Patients In Early Stages Of Disease Research Articles

Disease progression of spinocerebellar ataxia types 1, 2, 3 and 6 before and after ataxia onset.

Our aim was to study the evolution of ataxia and neurological symptoms before and after ataxia onset in the most common spinocerebellar ataxias (SCAs), SCA1, SCA2, SCA3 and SCA6. We therefore jointly analysed the data of the EUROSCA and RISCA studies, which recruited ataxic and non-ataxic mutation carriers. We used mixed effect models to analyse the evolution of Scale for the Rating and Assessment of Ataxia (SARA) scores, SCA Functional Index (SCAFI) and Inventory of Non-Ataxia Signs (INAS) counts. We applied multivariable modelling to identify factors associated with SARA progression. In the time interval 5 years prior to and after ataxia onset, we calculated sensitivity to change ratios (SCS) of SARA, SCAFI and INAS. 2740 visits of 677 participants were analysed. All measures showed non-linear progression that was best fitted by linear mixed models with linear, quadratic and cubic time effects. R2 values indicating quality of the fit ranged from 0.70 to 0.97. CAG repeat was associated with faster progression in SCA1, SCA2 and SCA3, but not SCA6. 5 years prior to and after ataxia onset, SARA had the highest SCS of all measures with a mean of 1.21 (95% CI: 1.20, 1.21) in SCA1, 0.94 (0.93, 0.94) in SCA2 and 1.23 (1.22, 1.23) in SCA3. Our data have important implications for the understanding of disease progression in SCA1, SCA2, SCA3 and SCA6 across the lifespan. Furthermore, our study provides information for the design of interventional trials, especially in pre-ataxic mutation carriers close to ataxia onset and patients in early disease stages.

The impact of social risk factors on the presentation, treatment and survival of patients with hepatocellular carcinoma at an urban, academic safety-net hospital

BackgroundVulnerable populations have worse hepatocellular carcinoma (HCC) outcomes. We sought to understand if this could be mitigated at a safety-net hospital. MethodsA retrospective chart review of HCC patients was conducted (2007–2018). Stage at presentation, intervention and systemic therapy were analyzed (Chi-square for categorical variables and Wilcoxon tests for continuous variables) and median survival calculated by Kaplan-Meier method. Results388 HCC patients were identified. Sociodemographic factors were similar for stage at presentation, except insurance status (diagnosis at earlier stages for commercial insurance and later stages for safety-net/no insurance). Higher education level and origin of mainland US increased intervention rates for all stages. Early-stage disease patients had no differences in receipt of intervention or therapy. Late-stage disease patients with higher education level had increased intervention rates. Median survival was not impacted by any sociodemographic factor. ConclusionUrban safety-net hospitals with a focus on vulnerable patient populations provide equitable outcomes and can serve as a model to address inequities in HCC management.

A randomized, placebo‐controlled, double‐blind, Phase 1b study to evaluate the safety, tolerability and pharmacodynamics of PRI‐002 in early AD

