Update: Anterior cervical discectomy and fusion complications

Anterior cervical discectomy and fusion complications

A 2-page survey was distributed to attendees at the 2015 Cervical Spine Research Society (CSRS) meeting. Respondents were asked to categorize 18 anterior cervical discectomy and fusion-related adverse events as either: “common and acceptable,” “uncommon and acceptable,” “uncommon and sometimes acceptable,” or “uncommon and unacceptable.” Results were compiled to generate the relative frequency of these responses for each complication. Responses for each complication event were also compared between respondents based on practice location (US vs. non-US), primary specialty (orthopedics vs. neurosurgery) and years in practice.

Of 150 surveys distributed, 115 responses were received (76.7% response rate), with the majority of respondents found to be US-based (71.3%) orthopedic surgeons (82.6%). Wrong level surgery, esophageal injury, retained drain, and spinal cord injury were considered by most to be unacceptable and uncommon complications. Dysphagia and adjacent segment disease occurred most often, but were deemed acceptable complications. Although surgeon experience and primary specialty had little impact on responses, practice location was found to significantly influence responses for 12 of 18 complications, with non-US surgeons found to categorize events more toward the uncommon and unacceptable end of the spectrum as compared with US surgeons.

These results serve to aid communication and transparency within the field of spine surgery, and will help to inform future quality improvement and best practice initiatives 1).

Vocal cord palsy

Cervical adjacent segment disease

Hoarseness

Hoarseness, approximately in 5% 2).

Dysphagia

Soft tissue damage due to the use of automatic retractors in MACDF is not minor and leads to general discomfort in the patient in spite of good neurological results. These problems most often occur when automatic retractors are used continuously for more than 1 hour, as well as when they are used in multiple levels. Dysphagia, dysphonia and local pain decreased with the use of transient manual blades for retraction, and with intermittent release following minimally invasive principles 3).

Postoperative dysphagia is a significant concern.

Dexamethasone, although potentially protective against perioperative dysphagia and airway compromise, could inhibit fusion, a generally proinflammatory process.

Postoperative hemorrhage

Cerebrospinal fluid (CSF) leaks

Cerebrospinal fluid (CSF) leaks, although uncommon, may occur and can be a potentially serious complication. Little is known regarding the fusion rate after durotomy in ACDF.

In a single-institution retrospective review, 14 patients who experienced CSF leak after ACDF between 1995 and September 2014 were identified.

The median follow-up was 13.1 months. The diagnoses included spondylosis/degenerative disc disease (n = 10), disc herniation with radiculopathy (n = 3), and kyphotic deformity (n = 1). Of ACDFs, 7 were 1-level, 5 were 2-level, and 2 were 3-level procedures. The posterior longitudinal ligament was intentionally opened in all cases, and the microscope was used in 9 cases. Durotomy was discovered intraoperatively in all cases and was generally repaired with a combination of fibrin glue and synthetic dural replacement. Lumbar drainage was used in 5 patients, and 3 patients reported orthostatic headaches, which resolved within 1 month. Two patients reported hoarseness, and 8 patients reported dysphagia; all cases were transient. Follow-up imaging for fusion assessment was available for 12 patients, and a 100% fusion rate was achieved with no postoperative infections.

ACDFs with CSF leak had a 100% fusion rate in this series, with generally excellent clinical outcomes, although it is difficult to conclude definitively that there is no effect on fusion rates because of the small sample size. However, given the relative rarity of this complication, this study provides important data in the clinical literature regarding outcomes after CSF leak in ACDFs 4).

Pharyngoesophageal perforation

Spinal subdural hematoma

A spinal subdural hematoma is a rare clinical entity with considerable consequences without prompt diagnosis and treatment. Throughout the literature, there are limited accounts of spinal subdural hematoma formation following spinal surgery. This report is the first to describe the formation of a spinal subdural hematoma in the thoracic spine following surgery at the cervical level. A 53-year-old woman developed significant paraparesis several hours after anterior cervical discectomy and fusion of C5-6. Expeditious return to operating room for anterior cervical revision decompression was performed, and the epidural hematoma was evacuated without difficulty. Postoperative imaging demonstrated a subdural hematoma confined to the thoracic level, and the patient was returned to the operating room for a third surgical procedure. Decompression of T1-3, with evacuation of the subdural hematoma was performed. Postprocedure, the patient’s sensory and motor deficits were restored, and, with rehabilitation, the patient gained functional mobility. Spinal subdural hematomas should be considered as a rare but potential complication of cervical discectomy and fusion. With early diagnosis and treatment, favorable outcomes may be achieved 5).

Carotid artery compression

Legatt et al., report herein a case of anterior cervical discectomy and fusion (ACDF) surgery in which findings on somatosensory evoked potential(SSEP) monitoring led to the correction of carotid artery compression in a patient with a vascularly isolated hemisphere (no significant collateral blood vessels to the carotid artery territory). The amplitude of the cortical SSEP component to left ulnar nerve stimulation progressively decreased in multiple runs, but there were no changes in the cervicomedullary SSEP component to the same stimulus. When the lateral (right-sided) retractor was removed, the cortical SSEP component returned to baseline. The retraction was then intermittently relaxed during the rest of the operation, and the patient suffered no neurological morbidity. Magnetic resonance angiography demonstrated a vascularly isolated right hemisphere. During anterior cervical spine surgery, carotid artery compression by the retractor can cause hemispheric ischemia and infarction in patients with inadequate collateral circulation. The primary purpose of SSEP monitoring during ACDF surgery is to detect compromise of the dorsal column somatosensory pathways within the cervical spinal cord, but intraoperative SSEP monitoring can also detect hemispheric ischemia. Concurrent recording of cervicomedullary SSEPs can help differentiate cortical SSEP changes due to hemispheric ischemia from those due to compromise of the dorsal column pathways. If there are adverse changes in the cortical SSEPs but no changes in the cervicomedullary SSEPs, the possibility of hemispheric ischemia due to carotid artery compression by the retractor should be considered 6).

Heterotopic Ossification

Heterotopic ossification (HO) has been reported following total hip, knee, cervical arthroplasty, and lumbar arthroplasty, as well as following posterolateral lumbar fusion using recombinant human morphogenetic protein 2 (rhBMP-2). Data regarding HO following anterior cervical discectomy and fusion (ACDF) with rhBMP-2 are sparse. A subanalysis was done of the prospective, multicenter, investigational device exemption trial that compared rhBMP-2 on an absorbable collagen sponge (ACS) versus allograft in ACDF for patients with symptomatic single-level cervical degenerative disc disease.

To assess differences in types of HO observed in the treatment groups and effects of HO on functional and efficacy outcomes, clinical outcomes from previous disc replacement studies were compared between patients who received rhBMP-2/ACS versus allograft. Rate, location, grade, and size of ossifications were assessed preoperatively and at 24 months, and correlated with clinical outcomes. RESULTS Heterotopic ossification was primarily anterior in both groups. Preoperatively in both groups, and including osteophytes in the target regions, HO rates were high at 40.9% and 36.9% for the rhBMP-2/ACS and allograft groups, respectively (p = 0.350). At 24 months, the rate of HO in the rhBMP-2/ACS group was higher than in the allograft group (78.6% vs 59.2%, respectively; p < 0.001). At 24 months, the rate of superior-anterior adjacent-level Park Grade 3 HO was 4.2% in both groups, whereas the rate of Park Grade 2 HO was 19.0% in the rhBMP-2/ACS group compared with 9.8% in the allograft group. At 24 months, the rate of inferior-anterior adjacent-level Park Grade 2/3 HO was 11.9% in the rhBMP-2/ACS group compared with 5.9% in the allograft group. At 24 months, HO rates at the target implant level were similar (p = 0.963). At 24 months, the mean length and anteroposterior diameter of HO were significantly greater in the rhBMP-2/ACS group compared with the allograft group (p = 0.033 and 0.012, respectively). Regarding clinical correlation, at 24 months in both groups, Park Grade 3 HO at superior adjacent-level disc spaces significantly reduced range of motion, more so in the rhBMP-2/ACS group. At 24 months, HO negatively affected Neck Disability Index scores (excluding neck/arm pain scores), neurological status, and overall success in patients in the rhBMP-2/ACS group, but not in patients in the allograft group.

