Low-Cost High-Resolution Microendoscopy for the Detection of Esophageal Squamous Cell Neoplasia: An International Trial.

BACKGROUND & AIMS: Esophageal squamous cell neoplasia has a high mortality rate as a result of late detection. In high-risk regions such as China, screening is performed by Lugol's chromoendoscopy (LCE). LCE has low specificity, resulting in unnecessary tissue biopsy with a subsequent increase in procedure cost and risk. The purpose of this study was to evaluate the accuracy of a novel, low-cost, high-resolution microendoscope (HRME) as an adjunct to LCE. METHODS: In this prospective trial, 147 consecutive high-risk patients were enrolled from 2 US and 2 Chinese tertiary centers. Three expert and 4 novice endoscopists performed white-light endoscopy followed by LCE and HRME. All optical images were compared with the gold standard of histopathology. RESULTS: By using a per-biopsy analysis, the sensitivity of LCE vs LCE + HRME was 96% vs 91% (P = .0832), specificity was 48% vs 88% (P < .001), positive predictive value was 22% vs 45% (P < .0001), negative predictive value was 98% vs 98% (P = .3551), and overall accuracy was 57% vs 90% (P < .001), respectively. By using a per-patient analysis, the sensitivity of LCE vs LCE + HRME was 100% vs 95% (P = .16), specificity was 29% vs 79% (P < .001), positive predictive value was 32% vs 60%, 100% vs 98%, and accuracy was 47% vs 83% (P < .001). With the use of HRME, 136 biopsies (60%; 95% confidence interval, 53%-66%) could have been spared, and 55 patients (48%; 95% confidence interval, 38%-57%) could have been spared any biopsy. CONCLUSIONS: In this trial, HRME improved the accuracy of LCE for esophageal squamous cell neoplasia screening and surveillance. HRME may be a cost-effective optical biopsy adjunct to LCE, potentially reducing unnecessary biopsies and facilitating real-time decision making in globally underserved regions. ClinicalTrials.gov, NCT 01384708.

Modulation of endogenous antioxidant defense and the progression of kidney disease in multi-heritage groups of patients with type 2 diabetes: PRospective EValuation of Early Nephropathy and its Treatment (PREVENT).

BACKGROUND: Diabetes is the western world's leading cause of end-stage renal disease. Glucose-dependent, oxidative stress is linked to the development of renal inflammation and sclerosis, which, in animal models of diabetes, can be prevented by anti-oxidative treatment. Patients of non-Caucasian heritage have low activity of the selenoprotein, antioxidant enzyme, glutathione peroxidase (GPx) and its co-factor vitamin E, which may be linked to their increased propensity to developing end-stage renal disease. RESEARCH DESIGN AND METHODS: We have designed a double-blind, randomized, placebo controlled study with selenium and/or vitamin E versus placebo as the interventions for patients with type 2 diabetes and chronic kidney disease (CKD) stages 1-3. A 2 × 2 factorial design will allow a balanced representation of the heritage groups exposed to each intervention. The primary biochemical outcome is change in GPx activity, and clinical outcome measure is the actual, rate of-and/or percentage change in estimated glomerular filtration rate (eGFR) from baseline. Analysis will be with a marginal model for longitudinal data using Generalized Estimating Equations corrected for measures of baseline serum antioxidant enzyme activities (GPx, superoxide dismutase and catalase), micronutrient levels (vitamins E and C), measures of inflammation (interleukin 6, c-reactive protein and monocyte chemoattractant protein-1) and markers of oxidative damage (plasma 8-isoprostaglandin F2α and urinary 8-hydroxydeoxyguanosine). EXPECTED RESULTS: The study will assess the relationship between GPx activity, oxidative stress, inflammation and eGFR. It will test the null hypothesis that antioxidant therapy does not influence the activity of GPx or other antioxidant enzymes and/or alter the rate of change in eGFR in these patient groups. CONCLUSIONS: Outcome data on the effect of antioxidants in human diabetic renal disease is limited. Previous post hoc analyses have not shown a beneficial effect of vitamin E on renal function. A recent trial of a pharmaceutical antioxidant agent, improved eGFR, but in patients with advanced diabetes-related chronic kidney disease its use was associated with an increased incidence of cardiovascular events. We will explore whether the nutritional antioxidants, vitamin E and selenium alone, or in combination in patients at high risk of renal disease progression, forestalls a reduction in eGFR. The study will describe whether endogenous antioxidant enzyme defenses can be safely modified by this intervention and how this is associated with changes in markers of oxidative stress. Trial registration ISRCTN 97358113. Registered 21st September 2009.