AbstractBackgroundPRI‐002 is an all‐D‐enantiomeric peptide developed to disassemble Abeta oligomers, which has shown to improve cognition in animal models and which has demonstrated its safety profile in healthy young volunteers (Kutzsche et al. 2020).Method20 AD patients in early disease stages fulfilling the ATN‐criteria were recruited to participate in a single center, randomized, placebo –controlled, double‐blind study. Patients received once daily oral doses of 300 mg PRI‐002 or placebo for 28 days. Safety and efficacy assessments were executed at baseline, day 14, day 28 and day 56 (follow up). Blood sampling was carried out at each time point, EEG and CSF measurements before and at the end of treatment. Imaging (MRI) and functional tests (CERAD, CDR) were performed in parallel to EEG/CSF and additionally at follow up.Result10 patients (age 76.9±3.4, MMSE 28±1.6) received placebo and 9 patients PRI‐002 (72.4±6.9, 27.2±2.9). One patient withdraw informed consent before treatment was started. 13 patients reported in total 27 adverse events while no serious adverse event was noted. There was no statistical difference regarding adverse events between treatment and placebo. EEG and MRI revealed no changes after treatment. While no significant changes were detected in p‐TAU, Abeta1‐42 and Abeta oligomers in CSF before and after treatment, patients receiving PRI‐002 significantly performed better than those receiving placebo in the CERAD word list at follow up (p≤0.05).ConclusionPRI‐002 showed an excellent safety profile in AD patients. While no biomarker changes were detected after 4 weeks of treatment interestingly, an improvement of memory function was noted at follow up. A phase 2 study is scheduled.Kutzsche J, Jürgens D, Willuweit A, Adermann K, Fuchs C, Simons S, Windisch M, Hümpel M, Rossberg W, Wolzt M, Willbold D. Safety and pharmacokinetics of the orally available antiprionic compound PRI‐002: A single and multiple ascending dose phase I study. Alzheimers Dement (N Y). 2020 Mar 20;6(1):e12001. https://doi.org/10.1002/trc2.12001.

CD56-Negative Extranodal Natural Killer/T-Cell Lymphoma: A Retrospective Study in 443 Patients Treated by Chemotherapy With or Without Asparaginase.

ObjectiveExtranodal natural killer/T cell lymphoma (NKTCL) is an aggressive EBV-related lymphoma, originating from NK cells or T cells. Previous study demonstrated that CD56 negative NKTCL should be recognized as a distinct subtype. In this study, the value of CD56 in NKTCL is validated in the era of asparaginase, and genomic analysis was done to dissect the differences between CD56-negative and positive NKTCL.Methods443 patients with newly diagnosed NKTCL were enrolled in this retrospective study, and correlation between CD56 positivity and survival outcomes was analyzed. The gene sequencing data was downloaded (http://www.biosino.org/node/project/detail/OEP000498), and bioinformatics analysis was done to delineate the tumor microenvironment and differentially expressed genes.ResultsCD56 was expressed in 337 patients (76.1%). Within a median follow-up time of 51 months, the 5-year overall survival (OS) and progression free survival (PFS) rates were 63.8% and 51.9%, respectively. For the whole cohort, patients who were CD56-positive had superior OS (5-year OS, 86.2% vs. 51.9%, p=0.019) and PFS (5-year PFS, 55.9% vs. 40.1%, p=0.016). For patients in early stage disease, CD56 positivity was associated with superior OS and PFS (p=0.008 and 0.005, respectively). In patients who received non-asparaginase-based chemotherapy, CD56-negative was associated with shorter OS and PFS (p<0.001), and in patients who received asparaginase-based chemotherapy, CD56-negative was not related to inferior OS and PFS (p=0.093 and p=0.829, respectively). The genomic analysis demonstrated that CD56 positive NKTCL probably originated from NK cells and CD56 negative NKTCL originated from T cells. CD56 positive NKTCL had significantly higher proportion of resting NK cells, activated NK cells, and activated CD8+ and CD4+ T cells in the tumor microenvironment.ConclusionsCD56 negative NKTCL differs from CD56 positive NKTCL in both the tumor microenvironment and survival outcomes, and asparaginase-based treatment may overcome the poor prognosis brought by CD56 negativity.

Concept of the Munich/Augsburg Consortium Precision in Mental Health for the German Center of Mental Health.

