BACKGROUND Interleukin‐18 (IL‐18) is a novel immunoregulatory cytokine that was known previously as interferon‐γ–inducing factor. IL‐18 levels can be used as a serum indicator for monitoring the clinical course of patients with hematologic malignancies and gastric carcinoma. Nitric oxide (NO) is a pleiotropic molecule that participates in the multistep processing of carcinogenesis. METHODS In the current study, we measured serum IL‐18 and nitrate and nitrite levels in 38 metastatic and 26 nonmetastatic breast carcinoma patients and 16 healthy control subjects. Serum nitrate and nitrite levels were measured as an index of NO generation. RESULTS The levels of serum IL‐18 and nitrate and nitrite were increased significantly in breast carcinoma patients compared with control subjects (P < 0.001). Serum IL‐18 levels were significantly higher in the metastatic patients compared with the nonmetastatic patients (P < 0.001). There was no difference in serum nitrate and nitrite levels between metastatic and nonmetastatic patients (P > 0.05). Patients with bone metastasis have higher serum IL‐18 levels and lower serum nitrate and nitrite levels compared with patients with liver, lung, and local metastasis (P < 0.001). There was no correlation among serum IL‐18, nitrate and nitrite, CA 15‐3, and carcinoemybryonic antigen levels (P > 0.05). CONCLUSIONS These findings suggest that serum IL‐18 and nitrate and nitrite levels may be useful markers in monitoring metastatic breast carcinoma pateints. IL‐18 and NO activities in breast carcinoma patients with bone metastasis may be more valuable in the follow‐up of these patients. Cancer 2002;95:663–7. © 2002 American Cancer Society. DOI 10.1002/cncr.10705

Summary. To date, no randomized study has compared different doses of recombinant human granulocyte colonystimulating 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 lg/kg/d (n 25) of rhG-CSF following mobilization chemotherapy. The median number of CD34 + cells collected after 8 lg/kg/d of rhG-CSF was 2á36´10 6 /kg (range, 0á21±7á80), compared with 7á99 (2á76±14á89) after 16 lg/kg/d (P < 0á001). 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 lg/kg and 16 lg/kg of rhG-CSF were 12 (10±20) and 9 (8±11) respectively (P < 0á001). There was no difference between the two groups regarding the other parameters of peritransplant morbidity: days to platelet engraftment (P 0á10), number of red blood cell (P 0á56) and platelet transfusions (P 0á22), days of total parenteral nutrition requirement (P 0á84), fever (P 0á93) and antibiotics (P 0á77), and number of different antibiotics used (P 0á58). 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 lg/kg/d was as effective as 16 lg/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.

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 lg/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 < 0AE001 for ANC ‡ 0AE5 and 1 · 10 9 /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 ¼ 0AE002 and 0AE001 respectively), antibiotic administration (P < 0AE001 and 0AE006 respectively) and shorter hospitalization (P < 0AE001 and 0AE001 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 nonprophylactic 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 costconscious era.

