Search

Objectives: A prospective clinical trial evaluated the effect of Ga-DOTATOC positron emission tomography-computerized axial tomography (PET-CT) on change in management of patients with lung, pancreatic, and small bowel neuroendocrine tumors. The primary eligibility criterion was a histologically proven tumor with positive somatostatin receptor subtype 2A immunohistochemistry. The primary and secondary end points were change in patient management and safety., Methods: Referring physicians completed questionnaires pre- and post-Ga-DOTATOC PET-CT, stating current and planned patient management, respectively, with tumor board adjudication of final management decisions. Change in management was categorized as follows: no change; minor change (additional imaging, supportive care); or major change (octreotide/lanreotide therapy, tumor biopsy, surgery, peptide receptor radiotherapy, chemotherapy, biological therapy, liver embolization)., Results: A major change in management was recommended for 54 (47.37%) of 114 subjects and a minor change for 6 (5.26%) of 114 subjects, with no change for 54 (47.37%) of 114 subjects. Grade 1 adverse events were observed in 26 of 114 subjects (nausea, headache, back pain, diarrhea); one grade 2 (petechiae) and one grade 3 (abdominal pain) adverse event were observed. No grade 2 or 3 adverse events were related to study drug and none required intervention., Conclusions: Imaging with Ga-DOTATOC PET-CT has a significant impact on management of patients with neuroendocrine tumors.

Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically, but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and PNET pathogenesis is needed to improve current therapies. We discovered that RABL6A, a new oncogenic driver of PNET proliferation, is required for AKT activity. Silencing RABL6A caused PNET cell-cycle arrest that coincided with selective loss of AKT-S473 (not T308) phosphorylation and AKT/mTOR inactivation. Restoration of AKT phosphorylation rescued the G1 phase block triggered by RABL6A silencing. Mechanistically, loss of AKT-S473 phosphorylation in RABL6A-depleted cells was the result of increased protein phosphatase 2A (PP2A) activity. Inhibition of PP2A restored phosphorylation of AKT-S473 in RABL6A-depleted cells, whereas PP2A reactivation using a specific small-molecule activator of PP2A (SMAP) abolished that phosphorylation. Moreover, SMAP treatment effectively killed PNET cells in a RABL6A-dependent manner and suppressed PNET growth in vivo. The present work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and an essential activator of AKT in PNET cells. Our findings offer what we believe is a novel strategy of PP2A reactivation for treatment of PNETs as well as other human cancers driven by RABL6A overexpression and PP2A inactivation.

Glaucoma is the second leading cause of blindness in the USA. A visual field test (perimetry) is used to sample and quantitate visual field function in preselected regions in the eye. These regions can be considered a spatial field with replications across independently measured individuals. At return visits, a new set of visual field measurements is obtained producing a subject specific spatio-temporal dataset. We develop a Bayesian hierarchical modeling framework to analyze these spatio-temporal datasets both for individual level spread and as aggregate population level trends. Our model extends previous research utilizing a dimension reduction matrix and individual specific latent variables. Human characteristics are incorporated into the model to help explain glaucoma progression. One beneficial product of our model is smoothed estimates for individuals. We also specify how progression rates are computed for monitoring purposes so that clinicians can track changes and predict forward in time. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Objective: To estimate prevalence of childhood-onset Duchenne and Becker muscular dystrophies (DBMD) in 6 sites in the United States by race/ethnicity and phenotype (Duchenne muscular dystrophy [DMD] or Becker muscular dystrophy [BMD])., Methods: In 2002, the Centers for Disease Control and Prevention established the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) to conduct longitudinal, population-based surveillance and research of DBMD in the United States. Six sites conducted active, multiple-source case finding and record abstraction to identify MD STARnet cases born January 1982 to December 2011. We used cross-sectional analyses to estimate prevalence of DBMD per 10 000 boys, ages 5 to 9 years, for 4 quinquennia (1991-1995, 1996-2000, 2001-2005, and 2006-2010) and prevalence per 10 000 male individuals, ages 5 to 24 years, in 2010. Prevalence was also estimated by race/ethnicity and phenotype., Results: Overall, 649 cases resided in an MD STARnet site during ≥1 quinquennia. Prevalence estimates per 10 000 boys, ages 5 to 9 years, were 1.93, 2.05, 2.04, and 1.51, respectively, for 1991-1995, 1996-2000, 2001-2005, and 2006-2010. Prevalence tended to be higher for Hispanic individuals than non-Hispanic white or black individuals, and higher for DMD than BMD. In 2010, prevalence of DBMD was 1.38 per 10 000 male individuals, ages 5 to 24 years., Conclusions: We present population-based prevalence estimates for DBMD in 6 US sites. Prevalence differed by race/ethnicity, suggesting potential cultural and socioeconomic influences in the diagnosis of DBMD. Prevalence also was higher for DMD than BMD. Continued longitudinal surveillance will permit us to examine racial/ethnic and socioeconomic differences in treatment and outcomes for MD STARnet cases., (Copyright © 2015 by the American Academy of Pediatrics.)

