Posts Tagged ‘Myeloablative therapy’

Ablation Techniques in Interventional Oncology

Author and Curator: Dror Nir, PhD

“Ablation is removal of material from the surface of an object by vaporization, chipping, or other erosive processes.”; WikipediA.

The use of ablative techniques in medicine is known for decades. By the late 90s, the ability to manipulate ablation sources and control their application to area of interest improved to a level that triggered their adaptation to cancer treatment. To date, ablation  is still a controversial treatment, yet steadily growing in it’s offerings to very specific cancer patients’ population.

The attractiveness in ablation as a form of cancer treatment is in the promise of minimal invasiveness, focused tissue destruction and better quality of life due to the ability to partially maintain viability of affected organs.  The main challenges preventing wider adaptation of ablative treatments are: the inability to noninvasively assess the level of cancerous tissue destruction during treatment; resulting in metastatic recurrence of the disease and the insufficient isolation of the treatment area from its surrounding.   This frequently results In addition, post-ablation salvage treatments are much more complicated. Since failed ablative treatment represents a lost opportunity to apply effective treatment to the primary tumor the current trend is to apply such treatments to low-grade cancers.

Nevertheless, the attractiveness of treating cancer in a focused way that preserves the long-term quality of life continuously feeds the development efforts and investments related to introduction of new and improved ablative treatments giving the hope that sometime in the future focused ablative treatment will reach its full potential.

The following paper reviews the main ablation techniques that are available for use today: Percutaneous image-guided ablation of bone and soft tissue tumours: a review of available techniques and protective measures.



Primary or metastatic osseous and soft tissue lesions can be treated by ablation techniques.


These techniques are classified into chemical ablation (including ethanol or acetic acid injection) and thermal ablation (including laser, radiofrequency, microwave, cryoablation, radiofrequency ionisation and MR-guided HIFU). Ablation can be performed either alone or in combination with surgical or other percutaneous techniques.


In most cases, ablation provides curative treatment for benign lesions and malignant lesions up to 3 cm. Furthermore, it can be a palliative treatment providing pain reduction and local control of the disease, diminishing the tumor burden and mass effect on organs. Ablation may result in bone weakening; therefore, whenever stabilization is undermined, bone augmentation should follow ablation depending on the lesion size and location.


Thermal ablation of bone and soft tissues demonstrates high success and relatively low complication rates. However, the most common complication is the iatrogenic thermal damage of surrounding sensitive structures. Nervous structures are very sensitive to extremely high and low temperatures with resultant transient or permanent neurological damage. Thermal damage can cause normal bone osteonecrosis in the lesion’s periphery, surrounding muscular atrophy and scarring, and skin burns. Successful thermal ablation requires a sufficient ablation volume and thermal protection of the surrounding vulnerable structures.

Teaching points

Percutaneous ablations constitute a safe and efficacious therapy for treatment of osteoid osteoma.

Ablation techniques can treat painful malignant MSK lesions and provide local tumor control.

Thermal ablation of bone and soft tissues demonstrates high success and low complication rates.

Nerves, cartilage and skin are sensitive to extremely high and low temperatures.

Successful thermal ablation occasionally requires thermal protection of the surrounding structures.

For the purpose of this chapter we picked up three techniques:

Radiofrequency ablation

Straight or expandable percutaneously placed electrodes deliver a high-frequency alternating current, which causes ionic agitation with resultant frictional heat (temperatures of 60–100 ˚C) that produces protein denaturation and coagulation necrosis [8]. Concerning active protective techniques, all kinds of gas dissection can be performed. Hydrodissection is performed with dextrose 5 % (acts as an insulator as opposed to normal saline, which acts as a conductor). All kinds of skin cooling, thermal and neural monitoring can be performed.


Microwave ablation

Straight percutaneously placed antennae deliver electromagnetic microwaves (915 or 2,450 MHz) with resultant frictional heat (temperatures of 60–100 ˚C) that produces protein denaturation and coagulation necrosis [8]. Concerning active protective techniques, all kinds of gas dissection can be performed, whilst hydrodissection is usually avoided (MWA is based on agitation of water molecules for energy transmission). All kinds of skin cooling, thermal and neural monitoring can be performed.

