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Ewing sarcoma is the second most common primary malignant bone cancer in children and adolescents. This rare type of cancer is characterized by its high malignancy and therefore high risk of metastases. Typically, Ewing sarcomas originate from bones. However, extraosseous Ewing sarcoma such as pulmonary Ewing sarcoma can also be found. In this case report, we present a 55-year old male patient who was initially diagnosed with non-small cell lung cancer at his local district hospital. However, the diagnosis was changed to one of pulmonary Ewing sarcoma after subsequent histopathological and molecular pathological analysis performed in a reference pathology laboratory. After patient referral to a certified (according to the German Cancer Society) high-volume sarcoma center, multimodal chemotherapy was initiated based on recently published clinical data as opposed to the more commonly used treatment regimen in Europe. The patient responded well to treatment and underwent a complete surgical tumor resection followed by radiotherapy. In summary, this case report highlights the importance of a rigorous and timely histopathological examination of biopsy samples by a specialized cancer center to enable a correct diagnosis of the cancer type. Additionally, molecular pathology plays a crucial part in this analysis and allows the necessary differentiation between cancer types. Up to now, there is no international treatment guideline available for the treatment of Ewing sarcoma. Patients should be referred to specialist centers to allow the best possible treatment of the cancer type in view of current published clinical data. In the case of Ewing sarcoma, and in accordance with the most recent research, patients should be treated with vincristine, doxorubicin and cyclophosphamide plus ifosfamide and etoposide in combination with local treatment such as surgery and/or radiotherapy because this has been demonstrated to be the more effective therapy.

Institutes for pathology act as operators, users and in-house manufacturers of in vitro diagnostic medical devices and are subject to national and European regulations depending on their function. The entry into force of the EU regulation on medical devices (Regulation (EU) 2017/745, MDR) and the EU regulation on in vitro diast medical devices (Regulation (EU) 2017/746, IVDR) resulted in a need for regulatory adjustments to German medical device law. This has created a new legal framework in which institutes for pathology operate, depending on their function as users, operators or in-house manufacturers of in vitro diagnostic medical devices. This overview of the current legal situation represents a snapshot and provides an up-to-date overview of the landscape of European and German medical device law.

Several studies have demonstrated, both in vitro and in animal models, the anti-tumor efficacy of high-dose ascorbate treatment against a variety of tumor entities, including glioblastoma, the most common and aggressive primary malignant brain tumor. The aim of this study was to investigate the effects of high-dose ascorbate as well as dehydroascorbic acid on human glioblastoma cell lines and to evaluate different treatment conditions for the combined administration of ascorbate with magnesium (Mg2+) and iron (Fe3+). Intracellular levels of reactive oxygen species and the induction of cell death following ascorbate treatment were also investigated. We demonstrated high cytotoxicity and antiproliferative efficacy of high-dose ascorbate in human glioblastoma cells, whereas much weaker effects were observed for dehydroascorbic acid. Ascorbate-induced cell death was independent of apoptosis. Both the reduction in cell viability and the ascorbate-induced generation of intracellular reactive oxygen species could be significantly increased by incubating the cells with Fe3+ before ascorbate treatment. This work demonstrates, for the first time, an increase in ascorbate-induced intracellular ROS formation and cytotoxicity in human glioblastoma cells by pre-treatment of the tumor cells with ferric iron, as well as caspase-3 independence of cell death induced by high-dose ascorbate. Instead, the cell death mechanism caused by high-dose ascorbate in glioblastoma cells shows evidence of ferroptosis. The results of the present work provide insights into the efficacy and mode of action of pharmacological ascorbate for the therapy of glioblastoma, as well as indications for possible approaches to increase the effectiveness of ascorbate treatment.

Abstract The analysis of public debt determinants is well documented in the literature. However, previous studies give more focus to the economic determinants neglecting the role played by socio‐political factors. The purpose of this study is to fill that gap observed in the literature by investigating the impact of socio‐political factors on CEMAC countries' public debt accumulation in a bivariate relationship. The paper employs the OLS and GLS as baseline models using panel data covering the period from 1980 to 2021. The study uses as alternative techniques the FE, FE‐IV, and the GMM for robustness checks. The empirical findings highlight the system (both presidential and legislative), corruption, Electoral openness and Competitiveness for legislative election (Liec), and fraud as the main driving factors of public debt in CEMAC countries. This paper suggests further studies to give a particular interest to socio‐political factors while investigating the determinants of public debt in developing countries.

