Genetic variant in the osteoprotegerin gene is associated with aromatase inhibitor-related musculoskeletal toxicity in breast cancer patients.

BACKGROUND: Aromatase inhibitor (AI) therapy is associated with musculoskeletal (MS) toxicity, which adversely affects quality of life and therapy adherence. Our objective was to evaluate whether genetic variants may predict endocrine therapy-related MS pain and hot flashes in a prospective observational cohort study. PATIENTS & METHODS: 254 early breast cancer patients starting AI (n = 159) or tamoxifen therapy (n = 95) were included in this genetic biomarker study. MS and vasomotor symptoms were assessed at baseline and after 3, 6 and 12 months of therapy. AI-induced MS pain was defined as an increase in arthralgia or myalgia relative to baseline. Single nucleotide polymorphisms (SNP) in candidate genes involved in oestrogen signalling or previously associated with AI-related MS pain or oestrogen levels were selected. RESULTS: Overall, 13 SNPs in CYP19, CYP17, osteoprotegerin (OPG) and oestrogen receptor 1 exhibited an allele frequency >0.05 and were included in the analysis. Patients carrying the G allele of rs2073618 in OPG experienced significantly more AI-induced MS toxicity compared to the wildtype allele, after correction for multiple testing (P = 0.046). Furthermore, this SNP was associated with severity of pain (P = 0.018). No association was found with regard to the other SNPs, both in AI and tamoxifen-treated patients. Neither could an association with vasomotor symptoms be demonstrated. CONCLUSION: The SNP rs2073618 in OPG is associated with an increased risk of MS symptoms and pain with AI therapy, which has not been reported previously. Validation of this finding in larger cohorts and further functional studies are required.

Effect of stenting on cerebral CT perfusion in symptomatic and asymptomatic patients with carotid artery stenosis.

BACKGROUND AND PURPOSE: The introduction of CAS has led to increased treatment of both symptomatic and asymptomatic patients with internal carotid stenosis. This study was performed to compare the effect of stent placement on cerebral perfusion in symptomatic and asymptomatic patients using CT perfusion. MATERIALS AND METHODS: We included 45 patients with carotid artery stenosis of ≥70% who underwent arterial stent placement. Thirty-one patients were treated because of symptoms; 14 asymptomatic patients were treated before coronary artery bypass grafting. Patients underwent CTP before and after stent placement. We calculated MTT, CBV, and CBF, and derived relative numbers that compared treated with untreated hemispheres: ratios of CBV and CBF and difference in MTT. We compared the effect of carotid stent placement on cerebral perfusion in symptomatic and asymptomatic patients. RESULTS: All perfusion parameters changed significantly after treatment in symptomatic patients: rCBF increased from 0.81 to 0.93 (P < .001), rCBV decreased from 1.02 to 0.95 (P < .05), and dMTT decreased from 1.29 to 0.14 (P < .001). In asymptomatic patients only, rCBF changed significantly with an increase from 0.92 to 1.03 (P < .05). When we compared symptomatic and asymptomatic patients before treatment, rCBF in symptomatic patients was significantly lower. The decrease of rCBV after treatment in symptomatic patients resulted in a significantly lower value than in asymptomatic patients. CONCLUSIONS: Carotid artery stent placement improves blood flow in the affected hemisphere in symptomatic and asymptomatic patients. CBF before treatment is more strongly impaired in patients with symptomatic carotid stenosis. Compensatory hyperemia on the symptomatic side before treatment (rCBV > 1) turns into hypoxemia after treatment, suggesting impaired autoregulation in these patients.

Cognition after carotid endarterectomy or stenting: a randomized comparison.

OBJECTIVE: To compare the effect on cognition of carotid artery stenting (CAS) and carotid endarterectomy (CEA) for symptomatic carotid artery stenosis. METHODS: Patients randomized to CAS or CEA in the International Carotid Stenting Study (ICSS; ISRCTN25337470) at 2 participating centers underwent detailed neuropsychological examinations (NPE) before and 6 months after revascularization. Ischemic brain lesions were assessed with diffusion-weighted imaging before and within 3 days after revascularization. Cognitive test results were standardized into z scores, from which a cognitive sumscore was calculated. The primary outcome was the change in cognitive sumscore between baseline and follow-up. RESULTS: Of the 1,713 patients included in ICSS, 177 were enrolled in the 2 centers during the substudy period, of whom 140 had an NPE at baseline and 120 at follow-up. One patient with an unreliable baseline NPE was excluded. CAS was associated with a larger decrease in cognition than CEA, but the between-group difference was not statistically significant: -0.17 (95% CI -0.38 to 0.03; p = 0.092). Eighty-nine patients had a pretreatment MRI and 64 within 3 days after revascularization. New ischemic lesions were found twice as often after CAS than after CEA (relative risk 2.1; 95% CI 1.0 to 4.4; p = 0.041). CONCLUSIONS: Differences between CAS and CEA in effect on cognition were not statistically significant, despite a substantially higher rate of new ischemic lesions after CAS than after CEA. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that any difference between the effects of CAS and CEA on cognition at 6 months after revascularization is small.

Prevalence and clinical consequences of carotid artery residual defects following endarterectomy: a prospective CT angiography evaluation study.