Implantation of rhBMP-2/ACS at 1.5 mg/ml with polyetheretherketone spacer and titanium plate is effective in inducing fusion and improving pain and function in patients undergoing ACDF for symptomatic single-level cervical degenerative disc disease. At 24 months, the rate and dimensions (length and anteroposterior diameter) of HO were higher in the rhBMP-2/ACS group. At 24 months, range of motion was reduced, with Park Grade 3 HO in both treatment groups. The impact of Park Grades 2 and 3 HO on Neck Disability Index success, neurological status, and overall success was not consistent among the treatment groups. The study data may offer a deeper understanding of HO after ACDF and may pave the way for improved device designs 7).

Subsidence

There is evidence documenting relatively frequent complications in stand-alone cage assisted ACDF, such as cage subsidence and cervical kyphosis 8).

Subsidence irrespective of the measurement technique or definition does not appear to have an impact on successful fusion and/or clinical outcomes. A validated definition and standard measurement technique for subsidence is needed to determine the actual incidence of subsidence and its impact on radiographic and clinical outcomes 9).


The results of a observational study were in accordance with those of the published randomized controlled trials (RCTs), suggesting substantial pain reduction both after anterior cervical interbody fusion (AIF) and Cervical total disc replacement, with slightly greater benefit after arthroplasty. The analysis of atypical patients suggested that, in patients outside the spectrum of clinical trials, both surgical interventions appeared to work to a similar extent to that shown for the cohort in the matched study. Also, in the longer-term perspective, both therapies resulted in similar benefits to the patients 10).

Case series

Analysis of 1000 consecutive patients undergoing Anterior cervical discectomy and fusion (ACDF) in an outpatient setting demonstrated surgical complications occur at a low rate (<1%) and can be appropriately diagnosed and managed in 4-hour ASC PACU window. Comparison with inpatient ACDF surgery cohort demonstrated similar results, highlighting that ACDF can be safely performed in an outpatient ambulatory surgery setting without compromising surgical safety. To decrease cost of care, surgeons can safely consider performing 1- and 2-level ACDF in an ASC environment 11).


A retrospective case series of 37 patients, paying special attention to immediate complications related to the use of mechanical retraction of soft tissue (dysphagia, dysphonia, esophageal lesions and local hematoma); and a comparative analysis of the outcomes after changes in the retraction method.

All selected cases had a positive neurological symptom response in relation to neuropathic pain. Dysphagia and dysphonia were found during the first 72 h in 94.1% of the cases in which automatic mechanical retraction was used for more than one hour during the surgical procedure. A radical change was noted in the reduction of the symptoms after the use of only manual protective blades without automatic mechanical retraction: 5.1% dysphagia and 0% dysphonia in the immediate post-operative period, P = 0.001.

Soft tissue damage due to the use of automatic retractors in MACDF is not minor and leads to general discomfort in the patient in spite of good neurological results. These problems most often occur when automatic retractors are used continuously for more than 1 hour, as well as when they are used in multiple levels. Dysphagia, dysphonia and local pain decreased with the use of transient manual blades for retraction, and with intermittent release following minimally invasive principles 12).

1)

Wilson JR, Radcliff K, Schroeder G, Booth M, Lucasti C, Fehlings M, Ahmad N, Vaccaro A, Arnold P, Sciubba D, Ching A, Smith J, Shaffrey C, Singh K, Darden B, Daffner S, Cheng I, Ghogawala Z, Ludwig S, Buchowski J, Brodke D, Wang J, Lehman RA, Hilibrand A, Yoon T, Grauer J, Dailey A, Steinmetz M, Harrop JS. Frequency and Acceptability of Adverse Events After Anterior Cervical Discectomy and Fusion: A Survey Study From the Cervical Spine Research Society. Clin Spine Surg. 2018 Apr 27. doi: 10.1097/BSD.0000000000000645. [Epub ahead of print] PubMed PMID: 29708891.
2)

Morpeth JF, Williams MF. Vocal fold paralysis after anterior cervical diskectomy and fusion. Laryngoscope. 2000 Jan;110(1):43-6. PubMed PMID: 10646714.
3) , 12)

Ramos-Zúñiga R, Díaz-Guzmán LR, Velasquez S, Macías-Ornelas AM, Rodríguez-Vázquez M. A microsurgical anterior cervical approach and the immediate impact of mechanical retractors: A case control study. J Neurosci Rural Pract. 2015 Jul-Sep;6(3):315-9. doi: 10.4103/0976-3147.158748. PubMed PMID: 26167011; PubMed Central PMCID: PMC4481782.
4)

Elder BD, Theodros D, Sankey EW, Bydon M, Goodwin CR, Wolinsky JP, Sciubba DM, Gokaslan ZL, Bydon A, Witham TF. Management of Cerebrospinal Fluid Leakage During Anterior Cervical Discectomy and Fusion and Its Effect on Spinal Fusion. World Neurosurg. 2015 Nov 30. pii: S1878-8750(15)01588-0. doi: 10.1016/j.wneu.2015.11.033. [Epub ahead of print] PubMed PMID: 26654925.
5)

Protzman NM, Kapun J, Wagener C. Thoracic spinal subdural hematoma complicating anterior cervical discectomy and fusion: case report. J Neurosurg Spine. 2015 Oct 13:1-5. [Epub ahead of print] PubMed PMID: 26460756.
6)

Legatt AD, Laarakker AS, Nakhla JP, Nasser R, Altschul DJ. Somatosensory evoked potential monitoring detection of carotid compression during ACDF surgery in a patient with a vascularly isolated hemisphere. J Neurosurg Spine. 2016 Nov;25(5):566-571. PubMed PMID: 27285667.
7)

Arnold PM, Anderson KK, Selim A, Dryer RF, Kenneth Burkus J. Heterotopic ossification following single-level anterior cervical discectomy and fusion: results from the prospective, multicenter, historically controlled trial comparing allograft to an optimized dose of rhBMP-2. J Neurosurg Spine. 2016 Sep;25(3):292-302. doi: 10.3171/2016.1.SPINE15798. Epub 2016 Apr 29. PubMed PMID: 27129045.
8)

Cloward RB: The anterior approach for removal of ruptured cervical disks. 1958. J Neurosurg Spine 6:496-511, 2007
9)

Karikari IO, Jain D, Owens TR, Gottfried O, Hodges TR, Nimjee SM, Bagley CA. Impact of Subsidence on Clinical Outcomes and Radiographic Fusion Rates in Anterior Cervical Discectomy and Fusion: A Systematic Review. J Spinal Disord Tech. 2014 Feb;27(1):1-10. PubMed PMID: 24441059.
10)

Staub LP, Ryser C, Röder C, Mannion AF, Jarvik JG, Aebi M, Aghayev E. Total disc arthroplasty versus anterior cervical interbody fusion: use of the spine tango registry to supplement the evidence from RCTs. Spine J. 2015 Dec 7. pii: S1529-9430(15)01763-5. doi: 10.1016/j.spinee.2015.11.056. [Epub ahead of print] PubMed PMID: 26674445.
11)

McGirt MJ, Mehrlich M, Parker SL, Asher AL, Adamson TE. 165 ACDF in the Outpatient Ambulatory Surgery Setting: Analysis of 1000 Consecutive Cases and Comparison to Hospital Inpatient ACDF. Neurosurgery. 2015 Aug;62 Suppl 1:220. doi: 10.1227/01.neu.0000467129.12773.a3. PubMed PMID: 26182011.