Percutaneous ablation of malignant metastatic lesions is performed under imaging guidance, extended local sterility measures and antibiotic prophylaxis. Whenever the ablation zone is expected to extend up to 1 cm close to critical structures (e.g. the nerve root, skin, etc.), all the necessary thermal protection techniques should be applied (Fig. 3).


a Painful soft tissue mass infiltrating the left T10 posterior rib. b A microwave antenna is percutaneously inserted inside the mass. Due to the proximity to the skin a sterile glove filled with cold water is placed over the skin. c CT axial scan 3 months

Irreversible Electroporation (IRE)

Each cell membrane point has a local transmembrane voltage that determines a dynamic phenomenon called electroporation (reversible or irreversible) [16]. Electroporation is manifested by specific transmembrane voltage thresholds related to a given pulse duration and shape. Thus, a threshold for an electronic field magnitude is defined and only cells with higher electric field magnitudes than this threshold are electroporated. IRE produces persistent nano-sized membrane pores compromising the viability of cells [16]. On the other hand, collagen and other supporting structures remain unaffected. The IRE generator produces direct current (25–45 A) electric pulses of high voltage (1,500–3,000 V).

Lastly we wish to highlight a method that is mostly used on patients diagnosed at intermediate or advanced clinical stages of Hepatocellular Carcinoma (HCC); transarterial chemoembolization  (TACE)

“Transcatheter arterial chemoembolization (also called transarterial chemoembolization or TACE) is a minimally invasive procedure performed in interventional radiology  to restrict a tumor’s blood supply. Small embolic particles coated with chemotherapeutic agents are injected selectively into an artery directly supplying a tumor. TACE derives its beneficial effect by two primary mechanisms. Most tumors within the liver are supplied by the proper hepatic artery, so arterial embolization preferentially interrupts the tumor’s blood supply and stalls growth until neovascularization. Secondly, focused administration of chemotherapy allows for delivery of a higher dose to the tissue while simultaneously reducing systemic exposure, which is typically the dose limiting factor. This effect is potentiated by the fact that the chemotherapeutic drug is not washed out from the tumor vascular bed by blood flow after embolization. Effectively, this results in a higher concentration of drug to be in contact with the tumor for a longer period of time. Park et al. conceptualized carcinogenesis of HCC as a multistep process involving parenchymal arterialization, sinusoidal capillarization, and development of unpaired arteries (a vital component of tumor angiogenesis). All these events lead to a gradual shift in tumor blood supply from portal to arterial circulation. This concept has been validated using dynamic imaging modalities by various investigators. Sigurdson et al. demonstrated that when an agent was infused via the hepatic artery, intratumoral concentrations were ten times greater compared to when agents were administered through the portal vein. Hence, arterial treatment targets the tumor while normal liver is relatively spared. Embolization induces ischemic necrosis of tumor causing a failure of the transmembrane pump, resulting in a greater absorption of agents by the tumor cells. Tissue concentration of agents within the tumor is greater than 40 times that of the surrounding normal liver.”; WikipediA

A recent open access research paper: Conventional transarterial chemoembolization versus drug-eluting bead transarterial chemoembolization for the treatment of hepatocellular carcinoma is discussing recent clinical approaches  related to this techniques.



To compare the overall survival of patients with hepatocellular carcinoma (HCC) who were treated with lipiodol-based conventional transarterial chemoembolization (cTACE) with that of patients treated with drug-eluting bead transarterial chemoembolization (DEB-TACE).


By an electronic search of our radiology information system, we identified 674 patients that received TACE between November 2002 and July 2013. A total of 520 patients received cTACE, and 154 received DEB-TACE. In total, 424 patients were excluded for the following reasons: tumor type other than HCC (n = 91), liver transplantation after TACE (n = 119), lack of histological grading (n = 58), incomplete laboratory values (n = 15), other reasons (e.g., previous systemic chemotherapy) (n = 114), or were lost to follow-up (n = 27). Therefore, 250 patients were finally included for comparative analysis (n = 174 cTACE; n = 76 DEB-TACE).


