Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis: A potential model for rare diseases.

Background: Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments. Methods: Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts. Results: The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF. Conclusions: These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials.

Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma.

PURPOSE: Ewing Sarcoma (ES), a rare cancer with a pathognomonic translocation resulting in the Ewing sarcoma gene (EWS)::FLI1 oncoprotein, has a poor prognosis in the relapsed/refractory (R/R) setting. Tokalas (TK)216 was designed to bind EWS::FLI1 proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine showed synergistic activity in preclinical tumor models. To our knowledge, we report the results of a first-in-class, first-in-human phase I/II trial of TK216 in R/R ES. PATIENTS AND METHODS: TK216 was administered intravenously as a continuous infusion to patients with R/R ES in 11 cohorts. The dosing duration of 7 days was later extended to 10, 14, and 28 days. Vincristine could be added on day 1 after cycle 2, per investigators' choice. The trial used a 3 + 3 design with an expansion cohort at the recommended phase II dose (RP2D). RESULTS: A total of 85 patients with a median age of 27 years (range, 11-77) were enrolled. The maximum tolerated dose for the 14-day infusion of TK216, 200 mg/m2 once daily, was determined in cohort 9 and selected as the RP2D. The median previous number of systemic therapies regimens was three (range, 1-10). The most frequent-related adverse events in patients treated at the RP2D included neutropenia (44.7%), anemia (29.4%), leukopenia (29.4%), febrile neutropenia (15.3%), thrombocytopenia (11.8%), and infections (17.6%). In cohorts 9 and 10, two patients had a complete response, one had a partial response, and 14 had stable disease; the 6-month progression-free survival was 11.9%. There were no responses among the eight patients in cohort 11. CONCLUSION: TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.

Phase II study of vemurafenib in children and young adults with tumors harboring BRAF V600 mutations: NCI-COG pediatric MATCH trial (APEC1621) Arm G.

BACKGROUND: This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. METHODS: Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. RESULTS: Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (nâ=â7) and prior BRAF inhibitor therapy (nâ=â7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. CONCLUSION: There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).

Early detection of malignant and pre-malignant peripheral nerve tumors using cell-free DNA fragmentomics.

Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.

Development and pilot validation of a novel disfigurement severity scale for plexiform neurofibromas in children with neurofibromatosis type 1.

BACKGROUND/AIMS: We developed an observer disfigurement severity scale for neurofibroma-related plexiform neurofibromas to assess change in plexiform neurofibroma-related disfigurement and evaluated its feasibility, reliability, and validity. METHODS: Twenty-eight raters, divided into four cohorts based on neurofibromatosis type 1 familiarity and clinical experience, were shown photographs of children in a clinical trial (NCT01362803) at baseline and 1 year on selumetinib treatment for plexiform neurofibromas (n = 20) and of untreated participants with plexiform neurofibromas (n = 4). Raters, blinded to treatment and timepoint, completed the 0-10 disfigurement severity score for plexiform neurofibroma on each image (0 = not at all disfigured, 10 = very disfigured). Raters evaluated the ease of completing the scale, and a subset repeated the procedure to assess intra-rater reliability. RESULTS: Mean baseline disfigurement severity score for plexiform neurofibroma ratings were similar for the selumetinib group (6.23) and controls (6.38). Mean paired differences between pre- and on-treatment ratings was -1.01 (less disfigurement) in the selumetinib group and 0.09 in the control (p = 0.005). For the disfigurement severity score for plexiform neurofibroma ratings, there was moderate-to-substantial agreement within rater cohorts (weighted kappa range = 0.46-0.66) and agreement between scores of the same raters at repeat sessions (p > 0.05). In the selumetinib group, change in disfigurement severity score for plexiform neurofibroma ratings was moderately correlated with change in plexiform neurofibroma volume with treatment (r = 0.60). CONCLUSION: This study demonstrates that our observer-rated disfigurement severity score for plexiform neurofibroma was feasible, reliable, and documented improvement in disfigurement in participants with plexiform neurofibroma shrinkage. Prospective studies in larger samples are needed to validate this scale further.

Recommendations for the collection and annotation of biosamples for analysis of biomarkers in neurofibromatosis and schwannomatosis clinical trials.

