Publications by authors named "Christian Seitz"

192 Publications

Architecture and self-assembly of the jumbo bacteriophage nuclear shell.

Nature 2022 Aug 3. Epub 2022 Aug 3.

Department of Molecular Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA.

Bacteria encode myriad defences that target the genomes of infecting bacteriophage, including restriction-modification and CRISPR-Cas systems. In response, one family of large bacteriophages uses a nucleus-like compartment to protect its replicating genomes by excluding host defence factors. However, the principal composition and structure of this compartment remain unknown. Here we find that the bacteriophage nuclear shell assembles primarily from one protein, which we name chimallin (ChmA). Combining cryo-electron tomography of nuclear shells in bacteriophage-infected cells and cryo-electron microscopy of a minimal chimallin compartment in vitro, we show that chimallin self-assembles as a flexible sheet into closed micrometre-scale compartments. The architecture and assembly dynamics of the chimallin shell suggest mechanisms for its nucleation and growth, and its role as a scaffold for phage-encoded factors mediating macromolecular transport, cytoskeletal interactions, and viral maturation.
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http://dx.doi.org/10.1038/s41586-022-05013-4DOI Listing
August 2022

International Alliance of Urolithiasis guideline on retrograde intrarenal surgery.

BJU Int 2022 Jun 22. Epub 2022 Jun 22.

Department of Urology, Medical School, Biruni University, Istanbul, Turkey.

Objectives: To set out the second in a series of guidelines on the treatment of urolithiasis by the International Alliance of Urolithiasis that concerns retrograde intrarenal surgery (RIRS), with the aim of providing a clinical framework for urologists performing RIRS.

Materials And Methods: After a comprehensive search of RIRS-related literature published between 1 January 1964 and 1 October 2021 from the PubMed database, systematic review and assessment were performed to inform a series of recommendations, which were graded using modified GRADE methodology. Additionally, quality of evidence was classified using a modification of the Oxford Centre for Evidence-Based Medicine Levels of Evidence system. Finally, related comments were provided.

Results: A total of 36 recommendations were developed and graded that covered the following topics: indications and contraindications; preoperative imaging; preoperative ureteric stenting; preoperative medications; peri-operative antibiotics; management of antithrombotic therapy; anaesthesia; patient positioning; equipment; lithotripsy; exit strategy; and complications.

Conclusion: The series of recommendations regarding RIRS, along with the related commentary and supporting documentation, offered here should help provide safe and effective performance of RIRS.
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http://dx.doi.org/10.1111/bju.15836DOI Listing
June 2022

Novel adapter CAR-T cell technology for precisely controllable multiplex cancer targeting.

Oncoimmunology 2021 2;10(1):2003532. Epub 2021 Dec 2.

Department of General Pediatrics, Hematology and Oncology, University Children's Hospital Tuebingen, Germany.

Chimeric antigen receptor (CAR)-T therapy holds great promise to sustainably improve cancer treatment. However, currently, a broad applicability of CAR-T cell therapies is hampered by limited CAR-T cell versatility and tractability and the lack of exclusive target antigens to discriminate cancerous from healthy tissues. To achieve temporal and qualitative control on CAR-T function, we engineered the Adapter CAR (AdCAR) system. AdCAR-T are redirected to surface antigens via biotin-labeled adapter molecules in the context of a specific linker structure, referred to as Linker-Label-Epitope. AdCAR-T execute highly specific and controllable effector function against a multiplicity of target antigens. In mice, AdCAR-T durably eliminate aggressive lymphoma. Importantly, AdCAR-T might prevent antigen evasion by combinatorial simultaneous or sequential targeting of multiple antigens and are capable to identify and differentially lyse cancer cells by integration of adapter molecule-mediated signals based on multiplex antigen expression profiles. In consequence the AdCAR technology enables controllable, flexible, combinatorial, and selective targeting.
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http://dx.doi.org/10.1080/2162402X.2021.2003532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9172918PMC
December 2021

Paediatric stone management: innovations and standards.

Curr Opin Urol 2022 07 9;32(4):420-424. Epub 2022 Jun 9.

Department of Urology, Medical University of Vienna, Vienna, Austria.

Purpose Of Review: The aim of this study was to discuss current trends and recent developments in the surgical management of paediatric urolithiasis.

Recent Findings: Medical expulsive therapy (MET) is considered as an option for the treatment of children with ureter stones. Extracorporeal shockwave lithotripsy (SWL) remains as a first option for majority of kidney stones and upper ureter stones. Advances in endourology have led to increased adoption of retrograde intrarenal surgeries (RIRS) and percutaneous nephrolithotomy (PCNL/mini-PCNL/ultra-mini-PCNL/micro-PCNL).

Summary: Management of paediatric stone disease has developed significantly in the past decade. However, the evidence in the literature remains disproportional to these advances. Well designed multicentric studies are still needed to compare effectiveness and safety of these procedures.
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http://dx.doi.org/10.1097/MOU.0000000000001004DOI Listing
July 2022

A Global Survey of Ergonomics Practice Patterns and Rates of Musculoskeletal Pain Among Urologists Performing Retrograde Intrarenal Surgery.

J Endourol 2022 May 25. Epub 2022 May 25.

Department of Urology, Ng Teng Fong General Hospital, Singapore, Singapore.

