Diffuse astrocytoma

Diffuse astrocytoma

Types

Diffuse astrocytoma IDH Mutant 9400/3

Gemistocytic astrocytoma 9411/3

Diffuse astrocytoma IDH wild type 9400/3

Diffuse astrocytoma NOS 9400/3


WHO grade determinations are still made on the basis of histologic criteria. Another reason why phenotype remains essential is that, there are individual tumors that do not meet the more narrowly defined phenotype and genotype criteria, e.g., the rare phenotypically classical diffuse astrocytoma that lacks the signature genetic characteristics of IDH and ATRX mutations. Nevertheless, it remains possible that future WHO classifications of the diffuse gliomas, in the setting of deeper and broader genomic capabilities, will require less histological evaluation—perhaps only a diagnosis of “diffuse glioma.” For now, the World Health Organization Classification of Tumors of the Central Nervous System 2016 is predicated on the basis of combined phenotypic and genotypic classification, and on the generation of “integrated” diagnoses.

Diffuse astrocytoma and oligodendrogliomas are in this classification now nosologically more similar than are diffuse astrocytoma and pilocytic astrocytoma; the family trees have been redrawn.

In the setting of a diffuse astrocytoma or anaplastic astrocytoma, if IDH testing is not available or cannot be fully performed (e.g., negative immunohistochemistry without available sequencing), the resulting diagnosis would be diffuse astroctyoma, NOS, or anaplastic astrocytoma, NOS, respectively.

Historically, the prognostic differences between WHO grade II diffuse astrocytomas and WHO grade III anaplastic astrocytomas were highly significant.

Some studies, however, have suggested that the prognostic differences between IDH-mutant WHO grade II diffuse astrocytomas and IDH-mutant WHO grade III anaplastic astrocytomas are not as marked.

Nonetheless, this has not been noted in all studies. At this time, it is recommended that WHO grading is retained for both IDH-mutant and IDH-wildtype astrocytomas, although the prognosis of the IDH-mutant cases appears more favorable in both grades. Cautionary notes have been added to the 2016 classification in this regard.

Of note, two diffuse astrocytoma variants have been deleted from the WHO classification: protoplasmic astrocytoma, a diagnosis that was previously defined in only vague terms and is almost never made any longer given that tumors with this histological appearance are typically characterized as other more narrowly defined lesions; and fibrillary astrocytoma, since this diagnosis overlaps nearly entirely with the standard diffuse astrocytoma. As a result, only gemistocytic astrocytoma remains as a distinct variant of diffuse astrocytoma IDH-mutant.

Outcome

For the diffuse astrocytomas, there have been many such studies over the past century and these have proven useful in estimating prognosis for patients. With the advent of molecular diagnostics and the recent World Health Organization (WHO) Classification of Tumors of the Central Nervous System it is necessary testing for isocitrate dehydrogenase (IDH) gene status in the classification of diffuse astrocytic gliomas. Novel approaches to diffuse astrocytic tumor grading are required in the era of IDH testing 1).


Alattar et al. determined the influence of age and tumor location on survival benefit from GTR in diffuse astrocytoma (DA).

They used The Surveillance, Epidemiology and End Results (SEER) database (1999-2010). They used Kaplan-Meier curves and Cox survival models to determine the survival benefit from GTR in populations stratified by age and tumor location. They determined the prevalence of the IDH mutation (mIDH) using The Cancer Genome Atlas (TCGA).

They identified 1980 patients with DA. For frontal DAs, GTR resulted in improved survival relative to subtotal resection in all ages (age ≤50 years hazard ratio [HR], 0.56; P = 0.002; age >50 years HR, 0.41; P < 0.001). For nonfrontal DAs, only patients ≤50 years experienced improved survival with GTR (age ≤50 years HR, 0.55; P = 0.002; age >50 years HR, 0.78; P = 0.114). For patients ≤50 years with frontal tumors, survival was comparable between DA and AA after GTR (75% survival DA: 80 months, AA: 89 months, P = 0.973). In TCGA, these tumors were nearly uniformly mIDH (DA: 98%; AA: 90%, P = 0.11). However, for patients ≤50 years with nonfrontal tumors, there was a survival difference after GTR (75% survival DA: 80 months, AA: 30 months, P = 0.001) despite comparable mIDH prevalence (DA: 82%, AA: 75%, P = 0.49).

Age and tumor location modify the survival benefit derived from GTR in DA. Survival patterns in SEER imperfectly correlated with mIDH prevalence in TCGA, suggesting that tumor grade and mIDH status convey nonredundant prognostic information in select clinical contexts 2).

References

1)

von Deimling A, Ono T, Shirahata M, Louis DN. Grading of Diffuse Astrocytic Gliomas: A Review of Studies Before and After the Advent of IDH Testing. Semin Neurol. 2018 Feb;38(1):19-23. doi: 10.1055/s-0038-1636430. Epub 2018 Mar 16. PubMed PMID: 29548048.
2)

Alattar AA, Carroll KT, Bryant AK, Hirshman B, Joshi R, Carter BS, Harismendy O, Chen CC. Prognostic Importance of Age, Tumor Location, and Tumor Grade in Grade II Astrocytomas: An Integrated Analysis of the Cancer Genome Atlas and the Surveillance, Epidemiology, and End Results Database. World Neurosurg. 2019 Jan;121:e411-e418. doi: 10.1016/j.wneu.2018.09.124. Epub 2018 Sep 26. PubMed PMID: 30266697.

Non small cell lung cancer intracranial metastases treatment

Non small cell lung cancer intracranial metastases treatment

Brain metastases are common in patients with non small cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients. Novel compounds for epidermal growth factor receptor-dependent and anaplastic lymphoma kinase-dependent lung cancer have demonstrated blood-brain barrier permeability and have led to important improvements in central nervous system outcomes. Studies of targeted therapies for oncogene-driven tumors and of immunotherapies in patients with brain metastases have shown promise and, allied with novel radiation techniques, are driving a rapid evolution in treatment and prognosis for NSCLC brain metastases 1).


KPS score ≥ 70, RPA class I/II, and postoperative chemotherapy could benefit post-metastasectomy patients with brain metastases (BM) from Non small cell lung cancer (NSCLC). Conversely, the initial onset of intracranial lesions is an unfavorable factor that increases the risk of death. These findings support the use of personalized therapy for patients with BM from NSCLC 2).


EGFR and ALK tyrosine kinase inhibitors (TKIs) provide significantly superior systemic response rates and progression free survival compared to standard chemotherapy in the molecularly defined Non small cell lung cancer (NSCLC) subpopulations. An apparent intracranial activity of new generation TKIs triggered the discussion on their role in brain metastases in lieu of local therapies 3).


A article of Preusser et al., is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose was to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non-small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context 4).


PUBMEDEMBASE, the Cochrane LibraryWeb of Knowledge, Current Controlled Trials, Clinical Trials, and 2 conference websites were searched to select NSCLC patients with only single brain metastasis (SBM) who received brain surgery or SRS. SPSS 18.0 software was used to analyze the mean median survival time (MST) and Stata 11.0 software was used to calculate the overall survival (OS).

A total of 18 trials including 713 patients were systematically reviewed. The MST of the patients was 12.7 months in surgery group and 14.85 months in SRS group, respectively. The 1, 2, and 5 years OS of the patients were 59%, 33%, and 19% in surgery group, and 62%, 33%, and 14% in SRS group, respectively. Furthermore, in the surgery group, the 1 and 3 years OS were 68% and 15% in patients with controlled primary tumors, and 50% and 13% in the other patients with uncontrolled primary tumors, respectively. Interestingly, the 5-year OS was up to 21% in patients with controlled primary tumors.

There was no significant difference in MST or OS between patients treated with neurosurgery and SRS. Patients with resectable lung tumors and SBM may benefit from the resection of both primary lesions and metastasis 5).

Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms 6).


Response rates after platinum based antineoplastics, range from 23% to 45%. Development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): gefitinib or erlotinib, was an improvement in treatment of advanced NSCLC patients. EGFR mutations are present in 10-25% of NSCLC (mostly adenocarcinoma), and up to 55% in never-smoking women of East Asian descent. In the non-selected group of patients with BMF-NSCLC, the overall response rates after gefitinib or erlotinib treatment range from 10% to 38%, and the duration of response ranges from 9 to 13.5 months. In the case of present activating EGFR mutation, the response rate after EGRF-TKIs is greater than 50%, and in selected groups (adenocarcinoma, patients of Asian descent, never-smokers, asymptomatic BMF-NSCLC) even 70%. Gefitinib or erlotinib treatment improves survival of BMF-NSCLC patients with EGFR mutation in comparison to cases without the presence of this mutation. There is no data on the activity of the anti-EML4-ALK agent crizotinib. Bevacizumab, recombinant humanised monoclonal antibody anti-VEGF, in the treatment of advanced non-squamous NSCLC patients is a subject of intense research. Data from a clinical trial enrolling patients with pretreated or occult BMF-NSCLC proved that the addition of bevacizumab to various chemotherapy agents or erlotinib is a safe and efficient treatment, associated with a low incidence of CSN haemorrhages. However, the efficacy and safety of bevacizumab used for therapeutic intent, regarding active brain metastases is unknown 7).

Non small cell lung cancer intracranial metastases whole brain radiotherapy

Non small cell lung cancer intracranial metastases radiosurgery

Non small cell lung cancer intracranial metastases surgery

References

1)

Bulbul A, Forde PM, Murtuza A, Woodward B, Yang H, Bastian I, Ferguson PK, Lopez-Diaz F, Ettinger DS, Husain H. Systemic Treatment Options for Brain Metastases from Non-Small-Cell Lung Cancer. Oncology (Williston Park). 2018 Apr 15;32(4):156-63. Review. PubMed PMID: 29684234.
2)

She C, Wang R, Lu C, Sun Z, Li P, Yin Q, Liu Q, Wang P, Li W. Prognostic factors and outcome of surgically treated patients with brain metastases of non-small cell lung cancer. Thorac Cancer. 2018 Nov 28. doi: 10.1111/1759-7714.12913. [Epub ahead of print] PubMed PMID: 30485664.
3)

Wrona A, Dziadziuszko R, Jassem J. Management of brain metastases in non-small cell lung cancer in the era of tyrosine kinase inhibitors. Cancer Treat Rev. 2018 Dec;71:59-67. doi: 10.1016/j.ctrv.2018.10.011. Epub 2018 Oct 21. Review. PubMed PMID: 30366200.
4)

Preusser M, Winkler F, Valiente M, Manegold C, Moyal E, Widhalm G, Tonn JC, Zielinski C. Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion. ESMO Open. 2018 Jan 26;3(1):e000262. doi: 10.1136/esmoopen-2017-000262. eCollection 2018. Review. PubMed PMID: 29387475; PubMed Central PMCID: PMC5786916.
5)

Qin H, Wang C, Jiang Y, Zhang X, Zhang Y, Ruan Z. Patients with single brain metastasis from non-small cell lung cancer equally benefit from stereotactic radiosurgery and surgery: a systematic review. Med Sci Monit. 2015 Jan 12;21:144-52. doi: 10.12659/MSM.892405. PubMed PMID: 25579245.
6)

Kim SY, Hong CK, Kim TH, Hong JB, Park CH, Chang YS, Kim HJ, Ahn CM, Byun MK. Efficacy of surgical treatment for brain metastasis in patients with non-small cell lung cancer. Yonsei Med J. 2015 Jan 1;56(1):103-11. doi: 10.3349/ymj.2015.56.1.103. PubMed PMID: 25510753; PubMed Central PMCID: PMC4276743.
7)

Cedrych I, Kruczała MA, Walasek T, Jakubowicz J, Blecharz P, Reinfuss M. Systemic treatment of non-small cell lung cancer brain metastases. Contemp Oncol (Pozn). 2016;20(5):352-357. doi: 10.5114/wo.2016.64593. Epub 2016 Dec 20. Review. PubMed PMID: 28373815; PubMed Central PMCID: PMC5371701.

Fluorescence-Guided Neurosurgery

Fluorescence-Guided Neurosurgery

see 5 aminolevulinic acid fluorescence guided resection.

see Fluorescein sodium guided resection.

see Fluorescence guided surgery of glioma.

The first use of fluorescence for brain tumour surgery was in 1948 by G.E. Moore 1) using fluorescein sodium.

Achieving a maximal safe extent of resection during brain tumor surgery is the goal for improved patient prognosisFluorescence-guided neurosurgery using 5-aminolevulinic acid (5-ALA) induced Protoporphyrin IX has thereby become a valuable tool enabling a high frequency of complete resections and a prolonged progression free survival in glioblastoma patients.

Erkkilä et al., from the Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Advanced Development Microsurgery, Carl Zeiss Meditec AG, Christian Doppler Laboratory for Innovative Optical Imaging and Its Translation to Medicine, Medical University of Vienna, Institute of Neurology, Department of Neurosurgery, General Hospital and Medical University of Vienna, presented a widefield fluorescence lifetime imaging device with 250 mm working distance working under similar conditions like surgical microscopes based on a time-of-flight based dual tap CMOS camera. In contrast to intensity-based fluorescence imaging this method is invariant to light scattering and absorption while being sensitive to the molecular composition of the tissue. They evaluated the feasibility of lifetime imaging of Protoporphyrin IX using the system to analyze brain tumor phantoms and fresh 5-ALA labeled human tissue samples. The results demonstrate the potential of this lifetime sensing device to go beyond the limitation of current intensity-based fluorescence-guided neurosurgery 2).

Books

Fluorescence-Guided Neurosurgery: Neuro-oncology and Cerebrovascular Applications September 10, 2018 The definitive textbook on state-of-the-art fluorescence-guided neurosurgery

Advances in fluorescence-guided surgery (FGS) have resulted in a paradigm shift in neurosurgical approaches to neuro-oncological and cerebrovascular pathologies. Edited by two of the foremost authorities on the topic, Fluorescence-Guided Neurosurgery: Neuro-oncology and Cerebrovascular Applications encompasses the depth and breadth of this groundbreaking, still nascent technology. The book reflects significant contributions made by world renowned neurosurgeons Constantinos Hadjipanayis, Walter Stummer, and esteemed contributors on the growing uses of 5-aminolevulinic acid (5-ALA) and other FGS agents.

The European Medicine Agency approved 5-ALA in 2007, heralding the birth of FGS globally. In 2017, the U.S. Food and Drug Administration approved 5-ALA (Gleolan) as an imaging agent to facilitate realtime detection and visualization of malignant tissue during glioma surgery. In the two decades since Dr. Stummer’s initial description of 5-ALA FGS in a human patient, major strides have been made in its practical applications, leading to improved resection outcomes. As FGS is increasingly incorporated into neurosurgical practice, it holds promise for future innovations. Generously-illustrated and enhanced with online videos, this textbook is the definitive resource on the subject.

Key Features

The improved efficacy of 5-ALA for resecting high- and low-grade gliomas, recurrences, meningiomas, brain metastases, spinal cord tumors, pediatric brain tumors, and other adult tumors The future of fluorescence, including potentially powerful new fluorophores molecularly targeted specifically to tumors The use of the fluorescent agent indocyanine green (ICG) for brain tumors, cerebral aneurysms, AVMs, and cerebral vascularization Special topics such as fluorescein, illuminating tumor paint, confocal microscopy, Raman spectroscopy, and integrating FGS with intraoperative imaging and brain mapping This single accessible reference presents the current state-of-the-art on this emerging, exciting surgical technology. As such, it is a must-have for neurosurgical residents, fellows, and practicing neurosurgeons.

