Advancing head and neck cancer management: Unveiling the diagnostic and therapeutic potentials of molecular profiling.

BACKGROUND: Head and neck cancers (HNC) present diagnostic challenges due to multifocal disease manifestations, posing difficulties in distinguishing between metastatic disease and second primary malignancies (SPM). This complexity underscores the need for advanced diagnostic approaches. Emerging technologies, such as next-generation sequencing (NGS) and molecular classifier assays, show promise in providing precise insights into the diverse etiologies of HNC. METHOD: In this article, we employed NGS and molecular classifier assays to delve into three distinct clinical cases. The objective was to showcase the instrumental role of these technologies in facilitating accurate diagnoses and differentiating between metastatic disease and SPM in HNC cases. RESULTS: The results of this series highlight the effectiveness of NGS and molecular classifier assays in enhancing diagnostic accuracy for HNC and contributing to the precise differentiation of disease etiologies. The utilization of these advanced technologies proved instrumental in avoiding unnecessary interventions and paved the way for more targeted and effective treatment strategies. CONCLUSION: Our findings underscore the necessity of incorporating advanced molecular testing technologies into the diagnostic and therapeutic approaches for HNC, thereby championing a more nuanced and effective approach to managing these complex cases.

Transportation model for acute aortic dissection: implications for reduced treatment centres.

OBJECTIVES: The objective of the present study was to model the effects of a reduced number of treatment centres for acute type A aortic dissection on preclinical transportation distance and time. We examined whether treatment in selected centres in Germany would be implementable with respect to time to treatment. METHODS: For our transportation model, the number of aortic dissections and respective mean annual volume were collected from the annual quality reports (2015-2017) of all German cardiac surgery centres (n = 76). For each German postal code, the fastest and shortest routes to the nearest centre were calculated using Google Maps. Furthermore, we analysed data from the German Federal Statistical Office from January 2005 to December 2015 to identify all surgically treated patients with acute type A aortic dissection (n = 14 102) and examined the relationship between in-hospital mortality and mean annual volume of medical centres. RESULTS: Our simulation showed a median transportation distance of 27.13 km and transportation time of 35.78 min for 76 centres. Doubling the transportation time (70 min) would allow providing appropriate care with only 12 medical centres. Therefore, a mean annual volume of >25 should be obtained. High mean annual volume was associated with significantly lower in-hospital mortality rates (P < 0.001). A significantly lower mortality rate of 14% was observed (P < 0.001) if a mean annual volume of 30 was achieved. CONCLUSIONS: Operationalizing the volume-outcome relationship with fewer but larger medical centres results in lower mortality, which outweighs the disadvantage of longer transportation time.

Modelling years of life lost due to acute type A aortic dissection in the German healthcare setting: a predictive study.

OBJECTIVES: This study aimed to develop a patient-centred approach to the burden of acute type A aortic dissection (ATAAD) through modelling. The main objective was to identify potential improvements in managing this life-threatening cardiovascular condition and to provide evidence-based recommendations to optimise outcomes. DESIGN: We developed a predictive model along patient pathways to estimate the burden of ATAAD through the years of life lost (YLLs) metric. The model was created based on a systematic review of the literature and was parameterised using demographic data from the German healthcare environment. The model was designed to allow interactive simulation of different scenarios resulting from changes in key impact factors. SETTING: The study was conducted using data from the German healthcare environment and results from the literature review. PARTICIPANTS: The study included a comprehensive modelling of ATAAD cases in Germany but did not directly involve participants. INTERVENTIONS: There were no specific interventions applied in this study based on the modelling design. PRIMARY AND SECONDARY OUTCOME MEASURES: The single outcome measure was the estimation of YLL due to ATAAD in Germany. RESULTS: Our model estimated 102 791 YLL per year for ATAAD in Germany, with 62 432 and 40 359 YLL for men and women, respectively. Modelling an improved care setting yielded 93 191 YLL or 9.3% less YLL compared with the current standard while a worst-case scenario resulted in 113 023 or 10.0% more YLL. The model is accessible at https://acuteaorticdissection.com/ to estimate custom scenarios. CONCLUSIONS: Our study provides an evidence-based approach to estimating the burden of ATAAD and identifying potential improvements in the management of pathways. This approach can be used by healthcare decision-makers to inform policy changes aimed at optimising patient outcomes. By considering patient-centred approaches in any healthcare environment, the model has the potential to improve efficient care for patients suffering from ATAAD.

