@article{BittnerBoonDelbancoetal.2022, author = {Bittner, Nataly and Boon, Andy and Delbanco, Evert H. and Walter, Christof and Mally, Angela}, title = {Assessment of aromatic amides in printed food contact materials: analysis of potential cleavage to primary aromatic amines during simulated passage through the gastrointestinal tract}, series = {Archives of Toxicology}, volume = {96}, journal = {Archives of Toxicology}, number = {5}, doi = {10.1007/s00204-022-03254-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324697}, pages = {1423-1435}, year = {2022}, abstract = {Recent analyses conducted by German official food control reported detection of the aromatic amides N-(2,4-dimethylphenyl)acetamide (NDPA), N-acetoacetyl-m-xylidine (NAAX) and 3-hydroxy-2-naphthanilide (Naphthol AS) in cold water extracts from certain food contact materials made from paper or cardboard, including paper straws, paper napkins, and cupcake liners. Because aromatic amides may be cleaved to potentially genotoxic primary amines upon oral intake, these findings raise concern that transfer of NDPA, NAAX and Naphthol AS from food contact materials into food may present a risk to human health. The aim of the present work was to assess the stability of NDPA, NAAX and Naphthol AS and potential cleavage to 2,4-dimethylaniline (2,4-DMA) and aniline during simulated passage through the gastrointestinal tract using static in vitro digestion models. Using the digestion model established by the National Institute for Public Health and the Environment (RIVM, Bilthoven, NL) and a protocol recommended by the European Food Safety Authority, potential hydrolysis of the aromatic amides to the respective aromatic amines was assessed by LC-MS/MS following incubation of the aromatic amides with digestive fluid simulants. Time-dependent hydrolysis of NDPA and NAAX resulting in formation of the primary aromatic amine 2,4-DMA was consistently observed in both models. The highest rate of cleavage of NDPA and NAAX was recorded following 4 h incubation with 0.07 M HCl as gastric-juice simulant, and amounted to 0.21\% and 0.053\%, respectively. Incubation of Naphthol AS with digestive fluid simulants did not give rise to an increase in the concentration of aniline above the background that resulted from the presence of aniline as an impurity of the test compound. Considering the lack of evidence for aniline formation from Naphthol AS and the extremely low rate of hydrolysis of the amide bonds of NDPA and NAAX during simulated passage through the gastrointestinal tract that gives rise to only very minor amounts of the potentially mutagenic and/or carcinogenic aromatic amine 2,4-DMA, risk assessment based on assumption of 100\% cleavage to the primary aromatic amines would appear to overestimate health risks related to the presence of aromatic amides in food contact materials.}, language = {en} } @article{ZamoGerhardHartmannOttetal.2022, author = {Zam{\`o}, Alberto and Gerhard-Hartmann, Elena and Ott, German and Anagnostopoulos, Ioannis and Scott, David W. and Rosenwald, Andreas and Rauert-Wunderlich, Hilka}, title = {Routine application of the Lymph2Cx assay for the subclassification of aggressive B-cell lymphoma: report of a prospective real-world series}, series = {Virchows Archiv}, volume = {481}, journal = {Virchows Archiv}, number = {6}, doi = {10.1007/s00428-022-03420-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324686}, pages = {935-943}, year = {2022}, abstract = {The subclassification of diffuse large B-cell lymphoma (DLBCL) into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes has become mandatory in the 2017 update of the WHO classification of lymphoid neoplasms and will continue to be used in the WHO 5\(^{th}\) edition. The RNA-based Lymph2Cx assay has been validated as a reliable surrogate of high-throughput gene expression profiling assays for distinguishing between GCB and ABC DLBCL and provides reliable results from formalin-fixed, paraffin-embedded (FFPE) material. This test has been previously used in clinical trials, but experience from real-world routine application is rare. We routinely applied the Lymph2Cx assay to day-to-day diagnostics on a series of 147 aggressive B-cell lymphoma cases and correlated our results with the immunohistochemical subclassification using the Hans algorithm and fluorescence in situ hybridization findings using break-apart probes for MYC, BCL2, and BCL6. The routine use of the Lymph2Cx assay had a high technical success rate (94.6\%) with a low rate of failure due to poor material and/or RNA quality. The Lymph2Cx assay was discordant with the Hans algorithm in 18\% (23 of 128 cases). Discordant cases were mainly classified as GCB by the Hans algorithm and as ABC by Lymph2Cx (n = 11, 8.6\%). Only 5 cases (3.9\%) were classified as non-GCB by the Hans algorithm and as GCB by Lymph2Cx. Additionally, 5.5\% of cases (n = 7) were left unclassified by Lymph2Cx, whereas they were defined as GCB (n = 4) or non-GCB (n = 3) by the Hans algorithm. Our data support the routine applicability of the Lymph2Cx assay.