Category Archives: Neurooncology

Update Cerebellopontine angle epidermoid cyst

The cerebellopontine angle epidermoid cyst is a posterior fossa epidermoid cyst.

It account for 3-6% of cerebellopontine angle tumors. Comparatively, vestibular schwannomas, the most common CPA angle tumor, account for 85%.

Men and women are equally affected and the symptoms usually arise between the mid-20’s and early 50’s 1) with a mean age of 38.8 years at presentation 2).

Pathophysiology

Although several mechanisms for cranial nerve dysfunction due to these tumors have been proposed.

Hasegawa et al. report the first direct evidence of etiology of cranial nerve dysfunction caused by cerebellopontine angle epidermoid tumors. Young age and rapidly progressive neurological deficit might be the characteristics for strangulation of the affected nerves by the cyst capsule 3).

Clinical features

CPA epidermoid cysts can compress the surrounding cranial nerves, brainstem, and cerebellum. Ataxia and cranial nerve palsies often result 4).Thirty cases of cerebellopontine angle epidermoid cysts treated over a period of 20 years werw reviewed with regard to their clinical features, the pathophysiology of their symptoms and their management. The predominating symptoms were related to the 7th and 8th cranial nerves and headaches. The signs and symptoms were present for an average period of 4 months. It was not always possible to determine if the signs and symptoms were due to local involvement by the epidermoid, increased intracranial pressure, or both 5).

Diagnosis

Diagnostic procedures evolved from angiography and ventriculography to non-invasive computed tomography and MRI 6).


cerebelloponineangleepidermoidcyst.jpg

Treatment

The posterior cranial fossa approach was used in 27 cases in the case series of deSouza et al. Total excision of the epidermoid was the aim and was carried out in five (18%) patients but concern regarding the preservation of nearby important neurovascular structures forced partial removal in 22 patients. To minimise reformation, the residual epidermoid was carefully coagulated with the aid of the operating microscope and bipolar cautery without damaging surrounding neurovascular structures 7).


The characteristics of epidermoid cysts make them amenable to whole course neuroendoscopic resection. Use of physiologic/pathologic interspaces and neuroendoscopic angulations decreases traction on the brain, improves complete resection rates, and decreases postoperative complications 8).

Case series

2016

Twenty-two cases with epidermoid cysts of CPA micro-neurosurgically treated since 2005 were reviewed. Clinical status of the patients before the surgery and post-operative functional outcome were recorded. Available data from the English literature were summarized for comparison. Mass reduction of cyst contents in most cases was usually associated with prompt and marked improvement of the symptoms suggesting neuroapraxia caused by compression of the tumor content and/or mild ischemia. Among them, two cases showed strangulation of the affected nerves by the tumor capsule whose preoperative dysfunction did not improve after surgery in spite of meticulous microsurgical removal of the lesion. Involved facial and abducent nerves in these two cases showed distortion of nerve axis and nerve atrophy distal to the strangulation site.

Hasegawa et al. report the first direct evidence of etiology of cranial nerve dysfunction caused by cerebellopontine angle epidermoid tumors. Young age and rapidly progressive neurological deficit might be the characteristics for strangulation of the affected nerves by the cyst capsule. Even though the number of cases might be limited, immediate decompression and release of the strangulating band might be urged in such patients to prevent irreversible deficits 9).


17 patients, including 7 with tumor limited to the cerebellopontine angle, 7 with cerebellopontine angle tumor penetrating supratentorially, and 3 with cerebellopontine angle tumor extending along skull base to contralateral cerebellopontine angle. All patients were followed-up for the mean duration of 126 months.

On admission cranial nerve symptoms predominated. Total tumor removal was achieved in 5 patients, and incomplete removal (with small tumor remnants left on vessels, nerves, or brainstem) in 12 patients. Postoperatively, preoperative deficits worsened in 2 and new postoperative deficits occurred in 10 patients. The extent of tumor expansion had no effect on postoperative morbidity and risk of recurrence. During long-term follow-up, improvement or resolution of preoperative deficits was seen in 11 of 17 patients, and new postoperative deficits in 8 of 10 patients. Symptomatic recurrences after an average of more than 9 years were noted in 5 patients, 3 of whom were reoperated. Recurrences occurred in some younger patients and always in area of primary tumor. No effect of extent of tumor removal on risk of recurrence was found.

The extent of tumor removal had no effect on the risk of recurrence, and thus it may be acceptable to leave tumor capsule fragments adhering closely to nerves, vessels, or brainstem. During long-term follow-up, resolution or improvement of present preoperatively and new postoperative neurological deficits may be expected in most patients 10).

2015

In a case series, pathophysiology of cranial nerve dysfunction in CPA epidermoid cysts was evaluated with special attention to a new mechanism of capsule strangulation caused by stratified tumor capsule. Twenty-two cases since 2005 were reviewed. Clinical status of the patients before the surgery and post-operative functional outcome were recorded. Available data from the English literature were summarized for comparison. Mass reduction of cyst contents in most cases was usually associated with prompt and marked improvement of the symptoms suggesting neurapraxia caused by compression of the tumor content and/or mild ischemia. Among them, two cases showed strangulation of the affected nerves by the tumor capsule whose preoperative dysfunction did not improve after surgery in spite of meticulous microsurgical removal of the lesion. Involved facial and abducent nerves in these two cases showed distortion of nerve axis and nerve atrophy distal to the strangulation site. Hasegawa et al. report the first direct evidence of etiology of cranial nerve dysfunction caused by cerebellopontine angle epidermoid tumors. Young age and rapidly progressive neurological deficit might be the characteristics for strangulation of the affected nerves by the cyst capsule. Even though the number of cases might be limited, immediate decompression and release of the strangulating band might be urged in such patients to prevent irreversible deficits 11)


Hu et al. performed a retrospective analysis of clinical data of 13 male and 17 female patients (mean age: 42.4 ± 11.4 years) who presented with a CPA epidermoid cyst and underwent whole course neuroendoscopy. Complications and tumor recurrence were assessed at follow-up. Results Clinical manifestations included an initial symptom of headache (n = 21), gait instability (n = 6), intracranial hypertension (n = 13), posterior cranial nerve symptoms (n = 6), ataxia (n = 5), and hydrocephalus (n = 1). All patients tolerated tumor resection with subsequent symptomatic improvement, and the results of the postoperative magnetic resonance imaging scan did not show any remnants of tumor. Mean duration of surgery was 2.61 ± 0.47 hours, mean loss of blood was 96.8 ± 35.4 mL, and the mean duration of hospitalization was 7.5 ± 2.25 days. Postoperative complications (8 of 30 [26.7%]) included fever (n = 5), communicating hydrocephalus (n = 1), facial nerve paralysis (n = 1), and abducens nerve palsy (n = 1). Tumor recurrence was observed in two patients (6.7%). No deaths or intracranial hemorrhage was reported.

The characteristics of epidermoid cysts make them amenable to whole course neuroendoscopic resection. Use of physiologic/pathologic interspaces and neuroendoscopic angulations decreases traction on the brain, improves complete resection rates, and decreases postoperative complications 12).

2010

Between 1996 and 2004, 10 patients with typical symptoms of trigeminal neuralgia were found to have cerebellopontine angle epidermoids and treated surgically.

Total resection was done in 6 patients (60%). Surgical removal of tumor and microvascular decompression of the trigeminal nerve were performed simultaneously in one case. One patient died due to postoperative aseptic meningitis. The others showed total relief from pain. During follow-up, no patients experienced recurrence of their trigeminal neuralgia (TN).

The clinical features of TN from CPA epidermoids are characterized by symptom onset at a younger age compared to TN from vascular causes. In addition to removal of the tumor, the possibility of vascular compression at the root entry zone of the trigeminal nerve should be kept in mind. If it exists, a microvascular decompression (MVD) should be performed. Recurrence of tumor is rare in both total and subtotal removal cases, but long-term follow-up is required 13).

1989

Thirty cases of cerebellopontine angle epidermoid cysts treated over a period of 20 years are reviewed with regard to their clinical features, the pathophysiology of their symptoms and their management. The predominating symptoms were related to the 7th and 8th cranial nerves and headaches. The signs and symptoms were present for an average period of 4 months. It was not always possible to determine if the signs and symptoms were due to local involvement by the epidermoid, increased intracranial pressure, or both. Diagnostic procedures evolved from angiography and ventriculography to non-invasive computed tomography and MRI. The posterior cranial fossa approach was used in 27 cases. Total excision of the epidermoid was the aim and was carried out in five (18%) patients but concern regarding the preservation of nearby important neurovascular structures forced partial removal in 22 patients. To minimise reformation, the residual epidermoid was carefully coagulated with the aid of the operating microscope and bipolar cautery without damaging surrounding neurovascular structures 14).

Case reports

2016

Malignant transformation of a residual cerebellopontine angle epidermoid cyst 15).

2015

Guan et al. the case of a 13-year-old female with a newly diagnosed cerebellopontine angle EC who presented with worsening headaches, photophobia, and emesis. Magnetic resonance imaging demonstrated significant pericystic brainstem edema and mass effect with effacement of the fourth ventricle. Refractory symptoms prompted repeat imaging, revealing cyst enlargement and dense rim enhancement. Resection of the EC resolved both her symptoms and the brainstem edema. This case documents the radiographic evolution of EC rupture and subsequent clinical course 16).


A case of an unusual epidermoid cyst of the cerebellopontine angle extending into the upper cervical canal that appeared hyper-dense on computed tomography scanning, hyper-intense on T1-weighted magnetic resonance (MR) images, and hypo-intense on T2-weighted MR images 17).

