Standard Clinical Setting Research Articles

Prospective Connectomic-Based Deep Brain Stimulation Programming for Parkinson's Disease.

Efficacy of deep brain stimulation (DBS) relies on accurate lead placement as well as optimization of the stimulation parameters. Although clinical software tools are now available, programming still largely relies on a monopolar review, a tedious process for both patients and programmers. This study investigates the safety and feasibility of prospective automated connectomic DBS programming (automated connectomic programming [ACP]), focusing on the recruitment of specific white matter pathways. After DBS implantation, a detailed connectomic DBS model in patient-specific space was developed for each study participant. A driving-force model was used to quantify pathway recruitment across 2400 different DBS settings. Optimization algorithms maximized recruitment of therapeutic pathways while minimizing recruitment of side-effect pathways. Thirteen subjects were enrolled in two study phases that compared DBS settings derived from ACP to standard clinical DBS settings. Nine patients underwent reprogramming with ACP (5 globus pallidus interna [GPi], 4 subthalamic nucleus [STN]). Four patients underwent initial programming with ACP (3 GPi, 1 STN). All patients tolerated ACP without persistent side effects. In the reprogramming cohort, 3 patients preferred their ACP program, and 1 patient felt it was comparable to their clinical program. Unified Parkinson's Disease Rating Scale, Part III, scores for the initial ACP cohort (3 GPi, 1 STN) improved by an average of 43.5% (40.4-52.6 ± 5.6%). ACP appeared clinically safe and feasible. It provided reasonable motor improvement, which can be further optimized with subsequent clinical adjustment. Additional investigation is required to refine the optimization algorithm and to quantify the clinical benefit of ACP in a larger cohort. © 2024 International Parkinson and Movement Disorder Society.

Real-World Assessment of Second-Generation Trabecular Micro-Bypass Stents in Open-Angle Glaucoma Patients

Background/Purposes/Objective: To assess the safety and efficacy of iStent inject placement in individuals with glaucoma with open angles in real world clinical settings. MethodsA review was conducted on the medical records of individuals who received iStent inject implants starting from March 2018. The analysis focused on reductions in intraocular pressure (IOP) and glaucoma medication usage. Safety assessments encompassed intraoperative and postoperative issues, additional surgeries, and improvements in best-corrected visual acuity (BCVA). ResultsAnalysis of 55 eyes of 48 patients that underwent iStent implantation revealed a mean age of 77 years (range: 51-97). The initial average intraocular pressure (IOP) in these eyes was 20.2 ± 6.4 mm Hg. Following surgery, IOP decreased by ≥ 20% compared to preoperative levels in 21 eyes (43.8%) over the 12-month follow-up period. Notably, there was a significant reduction in medication usage by the 12-month mark (p < 0.0042). Among the evaluated eyes, 9 exhibited a response to steroids, 3 had stents that were improperly positioned, 5 had stents that were over implanted, and 1 eye experienced an episode of iris prolapse. ConclusionsThe findings from the 12-month follow-up of iStent inject implants in standard clinical settings demonstrate a notable decrease in both intraocular pressure (IOP) and medication usage in eyes with concurrent open-angle glaucoma.

Use of Telehealth in Autism Spectrum Disorder Assessment in Children: Evaluation of anOnline Diagnostic Protocol Includingthe Brief Observation of Symptoms of Autism.

The COVID-19 pandemic revealed the need to develop the field of remote assessment for autism spectrum disorders (ASD). The purpose of the study was to evaluate an online assessment protocol that includes the Brief Observation of Symptoms of Autism (BOSA). The online protocol consisting of BOSA and the Autism Diagnostic Interview-Revised (ADI-R) was administered by experienced examiners to 29 children with suspected ASD. The participants were then evaluated by clinical psychologists in a standard clinical setting using the Autism Diagnostic Observation Schedule-2 (ADOS-2) and other methods, and the ASD diagnosis was confirmed or ruled out. The results show substantial to moderate inter-rater agreement between the online and face-to-face raters with the value of Cohen's Kappa = 0.66 (P < 0.001); this corresponds with 79.8% agreement. The sensitivity of the protocol was approx. 94.7%, the specificity was 70%, the positive predictive value was 85.7%, and the negative predictive value was 87.5%. Further, direct false positive or false negative diagnostic conclusions based on the online protocol were absent when the possible conclusion of "I cannot decide" was included. The items B9 Showing, B10 Spontaneous Initiation of Joint Attention, B1 Unusual Eye Contact, B3 Facial Expressions Directed to Others, and C2 Imagination/Creativity were shown to be well observable in BOSA when related to ADOS-2 scoring. The results indicate that the protocol consisting of BOSA and ADI-R administered by an experienced examiner is a promising combination of tools for remote autism assessment.