The Federal Ministry of Education and Research (BMBF) issued a call for a new nationwide research network on mental disorders, the German Center of Mental Health (DZPG). The Munich/Augsburg consortium was selected to participate as one of six partner sites with its concept “Precision in Mental Health (PriMe): Understanding, predicting, and preventing chronicity.” PriMe bundles interdisciplinary research from the Ludwig-Maximilians-University (LMU), Technical University of Munich (TUM), University of Augsburg (UniA), Helmholtz Center Munich (HMGU), and Max Planck Institute of Psychiatry (MPIP) and has a focus on schizophrenia (SZ), bipolar disorder (BPD), and major depressive disorder (MDD). PriMe takes a longitudinal perspective on these three disorders from the at-risk stage to the first-episode, relapsing, and chronic stages. These disorders pose a major health burden because in up to 50% of patients they cause untreatable residual symptoms, which lead to early social and vocational disability, comorbidities, and excess mortality. PriMe aims at reducing mortality on different levels, e.g., reducing death by psychiatric and somatic comorbidities, and will approach this goal by addressing interdisciplinary and cross-sector approaches across the lifespan. PriMe aims to add a precision medicine framework to the DZPG that will propel deeper understanding, more accurate prediction, and personalized prevention to prevent disease chronicity and mortality across mental illnesses. This framework is structured along the translational chain and will be used by PriMe to innovate the preventive and therapeutic management of SZ, BPD, and MDD from rural to urban areas and from patients in early disease stages to patients with long-term disease courses. Research will build on platforms that include one on model systems, one on the identification and validation of predictive markers, one on the development of novel multimodal treatments, one on the regulation and strengthening of the uptake and dissemination of personalized treatments, and finally one on testing of the clinical effectiveness, utility, and scalability of such personalized treatments. In accordance with the translational chain, PriMe’s expertise includes the ability to integrate understanding of bio-behavioral processes based on innovative models, to translate this knowledge into clinical practice and to promote user participation in mental health research and care.

Tissue donations for multiple sclerosis research: current state and suggestions for improvement

Although major progress in multiple sclerosis research has been made during the last decades, key questions related to the cause and the mechanisms of brain and spinal cord pathology remain unresolved. These cover a broad range of topics, including disease aetiology, antigenic triggers of the immune response inside and/or outside the CNS and mechanisms of inflammation, demyelination neurodegeneration and tissue repair. Most of these questions can be addressed with novel molecular technologies in the injured CNS. Access to brain and spinal cord tissue from multiple sclerosis patients is, therefore, of critical importance. High-quality tissue is provided in part by the existing brain banks. However, material from early and highly active disease stages is limited. An initiative, realized under the patronage of the European Charcot Foundation, gathered together experts from different disciplines to analyse the current state of multiple sclerosis tissues collected post-mortem or as biopsies. Here, we present an account of what material is currently available and where it can be accessed. We also provide recommendations on how tissue donation from patients in early disease stages could be potentially increased and for procedures of tissue sampling and preservation. We also suggest to create a registry of the available tissues that, depending on the source (autopsy versus biopsy), could be made accessible to clinicians and researchers.

Hsa_circ_001659 serves as a novel diagnostic and prognostic biomarker for colorectal cancer

Colorectal cancer (CRC) is prevalent worldwide and novel diagnostic and prognostic biomarkers are needed to improve precision medicine. Circular RNAs (circRNAs) are currently being considered as emerging tumor biomarkers. Herein, we aimed to explore the possible clinical application of circRNAs in the early diagnosis and prognostic prediction of CRC. First, candidate circRNA was selected by integrating analysis of Gene Expression Omnibus (GEO) database using GEO2R program. ROC curve analysis demonstrated the predictive values and likelihood ratios of circ_001659 were satisfactory for the diagnosis of CRC, including patients in early-stage disease or patients with carcinoembryonic antigen (CEA)-negative status. Moreover, serum circ_001659 may be a novel biomarker in the assessment of successful treatment and remission of cancer tracking. We further investigated the oncogenic role of circ_001659. In vivo and in vitro experiments indicated that circ_001659 could promote CRC cell invasion and migration. Mechanistically, circ_001659 was localized in the nucleus, recruited the RBBP5 to Vimentin promoter and increased H3K4 trimethylation level on the Vimentin promoter region, which epigenetically activated Vimentin transcription. Our findings demonstrate that circ_001659 could be a useful serum biomarker for CRC diagnosis and prognosis. Targeting circ_001659 and its pathway may be meaningful for treating patients with CRC.

