Beta-2-adrenoceptor agonists as inhibitors of lung vascular permeability to radiolabelled transferrin in the adult respiratory distress syndrome in man

Increased lung vascular permeability leading to increased plasma protein extravasation and accumulation (PPA) is a characteristic feature of acute lung injury. Using a previously described technique, PPA was monitored in the lungs of patients with the adult respiratory distress syndrome (ARDS)--an extreme example of acute lung injury in man. An external radiation probe detector was used to monitor the pulmonary accumulation of the plasma protein transferrin radiolabelled in-vivo with 113mIn. Ten patients with ARDS exhibiting increased PPA indices (greater than 1.0 x 10(-3)/min) were given an intravenous infusion of terbutaline (7 micrograms/kg) over 30 min. Of the four patients in whom the post-drug PPA indices remained within the ARDS range, none survived, whilst five of the six patients in whom the post-drug PPA indices were reduced to below 1.0 x 10(-3)/min survived. PPA indices prior to the administration of terbutaline were not significantly different between the survivor (n = 5) and non-survivor (n = 5) groups. There was a significant decrease in the PPA indices following terbutaline in survivors (p less than 0.01) but not in non-survivors. Thus beta-2-agonists in therapeutic doses can inhibit increased lung vascular permeability in man. These findings may have prognostic and therapeutic implications for beta-2-agonists in ARDS.     

Assessment of alveolar epithelial permeability in Behçet’s disease with <Superscript>99m</Superscript>Tc-DTPA aerosol scintigraphy

Objective

Behçet’s disease (BD) is a multisystem disorder characterized by vasculitis, and consists of a triad of recurrent ulcers of the oral and genital mucosa with relapsing uveitis. The prevalance of pulmonary involvement varies in the range of 1–10% in various studies and its complications are severe and life threatening. In this study, we investigated the changes of pulmonary epithelial permeability of patients with BD using technetium-99m diethylene triamine penta-acetic acid (^99mTc-DTPA) aerosol scintigraphy, so as to begin the therapy regimen as soon as possible.

Methods

Twenty-one nonsmoking patients with BD (8 women, 13 men; mean age 38.67 ± 8.86 years) and 15 healthy volunteer nonsmoking controls (8 women, 7 men; mean age 50.87 ± 12.45 years) underwent ^99mTc-DTPA aerosol inhalation scintigraphy and pulmonary function tests (PFTs). Subjects inhaled 1480 MBq of ^99mTc-DTPA for 4 min in the supine position. Scintigraphic data were recorded dynamically (1 frame/min) in the posterior projection on a 64 × 64 matrix for a 30-min period using a double-headed gamma camera (Infinia, GE, Tirat Hacarmel, Israel) equipped with a low-energy all-purpose parallel hole collimator. Half time of ^99mTc-DTPA clearance (T _1/2) was calculated by placing a mono-exponential fit on the curves. Penetration index (PI) was also calculated by dividing the peripheral total counts by the sum of the peripheral and central total counts on the first minute image, in order to quantify the distribution of the inhaled aerosol.

Results

The clearance half time of ^99mTc-DTPA radioaerosols in the BD patients (24.81 ± 6.22 min) was faster than in the normal control group (46.53 ± 22.41 min) (P = 0.004). There was also a significant difference between PI of the patients with BD (0.15 ± 0.03) and that of the controls (0.21 ± 0.06) (P = 0.002). No correlation was found between the mean T _1/2 values of ^99mTc-DTPA clearance or the spirometric measurements in the BD patients. Penetration indices were not correlated with PFT in the BD patients.

Conclusions

Lung epithelial permeability of the patients with BD was significantly higher than that of the normal subjects. The results of this study demonstrated that the assessment of lung epithelial permeability using ^99mTc-DTPA aerosol scintigraphy could predict the presence of lung involvement in the early stages of BD.

     

131I-metaiodobenzylguanidine uptake in the isolated rat lung: A potential marker of endothelial cell function

The pulmonary vascular endothelial cell plays an important role in the uptake of circulating biogenic amines. In cultured adrenomedullary cells, metaiodobenzylguanidine (MIBG) and norepinephrine (NE) are taken up by the same sodium-dependent active transport system. To examine whether a similar process occurs in the lung, the mechanism of single pass ¹³¹I-MIBG accumulation was studied in rat lungs perfused with a Krebs-Ringer bicarbonate buffer containing 4.5% bovine albumin. MIBG lung accumulation was measured as the percent extraction per g of lung tissue. In control experiments the extraction was 19.7±2.3%/g (n=38) using a perfusate containing 0.01 M MIBG. MIBG accumulation was significantly depressed (% decrease from control) by: cold media at 4° C (84%), 0.5 mM ouabain (67%), 10 M imipramine (70%), 0.7 M serotonin (22%) and 40 mM K⁺ (48%). Pulmonary uptake of MIBG was characterized by Michaelis-Menten kinetics (K _m=0.92×10^-6 M and V _max=2.09×10^-9 moles/g per min). The addition of NE (0.5 M) also altered MIBG uptake such that the K _m and V _max became 0.52×10^-6 M and 0.93×10^-9 moles/g per min, respectively. The results indicate that MIBG accumulation in the lung involves sodium-dependent, energy-requiring, active transport mechanisms similar to those known to exist for norepinephrine, and suggest that MIBG may be useful as a marker of pulmonary endothelial cell function.     

