Thalidomide for improving cutaneous and pulmonary sarcoidosis in patients resistant or with contraindications to corticosteroids.

BACKGROUND: Limited data report thalidomide improves cutaneous sarcoidosis; no benefit has been reported for pulmonary localization. OBJECTIVES: To evaluate feasibility and efficacy of prolonged treatment with thalidomide for cutaneous sarcoidosis associated to pulmonary involvement in patients with resistance or contraindications to steroids. METHODS: Nineteen patients were treated with thalidomide for 24 months starting with 200 mg/d for first 2 weeks, followed by 100 mg/d for 11 weeks and a maintenance dose of 100mg on alternate days for 35 weeks, and a gradual scaling down until therapy interruption. Criteria of efficacy were: skin score, serum ACE levels (s-ACE), chest X-ray (CXR), lung function tests (LFTs), and diffusing lung capacity for CO (DLCO). The skin score was computed as arithmetic sum of seven score parameters (min: 0, max: 28). RESULTS: Skin score significantly decreased (P<0.001). Lower skin scores occurred after 3 and 6 months (P<0.05). s-ACE levels decreased over time at the third month (P<0.001). CXR assessed by radiological stage significantly improved during the first 6 months (P<0.001). DLCO showed a continuous trend of improvement. Minor side effects that have forced the suspension of the drug were drowsiness/sedation (74%), constipation (68%), and weight gain (53%). Deep vein thrombosis of the lower limbs occurred in one patient (who did not drop out the study). Eight patients (42%) abandoned thalidomide for axonal sensitive peripheral neuropathy (PN) between the ninth and the 24th month of treatment. CONCLUSIONS: Thalidomide, long-term at mid-low doses, can be considered as an effective therapeutic alternative in chronic sarcoidosis with resistance or contraindications to steroids.

Comparative performance of two inhaler systems to assess distribution of convective ventilation by 99mTc-labeled aerosol scintigraphy in patients with airway obstruction.

AIM: Redistribution of convective ventilation, the leading disorder in airway obstruction, is a target of pharmacological and mechanical ventilation treatments for patients with chronic obstructive pulmonary disease (COPD). Convective ventilation is visualized by ventilation scintigraphy using radiolabeled aerosol particles that should ideally deposit in the terminal airspaces, but not in the conducting airways, and have no Brownian motion (which characterizes diffusive ventilation). Currently available commercial systems do not meet these requirements as they do not ensure an optimal size of aerosol droplets delivered at the mouthpiece. METHODS: A new inhaling system (FAI) was developed and designed so as to yield radioaerosol droplets with smaller particle size and to ensure more efficient aerosol delivery to the terminal airways than that obtained with a widely available commercial system (MMI). A cascade impactor was employed to measure the size of the radioactive droplets at the mouthpiece. Preliminary comparative validation was based on ventilation scintigraphy using the two systems (both followed by a standard lung perfusion scan) in control subjects and in patients with airway obstruction. The time required to reach a certain count rate in the lung fields (1 kc/s) was recorded by means of dynamic g camera acquisition during breathing. Subsequent static images allowed assessment of intrapulmonary distribution of ventilation (by both visual and quantitative evaluation) and of the ventilation/perfusion (V/Q) ratios relative to the upper, middle, and lower thirds of the lung fields. RESULTS. FAI yielded 99mTc-labeled droplets with a count median diameter of 1.4 microm and a geometric standard deviation of 2 microm , versus 3 microm and 2, respectively, produced by the commercial inhaler (MMI). The mean time to reach the 1 kc/s count rate was significantly shorter with the FAI than with the MMI both in control subjects (4.7+/-1.7 min versus 8.2+/-2 min, P<0.04) and in airway-obstructed patients (3.4+/-0.8 min versus 8.4+/-2 min, P<0.001). With the MMI, appreciable radioaerosol deposition in the large bronchi prevented reliable quantitative assessment of ventilation, even in the control subjects. With the FAI, radioaerosol deposition in the central large airways was never observed in the controls and was only sporadically or occasionally observed in patients with COPD or asthma, respectively. This feature allowed quantitative ventilation assessment. The FAI-generated radioaerosol particles reached the peripheral respiratory spaces more efficiently than those generated by MMI; on the ventilation scans, the FAI allowed better discrimination than the MMI of the different pathophysiologic conditions. CONCLUSION: These findings consistently indicate that the smaller-sized radiolabeled droplets generated by FAI, combined with the better breathing dynamics of the inhaler device, result in better overall performance as compared to the commercial system. This makes scintigraphic images obtained with the new device especially suitable for assessing convective ventilation in COPD patients, a particularly helpful feature for analytically describing the distribution patterns observed in airway-obstructed patients and for evaluating the effects of drugs, mechanical ventilation, and other interventions in such patients.

