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ObjectivesAssess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study.MethodsPatients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96.ResultsOverall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period.ConclusionsSkin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab.Trial registration numberNCT01532869; Results.

Background The treatment of severe dermatological autoimmune diseases and toxic epidermal necrolysis (TEN) with high-dose intravenous immunoglobulin (IVIg) is a well-established procedure in dermatology. As treatment with IVIg is usually considered for rare clinical entities or severe clinical cases, the use of immunoglobulin is not generally based on data from randomized controlled trials that are usually required for the practice of evidence-based medicine. Owing to the rarity of the indications for the use of IVIg, it is also unlikely that such studies will be available in the foreseeable future. Because the high costs of IVIg treatment also limit its first-line use, the first clinical guidelines on its use in dermatological conditions were established in 2008 and renewed in 2011. Materials and methods The European guidelines presented here were prepared by a panel of experts nominated by the EDF and the EADV. The guidelines were developed to update the indications for treatment currently considered as effective and to summarize the evidence base for the use of IVIg in dermatological autoimmune diseases and TEN. Results and conclusion The current guidelines represent consensual expert opinions and definitions on the use of IVIg reflecting current published evidence and are intended to serve as a decision-making tool for the use of IVIg in dermatological diseases.

Objective.Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry.Methods.The data of 3248 patients with SSc were analyzed.Results.Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005.Conclusion.These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.

Introduction Complete lymph node dissection (CLND) after a positive sentinel node (SN) biopsy provides important prognostic information in melanoma patients but has been questioned for therapeutic use recently. We explored whether quantification of the tumour spread to SNs may replace histopathology of non-sentinel nodes (NSNs) for staging purposes. Patients and methods We quantified melanoma spread in SNs and NSNs in 128 patients undergoing CLND for a positive SN. In addition to routine histopathology, one-half of each of all 1496 SNs and NSNs was disaggregated into a single cell suspension and stained immunocytochemically to determine the number of melanoma cells per 106 lymph node cells, i.e. the disseminated cancer cell density (DCCD). Results We uncovered melanoma spread to NSNs in the majority of patients; however, the tumour load and the proportion of positive nodes were significantly lower in NSNs than in SNs. The relation between SN and NSN spread could be described by a mathematical function with DCCDNSN = DCCDSNc/101−c (c = 0.69; 95% confidence interval [CI]: 0.62–0.76). At a median follow-up of 67 months, multivariable Cox regression analyses revealed that DCCDSN (p = 0.02; HR 1.34, 95% CI: 1.05–1.71) and the total number of pathologically positive nodes (p = 0.02; HR 1.53, 95% CI: 1.07–2.22) were significant risk factors after controlling for age, gender, thickness of melanoma and ulceration status. A prognostic model based on DCCDSN and melanoma thickness predicted outcome as accurately as a model including pathological information of both SNs and NSNs. Conclusion The assessment of DCCDSN renders CLND for staging purposes unnecessary.

OBJECTIVES: Patient acceptable symptom state (PASS) as an absolute state of well-being has shown promise as an outcome measure in many rheumatologic conditions. We aimed to assess whether PASS may be effective in active diffuse cutaneous SSc differentiating active from placebo. METHODS: Data from the phase 2 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial were used, which compared tocilizumab (TCZ) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks. Three different types of PASS questions were evaluated at weeks 8, 24, 48 and 96, including if a current state would be acceptable over time as a yes vs no response and Likert scales about how acceptable a current state is if remaining over time. Additional outcomes assessed included modified Rodnan skin score, HAQ disability index (HAQ-DI), physician and patient global assessments on a visual analogue scale, CRP and ESR. RESULTS: The placebo group consisted of 44 patients and the TCZ group had 43 patients. At baseline, 33% achieved a PASS for all three PASS questions, with the proportion increasing to 69, 71 and 78%, respectively, at 96 weeks. Changes in PASS scores showed a moderately negative correlation with HAQ-DI and patient and physician global assessments visual analogue scales, which indicates expected improvements as PASS improved. The PASS question, 'Considering all of the ways your scleroderma has affected you, how acceptable would you rate your level of symptoms?' showed significant correlations with patient-reported outcomes and differentiating placebo vs TCZ at 48 weeks (P = 0.023). Conclusion: PASS may be used as a patient-centred outcome in SSc, especially as a 7-point Likert scale. Further validation is required to determine the utility as an outcome measure in trials and clinical practice.

Background: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. Objectives: To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). Methods: The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. Results: Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often ‘other antibodies’ (68.0%; p

The exact prevalence of psoriatic arthritis (PsA) among patients with psoriasis is still not conclusive. Data in the literature vary between 5.8 and 30 %. Objective of this study was to gain more information on the prevalence of PsA among patients with psoriasis in Germany. Between 09/2010 and 05/2011, consecutive patients from dermatological private practices and a university hospital with psoriasis were asked to fill out the validated German Psoriatic Arthritis Diagnostic (GEPARD) Questionnaire. Patients who answered ≥4 questions with "yes" were invited to come for a rheumatological check up. Those patients who refused a rheumatological examination were counted as "absence of PsA". Laboratory tests for inflammatory markers as well as the severity of skin manifestations were assessed. The diagnosis of PsA was made according to the CASPAR criteria, and imaging was performed in addition. A total of 404 questionnaires were evaluated; 50.5 % answered ≥4 questions positively; 19.3 % had a history of PsA confirmed by a rheumatologist; and in 10.9 %, PsA or spondyloarthritis was newly diagnosed during the present study. This leads to an overall prevalence of PsA in patients with psoriasis of 30.2 %. The frequency of psoriatic arthritis in the present study is higher than expected from previous studies in Germany. The prevalence is consistent with findings of a large observational survey from Scandinavia. Using the CASPAR criteria and imaging in all patients, certainty of the diagnosis is very high. The GEPARD Questionnaire is a helpful tool to identify people at risk for psoriatic arthritis.

