Predictors of low and very low bone mineral density in long-term childhood acute lymphoblastic leukemia survivors: Toward personalized risk prediction.

BACKGROUND: Cohorts of childhood acute lymphoblastic leukemia (cALL) survivors reaching adulthood are increasing. Approximately 30% of survivors meet criteria for low bone mineral density (BMD) 10 years after diagnosis. We investigated risk factors for low BMD in long-term cALL survivors. METHODS: We recruited 245 cALL survivors from the PETALE (Prévenir les effets tardifs des traitements de la leucémie aiguë lymphoblastique chez l'enfant) cohort, who were treated with the Dana Farber Cancer Institute protocols, did not experience disease relapse or hematopoietic stem cell transplants, and presented with more than 5 years of event-free survival. Median time since diagnosis was 15.1 years. RESULTS: Prevalence of low DXA-derived BMD (Z-score ≤-1) ranged between 21.9% and 25.3%, depending on site (lumbar spine (LS-BMD), femoral neck (FN-BMD), and total body (TB-BMD), and between 3.7% and 5.8% for very low BMD (Z-score ≤-2). Males had a higher prevalence of low BMD than females for all three outcomes (26%-32% vs. 18%-21%), and male sex acted as a significant risk factor for low BMD in all models. Treatment-related factors such as cumulative glucocorticoid (GC) doses and cranial radiation therapy (CRT) were associated with lower BMDs in the full cohort and in females at the FN-BMD site. CONCLUSION: Low and very low BMD is more prevalent in male cALL survivors. Male sex, high cumulative GC doses, CRT, risk group, and low body mass index (BMI) were identified as risk factors for low BMD. A longer follow-up of BMD through time in these survivors is needed to establish if low BMD will translate into a higher risk for fragility fractures through adulthood.

Physical impairments, activity limitations, and participation restrictions of childhood acute lymphoblastic leukemia survivors with and without hip osteonecrosis: a PETALE cohort study.

PURPOSE: Long-term musculoskeletal complications represent a growing burden for survivors of childhood acute lymphoblastic leukemia (cALL). This study aimed to describe physical impairments, activity limitations, and participation restrictions in a high-risk subgroup of cALL survivors of the PETALE cohort. METHODS: This cross-sectional study, using observational data from the PETALE cohort, included a subgroup of survivors who presented high-risk criteria for late effects. Outcomes measures consisted of hip magnetic resonance imaging, maximal isometric muscle strength (MIMS) or torque (MIMT), range of motion (ROM), Near Tandem Balance (NTB), 6-Minute Walk Test (6MWT), Five Time Sit-to-Stand Test (FTSST), and health-related quality of life. Descriptive statistics and regression analyses were performed. RESULTS: Survivors (n = 97, 24.2 ± 6.7 years old) showed limited grip strength, FTSST, and NTB performance compared to reference values (p < 0.001). Thirteen participants (14.6%, 18 hips) had hip osteonecrosis (ON) (53.8% male). Higher severity hip ON was found in female survivors (66.7% vs. 22.2%). Survivors with hip ON had reduced hip external rotation ROM compared to those without (p < 0.05). Relationships were found between MIMS and ROM outcomes (r = 0.32, p < 0.01) and with 6MWT (r = 0.39-0.41, p < 0.001). Our multiple linear regression model explained 27.6% of the variance of the 6MWT. CONCLUSIONS: Survivors in our subgroup had clinically significant physical impairments and activity limitations, and those with hip ON showed worst hip impairment outcomes. IMPLICATIONS FOR CANCER SURVIVORS: These findings emphasize the importance of long-term follow-up including physical therapy assessment to help early identification and management of physical impairments and activity limitations in survivors of cALL.

Vertebral Body Reshaping after Fractures: An Important Index of Recovery in Glucocorticoid-Treated Children.

