Musical instruments as dynamic sound sources.

Unlike electro-acoustic sound sources, musical instruments have a time-varying, dynamic directivity, due to the note-dependent radiation behavior of the instrument and due to the expressive movements that musicians perform with their instrument. While previous studies have generally examined the directivity of the static, unmoved instrument for specific notes played, we show the individual and combined contributions of these two factors to a temporal modulation of the radiation behavior, based on motion tracking of typical movement patterns for all instruments of a classical symphony orchestra and on the directivity measured for all partials over the entire pitch range of these instruments. The effect of this modulation, which is manifested by changes in timbre and room acoustic excitation, was determined by spectral variations in the free field and under reverberant conditions, as well as by a modulation of room acoustic parameters. Our results show that these effects are well above the just noticeable differences for all musical instruments and all perceptual variables considered. While the effect of motion dominates for brass instruments, string and woodwind instruments exhibit large note-related differences, which should be taken into account in virtual acoustic realities if an auditory liveliness comparable to physical reality is to be achieved.

Concomitant inhibition of PI3K/mTOR signaling pathways boosts antiproliferative effects of lanreotide in bronchopulmonary neuroendocrine tumor cells.

Introduction: Somatostatin analogues (SSAs) are commonly used in the treatment of hormone hypersecretion in neuroendocrine tumors (NETs), however the extent to which they inhibit proliferation is much discussed. Objective: We studied the antiproliferative effects of novel SSA lanreotide in bronchopulmonary NETs (BP-NETs). We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide. Methods: BP-NET cell lines NCI-H720 and NCI-H727 were treated with PI3K inhibitor BYL719 (alpelisib), mTOR inhibitor everolimus and SSA lanreotide to determine the effect on NET differentiation markers, cell survival, proliferation and alterations in cancer-associated pathways. NT-3 cells, previously reported to express somatostatin receptors (SSTRs) natively, were used as control for SSTR expression. Results: SSTR2 was upregulated in NCI-H720 and NT-3 cells upon treatment with BYL719. Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner. Production of proteins activating cell death mechanisms was also induced. Notably, a multiplexed gene expression analysis performed on NCI-H720 revealed that BYL719 plus lanreotide had a stronger effect on the downregulation of mitogens than lanreotide alone. Discussion/Conclusion: We report a widespread analysis of changes in BP-NET cell lines at the genetic/protein expression level in response to combination of lanreotide with pretreatment consisting of BYL719 and everolimus. Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.

Type of anesthesia for cancer resection surgery: No differential impact on cancer recurrence in mouse models of breast cancer.

BACKGROUND: Surgery is essential for curative treatment of solid tumors. Evidence from recent retrospective clinical analyses suggests that use of propofol-based total intravenous anesthesia during cancer resection surgery is associated with improved overall survival compared to inhaled volatile anesthesia. Evaluating these findings in prospective clinical studies is required to inform definitive clinical guidelines but will take many years and requires biomarkers to monitor treatment effect. Therefore, we examined the effect of different anesthetic agents on cancer recurrence in mouse models of breast cancer with the overarching goal of evaluating plausible mechanisms that could be used as biomarkers of treatment response. METHODS: To test the hypothesis that volatile anesthesia accelerates breast cancer recurrence after surgical resection of the primary tumor, we used three mouse models of breast cancer. We compared volatile sevoflurane anesthesia with intravenous propofol anesthesia and used serial non-invasive bioluminescent imaging to track primary tumor recurrence and metastatic recurrence. To determine short-term perioperative effects, we evaluated the effect of anesthesia on vascular integrity and immune cell changes after surgery in animal models. RESULTS: Survival analyses found that the kinetics of cancer recurrence and impact on survival were similar regardless of the anesthetic agent used during cancer surgery. Vascular permeability, immune cell infiltration and cytokine profiles showed no statistical difference after resection with inhaled sevoflurane or intravenous propofol anesthesia. CONCLUSIONS: These preclinical studies found no evidence that choice of anesthetic agent used during cancer resection surgery affected either short-term perioperative events or long-term cancer outcomes in mouse models of breast cancer. These findings raise the possibility that mouse models do not recapitulate perioperative events in cancer patients. Nonetheless, the findings suggest that future evaluation of effects of anesthesia on cancer outcomes should focus on cancer types other than breast cancer.

Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: Results from a German real-world cohort.

