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1.  Adjuvant Chemoradiation Therapy for Pancreatic Adenocarcinoma: Who Really Benefits? 
BACKGROUND
The role of adjuvant chemoradiation therapy (CRT) in pancreatic cancer remains controversial. The primary aim of this study was to determine if CRT improved survival in patients with resected pancreatic cancer in a large, multiinstitutional cohort of patients.
STUDY DESIGN
Patients undergoing resection for pancreatic adenocarcinoma from seven academic medical institutions were included. Exclusion criteria included patients with T4 or M1 disease, R2 resection margin, preoperative therapy, chemotherapy alone, or if adjuvant therapy status was unknown.
RESULTS
There were 747 patients included in the initial evaluation. Primary analysis was performed between patients that had surgery alone (n = 374) and those receiving adjuvant CRT (n = 299). Median followup time was 12.2 months and 14.5 months for survivors. Median overall survival for patients receiving adjuvant CRT was significantly longer than for those undergoing operation alone (20.0 months versus 14.5 months, p = 0.001). On subset and multivariate analysis, adjuvant CRT demonstrated a significant survival advantage only among patients who had lymph node (LN)-positive disease (hazard ratio 0.477, 95% CI 0.357 to 0.638) and not for LN-negative patients (hazard ratio 0.810, 95% CI 0.556 to 1.181). Disease-free survival in patients with LN-negative disease who received adjuvant CRT was significantly worse than in patients who had surgery alone (14.5 months versus 18.6 months, p = 0.034).
CONCLUSIONS
This large multiinstitutional study emphasizes the importance of analyzing subsets of patients with pancreas adenocarcinoma who have LN metastasis. Benefit of adjuvant CRT is seen only in patients with LN-positive disease, regardless of resection margin status. CRT in patients with LN-negative disease may contribute to reduced disease-free survival.
doi:10.1016/j.jamcollsurg.2008.12.020
PMCID: PMC4167601  PMID: 19476845
2.  Assessing gonadal function after childhood ovarian surgery 
Journal of pediatric surgery  2012;47(6):1272-1279.
Purpose
We aimed to assess the late effects of ovarian salvage or oophorectomy on gonadal function and fertility as measured by menstrual regularity.
Methods
We performed a 10-year retrospective review of females aged 20 years or younger who required surgery to treat an ovarian disorder. A mail survey was distributed to these patients to evaluate the effects of ovarian surgery on menarche, menstrual regularity, and pregnancy.
Results
A total of 180 females had surgery to treat an ovarian disorder. Eighty-six of these underwent unilateral oophorectomy (48%), whereas 94 (52%) had an ovary sparing procedure. Eighty-one patients (45%) returned completed surveys. Of the respondents, 44 had oophorectomy, and 37 had ovarian salvage. Ages of menarche were similar between surgical groups. Symptoms of menstrual irregularity differed most significantly according to painful menses (oophorectomy, 27.3%; salvage, 59.5%; P < .04). Interestingly, continuation of regular menses after surgery was higher in the oophorectomy group (oophorectomy, 70%; salvage, 15%; P = .013).
Conclusions
Unilateral oophorectomy does not appear to impair late gonadal function when compared with ovarian salvage. Surprisingly, oophorectomy appears to maintain more normal ovarian activity as estimated by menstrual regularity. Oophorectomy may be performed without apparent adverse effect on gonadal activity.
doi:10.1016/j.jpedsurg.2012.03.038
PMCID: PMC4148072  PMID: 22703805
Oophorectomy; Ovarian salvage; Fertility; Ovarian function; Menstrual irregularity; Children
3.  Clinical Utility of KRAS and BRAF Mutations in a Cohort of Patients With Colorectal Neoplasms Submitted for Microsatellite Instability Testing 
Clinical colorectal cancer  2013;12(3):168-178.
Background
Molecular analysis has become important in colorectal carcinoma (CRC) evaluation. Alterations in KRAS, BRAF, or mismatch repair (MMR) genes may determine therapeutic response or define a hereditary cancer syndrome. Correlation of DNA studies with clinical findings will further clarify the clinical utility of these markers.
