Somatic Outcomes Research Articles

Somatic outcomes in a phase 1/2 study of weekly intravenous DNL310 (brain-penetrant enzyme replacement therapy) in mucopolysaccharidosis type II

Somatic outcomes in a phase 1/2 study of weekly intravenous DNL310 (brain-penetrant enzyme replacement therapy) in mucopolysaccharidosis type II

The nocebo effect across health outcomes: A systematic review and meta-analysis.

The nocebo effect represents a growing concern in clinical settings. Nocebo effects occur when the treatment context generates negative expectancies that trigger the experience or worsening of negative symptoms beyond any effects attributable to the treatment itself. Despite being identified in a range of outcomes and conditions, from pain to Parkinson's disease, there has not been an attempt to systematically quantify the nocebo effects across health outcomes. The purpose of the present review was thus to systematically review and meta-analyze the nocebo literature to quantify the size of the nocebo effect across outcomes and examine which factors moderate the size of the nocebo effect, including process of induction, treatment type, or health outcome. Systematic searches of PubMed, PychInfo, Medline, and Web of Science identified 130 (n = 8,219) independent eligible studies. To be included, studies had to include both a nocebo and control group/condition, which were compared to isolate the nocebo effect size. Overall, the magnitude of the nocebo effect was medium (g = 0.522) and highly heterogeneous. Two key moderators emerged: health outcome and process of induction. Here, the nocebo effect was medium for most somatic outcomes and affect, with no significant effect on worsening cognitive performance. Further, inducing nocebo effects through instruction in combination with conditioning produced larger nocebo effects. The present review suggests nocebo effects can be reliably induced across somatic health outcomes, and interventions that target the effect of instructions will be of critical importance to reducing the occurrence of nocebo effects. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Corpus delicti: the medico-legal evaluation of somatic outcomes in asylum seekers victims of torture and other inhuman and degrading treatments in the Metropolitan City of Rome, Italy

Corpus delicti: the medico-legal evaluation of somatic outcomes in asylum seekers victims of torture and other inhuman and degrading treatments in the Metropolitan City of Rome, Italy

Becoming a Teenager after Early Surgical Ventricular Septal Defect (VSD) Repair: Longitudinal Biopsychological Data on Mental Health and Maternal Involvement

Beside somatic strains of congenital heart diseases (CHD), affected children often show developmental impairments in the long term. Ventricular septal defect (VSD) is the most common congenital heart defect and early surgical repair is associated with positive somatic outcomes. However, psychological adjustment is of lifelong relevance. We investigated 24 children with a surgically-corrected isolated VSD and their mothers from primary school (6-9 years) to adolescence (10-14 years) and compared them to controls. Both times, mothers reported child internalizing/externalizing problems, mothers and children rated child quality of life, and children performed neurodevelopmental tests. Adolescents also rated internalizing/externalizing problems themselves, and their hair cortisol levels were analyzed. Maternal anxiety and proactive parenting behavior were considered as moderators. Results revealed no group differences in child neurodevelopment (language, cognition), externalizing problems, and cortisol levels at any time. In reports from mothers, internalizing problems (depression, anxiety) were elevated in children with a VSD at both times-when mothers reported anxiety symptoms themselves. In adolescent reports, VSD patients' quality of life was increased and internalizing problems were decreased-proactive parenting behavior went along with decreased symptoms in VSD-affected adolescents and with increased symptoms in controls. The findings pronounce the crucial role of parenting behavior and the influence of maternal anxieties on child mental health after surgical VSD repair and might highlight the need for parent-centered interventions.

Virtual Reality in Palliative Care: A Systematic Review.