1)

Fleming JF, Botterell EH. Cranial dermoid and epidermoid tumors. Surg Gynecol Obstet. 1959;109:403–411.
2)

Fawcitt RA, Isherwood I. Radiodiagnosis of intracranial pearly tumours with particular reference to the value of computer tomography. Neuroradiology. 1976;11:235–242.
3) , 11)

Hasegawa M, Nouri M, Nagahisa S, Yoshida K, Adachi K, Inamasu J, Hirose Y, Fujisawa H. Cerebellopontine angle epidermoid cysts: clinical presentations and surgical outcome. Neurosurg Rev. 2015 Nov 14. [Epub ahead of print] PubMed PMID: 26566990.
4)

Berger M, Wilson C. Epidermoid cysts of the posterior fossa. J Neurosurg. 1985;62:214–219.
5) , 6) , 7) , 14)

deSouza CE, deSouza R, da Costa S, Sperling N, Yoon TH, Abdelhamid MM, Sharma RR, Goel A. Cerebellopontine angle epidermoid cysts: a report on 30 cases. J Neurol Neurosurg Psychiatry. 1989 Aug;52(8):986-90. PubMed PMID: 2795068; PubMed Central PMCID: PMC1031839.
8) , 12)

Hu Z, Guan F, Kang T, Huang H, Dai B, Zhu G, Mao B, Kang Z. Whole Course Neuroendoscopic Resection of Cerebellopontine Angle Epidermoid Cysts. J Neurol Surg A Cent Eur Neurosurg. 2015 Aug 24. [Epub ahead of print] PubMed PMID: 26302403.
9)

Hasegawa M, Nouri M, Nagahisa S, Yoshida K, Adachi K, Inamasu J, Hirose Y, Fujisawa H. Cerebellopontine angle epidermoid cysts: clinical presentations and surgical outcome. Neurosurg Rev. 2016 Apr;39(2):259-66; discussion 266-7. doi: 10.1007/s10143-015-0684-5. PubMed PMID: 26566990.
10)

Czernicki T, Kunert P, Nowak A, Wojciechowski J, Marchel A. Epidermoid cysts of the cerebellopontine angle: Clinical features and treatment outcomes. Neurol Neurochir Pol. 2016;50(2):75-82. doi: 10.1016/j.pjnns.2015.11.008. PubMed PMID: 26969562.
13)

Son DW, Choi CH, Cha SH. Epidermoid tumors in the cerebellopontine angle presenting with trigeminal neuralgia. J Korean Neurosurg Soc. 2010 Apr;47(4):271-7. doi: 10.3340/jkns.2010.47.4.271. PubMed PMID: 20461167; PubMed Central PMCID: PMC2864819.
15)

Pikis S, Margolin E. Malignant transformation of a residual cerebellopontine angle epidermoid cyst. J Clin Neurosci. 2016 Nov;33:59-62. doi: 10.1016/j.jocn.2016.04.008. Review. PubMed PMID: 27519146.
16)

Guan Z, Hollon T, Bentley JN, Garton HJ. Ruptured pediatric cerebellopontine angle epidermoid cyst: a case report detailing radiographic evolution and clinical course. J Neurosurg Pediatr. 2015 Aug 21:1-5. [Epub ahead of print] PubMed PMID: 26295366.
17)

Lim J, Cho K. Epidermoid cyst with unusual magnetic resonance characteristics and spinal extension. World J Surg Oncol. 2015 Aug 7;13:240. doi: 10.1186/s12957-015-0651-1. PubMed PMID: 26245481; PubMed Central PMCID: PMC4527251.

Update: Parinaud’s Syndrome

Parinaud’s syndrome (Paralysie des mouvements associe´s des yeux named for Henri Parinaud (1844–1905). 1) is a supranuclear paralysis of vertical gaze 2) resulting from damage to the mesencephalon 3).

Associations

Variants

Etiology

Parinaud’s Syndrome results from injury, which compresses the the quadrigeminal plate at the rostral interstitial nucleus of medial longitudinal fasciculus (riMLF), specifically, compression or ischemic damage of the mesencephalic tectum, including the superior colliculus adjacent oculomotor (origin of cranial nerve III) and Edinger-Westphal nuclei, causing dysfunction to the motor function of the eye.

Pineal region tumors.

A dilated suprapineal recess can compress the mesencephalic tectum, due to hydrocephalus.

Stroke or brainstem hemorrhage in the upper part.

Guillain Barré syndrome

Myasthenia gravis

Botulism

Hypothyroidism

Gradual benign loss of upgaze in senescence.


Sylvian aqueduct syndrome

Aberrant regeneration of the third nerve

Limited upgaze in elderly patients

Progressive supranuclear palsy

Niemann-pick disease

Whipple’s disease.


Classically, it has been associated with three major groups:

Pineal region tumor: Pinealoma (intracranial germinomas) are the most common lesion producing this syndrome).

Women in their 20s-30s with multiple sclerosis.


A 26 year old Pakistani lady with first presentation of a demyelinating event, presenting as Parinaud’s syndrome. A video demonstrates a convergence-retraction nystagmus on upgaze and failure of accommodation, and her brain imaging confirms a corresponding pre-tectal contrast enhancing T2 hyperintense lesion suggestive of demyelination 4).


Older patients following stroke of the upper brainstem However, any other compression, ischemia or damage to this region can produce these phenomena: obstructive hydrocephalus, midbrain hemorrhage, cerebral arteriovenous malformation, trauma and brainstem toxoplasmosis infection. Neoplasms and giant aneurysms of the posterior fossa have also been associated with the midbrain syndrome.

Vertical supranuclear ophthalmoplegia has also been associated with metabolic disorders, such as Niemann-Pick disease, Wilson’s disease, kernicterus, and barbiturate overdose.


Isolated Oculomotor Nerve Nucleus Infarct 5).


Unilateral vascular ischemic lesion 6).


A case of longstanding, undiagnosed spontaneous intracranial hypotension (SIH) with an acute presentation of Parinaud’s syndrome, in whom serial imaging demonstrated development of a midbrain mass. The patient was ultimately diagnosed with tumefactive venous infarction secondary to SIH. However, this patient underwent a brainstem biopsy, which in retrospect may have been avoidable. This case demonstrates the imaging features of tumefactive venous infarction in SIH and highlights the risk of misinterpretation as a neoplasm with potentially catastrophic consequences 7).


Migraine 8).


Miller Fisher syndrome 9).

Clinical features

Parinaud’s syndrome, includes multiple clinical signs, with the most prominent being paralysis of upward gaze.

Parinaud’s Syndrome is a cluster of abnormalities of eye movement and pupil dysfunction, characterized by:

Paralysis of upgaze: Downward gaze is usually preserved. This vertical palsy is supranuclear, so doll’s head maneuver should elevate the eyes, but eventually all upward gaze mechanisms fail.

Pseudo-Argyll Robertson pupils: Accommodative paresis ensues, and pupils become mid-dilated and show light-near dissociation.

Convergence-Retraction nystagmus: Attempts at upward gaze often produce this phenomenon. On fast up-gaze, the eyes pull in and the globes retract. The easiest way to bring out this reaction is to ask the patient to follow down-going stripes on an optokinetic drum.

Eyelid retraction (Collier’s sign) Conjugate down gaze in the primary position: “setting-sun sign”. Neurosurgeons will often see this sign most commonly in patients with failed ventriculoperitoneal shunts. It is also commonly associated with bilateral papilledema. It has less commonly been associated with spasm of accommodation on attempted upward gaze, pseudoabducens palsy (also known as thalamic esotropia) or slower movements of the abducting eye than the adducting eye during horizontal saccades, see-saw nystagmus and associated ocular motility deficits including skew deviation, oculomotor nerve palsy, trochlear nerve palsy and internuclear ophthalmoplegia.

Diagnosis

MRI is very helpful in determining the cause and thus guiding appropriate treatment.

Case reports

A 3-year-old boy presented with headache, disturbance of consciousness, and Parinaud’s syndrome. Magnetic resonance (MR) imaging revealed a pineal mass lesion, and total resection of the tumor was achieved. The histological diagnosis was mature teratoma. He did not receive further treatment, and did well without recurrence for 20 years. However, he suffered headache 21 years after resection, and MR imaging revealed a homogeneously enhanced pineal mass with low minimum apparent diffusion coefficient value and proton MR spectroscopy showed a huge lipid peak. The levels of tumor markers were not elevated. Cerebrospinal fluid (CSF) cytology found atypical cells with large nuclei and irregularly shaped nucleoli. To elucidate the relationship between the primary and recurrent tumors, we reviewed the histological specimens and CSF cytology at the initial treatment and found a subset of incompletely differentiated components resembling fetal tissues in the histological specimen and atypical large cells in the CSF. Based on these radiological and histological findings, Mano et al., presume that the recurrent disease was disseminated germinoma after the resection of disseminated IMT. He received chemotherapy and craniospinal radiation therapy, and the enhanced lesion and atypical cells in the CSF disappeared. This case demonstrates that disseminated IMT can be controlled for the long term without adjuvant therapy, but may recur as germinoma. Tumor dormancy may account for this unusual course 10).