Invasive meningioma

Invasive meningioma

Invasive intracranial meningioma is a common neoplasm of central nervous system, which can infiltrate adjacent tissues (dura materarachnoid membrane, vascular space and skull) without atypical hyperplasia 1) 2)

In general, the pathological nature of meningioma determines its association with the brain parenchyma, which is that benign meningioma is usually compressive to the brain parenchyma due to its expansive growth, and malignant meningioma is invasive into the neighboring brain parenchyma due to its intrusive growth 3) 4). However, clinical observations have indicated that there is a sub-group of benign meningioma displaying a malignant growth pattern, that is, invasion into the neighboring brain tissue 5) 6) 7) 8) 9).

According to the experience gained in 19 cases, it was observed that there were certain features shared by these invasive benign meningiomas. The peak age of onset was ~50 years; the main manifestation was mild focal neurological deficits, which included dysphasia, and decreased sensation and muscle power of the contralateral limb. The MRI findings usually had the following characteristics: The lesions were located at the convexity of the cerebral hemisphere involving the central lobe, with an extensive base at the dural matter and evident ‘tail sign’; there was a minimal boundary between the tumor and the neighboring brain cortex; finally, and probably most importantly, the apex of tumor often enwrapped the normal brain tissue and associated vessels.

Due to the malignant growth, it was challenging to completely remove this benign meningioma while ensuring that neurological function remained intact. Resection of the earliest 4 cases was performed according to the traditional extra-capsular strategy, which was to coagulate and divide the tumor base first, and then continue the dissection along the interface between the tumor and brain parenchyma. This approach inevitably damaged the vessels transiting from and into the tumor. The observation that all 4 cases had permanent neurological deficits confirmed the disadvantage associated with this surgical strategy. Following careful analysis of the surgical outcomes, the resection method was modified by combining intra- and extra-capsular approaches. The first step was the same as the classical method, which was to coagulate and divide the tumor base. Afterwards, intra-capsular extirpation of the central part of the tumor was performed. Care was taken not to damage the transit vessels when approaching the tumor-brain interface. The enucleation of the central part of the tumor created a working space, which greatly facilitated the identification of the transit vessels. After this, the tumor was separated from brain parenchyma along the sub-arachnoid membrane. The use of a sponge during this dissection process was important. Finally, it was critical to separate the enwrapped brain cortex and associated vessels from the invading ‘cauliflower-like’ nodules of the meningioma. It is recommended that no efforts are spared in this process, since the enwrapped brain tissue may have retained its ability to function. The observation that there was only 1 case with mild neurological impairment post-operatively in the later 15 cases confirms the advantage of the modified strategy.

In summary, the present study further revealed the clinical features of the invasive benign meningioma and indicated the advantage of combined intra-extra capsular strategy for the surgical resection 10).


Identification of risk factors for perioperative epilepsy remains crucial in the care of patients with meningioma. Moreover, associations of brain invasion with clinical and radiological variables have been largely unexplored. Brain invasion was identified as a new and strong predictor for preoperative, but not postoperative, seizures. Although also associated with increased peritumoral edema, seizures in patients with invasive meningioma might be facilitated substantially by cortical invasion itself. Consideration of seizures in consultations between the neurosurgeon and neuropathologist can improve the microscopic detection of brain invasion 11).

Case series

2018

Hess et al., hypothesized that invasion of the cortex and subsequent increased edema facilitate seizures, and they compared radiological data and perioperative seizures in patients with brain-invasive meningioma or noninvasive meningioma.

Correlations of brain invasion with tumor and edema volumes and preoperative and postoperative seizures were analyzed in univariate and multivariate analyses.

Totals of 108 (61%) females and 68 (39%) males with a median age of 60 years and harboring totals of 92 (52%) grade I, 79 (45%) grade II, and 5 (3%) grade III tumors were included. Brain invasion was found in 38 (22%) patients and was absent in 138 (78%) patients. The tumors were located at the convexity in 72 (41%) patients, at the falx cerebri in 26 (15%), at the skull base in 69 (39%), in the posterior fossa in 7 (4%), and in the ventricle in 2 (1%); the median tumor and edema volumes were 13.73 cm3 (range 0.81-162.22 cm3) and 1.38 cm3 (range 0.00-355.80 cm3), respectively. As expected, edema volume increased with rising tumor volume (p < 0.001). Brain invasion was independent of tumor volume (p = 0.176) but strongly correlated with edema volume (p < 0.001). The mean edema volume in noninvasive tumors was 33.0 cm3, but in invasive tumors, it was 130.7 cm3 (p = 0.008). The frequency of preoperative seizures was independent of the patients’ age, sex, and tumor location; however, the frequency was 32% (n = 12) in patients with invasive meningioma and 15% (n = 21) in those with noninvasive meningioma (p = 0.033). In contrast, the probability of detecting brain invasion microscopically was increased more than 2-fold in patients with a history of preoperative seizures (OR 2.57, 95% CI 1.13-5.88; p = 0.025). In univariate analyses, the rate of preoperative seizures correlated slightly with tumor volume (p = 0.049) but strongly with edema volume (p = 0.014), whereas seizure semiology was found to be independent of brain invasion (p = 0.211). In multivariate analyses adjusted for age, sex, tumor location, tumor and edema volumes, and WHO grade, rising tumor volume (OR 1.02, 95% CI 1.00-1.03; p = 0.042) and especially brain invasion (OR 5.26, 95% CI 1.52-18.15; p = 0.009) were identified as independent predictors of preoperative seizures. Nine (5%) patients developed new seizures within a median follow-up time of 15 months after surgery. Development of postoperative epilepsy was independent of all clinical variables, including Simpson grade (p = 0.133), tumor location (p = 0.936), brain invasion (p = 0.408), and preoperative edema volume (p = 0.081), but was correlated with increasing preoperative tumor volume (p = 0.004). Postoperative seizure-free rates were similar among patients with invasive and those with noninvasive meningioma (p = 0.372).

Brain invasion was identified as a new and strong predictor for preoperative, but not postoperative, seizures. Although also associated with increased peritumoral edema, seizures in patients with invasive meningioma might be facilitated substantially by cortical invasion itself. Consideration of seizures in consultations between the neurosurgeon and neuropathologist can improve the microscopic detection of brain invasion12).

2017

From February 2014 to February 2016, 59 patients with invasive meningioma were enrolled in a study. Invasive meningioma was confirmed in all patients by operation. Information about clinical manifestations, pathological features, preoperative imaging and surgical treatment were collected and analyzed. After surgery, pathological specimens were collected, and cases were confirmed as invasive meningioma by pathological examination. The course of disease ranged from 15 days to 7 years (average, 13.2 months). We used World Health Organization (WHO) criteria for classification of meningioma in the nervous system tumors as our reference. Symptoms were as follows: Intracranial hypertension (29 cases), cranial nerve dysfunction (10 cases), epilepsy (11 cases) and other symptoms (9 cases). We had 56 cases of WHO grade I; 6 cases of WHO grade II and 7 cases of WHO grade III. Surgical removal was: Simpson grade I (56 cases), Simpson grade II (2 cases), Simpson grade III and above (56 cases). We used before surgery imaging data to formulate our surgical plan. In general, during surgeries we did not proceed to complete resection, because in the majority of cases, some key structures were invaded and meningioma was very deep and any attempt for total resection could easily lead to significant damage to these structures 13).

