Subjects -> MEDICAL SCIENCES (Total: 8810 journals)
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INTERNAL MEDICINE (180 journals)                     

Showing 1 - 180 of 180 Journals sorted alphabetically
Abdomen     Open Access  
ACP Hospitalist     Full-text available via subscription   (Followers: 9)
ACP Internist     Full-text available via subscription   (Followers: 10)
ACP Journal Club     Full-text available via subscription   (Followers: 11)
Acta Clinica Belgica     Hybrid Journal   (Followers: 1)
Acute and Critical Care     Open Access   (Followers: 11)
Acute Medicine     Full-text available via subscription   (Followers: 9)
Advances in Hepatology     Open Access   (Followers: 4)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
African Journal of Primary Health Care & Family Medicine     Open Access   (Followers: 6)
African Journal of Thoracic and Critical Care Medicine     Open Access  
American Family Physician     Full-text available via subscription   (Followers: 38)
American Journal of Hypertension     Hybrid Journal   (Followers: 31)
Anales de Medicina Interna     Open Access   (Followers: 1)
Anatomy & Physiology : Current Research     Open Access   (Followers: 9)
Angiology     Hybrid Journal   (Followers: 5)
Annals of Colorectal Research     Open Access   (Followers: 1)
Annals of Internal Medicine     Full-text available via subscription   (Followers: 392)
AORN Journal     Hybrid Journal   (Followers: 27)
Apollo Medicine     Open Access  
Archives of Drug Information     Hybrid Journal   (Followers: 5)
Archivos de Medicina Interna     Open Access   (Followers: 1)
Asia Oceania Journal of Nuclear Medicine & Biology     Open Access   (Followers: 4)
Asian Pacific Journal of Tropical Disease     Full-text available via subscription   (Followers: 3)
Australasian Physical & Engineering Sciences in Medicine     Hybrid Journal   (Followers: 1)
BMI Journal : Bariátrica & Metabólica Iberoamericana     Open Access   (Followers: 1)
BMJ Open Diabetes Research & Care     Open Access   (Followers: 35)
BMJ Quality & Safety     Hybrid Journal   (Followers: 69)
Bone & Joint Journal     Hybrid Journal   (Followers: 138)
Brain Communications     Open Access   (Followers: 4)
Brain Science Advances     Open Access  
Canadian Journal of General Internal Medicine     Open Access   (Followers: 2)
Cardiovascular Medicine in General Practice     Full-text available via subscription   (Followers: 7)
Case Reports in Internal Medicine     Open Access   (Followers: 1)
Cell Death & Disease     Open Access   (Followers: 3)
Cellular and Molecular Gastroenterology and Hepatology     Open Access   (Followers: 3)
Cephalalgia     Hybrid Journal   (Followers: 8)
Cephalalgia Reports     Open Access   (Followers: 4)
Chronic Diseases and Injuries in Canada     Free   (Followers: 1)
Clinical Ethics     Hybrid Journal   (Followers: 13)
Clinical Liver Disease     Open Access   (Followers: 5)
Clinical Nutrition     Hybrid Journal   (Followers: 98)
Clinical Thyroidology     Full-text available via subscription   (Followers: 1)
CNE Pflegemanagement     Hybrid Journal  
Communication Law and Policy     Hybrid Journal   (Followers: 5)
Current Diabetes Reports     Hybrid Journal   (Followers: 30)
Current Hepatology Reports     Hybrid Journal  
Current Research: Integrative Medicine     Open Access  
CVIR Endovascular     Open Access   (Followers: 1)
Der Internist     Hybrid Journal   (Followers: 12)
Diabetes     Full-text available via subscription   (Followers: 603)
Diabetes Care     Full-text available via subscription   (Followers: 578)
Diabetes Internacional     Open Access  
Diabetes Spectrum     Full-text available via subscription   (Followers: 17)
Diagnosis     Hybrid Journal   (Followers: 1)
Egyptian Journal of Bronchology     Open Access  
Egyptian Journal of Internal Medicine     Open Access   (Followers: 1)
Egyptian Journal of Neurosurgery     Open Access  
Egyptian Liver Journal     Open Access   (Followers: 2)
Egyptian Spine Journal     Open Access  
EMC - Aparato Locomotor     Hybrid Journal  
Endovascular Neuroradiology / Ендоваскулярна нейрорентгенохірургія     Open Access   (Followers: 1)
eNeuro     Open Access   (Followers: 3)
Ergonomics     Hybrid Journal   (Followers: 24)
European Journal of Inflammation     Open Access   (Followers: 2)
European Journal of Internal Medicine     Full-text available via subscription   (Followers: 10)
European Journal of Translational Myology     Open Access  
European Radiology Experimental     Open Access   (Followers: 2)
Head and Neck Tumors     Open Access   (Followers: 1)
Health Sociology Review     Hybrid Journal   (Followers: 14)
HemaSphere     Open Access   (Followers: 2)
Hepatology Communications     Open Access  
Hepatoma Research     Open Access   (Followers: 3)
Human Physiology     Hybrid Journal   (Followers: 5)
ImmunoHorizons     Open Access  
Immunological Medicine     Open Access  
Infectious Diseases: Research and Treatment     Open Access   (Followers: 5)
Inflammation and Regeneration     Open Access   (Followers: 2)
Inflammatory Intestinal Diseases     Open Access  
Innere Medizin up2date     Hybrid Journal   (Followers: 1)
Internal and Emergency Medicine     Hybrid Journal   (Followers: 5)
Internal Medicine Journal     Hybrid Journal   (Followers: 9)
International Journal of Abdominal Wall and Hernia Surgery     Open Access   (Followers: 1)
International Journal of Anatomy and Research     Open Access   (Followers: 2)
International Journal of Angiology     Hybrid Journal  
International Journal of Artificial Organs     Hybrid Journal   (Followers: 3)
International Journal of Hyperthermia     Open Access  
International Journal of Internal Medicine     Open Access   (Followers: 3)
International Journal of Noncommunicable Diseases     Open Access  
International Journal of Psychiatry in Clinical Practice     Hybrid Journal   (Followers: 6)
Iranian Journal of Neurosurgery     Open Access   (Followers: 1)
Italian Journal of Anatomy and Embryology     Open Access   (Followers: 1)
JAC-Antimicrobial Resistance     Open Access   (Followers: 4)
JAMA Internal Medicine     Full-text available via subscription   (Followers: 364)
JCSM Clinical Reports     Open Access   (Followers: 3)
JHEP Reports     Open Access  
JIMD Reports     Open Access  
JMV - Journal de Médecine Vasculaire     Hybrid Journal   (Followers: 1)
Joint Commission Journal on Quality and Patient Safety     Hybrid Journal   (Followers: 41)
JOP. Journal of the Pancreas     Open Access   (Followers: 2)
Journal of Basic & Clinical Physiology & Pharmacology     Hybrid Journal   (Followers: 1)
Journal of Bone Oncology     Open Access   (Followers: 1)
Journal of Cancer & Allied Specialties     Open Access  
Journal of Clinical and Experimental Hepatology     Full-text available via subscription   (Followers: 3)
Journal of Clinical Movement Disorders     Open Access   (Followers: 3)
Journal of Community Hospital Internal Medicine Perspectives     Open Access  
Journal of Cutaneous Immunology and Allergy     Open Access  
Journal of Developmental Origins of Health and Disease     Hybrid Journal   (Followers: 2)
Journal of Endoluminal Endourology     Open Access  
Journal of Gastroenterology and Hepatology Research     Open Access   (Followers: 4)
Journal of General Internal Medicine     Hybrid Journal   (Followers: 23)
Journal of Hypertension     Hybrid Journal   (Followers: 14)
Journal of Infectious Diseases     Hybrid Journal   (Followers: 48)
Journal of Interdisciplinary Medicine     Open Access  
Journal of Internal Medicine     Hybrid Journal   (Followers: 11)
Journal of Liver : Disease & Transplantation     Hybrid Journal   (Followers: 7)
Journal of Medical Internet Research     Open Access   (Followers: 24)
Journal of Movement Disorders     Open Access   (Followers: 2)
Journal of Pain and Symptom Management     Hybrid Journal   (Followers: 46)
Journal of Pancreatic Cancer     Open Access  
Journal of Renal and Hepatic Disorders     Open Access  
Journal of Solid Tumors     Open Access   (Followers: 1)
Journal of Sports Medicine and Allied Health Sciences : Official Journal of the Ohio Athletic Trainers Association     Open Access   (Followers: 1)
Journal of the American Board of Family Medicine     Open Access   (Followers: 11)
Journal of the European Mosquito Control Association     Open Access  
Journal of Translational Internal Medicine     Open Access  
Jurnal Vektor Penyakit     Open Access  
La Revue de Medecine Interne     Full-text available via subscription   (Followers: 3)
Lege artis - Das Magazin zur ärztlichen Weiterbildung     Hybrid Journal   (Followers: 1)
Liver Cancer International     Open Access  
Liver Research     Open Access  
Molecular Diagnosis & Therapy     Hybrid Journal   (Followers: 3)
Molecular Therapy - Oncolytics     Open Access  
Multiple Sclerosis and Demyelinating Disorders     Open Access   (Followers: 7)
MYOPAIN. A journal of myofascial pain and fibromyalgia     Hybrid Journal   (Followers: 18)
Neuro-Oncology Advances     Open Access   (Followers: 1)
Neurobiology of Pain     Open Access   (Followers: 2)
Neurointervention     Open Access   (Followers: 6)
Neuromuscular Diseases     Open Access  
Nigerian Journal of Gastroenterology and Hepatology     Full-text available via subscription  
OA Alcohol     Open Access   (Followers: 5)
Oncological Coloproctology     Open Access  
Open Journal of Internal Medicine     Open Access  
Pleura and Peritoneum     Open Access  
Pneumo News     Full-text available via subscription  
Polish Archives of Internal Medicine     Full-text available via subscription   (Followers: 2)
Preventing Chronic Disease     Free   (Followers: 2)
Progress in Transplantation     Hybrid Journal   (Followers: 1)
Prostate International     Open Access   (Followers: 2)
Psychiatry and Clinical Psychopharmacology     Open Access   (Followers: 1)
Pulmonary Therapy     Open Access   (Followers: 2)
Quality of Life Research     Hybrid Journal   (Followers: 20)
Research and Practice in Thrombosis and Haemostasis     Open Access  
Revista Chilena de Fonoaudiología     Open Access   (Followers: 1)
Revista de la Sociedad Peruana de Medicina Interna     Open Access   (Followers: 4)
Revista del Instituto de Medicina Tropical     Open Access  
Revista Hispanoamericana de Hernia     Open Access   (Followers: 1)
Revista Médica Internacional sobre el Síndrome de Down     Full-text available via subscription   (Followers: 1)
Revista Virtual de la Sociedad Paraguaya de Medicina Interna     Open Access   (Followers: 1)
Romanian Journal of Diabetes Nutrition and Metabolic Diseases     Open Access   (Followers: 1)
Romanian Journal of Internal Medicine     Open Access  
Russian Journal of Child Neurology     Open Access   (Followers: 1)
Scandinavian Journal of Primary Health Care     Open Access   (Followers: 8)
Schlaf     Hybrid Journal  
Schmerzmedizin     Hybrid Journal  
Scientific Journal of the Foot & Ankle     Open Access   (Followers: 1)
SciMedicine Journal     Open Access   (Followers: 3)
SEMERGEN - Medicina de Familia     Full-text available via subscription   (Followers: 1)
The Journal of Critical Care Medicine     Open Access   (Followers: 9)
Therapeutic Advances in Chronic Disease     Open Access   (Followers: 8)
Therapeutic Advances in Musculoskeletal Disease     Hybrid Journal   (Followers: 6)
Thieme Case Report     Hybrid Journal   (Followers: 1)
Tijdschrift voor Urologie     Hybrid Journal  
Tissue Barriers     Hybrid Journal   (Followers: 1)
Transactions of the Royal Society of Tropical Medicine and Hygiene     Hybrid Journal   (Followers: 3)
Transgender Health     Open Access   (Followers: 3)
Trends in Anaesthesia and Critical Care     Full-text available via subscription   (Followers: 23)
US Cardiology Review     Open Access  
Vascular and Endovascular Review     Open Access   (Followers: 1)
Ожирение и метаболизм     Open Access  


