Greater Risk Of Relapse Research Articles

Language, 6-mercaptopurine adherence, and relapse in children with acute lymphoblastic leukemia.

Hispanic children with acute lymphoblastic leukemia (ALL) have lower 6-mercaptopurine (6MP) adherence and greater hazard of relapse compared with non-Hispanic White children. We examined the association between Spanish language and 6MP adherence, and hazard of relapse. 6MP adherence was measured electronically over a 6-month period. Participants were grouped by the language of demographic questionnaire completion: Non-Hispanic White-English Speaking (ES, n = 159), Hispanic-Spanish Speaking (Hispanic-SS, n = 59), and Hispanic-ES (n = 109). Hispanic-ES had significantly lower fitted median 6MP adherence compared with non-Hispanic White-ES participants (88.3%, 95% CI = 84.7% to 91.2% vs 95.0%, 95% CI = 93.6% to 96.2%, P < .001). There was no difference in fitted median 6MP adherence between Hispanic-ES and Hispanic-SS participants (88.3%, 95% CI = 84.1% to 91.5% vs 88.3%, 95% CI = 84.7% to 91.2%, P = .9) or adjusted hazard of relapse for Hispanic-SS participants (HR = 0.9, 95%CI = 0.3 to 2.4, P = .8). Spanish language use among Hispanic patients with ALL is not associated with lower 6MP adherence or greater relapse risk. Factors related to Hispanic ethnicity, apart from language, appear to influence adherence.

Association between tobacco exposure and bladder cancer recurrence: A systematic review and meta-analysis.

However, the connection between smoking and the prognosis of patients with bladder cancer remains unclear. To determine whether smoking is linked to the recurrence and progression of bladder cancer. As of July 20, 2022, relevant English-language research was identified by searching PubMed, the Web of Science, and the Cochrane Library. We pooled the available data from the included studies using a random effects model. Subgroup analysis and sensitivity analysis were also conducted. A total of 12 studies were included in this meta-analysis. The combined analysis revealed that tobacco exposure was associated with a significantly greater recurrence rate than nonsmoking status [odd ratios (OR) = 1.76, 95%CI: 1.84-2.93], and the progression of bladder cancer was significantly greater in smokers than in nonsmokers (OR = 1.21, 95%CI: 1.02-1.44). Stratified analysis further revealed that current smokers were more likely to experience relapse than never-smokers were (OR = 1.85, 95%CI: 1.11-3.07). Former smokers also had a greater risk of relapse than did never-smokers (OR = 1.73, 95%CI: 1.09-2.73). Subgroup analysis indicated that non-Caucasians may be more susceptible to bladder cancer recurrence than Caucasians are (OR = 2.13, 95%CI: 1.74-2.61). This meta-analysis revealed that tobacco exposure may be a significant risk factor for both the recurrence and progression of bladder cancer.

Effect of oncolytic herpes simplex virus on fusion-positive rhabdomyosarcoma to radiotherapy.

10063 Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite multimodal interventions including surgery, chemotherapy, and radiotherapy, nearly a third of patients with localized disease will experience tumor recurrence. Patients with tumors harboring an oncogenic FOXO1 fusion are at greater risk of relapse and are most in need of novel therapies. Oncolytic viruses are being explored as treatments for pediatric tumors, and data suggest that oncolytic viruses may enhance responses to chemoradiotherapy. M002 is a genetically engineered oncolytic herpes simplex virus (oHSV) that exhibits aneurovirulence in normal cells. M002 selectively replicates in malignant cells, eliminating these cells through cellular burst during the lytic cycle. In the present study, we explored the efficacy of the M002 virus alone and in combination with low-dose ionizing radiotherapy in a human patient-derived xenograft (PDX) model of fusion-positive RMS (FP-RMS). Methods: A human FP-RMS PDX was established and maintained by injection into the quadriceps femoris muscle of athymic nude mice under Institutional Animal Care and Use Committee guidelines (IACUC-09363). Tumors were dissociated and cells were treated with increasing multiplicity of infection (MOI) of either the oHSV, R3659 or its genetically engineered variant, M002. A colorimetric assay evaluated the cytotoxicity of oHSV treatments on the RMS PDX cells after 24, 48, and 72 hours of infection. In separate experiments, cells treated with vehicle (control) or infected with M002 were exposed to irradiation (2 Gy), and viability was determined at 24, 48, 72, and 96 hours. Results: Treatment with M002 or its parent construct, R3659, significantly reduced RMS PDX cell viability in a dose-dependent manner at all time points. M002 showed slightly higher cytotoxicity than R3659 as measured by lethal dose 50% (LD50, 37±1.25 vs 44±0.95 PFU/cell, M002 vs R3659, at 24 hours, p=0.02). When sub-lethal doses of M002 were combined with low-dose irradiation, RMS PDX cell viability was significantly decreased compared to cells treated with either M002 or irradiation alone (26% decrease at 10 PFU/cell). Conclusions: Our preliminary data highlight that M002 exhibits cytotoxicity in a PDX model of FP-RMS. Treatment with M002 further increased the cytotoxicity of ionizing radiation compared to individual treatments, suggesting that oHSV sensitized the cells to radiotherapy. Future studies in vivo may provide more pre-clinical evidence for the radio-sensitizing and therapeutic potential of M002 in FP-RMS.

