Baseline Polymorphisms and Emergence of Drug Resistance in the NS3/4A Protease of Hepatitis C Virus Genotype 1 following Treatment with Faldaprevir and Pegylated Interferon Alpha 2a/Ribavirin in Phase 2 and Phase 3 Studies.

Analysis of data pooled from multiple phase 2 (SILEN-C1 to 3) and phase 3 studies (STARTVerso1 to 4) of the hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) protease inhibitor faldaprevir plus pegylated interferon alpha/ribavirin (PR) provides a comprehensive evaluation of baseline and treatment-emergent NS3/4A amino acid variants among HCV genotype-1 (GT-1)-infected patients. Pooled analyses of GT-1a and GT-1b NS3 population-based pretreatment sequences (n = 3,124) showed that faldaprevir resistance-associated variants (RAVs) at NS3 R155 and D168 were rare (<1%). No single, noncanonical NS3 protease or NS4A cofactor baseline polymorphism was associated with a reduced sustained virologic response (SVR) to faldaprevir plus PR, including Q80K. The GT-1b NS3 helicase polymorphism T344I was associated with reduced SVR to faldaprevir plus PR (P < 0.0001) but was not faldaprevir specific, as reduced SVR was also observed with placebo plus PR. Among patients who did not achieve SVR and had available NS3 population sequences (n = 507 GT-1a; n = 349 GT-1b), 94% of GT-1a and 83% of GT-1b encoded faldaprevir treatment-emergent RAVs. The predominant GT-1a RAV was R155K (88%), whereas GT-1b encoded D168 substitutions (78%) in which D168V was predominant (67%). The novel GT-1b NS3 S61L substitution emerged in 7% of virologic failures as a covariant with D168V, most often among the faldaprevir breakthroughs; S61L in combination with D168V had a minimal impact on faldaprevir susceptibility compared with that for D168V alone (1.5-fold difference in vitro). The median time to loss of D168 RAVs among GT-1b-infected patients who did not have a sustained virologic response at 12 weeks posttreatment (non-SVR12) after virologic failure was 5 months, which was shorter than the 14 months for R155 RAVs among GT-1a-infected non-SVR12 patients, suggesting that D168V is less fit than R155K in the absence of faldaprevir selective pressure.

FDG PET evaluation of mucinous neoplasms: correlation of FDG uptake with histopathologic features.

OBJECTIVE: Our goal was to assess the sensitivity of positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) for the detection of mucinous carcinoma and to determine the histologic features of these tumors that may affect lesion detectability. MATERIALS AND METHODS: A retrospective review of all patients with mucinous carcinoma who had undergone FDG PET at our institution from 1995 through 1998 identified 25 patients with new or recurrent mucinous carcinoma at the time of PET. In 22 of these patients, tissue specimens available from either core biopsy or surgical resection allowed detailed histologic analysis. RESULTS: FDG PET revealed mucinous carcinoma in only 13 (59%) of 22 patients, resulting in an unusually high percentage (41%) of false-negative results. Two histologic features were found to be predictive of FDG PET results: tumor cellularity (p = 0.011) and the amount of mucin within the tumor mass (p = 0.009). There was a positive correlation between tumor FDG uptake and cellularity but a negative correlation with the amount of mucin. CONCLUSION: FDG PET is limited in the evaluation of mucinous tumors, particularly in hypocellular lesions with abundant mucin.

Stereotaxic summation analysis of human cerebral benzodiazepine binding maps.

Summation analysis strategies are recognized throughout diverse scientific fields as powerful means of differentially enhancing experimental signals over random fluctuations (noise). Such techniques, applied to emission tomographic cerebral blood flow scans, reveal subtle alterations in neuronal activity during specific behavioral states. In the present work, we extend the principles of intersubject image summation analysis to the evaluation of emission tomographic ligand-binding studies. A general methodology is presented that may be applied to a wide variety of binding site determinations. The procedure consists of anatomic standardization of individual brains to a common stereotaxic orientation, followed by statistical analyses of group versus group or individual versus group differences. We develop and evaluate performance of our technique with the use of positron emission tomographic [11C]flumazenil scans from normal volunteers, depicting the regional cerebral distribution of benzodiazepine binding sites.

Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli.

1. To identify the forebrain and brain stem structures that are active during the perception of acute heat pain in humans, we performed H2 15O positron emission tomographic (PET) analyses of cerebral blood flow (CBF) on nine normal volunteers while they received repetitive noxious (50 degrees C) and innocuous (40 degrees C) 5 s heat pulses to the forearm (average resting temperature of 31.8 degrees C). Each subject rated the subjective intensity of each stimulation series according to a magnitude estimation procedure in which 0 = no heat sensation, 7 = barely painful, and 10 = barely tolerable. 2. Three scans were performed at each temperature. Mean CBF images were created for each experimental condition and oriented onto standardized stereotaxic coordinates. Subtraction images were created between conditions for each subject and averaged across subjects. Volumes of interest (VOI) were chosen, based on a priori hypotheses and the results of previously published PET studies. In addition, a separate statistical summation analysis of individual voxels was performed. Statistical thresholds were established with corrections for multiple comparisons. 3. Significant CBF increases to 50 degrees C stimuli were found in the contralateral thalamus, cingulate cortex, S2 and S1 cortex, and insula. The ipsilateral S2 cortex and thalamus, and the medial dorsal midbrain and cerebellar vermis also showed significant CBF increases. All subjects rated the 50 degrees C stimuli as painful (average subjective rating = 8.9 +/- 0.9 SD) and the 40 degrees C stimuli as warm, but not painful (average subjective rating = 2.1 +/- 1.0).(ABSTRACT TRUNCATED AT 250 WORDS)

Optimization of Butterworth filter for brain SPECT imaging.

