Efficacy of a toxicity-adjusted topotecan therapy in recurrent small cell lung cancer.

The present prospective multicentre trial investigated whether topotecan, given at a starting dose of 1.25 mg.m(-2) with individual dose adjustment, can improve safety in patients with relapsed/refractory small cell lung cancer without loss of efficacy. Patients received topotecan intravenously on days 1-5, every 21 days, for up to six courses. In the absence of relevant haematotoxicities, topotecan was increased to 1.5 mg.m(-2) and reduced to 1.0 mg.m(-2) in case of severe haematotoxicities. Of 170 recruited patients, 73.2% had stage IV disease and 63.4% had platinum-containing pre-treatment. Patients received a total of 521 courses. In 72.6% of those courses, the dose remained at 1.25 mg.m(-2); in 9.1% it was reduced and in 18.3% it increased. Overall response rate was 14.1% including one complete response; 28.8% had stable disease. Median duration of response was 13.6 weeks and median survival was 23.4 weeks. Clinical benefit was obvious for sensitive as well as for refractory patients. Haematotoxicity of grade 3 or 4 was clearly lower compared with the standard dose of 1.5 mg.m(-2). In conclusion, topotecan at a dose of 1.25 mg.m(-2) appears to be as effective as the dose of 1.5 mg.m(-2), but with reduced toxicity. Since patients with recurrent small cell lung cancer have a poor prognosis, they benefit especially from good tolerability.

Synovial Epstein-Barr virus infection increases the risk of rheumatoid arthritis in individuals with the shared HLA-DR4 epitope.

OBJECTIVE: To investigate the presence of the Epstein-Barr virus (EBV) in rheumatoid arthritis (RA) synovium and its correlation with the HLA genotype in an attempt to elucidate the role of EBV in the pathogenesis of RA. METHODS: EBV DNA/RNA was investigated by polymerase chain reaction (PCR) analysis of synovial tissue from 84 patients with RA and from 81 patients with non-RA arthritis (controls) and was correlated with the patients' HLA genotype. RESULTS: EBV DNA and EBV-encoded RNA 1 transcripts were significantly more frequently present in synovial tissue from the RA patients (29 of 84) than in that from the non-RA patient controls (8 of 81). EBV DNA-positive individuals had a 5.47 times higher risk of presenting with RA than did EBV DNA-negative individuals. In HLA-DRB1*0401,0404,0405,0408-positive or shared epitope-positive patients, the risk was further increased (odds ratio for EBV and HLA-DR4 approximately 41, for EBV and the shared epitope approximately 15) compared with those who lacked both EBV DNA and RA-linked HLA genotypes. CONCLUSION: EBV seems to function as an environmental risk factor for RA, particularly in patients with the RA-linked HLA-DRB1 alleles.

Expression of cyclooxygenase 1 and cyclooxygenase 2 in human synovial tissue: differential elevation of cyclooxygenase 2 in inflammatory joint diseases.

OBJECTIVE: To compare the expression of the cyclooxygenase (COX) isoforms, COX-1 and COX-2, in synovial tissue samples between patients with inflammatory arthritis (i.e., rheumatoid arthritis [RA], ankylosing spondylitis [AS], or psoriatic arthritis [PsA]) and patients with osteoarthritis (OA). METHODS: Paraffin-embedded sections of synovial tissue from patients with OA (n = 18), RA (n = 35), AS (n = 9), and PsA (n = 16) were immunostained for COX-1 and COX-2. Staining intensity was quantified videodensitometrically from specific synovial cell areas. In addition, samples of OA and RA synovial tissue were analyzed for levels of COX-1 and COX-2 messenger RNA (mRNA) using reverse transcriptase-polymerase chain reaction. RESULTS: Strong COX-2 immunostaining was observed in synovial blood vessel endothelium, synovial lining cells, chondrocytes, and subsynovial fibroblast-like cells in patients with inflammatory arthritides. In the blood vessels, the mean (+/-SD) optical density (MOD) of staining was elevated, especially in AS samples (2.73 +/- 0.63), but also in PsA (1.99 +/- 0.66) and RA samples (1.54 +/- 0.73), in comparison with OA synovial tissue (0.84 +/- 0.30; P < 0.01 versus other groups). COX-1 staining was almost exclusively localized in synovial lining cells, with no significant differences in the MOD between the diseases. COX-2 mRNA expression was higher in RA than in OA samples (P < 0.05). CONCLUSION: The expression of COX-2, but not the expression of COX-1, was found to be elevated in a disease-related pattern in the synovial tissue from patients with RA, AS, or PsA in comparison with OA samples, and was especially high in AS synovial tissue. These results may improve our understanding of the pathogenesis of different arthritic diseases, and may have implications for the use of selective COX-2 inhibitors in the treatment of inflammatory joint symptoms.

