Age 10y Research Articles

Reduced mitochondrial DNA and OXPHOS protein content in skeletal muscle of children with cerebral palsy.

To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP). Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were analyzed with a focused query investigating metabolism- and mitochondria-related gene networks. The mtDNA to genomic DNA ratio was lower in the children with CP compared to the typically developing group (-23%, p=0.002). Out of five investigated complexes in the mitochondrial respiratory chain, we observed lower protein levels of all complexes (I, III, IV, V, -20% to -37%; p<0.05) except complex II. Total peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) messenger RNA (p<0.004), isoforms PGC1α1 (p=0.05), and PGC1α4 (p<0.001) were reduced in CP. Transcriptional similarities were observed between CP, aging, and 90 days' bed rest. Mitochondrial biogenesis, mtDNA, and oxidative phosphorylation protein content are reduced in CP muscle compared with typically developing muscle. Transcriptional pathways shared between aging and long-term unloading suggests metabolic dysregulation in CP, which may guide therapeutic strategies for combatting CP muscle pathology. What this paper adds Cerebral palsy (CP) muscle contains fewer energy-generating organelles than typically developing muscle. Gene expression in CP muscle is similar to aging and long-term bed rest.

Long-Term Morbidity Associated with Chronic Graft Vs. Host Disease (cGvHD) - a Blood or Marrow Transplant Survivor Study (BMTSS)

▪Background: Patients with cGvHD are at risk for morbidity and compromised quality of life. However, the risk of specific morbidities observed long-term in patients with cGvHD is not clearly understood. Furthermore, whether patients with cGvHD are more likely to be frail, with added vulnerability to an already compromised functional status, remains unstudied. Methods: Study participants were drawn from BMTSS - a retrospective cohort of patients who had received a BMT at City of Hope or University of Minnesota between 1974 and 1998 for a hematologic malignancies or severe aplastic anemia (SAA) and survived at least 2y post-BMT. This study included 581 allogeneic BMT recipients ≥18y of age at study participation and alive at baseline survey (2000-2004) or follow-up survey (2013-2017). The survey included a self-report of sociodemographic characteristics and physical health conditions (Blood. 2010;116:3129-3) . The frailty phenotype was constructed from responses provided by BMT survivors using modified Fried criteria (JAMA Oncol. 2016;2:1277-86) . Details regarding cGvHD were abstracted from medical records. We conducted a systematic evaluation of the association between cGvHD and key chronic health conditions (xerostomia, dry eyes, cataract, glaucoma, diabetes, hypothyroidism, cardiomyopathy, coronary artery disease, stroke, tremors, problems with balance, pain, sensory loss, subsequent malignancies, esophageal or rectal/anal stricture, cirrhosis and pulmonary complications), using multivariable cox regression analyses adjusted for sociodemographics, primary diagnosis, smoking status, pre-existing comorbidities and TBI. We also examined the association between cGvHD and frailty using logistic regression and adjusting for the variables listed above, as well as chronic health conditions. Results: The 581 study participants underwent BMT at a median age of 30.9y (0.4-62.9) and participated in the study at a median age of 48.0y (18.2-73.7), after a median of 17.1y (2.0-40.5) from BMT; 55% were males and 77% were non-Hispanic whites. Primary diagnoses included CML (37%), AML (28%), ALL (14%), SAA (9%), other (12%). In this cohort of 581 allogeneic BMT recipients, 304 (52.3%) carried a history of cGvHD. All patients received myeloablative conditioning; TBI was used in 85%. The frequency of the following chronic health conditions was statistically-significantly higher in BMT patients with a history of cGvHD vs. those without cGvHD. (Fig 1): oral (difficulty in tasting/swallowing/chewing) and/or ocular (dry eyes) conditions (54% vs. 34%, p<0.0001), diabetes (17% vs. 11%, p=0.04), osteonecrosis (13% vs. 5%, p=0.002), neurological symptoms (tremors/decreased sense/prolonged pain: 33% vs. 23%, p=0.007), pulmonary complications (fibrosis/scarring/oxygen supplementation: 23% vs. 12%, p=0.0005), and GI complications (esophageal strictures + rectal/ anal strictures: 13% vs. 8%, p=0.05). The frequency of frailty was also higher in those with cGvHD vs. those without cGvHD (17.1% vs. 6.14%, p <0.0001). Overall, 45% of the allogeneic BMT recipients with cGvHD vs. 25% of those without cGvHD had 2 or more chronic health conditions (p<0.0001). As shown in Fig 1, multivariable analyses showed statistically significant associations between cGvHD and oral/ocular complications (HR=1.91, 95%CI, 1.4-2.5, p<0.0001), diabetes (HR=1.58, 95%CI, 0.96-2.6, p=0.07), osteonecrosis (HR=2.59, 95%CI, 1.4-5.0, p=0.004), neurological complications (HR=1.52, 95%CI, 1.1-2.2, p=0.02), pulmonary complications (HR=2.04, 95%CI, 1.3-3.2, p=0.002), and GI complications (HR=1.87, 95%CI, 1.1-3.3, p=0.03). In a multivariable model, adjusting for demographic and clinical variables and chronic health conditions, the odds of frailty were 2.66-fold higher among those with cGvHD (95%CI, 1.4-5.1, p=0.003) when compared with those without cGvHD. Conclusions: Allogeneic BMT recipients with a history of cGvHD carry a significantly higher burden of long-term morbidity, and are also at a significantly higher risk of frailty. The association between cGvHD and key chronic health conditions provides evidence for developing targeted surveillance and intervention strategies to reduce the burden of morbidity and frailty. [Display omitted] DisclosuresArora:Takeda Oncology: Consultancy.