Patients and Methods
A retrospective study was performed on 111 paraffin-embedded tumor specimens submitted for microsatellite instability (MSI) testing based on clinical history or histologic examination, or both. DNA samples were screened for 7 KRAS mutations and the BRAF p.V600E mutation using fluorescent allele-specific polymerase-chain reaction (PCR) and capillary electrophoresis. Clinical data were collected through chart review.
Results
Fifty-eight male and 53 female patients were studied. The incidence of KRAS and BRAF mutations was 49.5% and 7.2%, respectively. Dideoxy sequencing verified KRAS mutation status in 46 of 49 specimens tested. There was a trend toward significance of individual KRAS mutations on survival (P = .003). Dually positive KRAS and MSI tumors exclusively demonstrated p.G12D and p.G13D mutations (G>A transitions). BRAF-mutated tumors were predominantly right-sided and associated with a borderline worse prognosis. Forty-eight percent of tumors with MSI were present in the left colon or rectum.
Conclusion
Allele-specific PCR is an accurate and convenient method to assess KRAS and BRAF mutations and may detect mutations not identified by dideoxy sequencing. KRAS mutation status, in conjunction with morphologic or clinical parameters, may be useful in determining whether a tumor should be tested for MSI. MSI testing should not be considered exclusively in right-sided lesions. BRAF analysis may not be useful in rectal adenocarcinomas and should be evaluated in larger studies.
doi:10.1016/j.clcc.2013.04.005
PMCID: PMC4090139  PMID: 23773459
Allele specific; Missense; Mutation; Transversion; Biomarker
4.  Eighteen year weight trajectories and metabolic markers of diabetes in modernising China 
Diabetologia  2014;57(9):1820-1829.
Aims/Hypothesis
Although obesity is a major risk factor for diabetes, little is known about weight gain trajectories across adulthood, and whether they are differentially associated with metabolic markers of diabetes.
Methods
We used fasting blood samples and longitudinal weight data for 5,436 adults (5,734 observations, aged 18–66 years) from the China Health and Nutrition Survey (1991–2009). Using latent class trajectory analysis, we identified different weight gain trajectories in six age and sex strata, and used multivariable general linear mixed effects models to assess elevated metabolic markers of diabetes (fasting glucose, HbA1c, HOMA-IR, insulin) across weight trajectory classes. Models were fitted within age and sex strata, and controlled for baseline weight (or baseline weight by weight trajectory interaction terms), height, and smoking habit, with random intercepts to control for community-level correlations.
Results
Compared with weight gain, classes with weight maintenance, weight loss, or a switch from weight gain to loss had lower values for metabolic markers of diabetes. These associations were stronger among younger women (aged 18–29 and 30–39 years) and men (18–29 years) than in older (40–66 years) men and women. An exception was HOMA-IR, which showed class differences across all ages (at least p < 0.004).
Conclusion
Trajectory analysis identified heterogeneity in adult weight gain associated with diabetes-related metabolic markers, independent of baseline weight. Our findings suggest that variation in metabolic markers of diabetes across patterns of weight gain is masked by a homogeneous classification of weight gain.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3284-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-014-3284-y
PMCID: PMC4119243  PMID: 24891020
Adult; China; Fasting glucose; Insulin resistance; Latent class trajectory analysis
5.  Radiographic Outcomes of Volar Locked Plating for Distal Radius Fractures 
The Journal of hand surgery  2012;38(1):40-48.
Purpose
To assess the ability of volar locked plating to achieve and maintain normal radiographic parameters for articular stepoff, volar tilt, radial inclination, ulnar variance, and radial height in distal radius fractures.
Methods
We performed a retrospective review of 185 distal radius fractures that underwent volar locked plating with a single plate design over a 5-year period. We reviewed radiographs and recorded measurements for volar tilt, radial inclination, ulnar variance, radial height, and articular stepoff. We used logistic regression to determine the association between return to radiographic standard norms and fracture type.
