Treatment of Disfiguring Cutaneous Lesions in Neurofibromatosis-1 with Everolimus: A Phase II, Open-Label, Single-Arm Trial.
ABSTRACT: BACKGROUND:Cutaneous neurofibromas cause disfigurement and discomfort in individuals with neurofibromatosis type 1 (NF-1). METHODS:The primary objective of this phase II, open-label, single-arm trial was to assess whether orally administered everolimus reduced the surface volume of cutaneous neurofibromas in patients with NF-1. RESULTS:Of 22 patients who took the study drug, 17 completed the trial; 5 patients withdrew due to adverse events. Sixteen patients had photographs of sufficient quality for assessment of the primary outcome. A significant reduction in lesion surface volume, defined as an end of trial volume > 2 standard errors (SE) less than baseline volume, was observed for 4/31 lesions (13%) from 3/16 patients (19%). Additionally, a statistically significant absolute change in average height for paired lesions was observed (p = 0.048). Although not a prespecified outcome measure, a dramatic reduction in the size of 3 large plexiform neurofibromas with a cutaneous component was also noted and documented by measurement of maximum circumference or magnetic resonance imaging-based volumetric analysis. Adverse events were common in this trial, but no serious adverse events occurred. CONCLUSIONS:Although this was a small, exploratory trial that was not powered for significance, the reduction in surface volume observed in this study is noteworthy assuming that the natural course for untreated lesions is to maintain or increase in volume. Future studies are needed with larger study populations that incorporate longer durations of treatment and better standardization of volumetric measurements. Trial Registration ClinicalTrials.gov Identifier: NCT02332902.
Project description:BACKGROUND:Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. METHODS:Eligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m(2) twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. FINDINGS:Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). INTERPRETATION:Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. FUNDING:Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.
Project description:Multiple cutaneous neurofibromas are a hallmark of neurofibromatosis 1 (NF1). They begin to appear during puberty and increase in number and volume during pregnancy, suggesting a hormonal influence. Ghrelin is a hormone that acts via growth hormone secretagogue receptor (GHS-R), which is overexpressed in many neoplasms and is involved in tumorigenesis. We aimed to investigate GHS-R expression in NF1 cutaneous neurofibromas and its relationship with tumors volume, and patient's age and gender.Sample comprised 108 cutaneous neurofibromas (55 large and 53 small tumors) from 55 NF1 individuals. GHS-R expression was investigated by immunohistochemistry in tissue micro and macroarrays and quantified using a digital computer-assisted method. All neurofibromas expressed GHS-R, with a percentage of positive cells ranging from 4.9% to 76.1%. Large neurofibromas expressed more GHS-R than the small ones. The percentage of GHS-R-positive cells and intensity of GHS-R expression were positively correlated with neurofibromas volume. GHS-R expression was more common in female gender.GHS-R is expressed in cutaneous neurofibromas. Larger neurofibromas have a higher percentage of positive cells and higher GHS-R intensity. Based on our results we speculate that ghrelin may have an action on the tumorigenesis of cutaneous neurofibromas. Future studies are required to understand the role of ghrelin in the pathogenesis of NF1-associated cutaneous neurofibroma.
