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BACKGROUND: Traumatic brain injury (TBI) is the most common cause of death and disability in trauma patients, affecting over 1 million Americans per year. Minorities are at disproportionate risk for TBI, and they account for nearly half of all brain injury hospitalizations. Little is known regarding racial disparities in TBI patients. The objective of this study was to investigate the association of race on mortality in patients with moderate to severe isolated TBI. METHODS: The Los Angeles County Trauma System database, consisting of admissions from five Level I and eight Level II trauma centers, was queried for all patients with isolated moderate to severe TBI admitted between 1998 and 2005. Demographics and mortality were compared between races: Asian, African American, Hispanic, White, and Other. Multivariate logistic regression was used to determine the relationship between race and mortality. RESULTS: A total of 17,977 (23.8% female, 76.2% male) severe TBI patients were evaluated. Of this study population, 7.1% were Asian, 13.5% were African American, 42.3% were Hispanic, 32.5% were White, and 4.7% where classified as Other. Overall, Asians (adjusted Odds Ratio AOR 1.4; 95% CI: 1.14-1.71, P = 0.001) had a significantly higher risk in mortality when compared with Whites. Surprisingly, neither African Americans (AOR 1.02; 95% CI: 0.87-1.2, P = 0.82), nor Hispanics (AOR 1.00; 95% CI: 0.89-1.13, P > 0.9) were at increased risk of death compared to their White counterparts. CONCLUSION: This data supports the hypothesis that race may play a role in mortality in moderate to severe TBI. However, only Asians were at higher risk for death. Language: en

Animal studies routinely demonstrate an alcohol (ETOH) -mediated increase in survival after experimental traumatic brain injury (TBI). Recent clinical studies also suggest ETOH plays a neuroprotective role in moderate to severe TBI. We sought to investigate the relationship between ETOH and outcomes in patients with moderate to severe TBI using a countywide database. The Los Angeles County Trauma System database was queried for all adult (older than 14 years) patients with isolated moderate to severe TBI trauma (head Abbreviated Injury Score [AIS] 3 or greater, all other AIS 3 or less) who had ETOH levels measured on admission between 1998 and 2005. A total of 7304 patients were evaluated with 3219 (44.1%) patients testing positive for serum ETOH. ETOH-positive patients with TBI had a significantly lower mortality rate compared with ETOH negative patients (8.5 vs 10.5%, P = 0.005). Even after logistic regression analysis, a positive ETOH was associated with reduced mortality (adjusted OR 0.82, 95% CI: 0.69-0.99, P = 0.035). Therefore, a positive serum ETOH level was independently associated with significantly improved survival in patients with isolated moderate to severe TBI. The neuroprotective role ETOH plays in TBI is in contrast to previous findings and deserves further attention as a potential therapeutic.

Increasing evidence indicates insurance status plays a role in the outcome of trauma patients; however its role on outcomes after traumatic brain injury (TBI) remains unclear. A retrospective review was queried within the National Trauma Data Bank. Moderate to severe TBI insured patients were compared with their uninsured counterparts with respect to demographics, Injury Severity Score, Glasgow Coma Scale score, and outcome. Multivariate logistic regression analysis was used to determine independent risk factors for mortality. Of 52,344 moderate to severe TBI patients, 41,711 (79.7%) were insured. Compared with the uninsured, insured TBI patients were older (46.1 ± 22.4 vs 37.3 ± 16.3 years, P < 0.0001), more severely injured (ISS > 16: 78.4% vs 74.4%, P < 0.0001), had longer intensive care unit length of stay (6.0 ± 9.4 vs 5.1 ± 7.6, P < 0.0001) and had higher mortality (9.3% vs 8.0%, P < 0.0001). However, when controlling for confounding variables, the presence of insurance had a significant protective effect on mortality (adjusted odds ratio 0.89; 95% confidence interval: 0.82-0.97, P = 0.007). This effect was most noticeable in patients with head abbreviated injury score = 5 (adjusted odds ratio 0.7; 95% confidence interval: 0.6-0.8, P < 0.0001), indicating insured severe TBI patients have improved outcomes compared with their uninsured counterparts. There is no clear explanation for this finding however the role of insurance in outcomes after trauma remains a topic for further investigation.

Background. Increasing data indicate treatment with β blockers might improve survival after traumatic brain injury (TBI); the optimal heart rate (HR) range for these patients is unknown. To guide treatment, admission HR in moderate to severe TBI patients was analyzed to determine if a specific range is associated with decreased mortality. Methods. The Los Angeles County Trauma System Database, consisting of five Level I and 8 Level II trauma centers, was queried for all injured patients admitted between 1998 and 2005 (n = 147,788). Isolated moderate to severe TBI patients (head abbreviated injury score ≥ 3) were then identified. Demographics and outcomes were compared at various admission HR subgroups ( < 50, 50―59, 60―69, 70―79, 80―89, 90―99, 100― 109, ≥110). Logistic regression was then performed to determine predictors of mortality. Results. After exclusions, a total of 11,977 isolated moderate to severe isolated TBI patients were analyzed, overall mortality was 11.5% with a trend toward lowest mortality at HR 80 to 89 (7.3%). Each HR subgroup had a significantly increased unadjusted odds ratio for mortality compared with HR 80 to 89, except HR 90 to 99 (OR 1.2, CI 1.0―1.5) and HR 100 to 109 (OR 1.2, CI 1.0―1.5). In multivariable logistic regression analysis, HR < 50, 50―59, 60―69, and ≥110 were independent predictors for increased mortality compared with HR 80―89. Conclusion. After isolated moderate to severe TBI, HR < 50, 50―59, 60―69, and ≥110 were independent predictors of increased mortality. HR outside the range 70―109 could serve as a marker for aggressive resuscitation. As mortality increased significantly with HR: < 50 (AOR 4.70), 50―59 (AOR 2.21), and 60―69 (AOR 1.63), our findings recommend avoiding HR < 70 in patients with moderate to severe TBI.

BACKGROUND Increased levels of angiotensin II type 1 receptor (AT1 R) antibody have been shown to be associated with allograft rejection. This study aims to determine the rate of development of antibody to AT1 R after mechanical circulatory support device (MCS) implantation, and if the development of strong binding AT1 R antibodies is associated with survival. METHODS Eighty-eight patients who had one MCS implantation were accessed based on serum availability. Mechanical circulatory support devices in this cohort included pneumatic bilateral paracorporeal ventricular assist device, continuous flow left ventricular assist device, and total artificial heart. RESULTS Of 88 patients, seven patients had AT1 R antibodies ≥40 U/mL preimplantation. For 81 patients who had AT1 R antibodies

We utilized the novel approach of 2D radial strain (2-DRS) to evaluate whether left ventricular (LV) mechanical dyssynchrony in mid-LV segments corresponding to papillary muscles insertion sites can predict early mitral regurgitation (MR) reduction post-cardiac resynchronization therapy (CRT).We evaluated 32 patients undergoing CRT (mean age 64 +/- 17 years, 54% males) with MR gradeor =3 determined by the MR jet area/left atrial area ratio (JA/LAA).Fifteen (47%) patients responded to CRT (JA/LAA)25%). Sixty-seven percent of responders had mild or no residual MR and 33% had mild-to-moderate MR, while 70% of nonresponders had grade 3 or 4 MR (P = 0.0001) post CRT. The percent reduction in LV end-systolic volume was significantly higher in responders (P = 0.03), as was improvement in LVEF (P = 0.007). Significant delay of time-to-peak 2-DRS in the midposterior and inferior segments prior to CRT was found in responders compared with nonresponders (580 +/- 58 vs. 486 +/- 94, P = 0.002 and 596 +/- 79 vs. 478 +/- 127 ms, P = 0.005, respectively). Responders also had higher peak positive systolic 2-DRS in the posterior and inferior segments compared to nonresponders (22 +/- 13 vs. 12 +/- 7%, P = 0.01 and 17 +/- 9 vs. 9 +/- 7%, P = 0.02, respectively). Logistic regression analysis showed that the differences in pre-CRT inferoanterior time-to-peak 2-DRS of110 ms and MRJA/LAA40% as well as 2-DRS18% in the posterior wall were significant predictors of post-CRT improvement in MR.The presence of a significant time-to-peak delay on 2-DRS between inferior and anterior LV segments, preserved strain of posterior wall, and MRJA/LAA40% were found to be associated with significant MR reduction in patients post-CRT.