Background: Virtual reality (VR) using head-mounted displays (HMDs) has demonstrated to be an effective tool for treating various somatic and psychological symptoms. Technological advances and increased affordability of VR technology provide an interesting option for delivering psychological interventions to patients in palliative care. The primary aim of this systematic review was to synthesise the available research on the use of VR for enhancing psychological and somatic outcomes for palliative care patients. Secondary aims included assessing general satisfaction and overall usability. Method: A pre-registered systematic literature search was conducted according to PRISMA guidelines using OVID Emcare, Cochrane Library, Embase, Medline, PsycINFO, and PubMed Care Search: Palliative Care Knowledge Network. Peer-reviewed experimental, quasi-experimental, observational, case, and feasibility studies consisting of single or multiple VR sessions using HMDs that reported psychological and/or somatic outcomes were included. Results: Eight studies published between 2019 and 2021 were included, representing 138 patients. While the reported quantitative psychological and somatic outcomes were ambiguous, the qualitative outcomes were largely positive. Participants were generally satisfied with VR, and most studies reported the VR interventions as usable, feasible, and acceptable. Conclusions: VR shows promise in palliative care and generally addresses a range of symptoms with few adverse effects. Future research should consist of adequately powered RCTs evaluating dosage and focusing on providing meaningful activities to enhance outcomes further.

The Psychological and Somatic Consequences of Digital Amputation.

Background:Major limb amputation is a devastating potential outcome of trauma, tumor, or disease. Much has been written about the physical, functional, economic, and psychological consequences of major limb loss. In contradistinction, considerably less has been written concerning the consequences of “minor” limb loss, specifically single partial digit amputations. Are minor limb (partial single digit) amputations associated with symptoms of psychological disorder similar to those reported for major limb amputations?Methods:We conducted a clinical research study through interview and examination of 25 adult patients (average age: 45 years) who had suffered a single partial digit amputation to determine if symptoms of depression, anxiety, anger, or posttraumatic stress disorder newly occurred, and if such symptoms correlated with the surgical outcome. Questionnaires for Quick-DASH, Michigan Hand Score, and Diagnostic and Statistical Manual of Mental Disorders-5 Psychological Profile testing were completed.Results:All but one of the patients suffered from psychological symptoms for a minimum of 3 months. Symptom resolution time averaged 6 months for seven of the 25 patients. For 18 of the 25 patients, both psychological disturbance and neuroma pain were ongoing. The Psychological Profile scores suggesting pathology were inversely related to the scores on the Quick-Dash and Michigan Hand (somatic) questionnaires indicating wellness (P < 0.03).Conclusions:(1) Even minor partial amputations of single digits can trigger significant psychological disturbance; the study hypothesis is validated. (2) Psychological and somatic outcomes are directly correlative. (3) Mitigating neuroma pain and verbally offering psychological support services early in the postamputation period should improve the clinical outcome of digital amputations.

The effect of active visual art therapy on health outcomes: protocol of a systematic review of randomised controlled trials

BackgroundArt therapy is a form of complementary therapy to treat a wide variety of health problems. Existing studies examining the effects of art therapy differ substantially regarding content and setting of the intervention, as well as their included populations, outcomes, and methodology. The aim of this review is to evaluate the overall effectiveness of active visual art therapy, used across different treatment indications and settings, on various patient outcomes.MethodsWe will include randomised controlled studies with an active art therapy intervention, defined as any form of creative expression involving a medium (such as paint etc.) to be actively applied or shaped by the patient in an artistic or expressive form, compared to any type of control. Any treatment indication and patient group will be included. A systematic literature search of the Cochrane Library, EMBASE (via Ovid), MEDLINE (via Ovid), CINAHL, ERIC, APA PsycArticles, APA PsycInfo, and PSYNDEX (all via EBSCOHost), ClinicalTrials.gov and the WHO’s International Clinical Trials Registry Platform (ICTRP) will be conducted. Psychological, cognitive, somatic and economic outcomes will be used. Based on the number, quality and outcome heterogeneity of the selected studies, a meta-analysis might be conducted, or the data synthesis will be performed narratively only. Heterogeneity will be assessed by calculating the p-value for the chi2 test and the I2 statistic. Subgroup analyses and meta-regressions are planned.DiscussionThis systematic review will provide a concise overview of current knowledge of the effectiveness of art therapy. Results have the potential to (1) inform existing treatment guidelines and clinical practice decisions, (2) provide insights to the therapy’s mechanism of change, and (3) generate hypothesis that can serve as a starting point for future randomised controlled studies.Systematic review registrationPROSPERO ID CRD42021233272