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Neuro-Oncology Advances
Number of Followers: 1  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2632-2498
Published by Oxford University Press Homepage  [416 journals]
  • Real-world validity of randomized controlled phase III trials in newly
           diagnosed glioblastoma: to whom do the results of the trials apply'

    • Authors: Skaga E; Skretteberg M, Johannesen T, et al.
      Abstract: BackgroundThe survival rates in population-based series of glioblastoma (GBM) differ substantially from those reported in clinical trials. This discrepancy may be attributed to that patients recruited to trials tend to be younger with better performance status. However, the proportion and characteristics of the patients in a population considered either eligible or ineligible for trials is unknown. The generalizability of trial results is therefore also uncertain.MethodsUsing the Cancer Registry of Norway and the Brain Tumor Database at Oslo University Hospital, we tracked all patients within a well-defined geographical area with newly diagnosed GBM during the years 2012–2017. Based on data from these registries and the medical records, the patients were evaluated for trial eligibility according to criteria employed in recent phase III trials for GBM.ResultsWe identified 512 patients. The median survival was 11.7 months. When we selected a potential trial population at the start of concurrent chemoradiotherapy (radiotherapy [RT]/ temozolomide [TMZ]) by the parameters age (18–70 y), passed surgery for a supratentorial GBM, Eastern Cooperative Oncology Group (ECOG) ≤2, normal hematologic, hepatic and renal function, and lack of severe comorbidity, 57% of the patients were excluded. Further filtering the patients who progressed during RT/TMZ and never completed RT/TMZ resulted in exclusion of 59% and 63% of the patients, respectively. The survival of patients potentially eligible for trials was significantly higher than of the patients not fulfilling trial eligibility criteria (P < .0001).ConclusionsPatients considered eligible for phase III clinical trials represent a highly selected minority of patients in a real-world GBM population.
      PubDate: Fri, 26 Feb 2021 00:00:00 GMT
      DOI: 10.1093/noajnl/vdab008
      Issue No: Vol. 3, No. 1 (2021)
  • Thrombospondin-1 mimetics are promising novel therapeutics for
           MYC-associated medulloblastoma

    • Authors: Chan T; Picard D, Hawkins C, et al.
      Abstract: BackgroundMedulloblastoma (MB) comprises four subtypes of which group 3 MB are the most aggressive. Although overall survival for MB has improved, the outcome of group 3 MB remains dismal. C-MYC (MYC) amplification or MYC overexpression which characterizes group 3 MB is a strong negative prognostic factor and is frequently associated with metastases and relapses. We previously reported that MYC expression alone promotes highly aggressive MB phenotypes, in part via repression of thrombospondin-1 (TSP-1), a potent tumor suppressor.MethodsIn this study, we examined the potential role of TSP-1 and TSP-1 peptidomimetic ABT-898 in MYC-amplified human MB cell lines and two distinct murine models of MYC-driven group 3 MBs.ResultsWe found that TSP-1 reconstitution diminished metastases and prolonged survival in orthotopic xenografts and promoted chemo- and radio-sensitivity via AKT signaling. Furthermore, we demonstrate that ABT-898 can recapitulate the effects of TSP-1 expression in MB cells in vitro and specifically induced apoptosis in murine group 3 MB tumor cells.ConclusionOur data underscore the importance of TSP-1 as a critical tumor suppressor in MB and highlight TSP-1 peptidomimetics as promising novel therapeutics for the most lethal subtype of MB.
      PubDate: Thu, 18 Feb 2021 00:00:00 GMT
      DOI: 10.1093/noajnl/vdab002
      Issue No: Vol. 3, No. 1 (2021)
  • Radiogenomic modeling predicts survival-associated prognostic groups in

