Fat fraction quantification of bone marrow in the lumbar spine using the LiverLab assessment tool in healthy adult volunteers and patients with Gaucher disease.

BACKGROUND: Magnetic Resonance Imaging is used for evaluation of bone in Gaucher disease (GD), but a widely available quantitative scoring method remains elusive. AIMS: The study purpose was to assess the reproducibility of the LiverLab tool for assessing bone marrow fat fraction (FF) and determine whether it could differentiate GD patients from healthy subjects. METHODS: Ten healthy volunteers and 18 GD patients were prospectively recruited. FF was calculated at L3, L4 and L5. GD patient bone marrow burden (BMB) score assessed by one observer. Inter and intra-rater agreement assessed with Bland-Altman data plots. Differences in FF between healthy volunteers versus GD patients and between subjects treated versus not treated assessed using two-sample t-tests. In GD patients, the relationship between FF, BMB and glucosylsphingosine was determined using the Pearson's correlation coefficient. RESULTS: Healthy volunteer mean FF was 0.36, standard deviation (SD) 0.10 (range 0.20-0.57). Intra and inter-rater SD were both 0.02. GD patient mean FF was 0.40, SD 0.13 (range 0.09-0.57). No statistical difference was shown between healthy volunteers and GD patients (P = 0.447) or between GD patients whether on enzyme replacement therapy or not (P = 0.090). No significant correlation between mean FF and total BMB (r = -0.525, P = 0.253) or between FF and glucosylsphingosine levels (r = 0.287, P = 0.248). CONCLUSION: Excellent reproducibility of LiverLab FF measurements across studies and observers is comparable to Dixon quantitative chemical shift imaging (QCSI). Lack of statistical difference between GD patients and controls may be explained by limited patient numbers, active treatment or mild disease severity in untreated patients.

A Teenage Boy With a Radiation-Induced High-Grade Astrocytoma.

ABSTRACT: A 12-year-old boy developed acute headache and vomiting. MRI brain showed a partially cystic suprasellar mass. He underwent cyst fenestration, but the cyst regrew, so he underwent transcranial subtotal resection of the mass. The pathologic diagnosis was adamantinomatous craniopharyngioma. Residual tumor was treated with proton beam radiation therapy, and panhypopituitarism was treated with hormone replacement therapy, including growth hormone. Serial brain MRI scans over several years showed no evidence of tumor recurrence. But at four years after radiation, surveillance MRI showed a new focus of nonenhancing FLAIR hyperintensity in the left basal ganglia attributed to gliosis caused by radiotherapy. Seven months later, he developed progressive right hemiparesis, expressive aphasia, and blurred vision, prompting reevaluation. MRI brain showed new enhancing and T2/FLAIR hyperintense lesions in the midbrain, basal ganglia, thalamus, anterior temporal lobe, and optic tract. The abnormal regions showed low diffusivity and relatively high regional blood flow. Stereotactic biopsy disclosed a WHO Grade 4 astrocytoma, likely radiation-induced. A germline ataxia telangiectasia mutation was found in the tumor tissue. The risk of radiation-induced pediatric brain malignancies is low but may have been increased by the mutation.

Thrombocytopenia in pediatric patients on concurrent cannabidiol and valproic acid.

In January 2019, a new plant-derived purified cannabidiol preparation, approved by the US Food and Drug Administration, became commercially available for patients ≥2 years old with Lennox-Gastaut syndrome or Dravet syndrome. Among our patients who were prescribed the new cannabidiol formulation, we observed several cases of thrombocytopenia and therefore embarked on this study. We conducted a single-center systematic chart review of all pediatric patients (<21 years old) who were prescribed cannabidiol from January to August 2019. We evaluated salient features of the patients' epilepsy syndrome, age, concurrent medications, and surveillance laboratory results before and after cannabidiol initiation. Among 87 patients, nine (10%) developed thrombocytopenia (platelet nadir range = 17 000-108 000) following initiation of cannabidiol. Each of these nine children was on combination therapy of cannabidiol with valproic acid. Whereas no children on cannabidiol without valproic acid (0/57) developed thrombocytopenia, nine of 23 treated with combination valproic acid and cannabidiol developed platelets < 110 000/µL (P < .0001). We report a novel and clinically important side effect of thrombocytopenia in one-third of patients treated concurrently with cannabidiol and valproic acid. If this finding is confirmed, clinicians should perform close monitoring for thrombocytopenia when adding cannabidiol to a regimen that includes valproic acid.