1) Parinaud H. Paralysie des movements associe´s des yeux. Archives de Neurologie 1883;5:145–72.
2) Pierrot-Deseilligny C, Chain F, Gray M, et al. Parinaud’s syndrome. Brain 1982;105:667–96.
3) Pearce JM. Parinaud’s syndrome. J Neurol Neurosurg Psychiatry. 2005 Jan;76(1):99. PubMed PMID: 15608003; PubMed Central PMCID: PMC1739319.
4) Gnanapavan S, Sillery E, Acheson JF, Toosy AT. Parinaud’s syndrome – A rare presentation of clinically isolated syndrome. Mult Scler Relat Disord. 2014 May;3(3):398-401. doi: 10.1016/j.msard.2013.09.003. PubMed PMID: 25876480.
5) Kumar Y, Hooda K, Sapire J. A Case Report of Isolated Oculomotor Nerve Nucleus Infarct: A Rare Cause of Parinaud’s Syndrome. Conn Med. 2016 Mar;80(3):167-8. PubMed PMID: 27169301.
6) Serino J, Martins J, Páris L, Duarte A, Ribeiro I. Parinaud’s syndrome due to an unilateral vascular ischemic lesion. Int Ophthalmol. 2015 Apr;35(2):275-9. doi: 10.1007/s10792-015-0045-y. PubMed PMID: 25649259.
7) Bray TJ, Chandrashekar H, Rees J, Burke A, Merve A, Thust S. Venous infarction mimicking a neoplasm in spontaneous intracranial hypotension: an unusual cause of Parinaud’s syndrome. J Surg Case Rep. 2016 Mar 17;2016(3). pii: rjw037. doi: 10.1093/jscr/rjw037. PubMed PMID: 26987945; PubMed Central PMCID: PMC4794942.
8) Jumma OK, Hamdalla HM. Parinaud’s syndrome due to migraine. Can J Neurol Sci. 2013 Jan;40(1):125. PubMed PMID: 23427358.
9) Mallia M, Chircop C, Aquilina J. An unusual case of Parinaud’s syndrome. BMJ Case Rep. 2012 Nov 21;2012. pii: bcr2012006722. doi: 10.1136/bcr-2012-006722. PubMed PMID: 23175005; PubMed Central PMCID: PMC4544412.
10) Mano Y, Kanamori M, Kumabe T, Saito R, Watanabe M, Sonoda Y, Tominaga T. Extremely Late Recurrence 21 Years after Total Removal of Immature Teratoma: A Case Report and Literature Review. Neurol Med Chir (Tokyo). 2017 Jan 15;57(1):51-56. doi: 10.2176/nmc.cr.2016-0241. PubMed PMID: 27928096; PubMed Central PMCID: PMC5243165.

Update: Cerebellopontine angle lipoma

Characteristically lipomas of the CPA have the facial nerve and vestibulocochlear nerve coursing through it on their way to the IAM. They are associated with intravestibular lipomas and sensorineural hearing loss.

Epidemiology

They account for ~10% of all intracranial lipomas.

Diagnosis

Radiographic features

MRI brain Signal characteristics are those of a lipoma

T1: high signal

images.radiopaedia.org_images_2107232_e3e8537790364cc8a2404efc00cdd4_gallery.jpg

https://images.radiopaedia.org/images/2107232/e3e8537790364cc8a2404efc00cdd4_gallery.jpg

T2: high signal

true FISP/FIESTA: low signal margin due to chemical shift artefact fat saturated sequences: shows signal dropout.

http://www.otosurgery.org/DJL_NEWSITE%20images/MRI_cpa-lipoma.gif

Differential diagnosis

Cerebellopontine angle tumors (CPA) are frequent; vestibular schwannomas and cerebellopontine angle meningiomas represent the great majority of such tumors. However, a large variety of unusual lesions can also be encountered in the CPA. The site of origin is the main factor in making a preoperative diagnosis for an unusual lesion of the CPA. In addition, it is essential to analyze attenuation at computed tomography (CT), signal intensity at magnetic resonance (MR) imaging, enhancement, shape and margins, extent, mass effect, and adjacent bone reaction. CPA masses can primarily arise from the cerebellopontine cistern and other CPA structures (arachnoid cyst, nonacoustic schwannoma, aneurysm, melanoma, miscellaneous meningeal lesions) or from embryologic remnants (epidermoid cyst, dermoid cyst, lipoma). Tumors can also invade the CPA by extension from the petrous bone or skull base (cholesterol granuloma, paraganglioma, chondromatous tumors, chordoma, endolymphatic sac tumor, pituitary adenoma, apex petrositis). Finally, CPA lesions can be secondary to an exophytic brainstem or ventricular tumor (glioma, choroid plexus papilloma, lymphoma, hemangioblastoma, ependymoma, medulloblastoma, dysembryoplastic neuroepithelial tumor). A close association between CT and MR imaging findings is very helpful in establishing the preoperative diagnosis for unusual lesions of the CPA 1).


The differential for lesions with high T1 signal includes:

haemorrhagic vestibular schwannoma

neurenteric cyst

thrombosed berry aneurysm

white epidermoid

ruptured intracranial dermoid

Treatment

They are not associated with malformations and can become symptomatic in a slowly progressive way by affecting the more susceptible of the cranial nerves in this region. As a result of the rare occurrence, the experience in treating and managing these tumors is limited. Consequently, the recommendations for treatment and for the role of surgery are very variable 2).

Free article https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1656654/pdf/skullbasesurg00018-0039.pdf

Resections are considered in symptomatic patients who are refractory to targeted medical therapies, but at those stages the lipomas have often reached considerable sizes and encompass critical neurovascular structures.

Scoring system

The objective of a study is to develop and to evaluate the utility of a scoring system for CPA lipomas. The hypothesis is that CPA lipomas with lower scores are probably best managed with early surgery.

The PubMed database was searched using relevant terms. Data on patient and lipoma characteristics were extracted and used to design a scoring system. CPA lipomas were stratified by scores with corresponding managements and outcomes analyzed.

One hundred and seventeen patients with CPA lipomas were identified and 40 CPA lipomas were scored. The remaining CPA lipomas were deficient in data and not scored. No lipomas were scored as 1. Score 2 lipomas (n = 12; 30%) most often underwent serial surveillances (n = 5; 41.6%), with the majority of symptoms remaining unimproved (n = 2; 40%). Patients with score 2 CPA lipomas treated with medical therapies (n = 3; 25%) often experienced symptom resolution (n = 2; 66.6%) (p = 0.0499). Patients with score 2 CPA lipomas undergoing surgical resections (n = 3; 25%) all experienced symptom resolution (n = 3; 100%) (p = 0.0499). Score 3 was most common (n = 16; 40%) and these lipomas were often surgically resected (n = 10; 62.5%). The majority of patients with score 3 CPA lipomas having undergone surgical resections (n = 10; 62.5%) experienced symptom improvement (n = 1; 10%) or resolution (n = 4; 40%).

Score 2 CPA lipomas are smaller and would be deemed non-surgical in general practice. However, the data of Lagman et al., suggest that these lipomas may benefit from either medical therapies or early surgical resections. The advantages of early surgery are maximal resection, decreased surgical morbidity, and improved symptom relief 3).

Case series

2014

Of 15 patients with CPA lipomas, six were female and nine were male, with an average age at presentation of 50.2 years (range, 31.7-76.4 yr) and an average follow-up time of 51.7 months (range, 6-216 mo). The lipomas were unilateral in all cases, nine on the right (60%) and six on the left (40%) side. None of the lipomas increased in size. All patients were treated conservatively. Sensorineural hearing loss was the main presenting symptom (80%) followed by tinnitus (46.7%) and vertigo (20%). None of the patients suffered from facial nerve dysfunction. There was no correlation between weight gain and tumor growth.

CPA lipomas can be diagnosed accurately with appropriate magnetic resonance imaging techniques and be managed conservatively with safety. Cochleovestibular are the most common presenting symptoms, whereas facial nerve involvement is rare. CPA lipomas do not tend to grow and can be monitored on a less regular basis 4).

2013

Between 1996 and 2012, 15 patients were diagnosed with a CPA or IAC lipoma at the authors’ institution and were included in the analysis. The mean duration of radiological and clinical follow-up was 3.4 years and 5.1 years, respectively. Eight lesions were confined to the IAC, while seven involved the CPA. The median tumor size at diagnosis was 7.2 mm; one patient demonstrated tumor growth on serial MRI while the remaining subjects did not have radiological progression. The most common presenting symptoms were sensorineural hearing loss (40%) and tinnitus (33%); five patients were diagnosed after incidental discovery on MRI. Fourteen patients were managed with observation, while one subject underwent subtotal resection. None of the observed patients reported worsening symptoms at last follow-up.

While rare, lipomas should be included in the differential diagnosis of CPA and IAC lesions. Owing to a generally benign clinical course and high morbidity associated with resection, microsurgery should only be considered in cases of definite tumor enlargement with intractable symptoms from mass effect. Careful radiological evaluation is critical for establishing an accurate diagnosis in order to prevent unnecessary morbidity associated with resection 5).

2006

A healthy 42-year-old woman who presented with left-sided hearing loss and facial synkinesis. T1-weighted magnetic resonance imaging revealed an enhancing lesion of the left CPA with no signal on fat suppression sequences. Despite conservative therapy, the patient developed progressive hemifacial spasm, and a suboccipital craniotomy approach was used to debulk the tumor, which encased cranial nerves V, VII, VIII, IX, X, and XI. Surgical histopathology demonstrated mature adipocytes, consistent with lipoma. Two years after surgery, the patient remains free of facial nerve symptoms. Cerebellopontine angle lipomas are rare lesions of the skull base and are reliably diagnosed with T1-weighted and fat suppression magnetic resonance sequences, which we recommend in the routine radiologic workup of CPA tumors. Accurate preoperative diagnosis is crucial because most CPA lipomas should be managed conservatively. Partial surgical resection is indicated only to alleviate intractable cranial neuropathies or relieve brainstem compression 6).

2002

Tankéré et al., report four new cases of CPA lipomas diagnosed in the Department of Otorhinolaryngology-Head and Neck Surgery of Hôpital Pitié-Salpêtrière and review 94 cases reported previously in the literature.

Lipomas represented 0.14% of CPA and internal acoustic meatus tumors. Localization was on the left side in 59.9%, on the right side in 37%, and bilateral in 3.1% of the patients. The diagnosis was confirmed radiologically in 33 of 98 patients, surgically in 60 patients, and by autopsy in 5 patients. The most frequent associated symptoms were of cochleovestibular origin, such as hearing loss (62.2%), dizziness (43.3%), and unilateral tinnitus (42.2%). Other associated symptoms involved the facial nerve (9%) or the trigeminal nerve (14.4%). Complete resection was performed in only 32.8% of the patients with frequent cranial nerve involvement. Frequent cranial nerve involvement was seen in 95.4% of all patients. After surgery, patient symptomatology was unchanged in 9.2% of the patients, and 50% were improved; however, new postoperative deficits occurred in two-thirds of the patients. Overall, 72.2% of the patients experienced new postoperative deficits such as hearing loss (64.8%). Preservation of hearing was possible in only 26% of the patients. Only 18% of patients were improved after surgery without any new postoperative deficits.

