Homogeneous Group Of Patients Research Articles

Cochlear Implantation Outcome in Children with DFNB1 locus Pathogenic Variants.

Almost 60% of children with profound prelingual hearing loss (HL) have a genetic determinant of deafness, most frequently two DFNB1 locus (GJB2/GJB6 genes) recessive pathogenic variants. Only few studies combine HL etiology with cochlear implantation (CI) outcome. Patients with profound prelingual HL who received a cochlear implant before 24 months of age and had completed DFNB1 genetic testing were enrolled in the study (n = 196). LittlEARS questionnaire scores were used to assess auditory development. Our data show that children with DFNB1-related HL (n = 149) had good outcome from the CI (6.85, 22.24, and 28 scores at 0, 5, and 9 months post-CI, respectively). A better auditory development was achieved in patients who receive cochlear implants before 12 months of age. Children without residual hearing presented a higher rate of auditory development than children with responses in hearing aids over a wide frequency range prior to CI, but both groups reached a similar level of auditory development after 9 months post-CI. Our data shed light upon the benefits of CI in the homogenous group of patients with HL due to DFNB1 locus pathogenic variants and clearly demonstrate that very early CI is the most effective treatment method in this group of patients.

Photodynamic Diagnosis and Therapy for Peritoneal Carcinomatosis from Gastrointestinal Cancers: Status, Opportunities, and Challenges.

Selective accumulation of a photosensitizer and the subsequent response in only the light-irradiated target are advantages of photodynamic diagnosis and therapy. The limited depth of the therapeutic effect is a positive characteristic when treating surface malignancies, such as peritoneal carcinomatosis. For photodynamic diagnosis (PDD), adjunctive use of aminolevulinic acid- protoporphyrin IX-guided fluorescence imaging detects cancer nodules, which would have been missed during assessment using white light visualization only. Furthermore, since few side effects have been reported, this has the potential to become a vital component of diagnostic laparoscopy. A variety of photosensitizers have been examined for photodynamic therapy (PDT), and treatment protocols are heterogeneous in terms of photosensitizer type and dose, photosensitizer-light time interval, and light source wavelength, dose, and dose rate. Although several studies have suggested that PDT has favorable effects in peritoneal carcinomatosis, clinical trials in more homogenous patient groups are required to identify the true benefits. In addition, major complications, such as bowel perforation and capillary leak syndrome, need to be reduced. In the long term, PDD and PDT are likely to be successful therapeutic options for patients with peritoneal carcinomatosis, with several options to optimize the photosensitizer and light delivery parameters to improve safety and efficacy.

Evolocumab (PCSK9 Inhibitor) in Hereditary Spastic Paraplegia Type 5

Background: Hereditary spastic paraplegia type 5 (SPG5) is an ultra-rare neurogenetic axon-degenerative disease. The absence of treatment to prevent disease progression represents a major unmet clinical need. With a greater understanding of the pathophysiological basis of SPG5, opportunities have emerged for providing a targeted mechanistic therapy. The aims of this preliminary study were to investigate the efficacy of a PCSK9 inhibitor, Evolocumab, as a cholesterol-lowering therapy for reducing the accumulation of neurotoxic oxysterols and to evaluate the effects on axonal degeneration. Methods: This was as an open-label, evaluator-blind, single-center pilot study in which 23 SPG5 patients each received a single subcutaneous injections of 420 mg Evolocumab. Clinical data, CSF and blood were collected for analysis at enrollment and subsequent day 30. Induced pluripotent stem cells (iPSCs) were generated from the fibroblasts of a SPG5 patient to assess the mechanism of PCSK9 inhibitor’s effect on treatment. Findings: This trial is the largest sample-size prospective study among any treatment trial for SPG5. In this relatively homogeneous group of SPG5 patients (96% carried the same known nonsense mutation c.334 C>T; the median age was 34 years; disease duration was 16 years), we found that PCSK9 inhibitor significantly lowered levels of the toxic metabolite 27-hydroxycholesterol (27-OHC) in plasma (median (IQR), 589(487-644) vs. 396(348-468) ng/ml , P < 0.001). CSF 27-OHC decreased in 12 (71%) patients with a median reduction by 11% from the median 10 ng/ml before treatment to 8.3 ng/ml after treatment (P = 0.012). Most importantly, axonal degeneration, assessed by using neurofilament light (NFL) as a quantitative biomarker, receded at 30 days after single-dose Evolocumab treatment. Additionally, using iPSC-derived motor neurons, this study also showed that PCSK9 inhibitor had anti-apoptosis activity in SPG5 patients. Interpretation: The potential biological activity of cholesterol modulation for SPG5 patients, that is, alleviation of damage to axons from the effects of neurotoxic oxysterol, as well as the absence of adverse effects associated with the use of PCSK9 inhibitor therapy documented here deserves, in fact urges, full evaluation by well-designed long-term clinical trials. Trial Registration: This study is registered with ClinicalTrials.gov, number: NCT01892345. Funding Statement: This work has been supported by grants U1905210 (W.-J.C.), 81771230(W.-J.C.) and 81801130 (X.L.) from the National Natural Science Foundation of China, Joint Funds for the Innovation of Science and Technology of Fujian Province (2017Y9094) (W.-J.C.) and (2018Y9082) (N.W.), the Natural Science Foundation of Fujian Province (2019J02010) (W.-J.C.) and (2019J05076) (X.L.), the Key Clinical Specialty Discipline Construction Program of Fujian (N.W.). Declaration of Interests: All authors report no conflict of interest. Fujian medical university school of public health have received consultant fees as statistician to perform the data analysis. Ethics Approval Statement: The study protocol and informed consent procedures were approved by the institutional review board. Written informed consent was provided by the patients and their health care proxies.