PURPOSE: In this 6-year study we identified factors associated with spontaneous vertebral body reshaping in glucocorticoid (GC)-treated children with leukemia, rheumatic disorders, and nephrotic syndrome. METHODS: Subjects were 79 children (mean age 7.4 years) who had vertebral fracture (VF) evaluation on lateral spine radiographs at least 1 year after VF detection. VF were graded using the modified Genant semiquantitative method and fracture burden for individuals was quantified using the spinal deformity index (SDI; sum of grades from T4 to L4). RESULTS: Sixty-five children (82.3%) underwent complete vertebral body reshaping (median time from VF detection to complete reshaping 1.3 years by Cox proportional hazard modeling). Of 237 VF, the majority (83.1%) ultimately reshaped, with 87.2% reshaping in the thoracic region vs 70.7% in the lumbar region (P = .004). Cox models showed that (1) every g/m2 increase in GC exposure in the first year after VF detection was associated with a 19% decline in the probability of reshaping; (2) each unit increase in the SDI at the time of VF detection was associated with a 19% decline in the probability of reshaping [hazard ratio (HR) = 0.81; 95% confidence interval (CI) = 0.71, 0.92; P = .001]; (3) each additional VF present at the time of VF detection reduced reshaping by 25% (HR = 0.75; 95% CI = 0.62, 0.90; P = .002); and (4) each higher grade of VF severity decreased reshaping by 65% (HR = 0.35; 95% CI = 0.21, 0.57; P < .001). CONCLUSION: After experiencing a VF, children with higher GC exposure, higher SDI, more severe fractures, or lumbar VF were at increased risk for persistent vertebral deformity.

Reductions in Bone Mineral Density Are Apparent Early in Children With Prevalent Osteonecrosis Lesions Following Leukemia Therapy.

Osteonecrosis (ON) is a serious complication of childhood acute lymphoblastic leukemia. We determined the prevalence of osteonecrotic lesions in our patient population by a one-time multisite magnetic resonance imaging (MRI) more than 1 year following leukemia therapy. MRI findings were evaluated in relationship to clinical factors (including longitudinal changes in bone mineral density [BMD]). Eighty-six children enrolled in the Steroid Associated Osteoporosis in the Pediatric Population (STOPP) study were evaluated for ON at 3.1 ± 1.3 years following therapy. Thirty children had a total of 150 confirmed ON lesions (35%). Lumbar spine (LS) BMD Z-scores (mean ± SD) were low at diagnosis and similar between patients with and without ON (-1.09 ± 1.53 versus -1.27 ± 1.25, p = 0.549). LS BMD Z-scores declined from baseline to 12 months in children with ON (-0.31 ± 1.02) but not in those without (0.13 ± 0.82, p = 0.035); the hip BMD Z-scores from baseline to 24 months declined in both groups, but to a greater extent in those with ON (-1.77 ± 1.22) compared to those without (-1.03 ± 1.07, p = 0.045). At the time of the MRI, mean total hip and total body (TB) BMD Z-scores were lower in children with ON (hip -0.98 ± 0.95 versus -0.28 ± 1.06, p = 0.010; TB -1.36 ± 1.10 versus -0.48 ± 1.50, p = 0.018). Pain occurred in 11/30 (37%) with ON versus 20/56 (36%) without, p = 0.841. In multivariable models, older age at diagnosis (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.15-2.13; p = 0.004), and hip BMD Z-score at MRI (OR 2.23; 95% CI, 1.02-4.87; p = 0.046) were independently associated with ON. Overall, one-third of children demonstrated ON after leukemia therapy. Those with ON had greater reductions in spine and hip BMD Z-scores in the first 1 and 2 years of therapy, respectively. Older age and lower hip BMD Z-scores at MRI were significantly associated with prevalent, off-therapy ON. These data assist in identifying children at risk of ON. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. OBJECTIVE: To evaluate safety and efficacy of intranasal carbetocin in PWS. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. SETTING: Twenty-four ambulatory clinics at academic medical centers. PARTICIPANTS: A total of 130 participants with PWS aged 7 to 18 years. INTERVENTIONS: Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. MAIN OUTCOME MEASURES: Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). RESULTS: Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. CONCLUSIONS: Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. CLINICAL TRIALS REGISTRATION NUMBER: NCT03649477.

