Molecular insights into disease-associated glutamate transporter (EAAT1 / SLC1A3) variants using in silico and in vitro approaches.

Glutamate is an essential excitatory neurotransmitter and an intermediate for energy metabolism. Depending on the tumor site, cancer cells have increased or decreased expression of excitatory amino acid transporter 1 or 2 (EAAT1/2, SLC1A3/2) to regulate glutamate uptake for the benefit of tumor growth. Thus, EAAT1/2 may be an attractive target for therapeutic intervention in oncology. Genetic variation of EAAT1 has been associated with rare cases of episodic ataxia, but the occurrence and functional contribution of EAAT1 mutants in other diseases, such as cancer, is poorly understood. Here, 105 unique somatic EAAT1 mutations were identified in cancer patients from the Genomic Data Commons dataset. Using EAAT1 crystal structures and in silico studies, eight mutations were selected based on their close proximity to the orthosteric or allosteric ligand binding sites and the predicted change in ligand binding affinity. In vitro functional assessment in a live-cell, impedance-based phenotypic assay demonstrated that these mutants differentially affect L-glutamate and L-aspartate transport, as well as the inhibitory potency of an orthosteric (TFB-TBOA) and allosteric (UCPH-101) inhibitor. Moreover, two episodic ataxia-related mutants displayed functional responses that were in line with literature, which confirmed the validity of our assay. Of note, ataxia-related mutant M128R displayed inhibitor-induced functional responses never described before. Finally, molecular dynamics (MD) simulations were performed to gain mechanistic insights into the observed functional effects. Taken together, the results in this work demonstrate 1) the suitability of the label-free phenotypic method to assess functional variation of EAAT1 mutants and 2) the opportunity and challenges of using in silico techniques to rationalize the in vitro phenotype of disease-relevant mutants.

Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood-brain barrier impairment.

Cerebral small vessel disease is characterised by decreased cerebral blood flow and blood-brain barrier impairments which play a key role in the development of white matter lesions. We hypothesised that cerebral hypoperfusion causes local hypoxia, affecting oligodendrocyte precursor cell-endothelial cell signalling leading to blood-brain barrier dysfunction as an early mechanism for the development of white matter lesions. Bilateral carotid artery stenosis was used as a mouse model for cerebral hypoperfusion. Pimonidazole, a hypoxic cell marker, was injected prior to humane sacrifice at day 7. Myelin content, vascular density, blood-brain barrier leakages, and hypoxic cell density were quantified. Primary mouse oligodendrocyte precursor cells were exposed to hypoxia and RNA sequencing was performed. Vegfa gene expression and protein secretion was examined in an oligodendrocyte precursor cell line exposed to hypoxia. Additionally, human blood plasma VEGFA levels were measured and correlated to blood-brain barrier permeability in normal-appearing white matter and white matter lesions of cerebral small vessel disease patients and controls. Cerebral blood flow was reduced in the stenosis mice, with an increase in hypoxic cell number and blood-brain barrier leakages in the cortical areas but no changes in myelin content or vascular density. Vegfa upregulation was identified in hypoxic oligodendrocyte precursor cells, which was mediated via Hif1α and Epas1. In humans, VEGFA plasma levels were increased in patients versus controls. VEGFA plasma levels were associated with increased blood-brain barrier permeability in normal appearing white matter of patients. Cerebral hypoperfusion mediates hypoxia induced VEGFA expression in oligodendrocyte precursor cells through Hif1α/Epas1 signalling. VEGFA could in turn increase BBB permeability. In humans, increased VEGFA plasma levels in cerebral small vessel disease patients were associated with increased blood-brain barrier permeability in the normal appearing white matter. Our results support a role of VEGFA expression in cerebral hypoperfusion as seen in cerebral small vessel disease.

Independent association of metabolic tumor response on FDG-PET with pulmonary toxicity following risk-adaptive chemoradiation for unresectable non-small cell lung cancer: Inherent radiosensitivity or immune response?