Abstract A12: Presence of circulating tumor cells is an adverse risk factor for early-stage uveal melanoma

Abstract Introduction: Uveal melanoma (UM) is a rare melanoma; only 5% of cases at initial presentation have distant metastasis. As approximately 50% of patients will develop metastatic disease, there is a need to detect minimal residual disease (MRD). Liquid biopsy using circulating tumor cells (CTCs) has been evaluated in multiple tumors; high CTC count predicts for increased risk of metastasis. We conducted a pilot study to check feasibility of CTCs in UM and evaluate if CTCs vary with risk status in early-stage UM. Methods: We enrolled 40 UM patients ≥18 years, after obtaining informed consent in an IRB-approved protocol from 12/1/2014 to 2/1/2018. Peripheral blood was obtained to detect CTCs using CellSearch Circulating Melanoma Cell Assay. Demographic information, mutational analysis, date of diagnosis of primary UM or metastasis, and dates of CTC collection were collected. Risk stratification was done by gene expression profiling (GEP) by DecisionDX-UM assay. Landmark overall survival (OS) was calculated using “Landest” R package comparing CTC detected vs. not detected in early-stage UM. Results: 39 patients were available for analysis. Median age of whole cohort was 52 years (20-83 years), 100% were non-Hispanic Caucasians, and 44% were male and 56% female. 20 patients had early-stage vs. 19 patients had metastatic disease at enrollment. 87% (13/15) of early-stage disease had class II disease. GNAQ &amp; GNA11 mutations were present in 36% (12/39) and 13% (5/29), respectively. At initial blood draw, 36% of the patients had detectable CTCs [30% (6/20) in early stage vs. 42% (8/19) in metastatic], which increased to 54% at median study follow-up of 16.4 months [40% (8/20) in early stage vs. 68% (13/19) in metastatic]. Mean CTCs were higher in metastatic (9) vs. early stage (1.83) (p&amp;gt;0.05). 5 patients in early-stage disease developed distant metastasis; 60% (3/5) had detectable CTCs before radiographic detection of metastasis. Out 5, 80% had class II disease and 20% had unknown GEP. Landmark overall survival (from study enrollment) at 24 months was statistically worse in CTC detected vs. not detected in early-stage UM (P&amp;lt;0.05). Conclusion: CTCs are more frequently detected in metastatic compared to early-stage UM. In early-stage UM, presence of CTCs predicts for increased risk of metastatic disease and is associated with worse outcome. Citation Format: Jason Roszik, Dan Gombos, Joshua Upshaw, Vanessa Sarli, Salyna Meas, Anthony Lucci, Carolyn Hall, Sapna Patel, Kartik Anand. Presence of circulating tumor cells is an adverse risk factor for early-stage uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A12.

The importance of chain context in assessing small nucleotide variants in titin: in silico case study of the I10-I11 tandem and its arrhythmic right ventricular cardiomyopathy linked position T2580

Non-synonymous small nucleotide variations (nsSNVs) in the giant muscle protein, titin, have key roles in the development of several myopathologies. Although there is considerable motive to screen at-risk individuals for nsSNVs, to identify patients in early disease stages while therapeutic intervention is still possible, the clinical significance of most titin variations remains unclear. Therefore, there is a growing need to establish methods to classify nsSNVs in a simple, economic and rapid manner. Due to its strong correlation to arrhythmogenic right ventricular cardiomyopathy (ARVC), one particular mutation in titin—T2580I, located in the I10 immunoglobulin domain—has received considerable attention. Here, we use the I10-I11 tandem as a case study to explore the possible benefits of considering the titin chain context—i.e. domain interfaces—in the assessment of titin nsSNVs. Specifically, we investigate which exchanges mimic the conformational molecular phenotype of the T2580I mutation at the I10-I11 domain interface. Then, we computed a residue stability landscape for domains alone and in tandem to define a Domain Interface Score (DIS) which identifies several hotspot residues. Our findings suggest that the T2580 position is highly sensitive to exchange and that any variant found in this position should be considered with care. Furthermore, we conclude that the consideration of the higher order structure of the titin chain is important to gain accurate insights into the vulnerability of positions in linker regions and that titin nsSNV prediction benefits from a contextual analysis. Communicated by Ramaswamy H. Sarma

