UpToDate: Primary spinal peripheral primitive neuroectodermal tumor

Primary spinal peripheral primitive neuroectodermal tumor

Epidemiology

Primary spinal peripheral primitive neuroectodermal tumors (pPNETs) are extremely rare entities that predominantly occur in children and young adults.

Treatment

Microsurgical GTR of the tumor is the preferred method of treatment. Radiotherapy plays an important role in improving the prognosis of patients with pPNETs. GTR combined with radiotherapy and chemotherapy may be the best treatment modality 1).

Outcome

Spinal PNETs, like their cranial counterparts, are aggressive tumors and patients with these tumors typically have short survival times despite maximal surgery, chemotherapy, and radiation. Because no standard management guidelines exist for treating these tumors, a multitude of therapeutic strategies have been employed with varying success 2).

Case series

The clinical data of 24 patients, who had been surgically treated from April 2003 to February 2018 in Department of Neurosurgery, Tongji HospitalWuhan, in whom immunohistochemical staining results had confirmed the diagnosis of primary spinal pPNETs, were retrospectively analyzed. To analyze the factors related to prognosis, the Kaplan-Meier method was used for univariate analysis, the log-rank method was used to test the significance of difference, and multivariate analysis was performed using Cox regression.

The overall 1-year, 2-year, and 5-year survival rates were 73.2%, 48.1%, and 12.0%, respectively. The median survival time (MST) of all patients was 21 months. Univariate analysis showed that the extent of tumor resection, adjuvant radiotherapy, and chemotherapy were the factors influencing patient prognosis after surgery (all P < 0.05); sex, age, tumor location, and preoperative Karnofsky performance scale (KPS) scores were not the influential factors for prognosis of patients after surgery (all P > 0.05). Multivariate analysis showed that gross total resection (GTR) of tumors and adjuvant radiotherapy were independent factors influencing the prognosis of patients with pPNETs (all P < 0.05).

Primary spinal pPNETs are extremely rare, and they have a poor prognosis. Microsurgical GTR of the tumor is the preferred method of treatment. Radiotherapy plays an important role in improving the prognosis of patients with pPNETs. GTR combined with radiotherapy and chemotherapy may be the best treatment modality 3).


13 patients (nine females and four males) with primary intraspinal pPNETs who were surgically treated from April 2008 to February 2014. Histopathologic findings revealed the expression of CD99 in all cases. Limb weakness was the most common initial symptom (11/13, 85 %). The tumors were located mainly at the cervical level (6/13, 46 %) and in the epidural space (10/13, 77 %). The radiological diagnosis was neurinoma or meningioma in most cases (10/13, 77 %). Gross total resection was achieved in 77 % (10/13) of patients. During a mean follow-up of 25.5 months, local relapse occurred in 8 (61.5 %) patients and distant metastases occurred in 8 (61.5 %) patients. The overall 1-year survival rate was 77 % (10/13), and the overall 2-year survival rate was 54 % (7/13). The 2-year survival rate was 57.1 % in patients with adjuvant chemotherapy and 50 % in those without chemotherapy. Gross total resection and adjuvant radiotherapy with or without chemotherapy demonstrated a longer survival period (1-year survival rate: 100 %; 2-year survival rate: 86 %). The data showed that primary spinal pPNETs are extremely rare and aggressive tumors with a poor prognosis. Radical resection is advocated. Gross total resection combined with adjuvant radiation may help to significantly improve patient survival period. Chemotherapy may also help to slightly prolong patient life 4).


Three patients of 8, 9 and 18 years of age, who presented with variable grades of neurological deficit were diagnosed as having a dorsal intramedullary lesion, a holocord lesion and cervical extradural tumor with extraspinal extension, respectively, and were operated at our institute. The histopathology of all 3 children revealed PNET. The clinical course, image characteristics and outcome of the 3 children are described, and the relevant literature is reviewed. The following conclusions were drawn from the present study and review of the literature. PNET may manifest itself as a primary lesion of the spine unlike the more common drop metastases from an intracranial lesion. PSPNET may be intramedullary, intradural and extradural with variable extraspinal extension. PSPNET may present as holocord intramedullary lesion, an entity which has not been described earlier. These lesions have a short history, significant neurological deficits and rapid course of illness. PSPNET, though an established entity, did not find a place in the WHO 2000 classification of CNS tumors. Hence its status has to be define 5).