546 Machine-learning based exploration of echocardiographic patterns and clinical parameters to understand their relation to death or transplant in pediatric dilated cardiomyopathy

Abstract Background Pediatric dilated cardiomyopathy (DCM) affects left ventricular (LV) function and carries a high risk of death or heart transplantation. However, the relation of LV regional function and inefficiency to clinical outcomes is underexplored. Purpose The aim of this study was to understand the relationship of regional LV mechanics, global LV function and clinical characteristics to the outcomes of death or heart transplant in children with DCM; through the integration of a vast amount of information enabled by unsupervised machine learning techniques. Methods DCM was defined by a LV end-diastolic dimension z-score &amp;gt; 2 and LV ejection fraction (EF) &amp;lt;55%. Longitudinal strain curves were sampled at 6 LV lateral wall and septal locations from the 4ch apical view. In addition, we analyzed other echo parameters including the aortic outflow pattern as a measure of LV pump function, QRS duration, LV EF, indexed end-diastolic LV dimension, global longitudinal strain and patient characteristics including age, weight, body surface area and medications (diuretics, ACE inhibitor, beta-blockers, mineralocorticoid receptor antagonist, digoxin, inotropes, antiarrhythmics). We used an unsupervised machine learning algorithm (multiple kernel learning) to reduce the dimensionality of these data, and position patients based on similarities. We subsequently used k-means clustering to recover homogeneous groups of patients. We then interpreted the data patterns associated to each of the groups for the occurrence of death or transplant through non-linear regression analysis (multi-scale kernel regression). Results 50 children with DCM (age 0 to 18 years) were analyzed. Clustering on the two first dimensions of the low-dimensional space resulted in three clusters (Figure A), with significantly different proportions of the composite outcome of death or heart transplant (Cl1 = 79%, Cl2 = 50%, Cl3 = 20%; p = 0.01). The group with the highest proportion of death or transplant (cluster 1) comprised the oldest and most frequently medicated subjects, with impaired LVEF and GLS, and with the widest QRS duration (p &amp;lt; 0.01) (Figure B). The group with the second highest proportion of death or transplant (cluster 2) comprised patients with the lowest LVEF (p &amp;lt; 0.01) and GLS (p &amp;lt; 0.001), reduced and delayed peak aortic outflow velocity and severely impaired basal and apical LV strain (Figure C). In contrast, the group with highest transplant-free survival (cluster 3) had the highest LVEF and GLS values, the most synchronous LV contraction as assessed by strain and QRS duration and the highest amplitude and earliest peaking aortic flow. Conclusion Our results serve as a proof-of-concept that machine-learning based approaches can be useful to explore and understand which regional and global echo parameters in combination with clinical parameters are associated with a higher risk of death or transplant in pediatric DCM. Abstract 546 Figure