    • Authors: Nuechterlein N; Li B, Feroze A, et al.
      Abstract: BackgroundCombined whole-exome sequencing (WES) and somatic copy number alteration (SCNA) information can separate isocitrate dehydrogenase (IDH)1/2-wildtype glioblastoma into two prognostic molecular subtypes, which cannot be distinguished by epigenetic or clinical features. The potential for radiographic features to discriminate between these molecular subtypes has yet to be established.MethodsRadiologic features (n = 35 340) were extracted from 46 multisequence, pre-operative magnetic resonance imaging (MRI) scans of IDH1/2-wildtype glioblastoma patients from The Cancer Imaging Archive (TCIA), all of whom have corresponding WES/SCNA data. We developed a novel feature selection method that leverages the structure of extracted MRI features to mitigate the dimensionality challenge posed by the disparity between a large number of features and the limited patients in our cohort. Six traditional machine learning classifiers were trained to distinguish molecular subtypes using our feature selection method, which was compared to least absolute shrinkage and selection operator (LASSO) feature selection, recursive feature elimination, and variance thresholding.ResultsWe were able to classify glioblastomas into two prognostic subgroups with a cross-validated area under the curve score of 0.80 (±0.03) using ridge logistic regression on the 15-dimensional principle component analysis (PCA) embedding of the features selected by our novel feature selection method. An interrogation of the selected features suggested that features describing contours in the T2 signal abnormality region on the T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI sequence may best distinguish these two groups from one another.ConclusionsWe successfully trained a machine learning model that allows for relevant targeted feature extraction from standard MRI to accurately predict molecularly-defined risk-stratifying IDH1/2-wildtype glioblastoma patient groups.
      PubDate: Mon, 15 Feb 2021 00:00:00 GMT
      DOI: 10.1093/noajnl/vdab004
      Issue No: Vol. 3, No. 1 (2021)
  • Extent of radiological response does not reflect survival in primary
           central nervous system lymphoma

    • Authors: van der Meulen M; Postma A, Smits M, et al.
      Abstract: BackgroundIn primary central nervous system lymphoma (PCNSL), small enhancing lesions can persist after treatment. It is unknown whether a difference in response category (complete response [CR], complete response unconfirmed [CRu], or partial response [PR]) reflects survival. We aimed to determine the value of a central radiology review on response assessment and whether the extent of response influenced progression-free and/or overall survival.MethodsAll patients in the HOVON 105/ALLG NHL 24 study with at least a baseline MRI and one MRI made for response evaluation available for central review were included. Tumor measurements were done by 2 independent central reviewers, disagreements were adjudicated by a third reviewer. Crude agreement and interobserver agreement (Cohen's kappa) were calculated. Differences in progression-free and overall survival between different categories of response at the end-of-protocol-treatment were assessed by the log-rank test in a landmark survival-analysis.ResultsAgreement between the central reviewers was 61.7% and between local and central response assessment was 63.0%. Cohen's kappa's, which corrects for expected agreement, were 0.44 and 0.46 (moderate), respectively. Progression agreement or not was 93.3% (kappa 0.87) between local and central response assessment. There were no significant differences in progression-free and overall survival between patients with CR, CRu, or PR at the end-of-protocol-treatment, according to both local and central response assessment.ConclusionsReliability of response assessment (CR/CRu/PR) is moderate even by central radiology review and these response categories do not reliably predict survival. Therefore, primary outcome in PCNSL studies should be survival rather than CR or CR/CRu-rate.
      PubDate: Mon, 15 Feb 2021 00:00:00 GMT
      DOI: 10.1093/noajnl/vdab007
      Issue No: Vol. 3, No. 1 (2021)
  • Phase I dose-escalation, safety, and CNS pharmacokinetic study of
           dexanabinol in patients with brain cancer

    • Authors: Juarez T; Piccioni D, Rose L, et al.
      Abstract: BackgroundDexanabinol is a synthetic analogue of tetrahydrocannabinol identified as a potential anti-cancer therapeutic by e-Therapeutics PLC. Dexanabinol was selected for further investigation based on its preclinical tumoricidal activity. This phase I dose-escalation trial examined the safety, drug penetration into the central nervous system (CNS), preliminary antitumor activity, and recommended phase II dose.MethodsDexanabinol formulated in cremophor/ethanol was administered once weekly via 3-hour intravenous infusion to patients with brain cancer.ResultsA total of 26 patients were dosed once weekly at 2, 4, 8, 16, 24, 28, and 36 mg/kg. Two patients at 36 mg/kg were nonevaluable for dose level confirmation, having withdrawn early for reasons unrelated to study treatment. A recommended phase II dose of dexanabinol was established at 28 mg/kg due to related, reversible adverse events at higher dose levels that required medications for symptomatic relief. The most common drug-related toxicities were the depressed level of consciousness and lightheadedness, diarrhea, itching, fatigue, chest discomfort, and tingling in the mouth. Systemic exposure to dexanabinol (AUC0-t and Cmax) increased from 2 to 36 mg/kg, with dose nonproportionality apparent at the highest dose; dexanabinol was present in appreciable levels in the cerebrospinal fluid (CSF), which implies the possibility of exposure of intracranial tumors to drug. Five of 24 efficacy-evaluable patients (21%) experienced stable disease with a median duration of 2 cycles (28-day cycle) as the best response.ConclusionsDexanabinol administered weekly by intravenous infusion was safe and well-tolerated up to 28 mg/kg in brain cancer patients, but has limited antitumor activity in patients with brain cancer.
      PubDate: Mon, 15 Feb 2021 00:00:00 GMT
      DOI: 10.1093/noajnl/vdab006
      Issue No: Vol. 3, No. 1 (2021)
  • Phase I trial of intranasal NEO100, highly purified perillyl alcohol, in
           adult patients with recurrent glioblastoma

    • Authors: Schönthal A; Peereboom D, Wagle N, et al.
      Abstract: BackgroundBetter treatments for glioblastoma (GBM) patients, in particular in the recurrent setting, are urgently needed. Clinical trials performed in Brazil indicated that intranasal delivery of perillyl alcohol (POH) might be effective in this patient group. NEO100, a highly purified version of POH, was current good manufacturing practice (cGMP) manufactured to evaluate the safety and efficacy of this novel approach in a Phase I/IIa clinical trial in the United States.MethodsA total of 12 patients with recurrent GBM were enrolled into Phase I of this trial. NEO100 was administered by intranasal delivery using a nebulizer and nasal mask. Dosing was 4 times a day, every day. Four cohorts of 3 patients received the following dosages: 96 mg/dose (384 mg/day), 144 mg/dose (576 mg/day), 192 mg/dose (768 mg/day), and 288 mg/dose (1152 mg/day). Completion of 28 days of treatment was recorded as 1 cycle. Adverse events were documented, and radiographic response via Response Assessment in Neuro-Oncology (RANO) criteria was evaluated every 2 months. Progression-free and overall survival were determined after 6 and 12 months, respectively (progression-free survival-6 [PFS-6], overall survival-12 [OS-12]).ResultsIntranasal NEO100 was well tolerated at all dose levels and no severe adverse events were reported. PFS-6 was 33%, OS-12 was 55%, and median OS was 15 months. Four patients (33%), all of them with isocitrate dehydrogenase 1 (IDH1)-mutant tumors, survived >24 months.ConclusionIntranasal glioma therapy with NEO100 was well tolerated. It correlated with improved survival when compared to historical controls, pointing to the possibility that this novel intranasal approach could become useful for the treatment of recurrent GBM.
      PubDate: Fri, 12 Feb 2021 00:00:00 GMT
      DOI: 10.1093/noajnl/vdab005
      Issue No: Vol. 3, No. 1 (2021)
  • A case series of pediatric survivors of anaplastic pleomorphic