Prediagnostic motor and non-motor symptoms in progressive supranuclear palsy: The step-back PSP study

BackgroundImproved knowledge of the prediagnostic phase of progressive supranuclear palsy (PSP) might provide information on when and how the disease starts, along with the opportunity to test therapies in disease stages with lesser neurodegeneration. ObjectiveTo explore the symptoms in years preceding the PSP diagnosis. MethodsThis is a single-center retrospective case-control study based on clinical charts review and a structured interview to PSP patients and their caregivers. Prediagnostic symptoms were defined as those present more than one year before the diagnosis. We explored 35 symptoms in the following domains: visual, dizziness, motor, mood/apathy, cognitive, behavioral, sleep, gastrointestinal/urinary and miscellaneous. Non-parametric statistics were applied, with significance set at <0.05 (FDR-corrected). ResultsWe included 150 subjects: 50 PSP patients (38% females, age 75.8) and an age- and sex-matched control group of 50 Parkinson's disease (PD) and 50 subjects (CS) without neurodegenerative disease. The frequencies of visual, motor, cognitive, behaviour and dizziness domains were significantly higher in PSP vs. PD, and so were the motor, mood/apathy, cognitive, behaviour and dizziness ones in PSP vs. CS. Over 50% of prediagnostic falls, apathy and anxiety, depression and memory-attention-executive symptoms, and over 30% of gait disturbances started more than three and up to ten years before the diagnosis. PSP patients had more consultations to ENT and ophthalmologists than PD patients. ConclusionPSP patients present a broad variety of motor and non-motor symptoms several years before the diagnosis. The definition of a prediagnostic PSP phase might be helpful to identify patients in early disease stages.

Postoperative outcomes in elderly patients undergoing pancreatic resection for pancreatic adenocarcinoma: A systematic review and meta-analysis.

Pancreatic cancer is a disease of the elderly. Surgical resection is usually offered to patients in early stage disease; however, pancreatic resection in the elderly is controversial. MEDLINE, EMBASE and Cochrane Library, were searched for studies comparing short- and long-term outcomes of elderly (above the age of 70) with non-elderly patients (below the age of 70) following pancreatic resection for pancreatic adenocarcinoma over the period from the inception of electronic database to 2017. Twelve articles documenting 4860 patients were included. A meta-analysis of data on patient characteristics, operative techniques, and perioperative outcomes were analysed. Our primary endpoint was postoperative mortality, defined as 30-day mortality or in-hospitalisation mortality. There were 919 patients in the elderly group and 3941 patients in the non-elderly group. Elderly patients had worse ASA scores (p < 0.001) and more cardiovascular comorbidities (p = 0.002). Tumour size, T-stage, N-stage and tumour grade were similar between the elderly and non-elderly group (p > 0.05). Fewer elderly patients received a concomitant venous resection with their pancreatectomy (RR0.80, p = 0.003, I2 = 0%), achieved a negative margin status (RR0.76, p = 0.02, I2 = 28%) and underwent adjuvant chemotherapy treatment (RR0.69, p < 0.001, I2 = 42%). Overall complication (RR1.15, p < 0.001, I2 = 47%), in particular, respiratory complications (RR2.33, p = 0.004, I2 = 39%), was higher in the elderly group. There was no difference in postoperative pancreatic fistula formation, postoperative haemorrhage, intraabdominal abscess and length of hospital stay between both groups (p > 0.05). Postoperative mortality was similar between both groups (p = 0.17). Subgroup analysis according to the time of enrolment (<2000, ≥2000) showed a significant subgroup effect (Chi2 = 3.44, p = 0.06, I2 = 70.9%) and revealed that postoperative mortality in the elderly group improved over time (Before 2000: n = 1654, subtotal RR2.27, p = 0.02, I2 = 0%; From 2000 onwards: n = 3206, subtotal RR1.00, p = 0.99, I2 = 0%). Fewer elderly patients received chemotherapy and portal vein resection to achieve a clear margin. Pancreatic resection of pancreatic adenocarcinoma can be performed safely on elderly patients with acceptable risks in experienced centres by specialist hepatobiliary surgeons. Age alone should not be the only determinant for the selection of patients for surgical treatment of pancreatic adenocarcinoma.