OBJECTIVES: It is still unclear whether residual defects seen after carotid endarterectomy (CEA) have clinical consequences. We investigated prevalence of residual defects in the carotid artery and their possible impact on clinical and Duplex ultrasound (DUS) follow-up. MATERIALS AND METHODS: Sixty-five patients who had undergone CEA were prospectively examined with 1-3 month postoperative computed tomographic angiography (CTA), clinical and DUS follow-up. Defects in common (CCA), external (ECA) and internal carotid artery (ICA) were scored as clamp marks, intimal step or flap, mural thrombus, kink, microdehiscence suture or residual stenosis. RESULTS: Fifty-eight patients (89.2%) had residual defects in CCA, ECA or ICA (143 defects). Intimal steps (n = 39) and residual stenosis (n = 17) were most noted defects. Only residual defects in ECA were significantly associated with significant higher PSV values both at short-term and long-term follow-up (1990 vs. 1400 mm s(-1) at 1 year and 2000 vs. 1230 mm s(-1) at 2 years, P-values 0.031 and 0.016). CONCLUSION: Carotid artery residual defects on CTA after CEA are very common, simple fingerprints of the operative procedure, have no clear consequence. When CTA is performed clinically after CEA, knowledge of high prevalence and type of defects detected on CTA may be of importance for radiologists and clinicians.

Interrelation between the degree of carotid stenosis, collateral circulation and cerebral perfusion.

BACKGROUND: In patients with carotid artery stenosis, ipsilateral hemodynamic compromise is associated with an increased risk of stroke. It is unclear which factors determine cerebral perfusion. We studied the effect of both the degree of the stenosis and the collateral circulation via the circle of Willis (CoW) on cerebral perfusion in patients with symptomatic carotid artery stenosis. METHODS: In 88 patients with unilateral symptomatic carotid artery stenosis of > or =50%, CT perfusion was used to measure the relative cerebral blood volume (rCBV), the difference in mean transit time (DeltaMTT) and the relative cerebral blood flow (rCBF). CT angiography was used to measure the degree of carotid stenosis and to assess the configuration of the CoW. Differences in mean rCBF, rCBV and DeltaMTT between patients with a carotid stenosis of < or =69, 70-79, 80-89 and 90-99%, and between patients with a complete and those with an incomplete CoW were determined by analysis of covariance. RESULTS: The ipsilateral rCBF showed a gradual decrease with increasing severity of carotid stenosis (1.09 +/- 0.06, 0.93 +/- 0.06, 0.90 +/- 0.04 and 0.83 +/- 0.04 ml/100 g/min, respectively; p = 0.005), and the DeltaMTT showed a gradual increase (-0.02 +/- 0.33, 0.16 +/- 0.34, 1.08 +/- 0.22 and 1.47 +/- 0.20 s, respectively; p < 0.001). The rCBV was not related to the severity of stenosis. No relation was found between the configuration of the CoW and the cerebral perfusion parameters. CONCLUSIONS: Cerebral perfusion is inversely related to the degree of stenosis in patients with symptomatic carotid artery stenosis. A relation between the configuration of the CoW and cerebral perfusion was not detected, suggesting that other collateral pathways play an important role.

Zero-field incommensurate spin-Peierls phase with interchain frustration in TiOCl.

We report on the magnetic, thermodynamic, and optical properties of the quasi-one-dimensional quantum antiferromagnets TiOCl and TiOBr, which have been discussed as spin-Peierls compounds. The observed deviations from canonical spin-Peierls behavior, e.g., the existence of two distinct phase transitions, have been attributed previously to strong orbital fluctuations. This can be ruled out by our optical data of the orbital excitations. We show that the frustration of the interchain interactions in the bilayer structure gives rise to incommensurate order with a subsequent lock-in transition to a commensurate dimerized state. In this way, a single driving force, the spin-Peierls mechanism, induces two separate transitions.

Structure and mesomorphism of neodymium(III) alkanoates.

The structural and thermal behavior of all members of the homologous series of neodymium(III) alkanoates, ranging from neodymium(III) butyrate to neodymium(III) eicosanoate are described. Neodymium(III) butyrate monohydrate, Nd(C3H7COO)3.H2O crystallizes in space group P1 (No. 2), Z = 2. The lattice parameters are a = 9.824(2) A, b = 11.974(2) A, c = 14.633(2) A, alpha = 86.21(2) degrees, beta = 75.92(2) degrees, gamma = 77.97(2) degrees. The crystal structure consists of ionic layers of neodymium ions, separated by bilayers of butyrate anions. In the ionic layers, the neodymium ions are connected by bridging tridentate carboxylate groups to zigzag chains, whereas the chains are connected among themselves by bridging bidentate carboxylate groups. The two crystallographically different neodymium ions are both having coordination number 9, with a geometry close to a monocapped square antiprism. The structure of the higher homologues can be derived from the structure of neodymium butyrate by extending the alkyl chains. These compounds have a lamellar bilayer structure with planes of neodymium(III) ions coordinated to the carboxylate groups and with the alkyl chains in an all-trans conformation. All homologous compounds from neodymium(III) pentanoate to neodymium(III) pentadecanoate display a thermotropic mesophase, which was identified by high-temperature X-ray diffraction as a smectic A phase. For the series from neodymium(III) pentanoate to neodymium(III) undecanoate an additional high viscosity mesophase is present between the crystalline state and the smectic A mesophase.