Elderly Hodgkin Lymphoma - Multicenter Retrospective Data Analysis from the Czech Hodgkin Lymphoma Registry

Introduction: The proportion of elderly Hodgkin lymphoma (HL) patients (age ≥ 60 years) ranges between 15% and 35%. Outcome of this group of patients (pts) is significantly inferior compared with younger pts. Management of therapy is still unclear, standard treatment is not yet defined, especially with concomitant cardiac and/or pulmonary diseases. Purpose of this study was to analyze treatment and outcome of elderly HL pts prospectively registered in Hodgkin Lymphoma Project in the Czech Republic.Patients and methods: The proportion of elderly patients in the Czech HL Registry was 11%. We analyzed 151 pts ≥ 60 years (y) with classical HL diagnosed between 1995 and 2016. Median age was 67y (60-84), 72.2% of them were 60-70y old and male gender represented 54% (82 pts). Histological subtype mixed cellularity occured most frequently (50%). Advanced clinical stage (CS) was confirmed in 67.3% pts. CS in 1 pt remained unknown. Chemotherapy (CT) alone was used in 103 (68.2%) of pts (initial/intermediate stages 15 pts, advanced stages 87 pts, CS unknown 1 pt). Combined modality of treatment (CT and radiotherapy, RT) was used in 42 pts (intial/intermediate stages 30 pts, advanced stages 12 pts). Anthracycline - based CT received 81.5 % of pts (119 pts). Three pts (2%) were treated with RT alone, 2 pts (1.3%) with CT+ other treatment and 1 pt was without treatment after surgery exstirpation.Results: The median follow-up was 4.2 years. Treatment response was evaluable in 138 (91.4%) pts. Overall response rate (CR+PR) after the first-line treatment was observed in 125 (82.8%) pts, with 99 (65.7%) CR. Stable disease was observed in 1 (0.7%) pt and primary disease progression in 12 (7.9%) of pts. Relapses occured in 10% and 1 pt underwent high dose CT and autologous stem cell transplantation in the 1st relapse (age 61y). Median PFS and OS was 8.7y and 10.3y, respectively. Four - year PFS and OS was 69.5% and 71.6%, respectively. Overall 59.6% pts are alive and 61 (40.4%) of pts died: HL progression 17 pts, toxicity of treatment 15 pts, secondary malignancy 8 pts, others causes 12 pts. The cause of death in 9 pts remained unknown.Univariate Cox regression analysis identifies age ≥ 75y (p=0.033), failure of CR achievement (p<0.001), no anthracycline based CT (p=0.018), low albumin level < 4.0g/dl (p=0.016), lymphopenia <8% (p=0.006), CIRS score > 3 (p=0.037) as risk factors for OS. All mentioned factors without CIRS score predicted a significantly shorter PFS. CIRS > 3 and lymphopenia <8% were independent factors for shorter OS and PFS in multivariate analysis (Table 1, Figure 1).Conclusions. Long-term survival of our pts depended on the CIRS score and lymphopenia. Interestingly, 4 IPS factors (sex, hemoglobin, leucocytes, GHSG advanced stage), ADL (activity of daily living) and performance status WHO/ECOG were not significant for survival in univariate analysis. Prospective clinical studies are still needed to determine an optimal effective regimen with low toxicity in elderly pts.This work was supported by grant awarded by AZV 16-29857A, Ministry of Health in Czech Republic and Research project P 27/2012 awarded by Charles University in Prague, Third Faculty of Medicine, Prague, Czech Republic [Display omitted] DisclosuresBelada:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants , Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants , Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants , Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau.

Risk-Adapted Therapy in Adults with Burkitt Lymphoma: Results of NCI 9177, a Multicenter Prospective Phase II Study of DA-EPOCH-R

Risk-Adapted Therapy in Adults with Burkitt Lymphoma: Results of NCI 9177, a Multicenter Prospective Phase II Study of DA-EPOCH-R

Concordance between Bone Marrow and Peripheral Blood Samples for Assessment of FLT3 Internal Tandem Duplication (ITD) Mutations: Data from Patients Screened for Participation in Quantum-R, a Global, Randomized, Open-Label, Phase 3 Study Examining the Effect of Quizartinib Monotherapy Vs Salvage Chemotherapy on Overall Survival in Patients with FLT3 - ITD - Mutated AML Who Are Refractory to or Have Relapsed

Concordance between Bone Marrow and Peripheral Blood Samples for Assessment of FLT3 Internal Tandem Duplication (ITD) Mutations: Data from Patients Screened for Participation in Quantum-R, a Global, Randomized, Open-Label, Phase 3 Study Examining the Effect of Quizartinib Monotherapy Vs Salvage Chemotherapy on Overall Survival in Patients with FLT3 - ITD - Mutated AML Who Are Refractory to or Have Relapsed

Immune Recovery Refines the Prognostic Impact of Minimal Residual Disease on Overall and Progression Free Survivals after Frontline Fludarabine, Cyclophosphamide and Rituximab (FCR) in CLL Patients