1)

Moore GE, Peyton WT, French LA, Walker WW (1948) The clinical use of fluorescein in neurosurgery; the localization of brain tumors. J Neurosurg 5:392–398
2)

Erkkilä MT, Bauer B, Hecker-Denschlag N, Madera Medina MJ, Leitgeb RA, Unterhuber A, Gesperger J, Roetzer T, Hauger C, Drexler W, Widhalm G, Andreana M. Widefield fluorescence lifetime imaging of protoporphyrin IX for fluorescence-guided neurosurgery: an ex vivo feasibility study. J Biophotonics. 2019 Jan 12. doi: 10.1002/jbio.201800378. [Epub ahead of print] PubMed PMID: 30636030.

Long noncoding RNA

Long noncoding RNA

Long non-coding RNAs (long ncRNAs, lncRNA) are non-protein coding transcripts longer than 200 nucleotides.

This somewhat arbitrary limit distinguishes long ncRNAs from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs.

They participate extensively in biological processes of various cancers. The majority of these transcripts are uniquely expressed in differentiated tissues or specific cancer types 1).

Emerging evidence reveal that long noncoding RNAs (lncRNAs) participates in the epigenetic regulation of pathophysiological process.

Long noncoding RNAs (lncRNAs) have been proposed as promoter or inhibitor in many cancer processes.

LncRNAs are involved in many cellular processes, such as angiogenesis, invasion, cell proliferation, and apoptosis.


Genome-wide transcriptional studies have demonstrated that tens of thousands of lncRNA genes are expressed in the CNS and that they exhibit tissue– and cell-type specificity. Their regulated and dynamic expression, and their co-expression with protein-coding gene neighbours, have led to the study of the functions of lncRNAs in CNS development and disorders.

In a review, Cuevas-Diaz Duran et al., from the Vivian L. Smith Department of Neurosurgery, Center for Stem Cell and Regenerative Medicine, UT Brown Foundation Institute of Molecular Medicine, Houston, Tecnologico de Monterrey, describe the general characteristics, localization, and classification of lncRNAs. They also elucidate examples of the molecular mechanisms of nuclear and cytoplasmic lncRNA actions in the CNS and discuss common experimental approaches used to identify and unveil the functions of lncRNAs. Additionally, they provide examples of lncRNA studies of cell differentiation and CNS disorders including CNS injuries and neurodegenerative diseases. Finally, they review novel lncRNA-based therapies. Overall, this review highlights the important biological roles of lncRNAs in CNS functions and disorder2).

Importance

see Long noncoding RNA in glioma.

see Long noncoding RNA in meningioma.

see Circular RNAs (circRNAs) are highly stable, circularized long noncoding RNAs.

see also Long noncoding RNA MALAT1.


Long non-coding RNAs (lncRNAs) have received increased research interest owing to their participation via distinct mechanisms in the biological processes of clinically nonfunctioning pituitary adenomas. However, changes in the expression of lncRNAs in gonadotrophin adenoma, which is the most common nonfunctional pituitary adenomas, have not yet been reported. In this study, we performed a genome-wide analysis of lncRNAs and mRNAs obtained from gonadotrophin adenoma patients’ samples and normal pituitary tissues using RNA-seq. The differentially expressed lncRNAs and mRNAs were identified using fold-change filtering. We identified 839 lncRNAs and 1015 mRNAs as differentially expressed. Gene Ontology analysis indicated that the biological functions of differentially expressed mRNAs were related to transcription regulator activity and basic metabolic processes. Ingenuity Pathway Analysis was performed to identify 64 canonical pathways that were significantly enriched in the tumor samples. Furthermore, to investigate the potential regulatory roles of the differentially expressed lncRNAs on the mRNAs, we constructed general co-expression networks for 100 coding and 577 non-coding genes that showed significantly correlated expression patterns in tumor cohort. In particular, we built a special sub-network of co-expression involving 186 lncRNAs interacting with 15 key coding genes of the mTOR pathway, which might promote the pathogenesis of gonadotrophin tumor. This is the first study to explore the patterns of genome-wide lncRNAs expression and co-expression with mRNAs, which might contribute to the molecular pathogenesis of gonadotrophin adenoma 3).

References

1)

Chen L, Zhang YH, Lu G, Huang T, Cai YD. Analysis of cancer-related lncRNAs using gene ontology and KEGG pathways. Artif Intell Med. 2017 Feb;76:27-36. doi: 10.1016/j.artmed.2017.02.001. Epub 2017 Feb 13. PubMed PMID: 28363286.
2)

Cuevas-Diaz Duran R, Wei H, Kim DH, Wu JQ. Long non-coding RNAs: important regulators in the development, function, and disorders of the central nervous system. Neuropathol Appl Neurobiol. 2019 Jan 13. doi: 10.1111/nan.12541. [Epub ahead of print] PubMed PMID: 30636336.
3)

Li J, Li C, Wang J, Song G, Zhao Z, Wang H, Wang W, Li H, Li Z, Miao Y, Li G, Zhang Y. Genome-wide analysis of differentially expressed lncRNAs and mRNAs in primary gonadotrophin adenomas by RNA-seq. Oncotarget. 2016 Dec 15. doi: 10.18632/oncotarget.13948. [Epub ahead of print] PubMed PMID: 27992366.

Raman spectroscopy

Raman spectroscopy

Raman spectroscopy named after Indian physicist Sir C. V. Raman is a spectroscopic technique used to observe vibrational, rotational, and other low-frequency modes in a system.

Raman spectroscopy is commonly used in chemistry to provide a structural fingerprint by which molecules can be identified.


Navigation-guided brain biopsies are the standard of care for diagnosis of several brain pathologies. However, imprecise targeting and tissue heterogeneity often hinder obtaining high-quality tissue samples, resulting in poor diagnostic yield.

Raman histology has potential for detecting viable tumor in biopsied tissue and for identifying tumor infiltration in vivo 1).

Desroches et al., from the Montreal Neurological Institute and Hospital, report the development and first clinical testing of a navigation-guided fiberoptic Raman probe that allows surgeons to interrogate brain tissue in situ at the tip of the biopsy needle, prior to tissue removal. The 900μm diameter probe can detect high spectral quality Raman signals in both the fingerprint and high wavenumber spectral regions with minimal disruption to the neurosurgical workflow. The probe was tested in 3 brain tumor patients, and the acquired spectra in both normal brain and tumor tissue demonstrated the expected spectral features, indicating the quality of the data. As a proof-of-concept, they also demonstrate the consistency of the acquired Raman signal with different systems and experimental settings. Additional clinical development is planned to further evaluate the performance of the system and develop a statistical model for real-time tissue classification during the biopsy procedure 2).


The aim of a study was to use Raman spectroscopy to analyze the biochemical composition of medulloblastoma and normal tissues from the safety margin of the CNS and to find specific Raman biomarkers capable of differentiating between tumorous and normal tissues.

The tissue samples consisted of medulloblastoma (grade IV) (n = 11). The tissues from the negative margins were used as normal controls. Raman images were generated by a confocal Raman microscope-WITec alpha 300 RSA.

Raman vibrational signatures can predict which tissue has tumorous biochemistry and can identify medulloblastoma. The Raman technique makes use of the fact that tumors contain large amounts of protein and far less lipids (fatty compounds), while healthy tissue is rich in both.

The ability of Raman spectroscopy and imaging to detect medulloblastoma tumors fills the niche in diagnostics. These powerful analytical techniques are capable of monitoring tissue morphology and biochemistry. The results demonstrate that RS can be used to discriminate between normal and medulloblastoma tissues 3).