1995

A study was undertaken to investigate the correlation between histological invasiveness and proliferating potential and clinical recurrence in meningioma. In 39 meningiomas, the histological findings at the tumour-brain interface zone were classified into 3 types, consisting of 29 cases of non-invasion (NON). 7 cases of nodular invasion (NOD), and 3 cases of intermingled invasion (INT). Proliferating cell nuclear antigen (PCNA) and argyrophilic nucleolar organizer region (AgNOR) indices were studied. PCNA indices (mean +/- standard error) of NON, NOD. and INT were 1.7 +/- 0.1%, 5.2 +/- 0.5%, and 7.5 +/- 0.7%. respectively, and the AgNOR indices (dot number/nucleus) were 1.50 +/- 0.03, 2.00 +/- 0.04, and 2.22 +/- 0.07, respectively. Significant differences were found among the three types in both parameters. Clinically, tumour recurrence was observed in 1/29 NON, 4/7 NOD, and 2/2 INT cases, indicating a higher incidence of recurrence in invasive meningiomas (NOD plus INT). Four of 32 patients who underwent gross total removal of the tumours showed recurrence, and all of these four tumours were invasive meningiomas. The results of the present study showed that tumour invasiveness as measured by PCNA + AgNOR indices correlated well with high proliferative potential and clinical recurrence 14).

1)

Gelabert-González M, Serramito-García R. Intracranial meningiomas: I. Epidemiology, aetiology, pathogenesis and prognostic factors. Rev Neurol. 2011;53:165–172.

2)

Bondy M, Ligon BL. Epidemiology and etiology of intracranial meningiomas: a review. J Neurooncol. 1996;29:197–205. doi: 10.1007/BF00165649.

3)

Riemenschneider MJ, Perry A, Reifenberger G. Histological classification and molecular genetics of meningiomas. Lancet Neurol. 2006;5:1045–1054. doi: 10.1016/S1474-4422(06)70625-1.

4)

Modha A, Gutin PH. Diagnosis and treatment of atypical and anaplastic meningiomas: A review. Neurosurgery. 2005;57:538–550. doi: 10.1227/01.NEU.0000170980.47582.A5.

5)

Trembath D, Miller CR, Perry A. Gray zones in brain tumor classification: Evolving concepts. Adv Anat Pathol. 2008;15:287–297. doi: 10.1097/PAP.0b013e3181836a03.

6)

Gay E, Lages E, Ramus C, Guttin A, El Atifi M, Dupré I, Bouamrani A, Salon C, Ratel D, Wion D, et al. The heterogeneity of meningioma revealed by multiparameter analysis: Infiltrative and non-infiltrative clinical phenotypes. Int J Oncol. 2011;38:1287–1297.

7)

Fritz J, Roser F, Tatagiba M, Bornemann A. The basement membrane at the tumour-brain interface of brain-invasive grade I meningiomas. Neuropathol Appl Neurobiol. 2005;31:339–342. doi: 10.1111/j.1365-2990.2005.00661.x.

8)

Utsuki S, Oka H, Sato Y, Kawano N, Tsuchiya B, Kobayashi I, Fujii K. Invasive meningioma is associated with a low expression of E-cadherin and beta-catenin. Clin Neuropathol. 2005;24:8–12.

9)

Suwa T, Kawano N, Oka H, Ito H, Kameya T. Invasive meningioma: A tumour with high proliferating and ‘recurrence’ potential. Acta Neurochir (Wien) 1995;136:127–131. doi: 10.1007/BF01410613.

10)

Lin Q, Ling F, Xu G. Invasive benign meningioma: Clinical characteristics, surgical strategies and outcomes from a single neurosurgical institute. Exp Ther Med. 2016 Jun;11(6):2537-2540. Epub 2016 Apr 4. PubMed PMID: 27284345; PubMed Central PMCID: PMC4887900.

11) , 12)

Hess K, Spille DC, Adeli A, Sporns PB, Brokinkel C, Grauer O, Mawrin C, Stummer W, Paulus W, Brokinkel B. Brain invasion and the risk of seizures in patients with meningioma. J Neurosurg. 2018 Apr 27:1-8. doi: 10.3171/2017.11.JNS172265. [Epub ahead of print] PubMed PMID: 29701550.

13)

Hou W, Ma Y, Xing H, Yin Y. Imaging characteristics and surgical treatment of invasive meningioma. Oncol Lett. 2017 May;13(5):2965-2970. doi: 10.3892/ol.2017.5833. Epub 2017 Mar 9. PubMed PMID: 28521402; PubMed Central PMCID: PMC5431211.

14)

Suwa T, Kawano N, Oka H, Ito H, Kameya T. Invasive meningioma: a tumour with high proliferating and “recurrence” potential. Acta Neurochir (Wien). 1995;136(3-4):127-31. PubMed PMID: 8748841.

Update: Bladder cancer intracranial metastases

Bladder cancer intracranial metastases

Epidemiology

Bladder cancer gives metastasis to the brain in less than 1%.

Transitional cell carcinoma (TCC), the most common type of urinary bladder cancer, is a rare cause of brain metastasis with an ominous prognosis.

Treatment

Case series

2018

Taylor et al. from the Wake Forest University School of Medicine, Winston-Salem, North Carolina, reported a series of patients with brain metastases from bladder cancer treated with stereotactic radiosurgery (SRS). The aim was to identify patients with brain metastases from bladder primaries treated with SRS with or without surgical resection and report the clinical outcomes.

Patients meeting eligibility criteria at the institution between 2000 and 2017 were included. The clinical variables of interest, including overall survival (OS), local recurrence, V12, distant brain failure (DBF), and initial brain metastases velocity, were calculated. Cox proportional hazards analysis was performed to identify predictors of time-to-event outcomes.

A total of 14 patients were included. The median OS from the time of treatment was 2.1 months. Factors predictive of OS include intracranial resection (HR 0.21, p = 0.03). The cumulative incidence of local failure was 21% at 6 months and 30% at 12 months. The cumulative incidence of DBF at 6 and 12 months was 23 and 31%, respectively.

The prognosis in this patient population remains guarded. Factors associated with improved survival include intracranial resection. Future, prospective work is needed to further define optimal management 1).

2002

Between January 1982 and November 1999, 16 patients with brain metastases from bladder carcinoma were treated at our institution. We reviewed patient and tumor characteristics at the time of the primary diagnosis and the brain metastasis diagnosis. We analyzed treatment results in regard to survival and local metastasis control.

Brain metastases from bladder carcinoma were commonly accompanied by uncontrolled systemic metastases. Multiple brain lesions developed in 14 of the 16 patients. Of the 16 patients 14 received radiation therapy with or without surgery, 1 was treated surgically and 1 did not receive any treatment. The 11 patients treated with whole brain radiation therapy had a median survival of only 2 months (range 0.5 to 11). A patient who received stereotactic radiosurgery survived 12 months after the brain metastasis diagnosis and 2 treated with radiation therapy after surgery survived 12.75 and 2.75 months, respectively (median 7.75). The patient treated with surgery alone survived 1.25 months after the brain metastasis diagnosis and 1 who received no treatment survived 1.75 months. Patients with multiple brain metastases had shorter survival than those with a single metastasis.