A case of sarcoidosis presenting as a non-specific intramedullary lesion.

Neurosarcoidosis occurs in 5-15% of sarcoidosis cases. Approximately 50% of patients with neurosarcoidosis present with a neurological disease at the time sarcoidosis is first diagnosed. Spinal sarcoidosis is rare. We report the case of a 61-year-old man with a highly aspecific intramedullary lesion as the first manifestation of sarcoidosis. One year after the onset of neurological symptoms, the high levels of angiotensin-converting enzyme and the results of a total body gallium scan and bronchoalveolar lavage supported the diagnosis of sarcoidosis. Isolated single reports indicate that spinal neurosarcoidosis may be the initial manifestation of sarcoidosis. In our case, magnetic resonance imaging of the dorsal spine showed a largely aspecific lesion. Neurosarcoidosis should be considered in the differential diagnosis of intramedullary cord lesion with leptomeningeal enhancement; a systematic search for evidence of sarcoidosis should be mandatory in all cases for a correct diagnosis and early treatment.

Functional significance of the decreased attenuation sign on expiratory CT in pulmonary sarcoidosis : report of four cases.

We describe four patients with proven sarcoidosis and minor pulmonary involvement according to high-resolution CT (HRCT) findings in whom the recently described sign of decreased attenuation on expiratory HRCT scan appeared associated with the reduction of the single-breath diffusing capacity of the lung for carbon monoxide (DLCO) and the DLCO adjusted for alveolar volume. These alterations were, in part, reversible under steroid treatment. Major indexes of airway obstruction (FEV(1)/vital capacity ratio and FEV(1)) were normal, while the maximum expiratory flow at 25% above the residual volume of FVC was reduced. These observations suggest that an expiratory HRCT mosaic pattern and diffusion impairment may be early findings in pulmonary sarcoidosis and may be useful for its detection and follow-up.

In vivo studies on possible adverse effects on reproduction of the fungicide methyl thiophanate.

The fungicide methyl thiophanate (MT), widely used to control some of the most common fungal diseases in crops, is metabolized in animals into benzimidazole compounds, including the well-known reproductive toxicant carbendazim. However, standard toxicological tests did not indicate that MT may cause testicular toxicity and/or embryotoxicity, which are typical effects of many benzimidazoles. In the present study some aspects of the MT potential for reproductive toxicity have been assayed by means of two non-conventional models. Following the oral administration of 700 and 1000 mg kg(-1) body wt. for five consecutive days, short-term testicular toxicity was examined in the B6C3F1 mouse through specific parameters (sperm head count, specific enzyme activities, histopathology on days 3-35 post-dosing). In spite of the high doses administered, none of the testicular parameters examined, including histopathology, showed significant alterations as compared to controls at any time post-dosing. Pregnant CD rat dams were administered orally the limit dose of 650 mg kg(-1) body wt. day(-1) during preimplantation (gestational day or GD 2-5) or peri-implantation (GD 6-9) phases; embryos and adnexa were evaluated morphologically on GD 12 as a window for the early observation of embryotoxicity. Evident maternal toxicity was present in both treated groups, whereas only marginal reductions of the growth of embryos and adnexa were observed. A full understanding of MT toxicology will need more quantitative data on metabolism, including plasma kinetics and dosimetry of carbendazim at the relevant targets. Nevertheless, the absence of any clear-cut effect on a number of specific endpoints may provide reassurance that no further testing of MT is needed with regard to testicular toxicity or embryotoxicity.

Interstitial lung fibrosis and rheumatic disorders in patients with hepatitis C virus infection.