BACKGROUND: In the context of a phase II trial of risk-adaptive chemoradiation, we evaluated whether tumor metabolic response could serve as a correlate of treatment sensitivity and toxicity. METHODS: Forty-five patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on the FLARE-RT phase II trial (NCT02773238). [18F]fluorodeoxyglucose (FDG) PET-CT images were acquired prior to treatment and after 24 Gy during week 3. Patients with unfavorable on-treatment tumor response received concomitant boosts to 74 Gy total over 30 fractions rather than standard 60 Gy. Metabolic tumor volume and mean standardized uptake value (SUVmean) were calculated semi-automatically. Risk factors of pulmonary toxicity included concurrent chemotherapy regimen, adjuvant anti-PDL1 immunotherapy, and lung dosimetry. Incidence of CTCAE v4 grade 2+ pneumonitis was analyzed using the Fine-Gray method with competing risks of metastasis or death. Peripheral germline DNA microarray sequencing measured predefined candidate genes from distinct pathways: 96 DNA repair, 53 immunology, 38 oncology, 27 lung biology. RESULTS: Twenty-four patients received proton therapy, 23 received ICI, 26 received carboplatin-paclitaxel, and 17 pneumonitis events were observed. Pneumonitis risk was significantly higher for patients with COPD (HR 3.78 [1.48, 9.60], p = 0.005), those treated with immunotherapy (HR 2.82 [1.03, 7.71], p = 0.043) but not with carboplatin-paclitaxel (HR 1.98 [0.71, 5.54], p = 0.19). Pneumonitis rates were similar among selected patients receiving 74 Gy radiation vs 60 Gy (p = 0.33), proton therapy vs photon (p = 0.60), or with higher lung dosimetric V20 (p = 0.30). Patients in the upper quartile decrease in SUVmean (>39.7%) were at greater risk for pneumonitis (HR 4.00 [1.54, 10.44], p = 0.005) and remained significant in multivariable analysis (HR 3.34 [1.23, 9.10], p = 0.018). Germline DNA gene alterations in immunology pathways were most frequently associated with pneumonitis. CONCLUSION: Tumor metabolic response as measured by mean SUV is associated with increased pneumonitis risk in a clinical trial cohort of NSCLC patients independent of treatment factors. This may be partially attributed to patient-specific differences in immunogenicity.

Utilizing Clinical Trial Data to Assess Timing of Surgical Treatment for Emphysema Patients.

BACKGROUND: Lung volume reduction surgery (LVRS) and medical therapy are 2 available treatment options in dealing with severe emphysema, which is a chronic lung disease. However, or there are currently limited guidelines on the timing of LVRS for patients with different characteristics. OBJECTIVE: The objective of this study is to assess the timing of receiving LVRS in terms of patient outcomes, taking into consideration a patient's characteristics. METHODS: A finite-horizon Markov decision process model for patients with severe emphysema was developed to determine the short-term (5 y) and long-term timing of emphysema treatment. Maximizing the expected life expectancy, expected quality-adjusted life-years, and total expected cost of each treatment option were applied as the objective functions of the model. To estimate parameters in the model, the data provided by the National Emphysema Treatment Trial were used. RESULTS: The results indicate that the treatment timing strategy for patients with upper-lobe predominant emphysema is to receive LVRS regardless of their specific characteristics. However, for patients with non-upper-lobe-predominant emphysema, the optimal strategy depends on the age, maximum workload level, and forced expiratory volume in 1 second level. CONCLUSION: This study demonstrates the utilization of clinical trial data to gain insights into the timing of surgical treatment for patients with emphysema, considering patient age, observable health condition, and location of emphysema. HIGHLIGHTS: Both short-term and long-term Markov decision process models were developed to assess the timing of receiving lung volume reduction surgery in patients with severe emphysema.How clinical trial data can be used to estimate the parameters and obtain short-term results from the Markov decision process model is demonstrated.The results provide insights into the timing of receiving lung volume reduction surgery as a function of a patient's characteristics, including age, emphysema location, maximum workload, and forced expiratory volume in 1 second level.

Characteristics of salivary cortisol and alpha-amylase as psychobiological study outcomes in palliative care research.

