Real-world adjuvant TAC or FEC-D for HER2-negative node-positive breast cancer in women less than 50 years of age.

PURPOSE: We compared the efficacy, toxicity, and use of granulocyte colony-stimulating factor (g-csf) with tac (docetaxel-doxorubicin-cyclophosphamide) and fec-d (5-fluorouracil-epirubicin-cyclophosphamide followed by docetaxel) in women less than 50 years of age. METHODS: The study included all women more than 18 years but less than 50 years of age with her2-negative, node-positive, stage ii or iii breast cancer diagnosed in Alberta between 2008 and 2012 who received tac (n = 198) or fec-d (n = 274). RESULTS: The patient groups were well-balanced, except that radiotherapy use was higher in the tac group (91.9% vs. 79.9%, p < 0.001). At a median follow-up of 49.6 months, disease-free survival was 91.4% for tac and 92.0% for fec-d (p = 0.76). Overall survival (os) was 96% with tac and 95.3% with fec-d (p = 0.86).The incidences of grades 3 and 4 toxicities were similar in the two groups (all p > 0.05). Overall, febrile neutropenia (fn) was reported in 11.6% of tac patients and 15.7% of fec-d patients (p = 0.26). However, use of g-csf was higher in the tac group than in the fec-d group (96.4% vs. 71.5%, p < 0.001). Hospitalization for fn was required in 10.5% of tac patients and 13.0% of fec-d patients (p = 0.41). In g-csf-supported and -unsupported patients receiving tac, fn occurred at rates of 11.1% and 33.3% respectively (p = 0.08); in patients receiving the fec portion of fec-d, those proportions were 2.9% and 8.1% respectively (p = 0.24); and in patients receiving docetaxel after fec, the proportions were 4.1% and 17.6% respectively (p < 0.001). CONCLUSIONS: In women less than 50 years of age receiving adjuvant tac or fec-d, we observed no differences in efficacy or other nonhematologic toxicities. Based on the timing and rates of fn, use of prophylactic g-csf should be routine for the docetaxel-containing portion of treatment; however, prophylactic g-csf could potentially be avoided during the fec portion of fec-d treatment.

Hyperammonemic encephalopathy in an adenocarcinoma patient managed with carglumic acid.

Hyperammonemic encephalopathy (he) is a rare complication of malignancy and chemotherapy. Although the cause of he is unclear, a functional arginine deficiency secondary to increased catabolism has been suggested as a possible mechanism. Either that deficiency or an undetermined metabolite could lead to inhibition of N-acetylglutamate synthase (nags), a urea cycle enzyme, resulting in hyperammonemia. We present a case of chemotherapy-induced he in a patient with no underlying primary urea cycle disorder. The patient had a successful trial of carglumic acid (a synthetic analog of the product of nags), which suggests that, at least in some cases, he can be treated by overcoming proximal inhibition of the urea cycle. Further, our case is the first in the literature to exclude genetic defects and disorders of the proximal urea cycle, suggesting that hyperammonemia in these patients is probably secondary to chemotherapy.

Optimal use of taxanes in metastatic breast cancer.

The role of taxanes in the treatment of breast cancer is becoming increasingly important. In clinical practice, the taxanes are now standard therapy in both early-stage and metastatic breast cancer. Since the 1990s, multiple randomized clinical trials have been evaluating the efficacy of taxanes in the treatment of metastatic breast cancer. These trials have included treatment with taxanes alone or in combination with other chemotherapeutic agents. Pre-existing published guidelines for the use of taxanes in the management of metastatic breast cancer are available. The mandate of the Alberta Cancer Board Provincial Breast Tumour Group Guideline Panel was to consider and adapt the recommendations of the existing guidelines and to develop de novo guidelines to account for current evidence. For this task, the panel used the ADAPTE process, which is a systematic process of guideline adaptation developed by the ADAPTE Collaboration.The recommendations formulated by the panel included the identification of taxane regimens that could be offered in anthracycline-naïve patients, anthracycline-pretreated or -resistant patients, and patients overexpressing the human epidermal growth factor receptor 2. Potential toxicities and benefits in terms of time to progression, progression-free survival, overall survival, and quality of life were also considered.

Vasodilatation produced by adenosine in isolated rat perfused mesenteric artery: a role for endothelium.