Preeclampsia, a cardiovascular disorder of late pregnancy, is characterized as a low-renin hypertensive state relative to normotensive pregnancy. Because other nonpregnant low-renin hypertensive disorders often exhibit and are occasionally dependent on elevated arginine vasopressin (AVP) secretion, we hypothesized a possible use for plasma AVP measurements in the prediction of preeclampsia. Copeptin is an inert prosegment of AVP that is secreted in a 1:1 molar ratio and exhibits a substantially longer biological half-life compared with AVP, rendering it a clinically useful biomarker of AVP secretion. Copeptin was measured throughout pregnancy in maternal plasma from preeclamptic and control women. Maternal plasma copeptin was significantly higher throughout preeclamptic pregnancies versus control pregnancies. While controlling for clinically significant confounders (age, body mass index, chronic essential hypertension, twin gestation, diabetes mellitus, and history of preeclampsia) using multivariate regression, the association of higher copeptin concentration and the development of preeclampsia remained significant. Receiver operating characteristic analyses reveal that as early as the sixth week of gestation, elevated maternal plasma copeptin concentration is a highly significant predictor of preeclampsia throughout pregnancy. Finally, chronic infusion of AVP during pregnancy (24 ng per hour) is sufficient to phenocopy preeclampsia in C57BL/6J mice, causing pregnancy-specific hypertension, renal glomerular endotheliosis, proteinuria, and intrauterine growth restriction. These data implicate AVP release as a novel predictive biomarker for preeclampsia very early in pregnancy, identify chronic AVP infusion as a novel and clinically relevant model of preeclampsia in mice, and are consistent with a potential causative role for AVP in preeclampsia in humans., (© 2014 American Heart Association, Inc.)

Background: Diagnosis of chronic obstructive pulmonary disease is based on detection of airflow obstruction on spirometry. There is no consensus regarding using a fixed threshold to define airflow obstruction versus using the lower limit of normal (LLN) adjusted for age. We compared the accuracy and discrimination of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommended fixed ratio of forced expiratory volume in the first second/forced vital capacity<0.70 with LLN in diagnosing smoking-related airflow obstruction using CT-defined emphysema and gas trapping as the disease gold standard., Methods: Data from a large multicentre study (COPDGene), which included current and former smokers (age range 45-80 years) with and without airflow obstruction, were analysed. Concordance between spirometric thresholds was measured. The accuracy of the thresholds in diagnosing emphysema and gas trapping was assessed using quantitative CT as gold standard., Results: 7743 subjects were included. There was very good agreement between the two spirometric cutoffs (κ=0.85; 95% CI 0.83 to 0.86, p<0.001). 7.3% were discordant. Subjects with airflow obstruction by fixed ratio only had a greater degree of emphysema (4.1% versus 1.2%, p<0.001) and gas trapping (19.8% vs 7.5%, p<0.001) than those positive by LLN only, and also smoking controls without airflow obstruction (4.1% vs 1.9% and 19.8% vs 10.9%, respectively, p<0.001). On follow-up, the fixed ratio only group had more exacerbations than smoking controls., Conclusions: Compared with the fixed ratio, the use of LLN fails to identify a number of patients with significant pulmonary pathology and respiratory morbidity.

