Administration of an adeno-associated viral vector expressing interferon-ß in patients with inflammatory hand arthritis, results of a phase I/II study.

OBJECTIVE: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-ß, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA. METHODS: In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 × 1012-1.2 × 1013 genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-ß immune responses were evaluated. A data review committee provided safety recommendations. RESULTS: Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-ß, nor IFN-ß antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose. CONCLUSION: Single IA doses of 0.6 × 1012 or 1.2 × 1012 ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. TRIAL REGISTRATION: NCT02727764.

Identification of an urinary metabolite profile associated with osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is one of the most common diseases among the elderly. The main characteristic is the progressive destruction of articular cartilage. We lack quantitative and sensitive biomarkers for OA to detect changes in the joints in an early stage of the disease. In this study, we investigated whether a urinary metabolite profile could be found that could serve as a diagnostic biomarker for OA in humans. We also compared the profile we obtained previously in the guinea pig spontaneous OA model. METHODS: Urine samples of 92 participants (47 non-OA controls and 45 individuals with radiographic OA of the knees or hips) were selected from the Johnston County Osteoarthritis Project (North Carolina, USA). Participants ranged in age from 60 to 84 years. Samples were measured by 1H nuclear magnetic resonance spectroscopy (NMR) with subsequent principal component discriminant analysis and partial least squares regression analysis. RESULTS: Differences were observed between urine NMR spectra of OA cases and controls (P<0.001 for both male and female subjects). A metabolite profile could be determined which was strongly associated with OA. This profile largely resembled the profile previously identified for guinea pigs with OA (approximately 40 out of the approximately 125 signals of the human profile were present in the guinea pig profile as well). A correlation was found between the metabolite profile and radiographic OA severity (R2 = 0.82 (male); R2 = 0.93 (female)). CONCLUSION: This study showed that a urine metabolite profile may serve as a novel discriminating biomarker of OA.

Diagnostic yield of computed tomography and densitometric measurements of the lung in thoracoscopically-defined idiopathic spontaneous pneumothorax.

In the present study, the diagnostic yield of high resolution computed tomography (HRCT) is evaluated in patients with thoracoscopically-verified idiopathic spontaneous pneumothorax (SP). Visual assessment as well as densitometry of lung parenchyma was performed. In eight of the 20 prospectively-evaluated SP patients, emphysema-like (EL) changes such as blebs and bullae could be detected. The SP patients with EL changes were significantly older and were more heavy smokers. Spirometrically-controlled CT lung densitometry showed no differences between the patient group with or without these EL changes. Comparing the densitometric measurements of the patient group with a healthy control group no significant differences in densitometry between both groups were found. In conclusion, this study confirms that HRCT is a reliable method of detecting blebs and bullae in patients with spontaneous pneumothorax. Furthermore CT lung densitometry revealed no parenchymal abnormalities or signs of air trapping in patients with spontaneous pneumothorax.

Prospective study on quality of life before and after radical radiotherapy in non-small-cell lung cancer.

PURPOSE: The purpose of this study was to investigate changes in respiratory symptoms and quality of life (QoL) in patients with non-small-cell lung cancer (NSCLC) receiving radical radiotherapy (60 Gy). Additionally, the association between the level of symptom relief and objective tumor response, as well as with radiation-induced pulmonary changes, was investigated. PATIENTS AND METHODS: One hundred sixty-four patients were entered onto this prospective study. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and EORTC QLQ-LC13 were used to investigate changes in QOL: Assessments were performed before radiotherapy and 2 weeks, 6 weeks, 3 months, 6 months, and 12 months after the completion of radiotherapy. RESULTS: The QoL response rates were excellent for hemoptysis (83%); good for chest pain (68%), arm/shoulder pain (63%), and appetite loss (60%); and poor for dyspnea (37%), cough (31%), and fatigue (28%). The QoL response rates for the five functioning scales of the QLQ-C30 varied from 35% for physical and role functioning to 55% for social and cognitive functioning. The response rate for global QoL was 36%. A significant association was found between tumor response and palliation of chest pain, arm/shoulder pain, and physical functioning. During radiotherapy, a significant increase for most general symptoms and a deterioration in functioning and QoL were noted. CONCLUSION: This study is the first to describe palliation and changes in QoL in radically irradiated patients with NSCLC. Radical radiotherapy offers palliation of respiratory symptoms and improved QoL in a substantial proportion of patients with NSCLC who have relatively good prognostic features. Although tumor reduction is associated with palliation of respiratory symptoms, it cannot serve as a surrogate for palliation.