IntroductionNeuroendocrine neoplasms (NEN) are a rare and heterogenous group of tumors arising from neuroendocrine cells in multiple organs. Neuroendocrine tumors (NET) G3 encompass a small subgroup accounting for less than 10% of all neuroendocrine neoplasms. In contrast to NET G1 and G2 as well as neuroendocrine carcinomas (NEC), in NET G3 data on treatment and patient outcomes are still limited. Especially in a metastasized tumor stage, the role of surgery, peptide receptor radionucleotide therapy (PRRT), and systemic chemotherapy is not clearly defined.MethodsIn this real-life cohort, we consecutively analyzed clinical outcome in NET G3 patients receiving different diagnostic and treatment.Results and discussionWe found that even metastasized NET G3 patients undergoing surgery, or receiving radiation, somatostatin analogues (SSA), and PRRT showed a clear survival benefit. Interestingly, all treatment regimen were superior to classical chemotherapeutic agents. In addition, somatostatin receptor (SSTR) PET-CT, FDG PET-CT, and repetitive biopsies were shown to be useful diagnostic and prognostic tools in NET G3. Our study demonstrates that patients with highly proliferative NET G3 might benefit from less aggressive treatment modalities commonly used in low proliferative NEN.

NUT (nuclear-protein-in-testis) carcinoma (NC) is a highly aggressive tumor disease. Given that current treatment regimens offer a median survival of six months only, it is likely that this type of tumor requires an extended multimodal treatment approach to improve prognosis. In an earlier case report, we could show that an oncolytic herpes simplex virus (T-VEC) is functional in NC patients. To identify further combination partners for T-VEC, we have investigated the anti-tumoral effects of T-VEC and five different small molecule inhibitors (SMIs) alone and in combination in human NC cell lines. Dual combinations were found to result in higher rates of tumor cell reductions when compared to the respective monotherapy as demonstrated by viability assays and real-time tumor cell growth monitoring. Interestingly, we found that the combination of T-VEC with SMIs resulted in both stronger and earlier reductions in the expression of c-Myc, a main driver of NC cell proliferation, when compared to T-VEC monotherapy. These results indicate the great potential of combinatorial therapies using oncolytic viruses and SMIs to control the highly aggressive behavior of NC cancers and probably will pave the way for innovative multimodal clinical studies in the near future.

We provide an overview of the status of Monte-Carlo event generators for high-energy particle physics. Guided by the experimental needs and requirements, we highlight areas of active development, and opportunities for future improvements. Particular emphasis is given to physics models and algorithms that are employed across a variety of experiments. These common themes in event generator development lead to a more comprehensive understanding of physics at the highest energies and intensities, and allow models to be tested against a wealth of data that have been accumulated over the past decades. A cohesive approach to event generator development will allow these models to be further improved and systematic uncertainties to be reduced, directly contributing to future experimental success. Event generators are part of a much larger ecosystem of computational tools. They typically involve a number of unknown model parameters that must be tuned to experimental data, while maintaining the integrity of the underlying physics models. Making both these data, and the analyses with which they have been obtained accessible to future users is an essential aspect of open science and data preservation. It ensures the consistency of physics models across a variety of experiments.