Retrograde intrarenal surgery (RIRS) requires urologists to adopt an awkward body posture for long durations. Few urologists receive training in ergonomics despite the availability of ergonomic best practices utilized by other surgical specialties. We characterize ergonomic practice patterns and rates of musculoskeletal (MSK) pain among urologists performing RIRS. A web-based survey was distributed through the Endourological Society, the European Association of Urology, and social media. Surgeon anthropometrics and ergonomic factors were compared with ergonomic best practices. Pain was assessed with the Nordic Musculoskeletal Questionnaire (NMQ). Overall, 519 of 526 participants completed the survey (99% completion rate). Ninety-three percent of urologists consider ergonomic factors when performing RIRS to reduce fatigue (68%), increase performance (64%), improve efficiency (59%), and reduce pain (49%). Only 16% received training in ergonomics. Residents/fellows had significantly lower confidence in ergonomic techniques compared with attending surgeons with any career length. Adherence to proper ergonomic positioning for modifiable factors was highly variable. On the NMQ, 12-month rates of RIRS-associated pain in ≥1 body part, pain limiting activities of daily living (ADLs), and pain requiring medical evaluation were 81%, 51%, and 29%, respectively. Annual case volume >150 cases (odds ratio [OR] 0.55 [0.35-0.87]) and higher adherence to proper ergonomic techniques (OR 0.67 [0.46-0.97]) were independently associated with lower odds of pain. Limitations include a predominantly male cohort, which hindered the ability to assess gender disparities in pain and ergonomic preferences. Adherence to ergonomic best practices during RIRS is variable and may explain high rates of MSK pain among urologists. These results underscore the importance of utilizing proper ergonomic techniques and may serve as a framework for establishing ergonomic guidelines for RIRS.
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http://dx.doi.org/10.1089/end.2022.0075DOI Listing
May 2022

Recurrent SARS-CoV-2 Infection and Impaired Immunologic Response in a Pediatric Oncologic Patient While Treated With Radiochemotherapy.

Pediatr Infect Dis J 2022 06 6;41(6):e259-e262. Epub 2022 May 6.

From the University Children's Hospital, Eberhard Karls University, Tuebingen, Germany.

Immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric patients with malignant disease may be affected by tumor therapy. Here, we report the case of a child with rhabdomyosarcoma and recurrent SARS-CoV-2 infection. Immunologic responses, analyzed by T-cell activity and anti-viral IgG levels, were impaired and not durable as a result of intensive radiochemotherapy.
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http://dx.doi.org/10.1097/INF.0000000000003515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9083311PMC
June 2022

Immunological recovery following HLA-matched CD3+ TCR αß+/CD19+ depleted hematopoietic stem cell transplantation in children.

Pediatr Transplant 2022 08 19;26(5):e14285. Epub 2022 Apr 19.

Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for children with both malignant and nonmalignant diseases. T-cell depletion techniques may result in reduced transplant-related mortality compared with unmanipulated grafts due to a lower incidence of GvHD.

Methods: Immune recovery and outcome were analyzed in a cohort of 23 patients with malignant and nonmalignant diseases who received CD3+TCRαβ+ T- and B-cell-depleted allografts from matched donors after reduced-intensity or myeloablative conditioning. The median number of CD34+, CD3+TCRαβ+, and CD19+B-cells infused was 12.7 × 10 /kg, 16.8 × 10 /kg, and 96 × 10 /kg bodyweight.

Results: With a median follow-up of 36 (range 1-73) months, overall survival and disease-free survival at 3 years were 65.2% and 60.8%. Eight patients died, six due to the underlying disease and two of extended visceral cGvHD. Immune reconstitution, disease-free, and overall survivals were similar compared with a historical cohort of 23 patients transplanted with matched unmanipulated bone marrow. A significant lower rate of higher grade (III-IV) aGvHD was observed in the manipulated HSCT group (8.7% vs. 26%; p = 0.001), whereas the incidence of cGvHD was equal.

Conclusions: Our data suggest that this graft manipulation strategy could be a safe and effective alternative to conventional HSCT techniques in matched donors.
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http://dx.doi.org/10.1111/petr.14285DOI Listing
August 2022

Endometrial hyperplasia in pre-menopausal women: A systematic review of incidence, prevalence, and risk factors.

Eur J Obstet Gynecol Reprod Biol 2022 Apr 17;271:158-171. Epub 2022 Feb 17.

Bayer AG, Berlin, Germany. Electronic address:

Objectives: Hormonal therapies have been associated with a range of effects on the endometrium, including endometrial hyperplasia (EH). With many medicinal products being developed for pre-menopausal women, epidemiological data regarding the population background risk could meaningfully supplement comparative risk data gathered in clinical trials. However, epidemiological studies on EH often focus on post-menopausal women. We aimed to assess the available observational evidence on the incidence and prevalence of EH among pre-menopausal women and to investigate the influence of specific risk factors.

Study Design: We conducted systematic literature searches on 27 August 2021, using the Embase and PubMed databases. Searches were designed to identify studies of EH epidemiology, published in English on or after 1 January 1995, in populations of predominantly pre-menopausal women. Studies were required to report diagnostic histopathology data for at least 500 women. Relevant outcomes were the prevalence and incidence of EH, and/or the impact of pre-specified risk factors including age, body mass index (BMI) and diabetes mellitus.

Results: In total, 3785 records were screened, and 31 references, describing 29 different studies, were included in the review. The incidence of EH among pre-menopausal women increased with age and was as high as 121 and 270 cases per 100,000 woman-years in South Korean women aged 46-50 years and US women aged 45-49 years, respectively. The prevalence of EH was highly dependent on the population studied. Estimates of EH prevalence in 14 studies of pre-menopausal women with abnormal uterine bleeding (AUB) ranged from 3.4% to 265%, higher than the reported prevalence in two studies of women with infertility (0.9% and 3.0%). Studies of risk factors found increasing age, BMI and diabetes to be associated with an increased prevalence of EH.

Conclusions: Published data on the epidemiology of EH in pre-menopausal women are heterogeneous, with considerable variation in study methodology and populations, and in how EH subtypes are reported. The main factors affecting the reported prevalence and incidence of EH are the reason a biopsy was performed - particularly whether patients had AUB, a key symptom associated with EH - and the presence of known risk factors.
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http://dx.doi.org/10.1016/j.ejogrb.2022.02.015DOI Listing
April 2022

Platelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer.

Nat Commun 2021 12 1;12(1):7005. Epub 2021 Dec 1.

Department of Medical Oncology & Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen, Germany.