Preoperative diagnosis of internal acoustic meatus/CPA lipomas is based on magnetic resonance imaging. The aim of surgery in these cases is not tumor removal but cranial nerve decompression or vestibular transection, and surgery is performed only in patients with disabling and uncontrolled symptoms 7).

1998

17 IAC/CPA lipomas, bringing the total number of documented cases to 84 in 1998. There appears to be a nearly 2:1 male to female predominance. Sixty percent were left-sided lesions, and three were bilateral. Hearing loss, dizziness, and tinnitus were the most common presenting symptoms. Surgical resection was performed in 52 (62%) of these lesions; however, total tumor removal was accomplished in only 17 (33%), which is most likely because of the fact that these tumors tend to have a poorly defined matrix and a dense adherence to neurovascular structures. Sixty-eight percent of patients experienced a new deficit postoperatively, 11% were unchanged, and only 19% improved with no new deficit. Only one documented case of tumor growth was identified; however, the reported follow-up was short (average, less than 3 years).

With the magnetic resonance imaging techniques now available, lipomas can be reliably differentiated from other masses within the CPA and IAC, so histopathologic diagnosis is rarely necessary. Because of the potential for significant morbidity with resection of these lesions, we believe that conservative follow-up is the best treatment option for patients with these rare lesions. Surgery is indicated only when significant progressive or disabling symptoms are present 8).

Case reports

2012

A 5-year-old boy was evaluated for recurrent primary generalized seizures of 20 days duration. He had preceding headache, vomiting for which he was subjected to a Magnetic resonance imaging (MRI) scan of the brain. Imaging studies revealed a hyperintense mass in the right CPA suggestive of lipoma/epidermoid. He was referred to us for further management.

Basic routine blood investigations were essentially normal. His vital parameters were stable. He was conscious, oriented, and obeying commands. Child was active and had no motor/sensory/cranial nerve deficits. Plantars were bilaterally flexor with normal deep tendon reflexes. MR imaging has now achieved a very high sensitivity and specificity for detecting lipomas. On T1-weighted MR images, lipomas typically appear hyperintense compared with brain tissue and hyperintense on T2-weighted MR images. MRI scan of the brain was done and the findings is given below.

Multiplanar, multisequences, MR imaging, including SE T1 axial, flair axial, FSE T2 axial were done. Postcontrast T1-weighted multiplanar sequences were also performed.

A 17mm (trans) ×15mm (AP) × 15mm (CC) well-encapsulated mass lesion noted in the right CP angle which was hyperintense on T1, T2, and FLAIR with inversion on fat suppression sequence. The lesion was situated inferior to the right Vth nerve and indenting upon right lower pons and medulla. The right VIIth and VIIIth nerves and superior cerebellar artery were encased by the lesion. No evidence of tumor extension into IAC was noted. There was neither significant shift nor hydrocephalus. Right cerebello pontine angle tumor–lipoma/epidermoid.

A right retro sigmoid suboccipital approach was chosen to expose the tumor. The lesion was extra-axial, yellowish and surrounding the seventh and eighth nerve complex. Branches of the AICA were embedded in the tumor. The lesion was partially decompressed. Neurovascular structures were preserved. There were no postoperative deficits.

Histopathological evaluation revealed it to be lipoma-right CP angle

These tumors can cause symptoms related to the VIII nerve involvement, such as hearing loss, tinnitus, and vertigo. However, trigeminal symptoms such as neuralgia, paresthesia or headache, can also occur with CPA lipomas extending to the trigeminal cisterns.

This patient presented with headache, and seizures. Neuroimaging revealed a hypodense mass in the right CPA suggestive of lipoma/epidermoid. He underwent surgical exploration and decompression of the tumor. Histopathology confirmed it as lipoma 9).

2009

A 13-year-old female patient was evaluated due to a 1-year history of headache and hearing loss. The physical examination was unremarkable. The audiometric evaluation demonstrated a discrete sensorineural hearing loss on the right side. The CT scan revealed a markedly hypodense non-enhancing mass in the right CPA. The MR imaging showed a lesion measuring 2.1 × 2.0 × 1.7 cm in the right CPA cistern. The mass was hyperintense on T1-weighted images and isointense with hypointense halo (chemical-shift) on T2-weighted images, with very low signal on T1-weighted images with fat suppression (Figs 1 and 2). The VII and VIII cranial nerves were seen as linear images with low signal inside the CPA mass. The diagnosis of CPA lipoma was suggested and the surgical treatment was chosen once the patient was young and the chance of lesion growing and future complications was considerable. A craniotomy with posterior fossa approach was performed, the lesion was partially removed, and the histological examination confirmed the diagnosis of lipoma. Six months after the surgery the patient remains asymptomatic. The parent signed the informed consent agreeing with the study.

Case 2

A 35-year-old woman presented with a six-month history of vertigo, without significant abnormalities on physical examination. A CT scan revealed a left-sided hypodense non-enhancing CPA mass. The MR imaging showed a left CPA cistern hyperintense lesion on T1-wheighted images and isointense with hypointense halo (chemical-shift) on T2-weighted images, measuring 1.4 × 1.3 cm and showing no enhancement after contrast administration (Fig 3). The diagnosis of CPA lipoma was suggested and the patient was managed conservatively. The symptoms were controlled with medical therapy. The follow-up MR imaging performed one year later showed no significant modifications 10).

1997

The case of an extensive lipoma of the cerebellopontine angle (CPA) represents 0.05% of all CPA tumors operated on in a department from 1978 to 1996. The lipoma constitutes an important differential diagnosis because the clinical management differs significantly from other CPA lesions. The clinical presentation and management of the presented case are analyzed in comparison to all previously described cases of CPA lipomas. The etiology and the radiological features of CPA lipomas are reviewed and discussed. CPA lipomas are maldevelopmental lesions that may cause slowly progressive symptoms. Neuroradiology enables a reliable preoperative diagnosis. Attempts of complete lipoma resection usually result in severe neurological deficits. Therefore, we recommend a conservative approach in managing these patients. Limited surgery is indicated if the patient has an associated vascular compression syndrome or suffers from disabling vertigo 11).

1994

Two patients with cerebellopontine angle (CPA) lipoma were studied. They were submitted to surgical treatment. Available literature was reviewed and 29 cases with same lesion were identified which had been treated by surgery. Clinical manifestations, possibility of diagnostic methods, surgical indications and treatment strategies are discussed. Attention is called to the peculiarities of CPA lipomas and the doubtful validity of attempting complete excision in all cases12).


1) Bonneville F, Sarrazin JL, Marsot-Dupuch K, Iffenecker C, Cordoliani YS, Doyon D, Bonneville JF. Unusual lesions of the cerebellopontine angle: a segmental approach. Radiographics. 2001 Mar-Apr;21(2):419-38. PubMed PMID: 11259705.
2) , 11) Schuhmann MU, Lüdemann WO, Schreiber H, Samii M. Cerebellopontine angle lipoma: a rare differential diagnosis. Skull Base Surg. 1997;7(4):199-205. PubMed PMID: 17171031; PubMed Central PMCID: PMC1656654.
3) Lagman C, Voth BL, Chung LK, Bui TT, Lee SJ, Barnette NE, Gopen Q, Yang I. Evaluating the utility of a scoring system for lipomas of the cerebellopontine angle. Acta Neurochir (Wien). 2017 Jan 21. doi: 10.1007/s00701-017-3076-5. [Epub ahead of print] PubMed PMID: 28110401.
4) Kontorinis G, Freeman SR, Potter G, Rutherford SA, Siripurapu R, King AT, Lloyd SK. Management of cerebellopontine angle lipomas: need for long-term radiologic surveillance? Otol Neurotol. 2014 Jun;35(5):e163-8. doi: 10.1097/MAO.0000000000000395. PubMed PMID: 24691513.
5) White JR, Carlson ML, Van Gompel JJ, Neff BA, Driscoll CL, Lane JI, Link MJ. Lipomas of the cerebellopontine angle and internal auditory canal: Primum Non Nocere. Laryngoscope. 2013 Jun;123(6):1531-6. doi: 10.1002/lary.23882. PubMed PMID: 23401141.
6) Brodsky JR, Smith TW, Litofsky S, Lee DJ. Lipoma of the cerebellopontine angle. Am J Otolaryngol. 2006 Jul-Aug;27(4):271-4. PubMed PMID: 16798407.
7) Tankéré F, Vitte E, Martin-Duverneuil N, Soudant J. Cerebellopontine angle lipomas: report of four cases and review of the literature. Neurosurgery. 2002 Mar;50(3):626-31; discussion 631-2. Review. PubMed PMID: 11841733.
8) Bigelow DC, Eisen MD, Smith PG, Yousem DM, Levine RS, Jackler RK, Kennedy DW, Kotapka MJ. Lipomas of the internal auditory canal and cerebellopontine angle. Laryngoscope. 1998 Oct;108(10):1459-69. Review. PubMed PMID: 9778284.
9) Venkataramana N, Rao SA, Naik AL, Chaitanya K, Murthy P. Cerebello pontine angle lipoma in a child. J Pediatr Neurosci. 2012 Jan;7(1):75-7. doi: 10.4103/1817-1745.97635. PubMed PMID: 22837790; PubMed Central PMCID: PMC3401666.
10) Borges RS, Brito CC, Carvalho GA, Domingues RC, Gasparetto EL. Cerebellopontine angle lipomas: magnetic resonance imaging findings in two cases. Arq Neuropsiquiatr. 2009 Jun;67(2B):496-8. PubMed PMID: 19623450.
12) Ferreira MP, Ferreira NP, Lenhardt R. Lipoma of the cerebellopontine angle. Case reports and literature review. Arq Neuropsiquiatr. 1994 Mar;52(1):58-63. Review. PubMed PMID: 8002809.