153 Multiparametric assessment of diastolic function in heart failure

Abstract Background The assessment of diastolic function is still challenging in the setting of heart failure (HF). We tested the hypothesis that applying a machine learning algorithm would detect heterogeneity in diastolic function and improve risk stratification in HF population. Methods This study included consecutive 279 patients with clinically stable HF referred for echocardiographic assessment, for whom diastolic function variables were measured according to the current guidelines. Cluster analysis, an unsupervised machine learning algorithm, was undertaken on these variables to form homogeneous groups of patients with similar profiles of the variables. Sequential Cox models paralleling the clinical sequence of HF assessment were used to elucidate the benefit of cluster-based classification over guidelines-based classification. The primary endpoint was a hospitalization for worsening HF. Results Cluster analysis identified 3 clusters with distinct properties of diastolic function that shared similarities with guidelines-based classification. The clusters were associated with brain natriuretic peptide level (p &amp;lt; 0.001, figure A). During follow-up period of 2.6 ± 2.0 years, 62 patients (22%) experienced the primary endpoint. Cluster-based classification exhibited a significant prognostic value (c2 = 20.3, p &amp;lt; 0.001, figure B), independent from and incremental to an established clinical risk score for HF (MAGGIC score) and left ventricular end-diastolic volume (hazard ratio = 1.677, p = 0.017, model c2: from 47.5 to 54.1, p = 0.015, figure D). Although guideline-based classification showed a significant prognostic value (c2 = 13.1, p = 0.001, figure C), it did not significantly improve overall prognostication from the baseline (model c2: from 47.5 to 49.9, p = 0.199, figure D). Conclusion Machine learning techniques help grading diastolic function and stratifying the risk for decompensation in HF. Abstract 153 Figure.

Understanding Childhood Neuroimmune Diseases of the Central Nervous System.

Immune-mediated diseases of the central nervous system (CNS) in childhood are a heterogeneous group of rare conditions sharing the inflammatory involvement of the CNS. This review highlights the growing knowledge of childhood neuroimmune diseases that primarily affect the CNS, outlining the clinical and diagnostic features, the pathobiological mechanisms and genetics, current treatment options, and emerging challenges. The clinical spectrum of these conditions is increasingly expanded, and the underlying mechanisms of dysregulation of the immune system could vary widely. Cell-mediated and antibody-mediated disorders, infection-triggered and paraneoplastic conditions, and genetically defined mechanisms can occur in previously healthy children and can contribute to different stages of the disease. The careful evaluation of the clinical presentation and temporal course of symptoms, the specific neuroimaging and immunological findings, and the exclusion of alternative causes are mandatory in clinical practice for the syndromic diagnosis. A common feature of these conditions is that immunotherapeutic agents could modulate the clinical course and outcomes of the disease. Furthermore, specific symptomatic treatments and comprehensive multidisciplinary care are needed in the overall management. We focus on recent advances on immune-mediated demyelinating CNS disorders, autoimmune encephalitis, interferonopathies, and possible neuroimmune disorders as Rasmussen encephalitis. Better knowledge of these conditions could allow prompt diagnosis and targeted immunotherapy, to decrease morbidity and mortality as well as to improve clinical outcomes, reducing the burden of the disease due to possible long-term neuropsychiatric sequelae. Persisting controversies remain in the rigorous characterization of each specific clinical entity because of the relative rarity in children; moreover, in a large proportion of suspected neuroimmune diseases, the immune “signature” remains unidentified; treatment guidelines are mostly based on retrospective cohort studies and expert opinions; then advances in specific molecular therapies are required. In the future, a better characterization of specific immunological biomarkers may provide a useful understanding of the underlying pathobiological mechanisms of these conditions in order to individualize more tailored therapeutic options and paradigms. Multicenter collaborative research on homogeneous groups of patients who may undergo immunological studies and therapeutic trials could improve the characterization of the underlying mechanisms, the specific phenotypes, and tailored management.