Immune-checkpoint inhibitors (ICI) have transformed oncological therapy. Up to 20% of all non-small cell lung cancers (NSCLCs) show durable responses upon treatment with ICI, however, robust markers to predict therapy response are missing. Here we show that blood platelets interact with lung cancer cells and that PD-L1 protein is transferred from tumor cells to platelets in a fibronectin 1, integrin α5β1 and GPIbα-dependent manner. Platelets from NSCLC patients are found to express PD-L1 and platelet PD-L1 possess the ability to inhibit CD4 and CD8 T-cells. An algorithm is developed to calculate the activation independent adjusted PD-L1 payload of platelets (pPD-L1), which is found to be superior in predicting the response towards ICI as compared to standard histological PD-L1 quantification on tumor biopsies. Our data suggest that platelet PD-L1 reflects the collective tumor PD-L1 expression, plays important roles in tumor immune evasion and overcomes limitations of histological quantification of often heterogeneous intratumoral PD-L1 expression.
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http://dx.doi.org/10.1038/s41467-021-27303-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636618PMC
December 2021

European Association of Urology Section of Urolithiasis and International Alliance of Urolithiasis Joint Consensus on Retrograde Intrarenal Surgery for the Management of Renal Stones.

Eur Urol Focus 2021 Nov 23. Epub 2021 Nov 23.

Department of Urology, West China Hospital of Sichuan University, Chengdu, China.

Background: Retrograde intrarenal surgery (RIRS) has become the preferred treatment modality for nephrolithiasis. However, because of ongoing uncertainties regarding the optimal perioperative management, operative technique, and postoperative follow-up, as well as a lack of standardization for outcome reporting, consensus is needed to achieve more uniform clinical practice worldwide.

Objective: To develop recommendations for RIRS on the basis of existing data and expert consensus.

Design, Setting, And Participants: A protocol-driven, three-phase study was conducted by the European Association of Urology Section of Urolithiasis (EULIS) and the International Alliance of Urolithiasis (IAU). The process included: (1) a nonsystematic review of the literature to define domains for discussion; (2) a two-round modified Delphi survey involving experts in this field; and (3) an additional group meeting and third-round survey involving 64 senior representative members to formulate the final conclusions.

Outcome Measurements And Statistical Analysis: The results from each previous round were returned to the participants for re-evaluation of their decisions during the next round. The agreement threshold was set at 70%.

Results And Limitations: The panel included 209 participants who developed 29 consensus statements on the following topics of interest: (1) perioperative infection management; (2) perioperative antithrombotic therapy; (3) fundamentals of the operative technique; and (4) standardized outcome reporting. Although this consensus can be considered as a useful reference for more clinically oriented daily practice, we also acknowledge that a higher level of evidence from further clinical trials is needed.

Conclusions: The consensus statements aim to guide and standardize clinical practice and research on RIRS and to recommend standardized outcome reporting.

Patient Summary: An international consensus on the best practice for minimally invasive surgery for kidney stones was organized and developed by two international societies. It is anticipated that this consensus will provide further guidance to urologists and may help to improve clinical outcomes for patients.
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http://dx.doi.org/10.1016/j.euf.2021.10.011DOI Listing
November 2021

Rare Tumors in Children and Adolescents - the STEP Working Group's Evolution to a Prospective Registry.

Klin Padiatr 2022 May 19;234(3):146-153. Epub 2021 Nov 19.

Clinic of Pediatrics, Municipal Hospital Dortmund, Dortmund, Germany.

Background Very rare tumors (VRT) in children and adolescents have such a low incidence that until recently, they have not been integrated into the clinical and scientific network of pediatric oncology. Data is very limited and consistent treatment strategies are missing. Thus, VRTs are classic orphan diseases. To counteract this problem, the Arbeitsgemeinschaft für Seltene Tumorerkrankungen in der Pädiatrie (STEP) was founded. Here we report on patient recruitment during the first 10 years. Patients Patients aged up to 18 years and not included in any other clinical trial or GPOH registry were included in this analysis. Methods Data was collected from 2008 to 2018 by means of a standardized form. The recorded diagnoses were descriptively analyzed focusing on histology, localization, and year of report. Results A total of 623 patients with VRTs were registered. During 2008-2014, the annual number of registrations was around 40 and is around 90 since 2015. Most frequent diagnoses included tumors of the skin (n=150), tumors of the gastrointestinal tract (n=102), tumors of the gonads (n=77), the ENT region (n=68), and miscellaneous tumors (n=107). Discussion With the establishment of central structures for clinical consultation and documentation of VRTs, the number of registrations increased. Comprehensively, VRTs are as common as other classic pediatric oncology tumors, but extremely heterogeneous in terms of localization, histology, and prognosis. By a centralized and complete registration and analysis of VRTs, also in collaboration with international partners, it is possible to develop treatment strategies and thus greatly increase treatment quality.
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http://dx.doi.org/10.1055/a-1675-3145DOI Listing
May 2022

Data for molecular dynamics simulations of cytochrome oxidase with the Amber force field.

Data Brief 2021 Oct 23;38:107401. Epub 2021 Sep 23.

San Diego Supercomputer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.

Cytochrome -type quinol oxidase is an important metalloenzyme that allows many bacteria to survive in low oxygen conditions. Since oxidase is found in many prokaryotes but not in eukaryotes, it has emerged as a promising bacterial drug target. Examples of organisms containing oxidases include the bacterium that causes tuberculosis (TB) in humans, the bacterium that causes cholera, the bacterium that contributes to antibiotic resistance and sepsis, and the bacterium that causes food poisoning. is another organism exhibiting the cytochrome oxidase. Since it has the highest sequence identity to (36%) and we are ultimately interested in finding drug targets for TB, we have built parameters for the oxidase (Protein Data Bank ID number: 6RKO) that are compatible with the all-atom Amber ff14SB force field for molecular dynamics (MD) simulations. Specifically, we built parameters for the three heme cofactors present in all species of bacterial cytochrome -type oxidases (heme b , heme b , and heme d) along with their axial ligands. This data report includes the parameter and library files that can be used with Amber's LEaP program to generate input files for MD simulations using the Amber software package. We also provide the PDB data files of the initial model both by itself and solvated with TIP3P water molecules and counterions.
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http://dx.doi.org/10.1016/j.dib.2021.107401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481974PMC
October 2021

The Abiotic Formation of Pyrrole under Volcanic, Hydrothermal Conditions-An Initial Step towards Life's First Breath?