Association of man-made mineral fibre exposure and sarcoidlike granulomas.

It is assumed that sarcoidosis is caused by inhalation of air borne agents in susceptible persons triggering the inflammatory reaction. The association of metallic dust exposure, such as beryllium and aluminium, and sarcoidlike pulmonary disorders is well known. The ability of man-made mineral fibres (MMMF) to cause granulomatous lung disease has not been appreciated until now. Recently, we observed the association of sarcoidlike granulomatous reaction and occupational history of glass fibre exposure. We hypothesized that there might be a relationship between MMMF exposure and the development of sarcoidlike granulomas. Therefore, the records of 50 sarcoidosis patients-who visited our outpatient clinic between 1996 and 1999 were reviewed. This revealed that 14 cases recalled a history of exposure to either glass fibres or rock wool, both MMMF fibres. The available obtained tissue specimens (n = 12) were reviewed. In six cases electron microscopy qualitative analysis of small fragments of the tissue revealed among others silica, aluminium and sometimes titanium. A distinct relation between fibre deposits fibre deposits and granulomas was found. These findings indicate that in susceptible people MMMF exposure might be related to a chronic granulomatous disease similar to chronic beryllium disease.

Different patterns of chronic tissue wasting among patients with chronic obstructive pulmonary disease.

BACKGROUND & AIMS: Nutritional depletion is frequently present in patients with chronic obstructive pulmonary disease, but it is unknown whether a difference exists between the two subtypes. The aim of this study was to determine whether patterns of tissue depletion were different between emphysema and chronic bronchitis patients and whether these were related to pulmonary function. METHODS: In 99 severe COPD patients and 28 healthy volunteers, body weight and composition were assessed by dual-energy X-ray absorptiometry. Patients were stratified into chronic bronchitis (n=50) and emphysema (n=49) by high-resolution computed tomography. RESULTS: Lean mass depletion was found in 37% of the emphysema patients and in 12% of the chronic bronchitis patients. The emphysema patients had lower values for body mass index than the other groups (P< 0.01), mainly due to a lower lean mass (P< 0.01) and bone mineral content (P< 0.01). Fat mass was also lower in the emphysema group compared to the chronic bronchitis group (P< 0.001). The chronic bronchitis patients had a higher fat mass (P< 0.05) and a lower bone mineral content (P< 0.01) than the healthy volunteers. CONCLUSIONS: Substantial differences in body composition were found not only between chronic obstructive pulmonary disease patients and healthy volunteers, but also between chronic bronchitis and emphysema patients.

Intrapulmonary gas mixing and the sloping alveolar plateau in COPD patients with macroscopic emphysema.

Chronic obstructive pulmonary disease patients, especially those with emphysema, show steep slopes of the alveolar plateau (S). This study tested the hypothesis that continued gas exchange between poorly and well-ventilated lung units by means of collateral ventilation would contribute to S in these patients. Nine young volunteers, nine older volunteers and 11 patients with macroscopic emphysema performed wash-out tests with helium (He) and sulphur hexafluoride (SF6). S was determined for breaths 1-5 (range 1), and for breaths between 95% and 98% of complete wash-out (range 2). An unequal ventilation index (UVI) was defined as the ratio between the estimated mean alveolar pressure and the end tidal pressure (PET) of each tracer gas, calculated over range 2. Over the same range, a phase III ratio was calculated by dividing PET by the estimated pressure at Fowler dead space. In all groups of subjects, the S for He and SF6 were greater for range 2 than for range 1 (p< or =0.012). In the emphysema patients, the correlations between S and UVI were 0.72 for He (p=0.012) and 0.81 for SF6 (p=0.002), while the mean phase III ratios were 1.7 for He and 2.4 for SF6, much less than their theoretical maxima. It was concluded that in patients collateral ventilation may account for only a small part of the increase in the alveolar plateau slope between ranges 1 and 2, and that this increase was mainly caused by unequal ventilation in combination with sequential emptying of lung units. The degree of sequential emptying, however, was modest compared with its full potential.

