Pet birds and risk of lung cancer in North-Western Germany

The relationship between non-small cell lung cancer and platelet counts, serum levels of vascular endothelial growth factor (VEGF) and endostatin, is unclear. Platelet counts and serum VEGF and endostatin levels were measured preoperatively in 99 patients with non-small cell lung cancer, and the relationship between these factors and clinicopathological features, including prognosis, was examined. Mean serum VEGF level was slightly higher in patients than in healthy subjects (P=0.23). Mean serum endostatin level was 42.4+/-40.4 ng/ml in patients compared to 16.3+/-10.3 ng/ml in healthy subjects (P=0.0003). Serum endostatin levels were significantly higher in patients with involvement greater than T2 or stage IB, compared to other patients. Platelet count and serum endostatin level greater than the median were associated with poor prognosis. Our results suggested that platelet count and serum endostatin level may be useful markers for non-small cell lung cancer.     

Serum endostatin levels are elevated in patients with soft tissue sarcoma

BACKGROUND: Solid tumors are angiogenesis dependent, and elevated levels of proangiogenic cytokines have been reported in a variety of histologies. Endostatin is an antiangiogenic fragment of the basement membrane protein, collagen XVIII. Because antiangiogenic protein fragments may be generated by tumor-derived proteases, the authors sought to determine whether circulating levels of endostatin were elevated in patients with localized soft tissue sarcoma. METHODS: The authors analyzed preoperative serum levels of endostatin, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in 25 patients (14 males and 11 females; mean age, 44 years) with soft tissue sarcoma. For each serum sample, two aliquots were assayed in duplicate using a competitive enzyme immunoassay. Serum levels were compared with levels from 34 age-matched and gender-matched volunteer blood donors. RESULTS: Endostatin levels were significantly higher in sera from sarcoma patients than in sera from healthy controls (43.0 ng/mL vs. 25.8 ng/mL, respectively; P = 0.0002; Mann-Whitney U test). Significant elevations also were noted in VEGF and bFGF levels (P = 0.0002 and P = 0.0001, respectively). Furthermore, endostatin levels > 2 standard deviations above the control mean (55 ng/mL) were associated with an increased risk of tumor recurrence after resection (P = 0.047; log-rank test). CONCLUSIONS: Serum endostatin, VEGF, and bFGF levels are elevated in patients with soft tissue sarcoma. Elevated endostatin levels appear to be associated with tumor aggressiveness. The role of these cytokines in sarcoma angiogenesis and as potential targets for therapy warrants further study.     

Circulating angiogenic cytokines in patients with advanced non-small cell lung cancer: correlation with treatment response and survival

Tumor angiogenesis is stimulated by a pro-angiogenic shift in both inducers and inhibitors of endothelial growth. To study this shift, we measured serum and plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), endostatin, and thrombospondin 1 (TSP1) in 21 advanced non-small cell lung cancer (NSCLC) patients and 46 healthy control subjects. In addition, we assessed the relevance of these levels to disease outcome. Cytokine levels were prospectively measured in plasma and serum by enzyme-linked immunosorbent assay at three times: before chemotherapy and at 1 and 12 weeks following initiation of chemotherapy. In NSCLC patients, serum VEGF levels (sVEGF) were elevated (p<0.001), whereas serum and plasma TSP1 levels were lower (p=0.012 and p=0.004, respectively) than in healthy control subjects. Pretreatment plasma endostatin and serum bFGF levels were higher in NSCLC patients than in healthy controls (p=0.05 and 0.01, respectively). Change in sVEGF at week 12 after initiation of chemotherapy correlated with response to therapy (p=0.002). Patients with pretreatment sVEGF levels <500 pg/mL had a median survival of 11 months, but those with sVEGF >500 pg/mL had only a 6 months' median survival (p < 0.03). In NSCLC patients, VEGF levels are increased, whereas TSP1 levels are decreased, which may trigger and sustain tumor angiogenesis. High levels of serum VEGF at the time of presentation with NSCLC may predict worse survival.     

Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma

BACKGROUND: To the authors' knowledge, little is known to date regarding the prognostic relevance of measuring serum levels of vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis, in patients with colon carcinoma who undergo surgery. METHODS: Preoperative and postoperative VEGF serum levels were determined by enzyme-linked immunoadsorbent assay in 81 patients with colon carcinoma who were undergoing surgery. Fifty healthy individuals served to define normal VEGF serum levels. RESULTS: Preoperative VEGF serum levels were significantly higher in the group of patients with colon carcinoma (mean, 504.1 pg/mL +/- 223 pg/mL; range, 285-1390 pg/mL; 95% confidence interval [95%CI], 49 pg/mL) compared with the control group (mean, 78.1 pg/mL +/- 22 pg/mL; range, 40-110 pg/mL; 95%CI, 4.3 pg/mL; P < 0.001). Multiple regression analysis demonstrated a significant correlation (r) between preoperative VEGF serum levels and age (r = - 0.275; P = 0.013), Dukes stage (r = 0.488; P < 0.001), and carcinoembryonic antigen (CEA) levels (r = 0.285; P < 0.018). No significant correlation was found between preoperative VEGF serum levels and disease site, patient gender, tumor size, tumor grade, or performance status. Moreover, preoperative VEGF serum levels were significantly lower in patients who underwent curative surgery compared with patients who underwent noncurative surgery (443 pg/mL +/- 117 pg/mL vs. 821 +/- 353 pg/mL, respectively; P < 0.0001). Logistic regression analysis selected preoperative VEGF and CEA serum levels as the only good prognostic indicators of curative and noncurative surgery (P < 0.001; relative risk, 2.98 and 2.03, respectively). Furthermore, VEGF serum levels dropped significantly after surgery, with a further downward trend until the 30th postoperative day (P < 0.001). Stepwise regression analysis selected preoperative VEGF serum level as the only variable associated significantly with the prediction of both disease-specific survival and disease-free survival (P = 0.001). CONCLUSIONS: Preoperative serum VEGF levels may be useful for predicting outcome in patients with colon carcinoma who undergo surgery.     

Prognostic Values of VEGF and Endostatin with Malignant Pleural Effusions in Patients with Lung Cancer

Aims: Angiogenesis is important in malignant pleural effusion (MPE) formation and it is regulated by anumber of pro- and anti-angiogenic cytokines. The purpose of this study was to evaluate the prognostic valueof angiogenic factor vascular endothelial growth factor (VEGF) and angiogenesis inhibitor endostatin in lungcancer patients with MPE, and investigate the relationship between these two kinds of agent. Methods: Usingenzyme-linked immunoadsorbent assay, the concentrations of VEGF and endostatin were measured in pleuraleffusions (PE) and serum from a total of 70 lung cancer patients with MPE and 20 patients with tuberculosis.Results: Compared to patients with tuberculosis, the levels of VEGF and endostatin in both PE and serum weresignificantly higher in patients with lung cancer. There were statistically significant correlations between VEGFlevels in PE and serum (r=0.696, p<0.001), endostatin levels in PE and serum (r=0.310, p=0.022), and VEGF andendostatin levels in PE (r=0.287, p=0.019). Cox multivariate analysis revealed that elevated pleural VEGF andendostatin levels and serum endostatin level were independent predictors of shorter overall survival. Conclusion:Both pro- and anti-angiogenic factors are likely contributors to PE formation. Our results suggest that the levelsof VEGF and endostatin in PE, together with endostatin in serum, may be potential prognostic parameters forlung cancer patients with MPE.     

Clinical utility of vascular endothelial growth factor in diagnosing malignant pleural effusions