Challenges and solutions in patient treatment strategies for stage II colon cancer.

Colorectal cancer remains one of the most common cancers worldwide and, despite improvements in treatment options for late-stage metastatic cancer, there are still questions surrounding how best to treat early-stage disease patients. Some recent advances have been made in the staging of cancer and improving the risk assessment of strategies for patient treatment. A number of high-risk features have been proposed that may help to stratify stage II cancer patients into groups that will truly benefit from adjuvant chemotherapy. Diagnostic tests are becoming available to measure these biomarkers, utilizing both currently available and novel technologies. This review will describe the challenges in treatment decisions for early-stage colon cancer and how personalized medicine can assist clinicians in making the best treatment choices for patients with stage II colon cancer in particular.

Divergent effects on macrophage biomarkers soluble CD163 and CD206 in axial spondyloarthritis

The chronic joint inflammation in axial spondyloarthritis (axSpA) is characterized by infiltration of activated macrophages. The haptoglobin–hemoglobin receptor CD163 and the mannose receptor CD206 are strongly expressed on M2c and M2a macrophages, respectively. We measured the soluble forms of the receptors (sCD163 and sCD206) in plasma (PL) in two axSpA cohorts. All patients fulfil the 2009 Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axSpA and/or the 1984 modified New York criteria for ankylosing spondylitis. The first cohort included anti-TNF-α treated patients with active axSpA (n = 30); the second cohort included patients in early disease stages (n = 38). Plasma sCD163 and sCD206 were both within the reference interval of healthy controls (HC), but sCD163 decreased slightly during anti-TNF-α treatment [baseline: 1.49 mg/L (IQR: 1.22–1.77 mg/L, 12 weeks: 1.29 (IQR: 1.09–1.57) mg/L, 20 weeks: 1.25 (IQR: 0.99–1.75) mg/L, 52 weeks: 1.39 (IQR: 1.15–1.78) mg/L], while sCD206 increased [baseline: 0.17 (IQR: 0.13–0.21) mg/L, 12 weeks: 0.19 (0.16–0.23) mg/L, 20 weeks: 0.20 (0.14–0.24) mg/L, 52: 0.19 (IQR: 0.14–0.23) mg/L], pointing toward a shift in polarization of involved macrophages. Plasma levels of sCD206 proved significantly higher in patients with early disease stages and definite radiological sacroiliitis (n = 10). This was not the case for sCD163. A significant increase in response to anti-TNF-α treatment, could suggest sCD206 as a marker of response to anti-TNF-α treatment, however, the potential for the two macrophage markers as diagnostic and prognostic indicators of disease in axSpA is weak.