INTRAVENOUS PAMIDRONATE IS ASSOCIATED WITH REDUCED MORTALITY IN PATIENTS WITH CHRONIC CRITICAL ILLNESS.

OBJECTIVE: Chronic critical illness (CCI), characterized by prolonged mechanical ventilation and tracheostomy, commonly manifests with elevated bone resorption, which has previously been shown to abate after treatment with intravenous (IV) bisphosphonates. Our study assessed the impact of pamidronate administration on clinical outcomes in a CCI cohort. METHODS: A retrospective case series was performed on 148 patients admitted to The Mount Sinai Hospital Respiratory Care Unit (RCU) from 2009-2010. We identified patients with CCI who did (n = 30) or did not (n = 118) receive IV pamidronate (30 to 90 mg). Both groups included patients with normal and abnormal renal function. Pamidronate was administered for elevated urine or serum N-telopeptide, hypercalciuria, or hypercalcemia. RESULTS: RCU and 1-year mortality were significantly lower in the pamidronate group (0 and 20%, respectively) compared to nonreceivers (19 and 56%, respectively) (P = .0077 and P = .0004, respectively). After adjusting for differences in baseline creatinine, estimated glomerular filtration rate, and serum calcium, the association with reduced mortality remained significant at 1 year (P = .0132) and with borderline significance for RCU mortality (P = .0911). Creatinine was significantly lower 7 days following pamidronate administration (P = .0025), with no significant difference at 14 days compared to baseline. Pamidronate receivers showed a greater increase in albumin during the RCU stay (2.49 to 3.23 g/dL), compared to nonreceivers (2.43 to 2.64 g/dL) (P = .0007). Pamidronate administration was associated with a significantly reduced rate of hypoglycemia compared to RCU patients not receiving pamidronate (0.09 versus 0.12; P = .0071). CONCLUSION: Pamidronate use in a CCI population is associated with reduced mortality, lower hypoglycemia rates, improved albumin, and stable renal function. ABBREVIATIONS: BMI = body mass index CCI = chronic critical illness CI = confidence interval CKD = chronic kidney disease CTx = C-telopeptide eGFR = estimated glomerular filtration rate ICU = intensive care unit IV = intravenous NTx = N-telopeptide PMV = prolonged mechanical ventilation RCU = respiratory care unit.

Safety, clinical, and immunologic efficacy of a Chinese herbal medicine (Food Allergy Herbal Formula-2) for food allergy.

BACKGROUND: Food Allergy Herbal Formula-2 (FAHF-2) is a 9-herb formula based on traditional Chinese medicine that blocks peanut-induced anaphylaxis in a murine model. In phase I studies FAHF-2 was found to be safe and well tolerated. OBJECTIVE: We sought to evaluate the safety and effectiveness of FAHF-2 as a treatment for food allergy. METHODS: In this double-blind, randomized, placebo-controlled study 68 subjects aged 12 to 45 years with allergies to peanut, tree nut, sesame, fish, and/or shellfish, which were confirmed by baseline double-blind, placebo-controlled oral food challenges (DBPCFCs), received FAHF-2 (n = 46) or placebo (n = 22). After 6 months of therapy, subjects underwent DBPCFCs. For those who demonstrated increases in the eliciting dose, a repeat DBPCFC was performed 3 months after stopping therapy. RESULTS: Treatment was well tolerated, with no serious adverse events. By using intent-to-treat analysis, the placebo group had a higher eliciting dose and cumulative dose (P = .05) at the end-of-treatment DBPCFC. There was no difference in the requirement for epinephrine to treat reactions (P = .55). There were no significant differences in allergen-specific IgE and IgG4 levels, cytokine production by PBMCs, or basophil activation between the active and placebo groups. In vitro immunologic studies performed on subjects' baseline PBMCs incubated with FAHF-2 and food allergen produced significantly less IL-5, greater IL-10 levels, and increased numbers of regulatory T cells than untreated cells. Notably, 44% of subjects had poor drug adherence for at least one third of the study period. CONCLUSION: FAHF-2 is a safe herbal medication for subjects with food allergy and shows favorable in vitro immunomodulatory effects; however, efficacy for improving tolerance to food allergens is not demonstrated at the dose and duration used.