While the early diagnosis of cancer has been fully respected, it is still however often difficult for clinicians to confirm malignant pleural effusions (PE), which essentially indicate the end-stage cancer. It has now been demonstrated that vascular endothelial growth factor (VEGF) is a pivotal angiogenesis factor and associated with tumor growth and metastasis. The aim of this study was then to assess the diagnostic performance of VEGF in malignant PE. In this controlled and blinded prospective study, 113 consecutive patients with PE were recruited. For each eligible case, the VEGF levels of pleural fluid (PF) and serum were examined simultaneously using enzyme immunoassay. The reference standard for malignant PE was clinical evaluation and PF cytology with pleural biopsy, other examination and follow-up added as needed. According to the final diagnoses, 81 qualified cases were grouped as malignant (n=32) and benign (n=49) PE. For PF VEGF level, the mean in malignant group was higher than that in benign group (1358+/-1493 pg/mL vs. 422+/-317 pg/mL, p=0.001). As did for serum VEGF level (650+/-533 pg/mL vs. 137+/-189 pg/mL, p<0.001). Using receiver operating characteristic analysis, the determined diagnostic cut-off points of VEGF levels of PF and serum for malignant PE were 959.25 pg/mL and 212.36 pg/mL, with sensitivities of 47%, 69% and specificities of 96%, 88%, respectively. For cascade connection and parallel operation of PF VEGF and serum VEGF, the sensitivities were 34%, 81% at specificities of 98%, 86%, respectively. These findings suggest that VEGF could be used in diagnosing malignant PE as a useful adjunct of conventional algorithm. Different VEGF test strategies, including test on PF, serum and both, may be selected according to practical needs.     

Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with stage IV clear cell renal cancer.

Clear cell renal carcinoma (CCRC) is a highly angiogenic tumor known to secrete vascular endothelial cell growth factor (VEGF). Endostatin is an endogenous antiangiogenic agent with antitumor activity in mice. The purpose of this study was to evaluate serum levels of endostatin in normal subjects and in patients with CCRC and to examine the relationship of these levels to circulating VEGF levels. Fifteen patients (mean age, 48 years) on a clinical protocol for stage IV CCRC at the National Cancer Institute were included in the study. Archived prenephrectomy serum samples were analyzed for endostatin and VEGF concentrations. Endostatin and VEGF levels were compared with those of an age-matched group of volunteer blood donors (n = 18) using a competitive enzyme immunoassay. Data were analyzed using the Mann-Whitney U test and the Spearman rank correlation. Median serum endostatin levels were 24.6 ng/ml (range, 15.1-54.0 ng/ml) in CCRC patients versus 14.1 ng/ml (range, 1.0-19.3 ng/ml) in healthy controls (P < 0.0001). Median VEGF levels were 3.4 ng/ml (range, 0.1-11.2 ng/ml) and 2.5 ng/ml (range, 0.1-4.2 ng/ml), respectively (P = 0.065). A highly significant correlation was observed between endostatin and VEGF levels among the CCRC patients (r = 0.81, P = 0.0003) but not among controls (r = -0.22, P = 0.37). Endostatin levels are detectable in serum from healthy subjects as well as from CCRC patients. Levels are significantly elevated and correlate with VEGF levels in CCRC patients. Elucidating the nature of this correlation may lend insight into the regulation of tumor angiogenesis in patients with renal cancer.     

VEGF, TNF-alpha and 8-isoprostane levels in exhaled breath condensate and serum of patients with lung cancer

The aim of the present study was to evaluate the levels of VEGF, 8-isoprostane and TNF-alpha in EBC and serum of patients with primary lung cancer prior to the initiation of any treatment, in order to evaluate their possible diagnostic role. Furthermore, associations between VEGF, 8-isoprostane and TNF-alpha levels in EBC and serum with clinicopathologic factors were investigated. We enrolled 30 patients with lung cancer (mean age 65.2+/-10.5 years) and 15 age and gender-matched healthy smokers as controls. Serum and EBC were collected before any treatment. TNF-alpha, VEGF and 8-isoprostane levels in EBC and serum were analyzed by an immunoenzymatic method (ELISA). A statistically significant difference was observed between lung cancer patients and the control group regarding the values of TNF-alpha, both in EBC (52.9+/-5.0 pg/ml vs. 19.4+/-3.9 pg/ml, p<0.0001) and serum (44.5+/-6.3 pg/ml vs. 22.2+/-4.3 pg/ml, p=0.035). Moreover, EBC VEGF levels were higher in patients with T3-T4 tumor stage compared to T1-T2 (9.3+/-2.8 pg/ml vs. 2.3+/-0.7pg/ml, p=0.047). A statistically significant correlation was also observed between serum and EBC values of VEGF (r=0.52, p=0.019). In addition, serum levels of VEGF were higher in lung cancer patients than in controls (369.3+/-55.1 pg/ml vs. 180.5+/-14.7 pg/ml, p=0.046). VEGF serum levels were also found higher in patients with advanced stage of disease (IIIB-IV) and distant nodal metastasis (N2-N3). No differences were observed in 8-isoprostane in EBC between lung cancer patients and controls. In contrast, serum 8-isoprostane levels were higher in lung cancer patients compared to controls (24.9+/-3.6 pg/ml vs. 12.9+/-1.6 pg/ml, p=0.027) and were higher in patients with advanced disease. All three biomarkers presented acceptable reproducibility in the EBC on two consecutive days. In conclusion, we have shown that TNF-alpha, VEGF and 8-isoprostane are elevated in the serum of lung cancer patients and increased serum VEGF and 8-isoprostane levels are related to advanced disease. In EBC, increased TNF-alpha levels were observed in lung cancer patients, whereas increased VEGF levels were observed in advanced T-stage. Further longitudinal studies are warranted for the evaluation of the prognostic role of these biomarkers in lung cancer.     

