A systematic review of tumor treating fields therapy for high-grade gliomas.

INTRODUCTION: Tumor treating fields (TTF) is a unique treatment modality that utilizes alternating electric fields to deliver therapy. Treatment effects have been assessed in patients with newly diagnosed and recurrent glioblastoma in clinical trials and retrospective studies. While the results of these studies led to FDA approval for both populations, a portion of the neuro-oncology and neurosurgery community remains skeptical of TTF. Thus, this review aims to systematically summarize and evaluate prior studies investigating the efficacy and safety of TTF in patients with high-grade gliomas. METHODS: A systematic review of the literature was performed according to PRISMA guidelines from database inception through February 2019. To be included, studies must have investigated the efficacy of TTF in adult high-grade glioma patients. RESULTS: In total, 852 studies were initially identified, 9 of which met final inclusion criteria. In total, 1191 patients were identified who received TTF. Included studies consisted of two pilot clinical trials, two randomized clinical trials, and five retrospective studies. In randomized clinical trials, TTF improved survival for newly diagnosed glioblastoma patients but not for recurrent glioblastoma patients. Adverse skin reactions were the primary adverse effect associated with TTF. CONCLUSION: While TTF has been evaluated for safety and efficacy in a number of studies, concerns remain regarding study design, quality of life, and cost of therapy. Further investigation is needed regarding the therapy, and ongoing trials are already underway to provide more data regarding therapy outcomes and interactions in combination regimens.

Whole body MRI with DWI in people with NF1 and Schwannomatosis: Are qualitative and quantitative imaging features of peripheral lesions comparable to localized MRI?

PURPOSE: To compare the qualitative and quantitative features of peripheral lesions on localized (L) and whole-body (WB) magnetic resonance imaging (MRI) in people with neurofibromatosis type 1 (NF1) and schwannomatosis. MATERIALS AND METHODS: This is a retrospective, HIPAA compliant study with twenty-seven patients (14 women, 13 men; mean age (years): 38 (3-67)) who underwent both L-MRI and WB-MRI without interval treatment. WB-MRI and L-MRI were comprised of T1-weighted, fat suppressed (FS) T2-weighted or short tau inversion recovery (STIR), diffusion-weighted imaging (DWI) using b-values of 50, 400, and 800 s/mm2, apparent diffusion coefficient (ADC) mapping and pre- and post-contrast FST1 sequences. Two readers recorded qualitative (T1 and T2/STIR signal intensity and heterogeneity, contrast enhancement and heterogeneity, perilesional enhancement, presence of a target sign and perilesional edema) and quantitative (size, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), ADC) features of peripheral lesions on L-MRI and WB-MRI.Descriptive statistics, Wilcoxon signed-rank test and McNemar's test were used. RESULTS: There were 31 peripheral lesions identified in 27 subjects, (mean size: 3.1 cm (range: 1-8.1 cm) on both L-MRI and WB-MRI).There were no differences in T1 signal and heterogeneity and T2/STIR signal and heterogeneity between WB-MRI and L-MRI ((p = 0.180, 0.083, 0.317 and 0.157 respectively). There were also no differences in contrast enhancement, heterogeneity and perilesional enhancement between WB-MRI and L-MRI (p = 1.000, 0.380 and 1.000 respectively). Presence of a target sign and perilesional edema did not differ between WB-MRI and L-MRI (p = 1.000 and 0.500 respectively). Craniocaudal (CC), mediolateral (ML) and anteroposterior (AP) size measurements on WB-MRI did not differ from CC, ML and AP size measurements on L-MRI (p = 0.597, 0.128 and 0.783 respectively). SNR on WB-DWI did not differ from SNR on L-DWI for b50, b400 and b800 images (p = 0.285, 0.166, and 0.974 respectively), and CNR on WB-DWI did not differ from CNR on L-DWI for b50, b400 and b800 images (p = 0.600, 0.124, and 0.787 respectively). There was no significant difference in minimum, mean and maximum ADC values between WB-DWI and L-DWI (p = 0.234, 0.481, and 0.441 respectively). Median minimum, mean and maximum ADC (×10(-3)mm(2)/s) differences between WB-DWI and L-DWI were 0.0 (range -1 to 0.7), 0.0 (range -0.5 to 0.6), and 0.1 (range -1.2 to 0.8) respectively. Relative ADC difference averages were 29.1% for minimum values, 10.1% for mean values, and 14.8% for maximum values. CONCLUSION: WB-MRI yields qualitative and quantitative features for peripheral lesions, including DWI and ADC measurements, that are comparable to L-MRI scans. WB-DWI can be reliably used for the assessment of peripheral nerve sheath tumors, obviating the need for a repeat follow-up L-DWI acquisition.

