Improved survival with dose-escalated radiotherapy in stage III non-small-cell lung cancer: analysis of the National Cancer Database.

BACKGROUND: Concurrent chemoradiation is the standard of care in non-operable stage III non-small-cell lung cancer (NSCLC). Data have suggested a benefit of dose escalation; however, results from the randomized dose-escalation trial RTOG 0617 revealed a lower survival rate with high-dose radiation. To evaluate the impact of dose escalation on overall survival (OS) in stage III NSCLC treated with chemoradiotherapy outside the controlled setting of a randomized trial, we carried out an observational, population-based investigation of the National Cancer Database (NCDB). PATIENTS AND METHODS: A total of 33 566 patients with stage III NSCLC treated with chemoradiation from 2004 to 2012 and radiation doses between 59.4 and 85 Gy were included. The primary end point was OS, with median survival calculated via Kaplan-Meier. Univariate, multivariable and propensity-score matching analyses were carried out. RESULTS: Patients were stratified by dose with median OS of: 18.8, 19.8 and 21.6 months for cohorts receiving 59.4-60, 61-69 and ≥70 Gy, respectively (P < 0.001). Granular dose analyses were carried out demonstrating increased OS with increasing radiation dose: median survival of 18.8, 21.1, 22.0 and 21.0 months for 59.4-60, 66, 70 and ≥71 Gy, respectively. While 66, 70 and ≥71 Gy resulted in increased OS in comparison with 59.4-60 Gy, no significant difference in OS was observed when comparing 66 with ≥71 Gy (P = 0.38). CONCLUSIONS: Dose escalation above 60 Gy was associated with improved OS in this cohort of stage III NSCLC patients treated with chemoradiotherapy. A plateau of benefit was observed, with no additional improvement in OS with increased dose (≥71 Gy) compared with 66-70 Gy. With evidence suggesting worse OS and quality of life with increased dose, these data support investigation of the role of intermediate-dose radiation, and in the absence of randomized evidence, may be leveraged to justify utilization of intermediate-dose radiation.

The National Environmental Respiratory Center (NERC) experiment in multi-pollutant air quality health research: IV. Vascular effects of repeated inhalation exposure to a mixture of five inorganic gases.

An experiment was conducted to test the hypothesis that a mixture of five inorganic gases could reproduce certain central vascular effects of repeated inhalation exposure of apolipoprotein E-deficient mice to diesel or gasoline engine exhaust. The hypothesis resulted from preceding multiple additive regression tree (MART) analysis of a composition-concentration-response database of mice exposed by inhalation to the exhausts and other complex mixtures. The five gases were the predictors most important to MART models best fitting the vascular responses. Mice on high-fat diet were exposed 6 h/d, 7 d/week for 50 d to clean air or a mixture containing 30.6 ppm CO, 20.5 ppm NO, 1.4 ppm NO2, 0.5 ppm SO2, and 2.0 ppm NH3 in air. The gas concentrations were below the maxima in the preceding studies but in the range of those in exhaust exposure levels that caused significant effects. Five indicators of stress and pro-atherosclerotic responses were measured in aortic tissue. The exposure increased all five response indicators, with the magnitude of effect and statistical significance varying among the indicators and depending on inclusion or exclusion of an apparent outlying control. With the outlier excluded, three responses approximated predicted values and two fell below predictions. The results generally supported evidence that the five gases drove the effects of exhaust, and thus supported the potential of the MART approach for identifying putative causal components of complex mixtures.

Prevalence of somatic small fiber neuropathy in obesity.

