Citations

Abstract Purpose: Controversy exists about CYP2D6 genotype and tamoxifen efficacy. Experimental Design: A matched case–control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non–breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor–node—metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism. Results: The common CYP2D6*4 allele was in Hardy–Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05–5.73, P = 0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95–2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86–6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03–2.30). Conclusion: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole. Clin Cancer Res; 19(2); 500–7. ©2012 AACR.

Improving professional attitudes and behaviors requires critical self reflection. Research on reflection is necessary to understand professionalism among medical students. The aims of this prospective validation study at the Mayo Medical School and Cleveland Clinic Lerner College of Medicine were: (1) to develop and validate a new instrument for measuring reflection on professionalism, and (2) determine whether learner variables are associated with reflection on the gross anatomy experience. An instrument for assessing reflections on gross anatomy, which was comprised of 12 items structured on five‐point scales, was developed. Factor analysis revealed a three‐dimensional model including low reflection (four items), moderate reflection (five items), and high reflection (three items). Item mean scores ranged from 3.05 to 4.50. The overall mean for all 12 items was 3.91 (SD = 0.52). Internal consistency reliability (Cronbach's α) was satisfactory for individual factors and overall (Factor 1 α = 0.78; Factor 2 α = 0.69; Factor 3 α = 0.70; Overall α = 0.75). Simple linear regression analysis indicated that reflection scores were negatively associated with teamwork peer scores ( P = 0.018). The authors report the first validated measurement of medical student reflection on professionalism in gross anatomy. Critical reflection is a recognized component of professionalism and may be important for behavior change. This instrument may be used in future research on professionalism among medical students. Anat Sci Educ 6: 232–238. © 2012 American Association of Anatomists.

Background and Purpose— Previous studies have suggested that family members with intracranial aneurysms (IAs) often harbor IAs in similar anatomic locations. IA location is important because of its association with rupture. We tested the hypothesis that anatomic susceptibility to IA location exists using a family-based IA study. Methods— We identified all affected probands and first-degree relatives (FDRs) with a definite or probable phenotype in each family. We stratified each IA of the probands by major arterial territory and calculated each family’s proband-FDR territory concordance and overall contribution to the concordance analysis. We then matched each family unit to an unrelated family unit selected randomly with replacement and performed 1001 simulations. The median concordance proportions, odds ratios (ORs), and P values from the 1001 logistic regression analyses were used to represent the final results of the analysis. Results— There were 323 family units available for analysis, including 323 probands and 448 FDRs, with a total of 1176 IAs. IA territorial concordance was higher in the internal carotid artery (55.4% versus 45.6%; OR, 1.54 [1.04–2.27]; P =0.032), middle cerebral artery (45.8% versus 30.5%; OR, 1.99 [1.22–3.22]; P =0.006), and vertebrobasilar system (26.6% versus 11.3%; OR, 2.90 [1.05–8.24], P =0.04) distributions in the true family compared with the comparison family. Concordance was also higher when any location was considered (53.0% versus 40.7%; OR, 1.82 [1.34–2.46]; P <0.001). Conclusions— In a highly enriched sample with familial predisposition to IA development, we found that IA territorial concordance was higher when probands were compared with their own affected FDRs than with comparison FDRs, which suggests that anatomic vulnerability to IA formation exists. Future studies of IA genetics should consider stratifying cases by IA location.

Thyroid disease is a common condition, and thyroid hormone excess or deficiency is known to have wide-ranging effects on a variety of organ systems. Our objective is to describe the magnitude, biochemical features, and clinical characteristics of hepatic abnormalities in patients with acute thyrotoxicosis. We performed a retrospective review of all patients admitted to our institution between January 1, 1998 and December 31, 2008 with a discharge diagnosis of acute thyrotoxicosis excluding iatrogenic causes. The records of these patients were reviewed and data extracted regarding demographic, biochemical, and clinical data particularly relevant to liver function. Fourteen patients were identified of which eleven had liver studies performed. The majority (90.9%) had Graves disease. Nine of eleven patients (81.8%) had some degree of hepatic abnormality. Seven patients (63.6%) had an elevation in one or both transaminases, and two (18.2%) had isolated synthetic dysfunction as manifested as an elevated INR and/or decreased albumin without transaminitis. The mean magnitude of deviation from the normal range was greater in the transaminases as compared to bilirubin, INR, or albumin. Definitive treatment was radioiodine ablation in six cases (54.5%) and surgical thyroidectomy in two cases (18.2%). Noniatrogenic acute thyrotoxicosis requiring hospitalization is a rare condition which is most frequently caused by Graves disease. The majority of patients have disordered liver tests of a highly variable nature, making the recognition of this association important in the care of patients presenting with acute thyrotoxicosis.

Background— Giant cell myocarditis (GCM) typically causes fulminant heart failure, arrhythmias, or heart block, necessitating aggressive immunosuppression, ventricular assist device insertion, or cardiac transplantation. We describe a novel variant of GCM, primarily involving the atria, that displays distinctive clinical features and follows a more benign course than ventricular GCM. Methods and Results— We identified 6 patients (median age 67.5 years, 4 male) with atrial GCM in our pathology consultation practices from 2010 to 2012. Clinical history, imaging, and pathology materials were reviewed. Clinically, 4 patients had atrial fibrillation, 1 had acute heart failure, and 1 had incidental disease at autopsy. Among the 5 living patients, echocardiography revealed severe atrial dilatation (5 cases), mitral/tricuspid regurgitation (5), atrial mural thrombus (3), atrial wall thickening (2), and atrial hypokinesis (2). Ventricular function was preserved in all 5. Histological review of surgically resected atria showed giant cell and lymphocytic infiltrates, lymphocytic myocarditis-like foci, cardiomyocyte necrosis, and cardiomyocyte hypertrophy in all cases. Other features included interstitial fibrosis (5), poorly-formed granulomas (4), eosinophils (4), neutrophils (1), and vasculitis (1). Treatment consisted of steroids and cyclosporine (1), pacemaker placement for sick sinus syndrome (1), and supportive care (3). All 5 living patients returned to baseline exercise tolerance after 6 to 16 weeks of follow-up. Conclusions— Atrial GCM represents a distinct clinicopathologic entity with a more favorable prognosis than classic ventricular GCM. This disorder should be included in the differential diagnosis of atrial dilatation, particularly when associated with atrial wall thickening. The utility of immunomodulatory therapy for this condition remains unknown.