Prognostic value of serum VEGF in melanoma patients: a pilot study

BACKGROUND: Vascular endothelial growth factor (VEGF) is involved in angiogenesis. We investigated the association of VEGF serum levels (pre-treatment and follow-up) with outcome in patients with melanoma. PATIENTS AND METHODS: Serum levels of VEGF in melanoma patients at diagnosis and during follow-up were analysed with enzyme-linked immunoassays. Patients were followed up with physical examination and ultrasound scans of the liver every three months and thorax X-ray annually. The VEGF serum level was evaluated six-monthly. RESULTS: From February 1996 to February 2000, 33 patients were enrolled. Ninety-two serum blood samples were collected. Patients had a median age of 60 years (range 32-82). Twenty patients were males, 13 females. One patient presented with stage IA disease, 2 with stage IB, 11 with stage IIA, 4 with stage IIB, 8 with stage III and 5 with stage IV. Two patients were affected by uveal melanoma. The melanomas were predominantly located at the extremities or trunk (26/33). The median serum level of VEGF at diagnosis was 249 ng/ml (minimum: 9 ng/ml, maximum: 1215 ng/ml). The median survival of all 33 patients was 45.1 months. The median time-to-progression was 36.7 months. Patients with lower or higher serum VEGF values showed no statistically significant differences in survival. In contrast, high serum VEGF values were associated with shorter disease-free survival as compared with lower values (median DFS: 25 vs 60 months, p = 0.048 at log-rank test). CONCLUSION: Our results suggest that serum VEGF could be of prognostic value in melanoma.     

Serum endostatin and bFGF as predictive factors in advanced breast cancer patients treated with letrozole

Introduction To investigate the value of baseline serum levels of VEGF, bFGF, endostatin and their ratio as predictive factors of response to endocrine therapy in patients with metastatic breast cancer (MBC) and positive ER treated with letrozole after tamoxifen failure. Materials and method The serum levels of endostatin, VEGF and bFGF were determined in post-menopausal patients with progressing MBC from serum samples obtained before initiation of letrozole. The relation between serum angiogenic factor levels and TTP was investigated. Results Seventy-six patients (45.2%) presented a high endostatin level (>24.6 ng/ml), 40% low bFGF levels (0 pg/ml) and 50.4% low VEGF (≤187 ng/ml). With a median follow-up of 22 months, the median TTP was 12.3 months. Median TTP was worse in patients with high endostatin concentration as well as in the low bFGF group, but was not affected when VEGF was considered. When the two factors were combined, the median TTP of patients with endostatin >24.6 ng/ml and bFGF equal 0 pg/ml was 9.5 months versus 19.5 months in patients with endostatin ≤24.6 ng/ml and bFGF>0 pg/ml. Conclusions The baseline levels of bFGF and endostatin are predictive factors of efficacy in patients with MBC treated with letrozole and can select groups with different TTP.     

