Early MRI Predictors of Relapse in Primary Central Nervous System Lymphoma Treated with MATRix Immunochemotherapy.

Primary Central Nervous System Lymphoma (PCNSL) is a highly malignant brain tumour. We investigated dynamic changes in tumour volume and apparent diffusion coefficient (ADC) measurements for predicting outcome following treatment with MATRix chemotherapy in PCNSL. Patients treated with MATRix (n = 38) underwent T1 contrast-enhanced (T1CE) and diffusion-weighted imaging (DWI) before treatment, after two cycles and after four cycles of chemotherapy. Response was assessed using the International PCNSL Collaborative Group (IPCG) imaging criteria. ADC histogram parameters and T1CE tumour volumes were compared among response groups, using one-way ANOVA testing. Logistic regression was performed to examine those imaging parameters predictive of response. Response after two cycles of chemotherapy differed from response after four cycles; of the six patients with progressive disease (PD) after four cycles of treatment, two (33%) had demonstrated a partial response (PR) or complete response (CR) after two cycles. ADCmean at baseline, T1CE at baseline and T1CE percentage volume change differed between response groups (0.005 < p < 0.038) and were predictive of MATRix treatment response (area under the curve: 0.672-0.854). Baseline ADC and T1CE metrics are potential biomarkers for risk stratification of PCNSL patients early during remission induction therapy with MATRix. Standard interim response assessment (after two cycles) according to IPCG imaging criteria does not reliably predict early disease progression in the context of a conventional treatment approach.

Tyrosine bioconjugation with hypervalent iodine.

Hypervalent iodine reagents have recently emerged as powerful tools for late-stage peptide and protein functionalization. Herein we report a tyrosine bioconjugation methodology for the introduction of hypervalent iodine onto biomolecules under physiological conditions. Tyrosine residues were engaged in a selective addition onto the alkynyl bond of ethynylbenziodoxolones (EBX), resulting in stable vinylbenziodoxolones (VBX) bioconjugates. The methodology was successfully applied to peptides and proteins and tolerated all other nucleophilic residues, with the exception of cysteine. The generated VBX were further functionalized by palladium-catalyzed cross-coupling and azide-alkyne cycloaddition reactions. The method could be successfully used to modify bioactive natural products and native streptavidin to enable thiol-mediated cellular uptake.

Filtration-Histogram Based Magnetic Resonance Texture Analysis (MRTA) for the Distinction of Primary Central Nervous System Lymphoma and Glioblastoma.

Primary central nervous system lymphoma (PCNSL) has variable imaging appearances, which overlap with those of glioblastoma (GBM), thereby necessitating invasive tissue diagnosis. We aimed to investigate whether a rapid filtration histogram analysis of clinical MRI data supports the distinction of PCNSL from GBM. Ninety tumours (PCNSL n = 48, GBM n = 42) were analysed using pre-treatment MRI sequences (T1-weighted contrast-enhanced (T1CE), T2-weighted (T2), and apparent diffusion coefficient maps (ADC)). The segmentations were completed with proprietary texture analysis software (TexRAD version 3.3). Filtered (five filter sizes SSF = 2-6 mm) and unfiltered (SSF = 0) histogram parameters were compared using Mann-Whitney U non-parametric testing, with receiver operating characteristic (ROC) derived area under the curve (AUC) analysis for significant results. Across all (n = 90) tumours, the optimal algorithm performance was achieved using an unfiltered ADC mean and the mean of positive pixels (MPP), with a sensitivity of 83.8%, specificity of 8.9%, and AUC of 0.88. For subgroup analysis with >1/3 necrosis masses, ADC permitted the identification of PCNSL with a sensitivity of 96.9% and specificity of 100%. For T1CE-derived regions, the distinction was less accurate, with a sensitivity of 71.4%, specificity of 77.1%, and AUC of 0.779. A role may exist for cross-sectional texture analysis without complex machine learning models to differentiate PCNSL from GBM. ADC appears the most suitable sequence, especially for necrotic lesion distinction.

World Health Organization Grade II/III Glioma Molecular Status: Prediction by MRI Morphologic Features and Apparent Diffusion Coefficient.