Intraobserver and interobserver variability of the bone marrow burden (BMB) score for the assessment of disease severity in Gaucher disease. Possible impact of reporting experience.

AIM: To evaluate the intraobserver and interobserver agreement for bone marrow burden (BMB) scores for individual examinations and for the change in BMB score over time in the same patient. METHODS: A total of 119 sets of MR images of the lumbar spine and femora from 60 patients with Gaucher disease were included. Each set of MR images was scored using the BMB score independently by two experienced MSK radiologists. One radiologist performed a second read four weeks later. Intraobserver and interobserver agreement was assessed using Bland-Altman analysis and weighted kappa scores. RESULTS: BMB scores (n=119) demonstrated fair intraobserver agreement (weighted kappa=0.53) with a mean difference of -0.20 and 95% limits of agreement (LOA) of (-3.41, 3.01). Inter observer agreement was poor with weighted kappa 0.28 with mean difference of -0.16 and 95% LOA of (-4.45, 4.11). Change in BMB scores over time (n=59) demonstrated poor/fair intraobserver agreement (weighted kappa 0.41, mean difference-0.20 and 95% LOA (-4.35, 3.94)). Interobserver agreement was poor (weighted kappa 0.25, mean difference -0.12 with wide 95% LOA (-6.23, 5.99)). CONCLUSION: Significant interobserver, and to a lesser extent intraobserver, variation occurs with blinded BMB scoring of Gaucher disease.

Development of the CNS TAP tool for the selection of precision medicine therapies in neuro-oncology.

The number of targeted therapies utilized in precision medicine are rapidly increasing. Neuro-oncology offers a unique challenge due to the varying blood brain barrier (BBB) penetration of each agent. Neuro-oncologists face a difficult task weighing the growing number of potential targeted therapies and their likelihood of BBB penetration. We developed the CNS TAP Working Group and performed an extensive literature review for the evidence-based creation of the CNS TAP tool, which was retrospectively validated by analyzing brain tumor patients who underwent therapy targeted based on genomic results from an academic sequencing study (MiOncoseq, n = 17) or private molecular profiling (Foundation One, n = 7). The CNS TAP tool scores relevant targeted agents by applying multiple variables (i.e., pre-clinical data, clinical data, BBB permeability) to patient specific genomic information and clinical trial availability. In the Michigan cohort, the CNS TAP tool predicted the selected agent 85.7% of the time. The CNS TAP tool predicted the agent independently selected by pediatric neuro-oncologists in the Colorado cohort 50% of the time. Patients with recurrent brain tumors treated with agents predicted by the CNS TAP tool demonstrated a median progression-free survival of 4 months and four patients with recurrent high-grade glioma maintained ongoing partial responses of at least 6 months. The CNS TAP tool is a formalized algorithm to assist clinicians select the optimal targeted therapy for neuro-oncology patients. The CNS TAP tool has relatively high concordance with selected therapies and clinical outcomes in patients receiving targeted therapy in this heterogeneous retrospective cohort were promising.

Changes in bone microarchitecture following kidney transplantation-Beyond bone mineral density.

Bone disease in kidney transplant recipients (KTRs) is characterized by bone mineral density (BMD) loss but bone microarchitecture changes are poorly defined. In this prospective cohort study, we evaluated bone microarchitecture using non-invasive imaging modalities; high-resolution magnetic resonance imaging (MRI), peripheral quantitative computed tomography (pQCT), dual energy X-ray absorptiometry (DXA), and the trabecular bone score (TBS) following kidney transplantation. Eleven KTRs (48.3 ± 11.2 years) underwent MRI (tibia), pQCT (radius) and DXA at baseline and 12 months post-transplantation. Transiliac bone biopsies, performed at transplantation, showed 70% of patients with high/normal bone turnover. Compared with baseline, 12-month MRI showed deterioration in indices of trabecular network integrity-surface to curve ratio (S/C; -15%, P = 0.03) and erosion index (EI; +19%, P = 0.01). However, cortical area increased (+10.3%, P = 0.04), with a non-significant increase in cortical thickness (CtTh; +7.8%, P = 0.06). At 12 months, parathyroid hormone values (median 10.7 pmol/L) correlated with improved S/C (r = 0.75, P = 0.009) and EI (r = -0.71, P = 0.01) while osteocalcin correlated with CtTh (r = 0.72, P = 0.02) and area (r = 0.70, P = 0.02). TBS decreased from baseline (-5.1%, P = 0.01) with no significant changes in BMD or pQCT. These findings highlight a post-transplant deterioration in trabecular bone quality detected by MRI and TBS, independent of changes in BMD, underlining the potential utility of these modalities in evaluating bone microarchitecture in KTRs.