Introduction: in chronic lymphocytic leukemia (CLL), treatment with FCR is the standard of care for treatment-naive and fit enough patients (pts). MRD threshold assessed 3 months after end of treatment (EOT) is considered as a surrogate for both progression free survival (PFS) and overall survival (OS). On the other hand, antibiotic prophylaxis is often started and maintained until CD4>200/mm3. We hypothesized that a monitoring of MRD versus normal immune cells recovery kinetics during follow-up (FU) could help refine the predictive power of MRD EOT evaluation, and allow identification of patients with increased risk of either infection and/or relapse.Methods: we prospectively collected fresh peripheral blood (PB) samples of 162 pts from 2 institutions in France (2006-2017) at the end of treatment (EOT), then every 6 months until month 24 (M24). We used 4-color flow cytometry to quantify both MRD (classified as 3 clusters: low (<10-4), intermediate (≥10-4 but <10-2) or high (≥10-2) level) and the reconstitution of normal lymphocyte subsets (CD4, CD8, NK). We plotted survival curves using Kaplan-Meier method and landmark analyses at different time points (9-15-21 months from day 1 cycle 1 FCR). Cox proportional model with time-dependent covariates (MRD, CD4, CD8 and NK counts) was also used to evaluate the correlation of covariates with outcomes.Results: one hundred and sixty-two pts (69% male, median age 58y) received a median of 6 courses of FCR. IGHV was mutated in 36.6%, and del13q was the most frequent cytogenetic abnormality (37.4%). Only 7 pts had del17p and/or mutation of TP53. After a median follow-up of 60.5 months, 46.3 % of pts have relapsed and/or died (median PFS estimation: 65.7 months, median OS not reached). At EOT, 65.3%, 27.2% and 7.5 % of pts achieved low, intermediate and high MRD respectively; 64.2% of pts had CD4≤200/mm3 while 35.8% had CD4>200/mm3.At landmark analysis of EOT, multivariate Cox model identified IgHV unmutated (HR 2.46), MRD intermediate (HR 3.3) or high (HR 19.57) (Figure 1), CD4 level (HR 1.22) as factors associated with PFS, and only MRD (HR 1.1) and CD4 counts (HR 1.2) were found to be associated with improved OS (Figure 2). In EOT intermediate MRD pts (n=34), those having EOT CD4≤200/mm3 had better 5-year PFS than those having CD4>200/mm3 (53.5% vs 7.7%, p=0.001) (Figure 3). This difference was not significant for low MRD pts (65% vs 58.9%, p=0.7). In landmark analysis at 21 months (=one year after EOT assessment), intermediate MRD pts (n=44) having CD4≤200/mm3 had significantly better 5-year PFS (85.7% vs 52.8%, p=0.0138). When performing successive landmark analyses on the whole population, CD4>200/mm3 was associated with worse 5-year PFS at EOT (34.1% vs 59.6%, p=0.016), 6 months (49.5% vs 58.8%, p=0.017) and 12 months (46.7% vs 68.3%, p=0.008) (Figure 4). In total, 20.4% of patients developed opportunistic infections, not correlated to CD4/CD8/NK counts.Conclusion: complementarily with MRD, CD4 count is an independent predictive factor of PFS and OS after FCR. As expected, MRD increase during FU is independently associated with worse PFS and OS, but CD4 counts at EOT and the first year post-FCR refine prognosis of the “MRD detectable” risk group (independently of CLL associated risk factors such as del17p/IgHV status). This is important in the interpretation and design of clinical trials dedicated to prolong PFS/OS using consolidation regimens based on MRD detection>10-4 in CLL. On the other hand, CD4>200/mm3 was not predictive of infectious events. [Display omitted] DisclosuresRecher:Celgene, Sunesis, Amgen, Novartis: Research Funding; Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy. Ysebaert:Janssen: Consultancy, Research Funding, Speakers Bureau.

Supplement Yogurt for Patients during Early Phase of Unrelated Cord Blood Transplantation: A Safety and Feasibility Pilot Study

Background: During last few years, intestinal microbiota, as a vital biological regulatory substance after hematopoietic stem cell transplantation (HSCT), has been attached with growing importance. Probiotics in yogurt may have positive effect in protecting intestinal microbiota diversity and improving the prognosis of patients after HSCT. However, the safety of supplement yogurt has not been evaluated in the early phase of HSCT. In order to evaluate the safety and feasibility of yogurt, we conducted a pilot study in patients who had undergone unrelated cord blood transplantation (UCBT).Method: Between February and June 2017, patients receiving UCBT was divided into two groups randomly. The experimental group (20 patients; mean age 17y, r 1-59; male 11) and control group (26 patients; mean age 24.3y, r 1-59; male 12) have no significant differences in age, gender, weight, underlying diseases and conditioning intensity (Table 1). Patients in experimental group (n=20) take in 200ml yogurt while children take in 100ml every day on day -7 and continue until day +30 (xinxiwang yogurt, including lactobacillus bulgaricus, streptococcus thermophilus, lactobacillus plantarum, lactobacillus rhamnosus, the number of lactobacillus≥108CFU/100g, produced at Jinrong Road 33rd, Shuangfeng economic industrial zone, Changfeng, Hefei, Anhui), while patients in control group (n=26) taking in nothing. All patients received CsA plus mycophenolate mofetil as GVHD prophylaxis.Results: we compared some indicators related to UCBT between the two group (Table 2). The primary engraftment rate is 95.0% (experimental group) and 96.2% (control group). The mortality in 60 day is 10% and 7.7% and the median time to 0.5×109/L ANC was 17 days (r 12-30) and 18.5 days(r 12-24). The incidence of acute GVHD gradeⅠ-Ⅳ (55.0% vs.57.7%, P= 0.972), bacteremia (45.0% vs.46.2%, P= 0.972), diarrhea (35.0% vs.53.8%, P= 0.444), and pre-engraftment syndrome (55.0% vs.80.8%, P= 0.154) show no significant differences between two group. While, the continuous change of CRP (P= 0.343), weight(P= 0.738), and albumin(P= 0.345) from day -7 to day +30 is also no significant difference between two groups. We don't observe any case of lactobacillus bacteremia (0%) in experimental group, together with none occurrence of lactobacillus-related unexpected adverse events through the whole study.Conclusion: Our data show it is safe and feasible to supplement yogurt during early phase of unrelated cord blood transplantation. It will not result in an increasing related risks including infection, diarrhea, aGVHD, and also not influence the nutritional status of patients. However, due to the limitation of the number of cases and short observation duration, we can not evaluate the effectiveness of the supplement yogurt. Further conclusion requires larger sample size and longer observation duration.No conflict of interest to declare. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mature Analysis of the Prospective Oxford Down Syndrome (DS) Cohort Study: Timing and Clinical Impact of Preleukemic GATA1 Mutations and Lessons for Management of Newborns with DS