Background A readily implemented MRI biomarker for glioma genotyping is currently lacking. Purpose To evaluate clinically available MRI parameters for predicting isocitrate dehydrogenase (IDH) status in patients with glioma. Materials and Methods In this retrospective study of patients studied from July 2008 to February 2019, untreated World Health Organization (WHO) grade II/III gliomas were analyzed by three neuroradiologists blinded to tissue results. Apparent diffusion coefficient (ADC) minimum (ADCmin) and mean (ADCmean) regions of interest were defined in tumor and normal appearing white matter (ADCNAWM). A visual rating of anatomic features (T1 weighted, T1 weighted with contrast enhancement, T2 weighted, and fluid-attenuated inversion recovery) was performed. Interobserver comparison (intraclass correlation coefficient and Cohen κ) was followed by nonparametric (Kruskal-Wallis analysis of variance) testing of associations between ADC metrics and glioma genotypes, including Bonferroni correction for multiple testing. Descriptors with sufficient concordance (intraclass correlation coefficient, >0.8; κ > 0.6) underwent univariable analysis. Predictive variables (P < .05) were entered into a multivariable logistic regression and tested in an additional test sample of patients with glioma. Results The study included 290 patients (median age, 40 years; interquartile range, 33-52 years; 169 male patients) with 82 IDH wild-type, 107 IDH mutant/1p19q intact, and 101 IDH mutant/1p19q codeleted gliomas. Two predictive models incorporating ADCmean-to-ADCNAWM ratio, age, and morphologic characteristics, with model A mandating calcification result and model B recording cyst formation, classified tumor type with areas under the receiver operating characteristic curve of 0.94 (95% confidence interval [CI]: 0.91, 0.97) and 0.96 (95% CI: 0.93, 0.98), respectively. In the test sample of 49 gliomas (nine IDH wild type, 21 IDH mutant/1p19q intact, and 19 IDH mutant/1p19q codeleted), the classification accuracy was 40 of 49 gliomas (82%; 95% CI: 71%, 92%) for model A and 42 of 49 gliomas (86%; 95% CI: 76%, 96%) for model B. Conclusion Two algorithms that incorporated apparent diffusion coefficient values, age, and tumor morphologic characteristics predicted isocitrate dehydrogenase status in World Health Organization grade II/III gliomas on the basis of standard clinical MRI sequences alone. © RSNA, 2020 Online supplemental material is available for this article.

Sickle Cell Disease is Associated With Elevated Levels of Skin Advanced Glycation Endproducts.

Sickle cell disease (SCD) is associated with increased oxidative stress which potentially enhances generation of advanced glycation endproducts (AGEs). We estimated skin accumulation of AGEs in SCD patients and assessed their relationship with hemolysis and nephropathy. Skin intrinsic fluorescence (SIF), an estimate of AGEs, was assessed in African American patients with and without SCD. After skin excitation with light at 375, 405, and 420 nm, raw autofluorescence was adjusted using specific intrinsic corrections. Group differences in SIF were evaluated by multiple variable regression using chronological age and sex as covariates. The relationship of SIF with reticulocyte count, serum lactate dehydrogenase, estimated glomerular filtration rate (GFR), plasma creatinine, bilirubin, and urine microalbumin was assessed. There were 48 SCD patients (29 male/19 female, age=13.4±3.6 y) and 51 controls (25 male/26 female, age=10.4±5.0 y). SIF375(1.0,0.0), SIF405(0.5,0.5), and SIF420(0.5,0.5) were significantly higher in SCD patients. There was no difference in SIF between SCD patients with and without microalbuminuria. SIF 420(0.5,0.5) was correlated with reticulocyte count (r=0.33; P=0.03). Skin AGEs as estimated by SIF were higher in children with SCD and weakly associated with 1 measure of hemolysis. Further study is needed to determine whether chronic increased deposition of AGEs is associated with development of complications of SCD.

Skin Intrinsic Fluorescence and Age-Related Macular Degeneration: The Beaver Dam Eye Study.