Existing and Developing Preclinical Models for Neurofibromatosis Type 1-Related Cutaneous Neurofibromas.

Neurofibromatosis type 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.

RAS Signaling Gone Awry in the Skin: The Complex Role of RAS in Cutaneous Neurofibroma Pathogenesis, Emerging Biological Insights.

Cutaneous neurofibromas (cNFs) are the most common tumor in people with the rasopathy neurofibromatosis type 1. They number in hundreds or even thousands throughout the body, and currently, there are no effective interventions to prevent or treat these skin tumors. To facilitate the identification of novel and effective therapies, essential studies including a more refined understanding of cNF biology and the role of RAS signaling and downstream effector pathways responsible for cNF initiation, growth, and maintenance are needed. This review highlights the current state of knowledge of RAS signaling in cNF pathogenesis and therapeutic development for cNF treatment.

cNF-Skindex in Adults Living with Neurofibromatosis 1: Severity Strata in France and Validation in United States Adults.

Cutaneous neurofibromas (cNF) contribute to the impairment of QOL in individuals with neurofibromatosis 1. The cNF-Skindex, validated in a French population, specifically assesses the cNF-related QOL. In this study, we first defined severity strata using an anchoring approach on the basis of patient's burden. In total, 209 patients answered the anchor question and the cNF-Skindex. We tested the agreement among the three strata, generated by all potential couples of cut-off values of the cNF-Skindex and the three strata defined in the anchor question. The cut-off values 12 and 49 provided the highest Kappa value (κ = 0.685, 95% confidence interval = 0.604-0.765). Second, we validated the score and the strata in a United States population using the answers provided by 220 French and 148 United States adults. In the multivariable linear regression analysis, the country of origin was not a factor associated with the score (P = 0.297). The number of cNF along the different severity strata was similar between the French and the United States populations. In conclusion, stratification constitutes a powerful tool to better interpret the cNF-Skindex in daily practice and in clinical trials. This study validates its use in two populations that together constitute a large cohort of patients willing to participate in clinical research.

Cutaneous Neurofibroma Heterogeneity: Factors that Influence Tumor Burden in Neurofibromatosis Type 1.

Neurofibromatosis type 1 is one of the most common genetic disorders of the nervous system and predisposes patients to develop benign and malignant tumors. Cutaneous neurofibromas (cNFs) are NF1-associated benign tumors that affect nearly 100% of patients with NF1. cNFs dramatically reduce patients' QOL owing to their unaesthetic appearance, physical discomfort, and corresponding psychological burden. There is currently no effective drug therapy option, and treatment is restricted to surgical removal. One of the greatest hurdles for cNF management is the variability of clinical expressivity in NF1, resulting in intrapatient and interpatient cNF tumor burden heterogeneity, that is, the variability in the presentation and evolution of these tumors. There is growing evidence that a wide array of factors are involved in the regulation of cNF heterogeneity. Understanding the mechanisms underlying this heterogeneity of cNF at the molecular, cellular, and environmental levels can facilitate the development of innovative and personalized treatment regimens.

Clinical, histological, and molecular features of gliomas in adults with neurofibromatosis type 1.