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Beyond Bone Mineral Density: The Impact of Childhood Cancer and Its Treatment on Bone Structure and Strength.

The spectrum of bone morbidity in childhood cancer survivors (CCS) is broad and extends beyond "low bone mineral density" to structural damage including fracture-induced vertebral deformity, and joint collapse due to osteonecrosis or slipped capital femoral epiphysis. In addition, short stature, scoliosis, leg length discrepancy, and vertebral deformity can arise from critical interference with growth plate activity. In some cases, insufficient residual growth potential or irreversible growth plate damage can lead to permanent structural deformity, leaving the patient with chronic functional limitations. In this chapter, we describe the clinical manifestations, natural history, and risk factors for cancer-related bone morbidity, approaches to monitoring and diagnosis, and the (paucity of) data available on prevention and treatment measures. In so doing, we unveil important biological principles about the potential for the pediatric skeleton to recover from bone morbidity, obviating the need for treatment, versus permanent structural damage that can negatively impact quality of life over the long-term. These observations, in turn, illuminate the unmet needs that drive future research to improve musculoskeletal strength and mobility in this setting.

A Validated Risk Prediction Model for Bone Fragility in Children With Acute Lymphoblastic Leukemia.

Although bone fragility may already be present at diagnosis of pediatric acute lymphoblastic leukemia (ALL), routine performance of dual-energy X-ray absorptiometry (DXA) in every child is not universally feasible. The aim of this study was to develop and validate a risk prediction model for low lumbar spine bone mineral density (LS BMD Z-score ≤ -2.0) at diagnosis, as an important indicator for fracture risk and further treatment-related BMD aggravation. Children with ALL (4-18 years), treated according to the Dutch Childhood Oncology Group protocol (DCOG-ALL9; model development; n = 249) and children from the Canadian Steroid-Associated Osteoporosis in the Pediatric Population cohort (STOPP; validation; n = 99) were included in this study. Multivariable logistic regression analyses were used to develop the prediction model and to confirm the association of low LS BMD at diagnosis with symptomatic fractures during and shortly after cessation of ALL treatment. The area under the receiver operating characteristic curve (AUC) was used to assess model performance. The prediction model for low LS BMD at diagnosis using weight (ß = -0.70) and age (ß = -0.10) at diagnosis revealed an AUC of 0.71 (95% CI, 0.63-0.78) in DCOG-ALL9 and 0.74 (95% CI, 0.63-0.84) in STOPP, and resulted in correct identification of 71% of the patients with low LS BMD. We confirmed that low LS BMD at diagnosis is associated with LS BMD at treatment cessation (OR 5.9; 95% CI, 3.2-10.9) and with symptomatic fractures (OR 1.7; 95% CI, 1.3-2.4) that occurred between diagnosis and 12 months following treatment cessation. In meta-analysis, LS BMD at diagnosis (OR 1.6; 95% CI, 1.1-2.4) and the 6-month cumulative glucocorticoid dose (OR 1.9; 95% CI, 1.1-3.2) were associated with fractures that occurred in the first year of treatment. In summary, a prediction model for identifying pediatric ALL patients with low LS BMD at diagnosis, as an important indicator for bone fragility, was successfully developed and validated. This can facilitate identification of future bone fragility in individual pediatric ALL patients. © 2021 American Society for Bone and Mineral Research (ASBMR).