Results
At the first and final postoperative follow-up visits, we observed articular congruence less than 2 mm in 92% of fractures at both times. Normal volar tilt (11°) was restored in 46% at the first follow-up and 48% at the final one. Radial inclination (22°) was achieved in 44% at the first follow-up and 43% at the final one, and ulnar variance (01 ± 2 mm) was achieved in 53% at the first follow-up and 53% at the final one. In addition, radial height (14 ± 1mm) was restored in 14% at the first follow-up and 12% at the final one. More complex, intra-articular fractures (AO class B and C and Frykman types 3, 4, 7, and 8) were less likely to be restored to normal radiographic parameters. However, because of the small sample size for some fracture types, it was difficult to discover significant associations between fracture type and radiographic outcome.
Conclusions
Volar locked plating for distal radius fractures achieved articular stepoff less than 2 mm in most fractures but only restored and maintained normal radiographic measurements for volar tilt, radial inclination, and ulnar variance in 50% of fractures. The ability of volar locked plating to restore and maintain ulnar variance and volar tilt decreased with more complex intra-articular fracture types.
doi:10.1016/j.jhsa.2012.10.007
PMCID: PMC3581353  PMID: 23218558
Distal radius fractures; volar locked plating
6.  Body Mass Index and Blood Pressure Changes over the Course of Treatment of Pediatric Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2011;56(3):372-378.
Background
Obesity and hypertension are reported among survivors of pediatric acute lymphoblastic leukemia (ALL). However, little is known about the trajectory of body mass index (BMI) and blood pressure over the course of ALL therapy.
Procedure
In a retrospective cohort of 183 pediatric ALL patients diagnosed from 2000-2008, prevalence, severity, and risk factors for obesity and hypertension were assessed during treatment.
Results
At diagnosis, 36% of patients were overweight and 19% were obese. Median BMI increased during induction therapy with a return to baseline soon after, but increased again over the first 22 months of maintenance therapy. At the end of therapy, 49% were overweight and 21% were obese. Increased BMI z-score at diagnosis was associated with increased z-score during maintenance (p<0.001). Elevated parental BMI was associated with elevated BMI at diagnosis. Median BMI z-score increased over the first 22 months of maintenance (p<0.001). Patients with high risk disease had lower BMI z-scores regardless of cranial radiotherapy exposure (p<0.001). Pre-hypertension was prevalent over the course of therapy (31.1% with systolic pre-hypertension and 18.6% with diastolic pre-hypertension). Hypertension was also highly prevalent with 41.5% meeting systolic criteria and 24.0% meeting diastolic criteria.
Conclusions
During ALL therapy, patients are at risk for early development of elevated BMI and blood pressure, which places them at potentially increased risk for future adverse health conditions. Future studies are needed to develop strategies to mitigate these risks, such as potential reduction of corticosteroid pulses or a family-based diet and exercise intervention during maintenance therapy.
doi:10.1002/pbc.22782
PMCID: PMC3713225  PMID: 20860019
Obesity; body mass index; acute lymphoblastic leukemia; metabolic syndrome; pediatrics; hypertension
7.  Development of High-Throughput Quantitative Assays for Glucose Uptake in Cancer Cell Lines 
Purpose
Metabolism, and especially glucose uptake, is a key quantitative cell trait that is closely linked to cancer initiation and progression. Therefore, developing high-throughput assays for measuring glucose uptake in cancer cells would be enviable for simultaneous comparisons of multiple cell lines and microenvironmental conditions. This study was designed with two specific aims in mind: the first was to develop and validate a high-throughput screening method for quantitative assessment of glucose uptake in “normal” and tumor cells using the fluorescent 2-deoxyglucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG), and the second was to develop an image-based, quantitative, single-cell assay for measuring glucose uptake using the same probe to dissect the full spectrum of metabolic variability within populations of tumor cells in vitro in higher resolution.
