70 results on '"Seitz AK"'
Search Results
2. Diagnostische Wertigkeit der 68Gallium-PSMA PET/CT zu Beurteilung des Therapieansprechens von Patienten mit metastasiertem Prostatakarzinom unter Docetaxel-Chemotherapie
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Seitz, AK, Rauscher, I, Haller, B, Kroenke, M, Luther, S, Heck, M, Horn, T, Gschwend, J, Schwaiger, M, Eiber, M, Maurer, T, Seitz, AK, Rauscher, I, Haller, B, Kroenke, M, Luther, S, Heck, M, Horn, T, Gschwend, J, Schwaiger, M, Eiber, M, and Maurer, T
- Published
- 2018
3. Detektion der Androgen-Rezeptor Splice Variante 7 im peripheren Vollblut beim kastrationsresistenten Prostatakarzinom: Vorhersage des Therapieansprechens unter Docetaxel, Abirateron und Enzalutamid
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Seitz, AK, Thöne, S, Bietenbeck, A, Nawroth, R, Tauber, R, Thalgott, M, Schmid, SC, Secci, R, Retz, M, Gschwend, JE, Ruland, J, Winter, C, Heck, MM, Seitz, AK, Thöne, S, Bietenbeck, A, Nawroth, R, Tauber, R, Thalgott, M, Schmid, SC, Secci, R, Retz, M, Gschwend, JE, Ruland, J, Winter, C, and Heck, MM
- Published
- 2017
4. A 2-gene panel derived from prostate cancer-enhanced transcripts in whole blood is prognostic for survival and predicts treatment benefit in metastatic castration-resistant prostate cancer
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Heck, MM, Thalgott, M, Schmid, SC, Oh, WK, Gong, Y, Wang, L, Zhu, J, Seitz, AK, Porst, D, Höppner, M, Retz, M, Gschwend, JE, and Nawroth, R
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Objective: To determine a prognostic model derived from prostate cancer-enhanced transcripts in whole blood of castration-resistant prostate cancer (CRPC) patients and explore its applicability as a surrogate of treatment response. Patients and methods: Six out of 23 selected transcripts were identified[for full text, please go to the a.m. URL], 42. Gemeinsame Tagung der Bayerischen Urologenvereinigung und der Österreichischen Gesellschaft für Urologie und Andrologie
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- 2016
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5. Chromogranin A and neuron-specific enolase serum levels as predictors of treatment outcome in metastatic castration-resistant prostate cancer patients under abiraterone therapy
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Heck, MM, Thaler, M, Schmid, SC, Seitz, AK, Tauber, R, Kübler, H, Maurer, T, Thalgott, M, Hatzchristodoulou, G, Höppner, M, Nawroth, R, Luppa, P, Gschwend, JE, Retz, M, Heck, MM, Thaler, M, Schmid, SC, Seitz, AK, Tauber, R, Kübler, H, Maurer, T, Thalgott, M, Hatzchristodoulou, G, Höppner, M, Nawroth, R, Luppa, P, Gschwend, JE, and Retz, M
- Published
- 2016
6. Diagnostische Wertigkeit der 68Gallium-PSMA PET/CT zu Beurteilung des Therapieansprechens von Patienten mit metastasiertem, hormonsensitivem Prostatakarzinom unter primärer Hormonchemotherapie
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Seitz, AK, Krönke, M, Luther, S, Heck, MM, Horn, T, Retz, M, Gschwend, JE, Schwaiger, M, Eiber, M, Maurer, T, Seitz, AK, Krönke, M, Luther, S, Heck, MM, Horn, T, Retz, M, Gschwend, JE, Schwaiger, M, Eiber, M, and Maurer, T
- Published
- 2016
7. SARS-CoV-2 antigen rapid detection tests: test performance during the COVID-19 pandemic and the impact of COVID-19 vaccination.
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Wagenhäuser I, Knies K, Pscheidl T, Eisenmann M, Flemming S, Petri N, McDonogh M, Scherzad A, Zeller D, Gesierich A, Seitz AK, Taurines R, Ernestus RI, Forster J, Weismann D, Weißbrich B, Liese J, Härtel C, Kurzai O, Dölken L, Gabel A, and Krone M
- Abstract
Background: SARS-CoV-2 antigen rapid detection tests (RDTs) emerged as point-of-care diagnostics alongside reverse transcription polymerase chain reaction (RT-qPCR) as reference., Methods: In a prospective performance assessment from 12 November 2020 to 30 June 2023 at a single centre tertiary care hospital, the sensitivity and specificity (primary endpoints) of RDTs from three manufacturers (NADAL®, Panbio™, MEDsan®) were compared to RT-qPCR as reference standard among patients, accompanying persons and staff aged ≥ six month in large-scale, clinical screening use. Regression models were used to assess influencing factors on RDT performance (secondary endpoints)., Findings: Among 78,798 paired RDT/RT-qPCR results analysed, overall RDT sensitivity was 34.5% (695/2016; 95% CI 32.4-36.6%), specificity 99.6% (76,503/76,782; 95% CI 99.6-99.7%). Over the pandemic course, sensitivity decreased in line with a lower rate of individuals showing typical COVID-19 symptoms. The lasso regression model showed that a higher viral load and typical COVID-19 symptoms were directly significantly correlated with the likelihood of a positive RDT result in SARS-CoV-2 infection, whereas age, sex, vaccination status, and the Omicron VOC were not., Interpretation: The decline in RDT sensitivity throughout the pandemic can primarily be attributed to the reduced prevalence of symptomatic infections among vaccinated individuals and individuals infected with Omicron VOC. RDTs remain valuable for detecting SARS-CoV-2 in symptomatic individuals and offer potential for detecting other respiratory pathogens in the post-pandemic era, underscoring their importance in infection control efforts., Funding: German Federal Ministry of Education and Research (BMBF), Free State of Bavaria, Bavarian State Ministry of Health and Care., Competing Interests: Declaration of interests Daniel Zeller receives honoraria from Angelini Pharma and Novartis outside of the submitted work. Manuel Krone receives honoraria from Abbott, GSK, Pfizer, and Sanofi outside of the submitted work. None of the other authors have any conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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8. A Propensity Score-Based Comparison regarding Renal, Functional, and Surgical Outcome of Continent Cutaneous Urinary Diversions in Patients with Benign Chronic Bladder Diseases and Patients with Bladder Cancer.
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Scheper V, Seitz AK, Kübler H, Kocot A, Kalogirou C, and Schwinger M
- Abstract
Introduction: Continent cutaneous urinary diversion post-cystectomy is an established approach addressing both oncological and functional indications. However, there is a noticeable gap of evidence when it comes to comparing outcomes between these indications, especially concerning the technique of Mainz pouch I (MPI). This study aimed to close the gap by analyzing the long-term functional and renal outcomes of patients with MPI after cystectomy due to both benign and malign bladder pathologies., Methods: In this retrospective study, we examined 173 patients, who underwent MPI surgery between 2000 and 2022. Patients were categorized into a study group (benign conditions, n = 26) and a control group (bladder cancer, n = 52) using propensity score matching. Clinical demographics, surgical outcomes, and functional/renal parameters were analyzed using unpaired t tests and χ2 tests., Results: Patients undergoing cystectomy with MPI due to benign bladder pathologies were significantly younger and had a lower comorbidity burden compared to those with bladder cancer. In contrast to a significantly higher incidence of chemotherapy in the oncological cohort, the long-term renal function was comparable between both populations. Surgical outcomes, revisions, and postoperative complications did not differ significantly between both groups. Nearly 90% of patients in both groups showed full continence., Conclusion: This study demonstrates the efficacy and safety of MPI surgery in both benign and malignant conditions, proving favorable long-term renal and functional outcomes., (© 2024 S. Karger AG, Basel.)
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- 2024
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9. Refluxing versus Non-Refluxing Ureteric Implantation in Continent Cutaneous Urinary Diversion: A Propensity-Scored Comparison regarding Long-Term Renal, Metabolic, and Functional Outcomes of Patients with Ileocecal Pouch.
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Schwinger M, Seitz AK, Kübler H, Kocot A, Riedmiller H, and Kalogirou C
- Abstract
Introduction: Studies comparing refluxing versus non-refluxing ureteric implantation in continent cutaneous urinary diversion (CCUD) are scarce and often characterized by heterogeneous study populations. This work therefore aimed at comparing both techniques regarding long-term outcomes in a propensity-scored approach., Methods: We identified n = 19 patients, totaling n = 38 renal units (RU), who underwent CCUD surgery at our hospital out of a pool of 120 patients. Of these 38 RU, 27 RU were implanted via refluxing ureteric implantation utilizing various procedures due to special intraoperative circumstances (short ureters, damage due to radiation). In terms of preoperative renal function, a comorbidity index (Age-Adjusted Charlson Comorbidity Index [ACCI]), and gender, we compared them to n = 38 patients with a total of 76 RU with non-refluxing ureteric implantation in all RU (1:2 matching). The mean follow-up was 56 (IQR: 23-112) months., Results: Long-term renal function was comparable in CCUD patients receiving refluxing versus non-refluxing ureteric implantation (estimated glomerular filtration rate: 63.11 mL/min vs. 71.7 mL/min, p = 0.22) with an average decline of 17.4 mL/min and 13.69 mL/min during the follow-up period, respectively. Also, the rate of new-onset chronic kidney disease (CKD) (both 15%, p = 1), the need for alkalizing medication, or the number of pyelonephritis episodes did not significantly differ between the groups. In Cox regression analysis, ACCI was the single most predictive parameter for the development of new-onset CKD (HR: 1.71 [1.10-2.66], p = 0.0167). None of the RU in the refluxing group needed revisional surgery concerning the ureterointestinal anastomosis, whereas 7 RU of the non-refluxing group did., Conclusions: Our study confirms that refluxing ureteric implantation in CCUDs is a valid and safe procedure regarding long-term renal, metabolic and functional outcomes. Our data also suggest that patients should be counseled according to their comorbidities regarding long-term renal function., (© 2024 S. Karger AG, Basel.)
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- 2024
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10. Reliability of continuous vital sign monitoring in post-operative patients employing consumer-grade fitness trackers: A randomised pilot trial.
