Early response monitoring during [177Lu]Lu-PSMA I&T therapy with quantitated SPECT/CT predicts overall survival of mCRPC patients: subgroup analysis of a Swiss-wide prospective registry study.

PURPOSE: To assess early tumor response with quantitated SPECT/CT and to correlate it with clinical outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with 177Lutetium-PSMA I&T therapy. METHODS: Single-center, observational study, part of the prospective Swiss national cancer registry study investigating the safety and efficacy of [177Lu]Lu-PSMA I&T (EKNZ: 2021-01271) in mCRPC patients treated with at least two cycles of [177Lu]Lu-PSMA I&T 6-weekly. After the first and second cycle quantitated SPECT/CT (Symbia Intevo, Siemens) was acquired 48 h after injection (three fields of view from head to thigh, 5 s/frame) and reconstructed using xQuant® (48i, 1 s, 10-mm Gauss). Image analysis: The PSMA-positive total tumor volumes (TTV) were semi-automatically delineated using a SUV threshold of 3 with MIMencore® (version 7.1.3, Medical Image Merge Software Inc.). Changes in TTV, highest tumor SUVmax, and total tumor SUVmean between cycles 1 and 2 were calculated and grouped into a) stable or decrease and b) increase. Serum PSA levels were assessed at each therapy cycle and at follow-up until progression or death. Changes in TTV, PSA, SUVmax, and SUVmean were correlated with PSA-progression-free survival (PSA-PFS) and the overall survival (OS) using the Kaplan-Meier methodology (log-rank test). RESULTS: Between 07/2020 and 04/2022, 111 patients were screened and 73 finally included in the data analysis. The median follow-up was 8.9 months (range 1.4-26.6 months). Stable or decreased TTV at cycle 2 was associated with longer OS (hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.09-0.86, p < 0.01). Similar, stable, or decreased PSA was associated with longer OS (HR 0.21; CI 0.07-0.62, p < 0.01) and PSA-PFS (HR 0.34; 95% CI 0.16-0.72, p < 0.01). Combining TTV and PSA will result in an augmented prognostic value for OS (HR 0.09; CI 0.01-0.63; p < 0.01) and for PSA-PFS (HR 0.11; CI 0.02-0.68; p < 0.01). A reduction of SUVmax or SUVmean was not prognostically relevant, neither for OS (p 0.88 and 0.7) nor for PSA-PFS (p 0.73 and 0.62, respectively). CONCLUSION: Six weeks after initiating [177Lu]Lu-PSMA I&T, TTV and serum PSA appear to be good prognosticators for OS. Combined together, TTV + PSA change demonstrates augmented prognostic value and can better predict PSA-PFS. Larger studies using TTV change prospectively as an early-response biomarker are warranted for implementing management change towards a more personalized clinical practice.

DMA of TPU Films and the Modelling of Their Viscoelastic Properties for Noise Reduction in Jet Engines.

Due to current developments in jet engine design, the acoustic performance of conventional acoustic liners needs to be improved with respect to lower frequency spectrums and broadband absorption. In this context, the present study aimed to determine the viscoelastic material properties of a thermoplastic polyurethane (TPU) film for targeted application in novel acoustic liners with integrated film material for enhanced noise reduction. Therefore, a dynamic mechanical analysis (DMA) was performed to determine these viscoelastic material properties. Based on the acquired data, the time-temperature shift (TTS) was applied to obtain the material's temperature- and frequency-dependent mechanical properties. In this regard, the William-Landel-Ferry (WLF) method and an alternative polynomial approach determining the shift factors were investigated and compared. Furthermore, a generalized Maxwell model-so-called Prony-series-with and without pre-smoothing utilizing of a fractional rheological model was applied to approximate the measured storage and loss modulus and to provide a material model that can be used in finite element analyses. Finally, the results were discussed concerning the application of the films in acoustic liners under the conditions of a standard flight cycle and the applied loads. The present investigations thus provide a method for characterizing polymer materials, approximating their mechanical behavior for vibration applications at different ambient temperatures and enabling the identification of their operational limits during the application in acoustic liners.

