Serum carbohydrate antigen 19-9 represents a marker of response to neoadjuvant therapy in patients with borderline resectable pancreatic cancer

Objectives

The purpose of this study was to determine the relationship between carbohydrate antigen (CA) 19-9 levels and outcome in patients with borderline resectable pancreatic cancer treated with neoadjuvant therapy (NT).

Methods

This study included all patients with borderline resectable pancreatic cancer, a serum CA 19-9 level of ≥40 U/ml and bilirubin of ≤2 mg/dl, in whom NT was initiated at one institution between 2001 and 2010. The study evaluated the associations between pre- and post-NT CA 19-9, resection and overall survival.

Results

Among 141 eligible patients, CA 19-9 declined during NT in 116. Following NT, 84 of 141 (60%) patients underwent resection. For post-NT resection, the positive predictive value of a decline and the negative predictive value of an increase in CA 19-9 were 70% and 88%, respectively. The normalization of CA 19-9 (post-NT <40 U/ml) was associated with longer median overall survival among both non-resected (15 months versus 11 months; P = 0.022) and resected (38 months versus 26 months; P = 0.020) patients. Factors independently associated with shorter overall survival were no resection [hazard ratio (HR) 3.86, P < 0.001] and failure to normalize CA 19-9 (HR 2.13, P = 0.001).

Conclusions

The serum CA 19-9 level represents a dynamic preoperative marker of tumour biology and response to NT, and provides prognostic information in both non-resected and resected patients with borderline resectable pancreatic cancer.     

Detection of pancreatic cancer with normal carbohydrate antigen 19-9 using protein chip technology

AIM: To develop a method to differentiate pancreatic cancer patients from healthy or benign individuals when carbohydrate antigen (CA) 19-9 is normal.METHODS: Forty-one serum samples from patients with pancreatic lesions and blood samples from 20 healthy individuals were collected at the first stage of the experiment according to the enrolment criteria. General characteristics and some clinical features were carefully compared to ensure that the results were reasonable. All the blood samples were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) combined with CM10 chips and a related bioinformatics analysis program to generate diagnostic models with different proteins. Forty-seven consecutive samples were tested at the next stage to verify the veracity and efficiency of the models.RESULTS: The sex, age, and serum CA19-9 levels among the three groups (malignant, benign, and healthy) were statistically matched (P values were 0.957, 0.145, and 0.382, respectively). Two patterns were generated. Pattern 1 with four proteins theoretically had a specificity and sensitivity of 100% in distinguishing pancreatic cancer from healthy individuals, while it was 86.7% and 86.4%, respectively, in the subsequent practical verification. The positive predictive value (PPV) of the model was 86.4%. One of the four proteins was expressed highly in pancreatic cancer while the other three were expressed weakly. Pattern 2 consisted of six proteins that showed a specificity of 70.0% and sensitivity of 77.3% for differentiating malignancy from benign tumors. Its PPV reached 85.0%. Only one of these six proteins showed high expression in the malignant group.CONCLUSION: SELDI-TOF-MS may facilitate diagnosis or differential diagnosis of pancreatic cancer when CA19-9 is normal. Pattern 1 may serve as a useful screening tool.     

Prognostic significance of SUVmax and serum carbohydrate antigen 19-9 in pancreatic cancer

AIM:To investigate the prognostic significance of pretreatment standardized maximum uptake value(SUVmax)and serum carbohydrate antigen(CA)19-9 in pancreatic cancer.METHODS:From January 2007 to October 2011,80 consecutive patients with pancreatic cancer who received positron emission/computed tomography before any treatment were enrolled in this study.The pretreatment SUVmax and CA19-9 level of the primary pancreatic tumor were obtained and compared with clinicopathological and prognostic factors.Student’s t test for unpaired data was used to analyze the differences between two groups.Univariate analysis and Cox proportional hazards regression were used to examine the independent effects of each significant variable.Survival was analyzed by the Kaplan-Meier method.RESULTS:There was a significant correlation between both the SUVmax and serum CA19-9 of pancreatic cancer and R0 surgical resection(P=0.043 and P=0.007).Lymph node metastasis was associated with SUVmax(P=0.017),but not serum CA19-9(P=0.172).On the contrary,the tumor stage was significantly related to serum CA19-9(P=0.035),but not SUVmax(P=0.110).The univariate analysis showed that survival time was significantly related to tumor stage(P<0.001),lymph node metastasis(P=0.043),R0 surgical resection(P<0.001),serum CA19-9(P=0.001),SUVmax(P<0.001)and SUVmax plus CA19-9(P=0.002).Multivariate analysis clearly showed that only tumor stage(hazard ratio=0.452;P=0.020)was an independent prognostic factor for overall survival in pancreatic cancer.Higher SUVmax or CA19-9showed worse prognosis.We found that high serum CA19-9 plus SUVmax was the most significant variable.CONCLUSION:Higher pretreatment SUVmax and serum CA19-9 indicates poor prognosis.SUVmax plus serum CA19-9 is the most significant variable in predicting survival.     

