Citations

Abstract Background Anthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC. Methods Intravenous pixantrone was administered at 180 mg/m2 every 3 weeks (group A) versus 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population. Results Forty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI]: 2.0-4.1) and 16.8 (95% CI: 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following: neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%). Conclusion Pixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID: NCT01086605).

Abstract Introduction The National Institute on Aging Late‐Onset Alzheimer's Disease Family Based Study (NIA‐LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD). Methods Recruitment focused on families with two living affected siblings and a third first‐degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E ( APOE ) genotypes, genome‐wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families. Results APOE genotype modified the age‐at‐onset in many large families. Novel variants and known variants associated with early‐ and late‐onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics. Discussion The NIA‐LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age‐at‐onset provides opportunities to investigate the complexity of familial AD.

Abstract Background A wide variety of techniques for the surgical repair of nasal septal perforations (NSPs) have been described. Surgical management of NSPs can be broadly divided into open versus endonasal approaches, with additional variables involving unilateral or bilateral flaps, use of grafts, and placement of splints. The objective of this study was to compare surgical approaches and their outcomes. Methods PubMed, EMBASE, and CINAHL Plus databases were examined for patients undergoing NSP repair. English‐language studies reporting surgical management of patients with the primary diagnosis of NSP were included. Outcome measures of interest included perforation size, surgical approach characteristics, and success rate defined as complete closure assessed by surgeon postoperatively. The quality of articles was assessed with the methodological index for nonrandomized studies (MINORS) criteria. A random‐effects model was used to calculate pooled proportions for the different outcomes. Results The electronic database search yielded 1076 abstracts for review. A total of 64 articles met the inclusion criteria, with 1591 patients: 1127 (71%) underwent an endonasal approach and 464 (29%) an open approach. The median (range) MINORS score was 10 (5–12) out of 16 points. Overall, 91% of patients had total closure (95% confidence interval [CI], 0.89–0.93, p < 0.01), with moderate heterogeneity between studies ( I 2 = 42.03%). There was no difference in closure success between open and endonasal approaches. Use of bilateral versus unilateral flaps, interposition grafts, and intranasal splints and packing were not associated with differences in outcomes. Conclusion Nasal septal perforation surgical repair success rates are comparable regardless of technique.

Background The epidemiology of ventricular arrhythmias (VAs) in patients with advanced heart failure (HF) is not well defined. Methods and Results Residents of Olmsted County, Minnesota, with advanced HF from 2007 to 2017 were identified using the 2018 European Society of Cardiology criteria. Billing codes were used to capture VAs; severe VAs requiring emergency care were defined as events associated with emergency department visits or hospitalizations. The cumulative incidence of VAs postadvanced HF was estimated with the Kaplan–Meier method. Multivariable Cox analyses were used to determine the following: (1) Predictors of severe VAs postadvanced HF; and (2) Impact of severe VAs on mortality. Of 936 patients with advanced HF, 261 (27.9%) had a history of VA. The 1‐year cumulative incidence of severe VAs postadvanced HF was 5.4%. Prior VAs (hazard ratio [HR] 2.22 [95% CI, 1.26–3.89], P =0.006) and left ventricular ejection fraction <40% (HR, 3.79 [95% CI, 1.72–8.39], P <0.001) were independently associated with increased severe VA risk postadvanced HF. New‐onset severe VAs were associated with increased mortality (HR, 4.41 [95% CI, 2.80–6.94]; P <0.001), whereas severe VAs in patients with prior VAs had no significant association with mortality risk (HR, 1.08 [95% CI, 0.65–1.78]; P =0.77). Severe VAs were associated with increased mortality in patients without implantable cardioverter defibrillators (HR, 4.89 [95% CI, 2.89–8.26]; P <0.001), but not in patients with implantable cardioverter defibrillators (HR, 1.42 [95% CI, 0.92–2.19]; P =0.11). Conclusions Patients with left ventricular ejection fraction <40% and prior VAs have increased risk of severe VA postadvanced HF. New‐onset severe VAs or severe VAs without implantable cardioverter defibrillators postadvanced HF are associated with increased mortality.

Objectives Quantitative magnetization transfer (qMT) is useful for measurement of murine renal fibrosis at high and ultrahigh field strengths. However, its utility at clinical field strengths and in human-like kidneys remains unknown. We tested the hypothesis that qMT would successfully detect fibrosis in swine kidneys with unilateral renal artery stenosis (RAS) at 3.0 T. Methods The qMT protocol is composed of MT scans with variable flip angles and offset frequencies, and of B0 , B1 , and T1 mapping. Pigs were scanned 10 weeks after RAS or control. A 2-pool model was used to fit the bound pool fraction f of the renal cortex (CO) and outer medulla (OM). Then qMT-derived f in 5 normal and 10 RAS pigs was compared with histological fibrosis determined using Masson's trichrome staining and to renal perfusion assessed with computed tomography. Results The qMT 2-pool model provided accurate fittings of data collected on swine kidneys. Stenotic kidneys showed significantly elevated f in both the CO (9.8% ± 2.7% vs 6.4% ± 0.9%, P = 0.002) and OM (7.6% ± 2.2% vs 4.7% ± 1.1%, P = 0.002), as compared with normal kidneys. Histology-measured renal fibrosis and qMT-derived f correlated directly in both the cortex (Pearson correlation coefficient r = 0.93, P < 0.001) and OM (r = 0.84, P = 0.002), and inversely with stenotic kidney perfusion (r = 0.85, P = 0.002). Conclusions This study demonstrates the feasibility of qMT for measuring fibrosis in human-like swine kidneys, and the association between tissue macromolecule content and renal perfusion. Therefore, qMT may be useful as a tool for noninvasive assessment of renal fibrosis in subjects with RAS at clinical field strengths.