Context: GH suppression after oral glucose load [oral glucose tolerance test (OGTT)] and normal age- and gender-matched IGF-I levels reflect biochemical control of acromegaly. The OGTT is the gold standard for determining control of GH secretion at diagnosis and after surgical treatment, but the usefulness of performing an OGTT in patients treated with medical therapy has not been determined. Objective: Our objective was to assess relationships between basal GH levels (basal GH), GH responses to OGTT [GH nadir (GHn)], and IGF-I levels. Design: This was a retrospective electronic database review. Setting: This study was performed at a tertiary outpatient pituitary center. Patients: A total of 166 patients with acromegaly (79 females, 87 males) were included in the study. Four categories of testing were performed: diagnosis, postoperative assessment without medication, testing during somatostatin analog (SA) therapy, and testing during dopamine agonist (DA) therapy. Main Outcome Measures: Basal serum GH and IGF-I levels and GH levels 2 h after 75 g OGTT were measured. Results: A total of 482 simultaneous OGTT and IGF-I measurements were observed from 1985–2008. Discordant results of oral glucose tolerance testing (GHn and IGF-I) were observed 33, 48, and 18% in postoperative assessment without medication, SA, and DA categories, respectively. In the SA category, 42% of tests were discordant with normal IGF-I and nonsuppressed GHn. In contrast, 4% of tests were discordant with normal IGF-I and nonsuppressed GH in those treated with DA. No significant differences in discordance were observed when basal GH was used. Conclusions: Both basal and GHn levels are highly discordant with IGF-I levels during medical therapy with SAs. The OGTT is not useful in assessing biochemical control in these subjects.

Percutaneous tracheostomy (PT) is performed routinely on neurosurgical patients in many critical care units. Some of these patients suffer from severe brain injury and require intracranial pressure (ICP) monitoring. It remains uncertain whether this procedure causes an increase in ICP or jeopardizes the cerebral perfusion pressure (CPP) in these patients. We studied the effects of PT on ICP and CPP in this group of patients.Our study group consisted of 52 neurosurgical patients in the surgical intensive care unit of an urban, Level I Trauma Center who had ICP monitoring and underwent PT between 2001 and 2005. Data were collected from 24 hours before to 24 hours after PT. ICP, CPP, and Glasgow Coma Score (GCS) scale were measured hourly during the study period.There was no statistically significant change in the mean ICP over the 48-hour study period or after the procedure. There was a temporary increase in ICP during the procedure (1.60 mm Hg) which was statistically not significant. There was statistically significant increase in the mean CPP after the procedure, although this increase was clinically not significant. The risk of having a critically high ICP (20 mm Hg) or low CPP (60 mm Hg) values did not increase after the procedure. There was no significant change in GCS after the procedure.PT in neurosurgical patients with ICP monitor does not cause clinically significant or hazardous changes in ICP, CPP, and GCS. We therefore consider PT to be safe in neurosurgical patients.

To assess the relative contribution of vitamin D insufficiency to loss of bone mineral density (BMD) in patients taking bisphosphonates.Patients were eligible for inclusion if they had osteoporosis or osteopenia and demonstrated a decline in BMD during the preceding year while taking stable doses of alendronate or risedronate, plus supplemental calcium and vitamin D. Patients with previously known secondary causes of osteoporosis were excluded from the study. Eligible patients underwent prospective measurement of bilateral hip and lumbar spine BMD by dual-energy x-ray absorptiometry, serum 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D, intact parathyroid hormone, osteocalcin, and thyroid-stimulating hormone (thyrotropin), and urinary calcium:creatinine ratio.Annual BMD was assessed in 175 previously bisphosphonate-responsive patients with low BMD. Of the 175 patients, 136 (78%) had either a significant interval increase or no change in BMD, whereas 39 (22%) had a significant decrease. Of the 39 patients who lost BMD, 20 (51%) had vitamin D insufficiency (25-OHD30 ng/mL). After a single course of orally administered vitamin D2 (500,000 IU during a 5-week period), the 25-OHD level returned to normal in 17 of the 20 vitamin D-insufficient patients and was associated with significant (P.02) 3.0% and 2.7% increases in BMD at the lumbar spine and the femoral neck, respectively. Failure to normalize the serum 25-OHD level was associated with further loss of BMD.Vitamin D insufficiency was the most frequently identified cause of bone loss in patients with declining BMD during bisphosphonate therapy. Correction of vitamin D insufficiency in these patients led to a significant rebound in BMD.

ObjectivesThe purpose of this study was to evaluate outcomes of heart transplantation (HTx) and changes in left ventricular wall thickness (LVWT) post-HTx using donors with left ventricular hypertrophy (LVH).BackgroundLimited data are available on use of donor hearts with LVH in HTx.MethodsWe reviewed 427 patients who underwent HTx: 62 received hearts with LVH (interventricular septum [IVS] or posterior wall [PW] thickness ≥1.2 cm) by echocardiography, and 365 received hearts without LVH. The median follow-up was 3.8 years (range 0 to 16.2 years).ResultsRecipient age was 56 ± 11 years and donor age was 30 ± 12 years. Baseline recipient characteristics were similar in both groups. Donors with LVH were older (35 ± 12 years vs. 29 ± 12 years, p = 0.001) and had higher rates of intracranial hemorrhage (38% vs. 15%, p = 0.001). The LVWT was increased in the LVH group compared with LVWT in the non-LVH group (IVS: 1.28 ± 0.18 cm vs. 0.85 ± 0.19 cm, PW: 1.27 ± 0.19 cm vs. 0.85 ± 0.20 cm, p = 0.0001 for both groups). Mild LVH (1.2 to 1.3 cm) was found in 42%, moderate (>1.3 to 1.7 cm) in 53%, and severe (>1.7 cm) in 5% of donors with LVH. Left ventricular wall thickness regression occurred in both IVS and PW (1.28 ± 0.18 cm vs. 1.10 ± 0.13 cm vs. 1.13 ± 0.14 cm, and 1.27 ± 0.19 cm vs. 1.11 ± 0.11 cm vs. 1.13 ± 0.14 cm, at baseline, 1 year, and 5 years, respectively; p < 0.001 for change from baseline to 1 and 5 years for both locations). Patients with or without donor LVH had similar 1-year (3.5% vs. 9.5%, p = 0.2) and 5-year survival rates (84 ± 5.9% vs. 70 ± 2.7%, p = 0.07).ConclusionsShort- and long-term survival rates and rates of LVH at follow-up were similar in both groups, suggesting that donor hearts with mild and moderate LVH can be safely used in HTx.

We aimed to determine the risk factors associated with mortality in patients with congenitally bicuspid aortic valve disease and dilation (5 cm) of the ascending aorta after aortic valve replacement.We reviewed 252 patients with bicuspid aortic valve undergoing aortic valve replacement at our institution from 1971 through 2000. Patients undergoing concomitant replacement of the ascending aorta were excluded.The average patient age was 61 +/- 15 years; 66.3% were male, and 40.5% of patients had coronary artery disease. The ascending aorta was normal (4.0 cm) in 60.3%, mildly dilated (4.0 to 4.4 cm) in 24.2%, and moderately dilated (4.5 to 4.9 cm) in 15.5% of patients. Patients with moderate aortic dilatation had significantly lower prevalence of coronary artery disease compared with patients with normal ascending aortas (20.5% and 45.4%; p = 0.006). Mean follow-up was 8.9 +/- 6.3 years. Long-term survival was significantly different across the three groups (p = 0.004). The 5-, 10-, and 15-year estimates were 78%, 59%, and 37%, respectively, in the normal aorta group; 88%, 77%, and 46%, respectively, in the mild aortic dilation group; and 92%, 83%, and 70%, respectively, in the moderate aortic dilation group. No significant difference in cardiac death was found among the groups (p = 0.08). The significant predictors of survival using the Cox regression model were coronary artery disease, age, decade of surgery, and ejection fraction. Aortic dilation was not significant after adjusting for these other variables. At follow-up, 18 patients required reoperation, 17 for aortic valve prosthesis failure and 1 for ascending aorta aneurysm.The present study highlights the important adverse effect of concomitant coronary artery disease, advanced age, earlier decade of surgery, and reduced left ventricular ejection fraction on survival after aortic valve replacement for bicuspid aortic valve in patients with no or mild and moderate (5 cm) dilation of the ascending aorta.