References

1)

Hollon T, Stummer W, Orringer D, Suero Molina E. Surgical Adjuncts to Increase the Extent of Resection: Intraoperative MRI, Fluorescence, and Raman Histology. Neurosurg Clin N Am. 2019 Jan;30(1):65-74. doi: 10.1016/j.nec.2018.08.012. Review. PubMed PMID: 30470406.
2)

Desroches J, Lemoine É, Pinto M, Marple E, Urmey K, Diaz R, Guiot MC, Wilson BC, Petrecca K, Leblond F. Development and first in-human use of a Raman spectroscopy guidance system integrated with a brain biopsy needle. J Biophotonics. 2019 Jan 12. doi: 10.1002/jbio.201800396. [Epub ahead of print] PubMed PMID: 30636032.
3)

Polis B, Imiela A, Polis L, Abramczyk H. Raman spectroscopy for medulloblastoma. Childs Nerv Syst. 2018 Jul 12. doi: 10.1007/s00381-018-3906-7. [Epub ahead of print] PubMed PMID: 30003328; PubMed Central PMCID: PMC6224026.

Esthesioneuroblastoma

Esthesioneuroblastoma (ENB)

AKA: Olfactory neuroblastoma.

Esthesioneuroblastoma is a rare malignant tumor of sinonasal origin. These tumors typically present with unilateral nasal obstruction and epistaxis, and diagnosis is confirmed on biopsy.

Treatment

Case series

Nineteen patients from Brescia received endoscopic resection with transnasal craniectomy and subpial dissection (ERTC-SD) and 11 had pathological-proven brain invasion. Histologies were 6 olfactory neuroblastomas (ONB), 3 neuroendocrine carcinomas, and 2 intestinal-type adenocarcinomas. Mean follow-up was 21.9 months. Three-year overall, local recurrence-free, and distance recurrence-free survivals were 65.5%, 81.8%, and 68.2%, respectively. Overall and distant recurrence-free survivals were significantly better in patients with ONB (P = 0.032 and P = 0.013, respectively). Hospitalization ratio was 4.1%. Complication rate was 10.5%.

In selected nasal-ethmoidal tumors with brain invasion, ERTC-SD can provide good local control, satisfactory survival, and limited morbidity 1).


Klironomos et al., presented the use of pure EEA in the management of ENB in the Toronto Western Hospital, along with a literature review. They retrospectively reviewed the clinical, radiology and pathology records of patients with ENB treated during the period July 2006 to January 2016. During the above period, ten patients with ENB were treated using pure EEA. The mean age was 47.5 years. The gender distribution was: eight males, two females. The most common presenting symptoms were nasal obstruction and discharge or epistaxis (8/10). The mean duration of symptoms was 1.5 years. All patients had preoperative confirmation of ENB by biopsy. Five patients received neoadjuvant radiation and four underwent postoperative radiation. One patient did not receive any radiotherapy and no patient received chemotherapy. Gross total resection was achieved in all patients and intraoperative microscopically negative surgical margins achieved in 9/10 (90%). No major intraoperative complications occurred. The most common postoperative complication was nasal infection. Cerebrospinal fluid leak was noted in one patient. During the follow-up period of 6-120 months (mean 74.8) two cases of neck lymph node recurrence were observed. No deaths due to the disease occurred during the follow-up period. Pure EEA offer excellent results in the management of ENB. Neoadjuvant radiation treatment is promising although more studies need to establish its role 2).


There is a scarcity of data about different treatment strategies. Intensity modulated radiotherapy (IMRT) and carbon ion radiotherapy (CIRT) are advanced radiation techniques that might improve local tumor control.

In a retrospective analysis of 17 patients with ENB (Kadish stage ≥ C: 88%; n = 15). Four patients had already undergone previous radiotherapy (RT). The treatment consisted of either IMRT (n = 5), CIRT (n = 4) or a combination of both techniques (n = 8). Median follow-up was 29 months. (3) Results: In patients that had not been irradiated before (n = 13), calculated overall survival (OS) and progression free survival (PFS) rates after 48 months were 100% and 81% respectively (Kaplan-Meier estimates). Two of four patients that underwent reirradiation died after RT, presumably due to tumor progression. Besides common toxicities, five patients (30%) showed mostly asymptomatic radiation-induced brain changes, most likely due to a disturbance of the blood-brain barrier.

The results demonstrate that IMRT, CIRT, a combined approach of IMRT and CIRT as well as reirradiation with CIRT seem to be feasible and effective treatment methods in ENB. 3).


ENB is safely and effectively treated with craniofacial resection (CFR) followed by proton beam irradiation. The high incidence of regional metastases warrants strong consideration for elective neck irradiation. Proton beam radiation is associated with lower rates of severe late-radiation toxicity than conventional radiotherapy 4).


The National Cancer Database (NCDB) was used to identify patients diagnosed with ENB between 2004 to 2015. Patients were excluded based on the ability to properly stage their disease as well as the availability of treatment data.

Eight-hundred eighty-three patients had sufficient data for analysis. On multivariate analysis, age and government insurance were associated with primary surgical treatment, whereas tumor stage, gender, race, hospital type and volume, and comorbidity score were not. Age, charlson-deyo comorbidity (CDCC) score, hospital volume, and nodal status were found to be predictors of survival. Multivariate-analysis controlling for stage failed to demonstrate clear survival differences between staging in both TNM and Kadish systems. T-stage and the presence of regional nodal metastasis were associated with an increased risk of positive margins on multivariate analysis.

Although primary surgical management and positive margins can be predicted by certain patient and tumor factors, clinical staging systems for ENB poorly predict prognosis over a 10-year horizon 5).

Esthesioneuroblastoma case reports

A case of non-contiguous meningeal recurrence of olfactory neuroblastoma presenting as a giant frontal mass. A 66-year-old woman was admitted with a left nasal intranasal localized tumor without cranial extension and gross total removal was achieved. Pathological examination showed olfactory neuroblastoma and radiation therapy was added in a limited region of the removal cavity. Radiological follow-up continued for 10 years and there was no local recurrence. Sixteen years after radiation therapy, the patient found a slight frontal mass gradually growing. Magnetic resonance imaging revealed an enhanced mass lesion of 7 cm in thickness and 9 cm in diameter associated with marked thickness of the frontal bone, intradural cystic mass compressing the bilateral frontal lobe, and no local recurrence. A second operation was performed followed by radiotherapy and we diagnosed no-contiguous meningeal recurrence of metastatic olfactory neuroblastoma. Olfactory neuroblastoma is a locally aggressive tumor. Although metastasis of this tumor has been reported, non-contiguous spread to the dura is rare. Understanding the route of remote metastasis and careful evaluation after primary treatment are needed to avoid misdiagnosis and treatment delays 6).

