Prognostic Assessment of Interim F18-Fluorodeoxyglucose Positron Emission Tomography in Esophageal Cancer Treated With Chemoradiation With or Without Surgery.

Purpose This study aimed to evaluate if the F18-fluorodeoxyglucose positron emission tomography (F18-FDG PET) response after two weeks of chemoradiation for locoregionally advanced esophageal cancer (staged Tumor (T) 3 and/or Nodes (N)+ Metastases (M) 0) was linked to the pathologic response for patients undergoing surgery, to disease-free survival (DFS) or overall survival (OS). Materials and Methods Between March 2006 and September 2017, 40 patients were prospectively enrolled in our study, gave written consent, and had PET scans performed before treatment and after two weeks of chemoradiation. One patient did not undergo his two-week PET without informing study coordinators and was excluded from analyses. Results The median age at diagnosis was 62 years. Seventy-two percent of patients had N+ disease. Median OS for the entire group was 24 months. Five-year overall survival was 17%. Survival curves for patients with no PET response, minor PET response, or good PET response overlapped and were not statistically different. For the 25 patients who underwent surgery, the positive predictive value (PPV) of the PET response relative to the pathologic response was 75% and the negative predictive value (NPV) was 62%. In study patients, the crude recurrence rate was 68% and there was no correlation between PET response and DFS. Conclusion In our study, interim PET response after two weeks of chemoradiation for locoregionally advanced esophageal cancer was not predictive of outcome or pathologic response. Based on our data and current literature, interim PET should not be used to alter treatment (whether to escalate neo-adjuvant treatment or omit surgery).

Assessment of oritavancin serum protein binding across species.

Biophysical methods to study the binding of oritavancin, a lipoglycopeptide, to serum protein are confounded by nonspecific drug adsorption to labware surfaces. We assessed oritavancin binding to serum from mouse, rat, dog, and human by a microbiological growth-based method under conditions that allow near-quantitative drug recovery. Protein binding was similar across species, ranging from 81.9% in human serum to 87.1% in dog serum. These estimates support the translation of oritavancin exposure from nonclinical studies to humans.

Oritavancin disrupts membrane integrity of Staphylococcus aureus and vancomycin-resistant enterococci to effect rapid bacterial killing.

Oritavancin is an investigational lipoglycopeptide in clinical development for the treatment of acute bacterial skin and skin structure infections. In this study, we demonstrate that oritavancin causes bacterial membrane depolarization and permeabilization leading to cell death of Gram-positive pathogens and that these effects are attributable to the 4'-chlorobiphenylmethyl group of the molecule.

Impact of human serum albumin on oritavancin in vitro activity against enterococci.

Oritavancin is a lipoglycopeptide with activity against gram-positive pathogens including vancomycin-resistant enterococci. The impact of human serum albumin (HSA) on oritavancin activity against enterococci was compared to those of vancomycin, daptomycin, teicoplanin, and linezolid in vitro using MIC and time-kill methods. Oritavancin MICs increased between 0- and 8-fold in the presence of HSA. In time-kill assays with HSA, oritavancin retained activity, killing or inhibiting enterococci more rapidly than did comparators when peak concentrations were simulated.

Time-kill kinetics of oritavancin and comparator agents against Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium.

OBJECTIVES: Oritavancin, a lipoglycopeptide, possesses bactericidal activity against Gram-positive bacteria including vancomycin-resistant Staphylococcus aureus and enterococci. To understand the time dependence of oritavancin activity, we have undertaken time-kill experiments against isolates of S. aureus, Enterococcus faecalis and Enterococcus faecium, including recent antibiotic-resistant strains. METHODS: Six strains of S. aureus [methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA)] and five strains of enterococci [vancomycin-susceptible enterococci (VSE) and vancomycin-resistant enterococci (VRE; both VanA and VanB)] were tested in time-kill assays; oritavancin assays included 0.002% polysorbate-80 to ensure quantitative drug recovery. Oritavancin and comparators vancomycin, teicoplanin, linezolid and daptomycin were tested at static concentrations approximating their free peak (fC(max)) and free trough (fC(min)) in plasma when administered at standard doses for complicated skin and skin structure infections. RESULTS: Oritavancin showed concentration-dependent killing of all strains tested: at its fC(max) predicted from a 200 mg dose in humans, oritavancin exerted bactericidal activity (> or =3 log kill relative to starting inoculum) against MSSA, MRSA and VRSA within 1 h and against VSE between 11 and 24 h. At predicted fC(max) from an 800 mg dose, oritavancin was bactericidal against VISA strains at 24 h and against VRE at 10 h. CONCLUSIONS: Oritavancin displayed concentration-dependent killing of MSSA, MRSA, VRSA, VISA, VSE and VRE. Oritavancin was more rapidly bactericidal against all strains tested than were vancomycin, teicoplanin, linezolid or daptomycin at physiologically relevant concentrations. These data support the conclusion that oritavancin exerts concentration-dependent bactericidal activity on recent, drug-resistant isolates of S. aureus and enterococci.