Association of DAZL expression with risk of recurrence in clinical stage 1 testicular germ cell tumors.

523 Background: One model for testicular germ cell tumor (TGCT) formation posits that these tumors arise from a failure of germ cell determination characterized by persistent pluripotency and apoptotic escape. Risk assessment for relapse in clinical stage 1 (CS1) TGCT is dictated by clinical factors; molecular biomarkers to improve patient stratification for post-orchiectomy care are lacking. In this study, we examined the relationship between protein expression of pluripotency and apoptosis factors and risk of relapse in clinical stage 1 TGCT. Methods: Orchiectomy specimens from 73 patients treated for clinical stage 1 TGCT at one institution (27 seminoma, 46 non-seminoma) were subjected to immunohistochemistry (IHC) to assess protein expression of DAZL, POU5F1, BAK1, DDX4, NANOG, and PMAIP1. Samples were dichotomized as negative or positive for target protein expression. Patients with CS1 TGCT managed with surveillance were annotated for baseline clinical characteristics and whether they experienced relapse within two years of orchiectomy. Exact logistic regression estimated odds ratios (OR) and 95% confidence intervals were calculated for the association between protein expression and relapse. Results: At two years, 17% of patients in our cohort experienced relapse. DAZL expression (score &gt; 0) was detected in 43% of seminoma samples and 13% of embryonal carcinomas. After adjusting for histology, tumors negative for DAZL expression were more likely to recur within two years (adjusted OR for recurrence 0.08, 95% CI 0 – 0.81, p = 0.03). The direction of this relationship was consistent in seminoma when adjusted for tumor size (adjusted OR 0.14, 95% CI 0-1.83, p = 0.18) and non-seminoma after adjustment for embryonal predominance and lymphovascular invasion (adjusted OR 0.53, 95% CI 0-3.10, p = 0.30). No notable findings were observed for POU5F1, BAK1, DDX4, NANOG, and PMAIP1. Validation studies in two independent cohorts from other institutions are ongoing. Conclusions: The absence of DAZL expression by IHC is associated with a greater risk of relapse in CS1 TGCT. As DAZL promotes germ cell commitment by suppressing the pluripotency program, absence of DAZL expression may promote an oncogenic germ cell phenotype and more aggressive tumor behavior. Validation in larger patient cohorts is required to credential DAZL as a biomarker for clinical stage 1 relapse on surveillance.

Recognizing and Treating Major Depression in Fibromyalgia: A Narrative Primer for the Non-Psychiatrist.

Fibromyalgia (FM) affects 2% to 8% of the general population. FM patients often experience self-stigma and feel rejected by healthcare providers and families, resulting in isolation and distressing symptoms of pain, fatigue, and poor cognitive functioning, increasing the risk of depressive symptoms. Major Depressive Disorder (MDD) is the most common comorbidity in FM patients (Any depression: 43%; MDD: 32%). Genome-wide association studies (GWAS) have identified a common genetic risk loci for major depression and fibromyalgia. Given that even minor symptoms of depression worsen the outcomes of FM patients, clinicians are challenged to identify and manage depression in these patients. However, due to overlapping symptoms, limited screening, and contamination bias, MDD often goes undiagnosed and presents a critical challenge. Unrecognized and untreated MDD in FM patients can exacerbate fatigue, sleep disturbances, and pain, reduce physical functioning, and increase the risk of developing comorbid conditions, such as substance abuse and cardiovascular disease. These comorbidities are associated with a lower treatment response rate, a higher dropout rate, and a greater risk of relapse. Clinicians may effectively identify and treat MDD in FM patients with appropriate pharmacologic agents combined with aerobic exercise and cognitive-behavioral therapies for core FM symptoms, thus significantly reducing symptom severity for both MDD and FM. Such a comprehensive approach will result in a much-improved quality of life. MedLine content was searched via PubMed to identify eligible articles between 1995 and 2023 using search terms fibromyalgia, major depressive disorder, and treatment of depression in fibromyalgia, and the most current information is presented. In this primer for clinicians caring for FM patients, we describe clinically relevant pharmacologic and non-pharmacologic management approaches for treating MDD in FM patients.