References

1)

Mattavelli D, Ferrari M, Bolzoni Villaret A, Schreiber A, Rampinelli V, Turri-Zanoni M, Lancini D, Taglietti V, Accorona R, Doglietto F, Battaglia P, Castelnuovo P, Nicolai P. Transnasal endoscopic surgery in selected nasal-ethmoidal cancer with suspected brain invasion: Indications, technique, and outcomes. Head Neck. 2019 Jan 12. doi: 10.1002/hed.25621. [Epub ahead of print] PubMed PMID: 30636181.
2)

Klironomos G, Gonen L, Au K, Monteiro E, Mansouri A, Turel MK, Witterick I, Vescan A, Zadeh G, Gentili F. Endoscopic management of Esthesioneuroblastoma: Our experience and review of the literature. J Clin Neurosci. 2018 Dec;58:117-123. doi: 10.1016/j.jocn.2018.09.011. Epub 2018 Oct 16. Review. PubMed PMID: 30340976.
3)

Liermann J, Syed M, Held T, Bernhardt D, Plinkert P, Jungk C, Unterberg A, Rieken S, Debus J, Herfarth K, Adeberg S. Advanced Radiation Techniques in the Treatment of Esthesioneuroblastoma: A 7-Year Single-Institution’s Clinical Experience. Cancers (Basel). 2018 Nov 20;10(11). pii: E457. doi: 10.3390/cancers10110457. PubMed PMID: 30463343; PubMed Central PMCID: PMC6267306.
4)

Herr MW, Sethi RK, Meier JC, Chambers KJ, Remenschneider A, Chan A, Curry WT, Barker FG 2nd, Deschler DG, Lin DT. Esthesioneuroblastoma: an update on the massachusetts eye and ear infirmary and massachusetts general hospital experience with craniofacial resection, proton beam radiation, and chemotherapy. J Neurol Surg B Skull Base. 2014 Feb;75(1):58-64. doi: 10.1055/s-0033-1356493. Epub 2013 Sep 20. PubMed PMID: 24498591.
5)

Joshi RR, Husain Q, Roman BR, Cracchiolo J, Yu Y, Tsai J, Kang J, McBride S, Lee NY, Morris L, Ganly I, Tabar V, Cohen MA. Comparing Kadish, TNM, and the modified Dulguerov staging systems for esthesioneuroblastoma. J Surg Oncol. 2019 Jan;119(1):130-142. doi: 10.1002/jso.25293. Epub 2018 Nov 22. PubMed PMID: 30466166.
6)

Saito A, Sasaki T, Inoue T, Narisawa A, Inoue T, Suzuki S, Ezura M, Uenohara H. Non-contiguous Meningeal Recurrence of Olfactory Neuroblastoma: A Case Report and Literature Review. NMC Case Rep J. 2018 Jun 28;5(3):69-72. doi: 10.2176/nmccrj.cr.2017-0233. eCollection 2018 Jul. PubMed PMID: 30023143; PubMed Central PMCID: PMC6048349.

Breast cancer pituitary metastases

Breast cancer pituitary metastases

Tumors that metastasize to the pituitary gland are unusual, and are typically seen in elderly patients with diffuse malignant disease. The most common metastases to the pituitary are from primary breast and lung cancers.

Cai et al., from Shengjing Hospital of China Medical University, Shenyangpresented a 57 year-old patient with pituitary gland metastasis from breast cancer that was treated with extensive radical mastectomy 16 years prior. The pituitary was the sole site of metastasis. The patient was admitted with the chief complaint of blurred vision for 1 year and episodic headaches for 1 month. Magnetic resonance imaging revealed a solid mass in the sellar region with heterogenous contrast enhancement. The preoperative diagnosis was a pituitary adenomaNeuroendoscopy-assisted tumor resection was conducted through a single-nostril sphenoid sinus approach. A pinkish-white, firm neoplasm was found, with an abundant blood supply and an indistinct boundary between the neoplasm and normal pituitary tissue; complete resection was achieved. The results of immunohistochemical analysis were positive for cytokeratinKi-67antigen, estrogen receptors, progesterone receptors, and prolactin induced protein. The neoplasm was negative for SALL4mammaglobin, and the Glycoprotein hormones, alpha polypeptide. These results were used to reach a final diagnosis of a pituitary gland metastasis from a primary breast carcinoma. The patient’s vision improved significantly after surgery, and no recurrence was detected during one year of follow-up.

Pituitary gland metastasis is rare and difficult to differentiate from a pituitary adenoma without a pathologic diagnosis. Surgery is the first choice for treatment. Surgery, radiotherapy and chemotherapy are combined with endocrine therapy to tailored treatment to the results of immunohistochemistry 1)


An 83-year-old woman developed pituitary metastasis while being treated for metastatic breast cancer. She presented with visual disturbance and headache followed by thirst, nocturia and polyuria. A visual field defect was present. MRI revealed a sellar mass consistent with metastasis to the pituitary gland. She was successfully treated with radiotherapy to the sella and had improvement of her visual symptoms and visual field defect. She then required ongoing treatment for diabetes insipidus. Her symptoms had not shown any sign of recurring up to 9 months after treatment. Pituitary metastases are rare but should be suspected in patients with metastatic cancer who present with features similar to those seen here. With improvements in survival in metastatic breast cancer, pituitary metastases may be seen more commonly and active local treatment is warranted given the possibility of resolution of symptoms related to the pituitary metastases 2).


Kim et al., reported a 65-year-old woman with pituitary metastasis from breast cancer who presented with recent-onset left progressive deterioration of visual acuity and visual field. The clinical diagnosis was made after brain and sellar magnetic resonance imaging showed a large sellar mass compressing the optic chiasm and invading the pituitary stalk. An otorhinolaryngology and neurosurgery team removed the tumor via a transsphenoidal approach, and this procedure obtained symptomatic relief. Postoperatively, metastasis from breast invasive ductal adenocarcinoma was confirmed histologically. We report this unusual case with a review of the relevant literature 3).


A 55-years-old woman presented with diabetes insipidus resulting from metastasis of the tumor to pituitary infundibulum, which is a rare site for metastasis, without significant complaint resulting from metastasis to other part of the body, or other primary diseases. Further evaluation revealed that in spite of previous reports, which metastasis usually happens in end stage of cancer, the patients had primary breast cancer. In subsequent evaluations of the case, hypofunction of adenohypophysis was also detected 4).

References

1)

Cai H, Liu W, Feng T, Li Z, Liu Y. Clinical Presentation and Pathologic Characteristics of Pituitary Metastasis From Breast Carcinoma: Cases and a Systematic Review of the Literature. World Neurosurg. 2019 Jan 7. pii: S1878-8750(18)32949-8. doi: 10.1016/j.wneu.2018.12.126. [Epub ahead of print] PubMed PMID: 30630045.
2)

Gormally JF, Izard MA, Robinson BG, Boyle FM. Pituitary metastasis from breast cancer presenting as diabetes insipidus. BMJ Case Rep. 2014 Apr 12;2014. pii: bcr2014203683. doi: 10.1136/bcr-2014-203683. PubMed PMID: 24729116; PubMed Central PMCID: PMC3987639.
3)

Kim YH, Lee BJ, Lee KJ, Cho JH. A case of pituitary metastasis from breast cancer that presented as left visual disturbance. J Korean Neurosurg Soc. 2012 Feb;51(2):94-7. doi: 10.3340/jkns.2012.51.2.94. Epub 2012 Feb 29. PubMed PMID: 22500201; PubMed Central PMCID: PMC3322215.
4)

Poursadegh Fard M, Borhani Haghighi A, Bagheri MH. Breast cancer metastasis to pituitary infandibulum. Iran J Med Sci. 2011 Jun;36(2):141-4. PubMed PMID: 23358184; PubMed Central PMCID: PMC3556747.

Extent of resection in glioblastoma

The value of incomplete resection in Glioblastoma surgery remains questionable. If gross total resection (GTR) cannot be safely achieved, biopsy only might be used as an alternative surgical strategy 1).

see Wounded glioma syndrome.

The impact of extent of resection (EOR) on survival in glioblastoma multiforme treatment (GBM) continues to be a point of debate despite multiple studies demonstrating that increasing EOR likely extends survival for these patients. In addition, contrast-enhancing residual tumor volume (CE-RTV) alone has rarely been analyzed quantitatively to determine if it is a predictor of outcome.

CE-RTV and EOR were found to be significant predictors of survival after GBM resection. CERTV was the more significant predictor of survival compared with EOR, suggesting that the volume of residual contrast-enhancing tumor may be a more accurate and meaningful reflection of the pathobiology of GBM 2).

Difficulties

It is difficult to reproducibly judge EOR in studies due to the lack of reliable tumor segmentation methods, especially for postoperative magnetic resonance imaging (MRI) scans. Therefore, a reliable, easily distributable segmentation method is needed to permit valid comparison, especially across multiple sites.