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Helmer P, Hottenrott S, Wienböker K, Pryss R, Drosos V, Seitz AK, Röder D, Jovanovic A, Brugger J, Kranke P, Meybohm P, Winkler BE, and Sammeth M
- Abstract
Introduction: Fitness trackers can provide continuous monitoring of vital signs and thus have the potential to become a complementary, mobile and effective tool for early detection of patient deterioration and post-operative complications., Methods: To evaluate potential implementations in acute care setting, we included 36 patients after moderate to major surgery in a recent randomised pilot trial to compare the performance of vital sign monitoring by three different fitness trackers (Apple Watch 7, Garmin Fenix 6pro and Withings ScanWatch) with established standard clinical monitors in post-anaesthesia care units and monitoring wards., Results: During a cumulative period of 56 days, a total of 53,197 heart rate (HR) measurements, as well as 12,219 measurements of the peripheral blood oxygen saturation (SpO
2 ) and 28,954 respiratory rate (RR) measurements were collected by fitness trackers. Under real-world conditions, HR monitoring was accurate and reliable across all benchmarked devices (r = [0.95;0.98], p < 0.001; Bias = [-0.74 bpm;-0.01 bpm]; MAPE∼2%). However, the performance of SpO2 (r = [0.21;0.68]; p < 0.001; Bias = [-0.46%;-2.29%]; root-mean-square error = [2.82%;4.1%]) monitoring was substantially inferior. RR measurements could not be obtained for two of the devices, therefore exclusively the accuracy of the Garmin tracker could be evaluated (r = 0.28, p < 0.001; Bias = -1.46/min). Moreover, the time resolution of the vital sign measurements highly depends on the tracking device, ranging from 0.7 to 117.94 data points per hour., Conclusion: According to the results of the present study, tracker devices are generally reliable and accurate for HR monitoring, whereas SpO2 and RR measurements should be interpreted carefully, considering the clinical context of the respective patients., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SH, KW, RP, VD, AKS, DR, AJ, JB, BEW and MS declare no conflicts of interest. PH received a research award from Vogel-Foundation and is a member of the Clinician Scientist Programme, Wuerzburg. PM received honoraria for scientific lectures from CSL Behring GmbH, Pharmacosmos GmbH and CSL Vifor GmbH. PK received lecturing fees from TEVA, Sintetica, CSL Behring GmbH, Senzyme, Vifor Pharma GmbH, Pharmacosmos and Grünenthal and consulted for TEVA, Milestone Scientific Inc, Sintetica and Amicus Ltd. All mentioned funders and especially the manufacturers of the investigated devices had no role in the design of the study; collection, analyses or interpretation of data; writing of the manuscript or in the decision to publish the results., (© The Author(s) 2024.)- Published
- 2024
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11. Prognostic Performance of RECIP 1.0 Based on [ 18 F]PSMA-1007 PET in Prostate Cancer Patients Treated with [ 177 Lu]Lu-PSMA I&T.
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Hartrampf PE, Hüttmann T, Seitz AK, Kübler H, Serfling SE, Higuchi T, Schlötelburg W, Michalski K, Gafita A, Rowe SP, Pomper MG, Buck AK, and Werner RA
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- Humans, Male, Dipeptides adverse effects, Heterocyclic Compounds, 1-Ring adverse effects, Lutetium, Positron Emission Tomography Computed Tomography methods, Prognosis, Retrospective Studies, Treatment Outcome, Niacinamide analogs & derivatives, Oligopeptides, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant radiotherapy, Urea analogs & derivatives
- Abstract
In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on
68 Ga- and18 F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18 F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18 F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean , SUVmax , PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 ( P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18 F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2024
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12. Comparison of PET/CT-based eligibility according to VISION and TheraP trial criteria in end-stage prostate cancer patients undergoing radioligand therapy.
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Michalski K, Kosmala A, Werner RA, Serfling SE, Seitz AK, Lapa C, Buck AK, and Hartrampf PE
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- Male, Humans, Retrospective Studies, Treatment Outcome, Fluorodeoxyglucose F18, Prostate pathology, Prostate-Specific Antigen, Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring therapeutic use, Lutetium therapeutic use, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Background: Two randomized clinical trials demonstrated the efficacy of prostate-specific membrane antigen (PSMA) radioligand therapy (PSMA RLT) in metastatic castration-resistant prostate cancer (mCRPC). While the VISION trial used criteria within PSMA PET/CT for inclusion, the TheraP trial used dual tracer imaging including FDG PET/CT. Therefore, we investigated whether the application of the VISION criteria leads to a benefit in overall survival (OS) or progression-free survival (PFS) for men with mCRPC after PSMA RLT., Methods: Thirty-five men with mCRPC who had received PSMA RLT as a last-line option and who had undergone pretherapeutic imaging with FDG and [
68 Ga]Ga-PSMA I&T or [18 F]PSMA-1007 were studied. Therapeutic eligibility was retrospectively evaluated using the VISION and TheraP study criteria., Results: 26 of 35 (74%) treated patients fulfilled the VISION criteria (= VISION+) and only 17 of 35 (49%) fulfilled the TheraP criteria (= TheraP+). Significantly reduced OS and PFS after PSMA RLT was observed in patients rated VISION- compared to VISION+ (OS: VISION-: 3 vs. VISION+: 12 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.0-9.1, p < 0.01; PFS: VISION-: 1 vs. VISION+: 5 months, HR 2.7, 95% CI 1.0-7.8, p < 0.01). For patients rated TheraP-, no significant difference in OS but in PFS was observed compared to TheraP+ patients (OS: TheraP-: 5.5 vs. TheraP+: 11 months, HR 1.6, 95% CI 0.8-3.3, p = 0.2; PFS: TheraP-: 1 vs. TheraP+: 6 months, HR 2.2, 95% CI 1.0-4.5, p < 0.01)., Conclusion: Retrospective application of the inclusion criteria of the VISION study leads to a benefit in OS and PFS after PSMA RL, whereas TheraP criteria appear to be too strict in patients with end-stage prostate cancer. Thus, performing PSMA PET/CT including a contrast-enhanced CT as proposed in the VISION trial might be sufficient for treatment eligibility of end-stage prostate cancer patients., (© 2023. The Author(s).)- Published
- 2024
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13. [Urinary incontinence after radical prostatectomy for prostate cancer-data from 17,149 patients from 125 certified centers].
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Kowalski C, Sibert NT, Hammerer P, Wesselmann S, Feick G, Carl EG, Klotz T, Apel H, Dieng S, Nyarangi-Dix J, Knoll T, Reike MJ, Duwe G, Bartolf E, Steiner T, Borowitz R, Lümmen G, Seitz AK, Pfitzenmaier J, Aziz A, Brock M, Berger FP, Kaftan BT, Grube C, Häfner T, Hamza A, Schmelz H, Haas J, Lenart S, Lafita A, Sippel C, Winter A, Kedia G, Hadaschik B, Varga Z, Buse S, Richter M, Distler F, Simon J, Wiegel T, Baltes S, Janitzky A, Sommer JP, Hijazi S, Fülkell P, Harke NN, Bolenz C, Khalil C, Breidenbach C, Tennstedt P, and Burchardt M
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- Male, Humans, Prostatectomy adverse effects, Urinary Incontinence epidemiology, Erectile Dysfunction epidemiology, Prostatic Neoplasms surgery
- Abstract
Background: In addition to erectile dysfunction, urinary incontinence is the most common functional limitation after radical prostatectomy (RPE) for prostate cancer (PCa). The German S3 guideline recommends informing patients about possible effects of the therapy options, including incontinence. However, only little data on continence from routine care in German-speaking countries after RPE are currently available, which makes it difficult to inform patients., Objective: The aim of this work is to present data on the frequency and severity of urinary incontinence after RPE from routine care., Materials and Methods: Information from the PCO (Prostate Cancer Outcomes) study is used, which was collected between 2016 and 2022 in 125 German Cancer Society (DKG)-certified prostate cancer centers in 17,149 patients using the Expanded Prostate Cancer Index Composite Short Form (EPIC-26). Changes in the "incontinence" score before (T0) and 12 months after RPE (T1) and the proportion of patients who used pads, stratified by age and risk group, are reported., Results: The average score for urinary incontinence (value range: 0-worst possible to 100-best possible) was 93 points at T0 and 73 points 12 months later. At T0, 97% of the patients did not use a pad, compared to 56% at T1. 43% of the patients who did not use a pad before surgery used at least one pad a day 12 months later, while 13% use two or more. The proportion of patients using pads differs by age and risk classification., Conclusion: The results provide a comprehensive insight into functional outcome 12 months after RPE and can be taken into account when informing patients., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)
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- 2024
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14. Impact of a High-Fat Diet at a Young Age on Wound Healing in Mice.
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Arnke K, Pfister P, Reid G, Vasella M, Ruhl T, Seitz AK, Lindenblatt N, Cinelli P, and Kim BS
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- Mice, Animals, Interleukin-6 pharmacology, Mice, Inbred C57BL, Wound Healing, Collagen metabolism, Mice, Inbred Strains, Cytokines pharmacology, Obesity, Diet, High-Fat adverse effects, Tumor Necrosis Factor-alpha pharmacology
- Abstract
As the prevalence of juvenile-onset obesity rises globally, the multitude of related health consequences gain significant importance. In this context, obesity is associated with impaired cutaneous wound healing. In experimental settings, mice are the most frequently used model for investigating the effect of high-fat diet (HFD) chow on wound healing in wild-type or genetically manipulated animals, e.g., diabetic ob / ob and db / db mice. However, these studies have mainly been performed on adult animals. Thus, in the present study, we introduced a mouse model for a juvenile onset of obesity. We exposed 4-week-old mice to an investigational feeding period of 9 weeks with an HFD compared to a regular diet (RD). At a mouse age of 13 weeks, we performed excisional and incisional wounding and measured the healing rate. Wound healing was examined by serial photographs with daily wound size measurements of the excisional wounds. Histology from incisional wounds was performed to quantify granulation tissue (thickness, quality) and angiogenesis (number of blood vessels per mm
2 ). The expression of extracellular matrix proteins (collagen types I/III/IV, fibronectin 1, elastin), inflammatory cytokines (MIF, MIF-2, IL-6, TNF-α), myofibroblast differentiation (α-SMA) and macrophage polarization (CD11c, CD301b) in the incisional wounds were evaluated by RT-qPCR and by immunohistochemistry. There was a marked delay of wound closure in the HFD group with a decrease in granulation tissue quality and thickness. Additionally, inflammatory cytokines (MIF, IL-6, TNF-α) were significantly up-regulated in HFD- when compared to RD-fed mice measured at day 3. By contrast, MIF-2 and blood vessel expression were significantly reduced in the HFD animals, starting at day 1. No significant changes were observed in macrophage polarization, collagen expression, and levels of TGF-β1 and PDGF-A. Our findings support that an early exposition to HFD resulted in juvenile obesity in mice with impaired wound repair mechanisms, which may be used as a murine model for obesity-related studies in the future.- Published
- 2023
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15. The Combination of Mechanically Isolated Stromal Vascular Fraction and Fibrin Hydrogel: A Processing Protocol.