BACKGROUND: People with NF1 have an increased prevalence of central nervous system malignancy. However, little is known about the clinical course or pathologic features of NF1-associated gliomas in adults, limiting clinical care and research. METHODS: Adults (≥18 years) with NF1 and histologically confirmed non-optic pathway gliomas (non-OPGs) at Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, and Washington University presenting between 1990 and 2020 were identified. Retrospective data were collated, and pathology was reviewed centrally. RESULTS: Forty-five patients, comprising 23 females (51%), met eligibility criteria, with a median of age 37 (18-68 years) and performance status of 80% (30%-100%). Tissue was available for 35 patients. Diagnoses included infiltrating (low-grade) astrocytoma (9), glioblastoma (7), high-grade astrocytoma with piloid features (4), pilocytic astrocytoma (4), high-grade astrocytoma (3), WHO diagnosis not reached (4) and one each of gliosarcoma, ganglioglioma, embryonal tumor, and diffuse midline glioma. Seventy-one percent of tumors were midline and underwent biopsy only. All 27 tumors evaluated were IDH1-wild-type, independent of histology. In the 10 cases with molecular testing, the most common genetic variants were NF1, EGFR, ATRX, CDKN2A/B, TP53, TERT, and MSH2/3 mutation. While the treatments provided varied, the median overall survival was 24 months [2-267 months] across all ages, and 38.5 [18-109] months in individuals with grade 1-2 gliomas. CONCLUSIONS: Non-OPGs in adults with NF1, including low-grade tumors, often have an aggressive clinical course, indicating a need to better understand the pathobiology of these NF1-associated gliomas.

Target Product Profile for Cutaneous Neurofibromas: Clinical Trials to Prevent, Arrest, or Regress Cutaneous Neurofibromas.

Cutaneous neurofibromas (cNFs) are benign tumors of the skin that affect >95% of adults with neurofibromatosis type 1. Despite their benign histology, cNFs can significantly impact QOL due to disfigurement, pain, and pruritus. There are no approved therapies for cNFs. Existing treatments are limited to surgery or laser-based treatments that have had mixed success and cannot be readily applied to a large number of tumors. We review cNF treatment options that are currently available and under investigation, discuss the regulatory considerations specific to cNFs, and propose strategies to improve cNF clinical trial design and standardize clinical trial endpoints.

Current and Emerging Imaging Techniques for Neurofibromatosis Type 1-Associated Cutaneous Neurofibromas.

A consistent set of measurement techniques must be applied to reliably and reproducibly evaluate the efficacy of treatments for cutaneous neurofibromas (cNFs) in people with neurofibromatosis type 1 (NF1). cNFs are neurocutaneous tumors that are the most common tumor in people with NF1 and represent an area of unmet clinical need. This review presents the available data regarding approaches in use or development to identify, measure, and track cNFs, including calipers, digital imaging, and high-frequency ultrasound sonography. We also describe emerging technologies such as spatial frequency domain imaging and the application of imaging modalities such as optical coherence tomography that may enable the detection of early cNFs and prevention of tumor-associated morbidity.

Quantitation of terameprocol in human plasma by liquid chromatography-tandem mass spectrometry.

The global transcription inhibitor terameprocol is being evaluated clinically as an oral formulation to treat high-grade glioma. A sensitive, reliable method was developed to quantitate terameprocol using LC-MS/MS to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of terameprocol and the internal standard, Sorafenib-methyl-d3, was achieved with a Zorbax XDB C18 column (2.1 × 50 mm, 3.5 µm) and gradient elution over a 2-minute total analytical run time. A SCIEX 4500 or SCIEX 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for terameprocol detection. The assay range of 5-1000 ng/mL was demonstrated to be accurate (92.7-107.4%) and precise (CV ≤ 11.3%). A sample diluted 1:10 (v/v) was accurately quantitated. Terameprocol in plasma has been proven stable for at least 20 months when stored at -70 °C. The method was applied to the measurement of total plasma concentrations of terameprocol in a patient with a high-grade glioma receiving a 300 mg oral dose.

Management of glioblastoma: a perspective from Mexico.

