Symptomatic Plexiform Neurofibromas Research Articles

Progress in neurosurgical treatment of neurofibromatosis type 1

To summarize the latest developments in neurosurgical treatments for neurofibromatosis type 1 (NF1) and explore therapeutic strategies to provide comprehensive treatment guidelines for clinicians. The recent domestic and international literature and clinical cases in the field of NF1 were reviewed. The main types of neurological complications associated with NF1 and their treatments were thorough summarized and the future research directions in neurosurgery was analyzed. NF1 frequently results in complex and diverse lesions in the central and peripheral nervous systems, particularly low-grade gliomas in the brain and spinal canal and paraspinal neurofibromas. Treatment decisions should be made by a multidisciplinary team. Symptomatic plexiform neurofibromas and tumors with malignant imaging evidence require neurosurgical intervention. The goals of surgery include reducing tumor size, alleviating pain, and improving appearance. Postoperative functional rehabilitation exercises, long-term multidisciplinary follow-up, and psychosocial interventions are crucial for improving the quality of life for patients. Advanced imaging guidance systems and artificial intelligence technologies can help increase tumor resection rates and reduce recurrence. Neurosurgical intervention is the primary treatment for symptomatic plexiform neurofibromas and malignant peripheral nerve sheath tumors when medical treatment is ineffective and the lesions progress rapidly. Preoperative multidisciplinary assessment, intraoperative electrophysiological monitoring, and advanced surgical assistance devices significantly enhance surgical efficacy and safety. Future research should continue to explore new surgical techniques and improve postoperative management strategies to achieve more precise and personalized treatment for NF1 patients.

NFS-27. SELUMETINIB FOR SYMPTOMATIC, INOPERABLE PLEXIFORM NEUROFIBROMAS IN NEUROFIBROMATOSIS TYPE 1: A SINGLE-INSTITUTION EXPERIENCE

Abstract BACKGROUND Half of patients with Neurofibromatosis type 1 (NF1) develop plexiform neurofibromas (PNs). PNs may grow during childhood causing significant complications, including pain, functional impairment, and disfigurement. Treatment options are limited, given their tendency to regrow following surgery and their propensity to transform into malignant tumors following radiation. Selumetinib is an oral selective inhibitor of RAS-mitogen activated protein kinase (MAPK) 1 and 2, which has shown efficacy for tumor shrinkage/ stabilisation and symptom improvement. METHODS Single-institution retrospective review of patients with NF1 treated with selumetinib for symptomatic PNs between 2020 and 2023. Clinical data were abstracted from medical records. Treatment consisted of selumetinib 25 mg/m2 BID. Patient follow-up included monthly complete physical examination, evaluation of treatment adherence, blood analysis, echocardiogram, ophthalmologic assessment every 3 months, and MRI every 6 months. Response evaluation criteria in solid tumors (RECIST) was used for assessment. RESULTS Ten patients were treated with selumetinib during the period indicated. Mean age 13.9 years (range 7-21). Predominant target locations were head and neck (60%), and abdomen-pelvis (30%). The most important comorbidities were disfigurement (50%) and pain (50%). The mean follow-up time was 519 days (range 45–1460). None of the patients presented grade 3-4 toxicities; all of them had associated grade 1-2 skin toxicity. None presented cardiac or ophthalmologic alterations. All the patients with pain had sustained clinical improvement in the first 35–60 days of treatment. At one year of treatment 6/8 patients showed stable disease and 2/8 partial response on MRI. In one patient, treatment was discontinued after 270 days (lack of clear benefit).Another patient has not reached one year of therapy yet. CONCLUSIONS In this study we expose that selumetinib for symptomatic, inoperable plexiform neurofibromas in NF1 was associated with clinical and radiological response. Our study also confirms the safety and good tolerance of this drug.