    • Authors: Ronsley R; Dunham C, Yip S, et al.
      Abstract: BackgroundAnaplastic pleomorphic xanthoastrocytoma (APXA) is a rare subtype of CNS astrocytoma. They are generally treated as high-grade gliomas; however, uncertainty exists regarding the optimal therapy. Here, we report on 3 pediatric cases of APXA.MethodsOur institutional database was queried for cases of APXA and 3 cases were identified. Surgical samples were processed for methylation profiling and chromosomal microarray analysis. Methylation data were uploaded to the online CNS tumor classifier to determine methylation-based diagnoses to determine copy number variations (CNVs).ResultsTwo patients were male, 1 female, and all were aged 12 years at diagnosis. All underwent a gross total resection (GTR) and were diagnosed with an APXA. Immunohistochemical analysis demonstrated that 2 cases were BRAF V600E positive. Methylation-based tumor classification supported the APXA diagnosis in all cases. CNV analyses revealed homozygous CKDN2A deletions in all and chromosome 9p loss in 2 cases. All patients received radiation therapy (54 Gy in 30 fractions) with concurrent temozolomide. Two patients received maintenance chemotherapy with temozolomide and lomustine for 6 cycles as per the Children’s Oncology Group ACNS0423. The third patient recurred and went on to receive a second GTR and 6 cycles of lomustine, vincristine, and procarbazine. All are alive with no evidence of disease >4 years post-treatment completion (overall survival = 100%, event free survival = 67%).ConclusionsThe natural history and optimal treatment of this rare pediatric tumor are not well understood. This case series supports the use of adjuvant chemoradiotherapy in the treatment of APXA. The genetic landscape may be informative for optimizing treatment and prognosis.
      PubDate: Sat, 30 Jan 2021 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa176
      Issue No: Vol. 3, No. 1 (2021)

    • Abstract: This meeting abstract has been retracted at the request of both the hospital and the authors because the authors did not obtain proper authorization for its publication prior to submission.
      PubDate: Sat, 30 Jan 2021 00:00:00 GMT
      DOI: 10.1093/noajnl/vdab001
      Issue No: Vol. 3, No. 1 (2021)
  • Association of plasma cell-free DNA with survival in patients with IDH
           wild-type glioblastoma

    • Authors: Bagley S; Till J, Abdalla A, et al.
      Abstract: BackgroundWe aimed to determine whether plasma cell-free DNA (cfDNA) concentration is associated with survival in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM).MethodsPre-operative and post-chemoradiotherapy blood samples were prospectively collected from patients with newly diagnosed IDH wild-type GBM. Patients underwent surgical resection or biopsy and received adjuvant radiotherapy with concomitant temozolomide. Cell-free DNA (cfDNA) was isolated from plasma and quantified using SYBR Green-based q polymerase chain reaction (qPCR).ResultsSixty-two patients were enrolled and categorized into high vs. low cfDNA groups relative to the pre-operative median value (25.2 ng/mL, range 5.7–153.0 ng/mL). High pre-operative cfDNA concentration was associated with inferior PFS (median progression-free survival (PFS), 3.4 vs. 7.7 months; log-rank P = .004; hazard ratio [HR], 2.19; 95% CI, 1.26–3.81) and overall survival (OS) (median OS, 8.0 vs. 13.9 months; log-rank P = .01; HR, 2.43; 95% CI, 1.19–4.95). After adjusting for risk factors, including O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, pre-operative cfDNA remained independently associated with PFS (HR, 2.70; 95% CI, 1.50–4.83; P = .001) and OS (HR, 2.65; 95% CI, 1.25–5.59; P = .01). Post-hoc analysis of change in cfDNA post-chemoradiotherapy compared to pre-surgery (n = 24) showed increasing cfDNA concentration was associated with worse PFS (median, 2.7 vs. 6.0 months; log-rank P = .003; HR, 4.92; 95% CI, 1.53–15.84) and OS (median, 3.9 vs. 19.4 months; log-rank P < .001; HR, 7.77; 95% CI, 2.17–27.76).ConclusionscfDNA concentration is a promising prognostic biomarker for patients with IDH wild-type GBM. Plasma cfDNA can be obtained noninvasively and may enable more accurate estimates of survival and effective clinical trial stratification.
      PubDate: Sat, 16 Jan 2021 00:00:00 GMT
      DOI: 10.1093/noajnl/vdab011
      Issue No: Vol. 3, No. 1 (2021)
  • Clinical, molecular, metabolic, and immune features associated with
           oxidative phosphorylation in melanoma brain metastases

    • Authors: Fischer G; Guerrieri R, Hu Q, et al.
      Abstract: BackgroundRecently, we showed that melanoma brain metastases (MBMs) are characterized by increased utilization of the oxidative phosphorylation (OXPHOS) metabolic pathway compared to melanoma extracranial metastases (ECMs). MBM growth was inhibited by a potent direct OXPHOS inhibitor, but observed toxicities support the need to identify alternative therapeutic strategies. Thus, we explored the features associated with OXPHOS to improve our understanding of the pathogenesis and potential therapeutic vulnerabilities of MBMs.MethodsWe applied an OXPHOS gene signature to our cohort of surgically resected MBMs that had undergone RNA-sequencing (RNA-seq) (n = 88). Clustering by curated gene sets identified MBMs with significant enrichment (High-OXPHOS; n = 21) and depletion (Low-OXPHOS; n = 25) of OXPHOS genes. Clinical data, RNA-seq analysis, and immunohistochemistry were utilized to identify significant clinical, molecular, metabolic, and immune associations with OXPHOS in MBMs. Preclinical models were used to further compare melanomas with High- and Low-OXPHOS and for functional validation.ResultsHigh-OXPHOS MBMs were associated with shorter survival from craniotomy compared to Low-OXPHOS MBMs. High-OXPHOS MBMs exhibited an increase in glutamine metabolism, and treatment with the glutaminase inhibitor CB839 improved survival in mice with MAPKi-resistant, High-OXPHOS intracranial xenografts. High-OXPHOS MBMs also exhibited a transcriptional signature of deficient immune activation, which was reversed in B16-F10 intracranial tumors with metformin treatment, an OXPHOS inhibitor.ConclusionsOXPHOS is associated with distinct clinical, molecular, metabolic, and immune phenotypes in MBMs. These associations suggest rational therapeutic strategies for further testing to improve outcomes in MBM patients.
      PubDate: Wed, 06 Jan 2021 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa177
      Issue No: Vol. 3, No. 1 (2021)
  • Inefficiencies in phase II to phase III transition impeding successful
           drug development in glioblastoma

    • Authors: Balasubramanian A; Gunjur A, Hafeez U, et al.
      Abstract: BackgroundImproving outcomes of patients with glioblastoma (GBM) represents a significant challenge in neuro-oncology. We undertook a systematic review of key parameters of phase II and III trials in GBM to identify and quantify the impact of trial design on this phenomenon.MethodsStudies between 2005 and 2019 inclusive were identified though MEDLINE search and manual bibliography searches. Phase II studies (P2T) were restricted to those referenced by the corresponding phase III trials (P3T). Clinical and statistical characteristics were extracted. For each P3T, corresponding P2T data was “optimally matched,” where same drug was used in similar schedule and similar population; “suboptimally matched” if dis-similar schedule and/or treatment setting; or “lacking.” Phase II/III transition data were compared by Pearson Correlation, Fisher’s exact or chi-square testing.ResultsOf 20 P3Ts identified, 6 (30%) lacked phase II data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T, and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). The 13 “optimally matched” dyads showed strong concordance for mPFS (r2 = 0.95, P < .01) and mOS (r2 = 0.84, P < .01), while 7 “suboptimally matched” dyads did not (P > .05). Overall, 7 P3Ts underwent an ideal transition from P2T to P3T. “Newly diagnosed” P2Ts with mPFS < 14 months and/or mOS< 22 months had subsequent negative P3Ts. “Recurrent” P2Ts with mPFS < 6 months and mOS< 12 months also had negative P3Ts.ConclusionOur findings highlight the critical role of optimally designed phase II trials in informing drug development for GBM.
      PubDate: Tue, 22 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa171
      Issue No: Vol. 3, No. 1 (2020)
  • Incidence and real-world burden of brain metastases from solid tumors and
           hematologic malignancies in Ontario: a population-based study