INTRODUCTION: Neurofibromatosis 1 and schwannomatosis are characterized by potential lifelong morbidity and life-threatening complications. To date, however, diagnostic and predictive biomarkers are an unmet need in this patient population. The inclusion of biomarker discovery correlatives in neurofibromatosis 1/schwannomatosis clinical trials enables study of low-incidence disease. The implementation of a common data model would further enhance biomarker discovery by enabling effective concatenation of data from multiple studies. METHODS: The Response Evaluation in Neurofibromatosis and Schwannomatosis biomarker working group reviewed published data on emerging trends in neurofibromatosis 1 and schwannomatosis biomarker research and developed recommendations in a series of consensus meetings. RESULTS: Liquid biopsy has emerged as a promising assay for neurofibromatosis 1/schwannomatosis biomarker discovery and validation. In addition, we review recommendations for a range of biomarkers in clinical trials, neurofibromatosis 1/schwannomatosis-specific data annotations, and common data models for data integration. CONCLUSION: These Response Evaluation in Neurofibromatosis and Schwannomatosis consensus guidelines are intended to provide best practices for the inclusion of biomarker studies in neurofibromatosis 1/schwannomatosis clinical trials, data, and sample annotation and to lay a framework for data harmonization and concatenation between trials.

Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas.

BACKGROUND: Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies. METHODS: This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index). RESULTS: For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment. CONCLUSIONS: With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.

Clinical Targeted Next-Generation Panel Sequencing Reveals MYC Amplification Is a Poor Prognostic Factor in Osteosarcoma.

PURPOSE: Osteosarcoma risk stratification, on the basis of the presence of metastatic disease at diagnosis and histologic response to chemotherapy, has remained unchanged for four decades, does not include genomic features, and has not facilitated treatment advances. We report on the genomic features of advanced osteosarcoma and provide evidence that genomic alterations can be used for risk stratification. MATERIALS AND METHODS: In a primary analytic patient cohort, 113 tumor and 69 normal samples from 92 patients with high-grade osteosarcoma were sequenced with OncoPanel, a targeted next-generation sequencing assay. In this primary cohort, we assessed the genomic landscape of advanced disease and evaluated the correlation between recurrent genomic events and outcome. We assessed whether prognostic associations identified in the primary cohort were maintained in a validation cohort of 86 patients with localized osteosarcoma tested with MSK-IMPACT. RESULTS: In the primary cohort, 3-year overall survival (OS) was 65%. Metastatic disease, present in 33% of patients at diagnosis, was associated with poor OS (P = .04). The most frequently altered genes in the primary cohort were TP53, RB1, MYC, CCNE1, CCND3, CDKN2A/B, and ATRX. Mutational signature 3 was present in 28% of samples. MYC amplification was associated with a worse 3-year OS in both the primary cohort (P = .015) and the validation cohort (P = .012). CONCLUSION: The most frequently occurring genomic events in advanced osteosarcoma were similar to those described in prior reports. MYC amplification, detected with clinical targeted next-generation sequencing panel tests, is associated with poorer outcomes in two independent cohorts.

Outcome of Patients With Malignant Peripheral Nerve Sheath Tumors Enrolled on Sarcoma Alliance for Research Through Collaboration (SARC) Phase II Trials.

BACKGROUND: Evaluation of prior phase II trials for malignant peripheral nerve sheath tumors (MPNST) may help develop more suitable trial endpoints in future studies. METHODS: We analyzed outcomes of patients with recurrent or unresectable/metastatic MPNST enrolled on prior Sarcoma Alliance for Research through Collaboration (SARC) phase II trials and estimated the progression-free survival (PFS). PFS from SARC006 (NCT00304083), the phase II trial of upfront chemotherapy in chemotherapy naïve patients, was analyzed separately. Impact of baseline enrollment characteristics on PFS was evaluated. RESULTS: Sixty-four patients (29 male, 35 female, median age 39 years (range 15-81)) with MPNST were enrolled on 1 of 5 trials of single agent or combination therapy that were determined to be inactive. Patients had received a median of 1 (range 0-5) prior systemic therapy, and most had undergone prior surgery (77%) and radiation (61%). Seventy-three percent had metastatic disease at enrollment. Median PFS was 1.77 months (95% CI, 1.61-3.45), and the PFS rate at 4 months was 15%. Greater number of prior systemic therapies and worse performance status were associated with inferior PFS. There was no significant difference in PFS based on age at enrollment, treatment trial, response criteria, presence of metastatic disease, disease site at enrollment, and prior surgery or radiation. In comparison, on the SARC006 trial the PFS rate at 4 months was 94% in 40 patients. CONCLUSION: These data provide a historical baseline PFS that may be used as a comparator in future clinical trials for patients with MPNST.

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer.

PURPOSE: Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of FGFR alterations (FGFR1-4) in pediatric cancers to inform future clinical trial design. METHODS: Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children's Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed. RESULTS: We identified 41 patients with tumors harboring an oncogenic FGFR alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions (FGFR3::TACC3 [n = 3], FGFR1::TACC1 [n = 1], FGFR1::EBF2 [n = 1], FGFR1::CLIP2 [n = 1], and FGFR2::CTNNA3 [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel FGFR1 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor. CONCLUSION: In summary, activating FGFR alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act.

MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus.

The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.

Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer.

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors.

Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity.

BACKGROUND: Selumetinib was recently approved for the treatment of inoperable symptomatic plexiform neurofibromas (PNs) in children with neurofibromatosis type 1 (NF1). This parallel phase II study determined the response rate to selumetinib in children with NF1 PN without clinically significant morbidity. METHODS: Children with NF1 and inoperable PNs, which were not yet causing clinically significant morbidity but had the potential to cause symptoms, received selumetinib at 25 mg/m2 orally twice daily (1 cycle = 28 days). Volumetric magnetic resonance imaging analysis and outcome assessments, including patient-reported (PRO), observer-reported, and functional outcome measures were performed every 4 cycles for 2 years, with changes assessed over time. A confirmed partial response (cPR) was defined as PN volume decrease of ≥20% on at least 2 consecutive scans ≥3 months apart. RESULTS: 72% of subjects experienced a cPR on selumetinib. Participants received selumetinib for a median of 41 cycles (min 2, max 67) at data cutoff. Approximately half of the children rated having some target tumor pain at baseline, which significantly decreased by pre-cycle 13. Most objectively measured baseline functions, including visual, motor, bowel/bladder, or airway function were within normal limits and did not clinically or statistically worsen during treatment. CONCLUSIONS: Selumetinib resulted in PN shrinkage in most subjects with NF1 PN without clinically significant morbidity. No new PN-related symptoms developed while on selumetinib, and PRO measures indicated declines in tumor-related pain intensity. This supports that selumetinib treatment may prevent the development of PN-related morbidities, though future prospective studies are needed to confirm these results. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01362803.

The Need for New Treatments Targeting MPNST: The Potential of Strategies Combining MEK Inhibitors with Antiangiogenic Agents.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas that represent an important clinical challenge, particularly given their strong tendency to relapse and metastasize and their relatively poor response to conventional therapies. To date, targeted, noncytotoxic treatments have demonstrated limited clinical success with MPNSTs, highlighting the need to explore other key pathways to find novel, improved therapeutic approaches. Here, we review evidence supporting the crucial role of the RAS/MEK/ERK pathway and angiogenesis in MPNST pathogenesis, and we focus on the potential of therapies targeting these pathways to treat this disease. We also present works suggesting that the combination of MEK inhibitors and antiangiogenic agents could represent a promising therapeutic strategy to manage MPNSTs. In support of this notion, we discuss the preclinical rational and clinical benefits of this combination therapy in other solid tumor types. Finally, we describe other emerging therapeutic approaches that could improve patient outcomes in MPNSTs, such as immune-based therapies.

Focused Ultrasound for Pediatric Diseases.

Focused ultrasound (FUS) is a noninvasive therapeutic technology with multiple pediatric clinical applications. The ability of focused ultrasound to target tissues deep in the body without exposing children to the morbidities associated with conventional surgery, interventional procedures, or radiation offers significant advantages. In 2021, there are 10 clinical pediatric focused ultrasound studies evaluating various musculoskeletal, oncologic, neurologic, and vascular diseases of which 8 are actively recruiting and 2 are completed. Pediatric musculoskeletal applications of FUS include treatment of osteoid osteoma and bone metastases using thermal ablation and high-intensity FUS. Pediatric oncologic applications of FUS include treatment of soft tissue tumors including desmoid tumors, malignant sarcomas, and neuroblastoma with high-intensity FUS ablation alone, or in combination with targeted chemotherapy delivery. Pediatric neurologic applications include treatment of benign tumors such as hypothalamic hamartomas with thermal ablation and malignant diffuse intrinsic pontine glioma with low-intensity FUS for blood brain barrier opening and targeted drug delivery. Additionally, low-intensity FUS can be used to treat seizures. Pediatric vascular applications of FUS include treatment of arteriovenous malformations and twin-twin transfusion syndrome using ablation and vascular occlusion. FUS treatment appears safe and efficacious in pediatric populations across many subspecialties. Although there are 7 Food and Drug Administration-approved indications for adult applications of FUS, the first Food and Drug Administration approval for pediatric patients with osteoid osteoma was obtained in 2020. This review summarizes the preclinical and clinical research on focused ultrasound of potential benefit to pediatric populations.

Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor.

PURPOSE: Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks. MATERIALS AND METHODS: Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation. RESULTS: One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events. CONCLUSION: A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition.

Feasibility of magnetic resonance-guided high-intensity focused ultrasound treatment targeting distinct nodular lesions in neurofibromatosis type 1.