Project description:<h4>Background</h4>Understanding the natural history of non-malignant peripheral nerve sheath tumors (PNSTs) in neurofibromatosis type 1 (NF1) is critical to optimal clinical care and the development of meaningful clinical trials.<h4>Methods</h4>We longitudinally analyzed growth of plexiform neurofibromas (PNs) and of PNSTs with distinct nodular appearance (distinct nodular lesions [DNLs]) using volumetric MRI analysis in patients enrolled on a natural history study (NCT00924196).<h4>Results</h4>DNLs were observed in 58/122 (45.6%) patients (median 2 DNLs/patient). In DNLs that developed during follow-up, median age of development was 17 years. A moderate negative correlation was observed between the estimated PN growth rate and patients' age at initial MRI (Spearman's r [95% CI]: -0.60 [-0.73, -0.43], n = 70), whereas only a weak correlation was observed for DNLs (Spearman's r [95% CI]: -0.25 [-0.47, 0.004]; n = 61). We observed a moderate negative correlation between tumor growth rate and baseline tumor volume for PNs and DNLs (Spearman's r [95% CI]: -0.52 [-0.67, -0.32] and -0.61 [-0.75, -0.42], respectively). Spontaneous tumor volume reduction was observed in 10 PNs and 7 DNLs (median decrease per year, 3.6% and 7.3%, respectively).<h4>Conclusion</h4>We corroborate previously described findings that most rapidly growing PNs are observed in young children. DNLs tend to develop later in life and their growth is minimally age related. Distinct growth characteristics of PNs and DNLs suggest that these lesions have a different biology and may require different clinical management and clinical trial design. In a subset of PNs and DNLs, slow spontaneous regression in tumor volume was seen.
Project description:Neurofibromatosis type 1 (NF1) is a multisystem disease with autosomal dominant inheritance and complete penetrance diagnosed by clinical findings. Cutaneous neurofibromas are present in almost all adult patients in the dermis, epidermis or along the peripheral nerves. Plexiform neurofibromas are subcutaneous or deep lesions involving nerve plexuses or roots. Neurofibromas can degenerate into malignant tumors, with important prognostic implications. NF1 shows a broad clinic variability even within a single family. Exceptions are cases reporting the in-frame microdeletion c.2970_2972delAAT, presenting with the typical pigmentary features of NF1, but no cutaneous or plexiform neurofibromas. We report a patient with a de novo c.2970_2972delAAT mutation who had few café-au-lait spots, only 2 of which measured >15 mm, axillary and submammary freckling, a flat angioma extending over the neck, arm and trunk, a high arched palate, micrognathia, macrocephaly, pes cavus and scoliosis. There was complete absence of observable cutaneous neurofibromas as well as external plexiform neurofibromas. She had had epileptic seizures since childhood; however, a diagnosis of NF1 had not been confirmed until she was 38, partly due to the paucity of characteristic cutaneous stigmata. We confirm the association of the c.2970_2972delAAT mutation in NF1 with a particular clinical phenotype, especially with lack of detectable neurofibromas. For an appropriate management of patients and family counseling, molecular study of the NF1 gene should be considered in patients not fulfilling NIH criteria when other features suggestive of NF1 are present. In the absence of neurofibromas, starting NF1 testing with the screening of exon 17 may be worthwhile.
Project description:BACKGROUND:Cutaneous neurofibromas (cNF) are physically disfiguring, painful, and cause extensive psychologic harm in patients with neurofibromatosis type 1 (NF1). There is currently no effective medical treatment and surgical procedures are inaccessible to most NF1 patients globally. OBJECTIVE:While research is underway to find an effective medical treatment for cNF, there is an urgent need to develop surgical approach that is accessible to all NF1 patients in the world with the skill set and equipment found in most general medical office settings. Here, we present a robust surgical approach to remove cNF that does not require sterile surgical field, utilizes accessible clinical equipment, and can be performed by any health care providers including family practitioners, and physician assistants. METHODS:In a prospective case-series, patients with NF1 underwent this surgical procedure which removes multiple cutaneous neurofibromas. The Dermatology Life Quality Index was given to subjects before and after the procedure as surrogate for patient satisfaction. RESULTS:83 tumors were removed throughout the body from twelve individuals. Examination at follow-up visits revealed well-healed scars without infection or adverse events including aberrant scarring. Patient satisfaction with the procedure was high with significant improvements in symptoms, daily activities, leisure, personal relationships, and treatment experience (P = 0.00062). CONCLUSION:This study demonstrates a robust surgical approach to management cutaneous neurofibromas which can be accessed world-wide to individuals with NF1 and performed by a wide-variety of medical specialists with high clinical efficacy and patient satisfaction.