Reliable measurement of auditory-driven gamma synchrony with a single EEG electrode: A simultaneous EEG-MEG study

ObjectiveAuditory-driven gamma synchrony (GS) is linked to the function of a specific cortical circuit based on a parvalbumin+ and pyramidal neuron loop. This circuit is impaired in neuropsychiatric conditions (i.e. schizophrenia, Alzheimer's disease, stroke etc.) and its relevance in clinical practice is increasingly being recognized. Auditory stimulation at a typical gamma frequency of 40 Hz can be applied as a ‘stress test’ of excitation/inhibition (E/I) of the entire cerebral cortex, to drive GS and record it with magnetoencephalography (MEG) or high-density electroencephalography (EEG). However, these two techniques are costly and not widely available. Therefore, we assessed whether a single EEG electrode is sufficient to provide an accurate estimate of the auditory-driven GS level of the entire cortical surface while expecting the highest correspondence in the auditory and somatosensory cortices. MethodsWe measured simultaneous EEG-MEG in 29 healthy subjects, utilizing 3 EEG electrodes (C4, F4, O2) and a full MEG setup. Recordings were performed during binaural exposure to auditory gamma stimulation and during silence. We compared GS measurement of each of the three EEG electrodes separately against full MEG mapping. Time-resolved phase locking value (PLVt) was computed between EEG signals and cortex reconstructed MEG signals. ResultsDuring auditory stimulation, but not at rest, EEG captures a significant amount of GS, especially from both auditory cortices and motor-premotor regions. This was especially true for frontal (C4) and central electrodes (F4). Discussion and ConclusionsWhile hd-EEG and MEG are necessary for accurate spatial mapping of GS at rest and during auditory stimulation, a single EEG channel is sufficient to detect the global level of GS. These results have great translational potential for mapping GS in standard clinical settings.

Perspectives on the clinical use of anti-amyloid therapy for the treatment of Alzheimer's disease: Insights from the fields of cancer, rheumatology, and neurology.

The advent of disease-modifying therapies for Alzheimer's disease (AD) has raised many questions and debates in the field as to the clinical benefits, risks, and costs of such therapies. The controversies have resulted in the perception that many clinicians are apprehensive about prescribing these medications to their patient populations. There also remains widespread uncertainty as to the economic impact, cost benefit ratio, and safety oversight for use of these medications in standard clinical care settings. To contextualize such issues, the present study compared anti-amyloid biologic therapy (lecanemab) to four commonly used biologic agents in other fields, including trastuzumab for breast cancer, bevacizumab for lung cancer, etanercept for rheumatoid arthritis, and ocrelizumab for multiple sclerosis. The data presented demonstrate comparable costs, clinical benefits, and risks for these biologic agents in their disparate disease states. These results provide context for the costs, clinical benefits, and safety regarding the mainstream use of anti-amyloid biologic agents for the prevention of cognitive loss. While the era of disease-modifying therapies for AD is now in its infancy, there is an expectation that these discoveries will be followed by improved therapies and combination treatments leading to greater efficacy in ameliorating the clinical trajectory of AD. Anti-amyloid therapy costs are comparable to other commonly used biologics.Anti-amyloid therapy efficacy is comparable to other commonly used biologics.Anti-amyloid therapy safety is compatible with other commonly used biologics.

Comparative genomic profiling of circulating tumor DNA and paired formalin-fixed paraffin-embedded (FFPE) DNA from Indian patients with breast cancer.