    • Authors: Habbous S; Forster K, Darling G, et al.
      Abstract: BackgroundAlthough intracranial metastatic disease (IMD) is a frequent complication of cancer, most cancer registries do not capture these cases. Consequently, a data-gap exists, which thwarts system-level quality improvement efforts. The purpose of this investigation was to determine the real-world burden of IMD.MethodsPatients diagnosed with a non-CNS cancer between 2010 and 2018 were identified from the Ontario Cancer Registry. IMD was identified by scanning hospital administrative databases for cranial irradiation or coding for a secondary brain malignancy (ICD-10 code C793).Results25,478 of 601,678 (4.2%) patients with a diagnosis of primary cancer were found to have IMD. The median time from primary cancer diagnosis to IMD was 5.2 (0.7, 15.4) months and varied across disease sites, for example, 2.1 months for lung, 7.3 months for kidney, and 22.8 months for breast. Median survival following diagnosis with IMD was 3.7 months. Lung cancer accounted for 60% of all brain metastases, followed by breast cancer (11%) and melanoma (6%). More advanced stage at diagnosis and younger age were associated with a higher likelihood of developing IMD (P < .0001). IMD was also associated with triple-negative breast cancers and ductal histology (P < .001), and with small-cell histology in patients with lung cancer (P < .0001). The annual incidence of IMD was 3,520, translating to 24.2 per 100,000 persons.ConclusionIMD represents a significant burden in patients with systemic cancers and is a significant cause of cancer mortality. Our findings support measures to actively capture incidents of brain metastasis in cancer registries.
      PubDate: Tue, 22 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa178
      Issue No: Vol. 3, No. 1 (2020)
  • Outcome and molecular analysis of young children with choroid plexus
           carcinoma treated with non-myeloablative therapy: results from the SJYC07

    • Authors: Liu A; Wu G, Orr B, et al.
      Abstract: BackgroundChoroid plexus carcinoma (CPC) is a rare and aggressive tumor of infancy without a clear treatment strategy. This study describes the outcomes of children with CPC treated on the multi-institutional phase 2 SJYC07 trial and reports on the significance of clinical and molecular characteristics.MethodsEligible children <3 years-old with CPC were postoperatively stratified to intermediate-risk (IR) stratum if disease was localized or high-risk (HR) stratum, if metastatic. All received high-dose methotrexate–containing induction chemotherapy. IR-stratum patients received focal irradiation as consolidation whereas HR-stratum patients received additional chemotherapy. Consolidation was followed by oral antiangiogenic maintenance regimen. Survival rates and potential prognostic factors were analyzed.ResultsThirteen patients (median age: 1.41 years, range: 0.21–2.93) were enrolled; 5 IR, 8 HR. Gross-total resection or near-total resection was achieved in ten patients and subtotal resection in 3. Seven patients had TP53-mutant tumors, including 4 who were germline carriers. Five patients experienced progression and died of disease; 8 (including 5 HR) are alive without progression. The 5-year progression-free survival (PFS) and overall survival rates were 61.5 ± 13.5% and 68.4 ± 13.1%. Patients with TP53-wild-type tumors had a 5-year PFS of 100% as compared to 28.6 ± 17.1% for TP53-mutant tumors (P = .012). Extent of resection, metastatic status, and use of radiation therapy were not significantly associated with survival.ConclusionsNon-myeloablative high-dose methotrexate–containing therapy with maximal surgical resection resulted in long-term PFS in more than half of patients with CPC. TP53-mutational status was the only significant prognostic variable and should form the basis of risk-stratification in future trials.
      PubDate: Tue, 15 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa168
      Issue No: Vol. 3, No. 1 (2020)
  • Lin28A/let-7 oncogenic circuit is a potential therapeutic target in
           neurocutaneous melanosis-associated CNS tumors in children

    • Authors: Jain M; Tran S, Thakur S, et al.
      Abstract: CNS cancerLin28Alet-7malignant melanomaneurocutaneous melanosis
      PubDate: Wed, 09 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa174
      Issue No: Vol. 3, No. 1 (2020)
  • The mutational landscape of spinal chordomas and their sensitive detection
           using circulating tumor DNA

    • Authors: Mattox A; Yang B, Douville C, et al.
      Abstract: Background Chordomas are the most common primary spinal column malignancy in the United States. The aim of this study was to determine whether chordomas may be detected by evaluating mutations in circulating tumor DNA (ctDNA).Methods Thirty-two patients with a biopsy-confirmed diagnosis of chordoma had blood drawn pre-operatively and/or at follow-up appointments. Mutations in the primary tumor were identified by whole exome sequencing and liquid biopsy by ddPCR and/or RACE-Seq was used to detect one or more of these mutations in plasma ctDNA at concurrent or later time points.Results At the time of initial blood draw, 87.1% of patients were ctDNA positive (P <.001). Follow-up blood draws in twenty of the patients suggest that ctDNA levels may reflect the clinical status of the disease. Patients with positive ctDNA levels were more likely to have greater mutant allele frequencies in their primary tumors (P = .004) and undergo radiotherapy (P = .02), and the presence of ctDNA may correlate with response to systemic chemotherapy and/or disease recurrence.Conclusions Detection of ctDNA mutations may allow for the detection and monitoring of disease progression for chordomas.
      PubDate: Tue, 08 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa173
      Issue No: Vol. 3, No. 1 (2020)
  • An updated histology recode for the analysis of primary malignant and
           nonmalignant brain and other central nervous system tumors in the
           Surveillance, Epidemiology, and End Results Program

    • Authors: Forjaz G; Barnholtz-Sloan J, Kruchko C, et al.
      Abstract: BackgroundThere are over 100 histologically distinct types of primary malignant and nonmalignant brain and other central nervous system (CNS) tumors. Our study presents recent trends in the incidence of these tumors using an updated histology recode that incorporates major diagnostic categories listed in the 2016 World Health Organization Classification of Tumours of the CNS.MethodsWe used data from the SEER-21 registries for patients of all ages diagnosed in 2000–2017. We calculated age-adjusted incidence rates and fitted a joinpoint regression to the observed data to estimate the Annual Percent Change and 95% confidence intervals over the period 2000–2017.ResultsThere were 315,184 new malignant (34.2%; 107,890) and nonmalignant (65.8%; 207,294) brain tumor cases during 2004–2017. Nonmalignant meningioma represented 46.5% (146,498) of all brain tumors (malignant and nonmalignant), while glioblastoma represented 50.8% (54,832) of all malignant tumors. Temporal trends were stable or declining except for nonmalignant meningioma (0.7% per year during 2004–2017). Several subtypes presented decreases in trends in the most recent period (2013–2017): diffuse/anaplastic astrocytoma (−1.3% per year, oligodendroglioma (−2.6%), pilocytic astrocytoma (−3.8%), and malignant meningioma (−5.9%).ConclusionsDeclining trends observed in our study may be attributable to recent changes in diagnostic classification and the coding practices stemming from those changes. The recode used in this study enables histology reporting to reflect the changes. It also provides a first step toward the reporting of malignant and nonmalignant brain and other CNS tumors in the Surveillance, Epidemiology, and End Results (SEER) Program by clinically relevant histology groupings.
      PubDate: Tue, 08 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa175
      Issue No: Vol. 3, No. 1 (2020)
  • The brain tumor not-for-profit and charity experience of COVID-19:
           reacting and adjusting to an unprecedented global pandemic in the 21st