In vivo classification of colorectal neoplasia using high-resolution microendoscopy: Improvement with experience.

BACKGROUND AND AIMS: High-resolution microendoscopy (HRME) is a novel, low-cost "optical biopsy" technology that allows for subcellular imaging. The study aim was to evaluate the learning curve of HRME for the differentiation of neoplastic from non-neoplastic colorectal polyps. METHODS: In a prospective cohort fashion, a total of 162 polyps from 97 patients at a single tertiary care center were imaged by HRME and classified in real time as neoplastic (adenomatous, cancer) or non-neoplastic (normal, hyperplastic, inflammatory). Histopathology was the gold standard for comparison. Diagnostic accuracy was examined at three intervals over time throughout the study; the initial interval included the first 40 polyps, the middle interval included the next 40 polyps examined, and the final interval included the last 82 polyps examined. RESULTS: Sensitivity increased significantly from the initial interval (50%) to the middle interval (94%, P = 0.02) and the last interval (97%, P = 0.01). Similarly, specificity was 69% for the initial interval but increased to 92% (P = 0.07) in the middle interval and 96% (P = 0.02) in the last interval. Overall accuracy was 63% for the initial interval and then improved to 93% (P = 0.003) in the middle interval and 96% (P = 0.0007) in the last interval. CONCLUSIONS: In conclusion, this in vivo study demonstrates that an endoscopist without prior colon HRME experience can achieve greater than 90% accuracy for identifying neoplastic colorectal polyps after 40 polyps imaged. HRME is a promising modality to complement white light endoscopy in differentiating neoplastic from non-neoplastic colorectal polyps.

Is prostate cancer changing?: evolving patterns of metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) most commonly metastasizes to the bone, and less commonly to nonosseous sites (eg, lymph nodes, liver, lung). With new therapies extending survival in mCRPC, it was hypothesized that the pattern of metastases is changing over time. The pattern of metastatic disease was evaluated in men with mCRPC, as reported in baseline characteristics of prospective clinical trials over 2 decades. METHODS: This study identified all phase 2 and 3 therapeutic studies in men with mCRPC in PubMed and American Society of Clinical Oncology abstracts from 1990 to 2012. Studies were excluded if they did not report demographic data and sites of metastasis, or excluded patients with a specific site of metastatic disease (except brain). For each type of metastasis, weighted least squares linear regression models were used to evaluate temporal trends. RESULTS: A total of 290 eligible studies (270 phase 2 studies and 20 phase 3 studies) involving 19,110 patients were identified. Between 1990 and 2012, the rate of nonosseous metastasis increased significantly at 1.6% per year (P < .0001), whereas the rate of osseous metastasis decreased at 0.5% per year (P < .0001). The rate of lymph node metastasis increased at 1.4% per year (P < .0001), but the rate of liver and lung metastasis remained relatively stable. CONCLUSIONS: A notable change was found in the pattern of metastasis in patients with mCRPC. Because these evolving patterns may have important implications in treatment selection and prognosis, it is crucial that future clinical trials of patients with mCRPC define patients with a uniform reporting of nonosseous metastasis.

Phase Ib/II trial of gemcitabine, cisplatin, and lenalidomide as first-line therapy in patients with metastatic urothelial carcinoma.

BACKGROUND: Outcomes with current chemotherapy in metastatic urothelial carcinoma (MUC) remain poor. Lenalidomide, an antiangiogenic and immunomodulatory agent, enhances the effects of chemotherapy in preclinical studies. In this phase Ib/II study, we sought to determine a tolerable dose of lenalidomide in combination with gemcitabine and cisplatin (GCL) in patients with MUC and to explore the safety and activity of this regimen. METHODS: Patients with chemotherapy-naïve MUC received gemcitabine 1,000 mg/m(2) on days 1 and 8 and cisplatin 70 mg/m(2) on day 1 every 21 days. In phase Ib, there were four planned escalating dose levels of lenalidomide (10, 15, 20, and 25 mg) daily on days 1-14. RESULTS: Seven patients received GCL in phase Ib. The dose of lenalidomide was not escalated beyond 10 mg because of cytopenias requiring repeated dose delays and reductions. Two additional patients were enrolled in phase II, but the study was ultimately terminated due to poor tolerability and slow accrual. The most frequent grade ≥ 3 adverse events were cytopenias and diarrhea. Three of the nine patients experienced an objective response (one complete response, two partial responses). CONCLUSION: Chronic administration of the GCL regimen was poorly tolerated because of additive and cumulative myelosuppression.

