markers of breast carcinoma

Serum levels of total sialic acid (TSA), lipid bound sialic acid (LSA), heat stable alkaline phosphatase (HSAP) and fucose were measured in 39 patients with breast carcinoma, 14 patients with benign breast diseases and 35 healthy female individuals. Elevated levels of the four biomarkers in breast carcinoma were significant when compared with controls (p less than 0.001). Fucose levels were most sensitive (71.8%), while TSA levels were most specific (64.3%) for breast carcinoma. Sensitivity and specificity were 100% when combinations of LSA with fucose and TSA with HSAP were studied respectively. LSA was significantly elevated in infiltrating duct carcinoma patients compared with lobular carcinoma (p less than 0.001). TSA, HSAP and fucose also had lower mean values in lobular carcinoma as compared to infiltrating duct carcinoma. Increase in the levels of LSA and HSAP after surgical removal of the tumor in breast carcinoma occurred prior to the clinical evidence of the recurrence. The results indicate that the combination of the markers studied might be useful in breast cancer diagnosis and treatment monitoring.     

Ovarian cancer and tumor markers: sialic acid, galactosyltransferase and CA-125

In an effort to correlate the serum values of potential markers, including CA-125, galactosyltransferase, and total sialic acid, with residual tumor mass after initial surgery, 43 patients with FIGO stage IIb and c, III and IV ovarian cancer were studied. The sensitivity of galactosyltransferase and sialic acid levels was sufficient to correlate their serum values with the corresponding residual tumor mass. Furthermore, 28 patients were histopathologically evaluated for their response to chemotherapy. Determination of these tumor markers did not permit discrimination between small residual disease (less than or equal to 1 cm) and a state of 'no evidence of disease'. Conversely, progression of disease has been associated with a sensitive increase in the level of all three markers. CA-125 has been found to be the most useful of the three for distinguishing between responders and nonresponders.     

Individual and combined usefulness of lipid associated sialic acid, mucoid proteins and hexoses as tumor markers in breast carcinoma

Serum levels of lipid associated sialic acid (LASA), mucoid proteins (MP) and hexoses (galactose + mannose) were measured in 41 breast cancer patients, 14 patients with benign breast diseases and 36 healthy age matched female individuals. In breast carcinoma patients, we have observed significant increase in the levels of the three markers compared with the controls (P less than 0.001) and in MP and hexoses compared to the patients with benign breast diseases (P less than 0.001). LASA and hexoses levels were significantly higher in benign breast diseases with respect to controls (P less than 0.001 and P less than 0.01, respectively). We evaluated the sensitivity and specificity of the markers individually and in combination. MP were most sensitive (71.8%) and specific (71.4%). Both sensitivity and specificity were increased when combinations of the markers were studied. Combination of MP with LASA was most sensitive (97.4%) while the combination of MP and hexoses was most specific (92.9%). LASA was significantly elevated in infiltrating duct carcinoma compared to lobular carcinoma (P less than 0.001). MP and hexoses also showed higher mean value in infiltrating duct carcinoma than lobular carcinoma. The present study suggests that the combination of the markers investigated might be useful for diagnosis and classification of breast carcinoma.     

血清唾液酸对消化道恶性肿瘤诊断与治疗临床价值探讨

目的：研究血清唾液酸（sialicacid,SA）在消化道恶性肿瘤诊断及治疗监测中的临床价值。方法：2010-10-01-2012-10-30烟台市烟台山医院收治的恶性肿瘤患者318例作为恶性肿瘤组,同时选取同期同院查体中心的健康体检者100名作为健康对照组,以及同期同院确诊的消化系统良性疾病患者167例作为良性疾病组。采用BECKMANCOUL-TERUniCelDxC800全自动分析仪对各组患者的血清SA含量进行检测,并对各组患者的血清SA进行统计学分析。结果：恶性肿瘤Ⅰ～Ⅳ期患者血清SA分别为（623±89）、（719±122）、（782±176）和（913±235）mg／L。恶性肿瘤患者的血清SA水平明显高于良性疾病组和健康对照组,P〈0．01。45例接受手术治疗的肿瘤患者,血清SA浓度由术前的（685±98）mg／L降为术后的（605±90）mg／L。连续接受化疗的96例患者,病情好转或病情稳定的有72例,4次化疗后血清SA浓度明显降低为（624±95）mg／L。结论：血清唾液酸对消化道恶性肿瘤的诊断和治疗监测等有重要临床价值。     