Evaluation of carbohydrate antigens 19-9 and 12-5 in patients with pancreatic cancer

The diagnostic value of the tumor-associated antigens Ca 19-9 and Ca 12-5 was tested in 130 subjects (38 healthy controls, 37 carcinomas of the pancreas, 23 chronic pancreatitis, 23 extrapancreatic gastrointestinal cancers, 9 endocrine pancreatic tumors). Ca 19-9 levels above 37 U/ml were obtained in 67.6% and Ca 12-5 levels above 39 U/ml in 45.9% of carcinomas of the pancreas, 4.3 and 8.7%, respectively, of chronic pancreatis, 21.7 and 17.4% of extrapancreatic gastrointestinal tumors, and 0 and 11.1% of endocrine pancreatic tumors and in none of the healthy controls. Results of preoperative determination of Ca 19-9 and Ca 12-5 gave a sensitivity of 67.6 and 45.9%, a specificity of 91.8 and 90.9%, a predictive value of a positive test of 80.6 and 70.8%. When elevation of both antigens was required, sensitivity decreased to 32.4% but specificity rose to 97.3%. All but one of the pancreatic cancer patients were at stage 3 and 4. The only patient with pancreatic cancer in stage 1 had normal levels of both markers. Ca 19-9 and Ca 12-5, whether alone or associated, represent a good diagnostic test for differentiating pancreatic cancer from chronic pancreatitis. Due to the low sensitivity of both markers, the tests are of limited value when any other diagnostic evidence of pancreatic cancer is absent.     

Diagnostic value of the assay of carbohydrate antigen 19-9 in patients with primary bronchial cancer

We studied the levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) in 90 patients with primary lung cancer. One or both markers were increased in 45 patients (50%): CEA only was increased in 13, CA 19-9 only was increased in 19, and both CEA and CA 19-9 were increased in 13. Increase of markers did not differ according to histologic subtype of cancer. Increase or decrease of the markers (mainly CA 19-9) usually parallelled evolution of the disease in our patients. Thus, measurement of both CEA and CA 19-9 levels are of diagnostic value in half the patients with primary lung cancer.     

Human equilibrative nucleoside transporter 1 level does not predict prognosis in pancreatic cancer patients treated with neoadjuvant chemoradiation including gemcitabine

Background

Gemcitabine is a key drug for the treatment of pancreatic cancer. Human equilibrative nucleoside transporter 1 (hENT1) is a major transporter responsible for gemcitabine uptake into cells. This study was conducted to elucidate the association between expression level of hENT1 and outcome for pancreatic cancer patients treated with neoadjuvant therapy including gemcitabine.

Methods

Sixty-three patients who underwent neoadjuvant chemoradiation followed by curative surgery for pancreatic ductal adenocarcinomas were included. Immunohistochemistry was performed using resected specimens and the staining intensity of hENT1 was scored as having no staining, low staining, or high staining; the former two were defined as negative expression of hENT1. The association between expression level of hENT1 and overall survival was evaluated by Cox proportional regression model.

Results

Expression level of hENT1 was evaluated as positive in 22 (35%) patients, and as negative in 41 (65%) patients. Univariate analysis showed that regional lymph node metastasis, vascular permeation, and perineural invasion are prognostic factors; however, expression level of hENT1 did not reach statistical significance. Multivariate analysis showed only vascular permeation as a prognostic factor.

