Publications by authors named "Jürgen Beer"

11 Publications

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Potential and pitfalls of 1.5T MRI imaging for target volume definition in ocular proton therapy.

Radiother Oncol 2021 01 3;154:53-59. Epub 2020 Sep 3.

Paul Scherrer Institut (PSI), Center for Proton Therapy, Switzerland.

Introduction: Ocular proton therapy (OPT) for the treatment of uveal melanoma has a long and remarkably successful history. This is despite that, for the majority of patients treated, the definition of the eye anatomy is based on a simplified geometrical model embedded in the treatment planning system EyePlan. In this study, differences in anatomical and tumor structures from EyePlan, and those based on 1.5T magnetic resonance imaging (MRI) are assessed.

Materials And Methods: Thirty-three uveal melanoma patients treated with OPT at our institution were subject to eye MRI. The target volumes were manually delineated on those images by two radiation oncologists. The resulting volumes were geometrically compared to the clinical standard. In addition, the dosimetric impact of using different models for treatment planning were evaluated.

Results: Two patients (6%) presented lesions too small to be visible on MRI. Target volumes identified on MRI scans were on average smaller than EyePlan with discrepancies arising mostly from the definition of the tumor base. Clip-to-tumor base distances measured on MRI models exhibited higher discrepancy to ophthalmological measurements than EyePlan. For 53% of cases, treatment plans optimized for lesions identified on MRI only, failed to achieve sufficient target coverage for EyePlan volumes.

Discussion: The analysis has shown that 1.5T MRI might be more susceptible to misses of flat tumor extension of the clinical target volume than the current clinical standard. Thus, a proper integration of ancillary imaging modalities, leading to a better characterization of the full lesion, is required.
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http://dx.doi.org/10.1016/j.radonc.2020.08.023DOI Listing
January 2021

Clinical outcomes of head and neck adenoid cystic carcinoma patients treated with pencil beam-scanning proton therapy.

Oral Oncol 2020 08 12;107:104752. Epub 2020 May 12.

Center for Proton Therapy, Paul Scherrer Institute, Villigen PSI, Switzerland; Radiation Oncology Department, University Hospital Zürich, Zürich, Switzerland; Radiation Oncology Department, University Hospital Bern, Inselspital, Bern, Switzerland. Electronic address:

Objective: The aim of this study was to evaluate the outcome of patients with head and neck adenoid cystic carcinoma (ACC) treated using pencil beam scanning proton therapy (PBS PT) at our institution.

Materials And Methods: Thirty-five patients who underwent treatment with PBS PT for ACC between 2001 and 2017 were included. Local control (LC), distant control (DC), progression-free survival (PFS), overall survival (OS) and their prognostic factors were evaluated. Adverse effects were prospectively assessed.

Results: The median patient follow-up was 30 months. Prior to PT, 26 patients (74.3%) underwent surgery with R0/R1/R2 outcome in 5, 13 and 8 cases, respectively. Nine patients (25.7%) presented with inoperable disease. The 2-year LC, DC, PFS and OS was 92.2%, 77.8%, 74.3% and 88.8%, respectively. LC was influenced by patient age (p = 0.002) with a significant difference between local and distant failure (median 61.3 vs. 42.3 years, p = 0.005). Tumor T stage was a significant risk factor for PFS (p = 0.045) and tumor prognostic group affected OS (p = 0.049). No significant survival advantage for operable vs. inoperable disease could be identified. The acute and late grade 3 toxicity rates were 14.3% and 6.1%, respectively. No acute or late grade 4/5 toxicities were observed.

Conclusions: PBS PT is an effective and safe treatment for patients with head & neck ACC in both definitive and adjuvant setting. Distant metastases are the main pattern of failure. Age, tumor stage and clinical stage had a significant negative impact on LC, OS and PFS.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104752DOI Listing
August 2020

Proton therapy for brain tumours in the area of evidence-based medicine.

Br J Radiol 2020 Mar 20;93(1107):20190237. Epub 2019 May 20.

Center for Proton Therapy, Paul Scherrer Institute, Villigen, Switzerland.

Advances In Knowledge: This review details the indication of brain tumors for proton therapy and give a list of the open prospective trials for these challenging tumors.
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http://dx.doi.org/10.1259/bjr.20190237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066950PMC
March 2020

PET-CT guided SIB-IMRT combined with concurrent 5-FU/MMC for the treatment of anal cancer.

Acta Oncol 2017 Dec 30;56(12):1734-1740. Epub 2017 May 30.

a Department of Radiation Oncology , Kantonsspital Graubünden , Chur , Switzerland.