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Pfister P, Reid G, Breckwoldt T, Vasella M, Seitz AK, Song SY, and Kim BS
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- Hydrogels, Stromal Cells, Adipose Tissue blood supply, Stromal Vascular Fraction, Fibrin
- Abstract
The regenerative potential of adipose-derived stromal cells (ASCs) has gained significant attention in regenerative and translational research. In the past, the extraction of these cells from adipose tissue required a multistep enzyme-based process, resulting in a heterogenous cell mix consisting of ACSs and other cells, which are jointly termed the stromal vascular fraction (SVF). More recently introduced mechanical SVF (mSVF) isolation protocols are less time-consuming and bypass regulatory concerns. We recently proposed a protocol that generates mSVF rich in stromal cells based on a combination of emulsification and centrifugation. One current issue in mSVF application for wound therapy application is the lack of a scaffold providing protection from mechanical manipulation and desiccation. Fibrin hydrogels have been shown to be a useful adjunct in cell transfer for wound healing purposes in the past. In the work herein, we delineate the preparation steps of an mSVF-fibrin hydrogel construct as a novel approach for translational research and clinical application.
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- 2023
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16. The Sensitivity of Rapid Tests for SARS-CoV-2 Antigen.
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Knies K, Wagenhäuser I, Hofmann D, Rauschenberger V, Eisenmann M, Reusch J, Flemming S, Andres O, Petri N, Topp MS, Papsdorf M, McDonogh M, Verma-Führing R, Scherzad A, Zeller D, Böhm H, Gesierich A, Seitz AK, Kiderlen M, Gawlik M, Taurines R, Wurmb T, Ernestus RI, Forster J, Weismann D, Weißbrich B, Liese J, Vogel U, Kurzai O, Dölken L, Gabel A, and Krone M
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- Humans, SARS-CoV-2, Sensitivity and Specificity, COVID-19
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- 2023
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17. Successful use of Rectal Pregabalin for the Treatment of Chemotherapy-Induced Neuropathic Pain-a Case Report.
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Roch C, Para S, Brandhofer C, Seitz AK, Rémi C, Berner J, and van Oorschot B
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- Female, Humans, Aged, Pregabalin therapeutic use, Analgesics therapeutic use, Carcinoma, Transitional Cell complications, Carcinoma, Transitional Cell drug therapy, Urinary Bladder Neoplasms complications, Urinary Bladder Neoplasms drug therapy, Neuralgia chemically induced, Neuralgia drug therapy, Antineoplastic Agents therapeutic use
- Abstract
Introduction: A 65-year-old female patient could no longer take oral food or medications due to a duodenal occlusion associated with metastatic urothelial carcinoma. Her pre-existing chemotherapy-induced polyneuropathy had been well treated with pregabalin orally., Methods: Since only preparations for oral use of pregabalin are available, pregabalin suppositories were compounded by the hospital pharmacy for rectal use in this patient., Results: With the rectal administration, the treatment was successfully continued; we measured a good increase in serum levels and the symptoms improved significantly., Discussion: Cancer patients often need to be treated with co-analgesics. At the end of life, treatment often cannot be continued due to lack of other than oral administration. Our case adds to the low evidence of pregabalin administered rectally., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2023
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18. SUV mean on baseline [ 18 F]PSMA-1007 PET and clinical parameters are associated with survival in prostate cancer patients scheduled for [ 177 Lu]Lu-PSMA I&T.
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Hartrampf PE, Hüttmann T, Seitz AK, Kübler H, Serfling SE, Schlötelburg W, Michalski K, Rowe SP, Pomper MG, Buck AK, Eberlein U, and Werner RA
- Subjects
- Male, Humans, Treatment Outcome, Retrospective Studies, Dipeptides therapeutic use, Positron-Emission Tomography, Heterocyclic Compounds, 1-Ring therapeutic use, Lutetium therapeutic use, Prostate-Specific Antigen therapeutic use, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Background: Quantification of [
68 Ga]-labeled PSMA PET predicts response in patients with prostate cancer (PC) who undergo PSMA-targeted radioligand therapy (RLT). Given the increasing use [18 F]-labeled radiotracers, we aimed to determine whether the uptake derived from [18 F]PSMA-1007 PET can also identify responders and to assess its prognostic value relative to established clinical parameters., Methods: We retrospectively analyzed 103 patients with metastatic, castration-resistant PC who were treated with [177 Lu]Lu-PSMA I&T. We calculated SUVmean , SUVmax , PSMA-avid tumor volume (TV), and total lesion PSMA (defined as PSMA-TV*SUVmean ) on pre-therapeutic [18 F]PSMA-1007 PET. Laboratory values for hemoglobin, C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alkaline phosphatase (AP) were also collected prior to RLT. We performed univariable Cox regression followed by multivariable and Kaplan-Meier analyses with overall survival (OS) serving as endpoint. Last, we also computed a risk factor (RF) model including all items reaching significance on multivariable analysis to determine whether an increasing number of RFs can improve risk stratification., Results: A total of 48 patients died and median OS was 16 months. On univariable Cox regression, SUVmean , CRP, LDH, hemoglobin, and the presence of liver metastases were significantly associated with OS. On multivariable Cox regression, the following significant prognostic factors for OS were identified: SUVmean (per unit, HR, 0.91; P = 0.04), the presence of liver metastases (HR, 2.37; P = 0.03), CRP (per mg/dl, HR, 1.13; P = 0.003), and hemoglobin (per g/dl, HR, 0.76; P < 0.01). Kaplan-Meier analysis showed significant separation between patients with a SUVmean below or above a median SUVmean of 9.4 (9 vs 19 months, HR 0.57; P = 0.03). Of note, patients with only one RF (median OS not reached) showed longest survival compared to patients with two (11 months; HR 2.43 95% CI 1.07-5.49, P = 0.02) or more than two RFs (7 months; HR 3.37 95% CI 1.62-7.03, P < 0.001)., Conclusion: A lower SUVmean derived from [18 F]PSMA-1007, higher CRP, lower hemoglobin, and the presence of liver metastases are associated with reduced OS in patients undergoing RLT. An early RF model also demonstrated that an increasing number of those factors is linked to worse outcome, thereby emphasizing the importance of clinical and imaging parameters for adequate risk stratification., (© 2023. The Author(s).)- Published
- 2023
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19. Elevated Body Mass Index Is Associated with Improved Overall Survival in Castration-Resistant Prostate Cancer Patients Undergoing Prostate-Specific Membrane Antigen-Directed Radioligand Therapy.
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Hartrampf PE, Mihatsch PW, Seitz AK, Solnes LB, Rowe SP, Pomper MG, Kübler H, Bley TA, Buck AK, and Werner RA
- Subjects
- Male, Humans, Body Mass Index, Prostate-Specific Antigen metabolism, Overweight chemically induced, Overweight complications, Overweight drug therapy, Prostate metabolism, Treatment Outcome, Lutetium therapeutic use, Retrospective Studies, Heterocyclic Compounds, 1-Ring therapeutic use, Dipeptides therapeutic use, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant complications, Sarcopenia chemically induced, Sarcopenia complications, Sarcopenia drug therapy
- Abstract
In patients with prostate cancer scheduled for systemic treatment, being overweight is linked to prolonged overall survival (OS), whereas sarcopenia is associated with shorter OS. We investigated fat-related and body composition parameters in patients undergoing prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) to assess their predictive value for OS. Methods: Body mass index (BMI, in kg/m
2 ) and CT-derived body composition parameters (total, subcutaneous, visceral fat area, and psoas muscle area at the L3-L4 level) were determined for 171 patients scheduled for PSMA-directed RLT. After normalization for stature, the psoas muscle index was used to define sarcopenia. Outcome analysis was performed using Kaplan-Meier curves and Cox regression including fat-related and other clinical parameters (Gleason score, C-reactive protein [CRP], lactate dehydrogenase [LDH], hemoglobin, and prostate-specific antigen levels). The Harrell C-index was used for goodness-of-fit analysis. Results: Sixty-five patients (38%) had sarcopenia, and 98 patients (57.3%) had increased BMI. Relative to the 8-mo OS in normal-weight men (BMI < 25), overweight men (25 ≥ BMI > 30) and obese men (BMI ≥ 30) achieved a longer OS of 14 mo (hazard ratio [HR], 0.63; 95% CI, 0.40-0.99; P = 0.03) and 13 mo (HR, 0.47; 95% CI, 0.29-0.77; P = 0.004), respectively. Sarcopenia showed no impact on OS (11 vs. 12 mo; HR, 1.4; 95% CI, 0.91-2.1; P = 0.09). Most of the body composition parameters were tightly linked to OS on univariable analyses, with the highest C-index for BMI. In multivariable analysis, a higher BMI (HR, 0.91; 95% CI, 0.86-0.97; P = 0.006), lower CRP (HR, 1.09; 95% CI, 1.03-1.14; P < 0.001), lower LDH (HR, 1.08; 95% CI, 1.03-1.14; P < 0.001), and longer interval between initial diagnosis and RLT (HR, 0.95; 95% CI, 0.91-0.99; P = 0.02) were significant predictors of OS. Conclusion: Increased fat reserves assessed by BMI, CRP, LDH, and interval between initial diagnosis and RLT, but not CT-derived body composition parameters, were relevant predictors for OS. As BMI can be altered, future research should investigate whether a high-calorie diet before or during PSMA RLT may improve OS., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2023
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20. Preliminary results regarding automated identification of patients with a limited six-month survival prognosis using nursing assessment in uro-oncology patients.
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Roch C, Kielkopf JA, Stefenelli U, Kübler H, van Oorschot B, and Seitz AK
- Subjects
- Humans, Male, Female, Retrospective Studies, Palliative Care methods, Prognosis, Nursing Assessment, Neoplasms
- Abstract
Introduction: Contrary to current recommendations, palliative co-management of tumor patients often occurs late in daily clinical practice. Palliative care specialist (PCS) co-management should be considered at the latest after a 6-month prognosis has been presumed. Therefore, identifying patients with a limited prognosis is a reasonable measure., Methods: Patients were identified using a screening tool for limited prognosis, which combined their tumor stage and data from the nursing anamnesis. In this retrospective study, a monocentric cohort of patients with urological malignancies-UICC (Union for International Cancer Control) stages III and IV - were enrolled from March to December 2019, with a 6-month follow-up period ending in May 2020., Results: Most patients were male and suffered from prostate cancer. Patients with uro-oncological tumors dying within 6 months correlated significantly with the presence of repeated hospitalizations within three months, pain on admission, malnutrition, impaired breathing and reduced mobility (P < 0.001). The test was fair in quality (AUC 0.727) at a cut-point of five; a sensitivity of 97% and a specificity of 25% were obtained. The PPV was 0.64 and NPV was 0.82., Discussion/conclusion: We specifically identified the predictors of limited prognosis in urological cancer patients across several entities using an automated scoring system based on tumor stage and data from the nursing anamnesis. Therefore, we recognized hospitalization as an important transition point and determined nurses to be valuable partners in identifying unmet palliative care needs without additional technical, personnel or financial effort., Competing Interests: Conflicts of interest The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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21. Virus variant-specific clinical performance of SARS coronavirus two rapid antigen tests in point-of-care use, from November 2020 to January 2022.