e14554 Background: Breast cancer (BC) is the most frequent malignancy and a leading cause of mortality in women worldwide. Although most BCs are treated with curative intent, 30-40 % patients experience disease progression or metastatic relapse. Considering high heterogeneity of BC, mutational profiling of solid biopsy may not be adequate for informed treatment decisions in all cases. Liquid biopsy based on circulating tumor DNA (ctDNA) analysis is emerging as an equivalent and alternative to tissue biopsy in clinical settings. Though extremely critical for management of BC, liquid biopsy is not a standard of care in India. Here we compared comprehensive genomic profiles of ctDNA and paired biopsy samples to determine the efficacy of ctDNA assay in detecting actionable mutational targets. Methods: Retrospectively, genomic DNA and matched ctDNA was isolated from both FFPE and blood samples of14 BC patients. The patients were confirmative with pathological findings, having metastatic infiltrating ductal carcinoma, or triple negative breast cancers. Genome-wide HRD, TMB and MSI scores based on the OncoIndx comprehensive gene panel (CGP) was determined. OncoIndx CGP targets 1080 cancer related genes along with 47 HRR genes and 1600 MSI signature sites. Libraries were prepared using a hybridization-capture method based on custom-designed OncoIndx 1080 CGP and sequenced (depth 5500 X) on Illumina Nextseq 2000 in a pair-end mode (150 x2). Variant calling was performed using a proprietary bioinformatics pipeline iCare. Results: All patients were diagnosed with metastatic infiltrating ductal carcinoma, or triple negative breast cancers. From the patient cohort, microsatellite instability (MSI) from ctDNA showed 100% concordance with FFPE DNA while tumor mutation burden (TMB) and homologous recombination deficiency (HRD) scores showed 71.4 % and 64.2 % concordance with FFPE DNA respectively. At the individual gene mutation level, the concordance TP53, BRCA1/2, PI3K family of genes, ESR1, PTEN, ERBB2, PALB2, and BRAF genes between ctDNA and FFPE DNA was 54.7%, 92.8%, 54.7%, 78.5%, 92.8%, 100%, 100%, and 100% respectively. Many important genomic alterations including PIK3CA:p.L334H, PIK3CA:p.E81K, ESR1:p.Q375L, BRCA2:p.X3040_splice, PTEN:p.D19H were exclusive to ctDNA thereby denoting potential tumor heterogeneities which could be missed from FFPE DNA. Conclusions: Our results suggest a high correlation between ctDNA and FFPE DNA detected by OncoIndx test in metastatic or triple negative breast cancer patients of Indian ethnicity. Although not a part of standard of care, liquid biopsy could be of significant potential for management of BC in the standard clinical settings. However, a thorough investigation of cancer stage, and clinical presentations are necessary to carefully evaluate the selection of ctDNA or FFPE DNA-based genomic profiling.

Abstract CT273: Unique multicenter trial design to investigate ARTIDIS nanomechanical generated measurements for early breast lesions (ANGEL)

Abstract Background: The conventional diagnosis of breast cancer followed by molecular subtyping for therapy selection is a lengthy process and associated with patient and clinician anxiety. Efficient, bedside approaches are desirable to drive fast diagnosis and early planning of clinical management. This clinical trial (NCT06085833) tackles the novel concept of automated and reliable tissue diagnostics (ARTIDIS) based on the measurement of nanomechanical signature of fresh clinical biopsies from patients with breast lesions. This study is based on our previous single center clinical study (Basel NANO) where tissue nanomechanical signature can: 1) reliably distinguish benign and malignant breast lesions, 2) predict the presence of metastatic disease based on imminent aggressiveness rating and 3) predict the response to neoadjuvant chemotherapy from baseline biopsies. The current study aims to prospectively validate the efficacy of ARTIDIS system as an aid to diagnosis, assessment of breast cancer prognosis and prediction of therapy response, particularly in the context of neoadjuvant therapy (Natira). Methods: A cohort of 2,705 patients with breast lesions, who are clinically indicated for core needle biopsy (CNB) are being enrolled, from diverse ethnic and socioeconomic backgrounds. Single fresh CNB will be transferred into tissue preservation buffer and measured by ARTIDIS device within 1-3 hours to collect thousands of nanomechanical measurements. Undisrupted CNB will be fixed and returned to standard diagnostic workflow, remaining unaltered for downstream assessments. Nanomechanical measurement data are prospectively analyzed in a blind manner before the collection of histopathology and follow up clinical data. The primary endpoint of the study is to validate ARTIDIS potential in diagnosis of breast lesions (benign vs malignant), secondary endpoints address whether nanomechanical signature can differentiate subtypes of breast cancer, associate with clinical outcome and guide treatment decisions in NAT setting. Follow up data will be collected regularly up to 10 years after patient enrollment. Results: The multicenter ANGEL study is a prospective validation of the NANO (University Hospital Basel, Switzerland) - first ever performed clinical study which investigated the diagnostic, prognostic, and predictive value of tissue nanomechanical signature in patients with breast cancer. The ANGEL study takes advantage of ARTIDIS non-disruptive technology and is fully integrated into routine clinical workflow. The study started enrollment in 11/02/2023, and is expected to complete by 2025. The seamless integration of ARTIDIS within the standard clinical settings, its automatization, bedside implementation, and the lack of additional burden to patients enables effective reach of a diverse population through local hospitals and communities. Conclusion: This study presents the first of its kind as a direct prospective, multicenter- based translation of the tissue nanomechanical signature into clinical settings. This unique trial design allows the prospective development of ARTIDIS as an aid to diagnosis, prognosis and therapy optimization in patients with breast cancer. The innovative trial design of this study may also further the development of strategies to increase reach to underrepresented communities. Citation Format: Karla A. Sepulveda, Ashley Roark, Sagar Dhamne, Chandandeep Nagi, Ivan Marin, Iqbal Tabish, Sara Nizzero, Mariam Gachechiladze, Tobias Appenzeller, Philipp Oertle, Marko Loparic, Susan G. Hilsenbeck, Marija Plodinec, Alastair Thompson. Unique multicenter trial design to investigate ARTIDIS nanomechanical generated measurements for early breast lesions (ANGEL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT273.

