Citations

BackgroundCerebral vasogenic edema (VE) has been reported to occur during antiamyloid immunotherapy. VE may be associated with central nervous system pathology with blood–brain barrier disruptions; however, less is known about the prevalence of naturally occurring VE in patients with Alzheimer's disease (AD).MethodsFluid‐attenuated inversion recovery imaging sequences were obtained from four ongoing multicenter, randomized, double‐blind, placebo‐controlled, phase 3 trials in patients with mild‐to‐moderate AD. The first set of baseline scans was from patients in volumetric magnetic resonance imaging addenda in the Interrupting Alzheimer's Dementia by EvaluatiNg Treatment of Amyloid PaThologY (IDENTITY) studies examining semagacestat, a γ‐secretase inhibitor (cohort 1, n = 621). The second set of baseline scans was from the EXPanding Alzheimer's Disease InvestigaTIONs (EXPEDITION) studies examining solanezumab, an anti‐Aβ monoclonal antibody (cohort 2, n = 2141). Readers were blinded to patient‐identifying information and future treatment. A third set of baseline scans was from the first 700 patients who underwent protocol‐specified magnetic resonance imaging before randomization in the EXPEDITION studies (cohort 3). The analysis used three neuroradiologists: two performed independent primary interpretations and the third was the adjudicator. Readers were blinded to patient information, treatment, protocol, and time point.ResultsFour cases of asymptomatic VE were detected at baseline/screening. Two VE cases were due to underlying extra‐axial mass lesions. The third VE case was associated with numerous microhemorrhages in keeping with cerebral amyloid angiopathy‐related inflammation or Aβ‐related angiitis. The final VE case demonstrated localized sulcal fluid‐attenuated inversion recovery imaging hyperintensity. No VE was detected in cohort 3 by readers blinded to patient baseline status.ConclusionsVE seems to be rare at baseline in patients with AD in clinical trials, 2 of 2762 associated with AD. Additional cohorts should be evaluated to support these findings.

Abstract Rationale Gastroesophageal reflux (GER) is highly prevalent in patients with idiopathic pulmonary fibrosis (IPF). Chronic microaspiration secondary to GER may play a role in the pathogenesis and natural history of IPF. Objectives To investigate the relationship between GER-related variables and survival time in patients with IPF. Methods Regression analysis was used to investigate the relationship between GER-related variables and survival time in a retrospectively identified cohort of patients with well-characterized IPF from two academic medical centers. Measurements and Main Results Two hundred four patients were identified for inclusion. GER-related variables were common in this cohort: reported symptoms of GER (34%), a history of GER disease (45%), reported use of GER medications (47%), and Nissen fundoplication (5%). These GER-related variables were significantly associated with longer survival time on unadjusted analysis. After adjustment, the use of GER medications was an independent predictor of longer survival time. In addition, the use of gastroesophageal reflux medications was associated with a lower radiologic fibrosis score. These findings were present regardless of center. Conclusions The reported use of GER medications is associated with decreased radiologic fibrosis and is an independent predictor of longer survival time in patients with IPF. These findings further support the hypothesis that GER and chronic microaspiration may play important roles in the pathobiology of IPF.

Rehabilitation offers means by which persons disabled after a stroke can be returned to patterns of daily living as close to normal as possible. Often simple and readily available restorative techniques suffice, but sophisticated methods and facilities may be needed in many cases. Certain complex problems require specialized attention by persons with detailed knowledge and specific training. Among these are rehabilitation of language and the management of incontinence, sensory loss, pain, spasticity, and psychosocial problems. High-quality rehabilitation is best delivered by a closely cooperating team, including the family physician, medical specialists, nurses, allied health professionals (physical therapist, occupational therapist, social worker, dietitian, rehabilitation counselor, speech therapist, psychologist), the patient's family, and also the patient. To accomplish these ends, hospitals, rehabilitation centers, extended care facilities, and nursing homes should give specific attention to the special needs of stroke patients. Careful discharge planning and follow-up are necessary in all cases. The home environment and the family attitudes may require considerable revision to meet the patient's individual needs. The family physician can offer many rehabilitation services in his office, and additional education in medical school and on a postgraduate level will belp him to reach his full potential in aiding both the acutely ill and the chronically disabled stroke patient.