Procedure
The kinetics of population-based glucose uptake was evaluated for MCF10A mammary epithelial and CA1d breast cancer cell lines, using 2-NBDG and a fluorometric microplate reader. Glucose uptake for the same cell lines was also examined at the single-cell level using high-content automated microscopy coupled with semi-automated cell-cytometric image analysis approaches. Statistical treatments were also implemented to analyze intra-population variability.
Results
Our results demonstrate that the high-throughput fluorometric assay using 2-NBDG is a reliable method to assess population-level kinetics of glucose uptake in cell lines in vitro. Similarly, single-cell image-based assays and analyses of 2-NBDG fluorescence proved an effective and accurate means for assessing glucose uptake, which revealed that breast tumor cell lines display intra-population variability that is modulated by growth conditions.
Conclusions
These studies indicate that 2-NBDG can be used to aid in the high-throughput analysis of the influence of chemotherapeutics on glucose uptake in cancer cells.
doi:10.1007/s11307-010-0399-5
PMCID: PMC3627351  PMID: 20809209
2-NBDG; Metabolism; High-throughput; Single-cell; Glycolysis
8.  Factors Associated With the Career Choices of Hematology and Medical Oncology Fellows Trained at Academic Institutions in the United States 
Journal of Clinical Oncology  2011;29(29):3932-3938.
Purpose
Factors that influence hematology-oncology fellows' choice of academic medicine as a career are not well defined. We undertook a survey of hematology-oncology fellows training at cancer centers designated by the National Cancer Institute (NCI) and the National Comprehensive Cancer Network (NCCN) to understand the factors fellows consider when making career decisions.
Methods
Program directors at all NCI and NCCN cancer centers were invited to participate in the study. For the purpose of analysis, fellows were grouped into three groups on the basis of interest in an academic career. Demographic data were tested with the Kruskal-Wallis test and χ2 test, and nondemographic data were tested by using the multiscale bootstrap method.
Results
Twenty-eight of 56 eligible fellowship programs participated, and 236 fellows at participating institutions responded (62% response rate). Approximately 60% of fellows graduating from academic programs in the last 5 years chose academic career paths. Forty-nine percent of current fellows ranked an academic career as extremely important. Fellows choosing an academic career were more likely to have presented and published their research. Additional factors associated with choosing an academic career included factors related to mentorship, intellect, and practice type. Fellows selecting nonacademic careers prioritized lifestyle in their career decision.
Conclusion
Recruitment into academic medicine is essential for continued progress in the field. Our data suggest that fewer than half the current fellows training at academic centers believe a career in academic medicine is important. Efforts to improve retention in academics should include focusing on mentorship, research, and career development during fellowship training and improving the image of academic physicians.
doi:10.1200/JCO.2011.35.8663
PMCID: PMC3189092  PMID: 21911716
9.  Significant 25-Hydroxyvitamin D Deficiency in Child and Adolescent Survivors of Acute Lymphoblastic Leukemia: Treatment with Chemotherapy Compared with Allogeneic Stem Cell Transplant 
Pediatric blood & cancer  2010;56(7):1114-1119.
Background
25-hydroxyvitamin D insufficiency is common in healthy children and adolescents. There have been limited studies of the 25-hydroxyvitamin D status of survivors of pediatric and adolescent acute lymphoblastic leukemia (ALL).
Procedure
In a cohort of 78 ALL survivors (52 chemotherapy-treated and 26 HCT-treated), we determined the prevalence of, and host, treatment and environmental risk factors for 25-hydroxyvitamin D insufficiency and deficiency.
Results
There were no differences in serum 25-hydroxyvitamin D levels between ALL survivors treated with conventional chemotherapy and those treated with HCT (median 26.0 vs 25.5 ng/ ml). Fifty-three percent of pediatric ALL survivors were 25-hydroxyvitamin D insufficient (15-29 ng/ dl), and 12% were deficient (<15 ng/ dl). Younger age, higher reported dietary vitamin D intake, use of vitamin D supplementation, and increased ambient ultraviolet light were associated with higher serum 25-hydroxyvitamin D levels. There was not enough evidence to suggest treatment type, gender, race, years since diagnosis or BMI were associated with serum 25-hydroxyvitamin D levels. Only 27% of conventional chemotherapy-treated ALL survivors and 8% of HCT-treated ALL survivors met RDA for dietary vitamin D intake.