Purpose: To determine if there is significant symptomatology in women with heterozygous α-galactosidase mutations. Methods: Data from medical records of the 44 heterozygous females followed at Cedars-Sinai Medical Center were compiled and analyzed for symptoms of Fabry disease. Quality of life data were also analyzed. Results: Seventy-six percent were referred due to an affected male relative; 76% reported acroparesthesias as their first symptom. A mean of 15.7 years elapsed from onset of first symptoms to the diagnosis. Quality of life, measured by the SF-36 survey, was globally reduced. Pain affected mood and enjoyment of life. Central/peripheral nervous, cardiopulmonary, and renal system manifestations of Fabry disease were present far above that predicted for random X-inactivation of the normal allele. Fatigue, present in 59%, was associated with reduced maximum oxygen consumption (P = 0.049); exercise intolerance, present in 83%, was associated with reduced maximal heart rate during exercise testing (P = 0.0089). Women diagnosed via family history experienced more angina (P = 0.035), decreased vibration sense (P = 0.026), and had a worse percentage predicted FEF25–75 (P = 0.037) compared to women diagnosed because of symptoms. Conclusions: This study indicates that the asymptomatic female carrier of Fabry disease is the exception, not the rule: heterozygotes suffer from significant multisystemic disease and reduced quality of life and must be monitored and treated accordingly.

Poor outcomes after thoracic transplantation with concurrent renal dysfunction are well described: without transplantation or with thoracic-only transplantation, patients face unacceptably high mortality. Outcomes after combined lung-kidney transplantation (LKT) remain largely uninvestigated. The United Network for Organ Sharing/Organ Procurement and Transplantation Network database was queried to identify all LKTs, lung transplantations (LTs), and kidney transplantations (KTs) performed in the United States from 1995 to 2013. Survival was calculated using the Kaplan-Meier method and compared using log-rank tests or Cox regression models. Thirty-one LKTs were performed. Mean recipient age was 45.4 ± 13.5 years; 48.3 per cent were male. Retransplantation for graft failure was the leading indication for LT (n = 13) and the most common renal indication was calcineurin inhibitor nephrotoxicity (n = 11). Mean lung allocation score was 46.6 ± 14.4, mean creatinine was 3.7 ± 2.8 g/dL, and glomerular filtration rate was 23.1 (interquartile range 11.9, 38.3) mL/min/1.7 m(2), and 11 (35.5%) were dialysis dependent. Patient survival after LKT was 92.9 per cent, 71.0 per cent, and 71.0 per cent at one month, six months, and one year, with a median survival of 95.2 months. One- and five-year survival after LKT, 71.0 per cent and 59.9 per cent, were similar to LT (n = 23,913), 81.7 per cent and 51.4 per cent (P = 0.061 and 0.55), and inferior to KT (n = 175,269), 94.9 per cent and 82.8 per cent (P0.0001), respectively. Patient survival after LKT was similar to isolated LT, and these results suggest that LKT is a feasible therapeutic option for LT candidates with significant renal dysfunction.

A single dose of allogeneic cardiosphere-derived cells (CDCs) improves cardiac function and reduces scarring, and increases viable myocardium in the infarcted rat and pig heart without eliciting a detrimental immune response. Clinical trials using single doses of allogeneic human CDCs are underway. It is unknown whether repeat dosing confers additional benefit or if it elicits an immune response.Wistar-Kyoto rats underwent coronary artery ligation and intramyocardial injection of CDCs, with a second thoracotomy and repeat CDC injection 3 weeks later. Treatment permutations included 2 doses of allogeneic Brown-Norway CDCs (n = 24), syngeneic Wistar-Kyoto CDCs (n = 24), xenogeneic human CDCs (n = 24) or saline (n = 8). Cardiac function was assessed by transthoracic echocardiography, infarct size and inflammatory infiltration by histology, and cellular and humoral immune responses by lymphocyte proliferation and alloantibody assays.Repeat dosing of allogeneic and syngeneic CDCs improved ejection fraction by 5.2% (95% CI 2.1 to 8.3) and 6.8% (95% CI 3.8 to 9.8) after the first dose, and by 3.4% (95% CI 0.1% to 6.8%) and 6.4% (95% CI 4.2% to 8.6%) after the second dose. Infarct size was equally reduced with repeat dosing of syngeneic and allogeneic CDCs relative to xenogeneic and control treatments (p0.0001). Significant rejection-like infiltrates were present only in the xenogeneic group; likewise, lymphocyte proliferation and antibody assays were positive in the xenogeneic and negative in syngeneic and allogeneic groups.Repeat dosing of allogeneic CDCs in immunocompetent rats is safe and effective, consistent with the known immunomodulatory and anti-inflammatory properties of CDCs. These findings motivate clinical testing of repeatedly dosed CDCs for chronic heart disease.

Aimee French, David Balfe, James M Mirocha, Jeremy A Falk, Zab Mosenifar Cedars-Sinai Medical Center, Division of Pulmonary and Critical Care Medicine, Los Angeles, CA, USA Background: Forced expiratory volume in 1 second (FEV1) grades severity of COPD and predicts survival. We hypothesize that the inspiratory capacity/total lung capacity (IC/TLC) ratio, a sensitive measure of static lung hyperinflation, may have a significant association with survival in an emphysematous phenotype of COPD.Objectives: To access the association between IC/TLC and survival in an emphysematous phenotype of COPD. Methods: We performed a retrospective analysis of a large pulmonary function (PF) database with 39,050 entries, from April 1978 to October 2009. Emphysematous COPD was defined as reduced FEV1/forced vital capacity (FVC), increased TLC, and reduced diffusing capacity of the lungs for carbon monoxide (DLCO; beyond 95% confidence intervals [CIs]). We evaluated the association between survival in emphysematous COPD patients and the IC/TLC ratio evaluated both as dichotomous (≤25% vs >25%) and continuous predictors. Five hundred and ninety-six patients had reported death dates.Results: Univariate analysis revealed that IC/TLC ≤25% was a significant predictor of death (hazard ratio [HR]: 2.39, P

Background Desensitization (DES) with intravenous immunoglobulin (IVIG) + rituximab is effective, safe, and increases the transplantation rate in human leukocyte antigen-sensitized patients. However, reports of progressive multifocal leukoencephalopathy (PML) caused by JC polyomavirus (JCPyV) in autoimmune patients treated with rituximab is concerning. Here, we report on the JCPyV viremia and PML status in kidney transplant patients with/without DES (non-DES). Methods In total 1195 and 699 DNA samples from plasma in 117 DES (78% lymphocyte-depleting [LyD] induction) and 100 non-DES patients (45% LyD), respectively, were submitted for JCPyV-polymerase chain reaction. Results were compared in both groups. Results No patients in either DES or non-DES developed PML or presented with any neurological symptoms. The JCPyV viremia rate was similar in DES and non-DES patients (3/117 vs. 9/100, P = 0.07). The JCPyV levels were low (median peak levels, 1025 copies/mL) and JCPyV viremia was observed only once during the study period in most patients. All 3 DES patients with JCPyV(+) received 1 dose rituximab and no DES patients with >1 dose rituximab showed JCPyV(+). All 3 JCPyV(+) DES patients received LyD induction, while only 2 of 9 JCPyV(+) non-DES patients did so, and the remaining 7 received non-LyD or no induction. JCPyV in leukocyte was mostly negative in DES and non-DES patients. Immunosuppression in patients with or without JCPyV(+) was similar. BK polyomavirus viremia was observed more commonly in patients with JCPyV(+) than in those without (P

Desensitization with intravenous immunoglobulin and rituximab (I+R) significantly improves transplant rates in highly sensitized patients, but antibody-mediated rejection (ABMR) remains a concern.Between July 2006 and December 2012, 226 highly sensitized patients received transplants after desensitization. Most received alemtuzumab induction and standard immunosuppression. Two groups were examined: ABMR (n = 181) and ABMR (n = 45, 20%). Risk factors for ABMR, pathology, and outcomes were assessed.Significant risks for ABMR included previous transplants and pregnancies as sensitizing events, donor-specific antibody (DSA) relative intensity scores greater than 17, presence of both class I and II DSAs at transplant and time on waitlist. The ABMR showed a significant benefit for graft survival and glomerular filtration rate at 5 years (P0.0001). Banff pathology characteristics for ABMR patients with or without graft loss did not differ. C4d versus C4d ABMR did not predict graft loss (P = 0.086). Thrombotic microangiopathy (TMA) significantly predicted graft failure (P = 0.045). The ABMR episodes were treated with I+R (n = 25), or, in more severe ABMR, plasma exchange (PLEX)+I+R (n = 20). Graft survival for patients treated with I+R was superior (P = 0.028). Increased mortality was seen in ABMR patients experiencing graft loss after ABMR treatment (P = 0.004). The PLEX + Eculizumab improved graft survival for TMA patients (P = 0.036).Patients desensitized with I+R who remain ABMR have long-term graft and patient survival. The ABMR patients have significantly reduced graft survival and glomerular filtration rate at 5 years, especially TMA. Severe ABMR episodes benefit from treatment with PLEX + Eculizumab. The DSA-relative intensity scores at transplant was a strong predictor of ABMR. Donor-specific antibody avoidance and reduction strategies before transplantation are critical to avoiding ABMR and improving long-term outcomes.