Effects of measured and simulated diffraction from a plate on sound source localization.

In daily life, natural or man-made structures influence sound propagation, causing reflections and diffraction with potential effects on auditory spatial perception. While the effect of isolated reflections on binaural localization has been investigated, consequences of edge diffraction on spatial perception have received less attention. Here, effects of edge diffraction on the horizontal localization of a sound source were assessed when a flat square plate occludes the direct sound or produces a reflection in an otherwise anechoic environment. Binaural recordings were obtained with an artificial head for discrete sound source positions along two horizontal trajectories in the vicinity of the plate, including conditions near the incident and reflection shadow boundary. In a listening test, the apparent source position was matched for conditions with and without the plate, resulting in azimuth offsets between the apparent and physical source of up to 12°. The perceived direction of occluded frontal sound sources was laterally shifted to the visible region near the edge of the plate. Geometrical-acoustics-based simulations with different methods to binaurally render diffracted sound paths were technically and perceptually compared to the measurements. The observed localization offset was reproduced with the acoustic simulations when diffraction was rendered considering the individual ear positions.

Imaging Assessment of Radiation Therapy-Related Normal Tissue Injury in Children: A PENTEC Visionary Statement.

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium has made significant contributions to understanding and mitigating the adverse effects of childhood cancer therapy. This review addresses the role of diagnostic imaging in detecting, screening, and comprehending radiation therapy-related late effects in children, drawing insights from individual organ-specific PENTEC reports. We further explore how the development of imaging biomarkers for key organ systems, alongside technical advancements and translational imaging approaches, may enhance the systematic application of imaging evaluations in childhood cancer survivors. Moreover, the review critically examines knowledge gaps and identifies technical and practical limitations of existing imaging modalities in the pediatric population. Addressing these challenges may expand access to, minimize the risk of, and optimize the real-world application of, new imaging techniques. The PENTEC team envisions this document as a roadmap for the future development of imaging strategies in childhood cancer survivors, with the overarching goal of improving long-term health outcomes and quality of life for this vulnerable population.

Rate dependent neural responses of interaural-time-difference cues in fine-structure and envelope.

Advancements in cochlear implants (CIs) have led to a significant increase in bilateral CI users, especially among children. Yet, most bilateral CI users do not fully achieve the intended binaural benefit due to potential limitations in signal processing and/or surgical implant positioning. One crucial auditory cue that normal hearing (NH) listeners can benefit from is the interaural time difference (ITD), i.e., the time difference between the arrival of a sound at two ears. The ITD sensitivity is thought to be heavily relying on the effective utilization of temporal fine structure (very rapid oscillations in sound). Unfortunately, most current CIs do not transmit such true fine structure. Nevertheless, bilateral CI users have demonstrated sensitivity to ITD cues delivered through envelope or interaural pulse time differences, i.e., the time gap between the pulses delivered to the two implants. However, their ITD sensitivity is significantly poorer compared to NH individuals, and it further degrades at higher CI stimulation rates, especially when the rate exceeds 300 pulse per second. The overall purpose of this research thread is to improve spatial hearing abilities in bilateral CI users. This study aims to develop electroencephalography (EEG) paradigms that can be used with clinical settings to assess and optimize the delivery of ITD cues, which are crucial for spatial hearing in everyday life. The research objective of this article was to determine the effect of CI stimulation pulse rate on the ITD sensitivity, and to characterize the rate-dependent degradation in ITD perception using EEG measures. To develop protocols for bilateral CI studies, EEG responses were obtained from NH listeners using sinusoidal-amplitude-modulated (SAM) tones and filtered clicks with changes in either fine structure ITD (ITDFS) or envelope ITD (ITDENV). Multiple EEG responses were analyzed, which included the subcortical auditory steady-state responses (ASSRs) and cortical auditory evoked potentials (CAEPs) elicited by stimuli onset, offset, and changes. Results indicated that acoustic change complex (ACC) responses elicited by ITDENV changes were significantly smaller or absent compared to those elicited by ITDFS changes. The ACC morphologies evoked by ITDFS changes were similar to onset and offset CAEPs, although the peak latencies were longest for ACC responses and shortest for offset CAEPs. The high-frequency stimuli clearly elicited subcortical ASSRs, but smaller than those evoked by lower carrier frequency SAM tones. The 40-Hz ASSRs decreased with increasing carrier frequencies. Filtered clicks elicited larger ASSRs compared to high-frequency SAM tones, with the order being 40 > 160 > 80> 320 Hz ASSR for both stimulus types. Wavelet analysis revealed a clear interaction between detectable transient CAEPs and 40-Hz ASSRs in the time-frequency domain for SAM tones with a low carrier frequency.

Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation.

A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.

Positron emission tomography in the diagnosis and management of primary pediatric lung tumors.

Primary pediatric lung tumors are uncommon and have many overlapping clinical and imaging features. In contrast to adult lung tumors, these rare pediatric neoplasms have a relatively broad histologic spectrum. Informed by a single-institution 13-year retrospective record review, we present an overview of the most common primary pediatric lung neoplasms, with a focus on the role of positron emission tomography (PET), specifically 18F-fluorodeoxyglucose (FDG) PET and 68Ga-DOTATATE PET, in the management of primary pediatric lung tumors. In addition to characteristic conventional radiographic and cross-sectional imaging findings, knowledge of patient age, underlying cancer predisposition syndromes, and PET imaging features may help narrow the differential. While metastases from other primary malignancies remain the most commonly encountered pediatric lung malignancy, the examples presented in this pictorial essay highlight many of the important conventional radiologic and PET imaging features of primary pediatric lung malignancies.

A phase 1 trial utilizing a pharmacokinetic endpoint to determine the optimal dose of ramucirumab in children and adolescents with relapsed or refractory solid tumors, including central nervous system tumors.

BACKGROUND: Ramucirumab is a monoclonal antibody that binds the extracellular domain of vascular endothelial growth factor receptor (VEGFR-2) and prevents binding of VEGF ligands. Based on population pharmacokinetic (PK) analysis and correlation with efficacy in adults, a target steady state trough concentration (Css,min ) ≥ 50 µg/mL was established. PROCEDURES: This phase 1 trial (ADVL1416) used a rolling six design and a PK primary endpoint to define the recommended phase 2 dose (RP2D) of ramucirumab in children with recurrent/refractory solid tumors. Two dose levels (DL) were planned (DL1: 8 mg/kg, DL2: 12 mg/kg administered intravenously [IV] every 2 weeks). Toxicity during the initial 6 weeks was used to assess maximum tolerated dose (MTD). Cycle 1 Day 42 trough (Cmin ) ≥ 50 µg/mL was the target concentration for the PK endpoint. At the RP2D, cohorts for PK expansion and children with central nervous tumors were planned. RESULTS: Twenty-nine patients were enrolled; 28 were eligible; median age [range] = 13.5 [1-21] years; 22 were evaluable for the PK endpoint. Dose-limiting proteinuria occurred at both DLs; however, the MTD was not exceeded. At DL2 (12 mg/kg), the median Day 42 Cmin (n = 16) was 87.8 µg/mL; 15 of 16 patients achieved a Cmin  ≥ 50 µg/mL. CONCLUSION: Ramucirumab was well tolerated in children and adolescents with solid tumors. The RP2D for ramucirumab was 12 mg/kg IV every 2 weeks. This trial demonstrates the feasibility of incorporating a primary PK endpoint to determine dose escalation and the RP2D in children. Studies of ramucirumab in children with selected solid tumors are ongoing.

Analysis of factors affecting outcome in acute type A aortic dissection complicated by preoperative cardiopulmonary resuscitation.