Does the cellular bronchoalveolar lavage fluid profile reflect the severity of sarcoidosis?

The aim of this study was to assess whether the cellular bronchoalveolar lavage fluid (BALF) profile, particularly the number of polymorphonuclear neutrophils (PMNs), is associated with disease severity of sarcoidosis and its usefulness in determining remission. Twenty-six nonsmoking outpatients with sarcoidosis were included in this study. The patients were divided into two subgroups according to the absolute number of PMNs in BALF: < or =0.2x10(4) cells x mL(-1) (group 1; n = 15) and >0.2x10(4) cells x mL(-1) (group 2; n = 11). The radiographic stage, high-resolution computed tomography (HRCT) findings, 67Ga lung uptake as well as lung function tests differed significantly between group 1 and 2. Follow-up revealed that 14 (93.3%) patients of group 1 compared to four (36.4%) of group 2 recovered spontaneously without the help of corticosteroids. In contrast, no differences were found in the number of lymphocytes in BALF nor in the serum angiotensin converting enzyme (sACE) level between both groups. The number of PMNs, the transfer factor of the lungs for carbon monoxide (TL,CO), the forced expiratory volume in one second (FEV1) and one of the HRCT subscores discriminated between patients with different disease progression. Of these parameters the PMNs appeared to be the only one which differentiated patients who demonstrated remission and those who deteriorated. In conclusion, these results indicate that the number of polymorphonuclear neutrophils in bronchoalveolar lavage fluid distinguish between sarcoidosis patients who demonstrated remission and those having a more severe course of the disease. Whether polymorphonuclear neutrophils may be considered as markers of disease activity and/or prognosis in sarcoidosis needs further investigation.

Preliminary study on the effect of miniaturisation and use of volatile mobile phases in LC for the on-line LC-MS analysis of basic pharmaceuticals.

To enhance to compatibility of the on-line coupling of liquid chromatography (LC) with mass spectrometry (MS) for the analysis of basic pharmaceuticals, the use of volatile mobile phase systems in combination with miniaturised LC was investigated. Multifactor analysis of variance (MANOVA) was used to evaluate the data obtained for the various variables (modifier, stationary phase, buffer, buffer pH and buffer concentration) on the resolution, peak symmetry and retention of four basic compounds analysed using LC columns with internal diameters (I.D.) of 0.3, 1.0 and 4.6 mm (conventional). Preliminary results obtained with the investigated micro and conventional columns showed similar behaviour with respect to ruggedness. The various investigated variables showed that miniaturisation by simply downscaling dimensions can result in varying selectivity and peak shapes for basic compounds. When comparing volatile mobile phases (containing ammonium acetate or ammonium citrate) and a conventional non-volatile mobile phase (containing sodium phosphate) under pH 3 conditions, similar separation performances were observed. In the present study, ammonium citrate as the buffering salt, a high buffer concentration and methanol as the modifier showed the best peak symmetry.

Intense muscle uptake of gallium-67 in a patient with sarcoidosis.

Sarcoidosis has been associated with muscle involvement. In general, this involvement remains asymptomatic. The following case report demonstrates a patient with a 4-mo history of sarcoidosis who reported severe fatigue and slight muscular complaints at a regular checkup. Gallium scintigraphy indicated unexpected and unusually extensive muscular localizations of the disease. The latter findings were confirmed by examination of biopsy specimens. The importance of gallium scintigraphy lies in the possibility of wholebody screening for inflammation localizations, particularly when physical, laboratory, lung function and radiographic examinations fail to provide convincing evidence of active sarcoidosis. Furthermore, it can be helpful in the follow-up of the effect of supportive treatment.

Is the chest radiograph a reliable tool in the assessment of tumor response after radiotherapy in nonsmall cell lung carcinoma?

