Citations

A newly identified gene fusion defines the vascular cancer epithelioid hemangioendothelioma and encodes a chimeric transcription factor.

Although there are small animal platforms that recapitulate some of the histological features of nonalcoholic fatty liver disease, there are no small animal models of nonalcoholic steatohepatitis (NASH) with consistent hepatocellular ballooning and progressive fibrosis that also exhibit fidelity to the human condition physiologically. We examined the metabolic and histological effects of a diet on the basis of the composition of “fast food” (high saturated fats, cholesterol, and fructose). Mice ( n = 8 in each group) were assigned to diets as follows: 1) standard chow (SC), i.e., 13% energy as fat [1% saturated fatty acids (SFA)], 2) high fat (HF), i.e., 60% energy as fat (1% SFA), and 3) fast food (FF), i.e., 40% energy as fat (12% SFA, 2% cholesterol). All three diets were supplemented with high fructose. All diets produced obesity. The HF and FF diets produced insulin resistance. Liver histology was normal in animals fed the SC diet. Steatohepatitis with pronounced ballooning and progressive fibrosis (stage 2) was observed in mice fed the FF diet. Although the HF diet produced obesity, insulin resistance, and some steatosis; inflammation was minimal, and there was no increase in fibrosis. The FF diet produced a gene expression signature of increased fibrosis, inflammation, and endoplasmic reticulum stress and lipoapoptosis. A diet based on high cholesterol, high saturated fat, and high fructose recapitulates features of the metabolic syndrome and NASH with progressive fibrosis. This represents a novel small animal model of fibrosing NASH with high fidelity to the human condition. These results highlight the contribution of dietary composition to the development of nonalcoholic fatty liver disease and NASH.

Purpose The WHO diagnostic criteria underscore the role of bone marrow (BM) morphology in distinguishing essential thrombocythemia (ET) from early/prefibrotic primary myelofibrosis (PMF). This study examined the clinical relevance of such a distinction. Methods Representatives from seven international centers of excellence for myeloproliferative neoplasms convened to create a clinicopathologic database of patients previously diagnosed as having ET (N = 1,104). Study eligibility criteria included availability of treatment-naive BM specimens obtained within 1 year of diagnosis. All bone marrows subsequently underwent a central re-review. Results Diagnosis was confirmed as ET in 891 patients (81%) and was revised to early/prefibrotic PMF in 180 (16%); 33 patients were not evaluable. In early/prefibrotic PMF compared with ET, the 10-year survival rates (76% and 89%, respectively) and 15-year survival rates (59% and 80%, respectively), leukemic transformation rates at 10 years (5.8% and 0.7%, respectively) and 15 years (11.7% and 2.1%, respectively), and rates of progression to overt myelofibrosis at 10 years (12.3% and 0.8%, respectively) and 15 years (16.9% and 9.3%) were significantly worse. The respective death, leukemia, and overt myelofibrosis incidence rates per 100 patient-years for early/prefibrotic PMF compared with ET were 2.7% and 1.3% (relative risk [RR], 2.1; P < .001), 0.6% and 0.1% (RR, 5.2; P = .001), and 1% and 0.5% (RR, 2.0; P = .04). Multivariable analysis confirmed these findings and also identified age older than 60 years (hazard ratio [HR], 6.7), leukocyte count greater than 11 × 10 9 /L (HR, 2.01), anemia (HR, 2.95), and thrombosis history (HR, 2.81) as additional risk factors for survival. Thrombosis and JAK2V617F incidence rates were similar between the two groups. Survival in ET was similar to the sex- and age-standardized European population. Conclusion This study validates the clinical relevance of strict adherence to WHO criteria in the diagnosis of ET and provides important information on survival, disease complication rates, and prognostic factors in strictly WHO-defined ET and early/prefibrotic PMF.