99mTc-sestamibi thyroid uptake in euthyroid individuals and in patients with autoimmune thyroid disease

Purpose We investigated the biokinetics of ^99mTc-sestamibi in the thyroid of euthyroid volunteers (EVs) and in patients with autoimmune thyroid diseases and determined the best time interval between ^99mTc-sestamibi injection and calculation of uptake.Methods Forty EVs, 30 patients with Graves disease (GD), 15 patients with atrophic Hashimotos thyroiditis (AHT) and 15 patients with hypertrophic Hashimotos thyroiditis (HHT) underwent ^99mTc-sestamibi thyroid scintigraphy. Dynamic images were acquired for 20 min, and static images were obtained 20 min, 60 min and 120 min post injection. Five-, 20-, 60- and 120-min uptake, time to maximal uptake (T_max) and T_1/2 of tracer clearance were calculated. Thyroid hormones and antibodies were measured. ^99mTc-pertechnetate uptake was investigated in GD patients.Results T_max was approximately 5 min in all four groups. The mean T_1/2 value for EVs was similar to the GD value and lower than the HHT and AHT values. The mean (±SD) 5-min uptake was 0.13% (±0.05%) for EVs. The 5-min uptake in GD was higher than that in EVs(P<0.001) and correlated with free thyroxine (r=0.54) and with ^99mTc-pertechnetate uptake (r=0.68). Uptake in HHT was higher than that in AHT (P=0.0003) and EVs (P=0.002). Uptake in AHT was lower than uptake in EVs (P=0.0001).Conclusion Five minutes is the optimal time interval between ^99mTc-sestamibi injection and calculation of thyroid uptake. Five-minute uptake differentiates euthyroid individuals from GD patients. There is a high correlation between ^99mTc-sestamibi and ^99mTc-pertechnetate uptake in GD. The reduced ^99mTc-sestamibi uptake in AHT patients is probably due to glandular destruction and fibrosis. Inflammatory infiltrate and high mitochondrial density in thyrocytes possibly explain the increased uptake in GD and HHT.     

Comparison of methodologies for the in vivo assessment of <Superscript>18</Superscript>FLT utilisation in colorectal cancer

Fluorine-18 3-deoxy-3-fluorothymidine (¹⁸FLT) is a tissue proliferation marker which has been suggested as a new tumour-specific imaging tracer in positron emission tomography (PET). The objectives of this study were to investigate the pharmacokinetics of ¹⁸FLT in patients with colorectal cancer, defining methodologies for the quantitative analysis of the in vivo ¹⁸FLT uptake and subsequently assessing the accuracy of semi-quantitative measures. Dynamic acquisitions over a single field of view of interest identified by computed tomography were carried out for up to 60 min following injection of ¹⁸FLT (360±25 MBq). Dynamic arterial blood sampling was carried out in order to provide a blood input function. Simultaneous venous samples were also taken in order to investigate their potential utilisation in deriving a hybrid input function. Arterial and venous blood samples at 5, 15, 30, 60 and 90 min p.i. were used for metabolite analysis. Eleven patients with primary and/or metastatic colorectal cancer were studied on a lesion by lesion basis (n=21). All acquired images were reconstructed using ordered subsets expectation maximisation and segmented attenuation correction. Time-activity curves were derived by image region of interest (ROI) analysis and image-based input functions were obtained using abdominal or thoracic aorta ROIs. Standardised uptake values (SUVs) were calculated to provide semi-quantitative indices of uptake, while non-linear regression (NLR) methodology in association with a three-compartment model and Patlak analysis were carried out to derive the net influx constant K _i . The metabolite analysis revealed two radioactive metabolites, with the parent compound representing ~80% of the total radioactivity in the 30-min plasma sample. In the case of NLR, better fits were obtained with a 3k model (i.e. k ₄=0) for both lesion and bone marrow time-activity curves. For the same lesions, a high correlation was observed between the K _i derived from either Patlak analysis or NLR(3k) and the corresponding SUVs. Our results also suggest that the quantitative behaviour of ¹⁸FLT in vivo (up to 60 min p.i.) may be characterised using a 3k model or Patlak analysis in combination with image-derived input functions. The good correlation found between the SUVs (at 60 min) and K _i values supports the use of semi-quantitative indices to assess the proliferation rate of colorectal cancer lesions in vivo with ¹⁸FLT.The work included in this paper was selected for consideration in the Marie-Curie award during the European Association of Nuclear Medicine 2002 meeting in Vienna.     