Purpose: To determine if skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation endproducts and oxidative stress in skin is associated with AMD. Methods: SIF was measured with the SCOUT DS skin fluorescence spectrometer in a cross-sectional cohort study of 969 persons aged 68 to 102 years from the 1181 who participated in the 25-year follow-up examination in the Beaver Dam Eye Study (BDES) in 2014 to 2016. The SCOUT DS skin fluorescence spectrometer uses five light-emitting diodes, centered at 375 nm to 456 nm. AMD was assessed by grading of digital color 45° stereoscopic fundus photographs of the macula using the Wisconsin Age-Related Maculopathy grading scheme. Analyses included logistic regression with generalized estimating equations to account for correlation between the eyes of a person. Results: There were data for 1827 eyes for analyses. Early AMD was present in 22% and late AMD in 4% of the eyes. While adjusting for age, sex, smoking status, and history of cardiovascular disease, there were no significant associations of any SIF measure with any AMD or exudative AMD. SIF01 (odds ratio per 1 SD difference on the log scale, 95% confidence interval) (1.66, 1.00-2.74, P = 0.05) and SIF03 (1.81, 1.16-2.81, P = 0.008) were associated with geographic atrophy. Conclusions: There was a suggestive relationship of two SIF measures, SIF01 and SIF03, using different correction factors from the excitation centered at 375 nm, with the prevalence of geographic atrophy in the BDES. Longitudinal follow-up is indicated to assess a temporal relationship.

New Locus for Skin Intrinsic Fluorescence in Type 1 Diabetes Also Associated With Blood and Skin Glycated Proteins.

Skin fluorescence (SF) noninvasively measures advanced glycation end products (AGEs) in the skin and is a risk indicator for diabetes complications. N-acetyltransferase 2 (NAT2) is the only known locus influencing SF. We aimed to identify additional genetic loci influencing SF in type 1 diabetes (T1D) through a meta-analysis of genome-wide association studies (N = 1,359) including Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). A locus on chromosome 1, rs7533564 (P = 1.9 × 10(-9)), was associated with skin intrinsic fluorescence measured by SCOUT DS (excitation 375 nm, emission 435-655 nm), which remained significant after adjustment for time-weighted HbA1c (P = 1.7 × 10(-8)). rs7533564 was associated with mean HbA1c in meta-analysis (P = 0.0225), mean glycated albumin (P = 0.0029), and glyoxal hydroimidazolones (P = 0.049), an AGE measured in skin biopsy collagen, in DCCT. rs7533564 was not associated with diabetes complications in DCCT/EDIC or with SF in subjects without diabetes (nondiabetic [ND]) (N = 8,721). In conclusion, we identified a new locus associated with SF in T1D subjects that did not show similar effect in ND subjects, suggesting a diabetes-specific effect. This association needs to be investigated in type 2 diabetes.

Dietary HMB and ß-alanine co-supplementation does not improve in situ muscle function in sedentary, aged male rats.

This study evaluated the effects of dietary ß-hydroxy-ß-methylbutyrate (HMB) combined with ß-alanine (ß-Ala) in sedentary, aged male rats. It has been suggested that dietary HMB or ß-Ala supplementation may mitigate age-related declines in muscle strength and fatigue resistance. A total of 20 aged Sprague-Dawley rats were studied. At age 20 months, 10 rats were administered a control, purified diet and 10 rats were administered a purified diet supplemented with both HMB and ß-Ala (HMB+ß-Ala) for 8 weeks (approximately equivalent to 3 and 2.4 g per day human dose). We measured medial gastrocnemius (MG) size, force, fatigability, and myosin composition. We also evaluated an array of protein markers related to muscle mitochondria, protein synthesis and breakdown, and autophagy. HMB+ß-Ala had no significant effects on body weight, MG mass, force or fatigability, myosin composition, or muscle quality. Compared with control rats, those fed HMB+ß-Ala exhibited a reduced (41%, P = 0.039) expression of muscle RING-finger protein 1 (MURF1), a common marker of protein degradation. Muscle from rats fed HMB+ß-Ala also exhibited a 45% reduction (P = 0.023) in p70s6K phosphorylation following fatiguing stimulation. These data suggest that HMB+ß-Ala at the dose studied may reduce muscle protein breakdown by reducing MURF1 expression, but has minimal effects on muscle function in this model of uncomplicated aging. They do not, however, rule out potential benefits of HMB+ß-Ala co-supplementation at other doses or durations of supplementation in combination with exercise or in situations where extreme muscle protein breakdown and loss of mass occur (e.g., bedrest, cachexia, failure-to-thrive).

