Prognostic markers in esophageal cancer: from basic research to clinical use

Esophageal cancer (EC) remains a leading cause of cancer-related death in Asian countries. Due to the biology of EC, including aggressive local invasion, early metastasis and drug resistance, EC has a low survival rate. Therefore, molecular markers for prognosis judgment are urgently required so as to identify subgroups of patients that will benefit from more aggressive therapeutic interventions. So far, many genes and miRNAs, such as VEGF, cyclin D1, and miR-21, have been shown to be valuable when predicting the prognosis of EC. Some circulating molecules, including miR-200c, miR-1246, miR-31, have been identified as the independent risk factors for poor survival. However, the function and mechanism of these molecules in EC remains unclear. More clinical studies should be performed to promote the clinical use of prognosis-related markers in the management of EC.     

Prognostic value of serum markers for prostate cancer

The incidence of prostate cancer has increased dramatically during the last 10-15 years and it is now the commonest cancer in males in developed countries. The increase is mainly caused by the increasing use of opportunistic screening or case-finding based on the use of prostate-specific antigen (PSA) testing in serum. With this approach, prostate cancer is detected 5-10 years before giving rise to symptoms and on average 17 years before causing the death of the patient. While this has led to detection of prostate cancer at a potentially curable stage, it has also led to substantial overdiagnosis, i.e. detection of cancers that would not surface clinically in the absence of screening. A major challenge is thus to identify the cases that need to be treated while avoiding diagnosing patients who will not benefit from being diagnosed and who will only suffer from the stigma of being a cancer patient. It would be useful to have prognostic markers that could predict which patients need to be diagnosed and which do not. Ideally, it should be possible to measure these markers using non-invasive techniques, i.e. by means of serum or urine tests. As it is very useful for both early diagnosis and monitoring of prostate cancer, PSA is considered the most valuable marker available for any tumor. Although the prognostic value of PSA is limited, measurement of the proportion of free PSA has improved the identification of patients with aggressive disease. Furthermore, the rate of increase in serum PSA reflects tumor growth rate and prognosis but, due to substantial physiological variation in serum PSA, reliable estimation of the rate of PSA increase requires follow-up for at least 2 years. Algorithms based on the combined use of free and total PSA and prostate volume in logistic regression and neural networks can improve the diagnostic accuracy for prostate cancer, and assays for minor subfractions of PSA and other new markers may provide additional prognostic information. Markers of neuroendocrine differentiation are useful for the monitoring of androgen-independent disease and various bone markers are useful in patients with metastatic disease.     

食管癌血清肿瘤标志物诊断价值的研究

为探讨肿瘤标志物联合检测在食管癌诊断中的临床意义,分别用酶免法（EIA）、酶法、高效液相色谱法（HPLC）等测定了49例食管癌及272例非肿瘤患者的29种血清肿瘤标志物,应用特异性、阳性预期值、敏感性、阴性预期值、总有效率、5项平均值6个指标综合评价各种肿瘤标志物的价值。结果29种肿瘤标志物中,平均排序前6位的是糖类抗原242（CA^242)、精眯（SPM）、腐胺（PU）、肿瘤相关物质群（TSGF）、谷胱甘肽转移酶（GST）、角蛋白－19（CYFRA211）,TSGF、GST和癌胚抗原（CEA）的敏感性为84．62％。其中前二项敏感性为75．51％,三项中任一项阳性所致的特异性为48．68％。提示TSGF、GST、CEA联合检测对食管癌诊断有实用价值。     

Prognostic significance of perioperative blood transfusions in resectable thoracic esophageal cancer