Evaluation of synovial cytokine patterns in rheumatoid arthritis and osteoarthritis by quantitative reverse transcription polymerase chain reaction.

To compare the cytokine profile with the degree and composition of cellular infiltration in rheumatoid arthritis (RA) and osteoarthritis (OA) synovium, synovial membranes from patients with RA (n = 14) and OA (n = 5) were examined, employing immunohistochemistry and competitive reverse-transcriptase polymerase chain reaction (RT-PCR), for interleukin (IL)-I beta, IL-2, IL-4, IL-5, IL-6, and IL-10, and tumour necrosis factor-alpha (TNF-alpha) gene expression. It was found that the strength of cytokine gene expression within the synovial membranes of patients with RA was not significantly correlated with the degree of synovial infiltration of T-cells, B-cells, or macrophages. No IL-2, IL-4, or IL-5 RNA was detected in the synovium of either RA or OA. Quantitative cytokine determination showed a similar pattern in RA and OA, although the two diseases differed in total synovial infiltration and the composition of infiltrating cellular elements. Thus the number of cell types known to produce certain cytokines does not appear to determine the strength of synovial cytokine expression measured by quantitative RT-PCR. Furthermore, the pattern of T-cell specific cytokines found in RA synovium does not accord with the concept of the TH0, TH1, and TH2.

Erosive arthritis and posterior uveitis in Behçet's disease: treatment with interferon alpha and interferon gamma.

Very few patients with Behçet's disease (BD) have been treated with interferon alpha (IFN alpha) or interferon gamma (IFN gamma) to date. We report the successful longterm treatment of a female German patient with erosive arthritis and posterior uveitis with IFN alpha and IFN gamma sequentially and in combination.

[Psychosomatic aspects of patients with primary keratoconjunctivitis sicca]. / Psychosomatische Aspekte bei Patienten mit primärer Keratoconjunctivitis sicca.

PURPOSE: To evaluate the extent of psychosomatical complaints in patients with primary keratoconjunctivitis sicca (pKCS). METHODS: 20 patients (m:f = 1.19; mean age 49 +/- 7 years) with pKCS were rated according to the von Zerssen Symptom List (psychosomatical discomfort), the Maudsley Personality Inventory (MPI)-N (emotional status) and -E (extroverted-introverted) and to Beck Depression Inventory (BDI). 54 subjects (m:f = 35:17; mean age 46 +/- 17 years) without any ocular or general chronic disease were used as control group. RESULTS: In comparison to the control group the patients with pKCS showed significantly (p < 0.0001) more complaints (von Zerssen Symptom List), were more (p < 0.0001) emotionally unstable (MPI-N) and more (p < 0.0001) depressive (BDI). No group differences were found regarding extroversion-introversion (MPI-E). CONCLUSION: Our results demonstrate that many patients with pKCS showed psychological problems and disturbances. We therefore recommend an additional psychological treatment (e.g. autogenic training) for these patients to stabilize their emotional condition, which may even have a positive effect on their dry eye problems.

Immunohistochemical detection of factor XIIIa and factor XIIIs in synovial membranes of patients with rheumatoid arthritis or osteoarthritis.