Although the Fontan procedure has been enormously successful in palliation of single-ventricle patients, many seem to experience progressive failure of the Fontan circulation over time. Ventricular assist devices (VADs) have developed into stable platforms for long-term support of adult patients with heart failure. Given the success of axial flow devices, it was hypothesized that the technology could provide clinical benefit to failing Fontan patients. The aim of this study was to use a computer model to evaluate VAD support in failing Fontan physiology. A computer model of Fontan circulation with heart failure was developed and the HeartMate II (HM II) (Thoratec Corp) axial flow ventricular assist device was connected to this model in a systemic configuration to examine its impact. Cardiac catheterization data from 7 patients (8 catheterization studies) with failing Fontan physiology were applied to this model to evaluate the impact of using the HM II in this manner. When the HM II was used in a systemic configuration at 8000 rpm, there was a 35% decrease in the systemic venous pressure in the Fontan circuit and a 63% decrease in pulmonary capillary wedge pressure with a resultant 41% increase in CI. The model also predicted patient-specific parameters where the VAD may not benefit the patient, such as fixed elevated pulmonary vascular resistance, low systemic ventricular end-diastolic pressure, and high unresponsive systemic vascular resistance. These data suggest a potential benefit from application of axial flow VAD technology in the management of failing Fontan physiology. Clinical correlation will allow for refinement of this model as a predictive tool in discerning which patients may benefit from placement of a VAD and what issues must be addressed prior to implanting the device.

Purpose This phase III study compared the efficacy and safety of bevacizumab (BV) when combined with several standard chemotherapy regimens versus those regimens alone for first-line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer. Patients and Methods Patients were randomly assigned in 2:1 ratio to chemotherapy plus BV or chemotherapy plus placebo. Before random assignment, investigators chose capecitabine (Cape; 2,000 mg/m 2 for 14 days), taxane (Tax) -based (nab-paclitaxel 260 mg/m 2 , docetaxel 75 or 100 mg/m 2 ), or anthracycline (Anthra) -based (doxorubicin or epirubicin combinations [doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide, or fluorouracil/doxorubicin/cyclophosphamide]) chemotherapy administered every 3 weeks. BV or placebo was administered at 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), 1-year survival rate, objective response rate, duration of objective response, and safety. Two independently powered cohorts defined by the choice of chemotherapy (Cape patients or pooled Tax/Anthra patients) were analyzed in parallel. Results RIBBON-1 (Regimens in Bevacizumab for Breast Oncology) enrolled 1,237 patients (Cape cohort, n = 615; Tax/Anthra cohort, n = 622). Median PFS was longer for each BV combination (Cape cohort: increased from 5.7 months to 8.6 months; hazard ratio [HR], 0.69; 95% CI, 0.56 to 0.84; log-rank P < .001; and Tax/Anthra cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52 to 0.80; log-rank P < .001). No statistically significant differences in OS between the placebo- and BV-containing arms were observed. Safety was consistent with results of prior BV trials. Conclusion The combination of BV with Cape, Tax, or Anthra improves clinical benefit in terms of increased PFS in first-line treatment of metastatic breast cancer, with a safety profile comparable to prior phase III studies.