PET/CT-guided percutaneous biopsy of FDG-avid metastatic bone lesions in patients with advanced lung cancer: a safe and effective technique

Purpose

¹⁸F-FDG PET/CT should be performed before a diagnostic biopsy site is chosen in patients with a high clinical suspicion of aggressive, advanced tumour. The aim of this study was to evaluate the safety and efficacy of ¹⁸F-FDG PET/CT in guiding biopsy of bone metastases in patients with advanced lung cancer.

Methods

PET/CT-guided percutaneous core biopsies were performed in 51 consecutive patients with suspected lung cancer and ¹⁸F-FDG-avid bone lesions after whole-body ¹⁸F-FDG PET/CT scans. Generally, one tissue sample was obtained from each patient. The final diagnoses were established on the basis of the histology results. The histopathological and molecular testing results were systematically evaluated.

Results

A total of 53 samples were obtained for histological examination or molecular testing as a second biopsy was required in two patients in whom the pathological diagnosis was unclear following the first biopsy. The pathological diagnosis and lung cancer classification were confirmed in 48 patients. The epidermal growth factor receptor mutation status was determined in 23 biopsies, and the mutation rate was 30.4 % (7/23). The anaplastic lymphoma kinase mutation status was determined in 19 biopsies, and the mutation rate was 31.6 % (6/19). Two of the 51 biopsies were positive for non-Hodgkin’s lymphoma and one was positive for metastatic renal cell carcinoma. The first-time diagnostic success rate of biopsy was 96.1 % (49/51) and the overall diagnostic success rate and sensitivity were 100 %. All 51 patients were eventually confirmed as having stage IV disease. No serious complications were encountered and the average biopsy time was 30 min.

Conclusion

PET/CT-guided percutaneous biopsy of ¹⁸F-FDG-avid bone metastases is an effective and safe method that yields a high diagnostic success rate in the evaluation of hypermetabolic bone lesions in patients with suspected advanced lung cancer.

     

Can MRI Visual Assessment Differentiate the Variants of Primary-Progressive Aphasia?

BACKGROUND AND PURPOSE:Primary-progressive aphasia is a clinically and pathologically heterogeneous condition. Nonfluent, semantic, and logopenic are the currently recognized clinical variants. The recommendations for the classification of primary-progressive aphasia have advocated variant-specific patterns of atrophy. The aims of the present study were to evaluate the sensitivity and specificity of the proposed imaging criteria and to assess the intra- and interrater reporting agreements.MATERIALS AND METHODS:The cohort comprised 51 patients with a root diagnosis of primary-progressive aphasia, 25 patients with typical Alzheimer disease, and 26 matched control participants. Group-level analysis (voxel-based morphometry) confirmed the proposed atrophy patterns for the 3 syndromes. The individual T1-weighted anatomic images were reported by 3 senior neuroradiologists.RESULTS:We observed a dichotomized pattern of high sensitivity (92%) and specificity (93%) for the proposed atrophy pattern of semantic-variant primary-progressive aphasia and low sensitivity (21% for nonfluent-variant primary-progressive aphasia and 43% for logopenic-variant primary-progressive aphasia) but high specificity (91% for nonfluent-variant primary-progressive aphasia and 95% for logopenic-variant primary-progressive aphasia) in other primary-progressive aphasia variants and Alzheimer disease (sensitivity 43%, specificity 92%). MR imaging was least sensitive for the diagnosis of nonfluent-variant primary-progressive aphasia. Intrarater agreement analysis showed mean κ values above the widely accepted threshold of 0.6 (mean, 0.63 ± 0.16). Pair-wise interobserver agreement outcomes, however, were well below this threshold in 5 of the 6 possible interrater contrasts (mean, 0.41 ± 0.09).CONCLUSIONS:While the group-level results were in precise agreement with the recommendations, semantic-variant primary-progressive aphasia was the only subtype for which the proposed recommendations were both sensitive and specific at an individual level.

Primary-progressive aphasia (PPA) is a clinically and pathologically heterogeneous condition characterized by insidious onset and gradual worsening of language due to degeneration of brain language areas. Clinical heterogeneity, compounded by the evolution of signs and symptoms, makes accurate classification of patients a challenging task. Making a reliable clinical diagnosis, on the other hand, is important. Despite lack of a one-to-one relationship between the clinical diagnosis and the underlying pathology, previous clinicopathologic series have identified probabilistic associations among the 3 recognized clinical presentations of PPA and certain pathologies. There are established associations between semantic-variant PPA (svPPA) and frontotemporal lobar degeneration–TAR DNA binding protein 43 (TDP-43); nonfluent-variant PPA (nfvPPA) and frontotemporal lobar degeneration-tau; and logopenic-variant PPA (lvPPA) and Alzheimer pathology.^1–5The recommendations on clinical subtyping of PPA have proposed that clinical classification can be supported by imaging according to the pattern of regional atrophy or metabolic impairment.⁶ Left posterior frontoinsular atrophy in nfvPPA, anterior temporal atrophy in svPPA, and left posterior peri-Sylvian or parietal atrophy in lvPPA are the recommended atrophy patterns. Remarkably, these imaging recommendations are derived from studies that either used group-averaged data—which though highly replicated,^7–10 are not necessarily valid for single-patient diagnosis—or were based on observed atrophy in convenience samples^9–14 without qualification of sensitivity, specificity, or reliability. Little is known about whether individual patients, as opposed to groups, fulfilling the clinical criteria for these variants reliably present with the prescribed patterns of atrophy and whether these patterns have sufficient reliability to be exploited to arrive at an accurate syndromic diagnosis.The aims of the present study were the following: 1) to evaluate the utility of the proposed imaging criteria for the diagnosis of PPA variants by contrasting the patterns of atrophy in individual patients with PPA, as reported by senior neuroradiologists, with the recommendations from the criteria; and 2) to assess the neuroradiologists'' intra- and interrater agreement, which, in turn, would be an indication of the robustness of the observed abnormalities.     