What is day hospital treatment for anorexia nervosa really like? A reflexive thematic analysis of feedback from young people

BackgroundA significant proportion of young people do not respond to the NICE recommended treatment for anorexia nervosa: Family Therapy. Whilst historically these young people would be admitted to inpatient services, which are associated with greater treatment cost, greater risk of relapse, and worse outcome, more recently evidence is building for the effectiveness of day programmes. One day programme that has been found to be effective is the Intensive Treatment Programme (ITP) of the Maudsley Centre for Child & Adolescent Eating Disorders in London, UK. However, to-date no studies have investigated how young people experience such a day programme.MethodAnonymous feedback was completed via online survey by 51 young people over a 5-year period (2018–2023) on discharge from ITP.ResultsFour main themes were identified: (1) Support—young people expressed the importance of boundaries but also of feeling validated, and encouraged; (2) Uniqueness: an experience like no other—ITP was described as different to any other treatment received before (both outpatient and inpatient); (3) Relationships – young people valued connecting with others in a similar situation and reflected that relationships at home changed throughout treatment; (4) Self-development – learning skills, developing independence, and exploring an identity outside of the eating disorder was valued.ConclusionsIt is hoped that the reflections from these young people can help to inform clinicians working in DPs and those hoping to set up novel DPs about key aspects of treatment.

Comparison of Two Therapeutic Approaches (Pediatric vs. Adult) for Treating Acute Lymphoblastic Leukemia. Experience of Two Centers in Mexico City

Background: Chemotherapy is the most frequently used strategy in treating adult acute lymphoblastic leukemia (ALL) in conjunction with monoclonal antibodies and tyrosine kinase inhibitors. One of the primary considerations is the type of treatment based on pediatric inspiration regimens (CALGB10403, BFM, St Jude XIII) or regimens for adult patients (HyperCVAD), with pediatric regimens being those that have improved the prognosis in the young adult population. Along with this scheme, strict monitoring through measurable residual disease (MRD) is the main dynamic prognostic factor since its positivity is associated with a greater risk of relapse. We aimed to compare the effect on the clinical prognosis of two treatment regimens based on a pediatric regimen versus an adult regimen in patients with ALL. Material and methods: A retrospective, observational, descriptive study of 5 years of follow-up was carried out in patients with ALL at the Hospital General de México and the Hospital Regional de Alta Especialidad de Ixtapaluca, classifying the treatment into two types of regimens (adult regimen vs. pediatric inspiration) evaluating the impact on survival as well as the association of different factors both to diagnosis and measurable residual disease (MRD). Results: A total of 450 patients were studied, 50.4% (n=227) were male, and 49.6% (n=223) were female. 21.1% (n=95) received a pediatric-inspired protocol (CALGB-10403), and 78.9% (n=355) received an adult protocol (Hyper-CVAD). 71.8% (n=323) were considered high risk, and 8.4% (n=38) were identified with Philadelphia positive ALL. 94.4% had a B-cell precursor phenotype ALL, and 8.7% had a nervous system infiltration at diagnosis. Overall, 60.4% integrated complete remission (n=272), with 31.3% (n=141) post-induction MRD negative. The percentage of negative MRD was higher in the pediatric protocol (38.5% vs 29.6%, p=0.000). Relapses occurred in 34% (n=153), and 21.3% (n=96) had a relapse to the central nervous system. Survival at 1000 days of follow-up was 32%, with significant differences in favor of the pediatric protocol (Log Rank 0.000) with 42% at 1000 days (Figure 1), the use of MRD as an impact tool with the prognosis (0.000) (Figure 2), the presence of a post-induction MRD+ (0.000) and high risk (Log-Rank 0.004) were the significant variables. Conclusions: The prognosis of a patient with ALL depends on the type of treatment. The prognosis is favorable when treated with a pediatric protocol. The detection of MRD by flow cytometry is the best follow-up tool, and its positivity decreases survival in adults with ALL.

Correlates and trajectories of relapses in relapsing–remitting multiple sclerosis

Background and aimsIn people with relapsing–remitting multiple sclerosis (pwRRMS), data from studies on non-pharmacological factors which may influence relapse risk, other than age, are inconsistent. There is a reduced risk of relapses with increasing age, but little is known about other trajectories in real-world MS care.MethodsWe studied longitudinal questionnaire data from 3885 pwRRMS, covering smoking, comorbidities, disease-modifying therapy (DMT), and patient-reported outcome measures, as well as relapses during the past year. We undertook Rasch analysis, group-based trajectory modelling, and multilevel negative binomial regression.ResultsThe regression cohort of 6285 data sets from pwRRMS over time showed that being a current smoker was associated with 43.9% greater relapse risk; having 3 or more comorbidities increased risk and increasing age reduced risk. Those diagnosed within the last 2 years showed two distinct trajectories, both reducing in relapse frequency but 25.8% started with a higher rate and took 4 years to reduce to the rate of the second group. In the cohort with at least three data points completed, there were three groups: 73.7% followed a low stable relapse rate, 21.6% started from a higher rate and decreased, and 4.7% had an increasing then decreasing pattern. These different trajectory groups showed significant differences in fatigue, neuropathic pain, disability, health status, quality of life, self-efficacy, and DMT use.ConclusionsThese results provide additional evidence for supporting pwRRMS to stop smoking and underline the importance of timely DMT decisions and treatment initiation soon after diagnosis with RRMS.