Left ventricular (LV) diastolic function is an important predictor of morbidity and mortality after acute myocardial infarction (AMI). We evaluated the role of diastolic function in predicting in-hospital events and LV ejection fraction (EF) 6 months after a first AMI that was treated with primary percutaneous coronary intervention (PCI). We prospectively enrolled 59 consecutive patients who were 60 +/- 15 years of age (48 men), presented at our institution with their first AMI, and were treated with primary PCI. Patients underwent 2-dimensional and Doppler echocardiography, including tissue Doppler imaging of 6 basal mitral annular regions within 24 hours after primary PCI and were followed until discharge. Clinical and echocardiographic variables at index AMI were compared with a combined end point of cardiac death, ventricular tachycardia, congestive heart failure, or emergency in-hospital surgical revascularization. Follow-up echocardiographic assessment was performed at 6 months in 24 patients. During hospitalization, 3 patients died, 7 developed congestive heart failure, 4 had ventricular tachycardia, and 1 required emergency surgical revascularization. Stepwise logistic regression analysis showed the ratio of early mitral inflow diastolic filling wave (E) to peak early diastolic velocity of non-infarct-related mitral annulus (p < 0.01) (E') and mitral inflow E-wave deceleration time (p < 0.02) to be independent predictors of in-hospital cardiac events (generalized R2 = 0.66). In a stepwise multiple linear regression model, independent predictors of follow-up LVEF were mitral inflow deceleration time (R2 = 0.39, p = 0.002), baseline LVEF (R2 = 0.54, p < 0.02), and mitral inflow peak early velocity/mitral annular peak early velocity (or E/E') of infarct annulus (R2 = 0.66, p = 0.02). In conclusion, in patients who are treated with primary PCI for a first AMI, E/E' velocity ratio and mitral inflow E-wave deceleration time are strong predictors of in-hospital cardiac events and of LVEF at 6-month follow-up.

Aims Paravalvular aortic regurgitation (PVAR) after balloon-expandable transcatheter aortic valve implantation (TAVI) remains difficult to quantify, and the utility of the AR index (ARi) to create a composite aortic insufficiency (CAI) score was an important advance. Heart rate (HR) influences the ARi but the clinical relevance of this phenomenon remains poorly appreciated. We sought to validate a new composite heart-rate-adjusted haemodynamic-echocardiographic aortic insufficiency (CHAI) score in the prognostic evaluation of PVAR after balloon-expandable TAVI. Methods and results The severity of PVAR was assessed immediately post TAVI by transoesophageal echocardiography (TOE) with simultaneous assessment of transcatheter haemodynamics. A total of 303 patients were studied. The CHAI score, incorporating the HR-adjusted diastolic-delta (HRA-DD, the difference between left ventricular and aortic diastolic pressures/HR*80), had a greater discriminatory value for one-year mortality than both PVAR by TOE (p=0.0018) and the previously proposed CAI score, based on the ARi without HR adjustment (p=0.0029). The CHAI score also better stratified percentage increases in left ventricular systolic chamber dimensions at one month and serum natriuretic peptide levels at one to three months. Conclusions Prognostication of PVAR in the intermediate range of echocardiographic severity remains unreliable and is greatly enhanced by the integration of heart-rate-adjusted transcatheter haemodynamics.

To compare the utility of PAX6 and PAX8 as immunohistochemical markers for neuroendocrine tumors (NETs) of pancreatic origin, we performed PAX6 and PAX8 immunostains on 178 NETs, including 110 primary NETs (26 pancreatic, 10 gastric, 12 duodenal, 22 jejuno-ileal, 10 rectal, 30 pulmonary) and 68 NETs metastatic to the liver (24 pancreatic, 1 duodenal, 37 jejuno-ileal, 1 rectal, 5 pulmonary). Among primary NETs, PAX6 and PAX8 were positive in 65 % (17/26) and 73 % (19/26) of pancreatic, 0 % (0/10) and 10 % (1/10) of gastric, 92 % (11/12) and 92 % (11/12) of duodenal, 0 % (0/22) and 0 % (0/22) of jejuno-ileal, 90 % (9/10) and 80 % (8/10) of rectal, and 0 % (0/30) and 23 % (7/30) of pulmonary NETs, respectively. PAX6 and PAX8 positivity was seen in 46 % (11/24) and 50 % (12/24) of metastatic pancreatic NETs to the liver, respectively. None of the nonpancreatic NETs metastatic to the liver were immunoreactive for either PAX6 or PAX8. PAX6 showed a slightly but statistically significant higher specificity for pancreatic NETs than did PAX8 (P = 0.039), while the sensitivities were similar (P = 0.51). PAX6 had the additional advantages over PAX8 of not exhibiting nonspecific cytoplasmic staining of tumor cells and only infrequently staining background lymphocytes. Since rectal NETs rarely present with metastatic disease, positive staining of a metastatic NET of unknown primary origin for PAX6 and/or PAX8 favors a pancreatic or duodenal origin. This information may be helpful in directing further diagnostic studies to identify the primary site of the metastatic tumor.

This study compared the accuracy of cardiovascular diagnoses by medical students operating a small hand-carried ultrasound (HCU) device with that of board-certified cardiologists using standard physical examinations. Sixty-one patients (38% women; mean age 70 +/- 19 years) with clinically significant cardiac disease had HCU studies performed by 1 of 2 medical students with 18 hours of training in cardiac ultrasound and physical examinations by 1 of 5 cardiologists. Diagnostic accuracy was determined by standard echocardiography. Two-hundred thirty-nine abnormal findings were detected by standard echocardiography. The students correctly identified 75% (180 of 239) of the pathologies, whereas cardiologists found 49% (116 of 239) (p0.001). The students' diagnostic specificity of 87% was also greater than cardiologists' specificity of 76% (p0.001). For nonvalvular pathologies (115 findings), students' sensitivity was 61%, compared with 47% for cardiologists (p = 0.040). There were 124 clinically significant valvular lesions (111 regurgitations, 13 stenoses). Students' and cardiologists' sensitivities for recognizing lesions that cause a systolic murmur were 93% and 62% (p0.001), respectively. Students' sensitivity for diagnosing lesions that produce a diastolic murmur was 75%; cardiologists recognized 16% of these lesions (p0.001). The diagnostic accuracy of medical students using an HCU device after brief echocardiographic training to detect valvular disease, left ventricular dysfunction, enlargement, and hypertrophy was superior to that of experienced cardiologists performing cardiac physical examinations.