Estimation of glomerular filtration rate and technetium-99m diethylene triamine penta-acetic acid using chromium-51 ethylene diamine tetra-acetic acid

Simultaneous measurements of the clearance rate of chromium-51 ethylene diamine tetra-acetic acid (⁵¹Cr-EDTA) and technetium-99m diethylene triamine penta-acetic acid (^99mTc-DTPA) were performed in 54 patients with a range of function between 9 and 176 ml/min. Using multiple blood samples the two clearance values correlated well (r = 0.97, SEE 8.6 ml/min) and DTPA clearance was higher by 2.9%. For each radiopharmaceutical the plasma clearance rates obtained using multiple blood samples were compared with those obtained with simplified methods, i.e., the 60–180 min two-sample method of Russell and the mono-exponential method with the Brochner-Mortensen correction. For both radiopharmaceuticals the clearance values correlated well with the Russell method (r = 0.99, SEE = 4.1 ml/min for EDTA;r = 0.99, SEE 4.9 ml/min for DTPA) and the mono-exponential method (r = 0.99, SEE 3.6 ml/min for EDTA;r = 0.99, SEE 3.9 ml/min for DTPA). The mean plasma clearance obtained using multiple blood samples did not differ significantly from that obtained with the Russell method, either in patients with a glomerular filtration rate (GFR)<30 ml/min or in patients with GFR30 ml/min. The mean plasma clearance obtained using multiple blood samples differed significantly from that obtained with the mono-exponential method because of the great difference observed in patients with GFR30 ml/min. It is concluded that the Russell two-sample method after injection of^99mTc-DTPA is accurate enough for routine clinical use.     

Comparison of radiographic infiltration versus pulmonary function in severely traumatized patients with and without adult respiratory distress syndrome: Correlation of lung structure and function

Lung structural changes were evaluated by radiographic infiltration and compared with functional changes by pulmonary venous admixture or shunt ( ) and blood gases (PaO₂/FiO₂ ratio, which is the ratio of arterial oxygen tension to oxygen concentration of inspired gas) in 70 consecutive severely traumatized patients. Of these, 36 (51%) developed adult respiratory distress syndrome (ARDS) by clinical and physiologic criteria, and 34 (49%) did not develop ARDS; 42 patients sustained direct pulmonary injury from penetrating stab or gunshot wounds; 24/36 (67%) of those with ARDS and 28 (40%) of the entire series died. The study showed a rough direct correlation of a semiquantitative infiltration score with pulmonary shunt and an indirect correlation with the PaO₂/FiO₂ ratio during the initial resuscitation and the subsequent posttrauma course in both ARDS and non-ARDS patients. The temporal pattern of the infiltration score closely paralleled that of the pulmonary shunt pattern and inversely paralleled the PaO₂/FiO₂ ratios throughout the period of observation, indicating that radiographic structural changes developed concomitantly with functional changes. To avoid confounding issues, we studied only young, previously healthy trauma victims without head injury. Data from patients with direct lung injury were stratified and evaluated separately. The earliest observed changes most often occurred in the upper and middle lung fields; by contrast, most mechanically ventilated trauma patients had varying degrees of infiltration in the bases with some dysfunction, but not enough to meet ARDS diagnostic criteria.     

Visual and statistical analysis of <Superscript>18</Superscript>F-FDG PET in primary progressive aphasia

Purpose

Diagnosing progressive primary aphasia (PPA) and its variants is of great clinical importance, and fluorodeoxyglucose (FDG) positron emission tomography (PET) may be a useful diagnostic technique. The purpose of this study was to evaluate interobserver variability in the interpretation of FDG PET images in PPA as well as the diagnostic sensitivity and specificity of the technique. We also aimed to compare visual and statistical analyses of these images.

Methods

There were 10 raters who analysed 44 FDG PET scans from 33 PPA patients and 11 controls. Five raters analysed the images visually, while the other five used maps created using Statistical Parametric Mapping software. Two spatial normalization procedures were performed: global mean normalization and cerebellar normalization. Clinical diagnosis was considered the gold standard.

