Background: One of the most important factors in breast cancer (BC) mortality is treatment delay. The primary goal of this survey was to identify factors affecting the total delay time (TDT) in Turkish BC patients. Methods: A total of 1031 patients with BC were surveyed using a uniform questionnaire. The time between discovering the first symptom and signing up for the first medical visit (patient delay time; PDT) and the time between the first medical visit and the start of therapy (system delay time; SDT) were modelled separately with multilevel regression. Results: The mean PDT, SDT and TDT were 4.8, 10.5 and 13.8 weeks, respectively. In all, 42% of the patients had a TDT >12 weeks. Longer PDT was significantly correlated with disregarding symptoms and having age of between 30 and 39 years. Shorter PDT was characteristic of patients who: had stronger self-examination habits, received more support from family and friends and had at least secondary education. Predictors of longer SDT included disregard of symptoms, distrust in success of therapy and medical system and having PDT in excess of 4 weeks. Shorter SDT was linked to the age of >60 years. Patients who were diagnosed during a periodic check-up or opportunistic mammography displayed shorter SDT compared with those who had symptomatic BC and their first medical examination was by a surgeon. Conclusion: TDT in Turkey is long and remains a major problem. Delays can be reduced by increasing BC awareness, implementing organized population-based screening programmes and founding cancer centres.

We examined whether a proposed spatial proximity between Asp114(2.50) and Asn332(7.49)

Collagen activates platelets by transducing signals through glycoprotein VI (GPVI). It is not clear whether collagen can directly activate fibrinogen receptors on the adherent platelets without a role for positive feedback agonists. We investigated the contribution of secondary G protein signaling to the mechanism of GPVI-stimulated platelet aggregation using the GPVI-selective agonists, convulxin and collagen-related peptide (CRP) as well as collagen. Adenosine diphosphate (ADP) scavengers or ADP receptor antagonists shifted the concentrationresponse curve slightly to the right at low concentrations of convulxin, whereas platelet aggregation at higher concentrations of convulxin was unaffected by these agents. ADP receptor antagonists shifted the concentration-response curve of collagen-or CRP-induced platelet aggregation to the right at all the concentrations. Protein kinase C inhibitor, Ro 31-8220, or a calcium chelator 5,5-dimethyl-BAPTA shifted the concentration-response curve of convulxin-induced platelet aggregation to the right. In addition, pretreatment with both Ro 31-8220 and dimethyl-BAPTA resulted in total inhibition of convulxin-mediated aggregation. Blockade of either the calcium-or protein kinase C-regulated pathway leads to inhibition of fibrinogen receptor activation on platelets adherent to collagen, but inhibition of both pathways leads to abolished fibrinogen receptor activation. We conclude that collagen-induced activation of fibrinogen receptor on adherent platelets through GPVI signaling occurs without any significant role for secreted ADP or thromboxane A 2 . Furthermore, protein kinase C-and calcium-regulated pathways independently contribute to GPVI-mediated platelet aggregation. (Blood. 2002;99:3228-3234)

Phospholipase C␥2 (PLC␥2) has been implicated in collageninduced signal transduction in platelets and antigen-dependent signaling in B-lymphocytes. It has been suggested that tyrosine kinases activate PLC␥2. We expressed the full-length cDNA for human PLC␥2 in bacteria and purified the recombinant enzyme. The recombinant enzyme was Ca 2ϩ -dependent with optimal activity in the range of 1 to 10 M Ca 2ϩ . In vitro phosphorylation experiments with recombinant PLC␥2 and recombinant Lck, Fyn, and Lyn tyrosine kinases showed that phosphorylation of PLC␥2 led to activation of the recombinant enzyme. Using site-directed mutagenesis, we investigated the role of specific tyrosine residues in activation of PLC␥2. A mutant form of PLC␥2, in which all three tyrosines at positions 743, 753, and 759 in the SH2-SH3 linker region were replaced by phenylalanines, exhibited decreased Lckinduced phosphorylation and completely abolished the Lckdependent activation of PLC␥2. Individual mutations of these tyrosine residues demonstrated that tyrosines 753 and 759, but not 743, were responsible for Lck-induced activation of PLC␥2. To confirm these results, we procured a phosphospecific antibody to a peptide containing phosphorylated tyrosines corresponding to residues 753 and 759. This antibody recognized phosphorylated wild-type PLC␥2 on Western blots but did not interact with unphosphorylated PLC␥2 or with PLC␥2 containing mutated tyrosine residues at 753 and 759. Using this antibody, we showed in intact platelets that collagen, a PLC␥2-dependent agonist, induces phosphorylation of PLC␥2 at Y753 and Y759. These studies demonstrate the importance of these two tyrosine residues in regulating the activity of PLC␥2.

Objective: It was the aim of this study to evaluate maintenance therapy with bevacizumab + capecitabine following induction with bevacizumab + capecitabine + oxaliplatin (XELOX) versus bevacizumab + XELOX until progression as first-line therapy in metastatic colorectal cancer (mCRC). Methods: Patients received either bevacizumab (7.5 mg/kg) + XELOX (capecitabine 1,000 mg/m² twice daily on days 1-14 + oxaliplatin 130 mg/m² on day 1 every 3 weeks) until disease progression (arm A) or the same doses of bevacizumab + XELOX for 6 cycles followed by bevacizumab + capecitabine until disease progression (arm B). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. Results: One hundred and twenty-three patients were randomized. Treatment compliance was similar in both groups. Median PFS was significantly longer for arm B than for arm A (11.0 vs. 8.3 months; p = 0.002). There was no significant difference between the two arms for ORR (66.7 vs. 59.0%; p = 0.861) or median OS (23.8 vs. 20.2 months; p = 0.100). Tolerability was acceptable in both treatment arms; the most frequent grade 3/4 treatment-related adverse events (arm B vs. arm A) were fatigue (6.6 vs. 16.1%), diarrhoea (3.3 vs. 11.3%), anorexia (3.3 vs. 11.3%), and neuropathy (1.6 vs. 8.1%). Conclusions: Maintenance therapy with bevacizumab + capecitabine can be considered an appropriate option following induction bevacizumab + XELOX in patients with mCRC instead of continuation of bevacizumab + XELOX.