    • Authors: Amidei C; Arzbaecher J, Maher M, et al.
      Abstract: BackgroundThe Coronavirus Disease 2019 (COVID-19) pandemic has affected individuals as well as disease-specific brain tumor organizations. These organizations around the world exist to address unmet needs for patients and caregivers they serve. The direct impact of the pandemic on these organizations constitutes significant collateral damage. In order to better understand the effects of the COVID-19 pandemic on brain tumor organizations, the International Brain Tumour Alliance (IBTA) carried out an international survey to identify organizational changes induced by the virus and approaches adopted to address challenges.MethodsA 37-question online survey consisting of categorical and qualitative questions was developed and circulated to 130 brain tumor organizations across the world. Seventy-seven organizations from 22 countries completed the survey (59% return rate). Descriptive statistics and content analysis were used to present the results.ResultsResponses fell into the following 3 categories: (1) organizational characteristics, (2) impact of COVID-19 on services, and (3) COVID-19 impact on financial and human resources within organizations. Although organizational characteristics varied, common concerns reported were activity disruption which impacted organizations’ abilities to offer usual services and challenges to sustaining funding. Both financial and human resources were stressed, but integral adaptations were made by organizations to preserve resources during the pandemic.ConclusionsAlthough brain tumor organizations have been impacted by the COVID-19 pandemic, organizations quickly adjusted to this unprecedented global healthcare crisis. Nimble reactions and flexibility have been vital to organization sustainability. Innovative approaches are required to ensure organizations remain viable so that needs of brain tumor community at large are met.
      PubDate: Mon, 07 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa166
      Issue No: Vol. 3, No. 1 (2020)
  • The long-term caregiver burden in World Health Organization grade I and II
           meningioma: It is not just the patient

    • Authors: Zamanipoor Najafabadi A; van der Meer P, Boele F, et al.
      Abstract: BackgroundLittle is known about long-term caregiver burden in meningioma patients. We assessed meningioma caregiver burden, its association with informal caregiver’s well-being and possible determinants.MethodsIn this multicenter cross-sectional study, informal caregivers completed the Caregiver Burden Scale (five domains and total score). Patients completed a disease-specific health-related quality of life (HRQoL) questionnaire focusing on symptoms (EORTC QLQ-BN20) and underwent neurocognitive assessment. Both groups completed a generic HRQoL questionnaire (SF-36) and the Hospital Anxiety, and Depression Scale. We assessed the association between caregiver burden and their HRQoL, anxiety and depression. Furthermore, we assessed determinants for the caregiver burden. Multivariable regression analysis was used to correct for confounders.ResultsOne hundred and twenty-nine informal caregivers were included (median 10 years after patients’ treatment). Caregivers reported burden in ≥1 domain (34%) or total burden score (15%). A one-point increase in total caregiver burden score was associated with a clinically relevant decrease in caregiver’s HRQoL (SF-36) in 5/8 domains (score range: −10.4 to −14.7) and 2/2 component scores (−3.5 to −5.9), and with more anxiety (3.8) and depression (3.0). Patients’ lower HRQoL, increased symptom burden, and increased anxiety and depression were determinants for higher caregiver burden, but not patients’ or caregivers’ sociodemographic characteristics, patients’ neurocognitive functioning, or tumor- and treatment-related characteristics.ConclusionsTen years after initial treatment, up to 35% of informal caregivers reported a clinically relevant burden, which was linked with worse HRQoL, and more anxiety and depression in both patients and caregivers, emphasizing the strong interdependent relationship. Support for meningioma caregivers is therefore warranted.
      PubDate: Sat, 05 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa169
      Issue No: Vol. 3, No. 1 (2020)
  • Fast routine assessment of MGMT promoter methylation

    • Authors: Hench I; Monica R, Chiariotti L, et al.
      Abstract: Despite recent advances in targeted diffuse glioma therapy, temozolomide still remains a therapeutic mainstay that rests on MGMT promoter methylation state as key predictor. Despite its importance in clinical decision making, MGMT testing has neither been standardized nor is it rapidly available. We, therefore, implemented an integrative diagnostic pipeline, comprising a methylation-specific PCR (MSP) complemented by a STP-27-based MGMT promoter assessment1 within methylation array analysis. Here, we report on the diagnostic precision of this approach that provides both a rapid neuro-oncology tumor board decision tool and a safe fallback method at affordable cost.
      PubDate: Sat, 05 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa170
      Issue No: Vol. 3, No. 1 (2020)
  • A brain-penetrant microtubule-targeting agent that disrupts hallmarks of
           glioma tumorigenesis

    • Authors: Horne E; Diaz P, Cimino P, et al.
      Abstract: BackgroundGlioma is sensitive to microtubule-targeting agents (MTAs), but most MTAs do not cross the blood brain barrier (BBB). To address this limitation, we developed the new chemical entity, ST-401, a brain-penetrant MTA.MethodsSynthesis of ST-401. Measures of MT assembly and dynamics. Cell proliferation and viability of patient-derived (PD) glioma in culture. Measure of tumor microtube (TM) parameters using immunofluorescence analysis and machine learning-based workflow. Pharmacokinetics (PK) and experimental toxicity in mice. In vivo antitumor activity in the RCAS/tv-a PDGFB-driven glioma (PDGFB-glioma) mouse model.ResultsWe discovered that ST-401 disrupts microtubule (MT) function through gentle and reverisible reduction in MT assembly that triggers mitotic delay and cell death in interphase. ST-401 inhibits the formation of TMs, MT-rich structures that connect glioma to a network that promotes resistance to DNA damage. PK analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft flank tumor mouse model demonstrates significant antitumor activity and no over toxicity in mice. In the PDGFB-glioma mouse model, ST-401 enhances the therapeutic efficacies of temozolomide (TMZ) and radiation therapy (RT).ConclusionOur study identifies hallmarks of glioma tumorigenesis that are sensitive to MTAs and reports ST-401 as a promising chemical scaffold to develop brain-penetrant MTAs.
      PubDate: Thu, 03 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa165
      Issue No: Vol. 3, No. 1 (2020)
  • The impact of hospital safety-net status on inpatient outcomes for brain
           tumor craniotomy: a 10-year nationwide analysis

    • Authors: Tang O; Rivera Perla K, Lim R, et al.
      Abstract: BackgroundOutcome disparities have been documented at safety-net hospitals (SNHs), which disproportionately serve vulnerable patient populations. Using a nationwide retrospective cohort, we assessed inpatient outcomes following brain tumor craniotomy at SNHs in the United States.MethodsWe identified all craniotomy procedures in the National Inpatient Sample from 2002–2011 for brain tumors: glioma, metastasis, meningioma, and vestibular schwannoma. Safety-net burden was calculated as the number of Medicaid plus uninsured admissions divided by total admissions. Hospitals in the top quartile of burden were defined as SNHs. The association between SNH status and in-hospital mortality, discharge disposition, complications, hospital-acquired conditions (HACs), length of stay (LOS), and costs were assessed. Multivariate regression adjusted for patient, hospital, and severity characteristics.Results304,719 admissions were analyzed. The most common subtype was glioma (43.8%). Of 1,206 unique hospitals, 242 were SNHs. SNH admissions were more likely to be non-white (P < .001), low income (P < .001), and have higher severity scores (P = .034). Mortality rates were higher at SNHs for metastasis admissions (odds ratio [OR] = 1.48, P = .025), and SNHs had higher complication rates for meningioma (OR = 1.34, P = .003) and all tumor types combined (OR = 1.17, P = .034). However, there were no differences at SNHs for discharge disposition or HACs. LOS and hospital costs were elevated at SNHs for all subtypes, culminating in a 10% and 9% increase in LOS and costs for the overall population, respectively (all P < .001).ConclusionsSNHs demonstrated poorer inpatient outcomes for brain tumor craniotomy. Further analyses of the differences observed and potential interventions to ameliorate interhospital disparities are warranted.
      PubDate: Tue, 01 Dec 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa167
      Issue No: Vol. 3, No. 1 (2020)
  • Lack of survival advantage among re-resected elderly glioblastoma
           patients: a SEER-Medicare study