Pyoderma gangrenosum (PG) is a severe ulcerative skin disease. Despite systemic immunosuppressive therapy, PG ulcers often progress and can develop into life-threatening conditions. In this case series, we treated 6 patients suffering from recalcitrant PG with topical coagulation factor XIII, which has been shown to exert beneficial effects on tissue regeneration and wound healing. All 6 patients showed a positive response to treatment with a marked reduction in wound size that was maintained during a 3-month follow-up period. The treatment was well tolerated with no remarkable adverse effects or complications. Topical factor XIII has potential in combination with standard immunosuppressive therapy for the treatment of PG.

The purpose of this study was to assess the impact of enteric-coated mycophenolate sodium (EC-MPS) on skin and pulmonary manifestations of patients with progressive systemic sclerosis (Ssc). A prospective, open-label single-centre trial with EC-MPS 2 × 720 mg/day over 12 months and a long-term follow-up of 50 months were conducted. Modified Rodnan skin score (mRSS) was used to assess the skin and pulmonary function tests to assess the pulmonary involvement. In order to quantify the extent of alveolitis/fibrosis via densitometry, the high attenuation value, median lung density and percentiles of lung tissue densities were obtained by high-resolution computed tomography. Eleven patients were included. Three patients had to stop medication before month 6 (2× side effects, 1× progression). For the remaining eight patients, the median mRSS was non-significantly reduced from 13.5 at baseline to 11 at month 12. According to the CT histography, median lung density and high attenuation values remained stable. However, the course of percentiles -200 to -300 and particularly -300 to -400 Hounsfield units slightly increased in seven of eight patients after 12 months, suggesting worsening of pulmonary involvement. Accordingly, median diffusing capacity for carbon monoxide showed a tendency to decline (75.1 % vs. 70.2) while forced vital capacity non-significantly improved (78.0 vs. 85.5 %) during the study. Four patients are still on EC-MPS without clinical signs of progression after 50 months follow-up. EC-MPS showed non-significant improvement of the skin. Pulmonary fibrosis remained stable with only a slight tendency towards progression which might be ascribed to the medication as well as the natural course of the disease. CT histography appears to be a sensitive method for the detection of progression of pulmonary fibrosis and therefore should be considered for further studies in Ssc.

Summary Background Systemic sclerosis is a rare disabling autoimmune disease with few treatment options. The efficacy and safety of tocilizumab, an interleukin 6 receptor-α inhibitor, was assessed in the faSScinate phase 2 trial in patients with systemic sclerosis. Methods We did this double-blind, placebo-controlled study at 35 hospitals in Canada, France, Germany, the UK, and the USA. We enrolled adults with progressive systemic sclerosis of 5 or fewer years' duration from first non-Raynaud's sign or symptom. Patients were randomly assigned (1:1) to weekly subcutaneous tocilizumab 162 mg or placebo. The primary endpoint was the difference in mean change from baseline in modified Rodnan skin score at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT01532869. Findings We enrolled 87 patients: 43 assigned to tocilizumab and 44 assigned to placebo. The least squares mean change in modified Rodnan skin score at 24 weeks was −3·92 in the tocilizumab group and −1·22 in the placebo group (difference −2·70, 95% CI −5·85 to 0·45; p=0·0915). The least squares mean change at 48 weeks was −6·33 in the tocilizumab group and −2·77 in the placebo group (treatment difference −3·55, 95% CI −7·23 to 0·12; p=0·0579). In one of several exploratory analyses, fewer patients in the tocilizumab group than in the placebo group had a decline in percent predicted forced vital capacity at 48 weeks (p=0·0373). However, we detected no significant difference in disability, fatigue, itching, or patient or clinician global disease severity. 42 (98%) of 43 patients in the tocilizumab group versus 40 (91%) of 44 in the placebo group had adverse events. 14 (33%) versus 15 (34%) had serious adverse events. Serious infections were more common in the tocilizumab group (seven [16%] of 43 patients) than in the placebo group (two [5%] of 44). One patient died in relation to tocilizumab treatment. Interpretation Tocilizumab was not associated with a significant reduction in skin thickening. However, the difference was greater in the tocilizumab group than in the placebo group and we found some evidence of less decline in forced vital capacity. The efficacy and safety of tocilizumab should be investigated in a phase 3 trial before definitive conclusions can be made about its risks and benefits. Funding F Hoffmann-La Roche, Genentech.

To explore the role of whole-body magnetic resonance imaging (MRI) in detecting musculoskeletal involvement in patients with systemic scleroderma and musculoskeletal symptoms. Eighteen consecutive patients (8 men, 10 women) with systemic scleroderma (median age 46 years) presenting with musculoskeletal complaints underwent whole-body MRI at 1.5 T. Images were evaluated for abnormal signal intensity and/or thickening of subcutaneous fatty tissue septa, muscular fasciae, intramuscular perifascial septa, muscle signal intensity and articular or tendon sheath synovial abnormalities on STIR and post-gadolinium scans. Additionally, C-reactive protein, creatinine kinase and the modified Rodnan skin score were determined. MRI indicated evidence of fasciitis, articular synovial inflammation, and subcutaneous thickening in 16 (89 %) patients. MRI findings were compatible with myopathy or myositis in 14 (78 %) patients, tenosynovitis in 11 (61 %) patients and enthesitis in 10 (56 %) patients. Typically, these manifestations were distributed symmetrically and mostly generalised. We only found few correlations with modified Rodnan skin score, C-reactive protein and creatinine kinase. In patients with systemic scleroderma experiencing musculoskeletal symptoms, whole-body MRI is able to detect involvement of muscles, fasciae, joints and entheses more confidently compared with clinical and laboratory parameters. • Whole-body MRI reliably detects musculoskeletal involvement in patients with systemic scleroderma. • Abnormal MRI findings are frequently seen in patients with symptomatic systemic scleroderma. • Musculoskeletal MRI findings correlate only in part with the clinical score and laboratory biomarkers. • Early detection of musculoskeletal abnormalities by MRI may improve the staging.