Abstract 1422: NEBNext Direct® Custom Ready myeloid genes for NGS target enrichment

Abstract Comprehensive genetic evaluation of patients with blood cancer can be imperative for identifying and classifying myeloid malignancies in a patient. Since liquid tumors comprise of highly variable percentages of normal cells or multiple tumor clones, this type of screening is critical for early stage disease patients where a cytogenetic profile informs diagnosis or disease stratification, prognosis, and treatment options. For patients with late-stage disease, genetic testing can assist in choosing options for alternative treatments, including targeted therapies. Thus, next generation sequencing technologies are needed that can provide the sensitivity and specificity to identify these genetic complexities. Here we introduce a selection of over 50 genes from the NEBNext Direct® Custom Ready gene catalog that are known to be involved in myeloid malignancies. The NEBNext Direct® technology uses a novel approach to selectively enrich nucleic acid targets, and rapid customized panels can be generated by combining one to several hundred genes from the Custom Ready catalog. Unlike alternative hybridization methods, NEBNext Direct® does not require upfront library preparation. The approach rapidly hybridizes both strands of genomic DNA to biotinylated baits, captures the targets on streptavidin beads, enzymatically removes off-target sequence, and directly converts captured molecules into Illumina-compatible sequencing libraries in a single day protocol. A 12-base unique molecular identifier (UMI) tags each individual molecule prior to the final PCR amplification to enable identification of PCR duplicates, and an 8-base barcode is added to each library during PCR for high-throughput pooling. With 100ng of DNA input the panel provides highly uniform coverage and approximately 95% of sequence reads map to the targeted myeloid genes. The NEBNext Direct® Custom Ready myeloid genes demonstrate a high-throughput and cost-effective approach for the rapid and sensitive analysis of exon coding regions (~200kb) for over 50 oncogenic genes important in the pathogenesis of these types of blood disorders. These gene mutations are powerful prognostic markers that can be used as a guide for effective patient management. Citation Format: Scott M. Adams, Kruti M. Patel, Amy B. Emerman, Sarah K. Bowman, Charles D. Elfe, Evan Mauceli, Andrew Barry, Theodore Davis, Cynthia L. Hendrickson. NEBNext Direct® Custom Ready myeloid genes for NGS target enrichment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1422.

Partial volume-aware assessment of multiple sclerosis lesions.

White-matter lesion count and volume estimation are key to the diagnosis and monitoring of multiple sclerosis (MS). Automated MS lesion segmentation methods that have been proposed in the past 20 years reach their limits when applied to patients in early disease stages characterized by low lesion load and small lesions. We propose an algorithm to automatically assess MS lesion load (number and volume) while taking into account the mixing of healthy and lesional tissue in the image voxels due to partial volume effects. The proposed method works on 3D MPRAGE and 3D FLAIR images as obtained from current routine MS clinical protocols. The method was evaluated and compared with manual segmentation on a cohort of 39 early-stage MS patients with low disability, and showed higher Dice similarity coefficients (median DSC = 0.55) and higher detection rate (median DR = 61%) than two widely used methods (median DSC = 0.50, median DR < 45%) for automated MS lesion segmentation. We argue that this is due to the higher performance in segmentation of small lesions, which are inherently prone to partial volume effects.

Inhibition of \u03b2-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

Recent metabolomic reports connect dysregulation of glycosphingolipids, particularly ceramide and glucosylceramide, to neurodegeneration and to motor unit dismantling in amyotrophic lateral sclerosis at late disease stage. We report here altered levels of gangliosides in the cerebrospinal fluid of amyotrophic lateral sclerosis patients in early disease stage. Conduritol B epoxide is an inhibitor of acid beta-glucosidase, and lowers glucosylceramide degradation. Glucosylceramide is the precursor for all of the more complex glycosphingolipids. In SOD1G86R mice, an animal model of amyotrophic lateral sclerosis, conduritol B epoxide preserved ganglioside distribution at the neuromuscular junction, delayed disease onset, improved motor function and preserved motor neurons as well as neuromuscular junctions from degeneration. Conduritol B epoxide mitigated gene dysregulation in the spinal cord and restored the expression of genes involved in signal transduction and axonal elongation. Inhibition of acid beta-glucosidase promoted faster axonal elongation in an in vitro model of neuromuscular junctions and hastened recovery after peripheral nerve injury in wild type mice. Here, we provide evidence that glycosphingolipids play an important role in muscle innervation, which degenerates in amyotrophic lateral sclerosis from the early disease stage. This is a first proof of concept study showing that modulating the catabolism of glucosylceramide may be a therapeutic target for this devastating disease.