Life (Basel) 2021 Sep 17;11(9). Epub 2021 Sep 17.

Bayerisches NMR Zentrum, Strukturelle Membranbiochemie, Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85748 Garching, Germany.

Porphyrins, corrins, and tetrapyrroles constitute macrocycles in essential biomolecules such as heme, chlorophyll, cobalamin, and cofactor F430. The chemical synthesis as well as the enzymatic synthesis of these macrocycles starts from pyrrole derivatives. We here show that pyrrole and dimethyl pyrrole can be formed under the simulated volcanic, hydrothermal conditions of Early Earth, starting from acetylene, propyne, and ammonium salts in the presence of NiS or CoS as catalysts.
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http://dx.doi.org/10.3390/life11090980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471139PMC
September 2021

Primary lung carcinoma in children and adolescents - Clinical characteristics and outcome of 12 cases from the German registry for rare paediatric tumours (STEP).

Lung Cancer 2021 10 11;160:66-72. Epub 2021 Aug 11.

Paediatric Haematology/Oncology, Department of Paediatrics, University Hospital Tuebingen, Germany. Electronic address:

Objectives: Primary lung carcinomas are very rare paediatric tumours with an incidence of < 2/1.000.000 per year. They are clinically and histologically heterogeneous, and there are no therapeutic guidelines for this age group. Therefore, they represent a challenge for treating physicians. This analysis was performed to expand knowledge on characteristics, treatment and prognosis of primary lung carcinoma in paediatric patients.

Material And Methods: Between 2009 and 2019, twelve children and adolescents with lung carcinoma were identified in the prospective German registry for rare paediatric tumours (STEP). Data were analysed for histopathological entities, symptoms, diagnostics, therapy, clinical course and outcome.

Results: Mucoepidermoid carcinoma (MEC) was the most frequent entity (n = 7), followed by adenocarcinoma (n = 2), squamous cell carcinoma (SCC; n = 2) and adenosquamous carcinoma (n = 1). Patients presented with non-specific symptoms and often, they were initially mistreated for airway infections. Patients with MEC showed no metastases and were successfully treated with complete resection. Patients with adenocarcinoma and SCC were older than 16 years of age at diagnosis. While patients with SCC presented with distant metastases and died within one year after diagnosis, those with adenocarcinoma and adenosquamous carcinoma achieved complete remission after multimodal treatment.

Conclusions: Presenting symptoms of lung carcinomas are unspecific and therefore, diagnostic evaluation and treatment are difficult. In the absence of carcinogen exposure, etiology seems to differ from adult lung carcinoma. Children diagnosed with MEC face a favourable outcome. In contrast, patients with prognostically unfavourable adenocarcinoma and SCC might benefit from molecular profiling and targeted therapies. International collaboration for the establishment of treatment protocols adjusted for distinct features of primary lung carcinoma in childhood is essential.
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http://dx.doi.org/10.1016/j.lungcan.2021.08.004DOI Listing
October 2021

Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment.

Front Immunol 2021 22;12:690467. Epub 2021 Jul 22.

Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany.

Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor-ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.690467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339919PMC
October 2021

Assessment of the safe and efficacious dose of the selective progesterone receptor modulator vilaprisan for the treatment of patients with uterine fibroids by exposure-response modelling and simulation.

Br J Clin Pharmacol 2022 02 25;88(2):734-741. Epub 2021 Aug 25.

Bayer AG, Clinical Pharmacometrics, Germany.

Aims: We report population pharmacokinetic (popPK) and exposure-response (E-R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan. Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids.

Methods: A popPK model was developed using data from Phase 1 and 2 studies (including ASTEROID 1 and 2). The relationship between vilaprisan exposure (steady-state AUC) and IA after oral administration of 0.5, 1, 2 or 4 mg/day over 3 months was analysed in ASTEROID 1 using logistic regression and qualified in ASTEROID 2 by comparing simulated and observed probability for IA after 2 mg/day. The exposure-E2 relationship was analysed visually.

Results: Vilaprisan clearance was 22.7% lower in obese vs non-obese patients. The E-R relationship for IA in ASTEROID 1 was steep and consistent with ASTEROID 2, with a maximum probability (P ) of 59% (95% CI: 49-68%). The exposure at which 50% of P is obtained was 36.9 μg*h/L (95% CI: 27.7-48.7 μg*h/L). Simulations showed that 36% of the patients will be below 90% of P for IA after 1 mg/day compared to 2% after 2 mg/day. E2 levels tended to decrease with increasing exposure. While E2 levels remained largely within the physiologic follicular phase range, the clinical relevance of this decrease will be evaluated in long-term studies.

Conclusions: A 2 mg/day dose was selected for Phase 3 as E-R analyses show this dose results in a close to maximum probability for IA, without any safety concerns noted.
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http://dx.doi.org/10.1111/bcp.15014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9292591PMC
February 2022

Adapter Chimeric Antigen Receptor (AdCAR)-Engineered NK-92 Cells for the Multiplex Targeting of Bone Metastases.

Cancers (Basel) 2021 Mar 5;13(5). Epub 2021 Mar 5.

Department of Hematology and Oncology, University Hospital Tuebingen, Children's Hospital, 72076 Tuebingen, Germany.

Background: Since metastatic spreading of solid tumor cells often leads to a fatal outcome for most cancer patients, new approaches for patient-individualized, targeted immunotherapy are urgently needed.

Methods: Here, we established cell lines from four bone metastases of different tumor entities. We assessed AdCAR NK-92-mediated cytotoxicity in vitro in standard cytotoxicity assays as well as 3D spheroid models Results: AdCAR-engineered NK-92 cells successfully demonstrated distinct and specific cytotoxic potential targeting different tumor antigens expressed on cell lines established from bone metastases of mammary, renal cell and colorectal carcinoma as well as melanomas. In that process AdCAR NK-92 cells produced a multitude of NK effector molecules as well as pro inflammatory cytokines. Furthermore, AdCAR NK-92 showed increased cytotoxicity in 3D spheroid models which can recapitulate in vivo architecture, thereby bridging the gap between in vitro and in vivo models.