Der Morbus Behcet (MB) ist eine Systemerkrankung mit dem histopathologischen Korrelat einer leukozytoklastischen Vaskulitis. Die Klassifikationskriterien der Erkrankung beinhalten das Vorhandensein oraler Aphthen in Kombination mit mindestens 2 weiteren Organmanifestationen wie genitale Aphthen, Hautmanifestationen oder einer Augenbeteiligung. Als pathognomonisch kann ein positives Ergebnis des Pathergietests gewertet werden. Die Prognose des MB ist immer dann ungunstig, wenn lebenswichtige Organe mitbetroffen sind. Dies gilt v. a. fur die in ca. 10% auftretende Beteiligung des zentralen Nervensystems, die arteriellen und pulmonalarteriellen Aneurysmata sowie die gastrointestinale Beteiligung. Differenzialdiagnostische Schwierigkeiten bereitet v. a. die in ca. 50% vorhandene Oligoarthritis. Der MB ist in 50–80% der Falle mit HLA-B51 assoziiert. Eine besonders ungunstige Prognose besteht immer dann, wenn die Erkrankung sich bereits bei relativ jungen Mannern erstmanifestiert. Die Therapie der extraokularen Manifestationen richtet sich nach deren Aggressivitat. So werden leichtere Manifestationen der Erkrankung mit niedrig dosiertem Prednisolon und steroidsparenden Immunsuppressiva wie Azathioprin oder Cyclosporin A behandelt, bei schwereren Manifestationen, wie z. B. der ZNS Beteiligung, kommen auch Cyclophosphamid oder TNF-Antagonisten, in ausgewahlten Fallen auch Interferon-α in Betracht.

Objective To describe the long-term effects of infertility on life and partnership satisfaction. Design Longitudinal cohort study. Setting A university outpatient andrology and gynecology infertility clinic. Patient(s) 275 men and 272 women treated for infertility between August 2000 and December 2001. Intervention(s) None. Main Outcome Measure(s) The Life Satisfaction Questionnaire (FLZ), the Partnership Questionnaire (PFB), and sociodemographic items at baseline (T1) and 5 years later (T2). Result(s) Compared with a representative sample, our male and female participants had higher Finance and Partnership scores and lower Health scores on the FLZ at T1. They also had markedly higher PFB scores, with the exception of Conflict Behavior. After 5 years (T2), 101 men and 113 women rated the Partnership and Sexuality FLZ subscales as well as all the PFB subscales statistically significantly lower than at baseline. Only the women rated the Self-esteem FLZ subscale lower than at baseline (T1). Participants who became parents had lower Leisure and Partnership FLZ subscale scores, and fathers had lower Finance FLZ subscale scores. Conclusion(s) Satisfaction declined over 5 years for both men and women, but only in the partnership-related domains. Women were more affected than men. The success of infertility treatment had only a minor influence on a couple's future satisfaction.

Summary Metastases from uveal melanoma are often confined to the liver. Palliative hepatic chemoembolization has been considered to be a reasonable treatment approach. We enrolled 14 patients with hepatic metastases from uveal melanoma into a pilot trial of transarterial chemoembolization (TACE). All patients received additional systemic immuno-chemotherapy or best supportive care. In 31 procedures 100 mg/m 2 of cisplatine was continuously infused by means of a power injector preceding embolization by manual injection of polyvinyl alcohol particles. In three procedures cisplatine was replaced by 200 mg/m 2 carboplatine because of increased serum creatinine levels. Tumor response was evaluated using RECIST criteria. Fourteen patients received 34 TACE's (mean: 2.4 treatments). Eight patients (57%) achieved partial response (PR), four patients (29%) had stable disease and two patients (14%) tumor progression. Median time to progression was 8.5 months (5–35 months). Median survival after first TACE was 14.5 months in responders compared to 10 months in non-responders ( p = 0.18, not significant) and 11.5 months (3–69 months) in all patients. In seven patients with metastases occupying less than 25% of liver volume median survival was 17 months compared to 11 months in seven patients with tumor involvement of more than 25% (p = 0.02) with partial response rate of 86% and 29%, respectively. TACE of liver metastases from uveal melanoma is well tolerated and may prolong survival in patients with limited tumor extension.

Summary Background: Prostaglandin E1 ethyl ester (PGE1-EE) is a prodrug of prostaglandin E1 but with much improved transdermal penetration. Patients and Methods: We performed a randomized, double-blind, controlled study in 34 patients to assess the safety and efficacy of transdermally applied PGE1-EE for the treatment of erectile dysfunction. In a first single-blinded titration period the most appropriate PGE1-EE dose (maximum 1000 μg) was determined. PGE1-EE was applied to the shaft of the penis using an adhesive foil patch which contained the drug. For home use, the patients were provided with 4 patches with the appropriate dose and 2 patches with placebo containing a small dose of 5 μg PGE1-EE to use randomly prior to sexual intercourse, waiting three days between each use. Results: The median rigidity score as the primary outcome variable was significantly higher after verum versus placebo applications. Also, concerning the secondary outcome variable satisfactory sexual activity, superiority was shown for verum versus placebo. Although penetrating intercourse could not be performed significantly more frequently, 50 % of patients considered the treatment successful. It was well-tolerated and local side effects were generally mild. Conclusions: PGE1-EE could be a promising drug formulation in local penile therapy of ED. In further studies higher doses should be investigated in order to potentially achieve a higher level of efficacy.