Conclusions
The prevalence of vitamin D deficiency and insufficiency in ALL survivors is similar to that of the general pediatric population in the United States, and there is no difference in serum 25-hydroxyvitamin D status between chemotherapy-treated and HCT-treated ALL survivors. ALL survivors rarely meet the RDA requirements for vitamin D. Further studies are needed to determine whether dietary and behavioral interventions can improve the vitamin D status of ALL survivors.
doi:10.1002/pbc.22949
PMCID: PMC3135735  PMID: 21488156
vitamin D deficiency; acute lymphoblastic leukemia; cancer survivorship; late effects; vitamin D insufficiency
10.  Prehospital Statin and Aspirin Use and the Prevalence of Severe Sepsis and ALI/ARDS 
Critical care medicine  2011;39(6):1343-1350.
Objectives
To determine if prehospital statin use is associated with a lower risk of sepsis, ALI/ARDS, and mortality in critically ill patients. We also investigated the effect of combined prehospital use of both statins and aspirin.
Design
Cross-sectional analysis of a prospective cohort
Patients
575 critically ill patients admitted to the medical or surgical ICU of an academic tertiary-care hospital
Measurements and Main Results
Of 575 patients, 149 (26%) were on statin therapy prior to hospitalization. A multivariable analysis including age, gender, current tobacco use, prehospital aspirin use, race, and APACHE II score revealed that patients on statin therapy prior to hospitalization were less likely to have or develop severe sepsis (OR 0.62, 95% CI 0.40 to 0.96) or ALI/ARDS (OR 0.60, 95% CI 0.36 to 0.99) during the first four ICU days. In-hospital mortality for patients with and without prehospital statin use (OR 1.06, 95% CI 0.62 to 1.83) was similar. Patients who had prehospital use of both statins and aspirin had the lowest rates of severe sepsis, ALI/ARDS and mortality.
Conclusions
Prehospital use of statins may be protective against the sepsis and ALI. This effect may be potentiated by prehospital aspirin use.
doi:10.1097/CCM.0b013e3182120992
PMCID: PMC3102130  PMID: 21336116
Acute Lung Injury; Acute Respiratory Distress Syndrome; Severe Sepsis; Sepsis; Statin; Aspirin; Inflammation
11.  On the Assessment of Monte Carlo Error in Simulation-Based Statistical Analyses 
The American statistician  2009;63(2):155-162.
Statistical experiments, more commonly referred to as Monte Carlo or simulation studies, are used to study the behavior of statistical methods and measures under controlled situations. Whereas recent computing and methodological advances have permitted increased efficiency in the simulation process, known as variance reduction, such experiments remain limited by their finite nature and hence are subject to uncertainty; when a simulation is run more than once, different results are obtained. However, virtually no emphasis has been placed on reporting the uncertainty, referred to here as Monte Carlo error, associated with simulation results in the published literature, or on justifying the number of replications used. These deserve broader consideration. Here we present a series of simple and practical methods for estimating Monte Carlo error as well as determining the number of replications required to achieve a desired level of accuracy. The issues and methods are demonstrated with two simple examples, one evaluating operating characteristics of the maximum likelihood estimator for the parameters in logistic regression and the other in the context of using the bootstrap to obtain 95% confidence intervals. The results suggest that in many settings, Monte Carlo error may be more substantial than traditionally thought.
doi:10.1198/tast.2009.0030
PMCID: PMC3337209  PMID: 22544972
Bootstrap; Jackknife; Replication
12.  A Phase I Trial of Bortezomib with Temozolomide in Patients with Advanced Melanoma: Toxicities, Antitumor Effects, and Modulation of Therapeutic Targets 
Purpose
Preclinical studies show that bortezomib, a proteasome inhibitor, blocks NF-κB activation and, combined with temozolomide, enhances activity against human melanoma xenografts and modulates other critical tumor targets. We initiated a phase I trial of temozolomide plus bortezomib in advanced melanoma. Objectives included defining a maximum tolerated dose for the combination, characterizing biomarker changes reflecting inhibition of both proteasome and NF-κB activity in blood (if possible tumor), and characterizing antitumor activity.