BACKGROUND AND AIMS: Phase III trials have established atezolizumab plus bevacizumab as the novel standard of care for patients with unresectable hepatocellular carcinoma (HCC). However, these trials raised concerns regarding treatment efficacy in non-viral HCC, and it remains unclear whether combination immunotherapy is safe and effective in patients with advanced cirrhosis. METHODS: One hundred patients with unresectable HCC initiated therapy with atezolizumab plus bevacizumab at our centre between January 2020 and March 2022. The control cohort consisted of 80 patients with advanced HCC who received either sorafenib (n = 43) or lenvatinib (n = 37) as systemic treatment. RESULTS: Overall survival (OS) and progression-free survival (PFS) were significantly longer within the atezolizumab/bevacizumab group and comparable to phase III data. The benefits in terms of increased objective response rate (ORR), OS and PFS were consistent across subgroups, including non-viral HCC (58%). The ROC-optimised neutrophil-to-lymphocyte ratio (NLR) cut-off of 3.20 was the strongest independent predictor of ORR and PFS. In patients with advanced cirrhosis Child-Pugh B, liver function was significantly better preserved with immunotherapy. Patients with Child-Pugh B cirrhosis showed similar ORR but shorter OS and PFS compared to patients with preserved liver function. CONCLUSIONS: Atezolizumab plus bevacizumab showed good efficacy and safety in patients with unresectable HCC and partially advanced liver cirrhosis in a real-world setting. Moreover, the NLR was able to predict response to atezolizumab/bevacizumab treatment and may guide patient selection.

High-Sensitivity Cardiac Troponin T in Patients with Severe Chronic Kidney Disease and Suspected Acute Coronary Syndrome.

(1) Background: Patients with severe chronic kidney disease (CKD G4-G5) often have chronically elevated high-sensitivity cardiac troponin T (hs-cTnT) values above the 99th percentile of the upper reference limit. In these patients, optimal cutoff levels for diagnosing non-ST-elevation acute coronary syndrome (NSTE-ACS) requiring revascularization remain undefined. (2) Methods: Of 11,912 patients undergoing coronary angiography from 2012 to 2017 for suspected NSTE-ACS, 325 (3%) had severe CKD. Of these, 290 with available serial hs-cTnT measurements were included, and 300 matched patients with normal renal function were selected as a control cohort. (3) Results: In the CKD cohort, 222 patients (76%) had NSTE-ACS with indication for coronary revascularization. Diagnostic performance was high at presentation and similar to that of the control population (AUC, 95% CI: 0.81, 0.75-0.87 versus 0.85, 0.80-0.89, p = 0.68), and the ROC-derived cutoff value was 4 times higher compared to the conventional 99th percentile. Combining the ROC-derived cutoff levels for hs-cTnT at presentation and absolute 3 h changes, sensitivity increased to 98%, and PPV and NPV improved up to 93% and 86%, respectively. (4) Conclusions: In patients with severe CKD and suspected ACS, the diagnostic accuracy of hs-cTnT for the diagnosis of NSTE-ACS requiring revascularization is improved by using higher assay-specific cutoff levels combined with early absolute changes.

The APAC Score: A Novel and Highly Performant Serological Tool for Early Diagnosis of Hepatocellular Carcinoma in Patients with Liver Cirrhosis.

(1) Background: Surveillance of at-risk patients for hepatocellular carcinoma (HCC) is highly necessary, as curative treatment options are only feasible in early disease stages. However, to date, screening of patients with liver cirrhosis for HCC mostly relies on suboptimal ultrasound-mediated evaluation and α-fetoprotein (AFP) measurement. Therefore, we sought to develop a novel and blood-based scoring tool for the identification of early-stage HCC. (2) Methods: Serum samples from 267 patients with liver cirrhosis, including 122 patients with HCC and 145 without, were collected. Expression levels of soluble platelet-derived growth factor receptor beta (sPDGFRß) and routine clinical parameters were evaluated, and then utilized in logistic regression analysis. (3) Results: We developed a novel serological scoring tool, the APAC score, consisting of the parameters age, sPDGFRß, AFP, and creatinine, which identified patients with HCC in a cirrhotic population with an AUC of 0.9503, which was significantly better than the GALAD score (AUC: 0.9000, p = 0.0031). Moreover, the diagnostic accuracy of the APAC score was independent of disease etiology, including alcohol (AUC: 0.9317), viral infection (AUC: 0.9561), and NAFLD (AUC: 0.9545). For the detection of patients with (very) early (BCLC 0/A) HCC stage or within Milan criteria, the APAC score achieved an AUC of 0.9317 (sensitivity: 85.2%, specificity: 89.2%) and 0.9488 (sensitivity: 91.1%, specificity 85.3%), respectively. (4) Conclusions: The APAC score is a novel and highly accurate serological tool for the identification of HCC, especially for early stages. It is superior to the currently proposed blood-based algorithms, and has the potential to improve surveillance of the at-risk population.

An In Vivo Mouse Model of Total Intravenous Anesthesia during Cancer Resection Surgery.