- Author
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Wagenhäuser I, Knies K, Hofmann D, Rauschenberger V, Eisenmann M, Reusch J, Gabel A, Flemming S, Andres O, Petri N, Topp MS, Papsdorf M, McDonogh M, Verma-Führing R, Scherzad A, Zeller D, Böhm H, Gesierich A, Seitz AK, Kiderlen M, Gawlik M, Taurines R, Wurmb T, Ernestus RI, Forster J, Weismann D, Weißbrich B, Dölken L, Liese J, Kaderali L, Kurzai O, Vogel U, and Krone M
- Subjects
- Humans, Prospective Studies, RNA, Viral, SARS-CoV-2 genetics, Sensitivity and Specificity, Point-of-Care Systems, COVID-19 diagnosis
- Abstract
Objectives: Antigen rapid diagnostic tests (RDTs) for SARS coronavirus 2 (SARS-CoV-2) are quick, widely available, and inexpensive. Consequently, RDTs have been established as an alternative and additional diagnostic strategy to quantitative reverse transcription polymerase chain reaction (RT-qPCR). However, reliable clinical and large-scale performance data specific to a SARS-CoV-2 virus variant of concern (VOC) are limited, especially for the Omicron VOC. The aim of this study was to compare RDT performance among different VOCs., Methods: This single-centre prospective performance assessment compared RDTs from three manufacturers (NADAL, Panbio, MEDsan) with RT-qPCR including deduced standardized viral load from oropharyngeal swabs for detection of SARS-CoV-2 in a clinical point-of-care setting from November 2020 to January 2022., Results: Among 35 479 RDT/RT-qPCR tandems taken from 26 940 individuals, 164 of the 426 SARS-CoV-2 positive samples tested true positive with an RDT corresponding to an RDT sensitivity of 38.50% (95% CI, 34.00-43.20%), with an overall specificity of 99.67% (95% CI, 99.60-99.72%). RDT sensitivity depended on viral load, with decreasing sensitivity accompanied by descending viral load. VOC-dependent sensitivity assessment showed a sensitivity of 42.86% (95% CI, 32.82-53.52%) for the wild-type SARS-CoV-2, 43.42% (95% CI, 32.86-54.61%) for the Alpha VOC, 37.67% (95% CI, 30.22-45.75%) for the Delta VOC, and 33.67% (95% CI, 25.09-43.49%) for the Omicron VOC. Sensitivity in samples with high viral loads of ≥10
6 SARS-CoV-2 RNA copies per mL was significantly lower in the Omicron VOC (50.00%; 95% CI, 36.12-63.88%) than in the wild-type SARS-CoV-2 (79.31%; 95% CI, 61.61-90.15%; p 0.015)., Discussion: RDT sensitivity for detection of the Omicron VOC is reduced in individuals infected with a high viral load, which curtails the effectiveness of RDTs. This aspect furthert: limits the use of RDTs, although RDTs are still an irreplaceable diagnostic tool for rapid, economic point-of-care and extensive SARS-CoV-2 screening., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)- Published
- 2023
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22. mCRPC patients with PSA fluctuations under radioligand therapy have comparable survival benefits relative to patients with sustained PSA decrease.
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Hartrampf PE, Bundschuh RA, Weinzierl FX, Serfling SE, Kosmala A, Seitz AK, Kübler H, Buck AK, Essler M, and Werner RA
- Subjects
- Male, Humans, Lutetium, Heterocyclic Compounds, 1-Ring adverse effects, Dipeptides adverse effects, Biomarkers, Tumor, Retrospective Studies, Treatment Outcome, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant pathology
- 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., (© 2022. The Author(s).)
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- 2022
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23. Baseline clinical characteristics predict overall survival in patients undergoing radioligand therapy with [ 177 Lu]Lu-PSMA I&T during long-term follow-up.
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Hartrampf PE, Seitz AK, Weinzierl FX, Serfling SE, Schirbel A, Rowe SP, Kübler H, Buck AK, and Werner RA
- Subjects
- Aspartate Aminotransferases therapeutic use, C-Reactive Protein, Dipeptides therapeutic use, Follow-Up Studies, Heterocyclic Compounds, 1-Ring therapeutic use, Humans, Lactate Dehydrogenases, Ligands, Male, Prostate-Specific Antigen metabolism, Retrospective Studies, Treatment Outcome, Urea analogs & derivatives, Lutetium therapeutic use, Prostatic Neoplasms, Castration-Resistant metabolism
- 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 (intervalDiagnosis-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 intervalDiagnosis-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 intervalDiagnosis-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 intervalDiagnosis-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., (© 2022. The Author(s).)- Published
- 2022
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24. Any decline in prostate-specific antigen levels identifies survivors scheduled for prostate-specific membrane antigen-directed radioligand therapy.
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Hartrampf PE, Weinzierl FX, Seitz AK, Kübler H, Essler M, Buck AK, Werner RA, and Bundschuh RA
- Subjects
- Antigens, Surface, Dipeptides therapeutic use, Glutamate Carboxypeptidase II, Heterocyclic Compounds, 1-Ring therapeutic use, Humans, Lutetium therapeutic use, Male, Prostate pathology, Retrospective Studies, Survivors, Treatment Outcome, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Background: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly incorporated in the therapeutic algorithm of patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to elucidate the predictive performance of early biochemical response for overall survival (OS)., Materials and Methods: In this bicentric analysis, we included 184 mCRPC patients treated with
177 Lu-PSMA RLT. Response to treatment was defined as decrease in prostate-specific antigen (PSA) levels 8 weeks after the first cycle of RLT (any decline or >50% according to Prostate Cancer Working Group 3). OS of responders and nonresponders was then compared using Kaplan-Meier curves and log-rank comparison., Results: A total of 114/184 patients (62.0%) showed any PSA decline (PSA response >50%, 55/184 [29.9%]). For individuals exhibiting a PSA decline >50%, OS of 19 months was significantly longer relative to nonresponders (13 months; hazard ratio of death [HR] = 0.64, 95% confidence interval [95% CI] = 0.44-0.93; p = 0.02). However, the difference was even more pronounced for any PSA decline, with an OS of 19 months in responders, but only 8 months in nonresponders (HR = 0.39, 95% CI = 0.25-0.60; p < 0.001)., Conclusions: In mCRPC patients scheduled for RLT, early biochemical response was tightly linked to prolonged survival, irrespective of the magnitude of PSA decline. As such, even in patients with PSA decrease of less than 50%, RLT should be continued., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)- Published
- 2022
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25. Diverse PSMA expression in primary prostate cancer: reason for negative [ 68 Ga]Ga-PSMA PET/CT scans? Immunohistochemical validation in 40 surgical specimens.
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Cytawa W, Kircher S, Kübler H, Werner RA, Weber S, Hartrampf P, Bandurski T, Lass P, Połom W, Matuszewski M, Wester HJ, Lapa C, Rosenwald A, Seitz AK, and Buck AK
- Subjects
- Edetic Acid, Humans, Male, Oligopeptides, Positron Emission Tomography Computed Tomography methods, Urea analogs & derivatives, Gallium Radioisotopes, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms metabolism, Prostatic Neoplasms surgery
- Abstract
Purpose: The purpose of this study was to immunohistochemically validate the primary tumor PSMA expression in prostate cancer (PCa) patients imaged with [
68 Ga]Ga-PSMA PET/CT prior to surgery, with special consideration of PET-negative cases., Methods: The study included 40 men with newly diagnosed treatment-naïve PCa imaged with [68 Ga]Ga-PSMA I&T PET/CT as part of the diagnostic work-up prior to radical prostatectomy. All primary tumors were routinely stained with H&E. In addition, immunohistochemical staining of PSMA was performed and the immunoreactive score (IRS) was computed as semiquantitative measure. Subsequently, imaging findings were correlated to histopathologic results., Results: Eighty-three percent (33/40) of patients presented focal uptake of [68 Ga]Ga-PSMA I&T in the primary tumor in at least one prostate lobe. Among PSMA-PET positive patients, one-third had lymph node metastases (LNM) detected by post-operative histopathology, while in PET negative patients, only 1 out of 7 presented with regional LN involvement; PSMA-avid distant lesions, predominantly in bones, were observed in 15% and 0% of patients, respectively. The median IRS classification of PSMA expression in tumor tissue was 2 (range, 1-3) both in PSMA-PET positive and negative prostate lobes, with significantly different interquartile range: 2-3 vs. 2-2, respectively (p = 0.03). The median volume of PSMA-PET positive tumors was 5.4 mL (0.2-32.9) as compared to 1.6 mL (0.3-18.3) of PET-negative tumors (p < 0.001). There was a significant but weak correlation between SUVmax and percentage of PSMA-positive tumor cells (r = 0.46, p < 0.001). A total of 35/44 (~80%) lobes were positive in PSMA-PET imaging, when a cut-off percentage of PSMA-positive cells was ≥ 90%, while 19/36 (~53%) lobes with < 90% PSMA-positive cells were PSMA-PET negative., Conclusion: Positive [68 Ga]Ga-PSMA I&T PET/CT scan of primary tumor of PCa results from a combination of factors, such as homogeneity and intensity of PSMA expression, tumor volume and grade, with a cutoff value of ≥ 90% PSMA-positive cells strongly determining PET-positivity. Focal accumulation of [68 Ga]Ga-PSMA in the primary tumor may correlate positively with aggressiveness of prostate cancer, harboring higher risk of regional LN involvement and distant metastatic spread., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2022
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26. Matched-pair analysis of [ 177 Lu]Lu-PSMA I&T and [ 177 Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer.
- Author
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Hartrampf PE, Weinzierl FX, Buck AK, Rowe SP, Higuchi T, Seitz AK, Kübler H, Schirbel A, Essler M, Bundschuh RA, and Werner RA
- Subjects
- Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring therapeutic use, Humans, Lutetium therapeutic use, Male, Matched-Pair Analysis, Prostate-Specific Antigen, Treatment Outcome, Urea analogs & derivatives, Urea therapeutic use, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Background: Labelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT., Materials and Methods: A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [
177 Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [177 Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared., Results: Toxicity assessment revealed grade III anaemia in a single patient (1.8%) for [177 Lu]Lu-PSMA I&T and five (9.1%) for [177 Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [177 Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [177 Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [177 Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89)., Conclusion: In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed., (© 2022. The Author(s).)- Published
- 2022
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27. Concentrated Aqueous Peroxodicarbonate: Efficient Electrosyn- thesis and Use as Oxidizer in Epoxidations, S-, and N-Oxidations.
- Author
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Seitz AK, Kohlpaintner PJ, van Lingen T, Dyga M, Sprang F, Zirbes M, Waldvogel SR, and Gooßen LJ
- Abstract
Peroxodicarbonates are of substantial interest as potentially powerful and sustainable oxidizers but have so far been accessible only in low concentrations with unsatisfactory energy efficiency. Concentrated (> 0.9 mol L
-1 ) peroxodicarbonate solutions have now been made accessible by the electrolysis of aqueous K2 CO3 /Na2 CO3 /KHCO3 solutions at high current density of 3.33 A cm-2 in an efficiently cooled circular flow reactor equipped with a boron-doped diamond anode and a stainless-steel cathode. Their synthetic potential as platform oxidizers was clearly demonstrated in transformations including sulfoxidation, N-oxidation, and epoxidation., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)- Published
- 2022
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28. Ru-Catalyzed C-H Arylation of Acrylic Acids with Aryl Bromides.