There were no significant differences between the two groups regarding sex, overall status (Barcelona Clinic Liver Cancer classification), liver function (Child-Pugh), portal invasion, tumor load, or tumor grading (all p > 0.05). The mean number of treatment sessions was 4 ± 3.1 in the cTACE group versus 2.9 ± 1.8 in the DEB-TACE group (p = 0.01). Median survival was 409 days (95 % CI: 321–488 days) in the cTACE group, compared with 369 days (95 % CI: 310–589 days) in the DEB-TACE group (p = 0.76). In the subgroup of Child A patients, the survival was 602 days (484–792 days) for cTACE versus 627 days (364–788 days) for DEB-TACE (p = 0.39). In Child B/C patients, the survival was considerably lower: 223 days (165–315 days) for cTACE versus 226 days (114–335 days) for DEB-TACE (p = 0.53).


The present study showed no significant difference in overall survival between cTACE and DEB-TACE in patients with HCC. However, the significantly lower number of treatments needed in the DEB-TACE group makes it a more appealing treatment option than cTACE for appropriately selected patients with unresectable HCC.

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Author: Tilda Barliya PhD

Neuroblastoma: A Review

WordCloud created by Noam Steiner Tomer 8/10/2020

Neuroblastoma is the most common extracranial solid tumor of infancy. It is an embryonal tumor of the autonomic/sympathetic  nervous system arising from neuroblasts (pluripotent sympathetic cells).In the developing embryo, these cells invaginate, migrate along the neuraxis, and populate the sympathetic ganglia, adrenal medulla, and other sites. The patterns of distribution of these cells correlates with the sites of primary neuroblastoma presentation.

Age, stage, and biological features encountered in tumor cells are important prognostic factors and are used for risk stratification and treatment assignment. The differences in outcome for patients with neuroblastoma are striking.


The incidence of neuroblastoma per year is 10.5 per million children less than 15 years of age (1). Neuroblastoma accounts for 8% to 10% of all childhood cancers and for approximately 15% of cancer deaths in children.

  • No significant geographical variation in the incidence between North America and Europe
  • No differences between races.
  • slightly more frequently in boys than girls (ratio 1.2:1)
  • The incidence peaks at age 0 to 4 years
  • Cases of familial neuroblastoma have been reported (but rare).
  • Environmental factors are implicated in the development of neuroblastoma (eg, paternal exposure to electromagnetic fields or prenatal exposure to alcohol, pesticides, or phenobarbital). Yet, none of these environmental factors has been confirmed in independent studies
  • Asymptomatic tumors could be detected in infants by measurement of urinary catecholamine metabolites (2).

Note: The Quebec Neuroblastoma Screening Project and the German Neuroblastoma Screening studies demonstrate that screening for neuroblastoma at or under the age of 1 year identifies tumors with a good prognosis and molecular pathology, doubles the incidence, and fails to detect the poor-prognosis disease that presents clinically at an older age.


The peripheral neuroblastic tumors (pNTs), including neuroblastoma, belong to the ‘‘small blue round cell’’ neoplasms of childhood (3). “They are derived from progenitor cells of the sympathetic nervous system: the sympathogonia of the sympathoadrenal lineage. After migrating from the neural crest, these pluripotent sympathogonia form the sympathetic ganglia, the chromaffin cells of the adrenal medulla, and the paraganglia, reflecting the typical localization of neuroblastic tumors”.

Defects in embryonic genes controlling neural crest development are likely to underlie the proliferation and differentiation of neurobalstoma, yet the precise mechanism is unknown.Developmental programs controlling self-renewal in neuronal stem cells, including the Notch, Sonic hedgehog, and Wnt/b-catenin pathways, have been implicated in embryonal tumorigenesis (1,4,5).

Zhi F et al investigated the role of Wnt/β-catenin in modulation of cellular plasticity of the N2A cells-derived neurons and its possible functions in origination of neuroblastoma.  In human neuroblastoma specimens, the authors found that the amount of activated β-catenin in nucleus was up-regulated significantly in pace with clinical neuroblastoma risk (8).

Wickstorm M et al as well as others have investigated the role of Hedgehog (HH) signaling pathway and its role in the development of several types of cancer (9,10). Specific inhibitors revealed that inhibition of HH signaling at the level of GLI was most effective in reducing neuroblastoma growth. GANT61 sensitivity positively correlated to GLI1 and negatively to MYCN expression in the neuroblastoma cell lines tested. Wickstrom M and colleagues suggest that suggests that inhibition of HH signaling is a highly relevant therapeutic target for high-risk neuroblastoma lacking MYCN amplification and should be considered for clinical testing.