Acta Ophthalmol. 2011: 89: 17–24 Abstract. Purpose: To evaluate whether tumour therapy for malignant uveal melanoma leads to a shedding of melanoma cells into the systemic circulation. Methods: Ninety-four peripheral blood samples from 81 patients with malignant uveal melanoma were collected before and after different tumour therapies and the number of circulating melanoma cells (CMCs) was investigated (seven patients with enucleation, 49 patients with stereotactic radiotherapy, 19 patients with endoresection of the tumour, 15 patients with ruthenium-brachytherapy and four patients with transpupillary thermotherapy). A cellular approach was used to detect CMCs through an immunocytological assay with tumour cell enrichment by immunomagnetic cell sorting. The number of CMCs was analysed further according to specific patient characteristics, tumour parameters and the development of metastasis. Results: There was no significant difference between the number of CMCs before and after the different therapies (p = 0.78). There was also no significant association between established prognostic parameters of primary uveal melanoma and the detection of CMCs (all p >0.05). The number of CMCs was not related to the development of metastasis in a short median follow-up time of 16 months (p > 0.05). Conclusion: No changes in CMC values were observed before and after different tumour therapies. In the majority of cases therapy does not lead to a shedding of detectable melanoma cells into the systemic circulation.

Die Behandlung von schweren autoimmunbedingten Hauterkrankungen und der toxischen epidermalen Nekrolyse (ICD: L51.2) mit hochdosierten intravenosen Immunglobulinen (IVIg) stellt in der Dermatologie ein bewahrtes therapeutisches Procedere dar. Da IVIg in der Regel nur bei seltenen Autoimmunerkrankungen oder bei besonders schweren Krankheitsverlaufen verabreicht werden, beruht die Anwendung von Immunglobulinen in der Dermatologie meist nicht auf Erfahrungen aus kontrollierten und randomisierten Studien, die im Rahmen der evidenzbasierten Medizin ublicherweise gefordert werden. Angesichts der Seltenheit der Indikationen fur eine IVIg-Gabe ist es eher unwahrscheinlich, dass derartige Studien in absehbarer Zukunft durchgefuhrt werden. Da daruber hinaus die hohen Behandlungskosten einer IVIg-Behandlung den Einsatz von IVIg als First-line-Therapie limitieren, existieren bislang keine klaren Richtlinien fur deren Einsatz bei Hauterkrankungen. Die vorliegende Empfehlung beruht auf dem Konsens einer Working Group on European Guidelines (Arbeitsgruppe fur Europaische Richtlinien) des EDF (European Dermatology Forum) und der EADV (European Association of Dermato-Venerology) und soll als Entscheidungshilfe fur den Einsatz von IVIg bei der Behandlung dermatologischer Erkrankungen dienen.

The treatment of severe autoimmune skin diseases and of toxic epidermal necrolysis (ICD: L51.2) with high-dose intravenous immunoglobulins (IVIg) is an established therapeutic procedure in dermatology. As IVIg are usually only administered in rare autoimmune diseases or in particularly severe disease courses, use of immunoglobulins in dermatology is commonly not based on experience from controlled and randomized studies typically demanded by evidence-based medicine. In face of the rarity of indications for IVIg it is improbable that such studies will be performed in the foreseeable future. Further, as the high costs of IVIg treatment limits its use as first-line therapy, no clear guidelines exist yet on IVIg use in skin diseases. The present recommendation is based on a consensus of the Working Group on European Guidelines of the EDF (European Dermatology Forum) and the EADV (European Association of Dermato-Venereology) and should provide aid in decision making for the use of IVIg in treating dermatologic diseases

Zusammenfassung: Wahrend einer 5monatigen Tamoxifentherapie (2 times 10 bzw. 2 times 20 mg/die) kommt es zu einem signifikanten Anstieg von Testosteron, LH, FSH, Ostradiol, freiem Testosteron und SHBG. Der Prolaktinspiegel fallt ab. Im Ejakulat sinken innerhalb des Normwertes der pH-Wert und die Fruktose. Die Spermatozoendichte steigt signifikant an; dabei bleibt unsicher, ob mit 2 times 20 mg/die bessere Ergebnisse erzielt werden. Mit unseren bisherigen Untersuchungsmethoden war eine Auswahl der Patienten, die auf die Behandlung gut ansprechen, nicht moglich. Tamoxifen scheint bei normo-, aber auch bei hypo- und hypergonadotropen Patienten wirksam zu sein. Summary: Therapeutic Results with Tamoxifen in Oligozoospermia II. Hormonal Analysis and Semen Parameters During a five months lasting treatment with tamoxifen (2 times10 resp. 2 times 20 mg daily) a significant increase of testosterone, LH, FSH, estradiol, free testosterone and SHBG was found. The prolactin levels diminished. In semen analysis the values of pH and fructose decreased within the normal range. The sperm density increased significantly, but we could not ascertain whether a dosage of 2 times 20 mg/die will provide better therapeutic results. Furthermore the hormonal and seminal investigations described in this paper did not allow to predict those patients who would be good responders on tamoxifen therapy. Tamoxifen seems to be effective in normo-, but also in hypo- and hypergonado-tropic patients.