Frequency mixing magnetic detection (FMMD) is a sensitive and selective technique to detect magnetic nanoparticles (MNPs) serving as probes for binding biological targets. Its principle relies on the nonlinear magnetic relaxation dynamics of a particle ensemble interacting with a dual frequency external magnetic field. In order to increase its sensitivity, lower its limit of detection and overall improve its applicability in biosensing, matching combinations of external field parameters and internal particle properties are being sought to advance FMMD. In this study, we systematically probe the aforementioned interaction with coupled Néel–Brownian dynamic relaxation simulations to examine how key MNP properties as well as applied field parameters affect the frequency mixing signal generation. It is found that the core size of MNPs dominates their nonlinear magnetic response, with the strongest contributions from the largest particles. The drive field amplitude dominates the shape of the field-dependent response, whereas effective anisotropy and hydrodynamic size of the particles only weakly influence the signal generation in FMMD. For tailoring the MNP properties and parameters of the setup towards optimal FMMD signal generation, our findings suggest choosing large particles of core sizes dC>25 nm with narrow size distributions (σ<0.1) to minimize the required drive field amplitude. This allows potential improvements of FMMD as a stand-alone application, as well as advances in magnetic particle imaging, hyperthermia and magnetic immunoassays.

Abstract Background Immunotherapy with immune checkpoint inhibitors (ICI) has revolutionized cancer therapy. However, therapeutic targeting of inhibitory T cell receptors such as PD-1 not only initiates a broad immune response against tumors, but also causes severe adverse effects. An ideal future stratified immunotherapy would interfere with cancer-specific cell surface receptors only. Methods To identify such candidates, we profiled the surface receptors of the NCI-60 tumor cell panel via flow cytometry. The resulting surface receptor expression data were integrated into proteomic and transcriptomic NCI-60 datasets applying a sophisticated multiomics multiple co-inertia analysis (MCIA). This allowed us to identify surface profiles for skin, brain, colon, kidney, and bone marrow derived cell lines and cancer entity-specific cell surface receptor biomarkers for colon and renal cancer. Results For colon cancer, identified biomarkers are CD15, CD104, CD324, CD326, CD49f, and for renal cancer, CD24, CD26, CD106 (VCAM1), EGFR, SSEA-3 (B3GALT5), SSEA-4 (TMCC1), TIM1 (HAVCR1), and TRA-1-60R (PODXL). Further data mining revealed that CD106 (VCAM1) in particular is a promising novel immunotherapeutic target for the treatment of renal cancer. Conclusion Altogether, our innovative multiomics analysis of the NCI-60 panel represents a highly valuable resource for uncovering surface receptors that could be further exploited for diagnostic and therapeutic purposes in the context of cancer immunotherapy.

Background Reconstruction of large soft tissue defects of the lower extremity often requires the use of free flaps. The main limiting factor and potential for complications lie in the selection of proper donor and recipient vessels for microvascular anastomosis. While the superficial veins of the lower leg are easier to dissect, they are thought to be more vulnerable to trauma and lead to a higher complication rate when using them instead of the deep accompanying veins as recipient vessels. No clear evidence exists that proves this concept. Methods We retrospectively studied the outcomes of 97 patients who underwent free flap plasty to reconstruct predominantly traumatic defects of the lower extremity at our institute. The most used flap was the gracilis muscle flap. We divided the population into three groups based on the recipient veins that were used for microvascular anastomosis and compared their outcomes. The primary outcome was the major complication rate. Results Overall flap survivability was 93.81%. The complication rates were not higher when using the great saphenous vein as a recipient vessel when comparing to utilizing the deep concomitant veins alone or the great saphenous vein in combination to the concomitant veins. Conclusions In free flap surgery of the lower extremity, the selection of the recipient veins should not be restricted to the deep accompanying veins of the main vessels. The superficial veins, especially the great saphenous vein, offer an underrated option when performing free flap reconstruction.

Summary:. Three-dimensional printing (3DP) represents an emerging field of surgery. 3DP can facilitate the plastic surgeon’s workflow, including preoperative planning, intraoperative assistance, and postoperative follow-up. The broad clinical application spectrum stands in contrast to the paucity of research on the legal framework of 3DP. This imbalance poses a potential risk for medical malpractice lawsuits. To address this knowledge gap, we aimed to summarize the current body of legal literature on medical 3DP in the US legal system. By combining the promising clinical use of 3DP with its current legal regulations, plastic surgeons can enhance patient safety and outcomes.