OBJECTIVE: The perioperative blood transfusions have been associated with tumor recurrence and decreased survival in various types of alimentary tract cancer. There exist, however, contradictory studies showing no relationship between blood transfusions and survival. For patients with esophageal cancer, only one report suggested that blood transfusions did not by itself decrease the chance of cure after esophagectomy. METHODS: Among 235 patients with primary squamous cell carcinoma of the thoracic esophagus between December 1979 and March 1998, 143 patients (60.9%) underwent esophagectomy with curative intent (RO). To exclude the effects of surgery-related postoperative complications, 14 patients who died within 90 days during the hospital stay were excluded. Thus, clinicopathological characteristics and prognostic factors were retrospectively investigated between patients with no or few transfusions (< or = 2 units) (n = 58), and much transfused patients (> or = 3 units) (n = 71). RESULTS: Sixty-three patients are alive and free of cancer, and 66 patients are dead. A total of 98 patients (76%) received blood transfusions, whereas 31 patients (24%) had no transfusion. The amount of blood transfused was 1 or 2 units in 27 patients (27.6%), 3 or 4 units in 33 (33.7%), 5 or 6 units in 20 (20.4%), and > or = 7 units in 18 (18.4%). The 5-yr survival rate for patients with no or few transfusions was 69%, whereas that for much transfused patients was 31.7% (p < 0.0001). The much transfused patients had more prominent ulcerative tumor, longer time of operation, more estimated blood loss, and more marked blood vessel invasion than the group with no or few transfusions. The factors influencing survival rate were tumor location, Borrmann classification, size of tumor, depth of invasion, number of lymph node metastases, time of operation, amount of blood transfusions, lymph vessel invasion, and blood vessel invasion. Among those nine significant variables verified by univariate analysis, independent prognostic factors for survival determined by multivariate analysis were number of lymph node metastasis (0 or 1 vs > or = 2, p < 0.0001), amount of blood transfusions (< or = 2 units vs > or = 3 units, p < 0.0001), and blood vessel invasion (marked vs non-marked, p = 0.0207). CONCLUSIONS: There is an association between high amount of blood transfusions and decreased survival for patients with resectable esophageal cancer. To improve the prognosis, surgeons must be careful to reduce blood loss during esophagectomy with extensive lymph node dissection and subsequently must minimize blood transfusions.     

Prognostic value of serum tumor markers in patients with lung cancer

BACKGROUND: The role of tumor markers in the diagnosis and prognosis of lung cancer is under investigation. OBJECTIVES: The aim of this study was to investigate the diagnostic and prognostic significance of pre-therapeutic levels of various serum tumor markers, CYFRA 21-1, neuron-specific enolase (NSE), tissue polypeptide antigen (TPA), carcinoembryonic antigen (CEA), CA 125 and squamous cell carcinoma antigen (SCCAg), in patients with lung cancer. METHODS: We studied 102 consecutive patients (mean age 65.2 +/- 11 years) with newly diagnosed lung cancer (96 males, 94%, with a mean age of 66.3 +/-10.5 years). All patients had a 5-year follow-up. Measurements of the serum tumor markers were performed on initial diagnosis. RESULTS: Eighty-four patients (82%) had non-small-cell lung cancer (NSCLC) and 18 (18%) small-cell lung cancer (SCLC). From the 84 patients with NSCLC, 34 patients (33%) had squamous-cell lung cancer, 23 (22%) adenocarcinoma and 23 (22%) large-cell carcinomas. The overall median survival was 8.5 months. All SCLC patients had extensive disease with a median survival of 10.1 months and NSCLC patients of 8.4 months. Significant differences in the mean values of NSE and CYFRA 21-1 were observed between SCLC and NSCLC. In NSCLC, CYFRA 21-1, TPA, CA 125 and SCCAg serum levels were related to the stage of the disease at diagnosis, and CYFRA 21-1, NSE, TPA and CA-125 were related to a poor outcome. None of the above tumor markers was related to survival in the SCLC group. CONCLUSION: CYFRA 21-1 and NSE may help to differentiate cell types in lung cancer patients. Also, CYFRA 21-1 with TPA and CA 125 may provide useful information regarding the staging of the disease at diagnosis and the prognosis of patients with NSCLC.     

Prognostic factors in esophageal cancer

BACKGROUND/AIMS: Despite the advances in surgical treatment and the improvements in perioperative care for esophageal cancer, the long-term prognosis of this disease is poor. To improve long-term survival, it is essential to identify prognostic factors. This paper deals with the prognostic factors in esophageal cancer after potentially curative resection. Furthermore, correlation of the genetic alteration obtained from biopsy specimens with the prognostic factor was determined. METHODOLOGY: A total of 102 patients, who underwent transthoracic esophagectomy, were retrospectively analyzed. In 18 recent patients, the genetic alteration of E-cadherin, cyclin D1, and p16INK4 were evaluated in the biopsy specimens. RESULTS: Univariate analysis revealed that the number of metastatic lymph nodes and the tumor diameter significantly influenced prognosis. A Cox proportional regression hazard model showed that only the number of metastatic lymph nodes significantly affected prognosis. Overexpression of E-cadherin and amplification of cyclin D1 was correlated with the number of metastatic lymph nodes but not with p16INK4. CONCLUSIONS: Preoperative genetic assessment of biopsy specimens obtained endoscopically provides useful information concerning selection of treatment modalities.     

