Deniz Yamac

Serum YKL-40 levels as a prognostic factor in patients with locally advanced breast cancer.

IntroductionYKL-40 is a growth factor for connective tissue cells; it also stimulates the migration of endothelial cells. YKL-40 is secreted by cancer cells, and elevated serum levels have been associated with poorer prognosis in metastatic breast cancer. In the present study we evaluated the prognostic role of serum YKL-40 levels in patients with locally advanced breast cancer.MethodsYKL-40 levels were measured using ELISA in serum samples obtained from 45 breast cancer patients prior to surgery and chemotherapy. The median follow-up time was 46 months (range, 10–96 months). All patients underwent surgery after chemotherapy. During the follow-up period, 21 patients relapsed and there were 17 deaths.ResultsThe median serum YKL-40 concentration in patients with locally advanced breast cancer was 149.5 μg/l (range, 25.0–1021.3 μg/l). This was higher than levels observed in healthy female controls but the difference was not significant (P=0.44). Serum YKL-40 levels were also higher in patients with tumour size >2 cm and node-positive disease but again the differences were not significant (P>0.05). Tumour volume was correlated with serum YKL-40 levels (r=0.308, P=0.039). High serum YKL-40 levels were associated with shorter disease-free and overall survival although this trend failed to reach significance (P>0.05). Multivariate analysis including tumour size, lymph node status, oestrogen and progesterone receptor status, tumour grade, and serum YKL-40 levels indicated that serum YKL-40 levels were an independent prognostic variable for overall survival (hazard ratio, 1.004; 95% confidence intervals: 1.00, 1.07; P=0.027). Tumour size, lymph node status and oestrogen receptor status were also independent prognostic variables for overall survival (P<0.05).ConclusionOur results show that serum levels of the growth factor YKL-40 may be a useful prognostic indicator of outcome for patients with locally advanced breast cancer. Further studies are required to fully elucidate the biological function of YKL-40 in breast cancer.

Expression of MUC1 and MUC2 mucins in gastric carcinomas: Their relationship with clinicopathologic parameters and prognosis

The aim of this study was to investigate the relationship between MUC1 and MUC2 mucin expressions and clinicopathologic variables in gastric carcinomas with regard to survival times. MUC1 and MUC2 expressions were revealed immunohistochemically in 143 gastric carcinomas. Of these 143 patients, follow-up data were available for 45 (median survival time of 30 months, ranging from 2 to 80 months). MUC1 was detected in 82 (58%), and MUC2 in 60 (42%) out of 143 cases. Papillary adenocarcinomas showed significantly higher MUC1 and MUC2 immunoreactivity than did signet-ring cell and mucinous tumors (p = 0.045 and p = 0.01, respectively). MUC1 was highly positive in intestinal-type carcinomas (p = 0.006), whereas intestinal and diffuse carcinomas did not differ in MUC2 expression. There was a positive correlation between tumor differentiation and MUC1 expression. However, no correlation was found between MUC1 and MUC2 expressions and angiolymphatic invasion. According to the TNM classification, stage 1A tumors have significantly lower rates of MUC1 reactivity compared to higher stages (p = 0.04). The patients with gastric carcinomas expressing MUC1 showed significantly poorer survival than those without MUC1 expression (p = 0.04). The present study suggests that MUC1 expression be a useful prognostic factor for predicting the outcome of gastric carcinoma patients, whereas the role of MUC2 expression is still unclear.