Access to healthcare in Mexico is available to its population via publicly and privately funded institutions. The public sector, administered by both the local and federal government under the jurisdiction of the Department of Health, provides healthcare to the majority of the country's population. Privately funded institutions vary in size and scope of practice, ranging from small clinics focused on family practice, to large tertiary hospitals with capacity for treating patients with complex conditions and performing clinical research. The evaluation and treatment of patients with cancer in Mexico is also available through both sectors. In the country's capital, Mexico City, patients with glioblastoma are primarily treated at the National Institute of Neurology and Neurosurgery and the National Institute of Oncology. Epidemiological data is incomplete due to the lack of a national cancer registry. In the case of neoplasms of the central nervous system, the available information suggests that gliomas represent 33% of all intracranial tumors. The treatment of patients in Mexico diagnosed with glioblastoma has not been standardized owing to the lack of resources in some communities and the expense of antineoplastic agents. Current options range from a biopsy only to maximal safe resection followed by adjuvant treatment with radiation and chemotherapy. Currently, basic science and clinical research is being conducted in academic institutions associated with universities and in private hospitals. Studies include the evaluation of tumor biology, neuroimaging biomarkers and new treatment options such as the use of chloroquine.

Quantifying the utility of a multidisciplinary neuro-oncology tumor board.

OBJECTIVE: There has been limited research on the efficacy of multidisciplinary tumor boards (MDTBs) in improving the treatment of patients with tumors affecting the nervous system. The objective of the present study was to quantify the utility of MDTBs in providing alternative diagnostic interpretations and treatment plans for this patient population. METHODS: The authors performed a prospective study of patients in 4 hospitals whose cases were discussed at MDTBs between July and November 2019. Patient demographic data, diagnoses, treatment plans, and eligibility for clinical trials were recorded, among other variables. RESULTS: A total of 176 cases met eligibility criteria for study inclusion. The majority (53%) of patients were male, and the mean patient age was 52 years. The most frequent diagnosis was glioblastoma (32.4%). Among the evaluable cases, MDTBs led to 38 (21.6%) changes in image interpretation and 103 (58.2%) changes in patient management. Additionally, patients whose cases were discussed at MDTBs had significantly shorter referral times than patients whose cases were not discussed (p = 0.024). CONCLUSIONS: MDTB discussions led to significant numbers of diagnostic and treatment plan changes as well as shortened referral times, highlighting the potential clinical impact of multidisciplinary care for patients with nervous system tumors.

NCI-CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors-Histone Mutated Midline Glioma Workshop Proceedings.

Histone mutations occur in approximately 4% of different cancer types. In 2012, mutations were found in the gene encoding histone variant H3.3 (H3F3A gene) in pediatric diffuse intrinsic pontine gliomas and pediatric hemispheric gliomas. Tumors with mutations in the H3F3A gene are generally characterized as histone mutated gliomas (HMGs) or diffuse midline gliomas. HMGs are a rare subtype of glial tumor that is malignant and fast growing, carrying a poor prognosis. In 2017, the Beau Biden Cancer Moonshot Program appropriated $1.7 billion toward cancer care in 10 select areas. The National Cancer Institute (NCI) was granted support to focus specifically on rare central nervous system (CNS) tumors through NCI-CONNECT. Its mission is to address the challenges and unmet needs in CNS cancer research and treatment by connecting patients, providers, researchers, and advocacy organizations to work in partnership. On September 27, 2018, NCI-CONNECT convened a workshop on histone mutated midline glioma, one of the 12 CNS cancers included in its initial portfolio. Three leaders in the field provided an overview of advances in histone mutated midline glioma research. These experts shared observations and experiences related to common scientific and clinical challenges in studying these tumors. Although the clinical focus of this workshop was on adult patients, one important objective was to start a collaborative dialogue between pediatric and adult clinicians and researchers. Meeting participants identified needs for diagnostic and treatment standards, disease biology and biological targets for this cancer, disease-specific trial designs, and developed a list of action items and future direction.