BACKGROUND: Somatic cutaneous small sensory fiber neuropathy (SSFN) can be an early manifestation of impaired glucose tolerance and diabetes mellitus and/or insulin resistance among obese subjects and is often associated with pain, wound occurrence and impaired wound healing. It is yet unclear as to whether SSFN is prevalent among obese individuals without glucose and/or insulin dysregulation despite abundant evidence of delayed wound healing. OBJECTIVE: To observe whether there is hypofunctioning of stimulated capsaicin-sensitive cutaneous nerves (small sensory fibers) in obese subjects with/without hyperglycemia and hyperinsulinemia. DESIGN, SETTING AND PARTICIPANTS: Fifty-eight morbidly obese and 15 lean subjects were recruited for small fiber testing of the forearm in a cross-sectional study. Hyperglycemia was observed in 35 obese subjects. Of 25 obese subjects, hyperinsulinemia was noted in 15, 14 of which were hyperglycemic. No subjects demonstrated symptoms/signs of neuropathy over the hairy skin of the forearm. In fact, a neurological examination revealed that 37 subjects were asymptomatic in the legs and only four complained of a neuropathic pain in the foot. Virtually all subjects were exposed to a set of capsaicin-sensitive tests and measures which were identified by capsaicin desensitization procedures. These tests, conducted while in a supine position in bed at the Banner Good Samaritan Medical Center, Phoenix, examined the two principle roles of cutaneous SSFs, namely conveying pain signals to the CNS and controlling local neurogenic vasodilatation (flare; axon-reflex). MAIN OUTCOME MEASURES: Heat-induced pain was assessed by verbal reports of sensation after accommodation and heat-, capsaicin-, and transcutneous stimulation- induced blood flow was measured by laser Doppler flowmetry with probes placed at the site of stimulation and 1 cm remote from the site, the latter to evaluate flare latency and intensity of flare. RESULTS: Significant depression of pain and flare responses were observed in the obese subjects in all but one test. Decreased pain and flare responses were noted in all subjects without hyperglycemia and hyperinsulinemia. Age negatively correlated with capsaicin-induced flare in both the obese and normal groups. CONCLUSION: SSFN was prevalent in the cohort of morbidly obese subjects in a skin area without neurological symptoms or signs and in subjects with/without hyperglycemia and hyperinsulinemia. SSFN may be a serious factor in observations of impaired wound healing among obese subjects, a particularly worrisome problem in an obese aging population given the propensity for small fiber impairment in aging subjects. Small fiber impairment in the younger obese population may signal an early aging phenomenon.

Measurement of the electric form factor of the neutron at Q2=0.5 and 1.0 GeV2/c2.

The electric form factor of the neutron was determined from measurements of the d-->(e-->,e'n)p reaction for quasielastic kinematics. Polarized electrons were scattered off a polarized deuterated ammonia (15ND3) target in which the deuteron polarization was perpendicular to the momentum transfer. The scattered electrons were detected in a magnetic spectrometer in coincidence with neutrons in a large solid angle detector. We find G(n)(E)=0.0526+/-0.0033(stat)+/-0.0026(sys) and 0.0454+/-0.0054+/-0.0037 at Q(2)=0.5 and 1.0 (GeV/c)(2), respectively.

Immunohistochemical detection of p53 tumor-suppressor protein is a poor indicator of prognosis for canine cutaneous mast cell tumors.

Eighty-three canine cutaneous mast cell tumors were graded histologically and evaluated immunohistochemically for p53 tumor-suppressor protein expression. An avidin-biotin immunohistochemical protocol incorporated a rabbit polyclonal antibody (CM-1) directed against normal and mutant p53 protein. Positive staining was observed in 44.6% (37/83) of tumors and included 50% (12/24) of grade I (well differentiated) tumors, 46.9% (23/49) of grade II (intermediate differentiation) tumors, and 20% (2/10) of grade III (poorly differentiated) tumors. A statistically significantly higher proportion (P < 0.019) of tumors from the head and neck (83.3%, 10/12), stained positive for p53 than tumors from the thorax, back, abdomen, and axilla (39.4%, 13/33), legs (35.7%, 10/28), or prepuce, scrotal, or inguinal areas (44.4%, 4/9). No statistically significant difference between p53 labeling and histologic grade, breed, or tumor size was present. Survival data were available for 53/83 (63.9%) of dogs. Positive reactivity for p53 was observed in 47% (25/53) of tumors within this group, with 57.9% (11/19) of grade I, 43.3% (13/30) of grade II, and 25% (1/4) of grade III tumors labeled. Mean survival time for the 53 dogs was 12.1 months. The median survival time for dogs with grade III tumors or tumors >5 cm was statistically significantly shorter (P < 0.0001) than for dogs with grades I and II or smaller tumors. Although p53 protein abnormalities may play a role in tumor development or behavior in some canine cutaneous mast cell tumors, immunoreactivity was not associated with lack of tumor differentiation, tumor locations previously shown to demonstrate aggressive biological behavior, breed predisposition, or survival times.

Application of a pruning algorithm to optimize artificial neural networks for pharmaceutical fingerprinting.

The present study investigates an application of artificial neural networks (ANNs) for use in pharmaceutical fingerprinting. Several pruning algorithms were applied to decrease the dimension of the input parameter data set. A localized fingerprint region was identified within the original input parameter space from which a subset of input parameters was extracted leading to enhanced ANN performance. The present results confirm that ANNs can provide a fast, accurate, and consistent methodology applicable to pharmaceutical fingerprinting.

N-acetylcysteine and alpha-tocopherol reverse the inflammatory response in activated rat Kupffer cells.

