Fluorescence-Guided Neurosurgery: Neuro-oncology and Cerebrovascular Applications

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.

 

 

UpToDate: Fluorescence guided surgery of glioma

Fluorescence guided surgery of glioma

It must be remembered that intraoperative visualization of fluorescence depends on the sensitivity of both the microscope filters and the cameraused 1).


The use of the optical contrast agent sodium fluorescein (NaFl) to guide resection of gliomas has been under investigation for decades. Although this imaging strategy assumes the agent remains confined to the vasculature except in regions of blood brain barrier (BBB) disruption, clinical studies have reported significant NaFl signal in normal brain tissue, limiting tumor-to-normal contrast. A possible explanation arises from earlier studies, which reported that NaFl exists in both pure and protein-bound forms in the blood, the former being small enough to cross the BBB.

A study of Folaron et al. from the Thayer School of Engineering and Department of Surgery Geisel School of Medicine, Dartmouth College, Hanover; and Section of Neurosurgery, and Norris Cotton Cancer Center, Dartmouth Hitchcock Medical CenterLebanonNew Hampshire, aimed to elucidate the kinetic binding behavior of NaFl in circulating blood and its effect on NaFl accumulation in brain tissue and tumor contrast. Additionally, they examined the blood and tissue kinetics, as well as tumor uptake, of a pegylated form of fluorescein selected as a potential optical analog of gadolinium-based MRI contrast agents.

Cohorts of mice were administered one of the following doses/forms of NaFl: 1) high human equivalent dose (HED) of NaFl, 2) low HED of NaFl, or 3) pegylated form of fluorescein. In each cohort, groups of animals were euthanized 15, 30, 60, and 120 minutes after administration for ex vivo analysis of fluorescein fluorescence. Using gel electrophoresis and fluorescence imaging of blood and brain specimens, the authors quantified the temporal kinetics of bound NaFl, unbound NaFl, and pegylated fluorescein in the blood and normal brain tissue. Finally, they compared tumor-to-normal contrast for NaFl and pegylated-fluorescein in U251 glioma xenografts.

Administration of NaFl resulted in the presence of unbound and protein-bound NaFl in the circulation, with unbound NaFl constituting up to 70% of the signal. While protein-bound NaFl was undetectable in brain tissue, unbound NaFl was observed throughout the brain. The observed behavior was time and dose dependent. The pegylated form of fluorescein showed minimal uptake in brain tissue and improved tumor-to-normal contrast by 38%.

Unbound NaFl in the blood crosses the BBB, limiting the achievable tumor-to-normal contrast and undermining the inherent advantage of tumor imaging in the brain. Dosing and incubation time should be considered carefully for NaFl-based fluorescence-guided surgery (FGS) of glioma. A pegylated form of fluorescein showed more favorable normal tissue kinetics that translated to higher tumor-to-normal contrast. These results warrant further development of pegylated-fluorescein for FGS of glioma 2).


Senders et al., systematically review all clinically tested fluorescent agents for application in 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. 3).


Mounting evidence suggests that a more extensive surgical resection is associated with an improved life expectancy for both low grade glioma and high grade glioma patients. However, radiographically complete resections are not often achieved in many cases because of the lack of sensitivityand specificity of current neurosurgical guidance techniques at the margins of diffuse infiltrative gliomas. Intraoperative fluorescence imaging offers the potential to improve the extent of resection and to investigate the possible benefits of resecting beyond the radiographic margins.

Liu et al., in 2014 provided a review of wide-field and high-resolution fluorescence-imaging strategies that are being developed for neurosurgical guidance, with a focus on emerging imaging technologies and clinically viable contrast agents. The strengths and weaknesses of these approaches will be discussed, as well as issues that are being addressed to translate these technologies into the standard of care 4).


322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670.

FINDINGS: Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery.

INTERPRETATION: Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma 5).

References

1)

Moiyadi A, Syed P, Srivastava S. Fluorescence-guided surgery of malignant gliomas based on 5-aminolevulinic acid: paradigm shifts but not a panacea. Nat Rev Cancer. 2014 Feb;14(2):146. doi: 10.1038/nrc3566-c1. PubMed PMID: 24457418.
2)

Folaron M, Strawbridge R, Samkoe KS, Filan C, Roberts DW, Davis SC. Elucidating the kinetics of sodium fluorescein for fluorescence-guided surgery of glioma. J Neurosurg. 2018 Sep 7:1-11. doi: 10.3171/2018.4.JNS172644. [Epub ahead of print] PubMed PMID: 30192200.
3)

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.
4)

Liu JT, Meza D, Sanai N. Trends in fluorescence image-guided surgery for gliomas. Neurosurgery. 2014 Jul;75(1):61-71. doi: 10.1227/NEU.0000000000000344. Review. PubMed PMID: 24618801; PubMed Central PMCID: PMC4062574.
5)

Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006 May;7(5):392-401. PubMed PMID: 16648043.

UpToDate: Merkel cell carcinoma

Merkel cell carcinoma (MCC)

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy of neuroendocrine origin.

Harary et al., from the Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA, conducted a systematic review of the literature to identify cases reporting on management of distant MCC brain metastases (BM). A pooled survival analysiswas performed on the institutional and literature cases to assess predictors of OS.