In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study.

OBJECTIVES: High-resolution microendoscopy (HRME) is a low-cost, "optical biopsy" technology that allows for subcellular imaging. The purpose of this study was to determine the in vivo diagnostic accuracy of the HRME for the differentiation of neoplastic from non-neoplastic colorectal polyps and compare it to that of high-definition white-light endoscopy (WLE) with histopathology as the gold standard. METHODS: Three endoscopists prospectively detected a total of 171 polyps from 94 patients that were then imaged by HRME and classified in real-time as neoplastic (adenomatous, cancer) or non-neoplastic (normal, hyperplastic, inflammatory). RESULTS: HRME had a significantly higher accuracy (94%), specificity (95%), and positive predictive value (PPV, 87%) for the determination of neoplastic colorectal polyps compared with WLE (65%, 39%, and 55%, respectively). When looking at small colorectal polyps (less than 10 mm), HRME continued to significantly outperform WLE in terms of accuracy (95% vs. 64%), specificity (98% vs. 40%) and PPV (92% vs. 55%). These trends continued when evaluating diminutive polyps (less than 5 mm) as HRME's accuracy (95%), specificity (98%), and PPV (93%) were all significantly greater than their WLE counterparts (62%, 41%, and 53%, respectively). CONCLUSIONS: In conclusion, this in vivo study demonstrates that HRME can be a very effective modality in the differentiation of neoplastic and non-neoplastic colorectal polyps. A combination of standard white-light colonoscopy for polyp detection and HRME for polyp classification has the potential to truly allow the endoscopist to selectively determine which lesions can be left in situ, which lesions can simply be discarded, and which lesions need formal histopathologic analysis.

Morbidity and mortality in common variable immune deficiency over 4 decades.

The demographics, immunologic parameters, medical complications, and mortality statistics from 473 subjects with common variable immune deficiency followed over 4 decades in New York were analyzed. Median immunoglobulin levels were IgG, 246 mg/dL; IgA, 8 mg/dL; and IgM, 21 mg/dL; 22.6% had an IgG less than 100 mg/dL. Males were diagnosed earlier (median age, 30 years) than females (median age, 33.5 years; P = .004). Ninety-four percent of patients had a history of infections; 68% also had noninfectious complications: hematologic or organ-specific autoimmunity, 28.6%; chronic lung disease, 28.5%; bronchiectasis, 11.2%; gastrointestinal inflammatory disease, 15.4%; malabsorption, 5.9%; granulomatous disease, 9.7%; liver diseases and hepatitis, 9.1%; lymphoma, 8.2%; or other cancers, 7.0%. Females had higher baseline serum IgM (P = .009) and were more likely to develop lymphoma (P = .04); 19.6% of patients died, a significantly shorter survival than age- and sex-matched population controls (P < .0001). Reduced survival was associated with age at diagnosis, lower baseline IgG, higher IgM, and fewer peripheral B cells. The risk of death was 11 times higher for patients with noninfectious complications (hazard ratio = 10.95; P < .0001). Mortality was associated with lymphoma, any form of hepatitis, functional or structural lung impairment, and gastrointestinal disease with or without malabsorption, but not with bronchiectasis, autoimmunity, other cancers, granulomatous disease, or previous splenectomy.

The S curve: a novel morphological finding in the internal carotid artery in patients with fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease commonly affecting the renal and internal carotid arteries (ICAs). A previously unrecognized finding is a redundancy of the mid-distal ICA in FMD patients causing an 'S'-shaped curve. Carotid artery duplex ultrasounds were reviewed in 116 FMD patients to determine S-curve prevalence. FMD patients with an S curve were matched to four control patients divided equally into two groups: (1) age and sex-matched and (2) age ≥70 and sex-matched. S curves were present in 37 (32%) FMD patients. Of these, nine (24%) had angiographic evidence of FMD in their ICA only, 13 (35%) had renal artery FMD only, and 15 (41%) had both ICA and renal FMD. Two patients in the age and sex-matched group had S curves (odds ratio 16.86, 95% CI 3.92-72.48; p<0.0001) while 12 (16.2%) patients in the age ≥70 and sex-matched group had S curves (odds ratio 2.42, 95% CI 1.16-5.03; p=0.016). In conclusion, the S curve is a novel morphological pattern of the mid-distal ICA. While the S curve may not be specific, its presence in individuals <70 years old should alert the clinician to the possibility that FMD is present.