T cell-based immunotherapy has significantly improved treatment options for many malignancies. However, despite these and other therapeutic improvements over the last decades, gastrointestinal cancers, in particular pancreatic, hepatic and gastric cancer, are still characterized by high relapse rates and dismal prognosis, with an accordingly high unmet medical need for novel treatment strategies. We here report on the preclinical characterization of a novel bispecific antibody in an IgG-based format termed CC-3 with B7-H3xCD3 specificity. In many cancer entities including pancreatic, hepatic and gastric cancers, B7-H3 (CD276) is overexpressed on tumor cells and also on the tumor vasculature, the latter allowing for improved access of immune effector cells into the tumor site upon therapeutic targeting. We demonstrate that CC-3 induces profound T cell reactivity against various pancreatic, hepatic and gastric cancer cell lines as revealed by analysis of activation, degranulation and secretion of IL2, IFNγ as well as perforin, resulting in potent target cell lysis. Moreover, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. Together, our results emphasize the potential of CC-3, which is presently being GMP-produced to enable clinical evaluation for treatment of pancreatic, hepatic and gastric cancer.

Background and Purpose: The ATP‐dependent biliary efflux transporter ABCC2, also known as multidrug resistance protein 2 (MRP2), is essential for the cellular disposition and detoxification of various xenobiotics including drugs as well as endogenous metabolites. Common functionally relevant ABCC2 genetic variants significantly alter drug responses and contribute to side effects. The aim of this study was to determine functional consequences of rare variants identified in subjects with European ancestry using in silico tools and in vitro analyses. Experimental Approach: Targeted next‐generation sequencing of the ABCC2 gene was used to identify novel variants in European subjects (n = 143). Twenty‐six in silico tools were used to predict functional consequences. For biological validation, transport assays were carried out with membrane vesicles prepared from cell lines overexpressing the newly identified ABCC2 variants and estradiol β‐glucuronide and carboxydichlorofluorescein as the substrates. Key Results: Three novel rare ABCC2 missense variants were identified (W227R, K402T, V489F). Twenty‐five in silico tools predicted W227R as damaging and one as potentially damaging. Prediction of functional consequences was not possible for K402T and V489F and for the common linked variants V1188E/C1515Y. Characterisation in vitro showed increased function of W227R, V489F and V1188E/C1515Y for both substrates, whereas K402T function was only increased for carboxydichlorofluorescein. Conclusion and Implications: In silico tools were unable to accurately predict the substrate‐dependent increase in function of ABCC2 missense variants. In vitro biological studies are required to accurately determine functional activity to avoid misleading consequences for drug therapy. [ABSTRACT FROM AUTHOR]

Background: The radial forearm flap remains the gold standard in phalloplasty in gender-affirming surgery due to its versatility and functional outcome, but the significant donor site morbidity and its impact on daily functioning and aesthetic perception remains understudied. This study provides valuable insights into the mid-term functional and aesthetic outcomes of the forearm in transgender individuals following radial forearm flap phalloplasty using widespread instruments for assessment scoring systems and for the evaluation of postoperative wound healing of surgical interventions in general. Methods: Between January 2013 and March 2018, a total of 47 patients underwent radial phalloplasty at AGAPLESION Markus Hospital, and 20 consented to participate in this cross-sectional, retrospective study evaluating functional and aesthetic outcomes post-radial forearm flap phalloplasty using standardized questionnaires (DASH, POSAS, and SBSES). A univariate median regression of each score was performed to determine the associations with selected variables, and correlation analyses between scores was performed using a nonparametric Spearman rank correlation. Results: Among the 20 participants, the median Quick DASH, DASH functionality, DASH sport and music, and DASH work scores indicated minimal to no functional impairment. Scar evaluations using the PSAS, OSAS, and SBSES scales showed overall patient satisfaction with minimal concerns regarding pigmentation and scar texture. Notably, an increase of 0.27 cm2 in wound surface area added one point to the DASH sport and music score (p = 0.037). Statistical analysis also demonstrated a significant correlation between functional and aesthetic assessment scores. Conclusions: The radial forearm phalloplasty donor site, evaluated by the PSAS, OSAS, and SBSES scales, leads to minimal or no functional impairment; however, the worsening of the DASH sport and music score with increasing wound surface reflects a direct relation between wound size and functional impairment. [ABSTRACT FROM AUTHOR]