Cordova et al. report a segmentation method that combines versatile region-of-interest blob generation with automated clustering methods. Applied this to glioblastoma cases undergoing FGS and matched controls to illustrate the method’s reliability and accuracy. Agreement and interrater variability between segmentations were assessed using the concordance correlation coefficient, and spatial accuracy was determined using the Dice similarity index and mean Euclidean distance. Fuzzy C-means clustering with three classes was the best performing method, generating volumes with high agreement with manual contouring and high interrater agreement preoperatively and postoperatively. The proposed segmentation method allows tumor volume measurements of contrast-enhanced T 1-weighted images in the unbiased, reproducible fashion necessary for quantifying EOR in multicenter trials 3).

Maximal safe resection

Safely performed maximal surgical resection is shown to significantly increase progression free survival and overall survival while maximizing quality of life. Upon invariable tumor recurrence, re-resection also is shown to impact survival in a select group of patients. As adjuvant therapy continues to improve survival, the role of surgical resection in the treatment of glioblastoma looks to be further defined.


During surgery, identifying margins of brain tumors, particularly glioblastomas (GBMs) and highly invasive neoplasms, remains a technical challenge. Thus, for both benign and malignant brain tumors, the most common cause of relapse is local recurrence at the resection margins. At the time of the operation, surgeons typically use visual inspection and tactile discrimination to differentiate tumor margins from surrounding normal brain parenchyma. In addition, imaging adjuncts such as navigation and intraoperative ultrasound can provide value. However, this method has many limitations, which accounts for the high rate of local failure.

Intraoperative adjunctive technologies, such as imaging-based navigational systems, have been useful in allowing the surgeon to estimate areas of contrast enhancement, which likely represent tumor. Although ultrasound-based re-registration can be used to account for brain shift, navigation alone is hampered by the inaccuracies attributable to brain shift and poor resolution when performing surgery in vivo. For the past 2 decades, intraoperative fluorescent contrast agents have been proposed to aid the neurosurgeon in identifying tumor tissue during surgery. The most popular approach has been fluorescent-guided intraoperative imaging with 5 aminolevulinic acid fluorescence guided resection. This method has been studied since the 1990s 4) 5)

It is difficult to reproducibly judge extent of resection (EOR in these studies due to the lack of reliable tumor segmentation methods, especially for postoperative magnetic resonance imaging (MRI) scans. Therefore, a reliable, easily distributable segmentation method is needed to permit valid comparison, especially across multiple sites 6).

Treatment advances will depend on identifying agents that target mechanistic vulnerabilities that are relevant to specific subgroups of patients; increasing patient enrollment into clinical trials is essential to accelerate the development of patient-tailored treatments 7).


Most studies that examine the notion of gross total resection (GTR) in glioblastoma treatment are conducted with the assumption that extended survival is universally desirable 8).

There are limited data in terms of how such survival benefits should be weighed against the risk of the surgery and the impact of surgical morbidity on the patient’s quality of life 9).

To study this issue, Chen et al., designed a survey entitled Putting yourself in your patient’s shoes: a pilot study of physician personal preferences for treatment of glioblastoma (U.C.S.D. institutional review board protocol no. 151821), where they survey physician members who have cared for glioblastoma patients. These physicians are well-acquainted with the consequences of surgery performed for glioblastoma located in different regions.

They pose the question of whether the respondent would elect for GTR if s/he were afflicted with glioblastoma located in the right frontal lobe, right hemisphere, left hemisphere, or the posterior corpus callosum.

Information on physician age, marital status, medical specialty (neurosurgery, neuro-oncology, medical oncology, neuroradiology, neuropathology or radiation oncology), years of practice, and personal values will be collected.

They would like to make neurosurgeons in Europe aware of this study, and to invite them to take part in it. They hope this study will give us more insight into our own preferences as physicans, when faced with the decision we council our patients on how to make on a daily basis.

To participate in the study please go to the following webpage by 31 October 2016: http://www.surveymonkey.com/r/Eu_preference_GBM 10).

Case series

Data from Extent of resection in glioblastoma patients who underwent gross total resection (GTR), subtotal resection (STR), or open biopsybetween 2005 and 2014 were retrieved from the Surveillance, Epidemiology, and End Results database in the Seoul National University College of Medicine.

Univariate and multivariate analyses for overall survival (OS) were performed. Between 2005-2009 and 2010-2014, the proportion of GTR and STR performed increased from 41.4 to 42.3% and 33.0 to 37.1%, respectively. EOR only affected OS in the 3 years after diagnosis. Median survival in the GTR (n = 4155), STR (n = 3498), and open biopsy (n = 2258) groups was 17, 13, and 13 months, respectively (p < .001). STR showed no significant difference in OS from open biopsy (p = .33). GTR increased OS for midline-crossing tumors. Although STR was more frequently performed than GTR for tumors ≥ 6 cm in size, GTR significantly increased the OS rate relative to STR for tumors 6-8 cm in size (p = .001). For tumors ≥ 8 cm, STR was comparable to GTR (p = .61) and superior to open biopsy (p = .05). GTR needs to be performed more frequently for glioblastoma measuring ≥ 6 cm or that have crossed the midline to increase OS. STR was marginally superior to open biopsy when the tumor was ≥ 8 cm 11).

2017

Esquenazi et al. retrospectively evaluated 86 consecutive patients with primary GBM, managed by the senior author, using a subpial resection technique with or without carmustine wafer implantation. Multivariate Cox proportional hazards regression was used to analyze clinical, radiological, and outcome variables. Overall impacts of extent of resection (EOR) and BCNU wafer placement were compared using Kaplan-Meier survival analysis.

Mean patient age was 56 years. The median OS for the group was 18.1 months. Median OS for patients undergoing gross total, near-total, and subtotal resection were 54, 16.5, and 13.2 months, respectively. Patients undergoing near-total resection ( P = .05) or gross total resection ( P < .01) experienced statistically significant longer survival time than patients undergoing subtotal resection as well as patients undergoing ≥95% EOR ( P < .01) when compared to <95% EOR. The addition of BCNU wafers had no survival advantage.

The subpial technique extends the resection beyond the contrast enhancement and is associated with an overall survival beyond that seen in similar series where resection of the enhancement portion is performed. The effect of supratotal resection on survival exceeded the effects of age, Karnofsky performance score, and tumor volume. A prospective study would help to quantify the impact of the subpial technique on quality of life and survival as compared to a traditional resection limited to the enhancing tumor 12).

2015

Coburger et al. prospectively enrolled 33 patients with GBMs eligible for gross-total-resection(GTR) and performed a combined approach using 5-ALA and iMRI. As a control group, we performed a retrospective matched pair assessment, based on 144 patients with iMRI-assisted surgery. Matching criteria were, MGMT promotor methylation, recurrent surgery, eloquent location, tumor size and age. Only patients with an intended GTR and primary GBMs were included. We calculated Kaplan Mayer estimates to compare OS and PFS using the Log-Rank-Test. We used the T-test to compare volumetric results of EoR and the Chi-Square-Test to compare new permanent neurological deficits (nPND) and general complications between the two groups.

Median follow up was 31 months. No significant differences between both groups were found concerning the matching criteria. GTR was achieved significantly more often (p <0.010) using 5-ALA&iMRI (100%) compared to iMRI alone (82%). Mean EoR was significantly (p<0.004) higher in 5-ALA&iMRI-group (99.7%) than in iMRI-alone-group (97.4%) Rate of complications did not differ significantly between groups (21% iMRI-group, 27%5-ALA&iMRI-group, p<0.518). nPND were found in 6% in both groups. Median PFS (6 mo resp.; p<0.309) and median OS (iMRI:17 mo; 5-ALA&iMRI-group: 18 mo; p<0.708)) were not significantly different between both groups.