Overall survival after brain metastasis development in patients with bladder carcinoma was poor. Although the number of patients in this study was small, results indicate that radiation therapy alone is inadequate treatment. Therefore, when possible, we advocate more effective treatment by combining radiation therapy with other treatment modalities, as recommended in ongoing clinical trials 2).

1993

The records of 28 patients with transitional cell cancer who had brain metastases were retrospectively reviewed. Data from 19 patients were considered suitable for analysis and were included in this study. One patient was treated with surgery alone, 10 with radiation alone and 7 with radiation and surgery, while 1 received no treatment. Mean and median survival times, respectively, were 57 and 42 months from the initial diagnosis, and 11 and 4 months from diagnosis of central nervous system metastases. Patients treated with surgery and radiation demonstrated a mean survival time of 19 months compared to 6 months for patients treated with radiation alone (p = 0.03). There were 2 long-term survivors in the combined modality group at 50 and at 12 months. Enthusiasm for combined modality treatment should be tempered by the fact that selection bias favored the combined modality group; 13 patients with single lesions demonstrated a mean survival of 14 months compared to 3 months for 6 patients with multiple lesions (p = 0.009) and only patients with solitary lesions underwent surgical resection. Brain metastases have an ominous prognosis in patients with bladder cancer primaries. Considering the sum of the retrospective and prospective reports, we recommend that patients with solitary brain lesions and good performance status be aggressively managed with surgical resection and postoperative radiation therapy 3).

1992

Clinico-pathological study of six patients with cerebral metastasis from vesical carcinoma with no prior administration of systemic chemotherapy. In two cases the symptoms of intracranial mass were the initial reason for infiltrant vesical carcinoma examination. Despite the rarity of such occurrence, the possibility of vesical tumours showing in such a way must be taken into account. The singularity of cerebral metastatic seeding throughout the natural history of a vesical neoplasia is analyzed. Also, a review is made of the factors hypothetically responsible for the increase of cerebral metastasis establishment following current chemotherapy 4).

Case reports

A 68-year-old female presented with right-sided paresis and focal motor seizures of her right upper and lower extremities 14 years after being diagnosed and treated for primary TCC of the urinary bladder with gemcitabine-based chemotherapy. MRI imaging revealed a 3.1 × 3.1 × 2.7 cm heterogeneously enhancing mass located along the posterior aspect of the left frontal convexity. The lesion was accessed using a transsulcal approach and was surgically debulked along the motor cortex with motor strip mapping, followed by adjuvant whole-brain radiation therapy. Pathological examination confirmed metastatic carcinoma with features of TCC, a rare entity among metastatic brain tumors.

Brain metastases may present several years later in patients with TCC of the urinary bladder who have been treated with surgery and chemotherapy. Chemotherapeutic agents that penetrate the blood-brain barrier, such as gemcitabine, may delay development of cerebral metastasis from primary TCC of the urinary bladder 5).

A 57-year-old patient presenting with epileptic crises secondary to a brain metastasis from bladder carcinoma, who was investigated in our institution with (11)C-Methionine PET. The scan documented the disease recurrence in the left parietal lobe associated with a diffused tracer uptake in the surrounding cerebral circumvolutions, derived from the comitial status. After surgical removal of the metastatic lesion, the patient experienced a complete recovery of symptoms and no further onset of secondary seizure 6).

A 71-year-old man who was admitted to the emergency department after an episode of loss of consciousness. On neurological examination a left hemiparesis was observed. The patient’s previous history entailed a total cystectomy and radical prostatectomy 7 months ago because of a transitional cell carcinoma (TCC) of the urinary bladder. Brain imaging work-up revealed a cystic lesion with perifocal edema in the right frontal lobe. The patient was operated and the histological diagnosis was consistent with a metastatic carcinoma, with morphological, histochemical and immunohistochemical features comparable to those of the primary tumor. Postoperative the patient was in excellent neurological state and received complementary chemotherapy and total brain irradiation. Additional imaging and laboratory examinations excluded other metastatic lesion. The patient died 18 months later due to systemic disease. Although intracranial metastases from TCC of urinary bladder have a low incidence, in follow-up examinations any alterations in neurological status in these patients should be thoroughly evaluated 7).

1)

Taylor JM, McTyre ER, Tatter SB, Laxton AW, Munley MT, Chan MD, Cramer CK. Gamma Knife Stereotactic Radiosurgery for the Treatment of Brain Metastases from Primary Tumors of the Urinary Bladder. Stereotact Funct Neurosurg. 2018 Apr 26:1-5. doi: 10.1159/000488151. [Epub ahead of print] PubMed PMID: 29698968.
2)

Mahmoud-Ahmed AS, Suh JH, Kupelian PA, Klein EA, Peereboom DM, Dreicer R, Barnett GH. Brain metastases from bladder carcinoma: presentation, treatment and survival. J Urol. 2002 Jun;167(6):2419-22. PubMed PMID: 11992049.
3)

Rosenstein M, Wallner K, Scher H, Sternberg CN. Treatment of brain metastases from bladder cancer. J Urol. 1993 Mar;149(3):480-3. PubMed PMID: 8437250.
4)

Angulo JC, López JI, Unda-Urzaiz M, Flores N. [Bladder carcinoma and brain metastases before systemic chemotherapy]. Actas Urol Esp. 1992 Feb;16(2):140-3. Spanish. PubMed PMID: 1590088.
5)

Sarmiento JM, Wi MS, Piao Z, Stiner ES. Solitary cerebral metastasis from transitional cell carcinoma after a 14-year remission of urinary bladder cancer treated with gemcitabine: Case report and literature review. Surg Neurol Int. 2012;3:82. doi: 10.4103/2152-7806.99172. Epub 2012 Jul 28. PubMed PMID: 22937482; PubMed Central PMCID: PMC3424676.
6)

Lopci E, Bello L, Chiti A. (11)C-Methionine uptake in secondary brain epilepsy. Rev Esp Med Nucl Imagen Mol. 2014 Jul-Aug;33(4):234-6. doi: 10.1016/j.remn.2013.12.008. Epub 2014 Mar 12. PubMed PMID: 24630372.
7)

Zigouris A, Pahatouridis D, Mihos E, Alexiou GA, Nesseris J, Zikou AK, Argyropoulou MI, Goussia A, Voulgaris S. Solitary cystic cerebral metastasis from transitional cell carcinoma of the bladder. Acta Neurol Belg. 2009 Dec;109(4):322-5. PubMed PMID: 20120215.

Safety net hospital

Safety net hospital

A safety net hospital (SNH) is one of the medical centers in the United States that has a legal obligation to provide healthcare for individuals regardless of their insurance status (the United States does not have a policy of universal health care) and regardless of their ability to pay.

Because of this legal mandate to serve all populations, safety net hospitals typically serve a proportionately higher number of uninsured, MedicaidMedicare, Children’s Health Insurance Program (CHiP), low-income, and other vulnerable individuals than their non-safety net hospital counterpart.


SNH patients with brain metastases treated with SRS alone had fewer follow-up neuroimaging studies and were at higher risk for neurologic symptoms, hospitalization for brain metastases, and salvage neurosurgery in comparison with private hospital (PH) patients. Clinicians should consider the practice setting and patient access to follow-up care when they are deciding on the optimal strategy for the treatment of brain metastases 1).


