Nazan Günel

Mobilization of peripheral blood stem cells with chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF): a randomized evaluation of different doses of rhG-CSF.

Summary. To date, no randomized study has compared different doses of recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) following submyeloablative mobilization chemotherapy. Therefore, we evaluated the effect of different doses of rhG‐CSF following mobilization chemotherapy on yields of CD34+ peripheral blood stem cells (PBSC). Fifty patients were randomized to receive 8 (n = 25) versus 16 µg/kg/d (n = 25) of rhG‐CSF following mobilization chemotherapy. The median number of CD34+ cells collected after 8 µg/kg/d of rhG‐CSF was 2·36 × 106/kg (range, 0·21–7·80), compared with 7·99 (2·76–14·89) after 16 µg/kg/d (P < 0·001). Twenty out of 25 (80%) patients in the low‐dose and 23 out of 25 (92%) in the high‐dose rhG‐CSF arm underwent high‐dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Median days to white blood cell engraftment in patients mobilized with 8 µg/kg and 16 µg/kg of rhG‐CSF were 12 (10–20) and 9 (8–11) respectively (P < 0·001). There was no difference between the two groups regarding the other parameters of peritransplant morbidity: days to platelet engraftment (P = 0·10), number of red blood cell (P = 0·56) and platelet transfusions (P = 0·22), days of total parenteral nutrition requirement (P = 0·84), fever (P = 0·93) and antibiotics (P = 0·77), and number of different antibiotics used (P = 0·58). These data showed that higher doses of rhG‐CSF following submyeloablative mobilization chemotherapy were associated with a clear dose–response effect based on the collected cell yields. Based on the parameters of peritransplant morbidity, 8 µg/kg/d was as effective as 16 µg/kg/d except for a rapid neutrophil engraftment in the high‐dose arm. Therefore, in routine clinical practice, despite some advantage in the use of higher doses of rhG‐CSF, lower doses may be used for PBSC collections following chemotherapy‐based mobilization regimens in this cost‐conscious era.

Significance of serum vascular endothelial growth factor, insulin-like growth factor-I levels and nitric oxide activity in breast cancer patients

Vascular endothelial growth factor (VEGF) is used to evaluate the angiogenic activity in breast carcinoma. Nitric oxide (NO) and insulin-like growth factor-I (IGF-I) are also implicated in breast tumorigenesis, including angiogenesis. We measured serum VEGF, IGF-I and nitrate+nitrite levels in 38 patients with metastatic and 23 with nonmetastatic breast cancer and in 16 controls. Serum VEGF and IGF-I levels were higher in patients with metastatic disease than in those with nonmetastatic disease or in controls (P<0.001). Serum nitrate+nitrite levels were higher in patients with metastatic and nonmetastatic disease than in controls (P<0.001). Patients with visceral metastasis and local metastasis had higher serum VEGF and nitrate+nitrite levels than patients with bone metastasis (P<0.05). In the metastatic disease group, there was a positive correlation between serum VEGF levels and nitrate+nitrite levels (r=0.436, P<0.05). Within the group with nonmetastatic disease, premenopausal patients had higher serum IGF-I levels than did postmenopausal patients (P<0.001). NO may involve an angiogenic process that is stimulated by VEGF in breast carcinoma. Larger studies are required to clarify these suggestions.

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.

Prognostic value of serum IL-18 and nitric oxide activity in breast cancer patients at operable stage

Interleukin-18 (IL-18) is a multifunctional cytokine that was previously termed interferon-&ggr;-inducing factor. It has been suggested that serum IL-18 level may be used as a prognostic factor in some cancer types. Nitric oxide is a potent biologic molecule involved in the pathogenesis of cancer. In this study, we measured serum IL-18 and nitrate + nitrite levels in 56 patients with nonmetastatic breast cancer and 14 control subjects. Serum IL-18* and nitrate + nitrite** levels were significantly higher in patients with breast cancer when compared to the control subjects (*p < 0.05, **p < 0.001). Serum IL-18 levels were significantly higher in patients whose tumor size was greater than or equal to 5 cm when compared to patients whose tumor size was less than or equal to 2 cm (p < 0.05). Patients who were axillary lymph node negative (ALN) had lower serum IL-18 levels when compared to patients with positive ALN (p < 0.001). Serum IL-18 levels were significantly higher in patients with stage IIB or IIIA when compared to patients with stage I or IIA (p < 0.05). There was no significant difference in serum nitrate + nitrite levels in terms of age, tumor stage, estrogen receptor, and menopausal and ALN status (p > 0.05). In conclusion, serum IL-18 level may be a useful marker to predict prognosis of patients with breast cancer in complete remission after surgery. Long-term follow-up is required to clarify this hypothesis.