Bone mineral density surveillance for childhood, adolescent, and young adult cancer survivors: evidence-based recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult cancer survivors are at increased risk of reduced bone mineral density. Clinical practice surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could improve bone mineral density parameters and prevent fragility fractures. Discordances across current late effects guidelines necessitated international harmonisation of recommendations for bone mineral density surveillance. The International Late Effects of Childhood Cancer Guideline Harmonization Group therefore established a panel of 36 experts from ten countries, representing a range of relevant medical specialties. The evidence of risk factors for very low and low bone mineral density and fractures, surveillance modality, timing of bone mineral density surveillance, and treatment of very low and low bone mineral density were evaluated and critically appraised, and harmonised recommendations for childhood, adolescent, and young adult cancer survivors were formulated. We graded the recommendations based on the quality of evidence and balance between potential benefits and harms. Bone mineral density surveillance is recommended for survivors treated with cranial or craniospinal radiotherapy and is reasonable for survivors treated with total body irradiation. Due to insufficient evidence, no recommendation can be formulated for or against bone mineral density surveillance for survivors treated with corticosteroids. This surveillance decision should be made by the survivor and health-care provider together, after careful consideration of the potential harms and benefits and additional risk factors. We recommend to carry out bone mineral density surveillance using dual-energy x-ray absorptiometry at entry into long-term follow-up, and if normal (Z-score > -1), repeat when the survivor is aged 25 years. Between these measurements and thereafter, surveillance should be done as clinically indicated. These recommendations facilitate evidence-based care for childhood, adolescent, and young adult cancer survivors internationally.

Home-Based Telehealth Exercise Intervention in Early-On Survivors of Childhood Acute Lymphoblastic Leukemia: Feasibility Study.

BACKGROUND: Acute lymphoblastic leukemia is the most common type of pediatric cancer. Acute lymphoblastic leukemia causes an altered bone mineral homeostasis state, which can contribute to osteopenia, and bone fractures, most commonly vertebral fractures. With the increasing number of childhood cancer survivors, late adverse effects such as musculoskeletal comorbidities are often reported and are further influenced by inactive lifestyle habits. Physical activity has been shown to increase the mechanical workload of the bone, mitigating bone impairment in other cancer-specific populations. OBJECTIVE: This interventional pilot study aims to investigate the use of telehealth to deliver a home-based exercise intervention for early-on survivors of bone marrow-related hematological malignancies and to assess its impact on survivors' musculoskeletal and functional health. METHODS: We aimed to recruit a group of 12 early-on survivors of acute lymphoblastic leukemia, within 6 months to 5 years of treatment, to participate in and complete the proposed telehealth intervention with a parent. The 16-week intervention included 40 potential home-based physical activity interventions supervised by a kinesiologist through a telehealth internet platform, with monthly progression. Patients were recruited to the cohort if they were able to participate in the intervention during the first month (minimum 12 weeks of intervention). Evaluation before and after the intervention protocol highlighted differences in functional capacities and musculoskeletal health of patients using mechanography, peripheral quantitative computed tomography, 6-minute walk test, and grip force test. RESULTS: The recruitment rate for the intervention was low (12/57, 21% of contacted patients). Of 12 patients, 3 were excluded (1=relapse, 1=failure to meet technical requirements, and 1=abandoned). The 9 patients who completed the intervention (6 girls; mean age 10.93, SD 2.83 years; mean BMI 21.58, SD 6.55 kg/m2; mean time since treatment completion 36.67, SD 16.37 months) had a mean adherence of 89% and a completion rate of 75%. In addition, these patients showed functional improvements in lower limb muscle force and power as well as in the 6-minute walk test distance. Participants also showed improved bone health after the intervention on the following parameters: bone mineral content, stress-strain index, total and cortical cross-sectional area at the 14% site (P=.03, P=.01, P=.01, and P=.001, respectively) and 38% site of the tibia (P=.003, P=.04, P=.001, and P=.003, respectively). CONCLUSIONS: High adherence and participation rates suggest that telehealth is a feasible method to deliver exercise interventions to young early-on survivors of acute lymphoblastic leukemia. The proposed intervention seems promising in providing benefits to patients' functional performance and bone health, but a large-scale study is needed to confirm this assumption.

Rickets manifestations in a child with metaphyseal anadysplasia, report of a spontaneously resolving case.