YI02.03 Dose Limitations for Radiotherapy of Lung Cancer

YI02.03 Dose Limitations for Radiotherapy of Lung Cancer

Reversal learning reveals cognitive deficits and altered prediction error encoding in the ventral striatum in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative condition characterized by a triad of movement disorder, neuropsychiatric symptoms and cognitive deficits. The striatum is particularly vulnerable to the effects of mutant huntingtin, and cell loss can already be found in presymptomatic stages. Since the striatum is well known for its role in reinforcement learning, we hypothesized to find altered behavioral and neural responses in HD patients in a probabilistic reinforcement learning task performed during functional magnetic resonance imaging. We studied 24 HD patients without central nervous system (CNS)-active medication and 25 healthy controls. Twenty HD patients and 24 healthy controls were able to complete the task. Computational modeling was used to calculate prediction error values and estimate individual parameters. We observed that gray matter density and prediction error signals during the learning task were related to disease stage. HD patients in advanced disease stages appear to use a less complex strategy in the reversal learning task. In contrast, HD patients in early disease stages show intact encoding of learning signals in the degenerating left ventral striatum. This effect appears to be lost with disease progression.

Quality of life in Chilean breast cancer survivors

Quality of Life (QOL) assessment may evaluate the impact of diseases and their treatment on the overall well-being of patients. To assess QOL in Chilean breast cancer survivors. Ninety one female breast cancer patients aged 60 ± 10 years, who finished their oncologic treatment at least a year prior to the assessment, who were disease free and in medical follow-up were included in the study. They completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 core questionnaire and the breast cancer module QLQ-BR23. Forty eight percent of respondents were long term survivors (more than five years). Global QOL scores were high (73.6 ± 18.2), emotional scale had the lowest scores in QLQ-C30 functional scales (72.1). Symptoms with the highest scores were: Insomnia (= 21.2), pain (= 20.8), and fatigue (= 19.1). Body image, sexual function, and concern about the future were the most relevant problems. Body image was superior in patients with breast-conserving surgery (p = 0.008), and cognitive function was better in patients in early disease stage (p = 0.03) and in those with more than five years of survival (p = 0.04). Even when global QOL scores were high, some symptoms were prevalent. Awareness about these problems and symptoms should improve their diagnosis and treatment.

Tissue damage within normal appearing white matter in early multiple sclerosis: assessment by the ratio of T1- and T2-weighted MR image intensity.

Histopathological and magnetic resonance imaging (MRI) studies have shown white matter (WM) damage in early stages of multiple sclerosis (MS) beyond the apparent T2-hyperintense lesions. These changes in normal appearing WM (NAWM) are important with regard to the clinical picture and prognosis. However, the detection of changes within NAWM has so far required special imaging techniques commonly not available in clinical routine and, hence, at large scale. The purpose of this study was to detect MS-related damage of NAWM by conventional MRI. As, within NAWM, the myelin content mainly drives the T1-weighted (T1w) signal, we scaled it by the T2w signal. We tested the hypothesis that the mean T1w/T2w ratio of NAWM is decreased in MS compared to healthy controls (HC) and that it correlates with clinical measures. We developed a pipeline to determine the individual mean values of this ratio within NAWM. We studied 244 patients in early disease stages of MS (mean age 37±10years, mean disease duration 3.1±2.3, Expanded Disability Status Scale 1.3±1), and 78 HC (mean age 31±8years). Compared to HC, the mean T1w/T2w ratio was lowered in the patient group (P<0.001). The difference remained significant after restricting the analysis to patients with a disease duration of 5years or less and without disease modifying drugs. Our measures also correlated with clinical scores. We believe that the mean T1w/T2w ratio is a promising candidate to assess MS-related tissue damage within NAWM at large scale.