Understanding and identifying visual field progression.

Detecting deterioration of visual field sensitivity measurements is important for the diagnosis and management of glaucoma. This review surveys the current methods for assessing progression that are implemented in clinical devices, which have been used in clinical trials, alongside more recent advances proposed in the literature. Advice is also offered to clinicians on what they can do to improve the collection of perimetric data to help analytical progression methods more accurately predict change. This advice includes a discussion of how frequently visual field testing should be undertaken, with a view towards future developments, such as digital healthcare outside the standard clinical setting and more personalised approaches to perimetry.

Peripheral blood BDNF and soluble CAM proteins as possible markers of prolonged disorders of consciousness: a pilot study

Although clinical examination still represents the gold standard for the differential diagnosis of prolonged disorders of consciousness (pDoC), the introduction of innovative markers is essential for diagnosis and prognosis, due to the problem of covert cognition. We evaluated the brain-derived neurotrophic factor protein (BDNF) and the soluble cell adhesion molecules proteins (CAMs) in a cohort of prolonged disorders of consciousness patients to identify a possible application in the clinical context. Furthermore, peripheral blood determinations were correlated with imaging parameters such as white matter hyperintensities (WMH), cranial standardized uptake value (cSUV), electroencephalography (EEG) data and clinical setting. Our results, although preliminary, identify BDNF as a possible blood marker for the diagnosis of pDoC (p value 0.001), the soluble CAMs proteins CD44, Vcam-1, E-selectin (p value < 0.01) and Icam-3 (p value < 0.05) showed a higher peripheral blood value in pDoC compared with control. Finally, soluble Ncam protein could find useful applications in the clinical evolution of the pDoC, showing high levels in the MCS and EMCS subgroups (p value < 0. 001) compared to VS/UWS.

Improving CPAP Therapy with Superimposed Pressure Oscillation

Background: Continuous positive airway pressure (CPAP) is considered the gold standard therapy for Obstructive Sleep Apnea (OSA); however, many side effects, such as uncomfortable high titration pressure (TP) and mouth dryness, are associated with this treatment. This work proposes using pressure oscillations superimposed on a mean pressure to modulate the upper airways, reduce TP, and stimulate the salivary glands to reduce mouth dryness. Methods: Two nonconsecutive overnight randomized controlled clinical trials were designed, one with a standard CPAP setup but reduced TP and the other by adding superimposed pressure oscillations (SIPO) to the reduced TP CPAP setup. 33 OSA patients who usually received CPAP treatment with predetermined TP settings participated in the two trials. Complete polysomnography was performed for sleep and patient assessments. However, a spitting technique protocol was used on 15 randomly selected patients from the same group to investigate the effect of SIPO on mouth dryness. These trials are registered under ACTRN12622001518752. Results: The apnea-hypopnea index (AHI) was significantly reduced from 25.08 ± 2.32 to 17.56 ± 2.11 (p = 0.020*) with SIPO, indicating a 29.95% reduction in AHI and a decrease in breathing obstructions during enhanced therapy. Additionally, SIPO significantly decreased the oxygen desaturation index (ODI) (p = 0.002), maintaining the blood oxygen level within the normal range during the trials. ODI≥3 decreased significantly by 38.04% with SIPO. Saliva test results demonstrated that SIPO significantly increased saliva volume by 23.13% in non-stimulation and by 39.09% during stimulation compared to the CPAP trial. Conclusions: This work demonstrates that SIPO reduces the TP to 70% of its standard clinical setting and stimulates salivary secretion to reduce mouth dryness. Further, significant improvements in AHI, respiratory arousal index (RAI), Arousal index (AI), and sleep efficiency (SE) are observed. This work is proof of concept, and further trials should be undertaken to generalize the proposed technique.

INNV-20. PREDICTING RESPONSE TO CHEMOTHERAPY IN HIGH GRADE GLIOMAS USING EX VIVO 3D CELL CULTURE FUNCTIONAL PRECISION ONCOLOGY PLATFORM – A MULTI-INSTITUTIONAL EXPERIENCE

