Predictive Value of Multiparametric MRI for Response to Single-Cycle Induction Chemo-Immunotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma.

OBJECTIVES: To assess the predictive value of multiparametric MRI for treatment response evaluation of induction chemo-immunotherapy in locally advanced head and neck squamous cell carcinoma. METHODS: Twenty-two patients with locally advanced, histologically confirmed head and neck squamous cell carcinoma who were enrolled in the prospective multicenter phase II CheckRad-CD8 trial were included in the current analysis. In this unplanned secondary single-center analysis, all patients who received contrast-enhanced MRI at baseline and in week 4 after single-cycle induction therapy with cisplatin/docetaxel combined with the immune checkpoint inhibitors tremelimumab and durvalumab were included. In week 4, endoscopy with representative re-biopsy was performed to assess tumor response. All lesions were segmented in the baseline and restaging multiparametric MRI, including the primary tumor and lymph node metastases. The volume of interest of the respective lesions was volumetrically measured, and time-resolved mean intensities of the golden-angle radial sparse parallel-volume-interpolated gradient-echo perfusion (GRASP-VIBE) sequence were extracted. Additional quantitative parameters including the T1 ratio, short-TI inversion recovery ratio, apparent diffusion coefficient, and dynamic contrast-enhanced (DCE) values were measured. A model based on parallel random forests incorporating the MRI parameters from the baseline MRI was used to predict tumor response to therapy. Receiver operating characteristic (ROC) curves were used to evaluate the prognostic performance. RESULTS: Fifteen patients (68.2%) showed pathologic complete response in the re-biopsy, while seven patients had a residual tumor (31.8%). In all patients, the MRI-based primary tumor volume was significantly lower after treatment. The baseline DCE parameters of time to peak and wash-out were significantly different between the pathologic complete response group and the residual tumor group (p < 0.05). The developed model, based on parallel random forests and DCE parameters, was able to predict therapy response with a sensitivity of 78.7% (95% CI 71.24-84.93) and a specificity of 78.6% (95% CI 67.13-87.48). The model had an area under the ROC curve of 0.866 (95% CI 0.819-0.914). CONCLUSIONS: DCE parameters indicated treatment response at follow-up, and a random forest machine learning algorithm based on DCE parameters was able to predict treatment response to induction chemo-immunotherapy.

Morphological, functional, and molecular assessment of breast cancer bone metastases by experimental ultrasound techniques compared with magnetic resonance imaging and histological analysis.

BACKGROUND: The imaging of bone metastases, which is regularly performed by cross-sectional modalities, is clinically vital when characterizing and staging osseous lesions. In this paper, we aimed to establish a novel methodology using experimental ultrasound (US) techniques to assess the morphological, functional, and molecular features of breast cancer bone metastases in an animal model, compared with magnetic resonance imaging (MRI) and histological analysis. MATERIALS AND METHODS: Nude rats were implanted intra-arterially with MDA-MB-231 breast cancer cells to induce osteolytic metastasis in their right hind legs. Once tumors had developed, an experimental US technique using automatic 3D scanning and MRI were performed. For assessment of perfusion, functional imaging techniques included contrast-enhanced US (CEUS) and dynamic contrast-enhanced MRI (DCE-MRI). For molecular ultrasound, anti-VEGFR2 conjugated microbubbles were applied and correlated with immunostaining for VEGFR2 expression. RESULTS: 3D US enabled the automatic assessment of osteolytic lesions, including the largest tumor diameters along the x-, y- and z-axes as well as the segmented tumor volumes, without significant differences between US and MRI (p > 0.18). The CEUS and DCE-MRI of osseous lesions showed corresponding results for the parameters peak enhancement, wash-in area under the curve (both, r > 0.5) and wash-in perfusion index (r > 0.3) when differentiating between tumor, necrotic tissue and healthy muscle tissue (all, p < 0.01). Finally, molecular US allowed the non-invasive assessment of increased VEGFR2 expression in skeletal lesions compared with surrounding muscle tissue (p = 0.03), while a control antibody could not discriminate between these tissues (p = 0.44)-a factor which was confirmed by histological analysis. CONCLUSION: To the best of our knowledge, this is the first report on an imaging protocol for breast cancer bone metastasis using an experimental US scanner. Therefore, we present a novel methodology to characterize these osseous lesions on the morphological, functional, and molecular level in correlation with MRI and histological analysis.

Eligibility of Endovascular Repair for Popliteal Artery Aneurysms According the Instructions for Use.

BACKGROUND: Popliteal artery aneurysms (PAAs) are the most common peripheral aneurysms. Although rare and often asymptomatic, there is a significant risk of thrombosis, embolism, and limb loss. The aim of this study was to evaluate the eligibility for endovascular repair of patients treated for symptomatic and asymptomatic PAAs in accordance with the instructions for use (IFU). METHODS: All patients treated for PAA with open surgical repair between the years 2010 and 2017 were analyzed if suitable for endovascular treatment. Preoperative imaging was reviewed for applicability with an interventional radiologist and 2 vascular surgeons. Evaluation was performed in accordance with the following criteria adopted from the IFU of the Gore ® Viabahn stent graft: at least a single-vessel tibial runoff, proximal and distal landing zone more than 2 cm, no large difference in vessel diameter proximal and distal to the aneurysm, no overstenting of significant collaterals necessary, and no inadequate kinking of the artery. The patients were classified in 3 categories: the patient was eligible, endovascular treatment was feasible, and endovascular treatment was not appropriate. RESULTS: 51 patients with 61 symptomatic and asymptomatic PAAs were identified. Forty-five cases were asymptomatic, 11 cases showed clinical symptoms such as claudication, and in 5 cases, the patients presented with acute ischemia. Twenty-four patients were eligible for endovascular intervention, 14 cases were feasible, and in 23 cases, it was not appropriate in accordance with the IFU. CONCLUSIONS: In this study, more than one-third of the patients with PAA were not eligible for endovascular treatment in accordance with the IFU and another 23 % showed substantial reasons against endovascular treatment. These data suggest that endovascular repair remains a treatment option for selected patients only. Cross-sectional imaging is mandatory for procedure selection.