Background and Objectives: The effect of inflammatory bowel disease (IBD) on outcome in patients with colorectal cancer (CRC) remains unclear. Our objective is to evaluate oncologic outcomes of patients with IBD-associated CRC., Methods: We retrospectively reviewed a prospectively maintained database to identify patients with IBD-associated CRC. Clinicopathologic variables and overall survival were compared to patients with sporadic CRC using a 2:1 matched-controlled analysis., Results: Fifty-five patients with IBD and CRC were identified. On univariate analysis, CRC patients with IBD had a significantly shorter median overall survival (68.2 months vs. 204.3 months, P = 0.01) compared to patients with sporadic CRC. On multivariate analysis, after adjusting for N and M stage, IBD was associated with an increased risk of death compared to sporadic CRC (HR = 2.011, 95% CI 1.24-3.23, P = 0.004). Stage 3 CRC patients with IBD in particular showed significantly decreased survival (23.0 vs. 133.9 months, P = 0.008)., Conclusions: In this study, patients with node-positive IBD-associated CRC had a significant increased risk of death and a shorter overall survival than those with sporadic disease and may require tailored adjuvant therapy and surveillance protocols. Continued investigation to elucidate the mechanisms that contribute to these observations is justified., (© 2013 Wiley Periodicals, Inc.)

Rationale and Objectives: Density-based metrics assess severity of lung disease but vary with lung inflation and method of scanning. The aim of this study was to evaluate the repeatability of single center, CT-based density metrics of the lung in a normal population and assess study sample sizes needed to detect meaningful changes in lung density metrics when scan parameters and volumes are tightly controlled., Materials and Methods: Thirty-seven subjects (normal smokers and non-smokers) gave consent to have randomly assigned repeated, breath-held scans at either inspiration (90% vital capacity: TLC) or expiration (20% vital capacity: FRC). Repeated scans were analyzed for: mean lung density (MLD), 15 th percentile point of the density histogram (P 15 ), low attenuation areas (LAA) and alpha (fractal measure of hole size distribution). Using inter-subject differences and previously reported bias, sample size was estimated from month or yearly change in density metrics obtained from published literature (i.e. meaningful change)., Results: Inter-scan difference measurements were small for density metrics (ICC > 0.80) and average ICCs for whole lung alpha -910 and alpha -950 were 0.57 and 0.64, respectively. Power analyses demonstrated that, under the control conditions with minimal extrinsic variation, population sizes needed to detect meaningful changes in density measures for TLC or FRC repeated scans ranged from a few (20-40) to a few hundred subjects, respectively., Conclusion: A meaningful sample size was predicted from this study using volume-controlled normal subjects in a controlled imaging environment. Under proper breath-hold conditions, high repeatability was obtained in cohorts of normal smokers and non-smokers.