Although Sonic hedgehog, and Wnt/b-catenin pathways were found to be relevant in neuroblastoma progression, there were yet to be implied in the clinical practice.

According to the International Neuroblastoma Pathology Classification (INPC) the pNTs are assigned to one of the following
four basic morphological categories:

  • (1) Neuroblastoma (Schwannian-stroma poor)
  • (2) Ganglioneuroblastoma, intermixed (Schwannian stroma-rich)
  • (3) Ganglioneuroblastoma, nodular (composite Schwannian stroma-rich/stroma dominant and stroma-poor).
  • (4) Ganglioneuroma (Schwannian-stroma-dominant).

Shimada et al developed a histopathologic classification in patients with neuroblastoma (6) which was adapted by the INPC.

Important features of this classification include:

  • (1) the degree of neuroblast differentiation,
  • (2) the presence or absence of Schwannian stromal development (stroma-rich, stroma-poor),
  • (3) the index of cellular proliferation (known as mitosis-karyorrhexis index [MKI]),
  • (4) nodular pattern,
  • (5) age.

In a short summary, these pathological classification differentiate these patients into 2 major categories that prognosis:

  • Patients with low-risk and intermediate-risk neuroblastoma have excellent prognosis and outcome.
  • Patients with high-risk disease continue to have very poor outcomes despite intensive therapy.

Unfortunately, approximately 70-80% of patients older than 18 months present with metastatic disease, usually in the lymph nodes, liver, bone, and bone marrow, with particular predilection for metaphyseal, skull, and orbital bone sites. ” A classic presentation of periorbital swelling and ecchymoses (‘‘raccoon eyes’’) is seen in children who have disease spread to periorbital region”.

In contrast to the frequent lack of symptoms with locoregional disease, patients who have widespread disease are often ill appearing with fever, pain, and irritability.

Gene mutations and biomarkers:

Many chromosomal and molecular abnormalities have been identified in patients with neuroblastoma, some of these have been incorporated into the strategies used for risk assignment (7).

  • MYCN  amplification – is considered the most important biomarker in patients with neuroblastoma. “MYCN is an oncogene that is overexpressed in approximately one quarter of cases of neuroblastoma via the amplification of the distal arm of chromosome 2. This gene is amplified in approximately 25% of de novo cases and is more common in patients with advanced-stage disease. Patients whose tumors have MYCN amplification tend to have rapid tumor progression and poor prognosis, even in the setting of other favorable factors such as low-stage disease or 4S disease” (7).
  • H-ras expression – An oncogene correlates with lower stages of the disease
  • Deletion of Chromosome 1 – Deletion of the short arm of chromosome 1 is the most common chromosomal abnormality present in neuroblastoma and confers a poor prognosis. The 1p chromosome region likely harbors tumor suppressor genes or genes that control neuroblast differentiation. Deletion of 1p is associated with more advanced stage of the disease.
  • DNA index – a useful test that correlates with response to therapy in infants. DNA index >1 (=hyperdiploidy) have good therapeutic response while DNA index <1 are less responsive and require a more aggressive treatment. Note – DNA index does not have any prognostic significance in older children and this index occurs in the context of other chromosomal and molecular abnormalities that confer a poor prognosis.
  • Neurotrophin receptors (TrkA, TrkB and TrkC) – TrkA gene expression is inversely correlated with the amplification of the MYCN gene. In most patients younger than 1 year, a high expression of TrkA correlates with a good prognosis, especially in patients with stages 1, 2, and 4S. TrkC gene is correlated with TrkA expression. In contrast, TrkB is more commonly expressed in tumors with MYCN amplification. This association may represent an autocrine survival pathway.
  • Disruption of normal apoptotic pathways – Drugs that target DNA methylation, such as decitabine, are being explored in preliminary studies.
  • Others – other gene and protein expression were found such as glycoprotein  CD44 and multidrug resistance protein (MRP). Yet their role in the development of neuroblastoma is controversial.