Major vascular complications after transfemoral arterial closure system implantation: a single-center study.

BACKGROUND: During the past decades, the use of vascular closure devices (VCDs) has been established due to the increasing number of interventions. Of particular concern is the perceived risk of VCDs for development of implant-induced vascular major complications. Therefore, the aim of this analysis was to report the variety of vascular access side complications after the use of VCDs, and to analyze the referred risk factors. METHODS: All cases of vascular complications associated with VCD use requiring surgical repair from 2010 to 2016 were retrospectively analyzed in a single center trial. Systemic and local complications, risk factors as pre-existing diseases and their influence on the surgical outcome were evaluated. RESULTS: A total of 46 individuals were included in this study (male/female: 16/30). The total number of interventions in the involved departments of the study center during the same period was 9754 Therefore the complication rate after VCD implantation was 0.47%. The detected complications ranged from symptomatic claudication (N.=24) to acute leg ischemia (N.=19) and major bleeding (N.=3). Surgical reconstruction was performed by direct suture (N.=4), transverse arteriotomy with thrombectomy (N.=2), endarterectomy with patchplasty (N.=35), inguinal graft interposition or bypass (N.=3) and primary major amputation (N.=2). In regard to the risk factors, the study has concluded that atherosclerosis, female gender and diabetes mellitus are correlated with major vascular complications (bleeding and limb ischemia). However, in cases with therapeutic anticoagulation the rate of major bleeding was significantly elevated (P=0.028). CONCLUSIONS: Reported complication rates associated with femoral VCD implantation are low. However, in some cases VCD implantation may account for severe complications including limb losses. Therefore, an adequate patient selection is necessary to detect those cases at higher risk for complications.

Neurogranin and YKL-40: independent markers of synaptic degeneration and neuroinflammation in Alzheimer's disease.

INTRODUCTION: Neuroinflammation and synaptic degeneration are major neuropathological hallmarks in Alzheimer's disease (AD). Neurogranin and YKL-40 in cerebrospinal fluid (CSF) are newly discovered markers indicating synaptic damage and microglial activation, respectively. METHODS: CSF samples from 95 individuals including 39 patients with AD dementia (AD-D), 13 with mild cognitive impairment (MCI) due to AD (MCI-AD), 29 with MCI not due to AD (MCI-o) and 14 patients with non-AD dementias (non-AD-D) were analyzed for neurogranin and YKL-40. RESULTS: Patients with dementia or MCI due to AD showed elevated levels of CSF neurogranin (p < 0.001 for AD-D and p < 0.05 for MCI-AD) and YKL-40 (p < 0.05 for AD-D and p = 0.15 for MCI-AD) compared to mildly cognitively impaired subjects not diagnosed with AD. CSF levels of neurogranin and YKL-40 did not differ between MCI not due to AD and non-AD dementias. In AD subjects no correlation between YKL-40 and neurogranin was found. The CSF neurogranin levels correlated moderately with tau and p-tau but not with Aß42 or the MMSE in AD samples. No relevant associations between YKL-40 and MMSE or the core AD biomarkers, Aß42, t-tau and p-tau were found in AD subjects. CONCLUSIONS: Neurogranin and YKL-40 are promising AD biomarkers, independent of and complementary to the established core AD biomarkers, reflecting additional pathological changes in the course of AD.

Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer's disease patients and healthy controls.

INTRODUCTION: Synaptic dysfunction and degeneration are central events in Alzheimer's disease (AD) pathophysiology that are thought to occur early in disease progression. Synaptic pathology may be studied by examining protein biomarkers specific for different synaptic elements. We recently showed that the dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 to 76 (Ng48-76), is markedly increased in cerebrospinal fluid (CSF) in AD and that Ng48-76 is the dominant peptide in human brain tissue. The aim of this study was to characterize Ng in plasma and CSF using mass spectrometry and to investigate the performance of plasma Ng as an AD biomarker. METHODS: Paired plasma and CSF samples from patients with AD (n = 25) and healthy controls (n = 20) were analyzed in parallel using an immunoassay developed in-house on the Meso Scale Discovery platform and hybrid immunoaffinity-mass spectrometry (HI-MS). A second plasma material from patients with AD (n = 13) and healthy controls (n = 17) was also analyzed with HI-MS. High-resolution mass spectrometry was used for identification of endogenous plasma Ng peptides. RESULTS: Ng in human plasma is present as several endogenous peptides. Of the 16 endogenous Ng peptides identified, seven were unique for plasma and not detectable in CSF. However, Ng48-76 was not present in plasma. CSF Ng was significantly increased in AD compared with controls (P < 0.0001), whereas the plasma Ng levels were similar between the groups in both studies. Plasma and CSF Ng levels showed no correlation. CSF Ng was stable during storage at -20°C for up to 2 days, and no de novo generation of peptides were detected. CONCLUSIONS: For the first time, to our knowledge, we have identified several endogenous Ng peptides in human plasma. In agreement with previous studies, we show that CSF Ng is significantly increased in AD as compared with healthy controls. The origin of Ng in plasma and its possible use as a biomarker need to be further investigated. The results suggest that CSF Ng, in particular Ng48-76, might reflect the neurodegenerative processes within the brain, indicating a role for Ng as a potential novel clinical biomarker for synaptic function in AD.