Nanoparticles in Neurosurgery

Nanoparticles have been emerged as a promising platform to treat different types of tumors due to their ability to transport drugs to target sites while minimizing adverse effects.

Hyaluronan (HA)-grafted lipid-based nanoparticles (LNPs). These LNPs having an ionized lipid were previously shown to be highly effective in delivering small interfering RNAs (siRNAs) into various cell types. LNP’s surface was functionalized with hyaluronan (HA), a naturally occurring glycosaminoglycan that specifically binds the CD44 receptor expressed on GBM cells.

Cohen et al. found that HA-LNPs can successfully bind to glioblastoma GBM cell lines and primary neurosphers of GBM patients. HA-LNPs loaded with Polo-Like Kinase 1 (PLK1) siRNAs (siPLK1) dramatically reduced the expression of PLK1 mRNA and cumulated in cell death even under shear flow that simulate the flow of the cerebrospinal fluid compared with control groups. Next, a human GBM U87MG orthotopic xenograft model was established by intracranial injection of U87MG cells into nude mice. Convection of Cy3-siRNA entrapped in HA-LNPs was performed, and specific Cy3 uptake was observed in U87MG cells. Moreover, convection of siPLK1 entrapped in HA-LNPs reduced mRNA levels by more than 80% and significantly prolonged survival of treated mice in the orthotopic model. Taken together, this results suggest that RNAi therapeutics could effectively be delivered in a localized manner with HA-coated LNPs and ultimately may become a therapeutic modality for GBM 1).


Cy5.5 conjugated MnO nanoparticles for magnetic resonance/near-infrared fluorescence dual-modal imaging of brain gliomas 2).


Solid lipid nanoparticles (SLNs) conjugated with tamoxifen (TX) and lactoferrin (Lf) were applied to carry anticancer carmustine (BCNU) across the blood-brain barrier (BBB) for enhanced antiproliferation against glioblastoma multiforme (GBM). BCNU-loaded SLNs with modified TX and Lf (TX-Lf-BCNU-SLNs) were used to penetrate a monolayer of human brain-microvascular endothelial cells (HBMECs) and human astrocytes and to target malignant U87MG cells. The surface TX and Lf on TX-Lf-BCNU-SLNs improved the characteristics of sustained release for BCNU. When compared with BCNU-loaded SLNs, TX-Lf-BCNU-SLNs increased the BBB permeability coefficient for BCNU about ten times. In addition, TX-BCNU-SLNs considerably promoted the fluorescent intensity of intracellular acetomethoxy derivative of calcein (calcein-AM) in HBMECs via endocytosis. However, the conjugated Lf could only slightly increase the fluorescence of calcein-AM. Moreover, the order of formulation in the inhibition to U87MG cells was TX-Lf-BCNU-SLNs>TX-BCNU-SLNs>Lf-BCNU-SLNs>BCNU-SLNs. TX-Lf-BCNU-SLNs can be effective in infiltrating the BBB and delivering BCNU to GBM for future chemotherapy application 3)


Senders et al., systematically review all clinically tested fluorescent agents for application in fluorescence guided surgery (FGS) for glioma and all preclinically tested agents with the potential for FGS for glioma.

They searched the PubMed and Embase databases for all potentially relevant studies through March 2016.

They assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.

The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5 aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.

5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives. 4).


1) Cohen ZR, Ramishetti S, Peshes-Yaloz N, Goldsmith M, Wohl A, Zibly Z, Peer D. Localized RNAi Therapeutics of Chemoresistant Grade IV Glioma Using Hyaluronan-Grafted Lipid-Based Nanoparticles. ACS Nano. 2015 Jan 8. [Epub ahead of print] PubMed PMID: 25558928.
2) Chen N, Shao C, Li S, Wang Z, Qu Y, Gu W, Yu C, Ye L. Cy5.5 conjugated MnO nanoparticles for magnetic resonance/near-infrared fluorescence dual-modal imaging of brain gliomas. J Colloid Interface Sci. 2015 Jun 30;457:27-34. doi: 10.1016/j.jcis.2015.06.046. [Epub ahead of print] PubMed PMID: 26151564.
3) Kuo YC, Cheng SJ. Brain targeted delivery of carmustine using solid lipid nanoparticles modified with tamoxifen and lactoferrin for antitumor proliferation. Int J Pharm. 2016 Feb 29;499(1-2):10-9. doi: 10.1016/j.ijpharm.2015.12.054. Epub 2015 Dec 22. PubMed PMID: 26721730.
4) Senders JT, Muskens IS, Schnoor R, Karhade AV, Cote DJ, Smith TR, Broekman ML. Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir (Wien). 2017 Jan;159(1):151-167. doi: 10.1007/s00701-016-3028-5. Review. PubMed PMID: 27878374; PubMed Central PMCID: PMC5177668.

Update: Craniopharyngioma malignant transformation

Epidemiology

Sofela et al., conducted in 2014 conducted a PUBMED, SCOPUS, OVID SP, and INFORMA search with a combination of key words: craniopharyngioma, malignancy, transformation, neoplasm, radiation therapy, and anaplastic. They identified 23 cases relevant to our study.

Median age at the time of diagnosis of malignant craniopharyngiomas was 31 years (range, 10-66 years); 52.6% of the patients were female. Histologically, the most common tumor types were squamous cell carcinoma (80.96%), with adamantinomatous cell type being the most common morphology (89.47%).

Sofela et al., found that 21.7% of the cases were diagnosed as malignant craniopharyngioma at first biopsy. Of the rest, the median time from initial benign diagnosis to MT was 8.5 years (range, 3-55 years). Median overall survival after MT was 6 months (range, 2 weeks-5 years). Using the Spearman rank correlation, we found no correlation between the use of radiation therapy (correlation coefficient, -0.25; P < .05) or its dosage (correlation coefficient, -0.26; P < .05) and MT 2).

Pathogenesis

The exact cause and pathogenesis of this MT are unknown, although the literature has suggested a possible correlation with radiotherapy 3).

Radiation therapy and p53 mutations could be involved in malignant transformation in craniopharyngioma 4).

Histology

It assumes varied histologic appearances, usually after multiple recurrences and radiation therapy, and has a near uniformly fatal outcome. De novo malignancy in odontogenic tumors of the sella is even more unusual, but also has an ominous prognosis 5).

Outcome

Malignant craniopharyngiomas are associated with a poor prognosis. MTs occur years after the initial benign craniopharyngioma diagnosis and are associated with multiple benign craniopharyngioma recurrence. Results also show that, contrary to widespread belief, there is a poor correlation between radiotherapy and MT 6).

Case reports

2017

Jeong et al., report the case of a 26-year-old male patient who underwent suprasellar mass excision via an interhemispheric transcallosal approach. Histopathological examination indicated that the craniopharyngioma was of the adamantinomatous subtype. The patient received postoperative medical treatment for endocrine dysfunction and diabetes mellitus without radiation treatment. Two years after the operation, he presented with progressive visual disturbance and altered mentality. Magnetic resonance imaging revealed a huge mass in the suprasellar cistern and third ventricle. He underwent a second operation via the same approach. The histopathological examination showed an adamantinomatous craniopharyngioma with sheets of solid proliferation in a spindled pattern, indicating malignant transformation 7).

2015

A 29-year-old male patient was admitted into hospital with the main complaint of progressive visual disturbance. Both CT SCAN and MRI demonstrated a cystic-solid contrast-enhancing sellar-suprasellar mass with obvious calcification. Histopathological examination of the first resected specimen showed a typical appearance of adamantinomatous craniopharyngioma. The patient received gamma knife therapy after his first operation because of partial tumor removal. He experienced two relapses in the subsequent 2 years, for which only surgical resection was performed. The later histopathology presented malignant appearance with tumor cells moderate to severe pleomorphism, hyperchromasia, increased nuclear cytoplastic ratio, high mitotic activity (30/10 high power fields) and focal coagulative necrosis. The patient died 9 months after identification of histologic malignancy. Clinical and histopathological features, biological behavior of one case of malignant craniopharyngioma were discussed, with a brief review of the relevant literature 8).

2014

Malignant transformation of craniopharyngioma in an infradiaphragmatic case 9).

2011

A 66-year-old female who presented with visual disturbance and radiological evidence of a sellar and suprasellar tumor. The patient underwent transsphenoidal biopsy followed by pterional craniotomy with partial tumor removal. Histological diagnosis documented a malignant adamantinomatous type craniopharyngioma. The patient received adjuvant radiotherapy with a significant tumor reduction. She remained in good clinical conditions for 10 months; she deteriorated and died, due to tumor progression, 15 months after diagnosis.

This is the first case of de novo malignant craniopharyngioma with significant follow-up 10).


Gao et al., report a case of ameloblastic carcinoma arising from a previously benign craniopharyngioma in a 42-year-old woman. The patient was diagnosed with craniopharyngioma in August 2004 and underwent surgical resection of a typical craniopharyngioma, the pathological result was craniopharyngioma, papillary and adamantinomatous types. During the subsequent 5 years, this patient experienced two recurrences, for which surgical resections were performed without radiotherapy. The last two pathologic diagnoses were malignant craniopharyngiomas and there was more apparent sign of malignancy in the third pathologic section 11).

2010

Aquilina et al., describe 2 additional pediatric cases. Treatment in both of these cases consisted of multiple resections and external beam radiation therapy (EBRT). Malignant transformation occurred 7 and 8 years after EBRT. The authors also review another 6 cases in adults. A possible causative association with radiation therapy is discussed. As radiation is currently an important option in the management of craniopharyngiomas, this association requires further study 12).