Incidence and Predictors of Relapse After Weaning Immune Suppressive Therapy in Cardiac Sarcoidosis

Cardiac sarcoidosis (CS) is a relapsing-remitting disease, and immune suppression (IS) is the mainstay of therapy. Predictors of relapse for patients with CS in remission are not well characterized. We assessed incidence of relapse in consecutive patients with CS treated with high-dose steroids and/or steroid-sparing agents (SSA) in our center from 2000 to 2020. Remission was defined as reaching maintenance therapy (no IS, SSA, and/or prednisone ≤5mg/d) for ≥1month. Relapse was defined as recurrence of CS syndrome requiring IS intensification: heart failure, ventricular arrhythmia, decrease in left ventricular ejection fraction, or increased disease burden on imaging. Among 68 patients, the mean age was 50.7±9.0years; 25 (37%) were women, and 32 (47%) were Black. In total, 59 patients (87%) reached remission. Over a median follow-up of 39.5months (interquartile range 17.6, 92.5), 28 (48%) relapsed. Greater percentage of late gadolinium enhancement (LGE) on pretreatment magnetic resonance imaging corresponded with increased likelihood of relapse (odds ratio 1.396 per 5% increase [95% confidence interval (CI) 1.04 to 1.88]; p=0.028). LGE ≥11% predicted elevated risk of relapse (adjusted odds ratio 4.998 [1.34 to 18.64]; p=0.017). Shorter time to relapse was observed with isolated CS (adjusted hazard ratio 4.084 [1.44,11.56]; p=0.008) and LGE ≥11% (adjusted hazard ratio 3.007 [1.01, 8.98]; p=0.049). Approximately 1 in 2 patients with CS in remission experienced relapse. Greater burden of LGE on cardiac magnetic resonance imaging and isolated CS are associated with greater risk of relapse. Future work is needed to refine risk stratification for relapse and to optimize surveillance strategies on the basis of the burden of disease.

PD09 A prospective study of outcomes of narrowband ultraviolet B for the treatment of paediatric atopic dermatitis, with additional breakdown by ethnicity/skin type

Abstract Narrowband UVB (NBUVB) phototherapy is regarded as a second-line treatment for atopic dermatitis (AD) when response to first-line treatment is ineffective. We undertook a prospective study evaluating response to NBUVB treatment in paediatric AD to assess changes to pretreatment Eczema Area and Severity Index (EASI) score immediately postphototherapy and 12 months later. We subanalysed response in different skin types. All patients had NBUVB treatment three times weekly up to a maximum of 40 exposures. Follow-up was every 3 months for 1 year postphototherapy. In total, 58 patients were recruited for NBUVB phototherapy treatment [37 (64%) men, 21 (36%) women, mean age 10.6 years (range 4.1–16.9 years)]. Skin types/ethnicity were as follows: White, n = 22 (38%); South Asian (Pakistani/Indian/Bangladeshi), n = 17 (29%); Black African/Caribbean, n = 9 (16%); other, n = 10 (17%). The immediate post-treatment mean EASI reductions vs. pretreatment baseline scores were 10.0 (entire cohort), 12.4 (White), 8.6 (South Asian), 2.5 (Black African/Caribbean) and 7.5 (other). A ≥ 75% increase in EASI (EASI 75) was achieved in the 49% of the entire cohort, in 48% of White people, in 50% of South Asians, in 44% of Black African/Caribbean people and in 56% of others. A ≥ 90% increase in EASI (EASI 90) was achieved in 15% of the whole group, 14% of White people, 13% of South Asians, 22% of Black African/Caribbean people and 11% of others. At 12 months post-treatment, mean EASI reduction vs. pretreatment baseline score was 7.6 in the whole cohort, 9.0 in White people, 8.6 in South Asians, −2.1 (i.e. worsening) in Black African/Caribbean people and 8.0 in others. At 12 months post-treatment, EASI 75 was achieved in 28% of the whole group, 33% of White people, 40% of South Asians, 14% of Black African/Caribbean people and 13% of others. For those who responded, there were a similar proportion of those achieving EASI 75 across the different skin types. However, there was more variation in the reduction in EASI score in those with skin colour. We acknowledge that existing scoring systems may lead to underscoring of the severity of erythema and therefore overall EASI score in darker skin types. Although the mean EASI reduction was highest in the group of White patients, there was a higher proportion of Black/Caribbean patients achieving EASI 90 at the end of the NBUVB treatment; however, the overall number of patients in this group was small. Our study showed that White and South Asian paediatric patients had a more sustained response to NBUVB phototherapy up to 1 year after stopping treatment. Black African/Caribbean patients had a greater risk of relapse.