Project description:PURPOSE:This international, multicenter, single-arm trial assessed efficacy and safety of intralesional rose bengal (PV-10) in 80 patients with refractory cutaneous or subcutaneous metastatic melanoma. METHODS:Sixty-two stage III and 18 stage IV melanoma patients with disease refractory to a median of six prior interventions received intralesional PV-10 into up to 20 cutaneous and subcutaneous lesions up to four times over a 16-week period and were followed for 52 weeks. Objectives were to determine best overall response rate in injected target lesions and uninjected bystander lesions, assess durability of response, and characterize adverse events. RESULTS:For target lesions, the best overall response rate was 51 %, and the complete response rate was 26 %. Median time to response was 1.9 months, and median duration of response was 4.0 months, with 8 % of patients having no evidence of disease after 52 weeks. Response was dependent on untreated disease burden, with complete response achieved in 50 % of patients receiving PV-10 to all of their disease. Response of target lesions correlated with bystander lesion regression and the occurrence of locoregional blistering. Adverse events were predominantly mild to moderate and locoregional to the treatment site, with no treatment-associated grade 4 or 5 adverse events. CONCLUSIONS:Intralesional PV-10 yielded durable local control with high rates of complete response. Toxicity was confined predominantly to the injection site. Cutaneous bystander tumor regression is consistent with an immunologic response secondary to ablation. This intralesional approach for local disease control could be complementary to current and investigational treatments for melanoma.
Project description:BACKGROUND:Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. METHODS:We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. RESULTS:A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ?20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ?20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. CONCLUSIONS:Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).
Project description:<h4>Objective</h4>The purpose of this prospective multicenter study was to assess the safety and technical feasibility of volumetric Magnetic Resonance-guided High Intensity Focused Ultrasound (MR-HIFU) ablation for treatment of patients with symptomatic uterine fibroids.<h4>Methods</h4>Thirty-three patients with 36 fibroids were treated with volumetric MR-HIFU ablation. Treatment capability and technical feasibility were assessed by comparison of the Non-Perfused Volumes (NPVs) with MR thermal dose predicted treatment volumes. Safety was determined by evaluation of complications or adverse events and unintended lesions. Secondary endpoints were pain and discomfort scores, recovery time and length of hospital stay.<h4>Results</h4>The mean NPV calculated as a percentage of the total fibroid volume was 21.7%. Correlation between the predicted treatment volumes and NPVs was found to be very strong, with a correlation coefficient r of 0.87. All patients tolerated the treatment well and were treated on an outpatient basis. No serious adverse events were reported and recovery time to normal activities was 2.3?±?1.8 days.<h4>Conclusion</h4>This prospective multicenter study proved that volumetric MR-HIFU is safe and technically feasible for the treatment of symptomatic uterine fibroids.<h4>Key points</h4>• Magnetic-resonance-guided high intensity focused ultrasound allows non-invasive treatment of uterine fibroids. • Volumetric feedback ablation is a novel technology that allows larger treatment volumes • MR-guided ultrasound ablation of uterine fibroids appears safe using volumetric feedback.