- Author
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Belitz F, Seitz AK, Goebel JF, Hu Z, and Gooßen LJ
- Subjects
- Catalysis, Bromides, Palladium
- Abstract
In the presence of a [Ru( p -cymene)Cl
2 ]2 /triethylphosphine/lithium carbonate catalyst system, aryl bromides undergo ( Z )-selective couplings with unprotected 2-arylacrylic acids to form ( Z )-diarylacrylic acids. This vinylic C-H functionalization proceeds in high yields of up to 94% and ( Z / E )-ratios of up to 99:1, tolerating a wide range of functional groups. Mechanistic studies indicate that the vinylic C-H activation proceeds via base-assisted cyclometalation rather than via a Heck-type mechanism, which explains its orthogonal stereoselectivity.- Published
- 2022
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29. Reduced Segmentation of Lesions Is Comparable to Whole-Body Segmentation for Response Assessment by PSMA PET/CT: Initial Experience with the Keyhole Approach.
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Hartrampf PE, Krebs M, Peter L, Heinrich M, Ruffing J, Kalogirou C, Weinke M, Brumberg J, Kübler H, Buck AK, Werner RA, and Seitz AK
- Abstract
(1) Background: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-derived parameters, such as the commonly used standardized uptake value (SUV) and PSMA-positive tumor volume (PSMA-TV), have been proposed for response assessment in metastatic prostate cancer (PCa) patients. However, the calculation of whole-body PSMA-TV remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative lesions. (2) Methods: Sixty-five patients classified into different disease stages were assessed by PSMA PET/CT for staging and restaging after therapy. Whole-body PSMA-TV and whole-body SUV
max were calculated. We then repeated this calculation only including the five or ten hottest or largest lesions. The corresponding serum levels of prostate-specific antigen (PSA) were also determined. The derived delta between baseline and follow-up values provided the following parameters: ΔSUVmaxall , ΔSUVmax10 , ΔSUVmax5 , ΔPSMA-TVall , ΔPSMA-TV10 , ΔPSMA-TV5 , ΔPSA. Finally, we compared the findings from our whole-body segmentation with the results from our keyhole approach (focusing on a limited number of lesions) and correlated all values with the biochemical response (ΔPSA). (3) Results: Among patients with metastatic hormone-sensitive PCa (mHSPC), none showed a relevant deviation for ΔSUVmax10 /ΔSUVmax5 or ΔPSMA-TV10 /ΔPSMA-TV5 compared to ΔSUVmaxall and ΔPSMA-TVall . For patients treated with taxanes, up to 6/21 (28.6%) showed clinically relevant deviations between ΔSUVmaxall and ΔSUVmax10 or ΔSUVmax5 , but only up to 2/21 (9.5%) patients showed clinically relevant deviations between ΔPSMA-TVall and ΔPSMA-TV10 or ΔPSMA-TV5 . For patients treated with radioligand therapy (RLT), up to 5/28 (17.9%) showed clinically relevant deviations between ΔSUVmaxall and ΔSUVmax10 or ΔSUVmax5 , but only 1/28 (3.6%) patients showed clinically relevant deviations between ΔPSMA-TVall and ΔPSMA-TV10 or ΔPSMA-TV5 . The highest correlations with ΔPSA were found for ΔPSMA-TVall (r ≥ 0.59, p ≤ 0.01), followed by ΔPSMA-TV10 (r ≥ 0.57, p ≤ 0.01) and ΔPSMA-TV5 (r ≥ 0.53, p ≤ 0.02) in all cohorts. ΔPSA only correlated with ΔSUVmaxall (r = 0.60, p = 0.02) and with ΔSUVmax10 (r = 0.53, p = 0.03) in the mHSPC cohort, as well as with ΔSUVmaxall (r = 0.51, p = 0.01) in the RLT cohort. (4) Conclusion: Response assessment using PSMA-TV with a reduced number of lesions is feasible, and may allow for a simplified evaluation process for PSMA PET/CT.- Published
- 2022
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30. Hematotoxicity and Nephrotoxicity in Prostate Cancer Patients Undergoing Radioligand Therapy with [ 177 Lu]Lu-PSMA I&T.
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Hartrampf PE, Weinzierl FX, Serfling SE, Pomper MG, Rowe SP, Higuchi T, Seitz AK, Kübler H, Buck AK, and Werner RA
- Abstract
(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [
177 Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [177 Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [99m Tc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman's rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as <70% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1%; GFR, 1/49 (2%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2%); G3a to G3b, 2/49 (4.1%)). After three cycles, follow-up eGFR correlated negatively with age (r = -0.40, p = 0.005) and the eGFR change with Gleason score (r = -0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2%) (CTCAE I, 20/49 (41%)) and CTCAE I thrombocytopenia in 7/49 (14%), with an absolute decrease of 15.2% and 16.6% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20%) (CTCAE I, 36/49 (73%)) with a decrease in hemoglobin of 4.7%. (4) Conclusions: After PSMA-targeted therapy using [177 Lu]Lu-PSMA I&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent.- Published
- 2022
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31. Changing Threshold-Based Segmentation Has No Relevant Impact on Semi-Quantification in the Context of Structured Reporting for PSMA-PET/CT.
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Mihatsch PW, Beissert M, Pomper MG, Bley TA, Seitz AK, Kübler H, Buck AK, Rowe SP, Serfling SE, Hartrampf PE, and Werner RA
- Abstract
Prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) is increasingly utilized for staging of men with prostate cancer (PC). To increase interpretive certainty, the standardized PSMA reporting and data system (RADS) has been proposed. Using PSMA-RADS, we characterized lesions in 18 patients imaged with
18 F-PSMA-1007 PET/CT for primary staging and determined the stability of semi-quantitative parameters. Six hundred twenty-three lesions were categorized according to PSMA-RADS and manually segmented. In this context, PSMA-RADS-3A (soft-tissue) or -3B (bone) lesions are defined as being indeterminate for the presence of PC. For PMSA-RADS-4 and -5 lesions; however, PC is highly likely or almost certainly present [with further distinction based on absence (PSMA-RADS-4) or presence (PSMA-RADS-5) of correlative findings on CT]. Standardized uptake values (SUVmax , SUVpeak , SUVmean ) were recorded, and volumetric parameters [PSMA-derived tumor volume (PSMA-TV); total lesion PSMA (TL-PSMA)] were determined using different maximum intensity thresholds (MIT) (40 vs. 45 vs. 50%). SUVmax was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories ( p ≤ 0.0322). In particular, the clinically challenging PSMA-RADS-3A lesions showed significantly lower SUVmax and SUVpeak compared to the entire PSMA-RADS-4 or -5 cohort ( p < 0.0001), while for PSMA-RADS-3B this only applies when compared to the entire PSMA-RADS-5 cohort ( p < 0.0001), but not to the PSMA-RADS-4 cohort (SUVmax , p = 0.07; SUVpeak , p = 0.08). SUVmean ( p = 0.30) and TL-PSMA ( p = 0.16) in PSMA-RADS-5 lesions were not influenced by changing the MIT, while PSMA-TV showed significant differences when comparing 40 vs. 50% MIT ( p = 0.0066), which was driven by lymph nodes ( p = 0.0239), but not bone lesions ( p = 0.15). SUVmax was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories in18 F-PSMA-1007 PET/CT. As such, the latter parameter may assist the interpreting molecular imaging specialist in assigning the correct PSMA-RADS score to sites of disease, thereby increasing diagnostic certainty. In addition, changes of the MIT in PSMA-RADS-5 lesions had no significant impact on SUVmean and TL-PSMA in contrast to PSMA-TV.- Published
- 2022
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32. Development of Discordant Hypermetabolic Prostate Cancer Lesions in the Course of [ 177 Lu]PSMA Radioligand Therapy and Their Possible Influence on Patient Outcome.
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Hartrampf PE, Lapa C, Serfling SE, Buck AK, Seitz AK, Meyer PT, Ruf J, and Michalski K
- Abstract
Introduction: Positron emission tomography/computer tomography (PET/CT) targeting the prostate-specific membrane antigen (PSMA) is crucial for the assessment of adequate PSMA expression in patients with metastatic castration-resistant prostate cancer (mCRPC) prior to PSMA radioligand therapy (PSMA RLT). Moreover, initial dual tracer staging using combined PSMA and [
18 F]fluorodeoxyglucose (FDG) PET/CT provides relevant information, since discordant FDG-positive but PSMA-negative (FDG+/PSMA-) lesions constitute a negative prognostic marker of overall survival (OS) after PSMA RLT. However, little is known about the prognostic implications of dual tracer imaging for restaging at follow-up. The aim of this analysis was to investigate the prognostic implications of new FDG+/PSMA- lesions during or after PSMA RLT., Methods: This bicentric analysis included 32 patients with mCRPC who underwent both FDG and PSMA PET/CT imaging after two or four cycles of PSMA RLT. Patients with FDG+/PSMA- lesions prior to PSMA RLT were not considered. The presence of FDG+/PSMA- lesions was assessed with follow-up dual tracer imaging of patients after two or four cycles of PSMA RLT. Patients with at least one new FDG+/PSMA- lesion were compared to patients without any FDG+/PSMA- lesions at the respective time points. A log-rank analysis was used to assess the difference in OS between subgroups., Results: After two cycles of PSMA RLT, four of 32 patients (13%) had FDG+/PSMA- metastases. No significant difference in OS was observed ( p = 0.807), as compared to patients without FDG+/PSMA- lesions. Follow-up dual tracer imaging after the 4th cycle of PSMA RLT was available in 18 patients. Of these, four patients presented with FDG+/PSMA- findings ( n = 2 already after two cycles). After the fourth cycle of PSMA RLT, no significant difference in OS was observed between patients with and without FDG+/PSMA- lesions ( p = 0.442)., Conclusion: This study shows that FDG+/PSMA- lesions develop in a limited number of patients undergoing PSMA RLT. Further studies are needed to establish the clinical relevance of such lesions.- Published
- 2021
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33. MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer.
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Kalogirou C, Linxweiler J, Schmucker P, Snaebjornsson MT, Schmitz W, Wach S, Krebs M, Hartmann E, Puhr M, Müller A, Spahn M, Seitz AK, Frank T, Marouf H, Büchel G, Eckstein M, Kübler H, Eilers M, Saar M, Junker K, Röhrig F, Kneitz B, Rosenfeldt MT, and Schulze A
- Subjects
- Aged, Aged, 80 and over, Animals, Humans, Male, Mice, Middle Aged, Base Sequence, Cell Line, Tumor, Cell Proliferation genetics, Cell Survival, Cohort Studies, Computer Simulation, Disease Models, Animal, Drug Resistance, Neoplasm genetics, Mice, SCID, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Staging, Prostate-Specific Antigen metabolism, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology, Receptors, Androgen metabolism, Terbinafine pharmacology, Transcriptional Activation genetics, Cholesterol biosynthesis, Down-Regulation genetics, Gene Expression Regulation, Neoplastic, MicroRNAs genetics, MicroRNAs metabolism, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Squalene Monooxygenase antagonists & inhibitors, Squalene Monooxygenase genetics, Squalene Monooxygenase metabolism
- Abstract
Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa., (© 2021. The Author(s).)