P11.24.B PRELIMINARY RESULTS OF THE TRAIN STUDY: TRAMETINIB IN NEUROFIBROMATOSIS TYPE 1 RELATED SYMPTOMATIC PLEXIFORM NEUROFIBROMAS

Abstract BACKGROUND About half of the patients with neurofibromatosis type 1 (NF1) have plexiform neurofibromas (PN). PNs can cause pain, neurological deficit and cosmetic problems. The current standard treatment of PN is surgery, which is often difficult due to invasive growth and vascularisation. Recent data suggests promising effect of MEK inhibition on symptomatic PN in NF1. MATERIAL AND METHODS We started an open-label, single arm, phase 2 trial of trametinib 2 mg daily in 30 adults with NF1 and at least one symptomatic inoperable PN. The primary outcome measure is decrease in tumor volume of the PN target lesion, as measured on MRI every 6 months. A decrease of ≥20% will be considered as treatment response. The secondary outcome measures are pain, disfigurement, safety and toxicity. RESULTS Seventeen patients have been enrolled between July 2020 and July 2022 with an average follow-up duration of 16 months. In the 15 patients with at least 6 months follow-up, the average numeric pain rating scale (NRS-11) was reduced in 10/15 patients (67%) and a reduction of at least 3 points on the NRS-11 was achieved in 6/15 patients (40%). Tumor volume measurements have been completed in one patient with a PN in the left shoulder region. Tumor volume decreased from 160 cm3 to 100 cm3 (38%) after 18 months of treatment. The most common side effect was acneiform rash, which was present in 11/17 patients (65%). Four patients discontinued treatment permanently, 3 because of toxicity (acneiform rash (2) and CPK increase (1)) and one because of increased pain. Four cases of grade 3 adverse events have been reported: acneiform rash (2), hypertension (1) and asparatate aminotransferase increase (1). The only severe adverse event related to treatment was CPK increase grade 4, for which the patient was hospitalised for diagnostic work-up. Toxicity resolved completely in all patients after discontinuation of treatment. CONCLUSION From these preliminary results we can conclude that trametinib has a beneficial effect on PN related pain. Side effects are mild and toxicity resolved after discontinuation of treatment. At least one patient had a decrease in tumor volume of ≥20%.

Neurofibromatosis 1 (von Recklinghausen Disease).

Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. Because of medical progress, molecular testing for NF1 after genetic counseling is now available in Japan. In addition, revised diagnostic criteria for NF1 were proposed by NF1 experts of an international panel in 2021. Because the overall degree of severity and manifestations in each patient are not predictable, age-specific annual monitoring and patient education by a multidisciplinary team are important for the management of NF1. Although treatment of plexiform neurofibroma has been challenging, selumetinib (an oral selective MEK1/2 inhibitor), which targets a pathway downstream of RAS, was approved in 2022 for use in children with inoperable, symptomatic plexiform neurofibromas in Japan. This article summarizes recent progress in diagnosis, clinical characteristics, and treatment of various manifestations of NF1 and proposes the future direction required to resolve unmet needs in patients with NF1 in Japan.

Clinical Characteristics and Management of Children and Adults with Neurofibromatosis Type 1 and Plexiform Neurofibromas in Denmark: A Nationwide Study.

Plexiform neurofibromas (PN) are benign nerve sheath tumours that are a frequent and potentially debilitating complication in patients with neurofibromatosis type 1 (NF1). The objective of this study was to describe the natural history of PN in children, adolescents and adults with NF1. This was a nationwide, longitudinal cohort study of patients with NF1 under observation at the two national centres of NF1 expertise in Denmark between 2000 and 2020. Patient and clinical characteristics were documented from individual medical records. A total of 1099 patients with NF1 were included. Overall, 12% (35/296) of paediatric patients and 21% (172/803) of adult patients had ≥ 1 large PN (≥ 3cm). Approximately half of patients with a large PN had ≥ 1 symptomatic PN. The most frequent symptoms were pain, neurological deficits, cosmetic issues, disfigurement, compression, increased psychosocial burden and vision loss. Clinical evaluations of PN size were available for 40 PN in 34 paediatric patients and 191 PN in 159 adult patients with large PN. Surgery (complete resection or debulking) was performed in 38% (15/40) of PN in paediatric patients and 45% (86/191) in adult patients. In addition, 35% of PN in paediatric patients and 33% in adult patients were inoperable. In a subgroup analysis, the overall PN size increased 1.06-fold per year. Malignant peripheral nerve sheath tumours (MPNST) were diagnosed in 21 patients (two paediatric and 19 adult patients). This study shows that PN are common, their size and prevalence increase with age, many are often inoperable and pain and other symptoms are frequently associated. The results highlight the severe sequelae and unmet need for alternatives to analgesia and surgery in patients with PN.

