Animal model

Animal model

Is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the added risk of harming an actual human. The animal chosen will usually meet a determined taxonomic equivalency to humans, so as to react to disease or its treatment in a way that resembles human physiology as needed. Many drugs, treatments and cures for human diseases have been developed with the use of animal models.

Animal models representing specific taxonomic groups in the research and study of developmental processes are also referred to as model organisms.

There are three main types of animal models: Homologous, Isomorphic and Predictive. Homologous animals have the same causes, symptoms and treatment options as would humans who have the same disease. Isomorphic animals share the same symptoms and treatments, only. Predictive models are similar to a particular human disease in only a couple of aspects. However, these are useful in isolating and making predictions about mechanisms of a set of disease features.

Animal Model for microvascular anastomosis.

Animal models to understand the back pain mechanism, treatment modalities, and spinal cord injury are widely researched topics worldwide. Despite the presence of several animal models on disc degeneration and Spinal Cord Injury, there is a lack of a comprehensive review.

A methodological narrative literature review was carried out for the study. A total of 1273 publications were found, out of which 763 were related to spine surgery in animals. The literature with full-text availability was selected for the review. Scale for the Assessment of Narrative Review Articles (SANRA) guidelines was used to assess the studies. Only English language publications were included which were listed on PubMed. A total of 113 studies were shortlisted (1976-2019) after internal validation scoring.

The animal models for spine surgery ranged from rodents to primates. These are used to study the mechanisms of back pain as well as spinal cord injuries. The models could either be created surgically or through various means like use of electric cautery, chemicals or trauma. Genetic spine models have also been documented in which the injuries are created by genetic alterations and knock outs. Though the dorsal approach is the most common, the literature also mentions the anterior and lateral approach for spine surgery animal experiments.

There are no single perfect animal models to represent and study human models. The selection is based on the application and the methodology. Careful selection is needed to give optimum and appropriate results 1).

Dejerine Roussy syndrome or thalamic pain syndrome is a condition developed after a thalamic stroke, a stroke causing damage to the thalamus. Ischemic strokes and hemorrhagic strokes can cause lesioning in the thalamus. The lesions, usually present in one hemisphere of the brain, most often cause an initial lack of sensation and tingling in the opposite side of the body. Weeks to months later, numbness can develop into severe and chronic pain that is not proportional to an environmental stimulus, called dysaesthesia or allodynia. As initial stroke symptoms, numbness and tingling, dissipate, an imbalance in sensation causes these later syndromes, characterizing Dejerine–Roussy syndrome. Although some treatments exist, they are often expensive, chemically based, invasive, and only treat patients for some time before they need more treatment, called “refractory treatment.” Thalamic pain syndrome is a condition developed after a thalamic stroke. Research into its underlying mechanisms and treatment options could benefit from a valid animal model. Nine different animal models have been published, but there are relatively few reports on successful reproductions of these models and so far only little advances in the understanding or the management have been made relying on these models. In general, the construct validity (similarity in underlying mechanisms) of these animal models is relatively high, although this cannot be evaluated into depth because of lack of understanding the mechanisms through which thalamic stroke can lead to thalamic pain syndrome. The face validity (symptom similarity) is relatively low, mainly because pain in these models is tested almost exclusively through evoked mechanical/thermal hypersensitivity assessed by reflexive measures and given the conflicting results with similar tests in patients with thalamic pain syndrome. The predictive validity (similarity in treatment efficacy) has not been evaluated in most models and incorporates difficulties that are specific to thalamic pain syndrome. De Vloo et al., compare the different models regarding these types of validity and discuss the robustness, reproducibility, and problems regarding the design and reporting of the articles establishing these models. They conclude with various proposals on how to improve the validity and reproducibility of thalamic pain syndrome animal models. Until further improvements are achieved, prudence is called for in interpreting results obtained through these models 2).

Kalkowski et al. combined the advantages of the demyelination model with experimental autoimmune encephalomyelitis (EAE) to provide a local autoimmune encephalomyelitis (LAE) inside the rat brain. They induced a demyelinating lesion by immunizing male Wistar rats, followed by blood-brain barrier opening protein (vascular endothelial growth factor) by stereotactic injection. They confirmed the immunization against myelin epitopes and minor neurological impairment. The histological assessment confirmed the lesion development after both 3- and 7 days post-injection. This approach was sufficient to develop a demyelinating lesion with high reproducibility and low morbidity 3).

Experimental Neurosurgery in Animal Models (Neuromethods) From Humana Press

This volume provides a full explanation and technical details to perform surgical techniques properly on small and large animal models. The first six chapters of Experimental Neurosurgery in Animal Models focus primarily on the brain, while the next six chapters concern the spinal cord in rodents. The last four chapters provide a description of operative procedures in large animals. Written for the popular Neuromethods series, chapters include the kind of detail and key implementation advice that ensures successful results in the laboratory.

