Gary T. Smith

Differentiating benign from malignant lung lesions using quantitative parameters of FDG PET images

UNLABELLEDnFluorine-18 labeled deoxyglucose positron-emission tomography (FDG-PET) applications in oncology include the differential diagnosis of chest masses and single pulmonary nodules. However, FDG is not tumor-specific; rather, it also accumulates in inflammatory processes. This study was performed to identify image parameters that would improve the specificity of PET.nnnMETHODSnTwenty-six patients who had benign and malignant lung lesions were examined retrospectively. Positron-emission tomography data were acquired in dynamic scanning mode after intravenous bolus of 250-402 MBq of FDG. Standardized uptake values (SUVs) were calculated and Patlak analyses were performed in selected regions of interest in the PET images. Positron-emission tomography results were related to histological diagnosis (N = 49) or clinical follow-up (N = 3).nnnRESULTSnThe specificity and sensitivity of the original PET scan reports, which was based on visual image interpretation and loosely applied SUVs, was 100% and 73%, respectively. Using the SUVs with a cut-off value of 3.8 and Kpat value with a cut-off at 0.025 min-1 improved the specificity to 81% and 85%.nnnCONCLUSIONnFDG-PET image interpretation can be facilitated by using SUV information or the accumulation rate of the radiotracer (Patlak). With additional validation, this method could have a significant cost-effective impact on the medical/surgical management of chest masses.

Effects of eicosapentaenoic and γ-linolenic acid on lung permeability and alveolar macrophage eicosanoid synthesis in endotoxic rats

OBJECTIVESnProinflammatory eicosanoids (cyclooxgenase and lipoxygenase metabolites of arachidonic acid) released by alveolar macrophages play an important role in endotoxin-induced acute lung injury. We investigated the effect of prefeeding rats for 21 days with enteral diets that provided the anti-inflammatory fatty acids, eicosapentaenoic acid and gamma-linolenic acid (derived from fish oil and borage oil, respectively), as compared with an n-6 fatty acid-enriched diet (corn oil) on the following: a) lung microvascular protein permeability, arterial blood pressure, and platelet and white blood cells in a model of endotoxin-induced acute lung injury; b) alveolar macrophage prostaglandin and leukotriene synthesis; and c) liver and alveolar macrophage phospholipid fatty acid composition.nnnDESIGNnProspective, randomized, controlled, double-blind study.nnnSETTINGnResearch laboratory at a university medical center.nnnSUBJECTSnMale Long-Evans rats, weighing 250 g.nnnINTERVENTIONSnRats were randomized into four dietary treatment groups and fed nutritionally complete diets (300 kcal/kg/day), containing 55.2% of the total calories from fat with either 97% corn oil, 20% fish oil, 20% fish and 5% borage oil, or 20% fish and 20% borage oil for 21 days. On day 22, lung microvascular protein permeability, mean arterial pressure, and platelet and white blood cell counts were determined for 2 hrs after an intravenous injection of Salmonella enteritidis endotoxin (10 mg/kg). In a second group of prefed rats, the phospholipid fatty acid composition was determined in liver and alveolar macrophages. Alveolar macrophages were harvested by bronchoalveolar lavage and stimulated in vitro with a calcium ionophore (A23187), and the concentrations of leukotrienes B4 and B5, thromboxane A2, prostaglandin E2, and 6-keto-prostaglandin F1 alpha were measured in a third group of prefed rats.nnnMEASUREMENT AND MAIN RESULTSnLung permeability was greatest with corn oil and was significantly attenuated with 20% fish oil and 20% fish and 5% borage oil, and this effect approached significance with 20% fish and 20% borage oil (p = .06). The early and late hypotensive effects of endotoxin were attenuated with 20% fish oil, 20% fish and 5% borage oil, and 20% fish and 20% borage oil, as compared with corn oil. Concentrations of leukotriene B4, prostaglandin E2, and thromboxane B2 released from A23187-stimulated alveolar macrophages were significantly lower with 20% fish oil and 20% fish and 20% borage oil, as compared with corn oil. The increase in lung microvascular protein permeability with 20% fish and 20% borage oil was not significantly different than the lung microvascular protein permeability that was found in animals receiving 20% fish oil (p = .20) and 20% fish and 5% borage oil (p = .31). Alveolar macrophage and liver phospholipid concentrations of arachidonic acid were lower, and the concentrations of eicosapentaenoic acid and docosahexaenic acid were higher, with 20% fish oil, and 5% borage oil, and 20% fish and 20% borage oil, as compared with corn oil. Dihomo-gamma-linolenic acid, the desaturated and elongated intermediate of gamma-linolenic acid, was increased with 20% fish and 20% borage oil, as compared with 20% fish oil and 20% fish and 5% borage oil.nnnCONCLUSIONSnThe severity of pulmonary microvascular protein permeability and the degree of hypotension were reduced with fish or fish and borage oil diets, as compared with corn oil, in endotoxic rats. The reduced synthesis of the proinflammatory arachidonic acid-derived mediators, leukotriene B4, thromboxane B2, and prostaglandin E2 from stimulated alveolar macrophages was indicative of a decrease in arachidonic acid and an increase in eicosapentaenoic acid and docosahexaenoic acid in cell membrane phospholipids.