Abstract BACKGROUND Treatment of high-grade glioma (HGG) remains a challenge. Several groups have developed ex vivo drug sensitivity assays to evaluate susceptibility of the tumor tissue to specific chemotherapeutics. This tool, in addition to molecular analysis of tumors might provide another layer of confidence in choosing treatments for patients with high-grade gliomas. METHODS 3D PredictTM platform (Kiyatec, Greenville, SC, USA) was tested at three academic medical centers in the United States. Twelve patients with newly diagnosed and recurrent HGGs were included. Tumor spheroids created ex vivo were exposed to twelve pre-selected drugs. Responses were reported as: no response, moderate response and response. We analyzed: demographics, histopathology, stage of disease, success rate and results of the ex vivo assay and clinical implications. RESULTS Majority of patients were women (67%). Median age was 58.5. Histology: GBM-83%, HGGs-17%. Eighty three percent of the samples represented recurrent disease. Sixty percent represented first recurrence while the remaining 40% represented 2nd or 3rd recurrence. Eight out of 12 tissue samples (67%) were successfully tested ex vivo. In six cases (75%), the information was used for immediate clinical decision making. In 2 cases, the decision was deferred until the next progression of the disease. The drugs chosen for treatment based on assay results included: olaparib (the assay was positive for response to rucaparib), temozolomide, lomustine, carboplatin and irinotecan. CONCLUSIONS This platform is easy to use in a standard clinical setting, the success rate for creating viable spheroids for drug sensitivity testing is high and the information obtained can be useful in clinical practice. Addition of other agents to the assay, correlation with molecular testing of the tumor tissue and attempt to assess response to drug combinations should be considered in further development of this technology. Prospective clinical trial is needed to validate this approach for routine clinical use.

Automated spatial localization of ankle muscle sites and model-based estimation of joint torque post-stroke via a wearable sensorised leg garment.

Assessing a patient's musculoskeletal function during over-ground walking is a primary objective in post-stroke rehabilitation, due to the importance of walking recovery for everyday life. However, the quantitative assessment of musculoskeletal function currently requires lab-constrained equipment, and labor-intensive analyses, which hampers assessment in standard clinical settings. The development of fully wearable systems for the online estimation of muscle-tendon forces and resulting joint torque would aid clinical assessment of motor recovery, it would enhance the detection of neuro-muscular anomalies and it would consequently enable highly personalized treatments. Here, we present a wearable technology that combines (1) a soft garment for the human leg sensorized with 64 flexible and dry electromyography (EMG) electrodes, (2) a generalized and automated algorithm for the localization of leg muscle sites, and (3) an EMG-driven musculoskeletal modeling framework for the estimation of ankle dorsi-plantar flexion torques. Our results showed that the automated clustering algorithm could detect muscle locations in both healthy and post-stroke individuals. The estimated muscle-specific EMG envelopes could be used to drive forward person-specific musculoskeletal models and estimate resulting joint torques accurately across all healthy and post-stroke individuals and across different walking speeds (R2 >0.82 and RMSD <0.16). The technology we proposed opens new avenues for automated muscle localization and quantitative musculoskeletal function assessment during gait in both healthy and neurologically impaired individuals.

Automated Lattice Treatment Planning for Bulky Tumors

Spatially-fractionated radiotherapy has potential to improve local control in bulky tumors by achieving both focally high intratumoral doses and acceptable dose fall-off to surrounding normal tissues. However, a standard of care does not exist for the optimal values and distribution of peak and valley doses in treatment plans. To evaluate these questions systematically using dosimetric analyses, the number of alternative treatment plans required exceeds the practical limits of manual planning. In this study, we report an approach for automated planning of volumetric arc-based lattice therapy resulting in over 1100 unique treatment plans. An automation script was generated using Python v3.6 and imported into departmental treatment planning software. A spreadsheet was created with varying combinations of the number of fractions, peak dose, valley dose, and peak-dose sphere size and spacing for 7 patients with bulky tumors (volume range, 159-593 cc). These values were imported into the script after which all planning was automated. For each combination, a bounding box was generated around the gross tumor target volume and divided into equal segments in the x, y, and z planes. Individual spheres were constructed for a given parameter set and those fully encompassed within the target contracted by 2 cm were used to create peak dose targets. The valley dose targets were generated by subtracting an 8 mm expansion of the peak dose spheres from the overall target volume. Multi-criteria optimization (MCO) was then applied to generate a final plan after which the script moved onto the next permutation in the spreadsheet. Following the creation of each plan, the script populated the source spreadsheet with data including doses to the target, fall-off structures, and organs-at-risk. Plans which resulted in an MCO infeasibility error were also noted. A total of 1188 combinations of peak dose, valley dose, and peak-dose sphere size and spacing for 1- and 5-fraction plans were evaluated. Peak and valley doses ranged from 6 to 27 Gy and 0.4 to 20 Gy, respectively, for 1-fraction plans and 30 to 50 Gy and 2 to 20 Gy, respectively, for 5-fraction plans. This resulted in a range of peak/valley ratios from 1.35 to 67.5. Of these combinations, 594 plans were successfully generated and 594 were infeasible, most often due to sphere distribution or peak/valley dose ratios greater than 5. The median time for generation of an individual plan was 21 minutes (range, 15-46). Our script allowed the evaluation of 1188 unique combinations of spatial dose distribution using automated planning. This rapid, yet systematic, assessment of parameters for spatially-fractionated radiation will be used to inform pre-clinical and clinical studies and would not have been feasible with manual planning. Moreover, the median plan generation time of 21 minutes demonstrates potential for wider use of this script in standard clinical settings.

