Individualized Mini-Panel Sequencing of ctDNA Allows Tumor Monitoring in Complex Karyotype Sarcomas

Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For metastasized STS, only limited inferences can be drawn from imaging data regarding therapy response. To date there are no established and evidence-based diagnostic biomarkers for STS due to their rarity and diversity. In a proof-of-concept study, circulating tumor DNA (ctDNA) was quantified in (n = 25) plasma samples obtained from (n = 3) patients with complex karyotype STS collected over three years. Genotyping of tumor tissue was performed by exome sequencing. Patient-individual mini-panels for targeted next-generation sequencing were designed encompassing up to 30 mutated regions of interest. Circulating free DNA (cfDNA) was purified from plasma and ctDNA quantified therein. ctDNA values were correlated with clinical parameters. ctDNA concentrations correlated with the tumor burden. In case of full remission, no ctDNA was detectable. Patients with a recurrence at a later stage showed low levels of ctDNA during clinical remission, indicating minimal residual disease. In active disease (primary tumor or metastatic disease), ctDNA was highly elevated. We observed direct response to treatment, with a ctDNA decline after tumor resections, radiotherapy, and chemotherapy. Quantification of ctDNA allows for the early detection of recurrence or metastases and can be used to monitor treatment response in STS. Therapeutic decisions can be made earlier, such as the continuation of a targeted adjuvant therapy or the implementation of extended imaging to detect recurrences. In metastatic disease, therapy can be adjusted promptly in case of no response. These advantages may lead to a survival benefit for patients in the future.     

Surprising Solid-State ESIPT Emission from Apparently Ordinary Salicyliden Glycinates Schiff Bases

Excited-State Intramolecular Photon Transfer (ESIPT) is known for the geometry-related phenolic and imine groups. The Schiff bases formed upon condensation of salicyl aldehyde and glycine led to the formation of ESIPT models. A series of alkali metal salicyliden glycinates were analyzed by X-ray diffraction of their monocrystals and spectroscopy measurements. The X-ray analysis revealed varied hydration levels between the salts. They adapted trans geometry on the imine groups and mostly anticlinal conformation with the neighboring atoms, which is different from the other structurally-related compounds in literature. Fluorescence of these compounds was found for the crystalline forms only. Protonation of the imine nitrogen atom and further proton distribution was consistent with the ESIPT theory, which also explained the observed fluorescence with the highest Stokes shift of 10,181 cm⁻¹ and 10.1% of fluorescence quantum yield for the sodium salt.     

Pathophysiological Concepts and Management of Pulmonary Manifestation of Pediatric Inflammatory Bowel Disease

Pulmonary manifestation (PM) of inflammatory bowel disease (IBD) in children is a rare condition. The exact pathogenesis is still unclear, but several explanatory concepts were postulated and several case reports in children were published. We performed a systematic Medline search between April 1976 and April 2022. Different pathophysiological concepts were identified, including the shared embryological origin, “miss-homing” of intestinal based neutrophils and T lymphocytes, inflammatory triggering via certain molecules (tripeptide proline-glycine-proline, interleukin 25), genetic factors and alterations in the microbiome. Most pediatric IBD patients with PM are asymptomatic, but can show alterations in pulmonary function tests and breathing tests. In children, the pulmonary parenchyma is more affected than the airways, leading histologically mainly to organizing pneumonia. Medication-associated lung injury has to be considered in pulmonary symptomatic pediatric IBD patients treated with certain agents (i.e., mesalamine, sulfasalazine or infliximab). Furthermore, the risk of pulmonary embolism is generally increased in pediatric IBD patients. The initial treatment of PM is based on corticosteroids, either inhaled for the larger airways or systemic for smaller airways and parenchymal disease. In summary, this review article summarizes the current knowledge about PM in pediatric IBD patients, focusing on pathophysiological and clinical aspects.     

Lorentzian-Corrected Apparent Exchange-Dependent Relaxation (LAREX) Ω-Plot Analysis—An Adaptation for qCEST in a Multi-Pool System: Comprehensive In Silico,In Situ,and In Vivo Studies

Based on in silico, in situ, and in vivo studies, this study aims to develop a new method for the quantitative chemical exchange saturation transfer (qCEST) technique considering multi-pool systems. To this end, we extended the state-of-the-art apparent exchange-dependent relaxation (AREX) method with a Lorentzian correction (LAREX). We then validated this new method with in situ and in vivo experiments on human intervertebral discs (IVDs) using the Kendall-Tau correlation coefficient. In the in silico experiments, we observed significant deviations of the AREX method as a function of the underlying exchange rate (k_ba) and fractional concentration (f_b) compared to the ground truth due to the influence of other exchange pools. In comparison to AREX, the LAREX-based Ω-plot approach yielded a substantial improvement. In the subsequent in situ and in vivo experiments on human IVDs, no correlation to the histological reference standard or Pfirrmann classification could be found for the f_b (in situ: τ = −0.17 p = 0.51; in vivo: τ = 0.13 p = 0.30) and k_ba (in situ: τ = 0.042 p = 0.87; in vivo: τ = −0.26 p = 0.04) of Glycosaminoglycan (GAG) with AREX. In contrast, the influence of interfering pools could be corrected by LAREX, and a moderate to strong correlation was observed for the fractional concentration of GAG for both in situ (τ = −0.71 p = 0.005) and in vivo (τ = −0.49 p < 0.001) experiments. The study presented here is the first to introduce a new qCEST method that enables qCEST imaging in systems with multiple proton pools.     

Inclusions of Nanometer-Sized Al2O3 Particles in a Crystalline (Sc,Lu)2(WO4)3 Matrix

Nanometer-sized Al₂O₃ particles were successfully synthesized as crystalline inclusions by mixing both components to form the nanometer-sized particles and the (Sc,Lu)₂(WO₄)₃ matrices in a crystal lattice by preparing a solid solution of (Sc,Lu)₂(WO₄)₃ and Al₂(MoO₄)₃ and then decomposing the solid solution. The particles were dispersed uniformly and without agglomeration, which is commonly observed with conventional preparation techniques. The average particle size of the Al₂O₃ was 3.5 nm, and the standard deviation was estimated to be 1.1 nm.     

The Kinetics of Heterogeneous Solid‐Liquid Reaction Crystallizations — An Overview and Examples

In dieser Arbeit werden heterogene Fest/Flüssig‐Reaktionen vorgestellt, bei denen kristalline Produkte entstehen. Es werden verschiedene Makrokinetiken der reagierenden festen Partikel gefunden, die auf der Kombination von Auflösungsprozessen des festen Reaktanten, der ablaufenden Reaktion und der Kristallisationskinetik beruhen. Dominierend dabei ist eine Oberflächenschicht des festen Reaktanten, die aus dem sich bildenden festen Produkt besteht. Verschiedene Beispiele von Fest/Flüssig‐Reaktionskristallisationen werden vorgestellt, um einen Überblick über diese Thematik zu geben. Darüber hinaus werden experimentelle Arbeiten (Herstellung von Borsäure und Zitronensäure) beschrieben mit dem Ziel, die Fest/Flüssig‐Reaktionskristallisation zu optimieren. Wenn Hydrate bei der Fest/Flüssig‐Reaktionskristallisation auftreten, beeinflusst deren Stabilität entscheidend die Gesamtreaktion. Es wird gezeigt, dass die Makrokinetiken von Fest/Flüssig‐Reaktionen und ihre Geschwindigkeit dadurch beeinflusst (kontrolliert) werden können, indem beispielsweise am Anfang ein bestimmter Anteil des Produktes oder Nebenproduktes zugesetzt wird.