    • Authors: Goldman D; Reiner A, Diamond E, et al.
      Abstract: BackgroundThe survival benefit of re-resection for glioblastoma (GBM) remains controversial, owing to the immortal time bias inadequately considered in many studies where re-resection was treated as a fixed, rather than a time-dependent factor. Using the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we assessed treatment patterns for older adults and evaluated the association between re-resection and overall survival (OS), accounting for the timing of re-resection.MethodsThis retrospective cohort study included elderly patients (age ≥66) in the SEER-Medicare linked database diagnosed with GBM between 2006 and 2015 who underwent initial resection. Time-dependent Cox regression was used to assess the association between re-resection and OS, controlling for age, gender, race, poverty level, geographic region, marital status, comorbidities, receipt of radiation + temozolomide, and surgical complications.ResultsOur analysis included 3604 patients with median age 74 (range: 66–96); 54% were men and 94% were white. After initial resection, 44% received radiation + temozolomide and these patients had a lower hazard of death (hazard ratio [HR]: 0.28, 95% confidence interval [CI]: 0.26–0.31, P < .001). In total, 9.5% (n = 343) underwent re-resection. In multivariable analyses, no survival benefit was seen for patients who underwent re-resection (HR: 1.12, 95% CI: 0.99–1.27, P = .07).ConclusionsRe-resection rates were low among elderly GBM patients, and no survival advantage was observed for patients who underwent re-resection. However, patients who received standard of care at initial diagnosis had a lower risk of death. Older adults benefit from receiving radiation + temozolomide after initial resection, and future studies should assess the relationship between re-resection and OS taking the time of re-resection into account.
      PubDate: Sun, 29 Nov 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa159
      Issue No: Vol. 3, No. 1 (2020)
  • Glycolytic expression in lower-grade glioma reveals an epigenetic
           association between IDH mutation status and PDL1/2 expression

    • Authors: Givechian K; Garner C, Benz S, et al.
      Abstract: BackgroundThe interplay between glycolysis and immunosuppression in cancer has recently emerged as an intriguing area of research. The aim of this study was to elucidate a potential epigenetic link between glycolysis, isocitrate hydrogenase (IDH) status, and immune checkpoint expression in human lower-grade glioma (LGG).MethodsGenomic analysis was conducted on 507 LGG samples from The Cancer Genome Atlas (TCGA). Data types analyzed included RNA-seq (IlluminaHiSeq) and DNA methylation (Methylation450K). Unsupervised clustering grouped samples according to glycolytic expression level and IDH status. Global promoter methylation patterns were examined, as well as methylation levels of LDHA/LDHB and immune checkpoint genes. Methylation data from a knock-in IDH1R132H/WT allele in HCT116 cells and ChIP-seq data from immortalized human astrocytes using an inducible IDH1R132H mutation were also assessed.ResultsGlycolytic expression distinguished a tumor cluster enriched for wild-type IDH and poorer overall survival (P < .0001). This cluster showed lower levels of LDHA promoter methylation and a higher LDHA/LDHB expression ratio. These samples also displayed lower PDL1/2 promoter methylation and higher PDL1/2 expression, which was more pronounced for PDL2. IDH1R132H/WT cell line data showed that induced changes in methylation were enriched for genes involved in immune regulation, and ChIP-seq data showed that promoter H3K4me3 decreased for LDHA, PDL2, and PDL1 upon induction of IDH1R132H.ConclusionsThese results suggest a previously unrecognized epigenetic link between glycolysis and immune checkpoint expression in LGG. This work advances our understanding of glioma genomics and provides support for further exploration of the metabolic-immune interface in LGG.
      PubDate: Fri, 27 Nov 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa162
      Issue No: Vol. 3, No. 1 (2020)
  • Clinical correlates for immune checkpoint therapy: significance for CNS

    • Authors: Ratnam N; Frederico S, Gonzalez J, et al.
      Abstract: Immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer immunotherapy. Most commonly, inhibitors of PD-1 and CTLA4 are used having received approval for the treatment of many cancers like melanoma, non-small-cell lung carcinoma, and leukemia. In contrast, to date, clinical studies conducted in patients with CNS malignancies have not demonstrated promising results. However, patients with CNS malignancies have several underlying factors such as treatment with supportive medications like corticosteroids and cancer therapies including radiation and chemotherapy that may negatively impact response to ICIs. Although many clinical trials have been conducted with ICIs, measures that reproducibly and reliably indicate that treatment has evoked an effective immune response have not been fully developed. In this article, we will review the history of ICI therapy and the correlative biology that has been performed in the clinical trials testing these therapies in different cancers. It is our aim to help provide an overview of the assays that may be used to gauge immunologic response. This may be particularly germane for CNS tumors, where there is currently a great need for predictive biomarkers that will allow for the selection of patients with the highest likelihood of responding.
      PubDate: Fri, 27 Nov 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa161
      Issue No: Vol. 3, No. 1 (2020)
  • Bone metastases in an adult patient with diffuse midline glioma: a case

    • Authors: Li S; Lai M, Zhen J, et al.
      Abstract: adultbone metastasisdiffuse midline glioma
      PubDate: Wed, 18 Nov 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa156
      Issue No: Vol. 3, No. 1 (2020)
  • Preoperative and early postoperative seizures in patients with
           glioblastoma—two sides of the same coin'

    • Authors: Ahmadipour Y; Rauschenbach L, Santos A, et al.
      Abstract: BackgroundSymptomatic epilepsy is a common symptom of glioblastoma, which may occur in different stages of disease. There are discrepant reports on association between early seizures and glioblastoma survival, even less is known about the background of these seizures. We aimed at analyzing the risk factors and clinical impact of perioperative seizures in glioblastoma.MethodsAll consecutive cases with de-novo glioblastoma treated at our institution between 01/2006 and 12/2018 were eligible for this study. Perioperative seizures were stratified into seizures at onset (SAO) and early postoperative seizures (EPS, ≤21days after surgery). Associations between patients characteristics and overall survival (OS) with SAO and EPS were addressed.ResultsIn the final cohort (n = 867), SAO and EPS occurred in 236 (27.2%) and 67 (7.7%) patients, respectively. SAO were independently predicted by younger age (P = .009), higher KPS score (P = .002), tumor location (parietal lobe, P = .001), GFAP expression (≥35%, P = .045), and serum chloride at admission (>102 mmol/L, P = .004). In turn, EPS were independently associated with tumor location (frontal or temporal lobe, P = .013) and pathologic laboratory values at admission (hemoglobin < 12 g/dL, [P = .044], CRP > 1.0 mg/dL [P = 0.036], and GGT > 55 U/L [P = 0.025]). Finally, SAO were associated with gross-total resection (P = .006) and longer OS (P = .030), whereas EPS were related to incomplete resection (P = .005) and poorer OS (P = .009).ConclusionsIn glioblastoma patients, SAO and EPS seem to have quite different triggers and contrary impact on treatment success and OS. The clinical characteristics of SAO and EPS patients might contribute to the observed survival differences.
      PubDate: Wed, 18 Nov 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa158
      Issue No: Vol. 3, No. 1 (2020)
  • New developments in neurofibromatosis type 2 and vestibular schwannoma

    • Authors: Ren Y; Chari D, Vasilijic S, et al.
      Abstract: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder characterized by the development of multiple nervous system tumors due to mutation in the NF2 tumor suppressor gene. The hallmark feature of the NF2 syndrome is the development of bilateral vestibular schwannomas (VS). Although there is nearly 100% penetrance by 60 years of age, some patients suffer from a severe form of the disease and develop multiple tumors at an early age, while others are asymptomatic until later in life. Management options for VS include surgery, stereotactic radiation, and observation with serial imaging; however, currently, there are no FDA-approved pharmacotherapies for NF2 or VS. Recent advancements in the molecular biology underlying NF2 have led to a better understanding of the etiology and pathogenesis of VS. These novel signaling pathways may be used to identify targeted therapies for these tumors. This review discusses the clinical features and treatment options for sporadic- and NF2-associated VS, the diagnostic and screening criteria, completed and ongoing clinical trials, quality of life metrics, and opportunities for future research.
      PubDate: Mon, 16 Nov 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa153
      Issue No: Vol. 3, No. 1 (2020)
  • An integrated disease-specific graded prognostic assessment scale for
           melanoma: contributions of KPS, CITV, number of metastases, and BRAF
           mutation status