Cyclooxygenase-2 expression and its association with angiogenesis, Helicobacter pylori, and clinicopathologic characteristics of gastric carcinoma

Cyclooxygenase-2 (COX-2) is upregulated in gastric carcinoma, and its increased levels were found to have a prognostic significance in some studies. Both angiogenesis and Helicobacter pylori infection have been reported to be associated with COX-2 expression of gastric cancer in recent studies. In this study, COX-2 expression and its association with CD31 staining, H.-pylori infection, and well-known clinicopathological factors were investigated in 65 gastric cancer patients. COX-2 and CD31 expression assessment was done by immunohistochemical methods. Whartin Starry stain was performed for H.-pylori infection. Of 65 patients, 32 (49%) revealed intense COX-2 immunostaining. Among various clinicopathologic characteristics, COX-2 expression was inversely correlated with tumor size, TNM stage, and lymph node status. Thirty-two (49%) patients revealed intense CD31 immunostaining. Among various clinicopathologic characteristics, CD31 expression was associated only with lymph node metastasis. COX-2 expression was not correlated with CD31 staining and H.-pylori infection. Both COX-2 and CD31 staining had no prognostic significance. In conclusion, we found that COX-2 expression was significantly higher in earlier stages of gastric cancer. It can be suggested that COX-2 expression may be important in the initial development of gastric cancer but not in progression of the disease. Other factors which may be associated with COX-2 in gastric cancer, including angiogenesis and H.-pylori infection, should be investigated in further studies.

Prognostic implication of nm23-H1 expression in colorectal carcinomas

Aims: Expression of nm23 has been identified as a potential metastatic suppressor. In this study, nm23‐H1 expression, clinicopathological parameters and influences on clinical outcomes were investigated in colorectal carcinoma patients. Methods: Immunostaining was performed on 185 colorectal carcinomas using a polyclonal anti‐nm23‐H1 antibody. Results: The nm23‐H1 immunoreactivity was weak in 31 (17%), moderate in 48 (26%) and strong in 106 (57%) cases. The well differentiated adenocarcinomas showed significantly strong staining for nm23‐H1 compared with the moderately and poorly differentiated adenocarcinomas ( h 2 test, P < 0.001). Advanced tumour stages were associated with reduced nm23‐H1 expression ( P < 0.001). There was an inverse correlation with angiolymphatic invasion, nodal metastasis and liver metastasis (univariate logistic regression analysis, P < 0.001). In univariate analysis, patients with reduced expression of nm23‐H1 had significantly shorter overall and disease‐free survival than the strong expression group (log‐rank test for trend, P = 0.002 and P = 0.003, respectively). Conclusions: Our results indicated that reduced nm23‐H1 expression showed poor prognosis in colorectal carcinomas. As a result, nm23‐H1 expression might be a useful marker to predict outcome while planning treatment.

Peritumoral Lymphatic Microvessel Density Associated with Tumor Progression and Poor Prognosis in Gastric Carcinoma

BACKGROUND Lymphangiogenesis and angiogenesis are critical processes for tumor growth, invasion, and metastasis, and are crucial for therapeutic strategies. The aim of the present study was to evaluate the clinical significance of lymphangiogenesis and its regulation in gastric carcinomas. METHODS The lymphatic vessel density (LVD) in 65 gastric carcinoma cases was investigated by immunohistochemistry using D2-40 antibody, and evaluated with prognostic parameters. The intratumoral microvessel density (MVD), using CD31 antibody, was assessed and correlated with LVD. RESULTS D2-40 identified peritumoral lymphatics in all cases, and lymphatic vessel density (LVD) ranged from 3 to 19 (median, 5; mean ± SD, 7.69 ± 4.67). The peritumoral LVD significantly correlated with large tumor size (P=0.0001), lymph node metastasis (P=0.004), visceral organ metastasis (P=0.0001), and TNM stage (P=0.001). Survival was also significantly lower in patients with high LVD tumors than in patients with low LVD tumors (P=0.04). Among various clinicopathologic characteristics, CD31 expression was associated only with lymph node metastasis (P=0.001). However, there was no significant correlation between CD31 and D2-40. CONCLUSION Our study showed that lymphangiogenesis plays an important role in the progression of gastric carcinoma. Therefore, D2-40, as an indicator for tumor lymphangiogenesis, may serve as a prognostic marker in gastric carcinoma.