Clinical significance of inflammatory markers

Inflammatory markers play a key role in the evaluation of patients with gastrointestinal symptoms. For patients presenting with nonspecific symptoms of abdominal pain and diarrhea, distinguishing inflammatory bowel disease from other disorders can be difficult, and invasive diagnostic procedures may be required. Inflammatory markers can be useful to differentiate patients who may require further workup from those who do not. Several serum, fecal, and other markers are reviewed for their use in clinical practice. Although no single ideal marker exists, a few show promise in diagnosing inflammatory disease, monitoring disease activity, and predicting relapse.     

The prognostic significance of cell cycle markers in esophageal cancer after neoadjuvant chemotherapy

Proliferating cell nuclear antigen (PCNA), p27 and cyclin A were analyzed by immunohistochemistry in 89 patients (untreated control n = 40, neoadjuvant chemotherapy n = 49) with esophageal cancer invading the submucosal lesion. The mitotic index (MI) was calculated as the percentage of mitotic cells. In control subjects, the mean PCNA, p27, cyclin A and MI were, respectively, 60.4%, 18.0%, 19.9% and 1.7%; in the chemotherapy group, these values were 46.8%, 15.1%, 18.0% and 1.2% respectively. Neoadjuvant chemotherapy decreased PCNA and the MI significantly. As prognostic indicators, PCNA and the MI were significant in control subjects and p27 and cyclin A were significant in the chemotherapy group. Using multivariate analysis, p27 was a prognostic factor in both groups and cyclin A was prognostic only in the chemotherapy group. Although PCNA and the MI were useful growth and prognostic markers in untreated control subjects, their significance was lost after neoadjuvant chemotherapy. p27 and cyclin A were determined to be significant markers in the neoadjuvant chemotherapy group, especially p27, which was independent in both groups.     

Prognostic significance of the endoscopic ultrasound defined lymph node metastasis count in esophageal cancer

The key prognostic factor which predicts outcome after esophagectomy for cancer is the number of malignant lymph node metastases, but data regarding the accuracy of endoscopic ultrasound (EUS) in determining and predicting the metastatic lymph node count preoperatively are limited. The aim of this study was to assess the prognostic significance of EUS defined lymph node metastasis count (eLNMC) in patients diagnosed with esophageal cancer. Two hundred and sixty‐seven consecutive patients (median age 63 years, 187 months) underwent specialist EUS followed by stage directed multidisciplinary treatment (183 esophagectomy [64 neoadjuvant chemotherapy, 19 neoadjuvant chemoradiotherapy], 79 definitive chemoradiotherapy, and 5 palliative therapy). The eLNMC was subdivided into four groups (0, 1, 2 to 4, >4) and the primary measure of outcome was survival. Survival was related to EUS tumor (T) stage (P < 0.0001), EUS node (N) stage (P < 0.0001), EUS tumor length (p < 0.0001), and eLNMC (P < 0.0001). Multivariable analysis revealed EUS tumor length (hazard ratio [HR] 1.071, 95% CI 1.008–1.138, P= 0.027) and eLNMC (HR 1.302, 95% CI 1.133–1.496, P= 0.0001) to be significantly and independently associated with survival. Median and 2‐year survival for patients with 0, 1, 2–4, and >4 lymph node metastases were: 44 months and 71%, 36 months and 59%, 24 months and 50%, and 17 months and 32%, respectively. The total number of EUS defined lymph node metastases was an important and significant prognostic indicator.     

食管癌新辅助放化疗患者血清肿瘤标记物水平动态变化及意义

目的：探讨血清肿瘤标记物水平动态变化判断食管癌新辅助放化疗患者疗效及预后的价值。方法对30例行新辅助放化疗食管癌切除术患者的血清细胞角化素蛋白片段19（ CYFRA21-1）、癌胚抗原（ CEA ）及糖链抗原19-9（CA19-9）水平行动态观察,分析其变化与临床疗效及预后的关系。结果治疗前CEA阳性者中位生存期明显短于CEA阴性者,P＜0．05;CA19-9阳性者中位生存期短于CA19-9阴性者（但因阳性例数过少,无法行统计学处理）;CYFRA21-1阳性与阴性者中位生存期无统计学差异。治疗过程中标志物呈下降趋势者中位生存期长于、有效率高于呈上升趋势者,P均＜0．05。结论对食管癌新辅助放化疗患者血清CYFRA21-1、CEA及CA19-9联合动态及变化趋势检测,可评价治疗效果及判断预后。     

Prognostic significance of high serum p53 antibody titers in patients with esophageal squamous cell carcinoma

Background

The p53 protein overexpression that usually results from genetic alterations reportedly induces serum antibodies against p53. However, little information is available about the prognostic significance of perioperative serum p53 antibody (s-p53-Abs) titers in patients with esophageal squamous cell carcinoma.