Conclusions: AdCAR NK-92 cells may provide an interesting and promising "off-the-shelf" cellular product for the targeted therapy of cancers metastasizing to the bone, while utilization of clinically approved, therapeutic antibodies, as exchangeable adapter molecules can facilitate quick clinical translation.
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http://dx.doi.org/10.3390/cancers13051124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961358PMC
March 2021

Innovations in urolithiasis management.

Curr Opin Urol 2021 03;31(2):130-134

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Vienna, Austria.

Purpose Of Review: This review provides a forecast about ongoing developments in the management of urolithiasis with a potential to challenge the current standard of care. We therefore emphasized innovative technology, which might be considered still experimental in the daily clinic or needs further clinical validation, but harbors the great potential to become a game changer for future stone management.

Recent Findings: Especially in the endoscopic stone treatment, we observed a multitude of groundbreaking technical innovations, which changed our treatment algorithms over the last decades. Some of this technology already found its way into daily practice. Others like artificial intelligence, burst wave lithotripsy, smart laser systems or gene therapy may not be standardized yet, but have the potential to further revolutionize current practice. Besides those technical features, we included innovations in prevention and diagnostics, as well as patient expectations and patient satisfaction into the analysis. A proper metaphylaxis and patient communication seems to be essential for a long-lasting treatment success.

Summary: The combination of technical innovations, improved stone metaphylaxis and proper patient communication presents the cornerstone of future kidney stone management.
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http://dx.doi.org/10.1097/MOU.0000000000000850DOI Listing
March 2021

Adapter chimeric antigen receptor (AdCAR)-engineered NK-92 cells: an off-the-shelf cellular therapeutic for universal tumor targeting.

Oncoimmunology 2020 09 29;9(1):1825177. Epub 2020 Sep 29.

Department of Hematology and Oncology, University Hospital Tuebingen, Children's Hospital, Tuebingen, Germany.

Despite the recent success of CAR T cells targeting CD19 and CD22 in hematological malignancies, the production of CAR T cells still requires an extensive manufacturing process. The well-established NK-92 cell line provides a promising alternative to produce CAR-modified effector cells in a GMP-compliant, cost-effective way. NK-92 can be redirected against a variety of surface antigens by our adapter CAR (AdCAR) system utilizing biotinylated antibodies (bAb) as adapter molecules. Selected bAb were capable of inducing significant AdCAR NK-92-mediated lysis of non-Hodgkin lymphoma (NHL) and mantle-cell lymphoma (MCL) cell lines as well as primary MCL and chronic lymphocytic leukemia (CLL) cells. AdCAR specificity was proven using a JeKo-1 CD19/CD20 knockout antigen-loss model. Moreover, through combinations of bAb, AdCAR NK-92 cells are capable of combatting tumor antigen evasion mechanisms. In conclusion, we successfully generated the AdCAR NK-92 cell line which can be manufactured as an "off-the-shelf, on-demand" product allowing universal and tunable tumor targeting.
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http://dx.doi.org/10.1080/2162402X.2020.1825177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781805PMC
September 2020

Patients' and clinicians' perspectives on item importance, scoring, and clinically meaningful differences for the Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS).

Health Qual Life Outcomes 2021 Jan 6;19(1). Epub 2021 Jan 6.

Bayer AG, Müllerstraße 178, 13353, Berlin, Germany.

Background: The Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS) are patient-reported outcome measures developed to evaluate efficacy in clinical trials and clinical practice. The ESD is a daily electronic diary assessing symptom severity; the EIS is a weekly electronic diary assessing symptom impact. This study explored the importance of symptoms (ESD items) and impacts (EIS domains), perspectives on scoring algorithms, and clinically important difference (CID) thresholds to inform clinical trial score interpretation.

Methods: Endometriosis patients in Germany (n = 8) and the US (n = 17), and expert clinicians (n = 4) in Germany, the US, Spain, and Finland participated in semi-structured qualitative interviews comprising structured tasks. Interview transcripts were analyzed using thematic analysis techniques.

Results: Quality and severity of endometriosis-associated pelvic pain varied considerably among patients; some experienced pelvic pain daily, others during menstrual bleeding (dysmenorrhea) only. Patients and clinicians ranked "worst pelvic pain" as the most meaningful pain concept assessed by the ESD, followed by constant and short-term pelvic pain. Preferences for summarizing daily pain scores over the 28-day menstrual cycle depended on individuals' experience of pain: patients experiencing pain daily preferred scores summarizing data for all 28 days; patients primarily experiencing pain during selected days, and their treating clinicians preferred scores based on the most severe pain days. Initial CID exploration for the "worst pelvic pain" 0-10 numerical rating scale (0-10 NRS) revealed that, for most patients, a 2- or 3-point reduction was considered meaningful, depending on baseline severity. Patients and clinicians ranked "emotional well-being" and "limitations in physical activities" as the most important EIS domains.

Conclusions: This study informs the use of the ESD and EIS as clinically relevant measures of endometriosis symptoms and their impact. Findings from the ESD highlight the importance of individual-patient assessment of pain experience and identify "worst pelvic pain" as the most meaningful symptom assessed. Aggregating scores over the 28-day menstrual cycle may inform meaningful endpoints for clinical trials. Diverse EIS concepts (e.g. impact on emotional well-being and physical activities) are meaningful to patients and clinicians, emphasizing the importance of evaluating the impact on both to comprehensively assess treatment efficacy and decisions.

Trial Registration: Not applicable. Qualitative, non-interventional study; registration not required.
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http://dx.doi.org/10.1186/s12955-020-01579-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789138PMC
January 2021

Guideline of the guidelines: urolithiasis.

Curr Opin Urol 2021 03;31(2):125-129

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose Of Review: We reviewed the latest guidelines on urolithiasis to highlight the commonalities and differences in the most important recommendations.