BACKGROUND: Psychosocial interventions are rapidly emerging in palliative care. However, randomized trials often fail to provide evidence for their effectiveness with regard to patient-reported outcomes. Stress biomarkers could complement self-report data, but little is known about their feasibility, acceptance, and interpretability. METHODS: Therefore, we designed a randomized crossover trial in which 42 patients in a palliative care unit participated in both a brief mindfulness intervention (MI) and a resting state control condition (CC) on two consecutive afternoons. On each day, we collected four saliva samples in 20-min intervals using Salivettes© to determine salivary cortisol (sCort) and alpha-amylase (sAA) concentration levels. At all measurement points, self-rated well-being and stress as well as cardiovascular markers were assessed. Baseline measurements further included self-rated quality of life and clinician-rated functional status. RESULTS: 78.6% of the patients provided the maximum number of 8 saliva samples and 62.2% reported no subjective difficulties with the sampling procedures. 66.6% (sCort) and 69.6% (sAA) of all possible samples were finally included in the analysis. Xerostomia and nausea were the main reasons for missing data. Higher sCort levels were associated with higher heart rate and lower quality of life, functional status, and heart rate variability. Corticosteroid and sedative medication as well as time since last meal were identified as potential confounders. Regarding reactivity to the MI, we found an overall decrease in sCort levels over time (b = -.03, p = .01), but this effect did not differ significantly between the study conditions (b = .03, p = .21). sAA levels were higher in men than in women. Trajectories over time did not significantly differ between the two conditions (b = -.02, p = .80) and associations with other stress and health-related constructs were weak. CONCLUSIONS: Findings indicate that sCort might serve as a psychobiological outcome in future palliative care trials. However, future research should refine the exact measurement and conceptualization strategies for sCort in palliative care research. High attrition rates should be expected in patients with xerostomia or nausea. TRIAL REGISTRATION: Registered at the German Clinical Trials Registry (DRKS00013135) at 04/12/2017.

Radiation and immune checkpoint inhibitor-mediated pneumonitis risk stratification in patients with locally advanced non-small cell lung cancer: role of functional lung radiomics?

BACKGROUND: Patients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (NSCLC) experience pulmonary toxicity at higher rates than historical reports. Identifying biomarkers beyond conventional clinical factors and radiation dosimetry is especially relevant in the modern cancer immunotherapy era. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in locally advanced NSCLC. METHODS: Patients with locally advanced NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while approximately half received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (size, shape, intensity, texture) were extracted on pre-treatment [99mTc]MAA SPECT/CT perfusion images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAE v4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout. RESULTS: Thirty-nine patients were included in the study and pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69-12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59-0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65-0.88]) or shape feature classes (c-index 0.79 [0.66-0.91]) but did not reach statistical significance compared to benchmark models (p > 0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59-0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R2 = 0.84-1.00), representing surrogates rather than independent predictors of pneumonitis risk. CONCLUSIONS: In patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor therapy for locally advanced NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Results from this novel functional lung radiomics exploratory study can inform future validation studies to refine pneumonitis risk models following combinations of radiation and immunotherapy. Our results support functional lung radiomics as surrogates of COPD for non-invasive monitoring during and after treatment. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis risk stratification in a larger patient population is warranted.

Impedance-Based Phenotypic Readout of Transporter Function: A Case for Glutamate Transporters.

Excitatory amino acid transporters (EAAT/SLC1) mediate Na+-dependent uptake of extracellular glutamate and are potential drug targets for neurological disorders. Conventional methods to assess glutamate transport in vitro are based on radiolabels, fluorescent dyes or electrophysiology, which potentially compromise the cell's physiology and are generally less suited for primary drug screens. Here, we describe a novel label-free method to assess human EAAT function in living cells, i.e., without the use of chemical modifications to the substrate or cellular environment. In adherent HEK293 cells overexpressing EAAT1, stimulation with glutamate or aspartate induced cell spreading, which was detected in real-time using an impedance-based biosensor. This change in cell morphology was prevented in the presence of the Na+/K+-ATPase inhibitor ouabain and EAAT inhibitors, which suggests the substrate-induced response was ion-dependent and transporter-specific. A mechanistic explanation for the phenotypic response was substantiated by actin cytoskeleton remodeling and changes in the intracellular levels of the osmolyte taurine, which suggests that the response involves cell swelling. In addition, substrate-induced cellular responses were observed for cells expressing other EAAT subtypes, as well as in a breast cancer cell line (MDA-MB-468) with endogenous EAAT1 expression. These findings allowed the development of a label-free high-throughput screening assay, which could be beneficial in early drug discovery for EAATs and holds potential for the study of other transport proteins that modulate cell shape.