Case reports

A 26-year-old male presented with progressive low back and lower limb pain for 1 month. Based on MRI and histopathological findings, he was diagnosed with primary intramedullary PNET. The patient was treated two times with microsurgical resections. Follow-up visit at 14 months after the first surgery showed that the patient is neurologically intact and free of disease. PNETs should be considered in the differential diagnosis of an intramedullary spinal cord tumor manifesting as progressive neurological deterioration 6)


A 5-year-old Moroccan boy, who presented with torticollis for 1 month. Computed tomography scan and Magnetic resonance imaging of the cervical spine revealed an extradural, dumbbell-shaped mass with extra-spinal extension at the left C1-C6 level. Multiple biopsy specimens were obtained. Histological examination revealed a highly cellular neoplasm composed of diffuse sheets of tumor cells having monomorphic, round to oval, finely vesicular nuclei. Immunohistochemical findings confirmed the diagnosis of intraspinal peripheral primitive neuroectodermal tumor 7).


A two years old female child presented with weakness both lower limbs. Preoperative MRI of the spine and paravertebral region Iso – hyper intense posterior placed extradural lesion, non contrast enhancing from D11-L2 levels with cord compression D9 to L3 laminectomy done. Granulation tissue found from D11 to L2. with cord compression. The granulation tissue removed in toto. The pathological findings were consistent with PNET. Post operative neurological improvement was minimal. Cranial screening ruled out any intracranial tumour. Hence a diagnosis of primary spinal PNET was made 8).


A 18-year-old female with conus intramedullary tumor diagnosed to be primary spinal primitive neuroectodermal tumor following histopathological examination after surgery. The diagnosis of such a tumor is very crucial as the management strategies for these are relatively unclear and are associated with a poorer outcome compared to the other common intramedullary spinal tumors 9).

2 cases Ellis JA, Rothrock RJ, Moise G, McCormick PC 2nd, Tanji K, Canoll P, Kaiser MG, McCormick PC. Primitive neuroectodermal tumors of the spine: a comprehensive review with illustrative clinical cases. Neurosurg Focus. 2011 Jan;30(1):E1. doi: 10.3171/2010.10.FOCUS10217. Review. PubMed PMID: 21194274 10).

References

1) , 3)

Chen J, Zheng YF, Tang SC, Zhao YQ, Chen J, Wang Y. Long-term outcomes of surgical resection with or without adjuvant therapy for treatment of primary spinal peripheral primitive neuroectodermal tumors. Clin Neurol Neurosurg. 2018 Sep 19;175:25-33. doi: 10.1016/j.clineuro.2018.09.025. [Epub ahead of print] PubMed PMID: 30312956.
2) , 10)

Ellis JA, Rothrock RJ, Moise G, McCormick PC 2nd, Tanji K, Canoll P, Kaiser MG, McCormick PC. Primitive neuroectodermal tumors of the spine: a comprehensive review with illustrative clinical cases. Neurosurg Focus. 2011 Jan;30(1):E1. doi: 10.3171/2010.10.FOCUS10217. Review. PubMed PMID: 21194274.
4)

Tong X, Deng X, Yang T, Yang C, Wu L, Wu J, Yao Y, Fu Z, Wang S, Xu Y. Clinical presentation and long-term outcome of primary spinal peripheral primitive neuroectodermal tumors. J Neurooncol. 2015 Jul 18. [Epub ahead of print] PubMed PMID: 26186903.
5)

Kumar R, Reddy SJ, Wani AA, Pal L. Primary spinal primitive neuroectodermal tumor: case series and review of the literature. Pediatr Neurosurg. 2007;43(1):1-6. Review. PubMed PMID: 17190980.
6)

Wang G, Guo F. Primary intramedullary primitive neuroectodermal tumor: A case report and review of the literature. Medicine (Baltimore). 2017 Dec;96(49):e9001. doi: 10.1097/MD.0000000000009001. PubMed PMID: 29245277; PubMed Central PMCID: PMC5728892.
7)

Khmou M, Malihy A, Lamalmi N, Rouas L, Alhamany Z. Peripheral primitive neuroectodermal tumors of the spine: a case report and review of the literature. BMC Res Notes. 2016 Sep 9;9(1):438. doi: 10.1186/s13104-016-2246-5. Review. PubMed PMID: 27613377; PubMed Central PMCID: PMC5016941.
8)

Venkataraman S, Pandian C, Kumar SA. Primary spinal primitive neuroectodermal tumour – a case report. Ann Neurosci. 2013 Apr;20(2):80-2. doi: 10.5214/ans.0972.7531.200211. PubMed PMID: 25206019; PubMed Central PMCID: PMC4117112.
9)

Harbhajanka A, Jain M, Kapoor SK. Primary spinal intramedullary primitive neuroectodermal tumor. J Pediatr Neurosci. 2012 Jan;7(1):67-9. doi: 10.4103/1817-1745.97631. PubMed PMID: 22837786; PubMed Central PMCID: PMC3401662.