Recent Findings: Most guidelines utilize systematic review of literature and grade evidence to generate the appropriate recommendations and statements. Only the latest versions of guidelines were included in this review.

Summary: Four national and international guidelines were included in this review, including those of the EAU (European Association of Urology), the AUA (American Urological Association)/ES (Endourological Society), the UAA (Urological Association of Asia) and the NICE (National Institute for Health and Care Excellence) guidelines. There are general similarities in the most important recommendations. The EAU guidelines provide the latest evidence updates.
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http://dx.doi.org/10.1097/MOU.0000000000000855DOI Listing
March 2021

Validation of a menstrual pictogram and a daily bleeding diary for assessment of uterine fibroid treatment efficacy in clinical studies.

J Patient Rep Outcomes 2020 Nov 13;4(1):97. Epub 2020 Nov 13.

Metronomia Clinical Research GmbH, Muenchen, Germany.

Background: To evaluate the psychometric and measurement properties of two patient-reported outcome instruments, the menstrual pictogram superabsorbent polymer-containing version 3 (MP SAP-c v3) and Uterine Fibroid Daily Bleeding Diary (UF-DBD). Test-retest reliability, criterion, construct validity, responsiveness, missingness and comparability of the MP SAP-c v3 and UF-DBD versus the alkaline hematin (AH) method and a patient global impression of severity (PGI-S) were analyzed in post hoc trial analyses.

Results: Analyses were based on data from up to 756 patients. The full range of MP SAP-c v3 and UF-DBD response options were used, with score distributions reflecting the cyclic character of the disease. Test-retest reliability of MP SAP-c v3 and UF-DBD scores was supported by acceptable intraclass correlation coefficients when stability was defined by the AH method and Patient Global Impression of Severity (PGI-S) scores (0.80-0.96 and 0.42-0.94, respectively). MP SAP-c v3 and UF-DBD scores demonstrated strong and moderate-to-strong correlations with menstrual blood loss assessed by the AH method. Scores increased in monotonic fashion, with greater disease severities, defined by the AH method and PGI-S scores; differences between groups were mostly statistically significant (P < 0.05). MP SAP-c v3 and UF-DBD were sensitive to changes in disease severity, defined by the AH method and PGI-S. MP SAP-c v3 and UF-DBD showed a lower frequency of missing patient data versus the AH method, and good agreement with the AH method.

Conclusions: This evidence supports the use of the MP SAP-c v3 and UF-DBD to assess clinical efficacy endpoints in UF phase III studies replacing the AH method.
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http://dx.doi.org/10.1186/s41687-020-00263-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666240PMC
November 2020

Multiscale Simulations Examining Glycan Shield Effects on Drug Binding to Influenza Neuraminidase.

Biophys J 2020 12 31;119(11):2275-2289. Epub 2020 Oct 31.

Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California; Department of Pharmacology, University of California, San Diego, La Jolla, California.

Influenza neuraminidase is an important drug target. Glycans are present on neuraminidase and are generally considered to inhibit antibody binding via their glycan shield. In this work, we studied the effect of glycans on the binding kinetics of antiviral drugs to the influenza neuraminidase. We created all-atom in silico systems of influenza neuraminidase with experimentally derived glycoprofiles consisting of four systems with different glycan conformations and one system without glycans. Using Brownian dynamics simulations, we observe a two- to eightfold decrease in the rate of ligand binding to the primary binding site of neuraminidase due to the presence of glycans. These glycans are capable of covering much of the surface area of neuraminidase, and the ligand binding inhibition is derived from glycans sterically occluding the primary binding site on a neighboring monomer. Our work also indicates that drugs preferentially bind to the primary binding site (i.e., the active site) over the secondary binding site, and we propose a binding mechanism illustrating this. These results help illuminate the complex interplay between glycans and ligand binding on the influenza membrane protein neuraminidase.
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http://dx.doi.org/10.1016/j.bpj.2020.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732775PMC
December 2020

Prevalence and Trends in Kidney Stone Among Adults in the USA: Analyses of National Health and Nutrition Examination Survey 2007-2018 Data.

Eur Urol Focus 2021 Nov 6;7(6):1468-1475. Epub 2020 Sep 6.

Department of Urology, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA. Electronic address:

Background: The contemporary prevalence and trends of kidney stones are not clear.

Objective: To evaluate the gender-specific prevalence and trends in kidney stones among the US population.

Design, Setting, And Participants: Data on self-reported history of kidney stones from 34 749 participants aged ≥20 yr from the National Health and Nutrition Examination Survey (NHANES) were analyzed.

Intervention: Six 2-yr study cycles (2007-2008 to 2017-2018) of nationally representative series of surveys evaluated the health status of the US population.

Outcome Measurements And Statistical Analysis: Weighted prevalence estimates of kidney stones and 95% confidence intervals (CIs) were calculated in each study cycle. Multivariable-adjusted logistic regression models were used to investigate the temporal trends.

Results And Limitations: In the 2017-2018 cycle, the prevalence of kidney stones was 10.9% (CI: 9.3-12.7) in men as compared with 9.5% (CI: 8-11.2) in women. The prevalence of kidney stones increased steadily from 6.5% in the 2007-2008 cycle to 9.4% in the 2017-2018 cycle (p = 0.001) among women but not among men (p = 0.1). These trends remained after adjusting for sociodemographic correlates in both genders. Sensitivity analyses further adjusting for dietary information held the same results in trends (men: p = 0.15; women: p = 0.001). Non-Hispanic white ethnicity, obesity, gout, history of two or more pregnancies, menopause, and using female hormones were associated with a higher prevalence of kidney stones. The main limitation is the cross-sectional design of the study.

Conclusions: Although kidney stones are more common in men than in women in the USA, the gender gap in kidney stone prevalence appears to be closing in the past decade. Kidney stones are consistently higher among non-Hispanic white and obese, and women who have had multiple pregnancies or have used female hormone therapy.