In spite of differences in etiology, RA and OA lead to astonishingly similar synovitic alterations. Fibroblastic transformation of the synovial membrane and an increase in monocytes constitute a rare but highly characteristic feature of RA. Monocytes synthesize factor (F) XIII, implying that FXIII (a and s) in synovial tissue might help to differentiate between RA and OA. Biopsies were obtained at open surgery from 98 unselected patients with the clinical diagnosis of RA (n = 54) or OA (n = 44). In a three-stage (ABC) immunoperoxidase technique, polyclonal antisera against factor XIIIa and factor XIIIs were investigated. Compared to OA sections. RA synovium showed more FXIIIa-positive cells-monocytes, fibrocytes, fibroblasts and synovial lining cells. In the subsynovial layer, band-like structure of FXIIIa-stained cells was observed in 27.8% of the RA patients, but in only one OA specimen. Higher proportions of FXIIIa-positive monocytes, macrophages, histiocytes and fibroblasts, as well as positive Langhans giant cells and vascular wall regions (except endothelial cells), were observed in RA. OA specimens revealed more intense FXIIIa labeling of these cells with a lower percentage of stained cells. Overall, labeling with FXIIIs antibody resulted in less intense staining. In conclusion, distinction between synovitis caused by RA and synovitis due to OA is possible, as the former show higher numbers of FXIIIa-positive cells, including monocytes, fibroblasts, fibrocytes and synovial lining cells. Further more, RA tissue is stained less intensely than OA tissue. There is evidence for continuous excretion of FXIII in the synovial membrane by the above-mentioned cell systems.

Quantitative photometrical assessment of iron deposits in synovial membranes in different joint diseases.

We investigated 86 synovial membranes from patients suffering either from rheumatoid arthritis (RA) or osteoarthritis (OA). Iron deposits in the synovial membrane were stained by the Prussian blue reaction, and the amount of stained iron was quantitatively assessed by microscope photometry. We found a statistically significant increase in iron deposits in the synovial membrane of RA patients when compared to OA patients. The amount of iron deposits correlated with the histological subtype of synovitis, those presenting with more exudative and proliferative features showing greater amounts of iron deposits. We also observed an inverse correlation between the haemoglobin concentration and erythrocytes in the serum and the amount of iron in the synovial membrane. From our data we concluded that iron deposits in the synovial membrane can contribute by several mechanisms, including activation of oxygen radicals, to the chronic inflammatory reaction in RA synovitis.

[Cryoglobulinemia in chronic hepatitis C. Improvement by alpha-interferon is independent of virus elimination]. / Kryoglobulinämie bei chronischer Hepatitis C. Besserung durch alpha-Interferon unabhängig von der Viruselimination.

BACKGROUND: During the last few years, the association of mixed cryoglobulinemia with chronic viral infections has gained increasing interest. Chronic hepatitis C seems to play a major role. As alpha-interferon is an established therapy for chronic hepatitis C, it was also tried successfully in cryoglobulinemia type II, associated with chronic hepatitis C virus infection. PATIENTS: The course of 3 patients with cryoglobulinemia type II and chronic hepatitis C is presented. RESULTS: Two patients received immunosuppressive therapy prior to alpha-interferon without success. In all cases, remission or improvement of the cryoglobulinemia was noticed with alpha-interferon, but none of the patients cleared the hepatitis C virus. Although the treatment was well tolerated, two patients developed neurologic resp. psychiatric side effects, probably due to alpha-interferon. CONCLUSION: From our results and from data reported previously, immunomodulating treatment with alpha-interferon can be recommended for therapy of virus-associated cryoglobulinemia rather than the "classical" treatment with immunosuppressive agents. The specific side effects of alpha-interferon have to be monitored carefully.

Sacroiliitis in sarcoidosis: case reports and review of the literature.

We report the occurrence of bilateral sacroiliitis in 2 cases of biopsy-proven sarcoidosis. Tuberculosis was excluded by tuberculin testing and bronchoalveolar lavage in both cases. In the literature, 5 cases of sacroiliitis and sarcoidosis have thus far been described, but in all tuberculosis was not excluded (tuberculin testing was not performed or revealed a positive test result). In 1 of these cases tuberculosis was even simultaneously suspected to be present. In all previous cases, antituberculous or other antimicrobial agents were given. Previously reported cases of sacroiliitis in sarcoidosis are briefly reviewed, and possible relations between seronegative spondylarthropathies, slow bacterial infections, sarcoidosis and other granulomatous diseases are discussed.

[Virus-associated arthritis]. / Virusassoziierte Arthritiden.

From the about 400 virus species known to cause illness in man, only a small but growing list of representatives are able to induce arthritis. Although virus-associated arthritides are mostly of acute and short-living type, some patients develop long-lasting or even chronic joint inflammation. The viral or host factors which contribute to chronicity or severity of viral joint disease are not known. However, the study of patients with long-lasting viral arthritis and of patients with idiopathic chronic arthritides may allow unique insights into the potential role of viruses in the pathogenesis of inflammatory joint disease.