Molecular characterization reveals NF1 deletions and FGFR1-activating mutations in a pediatric spinal oligodendroglioma.

Pediatric spinal oligodendrogliomas are rare and aggressive tumors. They do not share the same molecular features of adult oligodendroglioma, and no previous reports have examined the molecular features of pediatric spinal oligodendroglioma. We present the case of a child with a recurrent spinal anaplastic oligodendroglioma. We performed whole exome (paired tumor and germline DNA) and transcriptome (tumor RNA) sequencing, which revealed somatic mutations in NF1 and FGFR1. These data allowed us to explore potential personalized therapies for this patient and expose molecular drivers that may be involved in similar cases.

Loss of CDKN1C in a Recurrent Atypical Teratoid/Rhabdoid Tumor.

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant tumor that is commonly associated with biallelic alterations of SMARCB1. Recurrent or refractory AT/RT has not been molecularly characterized as well. We present the case of a child with recurrent AT/RT who underwent clinically integrated molecular profiling (germline DNA and tumor DNA/RNA sequencing). This demonstrated a somatic lesion in CDKN1C alongside hallmark loss of SMARCB1. This data allowed us to explore potential personalized therapies for this patient and expose a molecular driver that may be involved in similar cases.

Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth.

IMPORTANCE: Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging. OBJECTIVE: To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer. DESIGN, SETTING, AND PARTICIPANTS: Single-site, observational, consecutive case series (May 2012-October 2014) involving 102 children and young adults (mean age, 10.6 years; median age, 11.5 years, range, 0-22 years) with relapsed, refractory, or rare cancer. EXPOSURES: Participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed by a precision medicine tumor board, which made recommendations to families and their physicians. MAIN OUTCOMES AND MEASURES: Proportion of patients with potentially actionable findings, results of clinical actions based on integrative clinical sequencing, and estimated proportion of patients or their families at risk of future cancer. RESULTS: Of the 104 screened patients, 102 enrolled with 91 (89%) having adequate tumor tissue to complete sequencing. Only the 91 patients were included in all calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Forty-two patients (46%) had actionable findings that changed their cancer management: 15 of 28 (54%) with hematological malignancies and 27 of 63 (43%) with solid tumors. Individualized actions were taken in 23 of the 91 (25%) based on actionable integrative clinical sequencing findings, including change in treatment for 14 patients (15%) and genetic counseling for future risk for 9 patients (10%). Nine of 91 (10%) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening. CONCLUSIONS AND RELEVANCE: In this single-center case series involving young patients with relapsed or refractory cancer, incorporation of integrative clinical sequencing data into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling for a small proportion of patients. The lack of a control group limited assessing whether better clinical outcomes resulted from this approach than outcomes that would have occurred with standard care.

The impact of recent vincristine on human hematopoietic progenitor cell collection in pediatric patients with central nervous system tumors.