White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes.

OBJECTIVE: Although microvascular complications are common in type 1 diabetes mellitus (T1DM), few studies have quantified the severity, risk factors, and implications of cerebral microvascular damage in these patients. As life expectancy in patients with T1DM increases, patients are exposed to age- and disease-related factors that may contribute to cerebral microvascular disease. METHODS: Severity and volume of white matter hyperintensities (WMH) and infarcts were quantified in 97 middle-aged patients with childhood-onset T1DM (mean age and duration: 50 and 41 years, respectively) and 81 non-T1DM adults (mean age: 48 years), concurrent with cognitive and health-related measures. RESULTS: Compared with non-T1DM participants, patients had more severe WMH (Fazekas scores 2 and 3 compared with Fazekas score 1, p < 0.0001) and slower information processing (digit symbol substitution, number correct: 65.7 ± 10.9 and 54.9 ± 13.6; pegboard, seconds: 66.0 ± 9.9 and 88.5 ± 34.2; both p < 0.0001) independent of age, education, or other factors. WMH were associated with slower information processing; adjusting for WMH attenuated the group differences in processing speed (13% for digit symbol, 11% for pegboard, both p ≤ 0.05). Among patients, prevalent neuropathies and smoking tripled the odds of high WMH burden, independent of age or disease duration. Associations between measures of blood pressure or hyperglycemia and WMH were not significant. CONCLUSIONS: Clinically relevant WMH are evident earlier among middle-aged patients with childhood-onset T1DM and are related to the slower information processing frequently observed in T1DM. Brain imaging in patients with T1DM who have cognitive difficulties, especially those with neuropathies, may help uncover cerebral microvascular damage. Longitudinal studies are warranted to fully characterize WMH development, risk factors, and long-term effects on cognition.

Noninvasive skin fluorescence spectroscopy is comparable to hemoglobin A1c and fasting plasma glucose for detection of abnormal glucose tolerance.

AIM: We compare performance of noninvasive skin fluorescence spectroscopy (SFS), fasting plasma glucose (FPG), and hemoglobin A1c (A1C) for detection of abnormal glucose tolerance (AGT). METHODS: The NSEEDS trial evaluated SFS, FPG, and A1C in an at-risk population of 479 previously undiagnosed subjects from nine US centers, each of whom received a 75 g, 2 h oral glucose tolerance test (OGTT). Skin fluorescence spectra were collected and analyzed with SCOUT DS® devices. Disease truth was AGT, defined as OGTT ≥140 mg/dl. Abnormal glucose tolerance sensitivity, false positive rate (FPR), and receiver operating characteristic (ROC) curves were computed for each measurement technique. Skin fluorescence spectroscopy reproducibility was also assessed. RESULTS: The AGT sensitivity of SFS was 68.2%, higher than that of FPG (thresholds of 100 and 110 mg/dl) and A1C (thresholds of 5.7% and 6.0%). The FPR of SFS was 37.7%, comparable to A1C at the 5.7% threshold (30.7%). Partial ROC areas of SFS, FPG, and A1C were similar for FPRs of 20-50% (average sensitivities of 64.0%, 59.0%, and 68.6%, respectively). The interday coefficient of variation for SFS was 7.6%. CONCLUSIONS: Skin fluorescence spectroscopy has similar screening performance to FPG and A1C and is a viable approach for detection of AGT.

Clinical and technical factors associated with skin intrinsic fluorescence in subjects with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study.