Primary systemic amyloidosis leading to advanced renal and cardiac involvement in a 30-year old man.

The case of a 30-year-old man with primary systemic amyloidosis is reported. Three months prior to admission the patient developed fever, night sweats, dyspnea, and bilateral ankle swelling. Recurrent left-sided pleural effusion led to further investigation when massive proteinuria with free monoclonal lambda chains in the urine became evident. Abdominal subcutaneous fat aspiration and renal biopsy confirmed the diagnosis of amyloidosis. Bone marrow biopsy and bone scan did not reveal multiple myeloma. Echocardiography showed a sparkling texture of the interventricular septum. Pulsed-wave Doppler recording of the left ventricular inflow profile showed the pattern of advanced cardiac amyloidosis consistent with markedly impaired diastolic heart function. Electrocardiogram-gated magnetic resonance imaging was carried out for noninvasive evaluation of cardiac function. The patient was started on repeated courses of melphalan, prednisone, and colchicine therapy. Despite increasing deterioration of renal function the therapy was tolerated quite well, and the patient is still alive 10 months after initial diagnosis. Although very rare in this age, primary systemic amyloidosis should be considered as a cause of pleural effusion, proteinuria, and congestive heart failure and should lead to further investigation.

Sweet's syndrome associated with myelodysplasia: possible role of cytokines in the pathogenesis of the disease.

The clinical course of a 56-year-old female patient with Sweet's syndrome (SS) preceded by a myelodysplastic syndrome (MDS) is described. During the acute phase of the disease with high remittent fever, painful skin lesions and maximal leucocytosis IL-6 and G-CSF serum levels were extremely high, while TNF-alpha was only slightly elevated and gamma-interferon and IL1-beta were not increased. On clinical improvement IL-6 serum levels rapidly fell, whereas G-CSF values already slightly elevated before the manifestation of the disease slowly declined. High G-CSF levels triggered by a yet unknown factor could explain the leucocytosis, neutrophilic dermatosis and skin lesions in SS, while IL-6 probably induced the associated clinical symptoms of fever and pain.

Determination of cytokines in synovial fluids: correlation with diagnosis and histomorphological characteristics of synovial tissue.

In a study aimed at correlating cytokine levels in synovial fluid with the pathology of rheumatoid arthritis (RA), tumour necrosis factor alpha, interleukin 1 beta and interferon gamma were immunoassayed in 27 patients with RA, 16 patients with other arthritides, 23 with osteoarthritis, 13 patients with trauma, and 18 patients at necropsy without inflammatory disease and not known to have had joint disease (median 27 hours after death). The results for interleukin 1 beta clearly show higher cytokine levels in patients with RA and other arthritides than in patients with osteoarthritis, trauma, or the patients at necropsy. Interferon gamma levels in patients with osteoarthritis and the patients at necropsy, however, were significantly greater than in patients with RA, and tumour necrosis factor alpha levels were also greater in the patients at necropsy compared with patients with RA. This study also correlated histomorphological patterns of synovitis and indicators of local inflammatory activity with synovial fluid cytokine levels, showing, for example, a positive association of interleukin 1 beta titre and a negative association of interferon gamma titre with ulcerogranulomatous synovitis (itself associated with RA). Taken together, these results extend and strengthen data suggesting a possible part played by increased synovial fluid levels of interleukin 1 beta in joint destruction in RA, but provide no evidence for increases in levels of tumour necrosis factor alpha or interferon gamma affecting the disease pathology.

Demonstration of cytomegalovirus (CMV) DNA and anti-CMV response in the synovial membrane and serum of patients with rheumatoid arthritis.

One hundred forty-seven synovial membranes were investigated for the presence of human cytomegalovirus (CMV). In 11 of 83 synovial membranes of patients with rheumatoid arthritis (RA), but only in 2 of 64 synovial membranes from patients with other joint disorders, CMV-DNA could be detected by the polymerase chain reaction (PCR) technique (p less than 0.05). In contrast, the percentage of seropositive patients was not significantly different between the 2 groups of patients and no blood sample from any patient tested revealed the presence of CMV by PCR. Only in patients with RA and CMV positive synovial membranes was the titer of CMV specific antibodies in the synovia higher than in the serum. Thus, the local presence of CMV in the synovial membrane and associated local antiviral responses might participate in the pathogenesis of synovitis in a minority of patients with RA.