Conclusions

Expression level of hENT1 was not associated with prognosis for pancreatic cancer patients who were treated with neoadjuvant chemoradiation including gemcitabine.     

Noninvasive diagnosis of advanced pancreatic cancer by real-time ultrasonography, carcinoembryonic antigen, and carbohydrate antigen 19-9

One-hundred-forty patients with clinical impression of pancreatic cancer were examined prospectively with three noninvasive tests: real-time ultrasonography, determination of serum carcinoembryonic antigen (CEA), and carbohydrate antigen (CA 19-9). Among them, 24 (17.1%) patients were found to have pancreatic cancer. The sensitivity of ultrasonography, CEA, and CA 19-9 was 72.9%, 70.8%, and 83.3%, respectively; the specificity was 94.0%, 77.6%, and 90.5%, respectively, and the diagnostic accuracy was 91.4%, 76.4%, and 89.3%, respectively. The combination of ultrasonography and determination of serum CA 19-9 had better sensitivity (95.8%), comparable specificity (84.5%), and comparable diagnostic accuracy (86.4%) to any individual test alone or any other combination. It was suggested that combined use of real-time ultrasonography and determination of serum CA 19-9 provided excellent noninvasive screening for patients suspected of having pancreatic cancer.     

预测胰腺导管腺癌新辅助治疗反应的常用生物标志物

［摘要］　胰腺导管腺癌（PDAC）恶性程度高,预后差,发病率逐年升高。PDAC的治疗方式不仅取决于诊断时的疾病分期,还与复杂的解剖关系密不可分。近年来,对于技术上可切除的病变的首选治疗方法已经从先行手术逐渐转向了新辅助治疗。选择合适的方案并判断治疗反应对于最佳的肿瘤学结果至关重要,尤其是在这种情况下传统影像学方法已被证明并不可靠。肿瘤生物标志物作为辅助实验室检查,有可能在治疗计划选择、治疗监测中发挥关键作用。该文将介绍目前常用的PDAC生物标志物,并讨论这些标志物在新辅助治疗中可能的应用价值,并确定将其用作治疗方案选择、评估治疗进展、预后或潜在复发的标志物的能力。     

Preoperative serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels for the evaluation of curability and resectability in patients with pancreatic adenocarcinoma

Background Purpose

Although carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are the most studied serum tumor markers that have been evaluated for diagnosis and prognosis in patients with pancreatic cancer, little is known of the value of these markers for the prediction of curability and resectability.

Methods

We retrospectively reviewed preoperative serum levels of CEA and CA 19-9 in 244 consecutive patients with pancreatic operations.

Results

Although 159 pancreatic operations seemed “resectable”, 93 of them were judged curative (R0) and the other 66 turned out to be noncurative (R1/2). The remaining 85 failed resection because of unexpected metastasis or locally advanced disease (LD), which was unresectable compared with levels in those patients without liver metastasis or LD. CEA levels were significantly higher in patients with liver metastasis and LD, while CA 19-9 levels were correlated with liver and peritoneal metastases. When both markers were negative, curative (R0) and respectable (R0 + R1/2) operation were performed in 70% and 85% of patients, respectively. Logistic regression analysis indicated that under conditions where both CEA and CA 19-9 were negative, the odds ratios for curative and respectable operations were 4.43 and 3.58, respectively.

Conclusions

Our data suggest that combined preoperative CEA and CA 19-9 levels are suitable for assessing expected curability and resectability in patients with pancreatic cancer.

     

Endoscopic ultrasonography in patients with elevated carbohydrate antigen 19-9 of obscure origin

AIM: To evaluate the efficacy of endoscopic ultrasonography (EUS) in patients with elevated carbohydrate antigen (CA) 19-9 levels of obscure origin. METHODS: Patients who had visited Pusan National University Hospital because of elevated serum CA 19-9 levels, between January 2007 and December 2009, were retrospectively enrolled. EUS had been performed on all subjects, in addition to routine blood tests, endoscopy, abdominal computed tomography (CT) and other clinical exams, which had not revealed any abnormal findings suggestive of the origin of the elevated CA 19-9 levels. RESULTS: Of the 17 patients, gallbladder sludge was detected in 16 patients (94.1%) and common bile duct sludge was observed in 3 patients (17.6%). After the administration of ursodeoxycholic acid to 12 of the patients with gallbladder sludge, CA 19-9 levels normalized in 6 of the patients after a median of 4.5 mo. CONCLUSION: EUS is a useful diagnostic method for patients with elevated CA 19-9 levels of obscure origin, even if the reason for abnormal levels of this serum marker cannot be determined through prior examinations, including abdominal CT.     