BACKGROUND: The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications(EDIC) studies have established multiyear mean hemoglobin A1c (HbA1c) as predictive of microvascular complications in persons with type 1 diabetes. However, multiyear mean HbA1c is not always available in the clinical setting. Skin advanced glycation end products (AGEs) are thought to partially reflect effects of hyperglycemia over time, and measurement of skin AGEs might be a surrogate for multiyear mean HbA1c. As certain AGEs fluoresce and skin fluorescence has been demonstrated to correlate with the concentration of skin AGEs, noninvasive measurement by skin intrinsic fluorescence(SIF) facilitates the exploration of the association of mean HbA1c and other clinical/technical factors with SIF using the detailed phenotypic database available in DCCT/EDIC. SUBJECTS AND METHODS: Of the subjects, 1,185 (53% male) had measurements of SIF during years 16/17 of EDIC with mean age and diabetes duration of 51.5 and 29.8 years, respectively. SIF measurements were obtained on the underside of the forearm near the elbow using a skin fluorescence spectrometer. Demographic data and health history were self-reported, and an annual standardized examination measured clinical status. Linear regression models were constructed to identify significant clinical and technical factors associated with SIF, and the final models only used factors that were significant. RESULTS: SIF ranged from 8.7 to 54.0 arbitrary units and was log-normally distributed. Log(SIF) correlated more with mean HbA1c as the time period increased. In multivariate analyses log(SIF) was significantly associated with mean HbA1c, age,estimated glomerular filtration rate < 60mL/min/m2, smoking status, skin tone, and clinic latitude <37 N. CONCLUSIONS: SIF reflects age, mean HbA1c over time, smoking, and renal damage, which are known risk factors for diabetes complications.

Bioactivation of sitaxentan in liver microsomes, hepatocytes, and expressed human P450s with characterization of the glutathione conjugate by liquid chromatography tandem mass spectrometry.

Sitaxentan is a selective endothelin-A receptor antagonist that was marketed as Thelin in several European countries and Canada for pulmonary arterial hypertension. Sitaxentan was undergoing further clinical trials in the United States but due to four deaths and one case of liver transplantation from severe liver toxicity that appeared to be idiosyncratic in nature, it was withdrawn worldwide in December, 2010. Sitaxentan contains a 1,3-benzodioxole ring that undergoes enzymatic demethyleneation to an ortho-catechol metabolite that can further oxidize to a reactive ortho-quinone metabolite. Here, we report the detection and mass spectral characterization of a glutathione conjugate of this sitaxentan quinone reactive metabolite that was trapped in vitro using mouse, rat, dog, and human liver microsomes supplemented with NADPH and glutathione and that was also observed in rat and human hepatocytes. Using human liver microsomes, we also demonstrated that P450 3A4 undergoes time-dependent inhibition. Density functional calculations on the catechol metabolite of sitaxentan indicated that the reaction leading to the quinone was thermodynamically favorable with an enthalpy change of -6.3 kcal/mol. Using density functional methodology, we modeled the attack of glutathione on the quinone with an S-methyl thiolate anion which allowed us to predict, based on the difference in transition state energies, that the 2-position on the phenyl ring was more likely than the 5-position as the site of glutathione conjugation. Overall, our results demonstrated that sitaxentan is capable of facile formation of a reactive ortho-quinone metabolite capable of reacting with glutathione and may rationalize the idiosyncratic nature of the hepatotoxicity that led to its withdrawal.

Screening for HbA1c-defined prediabetes and diabetes in an at-risk greek population: performance comparison of random capillary glucose, the ADA diabetes risk test and skin fluorescence spectroscopy.

BACKGROUND: We examined the accuracy of random capillary glucose (RCG) and two noninvasive screening methods, the ADA diabetes risk test (DRT) and skin fluorescence spectroscopy (SFS) as measured by Scout DS for detecting HbA1c-defined dysglycemia or type 2 diabetes in an at-risk cohort. METHODS: Subjects were recruited at two clinical sites for a single non-fasting visit. Each subject had measurements of height, weight and waist circumference. A diabetes score was calculated from skin fluorescence measured on the left forearm. A finger prick was done to measure RCG and HbA1c (A1C). Health questionnaires were completed for the DRT. Increasing dysglycemia was defined as A1C ≥ 5.7% (39 mmol/mol) or ≥ 6.0% (42 mmol/mol). Type 2 diabetes was defined as A1C ≥ 6.5% (47.5 mmol/mol). RESULTS: 398 of 409 subjects had complete data for analysis with means for age, body mass index, and waist of 52 years, 27 kg/m(2) and 90 cm. 51% were male. Prevalence of A1C ≥ 5.7%, ≥ 6.0% and ≥ 6.5% were 54%, 34% and 12%, respectively. Areas under the curve (AUC) for detection of increasing levels dysglycemia or diabetes for RCG were 63%, 66% and 72%, for the ADA DRT the AUCs were 75%, 76% and 81% and for SFS the AUCs were 82%, 84% and 90%, respectively. For each level of dysglycemia or diabetes, the SFS AUC was significantly higher than RCG or the ADA DRT. CONCLUSIONS: The noninvasive skin fluorescence spectroscopy measurement outperformed both RCG and the ADA DRT for detection of A1C-defined dysglycemia or diabetes in an at-risk cohort.