The table below outlines criteria for risk assignment based on the International Neuroblastoma Staging System (INSS), age, and biologic risk factors.

These criteria are based on the analysis of several thousands of patients treated in cooperative group protocols in Australia, Canada, Europe, Japan, and the United States.

Treatment regimes is carefully designed upon risk assessment and staging (1):

Low-risk neuroblastoma  Survival rates for patients who have INSS stage 1 disease, regardless of biologic factors, are excellent with surgery alone. Chemotherapy may be needed as an effective salvage therapy for patients who have INSS stage 1 disease who relapse after surgery only.

For patients who have INSS stage
1, 2A, or 2B disease, chemotherapy should be reserved for those who have localized neuroblastoma and experience life- or organ-threatening symptoms at diagnosis or for the minority of patients who experience recurrent or progressive disease.Patients with stage 2A/2B disease with amplified MYCN are considered high risk regardless of age and histology

Stage 4S neuroblastoma withoutMYCN amplification undergoes spontaneous regression in the majority of cases.  Chemotherapy or low-dose radiotherapy is used in patients who have large tumors or massive hepatomegaly.

Intermediate-risk neuroblastoma

Surgical resection and moderate–dose, multiagent chemotherapy (cyclophosphamide, doxorubicin, carboplatin, etoposide) are the standard of care. Chemo rounds are of either 4 cycles, 6 cycles, or 8 cycles, depending on histology and DNA index and response to treatment.  If residual disease is present after chemotherapy and surgery, radiation therapy could be considered. However, the use of radiation is controversial.

High-risk neuroblastoma

Patients with high-risk neuroblastoma require treatment with multiagent chemotherapy, surgery, and radiotherapy. Current therapeutic protocols involve 4 phases of therapy, including induction, local control, consolidation and treatment of minimal residual disease. Induction therapy currently involves multiagent chemotherapy with non–cross-resistant profiles, including: alkylating agents, platinum, and anthracyclines and topoisomerase II inhibitors. Topoisomerase I inhibitor are also being considered. Local control involves surgical resection of primary tumor site as well as radiation to primary tumor site.

Myeloablative consolidation therapy – myeloablative consolidation therapy with etoposide, carboplatin, and melphalan have improved the outcome of patients. most centers now recommend the use of peripheral blood stem cell support over bone marrow for consolidation therapy in patients with high-risk neuroblastoma.

Other consideration – Use of 13-cis -retinoic acid in a maintenance phase of therapy. Recent data have showed improved survival in patients receiving 13-cis -RA in combination with immunomodulatory therapy with interleukin (IL)-2, granulocyte macrophage colony-stimulating factor (GM-CSF), and the chimeric anti-GD2 (gangliosidase) antibody when compared with 13-cis -RA alone.


“Neuroblastoma is a heterogenous tumor for which biology dictates clinical behavior”.  The main the goal is to have patient-tailored prognosis. Additional research in search for new therapeutics for high-risk patients is needed. Some therapies under investigation include aurora kinase inhibitors, antiangiogenic agents, histone deacetylase inhibitors, and therapeutic metaiodobenzylguanidine (MIBG).  According to Park et al: “we must minimize the lasting effects of therapy,For the remaining patients who have low- and intermediate-risk disease,specifically avoiding organ damage or organ loss from surgery and organ dysfunction or risk for secondary malignancy after chemotherapy”.

Other future aspect of therapeutics may include specific inhibitor of this pathway, viz Cyclopamine and other kinase inhibitors like LY294002 for PI3K inhibition or  GSK-3β inhibitors in order to inhibit the Hedgehog and the β-catenin pathways, respectively.


1. Park JR., Eggert A and Caron H.Neuroblastoma: Biology, Prognosis and Treatment. Pediatric Clinics of North America 2008; 55(1): 97-120. http://www.sciencedirect.com/science/article/pii/S0031395507001575

2. Yamamoto K, Hayashi Y, Hanada R, et al. Mass screening and age-specific incidence of neuroblastoma in Saitama Prefecture, Japan. J Clin Oncol 1995;13(8):2033–2038. http://www.ncbi.nlm.nih.gov/pubmed/?term=Mass+screening+and+age-specific+incidence+of+neuroblastoma+in+Saitama+Prefecture%2C+Japan

3. Triche TJ. Neuroblastoma: biology confronts nosology. Arch Pathol Lab Med 1986;110(11):994–996. no available abstract.

4. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004;432(7015):396–401. http://www.ncbi.nlm.nih.gov/pubmed/15549107

5. Tirode F, Laud-Duval K, Prieur A, et al. Mesenchymal stem cell features of Ewing tumors.Cancer Cell 2007;11(5):421–429. http://www.ncbi.nlm.nih.gov/pubmed/17482132

6. Shimada H, Chatten J, Newton WA Jr, et al. Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas.J Natl Cancer Inst. Aug 1984;73(2):405-416. http://www.ncbi.nlm.nih.gov/pubmed/6589432

7. Norman J Lacayo and Max J Coppes. Pediatric Neuroblastoma. MedScape Reference June 2012. http://emedicine.medscape.com/article/988284-overview#a0104

8. Zhi F., Gong G., Xu Y., Zhu Y., Hu D., Yang Y and Hu Y.Activated β-catenin Forces N2A Cell-derived Neurons Back to Tumor-like Neuroblasts and Positively Correlates with a Risk for Human Neuroblastoma. Int J Biol Sci. 2012; 8(2): 289–297. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269611/

9. Shahi MH., Sinha S., Afzal M and Castresana JS. Role of Sonic hedgehog signaling pathway in neuroblastoma development. Biology and Medicine 2009, 1 (4): Rev2, 1-6. http://biolmedonline.com/Articles/vol1_4_Rev2.pdf

10. Wickstrom M., Dyberg C, Shimokawa T., Milosevic J., Baryawno N., Fuskevag OM., Larsson R., Kogner P, Zaphiropoulos PG and Johnsen JI. Targeting the hedgehog signal transduction pathway at the level of GLI inhibits neuroblastoma cell growth in vitro and in vivo.  Int J. Cancer 2013 Apr 1;132(7):1516-1524. http://www.ncbi.nlm.nih.gov/pubmed/22949014

Other related articles on Open Access Leaders in Pharmaceutical Intelligence:

1.By: Larry H Bernstein. AKT signaling variable effects. http://pharmaceuticalintelligence.com/2013/03/04/akt-signaling-variable-effects/

2. By: Aviva Lev-Ari PhD RN. Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence. http://pharmaceuticalintelligence.com/2012/11/24/human-variome-project-encyclopedic-catalog-of-sequence-variants-indexed-to-the-human-genome-sequence/

3. By: Aviva Lev-Ari PhD RN. Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors. http://pharmaceuticalintelligence.com/2012/11/23/neuroprotective-therapies-pharmacogenomics-vs-psychotropic-drugs-and-cholinesterase-inhibitors/

4. By:  Aviva Lev-Ari PhD RN.  arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data. http://pharmaceuticalintelligence.com/2012/11/01/arraymap-genomic-feature-mining-of-cancer-entities-of-copy-number-abnormalities-cnas-data/

5. By: Venkat S Karra. $20 million Novartis deal with ‘University of Pennsylvania’ to develop Ultra-Personalized Cancer Immunotherapy. http://pharmaceuticalintelligence.com/2012/08/08/20-million-novartis-deal-with-university-of-pennsylvania-to-develop-ultra-personalized-cancer-immunotherapy/

7.  By: Aviva Lev-Ari PhD RN. Acoustic Neuroma, Neurinoma or Vestibular Schwannoma: Treatment Options. http://pharmaceuticalintelligence.com/2012/10/30/acoustic-neuroma-neurinoma-or-vestibular-schwannoma-treatment-options/

8.  By: Aviva Lev-Ari PhD RN. Clinical Trials on Schwannoma & Benign Intracranial Tumors Radiosurgery Treatment. http://pharmaceuticalintelligence.com/2012/10/30/clinical-trials-on-schwannoma-benign-intracranial-tumors-radiosurgery-treatment/

9. By: Aviva Lev-Ari PhD RN. Facial Nerve, Intracanalicular Meningiomas, Vestibular Schwannomas: Surgical Planning. http://pharmaceuticalintelligence.com/2012/10/15/facial-nerve-intracanalicular-meningiomas-vestibular-schwannomas-surgical-planning/

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