Children with Down syndrome (DS) have a high risk of developing a unique form of AML known as myeloid leukaemia of DS (ML-DS) defined by the presence of one or more acquired N-terminal truncating mutations in the hematopoietic transcription factor gene GATA1 . ML-DS is confined to children <4 y of age and preceded by a neonatal preleukemic syndrome, Transient Abnormal Myelopoiesis (TAM). Although the same GATA1 mutations are present in ML-DS and TAM, indicating they are clonally-linked disorders, chemotherapy is essential to cure ML-DS whereas most cases of TAM spontaneously resolve without treatment.To determine the natural history of GATA1 mutations in DS and the true risk of subsequent leukemia conferred by GATA1 mutations we established the Oxford DS Cohort Study that prospectively analyses serial clinical, hematological and GATA1 mutational data from children with DS from birth to age 4y. All children had serial blood counts and smears and mutation analysis of exon 2/3 of GATA1 by next-generation-sequencing (NGS). A diagnosis of TAM was made if peripheral blood (PB) blasts were >10% and a GATA1 mutation was detected. DS neonates with PB blasts <10% and a GATA1 mutation were designated Silent TAM as our previous data on 18/80 DS neonates with blasts <10% showed that small mutant GATA1 clones were clinically and hematologically undetectable [Roberts et al, Blood 2013].We have now studied 471 neonates (gestational age [GA] at birth 29-42 wks) with karyotypically-confirmed DS. 130/471 (27.6%) had >1 GATA1 mutation confirming the high frequency of GATA1 mutations in DS neonates. Multiple GATA1 clones (2-7) were detected in 19% of TAM and 21% of Silent TAM (p=ns). A diagnosis of TAM was made in 55/471 (11.7%). 75/471 (15.9%) had Silent TAM and 341/471 had no GATA1 mutations. Typical clinical findings of TAM (hepatomegaly, splenomegaly, skin rash and effusions) were uncommon in Silent TAM, affecting 7%, 1.3%, 1.3% and 3% neonates respectively compared to 40%, 29%, 17% and 10% of neonates with TAM (p<0.0001). There were no specific hematological abnormalities in Silent TAM: median WBC and blasts were not increased: 13.1x109/L v 14.5x109/L and 4% v 4% (Silent TAM v no GATA1 mutation) and no neonates with Silent TAM had leucocytosis (WBC >35x109/L) or anemia. There was a strong correlation (r=0.753; p<0.0001) between PB blast% and mutant GATA1 clone size (assessed by VAF) with a greater mutant clone size in TAM v Silent TAM (median VAF 17.1% v 1.2%; p<0.0001).Unexpectedly, clone size was inversely proportional to GA (r=-0.2569; p=0.004). Despite similar median GA at delivery for all 3 groups, no GATA1 mutations were detected before 31 wks GA and no cases of TAM before 33 wks; the highest frequency of GATA1 mutations was seen at 34-35 wks GA (40%) reducing to 7% at >40 wks. This suggests GATA1 mutations are likely to be acquired and expand during a narrow time window early in the 3rd trimester of fetal life. Consistent with this, GATA1 mutations were not detected in 16 DS fetal liver samples (GA 8-19 wks) analysed over the same period. Similarly, in a case of TAM presenting in utero with fetal pericardial effusion and 96% PB blasts at 27 wks GA, the blast% and mutant GATA1 VAF spontaneously fell progressively (blasts 19%; VAF 23% at birth at 34 wks GA; undetectable at 4 wks postnatal age).Outcome: 7 neonates developed ML-DS: 6/52 survivors with TAM; 1/71 survivors with Silent TAM and 0/328 survivors without neonatal GATA1 mutations; 2/451 survivors developed ALL (1 Silent TAM, 1 no GATA1 mutation). 5 yr overall survival was the same in all 3 groups (95.1%, 95.8%, 95.1% for TAM, Silent TAM and no GATA1 mutations; Plog-rank 0.8994) while 5 yr event-free survival was lower in TAM (89.2%, 92.8%, 95.1% in TAM, Silent TAM and neonates with no GATA1 mutations; Plog-rank=0.0262). ML-DS was diagnosed at a median age of 14 m (range 3-18 m) preceded in all cases by a fall in platelet count. No single risk factor at birth specifically predicted for ML-DS although all 6 neonates with TAM who developed ML-DS had a mutant GATA1 VAF of >15% and blasts >20% at birth. The DS neonate with Silent TAM had a VAF of 2.5% and 4% blasts; this neonate was the only one of the cohort with a partial trisomy 21. Conclusion: Acquired N-terminal mutations in GATA1 are very frequent in neonates with DS and most probably occur or expand in the 3rd trimester; in the majority of cases mutant GATA1 clones are very small, clinically silent, resolve spontaneously and confer an extremely low risk of ML-DS. DisclosuresVyas:Jazz Pharmaceuticals: Speakers Bureau; Celgene Corporation: Speakers Bureau.