Cross-sectional evaluation of noninvasively detected skin intrinsic fluorescence and mean hemoglobin a1c in type 1 diabetes.

BACKGROUND: This study evaluated the relationship between skin intrinsic fluorescence (SIF) and long-term mean hemoglobin A1c (HbA1c) in individuals with type 1 diabetes. SUBJECTS AND METHODS: We undertook a cross-sectional analysis of 172 individuals with type 1 diabetes followed longitudinally with HbA1c data available over an average of 16.6 years. SIF was evaluated cross-sectionally using the SCOUT DS device (VeraLight Inc., Albuquerque, NM) and correlated with most recent HbA1c and long-term mean HbA1c. Potential determinants of this relationship, including age, gender, smoking status, duration of diabetes, and renal function, were also evaluated. RESULTS: Age-adjusted skin intrinsic fluorescence significantly correlated with long-term mean HbA1c (R=0.44, P<0.0001). In contrast, there was no significant relationship between SIF and most recent HbA1c (R=0.14, P=0.075). The best-fit model describing the relationship between SIF and mean HbA1c controlled for factors of age, duration of disease, renal function, and site of study conduct. Controlling for these factors was also important in understanding the relationship between most recent HbA1c and SIF. Evaluating longer-term HbA1c data also strengthened the relationship between SIF and mean HbA1c. In the presence of renal dysfunction or damage, as indicated by an estimated glomerular filtration rate of <60 mL/min/1.73 m2 or presence of gross proteinuria, there was no significant correlation between SIF and mean HbA1c. CONCLUSIONS: Noninvasive detection of SIF significantly correlates with long-term mean HbA1c, providing insight into long-term glycemic exposure. Age, duration of diabetes, and renal function are potential contributors to this relationship.

Skin fluorescence correlates strongly with coronary artery calcification severity in type 1 diabetes.

BACKGROUND: Coronary artery calcification (CAC) is more severe and occurs at an earlier age in type 1 diabetes. Risk factors for this subclinical marker of atherosclerotic burden, like coronary artery disease (CAD) itself, are not fully identified. One postulated mechanism for the increased CAC observed in type 1 diabetes is the accumulation of advanced glycation end products (AGEs). As certain collagen AGEs fluoresce, skin intrinsic fluorescence (SIF) can act as a novel marker of levels of collagen AGEs. We thus sought to determine the relationship between skin intrinsic fluorescence and CAC in type 1 diabetes. METHODS: One hundred five participants in the Pittsburgh Epidemiology of Diabetes Complications study of childhood-onset (age <17 years) type 1 diabetes who had previously undergone electron beam tomography scanning for CAC (80 of whom had follow-up data) had SIF measurements taken using the SCOUT DM (VeraLight, Inc., Albuquerque, NM). Mean age and diabetes' duration were 49 and 40 years, respectively, at the time of SIF measurement. RESULTS: Seventy-one percent of the study participants had some measurable CAC that was univariately (but not after age adjustment) cross-sectionally associated with SIF (odds ratio = 2.51, 1.37-4.59). However, for CAC severity using natural logarithmically transformed scores, SIF was both univariately (P < 0.0001) and multivariably (P = 0.03) associated with CAC. This relationship was independent of age, a history of CAD, renal function, or renal damage. Receiver operator characteristic analyses revealed that the discriminative ability of SIF to detect CAC went from an area under the curve of 71% for the presence of any CAC to 85% for those with a CAC score >400. CONCLUSIONS: The relationship between SIF and CAC appears stronger with more severe calcification. Given the strong relationship of CAC with CAD this finding has important implications and suggests that SIF maybe a useful marker of CAC/CAD risk and potentially a therapeutic target.

Noninvasive optical screening for diabetes.