Sex Differences in Cocaine Sensitization Vary by Mouse Strain

Introduction: Preclinical literature, frequently utilizing rats, suggests females display a more rapid advancement of substance abuse and a greater risk of relapse following drug abstinence. In clinical populations, it is less clear as to what extent biological sex is a defining variable in the acquisition and maintenance of substance use. Even without considering environmental experiences, genetic factors are presumed to critically influence the vulnerability to addiction. Genetically diverse mouse models provide a robust tool to examine the interactions between genetic background and sex differences in substance abuse. Methods: We explored mouse strain variability in male versus female behavioral sensitization to cocaine. Locomotor sensitization was observed following 5 consecutive days of subcutaneous cocaine across three genetically different mice strains: C57BL/6J, B6129SF2/J, and Diversity Outbred (DO/J). Results: Sex differences in cocaine locomotor sensitization were dependent on mouse strain. Specifically, we observed opposing sex differences in locomotor sensitization, with male C57BL/6J and female B6129SF2/J mice displaying heightened activity compared to their opposite sex counterparts. Conversely, no sex differences were observed in the DO/J mice. Acute cocaine administration resulted in locomotor differences across strains in male, but not female, mice. The magnitude of sensitization (or lack thereof) also varied by genetic background. Conclusions: While sex differences in drug addiction may be observed, these effects can be mitigated, or even reversed, depending on genetic background. The clinical implications are that in the absence of understanding the genetic variables underlying vulnerability to addiction, sex provides little information regarding the predisposition of an individual to drug abuse.

Major depressive disorder with anxious features - the role of pregabalin

IntroductionPatients with unipolar major depression often present with symptoms of anxiety. Presentations with high levels of anxiety, restlessness, and somatic correlates of anxiety can be clinically identified as anxious depression. The comorbidity of anxious and depressive symptoms is a marker of poor prognosis, with greater risk of relapse and increased suicidal risk.ObjectivesBrief review of the role of pregabalin in the treatment of major depressive disorder (MDD), based on a case study.MethodsConsultation of the clinical record and brief review of the literature on this subject.ResultsWe present the case of a 25-year-old woman, with no past psychiatric history, admitted to a psychiatric consultation with depressive symptoms, and marked anxiety and somatic complaints, such as restlessness, palpitations, gastrointestinal discomfort. She fulfilled diagnostic criteria for Major depressive disorder (MDD), and was initially treated with sertraline 50 mg, with partial response, but maintenance of prominent anxious symptoms with important functional impairment. Then, we raised the dose of sertraline to 100 mg and added pregabalin 50 mg, with up-titration to 150 mg per day, divided in three doses. We observed rapid response, particularly on the anxious symptoms, and subsequently on the patient functionality.The anxiety symptoms can increase in the first days of treatment with a selective serotonin reuptake inhibitor, which is the first-line therapy for major depression. Those are particularly difficult to treat, resulting often in treatment resistance and functional impairment. Pregabalin has a proven rapid-onset anxiolytic effect, with less cognitive and motor effects and less risk for dependence than benzodiazepines. It has demonstrated efficacy for the treatment of generalized anxiety disorder, but the use for patients with MDD has not been clearly studied.ConclusionsAlthough the evidence on this subject is sparse, pregabalin augmentation of antidepressants could be an adequate option for the treatment of depression, allowing a faster action on the anxiety symptoms, especially on the first weeks of treatment, without some of the risks of the benzodiazepines.Disclosure of InterestNone Declared

Body mass index during maintenance therapy and relapse risk in children with acute lymphoblastic leukemia: AChildren's Oncology Group report.

Obesity at diagnosis of childhood acute lymphoblastic leukemia (ALL) is associated with greater risk of relapse; whether this association extends to obesity during maintenance is unstudied. This study used data from AALL03N1 to calculate median body mass index (BMI) for 676 children over 6 consecutive months during maintenance therapy; BMI percentile (BMI%ile) were operationalized as normal/underweight (<85%ile), overweight/obese (85%-98%ile), and extreme obesity (≥99%ile). Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression after adjusting for all relevant demographic and clinical predictors. Median age at study enrollment was 6 years and median length of follow-up was 7.9years. Overall, 43.3% of the cohort was underweight/normal weight, 44.8% was overweight/obese, and 11.8% had extreme obesity. Cumulative incidence of relapse at 4 years from study enrollment was higher among those with extreme obesity (13.6%±4.5%) compared to those with underweight/normal weight (9.0%±2.1%). Multivariable analysis revealed that children with extreme obesity had a 2.4-fold (95% confidence interval [CI], 1.1-5.0; p=.01) greater hazard of relapse compared to those who were underweight/normal weight. Overweight/obese patients were at comparable risk to those who were underweight/normal weight (hazard ratio, 0.8; 95% CI, 0.4-1.6). Erythrocyte thioguanine nucleotide (TGN) levels were significantly lower among children with extreme obesity compared to those with underweight/normal weight (141.6 vs. 168.8 pmol/8×108 erythrocytes; p=.0002), however, the difference in TGN levels did not explain the greater hazard of relapse among those with extreme obesity. Extreme obesity during maintenance therapy is associated with greater hazard of relapse in children with ALL. Underlying mechanisms of this association needs further investigation. Findings from this study demonstrate that extreme obesity during maintenance therapy is associated with a greater hazard of relapse among children with acute lymphoblastic leukemia. We show that children with obesity have lower levels of erythrocyte thioguanine nucleotides even after adjusting for adherence to oral chemotherapy. However, these lower levels do not explain the greater hazard of relapse, paving the way for future studies to explore this association.