Methods

In this study, we retrospectively evaluated the clinical significance of perioperative s-p53-Abs in 135 patients with esophageal squamous cell carcinoma. Of these, 58 patients received neoadjuvant chemotherapy comprising 5-FU and CDDP. While the cutoff level at 1.3 U/ml indicated seropositive patients, level of 13.4 U/ml was used to identify high-titer patients. We monitored serum titers seropositive patients after surgery and evaluated the prognostic significance by the univariate and multivariate analyses.

Results

In this study, 29 patients (21.5%) were positive for s-p53-Abs before treatment. The frequency of both seropositive patients and high-titer patients (>?13.4 U/ml) was not significantly associated with tumor progression. While seropositive patients did not demonstrate significant poor overall survival, high-titer patients demonstrated significant poor overall survival based on the multivariate analysis (P?<?0.001). Moreover, the s-p53-Abs titer did not correlate with the response to neoadjuvant chemotherapy. Among seropositive patients, the negative conversion of s-p53-Abs more likely led to be long-term survival.

Conclusions

This study determined that the high-titer of s-p53-Abs was an independent risk factor to reduce the overall survival of patients with esophageal cancer patients. The negative conversion of s-p53-Abs could be a good indicator of favorable prognosis.

     

Prognostic significance of failure to cross esophageal tumors by endoluminal ultrasound

SUMMARY. Failure to intubate and cross esophageal tumors by endosonography is reported in as many as 30% of cases and is thought to be associated with an especially poor prognosis. The aim of this study was to audit the above in a large consecutive case series of Endoscopic Ultrasound (EUS) examinations for esophageal cancer performed in a regional specialist cancer network with particular reference to outcome. A consecutive series of 411 patients underwent EUS examination by a specialist radiologist over a period of 9 years. Forty (10%) of patients required dilation, and there was total failure to cross the tumor in 12 patients (2.9%). Failure to traverse the primary tumor was associated with a diagnosis of squamous cell cancer (8 of 12 patients, 66%, rho = ?0.182, P = 0.011). Limited staging information was obtained in 7 of these patients, which altered the computed tomography stage in 5 patients (71%, 3 upstaged, 2 downstaged). Six patients received definitive chemoradiotherapy, two patients surgery and four patients palliative chemotherapy. The median and 5‐year survival in patients whose tumors were not crossed was 10 months and 28%, respectively, compared with 24 months and 24%, respectively in patients whose tumors were fully assessed. Failure to cross esophageal tumors in practice was far less common than the literature suggests, and esophageal tumor luminal stenosis should no longer be considered a limitation of endosonography.     

Prognostic significance of serum CA19-9 levels in resected pancreatic cancer

Twenty-eight patients with histologically proven pancreatic adenocarcinoma were investigated to evaluate the utility of serum CA19-9 levels as a prognostic indicator after pancreatic resection. Three patients were excluded from the study because their serum CA19-9 levels remained normal throughout the course of the disease. Of the remaining 25 patients, those with preoperative serum CA19-9 levels ≤200U/ml had a better prognosis than those with serum CA19-9 levels >200 U/ml; however, the difference between the two groups was not significant (P=0.13). Serum CA19-9 levels 30 days after pancreatic resection were normalized (≤37 U/ml) in 11 patients (group A), and the survival rate of this group was significantly higher than that of the group of patients with persistently elevated CA19-9 levels (>37 U/ml) (group B) (P<0.005). Other factors i.e., preoperative CA19-9 values, tumor size, lymph node metastasis, histology, and stage classification showed no significant differences between group A and group B. Univariate analysis of the findings for the 25 patients showed that the stage classification and postoperative CA19-9 levels were of prognostic significance for prolonged survival. Other factors, i.e., gender, age, histology, preoperative CA19-9 levels, location of the tumor, and mode of operation, had no significance as prognostic indicators. Multivariate analysis showed that postoperative CA19-9 level was the only significant independent predictor of poor survival. Postoperative serum CA19-9 level appears to be useful as a prognostic indicator after resection of pancreatic cancer.     