Certain patients who receive granulocyte colony-stimulating factor (GCSF) for autologous hematopoietic stem cell (AHSC) collection fail to mobilize well enough to proceed with transplant. When plerixafor is used with GCSF, the likelihood of achieving the CD34⁺ stem cell target in fewer collections is higher; plerixafor use in all patients is unlikely to be cost-effective. This study retrospectively evaluated the effectiveness of utilizing a peripheral blood CD34⁺ stem cell count (PBCD34) ≤8/µL on day 4 of GCSF-based AHSC mobilization as a threshold for plerixafor administration, and compared the efficacy of collection and cost analysis using historical controls. All patients in the study cohort reached their CD34⁺ targets in ≤3 collections. Significantly more patients who received plerixafor + GCSF versus GCSF alone reached their CD34⁺ target in one collection (P = 0.045); however, there were no significant differences in the number of collections or in cumulative product yields. The historical cohort had 10.3% mobilization failures; the number of collections per patient needed to reach the target was significantly higher in the historical cohort versus study cohort (P = 0.001) as was the number of patients requiring more than one collection to reach their target (P = 0.023). However, the average cost per patient was also significantly higher in the study cohort (P = 0.025). Further refinement of the algorithm may reduce the difference in cost between the two mobilization strategies., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: To evaluate the repeatability of gallium-68 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic (DOTA)-D-Phe1-Try3-octreotide (68Ga-DOTATOC) positron emission tomography (PET) in neuroendocrine tumors., Methods: Five patients with neuroendocrine tumors were imaged with 68Ga-DOTATOC PET twice within 5 days. Maximum and mean standardized uptake values (SUVmax and SUVmean) and kinetic parameters (K-Patlak and K-influx) of target lesions were measured. The repeatability of these measurements was investigated., Results: Forty-seven target lesions were identified on whole-body PET and 21 lesions on dynamic images. There was excellent repeatability with intraclass correlation coefficient of 0.99 for SUVmax, SUVmean, and K-Patlak, and 0.85 for K-influx. The median absolute percent differences and the interquartile ranges (IQR) between 2 scans for SUVmax and SUVmean were 7.4% (IQR, 14.1%) and 9.3% (IQR, 10.6%), respectively. The median absolute percent differences for K-Patlak and K-influx were 12.5% (IQR, 12.6%) and 29.9% (IQR, 22.4%), respectively. The SUVmax of target lesions did not differ by more than 25% between the 2 scans., Conclusions: 68Ga-DOTATOC PET imaging of neuroendocrine tumors is highly reproducible. A difference of more than 25% in SUVmax represents a change that is larger than the measurement error observed on repeated studies and should reflect a significant change in the biological character of the tumor.

Purpose: To determine if patients with macular hole report an increased family history of macular hole compared with control patients and compare the report of family history between patients with unilateral and bilateral macular holes., Methods: This was a multicenter case-control study. Charts of patients coded with diagnosis of macular hole were reviewed, and the diagnosis of idiopathic full-thickness macular hole was ascertained in 166 patients. The control group comprised 136 patients without macular hole or trauma who presented with senile cataract. Family history was obtained from all patients through a telephone interview., Results: Six of 166 (3.6%) macular hole patients surveyed reported a history of macular hole in a primary relative compared with none of 136 (0.0%) control patients (odds ratio is infinity, with 95% confidence interval 1.295 to infinity); however, this finding may be explained by confounders such as age and number of family members. Two of the 142 (1.4%) patients with unilateral holes versus 4 of the 24 (16.7%) patients with bilateral holes reported a family history (odds ratio is 0.0714, with 95% confidence interval 0.0063 to 0.5537), and this finding remains significant when logistic regression is performed to evaluate variables of age and number of family members as potential confounders., Conclusion: There is an increased report of familial occurrence of macular hole in patients with macular holes compared with control patients; however, logistic regression relates this finding to variables of age and number of family members. Patients with bilateral macular holes are more likely to report a family history of macular hole than patients with unilateral macular holes, and this finding remains significant in the presence of age and number of family members. These findings may suggest a familial component to macular hole.

Background: The incidence, survival, and prevalence of neuroendocrine tumors (NETs) in children were determined as a first step in improving diagnosis and therapy. Outcomes were compared with neuroblastoma, a pediatric malignancy that shares several biomarkers., Methods: Incidence rates, observed survival rates and 31-year limited duration prevalence counts were obtained from SEER*Stat for diagnosis years 1975 to 2006. These rates were compared between and within NETs and neuroblastoma for demographic and tumor-related variables from nine standard SEER registries for ages 0-29 years. Multivariate Cox regression was performed to identify prognostic factors for survival in NETs., Results: The number of NETs was 1,073 compared to 1,664 neuroblastomas. The most common NET sites were lung, breast, and appendix. NET 5-year observed survival rates increased from 83% between 1975 and 1979 to 84% for the 2000-2006 period, while analogous neuroblastoma survival rates steadily increased from 45-73%. Five-year observed survival was less than 30% in females with NETs of the cervix and ovary. The estimated 31-year limited duration prevalence for NETs as of January 1, 2006 in the U.S. population was 7,724 compared to 9,960 for neuroblastomas. Age-adjusted multivariate Cox Regression demonstrated small cell histology, primary location in the breast, and distant stage as major predictors of decreased survival., Conclusions: While survivorship has significantly increased for neuroblastoma, those diagnosed with NETs have shown no increase in survival during this 31-year period. NETs constitute an unrecognized cancer threat to children and young adults comparable to neuroblastoma in both number of affected persons and disease severity.