Background— Left ventricular assist device (LVAD) is being increasingly used in patients with end-stage dilated and ischemic cardiomyopathy. There have been no clinical trials addressing the use of LVAD therapy in patients with end-stage heart failure caused by restrictive (RCM) or hypertrophic cardiomyopathy (HCM). The purpose of this study was therefore to analyze the outcome of LVAD therapy in these patients. Methods and Results— Eighty-three patients received continuous axial flow LVAD (Heart mate II, Thoratec, Pleasanton, CA) from February 2007 to May 2010 at our institution. We analyzed the baseline characteristics and surgical and long-term impact of LVAD therapy in 8 patients with RCM or HCM and compared their outcomes with the 75 patients with dilated and ischemic cardiomyopathy. Compared with patients with ischemic or dilated cardiomyopathy, patients with RCM and HCM have significantly smaller left ventricular end-diastolic dimensions (52.5±6 mm versus 68.6±8 mm; P <0.0001) and increased thickness of septal (16 [12, 19] mm versus 10[8.5, 11] mm, P =0.0003) and higher left ventricular ejection fraction (21 [20, 36]% versus 17 [15, 22]%; P =0.0009). We found no difference in early mortality (12.5% versus 9.3%, P =0.57) or length of hospital stay (11 [8, 45] days versus 18.5 [12.2, 27.7] days; P =0.51) between the 2 groups. The right atrial pressure was higher (18 [15, 20] mm Hg versus 12 [9, 15] mm Hg, P =0.03), and pump flow was lower (4.3 [3.8, 4.5] L versus 5.2 [4.7, 5.5] L, P =0.001) after LVAD implantation in patients with RCM and HCM. Central venous catheter related infections were more common in patients with RCM and HCM (87.5% versus 44.5%, P =0.006). There was no difference in the total number of blood units transfused. Median (min, max) follow-up duration after LVAD implantation was 166 [1, 1044] days. The 1-year actuarial survival rate was not different between the 2 groups (87.5% [95% confidence interval, 52.9% to 97.8%] versus 73.2 [95% confidence interval, 60% to 85%]; P =0.77). Conclusions— Our preliminary data show that patients with end-stage heart failure caused by RCM or HCM may benefit from continuous axial flow LVAD therapy. This small study suggests that mortality is comparable with those patients who have dilated or ischemic cardiomyopathy, but right heart failure, prolonged inotropic use, and central venous catheter infections are more common in patients with RCM and HCM who were treated with LVAD. Because of the small numbers the differences should be interpreted cautiously, and prospective clinical trials would be required to recommend this therapy for these patients as bridge to transplantation or destination treatment.

Abstract BackgroundRIBBON-1, a Phase III, multicenter, randomized, placebo-controlled trial in patients with previously untreated MBC was designed to evaluate the efficacy and safety of adding bevacizumab (B) to chemotherapy regimens including capecitabine (Cape; n=615); a taxane (T; n=307), or an anthracycline (Anth; n=315) compared with chemotherapy alone. Pre-specified analyses of progression-free survival PFS) in the Cape and pooled T/Anth cohorts, the primary endpoints of the study were increased upon addition of B. In the Cape cohort, median PFS increased from 5.7 to 8.6 mo (HR=0.69, p-value=0.0002) and in the T/Anth cohort, it increased from 8.0 to 9.2 mo (HR=0.64; p-value&lt;0.0001).MethodsRECIST was used to determine objective response rate (ORR). Patients without a post-baseline tumor assessment were considered non-responders. The primary analysis for the ORR and the duration of response was performed using only patients with measurable disease at baseline. ORR was formally compared between the two treatment arms using the Mantel-Haenszel Chi-squared test, using the randomization stratification factors. Fisher's exact test was also performed. Clinical benefit rate (CBR) was defined as the proportion of patients with a complete or partial response or with stable disease at Week 24. Exploratory analyses of CBR and time to response are provided here. Summary statistics of time to response at Week 9 will be presented as will the final analysis of the secondary endpoint of overall survival.ResultsAnalyses of ORR and CBR are provided in the following table. CapeTaxaneAnth PL (n=206)B (n=409)PL (n=104)B (n=203)PL (n=103)B (n=212)Patients with measurable disease, n (%)161 (78.2)325 (61.1)85 (81.7)161 (79.3)92 (89.3)184 (86.8)ORR, %23.635.435.350.340.252.2CR, n (%)1 (0.6)7 (2.2)3 (3.5)4 (2.5)2 (2.2)3 (1.6)PR, n (%)37 (23.0)108 (33.2)27 (31.8)77 (47.8)35 (38.0)93 (50.5)Difference between arms, %11.815.012.0p-value, unstratified0.00940.030.073Duration of ORMedian, mo7.29.28.68.46.08.1HR (95% CI)0.61 (0.39–0.96)0.75 (0.45–1.27)0.53 (0.34–0.83)Log-rank p-value0.03260.2840.0047Clinical benefit rate*, %47.164.365.471.969.980.7p-value, unstratified&lt;0.00010.240.04CR+PR at Week 9, %20.229.438.354.544.451.1B=bevacizumab, cape=capecitabine, CI=confidence interval, HR=hazard ratio, OR=objective response, PL=placebo, T/Anth=taxane/anthracycline.*For randomized patients.ConclusionsIn patients with HER2-negative MBC, the addition of bevacizumab to capecitabine, taxane or anthracycline chemotherapy induces more responses and those responses occur more rapidly. For capecitabine and anthracycline the addition of bevacizumab leads to objective responses that last longer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6084.