BACKGROUND: Patients with Neurofibromatosis Type 1 (NF1) and plexiform neurofibromas (PN) often have radiographically diagnosed distinct nodular lesions (DNL) which can cause pain and weakness. Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) can precisely and accurately deliver heat to thermally ablate target tissue. The aim of this study is to evaluate whole-body MRIs from patients with NF1 and DNL, applying volumetrics and a consistent treatment planning approach to determine the feasibility of MR-HIFU ablation of DNL. METHODS: A retrospective review of whole-body MRI scans from patients with NF1 and PN from CNH and NCI was performed. DNL are defined as lesions >3 cm, distinct from PN and lacking the "central dot" feature. Criteria for MR-HIFU thermal ablation include target location 1-8 cm from skin surface; >1 cm from visible plexus, spinal canal, bladder, bowel, physis; and ability to ablate ≥50% of lesion volume. Lesions in skull and vertebral body were excluded. RESULTS: In 26 patients, 120 DNL were identified. The majority of DNL were located in an extremity (52.5%). Other sites included head/neck (7%), chest (13%), and abdomen/pelvis (28%). The predefined HIFU ablation criteria was not met for 47.5% of lesions (n = 57). The main limitation was proximity to a vital structure or organ (79%). Complete and partial HIFU ablation was feasible for 25% and 27.5% of lesions, respectively. CONCLUSION: Based on imaging review of lesion location, technical considerations and ability to target lesions, thermal ablation with MR-HIFU may be a feasible noninvasive alternative for symptom management in patients with NF1 and symptomatic DNL.

Phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors.

BACKGROUND: Sorafenib,an orally bioavailable, multitarget tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated activity in pediatric and adult malignancies. We evaluated the toxicity, pharmacokinetic (PK), and pharmacogenomic (PGX) profile of sorafenib with irinotecan in children with relapsed or refractory solid tumors and assessed the feasibility of incorporating patient-reported outcome (PRO) measures as an adjunct to traditional endpoints. METHODS: Sorafenib, continuous oral twice daily dosing, was administered with irinotecan, orally, once daily days 1-5, repeated every 21 days (NCT01518413). Based on tolerability, escalation of sorafenib followed by escalation of irinotecan was planned. Three patients were initially enrolled at each dose level. Sorafenib and irinotecan PK analyses were performed during cycle 1. PRO measurements were collected during cycles 1 and 2. RESULTS: Fifteen patients were evaluable. Two of three patients at dose level 2 experienced dose-limiting toxicity (DLT), grade 3 diarrhea, and grade 3 hyponatremia. Therefore, dose level 1 was expanded to 12 patients and two patients had DLT, grade 4 thrombocytopenia, grade 3 elevated lipase. Nine of 15 (60%) patients had a best response of stable disease with four patients receiving ≥6 cycles. CONCLUSIONS: The recommended dose for pediatric patients was sorafenib 150 mg/m2 /dose twice daily with irinotecan 70 mg/m2 /dose daily × 5 days every 21 days. This oral outpatient regimen was well tolerated and resulted in prolonged disease stabilization. There were no significant alterations in the PK profile of either agent when administered in combination. Patients were willing and able to report their subjective experiences with this regimen.

Genotype-Phenotype Correlations in Neurofibromatosis and Their Potential Clinical Use.

OBJECTIVE: Because clinically validated biomarkers for neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2) have not been identified, we aimed to determine whether genotype-phenotype correlations are useful in clinical trials in NF1 and NF2. METHODS: The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Biomarker Group first performed a systematic literature search and reviewed existing data on genetic biomarkers in NF1 and NF2 and in in malignant peripheral nerve sheath tumors. The group then met during a series of consensus meetings to develop a joint report. RESULTS: We found that in NF2, the genetic severity score is clearly of potential clinical use. In NF1, despite over 3,000 constitutional variants having been described in the NF1 gene, only 4 actionable genotype-phenotype correlations exist. The diagnosis and treatment decision of these tumors should ideally include histopathology and compilation of some of the genetic markers. CONCLUSION: We summarized emerging clinical use of genotype-phenotype correlations in neurofibromatosis.

Emerging hyperthermia applications for pediatric oncology.

Local application of hyperthermia has a myriad of effects on the tumor microenvironment as well as the host's immune system. Ablative hyperthermia (typically > 55 °C) has been used both as monotherapy and adjuvant therapy, while mild hyperthermia treatment (39-45 °C) demonstrated efficacy as an adjuvant therapy through enhancement of both chemotherapy and radiation therapy. Clinical integration of hyperthermia has especially great potential in pediatric oncology, where current chemotherapy regimens have reached maximum tolerability and the young age of patients implies significant risks of late effects related to therapy. Furthermore, activation of both local and systemic immune response by hyperthermia suggests that hyperthermia treatments could be used to enhance the anticancer effects of immunotherapy. This review summarizes the state of current applications of hyperthermia in pediatric oncology and discusses the use of hyperthermia in the context of other available treatments and promising pre-clinical research.