Alpha-fetoprotein,carcinoembryonic antigen,and carbohydrate antigen 19-9-producing gallbladder cancer

We report a rare case of alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9-producing gallbladder cancer with high levels of CA125 and protein induced by vitamin K absence or antagonist II (PIVKA II). A 63-year-old man was diagnosed with gallbladder cancer with metastases to the liver, based on ultrasonography and computed tomography of the abdomen showing multiple tumorous lesions in the liver and a thickened gallbladder wall. Laboratory data showed high levels of tumor markers: 4647.4 ng/ml AFP, 9987.1 ng/ml CEA, 11704.0 U/ml CA19-9, 847.6 U/ml CA125, and 0.2 AU/ml PIVKA II. AFP in the present case showed an increase in Concanavalin A-nonbinding fraction and an increase inLens culinaris lectin-binding fraction by affinity column chromatography. The patient died of hepatic failure. Autopsy revealed gallbladder cancer consisting of papillary adenocarcinoma and moderately differentiated tubular adenocarcinoma. By immunohistochemical staining, AFP was detected in the papillary adenocarcinoma portion of the primary focus and metastatic tumor cells in the liver, but was not detected in noncancerous liver tissue. CEA and CA19-9 were detected mainly in the tubular adenocarcinoma portion.     

进展期大肠癌患者术中应用化疗药物外周血CEA、CA19-9的检测及临床意义

目的:检测大肠癌患者术中应用化疗药物后,手术前后血清CEA和CAl9-9的变化,确定其对预防大肠癌微转移,降低术后复发率和死亡率的临床意义.方法:采用ELISA方法测定30例术中应用化疗药物大肠癌患者及30例术中未应用化疗药物大肠癌患者手术前后外周血中CEA和CAl9-9含量的变化,同时选用30例非肿瘤人群作为正常对照.结果:60例大肠癌患者(Duck C期)术前外周血中CEA,CAl9-9均值高于正常值(60.73±25.99 mg/L vs 2.67±1.643 mg/L,P＜0.01;112.73±78.76 kU/L vs 14.6±6.68 kU/L,P＜0.01).30例术中应用化疗药物的大肠癌患者手术后血清CEA、CAl9-9下降较快(术后7 d:7.96±3.32 mR/L,29.34±11.05 kU/L,P＜0.01 vs术前),术中未应用化疗药物组的大肠癌患者术后血清CEA和CA-199下降缓慢(术后7 d:34.23±20.59 mg/L,88.12±32.28 kU/L,P＞0.05 vs 术前).结论:通过定量检测大肠癌患者外周血CEA和CAl9-9的含量,证明手术中温热灌注化疗 动脉化疗以及术后联合化疗的辅助治疗是十分必要的,对预防大肠癌微转移,降低术后复发率和死亡率的有重要的临床意义.     

Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population

BACKGROUND AND AIM: Although the prognosis for pancreatic cancer is generally poor, it is well known that the survival rate for resected pancreatic cancer is much higher than that for more conservative treatment. The importance of early detection is emphasized for resection of pancreatic cancer. Measurement of serum carbohydrate antigen (CA) 19-9 has shown satisfactory sensitivity and predictive value in symptomatic patients, but no available data has been found on healthy asymptomatic subjects. Thus, the authors aimed to determine the clinical usefulness of CA 19-9 as a screening tool for pancreatic cancer in asymptomatic subjects. METHODS: From December 1994 to November 2000, 70 940 asymptomatic persons visiting the Health Promotion Center at the Samsung Medical Center, Seoul, Korea, participated. All subjects underwent abdominal ultrasonography and serum CA 19-9 measurement. The authors analyzed the sensitivity, specificity, and predictive values of CA 19-9 for detecting pancreatic cancer. Also, those subjects who had a serum CA 19-9 level above the cut-off value were followed up using a serial check of CA 19-9, computed tomography, or endoscopic retrograde cholangiopancreatography. RESULTS: The number of subjects with a level of CA 19-9 above the cutoff of 37 U/mL was 1063 (1.5%), including four cases diagnosed with pancreatic cancer. The prevalence of pancreatic cancer over the age of 30 years is 13.66 per 100 000 population in Korea. Therefore, the sensitivity is 100% and the specificity 98.5%. However, the positive predictive value of CA 19-9 for detecting pancreatic cancer is only 0.9% in the asymptomatic population. CONCLUSION: Mass screening for pancreatic cancer using CA 19-9 levels in asymptomatic subjects is ineffective because of a very low positive predictive value, despite its high sensitivity and specificity.     

Clinical importance of preoperative carcinoembryonic antigen and carbohydrate antigen 19-9 levels in gastric cancer

Although serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are commonly measured before surgery for gastric carcinoma, this clinical significance is not fully understood. We evaluated a total of 549 patients with gastric cancer who underwent gastrectomy. Levels of CEA and CA19-9 were measured preoperatively in all patients. We retrospectively analyzed correlations between CEA or CA19-9 and clinicopathologic features, and estimated the prognostic utility of the tumor markers by analyzing clinicopathologic characteristics of the carcinoma as a function of seropositivity or negativity of the antigens in combination or by raising the levels. The positivity rates of CEA (> or =5 ng/mL) and CA19-9 (> or =37 U/mL) were 19.5% and 18%, respectively. Serum CEA and CA19-9 positivity significantly correlated with depth of invasion, hepatic metastasis, and curativity. Forty-nine patients positive for both CEA and CA19-9 had significantly higher frequencies of lymph node metastasis, deeper invasion by the tumor, lower rates of curative resection (p < 0.01), and higher rates of hepatic metastasis (p < 0.05) than 377 patients with normal levels of CEA and CA19-9. Surgical outcomes of patients who were CEA- and CA19-9-positive were poorer than those of patients with normal CEA and CA19-9 levels (p < 0.01). Significant correlation was found between serum CEA and CA19-9 level (p < 0.001, r = 0.24). Doubling the threshold level of serum positivity to 10 ng/mL (CEA) and 74 U/mL (CA19-9) improved the prognostic value of these factors. However, multivariate analysis using Cox's hazards model revealed that only CEA positivity using the doubled threshold value (10 ng/mL) (p = 0.04, hazard ratio = 1.7), nodal involvement (p = 0.01, hazard ratio = 1.9), and depth of invasion (p = 0.02 hazard ratio = 1.5) significantly predicted prognosis. Carcinoembryonic antigen positivity using the doubled threshold level (10 ng/mL) was an important prognostic factor in patients with gastric cancer.     

Kinetics of carcinoembryonic antigen and carbohydrate antigen 19-9 production in a human pancreatic cancer cell line (SUIT-2)

Kinetics of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) production in a human pancreatic cancer cell line (SUIT-2) were investigated. Production of CEA reached a maximum, 31.0 ng/1 X 10(6) cells, in the late stationary phase with transient decline during the early exponential phase and 15.5% of the produced CEA was released into the medium, while production of CA19-9 reached a maximum, 421 U/1 X 10(6) cells, in the early stationary phase and 68.8% of the produced CA19-9 was released into the medium. Accordingly, the kinetics of CEA and CA19-9 production of SUIT-2 in vitro might be independent. CEA was stained immunohistochemically in the cytoplasm of the cells forming small buds above the monolayer cell sheet. On the contrary, CA19-9 positive cells were observed scattered in the monolayer cell sheet and CA19-9 was stained in the cytoplasm, predominantly at the projections of the cell surface. CEA and CA19-9 were also detected in the sera of nude mice bearing SUIT-2 tumors and their concentrations correlated well with tumor volume. Correlation coefficients between tumor markers and tumor volume were 0.79 (p less than 0.01) for CEA and 0.90 (p less than 0.01) for CA19-9.