Anesthesia is a routine component of cancer care that is used for diagnostic and therapeutic procedures. The anesthetic technique has recently been implicated in impacting long-term cancer outcomes, possibly through modulation of adrenergic-inflammatory responses that impact cancer cell behavior and immune cell function. Emerging evidence suggests that propofol-based total intravenous anesthesia (TIVA) may be beneficial for long-term cancer outcomes when compared to inhaled volatile anesthesia. However, the available clinical findings are inconsistent. Preclinical studies that identify the underlying mechanisms involved are critically needed to guide the design of clinical studies that will expedite insight. Most preclinical models of anesthesia have been extrapolated from the use of anesthesia in in vivo research and are not optimally designed to study the impact of anesthesia itself as the primary endpoint. This paper describes a method for delivering propofol-TIVA anesthesia in a mouse model of breast cancer resection that replicates key aspects of clinical delivery in cancer patients. The model can be used to study mechanisms of action of anesthesia on cancer outcomes in diverse cancer types and can be extrapolated to other non-cancer areas of preclinical anesthesia research.

Atezolizumab and bevacizumab-induced encephalitis in advanced hepatocellular carcinoma: Case report and literature review.

INTRODUCTION: On the basis of the results of the IMBRAVE-150 trial, the combination of atezolizumab, a programmed cell death ligand 1 (PD-L1) antibody, as well as bevacizumab, a vascular endothelial growth factor (VEGF) antibody, represents a promising novel first-line therapy in patients with advanced hepatocellular carcinoma (HCC). Despite favorable safety data, serious adverse events have been described. However, central nervous system complications such as encephalitis have rarely been reported. We present the case of a 70-year-old woman with hepatitis C virus (HCV)-related liver cirrhosis and advanced HCC who developed severe encephalitis after only one cycle of atezolizumab/bevacizumab. PATIENT CONCERNS: Ten days after administration, the patient presented with confusion, somnolence, and emesis. Within a few days, the patient's condition deteriorated, and mechanical ventilation became necessary. DIAGNOSIS: Cerebrospinal fluid (CSF) analysis showed increased cell count and elevated protein values. Further work-up revealed no signs of an infectious, paraneoplastic, or other autoimmune cause. INTERVENTION: Suspecting an atezolizumab/bevacizumab-related encephalitis, we initiated a high-dose steroid pulse therapy as well as repeated plasmapheresis, which resulted in clinical improvement and remission of CSF abnormalities. OUTCOME: Despite successful weaning and transfer to a rehabilitation ward, the patient died of progressive liver cancer 76 days after initial treatment with atezolizumab/bevacizumab, showing no response. CONCLUSION: This case illustrates that rapid immunosuppressive treatment with prednisolone can result in remission even of severe encephalitis. We discuss this case in the context of available literature and previously reported cases of atezolizumab-induced encephalitis in different tumor entities, highlighting the diagnostic challenges in oncologic patients treated with immune checkpoint-inhibitors.

Lessons From Immune Checkpoint Inhibitor Trials in Hepatocellular Carcinoma.

The implementation of immune checkpoint inhibitors (ICI) into the clinical management of different malignancies has largely changed our understanding of cancer treatment. After having proven efficacy in different tumor entities such as malignant melanoma and lung cancer, ICI were intensively tested in the setting of hepatocellular carcinoma (HCC). Here they could achieve higher and more durable response rates compared to tyrosine-kinase inhibitors (TKI), that were sole standard of care for the last decade. Most recently, ICI treatment was approved in a first line setting of HCC, for cases not suitable for curative strategies. However, only a subset of patients benefits from ICI therapy, while others experience rapid tumor progression, worsening of liver function and poor prognosis. Efforts are being made to find immune characteristics that predict tumor responsiveness to ICI, but no reliable biomarker could be identified so far. Nevertheless, data convincingly demonstrate that combination therapies (such as dual inhibition of PD-L1 and VEGF) are more effective than the application of single agents. In this review, we will briefly recapitulate the current algorithms for systemic treatment, discuss available results from checkpoint inhibitor trials and give an outlook on future directions of immunotherapy in HCC.

Head-related transfer function recommendation based on perceptual similarities and anthropometric features.

Individualization of head-related transfer functions (HRTFs) can improve the quality of binaural applications with respect to the localization accuracy, coloration, and other aspects. Using anthropometric features (AFs) of the head, neck, and pinna for individualization is a promising approach to avoid elaborate acoustic measurements or numerical simulations. Previous studies on HRTF individualization analyzed the link between AFs and technical HRTF features. However, the perceptual relevance of specific errors might not always be clear. Hence, the effects of AFs on perceived perceptual qualities with respect to the overall difference, coloration, and localization error are directly explored. To this end, a listening test was conducted in which subjects rated differences between their own HRTF and a set of nonindividual HRTFs. Based on these data, a machine learning model was developed to predict the perceived differences using ratios of a subject's individual AFs and those of presented nonindividual AFs. Results show that perceived differences can be predicted well and the HRTFs recommended by the models provide a clear improvement over generic or randomly selected HRTFs. In addition, the most relevant AFs for the prediction of each type of error were determined. The developed models are available under a free cultural license.