Saisie des données des patients faisant l’objet d’un traitement par cellules CAR-T : recommandations de la Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™) are the first two approved drug products that belong to of a new class of therapies manufactured through an industrial process that includes the ex vivo genetic modification of human autologous T lymphocytes with viral vectors. Since CAR-T Cells qualify as gene therapy medicinal products, there is a requirement for long-term (15years) follow-up of treated patients. As part of a global initiative aiming at a better use of continental registries to study the outcome of homogeneous groups of patients, EMA issued a positive opinion on the use of the EBMT registry to capture LTFU of patients treated with CAR-T Cell in EU Member states. The use of a European registry will provide a global view of this new field across EU countries and across diverse indications, and bears advantages over the use of registries dedicated to specific categories of diseases, or national registries. This is an important asset to fully measure the medical value of these innovative therapies in real-life conditions, and assess whether pricing is fully justified. To fulfill EMA requirements, as well as requirements from Pharma companies, EBMT has designed a new Cellular Therapy Med-A form that allows to capture the essential information on the administered drug product, disease and patient. Registering patients and capturing follow-up data is already possible in Promise, and will be made easier when the full migration of the EBMT database from Promise to MACRO is completed in the forthcoming weeks. Negotiations are ongoing with all interested parties including patients to define in which conditions data will be accessed and analyzed; the underlying principle is to favor rather than restrict the use of data, with a view to build cooperative projects involving relevant cooperative groups and professional associations. Here, we present practical recommendations issued by SFGM-TC to help data managers capture information related to patients treated with CAR-T Cells.

Data Mining Approach for the Characterization of Functional Bowel Disorders According to Symptom Intensity Provides a Small Number of Homogenous Groups

Background/Aims: The aim of the present study is to evaluate if the intensity of the cardinal symptoms of functional bowel disorders could be used to identify homogenous groups of patients defined by the Rome criteria. Method: In this observational study, 1,729 consecutive outpatients (73% females) filled out the Rome III questionnaire and 10-point Likert scales for constipation, diarrhea, bloating (BL)/distension, abdominal pain (AP) during the week before the medical consultation. A Gaussian mixture model was used for clustering the patients according to the intensity of symptoms without a priori information, and a classification tree was constructed from this clustering. Data were analyzed using analysis of variance and logistic regression analysis. Results: According to the intensity of symptoms, the patients are divided into 8 groups named according to their main symptomatology: “painful constipation” (PFC), “mild pain constipation” (MPC), “painful diarrhea” (PFD), “mild pain diarrhea” (MPD), “mixed transit” (MT), “BL,” “AP,” and “nonspecific” (NS). The study of the relationship between the Rome III classification and this new grouping shows that irritable bowel syndrome (IBS)-constipation is associated with PFC, IBS-diarrhea with PFD and MPD, SII-mixed with MT, SII-unspecified with BL, functional constipation with PFC and MPC, functional diarrhea with MPD and NS, BL with “BL” and NS, nonspecific functional bowel disorders (FBD) with NS, and functional AP with “BL” and AP (p < 0.01 for all associations). Conclusion: A symptom intensity-based classification of FBD patients could simplify clinical phenotype, give homogeneous groups of patients, and could eventually be used by nongastroenterologists and in clinical research.

Severity Classification for Sickle Cell Disease: A RAND/UCLA Modified Delphi Panel

Severity Classification for Sickle Cell Disease: A RAND/UCLA Modified Delphi Panel

Healthcare costs and outcomes: a value-based assessment tool for Clinical Governance

Abstract Issue/problem Health systems sustainability is a critical public health issue. A value-based approach is essential to improve patient-centeredness, appropriateness, quality and funding allocation in healthcare. Description of the problem This project was aimed to develop an innovative transferable tool to assess value-based activities in Hospital by monitoring care pathways costs and outcomes. Main questions were to: assess cost and outcome variance in homogeneous groups of patients; evaluate clinical activities contribution to the hospital budget; identify and monitor critical points. In 2018 a Business Intelligence system fed by different Hospital datasets was developed and tested in a Teaching Hospital in Rome to quantify and integrate data on pathways efficacy and costs. It was based on an algorithm of 20 indicators related to Women and Child Care Pathways. Results Preliminary results showed a great variance for the same intervention/procedure concerning length of stay (3-8 days), waiting times (1-4 days), innovative technologies costs (2000-6000€) and obsolete reimbursement rates (2000-5000€) that do not guarantee adequate economic contribution margins. Improvement actions were defined concerning pathways’ workflow and organizational appropriateness. The need for negotiations with Ministry of Health was highlighted, aimed to update reimbursement rates. Lessons The tool, built on a value-based process view, allowed analyzing online outcomes and costs data aggregated by path, benchmarking results, identifying critical issues and providing improvement solutions. It turned out to be an innovative methodology - also applicable in other settings/countries - to trigger changes in health management and pursue quality and efficiency in healthcare. Key messages Value-based healthcare is the new public health paradigm. Assessing simultaneously Hospital costs and outcomes is a valuable way to derive overall healthcare value, improve quality and rationalize resources allocation.