}, language = {en} } @article{ScorcellettiKaraZangeetal.2022, author = {Scorcelletti, Matteo and Kara, Serhan and Zange, Jochen and Jordan, Jens and Semler, Oliver and Sch{\"o}nau, Eckhard and Rittweger, J{\"o}rn and Ireland, Alex and Seefried, Lothar}, title = {Lower limb bone geometry in adult individuals with X-linked hypophosphatemia: an observational study}, series = {Osteoporosis International}, volume = {33}, journal = {Osteoporosis International}, number = {7}, doi = {10.1007/s00198-022-06385-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324655}, pages = {1601-1611}, year = {2022}, abstract = {Summary We assessed lower-limb geometry in adults with X-linked hypophosphatemia (XLH) and controls. We found large differences in multiple measures including femoral and tibial torsion, bowing and cross-sectional area and acetabular version and coverage which may contribute to clinical problems such as osteoarthritis, fractures and altered gait common in XLH. Purpose Individuals with X-linked hypophosphatemia (XLH) are at risk of lower-limb deformities and early onset of osteoarthritis. These two factors may be linked, as altered biomechanics is a risk factor for osteoarthritis. This exploratory evaluation aims at providing clues and concepts for this association to facilitate future larger-scale and longitudinal studies on that aspect. Methods For this observational study, 13 patients with XLH, aged 18-65 years (6 female), were compared with sex-, age- and weight-matched healthy individuals at a single German research centre. Femoral and hip joint geometry, including femoral and tibial torsion and femoral and tibial shaft bowing, bone cross-sectional area (CSA) and acetabular version and coverage were measured from magnetic resonance imaging (MRI) scans. Results Total femoral torsion was 29° lower in individuals with XLH than in controls (p < 0.001), mainly resulting from lower intertrochanteric torsion (ITT) (p < 0.001). Femoral lateral and frontal bowing, tibial frontal bowing, mechanical axis, femoral mechanical-anatomical angle, acetabular version and acetabular coverage were all greater and tibial torsion lower in individuals with XLH as compared to controls (all p < 0.05). Greater femoral total and marrow cavity CSA, greater tibial marrow cavity CSA and lower cortical CSA were observed in XLH (all p < 0.05). Discussion We observed large differences in clinically relevant measures of tibia and particularly femur bone geometry in individuals with XLH compared to controls. These differences may plausibly contribute to clinical manifestations of XLH such as early-onset osteoarthritis, pseudofractures and altered gait and therefore should be considered when planning corrective surgeries.}, language = {en} } @article{HiguchiSerflingRoweetal.2022, author = {Higuchi, Takahiro and Serfling, Sebastian E. and Rowe, Steven P. and Werner, Rudolf A.}, title = {Therapeutic effects of lipid lowering medications on myocardial blood flow, inflammation, and sympathetic nerve activity using nuclear techniques}, series = {Current Cardiology Reports}, volume = {24}, journal = {Current Cardiology Reports}, number = {12}, doi = {10.1007/s11886-022-01792-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324599}, pages = {1849-1853}, year = {2022}, abstract = {Purpose of Review Statins are routinely applied in patients with coronary artery disease, as they allow significantly to reduce blood cholesterol levels. Although those drugs are endorsed by current guidelines and prescribed routinely, a substantial portion of patients are still statin-intolerant and image-piloted strategies may then be helpful to identify patients that need further intensified treatment, e.g., to initiate treatment with proprotein convertase subtilisin / kexin type 9 inhibitors (PCSK9i). In addition, it has also been advocated that statins exhibit nonlipid, cardio-protective effects including improved cardiac nerve integrity, blood flow, and anti-inflammatory