Forty cases were included for analysis, describing operative [14] and non-operative [26] management. Median time to central nervous systeminvolvement was 17.0-mos (interquartile range 10.5-26.5), and most patients had a single BM (62.5%). Management of intracranial disease included radiotherapy (82.5%), systemic therapy (59.5%) and surgical resection (35%). Operative management was associated with a lower intracranial disease burden (DB), but similar DB. Both neurosurgery (hazard ratio [HR] 0.18, 95% confidence interval [CI]: 0.06-0.54, p = 0.002), having RT (HR 0.37, 95% CI: 0.14:0.93, p = 0.04) and having a single BM (extensive intracranial DB: HR 2.51, 95% CI: 1.12-5.6, p = 0.03) conferred an OS benefit on risk-unadjusted analysis. Only, neurosurgical resection was an independent predictor of OS (HR 0.12, 95% CI: 0.03-0.49, p = 0.003), controlling for age, DB and radiotherapy.

Resection of MCC BM may confer a survival benefit given appropriate patient selection. Prospective investigation of multimodal management of neurometastatic MCC is warranted, especially given the promise of new immunotherapy agents in treating MCC 1).

Case reports

A 59-year-old woman was admitted with a 4-month history of progressive and severe dorsal back pain, without neurological signs. The patient had been surgically treated for a recidivated MCC in the occipital region in 2007, 2011, and 2013. (In 2013, the surgical treatment also included lateral cervical lymph node dissection). Chemotherapy and radiotherapy had come after the treatments. Magnetic resonance imaging (MRI) of the dorsal spine showed metastatic vertebral involvement with cord impingement of the T7-T8 levels. A total body CT scan revealed lungs and liver metastases, besides vertebral district. After a multidisciplinary consult a palliative surgery was decided and a posterior dorsal approach was employed: Radiofrequency (RF) thermoablation was followed by the injection of cement of T7 and T8 and transpedicle fixation T5-T9. The postoperative course was uneventful and followed by a further adjuvant therapy.

Spinal metastases from MCC are described in literature only exceptionally. The clinical course is presented, along with a review of literature 2).


This case is particularly unusual in that, not only was no established primary lesion identified, but also the patient has survived for 10 years following initial diagnosis and for 9 years following excision of a single brain metastasis 3).


A case of Merkel cell carcinoma of the spine and evaluate the treatment paradigms utilized in the prior reports. Result A 76-year-old man with a history of Merkel cell carcinoma presented with 2-week history of progressive difficulty ambulating and a solitary T5 epidural mass encasing the spinal cord. The patient underwent a T5 corpectomy with cage placement and T3 to T7 posterior fusion with postoperative neurologic improvement and a return to ambulation. Three weeks postoperatively, the patient re-presented with new-onset weakness and widespread metastatic spinal disease with epidural compression at the T8 level. Six weeks postoperatively, he was placed in hospice care. Conclusion Prior reports in the literature demonstrated a poor prognosis for Merkel cell carcinoma metastasis to the spine with survival ranging from 1 to 9 months after diagnosis. Although neurologic decline necessitates a surgical intervention, the assessment of operative benefit should take into account the prognosis associated with the primary tumor subtype 4).


In this report Jacob et al., propose a novel approach to treat merkel cell carcinoma (MCC) brain metastases and present a review of the literature in an attempt to establish a treatment algorithm and provide prognosis. MCC is a rare neuroendocrine malignancy affecting the aging population. This malignancy has a very aggressive behavior with frequent metastases. We report a 61-year-old man with a prior history of MCC who presented with diplopia. Brain MRI revealed a single right thalamic lesion consistent with metastasis. In the two weeks following GammaKnife stereotactic radiosurgery (Elekta, Stockholm, Sweden) the diplopia improved. A brain MRI demonstrated shrinkage of the tumor. From our literature search we found only six other patients with MCC brain metastases. The majority of these patients were treated with whole brain radiation in conjunction with chemotherapy. We propose that stereotactic radiosurgery can be used as a first line therapy for patients with MCC metastatic brain disease 5).


A case of Merkel cell carcinoma displaying unique patterns of differentiation in the primary focus and brain metastasis. The skin primary was almost uniformly small cell carcinoma positive for epithelial and neuroendocrine markers, with a few glial fibrillary acidic protein- and cytokeratin 20-positive cells. The neoplasm contained giant cells immunoreactive for neurofilament and negative for epithelial markers. The neck lymph node metastasis was a typical neuroendocrine Merkel cell carcinoma positive for cytokeratin 20. A solitary dural intracranial metastasis displayed features of aggressive ganglioneuroblastoma, expressing many neuronal antigens with no evidence of glial or epithelial differentiation. After total gross resection, the tumor recurred within 3 months, and the patient developed skeletal metastases and died 6 months after craniotomy 6).


Madden et al., report a rare case of MCC metastatic to the spine in an immunocompromised patient. Methods A 55-year-old male with previously resected MCC, immunocompromised due to cardiac transplant, presented with sharp mid-thoracic back pain radiating around the trunk to the midline. Computed tomography of the thoracic spine showed a dorsal epidural mass from T6 to T8 with compression of the spinal cord. Laminectomy and subtotal tumor resection were performed, and pathology confirmed Merkel cell tumor through immunohistochemistry staining positive for cytokeratin 20 and negative for thyroid transcription factor-1. Results Further treatment with radiation therapy was initiated, and the patient did well for 4 months after surgery, but returned with a lesion in the cervical spine. He then opted for hospice care. Conclusions With an increasing number of immunocompromised patients presenting with back pain, MCC should be considered in the differential diagnosis of spinal metastatic disease 7).