Blood transcriptome profiling captures dysregulated pathways and response to treatment in neuroimmunological disease.

Blood transcriptome profiling captures dysregulated pathways and response to treatment in neuroimmunological disease.

Digital biomarkers: Importance of patient stratification for re-irradiation of glioma patients – Review of latest developments regarding scoring assessment

PurposeTo review scoring assessments in re-irradiation of high-grade glioma (HGG) patients and how to use scoring for patient stratification. The next aim was to investigate the different approaches employed by the scoring systems and the way they can be applied to build homogeneous patient groups for a reliable prognosis. MethodsWe searched the Medline/Pubmed and Web of science databases for relevant articles regarding scores for re-irradiation of recurrent HGG. All references were divided into the following groups: novel score establishment (n = 5), score validation (n = 6), not relevant to this evaluation (n = 26). ResultsWe identified five scoring systems. Two are modifications of an already existing score. Calculations differ immensely from easy point addition to a more complex formula with including three up to 10 individual parameters. Six validation articles were found for three of the scores; one was validated four times. Two scores were never validated. ConclusionFor recurrent HGG, the clinical situation remains demanding. Due to the heterogeneity of data at re-irradiation, patient stratification is important. Several scoring systems have been developed to predict prognosis. As a digital biomarker, scores are of high value regarding quick patient assessment and therapy decision making. For the next generation of digital biomarkers, easy calculation, and inclusion of easily available parameters are crucial.

P029 - Use of road runner guide in operative ureteroscopy for ureteral stones: Comparison of two homogeneous groups of patients

P029 - Use of road runner guide in operative ureteroscopy for ureteral stones: Comparison of two homogeneous groups of patients

Telomere Length Changes during Critical Illness: A Prospective, Observational Study.

Objective: evaluation of telomere length change in acutely ill adult patients. Design: Blood samples were drawn on the first and seventh day of intensive care unit (ICU) stay to assess telomere length using a polymerase chain reaction (PCR)-based technique. Demographic data collected included age, weight, admission diagnosis, baseline laboratory values (pH, C- reactive protein (CRP), serum albumin level, white blood cell count (WBC) count, platelet count), and baseline SOFA and APACHE II scores. Additional data collected during the ICU stay included a repeated WBC count, the presence of positive blood cultures and outcome data, including death in the ICU or following discharge, whether ventilated or not at ICU discharge, and destination following discharge, i.e., medical ward or rehabilitation. Setting: General ICU in tertiary hospital. Patients: Forty patients admitted to the ICU within 72 h of hospital admission suffering from an acute illness were included in this prospective, observational study. Main results: Of the 40 patients studied, telomere shortening was noted in 21, telomere lengthening in 11, and no significant change in the other eight. The age of patients demonstrating telomere shortening was statistically significantly younger (45.4 vs. 61.5 years, p < 0.023) compared to those showing increased telomere length. In addition, a significant correlation was observed between the difference in telomere length and the corresponding difference in WBC count (telomere shortening was associated with a decreased WBC count and vice versa). A trend toward shortening was seen in patients with sepsis (p = 0.07). No significant correlations were found for any other demographic or outcome parameter and changes in telomere length. Conclusion: Changes in telomere length, both shortening and lengthening, were evident in the acute setting, but no associations between such changes with outcome were noted. Further studies in more homogeneous groups of patients appear to be warranted.

Psychosocial Interventions for Patients with Severe COPD-An Up-to-Date Literature Review.

Background and Objectives: Chronic obstructive pulmonary disease (COPD) is a life limiting condition with a long list of serious psychosocial consequences, aggravating with illness progression. In advanced stages, chronic respiratory failure often develops, which might undermine mental health and reduce activity. The study objective was to review the recent studies concerning psychosocial interventions dedicated to patients with severe COPD. Materials and Methods: The PubMed database was searched for terms, such as ‘COPD and long-term oxygen therapy, non-invasive ventilation, severe or respiratory failure’ and ‘psychological or psychosocial or mental health and intervention.’ Studies were included that described patients with stable, severe COPD and the outcomes of psychosocial interventions. Results and Conclusions: Thirty-four studies were identified and divided into four thematic groups: home medical support, exercise, self-management and mental health. The number of studies that focused on mental health preservation in severe COPD was very limited; i.e., none refer directly to those treated with respiratory failure. Improving patients’ self-efficacy gave promising effects to the acceptance of palliative care, pulmonary rehabilitation completion and mental health. Physical activity might be recommended to be included in interventions for mental health enhancement, although little is known about the role of the particular forms of exercise. An increasing beneficial use of new technologies for psychosocial interventions was noted. Psychosocial interventions applied in advanced COPD underline the roles of self-efficacy, telehealth and physical activity in physical and mental health preservation. However, all of the above elements need to be independently tested on more homogenous groups of patients and have the possible modes of their treatment analysed.