We found a significant increase of EoR when combining 5-ALA&iMRI compared to use of iMRI alone. Maximizing EoR did not lead to an increase of complications or neurological deficits if used with neurophysiological monitoring in eloquent lesions. No final conclusion can be drawn whether a further increase of EoR benefits patient’s progression free survival and overall survival 13).

2014

retrospective review of 128 patients who underwent primary resection of supratentorial GBM followed by standard radiation/chemotherapy was undertaken utilizing quantitative, volumetric analysis of pre- and postoperative MR images. The results were compared with clinical data obtained from the patients’ medical records.

At analysis, 8% of patients were alive, and no patients were lost to follow-up. The overall median survival was 13.8 months, with a median Karnofsky Performance Scale (KPS) score of 90 at presentation. The median contrast-enhancing preoperative tumor volume (CE-PTV) was 29.0 cm3, and CE-RTV was 1.2 cm3, equating to a 95.8% median EOR. The median T2/F-RV was 36.8 cm3. CE-PTV, CE-RTV, T2/F-RV, and EOR were all statistically significant predictors of survival when controlling for age and KPS score. A statistically significant benefit in survival was seen with a CE-RTV less than 2 cm3 or an EOR greater than 98%. Evaluation of the volumetric analysis methodology was performed by observers of varying degrees of experience-an attending neurosurgeon, a fellow, and a medical student. Both the medical student and fellow recorded correlation coefficients of 0.98 when compared with the attending surgeon’s measured volumes of CE-PTV, while for CE-RTV, correlation coefficients of 0.67 and 0.71 (medical student and fellow, respectively) were obtained.

CE-RTV and EOR were found to be significant predictors of survival after GBM resection. CERTV was the more significant predictor of survival compared with EOR, suggesting that the volume of residual contrast-enhancing tumor may be a more accurate and meaningful reflection of the pathobiology of GBM 14).

2013

Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31).

The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy 15).

1999

retrospectively analyzed preoperative and postoperative radiographic tumor volumes in 92 patients who underwent hemispheric glioblastoma multiforme operations (107) to determine the factors that affect time to tumor progression (TTP) and overall survival.

METHODS: Quantification of tumor volumes was based on a previously described method involving computerized image analysis of contrast enhancing tumor on computerized tomography or magnetic resonance imaging scans.

RESULTS: Among the variables analyzed, preoperative Karnofsky Performance Status (KPS) (p < 0.05), chemotherapy (p < 0.05), percent of resection (POR) (p < 0.001), and volume of residual disease (VRD) (p < 0.001) had a significant effect on TTP. Factors that affected survival were age (p < 0.05), preoperative KPS (p = 0.05), postoperative KPS (p < 0.005), POR (p < 0.0005), and VRD (p < 0.0001). Greater resections did not compromise the quality of life, and patients without any residual disease had a better postoperative KPS than those patients who received less than total resections.

CONCLUSIONS: The extent of tumor removal and the amount of residual tumor volume, documented on postoperative imaging studies, are highly significant factors affecting the median time to tumor progression and median survival for patients with glioblastoma multiforme of the cerebral hemisphere 16).

1) , 15)

Kreth FW, Thon N, Simon M, Westphal M, Schackert G, Nikkhah G, Hentschel B, Reifenberger G, Pietsch T, Weller M, Tonn JC; German Glioma Network.. Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy. Ann Oncol. 2013 Dec;24(12):3117-23. doi: 10.1093/annonc/mdt388. PubMed PMID: 24130262.
2)

Grabowski MM, Recinos PF, Nowacki AS, Schroeder JL, Angelov L, Barnett GH, Vogelbaum MA. Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma. J Neurosurg. 2014 Nov;121(5):1115-23. doi: 10.3171/2014.7.JNS132449. Epub 2014 Sep 5. PubMed PMID: 25192475.
3)

Cordova JS, Schreibmann E, Hadjipanayis CG, Guo Y, Shu HK, Shim H, Holder CA. Quantitative tumor segmentation for evaluation of extent of glioblastoma resection to facilitate multisite clinical trials. Transl Oncol. 2014 Feb 1;7(1):40-7. eCollection 2014 Feb. PubMed PMID: 24772206; PubMed Central PMCID: PMC3998691.
4)

Zhao S, Wu J, Wang C, et al. Intraoperative fluorescence-guided resection of high-grade malignant gliomas using 5-Aminolevulinic acid-induced porphyrins: a systematic review and meta-analysis of prospective studies. PLoS One. 2013:8(5):e63682.
5)

Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392–401.) ((Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ. Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg. 2000;93(6):1003–1013.
6)

Cordova JS, Schreibmann E, Hadjipanayis CG, Guo Y, Shu HK, Shim H, Holder CA. Quantitative tumor segmentation for evaluation of extent of glioblastoma resection to facilitate multisite clinical trials. Transl Oncol. 2014 Feb 1;7(1):40-7. eCollection 2014 Feb. PubMed PMID: 24772206.
7)

Thomas AA, Brennan CW, DeAngelis LM, Omuro AM. Emerging Therapies for Glioblastoma. JAMA Neurol. 2014 Sep 22. doi: 10.1001/jamaneurol.2014.1701. [Epub ahead of print] PubMed PMID: 25244650.
8)

Kramm CM, Wagner S, Van Gool S, Schmid H, Strater R, Gnekow A, Rutkowski S, Wolff JE (2006) Improved survival after gross total resection of malignant gliomas in pediatric patients from the HITGBM studies. Anticancer Res 26:3773–3779
9)

Ausman JI (2014) Gross total resection: do we want survival statistics or quality of life measurements. Surg Neurol Int 5:77
10)

Chen CC, Depp C, Wilson B, Bartek J Jr, Carter B. A pilot study of physician personal preferences for treatment of glioblastoma. Acta Neurochir (Wien). 2016 Oct;158(10):1933. doi: 10.1007/s00701-016-2913-2. Epub 2016 Aug 19. PubMed PMID: 27541491.
11)

Kim YJ, Lee DJ, Park CK, Kim IA. Optimal extent of resection for glioblastoma according to site, extension, and size: a population-based study in the temozolomide era. Neurosurg Rev. 2019 Jan 5. doi: 10.1007/s10143-018-01071-3. [Epub ahead of print] PubMed PMID: 30612289.
12)

Esquenazi Y, Friedman E, Liu Z, Zhu JJ, Hsu S, Tandon N. The Survival Advantage of “Supratotal” Resection of Glioblastoma Using Selective Cortical Mapping and the Subpial technique. Neurosurgery. 2017 Mar 23. doi: 10.1093/neuros/nyw174. [Epub ahead of print] PubMed PMID: 28368547.
13)

Coburger J, Hagel V, Wirtz CR, König R. Surgery for Glioblastoma: Impact of the Combined Use of 5-Aminolevulinic Acid and Intraoperative MRI on Extent of Resection and Survival. PLoS One. 2015 Jun 26;10(6):e0131872. doi: 10.1371/journal.pone.0131872. eCollection 2015. PubMed PMID: 26115409; PubMed Central PMCID: PMC4482740.
14)

Grabowski MM, Recinos PF, Nowacki AS, Schroeder JL, Angelov L, Barnett GH, Vogelbaum MA. Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma. J Neurosurg. 2014 Sep 5:1-9. [Epub ahead of print] PubMed PMID: 25192475.
16)

Keles GE, Anderson B, Berger MS. The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. Surg Neurol. 1999 Oct;52(4):371-9. PubMed PMID: 10555843.

Pediatric glioblastoma

Glioblastoma in children, when compared with adults, is relatively rare.