Prognostic significance of perigastric lymph nodes metastases on survival in patients with thoracic esophageal cancer

Several publications have showed that the number of metastatic lymph node (LN) should be taken into consideration in nodal category of esophageal cancer, but seldom considered extent of involved regional LNs. The aim of this study is to evaluate the significance of the extent of regional LN metastasis on survival in patients with esophageal cancer. A total of 245 thoracic esophageal cancer patients underwent transthoracic esophagectomy with standard lymphadenectomy between January 2000 and December 2006 were included in the study. Data including demographic factors, pathologic findings, LN parameters and survival outcomes were collected. The survival experience was depicted using Kaplan‐Meier method. A multivariate Cox proportional hazard model was used to screen the significant prognostic factors. The univariate analysis to further explore the significant prognostic factor was done by log‐rank test. After a median follow‐up of 53.2 months, the 5‐year survival rate was 46.3% for the entire cohort. Cox model regression indicated that the LN status and perigastric nodal status, aside from residual tumor status, histological tumor type and depth of invasion, were the independent prognostic factors. Patients without LN metastasis had better 5‐year survival than those with positive nodes (64.2% vs. 18.9%, X²= 35.875, P < 0.001). However, For those patients with nodal involvement, there was no difference in 5‐year survival between patients with involved nodes <3 and ≥3 (27.8% vs. 0%, X²= 0.925, P= 0.336). When considering the location of LN metastasis, patients could be further stratified according to whether the perigastric nodes were involved or not (37.5% vs. 10.0%, X²= 4.295, P= 0.038). In conclusion, involved LN number had no prognostic implication in nodal involved patients based on our data. Whereas, perigastric nodal involvement should be used to refine the N category (N0, no nodal metastasis, N1, non‐perigastric node metastasis, N2, perigastric node metastasis) for the future esophageal cancer staging criteria.     

Septic versus inflammatory arthritis: discriminating the ability of serum inflammatory markers

Early diagnosis of septic arthritis is very important. Few studies showed diagnostic accuracy of serum inflammatory markers in septic arthritis. The aim of our study was to compare the serum and synovial fluid markers [procalcitonin, serum IL-6, TNF-α, C-reactive protein, erythrocyte sedimentation rate, synovial fluid white blood cell counts and PMN percentage] in septic and inflammatory arthritis. Seventy-five patients, including 25 and 50 septic and non-septic arthritis, were enrolled in the study. The serum and synovial fluid markers [procalcitonin, serum IL-6, TNF-α, C-reactive protein, erythrocyte sedimentation rate, synovial fluid white blood cell counts, and PMN percentage] were compared in septic and inflammatory arthritis. Patients with septic arthritis had significantly elevated levels of procalcitonin, serum TNF-α, C-reactive protein, erythrocyte sedimentation rate, synovial fluid white blood cell counts, and PMN percentage in comparison with the inflammatory arthritis group (P < 0.00). Serum IL-6 level does not differ among the two groups. In a receiver operating characteristic curve analysis, synovial fluid WBC counts, PMN percentage, TNF-α, ESR, and serum PCT preformed best in distinguishing between septic and non-septic arthritis. Our study suggests that PCT can be used to diagnose the septic arthritis, but more studies warranted in order to determine the specificity and sensitivity of the test.     

Prognostic significance of serum bile acids in cirrhosis

The value of serum bile acid concentrations for predicting prognosis in cirrhotics was compared with the prognostic significance of clinical and laboratory findings in a prospective 1-year study of 76 patients with cirrhosis. A commercial radioimmunoassay for total serum-conjugated primary bile acids was used. Of 76 patients, 16 died within the follow-up period. The concentration of bile acids in serum more closely correlated with mortality in cirrhosis than the commonly used clinical and laboratory parameters such as the Number Connection Test, ascites, albumin, pseudocholinesterase, bilirubin, prothrombin time and nutritional state. Serum bile acids alone yielded a prediction of mortality comparable to the Child classification. When logistic regression analysis was performed, optimal prediction of prognosis was achieved with the combination of serum bile acids and the Number Connection Test. Serum bile acid levels alone or in combination with the Number Connection Test may be a clinically useful prognostic index in cirrhosis.