Association of glycemic control parameters with clinical outcomes in chronic critical illness.

OBJECTIVE: Chronic critical illness (CCI) is a term used to designate patients requiring prolonged mechanical ventilation and tracheostomy with associated poor outcomes. The present study assessed the impact of glycemic parameters on outcomes in a CCI population. METHODS: A retrospective case series was performed including 148 patients in The Mount Sinai Hospital Respiratory Care Unit (2009-2010). Utilizing a semi-parametric mixture model, trajectories for the daily mean blood glucose (BG), BG range, and hypoglycemia rate over time identified low- (n = 87) and high-risk (n = 61) hyperglycemia groups and low- (n = 90) and high-risk (n = 58) hypoglycemia groups. The cohort was also classified into diabetes (DM, n = 48), stress hyperglycemia (SH, n = 85), and normal glucose (n = 15) groups. RESULTS: Hospital- (28% vs. 13%, P = .0199) and 1-year mortality (66% vs. 46%, P = .0185) rates were significantly greater in the high- versus low-risk hyperglycemia groups, respectively. The hypoglycemia rate (<70 mg/dL) was lower among ventilator-liberated patients compared to those who failed to liberate (0.092 vs. 0.130, P<.0001). In the SH group, both hospital mortality (high-risk hyperglycemia 48% and low-risk hyperglycemia 15%, P = .0013) and 1-year mortality (high-risk 74% and low-risk 50%, P = .0482) remained significantly different, while no significant difference in the diabetes group was observed. There were lower hypoglycemia rates with SH compared to diabetes (<70 mg/dL: 0.086 vs. 0.182, P<.0001; <40 mg/dL: 0.012 vs. 0.022, P = .0118, respectively). CONCLUSION: Tighter glycemic control was associated with improved outcomes in CCI patients with SH but not in CCI patients with diabetes. Confirmation of these findings may lead to stratified glycemic control protocols in CCI patients based on the presence or absence of diabetes.

The Israel Diabetes and Cognitive Decline (IDCD) study: Design and baseline characteristics.

BACKGROUND: Type 2 diabetes (T2D) is associated with increased risk of dementia. The prospective longitudinal Israel Diabetes and Cognitive Decline study aims at identifying T2D-related characteristics associated with cognitive decline. METHODS: Subjects are population-based T2D 65+, initially cognitively intact. Medical conditions, blood examinations, and medication use data are since 1998; cognitive, functional, demographic, psychiatric, DNA, and inflammatory marker study assessments were conducted every 18 months. Because the duration of T2D reflects its chronicity and implications, we compared short (0-4.99 years), moderate (5-9.99), and long (10+) duration for the first 897 subjects. RESULTS: The long duration group used more T2D medications, had higher glucose, lower glomerular filtration rate, slower walking speed, and poorer cognitive functioning. Duration was not associated with most medical, blood, urine, and vital characteristics. CONCLUSIONS: Tracking cognition, with face-to-face evaluations, exploiting 15 years of historical detailed computerized, easily accessible, and validated T2D-related characteristics may provide novel insights into T2D-related dementia.

Relationship between 6- and 9-month progression-free survival and overall survival in patients with metastatic urothelial cancer treated with first-line cisplatin-based chemotherapy.