210 males with idiopathic oligozoospermia or oligo-astheno-teratozoospermia were treated with tamoxifen (2 X 10 resp. 2 X 20 mg daily) over a period of five months. Investigations which were performed concomitantly revealed no significant changes in body weight, blood pressure, blood sedimentation rate, red and white blood count including the number of thrombocytes. In the multi-analysis of serum we found significant differences within the normal range concerning the following parameters: creatinine, albumin, cholesterol, phosphorus, sodium, calcium, alkaline phosphatase, LAP and gamma-GT. Most of those changes in serum values could be explained by an anabolic metabolism due to an increased testosterone level and by additional stress of the liver function. On 41 of those patients an ultrasonography of the testes was performed; in more than 50% the testicular volume increased during therapy with tamoxifen.

Purpose: In patients with uveal melanoma, tumor cell dissemination and subsequent formation of metastases are confined mainly to the hematogenous route. Here, we sought to isolate circulating melanoma cells in peripheral blood of patients with primary uveal melanoma and clinically localized disease. Experimental Design: Blood samples from 52 patients with clinically localized uveal melanoma and from 20 control individuals were prospectively collected before therapy of the primary tumor. Tumor cells expressing the melanoma-associated chondroitin sulfate proteoglycan were enriched by immunomagnetic cell sorting and visualized by immunocytologic staining. Results were compared with clinical data at presentation. Results: In 10 of 52 patients [19%; 95% confidence interval (95% CI), 10-33%], between 1 and 5 circulating melanoma cells were detected in 50 mL peripheral blood. No melanoma-associated chondroitin sulfate proteoglycan–positive cells were detected in any of the 20 controls examined. The presence of tumor cells in peripheral blood was associated with ciliary body invasion [odds ratio (OR), 20.0; 95% CI, 3.0-131.7], advanced local tumor stage (OR, 6.7; 95% CI, 1.8-25.4), and anterior tumor localization (OR, 4.0; 95% CI, 1.2-12.7), all established factors for uveal melanoma progression. Conclusions: Immunomagnetic enrichment enables detection of intact melanoma cells in peripheral blood of patients with clinically localized ocular disease. Visualization and capturing of these cells provide a unique tool for characterizing potentially metastasizing tumor cells from a primary melanoma at an early stage of the disease.

To describe musculocutaneous MR-findings responsible for disability in chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT).Between June 2005 and February 2008, we performed whole-body musculoskeletal magnetic resonance imaging (MRI; n = 12) or regional MRI (n = 4) in 16 consecutive patients presenting with disabling sclerodermatous cGVHD (e.g., skin edema, fixed deep dermal sclerosis, joint contractures, painful muscular contractures, or myalgia).In all patients, MRI showed musculocutaneous abnormalities reflecting different degrees of inflammation and collagen tissue involvement of the skin (n = 10), subcutaneous fat tissue (n = 13), muscle fasciae (n = 16), subfascial muscular septae (n = 6), or findings compatible with myositis (n = 3). The most frequently involved muscle fasciae comprised those of the vastus lateralis muscle (n = 12), biceps femoris muscle (n = 11), gastrocnemius medialis muscle (n = 8), serratus anterior muscle, and latissimus dorsi muscle (each, n = 5). Increased signal of involved tissues on STIR-images and fat-saturated postgadolinium T1-weighted images represented the most frequent MR-signal abnormalities.MR imaging of musculocutaneous cGVHD allows accurate evaluation including assessment of deep tissue infiltration and assists in the differential diagnosis.

Objective. Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. Methods. A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. Results. Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). Conclusion. In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

OBJECTIVE. Our objective was to describe the spectrum of MRI features in patients with deep and generalized morphea.CONCLUSION. Imaging features of morphea are not specific and usually overlap with those of other disorders involving the skin, fascia, and musculature, such as some types of fasciitis, myositis, and so forth. Nevertheless, the imaging features of morphea reflect pathomorphologic changes of this rare disorder and enable a complete assessment of the disease extent, including depth of infiltration and disease activity.

BACKGROUND Interferons have been reported to significantly contribute to tumor suppression via both induction of p53 gene expression and inhibition of angiogenesis. OBJECTIVE The assessment of treatment toxicity and antitumoral effectiveness of continuous IV administration of interferon-beta based on an overall evaluation of laboratory, radiographic, and clinical parameters observed during the trial. METHODS The authors treated patients with advanced malignant melanoma with continuous IV infusions of 1 x 10(6) IU interferon-beta daily ( approximately 0.6 x 10(6) IU interferon-beta/m2 daily). RESULTS Continuous IV administration of interferon-beta had no significant effect on overall patient outcome. Interferon side effects were not a reason for treatment discontinuation in any of the patients observed during this trial. CONCLUSIONS Continuous IV interferon-beta had no significant effect on overall patient outcome in a group of patients with advanced malignant melanoma. To our knowledge, this is the first report on the continuous IV administration of interferon-beta in patients with advanced malignant melanoma.

The aim of this study was to evaluate the incidence of neurological manifestations of Behcet's disease (BD) in patients on cyclosporin A (CSA) compared with those on other medications. The records of 117 patients with BD who visited our hospital between 1990 and 2003 were reviewed with respect to symptoms and medication. All episodes of constant therapy prior to central nervous system (CNS) involvement were counted, and then the associations were analysed by the exact Fisher-Freeman-Halton test and adjusted for multiple tests by the Bonferroni-Holm method. We observed ten new cases of CNS manifestations in our patients with BD being regularly seen and treated in our tertiary care centre. The overall prevalence of neuro-BD in our patient group was 8.5%. In a retrospective analysis, the incidence of new-onset neurological disease (neuro-BD) in all patients with BD who regularly visited our hospital was significantly higher in patients on CSA than in those on other medications (6 of 21 vs 0 of 175 episodes, P