Purpose: To observe the growth and resolution of decompression gas bubbles in the spinal cord of live rats in real time using MRI. Methods: We constructed an MRI‐compatible pressure chamber system to visualize gas bubble dynamics in deep tissues in real time. The system pressurizes and depressurizes rodents inside an MRI scanner and monitors their respiratory rate, heart rate, and body temperature while providing gaseous anesthesia under pressure during the experiments. Results: We observed the formation of decompression gas bubbles in the spinal cord of rats after compression to 7.1 bar absolute and rapid decompression inside the MRI scanner while maintaining continuous gaseous anesthesia and vital monitoring. Conclusion: We have shown the direct observation of decompression gas bubble formation in real time by MRI in live, anesthetized rats. [ABSTRACT FROM AUTHOR]

The stomach's ability to store, mix, propel, and empty its content requires highly coordinated motor functions. However, current diagnostic tools cannot simultaneously assess these motor processes. This study aimed to use magnetic resonance imaging (MRI) to map multifaceted gastric motor functions, including accommodation, tonic and peristaltic contractions, and emptying, through a single noninvasive experiment for both humans and rats. Ten humans and 10 Sprague-Dawley rats consumed MRI-visible semisolid meals and underwent MRI scans. We used a surface model to analyze MRI data, capturing the deformation of the stomach wall on ingestion or during digestion. We inferred muscle activity, mapped motor processes, parcellated the stomach into functional regions, and revealed cross-species distinctions. In humans, both the fundus and antrum distended postmeal, followed by sustained tonic contractions to regulate intragastric pressure. Peristaltic contractions initiated from the distal fundus, including three concurrent wavefronts oscillating at 3.3 cycles/min and traveling at 1.7 to 2.9 mm/s. These motor functions facilitated linear gastric emptying with a 61-min half-time. In contrast, rats exhibited peristalsis from the midcorpus, showing two wavefronts oscillating at 5.0 cycles/min and traveling at 0.4 to 0.9 mm/s. For both species, motility features allowed functional parcellation of the stomach along a midcorpus division. This study maps region- and species-specific gastric motor functions. We demonstrate the value of MRI with surface modeling in understanding gastric physiology and its potential to become a new standard for clinical and preclinical investigations of gastric disorders at both individual and group levels. NEW & NOTEWORTHY: A novel MRI technique can visualize how the stomach accommodates, mixes, and propels food for digestion in humans and animals alike. Digital models of gastric MRI reveal the functional maps, organization, and distinction of the stomach across individuals and species. This technique holds the unique potential to advance basic and clinical studies of functional gastric disorders. [ABSTRACT FROM AUTHOR]

Several studies have demonstrated, both in vitro and in animal models, the anti-tumor efficacy of high-dose ascorbate treatment against a variety of tumor entities, including glioblastoma, the most common and aggressive primary malignant brain tumor. The aim of this study was to investigate the effects of high-dose ascorbate as well as dehydroascorbic acid on human glioblastoma cell lines and to evaluate different treatment conditions for the combined administration of ascorbate with magnesium (Mg2+) and iron (Fe3+). Intracellular levels of reactive oxygen species and the induction of cell death following ascorbate treatment were also investigated. We demonstrated high cytotoxicity and antiproliferative efficacy of high-dose ascorbate in human glioblastoma cells, whereas much weaker effects were observed for dehydroascorbic acid. Ascorbate-induced cell death was independent of apoptosis. Both the reduction in cell viability and the ascorbate-induced generation of intracellular reactive oxygen species could be significantly increased by incubating the cells with Fe3+ before ascorbate treatment. This work demonstrates, for the first time, an increase in ascorbate-induced intracellular ROS formation and cytotoxicity in human glioblastoma cells by pre-treatment of the tumor cells with ferric iron, as well as caspase-3 independence of cell death induced by high-dose ascorbate. Instead, the cell death mechanism caused by high-dose ascorbate in glioblastoma cells shows evidence of ferroptosis. The results of the present work provide insights into the efficacy and mode of action of pharmacological ascorbate for the therapy of glioblastoma, as well as indications for possible approaches to increase the effectiveness of ascorbate treatment. [ABSTRACT FROM AUTHOR]