In this study we compared the surgical management of ischemic mitral regurgitation (IMR) by revascularization alone and by revascularization combined with mitral valve repair.We studied 355 patients who underwent revascularization alone (n = 168) or revascularization combined with mitral valve repair (n = 187) for IMR from March 1994 to September 2003. Preoperative and operative characteristics, postoperative mitral regurgitation severity, operative mortality, and late survival were examined for each surgical group.No differences were noted between the two groups in age, sex, history of diabetes or hypertension, and number of bypass grafts. The combined surgical group had a lower preoperative left ventricular ejection fraction (0.38 +/- 0.14 versus 0.44 +/- 0.15), greater severity of IMR, higher frequency of prior myocardial infarction, and longer cross-clamp and pump times (p0.01). The combined surgical group had a greater reduction in IMR grade (2.7 +/- 0.1 grades versus 0.2 +/- 0.1 grade), a lower postoperative IMR grade (0.9 +/- 0.1 versus 2.3 +/- 0.1), and a higher success with reduction of IMR by two or more grades (89% versus 11%) (p0.001). In patients with 3+ or 4+ IMR, both groups had similar operative mortality (11.0% in the combined group compared with 4.7% for revascularization alone, p = 0.11) and actuarial survival at 5 years (44% +/- 5% versus 41% +/- 7%, p = 0.53). Independently predictive of higher early mortality (or = 30 days) by Cox analysis were longer pump time (p0.001) and older age (p0.02). Predictive of late mortality (30 days) were older age (p0.001), fewer bypass grafts (p0.01), and lower ejection fraction (p0.01). After adjustment for these variables, there was a trend (p = 0.08) toward a higher late survival with the combined surgical procedure.In patients with IMR, combined mitral valve repair and revascularization resulted in less postoperative mitral regurgitation and similar 5-year survival when compared with revascularization alone. Attempts to reduce pump time by using off-pump techniques may reduce early mortality in these high-risk patients.

The accuracy of a hand-carried cardiac ultrasound (HCCU) device for the diagnosis of valvular regurgitations using color-flow Doppler was assessed. One hundred twenty hospitalized patients with at least mild valvular regurgitation by standard echocardiography were evaluated by 2 cardiologists using HCCU. The HCCU operator identified 99% of clinically significant valvular regurgitations and assessed the severity correctly in 83% of cases. For mild regurgitation, the HCCU sensitivity and specificity were 82% and 93%, respectively, resulting in correct assessments of severity in 71% of cases. HCCU used by trained cardiologists has high sensitivity for the detection and accurate assessment of the severity of clinically relevant valvular regurgitation.

To determine the possible causative agents of eosinophilic or hypersensitivity myocarditis in patients awaiting heart transplantation.Consecutive patient series.Large university-affiliated hospital.A total of 190 consecutive patients who had heart transplantation at our center.The myocardium of the explanted heart was examined for a mixed inflammatory cell infiltrate containing an identifiable component of eosinophils. The relative quantity of each cell type was evaluated by a semiquantitative grading system (scored 0 to 3). The clinical findings and medications were reviewed, and patients were followed after heart transplantation.Eosinophilic myocarditis (EM) was found in the explanted heart in 14 patients (7.4%). Myocardial infiltration by eosinophils ranged from mild (n = 6), often focal involvement to marked (n = 8), usually multifocal or widespread involvement. Twelve patients (86%) had peripheral blood eosinophilia before transplant, and in ten (71%), the eosinophil count at least doubled. Loop or thiazide diuretics were used in all 14 patients, and angiotensin-converting enzyme inhibitors were used in 12. Preoperative characteristics were similar in patients with and without EM, except for a higher frequency of inotropic support and assist devices in EM patients. Dobutamine was used in 12 (86%) and dopamine in seven (50%; one with dopamine alone), and one patient (7%) received neither dopamine nor dobutamine. In two patients receiving dobutamine and one receiving dopamine, tapering or discontinuation of the inotropic infusion resulted in a significant diminution of the peripheral eosinophilia and the EM before transplantation. Postoperative survival in patients with and without EM was similar at 8 yrs (50% +/- 13% and 54% +/- 4%, p =.34). No patient in this study has had EM on biopsy after transplant.EM is a complication of multiple drug therapy in patients awaiting heart transplantation, and should be suspected when peripheral blood eosinophilia is present or the eosinophil count increases by at least two-fold. EM may be related to intravenous inotropic therapy, and this is the first study to document improvement in myocardial pathology after inotropic drug withdrawal. Hypersensitivity to thiazide and loop diuretics, angiotensin-converting enzyme inhibitors, and antibiotics must also be considered. Survival after heart transplantation is not impaired, and postoperative steroid therapy may prevent EM.

Background— We have previously demonstrated vasculoprotective effects after repeated intravenous administration of recombinant apolipoprotein A-I Milano (apoA-I m )/phospholipid complex. In this study, we sought to determine the effects of local recombinant apoA-I m /1-palmitoyl,2-oleoyl phosphatidylcholine complex (ETC-216) delivered intramurally via the Infiltrator catheter on luminal narrowing in a porcine coronary artery stent overstretch injury model. Methods and Results— In twelve domestic swine (≈25 kg), two arteries each were infiltrated with 0.4 mL ETC-216 (14 mg/mL) or vehicle control immediately before deployment of GFX stents (stent:artery ratio=1.3:1). Animals were euthanized at day 28, and evaluation by QCA revealed a significant improvement in mean lumen loss index with ETC-216 treatment (21±22% versus 43±13% lumen loss; P =0.01). Histomorphometric analysis showed that ETC-216 treatment significantly reduced the intimal area (6.7±1.5 versus 5.2±1.4 mm 2 , −22%; P =0.02) and the stenosis index (0.76±0.15 versus 0.59±0.15; P =0.01), and increased the lumen area (2.1±1.4 versus 3.7±1.8 mm 2 , +76%; P =0.02). Regression analysis showed significant differences in lumen area ( P =0.004), neointimal area ( P =0.003), stenosis index ( P =0.001), and neointimal thickness ( P =0.003) adjusted for injury score in favor of ETC-216. Conclusions— A single intramural administration of ETC-216 significantly inhibited injury-induced luminal narrowing in the porcine stent overstretch model through reduction of intimal hyperplasia. These data show that local intracoronary delivery of ETC-216 may be useful to prevent restenosis after coronary stenting.

Objectives We evaluated the coronary vasodilatory effects of transcutaneous low-frequency (27-kHz) ultrasound (USD). Background Ultrasound has been shown to affect vascular function. Methods Ultrasound energy was administered transcutaneously to 12 dogs. Coronary arterial dimensions were assessed using intravascular coronary ultrasound (IVUS) and quantitative coronary angiography (QCA). Results The IVUS mid-left anterior descending (LAD) luminal area was 6.77 ± 1.27 mm2at baseline. After 30 s of ultrasound, this area increased by 9% (7.40 ± 1.44 mm2, p Conclusions Noninvasive, transthoracic low-frequency USD energy results in coronary artery vasodilation within seconds of exposure. The vasodilation is reversible and is similar in magnitude to that induced by NTG. Further evaluation is needed to assess its potential applications in humans.

Background: We examined the agreement between transthoracic echocardiography (TTE) and intraoperative prepump transesophageal echocardiography (TEE) in the assessment of left-sided regurgitant lesions and echocardiographic variables associated with grading discrepancies. Methods: The TTE and prepump TEE studies of 54 patients undergoing aortic-valve replacement for aortic stenosis were reviewed. Agreement and correlation in assessment of aortic (AR) and mitral regurgitation (MR) severity were evaluated. Results: There was no significant difference between mean TTE and prepump TEE grading of MR (0.23 ± 0.19 vs. 0.21 ± 0.15 jet area/area of the left atrium, p = 0.49), but the correlation between the two methods was weak (r = 0.40, p = 0.003), with an exact agreement of 54%. Prepump TEE tended to grade AR as more severe (mean grade 1.43 ± 0.94 vs. 1.24 ± 0.75, p = 0.058). The correlation between the two methods in AR assessment was fair (r = 0.70, p = 0.0001) with an agreement of 59%. For MR and AR grading, no significant correlations between valvular regurgitation severity and blood pressure differences between preoperative TTE and prepump TEE were found. In 17% of cases, discrepancies in identifying severe mitral or aortic valve regurgitation could have affected patient management. Conclusions: There is modest agreement in MR and AR assessment between TTE and prepump TEE. Cardiologists, cardiac surgeons, and anesthesiologists must be aware of differences between these methods when using prepump TEE to guide intraoperative decisions.