The role of ADHD genetic risk in mid-to-late life somatic health conditions

Growing evidence suggests that ADHD, an early onset neurodevelopmental disorder, is associated with poor somatic health in adulthood. However, the mechanisms underlying these associations are poorly understood. Here, we tested whether ADHD polygenic risk scores (PRS) are associated with mid-to-late life somatic health in a general population sample. Furthermore, we explored whether potential associations were moderated and mediated by life-course risk factors. We derived ADHD-PRS in 10,645 Swedish twins born between 1911 and 1958. Sixteen cardiometabolic, autoimmune/inflammatory, and neurological health conditions were evaluated using self-report (age range at measure 42–88 years) and clinical diagnoses defined by International Classification of Diseases codes in national registers. We estimated associations of ADHD-PRS with somatic outcomes using generalized estimating equations, and tested moderation and mediation of these associations by four life-course risk factors (education level, body mass index [BMI], tobacco use, alcohol misuse). Results showed that higher ADHD-PRS were associated with increased risk of seven somatic outcomes (heart failure, cerebro- and peripheral vascular disease, obesity, type 1 diabetes, rheumatoid arthritis, and migraine) with odds ratios ranging 1.07 to 1.20. We observed significant mediation effects by education, BMI, tobacco use, and alcohol misuse, primarily for associations of ADHD-PRS with cardiometabolic outcomes. No moderation effects survived multiple testing correction. Our findings suggests that higher ADHD genetic liability confers a modest risk increase for several somatic health problems in mid-to-late life, particularly in the cardiometabolic domain. These associations were observable in the general population, even in the absence of medical treatment for ADHD, and appear to be in part mediated by life-course risk factors.

Effectiveness and implementation of a multidisciplinary lifestyle focused approach in the treatment of inpatients with mental illness (MULTI\u2009+): a stepped wedge study protocol

BackgroundPeople with mental illness have a reduced life expectancy compared to the general population. Despite the increasing evidence for the efficacy of lifestyle interventions there is little change in routine clinical care. This discrepancy is often referred to as the implementation gap and has caused a need for effectiveness and implementation research in real-world settings. Our study assesses the effectiveness and implementation of a multidisciplinary lifestyle focused approach in the treatment of inpatients with mental illness (MULTI +).MethodsAn open cohort stepped wedge cluster randomized trial in inpatients psychiatric wards of GGz Centraal, the Netherlands. The wards are divided into three clusters based on geographical region. These clusters are randomly allocated to one of the three pre-defined steps to integrate MULTI + . MULTI + can be tailored to fit individual psychiatric wards and includes 10 core components aimed at improving lifestyle factors. The primary outcome is to investigate the difference in the mean QRISK3 score of patients receiving MULTI + compared to patients receiving TAU. Secondary outcomes include somatic and mental health outcomes, lifestyle factors, and implementation factors. Findings will be analysed using mixed model analyses.DiscussionThe MULTI + study is the first large-scale study evaluating the long-term effects of a multidisciplinary, multicomponent approach aimed at improving lifestyle factors in routine inpatient mental health care. A limitation of this study is the risk of missing data due to the large-scale, real-world setting of this study. Furthermore, implementation monitoring and external events that may influence outcomes could be difficult to account for. Strengths of this study are the focus on effectiveness as well as implementation and the inclusion of both patient and health care professionals’ perspectives. Effectiveness studies in routine clinical care can advance our knowledge on lifestyle interventions in real-world settings.Trial registrationClinicalTrials.gov registration. Identifier: NCT04922749. Retrospectively registered 3th of June 2021.

How do US military veterans with serious mental illness manage insomnia? A phenomenological analysis.

Insomnia is a prevalent experience for individuals with serious mental illness, and is one of the most common reasons for mental health referrals in the Veterans Health Administration. Insomnia also critically impacts psychiatric, cognitive and somatic outcomes. However, there is limited information about how people with serious mental illness (i.e. schizophrenia spectrum, bipolar, or major depressive disorders, with serious functional impairments) understand and respond to problems with their own sleep. Bringing this information to light will yield novel methods of research and treatment. The purpose of this study was to examine reactions to insomnia among veterans with serious mental illness and insomnia. An inductive phenomenological approach was used to collect data from 20 veterans with serious mental illness and insomnia using semi-structured interviews. Six themes were identified: Becoming Aware that Insomnia is a Problem; Response to and Dissatisfaction with Medications; Strategies to Get Better Sleep: Contrary to Usual Guidelines; Personal Responsibility for Getting Sleep; Resigned and Giving Up; and Acceptance and Persistence. These results provide insight into the process of identifying insomnia and the subsequent cognitive and behavioural responses that are used to manage sleep disturbances among veterans with serious mental illness, a group often excluded from gold-standard treatments for chronic insomnia. Clinical implications and recommendations for improving treatment efficacy are discussed.