Clinical experience with combined reconstruction of the anterior cruciate and anterolateral ligaments of the knee in sportsmen.

Rupture of the anterior cruciate ligament (ACL) is one of the most common sports injuries of the knee joint. Today, we have a large number of approaches to arthroscopic reconstruction of the anterior cruciate ligament that lead to successful outcomes and allow the patients to return to a significant level of activity post-operatively. Nevertheless, the return to competitions rate stays relatively low. The functional state is thought to be dependent on rotational and anteroposterior stability of the knee. These data encourage search for methods of additional stabilization of the knee joint, one of them being extra-articular tenodesis, or reconstruction of anterolateral ligament of the knee. To evaluate medium-term results of combined simultaneous arthroscopic reconstruction of anterior cruciate ligament and anterolateral ligament of the knee joint in sportsmen and to access the probability of return to competitions. The surgeries were performed in 2014-2015 in 50 patients who fulfilled the entry criteria: 20 patients (including 10 professional sportsmen) underwent arthroscopic ACL reconstruction together with reconstruction of anterolateral ligament-group 1 (main group), and 30 patients (including 10 professional sportsmen) underwent arthroscopic ACL reconstruction-group 2 (control group). Group 1: All patients of group 1 were able to return to the pre-operative sports level in two years after the surgery. The mean Tegner Lysholm score was 72.6 ± 6.45 (hereinafter, SE-standard error) before the surgery and 97.4 ± 1.18 after the surgery. The mean IKDC score was 63.1 ± 4.8% before the surgery and 96.3 ± 1.8% after the surgery. Group 2: 20 of 30 patients (66.7%) returned to the pre-operative level of activity and returned to competitions (if they were professional sportsmen) in a year after the surgery. Five of ten patients (50%) (professional sportsmen) returned to competitions. Fifteen of 20 patients (75%) (amateur sportsmen) also returned to competitions. The mean pre-operative Tegner Lysholm score was 69.6 ± 3.5, and the mean post-operative score was 92.1 ± 3.9. The mean pre-operative IKDC score was 73.4 ± 3.2%, and the mean post-operative score was 90.3 ± 3.7%. The results of the study show that more patients with higher functional demands and more professional sportsmen returned to sports. Despite the results of our and other foreign studies, a need remains for studies that will compare outcomes of ALL reconstruction with the same surgical technique in homogenous groups of patients.

What is treatment resistance in psychiatry? A "difficult to treat" concept.

What is treatment resistance in psychiatry? A "difficult to treat" concept.

Symptom-based patient stratification in mental illness using clinical notes.

Mental illnesses are highly heterogeneous with diagnoses based on symptoms that are generally qualitative, subjective, and documented in free text clinical notes rather than as structured data. Moreover, there exists significant variation in symptoms within diagnostic categories as well as substantial overlap in symptoms between diagnostic categories. These factors pose extra challenges for phenotyping patients with mental illness, a task that has proven challenging even for seemingly well characterized diseases. The ability to identify more homogeneous patient groups could both increase our ability to apply a precision medicine approach to psychiatric disorders and enable elucidation of underlying biological mechanism of pathology. We describe a novel approach to deep phenotyping in mental illness in which contextual term extraction is used to identify constellations of symptoms in a cohort of patients diagnosed with schizophrenia and related disorders. We applied topic modeling and dimensionality reduction to identify similar groups of patients and evaluate the resulting clusters through visualization and interrogation of clinically interpretable weighted features. Our findings show that patients diagnosed with schizophrenia may be meaningfully stratified using symptom-based clustering.