effects in congestive heart failure (HF) patients. Recent Findings In subjects after myocardial infarction treated with statins, \(^{123}\)I-metaiodobenzylguanidine (MIBG) scintigraphy has already revealed enhanced cardiac nerve function relative to patients without statins. In addition, all of those aforementioned statin-targeted pathways in HF can be visualized and monitored using dedicated cardiac radiotracers, e.g., \(^{123}\)I-MIBG or \(^{18}\)F-AF78 (for cardiac nerve function), \(^{18}\)F-flurpiridaz (to determine coronary flow) or \(^{68}\)Ga-PentixaFor (to detect inflammation). Summary Statins exhibit various cardio-beneficial effects, including improvement of cardiac nerve function, blood flow, and reduction of inflammation, which can all be imaged using dedicated nuclear cardiac radiotracers. This may allow for in vivo monitoring of statin-induced cardioprotection beyond lipid profiling in HF patients.}, language = {en} } @article{HartrampfBundschuhWeinzierletal.2022, author = {Hartrampf, Philipp E. and Bundschuh, Ralph A. and Weinzierl, Franz-Xaver and Serfling, Sebastian E. and Kosmala, Aleksander and Seitz, Anna Katharina and K{\"u}bler, Hubert and Buck, Andreas K. and Essler, Markus and Werner, Rudolf A.}, title = {mCRPC patients with PSA fluctuations under radioligand therapy have comparable survival benefits relative to patients with sustained PSA decrease}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {13}, doi = {10.1007/s00259-022-05910-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324562}, pages = {4727-4735}, year = {2022}, abstract = {Introduction In men with metastatic castration-resistant prostate cancer (mCRPC) scheduled for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), biochemical response is assessed based on repeated measurements of prostate-specific antigen (PSA) levels. We aimed to determine overall survival (OS) in patients experiencing sustained PSA increase, decrease, or fluctuations during therapy. Materials and methods In this bicentric study, we included 176 mCRPC patients treated with PSMA-directed RLT. PSA levels were determined using blood samples prior to the first RLT and on the admission days for the following cycles. We calculated relative changes in PSA levels compared to baseline. Kaplan-Meier curves as well as log-rank test were used to compare OS of different subgroups, including patients with sustained PSA increase, decrease, or fluctuations (defined as change after initial decrease or increase after the first cycle). Results Sixty-one out of one hundred seventy-six (34.7\%) patients showed a sustained increase and 86/176 (48.8\%) a sustained decrease in PSA levels. PSA fluctuations were observed in the remaining 29/176 (16.5\%). In this subgroup, 22/29 experienced initial PSA decrease followed by an increase (7/29, initial increase followed by a decrease). Median OS of patients with sustained decrease in PSA levels was significantly longer when compared to patients with sustained increase of PSA levels (19 vs. 8 months; HR 0.35, 95\% CI 0.22-0.56; P < 0.001). Patients with PSA fluctuations showed a significantly longer median OS compared to patients with sustained increase of PSA levels (18 vs. 8 months; HR 0.49, 95\% CI 0.30-0.80; P < 0.01), but no significant difference relative to men with sustained PSA decrease (18 vs. 19 months; HR 1.4, 95\% CI 0.78-2.49; P = 0.20). In addition, in men experiencing PSA fluctuations, median OS did not differ significantly between patients with initial decrease or initial increase of tumor marker levels (16 vs. 18 months; HR 1.2, 95\% CI 0.38-4.05; P = 0.68). Conclusion Initial increase or decrease of PSA levels is sustained in the majority of patients undergoing RLT. Sustained PSA decrease was linked to prolonged survival and men with PSA fluctuations under treatment experienced comparable survival benefits. As such, transient tumor marker oscillations under RLT should rather not lead to treatment discontinuation, especially in the absence of radiological progression.