OBJECTIVES: Cardiopulmonary resuscitation (CPR) aggravates the pre-existing dismal prognosis of patients suffering from acute type A aortic dissection (ATAAD). We aimed to identify factors affecting survival and outcome in ATAAD patients requiring CPR at presentation at 2 European aortic centres. METHODS: Data on 112 surgical candidates and undergoing preoperative CPR were retrospectively evaluated. Patients were divided into 2 groups according to 30-day mortality. A multivariable model identified predictors for 30-day mortality. RESULTS: Preoperative death occurred in 23 patients (20.5%). In the remaining 89 surgical patients (79.5%) circulatory arrest time (41 ± 20 min in 30-day non-survivors vs 30 ± 13 min in 30-day survivor, P = 0.003) as well as cardiopulmonary bypass time (320 ± 132 min in 30-day non-survivors vs 252 ± 140 min in 30-day survivor, P = 0.020) time was significantly longer in patients with worse outcome. Thirty-day mortality of the total cohort was 61.6% (n = 69) with cardiac failure in 48% and aortic rupture or haemorrhagic shock (28%) as predominant reasons of death. Age [odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01-1.09, P = 0.034], preoperative coronary (OR 3.42, 95% CI 1.34-9.26, p = 0.012) and spinal malperfusion (OR 12.49, 95% CI 1.83-225.02, P = 0.028) emerged as independent predictors for 30-day mortality while CPR due to tamponade was associated with improved early survival (OR 0.29, 95% CI 0.091-0.81, P = 0.023). CONCLUSIONS: Assessment of underlying cause for CPR is mandatory. Pericardial tamponade, rapidly resolved with pericardial drainage, is a predictor for improved survival, while age and presence of coronary and spinal malperfusion are associated with dismal outcome in this high-risk patient group.

Perioperative hemostatic management of patients with type A aortic dissection.

Coagulopathy is common in patients undergoing thoracic aortic repair for Stanford type A aortic dissection. Non-critical administration of blood products may adversely affect the outcome. It is therefore important to be familiar with the pathologic conditions that lead to coagulopathy in complex cardiac surgery. Adequate care of these patients includes the collection of the medical history regarding the use of antithrombotic and anticoagulant drugs, and a sophisticated diagnosis of the coagulopathy with viscoelastic testing and subsequently adapted coagulation therapy with labile and stable blood products. In addition to the above-mentioned measures, intraoperative blood conservation measures as well as good interdisciplinary coordination and communication contribute to a successful hemostatic management strategy.

The DRESDEN PLATFORM is a research hub for ultra-high dose rate radiobiology.

The recently observed FLASH effect describes the observation of normal tissue protection by ultra-high dose rates (UHDR), or dose delivery in a fraction of a second, at similar tumor-killing efficacy of conventional dose delivery and promises great benefits for radiotherapy patients. Dedicated studies are now necessary to define a robust set of dose application parameters for FLASH radiotherapy and to identify underlying mechanisms. These studies require particle accelerators with variable temporal dose application characteristics for numerous radiation qualities, equipped for preclinical radiobiological research. Here we present the DRESDEN PLATFORM, a research hub for ultra-high dose rate radiobiology. By uniting clinical and research accelerators with radiobiology infrastructure and know-how, the DRESDEN PLATFORM offers a unique environment for studying the FLASH effect. We introduce its experimental capabilities and demonstrate the platform's suitability for systematic investigation of FLASH by presenting results from a concerted in vivo radiobiology study with zebrafish embryos. The comparative pre-clinical study was conducted across one electron and two proton accelerator facilities, including an advanced laser-driven proton source applied for FLASH-relevant in vivo irradiations for the first time. The data show a protective effect of UHDR irradiation up to [Formula: see text] and suggests consistency of the protective effect even at escalated dose rates of [Formula: see text]. With the first clinical FLASH studies underway, research facilities like the DRESDEN PLATFORM, addressing the open questions surrounding FLASH, are essential to accelerate FLASH's translation into clinical practice.

Use of intraoperative bone scintigraphy for resection of spinal osteoid osteoma.