血清miR-135及miR-601在胃癌患者中的表达及其诊断价值

背景与目的：胃癌是消化内科常见的恶性肿瘤。探讨血清miR-135及miR-601在胃癌患者中的表达及其诊断价值。方法：选取2016年1月1日—2019年9月30日三亚中心医院收治的胃癌患者152例,根据胃癌病情进展及临床病理学分期分为早期胃癌组（n=62）和进展期胃癌组（n=90）,Ⅰ～Ⅱ期（n=65）和Ⅲ～Ⅳ期（n=87）,无淋巴结转移组（n=73）和淋巴结转移组（n=79）。另选择96例非胃癌患者作为非胃癌组,60例健康体检正常者作为对照组。采用实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction,RTFQ-PCR）检测各组血清miR-135及miR-601表达水平,化学发光法测定糖类抗原72-4（carbohydrate antigen 72-4,CA72-4）及糖类抗原19-9（carbohydrate antigen 19-9,CA19-9）水平,分析其对早期胃癌的诊断价值。采用Pearson相关分析来分析胃癌患者血清miR-135、miR-601水平与CA72-4及CA19-9的相关性。结果：与非胃癌组和对照组比较,胃癌组血清miR-135、miR-601、CA72-4及CA19-9水平均明显升高（P均<0.001）。进展期胃癌组血清miR-135（5.70±1.84 vs 3.83±1.12）、miR-601（11.28±3.73 vs 7.36±2.15）、CA72-4［（41.75±10.14）U/mL vs（17.82±4.93）U/mL］及CA19-9［（63.72±17.50）U/mL vs （35.84±10.36）U/mL］水平均明显高于早期胃癌组（均P<0.001）。Ⅲ～Ⅳ期胃癌患者血清miR-135（6.10±1.90 vs 3.74±1.08）、miR-601（12.14±3.92 vs 7.05±2.04）、CA72-4［（44.68±12.35）U/mL vs（16.40±4.52）U/mL］和CA19-9［（68.53±19.13）U/mL vs（33.75±10.60）U/mL］水平均明显高于Ⅰ～Ⅱ期（均P<0.001）,而且Ⅱ期胃癌患者血清miR-135、miR-601、CA72-4及CA19-9水平均明显高于对照组（P<0.05）。淋巴结转移组血清miR-135（6.24±1.95 vs 3.65±0.97）、miR-601（12.60±4.13 vs 6.84±1.92）、CA72-4［（48.70±12.37）U/mL vs （14.85±4.20）U/mL］和CA19-9［（72.36±20.25）U/mL vs（31.60±10.17）U/mL］水平均明显高于无淋巴结转移组（均P<0.001）。受试者工作特征（receiver operating characteristic,ROC）曲线分析结果显示,血清miR-135、miR-601、CA72-4及CA19-9水平诊断早期胃癌的最佳截断值分别为3.78、7.14、17.63 U/mL、35.70 U/mL,四项联合诊断早期胃癌的 曲线下面积（area under curve,AUC）（0.920,95% CI：0.860～0.978）最大,其灵敏度和特异度分别为98.6%和77.4%。相关分析显示,胃癌患者血清miR-135、miR-601水平与CA72-4及CA19-9均呈正相关（r=0.748,P<0.001,r=0.694,P<0.001;r=0.815,P<0.001;r=0.716,P<0.001）。结论：胃癌患者血清miR-135、miR-601、CA72-4及CA19-9水平明显升高,四项联合检测有助于提高早期胃癌的诊断价值。     

Histologic and serum risk markers for noncardia early gastric cancer

Corpus dominant gastritis and intestinal metaplasia (IM) are considered markers of increased risk of gastric carcinoma. The aim of our study was to determine serum and histologic risk markers of gastric cancer. Antral and corpus histology, pepsinogen and gastrin 17 levels were compared among patients with history of endoscopic mucosal resection (EMR) for early gastric cancer and controls. Serum pepsinogen (PG) and gastrin 17 levels were measured by RIA. There were 53 gastric cancer patients and 75 controls. The scores for IM in each region and atrophy at the lesser curvature of the corpus were significantly higher in the cancer group than in the H. pylori-positive control group. IM at the greater curvature of the corpus and atrophy at the lesser curvature of the corpus were associated with multiple malignant lesions. Although corpus gastritis was associated with an increased risk of gastric cancer (odds ratio [OR] = 3.4; 95% confidence interval [CI] 1.6-7.0) (p = 0.001), the most important marker was the presence of IM at the lesser curvature of the corpus (OR = 15.1; 95% CI 4.3-52.6) (p < 0.001)). The best cut-off points of serum markers for gastric cancer were a PG I concentration of 45 ng/mL or less and a gastrin 17 >60 pg/mL (sensitivity = 83%; specificity = 68%). IM at the lesser curvature of the corpus and the combination of serum gastrin 17 and PG I identified a group at high risk for development of gastric cancer. Annual endoscopic follow-up is warranted for patients with IM found at the greater curvature of the corpus.     