- Published
- 2021
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34. Prognostic implications of dual tracer PET/CT: PSMA ligand and [ 18 F]FDG PET/CT in patients undergoing [ 177 Lu]PSMA radioligand therapy.
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Michalski K, Ruf J, Goetz C, Seitz AK, Buck AK, Lapa C, and Hartrampf PE
- Subjects
- Dipeptides, Fluorodeoxyglucose F18, Heterocyclic Compounds, 1-Ring, Humans, Ligands, Male, Prognosis, Positron Emission Tomography Computed Tomography, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant radiotherapy
- Abstract
Background: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with
177 Lu-labeled PSMA ligands has achieved remarkable results in advanced disease stages of metastatic castration-resistant prostate cancer (mCRPC). However, not all patients benefit from this therapy. Different treatment responses could be explained by tumor heterogeneity triggered by progression and the number of prior treatments. PSMA-negative lesions can be missed on PSMA ligand PET/CT, which subsequently results in an underestimation of tumor burden. Conversely, high FDG uptake may also be an indicator of tumor aggressiveness and thus a poor prognostic marker for response to RLT and overall survival (OS). The aim of this analysis was to investigate the prognostic value of combined PSMA ligand PET/CT and [18 F]fluorodeoxyglucose (FDG) PET/CT for outcome prediction in patients undergoing RLT., Materials and Methods: This bicentric analysis included 54 patients with mCRPC who underwent both FDG and PSMA ligand PET/CT imaging before RLT. In all patients, the pattern of PSMA ligand and FDG uptake was visually assessed. Patients with at least one FDG-positive, but PSMA-negative (FDG+/PSMA-) lesions were compared to patients without any FDG+/PSMA- lesions. A log-rank analysis was used to assess the difference in OS between subgroups., Results: Median OS was 11 ± 1.8 months (95% CI 7.4-14.6). A significantly lower OS (p < 0.001) was found in patients with at least one FDG+/PSMA- lesion at baseline PET/CTs (n = 18) with a median OS of 6.0 ± 0.5 months (95% CI: 5.0-7.0 months). In comparison, patients without any FDG+/PSMA- lesions (n = 36) had a median OS of 16.0 ± 2.5 months (95% CI: 11.2-20.8 months)., Conclusion: FDG+/PSMA- lesions are a negative predictor of overall survival in patients with mCRPC undergoing RLT. However, it remains to be determined if patients with FDG+/PSMA- lesions should be excluded from PSMA RLT.- Published
- 2021
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35. Coupling of Reformatsky Reagents with Aryl Chlorides Enabled by Ylide-Functionalized Phosphine Ligands.
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Hu Z, Wei XJ, Handelmann J, Seitz AK, Rodstein I, Gessner VH, and Gooßen LJ
- Abstract
The coupling of aryl chlorides with Reformatsky reagents is a desirable strategy for the construction of α-aryl esters but has so far been substantially limited in the substrate scope due to many challenges posed by various possible side reactions. This limitation has now been overcome by the tailoring of ylide-functionalized phosphines to fit the requirements of Negishi couplings. Record-setting activities were achieved in palladium-catalyzed arylations of organozinc reagents with aryl electrophiles using a cyclohexyl-YPhos ligand bearing an ortho-tolyl-substituent in the backbone. This highly electron-rich, bulky ligand enables the use of aryl chlorides in room temperature couplings of Reformatsky reagents. The reaction scope covers diversely functionalized arylacetic and arylpropionic acid derivatives. Aryl bromides and chlorides can be converted selectively over triflate electrophiles, which permits consecutive coupling strategies., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
- Published
- 2021
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36. Final results of the PräVAC trial: prevention of wound complications following inguinal lymph node dissection in patients with penile cancer using epidermal vacuum-assisted wound closure.
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Schmid SC, Seitz AK, Haller B, Fritsche HM, Huber T, Burger M, Gschwend JE, and Maurer T
- Subjects
- Adult, Aged, Aged, 80 and over, Humans, Inguinal Canal, Male, Middle Aged, Prospective Studies, Surgical Wound Dehiscence prevention & control, Surgical Wound Infection prevention & control, Vacuum, Lymph Node Excision, Negative-Pressure Wound Therapy, Penile Neoplasms surgery, Postoperative Complications prevention & control
- Abstract
Purpose: Inguinal lymphadenectomy in penile cancer is associated with a high rate of wound complications. The aim of this trial was to prospectively analyze the effect of an epidermal vacuum wound dressing on lymphorrhea, complications and reintervention in patients with inguinal lymphadenectomy for penile cancer., Patients and Methods: Prospective, multicenter, randomized, investigator-initiated study in two German university hospitals (2013-2017). Thirty-one patients with penile cancer and indication for bilateral inguinal lymph node dissection were included and randomized to conventional wound care on one side (CONV) versus epidermal vacuum wound dressing (VAC) on the other side., Results: A smaller cumulative drainage fluid volume until day 14 (CDF) compared to contralateral side was observed in 15 patients (CONV) vs. 16 patients (VAC), with a median CDF 230 ml (CONV) vs. 415 ml (VAC) and a median maximum daily fluid volume (MDFV) of 80 ml (CONV) vs. 110 ml (VAC). Median time of indwelling drainage: 7 days (CONV) vs. 8 days (VAC). All grade surgery-related complications were seen in 74% patients (CONV) vs. 74% patients (VAC); grade 3 complications in 3 patients (CONV) vs. 6 patients (VAC). Prolonged hospital stay occurred in 32% patients (CONV) vs. 48% patients (VAC); median hospital stay was 11.5 days. Reintervention due to complications occurred in 45% patients (CONV) vs. 42% patients (VAC)., Conclusions: In this prospective, randomized trial we could not observe a significant difference between epidermal vacuum treatment and conventional wound care.
- Published
- 2021
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37. Detection Rate of 68 Ga-PSMA Ligand PET/CT in Patients with Recurrent Prostate Cancer and Androgen Deprivation Therapy.
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Brumberg J, Beckl M, Dierks A, Schirbel A, Krebs M, Buck A, Kübler H, Lapa C, and Seitz AK
- Abstract
Prostate-specific membrane antigen (PSMA) ligand PET/CT enables the localization of tumor lesions in patients with recurrent prostate cancer, but it is unclear whether androgen deprivation therapy (ADT) influences diagnostic accuracy. The aim of this study was to evaluate the effect of ADT on the detection rate of
68 Ga-PSMA ligand PET/CT. Thus, 399 patients with initial radical prostatectomy and68 Ga-PSMA ligand PET/CT during PSA relapse were retrospectively evaluated. Propensity score matching was used to create two balanced groups of 62 subjects who either did or did not receive ADT within six months before imaging. All68 Ga-PSMA ligand PET/CT were evaluated visually and with semiquantitative measures. The detection rate of tumor recurrence was significantly higher in the group with ADT (88.7% vs. 72.6%, p = 0.02) and improved with increasing PSA-levels in both groups. In subjects with pathological PET/CT and ADT, whole-body total lesion PSMA ( p < 0.01) and PSMA-derived tumor volume ( p < 0.01) were significantly higher than in those without ADT. More PSMA-positive lesions and higher PSMA-derived volumetric parameters in patients with ADT suggest that a better detection rate is related to a (biologically) more advanced disease stage. Due to high detection rates in patients with PSA-levels < 2 ng/mL, the withdrawal of ADT before PSMA ligand PET/CT cannot be recommended.- Published
- 2020
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38. False-negative 18 F-PSMA-1007 PET/CT in metastatic prostate cancer related to high physiologic liver uptake.
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Hartrampf PE, Seitz AK, Krebs M, Buck AK, and Lapa C
- Subjects
- Aged, Humans, Liver, Male, Niacinamide analogs & derivatives, Oligopeptides, Positron Emission Tomography Computed Tomography, Prostatic Neoplasms diagnostic imaging
- Published
- 2020
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39. [Immuno-oncological approaches in the perioperative therapy of muscle invasive bladder cancer].
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Schmid SC, Koll FJ, Beckert F, and Seitz AK
- Subjects
- Antineoplastic Agents, Immunological adverse effects, Carcinoma, Transitional Cell immunology, Carcinoma, Transitional Cell pathology, Chemotherapy, Adjuvant, Combined Modality Therapy, Cystectomy, Humans, Neoadjuvant Therapy, Programmed Cell Death 1 Receptor immunology, Treatment Outcome, Urinary Bladder Neoplasms immunology, Urinary Bladder Neoplasms pathology, Urologic Neoplasms immunology, Urologic Neoplasms pathology, Antineoplastic Agents therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Carcinoma, Transitional Cell therapy, Immunotherapy, Perioperative Care methods, Practice Guidelines as Topic, Programmed Cell Death 1 Receptor therapeutic use, Urinary Bladder Neoplasms therapy, Urologic Neoplasms therapy
- Abstract
Perioperative chemotherapy has become a standard treatment for muscle invasive bladder cancer and is recommended by national and international guidelines. The treatment of metastatic urothelial cancer evolved by the use of immune-modulating therapies like checkpoint inhibitors. Many clinical trials have been initiated which try to evaluate the role of immune checkpoint inhibition in the neoadjuvant and adjuvant setting. These trials focus not only on monotherapy, but also on the combination of checkpoint inhibitors with classical chemotherapy or with local radiation therapy (radioimmunotherapy). In neoadjuvant radioimmunotherapy, the radiation is supposed to act as a sensitizer for the systemic effects of checkpoint inhibition, in addition to the local effects. This review presents and discusses current trials and published results for perioperative immunomodulating treatment-alone or in combination-in muscle invasive bladder cancer.
- Published
- 2020
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40. Metabolic Tumour Volume from PSMA PET/CT Scans of Prostate Cancer Patients during Chemotherapy-Do Different Software Solutions Deliver Comparable Results?