Results

Inter-rater concordance was moderate for visual analysis (Fleiss’ kappa 0.568) and substantial for statistical analysis (kappa 0.756–0.881). Agreement was good for all three variants of PPA except for the nonfluent/agrammatic variant studied with visual analysis. The sensitivity and specificity of each rater’s diagnosis of PPA was high, averaging 87.8 and 89.9 % for visual analysis and 96.9 and 90.9 % for statistical analysis using global mean normalization, respectively. In cerebellar normalization, sensitivity was 88.9 % and specificity 100 %.

Conclusion

FDG PET demonstrated high diagnostic accuracy for the diagnosis of PPA and its variants. Inter-rater concordance was higher for statistical analysis, especially for the nonfluent/agrammatic variant. These data support the use of FDG PET to evaluate patients with PPA and show that statistical analysis methods are particularly useful for identifying the nonfluent/agrammatic variant of PPA.

     

Effect of adrenergic receptor ligands on metaiodobenzylguanidine uptake and storage in neuroblastoma cells

The effects of adrenergic receptor ligands on uptake and storage of the radiopharmaceutical [¹²⁵I]metaiodobenzylguanidine (MIBG) were studied in the human neuroblastoma cell line SK-N-SH. For uptake studies, cells were incubated for 15 min with varying concentrations of -agonist (clonidine, methoxamine, and xylazine), -antagonist (phentolamine, tolazoline, phenoxybenzamine, yohimbine, and prazosin), -antagonist (proranolol, atenolol), -agonist (isoprenaline and salbutamol), mixed / antagonist (labetalol), or the neuronal blocking agent guanethidine, prior to the addition of [¹²⁵I]MIBG (0.1 M). The incubation was continued for 2 h and specific cell-associated radioactivity was measured. For the storage studies, cells were incubated with [¹²⁵I]MIBG for 2 h, followed by replacement with fresh medium with or without drug (MIBG, clonidine, or yohimbine). Cell-associated radioactivity was measured at various times over the next 20 h. Propanolol reduced [¹²⁵I]MIBG uptake by approximately 30% (P<0.01) at all concentrations tested, most likely due to nonspecific membrane changes. However, incubation with the other -agonists or antagonists failed to elicit significant reductions in uptake. In contrast, all of the -agonists significantly inhibited uptake (P<0.05); guanethidine >xylazine >clonidine=methoxamine. The -antagonists demonstrated a broad range of inhibition (phenoxybenzamine phentolamine prazosin yohimbine=tolazoline)(P<0.05). The mixed ligand, labetalol, inhibited MIBG uptake in a dose-dependent manner with an apparent IC₅₀ of 0.65 M. The retention studies demonstrated that unlabeled MIBG caused profound self-inhibition (P<0.01). Clonidine produced a modest inhibition of retention and yohimbine had no effect. Labetalol, phenoxybenzamine, guanethidine, and propranolol reduced uptake of [¹²⁵I]MIBG by neuroblastoma cells in culture. Although only labetalol has been reported to cause false-negative MIBG scans, our results suggest that these other drugs have the potential to interfere with MIBG imaging and therapy, particularly at high doses. Adrenergic drugs did not alter cytoplasmic retention of [¹²⁵I]MIBG in neuroblastoma cells but may have potential in tumors such as phenochromocytoma, where granular storage of MIBG has been observed. Inhibition of [¹²⁵I]MIBG retention by unlabeled MIBG supports the use of high specific activity radioiodinated MIBG for both diagnosis and therapy.     

Computed tomography findings from patients with ARDS due to Influenza A (H1N1) virus-associated pneumonia

Purpose

The purpose of this study was to retrospectively evaluate whether computed tomography (CT) findings have prognostic value for the prediction of mortality and severity of the clinical course in patients presenting with early stage of acute respiratory distress syndrome (ARDS) due to swine-origin influenza A (S-OIV).

Materials and methods

Chest CT (16-/64-row multidetector CT) of 23 patients (of whom 9 patients died) were retrospectively reviewed by three independent blinded observers. The CT findings were graded on a 3-point scale (1: normal attenuation, 2: ground-glass attenuation, 3: consolidation). The extent of each abnormality was determined by visually estimating the percentage (to the nearest 10%) of the affected lung parenchyma in each zone and multiplied by the CT-score described above.

Results

All patients presented with a mixture of bilateral patchy consolidations and ground glass opacities. Spearman rank correlation in evaluation of the presence and extent of lung abnormalities by the three different observers was good (correlation coefficient, 0.876–0.922; p < 0.001). The overall CT-score in survivors (mean, 96.0 (±26.2); range, 53–158) was significantly lower than that in non-survivors (mean, 116.2 (±14.0); range, 101–139). ROC analysis revealed an area under curve of 0.79 (p = 0.021) for the CT score with an optimal cutoff value of a CT-score of 100 for prediction of survival, with a sensitivity of 100% and a specificity of 64% (accuracy, 78%). For this optimal cutoff, Kaplan–Meier estimator showed a significant difference for the survival ratio (p = 0.011).