脑肿瘤治疗前后血清和脑脊液唾液酸含量变化

目的　通过检测治疗前后脑肿瘤患者血清和脑脊液 (CSF)中唾液酸 (SA)含量 ,探讨其变化与疗效和转归的关系 ,并比较两者的优劣。方法　用SA快速比色测定盒对 43例脑肿瘤患者治疗前后血清和CSF中SA检测、随访进行分析 ,并与对照组比较。结果　脑肿瘤患者血清SA含量术后较术前增加 (P >0 .0 5 )而CSF SA下降 ,良性肿瘤组有明显减低 (P <0 .0 0 1)。恶性肿瘤经放疗或 /和化疗后缓解期SA亦显著减低 (P <0 .0 0 1) ,复发胶质瘤则显著升高 (P <0 .0 0 1)。结论　血清和CSF中SA含量的变化都可作为脑肿瘤治疗后疗效、复发及转归的监测指标 ,而后者更为恰当、迅速 ,更敏感     

Five tumor markers in lung cancer: significance of total and "lipid"-bound sialic acid.

Total sialic acid (TSA) and "lipid-bound" sialic acid (LSA) were evaluated in comparison to carcinoembryonic antigen (CEA) and ferritin and neuron specific enolase (NSE) in 152 untreated patients with primary lung cancer, 107 benign pulmonary disease patients and 207 notmal controls. The mean concentrations of TSA, LSA and CEA in lung cancer patients, were significantly higher than in benign and normal controls (p less than 0.001), while the mean ferritin and NSE levels were significantly higher than in normal controls only (p less than 0.001). At the designated cut-off serum levels, sensitivities of the five markers for lung cancer were in decreasing order: TSA 86.5% (greater than 80 mg/dL), LSA 77% (greater than 20 mg/dL), CEA 46.4% (greater than 5 ng/mL), ferritin 36% (greater than 300 ng/mL) and NSE 34.5% (greater than 12.5 ng/mL). Using the benign pulmonary values as negative controls the specificity of each marker was as follows: CEA 88%, ferritin 72%, NSE 58%, TSA 44% and LSA 44%. In small cell lung cancer (SCLC) patients, NSE mean concentrations and sensitivity were significantly higher than in non-small lung cancer (NSCLC) patients (9.63 +/- 4.4 versus 23.54 +/- 16.9, p less than 0.001 and 74% versus 21.4% respectively). While in NSCLC patients only CEA levels correlated well with the stage of the disease, in SCLC patients concentrations of TSA, LSA and ferritin were significantly higher in extensive than in limited disease stages. These preliminary data suggest that, although TSA and LSA are highly sensitive markers in lung cancer, their specificity is low.     

Comparison of phaeomelanin and its precursor 5-S-cysteinyldopa in the serum of melanoma patients