Prognostic Value of Early Fluorodeoxyglucose-Positron Emission Tomography Response Imaging and Peripheral Immunologic Biomarkers: Substudy of a Phase II Trial of Risk-Adaptive Chemoradiation for Unresectable Non-Small Cell Lung Cancer.

Purpose: We sought to examine the prognostic value of fluorodeoxyglucose-positron emission tomography (PET) imaging during chemoradiation for unresectable non-small cell lung cancer for survival and hypothesized that tumor PET response is correlated with peripheral T-cell function. Methods and Materials: Forty-five patients with American Joint Committee on Cancer version 7 stage IIB-IIIB non-small cell lung cancer enrolled in a phase II trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). Fluorodeoxyglucose-PET was performed before treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactorial radiologic interpretation. PET responders received 60 Gy in 30 fractions, while nonresponders received concomitant boosts to 74 Gy in 30 fractions. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor sequencing, and plasma cytokine analysis were performed. Results: Median follow-up was 18.8 months, 1-year overall survival (OS) 82%, 1-year progression-free survival 53%, and 1-year locoregional control 88%. Higher midtreatment PET total lesion glycolysis was detrimental to OS (1 year 87% vs 63%, P < .001), progression-free survival (1 year 60% vs 26%, P = .044), and locoregional control (1 year 94% vs 65%, P = .012), even after adjustment for clinical/treatment factors. Twenty-nine of 45 patients (64%) were classified as PET responders based on a priori definition. Higher tumor programmed death-ligand 1 expression was correlated with response on PET (P = .017). Higher T-cell receptor richness and clone distribution slope were associated with improved OS (P = .018-0.035); clone distribution slope was correlated with PET response (P = .031). Conclusions: Midchemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral T-cell biomarkers.

Use of extracorporeal membrane oxygenation in non-elective major thoracic surgery for infectious lung abscess.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) support for elective cardiothoracic surgery is well established. In contrast, there are not much data regarding the usefulness and outcome of ECMO in non-elective major lung resections for infectious lung abscess. METHODS: All patients undergoing non-elective major lung surgery for infectious lung abscess at 5 centres in Germany, UK and Spain were enrolled in a prospective database. Malignant disorders and intrathoracic complications of other procedures were excluded. RESULTS: There were 127 patients. The median age was 59 years (interquartile range 18.75). The mean Charlson index of comorbidity was 2.83 (standard deviation 2.57). Surgical procedures were lobectomy (89), pneumectomy (20) and segmentectomy (18). ECMO was used for 10 patients (pneumectomy 2, lobectomy 8) and several more received pre-ECMO treatment. Mortality was 17/127. Intraoperatively no ECMO-associated complications were encountered. EMCO [1/10 vs 16/117; odds ratio (OR): 0.70, 95% confidence interval (CI) 0.08-5.91, P = 0.74] and the extent of pulmonary resection were not associated with higher mortality. Preoperative sepsis (OR: 17.84, 95% CI 2.29-139.28, P < 0.01), preoperative air leak (OR: 13.12, 95% CI 4.10-42.07, P < 0.001), acute renal failure (OR: 7.00, 95% CI 2.19-22.43, P < 0.01) and Charlson index of comorbidity ≥3 (OR: 10.83, 95% CI 2.36-49.71, P < 0.01) were associated with significantly higher mortality. CONCLUSIONS: The application of ECMO is widening the possibilities for successful surgical management of infectious, non-malignant lung abscesses. Particularly, patients with marginal functional operability benefit from the availability and readiness to use ECMO. Mortality is determined by the burden of pre-existent comorbidity, severe sepsis and septic shock.

Hybrid Laparoscopic Versus Open Pancreatoduodenectomy. A Meta-Analysis.