Activation of the resident macrophage populations of the reticuloendothelial system is a key component of the complex pathophysiology of sepsis. Macrophage activation leads to production and secretion of inflammatory mediators such as cytokines, vasoactive substances, free radicals, and chemokines, which have been associated with high morbidity and mortality in the septic patient. The goal of the present study was to determine whether antioxidants could suppress Kupffer cell activation at points beyond the initiation of activation. Kupffer cells were studied since they are central to the clearance of bacteria and endotoxins, and have been associated with hepatocellular dysfunction in sepsis. Cells were activated with 10 ng/ml LPS for various times whereupon N-acetylcysteine (30 mM) and alpha-tocopherol (50 microM) were added. Steady state levels of cytokine mRNA, activation of nuclear factor-kappaB, and TNF-alpha secretion were determined when expression was maximal in control cells. The results of this study show that antioxidants can be used to suppress Kupffer cell activation at points beyond the initiation of activation. Furthermore, we show that N-acetylcysteine-mediated inhibition of activation requires secondary protein synthesis, but does not modulate IkappaB-alpha mRNA expression. The inhibitory effect of these drugs occurs at the very earliest steps of the LPS signal transduction cascade as it is currently understood. The results of the present study suggest that the inflammatory response to sepsis may be controlled through appropriate antioxidant therapy.

Preprocessing of HPLC trace impurity patterns by wavelet packets for pharmaceutical fingerprinting using artificial neural networks.

The immediate objective of this research program is to evaluate several computer-based classifiers as potential tools for pharmaceutical fingerprinting based on analysis of HPLC trace organic impurity patterns. In the present study, wavelet packets (WPs) are investigated for use as a preprocessor of the chromatographic data taken from commercial samples of L-tryptophan (LT) to extract input data appropriate for classifying the samples according to manufacturer using artificial neural networks (ANNs) and the standard classifiers KNN and SIMCA. Using the Haar function, WP decompositions for levels L = 0-10 were generated for the trace impurity patterns of 253 chromatograms corresponding to LT samples that had been produced by six commercial manufacturers. Input sets of N = 20, 30, 40, and 50 inputs were constructed, each one consisting of the first N/2 WP coefficents and corresponding positions from the overall best level (L = 2). The number of hidden nodes in the ANNs was also varied to optimize performance. Optimal ANN performance based on percent correct classifications of test set data was achieved by ANN-30-30-6 (97%) and ANN-20-10-6 (94%), where the integers refer to the numbers of input, hidden, and output nodes, respectively. This performance equals or exceeds that obtained previously (Welsh, W.J.; et al.Anal.Chem. 1996, 68, 3473) using 46 inputs from a so-called Window preprocessor (93%). KNN performance with 20 inputs (97%) or 30 inputs (90%) from the WP preprocessor also exceeded that obtained from the Window preprocessor (85%), while SIMCA performance with 20 inputs (86%) or 30 inputs (82%) from the WP preprocessor was slightly inferior to that obtained from the Window preprocessor (87%). These results indicate that, at least for the ANN and KNN classifiers considered here, the WP preprocessor can yield superior performance and with fewer inputs compared to the Window preprocessor.

Pharmaceutical fingerprinting: evaluation of neural networks and chemometric techniques for distinguishing among same-product manufacturers.

The present study was undertaken to evaluate several computer-based classifiers as potential tools for pharmaceutical fingerprinting by utilizing normalized data obtained from HPLC trace organic impurity patterns. To assess the utility of this approach, samples of L-tryptophan (LT) drug substance were analyzed from commercial production lots of six different manufacturers. The performance of several artificial neural network (ANN) architectures was compared with that of two standard chemometric methods, K-nearest neighbors (KNN) and soft independent modeling of class analogy (SIMCA), as well as with a panel of human experts. The architecture of all three computer-based classifiers was varied with respect to the number of input variables. The ANNs were also optimized with respect to the number of nodes per hidden layer and to the number of hidden layers. A novel preprocessing scheme known as the Window method was devised for converting the output of 899 data entries extracted from each chromatogram into an appropriate input file for the classifiers. Analysis of the test set data revealed that an ANN with 46 inputs (i.e., ANN-46) was superior to all other classifiers evaluated, with 93% of the chromatograms correctly classified. Among the classifiers studied in detail, the order of performance was ANN-46 (93%) > SIMCA-46 (87%) > KNN-46 (85%) = ANN-899 (85%) > "human experts" (83%) > SIMCA-899 (78%) > or = ANN-22 (77%) = KNN-22 (77%) > or = KNN-899 (76%) > SIMCA-22 (73%). These results confirm that ANNs, particularly when used in conjunction with the Window preprocessing scheme, can provide a fast, accurate, and consistent methodology applicable to pharmaceutical fingerprinting. Particular attention was paid to variations in the HPLC patterns of same-manufacturer samples due to differences in LT production lots, HPLC columns, and even run-days to quantify how these factors might hinder correct classifications. The results from these classification studies indicate that the chromatograms evidenced variations across LT manufacturers, across the three HPLC columns and, for one manufacturer, across lots. The extent of column-to-column variations is particularly noteworthy in that all three columns had identical specifications with respect to their stationary-phase characteristics and two of the three columns were from the same vendor.