A 32-year-old man presented with malignant craniopharyngioma associated with moyamoya syndrome manifesting as right visual disturbance. Magnetic resonance (MR) imaging revealed a parasellar mass lesion diagnosed as adamantinomatous craniopharyngioma. He underwent three surgical procedures and repeated courses of radiotherapy, and was able to resume his daily life. MR imaging demonstrated tumor regrowth and bilateral occlusions of the internal carotid arteries (ICAs) with basal moyamoya phenomenon, which might have been induced by irradiation and/or tumor compression, 10 years after the initial manifestations. Sufficient debulking was safely achieved via the transsphenoidal route and histological examination revealed squamous cell carcinoma, indicating malignant transformation of craniopharyngioma. The tumor relapsed after only one month, so transsphenoidal tumor debulking was tried again. However, the postoperative course was unfavorable because of intraoperative bleeding from the right ICA. Malignant transformation of craniopharyngioma may be included in moyamoya syndrome. The treatment strategy should be carefully considered in such a complicated situation 13).


Ishida et al.,report a case of malignant transformation in craniopharyngioma after radiation therapy.

Histopathological and immunohistochemical analyses were carried out for specimens of the suprasellar tumor (from three resections, with the third surgery performed after radiation therapy).

The resected tumors from the first and second surgeries comprised islands of loosely cohesive aggregates of epithelial cells, so-called stellate reticulum. At the periphery of the nests, palisaded columnar epithelium was observed. Wet keratins were scattered, and few mitotic figures were seen. The third surgical specimen was composed of irregular large nests of basaloid cells that had large, round to oval nuclei with prominent nucleoli, and mitotic figures were frequently seen (21/10 high power fields). In the center of the nests, eosinophilic ghost cells, resembling wet keratin, were observed. Accordingly, the diagnosis of malignant transformation in craniopharyngioma was made. Immunohistochemical studies revealed that the p53 protein was over-expressed in the malignant component, whereas its expression was much lower in the benign component.

Similar to the ten previously reported cases of malignant transformation in craniopharyngioma, the present case occurred after radiation therapy. p53 protein overexpression was also observed in the earlier cases of malignant craniopharyngioma as well as in the present case (6/6 cases). They concluded that radiation therapy and p53 mutations could be involved in malignant transformation in craniopharyngioma 14).

2009

A case of malignant craniopharyngioma in a 46-year-old woman presenting clinically with visual disturbance and bifrontal headache is reported. Histopathologic examination of the suprasellar mass showed a lesion characterized by nests of epithelial cells with a basaloid appearance, round-to-oval nuclei, moderate pleomorphism, hyperchromasia, increased nuclear cytoplastic ratio and high mitotic activity. Immunohistochemically, the tumor cells were positive for Ki-67 (44.3%), p53 (98%), and p63 (100%), but negative for estrogen and progesterone receptors 15).

2007

Rodriguez et al., report 3 patients with craniopharyngiomas exhibiting histologic malignancy, 2 of which received radiation therapy before its appearance. Hematoxylin and eosin-stained slides and selected immunohistochemical stains were reviewed in all cases. Microvessel density analysis was performed in case 2. The patients included 2 men and 1 woman, age 14, 31, and 58 years at presentation, respectively. All patients expired 3 months to 9 years after first resection and 3 to 9 months after identification of histologic malignancy. The latter developed after multiple recurrences and radiation therapy in 2 cases, but seemed to arise de novo in 1 case resembling odontogenic ghost cell carcinoma and lacking any definite low-grade craniopharyngioma precursor. The malignant component of the other 2 cases resembled squamous cell carcinoma and low-grade myoepithelial carcinoma, respectively. The MIB-1 labeling index was markedly increased in the malignant component in comparison with the low-grade precursor 16).

2006

Malignant transformation of craniopharyngioma: a case report 17).

2004

A 21-year-old woman, who developed a malignant tumour arising from a craniopharyngioma 14 years after the original diagnosis. The remarkable response of this malignant tumour ex-craniopharyngioma to cis-platin based chemotherapy, together with other midline tumour characteristics of craniopharyngioma, raise the question as to whether craniopharyngioma should any longer be separately considered from suprasellar germ cell tumour 18).

2000

Kristopaitis et al., describe a case of squamous cell carcinoma arising in a previously benign craniopharyngioma in a 42-year-old woman. The patient was diagnosed with craniopharyngioma in 1982; during the subsequent 15 years she experienced 7 tumor recurrences, for which surgical resections and 3 courses of radiotherapy were performed. In 1998, the tumor recurred with involvement of the nasal cavity and sphenoid and ethmoid sinuses. Histologic evaluation revealed foci of typical adamantinomatous craniopharyngioma associated with a moderately differentiated squamous cell carcinoma. The transition of typical craniopharyngioma to squamous cell carcinoma was well demonstrated, suggesting that carcinoma arose from the underlying craniopharyngioma. Radiation may have been a contributing factor to carcinogenesis in this case 19).

1999

Virik et al., report a further case of malignant transformation in recurrent craniopharyngioma following radiotherapy 20).

1989

Two cases of a craniopharyngioma with malignant transformation are reported. Case 1 involved a 3-year-old male who had received a partial resection and radiotherapy for a suprasellar tumor. Histologically, a biopsy specimen showed craniopharyngioma. Eight years later, the child died of an intracerebral and nasopharyngeal invasion of the recurrent tumor. Case 2 involved a 9-year-old male who initially had been diagnosed as having a craniopharyngioma in the suprasellar region. Five years after the first operation, he died from growth of the tumor in spite of radiotherapy and a partial resection. The pathological examinations of these two cases showed an apparent transition of the craniopharyngioma into a squamous cell carcinoma 21).

1988

A 49-year-old woman presented with recurrence of a suprasellar craniopharyngioma diagnosed 35 years previously. The patient had been treated surgically for recurrence on five occasions. Radiation therapy had been administered 7 years before the final presentation. Tissue obtained from the fifth operation revealed malignant degeneration in a typical craniopharyngioma 22).

1987

Akachi et al., report a rare case of a 10-year-old girl with craniopharyngioma which showed malignant change after the first operation and irradiation. In June 1981, the patient complained of headache, nausea and vomiting. CT revealed obstructive hydrocephalus due to the calcified mass lesion which extended to the third ventricle. In order to alleviate the high intracranial pressure, the right ventriculo-peritoneal shunt was first settled and after that, partial removal of the tumor was performed. The pathological diagnosis of the specimen was typical adamantinomatous type of craniopharyngioma without any findings of malignancy. After this operation irradiation was performed. The tumor almost disappeared and the patient was discharged from the hospital and went to school, showing some signs of panhypopituitarism. In May 1984, she complained of decreased left visual acuity, right temporal anopsia, headache, nausea and vomiting. CT revealed recurrence of the tumor which obstract the foramen of Monro bilaterally. As an emergency measure, the left ventriculo-peritoneal shunt was added and the state of the patient became recovered. In order to improve decreased visual acuity, the tumor located around the optic nerves and over the frontal base was removed in June 1984, resulting in partial improvement of visual acuity bilaterally. The pathological examination of the second specimen showed, in addition to the part of adamantinomatous type of craniopharyngioma which was the same as before, the existence of thick layer of stratified large atypical cells which partially covered the cyst wall and partially invaded into the surrounding tissues. The pathological diagnosis was poorly differentiated squamous cell carcinoma with craniopharyngioma of ‘adamantinoma’ type 23).