Plexiform neurofibroma: shedding light on the investigational agents in clinical trials

Introduction Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic condition, which predisposes individuals to the development of plexiform neurofibromas (PN), benign nerve sheath tumors seen in 30-50% of patients with NF1. These tumors may cause significant pain and disfigurement or may compromise organ function. Given the morbidity associated with these tumors, therapeutic options for patients with NF1-related PN are necessary. Areas covered We searched the www.clinicaltrials.gov database for “plexiform neurofibroma.” This article summarizes completed and ongoing trials involving systemic therapies for PN. Expert opinion Surgery is the mainstay treatment; however, complete resection is not possible in many cases. Numerous systemic therapies have been evaluated in patients with NF1, with MEK inhibitors (MEKi) showing the greatest efficacy for volumetric reduction and improvement in functional and patient-reported outcomes. The MEKi selumetinib is now FDA approved for the treatment of inoperable, symptomatic PN in pediatric NF1 patients. Questions remain regarding the use of this drug class in terms of when to initiate therapy, overall duration, reduced dosing schedules, and side effect management. Future studies are needed to fully understand the clinical application of MEKi and to evaluate other potential therapies through appropriate trial designs for this potentially devastating, manifestation in NF1.

Treatment of Plexiform Neurofibromas with MEK Inhibitors: First Results with a New Therapeutic Option.

Neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PN) are peripheral nerve sheath tumors that can significantly affect the quality of life. Until recently, surgery was the only treatment for these tumors. However, in most cases, surgery cannot achieve complete tumor removal and carries a high risk of postoperative deficits. Therefore, the recent approval of the MEK inhibitor selumetinib for the treatment of NF1-associated PN provides a long-awaited novel therapeutic option. Here, we report our experience with MEK inhibitor treatment in 12 pediatric NF1 patients with inoperable symptomatic PN. Eight patients received trametinib (median therapy duration 12.13 months and range 4-29 months), and four patients received selumetinib (median therapy duration 6.25 months and range 4-11 months). Volumetric magnetic resonance imaging (MRI) after 6 months of treatment was available for seven trametinib patients (median tumor volume reduction of 26.5% and range 11.3-55.7%) and two selumetinib patients (21.3% tumor volume reduction in one patient and +3% tumor volume change in the other one). All patients reported clinical benefits such as improved range of motion or reduced disfigurement. Therapy-related adverse events occurred in 58.3% of patients and mainly consisted of skin toxicity, paronychia, and gastrointestinal symptoms. Two patients discontinued trametinib treatment after 14 and 29 months when severe skin toxicity occurred and no further reduction of tumor size was observed. In one patient, discontinuation of therapy resulted in a 27.2% tumor volume increase as demonstrated on volumetric MRI 6 months later. Our data show that MEK inhibition is a novel therapeutic approach for inoperable PN with promising results and a manageable safety profile.

EPID-04. THE NATURAL HISTORY OF NEUROFIBROMATOSIS-1, THE MONTEFIORE EXPERIENCE

Abstract Neurofibromatosis type 1 (NF1) is a genetic disorder with varying phenotypes that can affect many organ systems. Notably, it has significant clinical variability involving different systems in each individual. Manifestations may also develop and evolve with age. Although current literature has looked into the prevalence of the manifestations of NF1, few have compared the prevalence in populations of diversity. The objective of our study is to describe the clinical manifestations of NF1 seen in an urban neurocutaneous clinic that serves a diverse ethnic and socioeconomic population. We intend to see how the clinical manifestations of our patients compare to what is reported and to better understand the clinical impact and prognoses of NF1 in this population. We performed a retrospective study of patients in our neurocutaneous clinic from May 2014 to December 2020. Of the 89 that fit study criteria, we had a majority of Hispanic and Black patients. We compared our data to two recent NF1 natural history studies, Boulanger et al. and Cnossen et al., using chi-square or Fisher exact test. Results showed that we had a lower incidence of cutaneous neurofibromas (23.6% vs the reported 40%) and lisch nodules (32.6% vs the reported 50%), but a higher incidence of symptomatic plexiform neurofibromas (48.3% vs the reported 25%) and CNS tumors requiring intervention (4.5% vs estimated 2% in compared studies). This may indicate that our population is at higher risk for more serious complications. We speculate that socioeconomic and ethnic diversity may be the driver behind these differences. Our center has also initiated treatment using MEK inhibitors in indicated patients. Due to the differences in clinical manifestations and more severe complications, we recommend closer surveillance in diverse populations. We also advocate for further research in the application of MEK inhibitors beyond second-line therapy.