Experimental Design
Cohorts were enrolled onto escalating dose levels of temozolomide (50-75 mg/m2) daily, orally, for 6 of 9 weeks and bortezomib (0.75-1.5 mg/m2) by i.v. push on days 1, 4, 8, and 11 every 21 days. Peripheral blood mononuclear cells were assayed at specified time points for proteasome inhibition and NF-κB biomarker activity.
Results
Bortezomib (1.3 mg/m2) and temozolomide (75 mg/m2) proved to be the maximum tolerated dose. Dose-limiting toxicities included neurotoxicity, fatigue, diarrhea, and rash. Nineteen melanoma patients were enrolled onto four dose levels. This melanoma population (17 M1c, 10 elevated lactate dehydrogenase, 12 performance status 1-2) showed only one partial response (8 months) and three with stable disease ≥4 months. A significant reduction in proteasome-specific activity was observed 1 hour after infusion at all bortezomib doses. Changes in NF-κB electrophoretic mobility shift assay and circulating chemokines in blood failed to correlate with the schedule/dose of bortezomib, inhibition of proteasome activity, or clinical outcome.
Conclusions
We have defined phase II doses for this schedule of temozolomide with bortezomib. Although proteasome activity was inhibited for a limited time in peripheral blood mononuclear cells, we were unable to show consistent effects on NF-κB activation.
doi:10.1158/1078-0432.CCR-09-2087
PMCID: PMC3205975  PMID: 20028756
13.  DARPP-32 is over-expressed in early stages of gastric tumorigenesis 
Surgery  2010;148(2):354-363.
Background
Gastric adenocarcinoma is a leading cause of cancer mortality. The role of DARPP-32 overexpression in the gastric tumorigenesis cascade remains unclear.
Methods
The expression of DARPP-32 in the multi-step carcinogenesis cascade was examined using immunohistochemistry analysis on 533 samples. The contribution of DARPP-32 in cellular transformation and molecular signaling was investigated using NIH3T3, AGS, and SNU16 cells.
Results
The composite expression score (CES), calculated from immunostaining patterns, increased significantly from normal or gastritis to metaplasia, dysplasia, and adenocarcinoma (p<0.001). In patients with normal stomach or gastritis and tumor samples, there was a 76% and 77% chance respectively (p<0.001) that CES was higher in the tumor. High median CES correlated with well- or moderately-differentiated (p=0.03) gastric adenocarcinomas. NIH3T3 cells transfected with DARPP-32 demonstrated increased levels of phospho-AKT and a five-fold increase in the number of foci as compared to control (p =0.02). DARPP-32 expression in AGS cells led to increased protein levels of phospho-AKT and BCL-2. For validation, the knockdown of endogenous DARPP-32 expression in SNU16 cells using shRNA resulted in decreased levels of phospho-AKT phosphorylation and BCL-2.
Conclusion
Our results suggest that DARPP-32 overexpression may participate in transition to intestinal metaplasia and progression to neoplasia. The ability of DARPP-32 to transform NIH3T3 cells and regulate AKT and BCL-2 underscores its possible oncogenic potential.
doi:10.1016/j.surg.2010.05.011
PMCID: PMC2919779  PMID: 20580047
DARPP-32; gastric; premalignant; cancer; tumorigenesis; AKT
14.  Phase I Study of Intravenous Vascular Endothelial Growth Factor Trap, Aflibercept, in Patients With Advanced Solid Tumors 
Journal of Clinical Oncology  2009;28(2):207-214.
Purpose
Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks.
Patients and Methods
Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability.
Results
The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) –defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses ≥ 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker.