Authoritative and practical, Experimental Neurosurgery in Animal Models aims to ensure successful results in the further study of this vital field.

Murine model


1)

Goel SA, Varghese V, Demir T. Animal models of spinal injury for studying back pain and SCI. J Clin Orthop Trauma. 2020;11(5):816-821. doi:10.1016/j.jcot.2020.07.004
2)

De Vloo P, Morlion B, van Loon J, Nuttin B. Animal models for central poststroke pain: a critical comprehensive review. Pain. 2017 Jan;158(1):17-29. PubMed PMID: 27992392.
3)

Kalkowski L, Golubczyk D, Kwiatkowska J, Domzalska M, Walczak P, Malysz-Cymborska I. Local autoimmune encephalomyelitis model in a rat brain with precise control over lesion placement. PLoS One. 2022 Jan 21;17(1):e0262677. doi: 10.1371/journal.pone.0262677. PMID: 35061807.

Robotic pedicle screw placement

Robotic pedicle screw placement

Robotic spinal fixation is associated with increased screw placement accuracy and similar operative blood loss, length of stay, and operative duration. These findings support the safety and cost-effectiveness of robotic spinal surgery across the spectrum of robotic systems and screw types 1).


In addition to demonstrating excellent pedicle screw accuracy, early studies have explored the impact of robot-assisted spine surgery on reducing radiation time, length of hospital stay, operative time, and perioperative complications in comparison to conventional freehand technique. The Mazor X Stealth Edition was introduced in 2018. This robotic system integrates Medtronic’s Stealth navigation technology into the Mazor X platform, which was introduced in 2016. It is unclear what the impact of these advancements have made on clinical outcomes.


In a multicenter study, both robot systems achieved excellent screw accuracy and low robot time per screw. However, using Stealth led to significantly less fluoroscopic radiation time, lower robot abandonment rates, and reduced blood transfusion rates than Mazor X. Other factors including length of stay, and 90-day complications were similar 2)

Ha Y. Robot-Assisted Spine Surgery: A Solution for Aging Spine Surgeons. Neurospine. 2018 Sep;15(3):187-188. doi: 10.14245/ns.18edi.003. Epub 2018 Sep 11. PubMed PMID: 30196675.


In three cadavers 12 pedicle screws were implanted in thoraco-lumbar segments with the robotic surgery assistant. 3D-fluoroscopy was performed for preoperative referencing, planning and identification of postoperative screw position. The radiation exposure of fluoroscopy and a CT scanner was compared, measuring the Computed Tomography Dose Index (CTDIw ).

Pedicle screw positioning was graded according to the Gertzbein-Robbins classification: Eleven of 12 pedicle screws showed optimal transpedicular position (Grade 1), one was positioned less than 2 mm outside (Grade 2). No major deviations were observed. Referencing with 3D-fluoroscopy resulted in a CTDIw reduction of 84% in the cervical- and 33% in the lumbar spine.

Robot-guided PS placement, using 3D-fluoroscopy for referencing, is a reliable tool for minimally invasive PS implantation; radiation exposure can be reduced 3).


Menger et al., investigated the cost effectiveness of adding robotic technology in spine surgery to an active neurosurgical practice.

The time of operative procedures, infection rates, revision rates, length of stay, and possible conversion of open to minimally invasive spine surgery (MIS) secondary to robotic image guidance technology were calculated using a combination of institution-specific and national data points. This cost matrix was subsequently applied to 1 year of elective clinical case volume at an academic practice with regard to payor mix, procedural mix, and procedural revenue.

A total of 1,985 elective cases were analyzed over a 1-year period; of these, 557 thoracolumbar cases (28%) were analyzed. Fifty-eight (10.4%) were MIS fusions. Independent review determined an additional ~10% cases (50) to be candidates for MIS fusion. Furthermore, 41.4% patients had governmental insurance, while 58.6% had commercial insurance. The weighted average diagnosis-related group reimbursement for thoracolumbar procedures for the hospital system was calculated to be $25,057 for Medicare and $42,096 for commercial insurance. Time savings averaged 3.4 minutes per 1-level MIS procedure with robotic technology, resulting in annual savings of $5,713. Improved pedicle screw accuracy secondary to robotic technology would have resulted in 9.47 revisions being avoided, with cost savings of $314,661. Under appropriate payor mix components, robotic technology would have converted 31 Medicare and 18 commercial patients from open to MIS. This would have resulted in 140 fewer total hospital admission days ($251,860) and avoided 2.3 infections ($36,312). Robotic surgery resulted in immediate conservative savings estimate of $608,546 during a 1-year period at an academic center performing 557 elective thoracolumbar instrumentation cases.