BACKGROUND: Central nervous system (CNS) malignancies represent 20% of all childhood cancers. To improve outcomes in infants and children with high-risk disease, treatment can include adjuvant chemotherapy and early autologous peripheral blood human progenitor cell collection (AHPCC), followed by high-dose chemotherapy and stem cell rescue. In many protocols, postoperative chemotherapy includes the administration of weekly vincristine (VCR) between induction chemotherapy cycles, regardless of scheduled AHPCC. We observed anecdotal AHPCC failures in children receiving midcycle VCR (MC-VCR). STUDY DESIGN AND METHODS: The study was an 8-year retrospective chart review of all children with a CNS malignancy and who underwent AHPCC. Information included patient demographic and clinical data, mobilization regimen, VCR administration, product yields, infusion toxicity, and patient charges. Data were analyzed relative to MC-VCR administration. Graphics and statistical analysis (t-test, chi-square, linear regression) were performed with commercial software. RESULTS: Twenty-four patients and 47 AHPCCs were available for analysis. Nine patients (37%) received MC-VCR within 7 days of scheduled AHPCC. MC-VCR was associated with delayed marrow recovery (17.9 days vs. 14.9 days, p=0.0012), decreased median peripheral CD34 counts (75 × 10(6) CD34/L vs. 352 × 10(6) CD34/L, p=0.03), decreased median CD34 yields (2.4 × 10(6) CD34/L vs. 17.8 × 10(6) CD34/kg, p=0.08), more AHPCCs per mobilization (2.9 vs. 1.1, p=0.01), and an increased rate of remobilization (33% vs. 6%). Mean patient charges were 2.5× higher in patients receiving MC-VCR than controls (p=0.01). CONCLUSION: MC-VCR should be withheld before scheduled AHPCC to optimize CD34 collection.

Multimodality therapy for CNS mixed malignant germ cell tumors (MMGCT): results of a phase II multi-institutional study.

In order to improve outcomes for CNS mixed malignant germ cell tumors (MMGCT) we sought to increase complete responses (CR) to initial therapy, through intensifying neoadjuvant chemotherapy (CHT1) with added ifosfamide, encouraging second-look surgery, and administering dose-intensive, stem cell-supported chemotherapy (CHT2) to patients with residual tumor, all prior to radiation therapy (RT). Diagnosis was confirmed by biopsy or elevated germ cell tumor markers. After tumor staging was completed, patients received four cycles of chemotherapy (cisplatin, etoposide and ifosfamide, "CHT1"). In patients with

Cervical squamous cell carcinoma metastatic to placenta.

A pregnant 29-year-old gravida 4, para 3 woman with Stage IIB cervical cancer was admitted at 33 weeks and 4 days of gestation and delivered a healthy neonate. Her placenta was small but otherwise grossly unremarkable. Microscopic examination revealed metastatic squamous cell carcinoma. An immunohistochemical stain for p16 was positive in the carcinoma cells, supporting metastasis from the cervical tumor. Cervical squamous cell carcinoma metastatic to placenta is very rare. We report a case and discuss metastatic cancer during pregnancy with recommendations for infant follow-up.

Diffuse pontine lesions in children with neurofibromatosis type 1: making a case for unidentified bright objects.

Using an illustrative case of a presumed pontine unidentified bright object (UBO) with spontaneous lesion regression over 2 years, we review the importance of including UBOs in the differential diagnosis of children with confirmed or possible neurofibromatosis type 1 (NF1) who present with diffuse pontine enlargement and T2-weighted changes on MRI. Asymptomatic children with presumed NF1 and diffuse pontine lesions should not be treated with radiation and should not be biopsied. Prior reports of good prognosis associated with pontine glioma in patients with NF1 may have been unrecognized UBOs in some cases.

An Internet survey of demographic and health factors associated with risk of sexual dysfunction in women who have sex with women.

INTRODUCTION: There has been scant attention to predictors of sexual dysfunction in women who have sex with women (WSW). AIM: To investigate the associations of high risk for sexual dysfunction in an Internet cohort of WSW. MAIN OUTCOME MEASURE: A modified version of the Female Sexual Function Index (FSFI) was used to quantify each subject's sexual function. METHODS: Women who have sex with women were invited to participate in an Internet-based survey by invitations posted on e-mail listservs and on social media sites catering to WSW. Ethnodemographic, health status, and sexual/relationship data were collected. RESULTS: The study was completed by 2,433 adult women. Of these, 1,566 participants had complete data on the FSFI and comprised the study cohort; 388 (24.8%) met the FSFI criteria for high risk of female sexual dysfunction (HRFSD). On multivariable analysis, the following variables were found to be independently associated with the HRFSD; moderate or severe subjective bother regarding sexual function (OR 4.8, 95% CI 3.0-7.9 and 13.7, 95% CI 7.5-25.1, respectively), overactive bladder (OAB) (OR 2.1, 95% CI 1.0-4.5), having a nonfemale or no partner (OR 2.3, 95% CI 1.1-4.7 and 3.2, 95% CI 2.0-5.2, respectively). A history of pregnancy was associated with lower odds of HRFSD (OR 0.567, 95% CI 0.37-0.87). Mean FSFI domain scores for all domains except desire were negatively impacted by partner factors and OAB. CONCLUSIONS: A single-item question on sexual bother is strongly predictive of potentially distressing sexual problems in the WSW. A number of health and social factors are associated with risk of sexual problems in the WSW. Assessment of sexual well-being in the WSW is a priority for practicing healthcare providers.