5-S-Cysteinyldopa (5-S-CD) has been used as a biochemical marker of melanoma progression. Recently we have shown that the serum level of 5-S-CD is a sensitive and specific marker in predicting distant metastases. In melanocytes and melanoma cells, cysteinyldopa isomers are oxidized to phaeomelanin, the yellow to reddish melanin pigment. In this study we have developed a new method to measure levels of phaeomelanin in serum samples and have evaluated its clinical significance. The method is based on the production of 4-amino-3-hydroxyphenylalanine (4-AHP) and 3-amino-4-hydroxyphenylalanine (3-AHP) on reductive hydrolysis of phaeomelanin with hydriodic acid. 3-AHP is also derived from 3-nitrotyrosine-containing proteins. The isomeric 4-AHP and 3-AHP can be separated by high performance liquid chromatography. The mean +/- SD serum levels of 5-S-CD in control subjects (n = 36), in melanoma patients without recurrence (n = 92) and in melanoma patients with metastases (n = 24) were 2.7 +/- 1.2 nM (median 2.3 nM), 4.0 +/- 1.6 nM (median 3.8 nM) and 72 +/- 105 nM (median 35 nM), respectively. The serum levels of 4-AHP in these three groups were 45 +/- 21 nM (median 31 nM), 80 +/- 75 nM (median 53 nM) and 306 +/- 627 nM (median 133 nM), respectively. The serum levels of 4-AHP in patients with metastases (100 samples from 15 patients with progressive disease) correlated well (r = 0.887) with serum levels of 5-S-CD, while serum levels of 3-AHP did not (r = 0.240). The serum 5-S-CD and 4-AHP levels were serially analysed in the 15 patients with progressive disease. In two patients (13%), serum 4-AHP levels were elevated to abnormal levels before the serum 5-S-CD levels exceeded the cut-off value of 10 nM. In five patients (33%), the serum 4-AHP levels rose concurrently with the serum 5-S-CD levels. In the remaining eight patients (54%), serum 4-AHP levels were of less diagnostic value. Thus, the serum phaeomelanin level appears to be less sensitive than the serum 5-S-CD level in detecting distant metastases.     

临床常见五种恶性肿瘤各分期血清唾液酸检测及其临床意义

目的检测临床常见5种恶性肿瘤患者各分期血清唾液酸水平(SA)及初步评价SA在治疗过程中的临床意义. 方法血清唾液酸采用酶法测定.根据UICC分期,对Ⅰ期73例(肺癌15例、食管癌10例、胃癌13例、结肠癌10例、乳腺癌25例),Ⅱ期74例(肺癌15例、食管癌12例、胃癌14例、结肠癌18例、乳腺癌15例),Ⅲ期112例(肺癌36例、食管癌16例、胃癌22例、结肠癌17例、乳腺癌21例),Ⅳ期251例(肺癌90例、食管癌37例、胃癌49例、结肠癌41例、乳腺癌34例),进行SA检测.观察105例患者治疗前后的SA值动态变化.所有数据进行统计学分析. 结果Ⅰ、Ⅱ期恶性肿瘤患者与正常对照组比较差异无显著性(P＞0.05);Ⅲ、Ⅳ期患者SA水平升高,与正常对照组比较差异有显著性(P ＜0.05).治疗前后部分Ⅰ、Ⅱ期病例SA水平无明显变化;Ⅲ、Ⅳ期患者治疗后SA水平降低,且与疗效呈正相关(P＜0.05). 结论血清SA水平可作为常见恶性肿瘤分期的参考指标之一,特别是Ⅲ和Ⅳ期肿瘤,还可作为Ⅲ、Ⅳ期病例治疗效果的一个评价指标.     

Significance of serum protein and lipid-bound sialic acid as a marker for genitourinary malignancies

A prospective study was done to evaluate the roles of serum N-acetylneuraminic acid (NANA) and the lipid-bound subfraction of sialic acid (LSA) concentrations in the detection and staging of cancer, and the follow-up of treatment in patients with genitourinary malignancies. Multiple determinations were obtained in 177 subjects: 90 normal volunteers, 38 patients with prostate cancer, 20 patients with bladder cancer, 15 patients with renal cell cancer, and 14 patients with benign urologic diseases. The results showed a low incidence of elevated values in patients with early stages of cancer and a high incidence of false-positive values with serum NANA concentrations in patients with benign urologic diseases, especially prostatitis. Serum NANA and LSA concentrations were highly correlated with the stage and grade in patients with advanced urologic cancer, and may be used as markers of tumor activity during follow-up under treatment; currently, however, they are not useful in the screening of patients for urologic cancer. Their usefulness in prostatic cancer is at least comparable to that of acid phosphatase determinations by the enzymatic and radioimmunoassay methods, which were elevated in a smaller percentage of patients with prostate cancer than were the NANA or LSA concentrations.     