BACKGROUND: Use of progression-free survival (PFS) as a clinical trial endpoint in first-line treatment of patients with metastatic urothelial carcinoma (UC) is attractive, but would be enhanced by establishing a correlation between PFS and overall survival (OS). METHODS: Data was pooled from 7 phase 2 and 3 trials evaluating cisplatin-based chemotherapy in metastatic UC. An independent cohort of patients enrolled on a phase 3 trial was used for external validation. Landmark analyses for progression at 6 and 9 months after treatment initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS. RESULTS: A total of 364 patients were included in the initial cohort. The median PFS was 8.21 months (95% confidence interval = 7.43, 8.39) and the median OS was 13.50 months (95% confidence interval = 11.80, 15.67). In the landmark analysis, the median OS for patients who progressed at 6 months was 3.87 months compared with 15.06 months for those patients who did not progress (P < .0001) and the median OS for patients who progressed at 9 months was 5.65 months compared with 21.39 months for those patients who did not progress (P < .0001). A Fleischer model demonstrated a statistically significant dependent correlation between PFS and OS. The findings were externally validated in an independent cohort. CONCLUSIONS: PFS at 6 and 9 months predicted OS in this analysis of patients with metastatic UC treated with first-line cisplatin-based chemotherapy and could potentially serve as endpoints in (randomized) phase 2 trials to screen the activity of novel regimens.

Nomogram for predicting survival in patients with unresectable and/or metastatic urothelial cancer who are treated with cisplatin-based chemotherapy.

BACKGROUND: The current study was conducted to develop a pretreatment prognostic model for patients with unresectable and/or metastatic urothelial cancer who were treated with first-line, cisplatin-based chemotherapy. METHODS: Individual data were pooled from 399 patients who were enrolled on 8 phase 2 and 3 trials evaluating cisplatin-based, first-line chemotherapy in patients with metastatic urothelial carcinoma. Variables selected for inclusion in the model were combined in a Cox proportional hazards model to produce a points-based nomogram with which to predict the median, 1-year, 2-year, and 5-year survival. The nomogram was validated externally using data from a randomized trial of the combination of methotrexate, vinblastine, doxorubicin plus cisplatin versus docetaxel plus cisplatin. RESULTS: The median survival of the development cohort was 13.8 months (95% confidence interval, 12.1 months-16.0 months); 68.2% of the patients had died at the time of last follow-up. On multivariable analysis, the number of visceral metastatic sites, Eastern Cooperative Oncology Group performance status, and leukocyte count were each found to be associated with overall survival (P < .05), whereas the site of the primary tumor and the presence of lymph node metastases were not. All 5 variables were included in the nomogram. When subjected to internal validation, the nomogram achieved a bootstrap-corrected concordance index of 0.626. When applied to the external validation cohort, the nomogram achieved a concordance index of 0.634. Calibration plots suggested that the nomogram was well calibrated for all predictions. CONCLUSIONS: Based on routinely measured pretreatment variables, a nomogram was constructed that predicts survival in patients with unresectable and/or metastatic urothelial cancer who are treated with cisplatin-based chemotherapy. This model may be useful in patient counseling and clinical trial design.

The dominant negative ß isoform of the glucocorticoid receptor is uniquely expressed in erythroid cells expanded from polycythemia vera patients.

Glucocorticoid receptor (GR) agonists increase erythropoiesis in vivo and in vitro. To clarify the effect of the dominant negative GRß isoform (unable to bind STAT-5) on erythropoiesis, erythroblast (EB) expansion cultures of mononuclear cells from 18 healthy (nondiseased) donors (NDs) and 16 patients with polycythemia vera (PV) were studied. GRß was expressed in all PV EBs but only in EBs from 1 ND. The A3669G polymorphism, which stabilizes GRß mRNA, had greater frequency in PV (55%; n = 22; P = .0028) and myelofibrosis (35%; n = 20) patients than in NDs (9%; n = 22) or patients with essential thrombocythemia (6%; n = 15). Dexamethasone stimulation of ND cultures increased the number of immature EBs characterized by low GATA1 and ß-globin expression, but PV cultures generated great numbers of immature EBs with low levels of GATA1 and ß-globin irrespective of dexamethasone stimulation. In ND EBs, STAT-5 was not phosphorylated after dexamethasone and erythropoietin treatment and did not form transcriptionally active complexes with GRα, whereas in PV EBs, STAT-5 was constitutively phosphorylated, but the formation of GR/STAT-5 complexes was prevented by expression of GRß. These data indicate that GRß expression and the presence of A3669G likely contribute to development of erythrocytosis in PV and provide a potential target for identification of novel therapeutic agents.

The complementary roles of dynamic contrast-enhanced MRI and 18F-fluorodeoxyglucose PET/CT for imaging of carotid atherosclerosis.