A possible aetiopathogenetic role of hepatitis C virus (HCV) has been reported in various immune-mediated disorders, such as mixed cryoglobulinaemia, which may be complicated by interstitial lung involvement; moreover, different viruses, including HCV, have been correlated with idiopathic pulmonary fibrosis. Here, a cohort of eight HCV-positive patients (M/F = 4/4, mean age 61 +/- 8 S.D. yr) with interstitial lung fibrosis and a variable number of rheumatic disorders are described. Interstitial lung involvement appeared medially 4.5 +/- 3.2 S.D. yr after the clinical onset of chronic hepatitis. During the clinical follow-up, some rheumatic symptoms were also recorded: articular involvement (four patients): mild sicca syndrome (one patient); severe polymyositis and cranial neuropathy (one patient); serum cryoglobulins and/or autoantibodies (eight patients). In all patients, a moderate (four patients) or severe (four patients) lung fibrosis was evaluated by means of high-resolution computed tomography. The presence of parenchymal radiotracer uptake on 67Ga scan (7/7 patients) and increased percentages of neutrophils (4/4 patients) and lymphocytes (2/4) at bronchoalveolar lavage suggested an active lung involvement. Different degrees of reduction of single breath diffusing capacity for carbon monoxide (DLco) (mean value 57.6 +/- 15%, range 37-80) were observed in all cases, while spirometric abnormalities, consistent with a global restrictive pattern, were less frequently found. In all cases, anti-HCV antibodies and HCV viraemia were demonstrated: viral genome was also detected in peripheral lymphocytes from 4/4 subjects and in one case in lung biopsy specimens. A desquamative interstitial pneumonia pattern was demonstrated in two cases by lung biopsy. The present work supports the hypothesis that HCV chronic infection could represent a trigger factor for interstitial lung fibrosis and various rheumatic disorders.

Flow cytometric and histological assessment of 1,2:3,4-diepoxybutane toxicity on mouse spermatogenesis.

The effects of diepoxybutane (DEB) on mouse reproductive cells have been investigated by flow cytometric and histological description of testicular cell populations and alterations of sperm chromatin packaging. Mice were treated with single intraperitoneal injections of DEB, with doses ranging between 8.5 and 78 mg/kg (100-900 microM), and were killed after 7, 14, 21, 28 or 35 d. Dose-dependent reductions of tetraploid cells, round spermatids, and elongated spermatids were detected at 7, 21, and 28 d, respectively, reflecting cytotoxic damage on the differentiating spermatogonia compartment. The dose necessary to reduce the number of differentiating spermatogonia to half the control value was estimated equal to 650 microM or 55 mg/kg. Stem cells were not affected by this treatment. Histological section of seminiferous tubules showed depletion of spermatids and reduction of the secondary spermatocyte layers. In addition, a high although not statistically significant frequency of sperm with altered chromatin packaging was detected after DEB treatment. DEB is one of the key metabolites of butadiene, which is a compound of high environmental and occupational concern. These results contribute to the assessment of the reproductive health impact of butadiene in humans.

Sarcoidosis: single bulky mesenteric lymph node mimicking a lymphoma.

A previously healthy man presented with acute abdominal pain that extended from the left lumbar area to the left iliac fossa and to the omolateral testicular region. Abdominal ultrasonography and CT scan showed a bulky mesenteric mass and mesenteric, paraaortic, and paracaval lymph nodes. Biopsy specimens of the mass revealed non caseating granulomas. Chest CT scan and 67Gallium thoracic scan demonstrated lymph node and parenchymal pulmonary involvement. Bronchoalveolar lavage (BAL) confirmed the presence of a low intensity alveolitis. Serum angiotensin converting enzyme (SACE) level was elevated. Two years after steroid therapy, markers of disease activity and abdominal ultrasonography are in the normal range.

67Ga-citrate imaging in rhabdomyosarcoma.

A 22-year-old female patient with a swelling in the right forearm near the elbow underwent a 67Ga-citrate scan because of paraesthesia on the ulnar side of the right hand. The 67Ga total body scan showed intense focal uptake on the forearm in the same position as the swelling. At surgery a histological diagnosis of alveolar rhabdomyosarcoma was made. Five months later, a repeat 67Ga scan was normal. Eight months after the diagnosis, the patient complained of pain in the left lumbar region extending to the hypogastric area. A third 67Ga scan showed intense uptake near the spinal column which at surgery was found to be a metastasis of the primary tumor.

Sarcoidosis in Tuscany. A preliminary report.

A retrospective study was carried out by a computerized questionnaire in a sample of 109 sarcoidosis patients (43 men, 66 women) diagnosed between 1977 and 1990 in Pisa. 94% of the patients were resident in Tuscany. The onset of disease was earlier in the men than in the women; in 73% of the patients the symptoms were first noticed between February and July with two incidence peaks; 71% of them had never smoked; 10% of patients were symptom-free and the disease was discovered by chance; the other patients (90%) underwent chest X-ray because of joint symptoms (35%), erythema nodosum (34%), cough (28%), dyspnoea (27%), and fever (24%) which was often associated with other symptoms. Symptoms from the respiratory tract was present in 66 patients (61%); 58% of patients were resident in rural areas; the level of education was limited to primary school in 50% of the patients; as to the prevailing working positions, 27% were clerical workers, 24% manual workers, and 26% housewives.