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.

Influence of post‐transplant recombinant human granulocyte colony‐stimulating factor administration on peritransplant morbidity in patients undergoing autologous stem cell transplantation

Summary. This study evaluated of the effect of post‐transplant recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) administration on the parameters of peritransplant morbidity. Three sequential and consecutive cohorts of 20 patients each received either post‐transplant rhG‐CSF at a dose of 5 µg/kg/d i.v. in the morning, starting on d 0, d 5, or no rhG‐CSF. Patients who received rhG‐CSF starting on d 0 and 5 recovered granulocytes more rapidly than those not receiving rhG‐CSF (P < 0·001 for ANC ≥ 0·5 and 1 × 109/l). RhG‐CSF administration was not significantly associated with more rapid platelet engraftment. RhG‐CSF administration starting on d 0 and 5 was significantly associated with a decreased duration of fever (P = 0·002 and 0·001 respectively), antibiotic administration (P < 0·001 and 0·006 respectively) and shorter hospitalization (P < 0·001 and 0·001 respectively) compared with the reference group. There was no difference between the d 0 and d 5 arms regarding the parameters of peritransplant morbidity. In conclusion, rhG‐CSF administration was associated with a faster granulocyte recovery, shorter hospitalization, and shorter period of fever and non‐prophylactic antibiotic administration. This study also showed that starting rhG‐CSF administration on d 5 may be as effective as d 0 on the clinical outcome and may be an economical approach in routine clinical practice in this cost‐conscious era.

No association between serum levels of insulin-like growth factor-I, vascular endothelial growth factor, prolactin and clinicopathological characteristics of breast carcinoma after surgery.

Abstract

Effect of tamoxifen on serum IL-18, vascular endothelial growth factor and nitric oxide activities in breast carcinoma patients.

Vascular endothelial growth factor (VEGF) is a multi‐functional cytokine that has been suggested to be a major angiogenic factor in breast cancer. Nitric oxide (NO) is a potent biological molecule that partipicates in the multi‐step process of carcinogenesis. Interleukin (IL)‐18 has been shown to have potent anti‐tumour effects. In this study, we investigated the effect of tamoxifen therapy on serum VEGF, NO and IL‐18 activity in breast cancer patients. Serum levels of VEGF, nitrate + nitrite and IL‐18 were measured in 34 postmenopausal breast cancer patients before and 3 months after the tamoxifen therapy. Both serum VEGF and IL‐18 levels decreased after tamoxifen therapy (P = 0·051, P < 0·05, respectively). Serum VEGF levels increased in patients with endometrial thickness, while patients without endometrial thickness had a significant reduction in serum VEGF levels after therapy (P < 0·05). Serum nitrate + nitrite levels increased after the therapy, but this was not statistically significant (P > 0·05). A decrease in serum VEGF levels with tamoxifen therapy may be a reflection of reduced angiogenic activity in patients without endometrial thickness. The negative effect of tamoxifen therapy on IL‐18, which is known to have a potent antitumour activity, may be related to the decreased tumour growth by induction of NO and reduction of VEGF activity as a feedback mechanism.

Serum leptin levels are associated with tamoxifen-induced hepatic steatosis.

Summary Purpose: Tamoxifen, used in breast cancer treatment, may induce hepatic steatosis. It has been suggested that leptin, which has a relationship with body fat stores, may be involved in the pathogenesis of hepatic steatosis. In this study, we compared serum leptin levels in tamoxifen-treated patients with and without hepatic steatosis. Methods: Thirty-four women with breast cancer receiving tamoxifen were included in the study. Serum samples were obtained from the patients before and 3 months after tamoxifen therapy. Results: Increased hepatic steatosis was detected in 15 of 34 (44%) patients after 3 months of tamoxifen therapy. Serum leptin levels were found to be significantly elevated in patients with increased hepatic steatosis (37.3 ± 17.7 to 50.5 ± 22.4 ng/ml, p = 0.023) compared to patients without or stable hepatic steatosis (48.2 ± 20.2 to 42.6 ± 14.9 ng/ml, p > 0.05) after tamoxifen treatment. Conclusion: Leptin may play a role in tamoxifen-induced hepatic steatosis. The exact mechanism involved should be investigated in further studies.

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.