Application of robotic spine surgery is cost-effective, resulting in lesser revision surgery, lower infection rates, reduced length of stay, and shorter operative time. Further research is warranted, evaluating the financial impact of robotic spine surgery 4).


Several randomized controlled trials (RCTs) and cohort studies involving robotic-assisted (RA) and free-hand with fluoroscopy-guided (FH) and published before January 2017 were searched for using the Cochrane LibraryOvidWeb of SciencePubMed, and EMBASE databases. A total of 55 papers were selected. After the full-text assessment, 45 clinical trials were excluded. The final meta-analysis included 10 articles.

The accuracy of pedicle screw placement within the RA group was significantly greater than the accuracy within the FH group (odds ratio 95%, “perfect accuracy” confidence interval: 1.38-2.07, P < .01; odds ratio 95% “clinically acceptable” Confidence Interval: 1.17-2.08, P < .01).

There are significant differences in accuracy between RA surgery and FH surgery. It was demonstrated that the RA technique is superior to the conventional method in terms of the accuracy of pedicle screw placement 5).


In 2013 a study evaluated the outcomes of robotic-assisted screw placement in a consecutive series of 102 patients.

Data were recorded from technical notes and operative records created immediately following each surgery case, in which the robotic system was used to guide pedicle screw placement. All cases were performed at the same hospital by a single surgeon. The majority of patients had spinal deformity and/or previous spine surgery. Each planned screw placement was classified as: (1) successful/accurately placed screw using robotic guidance; (2) screw malpositioned using robot; (3) use of robot aborted and screw placed manually; (4) planned screw not placed as screw deemed non essential for construct stability. Data from each case were reviewed by two independent researchers to indentify the diagnosis, number of attempted robotic guided screw placements and the outcome of the attempted placement as well as complications or reasons for non-placement.

Robotic-guided screw placement was successfully used in 95 out of 102 patients. In those 95 patients, 949 screws (87.5 % of 1,085 planned screws) were successfully implanted. Eleven screws (1.0 %) placed using the robotic system were misplaced (all presumably due to “skiving” of the drill bit or trocar off the side of the facet). Robotic guidance was aborted and 110 screws (10.1 %) were manually placed, generally due to poor registration and/or technical trajectory issues. Fifteen screws (1.4 %) were not placed after intraoperative determination that the screw was not essential for construct stability. The robot was not used as planned in seven patients, one due to severe deformity, one due to very high body mass index, one due to extremely poor bone quality, one due to registration difficulty caused by previously placed loosened hardware, one due to difficulty with platform mounting and two due to device technical issues.

Of the 960 screws that were implanted using the robot, 949 (98.9 %) were successfully and accurately implanted and 11 (1.1 %) were malpositioned, despite the fact that the majority of patients had significant spinal deformities and/or previous spine surgeries. “Tool skiving” was thought to be the inciting issue with the misplaced screws. Intraoperative anteroposterior and oblique fluoroscopic imaging for registration is critical and was the limiting issue in four of the seven aborted cases 6).

Robotic pedicle screw placement learning curve.


1)

Himstead AS, Shahrestani S, Brown NJ, Produturi G, Shlobin NA, Al Jammal O, Choi EH, Ransom SC, Daniel Diaz-Aguilar L, Sahyouni R, Abraham M, Pham MH. Bony fixation in the era of spinal robotics: A systematic review and meta-analysis. J Clin Neurosci. 2022 Jan 19;97:62-74. doi: 10.1016/j.jocn.2022.01.005. Epub ahead of print. PMID: 35065405.
2)

Lee NJ, Zuckerman SL, Buchanan IA, Boddapati V, Mathew J, Leung E, Park PJ, Pham MH, Buchholz AL, Khan A, Pollina J, Mullin JP, Jazini E, Haines C, Schuler TC, Good CR, Lombardi JM, Lehman RA. Is There a Difference Between Navigated and Non-Navigated Robot Cohorts in Robot-Assisted Spine Surgery? A Multicenter, Propensity-Matched Analysis of 2,800 Screws and 372 Patients. Spine J. 2021 May 19:S1529-9430(21)00253-9. doi: 10.1016/j.spinee.2021.05.015. Epub ahead of print. PMID: 34022461.
3)

Spyrantis A, Cattani A, Seifert V, Freiman TM, Setzer M. Minimally invasive percutaneous robotic thoracolumbar pedicle screw implantation combined with three-dimensional-fluoroscopy can reduce radiation: a cadaver and phantom study. Int J Med Robot. 2019 Jun 19:e2022. doi: 10.1002/rcs.2022. [Epub ahead of print] PubMed PMID: 31216120.
4)