    • Authors: Ahluwalia M; Ali M, Joshi R, et al.
      Abstract: BackgroundStereotactic radiosurgery (SRS) remains a mainstay therapy in the treatment of melanoma brain metastases (BM). While prognostic scales have been developed for melanoma patients who underwent SRS treatment for BM, the pertinence of these scales in the context of molecularly targeted therapies remains unclear.MethodsThrough a multi-institutional collaboration, we collated the survival patterns of 331 melanoma BM patients with known BRAF mutation status treated with SRS. We established a prognostic scale that was validated in an independent cohort of 174 patients. All patients with BRAF mutations in this series were treated with BRAF inhibitors. Prognostic utility was assessed using Net Reclassification Index (NRI > 0) and integrated discrimination improvement (IDI) metrics.ResultsIn a multivariate Cox proportional hazards model, BRAF mutation status, KPS, number of metastases, and cumulative intracranial tumor volume (CITV) independently contributed to survival prognostication for melanoma patients with SRS-treated BM (P < .05 for all variables). These variables were incorporated into a prognostic scale using the disease-specific graded prognostic assessment (ds-GPA) framework. This integrated melanoma ds-GPA scale was validated in 2 independent cohorts collated through a multi-institutional collaboration. In terms of order of prognostic importance, BRAF mutation status exerted the greatest influence on survival, while KPS, the number of metastases, and CITV exhibited comparable, lesser impacts.ConclusionsOptimal survival prognostication for SRS-treated patients with melanoma BM requires an integrated assessment of patient characteristics (KPS), tumor characteristics (CITV and number of metastases), and the mutational profile of the melanoma (BRAF mutation status).
      PubDate: Thu, 12 Nov 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa152
      Issue No: Vol. 3, No. 1 (2020)
  • Mebendazole and temozolomide in patients with newly diagnosed high-grade
           gliomas: results of a phase 1 clinical trial

    • Authors: Gallia G; Holdhoff M, Brem H, et al.
      Abstract: BackgroundMebendazole is an anthelmintic drug introduced for human use in 1971 that extends survival in preclinical models of glioblastoma and other brain cancers.MethodsA single-center dose-escalation and safety study of mebendazole in 24 patients with newly diagnosed high-grade gliomas in combination with temozolomide was conducted. Patients received mebendazole in combination with adjuvant temozolomide after completing concurrent radiation plus temozolomide. Dose-escalation levels were 25, 50, 100, and 200 mg/kg/day of oral mebendazole. A total of 15 patients were enrolled at the highest dose studied of 200 mg/kg/day. Trough plasma levels of mebendazole were measured at 4, 8, and 16 weeks.ResultsTwenty-four patients (18 glioblastoma and 6 anaplastic glioma) were enrolled with a median age of 49.8 years. Four patients (at 200 mg/kg) developed elevated grade 3 alanine aminotransferase (ALT) and/or aspartate transaminase (AST) after 1 month, which reversed with lower dosing or discontinuation. Plasma levels of mebendazole were variable but generally increased with dose. Kaplan–Meier analysis showed a 21-month median overall survival with 41.7% of patients alive at 2 years and 25% at 3 and 4 years. Median progression-free survival (PFS) from the date of diagnosis for 17 patients taking more than 1 month of mebendazole was 13.1 months (95% confidence interval [CI]: 8.8–14.6 months) but for 7 patients who received less than 1 month of mebendazole PFS was 9.2 months (95% CI: 5.8–13.0 months).ConclusionMebendazole at doses up to 200 mg/kg demonstrated long-term safety and acceptable toxicity. Further studies are needed to determine mebendazole’s efficacy in patients with malignant glioma.
      PubDate: Thu, 12 Nov 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa154
      Issue No: Vol. 3, No. 1 (2020)
  • A validated integrated clinical and molecular glioblastoma long-term
           survival-predictive nomogram

    • Authors: Ferguson S; Hodges T, Majd N, et al.
      Abstract: BackgroundGlioblastoma (GBM) is the most common primary malignant brain tumor in adulthood. Despite multimodality treatments, including maximal safe resection followed by irradiation and chemotherapy, the median overall survival times range from 14 to 16 months. However, a small subset of GBM patients live beyond 5 years and are thus considered long-term survivors.MethodsA retrospective analysis of the clinical, radiographic, and molecular features of patients with newly diagnosed primary GBM who underwent treatment at The University of Texas MD Anderson Cancer Center was conducted. Eighty patients had sufficient quantity and quality of tissue available for next-generation sequencing and immunohistochemical analysis. Factors associated with survival time were identified using proportional odds ordinal regression. We constructed a survival-predictive nomogram using a forward stepwise model that we subsequently validated using The Cancer Genome Atlas.ResultsUnivariate analysis revealed 3 pivotal genetic alterations associated with GBM survival: both high tumor mutational burden (P = .0055) and PTEN mutations (P = .0235) negatively impacted survival, whereas IDH1 mutations positively impacted survival (P < .0001). Clinical factors significantly associated with GBM survival included age (P < .0001), preoperative Karnofsky Performance Scale score (P = .0001), sex (P = .0164), and clinical trial participation (P < .0001). Higher preoperative T1-enhancing volume (P = .0497) was associated with shorter survival. The ratio of TI-enhancing to nonenhancing disease (T1/T2 ratio) also significantly impacted survival (P = .0022).ConclusionsOur newly devised long-term survival-predictive nomogram based on clinical and genomic data can be used to advise patients regarding their potential outcomes and account for confounding factors in nonrandomized clinical trials.
      PubDate: Sat, 31 Oct 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa146
      Issue No: Vol. 3, No. 1 (2020)
  • Glucose transporter Glut1 controls diffuse invasion phenotype with
           perineuronal satellitosis in diffuse glioma microenvironment

    • Authors: Miyai M; Kanayama T, Hyodo F, et al.
      Abstract: BackgroundGliomas typically escape surgical resection and recur due to their “diffuse invasion” phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the “diffuse invasion” phenotype, designated the Scherer’s secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown.MethodsWe established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients.ResultsIncreased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients.ConclusionsTargeting the transporter Glut1 suppresses the unique phenotype, “diffuse invasion” in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.
      PubDate: Fri, 30 Oct 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa150
      Issue No: Vol. 3, No. 1 (2020)
  • Adult precision medicine: learning from the past to enhance the future

    • Authors: Ghiaseddin A; Hoang Minh L, Janiszewska M, et al.
      Abstract: Despite therapeutic advances for other malignancies, gliomas remain challenging solid tumors to treat. Complete surgical resection is nearly impossible due to gliomas’ diffuse infiltrative nature, and treatment is hampered by restricted access to the tumors due to limited transport across the blood–brain barrier. Recent advances in genomic studies and next-generation sequencing techniques have led to a better understanding of gliomas and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in the management of gliomas, with encouraging results in preclinical studies and early clinical trials. However, molecular characterization of gliomas revealed significant heterogeneity, which poses a challenge for targeted therapeutic approaches. In this context, leading neuro-oncology researchers and clinicians, industry innovators, and patient advocates convened at the inaugural annual Remission Summit held in Orlando, FL in February 2019 to discuss the latest advances in immunotherapy and precision medicine approaches for the treatment of adult and pediatric brain tumors and outline the unanswered questions, challenges, and opportunities that lay ahead for advancing the duration and quality of life for patients with brain tumors. Here, we provide historical context for precision medicine in other cancers, present emerging approaches for gliomas, discuss their limitations, and outline the steps necessary for future success. We focus on the advances in small molecule targeted therapy, as the use of immunotherapy as an emerging precision medicine modality for glioma treatment has recently been reviewed by our colleagues.
      PubDate: Sat, 24 Oct 2020 00:00:00 GMT
      DOI: 10.1093/noajnl/vdaa145
      Issue No: Vol. 3, No. 1 (2020)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Tel: +00 44 (0)131 4513762

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