PURPOSE: Inflammation and neovascularization in vulnerable atherosclerotic plaques are key features for severe clinical events. Dynamic contrast-enhanced (DCE) MRI and FDG PET are two noninvasive imaging techniques capable of quantifying plaque neovascularization and inflammatory infiltrate, respectively. However, their mutual role in defining plaque vulnerability and their possible overlap has not been thoroughly investigated. We studied the relationship between DCE-MRI and (18)F-FDG PET data from the carotid arteries of 40 subjects with coronary heart disease (CHD) or CHD risk equivalent, as a substudy of the dal-PLAQUE trial (NCT00655473). METHODS: The dal-PLAQUE trial was a multicenter study that evaluated dalcetrapib, a cholesteryl ester transfer protein modulator. Subjects underwent anatomical MRI, DCE-MRI and (18)F-FDG PET. Only baseline imaging and biomarker data (before randomization) from dal-PLAQUE were used as part of this substudy. Our primary goal was to evaluate the relationship between DCE-MRI and (18)F-FDG PET data. As secondary endpoints, we evaluated the relationship between (a) PET data and whole-vessel anatomical MRI data, and (b) DCE-MRI and matching anatomical MRI data. All correlations were estimated using a mixed linear model. RESULTS: We found a significant inverse relationship between several perfusion indices by DCE-MRI and (18)F-FDG uptake by PET. Regarding our secondary endpoints, there was a significant relationship between plaque burden measured by anatomical MRI with several perfusion indices by DCE-MRI and (18)F-FDG uptake by PET. No relationship was found between plaque composition by anatomical MRI and DCE-MRI or (18)F-FDG PET metrics. CONCLUSION: In this study we observed a significant, weak inverse relationship between inflammation measured as (18)F-FDG uptake by PET and plaque perfusion by DCE-MRI. Our findings suggest that there may be a complex relationship between plaque inflammation and microvascularization during the different stages of plaque development. (18)F-FDG PET and DCE-MRI may have complementary roles in future clinical practice in identifying subjects at high risk of cardiovascular events.

Trends and variations in utilization of nephron-sparing procedures for stage I kidney cancer in the United States.

PURPOSE: The incidental detection of early-stage kidney tumors is increasing in the United States. Nephron-sparing approaches (NS) to managing these tumors are equivalent to radical nephrectomy (RN) in oncologic outcomes and have a decreased impact on renal function. Our objective was to evaluate trends in the use of NS over the past decade and the socioeconomic factors associated with its use. METHODS: The National Cancer Database was queried to identify patients with stage I kidney cancer between 2000 and 2008. Patients were classified by the type of surgery as NS (local destruction and local excision) or RN. Patients were further categorized by age, race, insurance status, and income. Log-binomial regression was used to estimate prevalence ratios (PR) for the proportion of NS to RN according to demographic and socioeconomic characteristics. RESULTS: From 2000 to 2008, there were 142,194 cases of kidney cancer reported to the NCDB. In these cases, 43,034 (30.3 %) patients had NS, and 86,431 (60.78 %) patients had RN. The prevalence of NS increased 10 % per year (PR = 1.10, p < 0.0001)-from 20.0 % in 2000 to 45.1 % in 2008. Older age, lower income, Black race, Hispanic ethnicity, and lack of health insurance were associated with a decreased prevalence of NS. CONCLUSIONS: NS as a treatment for stage I kidney cancer has increased steadily since 2000. Age, racial, and socioeconomic differences may exist in the utilization of NS. Additional analyses, with patient level data, are required to address the independent significance of these variables in an effort to develop strategies to mitigate these potential disparities.

Cytoreductive nephrectomy for metastatic renal cell carcinoma in the era of targeted therapy in the United States: a SEER analysis.