Purpose: The finding of melanoma cells in the peripheral blood, thus far mainly inferred from the PCR-based demonstration of tyrosinase mRNA, has been associated with metastatic melanoma. Neither the malignant nature nor the prognostic significance of circulating cells could be established. To address this question, we analyzed immunomagnetically isolated circulating melanoma cells for chromosomal aberrations and performed a clinical follow-up study of the enrolled patients. Experimental Design: In a prospective study, blood samples were taken from 164 melanoma patients and 50 donors without malignant disease. Circulating melanoma cells were enriched by immunomagnetic cell sorting using a murine monoclonal antibody against the melanoma-associated chondroitin sulfate proteoglycan. To prove the malignant origin of the positive cells and to define their chromosomal aberrations, we analyzed the genomes of 15 individually isolated cells from seven patients by single-cell comparative genomic hybridization (SCOMP). Results: Absolute and relative frequencies of circulating melanoma cells were associated with stage and with the presence or absence of detectable tumor. The detection of two or more cells correlated significantly with a reduced survival of patients with metastatic melanoma. All of the cells that were analyzed by SCOMP displayed multiple chromosomal changes and carried aberrations typical for melanoma. Conclusions: Immunomagnetic enrichment enables isolation and genomic characterization of circulating melanoma cells. The prognostic impact on survival of metastatic patients apparently reflects the aggressiveness of an ongoing tumor spread. Direct genomic analysis of the enriched and isolated cells will help to clarify the molecular-genetic basis of the establishment of generalized melanoma.

Mycophenolate mofetil (MMF) is an immunosuppressive agent that has been shown to be effective in transplant patients. Some case reports and pilot studies have suggested efficacy against systemic lupus erythematosus (LE), particularly in the case of lupus nephritis. Reports on MMF treatment of skin manifestations of LE are still anecdotal. We report two cases with extensive skin lesions owing to subacute cutaneous LE (SCLE). Both patients had been treated with azathioprine and antimalarials without effect. Finally both patients were given highly dosed glucocorticosteroids, which were also ineffective but led to vertebral fractures because of long-term steroid treatment in one patient and steroid-induced psychosis in the other. MMF 2 g daily caused the skin manifestations to disappear within a few weeks in both patients. One patient was followed up for more than 24 months, and showed good toleration of MMF treatment. The skin remained stable over this period when at least 1 g MMF per day was administered. In conclusion, MMF appears to be an attractive treatment option in skin manifestations of SCLE, and seems to be beneficial for patients with steroid-refractory lesions that are also resistant to treatment with immunosuppressants or antimalarials. The observations suggest that further evaluation of this route in randomized controlled trials is warranted.

SummaryBackground Primary cutaneous γ/δ T-cell lymphoma (PCGD-TCL) is aggressive and has a poor prognosis. In contrast, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) of the α/β T-cell receptor phenotype is known to follow an indolent course and have a more favourable prognosis. In the past, PCGD-TCL and SPTCL were often considered to be a manifestation of the same disease, and aggressive systemic polychemotherapy has commonly been the first-line therapy for both. Given the understanding that SPTCL is a separate and less aggressive entity, clinical data exclusively evaluating the efficacy of conservative treatment in SPTCL are needed. Objectives To assess the overall clinical response to systemic corticosteroids in the treatment of SPTCL. Methods This was a retrospective cross-sectional study based on a patient data repository from two tertiary care university hospitals in Zurich (Switzerland) and Tubingen (Germany). The repository spanned 13 years. Results In four of the five patients (80%) with SPTCL, treatment with systemic corticosteroids induced a complete remission. Conclusions Systemic corticosteroids may be an excellent first-line single-agent therapy for SPTCL.

Das subkutane pannikulitische T-Zell-Lymphom gehort zu einer Untergruppe peripherer T-Zell-Lymphome. Klinisch ist die Erkrankung charakterisiert durch das Auftreten von subkutanen Knoten an Stamm und Extremitaten. Histologisch zeigen sich in der Subkutis atypische Lymphozyten und benigne phagozytierende Makrophagen, die so prominent sein konnen, das der Eindruck einer benignen Pannikulitis entsteht. Wir berichten uber eine 75jahrige Patientin mit einer 3wochigen Anamnese von asymptomatischen, subkutanen Knoten. Histologisch und molekularbiologisch wurde die Diagnose eines subkutanen T-Zell-Lymphoms gestellt. Eine Chemotherapie muste wegen rapider Verschlechterung des Allgemeinbefindens der Patientin abgebrochen werden. Die Patientin verstarb wenige Wochen nach Diagnosestellung.

Berichtet wird der Fall eines CREST-Syndroms mit ausgepragten Teleangiektasien im Bereich der Akren und des Gastrointestinaltraktes mit chronischen intestinalen Sickerblutungen und chronischer Blutungsanamie. Diese Teleangiektasien konnten eindeutig auf das CREST-Syndrom zuruckgefuhrt werden, eine Eisensubstitution ist z.Z. bei dem Patienten ausreichend. Bei weiterem Behandlungsbedarf steht die endoskopische Sklerosierungstherapie zur Verfugung. Gastrointestinale Blutungen beim CREST-Syndrom sind selten beschrieben, moglicherweise deshalb, weil sie unerkannt bleiben oder als erosive Gastritis fehlgedeutet werden. Beim CREST-Syndrom sollte daher an gastrointestinale Teleangiektasien mit Blutungsgefahr gedacht werden..