Impact of intravenous insulin on 18F-FDG PET in diabetic cancer patients.

UNLABELLED: The aims of this study were to evaluate the effectiveness of a standardized insulin protocol in reducing glycemia, review (18)F-FDG biodistribution with such a protocol, and assess its clinical impact. METHODS: Sixty-three patients with glycemia greater than 10 mmol/L received insulin doses intravenously according to a standardized protocol. One hundred six consecutive euglycemic patients (<6.2 mmol/L) served as controls. (18)F-FDG biodistribution was evaluated by 2 experienced PET readers on a 5-point visual scale based on muscular uptake. The 63 patients who received insulin were divided into insulin subgroup A, with adequate biodistribution (score 0, 1, or 2) and insulin subgroup B, with altered biodistribution (score 3 or 4). 18F-FDG biodistribution was also evaluated semiquantitatively by standardized uptake value (SUV) measurements over the liver, gluteal muscles, and myocardium. Clinical impact (complications and diagnostic accuracy) was assessed by follow-up. RESULTS: Glycemia decreased from 13+/-2 to 7+/-2 mmol/L after insulin injection. Images showed significantly more muscular uptake in patients who received insulin than in the control group (scores 1.6+/-1.5 vs. 0.4+/-0.6, P<0.05). Twenty-five percent of insulin patients studied had altered biodistribution (insulin subgroup B). The two most important factors increasing muscular uptake were the time interval between insulin and 18F-FDG injection (mean in insulin subgroup A, 80.2+/-17 min; mean in insulin subgroup B, 65.7+/-10 min; P<0.01) and the glycemia interval decrease after insulin injection (mean in insulin subgroup A, 5.3+/-2.6 mmol/L; mean in insulin subgroup B, 7.6+/-1.8 mmol/L; P<0.01). In insulin subgroup B, mean hepatic SUV was lower (1.3+/-0.4 vs. 2.1+/-0.4, P<0.01) and mean muscular SUV was higher (1.8+/-0.1 vs. 0.9+/-0.01, P<0.01). Of the 63 patients who received insulin, 6 had hypoglycemia, but only 2 were symptomatic. No patient had severe complications causing permanent disability. CONCLUSION: A standardized protocol of intravenous insulin before 18F-FDG injection in diabetic cancer patients was safe and effective in reducing glycemia. Acceptable 18F-FDG biodistribution was obtained in 75% of patients receiving insulin. In addition to visually increased muscular uptake, low hepatic 18F-FDG uptake was a good indicator of altered biodistribution.

Vascular retinal biomarkers improves the detection of the likely cerebral amyloid status from hyperspectral retinal images.

INTRODUCTION: This study investigates the relationship between retinal image features and ß-amyloid (Aß) burden in the brain with the aim of developing a noninvasive method to predict the deposition of Aß in the brain of patients with Alzheimer's disease. METHODS: Retinal images from 20 cognitively impaired and 26 cognitively unimpaired cases were acquired (3 images per subject) using a hyperspectral retinal camera. The cerebral amyloid status was determined from binary reads by a panel of 3 expert raters on 18F-florbetaben positron-emission tomography (PET) studies. Image features from the hyperspectral retinal images were calculated, including vessels tortuosity and diameter and spatial-spectral texture measures in different retinal anatomical regions. RESULTS: Retinal venules of amyloid-positive subjects (Aß+) showed a higher mean tortuosity compared with the amyloid-negative (Aß-) subjects. Arteriolar diameter of Aß+ subjects was found to be higher than the Aß- subjects in a zone adjacent to the optical nerve head. Furthermore, a significant difference between texture measures built over retinal arterioles and their adjacent regions were observed in Aß+ subjects when compared with the Aß-. A classifier was trained to automatically discriminate subjects combining the extracted features. The classifier could discern Aß+ subjects from Aß- subjects with an accuracy of 85%. DISCUSSION: Significant differences in texture measures were observed in the spectral range 450 to 550 nm which is known as the spectral region known to be affected by scattering from amyloid aggregates in the retina. This study suggests that the inclusion of metrics related to the retinal vasculature and tissue-related textures extracted from vessels and surrounding regions could improve the discrimination performance of the cerebral amyloid status.