PERIODICALLY, it appears to be appropriate and perhaps even necessary to pause for a moment to consider the question, "Where are we going and by what means are we moving along our course?" In the case of the Academy, the answers are to be found in a consideration of the present structure and activities of the components of the group. A very brief, even categorical review of the committees, liaison representatives and official subdivisions will tell us much, and will serve to remind us that we are participants in a great vital program dedicated to the health and welfare of children. Let us first consider the aims and activities of the various committees of the Academy. In the past few years, an increasing awareness of loss of child life through accidents has prompted the Committee on Accident Prevention to survey the causes and to initiate a program of prevention which has received nationwide attention. Unpleasant though it may be to contemplate the prospect of a world engaged in another holocaust of war, the need for preparedness has been recognized at all levels of our civil structure, and in consonance with the emphasis on national alertness, the Academy has established a Committee whose purpose it is to compile information as to the possible needs of children in wartime and the role that pediatricians can play in satisfying those needs, if the occasion demands it. During the lives of most of us, contagious and infectious diseases have become increasingly less common and less severe. In order that the most effective means of controlling, as well as treating, these diseases may be available to all, the Committee on Control of Infectious Diseases has issued and, at intervals, has revised a manual that contains the latest and most reliable information that can be supplied by a panel of experts in the field.

IN 1912 Crouzon presented his classic paper to the Medical Society of the Hospitals of Paris. It was a report on two patients, a 29-year-old mother and her 3-year-old son, with strange malformations of the face and head to which he gave the name "hereditary craniofacial dysostosis." In general Crouzon listed the following factors as characteristic of the disease: 1) cranial malformation that is a combination both of a skull in the shape of a boat (scaphocephaly) and in the shape of a wedge (trigonocephaly); 2) malformation of the face resulting in an arched nose resembling a parrot's beak and marked protrusion of the mandible beyond the maxilla (prognathism); 3) bilateral exophthalmos with external strabismus; and finally 4) a hereditary and familial occurrence of these malformations. In addition to these four main characteristics of the syndrome, the child described in Crouzon's paper also had suffered from epilepsy and urinary incontinence. In discussing the possible etiology of this disorder, the author favored the hypothesis that it represented a hereditary malformation of embryonic origin. Since this original report, Crouzon and others have had the opportunity to see and report on additional cases of this strange malady. Atkinson reviewed the literature in 1937 and found that, to that time, 86 certain cases of this condition had been reported. In 28 of the 86 cases occurrence of the disorder in other members of the afflicted member's family was not mentioned. Vogt described this condition associated with syndactylism, and in 1942 Arce and Arce reviewed the roentgenologic findings in eight cases of pathologic synostosis of the vault, including Crouzon's disease. Parks and Costenbader presented the cases of three patients having Crouzon's disease, one of whom had undergone operation, and Pinkerton and Pinkerton reported four cases of craniofacial dysostosis in a family of seven. Three members of the family reported by the Pinkertons, including the father, were normal. Four others in this family, including the mother, had Crouzon's disease. One of those affected was a 3½-year-old girl with marked visual impairment and ophthalmoscopic evidence of chronic increased intracranial pressure. Cranial surgery was recommended in this instance but was refused.

Presacral teratomas are seen most frequently during infancy and childhood. Eighteen children with presacral teratomas were seen at the Mayo Clinic between 1907 and 1953, inclusive. Seventeen were girls. The clinical and pathologic findings are presented. A mass in the presacral area usually is the only symptom as well as the only abnormal physical finding. Such a mass was seen at birth in 14 of the 18 patients. Occasionally symptoms or signs, or both, of obstruction of the urinary tract and/or the gastrointestinal tract constitute the presenting complain. Roentgenograms aid in diagnosis; other laboratory findings contribute little. Pathologically, the size of the tumor may vary greatly. It may contain almost any type of tissue. There was no orderly arrangement of the tissue in any case in our series. In 4 of the 18 cases malignant changes were found microscopically. This is in close agreement with the recorded incidence of malignant changes in presacral teratomas. It is interesting that in one case 2 types of tissue were involved in malignant metamorphosis. Adenocarcinoma is the commonest type of malignancy found, and this is usually papillary. Metastasis frequently occurs via the blood stream to the lungs. The lymph nodes likewise may be the seat of metastatic lesions. Surgical removal should be undertaken regardless of the size of the tumor on the age of the patient.