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Drug interactions have been reported between 5-fluorouracil and cytochrome P450 2C9 (CYP2C9) substrates, S-warfarin and phenytoin. This study was performed to determine the influence of 5-fluorouracil on cytochrome P450 2C9 (CYP2C9) activity in colorectal cancer patients (nΩ17) receiving 5-fluorouracil. Losartan was used as a marker to assess CYP2C9 activity. Losartan and its CYP2C9 dependent metabolite, E-3174, were determined in urine. The ratios of urinary losartan/E-3174 before and after the 5-fluorouracil treatment were compared for each patient. Genotyping was performed to detect the CYP2C9*2 and CYP2C9*3. At the end of the first cycle of 5-fluorouracil, losartan/E-3174 ratio was increased by 28.0% compared to the pre-treatment values (PΩ0.15). In five patients recruited for phenotyping after three 5-fluorouracil cycles, the metabolic ratio was increased significantly by 5.3 times (PΩ0.03). The results suggest that in most patients 5-fluorouracil inhibited CYP2C9 activity. This inhibition was more pronounced when the total administered dose increased. This finding may help explain the mechanism of interaction between 5-fluorouracil and CYP2C9 substrates.5-Fluorouracil is a fluorinated pyrimidine analogue used in the treatment of a variety of solid tumours including gastrointestinal, breast, head and neck cancer (Rich et al. 2004). The cytotoxicity of 5-fluorouracil is mainly due to the formation of fluoro-deoxyuridine-monophosphate metabolite, which inhibits thymidylate synthetase and incorporates into ribonucleic acid (Rich et al. 2004). 5-Fluorouracil has a rather short elimination half-life in plasma and is mostly eliminated by dihydropyrimidine dehydrogenase (Gonzalez & Fernandez-Salguero 1995). Due to many complications during chemotherapy, many other drugs are co-administrated during treatment with 5-fluorouracil. Increasing number of drug-drug interactions between warfarin and 5-fluorouracil-based chemotherapies have been reported. These interactions result in bleeding complications due to the prolongation of prothrombin time (Brown 1997(Brown & 1999Kolesar et al. 1999). 5-Fluorouracil has also been reported to interact with phenytoin, resulting in elevated phenytoin plasma concentrations and neurotoxic side effects (Gilbar & Brodribb 2001;Konishi et al. 2002;Rosemergy & Findlay 2002;Brickell et al. 2003). Both S-warfarin and phenytoin are established CYP2C9 substrates (Lee et al. 2002). The mechanism of these interactions is unclear. Available evidence from case reports and in vitro studies in liver microAuthor for correspondence: Umit Yasar, Hacettepe University, Faculty of Medicine, Department of Pharmacology, 06100 Sihhiye, Ankara, Turkey (fax π90 312 3105312, e-mail uyasar/hacettepe.edu. tr).somes suggests that the interaction is not due to a competitive inhibition of CYP2C9 (Brown 1999;Park & Kim 2003). The effect of 5-fluorouracil on in vivo CYP2C9 activity in man has not been studied. Prospective clinical studies are needed to clarify the mechanism of the interaction between the su...

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A 19‐year‐old man with a germ cell tumor who experienced hypertension, acute myocardial infarction, and cerebrovascular accident (CVA) associated with hypomag‐nesemia as late complications of cisplatin‐based chemotherapy is presented, and previously reported cases in the literature are reviewed. Different physiopathologic mechanisms are hypothesized for early and late vascular complications of cisplatin.

Aims and background p53, c-erbB-2 and Ki-67 protein expression and microvessel density (MVD) determined by CD34 antibody were evaluated by immunohistochemistry and their correlation with clinicopathological parameters including estrogen (ER) and progesterone (PR) receptor status and survival were investigated in patients with axillary lymph node-negative infiltrating ductal breast carcinoma. Methods The study population consisted of 47 patients with axillary lymph node-negative infiltrating ductal breast carcinoma. Results p53 and c-erbB-2 expression was detected in 36.2% and 31.9% of patients, respectively. Median Ki-67 expression was 10%. There were no statistically significant differences in the distribution of p53, Ki-67 and c-erbB-2 protein expression in relation to the age of the patients or to the size, histological grade or ER and PR status of the tumors. p53 protein expression correlated positively with c-erbB-2 and Ki-67 protein expression (P <0.05). The mean MVD was 63.65 ± 29.1 and it correlated positively with histological grade and Ki-67 expression (P <0.05). Survival analysis revealed that age, tumor size, p53 and c-erbB-2 expression and PR status had no significant prognostic impact, whereas histological grade, proliferative activity and angiogenic activity were significant prognostic factors. Although ER-positive patients had a statistically significant overall survival advantage, the difference in disease-free survival was not significant. Conclusion In axillary lymph node-negative breast carcinoma the histological grade and the proliferative and angiogenic activity of the tumor could be useful prognostic indicators.