INTRODUCTION: Rickets is not an unusual diagnosis for pediatricians even currently in developed countries. Children typically present with leg bowing, enlargement of wrists, rachitic rosary (swelling of costochondral junctions) and/or waddling gait. But not every child with growth delay and enlarged metaphyses is diagnosed with rickets. Metaphyseal anadysplasia (MAD) is a disorder of variable severity with metaphyseal flaring and irregularities, without vertebral abnormalities. MAD is characterized by an early onset and a regressive course in late childhood without treatment, despite persistent short stature. Autosomal dominant or recessive variants in the matrix metalloproteinase 13 gene (MMP13) are responsible for these transient metaphyseal changes. CASE PRESENTATION: We report a new pathogenic heterozygous variant in MMP13 (NM_002427.4: c.216G>C, p.Gln72His) in a toddler, initially thought to have rickets, and his father, with MAD phenotypes. Additionally, we review the seven reported MMP13 variants. CONCLUSION: One should keep a wide differential diagnosis in cases of suspected rickets, including skeletal dysplasias which might have a regressive course.

Patient and Parent Experiences with Group Telerehabilitation for Child Survivors of Acute Lymphoblastic Leukemia.

BACKGROUND: Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer. ALL and its treatment cause altered bone-mineral homeostasis, which can contribute to musculoskeletal late adverse effects (LAEs). With the increasing number of childhood cancer survivors, LAEs are reported often, and are aggravated by inactive lifestyles. A telerehabilitation program is proposed to strengthen the muscle-bone complex and prevent future impairment. OBJECTIVE: This study aimed to explore and better understand patient and parent experience of a telerehabilitation program after completion of ALL treatment. METHODS: ALL survivors (n = 12), 75% girls, 7.9 to 14.7 years old, within six months to five years of treatment, were recruited to participate in the proposed study, along with a parent. The 16-week group program included 40 potential home-based physical activities, with monthly progression, supervised by a kinesiologist, through an online telerehabilitation platform. Patients could be included in the study if they joined during the first month of intervention of their group (minimum 12 weeks of intervention). A semi-structured post-intervention interview was conducted with the patients and their parent during the final assessment, along with a review of the kinesiologist's clinical notes, to obtain a portrait of the participants' experience with the telerehabilitation program. Overarching themes were identified by one author and confirmed by two senior authors before extracting the various aspects of each theme. RESULTS: Of the 12 patients recruited, three were excluded from the analysis because they did not complete the minimum 12 weeks of intervention (one = relapse, one = failure to meet technical requirements, and one = abandoned due to parent's disinterest). The nine patients who completed the program (six girls; 10.93 ± 2.83 years) had a mean adherence of 89%. The overarching themes identified were the program modalities (group approach with patient-parent paired training, supervised by a kinesiologist), the telerehabilitation system, the participants' perception of the benefits, and recommendations and suggestions from the families. Both patients and parents expressed very high satisfaction with the program and perceived benefits. CONCLUSION: Participants appreciated the program and reported they would all recommend it to other families in similar situations. The telerehabilitation method of service delivery was perceived by some as decisive in choosing to participate, while the supervision and intra- and inter-family interactions were the motivating factors that were key to program adherence.

The Accuracy of Incident Vertebral Fracture Detection in Children Using Targeted Case-Finding Approaches.

Vertebral fractures are clinically important sequelae of a wide array of pediatric diseases. In this study, we examined the accuracy of case-finding strategies for detecting incident vertebral fractures (IVF) over 2 years in glucocorticoid-treated children (n = 343) with leukemia, rheumatic disorders, or nephrotic syndrome. Two clinical situations were addressed: the prevalent vertebral fracture (PVF) scenario (when baseline PVF status was known), which assessed the utility of PVF and low lumbar spine bone mineral density (LS BMD; Z-score <-1.4), and the non-PVF scenario (when PVF status was unknown), which evaluated low LS BMD and back pain. LS BMD was measured by dual-energy X-ray absorptiometry, vertebral fractures were quantified on spine radiographs using the modified Genant semiquantitative method, and back pain was assessed by patient report. Forty-four patients (12.8%) had IVF. In the PVF scenario, both low LS BMD and PVF were significant predictors of IVF. Using PVF to determine which patients should have radiographs, 11% would undergo radiography (95% confidence interval [CI] 8-15) with 46% of IVF (95% CI 30-61) detected. Sensitivity would be higher with a strategy of PVF or low LS BMD at baseline (73%; 95% CI 57-85) but would require radiographs in 37% of children (95% CI 32-42). In the non-PVF scenario, the strategy of low LS BMD and back pain produced the highest specificity of any non-PVF model at 87% (95% CI 83-91), the greatest overall accuracy at 82% (95% CI 78-86), and the lowest radiography rate at 17% (95% CI 14-22). Low LS BMD or back pain in the non-PVF scenario produced the highest sensitivity at 82% (95% CI 67-92), but required radiographs in 65% (95% CI 60-70). These results provide guidance for targeting spine radiography in children at risk for IVF. © 2021 American Society for Bone and Mineral Research (ASBMR).