Prior studies have identified poor outcomes, increased costs, and reduced access to certain complex, elective surgeries at Safety net hospitals (SNHs). However, it is unknown whether similar patterns exist for the Glioblastoma multiforme treatment (GBM). Brandel et al., sought to determine if patients treated at HBHs receive equitable care for GBM, and if safety-net burden status impacts post-treatment survival.

The National Cancer Database was queried for GBM patients diagnosed between 2010 and 2015. Safety-net burden was defined as the proportion of Medicaid and uninsured patients treated at each hospital, and stratified as low (LBH), medium (MBH), and high-burden (HBH) hospitals. The impact of safety-net burden on the receipt of any treatment, trimodality therapy, gross total resection (GTR), radiation, or chemotherapy was investigated. Secondary outcomes included post-treatment 30-day mortality, 90-day mortality, and overall survival. Univariate and multivariate analyses were utilized.

Overall, 40,082 GBM patients at 1202 hospitals (352 LBHs, 553 MBHs, and 297 HBHs) were identified. Patients treated at HBHs were significantly less likely to receive trimodality therapy (OR = 0.75, p < 0.001), GTR (OR = 0.84, p < 0.001), radiation (OR = 0.73, p < 0.001), and chemotherapy (OR = 0.78, p < 0.001) than those treated at LBHs. Patients treated at HBHs had significantly increased 30-day (OR = 1.25, p = 0.031) and 90-day mortality (OR = 1.24, p = 0.001), and reduced overall survival (HR = 1.05, p = 0.039).

GBM patients treated at SNHs are less likely to receive standard-of-care therapies and have increased short- and long-term mortality. Additional research is needed to evaluate barriers to providing equitable care for GBM patients at SNHs 2).

1)

Diao K, Sun Y, Yoo SK, Yu C, Ye JC, Trakul N, Jennelle RL, Kim PE, Zada G, Gruen JP, Chang EL. Safety-net versus private hospital setting for brain metastasis patients treated with radiosurgery alone: Disparities in follow-up care and outcomes. Cancer. 2018 Jan 1;124(1):167-175. doi: 10.1002/cncr.30984. Epub 2017 Sep 13. PubMed PMID: 28902402.
2)

Brandel MG, Rennert RC, Lopez Ramos C, Santiago-Dieppa DR, Steinberg JA, Sarkar RR, Wali AR, Pannell JS, Murphy JD, Khalessi AA. Management of glioblastoma at safety-net hospitals. J Neurooncol. 2018 Apr 24. doi: 10.1007/s11060-018-2875-8. [Epub ahead of print] PubMed PMID: 29691776.

Update: Skull base meningioma

Skull base meningioma

Epidemiology

As with intracranial meningiomas in other regions, skull base meningiomas demonstrate a femalepredominance, with a female-to-male ratio as high as 3:1.

Approximately 15% of meningiomas grow along the sphenoid ridge, with 10% developing in the posterior cranial fossa and 5% in the olfactory groove.

Meningiomas of the floor of the middle fossa are uncommon and tend to grow quite large before diagnosis.

Skull-base meningiomas are characterized by other recurrent mutations, including AKT1, SMOKLF4TRAF7 and POLR2A.

Classification

Treatment

Efforts to achieve a radical resection with dural margin are not suitable in many cases of skull base meningiomas, because of the neurovascular structures around the tumors.

Gamma knife radiosurgery (GKRS) is well established in the management of inaccessible, recurrent, or residual benign skull base meningiomas. Most series report clinical outcome parameters and complications in the short intermediate period after radiosurgery.

GKRS offers a highly durable rate of tumor control for World Health Organization grade 1 meningioma, with an acceptably low incidence of neurological deficits. The Karnofsky Performance Scale at the time of radiosurgery serves as a reliable long-term predictor of overall outcome 1).

Outcome

Peritumoral edema (PTE) in skull base meningiomas correlates to the absence of an arachnoid plane and difference in outcome.

A subset of benign (WHO grade I) skull base meningiomas show early progression/recurrence (P/R) in the first years after surgical resection.

Ko et al. retrospectively investigated the preoperative CT and MR imaging features for the prediction of P/R in skull base meningiomas, with emphasis on quantitative ADC values. Only patients had postoperative MRI follow-ups for more than 1 year (at least every 6 months) were included. From October 2006 to December 2015, total 73 patients diagnosed with benign (WHO grade I) skull base meningiomas were included (median follow-up time 41 months), and 17 (23.3%) patients had P/R (median time to P/R 28 months). Skull base meningiomas with spheno-orbital location, adjacent bone invasion, high DWI, and lower ADC value/ratio were significantly associated with P/R (P < 0.05). The cut-off points of ADC value and ADC ratio for prediction of P/R are 0.83 × 10- 3 mm2/s and 1.09 respectively, with excellent area under curve (AUC) values (0.86 and 0.91) (P < 0.05). In multivariate logistic regression, low ADC values (< 0.83 × 10- 3 mm2/s) and adjacent bone invasion are high-risk factors of P/R (P < 0.05), with odds ratios of 31.53 and 17.59 respectively. The preoperative CT and MRI features for prediction of P/R offered clinically vital information for the planning of treatment in skull base meningiomas 2).

Case series

2018

From a prospectively maintained database of 2022 meningioma patients who underwent Leksell stereotactic radiosurgery (SRS) during a 30-year interval, we found 98 patients with petroclival, 242 with cavernous sinus, and 55 patients with cerebellopontine angle meningiomas. Primary radiosurgery was performed in 245 patients. Patients included in this report had at least one CN deficit at the time of initial presentation and a minimum of 12 month follow up. Median age at the time of SRS was 58 years. Median follow up was 58 months (range 12-300 months), Median tumor volume treated with SRS was 5.9 cm3 (range 0.5-37.5 cm3), and median margin dose was 13 Gy (range 9-20Gy).

Tumor control was achieved in 229 patients (93.5%) at a median follow up of 58 months. Progression free survival rate (PFS) after SRS was 98.7% at 1 year, 96.4% at 3 years, 93.7% at 5 years, and 86.4% at 10 years Overall, 114 of the 245 patients (46.5%) reported improvement of CN function. Patients with CP angle meningiomas demonstrated lower rates of CN improvement compared to petroclival and cavernous sinus meningioma patients. Deterioration of CN function after SRS developed in 24 patients (10%). The rate of deterioration was 2.8% at 1 year, 5.2% at 3 years, and 8% at 10 years.

Primary SRS provides effective tumor control and favorable rate of improvement of preexisting CN deficit 3).

2011

Fourty-six patients harboring a skull base meningioma underwent an endoscope-assisted microsurgical resection. In 30 patients (65%), tumor parts which could not be visualized under the microscope were detected with the endoscope. In 26 patients (56%), these tumor remnants were removed under endoscopic view. Gross total resection was achieved in 35 patients (76%) and near-total resection in 11 (24%). There was no surgical mortality. The major complication was new cranial nerve deficit. The application of endoscopes was most useful in the small supraorbital craniotomies to look under the ipsilateral optic nerve and internal carotid artery as well as to visualize the diaphragm sellae and olfactory groove. In the retrosigmoid craniotomies, the endoscope was beneficial to inspect the internal auditory canal, to look into Meckel’s cave, or to inspect areas hidden behind the jugular tubercle and tentorial edge. There was no obvious complication related to the application of the endoscope. Endoscope assistance is particularly of value when skull base meningiomas are to be removed via small craniotomies to inspect blind corners which cannot be visualized in a straight line with the microscope. In addition, there is a benefit of using endoscopes with various angles of view in standard craniotomies and skull base approaches to look around bony and dural corners or to look behind neurovascular structures, by which the amount of skull base drilling and retraction to expose the tumor can be reduced 4).