Eso Masterclass In Neuro-Oncology: Multidisciplinary Management Of Adult Brain Tumour

September 20 — September 22

Milan, Italy

Programme

The European School of Oncology was founded by Umberto Veronesi and Laudomia Del Drago in 1982, with the aim of contributing to the reduction of deaths from cancer due to late diagnosis and/or inadequate treatment. By improving the skills of all health professionals dealing with cancer patients, ESO helps shorten the time needed to transfer knowledge from research centres to daily practice, combining advanced technology with humanism in care.

ESO’s mission is reflected in its motto “Learning to Care”, which emphasises the importance of the learning process, and the goal of caring for the patient in a holistic sense, in contrast to focusing purely on treating the disease.

Due to its financial independence, ESO has the rare privilege of being able to set its own priorities. It therefore pays particular attention to developing the transfer of knowledge in areas that are least supported by industry, such as surgery and in rare pathologies (including childhood tumours), and in countries and regions with limited economic resources.

Spinal Schwannoma Classification

Spinal Schwannoma Classification

Preoperative planning remains crucial for successful Spinal Schwannoma treatment and relies to a great extent on proper tumor classification. The literature includes multiple classification systems for spinal schwannomas, each of which is associated with both positive and negative ramifications for preoperative planning 1) 2) 3)4).

Consequently, there is a lack of consensus concerning the optimal system of classification for schwannomas 5).

The literature includes numerous schwannoma classification systems. Jinnai and Koyama 6) classified schwannomas into five groups based on the relationship between the tumor and the dura mater and/or intervertebral foramen. This classification system is useful, as it takes into consideration tumor localization relative to the dura, but it does not take into account volume, which is important for preoperative surgical planning.

Sridhar classification

Sridhar 7) was the first, in 2001, to suggest a classification system of benign spinal schwannoma including giant and invasive spinal schwannomas (type I to V).

Park et al. 8) reported the use of a new classification system, and Type VI and Type VII were added. But the classification system as defined by Park et al. were inadequate because both the figures and the tumors were not clearly described in their manuscript.

A case could not be classified based on Sridhar’s spinal schwannoma classification system. Thus, as shown in a case, of Kotil type VIII must be added to the modified Sridhar classification (Kotil classification) system of benign spinal schwannomas 9).

Sun and Pamir however, think classification of seven distinct types of schwannomas using Sridhar et al.’s system is not practical because the characteristics of seven tumors types are difficult to remember. Another drawback of their system is that tumor volume is only considered for dumbbell-shaped tumors, and craniocaudal dimension is not a consideration, which limit the diagnostic value and consistency of the classification system 10).

Asazuma Classification

Asazuma et al. 11) devised a schwannoma classification system for cervical dumbbell- shaped tumors that consisted of nine categories. An important drawback of their classification system is that it cannot be used for thoracic or lumbar schwannomas, which are as common as cervical schwannomas.

Asazuma et al. classification system for dumbbell spinal schwannoma:

Type 1 intradural extradural restricted to the spinal canal. The constriction occurs at the dura.

Type II are all extradural, and are subclassified as:

IIa do not expand beyond the neural foramen.

IIb inside spinal canal + paravertebral.

IIc foraminal + paravertebral.

Type IIIa are intradural and extradural foraminal, IIIb are intradural and extradural paravertebral.

Type IV are extradural and intravertebral.

Type V are extradural and extralaminar with laminar invasion.

Type VI show multidirectional bone erosion.

Craniocaudal spread: IF & TF designate the number of intervertebral foramina and transverse foramina involved, respectively (e.g. IF stage 2 = 2 foramens).

Schwannomas involving C1 & C2: May involve vertebral arteries and require additional caution.

Sun and Pamir Classification

It is based on consideration of tumor volume and localization relative to the dura and spinal canal. For approximate calculation of tumor volume, spinal schwannomas were considered ellipsoid bodies, and tumor volume was calculated using the following formula:

Tumor volume = 4 / 3 π × (craniocaudal length / 2) × (transverse diameter / 2)2 .