Predicting Late Radiation-Induced Xerostomia with Parotid PET Biomarkers and Dose Metrics

Xerostomia is a common long-term toxicity from head and neck radiotherapy that is only partially predicted by delivered dose to salivary glands. Associations between parotid gland imaging biomarkers and late radiation-induced xerostomia have recently been shown. The aim of this study was to assess predictive models for late xerostomia incorporating pre-treatment parotid PET biomarkers compared to a base model using parotid dose alone in a homogeneous group of patients treated for orophangeal cancer. 47 patients with p16+ oropharyngeal squamous cell carcinoma were treated on two prospective institutional protocols with 70 Gy IMRT and concurrent carboplatin/paclitaxel. The 90th percentile of standardized uptake value (SUV-P90) was generated from each parotid gland on pre and 3-month post-RT PET scans. Late xerostomia (12-months post-RT) was defined by the patient-reported University of Michigan Xerostomia Questionnaire (XQ), and parotid-specific salivary flow rate (SFR). XQ outcomes included both the summary score (XQ-sum12m) and the most variable eating-related item as determined by principal component analysis: frequency of sipping fluids to aid in swallowing food (XQ-sip12m). Univariate analysis was applied to dose and SUV-P90 features as predictors of late xerostomia using both continuous and discrete scales. Multivariate analysis was applied for dose only and combined dose and SUV-P90 using penalized logistic regression for feature selection and model prediction based on the LASSO technique. Mean parotid dose and SUV-P90 from both pre and post-RT PET scans were significantly associated with patient-reported xerostomia and stimulated SFR (Stim12m) but not unstimulated SFR. Associations were stronger for SUV-P90 from the contralateral parotid (SUV-P90CL) than the ipsilateral parotid, and from 3-month PET scans relative to pre-treatment scans. On multivariate analysis, the addition of pre-treatment SUV-P90CL and an interaction term for dose and SUV to the model significantly improved the prediction for late moderate or severe xerostomia compared to the base model, from AUC = 0.70 to 0.74 for XQ-sum12m and from 0.74 to 0.84 for XQ-sip12m. The improvements remained statistically significant upon cross-validation. The addition of pre-treatment parotid PET biomarkers significantly improved a predictive model for late patient-reported xerostomia over a model based on parotid dose alone. The improvement was greatest for the single eating-related item with the largest inter-patient variability (XQ-sip12m). Correlation between SUV-P90 from 3-month post-RT PET scans and late xerostomia was even higher than those from pre-treatment scans, suggesting that mid-treatment scans should be further explored for a potential role in adaptive radiotherapy.Abstract 121; Table 1SUV-P90CL (3m)Mean XQ-Sum12mMean XQ-Sip12mMean Stim12m< 1.551.37.50.171.5 - 2.029.04.40.392.0 - 2.521.92.80.48> 2.510.81.30.80 Open table in a new tab

Long-Term Dynamics of Three Dimensional Telomere Profiles in Circulating Tumor Cells in High-Risk Prostate Cancer Patients Undergoing Androgen-Deprivation and Radiation Therapy.

Patient-specific assessment, disease monitoring, and the development of an accurate early surrogate of the therapeutic efficacy of locally advanced prostate cancer still remain a clinical challenge. Contrary to prostate biopsies, circulating tumor cell (CTC) collection from blood is a less-invasive method and has potential as a real-time liquid biopsy and as a surrogate marker for treatment efficacy. In this study, we used size-based filtration to isolate CTCs from the blood of 100 prostate cancer patients with high-risk localized disease. CTCs from five time points: +0, +2, +6, +12 and +24 months were analyzed. Consenting treatment-naïve patients with cT3, Gleason 8-10, or prostate-specific antigen > 20 ng/mL and non-metastatic prostate cancer were included. For all time points, we performed 3D telomere-specific quantitative fluorescence in situ hybridization on a minimum of thirty isolated CTCs. The patients were divided into five groups based on the changes of number of telomeres vs. telomere lengths over time and into three clusters based on all telomere parameters found on diagnosis. Group 2 was classified as non-respondent to treatment and the Cluster 3 presented more aggressive phenotype. Additionally, we compared our telomere results with the PSA levels for each patient at 6 months of ADT, at 6 months of completed RT, and at 36 months post-initial therapy. CTCs of patients with PSA levels above or equal to 0.1 ng/mL presented significant increases of nuclear volume, number of telomeres, and telomere aggregates. The 3D telomere analysis of CTCs identified disease heterogeneity among a clinically homogeneous group of patients, which suggests differences in therapeutic responses. Our finding suggests a new opportunity for better treatment monitoring of patients with localized high-risk prostate cancer.