Conclusion

In patients with severe ARDS due to S-OIV-infection, the CT-score has a prognostic value in the prediction of mortality.     

Patterns of CT lung injury and toxicity after stereotactic radiotherapy delivered with helical tomotherapy in early stage medically inoperable NSCLC

Objective:

To evaluate toxicity and patterns of radiologic lung injury on CT images after hypofractionated image-guided stereotactic body radiotherapy (SBRT) delivered with helical tomotherapy (HT) in medically early stage inoperable non-small-cell lung cancer (NSCLC).

Methods:

28 elderly patients (31 lesions) with compromised pulmonary reserve were deemed inoperable and enrolled to undergo SBRT. Patterns of lung injury based on CT appearance were assessed at baseline and during follow up. Acute (6 months or less) and late (more than 6 months) events were classified as radiation pneumonitis and radiation fibrosis (RF), respectively.

Results:

After a median follow-up of 12 months (range, 4–20 months), 31 and 25 lesions were examined for acute and late injuries, respectively. Among the former group, 25 (80.6%) patients showed no radiological changes. The CT appearance of RF revealed modified conventional, mass-like and scar-like patterns in three, four and three lesions, respectively. No evidence of late lung injury was demonstrated in 15 lesions. Five patients developed clinical pneumonitis (four patients, grade 2 and one patient, grade 3, respectively), and none of whom had CT findings at 3 months post-treatment. No instance of symptomatic RF was detected. The tumour response rate was 84% (complete response + partial response). Local control was 83% at 1 year.

Conclusion:

Our findings show that HT-SBRT can be considered an effective treatment with a mild toxicity profile in medically inoperable patients with early stage NSCLC. No specific pattern of lung injury was demonstrated.

Advances in knowledge:

Our study is among the few showing that HT-SBRT represents a safe and effective option in patients with early stage medically inoperable NSCLC, and that it is not associated with a specific pattern of lung injury.Surgery is the standard treatment for early stage non-small-cell lung cancer (NSCLC), with an overall survival of about 50–70% in Stage I patients.¹ In clinical practice, however, patients with lung tumours, primary or metastatic, often present with related symptoms, advanced age and associated comorbid conditions. Unfortunately, most of them are excluded from clinical trials that are designed to inform practice, creating major evidence gaps. This clinical scenario is expected to further increase the number of cases in the elderly,^2,3 with the consequence that, if untreated, the survival rates of these patients can be severely poor.⁴ Tackling this population represents a therapeutic challenge, and new opportunities exist to improve the management and outcomes for elderly people with coexisting illnesses. In previous years, there has been much evidence of good outcomes obtained with stereotactic body radiotherapy (SBRT) for primary tumours or metastases in the lung for inoperable patients,^5–8 and the introduction of SBRT has improved population-based survival in Stage I NSCLC.^9,10Among the various treatment delivery units, helical tomotherapy (HT) is a kind of image-guided system that is able to deliver intensity-modulated radiation therapy (IMRT) by combining a continuously rotating fan beam with synchronous couch movement.^11,12 While dosimetric findings have shown that such capabilities can potentially translate into the delivery of an increased tumour dose with doses to normal tissues decreased compared with other techniques,^13,14 only a limited number of patients were included in recent studies that have addressed the feasibility of hypofractionated or ablative RT regimens for lung tumours treated with HT.^15–21 The helical radiation delivery method is associated with low-dose spread¹² to the normal lung and can potentially result in patterns of lung injury that might be different than those observed with conventional three-dimensional conformal RT (3D-CRT) or other SBRT techniques. These latter issues raise some concerns, especially in elderly patients, with frailties or comorbidities, given the risk that the potential benefits of SBRT might be hampered by an increased risk of toxicity that can be life threatening or at least substantially compromise their quality of life.The aim of the present study is to evaluate treatment-related toxicity and patterns of radiologic lung injury on CT images after image-guided SBRT delivered with HT (HT-SBRT) for patients with early stage medically inoperable NSCLC.     

Alterations in myocardial free fatty acid clearance precede mechanical abnormalities in canine tachycardia-induced heart failure

Background

The purpose of this study was to evaluate whether abnormalities of free fatty acid metabolism are present before the onset of overt mechanical dysfunction in dogs with tachycardia-induced heart failure. We studied six dogs chronically instrumented to allow assessment of left ventricular function in the pressure-volume plane.

Methods and Results

Free fatty acid clearance was assessed according to the washout rate of a free fatty acid analog, iodophenylpentadecanoic acid ([¹²³I]PPA or IPPA). IPPA clearance was measured within 1 hour of the hemodynamic assessment. The animals were studied under baseline conditions and 11.7±3.6 days after ventricular pacing at a rate of 240 beats/min. Hemodynamic studies after pacing showed a nonsignificant increase in left ventricular end-diastolic pressure (11.7±4.7 to 17.4±6.5 mm Hg) and a nonsignificant decrease in the maximum derivative of pressure with respect to time (1836±164 vs 1688±422 mm Hg/sec). There was also no change in the time constant of left ventricular relaxation, which was 34.8±7.67 msec before and 35.3±7.3 msec after pacing. However, a significant prolongation in the clearance half-time of [¹²³I]PPA, from 86.1±23.9 to 146.5±22.6 minutes (p<0.01) was found. Thus abnormal lipid clearance appears before the onset of significant mechanical dysfunction in tachycardia-induced heart failure.