}, language = {en} } @article{GoeringSchumannMuelleretal.2022, author = {G{\"o}ring, Lukas and Schumann, Sarah and M{\"u}ller, Jessica and Buck, Andreas K. and Port, Matthias and Lassmann, Michael and Scherthan, Harry and Eberlein, Uta}, title = {Repair of a-particle-induced DNA damage in peripheral blood mononuclear cells after internal ex vivo irradiation with \(^{223}\)Ra}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, doi = {10.1007/s00259-022-05860-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324557}, pages = {3981-3988}, year = {2022}, abstract = {Purpose As α-emitters for radiopharmaceutical therapies are administered systemically by intravenous injection, blood will be irradiated by α-particles that induce clustered DNA double-strand breaks (DSBs). Here, we investigated the induction and repair of DSB damage in peripheral blood mononuclear cells (PBMCs) as a function of the absorbed dose to the blood following internal ex vivo irradiation with [\(^{223}\)Ra]RaCl2. Methods Blood samples of ten volunteers were irradiated by adding [\(^{223}\)Ra]RaCl2 solution with different activity concentrations resulting in absorbed doses to the blood of 3 mGy, 25 mGy, 50 mGy and 100 mGy. PBMCs were isolated, divided in three parts and either fixed directly (d-samples) or after 4 h or 24 h culture. After immunostaining, the induced γ-H2AX α-tracks were counted. The time-dependent decrease in α-track frequency was described with a model assuming a repair rate R and a fraction of non-repairable damage Q. Results For 25 mGy, 50 mGy and 100 mGy, the numbers of α-tracks were significantly increased compared to baseline at all time points. Compared to the corresponding d-samples, the α-track frequency decreased significantly after 4 h and after 24 h. The repair rates R were (0.24 ± 0.05) h-1 for 25 mGy, (0.16 ± 0.04) h-1 for 50 mGy and (0.13 ± 0.02) h-1 for 100 mGy, suggesting faster repair at lower absorbed doses, while Q-values were similar. Conclusion The results obtained suggest that induction and repair of the DSB damage depend on the absorbed dose to the blood. Repair rates were similar to what has been observed for irradiation with low linear energy transfer.}, language = {en} } @article{HartrampfSeitzWeinzierletal.2022, author = {Hartrampf, Philipp E. and Seitz, Anna Katharina and Weinzierl, Franz-Xaver and Serfling, Sebastian E. and Schirbel, Andreas and Rowe, Steven P. and K{\"u}bler, Hubert and Buck, Andreas K. and Werner, Rudolf A.}, title = {Baseline clinical characteristics predict overall survival in patients undergoing radioligand therapy with [\(^{177}\)Lu]Lu-PSMA I\&T during long-term follow-up}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, doi = {10.1007/s00259-022-05853-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324573}, pages = {4262-4270}, year = {2022}, abstract = {Background Radioligand therapy (RLT) with \(^{177}\)Lu-labeled prostate-specific membrane antigen (PSMA) ligands is associated with prolonged overall survival (OS) in patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). A substantial number of patients, however, are prone to treatment failure. We aimed to determine clinical baseline characteristics to predict OS in patients receiving [\(^{177}\)Lu]Lu-PSMA I\&T RLT in a long-term follow-up. Materials and methods Ninety-two mCRPC patients treated with [\(^{177}\)Lu]Lu-PSMA I\&T with a follow-up of at least 18 months were retrospectively identified. Multivariable Cox regression analyses were performed for various baseline characteristics, including laboratory values, Gleason score, age, prior therapies, and time interval between initial diagnosis and first treatment cycle (interval\(_{Diagnosis-RLT}\), per 12 months). Cutoff values for significant predictors were determined using receiver operating characteristic (ROC) analysis. ROC-derived thresholds were then applied to Kaplan-Meier analyses. Results Baseline C-reactive protein (CRP; hazard ratio [HR], 1.10, 95\% CI 1.02-1.18; P = 0.01), lactate dehydrogenase (LDH; HR, 1.07, 95\% CI 1.01-1.11; P = 0.01), aspartate aminotransferase (AST; HR, 1.16, 95\% CI 1.06-1.26; P = 0.001), and interval\(_{Diagnosis-RLT}\) (HR, 0.95, 95\% CI 0.91-0.99; P = 0.02) were identified as independent prognostic factors for OS. The following respective ROC-based thresholds were determined: CRP, 0.98 mg/dl (area under the curve [AUC], 0.80); LDH, 276.5 U/l (AUC, 0.83); AST, 26.95 U/l (AUC, 0.73); and interval\(_{Diagnosis-RLT}\), 43.5 months (AUC, 0.68; P < 0.01, respectively). Respective Kaplan-Meier analyses demonstrated a significantly longer median OS of patients with lower CRP, lower LDH, and lower AST, as well as prolonged interval\(_{Diagnosis-RLT}\) (P ≤ 0.01, respectively). Conclusion In mCRPC patients treated with [\(^{177}\)Lu]Lu-PSMA I\&T, baseline CRP, LDH, AST, and time interval until RLT initiation (thereby reflecting a possible indicator for tumor aggressiveness) are independently associated with survival. Our findings are in line with previous findings on [\(^{177}\)Lu]Lu-PSMA-617, and we believe that these clinical baseline characteristics may support the nuclear medicine specialist to identify long-term survivors.