The extent and consequences of professional delay in diagnosis were analysed in 83 patients with palmoplantar and subungual melanomas treated from January 1986 to March 1997 in our department. Seventeen (52%) out of 33 subungual melanomas and 10 (20%) out of 50 palmoplantar melanomas were clinically misdiagnosed by physicians. Three palmoplantar melanomas (6%) were initially misinterpreted by pathologists. In 23 of the 27 cases (85%) the clinical misdiagnosis was made by non-dermatologists. Misdiagnosis caused a median delay of 12 months in the diagnosis of palmoplantar melanomas and 18 months in the diagnosis of subungual melanomas. Delay in diagnosis was associated with increased tumour thickness, more advanced stage at time of melanoma diagnosis and a lower estimated 5-year survival rate (15.4% versus 68.9% for palmoplantar; 68.5% versus 90.9% for subungual). Acral melanomas are frequently misdiagnosed due to their less common locations and because plantar and subungual melanomas often do not fit the 'changing mole' pattern. To Improve the patient's prognosis it is necessary to increase the physicians' skill in the diagnosis of acral melanomas. Histological examination should always be performed in acral lesions that do not heal.

Beim Scleroedema adultorum Buschke handelt es sich um eine seltene Bindegewebserkrankung unklarer Atiologie. Kennzeichnend ist eine odematose Induration der Haut. In der verbreiterten Dermis lassen sich vermehrt saure Proteoglykane nachweisen. Klassischerweise ist nur die Haut betroffen. In bisher 24 Fallen wurde uber eine assoziierte monoklonale Gammopathie berichtet. Im folgenden vorgestellt wird ein 75jahriger Patient mit Scleroedema adultorum und inzwischen 19jahriger Krankheitsdauer. Neben einer monoklonalen Gammopathie liegen bei dem Patienten eine ausgepragte Zungen-, Pharynx- und Osophagusbeteiligung vor. Nachweisbar ist weiterhin eine Augenbeteiligung in Form von Augenmotilitatsstorungen, eine Sicca-Symptomatik und eine Polyneuropathie. Uber das gemeinsame Auftreten der typischen Hautveranderungen eines Scleroedema und jeweils einzelner dieser Organbeteiligungen wurde kasuistisch berichtet. Bemerkenswert und bisher in der Literatur nicht beschrieben ist die Vielzahl der assoziierten extrakutanen Manifestationen, die bei dem hier vorgestellten Patienten vorlagen.

An 80-year-old woman was referred to our hospital with a spontaneously appearing bullous dermatosis limited to the soles of both feet, causing an intense pruritus. She also suffered from Parkinson's disease and depression, and had been treated with levodopa, benserazide, and mirtazapine for several years. On clinical examination, we found several tense and hemorrhagic bullae, with a diameter of up to 3 cm, at both plantar sites and multiple, confluent, dyshidrotic vesicles ( Figs 1 and 2). The rest of the skin, including the mucous membranes and palms, was normal. The first clinical diagnosis was podopompholyx, but histopathologic findings and direct immunofluorescence revealed a diagnosis of bullous pemphigoid, showing subepidermal blisters (Fig. 3) and linear deposits of C3 and immunoglobulin G (IgG). Indirect immunofluorescence was positive, the IgG autoantibodies bound to the epidermal site of salt-split skin, and circulating antibodies against bullous pemphigoid antigens 1 and 2 were found. Because of this typical clinical picture, a diagnosis of dyshidrotic pemphigoid, a localized form of bullous pemphigoid, was made. Under systemic treatment with prednisolone, 40 mg/day, the skin healed completely within 2 weeks. Descriptions of dyshidrotic pemphigoid limited to the soles of both feet are very rare, and the clinical findings might easily lead to a misdiagnosis of podopompholyx.

Daptomycin has proven efficacy in patients with Gram-positive complicated skin and soft tissue infections (cSSTIs), including those caused by Staphylococcus aureus, regardless of methicillin susceptibility. This study was undertaken to evaluate the efficacy and safety of daptomycin in elderly patients. This was an open-label, multicentre, randomized phase IIIb study conducted in hospitalized patients Patients aged ≥65 years with a diagnosis of Gram-positive cSSTIs with or without bacteraemia were included. In addition, infections were required to be of sufficient severity to require inpatient hospitalization and treatment with parenteral antibiotics for at least 96 h. The main exclusion criterion was the presence of a non-complicated SSTI that could heal by itself or be cured by surgical removal of the site of infection. Patients were randomized (2:1) to intravenous daptomycin or pooled intravenous standard therapies (semi-synthetic penicillin or vancomycin, referred to as the ‘comparator’). Duration of treatment was between 5 and 14 days for cSSTIs without bacteraemia and between 10 and 28 days for cSSTIs with bacteraemia. The primary objective was descriptive comparison of clinical success in clinically evaluable patients at test of cure, 7–14 days post treatment. Secondary objectives were microbiological outcome, duration of treatment and safety. In total, 120 patients were randomized (81 to daptomycin; 39 to the comparator) and 102 patients completed the study. Baseline characteristics were similar between the two groups. Common infections included cellulitis, ulcers and abscesses; six patients had bacteraemia [five documented (daptomycin, n = 3; comparator, n = 2); and one suspected (daptomycin, n = 1)]. Test-of-cure clinical success rates were numerically higher for daptomycin than for the comparator [89.0 % (65/73) vs. 83.3 % (25/30); odds ratio 1.65 (95 % confidence interval 0.49–5.54)]. For patients with S. aureus infections, cure rates were 89.7 % (35/39) versus 69.2 % (9/13), respectively; percentage points difference, 20.5 (95 % confidence interval −12.2 to 50.9)]. Rates of adverse events (AEs) and serious AEs were similar in both treatment arms; however, discontinuation rates for AEs/serious AEs were lower for daptomycin than for the comparator (3.8 % vs. 10.0 %). Three serious AEs were considered to be related to the study drug: one case each of pancytopenia (semi-synthetic penicillin), renal failure (vancomycin) and asymptomatic increase in creatine phosphokinase concentrations (daptomycin). In elderly patients, for whom data were previously limited, the efficacy and safety of daptomycin have been confirmed, including for infections caused by S. aureus, regardless of methicillin susceptibility.