BACKGROUND: Advanced glycation end products (AGEs) are implicated in the complications of diabetes. Advanced glycation end products also accumulate in the skin and are sensitive biomarkers for the risk of developing diabetes and related complications. Some AGEs fluoresce and can be measured noninvasively by optical spectroscopy. METHODS: Noninvasive screening for diabetes has been evaluated in an 18-site study involving a cohort of 2793 subjects meeting American Diabetes Association-based screening criteria. Subjects were measured with a specialized skin fluorimeter and also received traditional blood glucose and glycated hemoglobin tests. RESULTS: Retrospective results indicated that the noninvasive technology measuring dermal fluorescence is more sensitive at detecting abnormal glucose tolerance than either fasting plasma glucose or glycated hemoglobin A1C. CONCLUSIONS: These results suggest that noninvasive measurement of dermal fluorescence may be an effective tool to identify individuals at risk for diabetes and its complications. The noninvasive technology yields immediate results, and since measuring dermal fluorescence requires no blood draws or patient fasting, the instrument may be well suited for opportunistic screening.

Noninvasive type 2 diabetes screening: superior sensitivity to fasting plasma glucose and A1C.

OBJECTIVE: This study compared the performance of a novel noninvasive technology to fasting plasma glucose (FPG) and A1C tests for detecting undiagnosed diabetes and impaired glucose tolerance. RESEARCH DESIGN AND METHODS: The design was a head-to-head evaluation in a naïve population. Consented subjects received FPG and A1C tests and an oral glucose tolerance test (OGTT). Subjects were also measured by a noninvasive device that detects the fluorescence of skin advanced glycation end products. A total of 351 subjects participated. RESULTS: Subjects with 2-h OGTT values > or = 140 mg/dl defined the positive screening class. A total of 84 subjects (23.9% prevalence) screened positive. The performances of the noninvasive device, FPG, and A1C were evaluated for sensitivity and specificity against this classification. At the impaired fasting glucose threshold (FPG = 100 mg/dl), the FPG testing sensitivity was 58% and the specificity was 77.4%. At that same specificity, the sensitivity for A1C testing was 63.8%, while the noninvasive testing sensitivity was 74.7%. The sensitivity advantage of the noninvasive device over both blood tests for detecting diabetes and precursors was statistically significant (P < 0.05). CONCLUSIONS: The noninvasive technology showed clinical performance advantages over both FPG and A1C testing. The sensitivity differential indicated that the noninvasive device is capable of identifying 28.8% more individuals in the OGTT-defined positive screening class than FPG testing and 17.1% more than A1C testing. The combination of higher sensitivity and greater convenience--rapid results with no fasting or blood draws--makes the device well suited for opportunistic screening.

A multiinstitutional, concurrent chemoradiation trial of strontium-89, estramustine, and vinblastine for hormone refractory prostate carcinoma involving bone.

BACKGROUND: Estramustine phosphate (EMP) and vinblastine have radiosensitizing properties and significant activity against hormone refractory prostate carcinoma. Strontium-89 is a palliative agent that acts as a selective radiation source for bone metastasis. The combination of EMP, vinblastine, and strontium-89 was developed to exploit the potential for radiosynergy. PATIENTS AND METHODS Forty-four patients at the Brown Oncology Group affiliated hospitals were treated with oral EMP 600 mg/m2 daily on Weeks 1-4 and 7-10, vinblastine 4 mg/m2 intravenously once each week on Weeks 1-4 and 7-10, and strontium-89 2.2 MBq/kg on Day 1. Courses were repeated every 12 weeks. Response assessment was based on a change in the serum prostate specific antigen (PSA) levels, correlated with change in measurable disease and bone scan appearance. RESULTS: A greater than or equal to 50% decline in PSA for at least 6 weeks was observed in 21 patients (48%, 95% confidence interval, 33-62%). Median duration of response was 23 weeks (range, 6-70.8 weeks). The median survival was 13 months with 1- and 2-year survival rates of 55% and 25%, respectively. After completion of protocol therapy, a retrospective review showed that only nine patients received subsequent palliative external beam radiation after progression. CONCLUSIONS: The addition of strontium-89 to the regimen of EMP and vinblastine can be delivered safely and in repeated doses, provides effective palliation, and may decrease the need for future radiation therapy. A randomized trial is necessary to quantify these effects.