Conclusion

This suggests that abnormal substrate metabolism may play an important role in the pathogenesis of this condition.     

Extravascular chest wall technetium 99m diethylene triamine penta-acetic acid: implications for the measurement of renal function during renography

Measurement of individual kidney glomerular filtration rate (IKGFR) from the gamma-camera technetium 99m diethylene triamine penta-acetic acid (^99mTc-DTPA) renogram requires a continuous measurement of arterial activity. This is usually based on a region of interest (ROI) placed over the cardiac blood pool on the posterior view, with the assumption of negligible contamination from activity in the extravascular space of the chest wall. By injecting a small dose of technetium 99m human serum albumin (HSA) before the^99mTc-DTPA in 12 patients undergoing routine renography, the contribution of extravascular activity to the total signal recorded over the cardiac blood pool was calculated to be 11.0% (SE 2.1%) 1.5 min after DTPA injection, rising to 35.1% (SE 2.5%) at 15 min. Subtraction of the time-activity curve recorded from a ROI of the same size over the right lung generated a pure blood signal as shown by almost identical HSA/DTPA signal ratios recorded in blood samples taken 5 min after HSA and 15 min after DTPA and from the gamma-camera at the corresponding times. The effect of using a cardiac blood pool time-activity curve uncorrected for extravascular activity was to overestimate IKGFR by an average factor of 1.17 (SE 0.03). Offprint requests to: A.M. Peters     

Demonstration of pulmonary β2-adrenergic receptor binding in vivo with [18F]fluoroethyl-fenoterol in a guinea pig model

Purpose The new ₂ radioligand (R,R)(S,S) 5-(2-(2-[4-(2-[¹⁸F]fluoroethoxy)phenyl]-1-methylethylamino)-1-hydroxyethyl)-benzene-1,3-diol ([¹⁸F]FE-fenoterol; [¹⁸F]FEFE), a fluoroethylated derivative of racemic fenoterol, was evaluated in vivo and ex vivo using a guinea pig model.Methods Dynamic PET studies over 60 min with [¹⁸F]FEFE were performed in nine Hartley guinea pigs in which a baseline (group 1, n=3), a predose (group 2, n=3; 2 mg/kg fenoterol 5 min prior to injection of [¹⁸F]FEFE) or a displacement study (group 3, n=3; 2 mg/kg fenoterol 5 min post injection of [¹⁸F]FEFE) was conducted.Results In all animal groups, the lungs could be visualised and semi-quantified separately by calculating uptake ratios to non-specific binding in the neck area. Premedication with non-radioactive fenoterol and displacement tests showed significant reduction of lung uptake, by 94% and 76%, respectively.Conclusion These data demonstrate specific binding of the new radioligand to the pulmonary ₂-receptors in accordance with ex vivo measurements. Therefore, [¹⁸F]FEFE seems to be suitable for the in vivo visualisation and quantification of the pulmonary ₂-receptor binding in this animal model.     

Radiological findings of pneumonia in patients with swine-origin influenza A virus (H1N1)

Purpose

During spring 2009, a pandemic swine-origin influenza A (H1N1) virus (S-OIV) emerged and spread globally. We describe the chest X-ray and computed tomography (CT) findings of 40 patients with pneumonia due to S-OIV observed in our institution.

Material and methods

Among 534 patients with S-OIV, according to the US Centers for Disease Control and Prevention case definition, seen between June and November 2009, 121 underwent chest X-ray and 40 (median age 44 years, range 16–79) had pneumonia. The initial chest radiographs were evaluated for pattern, distribution and extent of lung abnormalities. Unenhanced chest CT scans were performed in two patients and were reviewed for the same findings. Underlying medical conditions were present in 42% of patients (17/40).

Results

Our patients had predominantly mild illness, and pneumonia was observed in 40 individuals (40/121 patients who had chest X-rays, 33%; and 40/534 patients with S-OIV, 7.5%). However, S-OIV can cause severe illness requiring admission to the intensive care unit for advanced mechanical ventilation and extracorporeal life support, including adult respiratory distress syndrome (ARDS) and death. The major radiological abnormalities observed were interstitial changes (60.0%), with (22.0%) or without patchy ground-glass appearance, mostly bilateral, and located in the lower lung zones (7.5%). Extensive disease was seen in 37.5% (15/40), and ARDS was observed in three individuals (0.30%)with underlying medical conditions. Subtle pleural effusion was noted in four patients.