NFB-07. USE OF PEGYLATED INTERFERON α- 2b IN PEDIATRIC PATIENTS AFFECTED BY UNRESECTABLE PLEXIFORM NEUROFIBROMAS: MONOCENTRIC EXPERIENCE

BACKGROUNDNeurofibromatosis type 1 (NF1) is autosomal dominant neurogenetic disorder characterized by progressive cutaneous, neurologic, skeletal, and neoplastic manifestations. Plexiform neurofibromas (PN) are one of the different types of neurofibromas that occur in these patients. Complete surgical resection is difficult due to the tumor infiltrative behavior. We evaluated pegylated interferon- α-2b (PI) in patients with unresectable progressive or symptomatic PN.METHODSPediatric patients (1–21 years old) affected by unresectable PN, followed at Bambino Gesù Hospital, were treated with PI. We administered PI as a weekly subcutaneous injection at a beginning dose of 1.0 mcg/kg/wk, increased to 3.0 mcg/kg/wk if well tolerated. Paracetamol (15mg/kg) was given 30 minutes prior the dose of PI and then every 4–6 hours as needed. Patients were evaluated with Magnetic Resonance Imaging (MRI) every 12 months after treatment start in case of stable disease.RESULTS10 patients (3 females, 7 males) were enrolled. Median age was 12 years old. The median duration of treatment was 12,6 months. Grade 3 neutropenia (30%) and increased liver transaminases level (20%) were the most common toxicity. 6/10 patients experienced an improvement about pain. 7/10 patients showed clinical response. 1/10 patient had a radiological response at MRI, 1/10 experienced progression disease and 8/10 showed a stable disease at MRI evaluation.CONCLUSIONSOur study demonstrated that PI could be a suitable treatment for unresectable PN in terms of stabilization of the tumour size due to its antitumor activity although clinical response does not correlate with radiographic changes.

NFB-12. TRAMETINIB THERAPY FOR PEDIATRIC PATIENTS WITH REFRACTORY LOW GRADE GLIOMA OR EXTENSIVE SYMPTOMATIC PLEXIFORM NEUROFIBROMA

OBJECTIVERefractory symptomatic plexiform neurofibromas (PNF) and inoperable refractory low grade gliomas (LGG) pose a clinical challenge that may be life threatening. Phase 1 and 2 clinical trials of MEK inhibition with selumetinib in inoperable PNF and LGG have demonstrated promising results in pediatrics, however access has been limited to enrollment on clinical trial. Phase 1 clinical trial for trametinib a MEK 1 and 2 inhibitor has been completed, publication is pending. Thus we have treated a series of children on a compassionate basis with extensive PN or LGG refractory disease with trametinib, as this is available in Canada.METHODSWe have treated children with trametinib on a compassionate basis in our province since 2017. Review of the clinical data regarding this therapy has been IRB approved.RESULTSTwo young patients were treated for indication of life threatening extensive PNF and have had tumor shrinkage and improvement of clinical status. Treatment has been complicated by paronychiae, eczema exacerbation, chondrodermatitis nodularis helicis, RSV and influenza B infection and CTCAE grade 2 pneumonia. In spite of the side effects these two patients remain on treatment due to clear benefit from therapy including: improved respiratory compromise, hearing and dysphagia. We will present the data of additional patients treated with trametinib.CONCLUSIONTrametinib is an effective therapy for life threatening PNF by changing the natural history of tumor growth in young children. Further data is required in terms of tolerance, efficacy and durability of response in such patients in the setting of clinical trials.