A case of a 78-year-old male with intracranial extra-axial metastatic MCC involving the left cerebellopontine angle is presented.

A retrosigmoid craniectomy was performed with complete resection of the metastatic focus. Adjuvant treatment included whole-brain radiation therapy followed by etoposide and carboplatin chemotherapy. Seven months postoperatively, the patient was free of metastatic disease.

Surgical resection should be performed when feasible to prevent local recurrence. This may be followed by early adjuvant fractionated whole-brain radiotherapy and systemic chemotherapy; however, no clinical trials have been performed to demonstrate a survival benefit 8).


A unique case of a pituitary metastasis of MCC in a 65-year-old patient with a history of pituitary adenoma. This case is particularly novel due to the fact that the primary site of the MCC is unknown 9).


A rare case of Merkel cell carcinoma with extra-dural spinal metastasis causing paraplegia. There are only four reported cases in literature. A 57-year-old lady presented with a breast lump, multiple truncal skin swellings, low back pain and rapidly progressive paraplegia. MRI showed multiple epidural soft tissue masses causing neural compression. A biopsy from the truncal skin lesion was diagnosed as Merkel cell carcinoma (MCC). Posterior decompression and tumor debulking at all three sites of neural compression was performed. Histopathology of the epidural tumor was consistent with MCC and the diagnosis was confirmed by immuno-histochemistry staining for cytokeratin-20. She was started on chemotherapy and radiotherapy. One month after diagnosis she died due to extensive metastasis. The short term palliative response seen in our patient demonstrates the poor prognosis for patients with spinal metastasis 10).


An unusual case of Merkel cell carcinoma presenting as a frontal scalp mass with apparent invasion into underlying brain parenchyma through grossly intact calvaria. Despite wide local excision, craniectomy, intracranial tumor resection, and postoperative adjuvant irradiation, widespread systemic metastases resistant to chemotherapy developed, and the patient died 9 months after surgery. This case report confirms that Merkel cell carcinoma of the head and neck, already known to be an aggressive tumor, has the capacity for rapid intracranial extension. We propose that in this case, the mechanism of intracranial metastasis was via communicating veins rather than through bone destruction or systemic metastasis. Appropriate preoperative imaging should be carried out to define the extent of this tumor when it is adjacent to the skull. We found contrast-enhanced magnetic resonance imaging to be superior to computed tomography for defining soft tissue extent and marrow space involvement within underlying bone 11).


A 63-year-old man presented with a rare metastatic Merkel cell carcinoma (MCC) involving the lumbosacral spine and causing nerve root compression. Magnetic resonance (MR) imaging revealed an extradural soft tissue mass at the L5-S1 levels. The tumor was subtotally removed and chemotherapy was administered, but he died of multiple metastases from the primary epigastric tumor. Lumbosacral metastatic epidural tumor can manifest as lumbar disc disease symptoms, but MR imaging can non-invasively and rapidly reveal the presence of spinal epidural tumor and any extension to the spinal canal. Extradural MCC metastasis in the lumbosacral area should be considered in the differential diagnosis of radicular symptoms caused by disc herniation 12).


A 48-year-old woman with MCC of the left elbow and a right cerebellar metastasis. After the right cerebellar mass was totally resected, radiation treatment and chemotherapy were performed. Eight cases of brain metastasis have been reported in the literature, but only 5 have been presented in sufficient detail for analysis. Therapy for brain metastases has always been palliative whole-brain irradiation and chemotherapy except for our patient, who underwent total removal of the tumor and survived for 11 months without neurological deficit. Except in the case of 1 with a particularly radiosensitive MCC, the patients with brain metastases died within 9 months after detection of the brain lesions. If possible, aggressive excision of brain metastases as well as of the primary lesion should be done 13).


A 57-year-old female, who had been complaining of anosmia for 8 years, was admitted to the otolaryngological department because an intranasal tumor was found. Then, removal of the tumor and radiotherapy was carried out. After these procedures, the patient suffered from a high fever and CSF rhinorrhea. At this stage, our neurosurgical department was consulted. CT scan revealed a partially calcified low density mass with a slight enhancement effect at the left frontal base. Under the diagnosis of intracranial invasion by intranasal neuroendocrine carcinoma, the patient was operated on. Through bifrontal craniotomy and a combination of extra- and intradural approach, the tumor was excised. After that, the dura and the skull base were reconstructed. On histological examination, the tumor was found to consist of NSE positive cells forming some glandular structures. Electron microscopic study disclosed neurosecretory granules in the cytoplasmic process. These findings are typical of neuroendocrine carcinoma and compatible to those of the intranasal tumor previously removed. Neuroendocrine carcinoma is rare in itself and there have been reported only two cases of its invasion of the skull base. The clinical features, diagnostic procedures, pathological findings, and treatment of this tumor are discussed in this report 14).


A case arising in the calvarium and involving the bone, dura, and underlying brain is presented. The histopathology and immunohistochemical staining characteristics of tumor were consistent with those of Merkel cell tumor. The natural history and histopathology of this tumor are discussed, along with the possible explanation for the origin of this tumor in the calvarium 15).