Background: Avoiding cardiopulmonary bypass in coronary artery bypass grafting is thought to reduce early mortality and morbidity. Methods: We used our prospective database to compare all patients having off-pump coronary surgery (n = 389) with those having on-pump coronary surgery (n = 2412) between March 15, 1995, and November 1, 2000. Patients were grouped by age (years) in decades (>90, 80-89, 70-79, 60-69

ObjectivesWe assessed an air-blood-saline mixture for Doppler measurement of pulmonary artery systolic pressure (PASP) and the mechanism of enhancement of the Doppler signal by this mixture.BackgroundUnderestimation of PASP by Doppler echocardiography occurs with inadequate continuous wave (CW) signals of tricuspid regurgitation (TR).MethodsWe assessed in vitro the diameter and concentration of microbubbles of agitated air-saline mixture, air-blood-saline mixture and 10% air-10% plasma-80% saline mixture immediately, 5, 10 and 20 s after agitation. In 20 patients, PASP was estimated by Swan-Ganz catheter and CW Doppler of TR: 1) without contrast injection; 2) with intravenous injection of 10% air-90% saline; and 3) 10% blood-10% air-80% saline mixture.ResultsCompared to air-saline, addition of blood or plasma to the air-saline solution significantly increased the concentration of microbubbles (p < 0.001). The air-blood-saline (26.7 ± 7.2 μ) and air-plasma-saline mixture (25.3 ± 7.4 μ) had smaller microbubbles than air-saline mixture (31.6 ± 8.2 μ) (p < 0.001). The correlation between Doppler- and catheter-measured PASP at baseline (r = 0.64) improved with agitated air-saline (r = 0.86). With the air-blood-saline mixture, the correlation further improved (r = 0.92) and the best limits of agreement were obtained.ConclusionsThe combination of the patient’s own blood is a method of making a sterile solution of numerous small microbubbles for injection into the right-sided cardiac chambers. Clinically, the air-blood-saline mixture is easily prepared at bedside and is superior to the air-saline mixture in assessing PASP in patients with inadequate CW Doppler signals.

ABMR remains a significant concern for early graft loss, especially for those who are HS against HLA antigens. We sought to determine the risk factors leading to ABMR in HS pediatric kidney transplant recipients. From January 2009 to December 2015, 16 HS pediatric kidney transplant patients at our center (age range 2-21) were retrospectively reviewed for outcomes and risk factors for ABMR. All HS patients received desensitization with high-dose IVIG/rituximab prior to transplant. Two groups were examined: ABMR+ (n = 7) and ABMR− (n = 9). Patient survival was 100%; however, one patient in the ABMR+ group suffered graft loss from ABMR 16 months post-transplant. ABMR+ patients had higher Class I PRA at the time of transplant (Class I: 73.1 ± 19.1 vs 49.1 ± 28.3, P = .075), although not statistically significant. ABMR+ patients were more likely to have a history of transplant nephrectomy (P = .013). The characteristic that most strongly correlated with ABMR was the DSA-RIS (P = .045), a scoring system used to quantify cumulative intensity of all DSA. In conclusion, DSA, as quantified by the RIS at the time of transplant, should be considered as part of the initial allocation strategy and patients with high RIS monitored closely for ABMR post-transplant.

e15688 Background: Management of liver metastasis in patients with small bowel neuroendocrine tumors (SBNET) remains unclear. Complete surgical resection improves long term survival however factors that influence overall prognosis are not clear. Methods: Database review identified 301 patients diagnosed with SBNET from 1990 to 2013. Only patients with known liver metastasis who underwent resection of the primary tumor were included. Outcomes among patients who underwent complete surgical resection, incomplete debulking of liver metastasis, and resection of the primary tumor alone were compared. The Kaplan-Meier method was used for survival estimates and Cox regression was used to identify predictors of death. Results: 111 patients met study criteria. Median age was 59 years (range 16-80); 49% were male. The terminal ileum (47/111, 42%) was the most common primary tumor location. The median number of liver lesions was 8.5 (range 1-31) and median lesions resected was 1 (range 0-31). In addition to resection of the primary tumor, 36 patients (32%) had no liver resection (NR), 41 (36.9%) had complete resection of liver disease (R0) and 34 (30%) had incomplete resection of liver metastasis (R1). 58 patients (36%) had one or more wedge resections, 12 (10.8%) underwent segmentectomy and 5 (4.5%) had a lobectomy. 33 (29.7%) patients underwent post-operative chemoembolization, 25 (22.5%) had radioembolization and 23 (20.7%) had radiofrequency ablation. The R1 group differed from the R0 group in median size of primary tumor (2.5 cm R1 vs 1.6 cm R0, p = 0.05) and median number of positive lymph nodes (5.0 R1 vs 3.0 R0, p = 0.05). The 5-year OS was 80.9%, 81.1% and 100% for NR, R1 and R0 groups respectively (p = 0.01). 10-year OS did not differ between groups (72.8% NR vs 81.1% R1vs 82.5% NR, p = 0.31). Cox regression showed post-operative administration of chemotherapy (HR = 3.68, p < 0.01) and higher tumor grade (HR = 18.4, p = 0.02) increased risk of death. Conclusions: In patients with SBNET with liver metastasis, higher tumor grade and post-operative chemotherapy increased risk of death. However, resection of the primary tumor along with liver metastasis improves the 5-year OS with complete cytoreduction providing the most benefit.

Background We previously demonstrated that natural killer (NK) cells activated via FcγRIIIa (CD16) interactions with anti-HLA antibodies binding to peripheral blood mononuclear cells (PBMCs) in the in vitro antibody-dependent cellular cytotoxicity (ADCC) assay produced IFNγ. Here we investigate if other CD16 bearing cells are responsive to alloantigen via alloantibody in the in vitro ADCC and if the ADCC-induced cytokine reactions and cytotoxicity can be modified by the anti-interleukin 6 receptor (IL-6R) monoclonal antibody, Tocilizumab (TCZ). Methods Whole blood from a normal individual was incubated overnight with irradiated allo-PBMCs pretreated with anti-HLA antibody positive (in vitro ADCC) or negative sera (mixed lymphocyte reaction [MLR]), with or without TCZ or control IgG. IFNγ+, TNFα+ or IL-6+ cell% in NK cells, monocytes and CD8+ T cells were enumerated by cytokine flow cytometry. ADCC using PBMCs (effector) and Farage B cells (FB, target) with anti-HLA antibody positive sera, with or without TCZ, was measured by flow cytometry. Results IFNγ+ and/or TNFα+ cell% in NK cells, monocytes and CD8+ T cells were elevated in the ADCC compared to the MLR condition. IL-6+ cells were significantly increased in ADCC versus MLR (10.2 ± 4.8% vs 2.7 ± 1.5%, P = 0.0003), but only in monocytes. TCZ treatment significantly reduced TNFα+ cell% in monocytes in ADCC, but had no effect on other cytokine+ cells. TCZ showed no effect on cytotoxicity in ADCC. Conclusions IFNγ, TNFα, and IL-6 production induced by HLA antibody-mediated CD16 bearing cell activation in NK cells, monocytes, and CD8+ T cells suggests a potential role for ADCC and these inflammatory cytokines in mediation of antibody-mediated rejection. TCZ suppressed TNFα production in monocytes in the ADCC condition, suggesting a role of IL-6/IL-6R pathway in monocytes activation. Inhibition of this pathway could reduce the inflammatory cascade induced by alloantibody, although the inhibitory effect on cytotoxicity is minimal.

BACKGROUND Coagulation abnormalities in critically ill surgical patients cause confusion in administration of venous thromboembolism (VTE) prophylaxis. Pharmaceutical VTE prophylaxis is often withheld because of presumed increased risk for bleeding and assumption that these patients would not benefit from it. Coagulopathic critically ill surgical patients are at risk for VTE and should be treated with chemical prophylaxis. METHODS A retrospective review was performed of all coagulopathic patients (international normalized ration >1.5 or platelets

Recent evidence suggests a survival advantage in trauma patients who receive controlled or hypotensive resuscitation volumes. This study examines the threshold crystalloid volume that is an independent risk factor for mortality after trauma.This study analyzed prospectively collected data from a Level I Trauma Center between January 2000 and December 2008. Demographics and outcomes were compared in elderly (≥70 years) and nonelderly (70 years) trauma patients who received crystalloid fluid in the emergency department (ED) to determine a threshold volume that was an independent predictor for mortality.A total of 3,137 patients who received crystalloid resuscitation in the ED were compared. Overall mortality was 5.2%. Mortality among the elderly population was 17.3% (41 deaths), whereas mortality in the nonelderly population was 4% (116 deaths). After multivariate logistic regression analysis, fluid volumes of 1.5 L or more were significantly associated with mortality in both elderly (odds ratio [OR]: 2.89, confidence interval [CI] [1.13-7.41], p=0.027) and nonelderly patients (OR: 2.09, CI [1.31-3.33], p=0.002). Fluid volumes up to 1 L were not associated with significantly increased mortality. At 3 L, mortality was especially pronounced in the elderly (OR: 8.61, CI [1.55-47.75] p=0.014), when compared with the nonelderly (OR=2.69, CI [1.53-4.73], p=0.0006).ED volume replacement of 1.5 L or more was an independent risk factor for mortality. High-volume resuscitations were associated with high-mortality particularly in the elderly trauma patient. Our finding supports the notion that excessive fluid resuscitation should be avoided in the ED and when required, operative intervention or intensive care admission should be considered.