The Dyskinetic Cerebral Palsy Functional Impact Scale: development and validation of a new tool.

To outline the development and examine the content and construct validity of a new tool, the Dyskinetic Cerebral Palsy Functional Impact Scale (D-FIS), which measures the impact of dyskinesia on everyday activities in children with cerebral palsy (CP). D-FIS content was informed by a systematic review of dyskinesia outcome measures, in collaboration with children with dyskinetic CP, parents, caregivers, and expert clinicians. The D-FIS uses parent proxy to rate impact of dyskinesia on everyday activities. Construct validity was determined by examining internal consistency; known groups validity with the Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), Communication Function Classification System (CFCS), and Eating and Drinking Ability Classification System (EDACS); and convergent validity with the Barry-Albright Dystonia Scale (BADS). Fifty-seven parents of children (29 males, 28 females, mean [SD] age 11y 8mo [4y 4mo], range 2y 6mo-18y) completed the D-FIS. Correlation between D-FIS and GMFCS was r=0.86 (95% confidence interval [CI]: 0.77-0.91, p<0.001); MACS r=0.84 (95% CI: 0.73-0.90, p<0.001); CFCS r=0.80 (95% CI: 0.67-0.88, p<0.001); and EDACS r=0.78 (95% CI: 0.66-0.87). Correlation between D-FIS and BADS was r=0.77 (95% CI: 0.64-0.86, p<0.001). Cronbach's alpha was 0.96. The D-FIS demonstrates good construct validity and high internal consistency. The D-FIS will be useful for identifying priorities for intervention. It adds to the measurement tool kit for children with dyskinetic CP by addressing functional impact of dyskinetic movements and postures. What this paper adds The Dyskinetic Cerebral Palsy Functional Impact Scale (D-FIS) assesses the perceived impact of dyskinesia on daily activities in children with cerebral palsy (CP). The D-FIS demonstrates good construct validity and high internal consistency. The D-FIS is a clinically feasible, family-centred tool that fills a current gap in the dyskinetic CP assessment toolkit.

Genetic testing in individuals with cerebral palsy.

AIM To determine which patients with cerebral palsy (CP) should undergo genetic testing, we compared the rate of likely causative genetic variants from whole-exome sequencing in individuals with and without environmental risk factors. METHOD Patients were part of a convenience and physician-referred cohort recruited from a single medical center, and research whole-exome sequencing was completed. Participants were evaluated for the following risk factors: extreme preterm birth, brain bleed or stroke, birth asphyxia, brain malformations, and intrauterine infection. RESULTS A total of 151 unrelated individuals with CP (81 females, 70 males; mean age 25y 7mo [SD 17y 5mo], range 3wks-72y) participated. Causative genetic variants were identified in 14 participants (9.3%). There was no significant difference in diagnostic rate between individuals with risk factors (10 out of 123; 8.1%) and those without (4 out of 28; 14.3%) (Fisher's exact p=0.3). INTERPRETATION While the rate of genetic diagnoses among individuals without risk factors was higher than those with risk factors, the difference was not statistically significant at this sample size. The identification of genetic diagnoses in over 8% of cases with risk factors suggests that these might confer susceptibility to environmental factors, and that further research should include individuals with risk factors. What this paper adds There is no significant difference in diagnostic rate between individuals with and without risk factors. Genetic variants may confer susceptibility to environmental risk factors. Six causative variants were identified in genes not previously associated with cerebral palsy. Global developmental delay/intellectual disability is positively associated with a genetic etiology. Extreme preterm birth, stroke/brain hemorrhage, and older age are negatively associated with a genetic etiology.

Severe speech impairment is a distinguishing feature of FOXP1-related disorder.

To delineate the speech and language phenotype of a cohort of individuals with FOXP1-related disorder. We administered a standardized test battery to examine speech and oral motor function, receptive and expressive language, non-verbal cognition, and adaptive behaviour. Clinical history and cognitive assessments were analysed together with speech and language findings. Twenty-nine patients (17 females, 12 males; mean age 9y 6mo; median age 8y [range 2y 7mo-33y]; SD 6y 5mo) with pathogenic FOXP1 variants (14 truncating, three missense, three splice site, one in-frame deletion, eight cytogenic deletions; 28 out of 29 were de novo variants) were studied. All had atypical speech, with 21 being verbal and eight minimally verbal. All verbal patients had dysarthric and apraxic features, with phonological deficits in most (14 out of 16). Language scores were low overall. In the 21 individuals who carried truncating or splice site variants and small deletions, expressive abilities were relatively preserved compared with comprehension. FOXP1-related disorder is characterized by a complex speech and language phenotype with prominent dysarthria, broader motor planning and programming deficits, and linguistic-based phonological errors. Diagnosis of the speech phenotype associated with FOXP1-related dysfunction will inform early targeted therapy. What this paper adds Individuals with FOXP1-related disorder have a complex speech and language phenotype. Dysarthria, which impairs intelligibility, is the dominant feature of the speech profile. No participants were receiving speech therapy for dysarthria, but were good candidates for therapy Features of speech apraxia occur alongside persistent phonological errors. Language abilities are low overall; however, expressive language is a relative strength.