Mortality and acute somatic events following electroconvulsive therapy in patients with pre-existing somatic comorbidity – A register-based nationwide Danish cohort study

Objective To examine whether electroconvulsive therapy (ECT) is associated with risk of mortality and acute somatic events in patients with or without somatic comorbidity. Methods A total of 174,495 patients with an affective disorder, of whom 41% had somatic comorbidity, were followed from 2005 through 2018 for ECT, mortality, and acute somatic outcomes using Danish registers. The association of ECT with outcomes was estimated using Cox proportional hazard regression. Results Patients, of whom 6943 (4.0%) had ECT, were followed for a median of 6.7 years. Compared to non-ECT treated patients, ECT was associated with a lower risk of death from natural causes, which was independent of somatic comorbidity. ECT was not associated with the risk of acute somatic events neither in patients with somatic comorbidity nor in patients without somatic comorbidity, except for cardiac events within 0–30 days of follow-up after the first ECT, for which there was a 3.7-fold higher risk in patients with no somatic comorbidity. This analysis, however, was based on few events. Conclusion In modern clinical practice, in patients with affective disorders and somatic comorbidity, ECT is not associated with a higher risk of death from natural causes or acute somatic events.

Diet, Physical Activity, and Disinhibition in Middle-Aged and Older Adults: A UK Biobank Study.

Disinhibition is a prominent feature of multiple psychiatric disorders, and has been associated with poor long-term somatic outcomes. Modifiable lifestyle factors including diet and moderate-to-vigorous physical activity (MVPA) may be associated with disinhibition, but their contributions have not previously been quantified among middle-aged/older adults. Here, among N = 157,354 UK Biobank participants aged 40–69, we extracted a single disinhibition principal component and four dietary components (prudent diet, elimination of wheat/dairy/eggs, meat consumption, full-cream dairy consumption). In addition, latent profile analysis assigned participants to one of five empirical dietary groups: prudent-moderate, unhealthy, restricted, meat-avoiding, low-fat dairy. Disinhibition was regressed on the four dietary components, the dietary grouping variable, and self-reported MVPA. In men and women, disinhibition was negatively associated with prudent diet, and positively associated with wheat/dairy/eggs elimination. In men, disinhibition was also associated with consumption of meat and full-cream dairy products. Comparing groups, disinhibition was lower in the prudent-moderate diet (reference) group compared to all other groups. Absolute βs ranged from 0.02–0.13, indicating very weak effects. Disinhibition was not associated with MVPA. In conclusion, disinhibition is associated with multiple features of diet among middle-aged/older adults. Our findings foster specific hypotheses (e.g., early malnutrition, elevated immune-response) to be tested in alternative study designs.

Organization of Community Mental Health Services for Persons with a Severe Mental Illness and Comorbid Somatic Conditions: A Systematic Review on Somatic Outcomes and Health Related Quality of Life.

It is well established that persons with a severe mental illness (SMI) have a greater risk of physical comorbid conditions and premature mortality. Most studies in the field of community mental health care (CMHC) have only focused on improving cardiovascular health in people with a SMI using lifestyle approaches. Studies using organizational modifications are rather scarce. This systematic review aimed to synthesize and describe possible organizational strategies to improve physical health for persons with a SMI in CMHC. The primary outcome was Health-related Quality of Life (HR-QOL). Results suggested modest effects on quality of life and were inconsistent throughout all the included studies. Despite these findings, it appears that a more integrated approach had a positive effect on health outcomes, patient satisfaction and HR-QOL. The complexity of the processes involved in community care delivery makes it difficult to compare different models and organizational approaches. Mental health nurses were identified as possible key professionals in care organization, but no clear description of their role was found. This review could provide new insights into contributing factors for integrated care. Future research targeting the identification of the nurses’ role and facilitating factors in integrated care, in order to improve treatment and follow-up of somatic comorbidities, is recommended.