Chronic Respiratory Diseases as a Risk Factor for Herpes Zoster Infection

IntroductionHerpes zoster (HZ) is a condition that results from the reactivation of the varicella zoster virus (VZV). Several diseases have been reported to increase the risk of developing HZ and postherpetic neuralgia (PHN). The objective of this study is to analyze the prevalence and risk factors for HZ and PHN in the most frequent chronic respiratory diseases, which are chronic obstructive pulmonary disease (COPD), asthma, lung cancer and obstructive sleep apnea (OSA). MethodsWe conducted an observational, retrospective, non-interventional study between January 2012 and December 2020 based on data from the Castilla-La Mancha Regional Health System in Spain. We used the Savana Manager 3.0 artificial intelligence-enabled system to collect information from electronic medical records. Results31765 subjects presented a diagnosis of HZ. Mean age was 64.5 years (95%CI 64.3–64.7), and 58.2% were women. The prevalence of HZ showed an increasing trend in patients over the age of 50. A risk analysis adjusted for sex and comorbidities in COPD, asthma, lung cancer and OSA presented a higher risk of developing HZ in the first three (OR 1.16 [95%CI 1.13–1.19], 1.67 [1.63–1.71], 1.68 [1.60–1.76], respectively), which further increased in all three when associated with comorbidities. Regarding postherpetic neuralgia, an increased risk was only observed related to COPD and lung cancer (OR 1.24 [95%CI 1.23–1.25], 1.14 [1.13–1.16], respectively), further increasing when associated with comorbidities. ConclusionsIn a standard clinical practice setting, the most prevalent respiratory diseases (asthma, COPD and lung cancer) are related to a higher risk of HZ and PHN. These data are fundamental to assess the potential impact of vaccination in this population.

P11.39.B PREDICTING RESPONSE TO CHEMOTHERAPY IN RECURRENT HIGH GRADE GLIOMAS USINGEX VIVO 3D CELL CULTURE FUNCTIONAL PRECISION ONCOLOGY PLATFORM

Abstract BACKGROUND Treatment of recurrent high-grade glioma remains a clinical challenge. There are very few agents active in this disease and short of enrollment in a clinical trial, the choice of therapy for a patient at the time of recurrence remains challenging. Several groups, including our own have developed ex vivo drug sensitivity assays to evaluate susceptibility of the tumor tissue to specific chemotherapeutics. To our knowledge, there is only one commercially available platform from the US based company Kiyatec. This tool, in addition to the molecular analysis of the tumor might provide another layer of confidence in choosing treatments for patients with recurrent high-grade gliomas. MATERIAL AND METHODS We present the data from our initial experience with the 3D PredictTM platform (Kiyatec, Greenville, SC, USA). We used the platform for 6 patients with recurrent high-grade gliomas undergoing tumor resection at the time of recurrence. We followed the company protocol for obtaining, preserving and shipping the tissue. RESULTS Out of the 6 specimens shipped for analysis, 4 assays were completed with full results available for analysis and clinical use. In two cases, the ex vivo tissue expansion was unsuccessful and drug testing was not completed. For the remaining 4 cases, spheroids created from the expansion of the harvested tissue were exposed to 12 drugs (temozolomide, lomustine, procarbazine, abemaciclib, carboplatin, dabrafenib, etoposide, everolimus, irinotecan, osimertinib, rucaparib and trametinib). We have observed different levels of sensitivity to several agents graded as: NO RESPONSE, MODERATE RESPONSE and RESPONSE. In 3 cases the results were used for clinical decision making and 2 patients were started on temozlomidede and carboplatin respectively and remain on treatment. In one case where sensitivity to etoposide was detected, we were not able to proceed with therapy due to insurance denial for the chosen drug. CONCLUSION In our experience, this platform is easy to use in a standard clinical setting, the success rate for creating viable spheroids for testing is high and the information derived from the drug sensitivity testing can be useful in clinical practice. Large, prospective clinical trial is need to validate this approach for routine clinical use.