Circulating stromal cell derived factor-1alpha (SDF-1alpha) is predictive of distant metastasis in gastric carcinoma

This study was conducted to investigate the value of the pretreatment circulating stromal cell derived factor-1alpha(SDF-1alpha) in patients with gastric carcinoma. We measured SDF-1alpha serum concentrations and evaluated the relationship between serum SDF-1alpha and serum vascular endothelial growth factor (VEGF) levels and clinical factors in 107 gastric cancer patients. Serum levels of SDF-1alpha and VEGF levels were higher in gastric cancer patients than in controls (p < 0.001). Serum SDF-1alpha levels were higher in metastatic patients than non-metastatic patients (p < 0.001). SDF-1alpha levels were correlated with the presence of distant metastases (r = 0.528; p < 0.001) and correlated with VEGF levels (r = 0.789; p < 0.001). SDF-1alpha might serve as a possible marker for predicting or monitoring distant metastasis in gastric carcinoma.     

Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial

BACKGROUND: The rationale for combining anticancer drugs has not been applied consistently to use of intravesical agents for treatment of superficial bladder cancer, for which immunotherapeutic BCG and chemotherapeutic mitomycin seem to be a potentially effective combination. We aimed to do a prospective, randomised comparison of BCG alone with that of sequential BCG and electromotive mitomycin in patients with stage pT1 bladder cancer. METHODS: After transurethral resection and multiple biopsies, 212 patients with stage pT1 bladder cancer were randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks (n=105); or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression; overall survival; and disease-specific survival. Analyses were done by intention to treat. This trial has been submitted for registration at the US National Cancer Institute website . FINDINGS: Median follow-up was 88 months (IQR 63-110). Patients assigned sequential BCG and electromotive mitomycin had higher disease-free interval than did those assigned BCG alone (69 months [95% CI 55-86] vs 21 months [15-54]; difference between groups 48 months [42-54], log-rank p=0.0012). Patients assigned sequential BCG and electromotive mitomycin also had lower recurrence (41.9% [32.7-51.5] vs 57.9% [48.7-67.5]; difference between groups 16.0% [2.7-29.3], log-rank p=0.0012); progression (9.3% [3.8-14.8] vs 21.9% [17.9-25.9]; difference between groups 12.6% [3.0-22.2], log-rank p=0.004); overall mortality (21.5% [13.5-29.5] vs 32.4% [23.4-41.4], difference between groups 10.9% [0.6-21.2], log-rank p=0.045); and disease-specific mortality (5.6% [1.2-10.0] vs 16.2% [6.1-23.3], difference between groups 10.6% [2.5-18.7], log-rank p=0.01). Side-effects were mainly localised to the bladder. INTERPRETATION: BCG-induced inflammation might increase the permeability of the bladder mucosa such that mitomycin can reach the target tissue more easily and exert its anticancer effect.     

Prognostic relevance of collagen XVIII expression in metastatic gastric carcinoma

Collagen XVIII is a component of vascular and epithelial basement membranes. The C-terminal fragment of the protein is termed endostatin, and is a potent inhibitor of angiogenesis. No reports on the clinical implications of collagen XVIII expression in human gastric cancer are currently available. Here, we investigate the clinical significance of collagen XVIII expression in gastric cancer. Seven gastric cancer cell lines were subjected to Western blotting. Collagen XVIII expression was examined in 118 gastric carcinoma tissues via immunohistochemistry. Western blotting revealed the presence of the 22-kDa collagen XVIII protein in four of seven gastric cancer cell lines. Immunohistochemistry detected collagen XVIII expression in the tumor cytoplasm in 115 of 118 gastric carcinoma patients (97%). No correlation was evident between collagen XVIII expression score and clinicopathologic findings when all patients were considered together. However, on subgroup analysis, 42 of 70 patients with distant metastasis were classified into low or moderate collagen XVIII expression groups, whereas the remaining 28 patients were grouped as showing high collagen XVIII expression. The prognosis for patients with high collagen XVIII-expressing gastric carcinoma was significantly worse than that for patients displaying low or moderate collagen XVIII expression (median survival time, 7.8 months vs. 18.3 months [log-rank, p = 0.01]; median time to progression, 3 months vs. 8 months [log-rank, p = 0.01]). High expression of collagen XVIII is associated with poor prognosis in patients with metastatic gastric carcinoma. Further studies on larger patient populations are warranted to validate the utility of collagen XVIII as a prognostic biomarker in gastric carcinoma.     