Despite this rarity, it is apparent from the limited number of publications that pediatric glioblastoma is quite distinct from their adult counterparts. The differences pertain to the molecular genetics, effectiveness of the adjuvant therapies, and possibly the prognosis after treatment. With a plethora of path-breaking translational research coming through in recent times, a host of new information is now available on pediatric glioblastomas that holds great promise as far as the future treatment options are concerned 1)

In contrast to adult GBM, few molecular prognostic markers for the pediatric counterpart have been established.


Some anaplastic pleomorphic xanthoastrocytomas (PXA) were reported to have extremely poor prognosis which showed a type of pediatric glioblastoma (GBM) molecular profile. Recent integrated molecular classification for primary central nervous system tumors proposed some differences between histological and molecular features. Herein, in a genome-wide molecular analysis, Nakamura et al., showed an extreme aggressive anaplastic PXA that resulted in a pediatric GBM molecular profile. A full implementation of the molecular approach is the key to predict prognosis and decide the treatment strategy for anaplastic PXA 2).


Korshunov et al. investigated the prognostic significance of genomic and epigenetic alterations through molecular analysis of 202 pedGBM (1-18 years) with comprehensive clinical annotation. Routinely prepared formalin-fixed paraffin-embedded tumor samples were assessed for genome-wide DNA methylation profiles, with known candidate genes screened for alterations via direct sequencing or FISH. Unexpectedly, a subset of histologically diagnosed GBM (n = 40, 20 %) displayed methylation profiles similar to those of either low-grade gliomas or pleomorphic xanthoastrocytomas (PXA). These tumors showed a markedly better prognosis, with molecularly PXA-like tumors frequently harboring BRAF V600E mutations and 9p21 (CDKN2A) homozygous deletion. The remaining 162 tumors with pedGBM molecular signatures comprised four subgroups: H3.3 G34-mutant (15 %), H3.3/H3.1 K27-mutant (43 %), IDH1-mutant (6 %), and H3/IDH wild-type (wt) GBM (36 %). These subgroups were associated with specific cytogenetic aberrations, MGMT methylation patterns and clinical outcomes. Analysis of follow-up data identified a set of biomarkers feasible for use in risk stratification: pedGBM with any oncogene amplification and/or K27M mutation (n = 124) represents a particularly unfavorable group, with 3-year overall survival (OS) of 5 %, whereas tumors without these markers (n = 38) define a more favorable group (3-year OS ~70 %).Combined with the lower grade-like lesions, almost 40 % of pedGBM cases had distinct molecular features associated with a more favorable outcome. This refined prognostication method for pedGBM using a molecular risk algorithm may allow for improved therapeutic choices and better planning of clinical trial stratification for this otherwise devastating disease 3)

Treatment

Total resection and receiving chemotherapy adjuvant to radiation or chemoradiation (CRT) are most closely associated with improved progression free survival (PFS) and overall survival (OS). For higher risk incompletely resected patients, temozolomide use and treatment intensification with concurrent CRT, adjuvant chemotherapy, and higher radiation dose were associated with improved outcomes 4).

Bevacizumab and irinotecan are a promising regimen for pediatric cases of recurrent glioblastoma after gross-total resection, although the optimal treatment schedule must be determined on a patient-by-patient basis 5).

Case reports

A rare case of primary pediatric glioblastoma multiforme in a 7-year-old girl with Turner’s syndrome is reported, and various aspects regarding clinical and pathophysiological issues have been discussed. Although Turner’s syndrome is not one of the congenital chromosomal abnormalities which demand routine CNS screening, neurological assessment may be of value in those with relevant clinical findings 6).

1)

Das KK, Kumar R. Pediatric Glioblastoma. In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 15. Available from http://www.ncbi.nlm.nih.gov/books/NBK469983/ PubMed PMID: 29251872.
2)

Nakamura T, Fukuoka K, Nakano Y, Yamasaki K, Matsushita Y, Yamashita S, Ikeda J, Udaka N, Tanoshima R, Shiba N, Tateishi K, Yamanaka S, Yamamoto T, Hirato J, Ichimura K. Genome-wide DNA methylation profiling shows molecular heterogeneity of anaplastic pleomorphic xanthoastrocytoma. Cancer Sci. 2019 Jan 4. doi: 10.1111/cas.13903. [Epub ahead of print] PubMed PMID: 30609203.
3)

Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, Meyer J, Schrimpf D, Kool M, Northcott PA, Zheludkova O, Milde T, Witt O, Kulozik AE, Reifenberger G, Jabado N, Perry A, Lichter P, von Deimling A, Pfister SM, Jones DT. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol. 2015 Mar 10. [Epub ahead of print] PubMed PMID: 25752754.
4)

Walston S, Hamstra DA, Oh K, Woods G, Guiou M, Olshefski RS, Chakravarti A, Williams TM. A multi-institutional experience in pediatric high-grade glioma. Front Oncol. 2015 Feb 18;5:28. doi: 10.3389/fonc.2015.00028. eCollection 2015. PubMed PMID: 25741472; PubMed Central PMCID: PMC4332307.
5)

Umeda K, Shibata H, Saida S, Hiramatsu H, Arakawa Y, Mizowaki T, Nishiuchi R, Adachi S, Heike T, Watanabe K. Long-term efficacy of bevacizumab and irinotecan in recurrent pediatric glioblastoma. Pediatr Int. 2015 Feb;57(1):169-71. doi: 10.1111/ped.12414. PubMed PMID: 25711258.
6)

Hanaei S, Habibi Z, Nejat F, Sayarifard F, Vasei M. Pediatric Glioblastoma Multiforme in Association with Turner’s Syndrome: A Case Report. Pediatr Neurosurg. 2015 Feb 25. [Epub ahead of print] PubMed PMID: 25720952.

Biodegradable wafer

One of the therapeutic options for Glioblastoma multiforme includes placing biodegradable wafers releasing BCNU (Gliadel®) into the tumor bed at the time of surgical removal of the tumor. Due to the significant benefit this polymer technology has had clinically, Shapira-Furman et al., from Johns Hopkins Hospital have prepared wafers releasing Temozolomide (TMZ), TMZ delivered via polymer wafer could be used as a complementary treatment with or as an alternative to Gliadel®. TMZ is an alkylating agent which is water soluble. To remain comparable with the preclinical studies that led to Gliadel® the same size of wafers were formulated with TMZ. Wafers were loaded with 50% w/w TMZ in poly(lactic acid-glycolic acid) (PLGA) and showed reliable release of high dose TMZ for a period of 4 weeks. To achieve this 30-day release of the highly water soluble drug, they developed an encapsulation method, where the drug powder was first coated with the polymer to form core-shell particles in which the coating shell served as a rate controlling membrane for the drug particles. Wafers were also made with a co-loading of TMZ and BCNU. All wafers were tested in vivo by treating an intracranial 9L gliosarcoma model in F344 rats. Rats that were either untreated or treated with blank wafer died within 11 days while the median survival for rats treated with systemic TMZ was 18 days. The group that received the BCNU alone wafer had a median survival of 15 days, the group that received the TMZ wafer alone had a median survival of 19 days, and the group treated with the BCNU-TMZ wafer had a median survival of 28 days with 25% of the animals living long term (p < .0038 vs. Control; p < .001 vs. Blank Polymer). These findings demonstrate the potential of this newly designed wafer for treating GBM. Moreover, this concept, can pave the way for other drug combinations that may improve the clinical application of numerous agents to treat solid tumors 1).

1)

Shapira-Furman T, Serra R, Gorelick N, Doglioli M, Tagliaferri V, Cecia A, Peters M, Kumar A, Rottenberg Y, Langer R, Brem H, Tyler B, Domb AJ. Biodegradable wafers releasing Temozolomide and Carmustine for the treatment of brain cancer. J Control Release. 2018 Dec 31. pii: S0168-3659(18)30753-3. doi: 10.1016/j.jconrel.2018.12.048. [Epub ahead of print] PubMed PMID: 30605703.
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