Contributing Factors of Unmet Needs Among Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia with Comorbidities.

Purpose: This study aimed to: (1) describe the domains and levels of unmet needs of young adult survivors of childhood acute lymphoblastic leukemia (cALL) with comorbidities, and (2) to explore the factors associated with higher levels of unmet needs. Unmet need was considered as supportive care needs not met. Methods: The most vulnerable cALL survivors from the PETALE study cohort completed the Short-Form Survivor Unmet Needs Survey, the Brief Pain Inventory and the 15D instrument of health-related quality of life. Demographic and clinical information, including comorbidities, were obtained from medical records or self-reporting. The participants' needs and contributing factors to their needs were evaluated using nonparametric tests. Results: Of the 72 participants, 9 (13%) reported moderate/high levels of overall unmet needs. "Worry about earning money" (56%) and "Dealing with feeling tired" (51%) were the most frequent unmet needs (all levels combined). The factors associated significantly with any domain of unmet needs were: having a comorbidity, reporting altered functional health status, high ALL risk status, pain, age (<26 years), and having previously received psychological support. Conclusion: A minority of young adult survivors of cALL with comorbidities interviewed reported moderate/high levels of unmet needs. However, financial concerns and emotional health and relationship are the two domains of greatest need. Survivors with altered health condition are most at risk of experiencing moderate/high levels of unmet needs. If confirmed in larger samples, interventions should target modifiable contributors of unmet needs such as physical health and comfort, fatigue, and emotional health.

Developing and validating equations to predict V˙O2 peak from the 6MWT in Childhood ALL Survivors.

INTRODUCTION: The 6-Minute Walking Test (6MWT) is a safe, standardized and well utilized method to assess the functional capacity. Recently, it was reported that the published prediction equations cannot accurately predict a valid maximal oxygen consumption (V̇O2 peak) value in cancer survivors. Thus, the aim of this study was to establish and to validate a new equation based on the 6MWT to predict V̇O2 peak in childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: A total of 200 childhood ALL survivors were enrolled in this study, among which 168 participants underwent a cardiopulmonary exercise test and a 6MWT to assess their functional capacity and their cardiorespiratory fitness. In addition, participants completed a physical activity questionnaire. Participants were randomly divided in two groups to establish the equations (n = 118 (70%)) and to validate it (n = 50 (30%)). Multiple linear regression analyses were used to determine a new prediction equation for V̇O2 peak from 6MWT using clinical and specific variables related to the disease. The accuracy in between V̇O2 peak measured and V̇O2 peak predicted were assessed using the Bland and Altman method. RESULTS: The new establish clinical V̇O2 peak equation is: V̇O2 peak (mL.kg-1.min-1) = (-0.283*age(years)) - (0.099*weight(kg)) + (0.071*6MWD(meters)) -(0.135*HR end(bpm)) + 22.789 with a mean bias of 2.67 mL.kg-1.min-1 (95% CI (-9.64 to 14.98)). The new establish disease-specific V̇O2 peak equation is: V̇O2 peak (mL.kg-1.min-1) = (-0.236*age(years)) - (0.094*weight(kg)) -(0.120*HR end(bpm)) + (0.067*6MWD(meters)) + (0.065*MVLPA(min/day)) - (0.204*DT(years)) + 25.145 with a mean bias of 2.51 mL.kg-1.min-1 (95% CI (-9.98 to 15.01)). CONCLUSION: This is the first study that predicted V̇O2 peak from a 6MWT using clinical and specific variables related to the disease of childhood ALL survivors. The availability of these newly established V̇O2 peak equations makes them an accurate tool to provide a better follow-up and better adapted physical training for survivors. We invite researchers to use our assessment procedures for their further studies.IMPLICATIONS FOR REHABILITATIONIt is critical to understand the cardiorespiratory fitness of the childhood ALL survivorsThe maximal oxygen consumption (i.e., V̇O2 peak) is recognized as the gold standard to measure the patient's cardiorespiratory fitness in the field of exercise physiologyThis study is novel and reports the validation of two new VO2 peak equations, from 6MWT, by using clinical and disease-specific variables of childhood ALL survivorsThe availability of such validated equations can better facilitate the follow-up of survivors' cardiorespiratory fitness, by relevant health care professionals and exercise physiologists.