Lung involvement in systemic sclerosis sine scleroderma treated by plasma exchange.

Systemic sclerosis sine scleroderma can present in some patients as pulmonary interstitial fibrosis. Until now ten cases with this particular clinical variant, all men, have been reported in the literature. The knowledge of systemic sclerosis sine scleroderma presenting as lung interstitial involvement is important in clinical practice for an early diagnosis and correct therapeutic strategy. This work reports the clinico-serological features of two further cases, one a woman, of systemic sclerosis sine scleroderma with prevalent lung involvement, and describes the effects of therapeutic plasma exchange.

Phase II study of high-dose epirubicin in untreated patients with small-cell lung cancer.

Eighteen previously untreated patients with histologically confirmed small-cell lung cancer were treated with high-dose epirubicin (course 1, 100 mg/m2; courses 2-6, 140 mg/m2, day 1), every 3 weeks. Overall response rate was 33% (95% confidence limits, 14-52%), including two complete and four partial responses. The response rates for limited (n = 11) and extensive (n = 7) disease patients were 45% and 14%, respectively. With a median follow-up of 18 months, estimated 2-year survival of all patients was 29% and the median duration of response 18.5 months. The dose-limiting toxicity was myelosuppression, with a median granulocyte nadir of 1,150/mm3; 39% of patients had neutropenic fever. Nausea/vomiting, alopecia, and stomatitis were the most common nonhematological toxicities, usually mild to moderate. Acute cardiac toxicity was unusual and no episodes of congestive heart failure were observed. Cumulative doses of 800 mg/m2 were associated with moderate cardiotoxicity (grade 2), as assessed by endomyocardial biopsy and electron microscopy analysis. These results indicate that epirubicin, at the present doses and schedule, is an active single agent in patients with small-cell lung cancer, with acceptable general and moderate cardiac toxicity.

Prevalence of respiratory symptoms in an unpolluted area of northern Italy.

Using a multistage stratified geographic cluster sample of households living in an unpolluted area of Northern Italy (near Venice), we enrolled 3289 inhabitants (aged 8-64 yr) for a longitudinal respiratory study. During the first cross-sectional survey, before the start of operation of a large oil-burning thermoelectric power plant, they completed a standardized administered questionnaire and performed several lung function tests. In the whole sample, dyspnoea grade 1 (11%), chronic cough and chronic phlegm (9%) were the most frequent respiratory symptoms; all the symptoms except dyspnoea were more prevalent in males than in females. Smokers (S) showed higher prevalence rates than ex-smokers (ES) and nonsmokers (NS), especially in males. In both sexes, the frequency of respiratory symptoms increased with increasing smoking as assessed by pack-years. An inverse relationship between prevalence of symptoms and socio-economic status was also observed. All tests of lung function were significantly impaired in S compared with NS in males; single-breath CO diffusing capacity and slope of alveolar plateau but not spirometric indices were significantly impaired in female S compared to female ES and NS. Finally, our prevalence rates were lower than in other epidemiological surveys: this result may be ascribed to the low levels of air pollution measured in the area.

Reference values for vital capacity and flow-volume curves from a general population study.

A longitudinal epidemiological respiratory study has been started in the North of Italy to investigate the natural history of obstructive airways disease and the long-term effect of SO2 exposure. The first cross-sectional study was completed in this unpolluted area before the activation of a thermoelectric power plant (500 tons of SO2 produced daily). Follow-up surveys are planned after pollution emission starts for a period of ten years. A sample (n = 3289) representative of the general population was drawn from the villages of the area according to the different risks of pollution exposure. Subjects completed questionnaires and performed lung function tests, including forced expiratory (FVC) manoeuvres. For 801 'normal' subjects, prediction equations have been derived in age/sex groups for slow vital capacity (VC) and variables from the FVC manoeuvre. Comparisons with predictions of other studies are reported. Differences among FVC predictions were found, indicating that the use of different criteria for determination of the FVC manoeuvre end-point can affect results. In 'normals' VC was higher than FVC in older subjects. The difference between VC and FVC may be hypothesized as an epidemiological indication of the ageing effect on the mechanical properties of the ventilatory system.