Adenosine and adenosine triphosphate (ATP) induced vasodilatation was studied in isolated rat perfused mesenteric artery at constant flow. Decrease in perfusion pressure was measured after induction of tone by continuous infusion with phenylephrine (5-7 microM). Adenosine and ATP caused dose-dependent vasodilation. Following infusion with selective A2 adenosine receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX) (10 microM), or non-selective adenosine receptor antagonist, theophylline (30 microM), vasodilation produced by adenosine were significantly reduced at lower doses. Responses to adenosine were not affected by pretreatment of tissues with either the P2-purinoceptor desensitizing agent, alpha, beta methylene ATP (30 microM), or the P2-purinoceptor antagonist, suramin (10 microM). In contrast, both alpha, beta methylene ATP and suramin significantly attenuate relaxation produced by ATP. Further, it was found that relaxation elicited by either adenosine or ATP was not significantly affected by the presence of glibenclamide (30 microM). Vasodilatation induced by adenosine and ATP was greatly reduced in denuded arteries but more so for ATP than adenosine. It is concluded that adenosine-mediated vasodilatation may hardly be due to the stimulation of A2 adenosine receptors and is strongly dependent on the presence of functional endothelium whereas ATP-mediated vasodilator responses were mediated via the activation of P2-purinoceptors and appeared to be entirely dependent upon the presence of functional endothelium. Further, vasodilator responses to neither adenosine nor ATP were sensitive to inhibition by the potassium channel blocker glibenclamide, in isolated mesenteric perfused bed. This would imply that ATP-sensitive potassium channels were not involved in adenosine and ATP mediated vasodilatation.

Preferences of patients and physicians concerning treatment options for relapsed follicular lymphoma: a discrete choice experiment.

The purpose of this study was to elicit relative preferences for common treatment options of relapsed follicular lymphoma, and their associated attributes, amongst lymphoma patients in Alberta, and lymphoma-treating physicians in Canada, using a discrete choice experiment (DCE). Treatment administration, toxicity, survival free of relapse and cost were the attributes evaluated for four treatment options: standard chemotherapy (CT), radioimmunotherapy (RIT), high-dose CT and auto-SCT, and allo-SCT. For the 81 patients and 48 physicians who participated in this study, survival free of relapse was a positive influence on choice (P<0.001), whereas negative influences on choice included toxicity of allo-SCT (P<0.001 for patients, P=0.005 for physicians) and cost (P=0.001 for physicians only). The estimated uptake of the treatment options for patients was as follows: auto-SCT (69%), RIT (14%), CT (11%) and allo-SCT (7%). The distribution for physicians was similar (56, 20, 19 and 4%, respectively). In conclusion, patients with relapsed follicular lymphoma are able to consider the different attributes of various treatment options and are willing to trade off the need for hospitalization, associated toxicity and cost associated with autologous transplantation in order to benefit from an increased PFS.

The effects of losartan and captopril on vasopressor actions of cirazoline in the absence and presence of SZL-49 and nifedipine.

The effects of the nonpeptide angiotensin II receptor antagonist losartan and the angiotensin-converting enzyme inhibitor captopril on pressor responses to the selective alpha 1-adrenoceptor agonist cirazoline (10 ng/kg-3.0 mg/kg) in the pithed rat were compared. In addition, the effects of losartan and captopril on pressor responses to cirazoline were compared in the presence of the selective irreversible alpha 1-adrenoceptor antagonist SZL-49 (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-bicyclo[2,2,2]octa-2,5- dienyl-carbonyl)-piperzine) and/or the Ca2+ channel antagonist nifedipine. Losartan (5.0 mg/kg) and captopril (3.0 mg/kg), as compared to saline, significantly lowered the blood pressure of intact, anaesthetized and pithed rats. Continuous infusion with vasopressin was used to restore the blood pressure of pithed rats pretreated with losartan or captopril to a level comparable to animals that had received saline. Losartan, captopril, nifedipine (1.0 mg/kg), and SZL-49 (10.0 mg/kg) antagonized the pressor actions of cirazoline, which displaced the dose-diastolic blood pressure response curve for the agonist to the right. Moreover, pressor responses to cirazoline were significantly reduced in rats that had received losartan and nifedipine in comparison to nifedipine alone. In contrast, in rats treated with nifedipine, further administration of captopril did not significantly reduce pressor responses to cirazoline as compared to nifedipine alone. Cirazoline-mediated pressor responses at all doses were significantly attenuated in rats treated with SZL-49 and either losartan or nifedipine combined as compared to SZL-49 alone. In contrast, only cirazoline-mediated pressor responses at lower doses were significantly reduced by pretreatment with a combination of SZL-49 and captopril as compared to SZL-49 alone.(ABSTRACT TRUNCATED AT 250 WORDS)