Predictors of Vertebral Deformity in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia: The PETALE Study.

BACKGROUND: The prevalence of vertebral deformities in long-term survivors of childhood acute lymphoblastic leukemia (ALL) is unknown. Our objectives were to identify the prevalence of vertebral deformities and their risk factors among long-term childhood ALL survivors. METHODS/RESULTS: We recruited 245 (49% male) long-term childhood ALL survivors from the Preventing Late Adverse Effects of Leukemia Cohort (French-Canadian ALL survivors treated between the years 1987 and 2010 with the Dana Farber Cancer Institute clinical trials protocols, who did not experience disease relapse and/or receive hematopoietic stem cell transplant). Median age at recruitment was 21.7 years (range, 8.5-41) and median time since diagnosis was 15.1 years (range, 5.4-28.2). All participants underwent spine radiograph and dual-energy X-ray absorptiometry scans. The prevalence of vertebral deformity was 23% with 88% classified as grade 1 according to the Genant method. The majority of vertebral deformities were clinically silent. Regression analysis confirmed male sex (risk ratio [RR] = 1.94; 95% confidence interval [CI], 1.16-3.24; P = 0.011), higher glucocorticoid cumulative dose (RR = 1.05; 95% CI, 1.00-1.10; P = 0.032), and back pain (RR = 2.44; 95% CI, 1.56-3.84; P < 0.001) as predictors of prevalent vertebral deformity. Sex differences in vertebral deformity predictors emerged. CONCLUSIONS: We report a significant prevalence of vertebral deformities in this young cohort. Male sex, cumulative glucocorticoid dose, and back pain were identified as predictors of prevalent vertebral deformity. Back pain emerging as a strong predictor of vertebral deformity underscores the importance of ongoing bone health surveillance in survivors with persistent vertebral deformities treated with these earlier protocols.

A de novo frameshift FGFR1 mutation extending the protein in an individual with multiple epiphyseal dysplasia and hypogonadotropic hypogonadism without anosmia.

Multiple epiphyseal dysplasia (MED) is a genetically and clinically heterogeneous disease with both dominant and recessive inheritance. Eight different genes are known to cause the disease but in 15% of cases of MED, no mutation is found. Fibroblast growth factor receptor 1 (FGFR1) is a crucial regulator of bone formation and when mutated, can cause diseases with skeletal manifestations; nevertheless, MED has not been described in individuals with FGFR1 mutations. In this report, we describe a proband with MED and congenital normosmic hypogonadotropic hypogonadism (HH). DNA analysis showed a de novo frameshift variant in FGFR1 likely explaining the HH (p.Arg852Thrfs*165). No other mutation was found after a large gene sequencing panel, exome sequencing and an array CGH, except for a variant of unknown significance in FBN1 (rs755375255), but there were no features of a disease associated with FBN1 mutations and this variant is found a few times in population databases. We thus discuss the possibility that MED might be a new skeletal feature associated with FGFR1 mutations.

The Accuracy of Prevalent Vertebral Fracture Detection in Children Using Targeted Case-Finding Approaches.