We conducted a longitudinal cohort study on the quality of life of infertile male patients measured at baseline and after 5 years with a specific quality of life instrument for male patients who are involuntarily childless. It was distributed to patients who were seen at the andrology and gynaecology clinics for infertility diagnoses and treatment. At baseline (T1), 275 patients took part in the study. A subset of these patients (N = 133) had released two semen samples, and the results of the semen analysis had been communicated to them before they received the questionnaire. Semen quality of this subset was assessed according to WHO recommendations. After 5 years (T2), the questionnaires were mailed again and were sent back by N = 101 patients. No significant quality of life difference was found between the semen quality groups. After 5 years, an improvement was found for the dimensions 'desire for a child' [mean score 1.92 (T1) versus 1.72 (T2)] and 'gender identity' [mean score 1.56 (T1) versus 1.42 (T2)] while no change was found for 'partnership' and 'psychological well-being'. We did not find significant differences between patients who had fathered a child in the meantime and patients who did not become fathers.

The purpose of this article is to explore the role of MRI in monitoring musculoskeletal involvement in patients with morphea who are undergoing treatment with methotrexate and prednisolone.Twenty-two consecutive patients (six men and 16 women; median age, 52 years) with systemic scleroderma and deep morphea prospectively underwent whole-body MRI twice, before treatment (time 1) and during follow-up after 6-12 months (time 2). Images were evaluated for abnormal signal intensity or thickening of sub-cutaneous fatty tissue septa, muscular fasciae, intramuscular perifascial septa, muscle signal intensity, and articular or tendon sheath synovial abnormalities on STIR and gadolinium-enhanced scans. For clinical assessment, the localized scleroderma (morphea) severity index and a 0-6 pain score were applied.From a clinical point of view, none of our patients had progression of the disease, 12 patients were responders (defined as an improvement of localized scleroderma severity index and pain score ≥ 50%), and 10 patients had stable disease. Among responders, the number of patients with subcutaneous septal thickening (time 1, n = 9; time 2, n = 2), fascial enhancement (time 1, n = 8; time 2, n = 3), and articular synovitis (time 1, n = 5; time 2, n = 1) decreased more than in the stable disease group (subcutaneous septal thickening: time 1, n = 9; time 2, n = 8; fascial enhancement: time 1, n = 5; time 2, n = 5; articular synovitis: time 1, n = 8; time 2, n = 6). Subcutaneous thickening, fascial thickening, and fascial enhancement were scored significantly lower at follow-up MRI in responders.MRI findings were sensitive to changes in musculoskeletal manifestations in patients with deep morphea undergoing systemic treatment with methotrexate and prednisolone. Thus, MRI can be recommended as an additional tool for response monitoring.

The pharmacodynamics and biologic activities of recombinant human interferon-beta (rHuIFN-beta) derived from chinese hamster ovary (CHO) cells were examined during long-term therapy in 7 melanoma patients. The CHO-derived rHuIFN-beta was given s.c. in a dose of 3 x 10(6) U three times per week for 24 weeks. Serum levels of IFN could not be detected before and 48 h after the s.c. injections. 2'-5'-Oligoadenylate synthetase (2-5 OAS), beta 2-microglobulin, and neopterin levels increased significantly 48 h after application, with a maximum after 96 h. Subsequently, the values decreased and remained only slightly elevated during the long-term therapy. Natural killer (NK) cell activity increased in the first 96 h significantly and fell below pretreatment values after 4 weeks. The decrease of biologic response could not be attributed to the occurrence of anti-IFN-beta antibodies because only 2 of the 7 patients developed neutralizing antibodies after 16 and 24 weeks of treatment, respectively. This trial confirms the biologic potency of CHO-derived rHuIFN-beta. However, the selected parameters demonstrate that immunostimulation is only possible over a short treatment period.

Malignant melanoma of the vulva is an uncommon disease. The amelanotic subtype is only rarely mentioned. We report a 60-year-old patient with a 6 month history of vulvar pruritus. Ivory lesions combined with erosions and fine "cigarette paper'-like wrinkling were suspicious for lichen sclerosus et atrophicus. Histologically the diagnosis of an amelanotic malignant melanoma was made. Amelanotic melanoma may present with a wide variety of clinical features. Even in the uncommon location of the vulva, amelanotic melanoma should be suspected in any nonhealing nonpigmented lesion.

The effect of 13-cis-retinoic acid and highly purified human leukocyte interferon alpha (Alphaferon) therapy for metastatic melanoma was studied. A group of 17 patients with disseminated malignant melanoma were treated over a 6-month period. They received 60 mg 13-cis-retinoic acid/day continuously and ten cycles of interferon alpha (IFN alpha). IFN was administered by subcutaneous injection, at a daily dose of 6 x 10(6) IU Alphaferon. The 5-day treatment period was followed by an IFN-free interval of 2 weeks. We were able to observe an overall response rate of 30% with 12% complete responses (2 out of 17 patients). Sites of response included the skin, lung, liver and lymph nodes. All responses have now lasted over 6 months. Therapy was generally well tolerated and could be performed on an outpatient basis. Side-effects of this combination therapy did not exceed the established side-effects of the two substances. We also studied 2'-5'-oligoadenylate synthetase, beta 2-microglobulin and neopterin levels during the whole treatment course. All patients were within the normal range before treatment and a sharp rise occurred during each IFN cycle. The maximum being observed 24 h after the third injection. This indicates a high biological activity of IFN alpha administered cyclically during the whole treatment course. This finding also corresponds well with the absence of neutralizing antibodies before and after the whole treatment period.