Alexander et al., reported a case of Merkel cell carcinoma with proven brain metastases and a solid choroidal tumor. The patient responded well to radiation and chemotherapy and is alive and neurologically intact three years after diagnosis. All previous patients with metastatic Merkel cell carcinoma to the brain died within two months of the diagnosis. They used this case to discuss possible routes of metastatic dissemination and to review the treatment options in patients with distant metastatic disease. This is the first reported case of presumed choroidal metastasis of Merkel cell carcinoma and the longest documented survival in a patient with brain involvement 16).

References

1)

Harary M, Kavouridis VK, Thakuria M, Smith TR. Predictors of survival in neurometastatic Merkel cell carcinoma. Eur J Cancer. 2018 Jul 30;101:152-159. doi: 10.1016/j.ejca.2018.07.002. [Epub ahead of print] PubMed PMID: 30071443.
2)

Maugeri R, Giugno A, Giammalva RG, Gulì C, Basile L, Graziano F, Iacopino DG. A thoracic vertebral localization of a metastasized cutaneous Merkel cell carcinoma: Case report and review of literature. Surg Neurol Int. 2017 Aug 10;8:190. doi: 10.4103/sni.sni_70_17. eCollection 2017. PubMed PMID: 28868202; PubMed Central PMCID: PMC5569392.
3)

Honeybul S. Cerebral metastases from Merkel cell carcinoma: long-term survival. J Surg Case Rep. 2016 Oct 7;2016(10). pii: rjw165. doi: 10.1093/jscr/rjw165. PubMed PMID: 27765804; PubMed Central PMCID: PMC5055286.
4)

Goodwin CR, Mehta AI, Adogwa O, Sarabia-Estrada R, Sciubba DM. Merkel Cell Spinal Metastasis: Management in the Setting of a Poor Prognosis. Global Spine J. 2015 Aug;5(4):e39-43. doi: 10.1055/s-0034-1398488. Epub 2015 Jan 7. PubMed PMID: 26225292; PubMed Central PMCID: PMC4516752.
5)

Jacob AT, Alexandru-Abrams D, Abrams EM, Lee JY. Stereotactic radiosurgery for merkel cell carcinoma brain metastases. J Clin Neurosci. 2015 Sep;22(9):1499-502. doi: 10.1016/j.jocn.2015.03.013. Epub 2015 May 11. PubMed PMID: 25975493.
6)

Lach B, Joshi SS, Murty N, Huq N. Transformation of Merkel cell carcinoma to ganglioneuroblastoma in intracranial metastasis. Hum Pathol. 2014 Sep;45(9):1978-81. doi: 10.1016/j.humpath.2014.03.021. Epub 2014 May 28. PubMed PMID: 24996688.
7)

Madden NA, Thomas PA, Johnson PL, Anderson KK, Arnold PM. Thoracic spinal metastasis of merkel cell carcinoma in an immunocompromised patient: case report. Evid Based Spine Care J. 2013 Apr;4(1):54-8. doi: 10.1055/s-0033-1341597. PubMed PMID: 24436699; PubMed Central PMCID: PMC3699249.
8)

Seaman B, Brem S, Fromm A, Staller A, McCardle T, Jain S. Intracranial spread of Merkel cell carcinoma to the cerebellopontine angle. J Cutan Med Surg. 2012 Jan-Feb;16(1):54-60. Review. PubMed PMID: 22417997.
9)

Feletti A, Marton E, Rossi S, Canal F, Longatti P, Billeci D. Pituitary metastasis of Merkel cell carcinoma. J Neurooncol. 2010 Apr;97(2):295-9. doi: 10.1007/s11060-009-0025-z. Epub 2009 Oct 6. PubMed PMID: 19806319.
10)

Vijay K, Venkateswaran K, Shetty AP, Rajasekaran S. Spinal extra-dural metastasis from Merkel cell carcinoma: a rare cause of paraplegia. Eur Spine J. 2008 Sep;17 Suppl 2:S267-70. Epub 2007 Dec 4. PubMed PMID: 18057968; PubMed Central PMCID: PMC2525916.
11)

Barkdull GC, Healy JF, Weisman RA. Intracranial spread of Merkel cell carcinoma through intact skull. Ann Otol Rhinol Laryngol. 2004 Sep;113(9):683-7. PubMed PMID: 15453522.
12)

Turgut M, Gökpinar D, Barutça S, Erkuş M. Lumbosacral metastatic extradural Merkel cell carcinoma causing nerve root compression–case report. Neurol Med Chir (Tokyo). 2002 Feb;42(2):78-80. PubMed PMID: 11944594.
13)

Ikawa F, Kiya K, Uozumi T, Yuki K, Takeshita S, Hamasaki O, Arita K, Kurisu K. Brain metastasis of Merkel cell carcinoma. Case report and review of the literature. Neurosurg Rev. 1999;22(1):54-7. Review. PubMed PMID: 10348209.
14)

Manome Y, Yamaoka R, Yuhki K, Hano H, Kitajima T, Ikeuchi S. [Intracranial invasion of neuroendocrine carcinoma: a case report]. No Shinkei Geka. 1990 May;18(5):483-7. Japanese. PubMed PMID: 2385325.
15)

Wojak JC, Murali R. Primary neuroendocrine (Merkel cell) carcinoma presenting in the calvarium: case report. Neurosurgery. 1990 Jan;26(1):137-9. PubMed PMID: 2294466.
16)

Alexander E 3rd, Rossitch E Jr, Small K, Rosenwasser GO, Abson P. Merkel cell carcinoma. Long term survival in a patient with proven brain metastasis and presumed choroid metastasis. Clin Neurol Neurosurg. 1989;91(4):317-20. PubMed PMID: 2555091.