Human xeno-autoantibodies against a non-human sialic acid serve as novel serum biomarkers and immunotherapeutics in cancer

Human carcinomas can metabolically incorporate and present the dietary non-human sialic acid Neu5Gc, which differs from the human sialic acid N-acetylneuraminic acid (Neu5Ac) by 1 oxygen atom. Tumor-associated Neu5Gc can interact with low levels of circulating anti-Neu5Gc antibodies, thereby facilitating tumor progression via chronic inflammation in a human-like Neu5Gc-deficient mouse model. Here we show that human anti-Neu5Gc antibodies can be affinity-purified in substantial amounts from clinically approved intravenous IgG (IVIG) and used at higher concentrations to suppress growth of the same Neu5Gc-expressing tumors. Hypothesizing that this polyclonal spectrum of human anti-Neu5Gc antibodies also includes potential cancer biomarkers, we then characterize them in cancer and noncancer patients' sera, using a novel sialoglycan microarray presenting multiple Neu5Gc-glycans and control Neu5Ac-glycans. Antibodies against Neu5Gcα2-6GalNAcα1-O-Ser/Thr (GcSTn) were found to be more prominent in patients with carcinomas than with other diseases. This unusual epitope arises from dietary Neu5Gc incorporation into the carcinoma marker Sialyl-Tn, and is the first example of such a novel mechanism for biomarker generation. Finally, human serum or purified antibodies rich in anti-GcSTn-reactivity kill GcSTn-expressing human tumors via complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity. Such xeno-autoantibodies and xeno-autoantigens have potential for novel diagnostics, prognostics, and therapeutics in human carcinomas.     

血清与脑脊液唾液酸含量测定对脑瘤与脊髓瘤诊断价值的比较

检测脑瘤与脊髓肿瘤患者血清和脑脊液中唾液酸的含量,比较两者对脑瘤与脊髓瘤的诊断价值。方法应用ＳＡ快速比色测定盒对１１３例脑肿瘤和２４例脊髓肿瘤患者血清及ＣＳＦ唾认酸含量进行测定,分别进行组间比较。结论血清和ＣＳＦ中ＳＡ含量可和为脑瘤与脊髓瘤的诊断指标之一,而ＣＳＦ中ＳＡ含量的测定对脑瘤与脊髓瘤的诊断更具临床价值。     

浆膜腔积液肿瘤标志物与血清肿瘤标志物及脱落细胞学相关性探讨

目的:探讨浆膜腔积液肿瘤标志物癌胚抗原(CEA)、糖类抗原199、125、724、153、242(CA199、CA125、CA724、CA153、CA242)及甲胎蛋白(AFP)与同时期血清肿瘤标志物及脱落细胞学之间的关系。方法:选择202例确诊为恶性肿瘤并伴有浆膜腔积液的患者,依据细胞学检查结果分为脱落细胞学阳性组和脱落细胞学阴性组。对脱落细胞学阳性组的恶性浆膜腔积液患者的同一时间点的血清及浆膜腔积液肿瘤标志物水平进行检测分析。并对脱落细胞学阳性组和阴性组间的浆膜腔积液肿瘤标志物检测分析。结果:恶性浆膜腔积液肿瘤标志物水平明显高于血清,二者比较差异有统计学意义(P<0.05)。恶性胸腹腔积液肿瘤标志物与血清肿瘤标志物相关性好(P<0.01)。胃癌患者脱落细胞学阳性组与阴性组的浆膜腔积液肿瘤标志物水平比较发现CEA、CA125、CA199差异无统计学意义(P>0.05),CA724差异有统计学意义(P<0.05)。结论:恶性浆膜腔积液中肿瘤标志物水平与血清中肿瘤标志物水平具有很好相关性,血清肿瘤标志物的检测可以很好的反应恶性浆膜腔积液中肿瘤标志物水平。且胃癌腹水中CA724水平具有辅助诊断浆膜腔积液良恶性的价值。