Dietary patterns acquired in early life are associated with cardiometabolic markers at school age

it has previously been described that dietary patterns established early in life tracked to late childhood. The aim of the present work was to analyse the association of dietary patterns that tracked from 2 to 8y with cardiometabolic markers at 8y of age. The 3 identified patterns at 2y (that previous analyses showed to track to age 8y) were: "CoreDP", loaded for vegetables, fruits, fish, olive oil, etc.; "F&SDP", loaded by poor-quality fats and sugars; and "ProteinDP", mainly loaded by animal protein sources. Cardiometabolic markers at 8y were systolic blood pressure (SBP), insulin resistance (HOMA-IR), and triglycerides, and BMI z-score. To examine whether the association of diet with the outcomes was the result of a direct effect of diet at either two or 8y, or synergy between them, we used structural equation models. the associations between the patterns and the health outcomes were: CoreDP was inversely associated with SBP and HOMA-IR; ProteinDP was directly associated with HOMA-IR and SBP; and adherence to F&SDP was directly associated with triglycerides and SBP. The associations between the patterns and the health outcomes were independent of BMI and were the result of a direct effect of diet at 2y, an indirect effect of diet at 2y through diet at 8y or a combination between both pathways. dietary patterns acquired in early life, persisting to later childhood, were associated with cardiometabolic markers at school age independently of BMI.

480-P: Impact of Medication Adherence and Glycemic Control on the Risk of Micro/Macrovascular Diseases in Patients with Diabetes

We investigated the impact of medication adherence for a one-year period and subsequent glycemic control and their combinations on the risk of micro/macrovascular diseases among Japanese using nationwide claims data. Analyzed were 19,565 patients with diabetes whose medication records for oral hypoglycemic agents (OHAs) were available for at least 1 year without prior treatment-requiring diabetic eye disease (TRDED), initiation of dialysis (dialysis), coronary artery disease (CAD), or cerebrovascular disease (CVD), respectively (mean age 53y, HbA1c 7.2%). Medication adherence was evaluated by the proportion of days covered (PDC), and PDC<0.8 was considered to have poor adherence. In each group, the percentage of poor adherence was approximately 30%. Cox regression revealed that poor adherence was an independent risk factor for dialysis. When participants were divided into four groups according to PDC and HbA1c, the risks of TRDED, dialysis, and CAD in the poor adherence/poor glycemic control group were significantly higher compared with the good adherence/good glycemic control group (Table). The risk of micro/macrovascular disease varied according to medication adherence and subsequent glycemic control, suggesting that clinicians should determine treatment strategies considering medication adherence and glycemic control separately.View largeDownload slideView largeDownload slide DisclosureY. Yaguchi: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. K. Fujihara: None. M. H. Yamada: None. Y. Matsubayashi: None. T. Yamada: None. M. Iwanaga: None. M. Kitazawa: None. M. Yamamoto: None. S. Kodama: None.

P244 Clinician preferences in treating steroid resistant ulcerative colitis: a discrete-choice experiment (DCE) survey

Abstract Background The optimum treatment for steroid resistant ulcerative colitis (SRUC) is not clear and a range of options can be considered. The aim of this study was to quantify the relative importance of different treatment characteristics to clinicians and understand their preferences for benefit-risk trade-offs. Methods A discrete choice experiment (DCE) was conducted in the UK via online survey of clinicians with expertise in inflammatory bowel disease. This involved 12 tasks where respondents selected a preferred treatment option when presented with two competing, hypothetical treatment profiles for a SRUC scenario. Profiles described five treatment characteristics focusing on clinical outcomes and safety, identified from qualitative interviews with clinicians and evidence from systematic reviews. DCE responses were analysed using conditional logistic regressions. Regression coefficients were used to calculate benefit-risk trade-offs, to find the rate at which clinicians are willing to trade levels of risks in exchange for the preferred levels of clinical outcomes. Regression coefficients were also used to predict uptake rates for selected drugs currently prescribed to patients with SRUC. Results 116 clinicians completed the survey (age 46y; female 42%; consultant 60%; nurse 26%; mean experience 11y). Figure 1 shows the treatment characteristics that make respondents more likely (positive coefficient) or less likely (negative coefficient) to choose a treatment. One unit increase in both lymphoma risk and serious infection risk were strongly considered when clinicians were choosing a treatment compared to one unit increase in the symptom improvement characteristics. Clinicians would accept a higher lymphoma risk of 5 per 10,000 patient years for a 10% improvement in remission rate compared to 4 and 2 cases per 10,000 patient years for 10% better rates of clinical response and mucosal healing respectively. Clinicians at secondary hospitals accepted a lymphoma risk of 4 cases per 10,000 patient years for a 10% improvement in remission vs 7 per 10,000 patient years at tertiary centres. Similar trade-off results were found for serious infection risks. Predicted uptake comparing preferred characteristics to existing treatments was infliximab (62%), tofacitinib (18%), vedolizumab (15%) and adalimumab (5%). Conclusion Clinicians are willing to make difficult trade-offs and tolerate elevated safety risks in exchange for therapeutic benefits. Risk tolerance was highest if the treatment improved long term remission rate, lowest for mucosal healing and higher in clinicians at tertiary centres. The results help to better understand treatment decisions and identify outcomes that might be considered in choosing agents to evaluate in clinical trials.