Background: To evaluate local control (LC), survival and toxicity in anal cancer patients treated with intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy at a single institution.

Material And Methods: From August 2010 to May 2015, 26 patients were treated at our institution with IMRT and concurrent 5-fluorouracil/mitomycin-C (5-FU/MMC) for localized squamous cell carcinoma of the anal canal (SCCAC). Radiotherapy (RT) with 50.4-60 Gy was delivered with a sequential boost in 31%, and a simultaneous-integrated boost (SIB-IMRT) in 69% of cases. Initial staging was based on PET-CT and MRI. Clinical measures of interest were the influence of PET-CT on staging and treatment planning, LC, disease free survival (DFS), overall survival (OS), colostomy free survival (CFS) and toxicities.

Results: Median age was 61 years, 22 patients (85%) were female, and no patient was HIV-positive. The proportion of patients with stage I, II, IIIA and IIIB disease was 15%, 35%, 23% and 27%, respectively. PET-CT modified the extent of nodal disease in 9/23 cases (39%) and lead to major changes in treatment planning in 4/23 patients (17%). MRI was more accurate at identifying T4 disease. RT was delivered at full dose in 26 patients (100%) and chemotherapy in 22/26 patients (85%). Two patients (7.7%) required RT breaks. Median follow-up was 35 months [IQR: 19-52]. The 2-year LC, DFS, OS and CFS were 100%, 100%, 100% and 92%. Acute grade ≥3 dermatitis and diarrhea occurred in 73% and 8% of cases, respectively. Grade 3-4 neutropenia was seen in 10/23 patients (43%). Four patients (15%) developed chronic grade 2 GI toxicity.

Conclusions: PET-CT provided additional information leading to major changes in treatment planning for 17% of patients. Considering our excellent outcomes, routine use of PET-CT as standard staging modality and IMRT planning procedure appears justified for patients with SCCAC.
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http://dx.doi.org/10.1080/0284186X.2017.1325003DOI Listing
December 2017

Activation of liver X receptors inhibits experimental fibrosis by interfering with interleukin-6 release from macrophages.

Ann Rheum Dis 2015 Jun 11;74(6):1317-24. Epub 2014 Mar 11.

Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.

Objectives: To investigate the role of liver X receptors (LXRs) in experimental skin fibrosis and evaluate their potential as novel antifibrotic targets.

Methods: We studied the role of LXRs in bleomycin-induced skin fibrosis, in the model of sclerodermatous graft-versus-host disease (sclGvHD) and in tight skin-1 (Tsk-1) mice, reflecting different subtypes of fibrotic disease. We examined both LXR isoforms using LXRα-, LXRβ- and LXR-α/β-double-knockout mice. Finally, we investigated the effects of LXRs on fibroblasts and macrophages to establish the antifibrotic mode of action of LXRs.

Results: LXR activation by the agonist T0901317 had antifibrotic effects in bleomycin-induced skin fibrosis, in the sclGvHD model and in Tsk-1 mice. The antifibrotic activity of LXRs was particularly prominent in the inflammation-driven bleomycin and sclGvHD models. LXRα-, LXRβ- and LXRα/β-double-knockout mice showed a similar response to bleomycin as wildtype animals. Low levels of the LXR target gene ABCA-1 in the skin of bleomycin-challenged and control mice suggested a low baseline activation of the antifibrotic LXR signalling, which, however, could be specifically activated by T0901317. Fibroblasts were not the direct target cells of LXRs agonists, but LXR activation inhibited fibrosis by interfering with infiltration of macrophages and their release of the pro-fibrotic interleukin-6.

Conclusions: We identified LXRs as novel targets for antifibrotic therapies, a yet unknown aspect of these nuclear receptors. Our data suggest that LXR activation might be particularly effective in patients with inflammatory disease subtypes. Activation of LXRs interfered with the release of interleukin-6 from macrophages and, thus, inhibited fibroblast activation and collagen release.
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http://dx.doi.org/10.1136/annrheumdis-2013-204401DOI Listing
June 2015

Growth rate of melanoma in vivo and correlation with dermatoscopic and dermatopathologic findings.

Dermatol Pract Concept 2011 31;1(1):59-67. Epub 2011 Jan 31.

Department of Dermatology, Division of General Dermatology, Medical University of Vienna, Austria.

Objectives: The aim of this study was to calculate the horizontal growth rate of melanoma in vivo and to correlate it with morphologic findings.