Serum levels of soluble receptors for tumor necrosis factor (p55 and p75 sTNFr) in patients with cervical cancer

The pretreatment serum levels of the soluble receptors for tumor necrosis factor (p55 and p75 sTNFr) were retrospectively measured in 54 patients with cervical cancer and in 55 patients with benign uterine disease as controls. Serum mean (+/- standard deviation) concentrations of both p55 and p75 sTNFr were higher in patients with cervical cancer than in controls (2.6+/-1.3 vs 1.9+/-0.7 ng/ml, p<0.0001, and, respectively, 7.8+/-4.3 vs 5.9+/-3.0 ng/ml, p=0.009). Both receptor levels were significantly higher in patients with stage IIb-IV than in those with stage I-IIa cervical cancer or with cervical intraepithelial neoplasia (CIN) 3. Among the 31 patients with stage I-IIa disease who underwent initial surgery, the preoperative serum p55 and p75 sTNFr values correlated neither with the common prognostic variables nor with the clinical outcome. In conclusion, serum p55 and p75 sTNFr levels are significantly elevated in patients with cervical cancer. However, the serum measurement of these soluble receptors seems to be of limited clinical value for the management of patients with this malignancy.     

Autoantibodies to endostatin in patients with breast cancer: correlation to endostatin levels and clinical outcome

Circulating autoantibodies to self-antigens overexpressed by cancer cells are common in cancer patients. As specific proteins are expressed during neoangiogenesis, a similar phenomenon might occur with particular antigens of tumour vessels. Collagen XVIII, from which endostatin is cleaved, is highly expressed in the perivascular basement membrane of tumour-associated blood vessels and autoantibodies to endostatin have been reported in cancer patients. The present study analyses the incidence of naturally occurring autoantibodies to endostatin in the sera of breast cancer patients and their relation to endostatin serum levels and patient clinical outcome. Serum samples from 36 patients with localised breast cancer and 59 patients with a fully documented history of metastatic breast cancer were used. The immunoreactivity of serum samples was tested against purified recombinant human endostatin and endostatin levels were determined by immunoassay. We could detect anti-endostatin antibodies in the sera of 66% of the patients with localised disease and 42% of the patients with metastatic disease (P=0.03). There was no correlation between the presence of antibodies to endostatin and circulating levels of endostatin. The detection of autoantibodies to endostatin was associated with better prognosis in metastatic breast cancer patients (median survival time: 20 vs 8 months, P = 0.03), as was the presence of low levels of serum endostatin (median survival time: 20 vs 9 months, P = 0.007). These results show that a natural immune reaction against endostatin can occur in breast cancer patients. This could have important therapeutic implications with regard to endostatin therapy and raises the question of a possible role of this humoral reaction against endostatin in the neoplastic process.     

Elevated serum endostatin is associated with poor outcome in patients with non-Hodgkin lymphoma

BACKGROUND: Endostatin is a cleaved fragment of collagen Type XVIII and has antiangiogenic activity. The clinical significance of circulating, soluble endostatin (S-endostatin) is not known. METHODS: Pretreatment S-endostatin and serum vascular endothelial growth factor (S-VEGF) levels were measured in 143 patients with non-Hodgkin lymphoma (NHL) using competitive enzyme immunoassays and were compared with the levels from a control group (n = 24 participants). RESULTS: S-endostatin levels varied widely from 4.5 ng/mL to 116 ng/mL (median, 29.6 ng/mL), and the median level was higher in patients with NHL compared with patients in the control group (16.4 ng/mL; P = 0.05). High S-endostatin levels were associated with advanced disease stage (P < 0.0001) and high serum VEGF levels at diagnosis (P = 0.017). The median 5-year survival rate for patients who had S-endostatin concentrations within the highest tertile (> 36.0 ng/mL) was only 34% compared with 57% in patients who had lower S-endostatin levels (P = 0.019). A high S-endostatin level also was associated with a poor outcome in patients with large cell diffuse and immunoblastic lymphoma, which was the largest subgroup within the series (n = 60 patients). Patients who had high pretreatment levels of both S-VEGF and S-endostatin had particularly poor outcomes. High S-endostatin levels had an independent, adverse influence on survival it was entered as a factor into a multivariate analysis together with the factors included in the International Prognostic Index (relative risk, 1.80; 95% confidence interval, 1.08-2.98; P = 0.0024). CONCLUSIONS: High pretreatment levels of S-endostatin are associated with high serum VEGF levels and poor survival in patients with NHL. Prospective studies are warranted to establish the clinical value of longitudinal S-endostatin measurements.     