Due to concerns about cumulative radiation exposure in the pediatric population, it is not standard practice to perform spine radiographs in most conditions that predispose to vertebral fracture (VF). In this study we examined the accuracy of two clinical predictors, back pain and lumbar spine bone mineral density (LS BMD), to derive four case-finding paradigms for detection of prevalent VF (PVF). Subjects were 400 children at risk for PVF (leukemia 186, rheumatic disorders 135, nephrotic syndrome 79). Back pain was assessed by patient report, LS BMD was measured by dual-energy X-ray absorptiometry, and PVF were quantified on spine radiographs using the modified Genant semiquantitative method. Forty-four patients (11.0%) had PVF. Logistic regression analysis between LS BMD and PVF produced an odds ratio (OR) of 1.9 (95% confidence interval [CI], 1.5 to 2.5) per reduction in Z-score unit, an area under the receiver operating characteristic curve of 0.70 (95% CI, 0.60 to 0.79), and an optimal BMD Z-score cutoff of -1.6. Case identification using either low BMD alone (Z-score < -1.6) or back pain alone gave similar results for sensitivity (55%, 52%, respectively), specificity (78%, 81%, respectively), positive predictive value (PPV; 24%, 25%, respectively), and negative predictive value (NPV; 93%, 93%, respectively). The paradigm using low BMD plus back pain produced lower sensitivity (32%), higher specificity (96%), higher PPV (47%), and similar NPV (92%). The approach using low BMD or back pain had the highest sensitivity (75%), lowest specificity (64%), lowest PPV (20%), and highest NPV (95%). All paradigms had increased sensitivities for higher fracture grades. Our results show that BMD and back pain history can be used to identify children with the highest risk of PVF so that radiography can be used judiciously. The specific paradigm to be applied will depend on the expected PVF rate and the clinical approach to the use of radiography. © 2019 American Society for Bone and Mineral Research.

Genes identified through genome-wide association studies of osteonecrosis in childhood acute lymphoblastic leukemia patients.

Aim: To evaluate top-ranking genes identified through genome-wide association studies for an association with corticosteroid-related osteonecrosis in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Patients & methods: Lead SNPs from these studies, as well as other variants in the same genes, pooled from whole exome sequencing data, were analyzed for an association with osteonecrosis in childhood ALL patients from Quebec cohort. Top-ranking variants were verified in the replication patient group. Results: The analyses of variants in the ACP1-SH3YL1 locus derived from whole exome sequencing data showed an association of several correlated SNPs (rs11553746, rs2290911, rs7595075, rs2306060 and rs79716074). The rs79716074 defines *B haplotype of the APC1 gene, which is well known for its functional role. Conclusion: This study confirms implication of the ACP1 gene in the treatment-related osteonecrosis in childhood ALL and identifies novel, potentially causal variant of this complication.

Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors.

Background: Although 80% of childhood acute lymphoblastic leukemia (ALL) cases are cured with current treatment protocols, exposure to chemotherapeutics or radiation therapy during a vulnerable period of child development has been associated with a high frequency of late adverse effects (LAE). Previous observations suggest important skeletal muscle size, density and function deficits in ALL survivors. Purpose: Given that only a fraction of all patients will suffer from this particular complication, we investigated whether it could be predicted by genetic markers.  Patients and methods: We analysed associations between skeletal muscle force (Fmax) and power (Pmax) and germline genetic variants from 1039 genes derived through whole-exome sequencing. Top-ranking association signals retained after correction for multiple testing were confirmed through genotyping, and further analysed through stratified analyses and multivariate models.  Results: Our results show that skeletal muscle function deficit is associated with two common single nucleotide polymorphisms (SNPs) (rs2001616DUOX2, P=0.0002 (Pmax) and rs41270041ADAMTS4, P=0.02 (Fmax)) and two rare ones located in the ALOX15 gene (P=0.001 (Pmax)). These associations were further modulated by sex, body mass index and risk groups, which reflected glucocorticoid dose and radiation therapy (P≤0.02).  Conclusion: Occurrence of muscle function deficit in childhood ALL is thus strongly modulated by variations in the DUOX2, ADAMTS4 and ALOX15 genes, which could lead to personalized prevention strategies in childhood ALL survivors.