A method has been described to optimize the cutoff frequency of the Butterworth filter for brain SPECT imaging. Since a computer simulation study has demonstrated that separation between an object signal and the random noise in projection images in a spatial-frequency domain is influenced by the total number of counts, the cutoff frequency of the Butterworth filter should be optimized for individual subjects according to total counts in a study. To reveal the relationship between the optimal cutoff frequencies and total counts in brain SPECT study, we used a normal volunteer and 99mTc hexamethyl-propyleneamine oxime (HMPAO) to obtain projection sets with different total counts. High quality images were created from a projection set with an acquisition time of 300-seconds per projection. The filter was optimized by calculating mean square errors from high quality images visually inspecting filtered reconstructed images. Dependence between total counts and optimal cutoff frequencies was clearly demonstrated in a nonogram. Using this nomogram, the optimal cutoff frequency for each study can be estimated from total counts, maximizing visual image quality. The results suggest that the cutoff frequency of Butterworth filter should be determined by referring to total counts in each study.

Automated detection of the intercommissural line for stereotactic localization of functional brain images.

A technique has been developed for automated detection of the intercommissural (AC-PC) line for positron emission tomography (PET). The AC-PC line is estimated from the location of four internal landmarks; the frontal and occipital poles, the inferior aspect of the anterior corpus callosum, and the subthalamic point. The landmarks are detected automatically in PET mid-sagittal slices by combining edge detection, interpolation and profile curve analysis techniques. The anatomical relationships between the true and estimated AC-PC lines from the landmarks was confirmed by analysis of magnetic resonance (MR) images. Accuracy of the automated estimation technique was assessed in co-registered PET and MR images, which showed minimal angular differences and displacements of the estimated from the true AC-PC lines. The automated detection of the AC-PC line in a PET study enables accurate stereotactic localization of functional signals without the need for additional anatomical imaging and provides a basis for objective and reproducible intersubject comparison.

An automated method for rotational correction and centering of three-dimensional functional brain images.

The display and analysis of functional brain images often benefit from head rotational correction and centering. An automated method was developed to align brain PET images into a standard three-dimensional orientation. The algorithm performs transverse and coronal rotational correction as well as centering of a brain image set. Optimal rotational correction and centering are determined by maximizing a bilateral hemispheric similarity index, the stochastic sign change criterion. Testing of this algorithm on simulated symmetrical brain image sets showed errors less than 1.0 degree and 0.5 pixels for rotational correction and centering, respectively. With actual PET data, the algorithm results correlated well with those obtained by visual inspection. Testing on asymmetrical brain image sets with simulated lesions indicated that performance of the algorithm is not sensitive to focal asymmetries. This automated method provides objective, reproducible image alignment into a standard orientation and facilitates subsequent data analysis techniques for functional brain images.

Comparison of oral feeding of peptide and amino acid meals to normal human subjects.

Intestinal perfusion studies performed in man have suggested that amino acid nitrogen may be absorbed more rapidly from peptides than free amino acids. The aim of the present study was to compare the effects of the oral administration of peptides and free amino acids. Two isonitrogenous liquid test meals, one containing 50 g of a partial enzymic hydrolysate of fish protein in which approximately 80% of the nitrogen content was present as small peptides (peptide meal), and the other a mixture of free amino acids (amino acid meal) the composition and molar pattern of which simulated that of the peptide meal, were administered on separate occasions to six normal subjects intubated with a triple lumen tube. Both meals contained the reference marker polyethylene glycol. Fractional absorption of amino acid residues one and two hours after ingestion of the two meals was similar at three intestinal locations situated 120, 160, and 200 cm from the mouth of each subject, and at two hours 73.8% and 72.0% of the amino acid residues had been absorbed respectively by the time the contents of the peptide and amino acid meals reached the middle sampling port of the tube. The total sum of individual amino acid increments in plasma was significantly greater 30 minutes (p < 0.025) and one hour (p < 0.05) after ingestion of the peptide than amino acid meals. By three hours the total area under the two plasma curves was similar. Normal human subjects thus appeared to be capable of assimilating orally administered mixtures of peptides and free amino acids with equal efficiency. Secretion of fluid into the lumen of the upper small intestine, assessed by reference to dilution of the polyethylene glycol, was less after ingestion of the peptide meal. In clinical situations characterised by fluid and electrolyte malabsorption consideration might be given to using small peptides rather than free amino acids as the nitrogen source in nutritional diets.