Mechanical ventricular assistance has become a reliable tool for the support of children and infants with heart failure. The devices have shown efficacy both as a bridge to transplantation and as a bridge to recovery. The potential complications that may occur with long-term support have not been fully described. This article reports the occurrence of a large pseudoaneurysm associated with the ascending aorta following explantation of the EXCOR Pediatric ventricular assist device. A management strategy for this potentially lethal complication is described.

Abstract Some data suggest that human calcitonin (CT) secretion is lower in women than in men, decreases with age and the menopause, and is absent in thyroidectomized persons. To further explore CT secretory physiology, we have studied basal and calcium-stimulated plasma immunoreactive CT (iCT) and silica-extractable monomeric CT concentrations in 148 healthy volunteers and 33 patients with a history of thyroid damage (total or subtotal thyroidectomy, radioiodine treatment for thyrotoxicosis). Both whole-plasma iCT and extractable CT levels were lower basally and after calcium infusion in women than in men, basal levels being reduced about 50% and calcium-stimulated values about 75% from those of male subjects. There were no significant changes in basal iCT or extractable CT concentrations with age, and CT secretory capacity (CT response to calcium infusion) likewise did not change with age. Infusion of monomeric CT to constant concentration in 27 persons permitted estimates of CT metabolic clearance rates (MCRs) and secretion rates (SRs). Calculated MCRs of about 9 ml/min · kg−1 (persons aged 21–30 yr) and 6 ml/min · kg−1 (persons aged 54–70 yr) were in good agreement with published data, and did not differ between the sexes. SRs were dependent upon the assay method used to estimate basal plasma CT concentrations, being highest when whole-plasma iCT values were used. Based on estimates of plasma monomeric CT from the silica extraction procedure, the SR of CT was 59 ± 6 (SE) ng/d · kg−1 in men, and 22 ± 3 ng/d · kg−1 in women. Thyroid damage reduced, but did not abolish, apparent CT immunoreactivity, even in silica extracts of plasma. However, all subsets of thyroiddamaged patients had absent-to-markedly-impaired CT secretion in response to calcium infusion. We conclude that CT secretion is substantially lower both basally and after stimulation in women than in men, and that this difference in CT immunoreactivity probably reflects differences in circulating CT bioactivity. The sex difference in plasma CT concentrations probably results from lower rates of CT secretion in women, not increased MCR. There is no age-related decrease of plasma CT concentrations (or CT secretory reserve), calling into question the concept that a progressive deficiency of CT is partly resonsible for age-related (“senile”) osteoporosis. Surgical or radiation damage to the thyroid gland commonly abolishes C-cell response to calcium; such CT-deficient patients form a population suitable for determining whether or not reduced CT secretion can impair skeletal homeostasis.