Objective. To determine whether angiomatous and microcystic meningiomas which mimic high grade meningiomas based on extent of peritumoral edema can be reliably differentiated as low grade tumors using normalized apparent diffusion coefficient (ADC) values.Methods. Preoperative magnetic resonance imaging (MRI) of seventy patients with meningiomas was reviewed. Morphologically, the tumors were divided into 3 groups. Group 1 contained 12 pure microcystic, 3 pure angiomatoid and 7 mixed angiomatoid and microcystic tumors. Group 2 included World Health Organization (WHO) grade II and WHO grade III tumors, of which 28 were atypical and 9 were anaplastic meningiomas. Group 3 included WHO grade I tumors of morphology different than angiomatoid and microcystic. Peritumoral edema, normalized ADC, and cerebral blood volume (CBV) were obtained for all meningiomas.Results. Edema index of tumors in group 1 and group 2 was significantly higher than in group 3. Normalized ADC value in group 1 was higher than in group 2, but not statistically significant between groups 1 and 3. CBV values showed no significant group differences.Conclusion. A combination of peritumoral edema index and normalized ADC value is a novel approach to preoperative differentiation between true aggressive meningiomas and mimickers such as angiomatous and microcystic meningiomas.

Activation in mitogen activated protein kinase signaling pathway has recently been described as a predominant event in pilocytic astrocytoma (PA) and is commonly caused by constitutively active mutation in BRAF protein. Whereas PA of posterior fossa in children have a high prevalence of BRAF duplication and fusion, primary molecularm abnormalities in supratentorial tumors of adults are more diverse and also include BRAF V600E point mutation. In our study we evaluated 51 PAs for BRAF duplication and BRAF V600E point mutation. We found a relatively high frequency of V600E mutation in our cohort. Histologically, V600E-carrying PA appeared more infiltrative, yet our limited clinical follow-up failed to detect a deleterious prognostic significance.

The virtual crossmatch relies on the assignment of unacceptable antigens (UAs) to identify compatible donors. The purpose of our study was to identify an algorithm for assignment of UAs such that a negative complement-dependent cytotoxicity (CDC) crossmatch and concomitant negative or weakly positive flow cytometric crossmatch (FXM) are obtained.We used 4 antibody methods: (1) Luminex single antigen (LSA), (2) LSA with a 1:8 serum dilution, (3) C1q LSA, and (4) CDC panel. The UAs were prioritized in the following order: (1) all C1q+/CDC+, (2) LSA 1:87,500 median fluorescence intensity, and (3) LSA10,000 median fluorescence intensity.Of 295 heart transplants that were performed at our center, 69 (23%) recipients had detectable human leukocyte antigen specific antibody at the time of transplant. All donor specific antibodies (DSAs) were avoided for 44 of 69 (64%) (DSA-). There were 25 recipients who had DSA at the time of transplant: 12 (48%) had negative FXM (DSA+/FXM-), and 13 (52%) had positive T-cell and/or B-cell FXM (DSA+/FXM+). Lower freedom from antibody-mediated rejection was observed for the DSA+/FXM+ group compared with the DSA- group (p0.0001). DSA remained detectable after transplant in the sera of 14 recipients, and de novo DSA was detected in 32 recipients. Freedom from antibody-mediated rejection was comparable for both groups (p = 0.53) but was lower than the DSA- group (p0.0001). Survival was comparable for all groups at 1,200 days post-transplant.Strategic prioritization of UA assignment has allowed transplantation of highly sensitized patients across the DSA barrier with survival rates comparable to DSA- heart transplant recipients.

Background Low infliximab (IFX) trough levels and high anti-infliximab antibodies (ATI) levels are associated with loss of response to IFX. Optimizing IFX levels to maintain target concentrations before loss of response may improve long-term efficacy. We hypothesized that trough levels at week 14 are predictive of IFX durability. Methods A prospective observational cohort of pediatric patients with inflammatory bowel disease initiating IFX had IFX and ATI levels drawn at weeks 14 and 54. Primary outcome was week 54 persistent remission (PR), defined as clinical remission without IFX dose intensification. Univariate analyses tested associations of week 14 IFX (IFX14) and ATI (ATI14) levels, clinical and laboratory data with week 54 outcomes. Receiver operating curve analysis and positive and negative predictive values for IFX14 cut-off points were examined. Results Of 58 patients enrolled, 8 (13%) stopped IFX before week 14 and 4 discontinued IFX between weeks 14 and 54. IFX14 level (P = 0.03), baseline C-reactive protein (CRP) level (P = 0.01), and week 14 CRP (CRP14) level (P = 0.0001) were associated with PR. A model with IFX14 levels predicting PR had an area under the receiver operating curve of 0.68 and a model with both IFX14 level and CRP14 >1.0 mg/dL had an area under the receiver operating curve of 0.74. IFX14 cut points of >3, >4, and >7 µg/mL had positive predictive values of 64%, 76% and 100%, respectively, for predicting PR. Conclusions Both IFX levels and CRP at week 14 were significantly associated with week 54 efficacy. A model combining both CRP and IFX at week 14 may help predict remission at week 54.

Patient reported outcomes (PROs) of quality of life (QoL), functioning, and depressive symptom severity are important in assessing the burden of illness of major depressive disorder (MDD) and to evaluate the impact of treatment. We sought to provide a detailed analysis of PROs before and after treatment of MDD from the large Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This analysis examines PROs before and after treatment in the second level of STAR*D. The complete data on QoL, functioning, and depressive symptom severity, were analyzed for each STAR*D level 2 treatment. PROs of QoL, functioning, and depressive symptom severity showed substantial impairments after failing a selective serotonin reuptake inhibitor trial using citalopram (level 1). The seven therapeutic options in level 2 had positive statistically (P values) and clinically (Cohen's standardized differences [Cohen's d]) significant impact on QoL, functioning, depressive symptom severity, and reduction in calculated burden of illness. There were no statistically significant differences between the interventions. However, a substantial proportion of patients still suffered from patient-reported QoL and functioning impairment after treatment, an effect that was more pronounced in nonremitters. PROs are crucial in understanding the impact of MDD and in examining the effects of treatment interventions, both in research and clinical settings.Los resultados percíbidos por el paciente (PROs) sobre la calídad de vida, el funcionamíento y la gravedad de los síntomas depresivos son importantes para la evaluación de la carga de enfermedad y para medír el impacto del tratamíento del trastorno depresívo mayor (TDM). Se íntenta proporcíonar un análísis detallado de los PROs antes y después del tratamíento del TDM a partír del gran estudio STAR*D (Sequenced Treatment Alternatives to Relíeve Depression). Este análísis examina los PROs antes y después del tratamíento en el segundo nivel del STAR*D. Los datos completes sobre calídad de vída, funcíonamíento y gravedad de los síntomas depresivos se analizaron para cada tratamiento del nivel 2 del STAR*D. Los PROs de calídad de vída, funcionamiento y gravedad de los síntomas depresivos mostraron un deterioro significaiivo después de fallar el ensayo con citalopram, un inhibidor selectivo de la recaptura de serotonina (en el nivel 1). Las siete opciones terapéuticas del nivel 2 tuvíeron un ímpacto estadística (valores de p) y clínicamente (diferencías estandarízadas de Cohen [d de Cohen]) signíficativo en cuanto a calídad de vída, funcionamíento, gravedad de los síntomas depresivos y reducción en el cálculo de la carga de enfermedad. No hubo díferencias estadísticamente sígnificatívas entre las intervencíones. Sin embargo, una proporción sígnificativa de pacíentes mantuvo un deterioro en la calídad de vída y el funcíonamíento después del tratamiento, y el efecto fue más pronunciado en aquellos que no remitíeron. Los PROs son clave para la comprensión del impacto del TDM y para examínar los efectos de las intervenciones terapéuticas tanto en investigación como en clínica.Les résultats rapportés par les patients ou PRO (Patient Reported Outcomes) de qualité de vie (QdV), de fonctionnement, et de sévérité du symptôme dépressif sont importants dans l'évaluation du fardeau de l'épisode dépressif majeur (EDM) et de l'impact du traitement. Nous avons cherché à analyser de façon détaillée les PRO avant et après le traitement d'un EDM au cours de la deuxième étape de la grande étude STAR*D (Sequenced Treatment Alternatives to Relieve Depression). Les données complètes de QdV, fonctionnement et sévérité du symptôme dépressif sont analysées pour chaque traitement de l'étape 2 de STAR*D. Dans l'étape 1 de l'étude, après l'échec du citalopram, un inhibiteur sélectif de recapture de la sérotonine, les PRO de QdV, de fonctionnement et de sévérite du symptôme dépressif étaient très médiocres. L'impact des sept choix thérapeutiques de l'étape 2 sur la QdV, le fonctionnement, la sévérité du symptôme dépressif et la diminution du fardeau calculé de la maladie, a montré des différences statistiquement (valeurs de p) et cliniquement (différences standardisées de Cohen [