Non-invasive in vivo hyperspectral imaging of the retina for potential biomarker use in Alzheimer's disease.

Studies of rodent models of Alzheimer's disease (AD) and of human tissues suggest that the retinal changes that occur in AD, including the accumulation of amyloid beta (Aß), may serve as surrogate markers of brain Aß levels. As Aß has a wavelength-dependent effect on light scatter, we investigate the potential for in vivo retinal hyperspectral imaging to serve as a biomarker of brain Aß. Significant differences in the retinal reflectance spectra are found between individuals with high Aß burden on brain PET imaging and mild cognitive impairment (n = 15), and age-matched PET-negative controls (n = 20). Retinal imaging scores are correlated with brain Aß loads. The findings are validated in an independent cohort, using a second hyperspectral camera. A similar spectral difference is found between control and 5xFAD transgenic mice that accumulate Aß in the brain and retina. These findings indicate that retinal hyperspectral imaging may predict brain Aß load.

Chilaiditi sign on FDG-PET.

A 66-year-old woman with a history of endometrial cancer underwent a F-18 fluorodeoxyglucose positron emission tomography (FDG-PET). Abnormal uptake was noted in the right lower chest. CT scan showed a loop of colon interposed between the liver and the diaphragm, an entity known as the Chilaiditi sign. This case illustrates the importance to correlate abnormal PET findings with CT images. The Chilaiditi sign should be included in the differential diagnosis of lower chest uptake on an FDG-PET study.

False-positive "necklace sign" on whole-body thyroid cancer survey--a case report.

A woman with papillary thyroid carcinoma treated with surgery and postoperative 131I returned 4 y later for a whole-body survey. The imaging results initially suggested disease recurrence but were later found to be false positive and due to 131I uptake in a necklace that had been contaminated by the patient's saliva. This case stresses the importance of having the patient remove all jewelry before undergoing a radioiodine survey.

SUV varies with time after injection in (18)F-FDG PET of breast cancer: characterization and method to adjust for time differences.

UNLABELLED: The purpose of this study was to measure how (18)F-FDG PET standardized uptake values (SUVs) change over time in breast cancer and to examine the feasibility of a method to adjust for modest variations in the time of uptake measurement experienced in clinical practice. METHODS: (18)F-FDG PET was performed as 60-min dynamic imaging with an additional image acquired at approximately 75 min after injection. For 20 newly diagnosed, untreated, locally advanced breast cancer patients, both the maximum SUV and the average SUV within the lesion were calculated with and without correction for blood glucose concentration. A linear regression analysis of the portion of the time-activity curves starting at 27 min after injection was used to estimate the rate of SUV change per minute during the interval from 27 to 75 min. The rate of SUV change with time was compared with the instantaneous SUV obtained at different times from 27 to 75 min. RESULTS: In untreated breast cancer, (18)F-FDG SUV values changed approximately linearly after 27 min at a rate ranging from -0.02 to 0.15 per minute. In addition, the rate of SUV change was linearly correlated with the instantaneous SUV measured at different times after injection (r(2) ranged from 0.82 to 0.94; P < 0.001). Using this information, an empirical linear model of SUV variation with time from injection to uptake measurement was formulated. The comparison method was then applied prospectively to a second set of 20 locally advanced breast cancer lesions not included in the initial analysis. The average percent error using the method to adjust for time differences was 8% and 5% for maximum SUVs and average SUVs ranging from 2 to 12. CONCLUSION: In untreated breast cancer, the SUV at any time point approximately predicts the rate of change of SUV over time. A comparison method based on this finding appears feasible and may improve the usefulness of the SUV by providing a means of comparing SUV acquired at different times after injection.

¹8F-FDG-PET imaging in radiotherapy tumor volume delineation in treatment of head and neck cancer.