Effects of Smoking Status on Remission and Metabolic and Cognitive Outcomes in Schizophrenia Patients Treated with Clozapine.

Even though clozapine is the recommended last-resort antipsychotic, many patients fail to respond and show treatment-refractory psychotic symptoms. Smoking has been suggested as a possible risk factor for poor clozapine response, hampering remission and negatively impacting somatic outcomes. Our aim was to test whether smoking status is associated with remission rates and other symptomatic and somatic outcomes. We therefore assessed remission rates according to The Remission in Schizophrenia Working Group (RSWG) criteria, and metabolic and cognitive outcomes among patients with schizophrenia-spectrum disorders treated with clozapine for at least 6 months. For analyses, we grouped our cohort into 3 groups according to clozapine treatment duration (6 months, 2 years, 5 years). One hundred five patients were included in our analyses and grouped according to their clozapine treatment duration. In the 6-months analyses, patients who smoked were significantly more likely to be younger of age (p=0.002) despite on average shorter duration of clozapine treatment (p=0.041) and significantly more likely to be treated with mood-stabilizing co-medication (p=0.030) compared to nonsmokers. Remission rates (p=0.490), as well as a set of metabolic and cognitive variables did not differ between the 2 groups. A related pattern could be observed for the 2- and 5-years analyses. Smoking behavior among clozapine-treated schizophrenia patients might delineate a cohort with an earlier onset of the disease. Nevertheless, most findings comparing disease-specific and clinical outcomes among smokers and nonsmokers were negative. Further research is needed to identify strategies to overcome insufficient remission rates in this patient group.

1164 Prospective Associations Between Sleep Duration, Variability and Timing and Diseases from an Electronic Health Record Biobank in 24,065 Individuals

Abstract Introduction Implementation of electronic health records (EHR) across healthcare systems linking clinical to survey data has enabled systematic assessments of longitudinal relationships between sleep traits and diseases classified by PheWAS codes where ICD-9/10 codes are collapsed to categories based on clinical similarity. In the Partners Biobank, a hospital-based virtual cohort from Mass General Brigham in greater Boston, MA, we aimed to assess associations between sleep traits and incident diseases. Methods Self-reported weekday/weekend bed and wake times from a survey at consent were used to derive sleep traits. Incident diseases were defined as two incident PheWAS codes on separate dates ≥1y after consent. Cox proportional hazards models compared short (&amp;lt;7h) and long (≥9h) sleep duration, with 7-8h (referent group), adjusted for age, gender, race/ethnicity, and employment status, then further adjusted for BMI. Similarly, sleep midpoint (midpoint between weekend wake/bed times), sleep debt (difference in weekend/weekday sleep duration), and social jetlag (difference in weekend/weekday sleep midpoint) were assessed. Results The analytical sample consisted of 24,065 adults (mean sleep duration =8.12h) seeking regular care with sleep data. Participants had a total of 7,513,649 ICD codes of which incident 323,946 ICD codes mapped to 137,137 PheWAS codes. Over a median follow-up of 2.73 years (interquartile range: 1.82-3.98), participants sleeping &amp;lt;7h had a significantly higher risk of incident Acute pain [hazard ratio(95% confidence interval)=1.46(1.2-1.78)], Tobacco use disorder [1.42(1.18-1.71)], Sciatica [1.72(1.3-2.27)], and Edema [1.69(1.25-2.28)]. Each additional hour of later sleep midpoint and increased sleep debt and social jetlag associated with higher risk of incident Major depressive disorder [midpoint:1.30(1.14-1.49); debt:1.23(1.09-1.38); jetlag:1.54(1.27-1.84)]. Associations retained significance upon further adjustment for BMI, except for Edema, and no other associations were observed at the Bonferroni threshold (P=0.0125). Conclusion Our findings in a large hospital-based virtual cohort support unique inter-relationships between sleep duration/timing on somatic, behavioral, and mental health outcomes. Support H.S.D. and R.S. are supported by NIDDK grant R01DK107859. B.C. is supported by K01-HL135405-01. S.R. and R.S. are partially supported by R35 NHLBI HL 135816.