Conclusion
IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.
doi:10.1200/JCO.2009.22.9237
PMCID: PMC2815710  PMID: 19949018
15.  Evidence for Latent Classes of IQ In Young Children with Autism Spectrum Disorder 
Autism is currently viewed as a spectrum condition including strikingly different severity levels. IQ is consistently described as one of the primary aspects of the heterogeneity in autism. To investigate the possibility of more than one distinct subtype of autism based on IQ, both latent class analysis and taxometric methods were used to classify Mullen IQ scores in a sample of children with autism spectrum disorder (N=456). Evidence for multiple IQ-based subgroups was found using both methods. Groups differed in level of intellectual functioning and patterns of verbal versus nonverbal ability. Results support the notion of distinct subtypes of autism which differ in severity of intellectual ability, patterns of cognitive strengths and weaknesses, and severity of autism symptoms.
doi:10.1352/2008.113:439-452
PMCID: PMC2991056  PMID: 19127655
16.  Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease 
AIM: To assess the role of IgM and IgG immunohistochemistry (IHC) in the evaluation of autoimmune liver conditions - autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).
METHODS: Forty one biopsies from untreated patients diagnosed with autoimmune liver disease (AIH, n = 20; PBC, n = 13; PSC, n = 8) and fourteen biopsies of patients with chronic hepatitis C were selected. IgM and IgG-positive plasma cells were counted in each sample.
RESULTS: A predominance of IgG-positive plasma cells was seen in AIH (90% of cases), PSC (75% of cases), and chronic hepatitis C (100% of cases), while IgM-positive plasma cells predominated in PBC (92.8% of cases). The IgM /IgG ratio (< 1 or ≥ 1) accurately distinguished PBC from AIH in 90.9% of cases (sensitivity = 92.3%, specificity = 90%), and PBC from either AIH or PSC in 87.8% of cases (sensitivity = 92.3%, specificity = 85.7%).
CONCLUSION: Plasmacytic infiltrates expressing predominantly IgM are characteristic of PBC, while other forms of liver disease analyzed in this study, including AIH, typically show an IgG-predominant plasma cell infiltrate. Our data indicate that IgM and IgG IHC may be a useful tool when PBC is a diagnostic consideration.
doi:10.3748/wjg.v16.i4.453
PMCID: PMC2811797  PMID: 20101770
Autoimmune hepatitis; Primary sclerosing cholangitis; Primary biliary cirrhosis; Immunoglobulin; Immunohistochemistry
17.  Cardiovascular Medication Use and Risk for Colorectal Cancer 
Objective
To evaluate the association between lipid-lowering agents, antihypertensive medications, and colorectal cancer risk. We hypothesized a reduction in colorectal cancer risk with 3-hydroxy-3-methylglutaryl coA reductase inhibitors (statins) and angiotensin-converting enzyme inhibitors.
Methods
We conducted a case-control study at Group Health Cooperative, an integrated delivery system in Washington State. Incident colorectal cancer cases diagnosed between January 1, 2000, and December 31, 2003, were identified from the western Washington Surveillance, Epidemiology, and End Results cancer registry. Controls were matched by age, sex, and duration of enrollment. Data on medication use and potential confounders were obtained from health plan records. We estimated odds ratios and 95% confidence intervals (95% CI) using multivariate conditional logistic regression.
Results
Risk for colorectal cancer was not associated with use of statins (odds ratio, 1.02; 95% CI, 0.65–1.59), other lipid-lowering agents (odds ratio, 1.31; 95% CI, 0.70–2.47), angiotensin-converting enzyme inhibitors (odds ratio, 0.98; 95% CI, 0.67–1.43), calcium channel blockers (odds ratio, 1.06; 95% CI, 0.72–1.55), or diuretics (odds ratio, 1.00; 95% CI, 0.70–1.44). Risk did not differ by duration of medication use, including long-term use.
Conclusions
Risk for colorectal cancer was not reduced by use of statins or angiotensin-converting enzyme inhibitors. Other lipid-lowering and antihypertensive medications were also not associated with colorectal cancer risk.
doi:10.1158/1055-9965.EPI-08-0095
PMCID: PMC2675612  PMID: 18957524

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