INTRODUCTION: Hybrid laparoscopic techniques have been proposed as a good transition from open to complete minimally invasive approach especially in complex surgical procedures. This meta-analysis aimed to compare the outcomes of hybrid laparoscopic pancreatoduodenectomy versus open pancreatoduodenectomy. METHODS: A systematic literature research was performed according to PRISMA guidelines. A broad search strategy with terms "laparoscopy" and "pancreatoduodenectomy" was used. Included studies were analyzed by quantitative meta-analysis using the metafor package for R software. RESULTS: Of 655 identified articles, 627 were excluded and 28 articles fully assessed, including 14 comparative studies, 8 case series and 6 case reports. Extracted data included intraoperative variables and postoperative outcome parameters. The predefined inclusion criteria were met by 14 comparative studies, and 371 patients were pooled in the meta-analysis. Hybrid laparoscopic pacreatoduodenectomy was associated with significantly longer operative time (I2 0%, p = 0,01, Mean HPD 494,6 min, Mean OPD 421,6 min, WMD 67 min, 95% CI 14-120 min). For all other postoperative outcome parameters, no statistically significant differences were found. A nonsignificant reduction in intraoperative transfusion rate (I2 20%, p = 0,2, proportion HPD 2%, proportion OPD 1,6%, OR 0,44, 95% CI 0,16-1,27) and blood loss (I2 95%, p = 0,1, Mean HPD 397,2 ml, Mean OPD 1017,8 ml, MD - 601 ml, 95% CI - 1311-108) was observed for hybrid pancreatoduodenectomy in comparison to open surgery. CONCLUSIONS: This meta-analysis demonstrates significantly increased operation time for hybrid laparoscopic compared to open pancreatoduodenectomy. Intraoperative variables as well as postoperative parameters and major morbidity were comparable for both techniques. Overall results of this meta-analysis demonstrated the hybrid technique as a safe procedure in high-volume centers offering aspects of a safe transition to fully laparoscopic pancreatoduodenectomy.

Intraoperative conversion and complications in robotic assisted primary and redo gastric bypass surgery.

The rise of robotic assisted surgery in the treatment of morbidly obese patients has enlarged the armamentarium for surgeons involved in bariatric surgery. This in particular is of great advantage not only in primary cases, but also in patients undergoing revisional procedures following preceding upper GI surgery. In the following, our experience with intraoperative conversions and complications in revisional robotic surgery using the Da Vinci robotic system will be reported and compared to primary robotic bypass surgery and the literature. In a 36-month period, a total of 157 minimally invasive bariatric procedures (48 robotic assisted, 109 laparoscopic) were performed. Out of 43 patients receiving a gastric bypass 32 (74%) were performed robotically. Out of these 20 (62.5%) had previous operations (RRBP): one hiatal mesh repair, one open Mason operation, eight gastric band, nine gastric sleeve, one sleeve with fundoplication. The Da Vinci Xi was used for all surgeries. 3/20 (15%) RRBP were converted to open laparotomy because of a huge left liver lobe (1), extreme adhesions (1) and short mesentery (1) (p = 0.631 vs 1/12 RBP). One out of these had to be reoperated for an insufficiency of the gastroenterostomy. 3/17 (23%) patients (RRBP) without conversion had complications: hemorrhage (1), insufficiency of biliodigestive anastomosis (1), insufficiency of gastroenterostomy (1). There was no mortality and length of hospital stay was 3.5 days in uncomplicated cases and 12.3 days in complicated cases (p < 0.05). This preliminary experience suggests, that robotic revisional surgery can be performed safely even in complicated cases. Conversion to laparoscopic or open surgery may be required when adverse anatomical conditions are present. However, the incidence of complications was not increased when conversion was performed. In this series, the incidence of complications was not greater in case of revisional surgery.

Psychoneuroendocrinological effects of music therapy versus mindfulness in palliative care: results from the 'Song of Life' randomized controlled trial.