Factor Analyses and Validity of the Transplant Evaluation Rating Scale (TERS) in a Large Sample of Lung Transplant Candidates.

ObjectiveIt is well known that the occurrence of mental disorders is more common in lung transplant candidates compared to the general population. After transplantation mental disorders may negatively affect quality of life, adherence to immunosuppressive medication, as well as overall survival. Therefore, the identification of patients at risk is of utmost importance and in Germany pre-transplant psychosocial evaluation of the patients is required. To ensure high quality and comparability of these assessments, the use of psychometrically sound instruments is recommended. We applied the Transplant Evaluation Rating Scale (TERS), a broadly used expert interview. Two research groups have detected a two-factor structure of the TERS in different transplant samples; however, with slightly different results. The present study investigated which of the models would fit best in our sample of lung transplant patients. Additionally, we assessed convergent and predictive validity of the best fitting model to evaluate its clinical usefulness.MethodsBetween 2016 and 2019, 390 lung transplant candidates were evaluated and included in the study. The median age was 53 years and 54% were male. TERS interviews were conducted by trained medical doctors and psychologists. The participants completed questionnaires assessing quality of life and levels of depression and anxiety. Transplant- and disease-specific variables (lung disease, listing date, oxygen use) were taken from the patient charts. Confirmatory factor analysis was used to test the two proposed TERS-models in the present sample.ResultsThe two-factor structure of the TERS reported by Hoodin and Kalbfleisch fit our sample best, showing good psychometric properties. The factor “emotional sensitivity” was highly correlated with quality of life and measures of psychosocial health while the factor “defiance” correlated with obstructive lung disease and older age but not with quality of life. The two factors showed differential predictive validity with regard to time until listing and pulmonary-specific quality of life 1 year after transplantation.ConclusionsThe two factors showed good psychometric properties, and differential convergent and predictive validity. However, further studies concentrating on the predictive value of the TERS and its factors regarding somatic outcomes (mortality, graft functioning) are required.

Somatic outcomes of young people with chronic diseases participating in transition programs: a systematic review

AbstractIntroductionThere is growing evidence that the health of young people with chronic health conditions deteriorates during the transfer from child-centred to adult-oriented health care. Risks include not only the deterioration of health status in general but also the occurrence of secondary diseases and adverse events. Transition programs have been implemented. However, there is a lack of evidence about whether they reduce these risks and which interventions should be principally included. Evidence-based guidelines for the transition of young people should be introduced. In this study we therefore aim to summarise actual evidence on somatic outcomes during the transition period.MethodsA systematic literature review was conducted. Two independent reviewers searched in electronic databases (Cochrane, Embase, PubMed, Web of Science) for intervention studies that aimed to improve transition. Last update of search was October 31st 2018. Grey literature was also searched. Studies were included if they examined participants aged 11 years or older suffering from a chronic health condition and evaluated interventions aimed to improve somatic outcomes after transition. Controlled trials or studies with a measurement before and after intervention were considered. The certainty of evidence was assessed using the GRADE approach. Additionally, each study was graded using a modified grading scale based on GRADE.Results28 studies met the inclusion criteria. Patients suffered from different chronic conditions such as type 1 diabetes, solid organ transplantation, inflammatory bowel disease or cystic fibrosis. Interventions had different components such as transition checklists, workshops, web-based interventions, transition plans, joint visits or transition coordinators. Outcomes included mortality and morbidity. They varied according to chronic condition. Thirteen studies showed beneficial effects in the intervention group or in post-intervention measurements. The certainty of evidence was very low.ConclusionA considerable number of studies evaluating transition interventions was identified. Transition interventions had some beneficial effects. Workshops, joint visits and longer or multidisciplinary appointments may be particularly effective components. Transition guidelines could be based on these results. However, due to the limitations of the included studies it is difficult to draw firm conclusions. More research is needed to further evaluate the effectiveness of transition interventions. It should address the deficits identified from prior studies, such as poor study design, short follow-up time or small sample sizes.

Case series examining somatic test results for patients with hereditary cancer syndromes associated with gastrointestinal cancer risk.