UpToDate: Glioma biomarker

Glioma biomarker

see also Glioblastoma biomarker.

Gliomas are difficult to classify precisely because of interobserver variability during histopathologic grading. Identifying biological signatures of each glioma subtype through protein biomarker profiling of tumor or tumor-proximal fluids is therefore of high priority. Such profiling not only may provide clues regarding tumor classification but may identify clinical biomarkers and pathologic targets for the development of personalized treatments.

In the past, differential proteomic profiling techniques have utilized tumor, cerebrospinal fluid, and plasma from glioma patients to identify the first candidate diagnostic, prognostic, predictive, and therapeutic response markers, highlighting the potential for glioma biomarker discovery. The number of markers identified, however, has been limited, their reproducibility between studies is unclear, and none have been validated for clinical use.

Technological advancements in methodologies for high-throughput profiling, which provide easy access, rapid screening, low sample consumption, and accurate protein identification, are anticipated to accelerate brain tumor biomarker discovery. Reliable tools for biomarker verification forecast translation of the biomarkers into clinical diagnostics in the foreseeable future 1).

Glioma shed extracellular vesicles (EVs), which invade the surrounding tissue and circulate within both the cerebrospinal fluid and the systemic circulation. These tumor-derived EVs and their content serve as an attractive source of biomarkers.

In a review, Hochberg et al., discuss the current state of the art of biomarkers for glioma with emphasis on their EV derivation 2).


A study identified an 18-cytokine signature for distinguishing glioma sera from normal healthy individual sera and also demonstrated the importance of their differential abundance in glioma biology 3).


Shi et al., from Hangzhou, Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai. Department of Neurosurgery, Huai’an Second People’s Hospital, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, China, extracted data sets from the Gene Expression Omnibus data set by using “glioma” as the keyword. Then, a coexpression module was constructed with the help of Weighted Gene Coexpression Network Analysis software. Besides, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the genes in these modules. As a result, the critical modules and target genes were identified. Eight coexpression modules were constructed using the 4,000 genes with a high expression value of the total 141 glioma samples. The result of the analysis of the interaction among these modules showed that there was a high scale independence degree among them. The GO and KEGG enrichment analyses showed that there was a significant difference in the enriched terms and degree among these eight modules, and module 5 was identified as the most important module. Besides, the pathways it was enriched in, hsa04510: Focal adhesion and hsa04610: Complement and coagulation cascades, were determined as the most important pathways. In summary, module 5 and the pathways it was enriched in, hsa04510: Focal adhesion and has 04610: Complement and coagulation cascades, have the potential to serve as glioma biomarkers 4).

References

1)

Kalinina J, Peng J, Ritchie JC, Van Meir EG. Proteomics of gliomas: initial biomarker discovery and evolution of technology. Neuro Oncol. 2011 Sep;13(9):926-42. doi: 10.1093/neuonc/nor078. Review. PubMed PMID: 21852429; PubMed Central PMCID: PMC3158015.

2)

Hochberg FH, Atai NA, Gonda D, Hughes MS, Mawejje B, Balaj L, Carter RS. Glioma diagnostics and biomarkers: an ongoing challenge in the field of medicine and science. Expert Rev Mol Diagn. 2014 May;14(4):439-52. doi: 10.1586/14737159.2014.905202. Review. PubMed PMID: 24746164; PubMed Central PMCID: PMC5451266.

3)

Nijaguna MB, Patil V, Hegde AS, Chandramouli BA, Arivazhagan A, Santosh V, Somasundaram K. An Eighteen Serum Cytokine Signature for Discriminating Glioma from Normal Healthy Individuals. PLoS One. 2015 Sep 21;10(9):e0137524. doi: 10.1371/journal.pone.0137524. eCollection 2015. PubMed PMID: 26390214.

4)

Shi T, Chen J, Li J, Yang BY, Zhang QL. Identification of key gene modules and pathways of human glioma through coexpression network. J Cell Physiol. 2018 Aug 1. doi: 10.1002/jcp.27059. [Epub ahead of print] PubMed PMID: 30067869.

UpToDate: ACTC1

ACTC1

ACTC1 encodes cardiac muscle alpha actin. This isoform differs from the alpha actin that is expressed in skeletal muscle, ACTA1. Alpha cardiac actin is the major protein of the thin filament in cardiac sarcomeres, which are responsible for muscle contraction and generation of force to support the pump function of the heart.

Actins are highly conserved proteins that are involved in various types of cell motility. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The protein encoded by this gene belongs to the actin family which is comprised of three main groups of actin isoforms, alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Defects in this gene have been associated with idiopathic dilated cardiomyopathy (IDC) and familial hypertrophic cardiomyopathy (FHC).

ACTC1, could function as a prognostic and predictive marker in clinical treatment of spinal cord injury (SCI) 1).

ACTC1 may serve as a novel independent prognostic and invasion marker in glioblastoma GBM 2).

A study of Wanibuchi et al., from the Department of Neurosurgery, Sapporo Medical University School of Medicine, Hokkaido Japan aimed to clarify whether the knockdown of highly expressed ACTC1 can inhibit the migratory capacity of cells in the GBM cell line.

ACTC1 expression was examined using immunocytochemistry and droplet digital polymerase chain reaction. The motility of GBM cells that were either treated with siRNA to knock down ACTC1 or untreated were investigated using a time-lapse study in vitro.