Assessment of physical activity in morbidly obese subjects is important especially in bariatric surgery. We examined the validity of Intelligent Device for Energy Expenditure and Activity (IDEEA) for measuring physical activity and sedentary behavior in morbidly obese women. Activity types, gait counts, and speed detected by the IDEEA monitor were compared to those reported by an observer. The IDEEA monitor detected activity types and gait counts with relatively high accuracy, although slightly lower in extremely obese women than in normal weight controls. The IDEEA monitor accurately estimated gait speeds in both groups. Since gait speed predicts energy expenditure more accurately than gait counts, it is of greater clinical relevance. Reliability of the IDEEA monitor was excellent. The IDEEA monitor is a valid instrument for measuring physical activity and sedentary behavior in extremely obese women, and therefore has potential applications in bariatric surgery both in preoperative evaluation and long-term follow-up.

Background: As more women survive breast cancer, long-term complications that affect quality of life, such as lymphedema of the arm, gain greater importance. Numerous studies have attempted to identify treatment and prognostic factors for arm lymphedema, yet the magnitude of these associations remains inconsistent., Methods: A PubMed search was conducted through January 2008 to locate articles on lymphedema and treatment factors after breast cancer diagnosis. Random-effect models were used to estimate the pooled risk ratio., Results: The authors identified 98 independent studies that reported at least one risk factor of interest. The risk ratio (RR) of arm lymphedema was increased after mastectomy when compared with lumpectomy [RR = 1.42; 95% confidence interval (CI) 1.15-1.76], axillary dissection compared with no axillary dissection (RR = 3.47; 95% CI 2.34-5.15), axillary dissection compared with sentinel node biopsy (RR = 3.07; 95% CI 2.20-4.29), radiation therapy (RR = 1.92; 95% CI 1.61-2.28), and positive axillary nodes (RR = 1.54; 95% CI 1.32-1.80). These associations held when studies using self-reported lymphedema were excluded., Conclusions: Mastectomy, extent of axillary dissection, radiation therapy, and presence of positive nodes increased risk of developing arm lymphedema after breast cancer. These factors likely reflected lymph node removal, which most surgeons consider to be the largest risk factor for lymphedema. Future studies should consider examining sentinel node biopsy versus no dissection with a long follow-up time post surgery to see if there is a benefit of decreased lymphedema compared with no dissection.

Determination of burn severity (i.e. burn depth) is important for effective medical management and treatment. Using a recently described acute burn model, we studied various morphological parameters to detect burn severity. Anaesthetized Sprague-Dawley rats received burns of various severity (0- to 14-s contact time) followed by standard resuscitation using intravenous fluids. Biopsies were taken from each site after 5 h, tissues fixed in 10% neutral-buffered formalin, processed and stained with haematoxylin and eosin. Superficial burn changes in the epidermis included early keratinocyte swelling progressing to epidermal thinning and nuclear elongation in deeper burns. Subepidermal vesicle formation generally decreased with deeper burns and typically contained grey foamy fluid. Dermal burns were typified by hyalinized collagen and a lack of detectable individual collagen fibres on a background of grey to pale eosinophilic seroproteinaceous fluid. Intact vascular structures were identified principally deep to the burn area in the collagen. Follicle cell injury was identified by cytoplasmic clearing/swelling and nuclear pyknosis, and these follicular changes were often the deepest evidence of burn injury seen for each time point. Histological scores (epidermal changes) or dermal parameter depths (dermal changes) were regressed on burn contact time. Collagen alteration (r(2) = 0.91) correlated best to burn severity followed by vascular patency (r(2) = 0.82), epidermal changes (r(2) = 0.76), subepidermal vesicle formation (r(2) = 0.74) and follicular cell injury was useful in all but deep burns. This study confirms key morphological parameters can be an important tool for the detection of burn severity in this acute burn model.