Prediction of speech intelligibility using pseudo-binaural room impulse responses.

Head orientation (HO) affects better-ear-listening and spatial-release-from-masking, which are two key aspects in binaural speech intelligibility. To incorporate HO in speech intelligibility prediction, binaural room impulse responses (BRIRs) for every HO of interest could be used. Due to the limited spectral bandwidth of speech, however, approximate representations might be sufficient, which can be measured more quickly. A comparison was done between pseudo-BRIRs generated with a motion tracked binaural microphone array and a first order Ambisonics microphone using the spatial decomposition method (SDM). The accuracy of the Ambisonics/SDM approach was comparable to that of real BRIRs, indicating its suitability for speech intelligibility prediction.

A round robin on room acoustical simulation and auralization.

A round robin was conducted to evaluate the state of the art of room acoustic modeling software both in the physical and perceptual realms. The test was based on six acoustic scenes highlighting specific acoustic phenomena and for three complex, "real-world" spatial environments. The results demonstrate that most present simulation algorithms generate obvious model errors once the assumptions of geometrical acoustics are no longer met. As a consequence, they are neither able to provide a reliable pattern of early reflections nor do they provide a reliable prediction of room acoustic parameters outside a medium frequency range. In the perceptual domain, the algorithms under test could generate mostly plausible but not authentic auralizations, i.e., the difference between simulated and measured impulse responses of the same scene was always clearly audible. Most relevant for this perceptual difference are deviations in tone color and source position between measurement and simulation, which to a large extent can be traced back to the simplified use of random incidence absorption and scattering coefficients and shortcomings in the simulation of early reflections due to the missing or insufficient modeling of diffraction.

Segmentation of binaural room impulse responses for speech intelligibility prediction.

The two most important aspects in binaural speech perception-better-ear-listening and spatial-release-from-masking-can be predicted well with current binaural modeling frameworks operating on head-related impulse responses, i.e., anechoic binaural signals. To incorporate effects of reverberation, a model extension was proposed, splitting binaural room impulse responses into an early, useful, and late, detrimental part, before being fed into the modeling framework. More recently, an interaction between the applied splitting time, room properties, and the resulting prediction accuracy was observed. This interaction was investigated here by measuring speech reception thresholds (SRTs) in quiet with 18 normal-hearing subjects for four simulated rooms with different reverberation times and a constant room geometry. The mean error with one of the most promising binaural prediction models could be reduced by about 1 dB by adapting the applied splitting time to room acoustic parameters. This improvement in prediction accuracy can make up a difference of 17% in absolute intelligibility within the applied SRT measurement paradigm.

On the authenticity of individual dynamic binaural synthesis.

A simulation that is perceptually indistinguishable from the corresponding real sound field could be termed authentic. Using binaural technology, such a simulation would theoretically be achieved by reconstructing the sound pressure at a listener's ears. However, inevitable errors in the measurement, rendering, and reproduction introduce audible degradations, as it has been demonstrated in previous studies for anechoic environments and static binaural simulations (fixed head orientation). The current study investigated the authenticity of individual dynamic binaural simulations for three different acoustic environments (anechoic, dry, wet) using a highly sensitive listening test design. The results show that about half of the participants failed to reliably detect any differences for a speech stimulus, whereas all participants were able to do so for pulsed pink noise. Higher detection rates were observed in the anechoic condition, compared to the reverberant spaces, while the source position had no significant effect. It is concluded that the authenticity mainly depends on how comprehensive the spectral cues are provided by the audio content, and the amount of reverberation, whereas the source position plays a minor role. This is confirmed by a broad qualitative evaluation, suggesting that remaining differences mainly affect the tone color rather than the spatial, temporal or dynamical qualities.

Spectral equalization in binaural signals represented by order-truncated spherical harmonics.

The synthesis of binaural signals from spherical microphone array recordings has been recently proposed. The limited spatial resolution of the reproduced signal due to order-limited reproduction has been previously investigated perceptually, showing spatial perception ramifications, such as poor source localization and limited externalization. Furthermore, this spatial order limitation also has a detrimental effect on the frequency content of the signal and its perceived timbre, due to the rapid roll-off at high frequencies. In this paper, the underlying causes of this spectral roll-off are described mathematically and investigated numerically. A digital filter that equalizes the frequency spectrum of a low spatial order signal is introduced and evaluated. A comprehensive listening test was conducted to study the influence of the filter on the perception of the reproduced sound. Results indicate that the suggested filter is beneficial for restoring the timbral composition of order-truncated binaural signals, while conserving, and even improving, some spatial properties of the signal.