The relatively high ACTC1 expression was confirmed in a GBM cell line, i.e., U87MG. The ACTC1 expression in U87MG cells was significantly inhibited by ACTC1-siRNA (p < 0.05). A cell movement tracking assay using time-lapse imaging demonstrated the inhibition of U87MG cell migration by ACTC1 knockdown. The quantitative cell migration analysis demonstrated that the distance traversed during 72 h was 3607 ± 458 (median ± SD) μm by untreated U87MG cells and 3570 ± 748 μm by negative control siRNA-treated cells. However, the distance migrated by ACTC1-siRNA-treated cells during 72 h was significantly shorter (1265 ± 457 μm, p < 0.01) than the controls.

ACTC1 knockdown inhibits U87MG cell migration. 3).

1)

Liu Y, Wang Y, Teng Z, Zhang X, Ding M, Zhang Z, Chen J, Xu Y. DNA Microarray Analysis in Screening Features of Genes Involved in Spinal Cord Injury. Med Sci Monit. 2016 May 10;22:1571-81. PubMed PMID: 27160807; PubMed Central PMCID: PMC4913819.
2)

Ohtaki S, Wanibuchi M, Kataoka-Sasaki Y, Sasaki M, Oka S, Noshiro S, Akiyama Y, Mikami T, Mikuni N, Kocsis JD, Honmou O. ACTC1 as an invasion and prognosis marker in glioma. J Neurosurg. 2016 Apr 15:1-9. [Epub ahead of print] PubMed PMID: 27081897.
3)

Wanibuchi M, Ohtaki S, Ookawa S, Kataoka-Sasaki Y, Sasaki M, Oka S, Kimura Y, Akiyama Y, Mikami T, Mikuni N, Kocsis JD, Honmou O. Actin, alpha, cardiac muscle 1 (ACTC1) knockdown inhibits the migration of glioblastoma cells in vitro. J Neurol Sci. 2018 Jul 17;392:117-121. doi: 10.1016/j.jns.2018.07.013. [Epub ahead of print] PubMed PMID: 30055382.

UpToDate: Positron emission tomography for intracranial meningioma

Positron emission tomography for intracranial meningioma

MET PET/CT showed a high sensitivity compared with FDG PET/CT for detection of newly diagnosed WHO grades I and II intracranial meningiomas. Both FDG and MET uptake were found to be useful for evaluating tumor proliferation in meningiomas 1).

Although positron emission tomography has not been routinely used in the diagnostic workup and follow-up of patients with meningiomas, it can be useful in cases of skull base meningiomas that are frequently difficult to visualize by using standard CT and MR imaging techniques 2).

Primary intracranial meningioma is typically reported as having low FDG uptake, because glucose metabolism in meningioma is similar to that of surrounding tissue 3).

There have been a few isolated reports describing the imaging features of metastatic meningioma on FDG-PET imaging. Ghodsian et al., described a moderately hypermetabolic sacral metastatic mass by FDG-PET/CT. This was a Grade III malignant meningioma on histology 4).

Meirelles et al., described a pulmonary meningioma that manifested as a solitary pulmonary nodule and had very high metabolic activity on PET scan. The current case also showed avid uptake of FDG; the SUV was >7 in each pulmonary lesion. The uptake was more avid in the periphery and slightly less in the centre of both lesions, corresponding to the central areas of low density on CT. It was useful to note that there were no other foci of abnormal FDG uptake elsewhere to suggest other metastases. It is reassuring to note that 10 months after the PET/CT with clinical follow-up, the patient remains asymptomatic with no evidence of local or distant spread. The diagnosis of pulmonary metastatic meningioma was confirmed histologically by CT-guided percutaneous biopsy, which has been previously reported 5).


In 2007, Rutten et al., described the combination of CT and MRI as limited in the diagnosis of local skull involvement from adjacent intracranial meningioma. In their study, the authors demonstrated that skull base tumors could be clearly visualised with 18Ftyrosine PET, even after radiation therapy 6) 7).

Meningiomas are also known to have high somatostatin receptor density allowing for the potential use of octreotide brain scintigraphy to help delineate extent of disease. This may be particularly useful in distinguishing residual tumor from postoperative scarring in subtotally resected/recurrent tumors 8).

References

1)

Mitamura K, Yamamoto Y, Norikane T, Hatakeyama T, Okada M, Nishiyama Y. Correlation of (18)F-FDG and (11)C-methionine uptake on PET/CT with Ki-67 immunohistochemistry in newly diagnosed intracranial meningiomas. Ann Nucl Med. 2018 Jul 21. doi: 10.1007/s12149-018-1284-6. [Epub ahead of print] PubMed PMID: 30032455.

2)

Rockhill J, Mrugala M, Chamberlain MC. Intracranial meningiomas: an overview of diagnosis and treatment. Neurosurg Focus. 2007;23(4):E1. Review. PubMed PMID: 17961033.

3)

Kaminski JM, Movsas B, King E, Yang C, Kronz JD, Alli PM, et al. Metastatic meningioma to the lung with multiple pleural metastases. Am J Clin Oncol 2001;24:579–82

4)

Ghodsian M, Obrzut SL, Hyde CC, Watts WJ, Schiepers C. Evaluation of metastatic meningioma with 2-deoxy-2-[18F] fluoro-d-glucose PET/CT. Clin Nucl Med 2005;30:717–20

5)

Brennan C, O’Connor OJ, O’Regan KN, Keohane C, Dineen J, Hinchion J, Sweeney B, Maher MM. Metastatic meningioma: positron emission tomography CT imaging findings. Br J Radiol. 2010 Dec;83(996):e259-62. doi: 10.1259/bjr/11276652. PubMed PMID: 21088084; PubMed Central PMCID: PMC3473618.