PURPOSE: To determine the impact of (18)F-fluorodeoxyglucose positron emission tomography (PET) in radiotherapy target delineation and patient management for head and neck squamous cell carcinoma (HNSCC) compared to computed tomography (CT) alone. MATERIALS AND METHODS: Twenty-nine patients with HNSCC were included. CT and PET/CT obtained for treatment planning purposes were reviewed respectively by a neuroradiologist and a nuclear medicine specialist who were blinded to the findings from each other. The attending radiation oncologist together with the neuroradiologist initially defined all gross tumor volume of the primary (GTVp) and the suspicious lymph nodes (GTVn) on CT. Subsequently, the same radiation oncologist and the nuclear medicine specialist defined the GTVp and GTVn on (18)F-FDG-PET/CT. Upon disagreement between CT and (18)F-FDG-PET on the status of a particular lymph node, an ultrasound-guided fine needle aspiration was performed. Volumes based on CT and (18)F-FDG-PET were compared with a paired Student's t-test. RESULTS: For the primary disease, four patients had previous diagnostic tonsillectomy and therefore, FDG uptake occurred in 25 patients. For these patients, GTVp contoured on (18)F-FDG-PET (GTVp-PET) were smaller than the GTVp contoured on CT (GTVp-CT) in 80% of the cases, leading to a statistically significant volume difference (p=0.001). Of the 60 lymph nodes suspicious on PET, 55 were also detected on CT. No volume change was observed (p=0.08). Ten biopsies were performed for lymph nodes that were discordant between modalities and all were of benign histology. Distant metastases were found in two patients and one had a newly diagnosed lung adenocarcinoma. CONCLUSIONS: GTVp-CT was significantly larger when compared to GTVp-PET. No such change was observed for the lymph nodes. (18)F-FDG-PET modified treatment management in three patients, including two for which no curative radiotherapy was attempted. Larger multicenter studies are needed to ascertain whether combined (18)F-FDG-PET/CT in target delineation can influence the main clinical outcomes.

Impact of human serum albumin on oritavancin in vitro activity against Staphylococcus aureus.

Human serum albumin (HSA) did not affect oritavancin MICs against non-vancomycin-intermediate Staphylococcus aureus (non-VISA) strains. In time-kill assays, oritavancin bactericidal activity in the presence of HSA was significantly more rapid than comparators against non-VISA strains. HSA increased oritavancin MICs by 4-fold for VISA strains, reflective of reduced oritavancin activity in time-kill assays with HSA.

Time-kill kinetics of oritavancin and comparator agents against Streptococcus pyogenes.

The activity of oritavancin in vitro against recent clinical isolates of Streptococcus pyogenes, including antibiotic-resistant strains, was characterised by determination of broth microdilution minimal inhibitory concentrations as well as time-kill assays. Ten clinical isolates of S. pyogenes, three of which were resistant to erythromycin, as well as one reference S. pyogenes strain were tested. In the time-kill assays, oritavancin and the comparators vancomycin, teicoplanin, linezolid, penicillin, erythromycin and daptomycin were tested at static concentrations approximating their free peak (fC(max)) and free trough (fC(min)) concentrations in plasma when administered at approved doses for skin and skin-structure infections. At its fC(max) predicted from a 200 mg dose in humans, oritavancin exerted bactericidal activity (> or = 3 log kill relative to the starting inoculum) within 15 min to 3 h against all tested strains. Daptomycin exhibited bactericidal activity at its fC(max) for all but one strain; time to cidality was between 15 min and 6 h. At fC(min), only oritavancin was bactericidal against all the tested strains. Oritavancin displayed concentration-dependent killing of all isolates in vitro. Oritavancin was more rapidly bactericidal than the comparators at physiologically relevant concentrations against all strains tested. These data support the potential utility of oritavancin in infections with contemporary isolates of S. pyogenes, including drug-resistant strains.

Positron emission tomography of schwannomas: emphasizing its potential in preoperative planning.

OBJECTIVE: In this article, we describe FDG uptake in schwannoma as measured on positron emission tomography (PET). FDG uptake is compared with tumor cellularity, tumor size, and tumor proliferation rate (Ki-67 index). CONCLUSION: Schwannomas generally have a high tumor-to-background ratio on FDG PET. Semiquantitative analysis with standardized uptake values (SUVs) reveals a wide variation in SUVs that can be explained by variations in the degree of cellularity. No correlation was found between FDG uptake and tumor size or tumor proliferation rate (Ki-67 index). Because these tumors often have a high level of FDG uptake, distinguishing schwannomas from malignant peripheral nerve sheath tumors before biopsy or surgery is not possible. Even in cases in which the maximum SUV or average SUV is greater than 6.0, schwannomas cannot be excluded. Therefore, schwannoma should be included in the differential diagnosis of peripheral nerve sheath tumors with low, intermediate, or high SUVs.