Project description:INTRODUCTION:Patients with Neurofibromatosis type 1 (NF1) develop plexiform neurofibromas (PNF) and cutaneous neurofibromas. These tumors are a major cause of the patient's morbidity and mortality. An influence of estrogen and progesterone on tumor growth has been suggested but reports on growth or malignant transformation of tumors during pregnancy remain anecdotal. The purpose of this study was to quantify growth of cutaneous and plexiform neurofibromas in NF1 patients during pregnancy, and to assess the onset of NF1 related symptoms. MATERIAL AND METHODS:Retrospectively, 13 mothers with NF1 were included and compared to nullipara, nulligravida, age-matched women with NF1. All women received whole-body magnetic resonance imaging (MRI) before and after pregnancy or after a matched time period. Presence of plexiform and cutaneous neurofibromas was evaluated. PNF were subjected to semi-automated volumetry (MedX). The sum of the longest diameters (SLD) of representative cutaneous neurofibromas was determined for both groups. Clinical symptoms and subjective tumor growth were assessed. RESULTS:PNF were identified in 12/26 women (46.2%). Follow up showed neither new PNF nor a significant difference in growth rate (median tumor-growth/year: pregnant group-0.38% (IQR -1.1-5.4%) vs control group 3.59% (IQR -2.1-5.5%; P = 0.69). Malignant transformation of PNF was not observed. There was a significant growth of cutaneous neurofibromas in both groups (median SLD increase: pregnant group 17mm; P = 0.0026 / control group 12mm; P = 0.0004) The difference in increase of SLD was not significant (P = 0.48). Singular cutaneous neurofibromas in the pregnant group displayed high levels of tumor growth (>20%/year). NF1-associated symptoms and subjective tumor growth were not significantly increased in pregnant patients. CONCLUSIONS:Growth of plexiform and cutaneous neurofibromas in pregnant patients is not significantly different compared to non-pregnant patients. Cutaneous neurofibromas show a significant increase in growth over time in both, pregnant and non-pregnant patients and NF1 related clinical symptoms do not significantly aggravate during the course of pregnancy.
Project description:Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder characterized by the development of numerous benign tumors. Renal angiomyolipoma (RAML) occur in up to 80% of TSC patients, which is a leading cause of TSC-related death in adult patients. The aim of the study was to evaluate the efficacy and safety profiles of everolimus in Chinese patients of TSC associated with RAML(TSC-RAML).In this 2-years, nonrandomized, open-label trial, 18 patients of TSC-RAML, with at least one RAML 3 cm or larger in its longest diameter, were enrolled to assess the efficacy and safety of everolimus therapy in Chinese patients. Everolimus was administered for the first 12 months only. The primary endpoint was a reduction of 50% or more relative in RAML volume to the baseline in the absence of new RAML ?1 cm and no RAML-related bleeding of grade???2. The secondary endpoints included: safety, lung function and skin lesions response rate. Serial computed tomography of RAML, magnetic resonance imaging of brain lesions and pulmonary-function tests were performed. Adverse events were investigated using CTCAE v4.0. All analyses used a significance level of 0.05 and were generated in SPSS19.0 software.The proportion of patients who achieved ?50% reduction from baseline in the sum of volumes of target lesions increased from 52.94% at 3 months, to 58.82% and 66.67% at months 6 and 12, respectively. During the period of everolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 s (FEV1) increased by 276?±?78 ml (P?<?0.001), the forced vital capacity (FVC) increased by 433?±?170 ml (P?<?0.001), and the residual volume decreased by 408?±?243 ml (P?=?0.009), as compared with baseline values. The angiomyolipoma volume and the lung function approached, but did not completely return to, the baseline values. The skin lesions response rate was 37.5% after 12 months of therapy falling to 21.4% at 12 months after stopping everolimus. The most common adverse events were mucositis oral, irregular menstruation, abdominal pain, hypertriglyceridemia and headache. The most common grade 3 adverse events were irregular menstruation and mucositis oral. In addition, one patient died from RAML spontaneous haemorrhage during treatment with everolimus, even with reduction in RAML volume of 60.68% at 3 months. A second death was due to epithelioid RAML progression, with metastasis to multiple retroperitoneal lymph node, who died from severe infection one month after surgery.Angiomyolipomas regressed somewhat during everolimus therapy but tended to increase in volume after the therapy was stopped. Everolimus was well tolerated and showed promising activity in Chinese patients with TSC-RAML, however, we should alert the life-threatening hemorrhage of large RAML in the early period and the lymph node metastasis of epithelioid RAML.ChiCTR-OPC-14005488 . Registered November 17, 2014.