6)

Rutten I, Cabay JE, Withofs N, Lemaire C, Aerts J, Baart V, et al.: PET/CT of skull base meningiomas using 2–18F-fluoro-L-tyro-sine: initial report. J Nucl Med 48:720–5, 2007

7)

Conti PS, Cham DK, editors. Singapore: Springer; 2005. PET/CT: a case based approach book.

8)

Klutmann S, Bohuslavizki KH, Brenner W, Behnke A, Tietje N, Kröger S, et al.: Somatostatin receptor scintigraphy in postsurgical follow-up examinations of meningioma. J Nucl Med 39:1913–1917, 1998

UpToDate: DOK7

DOK7

Docking protein 7 encoded by the DOK7 gene is essential for neuromuscular synaptogenesis 1).

The protein functions in aneural activation of MuSK (muscle-specific receptor kinase), which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants.


In Congenital Myasthenic Syndromes with Predominant Limb Girdle Weakness (LG-CMS) some of the currently used drugs can either ameliorate or aggravate the symptoms depending on the underlying genetic defect. The drug most frequently used for the treatment of CMS is pyridostigmine an acetylcholinesterase inhibitor. However, pyridostigmine is not effective or is even detrimental in DOK7- and COLQ-related LG-CMS, while beta-adrenergic agonists (ephedrine, salbutamol) show some sustained benefit. Standard clinical trials may be difficult, but standardized follow-up of patients and international collaboration may help to improve the standards of care of these conditions 2).


A 61-year-old female and her older sister showed bilateral ptosis, facial and proximal limb weakness, and scoliosis since childhood. Another female sibling had milder signs, while other family members were asymptomatic. Facial nerve repetitive stimulation in the proband showed decrement of muscle responses. Single fiber EMG revealed increased jitter and blocking. Muscle biopsy showed type 2-fiber atrophy, without tubular aggregates. Mutational analysis in the three affected siblings revealed two compound heterozygous mutations in DOK7: c.1457delC, that predicts p.Pro486Argfs*13 and truncates the protein C-terminal domain, and c.473G>A, that predicts p.Arg158Gln and disruption of the dok7-MuSK interaction in the phosphotyrosine binding (PTB) domain. Unaffected family members carried only one or neither mutation.

Two of the affected sisters showed marked improvement with salbutamol treatment, which illustrates the benefits of a correct diagnosis and treatment of DOK7-CMS 3).

Hua et al., llustrated that the expression of Dok7 was downregulation in human glioma tissues. Dok7 overexpression significantly inhibits proliferation and colony formation in vitro, and the xenograft tumor formation in vivo. In addition, 5-Azacitidine-2′-deoxycytidine (5-Aza), a DNA methylation inhibitor, preventing the loss of Dok7 expression by decreasing aberrant hypermethylation of Dok7 promoter in glioma cells. More importantly, DNMT1 knockdown induced the demethylation of Dok7 promoter, and enhanced the expression of Dok7 in gliomas. These results suggest that epigenetic silencing of Dok7 may provide a novel glioma treatment strategy 4).

References

1)

Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006 Jun 23;312(5781):1802-5. PubMed PMID: 16794080.

2)

Evangelista T, Hanna M, Lochmüller H. Congenital Myasthenic Syndromes with Predominant Limb Girdle Weakness. J Neuromuscul Dis. 2015 Jul 22;2(Suppl 2):S21-S29. PubMed PMID: 26870666; PubMed Central PMCID: PMC4746746.

3)

Bevilacqua JA, Lara M, Díaz J, Campero M, Vázquez J, Maselli RA. Congenital Myasthenic Syndrome due to DOK7 mutations in a family from Chile. Eur J Transl Myol. 2017 Sep 20;27(3):6832. doi: 10.4081/ejtm.2017.6832. eCollection 2017 Jun 27. PubMed PMID: 29118959; PubMed Central PMCID: PMC5658635.

4)

Hua CD, Bian EB, Chen EF, Yang ZH, Tang F, Wang HL, Zhao B. Repression of Dok7 expression mediated by DNMT1 promotes glioma cells proliferation. Biomed Pharmacother. 2018 Jul 4;106:678-685. doi: 10.1016/j.biopha.2018.06.156. [Epub ahead of print] PubMed PMID: 29990858.

UpToDate: Biomarker

Biomarker

Biological marker, generally refers to a measurable indicator of some biological state or condition. The term occasionally also refers to a substance whose presence indicates the existence of living organisms.

Biomarkers are often measured and evaluated to examine normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers are used in many scientific fields.


Extracellular vesicles secreted by human glioma cells contain a wealth of tumor-specific proteins and nucleic acids that can be isolated from patients with these neoplasms. Thus, EV contribute to the development of biomarkers, and additionally have certain therapeutic potential for possible use in neurooncology and neurosurgery 1).

see Molecular biomarker.

see Biochemical marker.

see Glioblastoma biomarkers.

see Red cell distribution width.

see Tumor marker.

Circulating microRNAs (miRNAs) are a new class of highly promising cancer biomarkers.