Buprenorphine & methadone dosing strategies to reduce risk of relapse in the treatment of opioid use disorder

BackgroundAlthough there is consensus that having a “high-enough” dose of buprenorphine (BUP-NX) or methadone is important for reducing relapse to opioid use, there is debate about what this dose is and how it should be attained. We estimated the extent to which different dosing strategies would affect risk of relapse over 12 weeks of treatment, separately for BUP-NX and methadone. MethodsThis was a secondary analysis of three comparative effectiveness trials. We examined four dosing strategies: 1) increasing dose in response to participant-specific opioid use, 2) increasing dose weekly until some minimum dose (16 mg BUP, 100 mg methadone) was reached, 3) increasing dose weekly until some minimum and increasing dose in response to opioid use thereafter (referred to as the “hybrid strategy”), and 4) keeping dose constant after the first 2 weeks of treatment. We used a longitudinal sequentially doubly robust estimator to estimate contrasts between dosing strategies on risk of relapse. ResultsFor BUP-NX, increasing dose following the hybrid strategy resulted in the lowest risk of relapse. For methadone, holding dose constant resulted in greatest risk of relapse; the other three strategies performed similarly. For example, the hybrid strategy reduced week 12 relapse risk by 13 % (RR: 0.87, 95 %CI: 0.83–0.95) and by 20 % (RR: 0.80, 95 %CI: 0.71–0.90) for BUP-NX and methadone respectively, as compared to holding dose constant. ConclusionsDoses should be targeted toward minimum thresholds and, in the case of BUP-NX, raised when patients continue to use opioids.

NIAAA Definition of Recovery Provides Measurable Endpoints for AUD Researchers

NIAAA Definition of Recovery Provides Measurable Endpoints for AUD Researchers

Association of Socioeconomic Status With Relapse After Ponseti Method Treatment of Idiopathic Clubfeet.

Background:The Ponseti method is today’s standard treatment of idiopathic talipes equinovarus (ITEV). Compliance with foot abduction bracing (FABO) and socioeconomic factors have been shown to impact treatment outcome. We wished to further study socioeconomic factors using the Area Deprivation Index (ADI), a more comprehensive way to evaluate socioeconomic status, which has not been done before.Methods:All TEV patients from 2010 through 2019 treated with the Ponseti method were reviewed. Standard demographic variables, as well as the number of casts to complete initial correction, FABO compliance, and occurrence of relapse were tabulated. Socioeconomic level was quantified with the 2018 ADI.Results:There were 168 children; 151 had typical and 17 complex TEV. Average follow-up was 4.3 ± 1.8 years; relapse occurred in 46%. There were no significant differences in the percentage of relapse by sex, race, or ADI. FABO noncompliance was present in 46%. Relapse increased with increasing time of follow-up and FABO noncompliance (76% vs 21%, P < 10−6). Multivariate logistic regression analysis revealed that only FABO compliance and length of follow-up were associated with relapse. The OR of relapse for FABO noncompliance was 17.9 (7.6, 42.4, P < 10–6) and for follow-up >4 years the OR was 4.97 (2.1, 11.70, P = .0003).Conclusion:The outcome of the Ponseti method for TEV treatment is dependent on local circumstances. In our state, socioeconomic status, as determined by the ADI, was not associated with the occurrence of relapse. Thus, each center needs to assess its results, and analyze its own reasons for relapse. There were no other demographic variables associated with relapse except FABO compliance and length of follow-up. Parents should be strongly advised that FABO compliance and follow-up appears paramount to achieving the best results, and that complex TEV are at greater risk for relapse.Level of Evidence:Level IV, case series

Abstract 3633: Disparities in relapse among a large multi-ethnic population of children diagnosed with acute lymphoblastic leukemia (ALL): A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium

Abstract Introduction: While end-induction minimal residual disease (MRD) is the strongest prognostic factor for relapsed ALL, approximately half of all relapses occur in children who are MRD negative. Latino ethnicity is also a risk factor for relapse. To further explore these associations, we conducted an interim analysis of risk factors for relapse in a large multi-ethnic population of children diagnosed with ALL. Methods: The REDIAL Consortium includes patients diagnosed with ALL at six major pediatric cancer centers in the Southwestern U.S. The study period was 2004 to 2018, and we included individuals who were 1-23 years of age when diagnosed with ALL. Time to relapse was defined as time from ALL diagnosis to the initial relapse event, with individuals censored at date of death, last follow-up, or bone marrow transplant. Demographic and clinical factors evaluated included race/ethnicity (Latino, non-Latino Black, non-Latino White, non-Latino other), sex, age at diagnosis (1-5, 6-10, 11-15, &amp;gt;15 years), ALL immunophenotype (B-cell, T-cell), National Cancer Institute (NCI) risk group, central nervous system involvement, enrollment on a Children’s Oncology Group clinical trial, end-induction disease failure, and end-induction bone marrow flow cytometric MRD. Cox proportional hazards models were used to calculate adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). Analyses were further stratified based on end-induction MRD status (positive ≥0.01%, negative &amp;lt;0.01%). Results: Overall, there were 1,710 ALL patients with a median age at diagnosis of 5 years (interquartile range: 3-11 years). The majority of patients were Latino (60.1%) and male (56.9%). Of the 379 MRD-positive patients, 74 (19.5%) relapsed, compared to 138 of 1,233 (11.2%) MRD-negative patients (p&amp;lt;0.0001). In adjusted models, factors associated with a greater risk of relapse included MRD positivity (HR=1.72, 95% CI: 1.26-2.36), older age at diagnosis (&amp;gt;15 vs. 1-5 years, HR=1.98, 95% CI: 1.19-3.29), and NCI high-risk group (HR=1.74, 95% CI: 1.20-2.52), while patients enrolled on a clinical trial were less likely to relapse (HR=0.76, 95% CI: 0.57-0.99). Among MRD-positive patients, Latinos were less likely to relapse (HR=0.60, 95% CI: 0.33-0.99) compared to non-Latino Whites, whereas Latinos who were MRD negative were more likely to relapse (HR=1.68, 95% CI: 1.09-2.59). Conclusion: In a large contemporary multi-ethnic cohort of &amp;gt;1,700 children with ALL, we observed significant disparities in relapse by MRD status, age at diagnosis, NCI risk group, clinical trial enrollment, and race/ethnicity. Notably, nearly 65% of relapse events occurred in MRD-negative patients. Further analyses are ongoing in REDIAL to evaluate the impact of other factors including cytogenetics and novel biomarkers of relapse. Citation Format: Pagna Sok, Austin L. Brown, Olga A. Taylor, M. Brooke Bernhardt, Juan C. Bernini, Rodrigo A. Erana, Timothy Griffin, Kenneth Heym, Van T. Huynh, Laura Klesse, Kathleen Ludwig, Sandi L. Pruitt, Karen R. Rabin, Michael E. Scheurer, Philip J. Lupo. Disparities in relapse among a large multi-ethnic population of children diagnosed with acute lymphoblastic leukemia (ALL): A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3633.

Predicting outcomes with circulating adrenergic neuroblastoma mRNAs in children with relapsed and refractory neuroblastoma: A BEACON-Neuroblastoma biomarker study.

10039 Background: Children with relapsed and refractory neuroblastoma (RR-NBL) have poor outcomes. Early identification of children at greatest risk of relapse could mean timelier modifications of treatment to improve outcomes. High levels of adrenergic neuroblastoma mRNAs in blood of children with stage M neuroblastoma receiving frontline treatment predict poor outcome (Viprey PMID: 24590653). Since these markers have not been thoroughly studied in the RR-NBL population, we have prospectively evaluated the prognostic potential of the adrenergic neuroblastoma mRNAs paired-like homeobox 2B (PHOX2B ) and tyrosine hydroxylase (TH) in blood from children with RR-NBL treated in the BEACON-Neuroblastoma trial (NCT02308527). Methods: Blood samples collected at baseline from 88 children were analysed by reverse transcriptase polymerase chain reaction (RTqPCR) for PHOX2B and TH mRNAs. The prognostic power of these mRNAs was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression. Progression-free (PFS) and overall survival (OS) were calculated from the date that the blood sample was taken at screening to the date of an event; progression, disease recurrence, death or censored alive at the last clinical evaluation. Results: Of the children in this cohort, 58 (66%) had relapsed and 30 (34%) had refractory disease. Twenty-three (26%) had MYC-N amplified tumours. TH and PHOX2B mRNAs were detected in 55% and 60% of blood samples respectively; the correlation coefficient between TH and PHOX2B was 0.75. Higher levels of TH, PHOX2B mRNAs or both combined were associated with reduced PFS and OS (Table). For TH, median PFS for children with TH levels below the median was 12 months (95%CI, 4.6–13 months) versus 5.5 months (95%CI, 1.8–9.4 months) for those children with TH levels above the median. For PHOX2B, median PFS for children with PHOX2B levels below the median was 11.5 months (95%CI, 7.6–34 months), compared to 5.7 months (95%CI, 1.8–10.5 months) where levels were above the median. Conclusions: TH and PHOX2B mRNAs in blood collected at baseline identify children with refractory or relapsed neuroblastoma at greatest risk of progression or death. In the RR-NBL setting, this simple blood test could be used to stratify treatment strategies. Clinical trial information: NCT02308527. [Table: see text]

Modeling the Dynamics of Heroin and Illicit Opioid Use Disorder, Treatment, and Recovery