Measuring acute effects of subanesthetic ketamine on cerebrovascular hemodynamics in humans using TD-fNIRS

Quantifying neural activity in natural conditions (i.e. conditions comparable to the standard clinical patient experience) during the administration of psychedelics may further our scientific understanding of the effects and mechanisms of action. This data may facilitate the discovery of novel biomarkers enabling more personalized treatments and improved patient outcomes. In this single-blind, placebo-controlled study with a non-randomized design, we use time-domain functional near-infrared spectroscopy (TD-fNIRS) to measure acute brain dynamics after intramuscular subanesthetic ketamine (0.75 mg/kg) and placebo (saline) administration in healthy participants (n = 15, 8 females, 7 males, age 32.4 ± 7.5 years) in a clinical setting. We found that the ketamine administration caused an altered state of consciousness and changes in systemic physiology (e.g. increase in pulse rate and electrodermal activity). Furthermore, ketamine led to a brain-wide reduction in the fractional amplitude of low frequency fluctuations, and a decrease in the global brain connectivity of the prefrontal region. Lastly, we provide preliminary evidence that a combination of neural and physiological metrics may serve as predictors of subjective mystical experiences and reductions in depressive symptomatology. Overall, our study demonstrated the successful application of fNIRS neuroimaging to study the physiological effects of the psychoactive substance ketamine in humans, and can be regarded as an important step toward larger scale clinical fNIRS studies that can quantify the impact of psychedelics on the brain in standard clinical settings.

A patient-specific deep learning framework for 3D motion estimation and volumetric imaging during lung cancer radiotherapy

Objective. Respiration introduces a constant source of irregular motion that poses a significant challenge for the precise irradiation of thoracic and abdominal cancers. Current real-time motion management strategies require dedicated systems that are not available in most radiotherapy centers. We sought to develop a system that estimates and visualises the impact of respiratory motion in 3D given the 2D images acquired on a standard linear accelerator. Approach. In this paper we introduce Voxelmap, a patient-specific deep learning framework that achieves 3D motion estimation and volumetric imaging using the data and resources available in standard clinical settings. Here we perform a simulation study of this framework using imaging data from two lung cancer patients. Main results. Using 2D images as input and 3D–3D Elastix registrations as ground-truth, Voxelmap was able to continuously predict 3D tumor motion with mean errors of 0.1 ± 0.5, −0.6 ± 0.8, and 0.0 ± 0.2 mm along the left–right, superior–inferior, and anterior–posterior axes respectively. Voxelmap also predicted 3D thoracoabdominal motion with mean errors of −0.1 ± 0.3, −0.1 ± 0.6, and −0.2 ± 0.2 mm respectively. Moreover, volumetric imaging was achieved with mean average error 0.0003, root-mean-squared error 0.0007, structural similarity 1.0 and peak-signal-to-noise ratio 65.8. Significance. The results of this study demonstrate the possibility of achieving 3D motion estimation and volumetric imaging during lung cancer treatments on a standard linear accelerator.

Psychodynamic techniques elicit emotional engagement in complex post-traumatic stress disorder

Therapies based on an exposure model have been shown to be effective in the treatment of uncomplicated Post-Traumatic Stress Disorder (PTSD), but less effective when used to treat Complex Post-Traumatic Stress Disorder (CPTSD), because an essential first step in the exposure model is a patient’s emotional engagement with traumatic material. This engagement is prevented by a suppressive/dissociative reaction typical of CPTSD. Several methods of overcoming this suppressive/dissociative reaction have been investigated, but have proved impractical. Familiar psychodynamic techniques appear to circumvent the suppressive/dissociative response and elicit the required emotional engagement in standard clinical settings.

Multicenter quantitative 18F-fluorodeoxyglucose positron emission tomography performance harmonization: use of hottest voxels towards more robust quantification.

Harmonization methods reduce variability between different make and models of positron emission tomography (PET) scanners. The study aims to explore harmonization strategies that lead to comparable and robust quantitative metrics in a multicenter setting. NEMA IEC Phantom data acquisition was performed for low and high spheres-to-background ratios (SBR4:1 and 10:1) on six PET/CT (computed tomography) scanners. Different reconstruction sets, including the number of sub-iterations, number of subsets, and full width at half maximum (FWHM) for each scanner, were evaluated towards optimized and harmonized reconstruction settings. Recovery coefficients (RCs) of four quantitative metrics, including standardized uptake value (SUV)max, SUVISO-50 (SUVmean in 50% isocontour), SUVpeak, and mean uptake of 10 highest concentration voxels were evaluated as RCmax, RCISO-50, RCpeak, and RC10V, representing percent difference relative to the static ground truth case as functions of sphere sizes. A set of image reconstruction parameters was proposed for harmonized reconstruction to minimize variability between scanners. The root mean square error (RMSE), curvature, and reproducibility were examined. The proposed reconstruction protocols for harmonization and standard clinical reconstruction settings were compared to each other across all scanners. A significant difference (P value <0.0001) was observed in the aforementioned quantitative metrics between SBR10 and SBR4. Reconstruction parameter sets with the smallest RMSE and RC values within 10% bias were identified as the best candidate for harmonization. The coefficient of variation of the mean value of RCs (CVMRC) shows a remarkable reduction of about 28%, 26%, 32%, and 19% in harmonized reconstruction settings for MRCmax, MRCISO-50, MRCpeak, and MRC10V, respectively. CVMRC for MRC10V in the harmonized reconstruction setting was 5.9% in SBR4, while the smallest value in SBR10 belongs to MRCpeak, with a value of 5.8%. The reproducibility of RC is improved by deriving the value from ten hottest voxels and is equally reproducible with RCpeak. Compared to RCmax and RCISO-50, the variability is reduced by 18% and 22% if ten voxels are pooled. Harmonizing PET/CT systems with and without point spread function/time of flight (PSF/TOF) using various vendor-developed image reconstruction algorithms improves the quantification reproducibility. RC10V, likewise RCpeak, is superior to the rest of the quantitative indices in terms of accuracy and reproducibility and helpful in quantifying lesion volume below 1 mL.