Background— Left atrium (LA) enlargement is common in organic mitral regurgitation (MR) and is an emerging prognostic indicator. However, outcome implications of LA enlargement have not been analyzed in the context of routine clinical practice and in a multicenter study. Methods and Results— The Mitral Regurgitation International DAtabase (MIDA) registry enrolls patients with organic MR due to flail leaflets, diagnosed in routine clinical practice, in 5 US and European centers. We investigated the relation between LA diameter and mortality under medical treatment and after mitral surgery in 788 patients in sinus rhythm (64±12 years; median LA, 48 [43 to 52] mm). LA diameter was independently associated with survival after diagnosis (hazard ratio, 1.08 [1.04 to 1.12] per 1 mm increment). Compared with patients with LA <55 mm, those with LA ≥55 mm had lower 8-year overall survival ( P <0.001). LA ≥55 mm independently predicted overall mortality (hazard ratio, 3.67 [1.95 to 6.88]) and cardiac mortality (hazard ratio, 3.74 [1.72 to 8.13]) under medical treatment. The association of LA ≥55 mm and mortality was consistent in subgroups. Similar excess mortality associated with LA ≥55 mm was observed in asymptomatic and symptomatic patients ( P for interaction, 0.77). In patients who underwent mitral surgery, LA ≥55 mm had no impact on postoperative outcome ( P >0.20). Mitral surgery was associated with greater survival benefit in patients with LA ≥55 mm compared with LA <55 mm ( P for interaction, 0.008). Conclusions— In MR caused by flail leaflets, LA diameter ≥55 mm is associated with increased mortality under medical treatment, independent of the presence of symptoms or left ventricular dysfunction.

The present studies were designed to determine the action of neutral endopeptidase inhibition (NEP-I), an inhibitor of the degradation of atrial natriuretic factor (ANF), in congestive heart failure (CHF). Studies were conducted in two groups of anesthetized dogs with CHF induced by 8 days of rapid right ventricular pacing. Group 1 (n = 5) received a specific NEP-I (SQ 28,603) at two doses administered sequentially -30 mg/kg followed by a 60 mg/kg i.v. bolus. Group 2 (n = 5) received intravenous infusion of exogenous ANF (100 ng/kg/min) to achieve increases in plasma ANF concentration as observed in group 1. NEP-I resulted in a diuresis and natriuresis (p less than 0.05) with increases in the fractional excretion of sodium and fractional excretion of lithium, the latter a marker for proximal tubule sodium delivery. Such tubular actions occurred in the absence of increases in glomerular filtration rate or renal blood flow but were associated with significant increases in urinary ANF and urinary cyclic GMP. Plasma ANF increased after the 30 mg/kg NEP-I dose. In contrast, in group 2 with exogenous ANF and despite a marked increase in plasma ANF, no natriuresis was observed. Arterial pressure did not change in either group. These studies demonstrate for the first time in CHF that NEP-I may potentiate the natriuretic action of endogenous ANF by a mechanism that is independent of systemic or renal hemodynamics and does not parallel increases in plasma ANF. These studies support an important therapeutic role for NEP-I in CHF.

Abstract Background: Clinical guidelines for breast cancer survivors with and at-risk for lymphedema have advised against upper body exercise, preventing them from obtaining established health benefits of weight-lifting. The primary hypotheses of the Physical Activity and Lymphedema Trial were that lymphedema onset and worsening would not differ after a one-year weightlifting intervention compared to no exercise among survivors at risk for and with breast cancer-related lymphedema. Methods: We performed a randomized controlled trial of a twice-weekly progressive weight-lifting intervention involving 141 breast cancer survivors with stable arm lymphedema at study entry and 154 survivors at-risk for lymphedema at study entry. Treatment group participants were provided a gym membership and 13 weeks of supervised instruction; the remaining nine months were unsupervised. Control group participants were provided the intervention after study completion. The primary outcome was the change in arm swelling at one year, as measured by water volumetry of the affected and unaffected arms. Secondary outcomes included the clinician defined incidence of onset and exacerbations of lymphedema, lymphedema symptoms, and muscle strength. Participants with lymphedema were required to wear a well-fitted compression garment while weight-lifting. Results: Among the women who entered the study with lymphedema, the proportion who experienced a 5% or greater increase in arm swelling (interlimb difference) was similar in the treatment and control groups (11% versus 12%; cumulative incidence ratio [95% confidence interval], 1.00 (0.88 to 1.13) As compared with the control group, the women in the intervention group with lymphedema had greater improvements in self-reported lymphedema symptom severity (p=0.03), and a lower incidence of lymphedema exacerbations as assessed by a certified lymphedema specialist (14% versus 29% in the control group, p= 0.04). Among the women who entered the study without lymphedema, more control than treatment group women experienced lymphedema onset defined by 5% increase in interlimb difference (17 versus 11%, p = 0.35). Among higher risk women (5+ lymph nodes removed), this comparison was statistically significant (22 versus 7%, p=0.04). Clinician-defined BCRL onset occurred in 1 treatment and 3 control group women (p=0.62). Conclusions: Slowly progressive weight-lifting had no significant impact on arm swelling among breast cancer survivors with lymphedema, and resulted in a reduced incidence of lymphedema flares and improvement in symptoms. In breast cancer survivors at risk for lymphedema, a program of slowly progressive weight-lifting, compared with no intervention, did not result in increased incidence of lymphedema. In secondary analyses, women with 5+ nodes removed who did weight-lifting were less likely to experience increases in arm swelling. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES9-3.