Material Selection Process for Acoustic and Vibration Applications Using the Example of a Plate Resonator.

In this work, a new method for selecting suitable materials is presented. This method has a high potential for a variety of engineering applications, such as the design of sound-absorbing and vibration-loaded structures, where a large number of different requirements have to be met. The method is based on the derivation of functional dependencies of selected material parameters. These dependencies can be used in parameter studies to consider parameter combinations that lie in the range of real existing and targeted material groups. This allows the parameter space to be reduced, the calculation to be accelerated, and suitable materials to be (pre-)selected for the respective application, which contributes to a more target-oriented design. The method is applied to the example of a plate resonator. For this purpose, a semi-analytical model is implemented to calculate the transmission loss as well as the reflected and dissipated sound power of plate silencers, taking into account the influence of flow velocity and fluid temperature on the performance of plate silencers.

Analysis of a Film Forming Process through Coupled Image Correlation and Infrared Thermography.

The aim of the present investigation was to determine the dependence of the material and process parameters of the bending process of thermoplastic films. In this context, parameter combinations leading to high resulting forming ratios were identified. To measure the relevant parameters within the hot bending process, a coupled evaluation of infrared thermography (IRT) and deformation measurement using digital image correlation (DIC) was performed. The coupled measurement enables the identification of the actual mechanically stressed bending area of the film as a result of the bending process. This allows for the specification of the local forming temperatures required for the desired forming ratios. Furthermore, the mechanical and thermal strain along the defined measuring sections and their deviation in individual tests as well as the effect of thermal strain on process control on a larger scale were determined. Based on the results, a process window was defined for the film materials investigated, which will serve as a starting point for future efforts to develop a continuous manufacturing process.

Development of a Function-Integrative Sleeve for Medical Applications.

Function-integrative textiles bear the potential for a variety of applications in the medical field. Recent clinical investigations suggest that the application of a function-integrative fabric could have a positive impact on currently applied diagnostic procedures of a specific type of tumour. In this context, the fabric should enable local warming of a patient's upper extremity as well as blood flow measurement. Existing solutions comprise a warming a warming system but lack a measuring apparatus for blood flow determination. With regard to the quality of results of current diagnostic procedures, the local warming of the patients' upper extremity and the simultaneous determination of the blood flow plateau are crucial. In the present paper, the development process of a function-integrative sleeve is introduced. Besides the development of an adaptable sleeve-design, the manufacturing process of an integrated warming system was also addressed. Furthermore, the identification of crucial physiological effects, using a Laser Doppler Perfusion Monitor, is introduced. During testing of the function-integrative sleeve, modulation of the desired physiological effects was observed. The results support the initial assumptions and dictate further investigations on increasing user-friendliness and cost-efficiency during adjusting and determining the physiological effects in the course of tumour diagnosis.

Targeting cyclin-dependent kinases for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease with poor prognosis and limited therapeutic options. We screened for pathways that may be responsible for the abnormal phenotype of pulmonary arterial smooth muscle cells (PASMCs), a major contributor of PAH pathobiology, and identified cyclin-dependent kinases (CDKs) as overactivated kinases in specimens derived from patients with idiopathic PAH. This increased CDK activity is confirmed at the level of mRNA and protein expression in human and experimental PAH, respectively. Specific CDK inhibition by dinaciclib and palbociclib decreases PASMC proliferation via cell cycle arrest and interference with the downstream CDK-Rb (retinoblastoma protein)-E2F signaling pathway. In two experimental models of PAH (i.e., monocrotaline and Su5416/hypoxia treated rats) palbociclib reverses the elevated right ventricular systolic pressure, reduces right heart hypertrophy, restores the cardiac index, and reduces pulmonary vascular remodeling. These results demonstrate that inhibition of CDKs by palbociclib may be a therapeutic strategy in PAH.