Overexpression of collagen XVIII is associated with poor outcome and elevated levels of circulating serum endostatin in non-small cell lung cancer.

PURPOSE: The aim of this study was to determine whether collagen XVIII expression is correlated with circulating serum endostatin and whether this has any prognostic value in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Serum endostatin levels were measured quantitatively by a competitive enzyme immunoassay, and collagen XVIII expression in tumor tissue was investigated with an immunohistochemical method in a series of 94 patients who underwent surgery for NSCLC. RESULTS: Sixty cases (63.8%) had positive immunohistochemical staining with anticollagen XVIII polyclonal antibodies, including strongly positive staining in 11 (11.7%) cases. The mean (+/- SD) serum endostatin level was 41.6 +/- 34.4 ng/ml in the patient group and 16.3 +/- 10.3 ng/ml in the control group (P < 0.0001). The 11 cases who were strongly collagen XVIII-positive had significantly higher serum endostatin levels than the cases who were negative or weakly positive (P = 0.0297). The 5-year survival rates of negative, weakly positive, and strongly positive patients were 77.8%, 56.9%, and 43.8%, respectively. The cases with strongly positive collagen XVIII expression had a significantly poorer outcome than cases with negative expression (P = 0.0027). A multivariate analysis with Cox proportional hazards model for disease-specific survival revealed that expression of collagen XVIII (strongly positive versus negative; weakly positive versus negative), tumor classification, and regional lymph node classification were independent prognostic factors. CONCLUSIONS: Our results suggest that expression of collagen XVIII in tumor tissue is strongly associated with a poorer outcome in NSCLC and correlates with elevated levels of circulating serum endostatin.     

Nodal dissection for patients with gastric cancer: a randomised controlled trial

BACKGROUND: The survival benefit and morbidity after nodal dissection for gastric cancer remains controversial. We aimed to do a single-institution randomised trial to compare D1 (ie, level 1) lymphadenectomy with that of D3 (ie, levels 1, 2, and 3) dissection for gastric cancer in terms of overall survival and disease-free survival. METHODS: From Oct 7, 1993, to Aug 12, 1999, 335 patients were registered. 221 patients were eligible, 110 of whom were randomly assigned D1 surgery and 111 of whom were randomly assigned D3 surgery, both with curative intent. Three participating surgeons had done at least 25 independent D3 dissections before the start of the trial, and every procedure was verified by pathological analyses. The primary endpoints were 5-year overall survival and 5-year disease-free survival. We also analysed risk of recurrence. Main analyses were done by intention to treat. This trial is registered at the US National Institute of Health website . FINDINGS: Median follow-up for the 110 (50%) survivors was 94.5 months (range 62.9-135.1). Overall 5-year survival was significantly higher in patients assigned D3 surgery than in those assigned D1 surgery (59.5% [95% CI 50.3-68.7] vs 53.6% [44.2-63.0]; difference beteween groups 5.9% [-7.3 to 19.1], log-rank p=0.041). 215 patients who had R0 resection (ie, no microscopic evidence of residual disease) had recurrence at 5 years of 50.6% [41.1-60.2] for D1 surgery and 40.3% [30.9-49.7] for D3 surgery (difference between groups 10.3% [-3.2 to 23.7], log-rank p=0.197). INTERPRETATION: D3 nodal dissection, compared with that of D1, offers a survival benefit for patients with gastric cancer when done by well trained, experienced surgeons.