1) Akachi K, Takahashi H, Ishijima B, Nakamura Y, Oda M, Takizawa T, Iwamoto M, Kuriyama G, Shizuki K. [Malignant changes in a craniopharyngioma]. No Shinkei Geka. 1987 Aug;15(8):843-8. Japanese. PubMed PMID: 3431651.
2) , 6) Sofela AA, Hettige S, Curran O, Bassi S. Malignant transformation in craniopharyngiomas. Neurosurgery. 2014 Sep;75(3):306-14; discussion 314. doi: 10.1227/NEU.0000000000000380. Review. PubMed PMID: 24978859.
3) Virik K, Turner J, Garrick R, Sheehy JP. Malignant transformation of craniopharyngioma. J Clin Neurosci. 1999 Nov;6(6):527-30. PubMed PMID: 18639199.
4) , 14) Ishida M, Hotta M, Tsukamura A, Taga T, Kato H, Ohta S, Takeuchi Y, Nakasu S, Okabe H. Malignant transformation in craniopharyngioma after radiation therapy: a case report and review of the literature. Clin Neuropathol. 2010 Jan-Feb;29(1):2-8. Review. PubMed PMID: 20040326.
5) , 16) Rodriguez FJ, Scheithauer BW, Tsunoda S, Kovacs K, Vidal S, Piepgras DG. The spectrum of malignancy in craniopharyngioma. Am J Surg Pathol. 2007 Jul;31(7):1020-8. PubMed PMID: 17592268.
7) Jeong TS, Yee GT, Kim NR. Malignant Transformation of Craniopharyngioma without Radiation Therapy: Case Report and Review of the Literature. J Korean Neurosurg Soc. 2017 Jan 1;60(1):108-113. doi: 10.3340/jkns.2015.0707.022. PubMed PMID: 28061501.
8) Wang W, Chen XD, Bai HM, Liao QL, Dai XJ, Peng DY, Cao HX. Malignant transformation of craniopharyngioma with detailed follow-up. Neuropathology. 2015 Feb;35(1):50-5. doi: 10.1111/neup.12142. PubMed PMID: 25112406.
9) Lu Y, Qi S, Peng J, Pan J, Zhang X. Malignant transformation of craniopharyngioma in an infradiaphragmatic case. Chin Med J (Engl). 2014;127(17):3187-8. PubMed PMID: 25189968.
10) Lauriola L, Doglietto F, Novello M, Signorelli F, Montano N, Pallini R, Maira G. De novo malignant craniopharyngioma: case report and literature review. J Neurooncol. 2011 Jun;103(2):381-6. doi: 10.1007/s11060-010-0382-7. Review. PubMed PMID: 20814809.
11) Gao S, Shi X, Wang Y, Qian H, Liu C. Malignant transformation of craniopharyngioma: case report and review of the literature. J Neurooncol. 2011 Jul;103(3):719-25. doi: 10.1007/s11060-010-0407-2. Review. PubMed PMID: 20872276.
12) Aquilina K, Merchant TE, Rodriguez-Galindo C, Ellison DW, Sanford RA, Boop FA. Malignant transformation of irradiated craniopharyngioma in children: report of 2 cases. J Neurosurg Pediatr. 2010 Feb;5(2):155-61. doi: 10.3171/2009.9.PEDS09257. PubMed PMID: 20121363.
13) Ujifuku K, Matsuo T, Takeshita T, Hayashi Y, Hayashi K, Kitagawa N, Hayashi T, Suyama K, Nagata I. Malignant transformation of craniopharyngioma associated with moyamoya syndrome. Neurol Med Chir (Tokyo). 2010;50(7):599-603. PubMed PMID: 20671391.
15) Boongird A, Laothamatas J, Larbcharoensub N, Phudhichareonrat S. Malignant craniopharyngioma; case report and review of the literature. Neuropathology. 2009 Oct;29(5):591-6. doi: 10.1111/j.1440-1789.2008.00986.x. Review. PubMed PMID: 19077042.
17) Yue Y, Da JP. [Malignant transformation of craniopharyngioma: a case report]. Zhonghua Bing Li Xue Za Zhi. 2006 Jul;35(7):439. Chinese. PubMed PMID: 17069689.
18) Plowman PN, Besser GM, Shipley J, Summersgill B, Geddes J, Afshar F. Dramatic response of malignant craniopharyngioma to cis-platin-based chemotherapy. Should craniopharyngioma be considered as a suprasellar ‘germ cell’ tumour? Br J Neurosurg. 2004 Oct;18(5):500-5. PubMed PMID: 15799153.
19) Kristopaitis T, Thomas C, Petruzzelli GJ, Lee JM. Malignant craniopharyngioma. Arch Pathol Lab Med. 2000 Sep;124(9):1356-60. PubMed PMID: 10975938.
20) Virik K, Turner J, Garrick R, Sheehy JP. Malignant transformation of craniopharyngioma. J Clin Neurosci. 1999 Nov;6(6):527-30. PubMed PMID: 18639199.
21) Suzuki F, Konuma I, Matsumoto M, Aoki M, Hayakawa I. [Craniopharyngioma with malignant transformation–a report of two cases]. Gan No Rinsho. 1989 May;35(6):723-8. Review. Japanese. PubMed PMID: 2657129.
22) Nelson GA, Bastian FO, Schlitt M, White RL. Malignant transformation in craniopharyngioma. Neurosurgery. 1988 Feb;22(2):427-9. PubMed PMID: 3352897.
23) Akachi K, Takahashi H, Ishijima B, Nakamura Y, Oda M, Takizawa T, Iwamoto M, Kuriyama G, Shizuki K. [Malignant changes in a craniopharyngioma]. No Shinkei Geka. 1987 Aug;15(8):843-8. Japanese. PubMed PMID: 3431651.

Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation in neurosurgery

Autologous stem-cell transplantation is distinguished from allogenic stem cell transplantation where the donor and the recipient of the stem cells are different people.


The number of studies examining the use of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) to treat high-risk or recurrent brain tumors is increasing.

Case series

2017

Lee et al., retrospectively reviewed the medical records of 30 patients with High Grade Gliomas (HGGs) (16 glioblastomas, 7 anaplastic astrocytomas, and 7 other HGGs) between 2006 and 2015. Gross total resection or near total resection was possible in 11 patients. Front-line treatment after surgery was radiotherapy (RT) in 14 patients and chemotherapy in the remaining 16 patients including 3 patients less than 3 years of age. Eight of 12 patients who remained progression free and 5 of the remaining 18 patients who experienced progression during induction treatment underwent the first high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) with carboplatin + thiotepa + etoposide (CTE) regimen and 11 of them proceeded to the second HDCT/auto-SCT with cyclophosphamide + melphalan (CyM) regimen. One patient died from hepatic veno-occlusive disease (VOD) during the second HDCT/auto-SCT; otherwise, toxicities were manageable. Four patients in complete response (CR) and 3 of 7 patients in partial response (PR) or second PR at the first HDCT/auto-SCT remained event free: however, 2 patients with progressive tumor experienced progression again. The probabilities of 3-year overall survival (OS) after the first HDCT/auto-SCT in 11 patients in CR, PR, or second PR was 58.2% ± 16.9%. Tumor status at the first HDCT/auto-SCT was the only significant factor for outcome after HDCT/auto-SCT. There was no difference in survival between glioblastoma and other HGGs. This study suggests that the outcome of HGGs in children and adolescents after HDCT/auto-SCT is encouraging if the patient could achieve CR or PR before HDCT/auto-SCT 1).

2016

Sung et al., prospectively evaluated the effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in improving the survival of patients with Atypical teratoid rhabdoid tumors while reducing the risks of late adverse effects from radiotherapy (RT).

For young children (< 3 years old), tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy. RT was deferred until after 3 years of age unless the tumor showed relapse or progression. For older patients (> 3 years old), RT including reduced-dose craniospinal RT (23.4 or 30.6 Gy) was administered either after two cycles of induction chemotherapy or after surgery, and tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy.

A total of 13 patients (five young and eight older) were enrolled from November 2004 to June 2012. Eight patients, including all five young patients, had metastatic disease at diagnosis. Six patients (four young and two older) experienced progression before initiation of RT, and seven were able to proceed to HDCT/auto-SCT without progression during induction treatment. Three of six patients who experienced progression during induction treatment underwent HDCT/auto-SCT as salvage treatment. All five young patients died from disease progression. However, four of the eight older patients remain progression-freewith a median follow-up period of 64 months (range, 39 to 108 months). Treatment-related late toxicities were acceptable.

The required dose of craniospinal RT might be reduced in older patients if the intensity of chemotherapy is increased. However, early administration of RT should be considered to prevent early progression in young patients 2).


Choi et al., retrospectively analyzed infectious complications during tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in children and adolescents with high-risk or recurrent solid tumors. A total of 324 patients underwent their first HDCT/auto-SCT between October 2004 and September 2014, and 283 of them proceeded to their second HDCT/auto-SCT (a total of 607 HDCT/auto-SCTs). During the early transplant period of 607 HDCT/auto-SCTs (from the beginning of HDCT to day 30 post-transplant), bacteremia, urinary tract infection (UTI), respiratory virus infection, and varicella zoster virus (VZV) reactivation occurred in 7.1%, 2.3%, 13.0%, and 2.5% of HDCT/auto-SCTs, respectively. The early transplant period of the second HDCT/auto-SCT had infectious complications similar to the first HDCT/auto-SCT. During the late transplant period of HDCT/auto-SCT (from day 31 to 1 year post-transplant), bacteremia, UTI, and VZV reactivation occurred in 7.5%, 2.5%, and 3.9% of patients, respectively. Most infectious complications in the late transplant period occurred during the first 6 months post-transplant. There were no invasive fungal infections during the study period. Six patients died from infectious complications (4 from bacterial sepsis and 2 from respiratory virus infection).This study suggests that infectious complications are similar following second and first HDCT/auto-SCT in children 3).

2014

Lee et al., retrospectively evaluated the toxicity of tandem HDCT/auto-SCT with carboplatin-thiotepa-etoposide (CTE) and cyclophosphamide-melphalan (CM) regimens when used to treat high-risk or recurrent brain tumors. A total of 109 patients who received a first HDCT/auto-SCT and 100 who proceeded to a second HDCT/auto-SCT between May 2005 and December 2013 were included. Hematologic recovery was rapid during both the first and second HDCT/auto-SCT. In the first HDCT/auto-SCT, mucositis-related gastrointestinal toxicity was frequent, and two (1.8 %) patients died from toxicity [one hepatic veno-occlusive disease (VOD) and one sepsis]. In the second HDCT/auto-SCT, mucositis-related toxicity was milder than in the first round. However, hepatic VOD frequency was high (20.0 %), and six (6.0 %) patients died from toxicity (four hepatic VODs, one asphyxia, and one sepsis). Multivariate analysis indicated that age younger than 8 years was the only significant predictor for hepatic VOD. All six patients who died from toxicity during the second HDCT/auto-SCT were younger than 9 years of age. This study demonstrates that tandem HDCT/auto-SCT using CTE/CM regimens was generally feasible. However, dose reduction during the second HDCT/auto-SCT in young children might be needed to decrease the death rate from toxicity 4).

2013

From January 2004 to December 2008, 50 consecutive patients with high-risk neuroblastoma were assigned to receive tandem HDCT (high-dose chemotherapy)/auto-SCT after nine cycles of induction chemotherapy. CEC (carboplatin + etoposide + cyclophosphamide) regimen and TM (thiotepa + melphalan)-TBI regimen (or TM regimen for stage 3 patients) were the first and second HDCT regimens. Local radiotherapy, differentiation therapy with 13-cis-retinoid acid and immunotherapy with interleukin-2 were given after tandem HDCT/auto-SCT. Of the 50 patients, 49 underwent a first HDCT/auto-SCT and 47 underwent a second HDCT/auto-SCT. The tumor relapsed or progressed in 14 patients, secondary malignancy developed in one patient and one patient died from chronic lung disease. Therefore, 34 patients remained event free with a median follow-up of 54.5 months (range, 14-94 months) from diagnosis. The probabilities of 5-year OS and EFS for all 50 patients were 77.0% (95% confidence interval (CI), 63.7-90.3) and 71.4% (95% CI, 58.7-84.1), respectively. However, all patients who remained event free for >3 years after tandem HDCT/auto-SCT experienced late adverse effects. Chemotherapeutic dose-escalation strategy using tandem HDCT/auto-SCT was very encouraging for survival. However, further studies incorporating newer treatment modalities are needed to reduce late adverse effects without jeopardizing the survival rate 5).