PURPOSE: Two randomized trials published in 2001 provided level 1 evidence for the use of cytoreductive nephrectomy (CyNx) for the treatment of metastatic renal cell carcinoma (mRCC). However, the regulatory approval of vascular endothelial growth factor tyrosine kinase inhibitors (VEGFR-TKI) in 2005 has left an "evidence void" regarding the use of CyNx. We evaluated the patterns in the use of CyNx in the cytokine and VEGFR-TKI eras, and the patient characteristics associated with the use of CyNx. METHODS: The Surveillance, Epidemiology, and End Results registry was used to identify patients with histologically or cytologically confirmed stage IV RCC between 2001 and 2008. Patients were classified as treated during the cytokine (2001-2005) or VEGFR-TKI (2006-2008) eras. A multivariate logistic regression analysis was performed to calculate the odds of undergoing CyNx according to treatment era and socioeconomic characteristics. RESULTS: Overall, 1,112 of 2,448 patients (45%) underwent CyNx. CyNx use remained stable between 2001 and 2005 (50%), but decreased to 38% in 2008. Logistic regression analysis revealed that older age (OR 0.82, 95% CI: 0.68, 0.99), black race (OR 0.64, 95% CI: 0.46, 0.91), Hispanic ethnicity (OR 0.71, 95% CI: 0.54, 0.93), and treatment in the VEGFR-TKI era (OR 0.82, 95% CI: 0.68, 0.99) were independently associated with decreased use of CyNx. CONCLUSIONS: Use of CyNx in the United States has declined in the VEGFR-TKI era. Older patients and minorities are less likely to receive CyNx. Results of ongoing phase III trials are needed to refine the role of this treatment modality.

Skeletal manifestations in pediatric and adult patients with Niemann Pick disease type B.

INTRODUCTION: Niemann-Pick disease (NPD) due to acid sphingomyelinase deficiency is a lipid storage disease resulting from the accumulation of sphingomyelin, predominantly within cells of the monocyte-macrophage system. In contrast to other lysosomal storage disorders, skeletal involvement in NPD has not been systematically studied. METHODS: Pediatric and adult NPD-B patients underwent medical histories and physical examinations, DEXA scans to measure bone mineral content (BMC), and bone mineral density (BMD) and computed tomography scan or MRI of the abdomen for spleen volume. Z and/or T scores were calculated for the DEXA results. For the pediatric patients adjusted mean BMC (g) and BMD (g/cm(2)) of the lumbar spine, hip, and femoral neck was compared to control subjects. For determination of the relationship between spleen volume and lumbar spine BMD Z score, linear correlation analyses were performed. RESULTS: Lumbar spine Z scores for pediatric patients ranged from 0.061 to -4.879. Statistically significant decreases were observed for the adjusted mean BMC and BMD at the lumbar spine, hip, and femoral neck between the pediatric NPD-B cohort and control subjects. Most NPD-B adults were osteopenic or osteoporotic at one or more sites according the WHO classification of BMD. In NPD-B patients, the degree of splenomegaly was inversely correlated with lumbar spine BMD Z scores. CONCLUSION: Skeletal involvement is a common and previously unrecognized manifestation of NPD-B. The association between splenomegaly and BMD lends further support to spleen size as an indicator of disease severity.

Significance of ovomucoid- and ovalbumin-specific IgE/IgG(4) ratios in egg allergy.

BACKGROUND: The role of specific IgG(4) antibodies in natural tolerance acquisition remains a matter of debate; the specific IgE/IgG(4) ratio might add value to the measurement of absolute amounts of IgE for assessing the ongoing status of egg reactivity. OBJECTIVE: We sought to determine the significance of IgG(4) antibodies to ovalbumin (OVA) and ovomucoid (OVM) in egg-allergic children. METHODS: One hundred seven egg-allergic children (mean age 6.9 years; range 1.6-18.6 years) were challenged to baked egg. The outcomes of the challenges were related to the level of specific IgE and IgG(4) to OVM and OVA, component IgE/IgG(4) ratios, and mediator release in a functional assay based on the rat basophil leukemia cell line. RESULTS: Baked egg-reactive children had significantly higher OVA and OVM ratios of IgE/IgG(4) and mediator release in the rat basophil leukemia-based assay than did tolerant children (P < .05 for both). The OVA- and OVM-specific IgE/IgG(4) ratios and mediator release were correlated. In the receiver operating characteristic analysis, the areas under the curve for a logistic regression model including specific IgE and IgG(4) to OVA and OVM were significantly greater compared with the areas under the curve for egg white-specific IgE and OVM-specific IgE. CONCLUSIONS: The balance between IgE and IgG(4) to OVA and OVM has functional consequences. A model that includes the interactions between IgE and IgG(4) to OVA and OVM accurately predicts reactivity to baked egg and warrants further investigation.