EANO, SNO and Euracan consensus review on the current management and future development of intracranial germ cell tumors in adolescents and young adults.

The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.

Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma.

BACKGROUND: Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. METHODS: We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). RESULTS: Change in H3.3K27M VAF over time ("VAF delta") correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF "spikes" (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression. CONCLUSION: Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.

Development and pilot testing of a reflective learning guide for medical education.

BACKGROUND: Reflection is increasingly incorporated into all levels of medical education but little is known about best practices for teaching and learning reflection. AIMS: To develop a literature-based reflective learning guide for medical education and conduct a pilot study to determine whether (1) guide use enhances medical students' reflective writing skills and (2) reflective scores correlate with participant demographics and satisfaction. METHODS: Guide development consisted of literature review, needs assessment, single institution survey, and educational leader consensus. The pilot cohort study compared professionalism reflections written with and without the guide by third-year medical students on their core obstetrics and gynecology rotation. Reflections were scored using a previously validated rubric. A demographics and satisfaction survey examined effects of gender and satisfaction, as well as qualitative analysis of optional written comments. Analyses used independent t-tests and Pearson's correlations. RESULTS: We developed a two-page, literature-based guide in clinical Subjective-Objective-Assessment-Plan (SOAP) note format. There was a statistically significant difference, p < 0.001, in the reflection scores between groups, but no effects of gender or satisfaction. Student satisfaction with the guide varied widely. CONCLUSIONS: A single exposure to a literature-based guide to reflective learning improved written reflections by third-year medical students.

Changes in bone microarchitecture following parathyroidectomy in patients with secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) has a significant effect on bone, affecting both trabecular and cortical compartments. Although parathyroidectomy results in biochemical improvement in mineral metabolism, changes in bone microarchitecture as evaluated by high-resolution imaging modalities are not known. Magnetic resonance imaging (MRI) provides in-depth three-dimensional assessment of bone microarchitecture, as well as determination of mechanical bone strength determined by finite element analysis (FEA). METHODS: We conducted a single-centre longitudinal study to evaluate changes in bone microarchitecture with MRI in patients with SHPT undergoing parathyroidectomy. MRI was performed at the distal tibia at baseline (time of parathyroidectomy) and at least 12 months following surgery. Trabecular and cortical topological parameters as well as bone mechanical competence using FEA were assessed. RESULTS: Fifteen patients with CKD (12 male, 3 female) underwent both MRI scans at the time of surgery and at least 12 months post-surgery. At baseline, 13 patients were on dialysis, one had a functioning kidney transplant, and one was pre-dialysis with stage 5 CKD. Seven patients received a kidney transplant following parathyroidectomy prior to follow-up MRI. MRI parameters in patients at follow up were consistent with loss in trabecular and cortical bone thickness (p = 0.006 and 0.03 respectively). Patients who underwent a kidney transplant in the follow-up period had reduction in trabecular thickness (p = 0.05), whereas those who continued on dialysis had reduction in cortical thickness (p = 0.04) and mechanical bone strength on FEA (p = 0.03). CONCLUSION: Patients with severe SHPT requiring parathyroidectomy have persistent changes in bone microarchitecture at least 12 months following surgery with evidence of ongoing decline in trabecular and cortical thickness.

Visual field fluctuations correlating with the menstrual cycle in a patient with optic pathway glioma.

Optic pathway gliomas are commonly associated with vision loss in children. We describe an 18-year-old woman with neurofibromatosis, type 1 and an optic nerve glioma who showed reproducible visual field defects that worsened midmenstrual cycle and returned to baseline during menses. To our knowledge, this is the first reported case of visual field fluctuations in a patient with an optic nerve glioma that correlated with her menstrual cycle.