Patients And Methods: We searched our database for melanomas for which sequential dermatoscopic images and histopathologic slides were available. The final sample consisted of 50 melanomas of 48 patients (mean age: 50 ± 15 years, 62% females). We calculated the horizontal growth rate in mm(2) per year by morphometric analysis of digital dermatoscopic images. Dermatoscopic and dermatopathologic findings were assessed according to predefined criteria and correlated with the horizontal growth rate.

Results: The median time interval between baseline and follow-up image was 12 months (range: 2-100 months). The majority of melanomas were in situ (n=28, 56%). The mean horizontal growth rate of all melanomas was 5.3 mm(2)/year (SD: ± 5.8 mm(2)/year). The histopathologic findings of numerous and large epidermal nests were associated with rapid growth. This histopathologic pattern corresponded to a pattern of clods ("globules") dermatoscopically. From a dermatoscopic point of view, melanomas with a main pattern of clods grew significantly faster (mean horizontal growth rate: 10.4 mm(2)/year, 95% CI: 6.4-14.4 mm(2)/year) than melanomas with mainly a reticular pattern (4.8 mm(2)/year, 95% CI: 2.7-7.0 mm(2)/year) or with other patterns (2.6 mm(2)/year, 95% CI: -0.5-5.6 mm(2)/ year, p=0.01).

Conclusion: Morphologic characteristics of melanoma are associated with biologic behavior. Large and numerous epidermal nests (corresponding to a pattern of clods dermatoscopically) indicate more rapid growth.
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http://dx.doi.org/10.5826/dpc.dp0101a13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881085PMC
January 2014

Decreased lymphatic vessel counts in patients with systemic sclerosis: association with fingertip ulcers.

Arthritis Rheum 2010 May;62(5):1513-22

University of Erlangen-Nuremberg, Erlangen, Germany.

Objective: Systemic sclerosis (SSc) is a connective tissue disease that is characterized by microvascular disease and tissue fibrosis. Progressive loss and irregular architecture of the small blood vessels are well characterized, but the potential involvement of the lymphatic vessel system has not been analyzed directly in SSc. This study was undertaken to assess whether the lymphatic vascular system is affected in SSc, and whether changes to the lymphatic vessels are associated with dystrophic changes and tissue damage in patients with SSc.

Methods: Lymphatic endothelial cells in skin biopsy samples from patients with SSc and age- and sex-matched healthy volunteers were identified by staining for podoplanin and prox-1, both of which are specifically expressed in lymphatic endothelial cells but not in blood vascular endothelial cells. CD31 was used as a pan-endothelial cell marker. Statistical analyses were performed using Kruskal-Wallis, Mann-Whitney U, and Spearman's rank correlation tests.

Results: The numbers of podoplanin- and prox-1-positive lymphatic vessels were significantly reduced in patients with SSc as compared with healthy individuals. The number of podoplanin-positive lymphatic precollector vessels was significantly lower in SSc patients with fingertip ulcers than in SSc patients without ulcers. Moreover, the number of lymphatic vessels correlated inversely with the number of fingertip ulcers at the time of biopsy and with the number of fingertip ulcers per year. The inverse correlation between lymphatic precollector vessel counts and fingertip ulcers remained significant after statistical adjustment for the blood vessel count, age, and modified Rodnan skin thickness score.

Conclusion: These results demonstrate a severe reduction in the number of lymphatic capillaries and lymphatic precollector vessels in patients with SSc. Patients with decreased lymphatic vessel counts may be at particularly high risk of developing fingertip ulcers.
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http://dx.doi.org/10.1002/art.27406DOI Listing
May 2010

The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis.

Arthritis Rheum 2009 Apr;60(4):1129-36

University of Erlangen-Nuremberg, Erlangen, Germany.

Objective: The cannabinoid receptor CB2 is predominantly expressed in non-neuronal tissue and exerts potent immunomodulatory effects. This study was undertaken to evaluate the role of CB2 in the pathogenesis of dermal fibrosis.

Methods: Mice deficient in CB2 (CB2(-/-) mice) and their wild-type littermates (CB2(+/+) mice) were injected with bleomycin to induce experimental fibrosis. Mice were treated with selective agonists and antagonists of CB2. Lesional skin was evaluated for dermal thickness and numbers of infiltrating leukocytes. Bone marrow transplantation experiments were performed.