Ultrastructural Damage in Vascular Endothelium in Rats Treated with Paclitaxel and Doxorubicin

Endothelium is the first physiological barrier between blood and tissues and can be injured by physical or chemical stress, particularly by the drugs used in the cancer therapy. Paclitaxel and doxorubicin are frequently used anticancer drugs and their cardiac side effects are well observed in clinical setting. Their side effects on the endothelium are still not clear enough. There are few investigations assessing the damages elicited by the combination use of chemotherapy agents in animal experimental models. The purpose of this study was to examine and compare the side effects of doxorubicin and paclitaxel on endothelium in vivo. The drugs were administered weekly to rats via intraperitoneal injections singly or in combinations. Lastly, aorta endothelium was examined. The most familiar parts of the aorta endothelium are the nucleus, free ribosomes, Weibel-Palada granules, plasmalemmal vesicles, and clear basement membrane. Examination of the endothelium and the related structures revealed some clear degenerative findings. Notably, administration of a paclitaxel and doxorubicin combinations caused the most dramatic change in ultrastructure, which may disrupt many functions of the endothelium.

Gemcitabine plus capecitabine combination in metastatic breast cancer patients previously treated with anthracyclines and taxanes.

Background: Treatment of patients with metastatic breast cancer (MBC) exposed to anthracyclines and taxanes is challenging. Effective and well-tolerated regimens are required. Gemcitabine plus capecitabine combination was assessed in MBC patients pretreated with anthracyclines and taxanes. Patients and Methods: A total of 31 patients treated between November 2004 and September 2005 were retrospectively evaluated in 4 institutions. The median age was 48 years (range 29–77). The patients were given gemcitabine 1,000 mg/m2 on days 1 and 8, and capecitabine 1,500 mg/m2 twice daily on days 1–14 every 3 weeks. Results: A total of 160 cycles of chemotherapy were administered with a median of 5 cycles per patient (range 2–12). Three patients achieved a partial response (10%) and 8 patients (26%) stable disease. The median time to disease progression was 6 months (95% CI 5–7), with a median survival of 18 months (95% CI 15–21) at a median follow-up of 16 months (range 2–28). One-year and 2-year survival rates were 67 and 28%, respectively. Grade 3–4 toxicities were as follows: neutropenia (n = 11, 35%), nausea and vomiting (n = 4, 13%), hand-foot syndrome (n = 2, 6%), anemia (n = 2, 6%), thrombocytopenia (n = 2, 6%) and asthenia (n = 1, 3%). Conclusion: The combination of gemcitabine plus capecitabine was a tolerable regimen with a mild but comparable survival efficacy to similar regimens in patients with MBC after anthracyclines and taxanes.

Bevacizumab Plus Irinotecan-Based Therapy in Metastatic Colorectal Cancer Patients Previously Treated With Oxaliplatin-Based Regimens

ABSTRACT Background: Treatment of patients with metastatic colorectal cancer (MCRC) previously exposed to oxaliplatin-based regimen is challenging. Efficacy and toxicity of bevacizumab plus irinotecan–based regimens were assessed in the second-line treatment of MCRC patients. Patients and Methods: Forty patients with a median age of 53years (range, 31–75) were retrospectively evaluated. Patients progressing or relapsing after treatment with oxaliplatin-based regimens were given bevacizumab 5 mg/kg every 2 weeks in combination with irinotecan-based regimens. All patients had previously received oxaliplatin either in the adjuvant setting (n = 8) or for metastatic disease (n = 32). Results: Three patients achieved a complete response (7.5%), 5 partial responses (12.5%) and 14(35%) stable disease resulting in an overall response rate of 20%. Median progression-free survival was 6 months(95% CI, 4.0–8.0) with a median overall survival of 14months (95% CI, 10.2–17.8). One-year survival rate was55.9%. Grade 3–4 toxicities were as follows: neutropenia(n = 15, 37.5%), febrile neutropenia (n = 2, 5%), diarrhea (n = 11, 27.5%), nausea and vomiting (n = 3,7.5%), gastrointestinal perforation (n = 2, 5%), and thromboembolism (n = 2, 5%). Conclusion: Bevacizumab plus irinotecan–based combination chemotherapyis an active and safe treatment option in patients failing oxaliplatin-based therapy.