BACKGROUND: The purpose of this study was to evaluate whether the chest radiograph is a reliable tool to assess response to radiotherapy. MATERIALS AND METHODS: Pre- and post-treatment chest radiographs and computed tomographs (CT) of 63 patients with nonsmall cell lung cancer (NSCLC) treated by radiotherapy were reviewed by four observers with regard to suitability for tumor measurement, and response. Suitability for tumor measurement was expressed as the number of measurable diameters. In addition, the consequences to clinical outcome were studied by survival analysis. RESULTS: The CT turned out to be more suited for tumor measurement before as well as after radiotherapy, resulting in an increase of the number of measurable cases. The number of measurable cases with CT was 52 (83%) as compared to 28 (44%) with chest radiography. Especially in case of centrally localized tumors, the presence of an atelectasis, or squamous cell carcinoma, CT contributed to a higher rate of measurable cases. The interobserver agreement with regard to response using chest radiograph was good (mean kappa = 0.74). In 25 of 28 cases (89%) measurable with CT as well as with chest radiograph, response was equally classified. When CT was used, the median survival of the responders was 14.2 months as compared to 6.8 months of the nonresponders. When chest radiograph was used, the median survival of these groups was 12.0 and 6.6 months respectively, which was not significantly different when response was assessed by CT. CONCLUSION: We conclude that CT is more suited for tumor measurement because more measurable lesions can be found and more evaluable lesions on chest radiograph become measurable on CT. The chest radiograph does have a valuable role to play in those lesions that are measurable because of the good interobserver agreement with regard to the response classification, the high overall agreement between CT and chest radiograph in case of measurable cases, and the lack of important differences with regard to survival.

Reproducibility of spirometrically controlled CT lung densitometry in a clinical setting.

The aim of this study was to assess the reproducibility of quantitative, spirometrically gated computed tomographic (CT) lung densitometry at defined levels of inspiration in hospitalized patients. On two consecutive days, spirometrically gated CT sections were obtained from 20 hospitalized patients at 5 cm above and 5 cm below the carina, and at 90 and 10% of the vital capacity (VC). The mean, modal and median lung densities were calculated, the cut-off points of the frequency distribution of Hounsfield units (HU) defining the lowest and the highest 10th percentile, as well as the histogram full width at half maximum. The lung density parameters of corresponding CT sections of both studies were compared. Reproducibility was expressed as the standard deviation of the signed difference between the results of Day 1 and Day 2 divided by the square root of 2. Reproducibility data were correlated with results of airflow limitation. At 90% VC, reproducibility was of the order of 3-14 HU in both lung zones. At 10% VC, reproducibility was worse by approximately a factor of three. No relationship was found between reproducibility and results of airflow limitation. In conclusion, objective measurement of lung density at spirometrically controlled levels of inspiration is a reproducible method in assessing pulmonary density. Reproducibility of lung density measurements is not influenced by severe respiratory insufficiency. The most reproducible computed tomographic lung density measurements can be obtained at 90% vital capacity.

On segmentation of lung parenchyma in quantitative computed tomography of the lung.

Our purpose in this study was to investigate the influence of segmentation threshold and number of erosions on parameters used in quantitative computed tomography (CT) of the lung (erosions are shrink operations on the segmented area). Parameters assessed were mean lung density, area of the segmented lung, two percentiles, and the pixel index, which is the relative area of the histogram below -905 Hounsfield Units (HU). We analyzed images of ten emphysematous and ten nonemphysematous patients, that had been scanned at carina level in inspiration and expiration, using sections of 1, 2, 3, 5, and 10 mm in combination with a standard, a smooth, and an ultrasmooth reconstruction kernel. The lungs were segmented using pixel tracing at thresholds of -200, -400, and -600 HU with 0-4 erosions, followed by histogram analysis. The area of the segmented lungs decreased with 0.9%-3.2% per 100 HU decrease in threshold and with 2.2%-3.1% per erosion, dependent on patient group and respiratory status. Estimated mean lung density changed up to 30% by changing the threshold and the number of erosions. The pixel index and the 10th percentile depended only slightly on threshold and number of erosions, but the 90th percentile showed a strong dependence of up to 40%. It is concluded that the segmentation protocol can have a large impact on densitometric parameters and that standardization is mandatory for obtaining comparable results. Ideally a threshold equal to the average of the densities of lung and soft tissue should be used, but -400 HU will do in a limited but common density range (-910 to -790 HU). For densitometry two erosions are recommended, for volumetry zero erosions should be used.

CT lung densitometry: dependence of CT number histograms on sample volume and consequences for scan protocol comparability.