Results: CB2(-/-) mice were more sensitive to bleomycin-induced dermal fibrosis than were CB2(+/+) mice, and showed increased dermal thickness. Leukocyte counts were significantly higher in the lesional skin of CB2(+/+) mice. Increased dermal fibrosis was also observed upon treatment with the CB2 antagonist AM-630. In contrast, the selective CB2 agonist JWH-133 reduced leukocyte infiltration and dermal thickening. The phenotype of CB2(-/-) mice was mimicked by transplantation of CB2(-/-) bone marrow into CB2(+/+) mice, whereas CB2(-/-) mice transplanted with bone marrow from CB2(+/+) mice did not display an increased sensitivity to bleomycin-induced fibrosis, indicating that leukocyte expression of CB2 critically influences experimental fibrosis.

Conclusion: Our findings indicate that CB2 limits leukocyte infiltration and tissue fibrosis in experimental dermal fibrosis. Since selective CB2 agonists are available and well tolerated, CB2 might be an interesting molecular target for the treatment of early inflammatory stages of systemic sclerosis.
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http://dx.doi.org/10.1002/art.24395DOI Listing
April 2009

A novel mechanism for translation initiation operates in haloarchaea.

Mol Microbiol 2009 Mar 23;71(6):1451-63. Epub 2009 Jan 23.

Goethe-University, Department of Biosciences, Biocentre, Institute for Molecular Biosciences, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.

Four different mechanisms for translation initiation are known, i.e. one prokaryotic mechanism involving a Shine-Dalgarno sequence, two eukaryotic mechanisms relying on ribosomal scanning or internal ribosomal entry sites, and one mechanism acting on leaderless transcripts. Recently it was reported that the majority of haloarchaeal transcripts is leaderless and that most leadered transcripts are devoid of a Shine-Dalgarno sequence, excluding the operation of a 'bacterial-like' initiation mechanism. Therefore, the current study concentrated on elucidating whether a 'eukaryotic-like' scanning mechanism might operate instead. GUG and UUG were efficiently used as start codons on leadered transcripts in vivo, in contrast to initiation on leaderless transcripts (and leadered eukaryotic transcripts). Deleted versions of the 5'-UTR initiated translation very inefficiently. Introduction of additional upstream AUGs did not influence the initiation efficiency at internal start codons. An additional in-frame AUG at the 5'-end led to the simultaneous usage of two start sites on the same message. A stable stem-loop structure at the 5'-end inhibited only initiation at the first AUG, but did not influence usage of the internal AUG. Taken together, operation of a scanning mechanism was excluded and the results indicate that a novel mechanism for translation initiation operates at least in haloarchaea.
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http://dx.doi.org/10.1111/j.1365-2958.2009.06615.xDOI Listing
March 2009

Protein binding of antimicrobials: methods for quantification and for investigation of its impact on bacterial killing.

AAPS J 2009 Mar 1;11(1):1-12. Epub 2009 Jan 1.

Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Plasma protein binding of antimicrobial agents is considered to be a key characteristic of antibiotics as it affects both their pharmacokinetics and pharmacodynamics. However, up to the present, no standard methods for measuring protein binding or for quantification of the influence of protein binding on antimicrobial activity exist. This short-coming has previously led to conflicting results on antibacterial activity of highly protein-bound antibiotics. The present review, therefore, set out to summarize (1) methods for quantification of protein binding, (2) microbiological growth media used for determination of the impact of protein binding on antimicrobial activity of antibiotics, and (3) different pharmacodynamic in vitro studies that are used in this context. The advantages and disadvantages of a wide range of different approaches are discussed and compared. The urgent call for international standardization by microbiological societies and laboratories may be considered as a logical consequence of the presented data.
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http://dx.doi.org/10.1208/s12248-008-9072-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664873PMC
March 2009

Lekteplase--a secreted tissue plasminogen activator derivative from Escherichia coli.

Arzneimittelforschung 2002 ;52(1):60-6

Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.

Fermentation studies of batch-mode cultivation in 4-L fermenters were carried out to obtain an active recombinant DNA-derived tissue plasminogen activator (t-PA) deletion mutant, lekteplase, secreted and correctly folded from Escherichia coli. The OmpA signal sequence was used to deliver the heterologous product composed of kringle 2 plus serine protease domain (K2S) to the medium. Supplementing the complex medium with 10% glycerol and 20 mmol/l magnesium chloride led to an increase in cell numbers with final cell density reaching an OD600 of 24. The expression level of lekteplase in the medium detected by sandwich ELISA was 100 mg/L. Enzymatic activity of lysine-sepharose purified product was demonstrated by amidolytic assay, in vitro fibrin clot lysis, and copolymerization PAGE.
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http://dx.doi.org/10.1055/s-0031-1299858DOI Listing
March 2002
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