Determination of sodium levothyroxine in bulk, tablet, and injection formulations by high-performance liquid chromatography.

Sodium levothyroxine was determined in bulk drugs, tablets, and injections by high-performance liquid chromatography (HPLC). Levothyroxine was separated from excipients and impurities on a 10-microns cyanoalkyl column using an acetonitrile-water-phosphoric acid mobile phase. The HPLC method is shown to be linear, accurate, and precise, and the results obtained by the HPLC and USP XX methods are compared.

Liquid chromatographic determination of prednisolone in tablets and bulk drugs: interlaboratory study.

A normal phase liquid chromatographic (LC) method for the determination of prednisolone in tablets and bulk drugs was studied by 7 analysts. An LC system, consisting of a methanol-water-ethylene dichloride-acetic acid mobile phase and a silica column, was used to analyze bulk drugs, individual tablets, and composite samples. Analysts were supplied with 16 samples, including simulated formulations, composites of commercial tablets, intact tablets, and bulk drug substances. Results agreed with those obtained by the author. The coefficients of variation of the analysts' results ranged from 1.34% for bulk drugs to 2.14% for tablet composites. The LC method is suggested as an alternative to the official AOAC and USP XX blue tetrazolium colorimetric methods.

Decomposition of aminophylline in suppository formulations.

An aminophylline suppository product, when stored at room temperature, was found to be deficient in ethylenediamine content by the USP XIX assay and by a specific method for primary amines. The product also had a melting point that was considerably higher than body temperature. An accelerated decomposition experiment, conducted on normal suppositories of identical original composition, yielded a product refractory at steam bath temperatures and containing no ethylenediamine measurable by the USP assay. The suppositories from both the original sample and the decomposition experiment contained considerable amounts of a white material, which melted at similar to or approximately 150 degrees and which consisted of the diamide products formed by the reaction of ethylenediamine and the fatty acids present in coconut and palm kernel oils. The results, which confirmed the work of Cieszynski, showed that the ethylenediamine constituent of aminophylline can react with suppository base materials to produce insoluble amide decomposition products.

High-performance liquid chromatographic separation and identification of epimeric 17-ketone impurities in commercial sample of dexamethasone sodium phosphate.

A commercial sample of dexamethasone sodium phosphate solution for injection was found to contain 56% of the label concentration and to be extensively contaminated (approximately 50%) with a white insoluble solid, which was identified as a mixture of the 16 alpha- and 16 beta-methyl epimers of 9-fluoro-11 beta-hydroxy-16-methylandrosta-1,4-diene-3,17-dione. High-performance liquid chromatography (HPLC) was used to separate, identify, and quantitate these epimers and to determine their presence in commercial samples. One epimer was identified by HPLC comparison with a synthesized specimen of 9-fluoro-11 beta-hydroxy-16 alpha-methylan-drosta-1,4-diene-3,17-dione. The second peak was identified as the 16 beta-epimer by epimerization of the synthesized alpha-component with alkali to obtain a product whose chromatogram matched that of the impurity. These conclusions are supported by data obtained by IR and UV spectrophotometry, TLC, and the blue tetrazolium test.

Collaborative study of a semiautomated method for the analysis of prednisolone and prednisone tablets.

A semiautomated colorimetric method for the determination of prednisolone and prednisone was collaboratively studied by 6 collaborators. In the method, an alcoholic solution of the drug is extracted with chloroform and the extract is reacted with tetramethylammonium hydroxide and blue tetrazolium; the absorbance of the resulting color is read at 525 nm. Collaborators were supplied with 4 composites of tablets of different dosage levels, 2 containing prednisolone and 2 containing prednisone. Results agreed with those obtained by the author using the USP total steroid assay method. The coefficients of variation of the individual collaborator's results for prednisolone and prednisone ranged from 0.54 to 2.38 and from 0.34 to 2.19%, respectively. This method has been adopted as official first action.

Extra-large Tribolium confusum: a new autosomal recessive mutant.

A new mutant of Tribolium confusum Jacquelin duVal (Coleoptera: Tenebrionidae), extra-large (designated xl), was isolated in mating competition tests with red-eye (re) and wild-type (+). Crosses showed that it was autosomal recessive gene with subvital effects. The pupal weights averaged 6.1 and 7.3 mg for males and females, respectively, about twice the weights of the ancestral wild-type. The generation time (egg to adult) was approximately 8 to 9 weeks compared with about 4 weeks for the wild-type. This increase resulted from a lengthening of the larval stage since the durations of the egg and pupal stages were within the ranges of the wild-type. Mean longivity of xl males and females was reduced to 8.5 and 6.0 weeks, respectively at 26.7 +/- 1 degree C and 60% RH.