Proceedings of the Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) Adult Medulloblastoma Workshop.

BACKGROUND: Medulloblastoma (MB) is a rare brain tumor occurring more frequently in children in whom research has been primarily focused. Treatment recommendations in adults are mainly based on retrospective data and pediatric experience; however, molecular features and treatment tolerance differ between the 2 age groups. In adults, prognostic tools are suboptimal, late recurrences are typical, and long-term sequelae remain understudied. Treatment has not adapted to molecular classification advances; thus, the survival rate of adult MB has not improved. METHODS: In 2017, the National Cancer Institute (NCI) received support from the Cancer Moonshot℠ to address the challenges and unmet needs of adults with rare central nervous system tumors through NCI-CONNECT, a program that creates partnerships among patients, health care professionals, researchers, and advocacy organizations. On November 25, 2019, NCI-CONNECT convened leading clinicians and scientists in a workshop to review advances in research, share scientific insights, and discuss clinical challenges in adult MB. RESULTS: Working groups identified unmet needs in clinical trial design, tissue acquisition and testing, tumor modeling, and measurement of clinical outcomes. CONCLUSIONS: Participants identified opportunities for collaboration; discussed plans to create a working group of clinicians, researchers, and patient advocates; and developed specific action items to expedite progress in adult MB.

Brain Metastases as a First Site of Recurrence in Patients Receiving Chemotherapy with Controlled Systemic Cancer: a Critical but Under-Recognized Clinical Scenario.

PURPOSE OF REVIEW: As the treatment of many malignancies has improved, brain metastases (BM) have been observed as a site of the first recurrence in patients with controlled systemic cancers. This suggests that while the administered chemotherapy is effective against systemic cancer, drug concentrations in the central nervous system (CNS) are likely too low to be effective. These findings are in accord with data suggesting that more than 98% of FDA-approved drugs on the market today are unable to cross the blood-brain barrier (BBB). RECENT FINDINGS: This retrospective literature review was conducted to estimate the proportion of patients with non-small lung cancer, breast cancer, and melanoma who develop BM as their initial site of recurrence while their systemic cancers are well controlled. Of 267 studies screened, 12 studies fit criteria for inclusion. These 12 studies reported on 923 patients. According to compiled data across these studies, 16% of patients on chemotherapy with stable or responding systemic cancer developed isolated BM as their initial site of relapse. These findings strongly suggest that while chemotherapy controlled systemic cancer, drug concentrations within the CNS were low enough to allow disease progression. Ultimately, reducing the incidence of BM in these patients will require novel therapeutic approaches that facilitate drug entry through an intact BBB early in their treatment.

Widely metastatic IDH1-mutant glioblastoma with oligodendroglial features and atypical molecular findings: a case report and review of current challenges in molecular diagnostics.

BACKGROUND: Gliomas with 1p/19q-codeletion as well as mutation of isocitrate dehydrogenase (IDH) 1 are typically characterized as oligodendrogliomas with comparatively good response to treatment with radiation and chemotherapy. CASE PRESENTATION: We present the case of a 28-year-old man with an IDH1 and TP53 mutant high grade glioma with abnormalities in chromosomes 1 and 19 suggestive of anaplastic oligodendroglioma that rapidly progressed to widespread metastatic disease. Biopsy of a liver lesion confirmed metastasis of the patient's known brain primary and chemotherapy with temozolomide was initiated. The patient's rapidly growing tumor burden with fulminant liver failure and tumor lysis led to multisystem failure of which the patient died. Further molecular testing illustrated features more consistent with glioblastoma: multiple large chromosomal aberrations including loss of whole chromosome 1 and 2q; gain/amplification of MYCN, MET, and CDK4; loss of CDKN2A/B; and an ATRX mutation. CONCLUSION: This case illustrates the importance of higher level molecular diagnostic testing for patients with particularly aggressive disease progression that is not concordant with standard prognoses. Additional data on cases with atypical alterations of 1p and 19q are needed to better understand the distinct biology of these cancers so that appropriate therapies can be developed.