680 Background: Somatic tumor testing may identify germline pathogenic variants (PV) associated with cancer predisposition syndromes. Labs differ whether they offer somatic only or paired germline analysis. Methods used by somatic testing labs, even those that include germline analysis, differ from designated germline labs that have optimized the identification of germline PV. Methods: Chart reviews were performed for patients who had testing through both somatic and designated germline laboratories. Cases with discrepant results in which germline PV were not detected by the somatic laboratory are summarized. Results: Nine cases with discrepant results. Five had paired germline testing and 4 somatic testing only. All 9 patients met the criteria to undergo designated germline testing, either for Lynch syndrome (3) or BRCA1/2 testing (6), based on personal and/or family history. Designated germline testing identified 4 MLH1, 1 BRCA1, 2 ATM, 1 MUTYH and 1 RAD50 PV not reported by the somatic labs’ tumor or germline analysis; 2 MLH1 PV were called variants of uncertain significance by somatic testing but classified as PV by ClinVar and designated germline labs. Three PV identified by designated germline labs are targets for PARP inhibitors and resulted in different treatment options. Three of the MLH1 PV were identified in patients meeting Lynch Syndrome test criteria while 1 was identified in a patient meeting BRCA1/2 criteria. Among the 5 other patients meeting BRCA1/2 test criteria, 3 had PV in breast cancer genes (2 ATM, 1 BRCA1) and 2 had PV in other cancer genes ( MUTYH and RAD50) not reported by the somatic labs, highlighting the importance of panel testing. Conclusions: Methods used by somatic labs, regardless of inclusion of germline analysis, are not equivalent to those of designated germline labs. Overlooked germline PV may miss identification of hereditary syndromes and targeted therapy opportunities (e.g. Anti-PD1 immunotherapy, PARP inhibitors). Patients meeting criteria for genetic evaluation should be referred for designated germline testing regardless of somatic testing outcomes.

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5–13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made.

Abstract 4352: Genetic effects on gene expression and survival in patients with multiple myeloma

Abstract Multiple myeloma (MM) is the second most common hematological cancer, accounting for 2% of all cancer deaths. MM is associated with a poor prognosis, with a 5-year overall survival of 50.7%. While the introduction of new therapies in the last decade has nearly doubled the survival rate, most patients still experience a relapse. To this end, The Multiple Myeloma Research Foundation developed the CoMMpass study. CoMMpass is a longitudinal clinical trial aimed at accelerating the discovery of more targeted treatments for MM. Clinical parameters and tumor specimens are collected from each of the 1,147 patients at baseline and through the eight-year observation period. To identify genetic determinants of clinical outcomes, each tumor specimen is characterized by Whole Genome, Exome and Transcriptome sequencing. This work has uncovered a number of somatic mutations and copy number alterations associated with tumor progression and response to therapy as well as a novel classification of MM into 12 distinct subtypes based on gene expression. However, the contribution of germline genetic variation to gene expression changes and MM outcome remains poorly understood. Genome-wide association studies have identified germline variants associated with MM risk, indicating inherited genetic susceptibility. Furthermore, MM exhibits a disparity in occurrence and mortality between the sexes and ethnicities, men and African Americans being in at a higher risk than women or those of European ancestry. To better understand the genetic and biological basis of MM predisposition, we utilize a systems genomics approach to examine non-coding inherited and somatic genetic effects on gene expression and MM outcome. Data from 607 CoMMpass participants with available WGS and RNAseq from normal blood and baseline tumor specimens were used to map cis-acting eQTLs. We identified 3929 genes with at least one cis-acting eQTL. Furthermore, we discovered a number of regulatory variants with differential effects on tumor gene expression between the sexes and ethnicities, as well as eQTLs overlapping MM GWAS risk loci, providing regulatory mechanisms connecting these loci to MM. Finally, we discovered eQTLs that modulate overall survival in patients with MM. To validate these putatively regulatory loci in vitro, we utilized MM cell lines and CRISPR activation/interference, successfully altering the expression of the target genes. These and analyses integrating germline and somatic variants, gene expression, and clinical outcomes support the development of personalized medicine approaches for the better treatment of MM. Citation Format: Heini M. Natri, Austin Gutierrez, Bianca Argente, Melissa Wilson Sayres, Kenneth Buetow, Nicholas Banovich. Genetic effects on gene expression and survival in patients with multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4352.