}, language = {en} } @article{BuckSerflingLindneretal.2022, author = {Buck, Andreas K. and Serfling, Sebastian E. and Lindner, Thomas and H{\"a}nscheid, Heribert and Schirbel, Andreas and Hahner, Stefanie and Fassnacht, Martin and Einsele, Hermann and Werner, Rudolf A.}, title = {CXCR4-targeted theranostics in oncology}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, doi = {10.1007/s00259-022-05849-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324545}, pages = {4133-4144}, year = {2022}, abstract = {A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [\(^{68}\)Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [\(^{68}\)Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [\(^{177}\)Lu]/[\(^{90}\)Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.}, language = {en} } @article{TaurinesFeketePreussWiedenhoffetal.2022, author = {Taurines, R. and Fekete, S. and Preuss-Wiedenhoff, A. and Warnke, A. and Wewetzer, C. and Plener, P. and Burger, R. and Gerlach, M. and Romanos, M. and Egberts, K. M.}, title = {Therapeutic drug monitoring in children and adolescents with schizophrenia and other psychotic disorders using risperidone}, series = {Journal of Neural Transmission}, volume = {129}, journal = {Journal of Neural Transmission}, number = {5-6}, doi = {10.1007/s00702-022-02485-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324833}, pages = {689-701}, year = {2022}, abstract = {Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose-concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20-60 ng/ml) is applicable for minors. In the 64 patients (aged 11-18 years) included, a positive correlation between daily dose and the active moiety (RIS\(_{am}\)) concentration was found (r\(_s\) = 0.49, p = 0.001) with variation in dose explaining 24\% (r\(_s\)\(^2\) = 0.240) of the variability in serum concentrations. While the RIS\(_{am}\) concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RIS\(_{am}\) concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RIS\(_{am}\) was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.}, language = {en} } @article{AugustinLuciusThurneretal.2022, author = {Augustin, Anne Marie and Lucius, Leonie Johanna and Thurner, Annette and Kickuth, Ralph}, title = {Malignant obstruction of the inferior vena cava: clinical experience with the self-expanding Sinus-XL stent system}, series = {Abdominal Radiology}, volume = {47}, journal = {Abdominal Radiology}, number = {10}, doi = {10.1007/s00261-022-03587-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324951}, pages = {3604-3614}, year = {2022}, abstract = {Purpose To evaluate the technical and clinical outcome of Sinus-XL stent placement in patients with malignant obstruction syndrome of the inferior vena cava. Methods Between October 2010 and January 2021, 21 patients with different malignant primary disease causing inferior vena cava obstruction were treated with Sinus-XL stent implantation. Procedural data, technical and clinical outcome parameters were retrospectively analyzed. Results Technical success was 100\%. Analysis of available manometry data revealed a significant reduction of the mean translesional pressure gradient following the procedure (p = 0.008). Reintervention rate was 4.8\% (1/21). The available follow-up imaging studies showed primary and primary-assisted stent patency rates of 93\% (13/14) and 100\% (14/14), respectively. Major complications did not occur. The clinical success regarding lower extremity edema was 82.4\% (14/17) for the first and 85.7\% (18/21) for the last follow-up. Longer lengths of IVC obstruction were associated with reduced clinical improvement after the procedure (p = 0.025). Improvement of intraprocedural manometry results and lower extremity edema revealed only minor correlation. Ascites and anasarca were not significantly positively affected by the procedure. Conclusion Sinus-XL stent placement in patients with malignant inferior vena cava obstruction showed high technical success and low complication rates. Regarding the clinical outcome, significant symptom improvement could be achieved in lower extremity edema, whereas ascites and anasarca lacked satisfying symptom relief. Based on our results, this procedure should be considered as a suitable therapy in a palliative care setting for patients with advanced malignant disease.}, language = {en} }