Tumors were then assigned to 1–3 volume groups (group A, B, and C) and designated as 1 of 4 types (type I, II, III, and IV) accord- ing to localization (i.e., group B type II tumor). Tumor volume <2 cm3 was considered group A, 2–4 cm3 group B, and >4 cm3 group C. Tumor typing was as follows: localized exclusively intra- durally: type I; intradural localization with extradural extension to the nerve root foramina, but restricted to the spinal canal: type II; intradural dumbbell-shaped tumor in the spinal canal extending to the extraforaminal region: type III; and localized completely outside the root foramina: type IV


Sridhar et al.’s 12) classification system is arguably the most similar of the previously reported systems to the novel classification system described by Sun and Pamir however, they think classification of seven distinct types of schwannomas using Sridhar et al.’s system is not practical because the characteristics of seven tumors types are difficult to remember. Another drawback of their system is that tumor volume is only considered for dumbbell-shaped tumors, and craniocaudal dimension is not a consideration, which limit the diagnostic value and consistency of the classification system 13).


Based on the findings, Sun and Pamir think that all schwannomas should be classified according to localization and volume, so as to achieve the desired benefit of classification—ease and reliability of preoperative decision making and preparation. In addition, this classification system makes tumor localization easier to understand, as compared to other systems, and is suitable for all schwannoma types.

It is a simple and effective tool that shows extremely helpful for avoiding unnecessary surgical approaches and complications. Due to the system’s simplicity of having only three tumor groups and its reliability—indicated by the associated low postoperative side effect rate, use of this novel classification system should be considered by any surgical department that seeks a standardized schwannoma surgery protocol. 14).


Dumbbell spinal schwannoma

Giant spinal schwannoma

Cervical spinal schwannoma

Thoracic spinal schwannoma

Lumbar spinal schwannoma

References

1)

Chowdhury FH, Haque MR, Sarker MH. High cervical spinal schwannoma; microneurosurgical management: an experience of 15 cases. Acta Neurol Taiwan (2013) 22:59–66.
2)

Fernandes RL, Lynch JC, Welling L, Gonçalevs M, Tragante R, Temponi V, et al. Complete removal of the spinal nerve sheath tumors. Surgical techniques and results from a series of 30 patients. Arq Neuropsiquiatr (2014) 72:312–7. doi:10.1590/0004-282×20140008
3)

Iwasaki Y, Hida K, Koyanagi I, Yoshimoto T, Abe H. Anterior approach for dumbbell type cervical neurinoma. Neurol Med Chir (1999) 39:835–9. doi:10.2176/nmc.39.835
4)

Kim P, Ebersold MJ, Onofrio BM, Quast LM. Surgery of spinal nerve schwannoma. Risk of neurological deficit after resection of involved root. J Neurosurg (1989) 71:810–4. doi:10.3171/jns.1989.71.6.0810
5)

Sun I, Pamir MN. Non-Syndromic Spinal Schwannomas: A Novel Classification. Front Neurol. 2017 Jul 17;8:318. doi: 10.3389/fneur.2017.00318. eCollection 2017. PubMed PMID: 28769861; PubMed Central PMCID: PMC5511849.
6)

Jinnai T, Koyama T. Clinical characteristics of spinal nerve sheath tumors: analysis of 149 cases. Neurosurgery (2005) 56:510–5. doi:10.1227/01. NEU.0000153752.59565.BB
7) , 12)

Sridhar K, Ramamurthi R, Vasudevan MC, Ramamurthi B. Giant invasive spinal schwannomas: definition and surgical management. J Neurosurg (2001) 94:210–5.
8)

Park SC, Chung SK, Choe G, Kim HJ. Spinal intraosseous schwannoma : a case report and review. J Korean Neurosurg Soc. 2009 Oct;46(4):403-8. doi: 10.3340/jkns.2009.46.4.403. Epub 2009 Oct 31. PubMed PMID: 19893734; PubMed Central PMCID: PMC2773402.
9)

Kotil K. An extremely giant lumbar schwannoma: new classification (kotil) and mini-open microsurgical resection. Asian Spine J. 2014 Aug;8(4):506-11. doi: 10.4184/asj.2014.8.4.506. Epub 2014 Aug 19. PubMed PMID: 25187870; PubMed Central PMCID: PMC4149996.
10) , 13) , 14)

Sun I, Pamir MN. Non-Syndromic Spinal Schwannomas: A Novel Classification. Front Neurol. 2017 Jul 17;8:318. doi: 10.3389/fneur.2017.00318. eCollection 2017. PubMed PMID: 28769861; PubMed Central PMCID: PMC5511849.
11)

Asazuma T, Toyama Y, Maruiwa H, Fujimura Y, Hirabayashi K. Surgical strategy for cervical dumbbell tumors based on a three-dimensional classification. Spine (2004) 29:E10–4. doi:10.1097/01.BRS.0000103662. 13689.76

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.
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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.
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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.
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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.
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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.
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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.
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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.
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