Abstract 038: Cumulative Exposure To Sleep Disordered Breathing From Childhood Through Young Adulthood Is Associated With Impaired Endothelial Function

Introduction: Clinical and population-based studies in adults have shown that sleep disordered breathing (SDB) is associated with impaired endothelial function. However, there is a lack of population-based studies demonstrating an association between SDB and endothelial dysfunction in young adults using a developmental approach. Hypothesis: Exposure to SDB since childhood is associated with long-term impaired flow-mediated dilation (FMD) in young adulthood. Methods: We tested this hypothesis in a subsample of the Penn State Child Cohort, a population-based study of 700 children (median age 9y), of whom 421 were followed-up 6-13 years later during adolescence (median age 16y), and 178 have been followed-up 11-19 years later during young adulthood (median age 24y). Subjects (54.5% female, 20.8% racial/ethnic minority) underwent in-lab polysomnography to ascertain the apnea/hypopnea index (AHI) at all three time points, and ultrasounds to assess FMD in young adulthood. Based on the AHI truncated at ≥5 events/hour of sleep to include subjects already on positive airway pressure therapy, we averaged the exposure to AHI over the three time points (cAHI). The study outcomes were FMD, as a continuous measure, and endothelial dysfunction, defined as FMD&lt;10.3% based on the median of the sample. Linear and logistic regression models simultaneously adjusted for sex, age, race/ethnicity, overweight and length of follow-up. Results: The mean cAHI was 1.31 (1.35) ranging from 0 to 5 and the mean FMD was 0.11 (0.04) ranging from 0.03 to 0.25. Linear models showed that cAHI was associated with significantly lower FMD in young adulthood (β = -0.006; 95% CI = -0.011, -0.0013; p = 0.014). To test the robustness of the analysis, we applied the same model with the square root of FMD as the outcome and similar results were obtained (β = -0.009; 95% CI = -0.016, -0.0017; p = 0.015). Logistic models showed that each point increase in cAHI was associated with 51% higher odds of endothelial dysfunction in young adulthood (OR = 1.51; 95% CI = 1.14, 2.06; p = 0.006). Conclusions: The preliminary data of this ongoing longitudinal study indicates that exposure to SDB during early stages of life is associated with increased risk for cardiovascular disease in young adults from the general population.

Cerebral visual impairment in CDKL5 deficiency disorder: vision as an outcome measure.

To characterize the neuro-ophthalmological phenotype of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) and assess visual acuity as a reproducible, quantitative outcome measure. We retrospectively analyzed clinical data from patients with CDD. Complete neuro-ophthalmological assessments, including visual acuity, were evaluated. Of 26 patients (22 females, four males; median age 4y, interquartile range 2y 1mo-7y 10mo), cerebral visual impairment (CVI), defined as visual dysfunction in the absence of ocular or anterior visual pathway abnormalities, was diagnosed in all those over 2years of age. Ophthalmological examinations revealed nystagmus in 10 patients and strabismus in 24 patients. Visual acuity was measured in 24 patients, by preferential looking in all and by sweep visual evoked potential in 13. Visual acuities were lower than age expectations and demonstrated improvement in the first 3years. Adjusting for age and sex, average preferential looking visual acuity after 2years of age was higher in patients with intact mobility than in those who were non-mobile. CVI was observed in patients with CDD. Visual acuity improved over time and correlated with mobility. Visual acuity, as a quantifiable measure of visual function, should be considered as an outcome measure in pre-clinical and clinical studies for CDD. What this paper adds Cerebral visual impairment is highly prevalent in cyclin-dependent kinase-like 5 deficiency disorder (CDD). Visual acuity is a measurable quantitative outcome measure in CDD. Visual acuity in CDD correlates with gross motor ability.

Prospective associations of different contexts of physical activity with psychological distress and well-being among middle-aged adults: An analysis of the 1970 British Cohort Study

BackgroundOur aim was to investigate whether different types and social contexts of physical activity (PA) participation are prospectively associated with psychological distress and well-being among middle-aged adults. MethodsData from the 1970 British Cohort Study was used (N = 5144–2733 women). At age 42y, participants reported their type of leisure-time PA, which was classified as individual PA or group PA (exposure). At age 46y, participants reported co-primary outcomes: psychological distress (Malaise Inventory) and well-being (Warwick-Edinburgh scale). Highest academic achievement, employment status, country of interview, baseline values of psychological distress and well-being, smoking, alcohol use, TV-viewing and total physical activity at 42y were used as covariates. Main analyses included linear regression stratifying by sex. ResultsJogging, cross-country, road-running (both sexes) as well as team sports (men) were associated with higher well-being. Health, fitness, gym or conditioning activities and jogging, cross-country (women), road-running (women) and team sports (men) were associated with lower psychological distress. Participation in both individual and group PA were associated with lower psychological distress and higher well-being for both sexes in crude models. However, adjusted models revealed that only group PA was associated with lower psychological distress (B: −0.106; 95%CI: −0.188 to −0.025) and higher well-being (0.835; 0.050 to 1.619) among men but not women. In the sensitivity analysis, group PA was associated with higher well-being (0.855; 0.094 to 1.616) when compared with individual PA among men. Group PA was not associated with psychological distress among both sexes and well-being among women when compared with individual PA. ConclusionGroup PA was prospectively associated with lower psychological distress and higher well-being among men but not females. Future PA interventions could focus on group activities for males. Further research to understand the relationship between individual/group PA and mental health is required in females.