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Hartrampf PE, Heinrich M, Seitz AK, Brumberg J, Sokolakis I, Kalogirou C, Schirbel A, Kübler H, Buck AK, Lapa C, and Krebs M
- Abstract
(1) Background: Prostate-specific membrane antigen (PSMA)-derived tumour volume (PSMA-TV) and total lesion PSMA (TL-PSMA) from PSMA PET/CT scans are promising biomarkers for assessing treatment response in prostate cancer (PCa). Currently, it is unclear whether different software tools for assessing PSMA-TV and TL-PSMA produce comparable results. (2) Methods:
68 Ga-PSMA PET/CT scans from n = 21 patients with castration-resistant PCa (CRPC) receiving chemotherapy were identified from our single-centre database. PSMA-TV and TL-PSMA were calculated with Syngo.via (Siemens) as well as the freely available Beth Israel plugin for FIJI (Fiji Is Just ImageJ) before and after chemotherapy. While statistical comparability was illustrated and quantified via Bland-Altman diagrams, the clinical agreement was estimated by matching PSMA-TV, TL-PSMA and relative changes of both variables during chemotherapy with changes in serum PSA (ΔPSA) and PERCIST (Positron Emission Response Criteria in Solid Tumors). (3) Results: Comparing absolute PSMA-TV and TL-PSMA as well as Bland-Altman plotting revealed a good statistical comparability of both software algorithms. For clinical agreement, classifying therapy response did not differ between PSMA-TV and TL-PSMA for both software solutions and showed highly positive correlations with BR. (4) Conclusions: due to the high levels of statistical and clinical agreement in our CRPC patient cohort undergoing taxane chemotherapy, comparing PSMA-TV and TL-PSMA determined by Syngo.via and FIJI appears feasible., Competing Interests: The authors declare no conflict of interest.- Published
- 2020
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41. 68 Ga-PSMA I&T PET/CT for primary staging of prostate cancer.
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Cytawa W, Seitz AK, Kircher S, Fukushima K, Tran-Gia J, Schirbel A, Bandurski T, Lass P, Krebs M, Połom W, Matuszewski M, Wester HJ, Buck AK, Kübler H, and Lapa C
- Subjects
- Edetic Acid analogs & derivatives, Gallium Isotopes, Gallium Radioisotopes, Humans, Male, Neoplasm Staging, Oligopeptides, Retrospective Studies, Positron Emission Tomography Computed Tomography, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology
- Abstract
Purpose: The present study is based on a retrospective analysis of Gallium-68 (
68 Ga)-labelled prostate-specific membrane antigen (68 Ga-PSMA I&T) PET/CT performed in newly diagnosed, treatment-naïve prostate cancer (PCa) patients prior to definitive treatment., Methods: A total of 82 men were included in the study and were imaged with68 Ga-PSMA I&T PET/CT to assess the distribution of PSMA-avid disease for staging purposes (11 with low-risk, 32 with intermediate-risk, and 39 with high-risk PCa). Forty patients (20 with intermediate- and 20 with high-risk disease) underwent subsequent radical prostatectomy with extended pelvic lymph node dissection which allowed for correlation of imaging findings with histopathologic data., Results: PSMA-positive disease was detected in 83% of patients with 66/82 (80.5%) primary tumours being visualized. PSMA-avid lymph nodes were recorded in 17/82 patients (20.7%, 3 with intermediate-risk and 14 with high-risk PCa); distant disease was found in 14/82 subjects (17.1%, 2 with intermediate-risk and 12 with high-risk PCa). No extraprostatic disease was found in low-risk PCa. SUVmax of primary tumours showed a weak but significant correlation with serum PSA values (r = 0.51, p < 0.001) and Gleason scores (GSC; r = 0.35, p = 0.001), respectively. In correlation with histopathology, calculated per-region sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detection of lymph node metastases were 35.0%, 98.4%, 63.6%, 95.0%, and 93.0%, respectively., Conclusions: In patients with initial diagnosis of intermediate- and high-risk prostate cancer,68 Ga-PSMA I&T PET/CT emerges as a relevant staging procedure by identifying nodal and/or distant metastases. Due to the low prevalence of extraprostatic disease, its value seems to be limited in low-risk disease.- Published
- 2020
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42. Ylide-Functionalized Phosphine (YPhos)-Palladium Catalysts: Selective Monoarylation of Alkyl Ketones with Aryl Chlorides.
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Hu XQ, Lichte D, Rodstein I, Weber P, Seitz AK, Scherpf T, Gessner VH, and Gooßen LJ
- Abstract
Ylide-functionalized phosphine (YPhos) ligands allow the palladium-catalyzed α-arylation of alkyl ketones with aryl chlorides with record setting activity. Using a cyclohexyl-substituted YPhos ligand, a wide range of challenging ketone substrates was efficiently and selectively monoarylated under mild conditions. A newly designed YPhos ligand bearing tert -butyl groups on the coordinating phosphorus atom is already active at room temperature. The synthetic potential was demonstrated by gram-scale reactions and the succinct synthesis of ε-caprolactone derivatives.
- Published
- 2019
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43. [Molecular tumor board prostate cancer].
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Seitz AK, Heck MM, Kamer MW, and Grüllich C
- Subjects
- Biomarkers, Tumor blood, Genetic Testing, Germany, Humans, Interdisciplinary Research, Male, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant genetics, Drug Resistance, Neoplasm genetics, Hormone Replacement Therapy, Molecular Targeted Therapy, Precision Medicine methods, Prostatic Neoplasms, Castration-Resistant therapy, Receptors, Androgen blood
- Abstract
In modern oncology, molecular tumor boards are the interface between the public healthcare system and clinical research institutions. An interdisciplinary team of medical and scientific experts assesses if extensive molecular testing for tumor profiling is appropriate and discusses therapeutic options for patients with newly diagnosed treatable alterations. In the field of metastatic prostate cancer, patients especially with a strong family history, young age of diagnosis and those who have exhausted standard treatments may benefit from molecular profiling. Expression of the androgen receptor splice variant 7 (AR-V7) predicts nonresponse to next-generation AR-directed therapy like abiraterone or enzalutamide. Different blood tests for AR-V7 detection are now commercially available. Mutations in the DNA repair pathway are another frequent event in metastatic prostate cancer. Homologous recombination defects sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors. In the TOPARP-A trial, the PARP inhibitor olaparib led to high response rates (88%) in patients with mutated DNA repair genes. Furthermore, patients with DNA mismatch repair deficiency and/or microsatellite instability seem to benefit from PD-1 inhibitors, particularly pembrolizumab. At this time neither PARP inhibitors nor PD-1 inhibitors are approved for metastatic prostate cancer treatment in Germany. Therefore, a recommendation of a molecular tumor board for biomarker-matched off-label use of approved drugs across entity barriers will support coverage by health insurance.
- Published
- 2019
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44. Preliminary results on response assessment using 68 Ga-HBED-CC-PSMA PET/CT in patients with metastatic prostate cancer undergoing docetaxel chemotherapy.
- Author
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Seitz AK, Rauscher I, Haller B, Krönke M, Luther S, Heck MM, Horn T, Gschwend JE, Schwaiger M, Eiber M, and Maurer T
- Subjects
- Aged, Docetaxel therapeutic use, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Prospective Studies, Prostatic Neoplasms drug therapy, Retrospective Studies, Edetic Acid analogs & derivatives, Positron Emission Tomography Computed Tomography, Prostatic Neoplasms diagnostic imaging, Radiopharmaceuticals
- Abstract
Purpose: To investigate the value of
68 Ga-HBED-CC PSMA (68 Ga-PSMA) PET/CT for response assessment in metastatic castration-sensitive and castration-resistant prostate cancer (mCSPC and mCRPC) during docetaxel chemotherapy., Methods:68 Ga-PSMA PET/CT was performed in seven mCSPC patients before and after six cycles of upfront docetaxel chemotherapy and in 16 mCRPC patients before and after three cycles of palliative docetaxel chemotherapy. Radiographic treatment response was evaluated separately on the68 Ga-PSMA PET and CT datasets. Changes in68 Ga-PSMA uptake (SUVmean) were assessed on a per-patient and a per-lesion basis using the PERCIST scoring system with slight modification. Treatment response was defined as absence of any PSMA uptake in all target lesions on posttreatment PET (complete response, CR) or a decrease in summed SUVmean of ≥30% (partial response, PR). The appearance of a new PET-positive lesion or an increase in summed SUVmean of ≥30% (progressive disease, PD) indicated nonresponse. A moderate change in summed SUVmean (between -30% and +30%) without a change in the number of target lesions was defined as stable disease (SD). For treatment response assessment on CT, RECIST1.1 criteria were used. Radiographic responses on68 Ga-PSMA PET [RR(PET)] and on CT [RR(CT)] were compared and correlated with biochemical response (BR). A decrease in serum PSA level of ≥50% was defined as biochemical PR., Results: Biochemical PR was found in six of seven patients with mCSPC (86%, 95% confidence interval 42% to 99.6%). The concordance rate was higher between BR and RR(PET) than between BR and RR(CT) (6/7 vs. 3/6 patients.68 Ga-PSMA PET and CT were concordant in only three patients (50%, 12% to 88%). In mCRPC patients, biochemical PR was found in six of 16 patients (38%, 15% to 65%). Outcome prediction was concordant between BR and RR(PET) in nine of 16 patients (56%), and between BR and RR(CT) in only four of 12 patients (33%) with target lesions on CT.68 Ga-PSMA PET and CT results corresponded in seven of 12 patients (58%, 28% to 85%)., Conclusion: Our preliminary results suggest that68 Ga-PSMA PET might be a promising method for treatment response assessment in mCSPC and mCRPC. The data indicate that for different metastatic sites, the performance of68 Ga-PSMA PET in response assessment might be superior to that of the conventional CT approach and could help differentiate between progressive disease and treatment response. Because of the limited number of patients, the differences revealed in our study were not statistically significant. Thus larger and prospective studies are clearly needed and warranted to confirm the value of68 Ga-PSMA PET as an imaging biomarker for response assessment.- Published
- 2018
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45. AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide.
- Author
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Seitz AK, Thoene S, Bietenbeck A, Nawroth R, Tauber R, Thalgott M, Schmid S, Secci R, Retz M, Gschwend JE, Ruland J, Winter C, and Heck MM
- Subjects
- Aged, Benzamides, Biomarkers, Tumor genetics, Disease-Free Survival, Drug Resistance, Neoplasm, Humans, Kallikreins blood, Liquid Biopsy, Logistic Models, Male, Multivariate Analysis, Neoplastic Cells, Circulating pathology, Nitriles, Odds Ratio, Phenylthiohydantoin therapeutic use, Polymerase Chain Reaction, Predictive Value of Tests, Proportional Hazards Models, Prostate-Specific Antigen blood, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant mortality, Protein Isoforms, RNA, Messenger blood, RNA, Messenger genetics, Receptors, Androgen genetics, Reproducibility of Results, Retrospective Studies, Risk Factors, Time Factors, Treatment Outcome, Androstenes therapeutic use, Antineoplastic Agents therapeutic use, Biomarkers, Tumor blood, Neoplastic Cells, Circulating chemistry, Neoplastic Cells, Circulating drug effects, Phenylthiohydantoin analogs & derivatives, Prostatic Neoplasms, Castration-Resistant blood, Prostatic Neoplasms, Castration-Resistant drug therapy, Receptors, Androgen blood
- Abstract
Background: It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide., Objective: To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients., Design, Setting, and Participants: Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction., Outcome Measurements and Statistical Analysis: The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed., Results and Limitations: High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; p<0.001), shorter clinical PFS (median 2.7 vs 5.5 mo; p<0.001), and shorter OS (median 4.0 vs. 13.9 mo; p<0.001). On multivariable Cox regression analysis, high AR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; p<0.001), shorter clinical PFS (HR 2.3, 95% CI 1.1-4.9; p=0.02), and shorter OS (HR 3.0, 95% CI 1.4-6.3; p=0.005)., Conclusions: Testing of AR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide., Patient Summary: We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
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- 2017
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46. Wntless promotes bladder cancer growth and acts synergistically as a molecular target in combination with cisplatin.