PURPOSE: Although research on psychosocial interventions in palliative care provided evidence for their effectiveness regarding patient-reported outcomes, few studies have examined their psychobiological effects yet. Therefore, the purpose of the present work as part of an overarching study was to investigate differential effects of music therapy versus mindfulness on subjective distress and both neuroendocrine and autonomic stress biomarkers. METHODS: A total of 104 patients from two palliative care units were randomly assigned to three sessions of either music therapy or mindfulness. Before and after the second session (completed by 89 patients), participants rated their momentary distress and provided three saliva samples for cortisol and α-amylase analysis. Furthermore, photoplethysmography recordings were continuously assessed to calculate mean heart rate and heart rate variability. Data were analyzed using multilevel modeling of all available data and sensitivity analysis with multiply imputed data. RESULTS: Between 67 and 75% of the maximally available data points were included in the primary analyses of psychobiological outcomes. Results showed a significant time*treatment effect on distress (b = - 0.83, p = .02) indicating a greater reduction in the music therapy group. No interaction effects were found in psychobiological outcomes (all p > .05), but multilevel models revealed a significant reduction in cortisol (b = - 0.06, p = .01) and mean heart rate (b = - 7.89, p = .05) over time following either intervention. CONCLUSION: Findings suggest a beneficial effect music therapy on distress while no differential psychobiological treatment effects were found. Future studies should continue to investigate optimal stress biomarkers for psychosocial palliative care research. TRIAL REGISTRATION: German Clinical Trials Register (DRKS)-DRKS00015308 (date of registration: September 7, 2018).

Adaptive Fluorodeoxyglucose-Positron Emission Tomography Based Chemotherapy Selection for Metastatic Non-small Cell Lung Cancer.

Objectives The change in tumor fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) scan after one cycle of platinum-based chemotherapy has been shown to predict progression-free and overall survival (PFS and OS) among advanced non-small cell lung cancer (NSCLC) patients. Using early FDG-PET response to determine subsequent chemotherapy, we aim to evaluate the role that adaptive chemotherapy regimens have on later CT response, PFS, and OS in patients with advanced NSCLC. Materials and Methods Chemotherapy-naïve patients with metastatic NSCLC received carboplatin and paclitaxel (CP) on day one and repeated FDG-PET on day 18. PET-responding patients continued CP chemotherapy for a total of four cycles. PET non-responders were switched to alternate docetaxel and gemcitabine (DG) for three additional cycles. The primary outcome was the CT Response Evaluation Criteria in Solid Tumors (RECIST 1.0) response. Secondary endpoints included PFS and OS. Results  Forty-six patients initiated treatment with chemotherapy on trial and were evaluable by PET/CT. Of these, 19 (41%) met the FDG-PET criteria for the response after a single cycle of CP. Only one non-responding patient had a CT response. Despite the lack of CT response in the DG arm, no trend for worse PFS or OS was seen between the two arms. Conclusions This work demonstrates that changing chemotherapy in the event of non-response by PET did not lead to improved CT RECIST response. However, non-responding patients who switched chemotherapy had similar PFS and OS to those who responded by PET and continued the same regimen.

Reliability of Quantitative 18F-FDG PET/CT Imaging Biomarkers for Classifying Early Response to Chemoradiotherapy in Patients With Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE OF THE REPORT: We evaluated the reliability of 18F-FDG PET imaging biomarkers to classify early response status across observers, scanners, and reconstruction algorithms in support of biologically adaptive radiation therapy for locally advanced non-small cell lung cancer. PATIENTS AND METHODS: Thirty-one patients with unresectable locally advanced non-small cell lung cancer were prospectively enrolled on a phase 2 trial (NCT02773238) and underwent 18F-FDG PET on GE Discovery STE (DSTE) or GE Discovery MI (DMI) PET/CT systems at baseline and during the third week external beam radiation therapy regimens. All PET scans were reconstructed using OSEM; GE-DMI scans were also reconstructed with BSREM-TOF (block sequential regularized expectation maximization reconstruction algorithm incorporating time of flight). Primary tumors were contoured by 3 observers using semiautomatic gradient-based segmentation. SUVmax, SUVmean, SUVpeak, MTV (metabolic tumor volume), and total lesion glycolysis were correlated with midtherapy multidisciplinary clinical response assessment. Dice similarity of contours and response classification areas under the curve were evaluated across observers, scanners, and reconstruction algorithms. LASSO logistic regression models were trained on DSTE PET patient data and independently tested on DMI PET patient data. RESULTS: Interobserver variability of PET contours was low for both OSEM and BSREM-TOF reconstructions; intraobserver variability between reconstructions was slightly higher. ΔSUVpeak was the most robust response predictor across observers and image reconstructions. LASSO models consistently selected ΔSUVpeak and ΔMTV as response predictors. Response classification models achieved high cross-validated performance on the DSTE cohort and more variable testing performance on the DMI cohort. CONCLUSIONS: The variability FDG PET lesion contours and imaging biomarkers was relatively low across observers, scanners, and reconstructions. Objective midtreatment PET response assessment may lead to improved precision of biologically adaptive radiation therapy.