Radioimmunodetection of amyloid deposits in patients with AL amyloidosis

Care of patients with AL amyloidosis currently is limited by the lack of objective means to document disease extent, as well as therapeutic options that expedite removal of pathologic deposits. To address these issues, we have initiated a Phase I Exploratory IND study to determine the biodistribution of the fibril-reactive, amyloidolytic murine IgG1 mAb 11-1F4 labeled with I-124. Patients were infused with less than 1 mg (∼ 74 MBq) of GMP-grade antibody and imaged by PET/CT scan 48 and 120 hours later. Among 9 of 18 subjects, there was striking uptake of the reagent in liver, lymph nodes, bone marrow, intestine, or, unexpectedly, spleen (but not kidneys or heart). Generally, positive or negative results correlated with those obtained immunohistochemically using diagnostic tissue biopsy specimens. Based on these findings, we posit that (124)I-mAb m11-1F4 can be used to identify AL candidates for passive immunotherapy using the chimeric form of the antibody.

Improved treatment planning for boron neutron capture therapy for glioblastoma multiforme using fluorine-18 labeled boronophenylalanine and positron emission tomography

Boron neutron capture therapy (BNCT) is a cancer brachytherapy based upon the thermal neutron reaction: 10B(n,alpha)7Li. The efficacy of the treatment depends primarily upon two conditions being met: (a) the preferential concentration of a boronated compound in the neoplasm and (b) an adequate fluence of thermal neutrons delivered to the neoplasm. The boronated amino acid, para-boronophenylalanine (BPA), is the agent widely used in clinical trials to deliver 10B to the malignancy. Positron emission tomography (PET) can be used to generate in vivo boron distribution maps by labeling BPA with the positron emitting nuclide fluorine-18. The incorporation of the PET-derived boron distribution maps into current treatment planning protocols is shown to provide improved treatment plans. Using previously established protocols, six patients with glioblastoma had 18BPA PET scans. The PET distribution maps obtained were used in the conventional BNCT treatment codes. The isodose curves derived from the PET data are shown to differ both qualitatively and quantitatively from the conventional isodose curves that were derived from calculations based upon the assumption of uniform uptake of the pharmaceutical in tumor and normal brain regions. The clinical course of each of the patients who eventually received BNCT (five of the six patients) was compared using both sets of isodose calculations. The isodose contours based upon PET derived distribution data appear to be more consistent with the patients clinical course.