1) Lee JW, Lim DH, Sung KW, Lee HJ, Yi ES, Yoo KH, Koo HH, Suh YL, Shin HJ. Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for High-Grade Gliomas in Children and Adolescents. J Korean Med Sci. 2017 Feb;32(2):195-203. doi: 10.3346/jkms.2017.32.2.195. PubMed PMID: 28049229.
2) Sung KW, Lim DH, Yi ES, Choi YB, Lee JW, Yoo KH, Koo HH, Kim JH, Suh YL, Joung YS, Shin HJ. Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Atypical Teratoid/Rhabdoid Tumor. Cancer Res Treat. 2016 Oct;48(4):1408-1419. PubMed PMID: 27034140; PubMed Central PMCID: PMC5080816.
3) Choi YB, Yi ES, Kang JM, Lee JW, Yoo KH, Kim YJ, Sung KW, Koo HH. Infectious Complications during Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Children with High-Risk or Recurrent Solid Tumors. PLoS One. 2016 Sep 14;11(9):e0162178. doi: 10.1371/journal.pone.0162178. PubMed PMID: 27627440; PubMed Central PMCID: PMC5023107.
4) Lee SH, Son MH, Sung KW, Choi YB, Lee NH, Yoo KH, Koo HH, Lim DH, Shin HJ. Toxicity of tandem high-dose chemotherapy and autologous stem cell transplantation using carboplatin-thiotepa-etoposide and cyclophosphamide-melphalan regimens for malignant brain tumors in children and young adults. J Neurooncol. 2014 Dec;120(3):507-13. doi: 10.1007/s11060-014-1576-1. PubMed PMID: 25108776.
5) Sung KW, Son MH, Lee SH, Yoo KH, Koo HH, Kim JY, Cho EJ, Lee SK, Choi YS, Lim DH, Kim JS, Kim DW. Tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk neuroblastoma: results of SMC NB-2004 study. Bone Marrow Transplant. 2013 Jan;48(1):68-73. doi: 10.1038/bmt.2012.86. PubMed PMID: 22635247.

Neuro-Oncology January 2017

1: Antonios JP, Soto H, Everson RG, Moughon D, Orpilla JR, Shin NP, Sedighim S,
Treger J, Odesa S, Tucker A, Yong WH, Li G, Cloughesy TF, Liau LM, Prins RM.
Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune
resistance via a PD-1/PD-L1 mechanism in glioblastoma. Neuro Oncol. 2017 Jan 23.
pii: now287. doi: 10.1093/neuonc/now287. [Epub ahead of print] PubMed PMID:
28115578.

2: Ramkissoon SH, Bandopadhayay P, Hwang J, Ramkissoon LA, Greenwald NF,
Schumacher SE, O’Rourke R, Pinches N, Ho P, Malkin H, Sinai C, Filbin M, Plant A,
Bi WL, Chang MS, Yang E, Wright KD, Manley PE, Ducar M, Alexandrescu S, Lidov H,
Delalle I, Goumnerova LC, Church AJ, Janeway KA, Harris MH, MacConaill LE,
Folkerth RD, Lindeman NI, Stiles CD, Kieran MW, Ligon AH, Santagata S, Dubuc AM,
Chi SN, Beroukhim R, Ligon KL. Clinical targeted exome-based sequencing in
combination with genome-wide copy number profiling: precision medicine analysis
of 203 pediatric brain tumors. Neuro Oncol. 2017 Jan 19. pii: now294. doi:
10.1093/neuonc/now294. [Epub ahead of print] PubMed PMID: 28104717.

3: Berghoff AS, Wolpert F, Holland-Letz T, Koller R, Widhalm G, Gatterbauer B,
Dieckmann K, Birner P, Bartsch R, Zielinski CC, Weller M, Preusser M. Combining
standard clinical blood values for improving survival prediction in patients with
newly diagnosed brain metastases-development and validation of the LabBM score.
Neuro Oncol. 2017 Jan 17. pii: now290. doi: 10.1093/neuonc/now290. [Epub ahead of
print] PubMed PMID: 28096493.

4: Altinoz MA, Guloksuz S, Elmaci I. Rabies virus vaccine as an immune adjuvant
against cancers and glioblastoma: new studies may resurrect a neglected
potential. Clin Transl Oncol. 2017 Jan 16. doi: 10.1007/s12094-017-1613-6. [Epub
ahead of print] Review. PubMed PMID: 28093702.

5: Sun Y, Alberta JA, Pilarz C, Calligaris D, Chadwick EJ, Ramkissoon SH,
Ramkissoon LA, Garcia VM, Mazzola E, Goumnerova L, Kane M, Yao Z, Kieran MW,
Ligon KL, Hahn WC, Garraway LA, Rosen N, Gray NS, Agar NY, Buhrlage SJ, Segal RA,
Stiles CD. A brain-penetrant RAF dimer antagonist for the noncanonical BRAF
oncoprotein of pediatric low-grade astrocytomas. Neuro Oncol. 2017 Jan 12. pii:
now261. doi: 10.1093/neuonc/now261. [Epub ahead of print] PubMed PMID: 28082416.

6: Boetto J, Bielle F, Sanson M, Peyre M, Kalamarides M. SMO mutation status
defines a distinct and frequent molecular subgroup in olfactory groove
meningiomas. Neuro Oncol. 2017 Jan 12. pii: now276. doi: 10.1093/neuonc/now276.
[Epub ahead of print] PubMed PMID: 28082415.

7: Teng J, Carla da Hora C, Kantar RS, Nakano I, Wakimoto H, Batchelor TT,
Chiocca EA, Badr CE, Tannous BA. Dissecting inherent intratumor heterogeneity in
patient-derived glioblastoma culture models. Neuro Oncol. 2017 Jan 6. pii:
now253. doi: 10.1093/neuonc/now253. [Epub ahead of print] PubMed PMID: 28062830.

8: Zhu C, Mustafa D, Zheng PP, van der Weiden M, Sacchetti A, Brandt M, Chrifi I,
Tempel D, Leenen PJ, Duncker DJ, Cheng C, Kros JM. Activation of CECR1 in M2-like
TAMs promotes paracrine stimulation-mediated glial tumor progression. Neuro
Oncol. 2017 Jan 3. pii: now251. doi: 10.1093/neuonc/now251. [Epub ahead of print]
PubMed PMID: 28053137.

9: Darlix A, Gozé C, Rigau V, Bauchet L, Taillandier L, Duffau H. The
etiopathogenesis of diffuse low-grade gliomas. Crit Rev Oncol Hematol. 2017
Jan;109:51-62. doi: 10.1016/j.critrevonc.2016.11.014. Review. PubMed PMID:
28010898.

10: Wei JW, Huang K, Yang C, Kang CS. Non-coding RNAs as regulators in
epigenetics (Review). Oncol Rep. 2017 Jan;37(1):3-9. doi: 10.3892/or.2016.5236.
PubMed PMID: 27841002.

11: Avila EK, Chamberlain M, Schiff D, Reijneveld JC, Armstrong TS, Ruda R, Wen
PY, Weller M, Koekkoek JA, Mittal S, Arakawa Y, Choucair A, Gonzalez-Martinez J,
MacDonald DR, Nishikawa R, Shah A, Vecht CJ, Warren P, van den Bent MJ, DeAngelis
LM. Seizure control as a new metric in assessing efficacy of tumor treatment in
low-grade glioma trials. Neuro Oncol. 2017 Jan;19(1):12-21. doi:
10.1093/neuonc/now190. Review. PubMed PMID: 27651472; PubMed Central PMCID:
PMC5193028.

12: Guidi M, Giunti L, Lucchesi M, Scoccianti S, Giglio S, Favre C, Oliveri G,
Sardi I. Brain tumors in Li-Fraumeni syndrome: a commentary and a case of a
gliosarcoma patient. Future Oncol. 2017 Jan;13(1):9-12. PubMed PMID: 27523101.

13: Hu LS, Ning S, Eschbacher JM, Baxter LC, Gaw N, Ranjbar S, Plasencia J, Dueck
AC, Peng S, Smith KA, Nakaji P, Karis JP, Quarles CC, Wu T, Loftus JC, Jenkins
RB, Sicotte H, Kollmeyer TM, O’Neill BP, Elmquist W, Hoxworth JM, Frakes D,
Sarkaria J, Swanson KR, Tran NL, Li J, Mitchell JR. Radiogenomics to characterize
regional genetic heterogeneity in glioblastoma. Neuro Oncol. 2017
Jan;19(1):128-137. doi: 10.1093/neuonc/now135. PubMed PMID: 27502248; PubMed
Central PMCID: PMC5193022.

14: Li S, Zeng A, Hu Q, Yan W, Liu Y, You Y. miR-423-5p contributes to a
malignant phenotype and temozolomide chemoresistance in glioblastomas. Neuro
Oncol. 2017 Jan;19(1):55-65. doi: 10.1093/neuonc/now129. PubMed PMID: 27471108;
PubMed Central PMCID: PMC5193021.

15: Goffart N, Lombard A, Lallemand F, Kroonen J, Nassen J, Di Valentin E,
Berendsen S, Dedobbeleer M, Willems E, Robe P, Bours V, Martin D, Martinive P,
Maquet P, Rogister B. CXCL12 mediates glioblastoma resistance to radiotherapy in
the subventricular zone. Neuro Oncol. 2017 Jan;19(1):66-77. doi:
10.1093/neuonc/now136. PubMed PMID: 27370398; PubMed Central PMCID: PMC5193023.

16: Zhang B, Chang K, Ramkissoon S, Tanguturi S, Bi WL, Reardon DA, Ligon KL,
Alexander BM, Wen PY, Huang RY. Multimodal MRI features predict isocitrate
dehydrogenase genotype in high-grade gliomas. Neuro Oncol. 2017
Jan;19(1):109-117. doi: 10.1093/neuonc/now121. PubMed PMID: 27353503; PubMed
Central PMCID: PMC5193019.