Citations

Purpose The sensitivity of magnetic resonance imaging (MRI) for breast cancer screening exceeds that of mammography. If MRI screening reduces mortality in women with a BRCA1 or BRCA2 mutation, it is expected that the incidence of advanced-stage breast cancers should be reduced in women undergoing MRI screening compared with those undergoing conventional screening. Patients and Methods We followed 1,275 women with a BRCA1 or BRCA2 mutation for a mean of 3.2 years. In total, 445 women were enrolled in an MRI screening trial in Toronto, Ontario, Canada, and 830 were in the comparison group. The cumulative incidences of ductal carcinoma in situ (DCIS), early-stage, and late-stage breast cancers were estimated at 6 years in the cohorts. Results There were 41 cases of breast cancer in the MRI-screened cohort (9.2%) and 76 cases in the comparison group (9.2%). The cumulative incidence of DCIS or stage I breast cancer at 6 years was 13.8% (95% CI, 9.1% to 18.5%) in the MRI-screened cohort and 7.2% (95% CI, 4.5% to 9.9%) in the comparison group (P = .01). The cumulative incidence of stages II to IV breast cancers was 1.9% (95% CI, 0.2% to 3.7%) in the MRI-screened cohort and 6.6% (95% CI, 3.8% to 9.3%) in the comparison group (P = .02). The adjusted hazard ratio for the development of stages II to IV breast cancer associated with MRI screening was 0.30 (95% CI, 0.12 to 0.72; P = .008). Conclusion Annual surveillance with MRI is associated with a significant reduction in the incidence of advanced-stage breast cancer in BRCA1 and BRCA2 carriers.

Introduction: Medication overuse headache (MOH) is a clinical concern in the management of migraine headache. MOH arises from the frequent use of medications used for the treatment of a primary headache. Medications that can cause MOH include opioid analgesics as well as formulations designed for the treatment of migraine, such as triptans, ergot alkaloids, or drug combinations that include caffeine and barbiturates. Literature review: Gathering evidence indicates that migraine patients are more susceptible to development of MOH, and that prolonged use of these medications increases the prognosis for development of chronic migraine, leading to the suggestion that similar underlying mechanisms may drive both migraine headache and MOH. In this review, we examine the link between several mechanisms that have been linked to migraine headache and a potential role in MOH. For example, cortical spreading depression (CSD), associated with migraine development, is increased in frequency with prolonged use of topiramate or paracetamol. Conclusions: Increased CGRP levels in the blood have been linked to migraine and elevated CGRP can be casued by prolonged sumatriptan exposure. Possible mechanisms that may be common to both migraine and MOH include increased endogenous facilitation of pain and/or diminished diminished endogenous pain inhibition. Neuroanatomical pathways mediating these effects are examined.

Abstract Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is being recognized with increasing frequency. Diagnostic and treatment information is limited. A systematic review is presented, focusing on patient demographics, clinical presentation, diagnosis, treatment options, and outcomes. A systematic electronic literature search was conducted for adult DIPNECH cases reported in the English literature during the past 6 years. Twenty-four DIPNECH cases were identified. Another case from our institution is contributed. Women represent 92% (23 of 25). Mean age at diagnosis was 58 years (range, 36–76 yr). Most were nonsmokers (16 of 24). Symptoms included cough (71%), dyspnea (63%), and wheezing (25%) occurring days to years before diagnosis. Pulmonary function testing showed obstructive ventilatory disease in 54%. Lung nodules were seen in 15 patients (63%), ground-glass attenuation in 7 patients (29%), and bronchiectasis in 5 patients (21%). Histological confirmation required surgical lung biopsy for 88%; however, transbronchial biopsies alone were diagnostic in three patients. Treatments strategies included systemic and inhaled corticosteroids, bronchodilators, and lung resection. Available follow-up data in 17 patients showed 6 clinically improved, 7 who remained stable, and 4 clinically deteriorated. The majority of patients presenting with DIPNECH are middle-aged females with symptoms of cough and dyspnea; obstructive abnormalities on pulmonary function testing; and radiographic imaging showing pulmonary nodules, ground-glass attenuation, and bronchiectasis. In general, the clinical course remains stable; however, progression to respiratory failure does occur. Long-term follow-up and treatment remains incomplete. Establishment of a national multicenter DIPNECH registry would allow formulation of optimal evidence-based guidelines for management of these patients.

Background and Purpose— Coronary artery disease is the leading cause of death after TIA. Reliable estimates of the risk of MI after TIA, however, are lacking. Methods— Our purpose was to determine the incidence of and risk factors for MI after TIA. We cross-referenced preexisting incidence cohorts from the Rochester Epidemiology Project for TIA (1985–1994) and MI (1979–2006) to identify all community residents with incident MI after incident TIA. Incidence of MI after TIA was determined using Kaplan–Meier life-table methods. This was compared to the age-, sex-, and period-specific MI incidences in the general population. Proportional hazards regression analysis was used to examine associations between clinical variables and the occurrence of MI after TIA. Results— Average annual incidence of MI after TIA was 0.95%. Relative risk for incident MI in the TIA cohort compared to the general population was 2.09 (95% CI, 1.52–2.81). This was highest in patients younger than 60 years old (relative risk, 15.1; 95% CI, 4.11–38.6). Increasing age (hazard ratio, 1.51 per 10 years; 95% CI, 1.14–2.01), male sex (hazard ratio, 2.19; 95% CI, 1.18–4.06), and the use of lipid-lowering therapy at the time of TIA (hazard ratio, 3.10; 95% CI, 1.20–8.00) were independent risk factors for MI after TIA. Conclusions— Average annual incidence of MI after TIA is ≈1%, approximately double that of the general population. The relative risk increase is especially high in patients younger than 60 years old. These data are useful for identifying subgroups of patients with TIA at highest risk for subsequent MI.