1)

Cohen-Inbar O, Lee CC, Schlesinger D, Xu Z, Sheehan JP. Long-Term Results of Stereotactic Radiosurgery for Skull Base Meningiomas. Neurosurgery. 2016 Jul;79(1):58-68. doi: 10.1227/NEU.0000000000001045. PubMed PMID: 26421592.
2)

Ko CC, Lim SW, Chen TY, Chen JH, Li CF, Shiue YL. Prediction of progression in skull base meningiomas: additional benefits of apparent diffusion coefficient value. J Neurooncol. 2018 Jan 20. doi: 10.1007/s11060-018-2769-9. [Epub ahead of print] PubMed PMID: 29353434.
3)

Faramand A, Kano H, Niranjan A, Johnson SA, Hassib M, Park KJ, Arai Y, Flickinger JC, Lunsford LD. Cranial nerve outcomes after primary stereotactic radiosurgery for symptomatic skull base meningiomas. J Neurooncol. 2018 Apr 24. doi: 10.1007/s11060-018-2866-9. [Epub ahead of print] PubMed PMID: 29691775.
4)

Schroeder HW, Hickmann AK, Baldauf J. Endoscope-assisted microsurgical resection of skull base meningiomas. Neurosurg Rev. 2011 Oct;34(4):441-55. doi: 10.1007/s10143-011-0322-9. Epub 2011 May 26. PubMed PMID: 21614425.

Ursodeoxycholic acid

Ursodeoxycholic acid

Tauroursodeoxycholic acid (TUDCA) is the taurine conjugate of ursodeoxycholic acid (UDCA), a US Food and Drug Administration-approved hydrophilic bile acid for the treatment of certain cholestatic liver diseases. There is a growing body of research on the mechanism(s) of TUDCA and its potential therapeutic effect on a wide variety of non-liver diseases. Both UDCA and TUDCA are potent inhibitors of apoptosis, in part by interfering with the upstream mitochondrial pathway of cell death, inhibiting oxygen-radical production, reducing endoplasmic reticulum (ER) stress, and stabilizing the unfolded protein response (UPR). Several studies have demonstrated that TUDCA serves as an anti-apoptotic agent for a number of neurodegenerative diseases, including amyotrophic lateral sclerosisAlzheimer’s diseaseParkinson’s disease, and Huntington’s disease. In addition, TUDCA plays an important role in protecting against cell death in certain retinal disorders, such as retinitis pigmentosa. It has been shown to reduce ER stress associated with elevated glucose levels in diabetes by inhibiting caspase activation, up-regulating the UPR, and inhibiting reactive oxygen species. Obesity, stroke, acute myocardial infarction, spinal cord injury, and a long list of acute and chronic non-liver diseases associated with apoptosis are all potential therapeutic targets for T/UDCA. A growing number of pre-clinical and clinical studies underscore the potential benefit of this simple, naturally occurring bile acid, which has been used in Chinese medicine for more than 3000 years 1).


Ursodeoxycholic acid (UDCA) inhibits the pro-inflammatory responses by lipopolysaccharide (LPS) in RAW 264.7 macrophages. UDCA also suppresses the phosphorylation by LPS on extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 in MAPKs and NF-κB pathway. These results suggest that UDCA can serve as a useful antiinflammatory drug 2).


The aim of a study was to investigate the anti-inflammatory effects by ursodeoxycholic acid (UDCA) in rats with a spinal cord injury (SCI). A moderate mechanical compression injury was imposed on adult Sprague-Dawley (SD) rats. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale and the tissue volume of the injured region was analyzed using hematoxylin and eosin staining. The pro-inflammatory factors were evaluated by immunofluorescence (IF) staining, a quantitative real-time polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA). The phosphorylation of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 in mitogen-activated protein kinase (MAPK) signaling pathways related to inflammatory responses were measured by Western blot assays. UDCA improved the BBB scores and promoted the recovery of the spinal cord lesions. UDCA inhibited the expression of glial fibrillary acidic protein (GFAP), tumor necrosis factor-α (TNF-α), ionized calcium-binding adapter molecule 1 (iba1), and inducible nitric oxide synthase (iNOS). UDCA decreased the pro-inflammatory cytokines of TNF-α, interleukin 1-β (IL-1β), and interleukin 6 (IL-6) in the mRNA and protein levels. UDCA increased the anti-inflammatory cytokine interleukin 10 (IL-10) in the mRNA and protein levels. UDCA suppressed the phosphorylation of ERK, JNK, and the p38 signals. UDCA reduces pro-inflammatory responses and promotes functional recovery in SCI in rats. These results suggest that UDCA is a potential therapeutic drug for SCI 3).

1)

Vang S, Longley K, Steer CJ, Low WC. The Unexpected Uses of Urso- and Tauroursodeoxycholic Acid in the Treatment of Non-liver Diseases. Glob Adv Health Med. 2014 May;3(3):58-69. doi: 10.7453/gahmj.2014.017. Review. PubMed PMID: 24891994; PubMed Central PMCID: PMC4030606.
2)

Ko WK, Lee SH, Kim SJ, Jo MJ, Kumar H, Han IB, Sohn S. Anti-inflammatory effects of ursodeoxycholic acid by lipopolysaccharide-stimulated inflammatory responses in RAW 264.7 macrophages. PLoS One. 2017 Jun 30;12(6):e0180673. doi: 10.1371/journal.pone.0180673. eCollection 2017. PubMed PMID: 28665991; PubMed Central PMCID: PMC5493427.
3)

Ko WK, Kim SJ, Jo MJ, Choi H, Lee D, Kwon IK, Lee SH, Han IB, Sohn S. Ursodeoxycholic Acid Inhibits Inflammatory Responses and Promotes Functional Recovery After Spinal Cord Injury in Rats. Mol Neurobiol. 2018 Mar 20. doi: 10.1007/s12035-018-0994-z. [Epub ahead of print] PubMed PMID: 29691718.

Glioblastoma immunotherapy

Glioblastoma immunotherapy

The application of immunotherapy for glioblastoma currently finds itself therefore at a pivotal crossroads. Critical to mapping a path forward will be the systematic characterization of the immunobiology of glioblastoma tumors utilizing currently available, state of the art technologies. Therapeutic approaches aimed at driving effector immune cells into the glioblastoma microenvironment as well as overcoming immunosuppressive myeloid cells, physical factors, and cytokines, as well as limiting the potentially detrimental, iatrogenic impact of dexamethasone, will likely be required for the potential of anti-tumor immune responses to be realized for glioblastoma 1).

Patients with glioblastoma (GBM) exhibit a complex state of immunodeficiency involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for GBM 2).


Progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas.

Trials have revealed promising trends in overall survival and progression free survival for patients with glioblastoma, and have paved the way for ongoing randomized controlled trials 3) 4)


Some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of glioblastoma multiforme and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature 5).


A recurrent theme of this work is that immunotherapy is not a one-size-fits-all solution. Rather, dynamic, tumor-specific interactions within the tumor microenvironment continually shape the immunologic balance between tumor elimination and escape. High-grade gliomas are a particularly fascinating example. These aggressive, universally fatal tumors are highly resistant to radiation and chemotherapy and inevitably recur after surgical resection. Located in the immune-privileged central nervous system, high-grade gliomas also employ an array of defenses that serve as direct impediments to immune attack. Despite these challenges, vaccines have shown activity against high-grade gliomas and anecdotal, preclinical, and early clinical data bolster the notion that durable remission is possible with immunotherapy. Realizing this potential, however, will require an approach tailored to the unique aspects of glioma biology 6).