Patient Summary: The prevalence of kidney stones remains higher in adult US men than in women, but the trend has been increasing only in women, closing the gender gap in kidney stone prevalence.
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http://dx.doi.org/10.1016/j.euf.2020.08.011DOI Listing
November 2021

Imaging modalities and treatment of paediatric upper tract urolithiasis: A systematic review and update on behalf of the EAU urolithiasis guidelines panel.

J Pediatr Urol 2020 Oct 4;16(5):612-624. Epub 2020 Jul 4.

Second Department of Urology, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Background: Prompt diagnosis and treatment of paediatric urolithiasis are required to avoid long term sequelae of renal damage.

Objective: To systematically review the literature regarding the diagnostic imaging modalities and treatment approaches for paediatric urolithiasis.

Study Design: PubMed, Science Direct, Scopus and Web of Science were systematically searched from January 1980-January 2019. 76 full-text articles were included.

Results: Ultrasound and Kidney-Ureter-Bladder radiography are the baseline diagnostic examinations. Non-contrast Computed Tomography (CT) is the second line choice with high sensitivity (97-100%) and specificity (96-100%). Magnetic Resonance Urography accounts only for 2% of pediatric stone imaging studies. Expectant management for single, asymptomatic lower pole renal stones is an acceptable initial approach, especially in patients with non-struvite, non-cystine stones<7 mm. Limited studies exist on medical expulsive therapy as off-label treatment. Extracorporeal shock wave lithotripsy (SWL) is the first-line treatment with overall stone free rates (SFRs) of 70-90%, retreatment rates 4-50% and complication rates up to 15%. Semi-rigid ureteroscopy is effective with SFRs of 81-98%, re-treatment rates of 6.3-10% and complication rates of 1.9-23%. Flexible ureteroscopy has shown SFRs of 76-100%, retreatment rates of 0-19% and complication rates of 0-28%. SFRs after first and second-look percutaneous nephrolithotomy (PNL) are 70.1-97.3% and 84.6-97.5%, respectively with an overall complication rate of 20%. Open surgery is seldom used, while laparoscopy is effective for stones refractory to SWL and PNL. Limited data exist for robot-assisted management.

Conclusions: In the initial assessment of paediatric urolithiasis, US is recommended as first imaging modality, while non-contrast CT is the second option. SWL is recommended as first line treatment for renal stones <20 mm and for ureteral stones<10 mm. Ureteroscopy is a feasible alternative both for ureteral stones not amenable to SWL as well as for renal stones <20 mm (using flexible). PNL is recommended for renal stones >20 mm.
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http://dx.doi.org/10.1016/j.jpurol.2020.07.003DOI Listing
October 2020

Tubeless percutaneous nephrolithotomy: evaluation of minimal invasive exit strategies after percutaneous stone treatment.

Curr Opin Urol 2020 09;30(5):679-683

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Vienna, Austria.

Purpose Of Review: To provide an updated overview of different exit strategies for percutaneous nephrolithotomy (PCNL) in times of miniaturization and minimal invasive surgery.

Recent Findings: The majority of the reported studies concluded that a tubeless procedure is associated with less patient discomfort and a shorter hospital stay compared to the standard PCNL. Additionally, no significant difference in the complication rate was observed, including postoperative fever, hematocrit decrease, stone-free rate, and urine extravasation.

Summary: Underlined by recent literature tubeless PCNL is a well tolerated and effective treatment. Nevertheless the decision whether or not to place a nephrostomy tube after PCNL is still depending on the clinical judgment and experience of the surgeon.
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http://dx.doi.org/10.1097/MOU.0000000000000802DOI Listing
September 2020

Efficacy and safety of vilaprisan in women with uterine fibroids: Data from the phase 2b randomized controlled trial ASTEROID 2.

Eur J Obstet Gynecol Reprod Biol 2020 Sep 31;252:7-14. Epub 2020 May 31.

Bayer AG, Müllerstraße 178, 13342, Berlin, Germany. Electronic address:

Objective: To assess the efficacy of vilaprisan compared with placebo in the management of the symptoms of uterine fibroids (UF), with a secondary objective to provide a descriptive comparison with ulipristal acetate.

Study Design: The randomized, parallel-group, double-blind, placebo- and active-controlled, multicenter ASTEROID 2 trial assessed the efficacy and safety of vilaprisan versus placebo and ulipristal acetate for two 12-week treatment periods in women with ≥1 UF experiencing heavy menstrual bleeding (HMB). The primary endpoint compared the efficacy of vilaprisan with placebo at 12 weeks, assessed as the absence of bleeding/spotting by bleeding diary. Secondary endpoints compared the efficacy of vilaprisan with ulipristal acetate. Results of the first 12-week treatment period are reported here.

Results: Women (mean age 42.5 years) were enrolled from 1 June 2015. At baseline, mean menstrual blood loss per 28 days was 214.1 mL and the volume of the three largest UF was 106.2 mL. In total, 155 women completed the initial 12-week treatment period. Complete absence of bleeding/spotting until the end of the 12-week treatment period was achieved by 62.9 % of women receiving vilaprisan versus 0.0 % with placebo (p < .001); 55.4 % of women treated with ulipristal acetate reported absence of bleeding/spotting. The predefined HMB response (<80 mL and >50 % reduction from baseline during the last 28 days of treatment) was observed in 95.7 % of subjects treated with vilaprisan and 86.5 % of subjects treated with ulipristal acetate. Vilaprisan and ulipristal acetate treatment reduced the sum of the volume of the three largest UF by 29.9 % and 23.8 %, respectively, whereas an increase of 6.3 % was observed in the placebo group. No safety concerns, including multiple laboratory parameters, were identified.

Conclusion: Daily administration of vilaprisan 2 mg induced amenorrhea, controlled bleeding, decreased UF size, and was well tolerated in women with HMB associated with UF.

Clinical Trial Registration: ClinicalTrials.gov number: NCT02465814 https://clinicaltrials.gov/ct2/show/NCT02465814.
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http://dx.doi.org/10.1016/j.ejogrb.2020.05.043DOI Listing
September 2020

Role of Endourological Procedures (PCNL and URS) on Renal Function: a Systematic Review.