Conclusions

In our series, the most frequent pneumonia patterns observed during S-OIV (H1N1) virus were interstitial changes and patchy ground-glass appearance, mostly bilateral, and located in the lower lung zones. CT, performed in severely ill patients, confirmed the ARDS identified with chest X-rays, better depicting the features and extent of lung abnormalities.     

Sequential 123I-iododexetimide scans in temporal lobe epilepsy: comparison with neuroimaging scans (MR imaging and 18F-FDG PET imaging)

Purpose Muscarinic acetylcholine receptors (mAChRs) play an important role in the generation of seizures. Single-photon emission computed tomography (SPECT) with ¹²³I-iododexetimide (IDEX) depicts tracer uptake by mAChRs. Our aims were to: (a) determine the optimum time for interictal IDEX SPECT imaging; (b) determine the accuracy of IDEX scans in the localisation of seizure foci when compared with video EEG and MR imaging in patients with temporal lobe epilepsy (TLE); (c) characterise the distribution of IDEX binding in the temporal lobes and (d) compare IDEX SPECT and ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in identifying seizure foci.Methods We performed sequential scans using IDEX SPECT imaging at 0, 3, 6 and 24 h in 12 consecutive patients with refractory TLE undergoing assessment for epilepsy surgery. Visual and region of interest analyses of the mesial, lateral and polar regions of the temporal lobes were used to compare IDEX SPECT, FDG PET and MR imaging in seizure onset localisation.Results The 6-h IDEX scan (92%; =0.83, p=0.003) was superior to the 0-h (36%; =0.01, p>0.05), 3-h (55%; =0.13, p>0.05) and 24-h IDEX scans in identifying the temporal lobe of seizure origin. The 6-h IDEX scan correctly predicted the temporal lobe of seizure origin in two patients who required intracranial EEG recordings to define the seizure onset. Reduced ligand binding was most marked at the temporal pole and mesial temporal structures. IDEX SPECT was superior to interictal FDG PET (75%; =0.66, p=0.023) in seizure onset localisation. MR imaging was non-localising in two patients in whom it was normal and in another patient in whom there was bilateral symmetrical hippocampal atrophy.Conclusion The 6-h IDEX SPECT scan is a viable alternative to FDG PET imaging in seizure onset localisation in TLE.     

Estimation of pulmonary hypertension by perfusion lung scintigraphy: gravitational effect of postural changes between the lateral decubitus positions

To estimate pulmonary hypertension in patients with various heart diseases, we devised a new method using perfuison lung scintigraphy with technetium-99m-labelled macroaggregated albumin. In this method, changes in the distribution of pulmonary perfusion caused by gravitational effects, namely, changes in the total count ratios of the right lung against the left lung between right and left lateral decubitus positions (rt/lt), were assessed in 62 patients and in 10 normal subjects. The rt/lt ratios were calculated as indices of the above changes. They correlated significantly with mean pulmonary arterial pressure (mPAP) (= –0.62,P < 0.001), pulmonary capillary wedge pressure ( = –0.63,P < 0.001) and pulmonary arteriolar resistance ( = 0.50,P < 0.001) in all subjects. In 17 patients with valvular heart diseases, the ratio correlated significantly with mPAP ( = – 0.84,P < 0.001). In 10 patients with various heart diseases, the U/S ratio, i.e. the index of changes in the count ratios of the upper field against the lower field for the right lung following postural change from the upright to the supine position, was also obtained as well as the rt/lt ratio. The latter evidenced a better correlation with mPAP ( = –0.90,P < 0.001) than the former (=–0.64,P < 0.05). We conclude that this method is valuable as a noninvasive approach for the estimation of pulmonary hypertension.     

Fluorine-18 deoxyglucose uptake in sarcoidosis measured with positron emission tomography

Regional pulmonary glucose metabolism (MR_glu; mol h^–1 g^–1), extravascular lung density (D_EV; g cm^–3) and vascular volume (V_B; ml cm^–3) were measured in a single midthoracic transaxial slice (2 cm thick) using positron emission tomography (PET) in seven patients with histologically proven sarcoidosis. The measurements were repeated 1–7 months later after steroid therapy (in two cases, no treatment) in order to assess MR_glu as an index of inflammation and relate it to routine pulmonary function tests, chest radiography and serum angiotensin converting enzyme (SACE) levels. MR^glu was computed from serial lung scans and peripheral venous blood samples for 60 min following an i.v. injection of¹⁸F-2-fluoro-2-deoxy-D-glucose (¹⁸FDG). Both MR_gu (which was increased in six of seven patients) and elevated SACE levels returned to normal in those patients treated with high-dose steroids. Regional vascular volume was normal in six of seven cases and did not change significantly with therapy. The high tissue density measured in all patients decreased significantly in two of three patients treated with 40 mg prednisolone daily. The abnormal MR& observed in active sarcoidosis becomes normal pari passu with SACE levels during high-dose steroid therapy. We conclude that MR^glu measured with¹⁸FDG and PET may reflect disease activity in sarcoidosis in quantitative terms (per gram lung tissue) and in respect of disease distribution.