AbstractAdvanced prostate tumors, which are androgen dependent, are often initially treated in the clinic with hormone ablation therapy, either through surgical castration or administration of small-molecule antiandrogens. Most tumors respond favorably to these treatments, exhibiting regression of the tumor, amelioration of symptoms, and a decrease of prostate-specific antigen in patient sera. However, with time, the majority of tumors recur in a more aggressive, castration-resistant (CR) phenotype. Currently, no effective treatment exists for this stage of the cancer, and patients ultimately succumb to metastatic disease. The androgen receptor (AR), which is a member of the nuclear hormone receptor superfamily of proteins, is the transcription factor that is responsible for mediating the effects of androgens upon target tissues, and it has been demonstrated to play a central role in the development and progression of prostate cancer. Despite CR tumor cells being able to continue to grow after hormonal therapy in which testosterone and dihydrotestosterone are markedly reduced, they still require the expression and activity of the AR. The AR can become transactivated in this low-androgen environment through a number of different mechanisms, including amplification and mutation of the receptor, cross talk with other signaling pathways, and altered regulation by coregulatory proteins. This review will summarize the most current data regarding non-ligand-mediated activation of the AR in prostate cancer cells. Developing work in this field aims to more clearly elucidate the signals that drive AR activity independently of androgens in CR disease so that better therapeutic targets can be developed for patients with this stage of highly aggressive prostate carcinoma.

Abstract Vitamin A metabolite retinoic acid (RA) regulates life-sustaining differentiation processes and metabolic homeostasis. The aldehyde dehydrogenase-1 (Aldh1) family of enzymes (Aldh1a1, a2, and a3) catalyzes RA production from retinaldehyde and thereby controls concentrations of this transcriptionally active metabolite. The hierarchy of Aldh1 functions in adipose tissue has not been elucidated. We hypothesized that Aldh1 enzymes produce endogenous RA and regulate adipogenesis and fat formation in a fat depot-specific manner. We demonstrate that adipogenesis in vitro is accompanied by RA production generated primarily by Aldh1a1. In Aldh1a1-deficient adipocytes, adipogenesis is impaired compared with wild-type adipocytes due to markedly reduced expression of PPARγ regulated through zinc-finger protein 423 (ZFP423)-dependent mechanisms. These effects were recovered to some extent either by RA stimulation or overexpression of any of the Aldh1 enzymes in Aldh1a1−/− cells arguing that Aldh1a1 plays a dominant role in autocrine RA production. In vivo studies in C57/BL6 and Aldh1a1−/− mice on a regular diet revealed that multiple Aldh1 enzymes regulate differences in the formation of sc and visceral fat. In Aldh1a1−/− mice, visceral fat essentially lacked all Aldh1 expression. This loss of RA-producing enzymes was accompanied by 70% decreased expression of ZFP423, PPARγ, and Fabp4 in visceral fat of Aldh1a1−/−vs. wild-type mice and by the predominant loss of visceral fat. Subcutaneous fat of Aldh1a1−/− mice expressed Aldh1a3 for RA production that was sufficient to maintain expression of ZFP423 and PPARγ and sc fat mass. Our data suggest a paradigm for regulation of fat depots through the concerted action of Aldh1 enzymes that establish RA-dependent tandem regulation of transcription factors ZFP423 and PPARγ in a depot-specific manner.

Background and Purpose— Age might differentially affect outcomes in patients treated for unruptured cerebral aneurysms with surgical clipping versus endovascular coil therapy. We evaluated a large administrative database to determine the effect of age on outcomes in patients treated for unruptured cerebral aneurysm. Methods— Using the National Inpatient Sample, we evaluated morbidity (discharge to long-term facility) and mortality of patients undergoing clipping or coiling of unruptured cerebral aneurysms in the United States between 2001 and 2008. Outcomes were evaluated in relation to four age strata: younger than 50 years; 50 to 64 years; 65 to 79 years; and patients 80 years or older. Results— Patients younger than 50 years old undergoing coiling had significantly lower morbidity rates when compared to patients who underwent clipping (3.5% versus 8.1%; P <0.0001), but no difference in mortality (0.6% versus 0.6%; P =0.72). Patients between 50 and 64 years old undergoing coiling had significantly decreased morbidity (4.0% versus 13.7%; P <0.0001) and mortality (0.5% versus 1.1%; P <0.0001) when compared to patients who underwent clipping. Coiled patients 65 to 79 years old had lower morbidity (6.9% versus 26.8%; P <0.0001) and mortality (0.8% versus 2.0%; P <0.0001) compared to patients who underwent clipping. Patients aged 80 years or older undergoing coiling also had lower morbidity (9.8% versus 33.5%; P <0.0001) and mortality (2.4% versus 21.4%; P <0.0001) when compared to patients who have undergone clipping. Conclusions— Patients treated with endovascular coiling have significantly less morbidity and mortality than those treated with surgical clipping, and these differences become more pronounced with age.