Genetic basis of neurofibromatosis type 1 and related conditions, including mosaicism.

Neurofibromatosis type 1 (NF1) is a frequent autosomal dominant disorder characterised by café-au-lait maculae (CALM), skinfold freckling, iris Lisch nodules and benign peripheral nerve sheath tumours (neurofibromas). The NF1 gene is a tumour suppressor gene and NF1 individuals have an increased risk for a long list of tumours, all resulting from a second hit in the normal copy of the NF1 gene. Remarkably, some non-tumour phenotypes such as CALM and pseudarthrosis are also caused by a "second hit". Germline mutations inactivating the NF1 gene show a large variability in genetic mechanisms ranging from single-nucleotide substitutions and somatic mosaicism to large deletions affecting neighbouring genes. Molecular confirmation of the clinical diagnosis is becoming increasingly more important to differentiate NF1 from other syndromes such as Legius syndrome, to investigate genotype-phenotype correlations relevant in 10% of cases and to detect somatic mosaicism. Some degree of learning difficulties, attention deficit and social problems are observed in most children and affect quality of life. There is a large individual variability in complications and the evolution of the disease is difficult to predict. Specialised outpatient clinics for children have been widely established and are important for surveillance and guidance. Regular surveillance is also important for adolescents and adults because many tumour complications can be detected by whole-body MRI and treated even before symptoms develop and irreversible damage occurs. Recent data on nodular plexiform neurofibromas with continued growth in adolescents and young adults show that many of these tumours are premalignant lesions called atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). Specific surveillance and timely local resection of these benign peripheral nerve sheath tumours might be important to prevent malignant degeneration. In the last years, targeted therapy with MEK inhibitors has shown promise to treat unresectable and symptomatic plexiform neurofibromas. Many more challenges remain to find the best way to monitor children and adults for potential complications and to find a satisfying cure for many complications in this disorder.

New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.

Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1. NF1 encodes neurofibromin, a negative regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic RAS gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.

Selumetinib for plexiform neurofibromas in neurofibromatosis type 1: a single-institution experience

Plexiform neurofibromas (PN) are the most frequent tumors associated with Neurofibromatosis type 1 (NF-1). PN can cause significant complications, including pain, functional impairment, and disfigurement. There is no efficient medical treatment and, surgical resection of large PN is frequently infeasible. Selumetinib (AZD6244/ARRY-142886) is a mitogen-activated protein kinase enzyme (MEK1/2) inhibitor and works by targeting the MAPK pathway. It is an investigational treatment option for inoperable symptomatic PN associated with NF-1. Herein, we describe a single institutional experience with selumetinib for inoperable PN in NF-1. Case series study of demographics, clinical, baseline characteristics, treatment effect, and follow-up of consecutive genetically confirmed NF1 patients with inoperable PN associated with significant or potential significant morbidity treated with selumetinib (April 2018 to April 2019). Nineteen patients were treated with selumetinib. Predominant target locations were head and neck (31.6%, 6/19), chest (26.3%, 5/19) and pelvis (21%, 4/19) and the most important comorbidities were disfigurement (47.4%, 9/19) and pain (26.3%, 5/19). The mean follow-up time was 223days (range 35-420days). All but one had sustained clinical improvement, mainly in the first 60-90days of treatment. In one patient, the treatment was suspended after 168days (lack of clear benefit and left ventricular ejection fraction drop). There were no adverse effects leading to treatment suspension. In the first observational study of selumetinib for NF-1 associated PN we showed that the drug was associated with clinical and radiological improvement. Our study also confirms the safety described in the clinical trials.