Prognostic importance of tumor angiogenesis in breast carcinoma with adjuvant chemotherapy.

Tumor angiogenesis is believed to be related to prognostic factors involved in tumor development and metastasis. Using immunohistochemical methods, we evaluated tumor angiogenesis in 42 early invasive breast cancer patients (T1-2, NO-1-2, M0). Four patients received tamoxifen, 25 patients received CAF or CA, and 15 patients received CMF as adjuvant therapy. The median follow-up was 47 (range 24-119) months. Ten patients (43.5%) in the node-positive group and 2 patients (10.5%) in the node-negative group relapsed (p = 0.019). The mean microvessel count (MVC) was 60.3 3.05 per 200x field (range: 16-95). MVCs of postmenopausal and premenopausal patients were 50.13 +/- 5.74 and 68.64 +/- 4.11, respectively, in the axillary lymph node (ALN)-negative patient group (p = 0.04). Staining was moderate to strong in 13 (68%) ALN-negative and in 17 (74%) ALN-positive patients (p > 0.05), and was also moderate to strong in 82% of premenopausal patients and in 50% of postmenopausal patients (p = 0.037). There was no significant relationship between angiogenesis and p53, nor was angiogenesis significantly associated with the patient ER status and tumor size. No significant correlations were found between OS/DFS and Factor VIII staining or p53 (log rank test, p > 0.05). Of all ALN-negative patients with increased angiogenesis, one patient of the CMF group relapsed, but no recurrence occurred in patients undergoing anthracycline-based chemotherapy (p > 0.05). On the other hand, of all ALN-positive patients with increased angiogenesis, 5/14 patients treated with anthracylcine and 2/2 CMF-treated patients relapsed (p = 0.175). Despite the statistical insignificance, anthracycline-based adjuvant chemotherapy appears to be more effective than CMF as regards relapse prevention particularly in early ALN-positive breast cancer patients with increased angiogenesis. Additional studies are necessary to demonstrate the clinical importance of angiogenesis.

Cisplatin plus vinorelbine as a salvage regimen in refractory breast cancer.

Aims and background Breast cancer refractory to known effective agents is one of the major clinical problems frequently encountered in practice. Cisplatin and vinorelbine are known to be active drugs in anthracycline-refractory cases. In this phase II study, the effectiveness and tolerability of cisplatin and vinorelbine was investigated when used in combination as a salvage regimen in the treatment of metastatic refractory breast cancer. Study design Twenty-four patients with advanced refractory breast cancer who had been previously treated with a regimen containing doxorubicin were included in the study. Six of the 24 patients also received taxanes after failure of doxorubicin. Cisplatin at 80 mg/m2 on day 1 and vinorelbine at 25 mg/m2 on days 1 and 8 were given every 3 weeks. Results A total of 98 cycles of chemotherapy was given, with a median of 4/patient. The response rate was 25% (2 [8.3%] complete and 4 [16.7%] partial responses). The median survival rates were 14 months in responders and 5.5 months in nonresponders (P = 0.0282). One complete and one partial response were observed in patients previously treated with paclitaxel (overall response rate, 33%). The median response duration was 12.5 mo (range, 4–21) in complete and 4.5 mo (range, 1.5–13) in the partial response group. Grade 3 and 4 neutropenia occurred in 9 patients, with no toxic deaths. Grade 2-3 nausea and vomiting in 6 patients and grade 1 neuropathy in 1 patient were noted. Conclusions Although the number of cases is insufficient to indicate that the combination will be effective, it is noteworthy in consideration of anthracycline and taxane refractory cases. A combination of cisplatin and vinorelbine seems to be a reasonable and acceptable choice as an alternative salvage regimen in such cases.