BACKGROUND: The location and proximity to the spinal cord in spinal osteoid osteoma can increase the likelihood of an incomplete resection. Intraoperative bone scintigraphy (IOBS) can be used to verify location and complete surgical resection. OBJECTIVE: To review our experience using IOBS for resection of intraspinal osteoid osteoma. METHODS: IRB approved, retrospective review of IOBS-guided resection over 10 years. Patients underwent injection of 200 uCi/kg (1-20 mCi) 99mTc-MDP 3-4 h prior surgery. Portable single-headed gamma camera equipped with a pinhole collimator (3- or 4-mm aperture) was used. Images were obtained pre-operatively, at the start of the procedure, and intraoperatively. Operative notes were reviewed. Evaluation of recurrence and clinical follow-up was performed. RESULTS: Twenty IOBS-guided resections were performed in 18 patients (median age 13.5 years, 6-22 years, 12 males). Size ranged 5-16 mm, with 38.9% (7/18) cervical, 22.2% (4/18) thoracic, 22.2% (4/18) lumbar, and 16.7% (3/18) sacral. In all cases, IOBS was able to localize the lesion. After suspected total excision, IOBS altered the surgical plan in 75% of cases (15/20), showing residual activity prompting further resection. Median length of follow-up was 6 months (range 1-156 months) with 90% (18/20) showing complete resection without recurrence. Two patients had osteoid osteoma recurrence at 7 and 10 months following the original resection, requiring re-intervention. CONCLUSIONS: IOBS is a useful tool for real-time localization and assessment of spinal osteoid osteoma resection. In all cases, IOBS was able to localize the lesion and changed surgical planning in 75% of cases. Ninety percent of patients achieved complete resection and remain recurrence free.

Dosimetry for radiobiologicalin vivoexperiments at laser plasma-based proton accelerators.

Objective.Laser plasma-based accelerators (LPAs) of protons can contribute to research of ultra-high dose rate radiobiology as they provide pulse dose rates unprecedented at medical proton sources. Yet, LPAs pose challenges regarding precise and accurate dosimetry due to the high pulse dose rates, but also due to the sources' lower spectral stability and pulsed operation mode. Forin vivomodels, further challenges arise from the necessary small field dosimetry for volumetric dose distributions. For these novel source parameters and intended applications, a dosimetric standard needs to be established.Approach.In this work, we present a dosimetry and beam monitoring framework forin vivoirradiations of small target volumes with LPA protons, solving aforementioned challenges. The volumetric dose distribution in a sample (mean dose value and lateral/depth dose inhomogeneity) is provided by combining two independent dose measurements using radiochromic films (dose rate-independent) and ionization chambers (dose rate-dependent), respectively. The unique feature of the dosimetric setup is beam monitoring with a transmission time-of-flight spectrometer to quantify spectral fluctuations of the irradiating proton pulses. The resulting changes in the depth dose profile during irradiation of anin vivosample are hence accessible and enable pulse-resolved depth dose correction for each dose measurement.Main results.A first successful small animal pilot study using an LPA proton source serves as a testcase for the presented dosimetry approach and proves its performance in a realistic setting.Significance.With several facilities worldwide either setting up or already using LPA infrastructure for radiobiological studies with protons, the importance of LPA-adapted dosimetric frameworks as presented in this work is clearly underlined.

The impact of malperfusion patterns in elderly patients undergoing surgery for acute type A aortic dissection.

OBJECTIVES: The aim of this study is to investigate the outcome of elderly patients with surgically treated acute type A aortic dissection (ATAAD) complicated by malperfusion. METHODS: Patients ≥70 years old who underwent surgical treatment for ATAAD between January 2000 and December 2020 were enrolled in this study and stratified by their specific Penn Classification into 4 different subgroups, where Penn Abc was defined as multilevel malperfusion. Short- and long-term outcomes were investigated. Multivariable binary logistic regression was performed to identify risk factors for 1-year mortality. RESULTS: Four hundred elderly patients underwent surgical treatment for ATAAD. A total of 204 (51%) patients had no evidence of malperfusion (Penn Aa), 106 (26.5%) had localized organic malperfusion (Penn Ab), 44 (11%) patients had systemic malperfusion (Penn Ac) and 46 (11.5%) suffered from multilevel malperfusion (Penn Abc). For the latter, in-hospital mortality was 70% (P < 0.001). Age (P < 0.006) and multilevel malperfusion (P < 0.001) were independent risk factors for 1-year mortality. Patients with multilevel malperfusion showed the worst 1-year survival (P < 0.001). In the case of Penn Aa, in-hospital mortality was 13% (P < 0.001). CONCLUSIONS: Surgery may lead to satisfactory results in the absence of malperfusion, even in octogenarians. Elderly patients with multilevel malperfusion show very poor surgical outcome. In these patients, the decision for surgery should be taken with caution. Operation, if performed, should be carried out by experienced teams only.