Plasma GDF-15 concentration is not elevated in open-angle glaucoma.

AIM: Recently, the level of growth differentiation factor 15 (GDF-15) in blood, was proposed as biomarker to detect mitochondrial dysfunction. In the current study, we evaluate this biomarker in open-angle glaucoma (OAG), as there is increasing evidence that mitochondrial dysfunction plays a role in the pathophysiology of this disease. METHODS: Plasma GDF-15 concentrations were measured with ELISA in 200 OAG patients and 61 age-matched controls (cataract without glaucoma). The OAG patient group consisted of high tension glaucoma (HTG; n = 162) and normal tension glaucoma (NTG; n = 38). Groups were compared using the Kruskal-Wallis nonparametric test with Dunn's multiple comparison post-hoc correction. GDF-15 concentration was corrected for confounders identified with forward linear regression models. RESULTS: Before correcting for confounders, median plasma GDF-15 levels was significantly lower in the combined OAG group (p = 0.04), but not when analysing HTG and NTG patients separately. Forward linear regression analysis showed that age, gender, smoking and systemic hypertension were significant confounders affecting GDF-15 levels. After correction for these confounders, GDF-15 levels in OAG patients were no longer significantly different from controls. Subgroup analysis of the glaucoma patients did not show a correlation between disease severity and plasma GDF-15, but did reveal that for NTG patients, intake of dietary supplements, which potentially improve mitochondrial function, correlated with lower plasma GDF-15. CONCLUSION: The present study suggests that plasma GDF-15 is not suited as biomarker of mitochondrial dysfunction in OAG patients.

[Hemiarthroplasty for geriatric femoral neck fractures]. / Hemiprothese bei geriatrischer Schenkelhalsfraktur.

OBJECTIVE: Restoration of pain-free joint function by implantation of a bipolar hemiarthroplasty via anterolateral approach. INDICATIONS: Elderly multimorbid patients >70 years, age >80 years, low functional demand. CONTRAINDICATIONS: Infection. Relative contraindications: dysplastic hip joint. SURGICAL TECHNIQUE: Supine position. Anterolateral approach. Incision of the iliotibial tract and entering the interval between tensor fasciae latae muscle/gluteus medius muscle. Capsulotomy. Femoral neck osteotomy. Removal of the femoral head and determination of the size of the bipolar prosthetic head. Inspection of the acetabulum. Adduction, external rotation ("figure 4" position) of the leg. Medullary preparation of the femur with rasps up to the correct level and size of the planed stem. Ensure the correct rotation of anteversion (10-15°). Trial reduction and examination of hip stability. Verification with image intensifier. Cement restrictor, jet lavage, drying the medullary canal, injection of bone cement and insertion of the prosthetic stem. Assembly/attachment of the definitive bipolar head to the stem. Reduction of the joint. Wound closure. POSTOPERATIVE MANAGEMENT: Early mobilization and full weight bearing. Limitation of hip flexion >90°, rotation and adduction for 6 weeks. Venous thromboembolism prophylaxis. Osteoporosis evaluation and management. Clinical-radiological control (after 6 weeks, 1/3/5 years). RESULTS: The implantation of a cemented hemiarthroplasty using the anterolateral approach is a muscle-sparing and dislocation-safe surgical procedure with a low risk of revision, which enables early patient mobilization and a good hip joint function.

"Song of Life": Results of a multicenter randomized trial on the effects of biographical music therapy in palliative care.