In obese patients with heart failure, weight reduction may be difficult due to physical restrictions, but may be necessary to achieve heart transplant candidacy. We report the outcomes of obese patients who underwent implantation of a left ventricular assist device (LVAD) using a pulsatile (HeartMate XVE [XVE]) or continuous flow (HeartMate II [HMII]) design and the effect on body mass index (BMI).Of 37 patients with BMI30 kg/m(2) who underwent LVAD implantation, 29 survived at least 30 days and were followed for weight change. In the 30-day survivors, end points of the study were continued LVAD support, heart transplant, or death. One patient underwent gastric bypass surgery and was excluded.In the 28 patients who met inclusion criteria, BMI was 35.6 ± 4.4 kg/m(2) at baseline, and at follow-up was 33.1 ± 5.5 kg/m(2) (mean BMI change -2.5 kg/m(2); P = .063), with a mean follow-up time of 301.6 ± 255.5 days. The XVE group showed a significant BMI reduction of 3.9 kg/m(2) (P = .016 vs baseline); however, the HMII group showed 0.1 kg/m(2) increase in BMI. BMI 30 kg/m(2) at follow-up was achieved in 6 patients (21%), 5 of 19 (26%) in XVE group, and 1 of 9 (11%) in HMII group. In the 14 patients (12 XVE, 2 HMII) or 50% who received a heart transplant, the mean decrease in BMI was 4.6 kg/m(2) (P = .003).LVAD placement in patients with BMI30 kg/m(2) provided significant weight loss in the pulsatile XVE group, but not in recipients of the continuous flow HMII. In patients successfully bridged to a heart transplant after LVAD insertion, mean reduction in BMI was 4.6 kg/m(2) (P = .003). LVAD implantation provides a period of hemodynamic support for obese patients with advanced heart failure, during which time opportunity may be available for weight loss. Pulsatile devices appear to be associated with greater weight loss than nonpulsatile continuous flow devices. Additional therapies may be necessary to achieve significant weight loss in recipients of the continuous flow LVAD.

The relevance of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial in patients with high-risk breast cancer has been questioned. We hypothesize that Z0011 applies to women with HER2-positive disease (HER2+), triple-negative breast cancer (TNBC), and/or age50 years at diagnosis (YA).Women with node-positive HER2+, TNBC, or YA were identified from a prospectively maintained database. Patients were grouped based on Z0011 trial eligibility criteria into those meeting criteria (eligible) and those who did not (ineligible). Patient and tumor characteristics were compared; survival of those meeting Z0011 criteria was determined.We identified 186 node-positive women undergoing lumpectomy/radiation for high-risk breast cancer: 57 of 186 (31 %) HER2+, 55 of 186 (30 %) TNBC, 74 of 186 (40 %) YA. Overall, 125 of 186 (67 %) met Z0011 criteria. HER2-positivity was associated with the lowest rate of ineligibility compared with TNBC and YA (16 vs. 53 and 31 %, respectively, p0.01). Larger tumor size, high grade, extranodal extension, and high Ki67 were associated with Z0011 ineligibility. Among those who were eligible, 105 of 125 (84 %) had ALND and 48 of 125 (38 %) had involvement of nonsentinel nodes (NSLN); median number of NSLNs involved was one (range 1-3). With median follow-up of 5.5 years, there was no difference in survival between those who had ALND and those who did not. After patients with clinically palpable nodes were excluded, 125 of 149 (84 %) met criteria.The Z0011 trial eligibility requirements apply to a significant proportion of patients with HER2+, TNBC, and YA. ALND can be avoided in 67 % node-positive cases and in 84 % of those with clinically negative nodes.

Background Recent technical advances in digital image capture and analysis greatly improve the measurement of protein expression in tissues. Breast cancer biomarkers provide a unique opportunity to utilize digital image analysis to evaluate sources of variability that are caused by the tissue preparation, in particular the decalcification treatment associated with the analysis of bone metastatic breast cancer, and to develop methods for comparison of digital data and categorical scores rendered by pathologists. Methods Tissues were prospectively decalcified for up to 24 hours and stained by immunohistochemistry (IHC) for ER, PR, Ki-67 and p53. HER2 positive breast cancer sections were retrieved from the pathology archives, and annotated with the categorical HER2 expression scores from the pathology reports. Digital images were captured with Leica and Aperio slide scanners. The conversion of the digital to categorical scores was accomplished with a Gaussian mixture model and tested for accuracy by comparison to clinical scores. Results We observe significant effects of the decalcification treatment on common breast cancer biomarkers that are used in the clinic. ER, PR and p53 staining intensities decreased 15 – 20%, whereas Ki-67 decreased > 90% during the first 6 hrs of treatment and stabilized thereafter. In comparison with the Aperio images, pixel intensities generated by the Leica system are lower. A novel statistical model for conversion of digital to categorical scores provides a systematic approach for conversion of nuclear and membrane stains and demonstrated a high concordance with clinical scores. Conclusion Digital image analysis greatly improves the quantification of protein expression in human tissues. Decalcification affects the accuracy of immunohistochemical staining results and cannot be reversed by image analysis. Measurement data obtained on a continuous scoring scale can be converted to categorical scores for comparison with categorical dataset that are generated by pathologists. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_213 Electronic supplementary material The online version of this article (doi:10.1186/s13000-014-0213-9) contains supplementary material, which is available to authorized users.

Antibody-mediated rejection (ABMR) is dependent on complement activating donor-specific anti-HLA antibodies (DSA). This is commonly detected by C4d deposition in allografts. However, recent data define a C4d negative ABMR phenotype suggesting a role for complement-independent DSA injury, antibody-dependent cellular cytotoxicity (ADCC).Here, we established an in vitro ADCC model that identified human ADCC-activated genes using microarray analysis. We subsequently interrogated renal allograft biopsies from patients with ABMR and controls for mRNA expression of the ADCC-activated gene set.We identified 13 ADCC-activated genes. Six gene expression assays including 8 of the 13 genes (CCL3, CCL4/CCL4L1/CCL4L2, CD160, IFNG, NR4A3 and XCL1/XCL2) were analyzed in 127 kidney biopsies obtained from HLA-sensitized (HS), non-HS patients and control individuals. Most ADCC-activated genes showed significantly higher expression in the transplant samples compared to the controls (p0.0005). The gene expression levels were significantly higher in HS and non-HS transplant patients who developed ABMR compared to those who did not (p=0.04-0.002). There was no difference in the gene expression levels between C4d positive and negative ABMR (p=0.26-0.99). Samples from high PRA (80%) or positive DSA patients showed higher gene expression levels for the ADCC-activated genes compared to low PRA (80%) and negative DSA patients (p=0.04-0.001).ADCC pathways are active in transplant patients with ABMR, and likely mediate allograft injury, providing a potential mechanism for C4d negative ABMR.