Summary Background Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten‐free diet ( GFD ), which is difficult for many patients. Larazotide acetate is a first‐in‐class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. Aim To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. Methods This exploratory, double‐blind, randomised, placebo‐controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run‐in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose‐to‐mannitol ( LAMA ) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale ( GSRS ) and anti‐transglutaminase antibody levels. Results No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1‐mg limited gluten‐induced symptoms measured by GSRS ( P = 0.002 vs. placebo). Mean ratio of anti‐tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 ( P = 0.010), 3.88 ( P = 0.005) and 7.72 ( P = 0.025) in the larazotide acetate 1‐, 4‐, and 8‐mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. Conclusions Larazotide acetate reduced gluten‐induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.

Abstract The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n = 182; 87%) and non–type A (n = 26; 13%) patients. At diagnosis, non–type A patients had lower white blood counts (P = .007), and more often trisomies of chromosomes 8 (P = .01) and 21 (P < .001) and less often trisomy 22 (P = .02). No patient with non–type A fusion carried a KIT mutation, whereas 27% of type A patients did (P = .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non–type A and type A patients with wild-type KIT were similar. We also derived a fusion-type–associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed—among others—an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non–type A patients. We conclude that non–type A fusions associate with distinctclinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile.

AbstractRationaleLow serum testosterone is commonly observed in men with type 2 diabetes (T2DM), but the neuroendocrine pathophysiology remains to be elucidated.ObjectivesThe hypothalamic neuropeptide kisspeptin integrates metabolic signals with the reproductive axis in animal models. We hypothesized that administration of exogenous kisspeptin‐10 will restore luteinizing hormone (LH) and testosterone secretion in hypotestosteronaemic men with T2DM.ParticipantsFive hypotestosteronaemic men with T2DM (age 33·6 ± 3 years, BMI 40·6 ± 6·3, total testosterone 8·5 ± 1·0 nmol/l, LH 4·7 ± 0·7 IU/l, HbA1c 7·4±2%, duration of diabetes <5 years) and seven age‐matched healthy men.Experiment 1Mean LH increased in response to intravenous administration of kisspeptin‐10 (0·3 mcg/kg bolus) both in healthy men (5·5 ± 0·8 to 13·9 ± 1·7 IU/l P < 0·001) and in men with T2DM (4·7 ± 0·7 to 10·7 ± 1·2 IU/l P = 0·02) with comparable ΔLH (P = 0·18).Experiment 2Baseline 10‐min serum sampling for LH and hourly testosterone measurements were performed in four T2DM men over 12 h. An intravenous infusion of kisspeptin‐10 (4 mcg/kg/h) was administered for 11 h, 5 days later. There were increases in LH (3·9 ± 0·1 IU/l to 20·7 ± 1·1 IU/l P = 0·03) and testosterone (8·5 ± 1·0 to 11·4 ± 0·9 nmol/l, P = 0·002). LH pulse frequency increased from 0·6 ± 0·1 to 0·9 ± 0 pulses/h (P = 0·05) and pulsatile component of LH secretion from 32·1 ± 8·0 IU/l to 140·2 ± 23·0 IU/l (P = 0·007).ConclusionsKisspeptin‐10 administration increased LH pulse frequency and LH secretion in hypotestosteronaemic men with T2DM in this proof‐of‐concept study, with associated increases in serum testosterone. These data suggest a potential novel therapeutic role for kisspeptin agonists in enhancing endogenous testosterone secretion in men with T2DM and central hypogonadism.

Background Screening individuals at increased risk for pancreatic cancer (PC) detects early, potentially curable, pancreatic neoplasia. Objective To develop consortium statements on screening, surveillance and management of high-risk individuals with an inherited predisposition to PC. Methods A 49-expert multidisciplinary international consortium met to discuss pancreatic screening and vote on statements. Consensus was considered reached if ≥75% agreed or disagreed. Results There was excellent agreement that, to be successful, a screening programme should detect and treat T1N0M0 margin-negative PC and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). It was agreed that the following were candidates for screening: first-degree relatives (FDRs) of patients with PC from a familial PC kindred with at least two affected FDRs; patients with Peutz–Jeghers syndrome; and p16 , BRCA 2 and hereditary non-polyposis colorectal cancer (HNPCC) mutation carriers with ≥1 affected FDR. Consensus was not reached for the age to initiate screening or stop surveillance. It was agreed that initial screening should include endoscopic ultrasonography (EUS) and/or MRI/magnetic resonance cholangiopancreatography not CT or endoscopic retrograde cholangiopancreatography. There was no consensus on the need for EUS fine-needle aspiration to evaluate cysts. There was disagreement on optimal screening modalities and intervals for follow-up imaging. When surgery is recommended it should be performed at a high-volume centre. There was great disagreement as to which screening abnormalities were of sufficient concern to for surgery to be recommended. Conclusions Screening is recommended for high-risk individuals, but more evidence is needed, particularly for how to manage patients with detected lesions. Screening and subsequent management should take place at high-volume centres with multidisciplinary teams, preferably within research protocols.