Pediatric Plexiform Neurofibromas: Impact on Morbidity and Mortality in Neurofibromatosis Type 1

To characterize morbidity, mortality, and surgical outcomes in pediatric patients with symptomatic plexiform neurofibromas (PNFs). We conducted retrospective analysis of data from clinical records of surgical history and other neurofibromatosis type 1 (NF1)-related complications in children with PNFs seen at Cincinnati Children's Hospital Medical Center between 1997 and 2007. A total of 154 children with NF1 and PNFs were identified. Children with symptomatic PNFs had increased incidence of other NF1-related tumors (P < .05). Patients with NF1 and PNFs had a higher mortality rate (5/154, 3.2%) when compared with patients without or with asymptomatic PNFs (2/366, 0.5%; P = .024). The most common morbidities leading to surgeries were neurologic, disfigurement, orthopedic, and airway complaints. Less extensive resection predicted a shorter interval to second surgery (P < .0019). The highest recurrence was seen in tumors located in the head, neck, and thorax (P < .001). These findings quantify the increased risk for additional tumors and mortality associated with symptomatic PNFs. Surgical interventions were required in many cases and resulted in added morbidity in some cases. Patients with PNFs were more likely to benefit from surgery when the indications were airway compression or disfigurement.

Plexiform Neurofibromas in Children with Neurofibromatosis Type 1: Frequency and Associated Clinical Deficits

To define the frequency and clinical features of plexiform neurofibromas (PN) in children with neurofibromatosis type 1. Sixty-five children received whole-body magnetic resonance imaging (MRI) and clinical-neurologic examination. Tumor sizes were calculated volumetrically with the program MedX v3.42. χ(2) test, Fisher exact test, t test, and Spearman rank correlation were used for statistical analysis. Seventy-three tumors were detected in 37 of these 65 children. The mean volume of the tumors was 145.4 mL or 4.8 mL/kg body weight. Eighteen of the 73 PNs caused clinical deficits in 17 children, and the other 56 PNs in 20 children were asymptomatic. Symptomatic tumors were larger than asymptomatic ones (9.6 vs 3.3 mL/kg body weight; P = .01). However, in certain body regions, for example, the head, small tumors also caused clinical deficits. Ten of 18 children ≥11.5 years (median age of the 37 children with PNs) had symptomatic PNs compared with 7 of 19 who were <11.5 years (P = .25). PNs cause clinical deficits in young children. Early detection and regular MRI monitoring help to estimate growth and possible upcoming complications, and are thus beneficial for optimizing treatment and management.

Phase I trial of pegylated interferon-α-2b in young patients with plexiform neurofibromas

Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-α-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN). PI was administered weekly in cohorts of 3-6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity. Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No dose-limiting toxicity (DLT) was seen in patients treated at the 3 μg/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 μg/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 μg/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 μg/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%-22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage. The RP2D of PI for pediatric patients with PN is 1 μg/kg/wk. Clinical and radiographic improvement and cessation of growth can occur. This study provides Class III evidence that pegylated interferon-α-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size.

18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a diagnostic tool for neurofibromatosis 1 (NF1) associated malignant peripheral nerve sheath tumours (MPNSTs): a long-term clinical study

BackgroundMalignant peripheral nerve sheath tumours (MPNSTs) are difficult to detect in neurofibromatosis 1 (NF1) individuals. The purpose was to evaluate [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) and PET computed tomography (CT) as a diagnostic tool for MPNST in NF1 patients with symptomatic plexiform neurofibromas and to verify the diagnosis by pathology and clinical follow-up. Patients and methodsNF1 individuals with symptomatic plexiform neurofibromas underwent clinical evaluation and magnetic resonance imaging. Qualitative FDG PET and PET CT associated with semi-quantitative maximum standard uptake value (SUVmax) assessed possible malignant change. Excision/biopsy verified the diagnosis when possible and clinical follow-up was undertaken in all patients. ResultsIn all, 116 lesions were detected in 105 patients aged 5–71 years, including 80 plexiform neurofibromas, five atypical neurofibromas, 29 MPNST and two other cancers. Biopsy confirmed the findings in 59 tumours and no MPNST was diagnosed on clinical follow-up of 23 lesions diagnosed as benign on FDG PET and PET CT. FDG PET and PET CT diagnosed NF1-associated tumours with a sensitivity of 0.89 [95% confidence interval (CI) 0.76–0.96] and a specificity of 0.95 (CI 0.88–0.98), but the SUVmax level did not predict tumour grade. ConclusionFDG PET and PET CT is a sensitive and specific diagnostic tool for NF1-associated MPNST. Other PET tracers will be required to solve the problem of predicting tumour grade.