Genomic Testing for Monogenic Diabetes in the UK: A Three-Fold Increase in Diagnoses Since 2009

Background: Maturity Onset Diabetes of the Young (MODY) is a rare monogenic form of diabetes. In 2009, >80% of UK cases were estimated to be misdiagnosed. Since then, there have been a number of initiatives to improve detection of MODY: the Genetic Diabetes Nurse (GDN) education programme, the MODY probability calculator, and targeted next generation sequencing (tNGS). We aimed to determine an up-to-date prevalence estimate for UK MODY and assess how these initiatives have impacted case finding. Methods:UK referrals for genetic testing for monogenic diabetes diagnosed >1y of age from 1/1/1996 to 31/12/2019 were examined. Positive-test rates were compared for referrals reporting involvement of the GDNs/MODY calculator with those that did not. Findings: A diagnosis of MODY was confirmed in 3860 individuals, >3-fold higher than 2009 (n=1177). Median age at diagnosis in probands was 21y. GDN involvement was reported in 21% of referrals; these referrals had a higher positive-test rate than those without GDN involvement (32% v 23%, p<0.001). MODY calculator usage was indicated on 74% of eligible referrals since 2014; these referrals had a higher positive-test rate than those not using the calculator (32% v 24%, p=0.001). 374 (10%) cases were identified through tNGS. MODY prevalence was estimated to be 248 cases/million (double that estimated in 2009 due to increased case-finding). Interpretation: Since 2009, referral rates and case diagnosis has increased three-fold. This is likely to be the consequence of tNGS, GDN education and the MODY calculator. Funding: NIHR, Scottish Government Declaration of Interest: None

Upfront autologous stem cell transplantation (ASCT) versus carfilzomib-cyclophosphamide-dexamethasone (KCd) consolidation with K maintenance in transplant-eligible, newly diagnosed (NDTE) multiple myeloma (MM).

8000 Background: Upfront ASCT for NDTE MM remains under evaluation with high MRD rates following novel induction and consolidation (cons) strategies. Current phase 3 trials support ASCT, however these employ lenalidomide maintenance which predominantly benefits standard risk (SR) patients (pts). The CARDAMON trial investigated the role of ASCT using K based induction and maintenance. Methods: NDTE pts received 4 x KCd induction (K 20/56 mg/m2 biweekly, C 500 mg D 1,8,15, d 40mg weekly) before 1:1 randomisation to ASCT or 4 x KCd cons. All received 18 months K maintenance (56mg/m2 D1,8,15). Flow cytometric MRD (10-5) was assessed post induction, pre-maintenance and at 6 months maintenance. Primary endpoints were ≥VGPR post induction and 2-year PFS from randomisation. 210 randomised pts were needed to exclude a 10% non-inferiority margin with 15% 1-sided alpha, 80% power. Results: 281 pts were registered, median age 59y (33–74), 24% high risk [t(4;14), t(14;16), t(14;20) or del(17p)]. Post induction, ≥VGPR rate was 58.5%, ORR was 87% with similar responses for high risk vs SR. 52 pts did not proceed to PBSCH (6 MR, 16 PD, 19 toxicity, 4 deaths: 3 infection, 1 cardiac event, 7 other). 109 were randomised to ASCT, 109 to KCd cons. ≥VGPR rate was 78.5% after cons and 80.0% after ASCT (p = 0.8). Median KCd cons dose was 55.5 mg/m2, 99 (90.8%) pts completed 4 cycles, 104 (95.4%) pts received ASCT. After 2.6 years follow-up, median PFS was not reached for ASCT vs 3.8 years for cons (HR: 0.82 (70% CI 0.65, 1.05, p = 0.4). Observed 2-year PFS for ASCT was 75.5% vs 70.7% for cons; calculated difference in 2-year PFS rate (cons vs ASCT) was -4.5% (70% CI -9.2%, +1.1%, non-inferior). High risk pts had inferior outcomes to SR overall regardless of randomisation (2-year PFS ASCT: 52% vs 82% (HR 4.09); cons 48% vs 77% (HR 2.83)). 2 year PFS did not differ according to randomisation: SR 82% (ASCT) vs 77% (cons) HR: 1.29 (0.71-2.35); high risk: 52% (ASCT) vs 48% (cons) HR: 1.06 (0.50-2.23). MRD negativity post induction was 24.3% and similar by genetic risk. MRD negative rates were higher post ASCT (53.1%) than cons (35.8%) (p = 0.02) independent of genetics: SR 49% (ASCT) vs 36% (cons); high risk: 57% (ASCT) vs 32% (cons). G3+ adverse events to induction were infections (18.7%), hypertension (11.2%), anaemia (10.4%), cardiac disorders (3.6%), vomiting (2.2%), fatigue (2.2%), diarrhoea (1.8%). Conclusions: In NDMM receiving KCd induction and K maintenance, KCd cons was non-inferior to ASCT. High risk pts had inferior outcomes, that were not influenced by ASCT or cons randomisation. Clinical trial information: NCT02315716. [Table: see text]

Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).

9508 Background: Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242). Methods: This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, &amp; safety. Results: A total of 76 pts (med f/u 54 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A &amp; 4/16 in cohort B were due to IC progression only. Conclusions: Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129). Clinical trial information: NCT02374242. [Table: see text]