Fabio Nunes

Spinal ependymomas in neurofibromatosis Type 2: a retrospective analysis of 55 patients

OBJECT The aim of this paper was to define the clinical characteristics of spinal ependymomas associated with neurofibromatosis Type 2 (NF2). METHODS The authors retrospectively reviewed the clinical records of patients with NF2 who had imaging findings consistent with ependymomas and were seen at Massachusetts General Hospital between 1994 and 2007. Clinical characteristics of these patients were obtained from hospital records, imaging studies, surgical reports, and pathology reports. Mutational analysis of the NF2 gene was performed in 37 of 44 unrelated patients. RESULTS Fifty-five patients met inclusion criteria for the study. The median age at diagnosis of NF2 was 21 years; the median time after diagnosis until identification of ependymomas was 5 years. Multiple ependymomas were present in 58% of patients. The most common site of involvement was the cervical cord or cervicomedullary junction (86% of imaging studies), followed by the thoracic and lumbar cords (62% and 8%, respectively). The majority of patients had no symptoms related to their tumors (42 patients [76%]). After a median follow-up of 50 months, surgery was performed in 11 patients (20%) for symptomatic progression (indications for surgery). Mutational analysis of the NF2 gene detected alterations in 28 (76%) of 37 unrelated patients, with nonsense and frameshift mutations accounting for 64% of detected mutations. The high rate of truncating mutations may help explain the high tumor burden in these patients. CONCLUSIONS Neurofibromatosis Type 2-related ependymomas exhibit an indolent growth pattern with tumor progression limited to a minority of patients. The authors believe that surveillance is reasonable for asymptomatic ependymomas, including those with cystic areas that expand the cord. For symptomatic tumors, resection may be warranted depending on age, overall clinical status, and ease of resectability.

Neurofibromatosis 2 in the Pediatric Population

Neurofibromatosis 2 is a severe autosomal dominant disorder characterized by the occurrence of bilateral vestibular schwannomas and other benign tumors of the nervous system. Excellent natural history studies exist for adults with neurofibromatosis 2, but limited outcome data are available for children with neurofibromatosis 2. In this study, we present clinical data on 12 patients with neurofibromatosis 2 and age at diagnosis before 18 years. Full record review included surgical reports, pathology reports, and imaging studies; all patients were personally examined by a single author. One third of the patients presented with hearing impairment and another third presented with other cranial nerve dysfunction. Tumor load was extensive, including cranial meningiomas in 75%, cranial schwannomas other than vestibular schwannomas in 83%, and spinal cord tumors in 75%. Family history was present in two thirds of the patients. Surgical removal of vestibular schwannomas was performed in 58%; none had full preservation of hearing postsurgery. Functionally, 75% of children had hearing loss, 83% had visual impairment, 25% had abnormal ambulation, and 25% were performing below grade level. In conclusion, increased clinical awareness, better imaging techniques, and molecular diagnostics have made pediatric diagnosis of neurofibromatosis 2 feasible, but outcomes appear to be worse than in adult patients. Further work is needed to determine optimal management of pediatric neurofibromatosis 2. (J Child Neurol 2003;18:718—724).

Bevacizumab Treatment for Meningiomas in NF2: A Retrospective Analysis of 15 Patients

Bevacizumab treatment can result in tumor shrinkage of progressive vestibular schwannomas in some neurofibromatosis 2 (NF2) patients but its effect on meningiomas has not been defined. To determine the clinical activity of bevacizumab against NF2-related meningiomas, we measured changes in volume of meningiomas in NF2 patients who received bevacizumab for treatment of progressive vestibular schwannomas. A radiographic response was defined as a 20% decrease in tumor size by volumetric MRI analysis. In addition, we determined the expression pattern of growth factors associated with tumor angiogenesis in paraffin-embedded tissues from 26 unrelated meningiomas. A total of 48 meningiomas in 15 NF2 patients were included in this study with a median follow up time of 18 months. A volumetric radiographic response was seen in 29% of the meningiomas (14/48). Tumor shrinkage was not durable: the median duration of response was 3.7 months and the median time to progression was 15 months. There was no significant correlation between pre-treatment growth rate and meningioma response in regression models. Tissue analysis showed no correlation between tumor microvascular density and expression of VEGF pathway components. This data suggests that, in contrast to schwannomas, activation of VEGF pathway is not the primary driver of angiogenesis in meningiomas. Our results suggest that a minority of NF2-associated meningiomas shrink during bevacizumab therapy and that these responses were of short duration. These results are comparable to previous studies of bevacizumab in sporadic meningiomas.

Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas

BackgroundMeningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the NF2 locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas.MethodsWe compared 73 meningiomas presenting as sporadic solitary (64), sporadic multiple (5) and familial multiple (4) tumors using genomic profiling by array comparative genomic hybridization (array CGH).ResultsSporadic solitary meningiomas revealed genomic rearrangements consistent with at least two mechanisms of tumor initiation, as unsupervised cluster analysis readily distinguished tumors with chromosome 22 deletion (associated with loss of the NF2 tumor suppressor) from those without chromosome 22 deletion. Whereas sporadic meningiomas without chromosome 22 loss exhibited fewer chromosomal imbalance events overall, tumors with chromosome 22 deletion further clustered into two major groups that largely, though not perfectly, matched with their benign (WHO Grade I) or advanced (WHO Grades II and III) histological grade, with the latter exhibiting a significantly greater degree of genomic imbalance (P < 0.001). Sporadic multiple meningiomas showed a frequency of genomic imbalance events comparable to the atypical grade solitary tumors. By contrast, familial multiple meningiomas displayed no imbalances, supporting a distinct mechanism for the origin for these tumors.ConclusionGenomic profiling can provide an unbiased adjunct to traditional meningioma classification and provides a basis for exploring the different genetic underpinnings of tumor initiation and progression. Most importantly, the striking difference observed between sporadic and familial multiple meningiomas indicates that genomic profiling can provide valuable information for differential diagnosis of subjects with multiple meningiomas and for considering the risk for tumor occurrence in their family members.

Progesterone and Estrogen Receptors in Neurofibromas of Patients with NF1

Neurofibromatosis type 1 (NF1) or von Recklinghausen disease is a genetic disorder affecting the growth of cells in nervous system. One of the most remarkable characteristics of this disease is the development of benign tumors of the nervous system (neurofibromas). The purpose of this study was to test tissue samples taken from neurofibromas and plexiform neurofibromas of NF1 patients for the presence of estrogen and progesterone receptors. We used previously collected samples from patients registered in the database of the Centro Nacional de Neurofibromatose (CNNF-Brazil). Samples from twenty-five patients in the database presenting plexiform neurofibromas (N1 group) and 25 samples from the same database from patients presenting neurofibromas (N2 group) were tested. We observed positive staining for progesterone receptors in 13 of the neurofibroma samples and 19 of the plexiform neurofibroma samples. Among the neurofibroma samples, we observed one sample with positive estrogen receptor staining, but none of the plexiform neurofibroma samples showed positive staining. We suggest further studies to investigate in greater depth possible hormonal influences on the development and growth of neurofibromas and plexiform neurofibromas in NF1.

Turner syndrome and meningioma: support for a possible increased risk of neoplasia in Turner syndrome.

Neoplasia is uncommon in Turner syndrome, although there is some evidence that brain tumors are more common in Turner syndrome patients than in the general population. We describe a woman with Turner syndrome (45,X) with a meningioma, in whom a second neoplasia, basal cell carcinomas of the scalp and nose, developed five years later in the absence of therapeutic radiation. Together with 7 cases of Turner syndrome with meningioma from a population-based survey in the United Kingdom, and 3 other isolated cases in the literature, we review this small number of patients for evidence of risk factors related to Turner syndrome, such as associated structural anomalies or prior treatment. We performed histological and fluorescent in situ hybridization (FISH) of 22q (NF2 locus) analyses of the meningeal tumor to search for possible molecular determinants. We are not able to prove causation between these two entities, but suggest that neoplasia may be a rare associated medical problem in Turner syndrome. Additional case reports and extension of population-based studies are needed.

Serum IgE levels in neurofibromatosis 1

A descriptive case study was performed on 75 patients with NF1 (neurofibromatosis type 1) from the CNNF (Brazil) database. Serum IgE levels were determined using the IgE radioimmunosorbent test, with the reference values of 75–502 IU mL−1. The patients were divided into groups, with 25 patients presenting plexiform neurofibromas, 25 presenting neurofibromas and 25 presenting no neurofibromas. The purposes of this study were to determine the serum IgE levels of patients with NF1 presenting plexiform neurofibromas, neurofibromas and no neurofibromas, as well as to determine possible correlations between serum IgE levels and the size of the plexiform neurofibromas and neurofibromas presented by these patients. Elevated serum IgE levels were observed in all the patient groups. We did not observe a correlation between IgE levels and age in these patients; however, we did observe correlations between IgE levels and neurofibroma and plexiform neurofibroma size. We suggest further studies to confirm these results and to investigate in greater depth the possible role of IgE in the development and growth of neurofibromas and plexiform neurofibromas in NF1.

Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study

Background: Baricitinib, an oral selective inhibitor of Janus kinase 1 and Janus kinase 2, modulates proinflammatory cytokine signaling. Objectives: The efficacy and safety of baricitinib were evaluated in patients with moderate‐to‐severe atopic dermatitis (AD). Methods: In this phase 2, randomized, double‐blind, placebo‐controlled study, 124 patients with moderate‐to‐severe AD applied topical corticosteroids (TCSs) for 4 weeks before randomization to once‐daily placebo, 2 mg of baricitinib, or 4 mg of baricitinib for 16 weeks. Use of TCSs was permitted during the study. The primary outcome was the proportion of patients achieving at least a 50% reduction in the Eczema Area and Severity Index (EASI‐50) compared with placebo. Results: Significantly more patients who received baricitinib, 4 mg, achieved EASI‐50 than did patients receiving placebo (61% vs 37% [P = .027]) at 16 weeks. The difference between the proportion of patients receiving baricitinib, 2 or 4 mg, who achieved EASI‐50 and the proportion of patients receiving placebo and achieving EASI‐50 was significant as early as week 4. Baricitinib also improved pruritus and sleep loss. Treatment‐emergent adverse events were reported in 24 of the patients receiving placebo (49%), 17 of those receiving 2 mg of baricitinib (46%), and 27 of those receiving 4 mg of baricitinib (71%). Limitations: A TCS standardization period before randomization reduced disease severity, limiting the ability to compare results with those of baricitinib monotherapy. Longer studies are required to confirm baricitinibs efficacy and safety in patients with AD. Conclusions: Baricitinib used with TCSs reduced inflammation and pruritus in patients with moderate‐to‐severe AD.

JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial

Abstract Background Inflammation signaled by Janus kinases (JAKs) promotes progression of diabetic kidney disease (DKD). Baricitinib is an oral, reversible, selective inhibitor of JAK1 and JAK2. This study tested the efficacy of baricitinib versus placebo on albuminuria in adults with Type 2 diabetes at high risk for progressive DKD. Methods In this Phase 2, double-blind, dose-ranging study, participants were randomized 1:1:1:1:1 to receive placebo or baricitinib (0.75 mg daily; 0.75 mg twice daily; 1.5 mg daily; or 4 mg daily), for 24 weeks followed by 4–8 weeks of washout. Results Participants (N = 129) were 63±9.1 (mean±standard deviation) years of age, 27.1% (35/129) women and 11.6% (15/129) African-American race. Baseline hemoglobin A1c (HbA1c) was 7.3±1% and estimated glomerular filtration rate was 45.0±12.1 mL/min/1.73 m2 with first morning urine albumin–creatinine ratio (UACR) of 820 (407–1632) (median; interquartile range) mg/g. Baricitinib, 4 mg daily, decreased morning UACR by 41% at Week 24 compared with placebo (ratio to baseline 0.59, 95% confidence interval 0.38–0.93, P = 0.022). UACR was decreased at Weeks 12 and 24 and after 4–8 weeks of washout. Baricitinib 4 mg decreased inflammatory biomarkers over 24 weeks (urine C–X–C motif chemokine 10 and urine C–C motif ligand 2, plasma soluble tumor necrosis factor receptors 1 and 2, intercellular adhesion molecule 1 and serum amyloid A). The only adverse event rate that differed between groups was anemia at 32.0% (8/25) for baricitinib 4 mg daily versus 3.7% (1/27) for placebo. Conclusions Baricitinib decreased albuminuria in participants with Type 2 diabetes and DKD. Further research is required to determine if baricitinib reduces DKD progression.

A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia

Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2V617F mutation. The study had a standard 3+3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2V617F-positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4h after single and multiple doses, and mean half-life on day 1 was approximately 6h. Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients. A ≥50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥50% reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52%) and 6/14 patients (43%) receiving ≥120mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120.