Clinical experiences with active specific immunotherapy demonstrate feasibility, safety and most importantly, but incompletely understood, prolonged long-term survival in a fraction of the patients. In relapsed patients, Van Gool et al developed an immunotherapy schedule and categorized patients into clinically defined risk profiles. He learned how to combine immunotherapy with standard multimodal treatment strategies for newly diagnosed glioblastoma multiforme patients. The developmental program allows further improvements related to newest scientific insights. Finally, he developed a mode of care within academic centers to organize cell therapy for experimental clinical trials in a large number of patients 7).


Current clinical trials take a multifaceted approach with the intention of harnessing the intrinsic cytotoxic capabilities of the immune system to directly target glioblastoma cancer stem cells (gCSC) or indirectly disrupt their stromal microenvironment. Monoclonal antibodies (mAbs), dendritic cell (DC) vaccines, and chimeric antigen receptor (CAR) T cell therapies have emerged as the most common approaches, with particular iterations incorporating cancer stem cell antigenic markers in their treatment designs. Ongoing work to determine the comprehensive antigenic profile of the gCSC in conjunction with efforts to counter the immunosuppressive tumor microenvironment holds much promise in future immunotherapeutic strategies against GBM. Given recent advancements in these fields, Esparza etal. believe there is tremendous potential to improve outcomes of GBM patients in the continuing evolution of immunotherapies targeted to cancer stem cell populations in GBM 8).


Immunostimulating oligodeoxynucleotides containing unmethylated cytosineguanosine motifs (CpG-ODN) have shown a promising efficacy in several cancer models when injected locally. A previous phase II study of CpG-ODN in patients with recurrent glioblastoma (GBM) has suggested some activity and has shown a limited toxicity. This multicentre single-blinded randomised phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with de novo glioblastomas.

Patients with a newly diagnosed glioblastoma underwent large surgical resection and CpG-ODN was randomly administrated locally around the surgical cavity. The patients were then treated according to standard of care (SOC) with radiotherapy and temozolomide. The primary objective was 2-year survival. Secondary outcomes were progression free survival (PFS), and tolerance.

Eighty-one (81) patients were randomly assigned to receive CpG-ODN plus SOC (39 patients) or SOC (42 patients). The 2-year overall survival was 31% (19%; 49%) in the CpG-ODN arm and 26% (16%; 44%) in the SOC arm. The median PFS was 9 months in the CpG-ODN arm and 8.5 months in the SOC arm. The incidence of adverse events was similar in both arms; although fever and post-operative haematoma were more frequent in the CpG-ODN arm.

Local immunotherapy with CpG-ODN injected into the surgical cavity after tumour removal and followed by SOC, although well tolerated, does not improve survival of patients with newly diagnosed GBM 9).


Epidermal growth factor receptor 3 (EGFRvIII) is present in approximately one-third of glioblastoma (GBM) patients. It is never found in normal tissues; therefore, it represents a candidate target for glioblastoma immunotherapy. PEPvIII, a peptide sequence from EGFRvIII, was designed to represent a target of glioma and is presented by MHC I/II complexes. Dendritic cells (DCs) have great potential to sensitize CD4+ T and CD8+ T cells to precisely target and eradicate GBM.

Li et al. show that PEPvIII could be loaded by DCs and presented to T lymphocytes, especially PEPvIII-specific CTLs, to precisely kill U87-EGFRvIII cells. In addition to inhibiting proliferation and inducing the apoptosis of U87-EGFRvIII cells, miR-326 also reduced the expression of TGF-β1 in the tumour environment, resulting in improved efficacy of T cell activation and killing via suppressing the SMO/Gli2 axis, which at least partially reversed the immunosuppressive environment. Furthermore, combining the EGFRvIII-DC vaccine with miR-326 was more effective in killing U87-EGFRvIII cells compared with the administration of either one alone. This finding suggested that a DC-based vaccine combined with miR-326 may induce more powerful anti-tumour immunity against GBM cells that express a relevant antigen, which provides a promising approach for GBM immunotherapy 10).

1)

Reardon DA, Wucherpfennig K, Chiocca EA. Immunotherapy for glioblastoma: on the sidelines or in the game? Discov Med. 2017 Nov;24(133):201-208. PubMed PMID: 29278673.
2)

Jackson CM, Lim M. Immunotherapy for glioblastoma: playing chess, not checkers. Clin Cancer Res. 2018 Apr 24. pii: clincanres.0491.2018. doi: 10.1158/1078-0432.CCR-18-0491. [Epub ahead of print] PubMed PMID: 29691293.
3)

Thomas AA, Fisher JL, Ernstoff MS, Fadul CE. Vaccine-based immunotherapy for glioblastoma. CNS Oncol. 2013 Jul;2(4):331-49. doi: 10.2217/cns.13.29. PubMed PMID: 25054578.
4)

Agrawal NS, Miller R Jr, Lal R, Mahanti H, Dixon-Mah YN, DeCandio ML, Vandergrift WA 3rd, Varma AK, Patel SJ, Banik NL, Lindhorst SM, Giglio P, Das A. Current Studies of Immunotherapy on Glioblastoma. J Neurol Neurosurg. 2014 Apr 5;1(1). pii: 21000104. PubMed PMID: 25346943.
5)

Kamran N, Calinescu A, Candolfi M, Chandran M, Mineharu Y, Assad AS, Koschmann C, Nunez F, Lowenstein P, Castro M. Recent advances and future of immunotherapy for glioblastoma. Expert Opin Biol Ther. 2016 Jul 13. [Epub ahead of print] PubMed PMID: 27411023.
6)

Jackson CM, Lim M, Drake CG. Immunotherapy for Brain Cancer: Recent Progress and Future Promise. Clin Cancer Res. 2014 Apr 25. [Epub ahead of print] PubMed PMID: 24771646.
7)

Van Gool SW. Brain Tumor Immunotherapy: What have We Learned so Far? Front Oncol. 2015 Jun 17;5:98. eCollection 2015. Review. PubMed PMID: 26137448.
8)

Esparza R, Azad TD, Feroze AH, Mitra SS, Cheshier SH. Glioblastoma stem cells and stem cell-targeting immunotherapies. J Neurooncol. 2015 Feb 15. [Epub ahead of print] PubMed PMID: 25682090.
9)

Ursu R, Carpentier A, Metellus P, Lubrano V, Laigle-Donadey F, Capelle L, Guyotat J, Langlois O, Bauchet L, Desseaux K, Tibi A, Chinot O, Lambert J, Carpentier AF. Intracerebral injection of CpG oligonucleotide for patients with de novo glioblastoma-A phase II multicentric, randomised study. Eur J Cancer. 2017 Jan 28;73:30-37. doi: 10.1016/j.ejca.2016.12.003. [Epub ahead of print] PubMed PMID: 28142059.
10)

Li J, Wang F, Wang G, Sun Y, Cai J, Liu X, Zhang J, Lu X, Li Y, Chen M, Chen L, Jiang C. Combination epidermal growth factor receptor variant III peptide-pulsed dendritic cell vaccine with miR-326 results in enhanced killing on EGFRvIII-positive cells. Oncotarget. 2017 Feb 17. doi: 10.18632/oncotarget.15445. [Epub ahead of print] PubMed PMID: 28412740.