- Author
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Schmid SC, Sathe A, Guerth F, Seitz AK, Heck MM, Maurer T, Schwarzenböck SM, Krause BJ, Schulz WA, Stoehr R, Gschwend JE, Retz M, and Nawroth R
- Subjects
- Cisplatin administration & dosage, Cisplatin pharmacology, Humans, Intracellular Signaling Peptides and Proteins metabolism, Receptors, G-Protein-Coupled metabolism, Transfection, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms pathology, Cisplatin therapeutic use, Intracellular Signaling Peptides and Proteins genetics, Receptors, G-Protein-Coupled genetics, Urinary Bladder Neoplasms drug therapy
- Abstract
Purpose: To analyze the contribution of Wnt signaling pathway to bladder cancer growth in order to identify suitable target molecules for therapy., Material and Methods: Expression of Wnt 2/4/7, LRP5/6, TCF1/2/4, LEF-1, and β-actin was detected by reverse transcription polymerase chain reaction in a panel of 9 and for Wntless (WLS) in 17 bladder cancer cell lines. Protein expression of WLS was detected in 6 cell lines. Wnt/β-catenin activity was analyzed using the TOPflash/FOPflash luciferase reporter assay. Expression level of β-catenin, WIF1, Dickkopf proteins (DKK), HSulf-2, sFRP4, and WLS was modulated by transfecting or infecting cells transiently or stably with respective shRNAs, siRNAs, or cDNAs. For protein detection, whole cell lysates were applied to sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by immunoblots. Effects on cell growth were determined by cell viability assays and BrdU/APC incorporation/staining. For 3-dimensional tumor growth, the chicken chorioallantoic membrane model was used. Tumor growth was characterized by weight., Results: Expression of molecular components and activation of the Wnt signaling pathway could be detected in all cell lines. Expression level of β-catenin, WIF1, DKK, WLS, and HSulf-2 influenced Wnt activity. Expression of WLS was confirmed in 17 cell lines by reverse transcription polymerase chain reaction and in 6 cell lines by immunoblotting. WLS positively regulates Wnt signaling, cell proliferation, and tumor growth in vitro and in vivo. These effects could be reversed by the expression of the Wnt antagonist WIF1 and DKK. Synergistic activity of cisplatin and WLS inactivation by genetic silencing could be observed on cell viability., Conclusion: The Wnt signaling pathway is ubiquitously activated in bladder cancer and regulates tumor growth. WLS might be a target protein for novel therapies in combination with established chemotherapy regimens., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2017
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47. Profiling of long non-coding RNAs identifies LINC00958 and LINC01296 as candidate oncogenes in bladder cancer.
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Seitz AK, Christensen LL, Christensen E, Faarkrog K, Ostenfeld MS, Hedegaard J, Nordentoft I, Nielsen MM, Palmfeldt J, Thomson M, Jensen MT, Nawroth R, Maurer T, Ørntoft TF, Jensen JB, Damgaard CK, and Dyrskjøt L
- Subjects
- Cell Line, Tumor, Cell Survival, Gene Expression Profiling, Humans, Transcriptome, Up-Regulation, Gene Expression Regulation, Neoplastic, Oncogenes, RNA, Long Noncoding genetics, Urinary Bladder Neoplasms genetics
- Abstract
Aberrant expression of long non-coding RNAs (lncRNAs) has been regarded as a critical component in bladder cancer (BC) and lncRNAs have been associated with BC development and progression although their overall expression and functional significance is still unclear. The aim of our study was to identify novel lncRNAs with a functional role in BC carcinogenesis. RNA-sequencing was used to identify aberrantly expressed lncRNAs in 8 normal and 72 BC samples. We identified 89 lncRNAs that were significantly dys-regulated in BC. Five lncRNAs; LINC00958, LINC01296, LINC00355, LNC-CMC1-1 and LNC-ALX1-2 were selected for further analyses. Silencing of LINC00958 or LINC01296 in vitro reduced both cell viability and migration. Knock-down of LINC00958 also affected invasion and resistance to anoikis. These cellular effects could be linked to direct/indirect regulation of protein coding mRNAs involved in cell death/survival, proliferation and cellular movement. Finally, we showed that LINC00958 binds proteins involved in regulation and initiation of translation and in post-transcriptional modification of RNA, including Metadherin, which has previously been associated with BC. Our analyses identified novel lncRNAs in BC that likely act as oncogenic drivers contributing to an aggressive cancerous phenotype likely through interaction with proteins involved in initiation of translation and/or post-transcriptional modification of RNA.
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- 2017
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48. [Modern networks : Topics in the working group "Bladder cancer research" of the GeSRU Academics].
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Hofbauer S, Kalogirou C, Roghmann F, Seitz AK, Vallo S, Wezel F, Worst T, and Nawroth R
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- Germany, Humans, Intersectoral Collaboration, Medical Oncology organization & administration, Models, Organizational, Organizational Objectives, Urinary Bladder Neoplasms, Urology organization & administration
- Abstract
In January 2015, the research group "bladder cancer research" was founded as part of the GeSRU Academics research initiative. A general challenge to work successfully in a novel network structure is to identify common scientific topics and technical expertise in the group. Thus, one of the first tasks was to learn about current research projects from members within the group in order to address a project that suits the group's expertise. The following review summarizes three different directions that are key projects in Urologic Departments at German Universities that will be the basis to start fruitful collaborations.
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- 2017
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49. Chromogranin A and neurone-specific enolase serum levels as predictors of treatment outcome in patients with metastatic castration-resistant prostate cancer undergoing abiraterone therapy.
- Author
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Heck MM, Thaler MA, Schmid SC, Seitz AK, Tauber R, Kübler H, Maurer T, Thalgott M, Hatzichristodoulou G, Höppner M, Nawroth R, Luppa PB, Gschwend JE, and Retz M
- Subjects
- Aged, Aged, 80 and over, Disease-Free Survival, Humans, Male, Middle Aged, Neoplasm Metastasis, Predictive Value of Tests, Prostate-Specific Antigen blood, Prostatic Neoplasms, Castration-Resistant pathology, Retrospective Studies, Treatment Outcome, Androstenes therapeutic use, Chromogranin A blood, Phosphopyruvate Hydratase blood, Prostatic Neoplasms, Castration-Resistant blood
- Abstract
Objective: To determine the impact of elevated neuroendocrine serum markers on treatment outcome in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing treatment with abiraterone in a post-chemotherapy setting., Patients and Method: Chromogranin A (CGa) and neurone-specific enolase (NSE) were determined in serum drawn before treatment with abiraterone from 45 patients with mCRPC. Outcome measures were overall survival (OS), prostate-specific antigen (PSA) response defined by a PSA level decline of ≥50%, PSA progression-free survival (PSA-PFS), and clinical or radiographic PFS., Results: The CGa and NSE serum levels did not correlate (P = 0.6). Patients were stratified in to low- (nine patients), intermediate- (18) or high-risk (18) groups according to elevation of none, one, or both neuroendocrine markers, respectively. The risk groups correlated with decreasing median OS (median OS not reached vs 15.3 vs 6.6 months; P < 0.001), decreasing median clinical or radiographic PFS (8.3 vs 4.4 vs 2.7 months; P = 0.001) and decreasing median PSA-PFS (12.0 vs 3.2 vs 2.7 months; P = 0.012). In multivariate Cox regression analysis the combination of CGa and NSE (≥1 marker positive vs both markers negative) remained significant predictors of OS, clinical or radiographic PFS, and PSA-PFS. We did not observe a correlation with PSA response (63% vs 35% vs 31%; P = 0.2)., Conclusion: Chromogranin A and NSE did not predict PSA response in patients with mCRPC treated with abiraterone. However, we observed a correlation with shorter PSA-PFS, clinical or radiographic PFS, and OS. This might be due to an elevated risk of developing resistance under abiraterone treatment related to neuroendocrine differentiation., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)
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- 2017
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50. The Role of PD-L1 Expression and Intratumoral Lymphocytes in Response to Perioperative Chemotherapy for Urothelial Carcinoma.
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Erlmeier F, Seitz AK, Hatzichristodoulou G, Stecher L, Retz M, Gschwend JE, Weichert W, Kübler HR, and Horn T
- Abstract
Introduction: Immunological pathways are relevant for the effectiveness of conventional cytotoxic chemotherapy. Recently, checkpoint inhibition of the PD-1/PD-L1 axis has been shown to be therapeutically relevant in urothelial carcinoma. Objective: To monitor PD-L1 expression on tumor cells and intratumoral infiltration with CD8 positive lymphocytes during perioperative chemotherapy for urothelial cancer and to evaluate their use as potential predictive markers for chemotherapy. Patients and Methods: Sixty-four patients with muscle-invasive urothelial cancer were included in the analysis. Twenty-two patients received preoperative chemotherapy and 42 were treated in an adjuvant setting for locally advanced disease or lymph node metastases. PD-L1 status and the density of infiltration with CD8-positive cells were assessed by immunohistochemistry and analysed for their association with survival (adjuvant group) and response to chemotherapy (preoperative group). For PD-L1 positivity we used a cutoff of 10% positive tumor cells. Results: In the adjuvant group, 11 of 42 patients (26.2%) had PD-L1 positive tumor cells. Twenty-six of 42 (61.9%) patients were highly infiltrated with CD8 + lymphocytes. There was no significant evidence of an association with overall survival for PD-L1 status nor for CD8 infiltration density ( p = 0.63 and 0.71). In the preoperative group, eight of the 22 (36.4%) patients were PD-L1 positive and 13 (59%) were highly infiltrated with CD8 + lymphocytes before chemotherapy. There was no evidence of associations with response or survival. Eight patients showed a pathological response to preoperative treatment. These had a significantly longer overall survival than non-responders ( p = 0.01). In the preoperative group the pre-treatment expression of the immunologic markers could be compared to the post-treatment status. Only one patient showed a changed PD-L1 status and three patients a changed CD8 status. Conclusions: The tumoral expression of PD-L1 in urothelial carcinoma does not seem to be largely influenced by chemotherapy. Our data do not provide evidence that tumoral expression of PD-L1 and CD8 are useful as prognostic or predictive markers. Small sample size is the major limitation of our study.
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- 2016
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