BACKGROUND: Awareness for the importance of psychological and spiritual needs in patients with terminal diseases has increased in recent years, but randomized trials on the effects of psychosocial interventions are still rare. AIM: To investigate the efficacy of the "Song of Life" music therapy intervention regarding the emotional and psycho-spiritual dimensions of quality of life. DESIGN: Patients were randomly assigned to either "Song of Life" or a relaxation intervention. "Song of Life" is a novel three-session music therapy intervention working with a biographically meaningful song. Primary outcome was the improvement in psychological quality of life. Secondary outcomes included spiritual well-being, ego-integrity, momentary distress, and global quality of life and the explorative assessment of treatment satisfaction (patient and family member version). Intention-to-treat analysis was conducted including adjustment for multiple testing in secondary outcomes. SETTING/PARTICIPANTS: Between December 2018 and August 2020, 104 patients receiving specialized palliative care were recruited from two palliative care wards. RESULTS: No significant differences were found regarding psychological and global quality of life, but "Song of Life" participants reported significantly higher spiritual well-being (p = 0.04) and ego-integrity (p < 0.01), as well as lower distress (p = 0.05) than patients in the control group. Both patients' and family members' treatment satisfaction was higher after "Song of Life" with large between-group effect sizes on items asking for meaningfulness (d = 0.96) and importance (d = 1.00). CONCLUSIONS: Our findings provide evidence that "Song of Life" is an effective and meaningful biographical music therapy intervention to facilitate psycho-spiritual integration in terminally ill patients. TRIAL REGISTRATION: German Clinical Trials Register (DRKS)-DRKS00015308 (date of registration: September 7th 2018).

C-reactive protein in spinal surgery: more predictive than prehistoric.

PURPOSE: In spinal surgery, surgical site infections (SSI) after dorsal spondylodesis lead to severe short- and long-term complications. Despite various clinical and serological evidence, the detection of a postoperative SSI remains crucial. In this retrospective cohort study, we determined the prognostic value of C-reactive protein (CRP) kinetics after open reduction and dorsal spondylodesis in the development of a SSI. METHODS: We retrospectively analyzed 192 patients from 2016 to 2018 undergoing open reduction and dorsal spondylodesis with and without SSI for 20 days at a level-I trauma center and assessed their serological and clinical characteristics. RESULTS: On day 7 and 8 after surgery, patients who developed a SSI displayed significantly higher CRP levels. A second peak after the initial maximum of CRP and a restricted failure to decline as well as a maximum CRP of more than 225 mg/l predict an infectious complication with a sensitivity of 92.9%, and a specificity of 78.2%. A binary logistic regression leads to 85.7% and 69.7%, respectively. A one-phase decay exponential regression can predict 75.6% of the variance after the initial peak of CRP. CONCLUSION: Our study demonstrates a high value of postoperative CRP kinetics in SSI detection after dorsal spondylodesis. Moreover, we observed typical CRP levels with a specific course as indicative predictors that may facilitate an early SSI detection in clinical practice.

Minimally Invasive Conversion of a Gastric Bypass into Sleeve Gastrectomy for Postprandial Hyperinsulinemic Hypoglycemia.

The treatment of postprandial hyperinsulinemic hypoglycemia following gastric bypass surgery for obesity can be challenging despite dietetic and medical treatment and eventually surgical treatment remains the exclusive treatment to resolve the problem for the patient. In the following, the experience with a conversion surgery from a complicated Roux-en-Y gastric bypass to sleeve gastrectomy using the Da Vinci robotic system will be reported.

A study of the dopamine transporter using the TRACT assay, a novel in vitro tool for solute carrier drug discovery.

Members of the solute carrier (SLC) transporter protein family are increasingly recognized as therapeutic drug targets. The majority of drug screening assays for SLCs are based on the uptake of radiolabeled or fluorescent substrates. Thus, these approaches often have limitations that compromise on throughput or the physiological environment of the SLC. In this study, we report a novel application of an impedance-based biosensor, xCELLigence, to investigate dopamine transporter (DAT) activity via substrate-induced activation of G protein-coupled receptors (GPCRs). The resulting assay, which is coined the 'transporter activity through receptor activation' (TRACT) assay, is based on the hypothesis that DAT-mediated removal of extracellular dopamine directly affects the ability of dopamine to activate cognate membrane-bound GPCRs. In two human cell lines with heterologous DAT expression, dopamine-induced GPCR signaling was attenuated. Pharmacological inhibition or the absence of DAT restored the apparent potency of dopamine for GPCR activation. The inhibitory potencies for DAT inhibitors GBR12909 (pIC50 = 6.2, 6.6) and cocaine (pIC50 = 6.3) were in line with values from reported orthogonal transport assays. Conclusively, this study demonstrates the novel use of label-free whole-cell biosensors to investigate DAT activity using GPCR activation as a readout. This holds promise for other SLCs that share their substrate with a GPCR.