Opioid use disorder (OUD) has become a serious leading health issue in the USA leading to addiction, disability, or death by overdose. Research has shown that OUD can lead to a chronic lifelong disorder with greater risk for relapse and accidental overdose deaths. While the prescription opioid epidemic is a relatively new phenomenon, illicit opioid use via heroin has been around for decades. Recently, additional illicit opioids such as fentanyl have become increasingly available and problematic. We propose a mathematical model that focuses on illicit OUD and includes a class for recovered users but allows for individuals to either remain in or relapse back to the illicit OUD class. Therefore, in our model, individuals may cycle in and out of three different classes: illicit OUD, treatment, and recovered. We additionally include a treatment function with saturation, as it has been shown there is limited accessibility to specialty treatment facilities. We used 2002–2019 SAMHSA and CDC data for the US population, scaled to a medium-sized city, to obtain parameter estimates for the specific case of heroin. We found that the overdose death rate has been increasing linearly since around 2011, likely due to the increased presence of fentanyl in the heroin supply. Extrapolation of this overdose death rate, together with the obtained parameter estimates, predict that by 2038 no endemic equilibrium will exist and the only stable equilibrium will correspond to the absence of heroin use disorder in the population. There is a range of parameter values that will give rise to a backward bifurcation above a critical saturation of treatment availability. We show this for a range of overdose death rate values, thus illustrating the critical role played by the availability of specialty treatment facilities. Sensitivity analysis consistently shows the significant role of people entering treatment on their own accord, which suggests the importance of removing two of the most prevalent SAMHSA-determined reasons that individuals do not enter treatment: financial constraints and the stigma of seeking treatment for heroin use disorder.

Does Body Mass Index (BMI) during Maintenance Influence Relapse Risk in Children with Acute Lymphoblastic Leukemia (ALL)? Results from COG-AALL03N1

▪Introduction: Higher BMI at ALL diagnosis is associated with an increased risk of post-induction residual leukemia (Orgel, Blood 2014) and relapse (Butturini, JCO 2007). However, children may experience significant changes in BMI during the pre-maintenance phases of ALL treatment (Withycombe, Pediatr Blood Cancer 2009), necessitating an examination of the association between BMI during maintenance and relapse risk. We hypothesized that higher BMI during maintenance would be associated with a greater risk of relapse. We also explored the association between BMI and red cell thioguanine (TGN) levels to understand whether BMI-associated variations in TGN biodistribution explained the BMI-relapse association.Methods: We used data from COG-AALL03N1 (primary aim was 6MP adherence) to examine the association between BMI during maintenance and relapse risk. Eligibility for enrollment on AALL03N1 included age ≤21y at ALL diagnosis and receiving maintenance therapy in first remission. The current analysis was limited to patients with wild-type thiopurine methyltransferase genotype. BMI (exposure variable) was calculated as sex- and age-based percentile per CDC normative data, and operationalized as normal/underweight [<85%ile], overweight/obese [85-98%ile] and morbidly obese [≥99%ile]). Hazard of relapse (any site) was estimated using multivariable proportional subdistributional hazards regression after adjusting for age at study enrollment, sex, race/ethnicity, NCI risk group, cytogenetics, 6MP dose intensity (6MPDI), and time from initiation of maintenance. We compared fitted means of red cell TGN levels by BMI groups after adjusting for age at enrollment, sex, race/ethnicity, 6MPDI and time from initiation of maintenance using generalized estimated equations. The association between BMI and relapse risk, as well as between BMI and TGN levels, was also examined in a sub-cohort of patients with available 6MP adherence.Results: The sociodemographic and disease characteristics of the 676 study participants are summarized in the Table. Median BMI%ile was 88.5 (range, 0-100); normal/underweight: 43%, overweight/obese: 45%, and morbidly obese: 12%. As shown in the Figure, cumulative incidence of relapse at 2y from start of maintenance therapy was significantly greater among patients with morbid obesity (11.9±4.3%) when compared to those who were overweight/obese (5.4±1.6%) and underweight/normal weight (4.1±1.4%). After adjusting for the variables listed above, we found that patients with morbid obesity had a 3.2-fold greater hazard of relapse (95%CI=1.4-7.5, P=0.008) when compared to patients who were normal/underweight. After adjusting for age at enrollment, sex, race/ethnicity, 6MPDI, and time from initiation of maintenance, patients with morbid obesity had lower mean red cell TGN levels compared to normal/underweight patients (mean difference: -27.2±7.4 pmol/8 x 10 8 erythrocytes, P=0.0002). However, inclusion of TGN in the model did not alter the association between BMI and hazard of relapse (HR=3.8, 95%CI, 1.6-9.0, P=0.003). These findings did not change after adjusting for 6MP adherence in the sub-cohort with available adherence data (n=435).Conclusion: Morbid obesity during maintenance for childhood ALL is associated with relapse as well as lower systemic exposure to 6MP. However, lower TGN levels do not explain the relation between BMI and relapse risk. Therefore, there is a need to understand the mechanism of the relation between morbid obesity during maintenance and relapse risk in children with ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.