Detection of overexpressed COX-2 in precancerous lesions of hamster pancreas and lungs by molecular imaging: implications for early diagnosis and prevention

The enzyme cyclooxygenase‐2 (COX‐2) is overexpressed in many cancers, cardiovascular disease, neurodegenerative disorders, and arthritis. Selective inhibitors of COX‐2 have been developed as therapeutics or preventive agents for these diseases. However, recent reports have revealed a significant increase in cardiovascular mortality in long‐term users of the COX‐2 inhibitors Vioxx and Celebrex, emphasizing the need for noninvasive tests that allow the identification of individuals whose COX‐2 levels are overexpressed prior to assignment to treatment with these drugs. In this study, we have prepared a radioiodinated analogue of the selective COX‐2 inhibitor celecoxib, and verified its binding to the COX‐2 enzyme inu2005vitro. Biodistribution studies in hamsters demonstrated significantly higher levels of radiotracer in animals treated with the tobacco carcinogen NNK in lung, pancreas, and liver. Assessment of COX‐2 levels by whole‐body planar nuclear imaging two hours after injection of the radiotracer was suggestive of a distinct increase in COX‐2 in the pancreas and liver of a hamster treated for 10 weeks with NNK, in the lungs and liver of a second animal, and in the liver only, in two additional animals from the same treatment group. Immunostains showed selective overexpression of COX‐2 in pre‐neoplastic lesions of the pancreas and lungs in only those animals that showed tracer accumulation in these organs and in the livers of all NNK‐treated hamsters. Immunostains for COX‐1 yielded detectable reactions in the intestinal epithelium but not in pancreas, lungs, or liver, supporting the specificity of the tracer for COX‐2. Our data provide proof of principle for the hypothesis that molecular imaging with radiolabeled COX‐2 inhibitors can be used for the noninvasive monitoring of overexpressed COX‐2 levels.

Linear least squares compartmental-model-independent parameter identification in PET

A simplified approach involving linear-regression straight-line parameter fitting of dynamic scan data is developed for both specific and nonspecific models. Where compartmental-model topologies apply, the measured activity may be expressed in terms of: its integrals, plasma activity and plasma integrals-all in a linear expression with macroparameters as coefficients. Multiple linear regression, as in spreadsheet software, determines parameters for best data fits. Positron emission tomography (PET)-acquired gray-matter images in a dynamic scan are analyzed: both by this method and by traditional iterative nonlinear least squares. Both patient and simulated data were used. Regression and traditional methods are in expected agreement. Monte-Carlo simulations evaluate parameter standard deviations, due to data noise, and much smaller noise-induced biases. Unique straight-line graphical displays permit visualizing data influences on various macroparameters as changes in slopes. Advantages of regression fitting are: simplicity, speed, ease of implementation in spreadsheet software, avoiding risks of convergence failures or false solutions in iterative Least squares, and providing various visualizations of the uptake process by straight line graphical displays. Multiparameter model-independent analyses on lesser understood systems is also made possible.

Fluorine-18 Fluorodeoxyglucose Accumulation in Blastomyces dermatitidis-Associated Inflammation in a Dog.

Whole-body positron emission tomography (PET) imaging with fluorine-18 fluorodeoxyglucose (F-18 FDG) was performed in a dog with blastomycosis. Prior to PET scanning, blastomycotic lesions had been identified in both eyes, lungs, and tracheobronchial lymph nodes. Increased F-18 FDG uptake was present in these sites in addition to multiple organs without previous clinical evidence of disease. All sites of F-18 FDG uptake were confirmed histologically to be blastomycotic granulomas. F-18 FDG-PET scanning may be useful for defining the extent of fungal disease and detecting persistent foci of infection.

2-Deoxy-2-[F-18]fluoro-d-glucose-Positron Emission Tomography Sensitivity to Serum Glucose: A Survey and Diagnostic Applications

ObjectiveThe positron emission tomography (PET) clinical utility of the sensitivity (γ) of uptake (Q) to a change in plasma glucose concentration (C) is investigated.Methodsγ is obtained from data as [ln(Q2/Q1)] / [ln(C2 / C1)], using previously published intrapatient studies varying C within a single patient and some interpatient ones. It can be theoretically related to the half-saturation constant in the Michaelis–Menten quantification of competitive uptake. One of its uses is making uptake corrections for desired vs. actual C using

Standardized uptake value and influx. Constant: relationships and variabilities, with: Model interpretation and clinical implications

Q_{2} = Q_{1} {left( {{C_{2} } mathord{left/ {vphantom {{C_{2} } {C_{1} }}} right. kern-nulldelimiterspace} {C_{1} }} right)}^{gamma } .