Curr Urol Rep 2020 Apr 21;21(5):21. Epub 2020 Apr 21.

Department of Urology, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, SO16 6YD, UK.

Purpose Of Review: To present the latest evidence related to the impact of ureteroscopy (URS) and percutaneous nephrolithotomy (PCNL) on the renal function.

Recent Findings: Our review suggests that the overall renal function is not detrimentally affected by endourological interventions (URS, PCNL). This is however influenced by the preoperative renal function, presence of comorbidities such as diabetes and hypertension. For PCNL procedures, tract multiplicity, preoperative UTI, and postoperative bleeding also contribute to a decline in renal function. This review suggests that endourological interventions do not adversely affect renal function and tend to improve it in patients who do not have a poor renal function prior to the procedure. Several factors including poor preoperative renal function, diabetes, hypertension, and multiple percutaneous tracts appear to predispose patients to declining renal function after procedure, and these patients should be counseled for and followed up appropriately.
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http://dx.doi.org/10.1007/s11934-020-00973-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228975PMC
April 2020

Protocol analysis of dual-energy CT for optimization of kidney stone detection in virtual non-contrast reconstructions.

Eur Radiol 2020 Aug 3;30(8):4295-4305. Epub 2020 Apr 3.

Diagnosezentrum Favoriten, Radiology Center, Am Hauptbahnhof 2/4, 1100, Vienna, Austria.

Objectives: Previous studies have shown that split-bolus protocols in virtual non-contrast (VNC) reconstructions of dual-energy computed tomography (DE-CT) significantly decrease radiation dose in patients with urinary stone disease. To evaluate the impact on kidney stone detection rate of stone composition, size, tube voltage, and iodine concentration for VNC reconstructions of DE-CT.

Methods: In this prospective study, 16 kidney stones of different sizes (1.2-4.5 mm) and compositions (struvite, cystine, whewellite, brushite) were placed within a kidney phantom. Seventy-two scans with nine different iodine contrast agents/saline solutions with increasing attenuation (0-1400 HU) and different kilovoltage settings (70 kV/150 kV; 80 kV/150 kV; 90 kV/150 kV; 100 kV/150 kV) were performed. Two experienced radiologists independently rated the images for the presence and absence of stones. Multivariate classification tree analysis and descriptive statistics were used to evaluate the diagnostic performance.

Results: Classification tree analysis revealed a higher detection rate of renal calculi > 2 mm in size compared with that of renal calculi < 2 mm (84.7%; 12.7%; p < 0.001). For stones with a diameter > 2 mm, the best results were found at 70 kV/Sn 150 kV and 80 kV/Sn 150 kV in scans with contrast media attenuation of 600 HU or less, with sensitivity of 99.6% and 96.0%, respectively. A higher luminal attenuation (> 600 HU) resulted in a significantly decreased detection rate (91.8%, 0-600 HU; 70.7%, 900-1400 HU; p < 0.001). In our study setup, the detection rates were best for cystine stones.

Conclusion: Scan protocols in DE-CT with lower tube current and lower contrast medium attenuation show excellent results in VNC for stones larger than 2 mm but have limitations for small stones.

Key Points: • The detection rate of virtual non-contrast reconstructions is highly dependent on the surrounding contrast medium attenuation at the renal pelvis and should be kept as low as possible, as at an attenuation higher than 600 HU the VNC reconstructions are susceptible to masking ureteral stones. • Protocols with lower tube voltages (70 kV/Sn 150 kV and 80 kV/Sn 150 kV) improve the detection rate of kidney stones in VNC reconstructions. • The visibility of renal stones in virtual non-contrast of dual-energy CT is highly associated with the size, and results in a significantly lower detection rate in stones below 2 mm.
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http://dx.doi.org/10.1007/s00330-020-06806-9DOI Listing
August 2020

Development and content validation of two new patient-reported outcome measures for endometriosis: the Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS).

J Patient Rep Outcomes 2020 Feb 18;4(1):13. Epub 2020 Feb 18.

Bayer AG, Berlin, Germany.

Background: Endometriosis is a common, chronic, impactful condition in women of reproductive age. In the absence of established sensitive and specific biomarkers, disease severity is determined by patient-reported symptoms and impacts. This article details the development of two new patient-reported outcome (PRO) measures designed to assess efficacy endpoints in clinical studies: The Endometriosis Symptom Diary (ESD) and the Endometriosis Impact Scale (EIS).

Methods: The ESD and EIS were developed according to best practice and scientific standards (including the Food and Drug Administration (FDA) PRO Guidance) and with extensive input from women with surgically-confirmed endometriosis. Research included: a review of published qualitative literature; concept elicitation interviews in the US, Germany and France (n = 45) to explore the experiences of women with endometriosis and to inform ESD and EIS development; and cognitive interviews in the US and Germany (n = 31) to assess relevance and understanding of the ESD and EIS and usability of administration using an electronic handheld device. The FDA and the European Medicines Agency (EMA) as well as PRO and clinical experts were consulted throughout the process.

Results: Pelvic pain was identified as the most frequent, severe and bothersome symptom for women with endometriosis. Pain was reported to be greatest during menstruation (dysmenorrhea) and during or after sexual intercourse (dyspareunia). Pain resulted in significant impairments in physical activities, work/study, social/leisure activities, household activities and sexual functioning. All women highlighted the emotional impact of endometriosis. Descriptions of pain and associated impacts were largely consistent across participants from the US and Europe, with the most notable differences being the words used to describe the location of pain (e.g., 'pelvis' vs. 'abdomen'). Testing during cognitive interviews indicated that the ESD and EIS were well understood and consistently interpreted. Furthermore, all participants found the ePRO devices easy to use and no issues regarding visual presentation, selection of responses or navigation were identified.

Conclusions: Evidence from extensive qualitative research supports the content validity of the ESD and EIS as patient-reported measures of the disease-defining symptoms of endometriosis and the associated impact on women's lives. Future research will seek to establish the measurement properties of the measures.
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http://dx.doi.org/10.1186/s41687-020-0177-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028881PMC
February 2020
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