Object Little information is available on follow-up MR imaging after treatment of spinal dural arteriovenous fistulas (DAVFs). The authors studied MR imaging findings in treated spinal DAVFs in relation to clinical outcomes. Methods A retrospective review of patients with spinal DAVFs who had undergone both pre- and postoperative spinal MR imaging was conducted. Postoperative MR images were obtained as routine follow-up studies or because of subjective or objective clinical deterioration. Several pre- and posttreatment MR imaging characteristics were evaluated by 2 neuroradiologists blinded to the clinical outcome. Clinical outcomes of motor, sensory, and urinary function (in relation to the patient's preoperative status) at the time of the postoperative MR imaging were obtained from the clinical record. The chi-square, Fisher exact, and rank-sum tests were performed to correlate imaging findings and changes with clinical outcomes. Results Thirty-four patients met inclusion criteria. Treatment was surgical in 33 patients and endovascular in 1 patient. Follow-up MR imaging was performed at a mean 168 ± 107 days after treatment. Twenty-seven patients (79.4%) were either clinically stable or improved, and 7 (20.6%) experienced worsening in one or more clinical outcomes. Most patients were found to have improvement of MR imaging changes. However, some degree of persistent spinal cord signal abnormality, enhancement, and swelling was observed in 31 (91.2%), 29 (85.3%), and 18 (52.3%) patients, respectively. Changes in these MR imaging characteristics compared with preoperative MR imaging did not correlate with clinical outcomes (p > 0.05), with the one exception of a significant correlation between change in urinary function and extent of spinal cord contrast enhancement (p = 0.026), a correlation of uncertain importance. Ten of the 34 patients underwent posttreatment digital subtraction angiography, and 3 of these patients had recurrent/residual DAVFs. Worsening of motor function significantly correlated with recurrent/residual DAVF (p = 0.053). Conclusions Spinal cord abnormalities persist on postoperative MR imaging studies in patients with treated spinal DAVFs, and although they tend to mildly improve with time, these changes may not correlate with clinical outcomes. However, regardless of imaging findings, worsening motor function may correlate with a recurrent or residual DAVF.

Patients with cancer often have complex needs that must be met within a short intervention window. The authors highlight opportunities for improved multidisciplinary care for patients with advanced cancer and their families.

Trafficking of cells between mother and fetus during the course of normal pregnancy is well documented. Similarly, cells are known to travel between twins that share either a placenta (i.e. monozygotic) or associated chorion (i.e. monochorionic). Transferred cells are thought to be channelled via the vessels of the placenta or vascular connections established via the chorion and the long-term presence of these cells (i.e. microchimerism) can have important consequences for immune system function and reparative capacity of the host. Whether cells can be transferred between twins with separate placentas and separate chorions (i.e. no vascular connections between placentas) has not been investigated nor have the biological consequences of such a transfer. In the present study, we tested the possibility of this type of cell transfer by injecting human cord blood-derived cells into a portion of the littermates of swine and probing for human cells in the blood and tissues of unmanipulated littermates. Human cells were detected in the blood of 78% of unmanipulated littermates. Human cells were also detected in various tissues of the unmanipulated littermates, including kidney (56%), spleen (33%), thymus (11%) and heart (22%). Human cells were maintained in the blood until the piglets were sacrificed (8 months after birth), suggesting the establishment of long-term microchimerism. Our findings show that the transfer of cells between fetuses with separate placentas and separate chorions is significant and thus such twins may be subject to the same consequences of microchimerism as monozygotic or monochorionic counterparts.