It is of great importance to seek further subclassifications in glioblastoma multiformebiomarkers, and new treatment modalities to make a significant change in survival for individuals 2).

Examples

1)

Santiago-Dieppa DR, Gonda DD, Cheung VJ, Steinberg JA, Carter BS, Chen CC. Extracellular Vesicles as a Platform for Glioma Therapeutic Development. Prog Neurol Surg. 2018;32:172-179. doi: 10.1159/000469689. Epub 2018 Jul 10. PubMed PMID: 29990983.
2)

Fekete B, Werlenius K, Örndal C, Rydenhag B. Prognostic factors for glioblastoma patients – a clinical population-based study. Acta Neurol Scand. 2016 Jun;133(6):434-41. doi: 10.1111/ane.12481. Epub 2015 Sep 11. PubMed PMID: 26358197.

UpToDate: Meningioangiomatosis

Free et al., from the Sanford Clinic, Sioux Falls, South Dakota reported two cases of sporadic meningioangiomatosis (MA) – a rare condition of the central nervous system known to cause headaches, seizures and other focal neurologic deficits. Both patients presented with headache and visionchange, somewhat suggestive of migraine. The combination of magnetic resonance imaging (MRI) and computerized tomography (CT) can establish the diagnosis of MA .

UpToDate: Subdural osteoma

Subdural osteoma

Subdural osteomas are benign neoplasms that are rarely encountered.

Case reports

Yang et al., report the case of a 64‑year‑old female patient with a left temporal subdural osteoma.

The patient presented with intermittent dizziness that first began two years earlier. Non-contrast computed tomography revealed a densely calcified left temporal extra-axial mass. Magnetic resonance imaging of the lesion revealed signal loss on T1-weighted and T2-weighted images and non-enhancement on Gadolinium enhanced T1-weighted images, and Diffusion weighted magnetic resonance imaging and ADC images demonstrated reduced values attributed to calcium-induced signal loss. Histologically, the lesion predominantly consisted of lamellar bone without bone marrow elements. The patient underwent stereotactic magnetic resonance imaging-guided neurosurgical resection and recovered without complication.

Subdural osteomas may not be enhanced on magnetic resonance imaging. Surgical tumourectomy can be considered for symptomatic patients with subdural osteomas 1).


A 29-year-old female presented with a 3-year history of headaches. Computed tomography scan revealed a homogeneous high-density lesion isolated from the inner table of the frontal bone (a lucent dural line) in the right frontal convexity. Magnetic resonance imaging revealed an extra-axial lesion with a broad base without dural tail sign and punctate enhancement pattern characteristic of abundant adipose tissue. Upon surgical excision, we found a hard bony mass clearly demarcated from the dura. The mass displayed characteristics of an osteoma upon histological examination. The symptom was relieved after operation 2).


Cheon JE, Kim JE, Yang HJ. CT and pathologic findings of a case of subdural osteoma. Korean J Radiol. 2002;3:211–213.


Kim JK, Lee KJ, Cho JK, et al. Intracranial intraparenchymal ostemoa. J Korean Neurosurg Soc. 1998;27:1450–1454.


Jung TY, Jung S, Jin SG, Jin YH, Kim IY, Kang SS. Solitary intracranial subdural osteoma: intraoperative findings and primary anastomosis of an involved cortical vein. J Clin Neurosci. 2007;14:468–470.


Lee ST, Lui TN. Intracerebral osteoma: case report. Br J Neurosurg. 1997;11:250–252.


Vakaet A, De Reuck J, Thiery E, vander Eecken H. Intracerebral osteoma: a clinicopathologic and neuropsychologic case study. Childs Brain. 1983;10:281–285.


Haddad FS, Haddad GF, Zaatari G. Cranial osteomas: their classification and management. Report on a giant osteoma and review of the literature. Surg Neurol. 1997;48:143–147.


Akiyama M, Tanaka T, Hasegawa Y, Chiba S, Abe T. Multiple intracranial subarachnoid osteomas. Acta Neurochir (Wien) 2005;147:1085–1089. discussion 1089.


Pau A, Chiaramonte G, Ghio G, Pisani R. Solitary intracranial subdural osteoma: case report and review of the literature. Tumori. 2003;89:96–98.


Aoki H, Nakase H, Sakaki T. Subdural osteoma. Acta Neurochir (Wien) 1998;140:727–728. [PubMed] 10. Choudhury AR, Haleem A, Tjan GT. Solitary intradural intracranial osteoma. Br J Neurosurg. 1995;9:557–559.


Constantinidis J. [Intrathalamic osteoma] Psychiatr Neurol (Basel) 1967;154:366–372.

1)

Yang H, Niu L, Zhang Y, Jia J, Li Q, Dai J, Duan L, Pan Y. Solitary subdural osteoma: A case report and literature review. Clin Neurol Neurosurg. 2018 Jul 2;172:87-89. doi: 10.1016/j.clineuro.2018.07.004. [Epub ahead of print] PubMed PMID: 29986201.
2)

Kim EY, Shim YS, Hyun DK, Park H, Oh SY, Yoon SH. Clinical, Radiologic, and Pathologic Findings of Subdural Osteoma: A Case Report. Brain Tumor Res Treat. 2016 Apr;4(1):40-3. doi: 10.14791/btrt.2016.4.1.40. Epub 2016 Apr 29. PubMed PMID: 27195262; PubMed Central PMCID: PMC4868817.