S-11-3: CLINICAL IMPLICATION OF AORTIC STIFFNESS

Modern clinical practice stresses the importance of basing healthcare practices and health policy on the best available clinical evidence. However, it is a long journey to translate research evidence into routine clinical practice through closing fundamental translational gaps. There have been numerous studies and meta-analyses demonstrating the prognostic value of arterial stiffness beyond established CVD risk factors, including age and blood pressure. Nevertheless, clinical practice guidelines rarely recommend the routine use of arterial stiffness in daily care. To facilitate the routine use of arterial stiffness measurements, the corresponding translational gaps in the clinical application should be analyzed and addressed. To justify the routine clinical use of any biomarkers, several criteria must be met. For the many methodologies to estimate arterial stiffness, their reliability and reproducibility in a standard clinical setting should be firstly demonstrated. Moreover, in a busy clinical environment, a less complicated measurement procedure with operator independence is more welcomed. Second, these techniques must carry the ability to add additional risk discrimination beyond the conventional risk prediction systems such as Framingham risk score or SCORE and should be cost effective. Not only the independent prognostic value but also the significant reclassification ability should be shown. Lastly, clear indication of the implementation of arterial stiffness techniques should be provided including but not limited to being used for risk stratification, treatment monitoring, or as a therapeutic target. Previous studies pertaining to arterial stiffness have been endeavored to address most but not all the above requirements. The independent value of arterial stiffness in predicting cardiovascular events have been presented. Moreover, its ability to predict incident hypertension and target organ damage, including brain, heart, and kidney have also been confirmed. In an individual patient data meta-analysis of cf-PWV for subjects at intermediate risk, adding cf-PWV into standard risk factors rendered a net reclassification of 15% and 27% for coronary heart disease events and CVD death, respectively. Such analysis provide justification to apply arterial stiffness measurements in routine clinical practice. They can make risk prediction more accurate by re-classifying subjects with intermediate cardiovascular risk into a higher risk level, in which treatment is indicated or into a lower risk level, in which further therapy could be safely avoided. In subjects with intermediate risk such as whitecoat hypertension, isolated diastolic hypertension, or borderline hypertension, the uncertainty in risk prediction may be further reduced by measuring arterial stiffness. Of the techniques for estimating arterial stiffness, advantages and disadvantages of each technique are observed. Although cf-PWV has the strongest evidence base supporting clinical value, the operator independence limits its widely use in routine practice. Cuff-based devices require less training, but may be less accurate. Further research is required to address this important unmet need. Besides, recommendation of the routine use of arterial stiffness techniques could be further supported by conducting randomized controlled trials adopting arterial stiffness as a treatment target, a treatment monitoring instrument, or as a tool incorporated in the intervention strategies such as risk stratification for subjects with intermediate risk profiles. To obtain health insurance reimbursement, cost-effectiveness analysis accompanied with the prospective studies for arterial stiffness is also warranted to support its routine clinical implement. In summary, the distinctive clinical value of arterial stiffness techniques relies on the ability of a single assessment to provide important information regarding blood pressure progression and susceptibility to end organ damage. The most useful scenario seems to be the more accurate risk classification for subjects at intermediate CVD risk, in which condition the need for treatment is uncertain, such as patients with masked or white coat hypertension. Therefore, arterial stiffness can be seen as complimentary to current blood pressure, and both should be considered when risk prediction is required for making timely and relevant treatment decisions. The role of arterial stiffness as a treatment target, treatment monitoring strategy in response to therapy, or a tool in the intervention strategy should be further uncovered in prospective studies or randomized controlled trials.