PURPOSE: Our goals were to determine the dependence of CT number histograms of the lung on section thickness and reconstruction filter and to evaluate the consequences for scan protocol conformity required for universally comparable densitometry of the lungs. METHOD: The effects of section thickness and reconstruction filter were parameterized with the CT's sample volume [V approximately (section thickness x in-plane resolution2)]. In a study of 31 patients, we determined as a function of V the following CT number histogram parameters: percentiles P(10) and P(90), pixel indexes PI(-905) and PI(-950), and standard deviation. RESULTS: Patient histogram parameters depended strongly on sample volume. Large differences were found between protocols using 1 and 10 mm sections. For small variations in somewhat larger sample volumes (> 8 mm3), discrepancies were much smaller. CONCLUSION: To obtain comparable histogram parameters, nearly identical sample volumes (> or = 8 mm3) should be used. When this condition is satisfied, available data suggest that universally comparable densitometry is feasible.

The CT's sample volume as an approximate, instrumental measure for density resolution in densitometry of the lung.

Ultimately CT-densitometry of the lung should give comparable results on all scanners. One prerequisite for this is the use of the same density resolution. Unfortunately, density resolution is impractical as a performance specifying parameter because it depends on the cellular material scanned. Therefore, another parameter that can be used for scanner and protocol characterization, and that does not depend on a special phantom, would be highly preferable. We investigated how well the CT's nominal sample volume (V), calculated from section thickness and in-plane spatial resolution as specified by the CT manufacturer, can serve as a simple measure, for density resolution. Six CT scanners were studied using foam and lung phantoms. On all scanners we observed for foam an approximately linear relation between density resolution and V-1/2. Density resolution on different scanners varied to some extent. These differences can be interpreted as being caused by deviations of the true sample volume from the nominal value: the 95%-confidence interval runs for instance for V = 8 mm3 from 4.6 mm3 to 16.9 mm3. Acceptability of this spread depends on the consequences for parameters of clinical interest, like percentiles and pixel indexes. To evaluate this we used data from a previous patient study on the dependence of histogram parameters on sample volume. With these data it is found that large interscanner differences in histogram parameters are possible for small values of V, as used in thin-section densitometry. For larger values of V, as required for a more adequate density resolution, the differences are much smaller and probably acceptable when compared to other sources of variability in lung densitometry. In conclusion, for sections of at least 2 mm and smooth reconstruction filters, corresponding to V > or = 8 mm3, the CT's nominal sample volume might be used for interscanner and interprotocol comparison of density resolution.

Recurrent respiratory distress associated with carbamazepine overdose.

Acute interstitial pneumonia or diffuse alveolar damage is uncommon as an adverse reaction to carbamazepine therapy. We report the case of a 36 yr old woman, who developed respiratory failure after auto-intoxication with carbamazepine. Analysis, including bronchoalveolar lavage and lung tissue biopsy, suggested diffuse alveolar damage due to carbamazepine.

Serum lactate dehydrogenase and its isoenzyme pattern in ex-coalminers.

Serum lactate dehydrogenase (LDH) activity, a marker of cell damage, is increased in several pulmonary disorders, especially when fibrosis is involved. In rats exposed to silica, high levels of LDH activity were found. A rise of serum LDH3 has been associated with lung tissue injury. The aim of this study was to investigate the serum LDH isoenzyme pattern after coal-dust exposure and the possible relation to pulmonary function tests. Ex-coalminers (n = 201), with a history of coal-dust exposure more than 20 yr ago, were admitted to the authors' hospital for a medical check-up and were included in the study. The serum LDH activity was found to be elevated in 79.1% of the ex-coalminers (634 +/- 245 U I-1). Moreover, in 196 of the 201 cases (97.5%), a high LDH3 level (31 +/- 4%) was demonstrated. A moderate negative relation was found between the forced expiratory volume in 1 s (FEV1) and the LDH activity (r = -0.26; P < 0.001), as well as between FEV1 and LDH3 activity (r = -0.23; P < 0.001), even in the subgroup (n = 42) with a normal LDH. All other liver function tests were within normal limits. These results suggest that coal-dust, even many years after the actual exposure, causes an increase in the total serum LDH activity and changes in the LDH-isoenzyme pattern, mainly characterized by a high LDH3 activity.