Menger RP, Savardekar AR, Farokhi F, Sin A. A Cost-Effectiveness Analysis of the Integration of Robotic Spine Technology in Spine Surgery. Neurospine. 2018 Aug 29. doi: 10.14245/ns.1836082.041. [Epub ahead of print] PubMed PMID: 30157583.
5)

Fan Y, Du JP, Liu JJ, Zhang JN, Qiao HH, Liu SC, Hao DJ. Accuracy of pedicle screw placement comparing robot-assisted technology and the free-hand with fluoroscopy-guided method in spine surgery: An updated meta-analysis. Medicine (Baltimore). 2018 Jun;97(22):e10970. doi: 10.1097/MD.0000000000010970. Review. PubMed PMID: 29851848; PubMed Central PMCID: PMC6392558.
6)

Hu X, Ohnmeiss DD, Lieberman IH. Robotic-assisted pedicle screw placement: lessons learned from the first 102 patients. Eur Spine J. 2013 Mar;22(3):661-6. doi: 10.1007/s00586-012-2499-1. Epub 2012 Sep 14. PubMed PMID: 22975723; PubMed Central PMCID: PMC3585630.

Programmed death ligand 1 in glioblastoma

Programmed death ligand 1 in glioblastoma

Reports of programmed death ligand 1 (PD-L1) expression in glioblastoma are highly variable (ranging from 6% to 88%) and its role as a prognostic marker has yielded conflicting results.

Data points to a putative role for PD-L1 expression in glioblastoma biology, which correlates to poor patient overall survival, as well as with a general systemic inflammatory status and immunosuppression 1).

A 5% PD-L1 expression cut-off identified a subset of glioblastoma that is associated with a worse clinical outcome. This association remained significant within the newly defined IDH wildtype classification. These findings could have implications for patient stratification in future clinical trials of PD-1/PD-L1 blockade 2).


For patients receiving Dendritic cell vaccine adjuvant therapy, better outcomes are predicted in patients with younger age, with TILs or PBMCs with lower PD-1+/CD8+ ratio, with gross tumor resection, and receiving CCRT 3).


In a retrospective cohort of 115 consecutive patients with GBM, PD-L1 expression was determined using immunohistochemistry (IHC). Membranous and fibrillary PD-L1 staining of any intensity in > 5% neoplastic cells and tumour infiltrating immune cells (TIIs) was considered positive staining. In addition, isocitrate dehydrogenase 1 (IDH-1) (R132H) expression and cluster of differentiation 3 (CD3)-positive T-cell infiltration were investigated using IHC. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation assay and fluorescence in situ hybridization (FISH) for the assessment of 1p/19q deletion were performed. Expression of PD-L1 in tumour cells and TIIs was found in 37 (32.2%) and 6 (5.2%) patients, respectively. Kaplan-Meier analysis indicated that PD-L1 expression in tumour cells was significantly associated with poor overall survival (OS) (P = 0.017), though multivariate Cox analysis did not confirm this association (hazard ratio 1.204; P = 0.615). PD-L1 expression in TIIs did not correlate with the patient prognosis (P = 0.545). In addition, MGMT methylation and IDH-1 (R132H) expression were associated with a better prognosis (P < 0.001 and P = 0.024, respectively). The expression of PD-L1 was associated with CD3-positive T-cell infiltration (P < 0.001), and IDH-1 wild type status (P = 0.008). A deeper insight into PD-L1 expression could help to ensure the success of future immunotherapy in GBM. Our study suggested that PD-L1 target therapy might be beneficial for PD-L1-expressing GBM patients with a poor prognosis 4).


Immunotherapies for glioblastoma multiforme including PD1/PD-L1 inhibition are currently tested in ongoing clinical trials. The purpose of a study was to investigate the molecular background of PD-L1 expression in glioblastoma multiforme and to find associated pathway activation and genetic alterations. Heiland et al., show that PD-L1 is up-regulated in IDH1/2 wildtype glioblastoma multiforme compared to lower-grade gliomas. In addition, a strong association of PD-L1 with the mesenchymal expression subgroup was observed. Consistent with that, NF1 mutation and corresponding activation of the MAPK pathway was strongly connected to PD-L1 expression. The findings may explain different response to PD-L1 inhibition of patients in ongoing trials and may help to select patients that may profit of immunotherapy in the future 5).


1)

Noronha C, Ribeiro AS, Taipa R, Leitão D, Schmitt F, Reis J, Faria C, Paredes J. PD-L1 tumor expression is associated with poor prognosis and systemic immunosuppression in glioblastoma. J Neurooncol. 2022 Jan 23. doi: 10.1007/s11060-021-03907-3. Epub ahead of print. PMID: 35066764.
2)

Pratt D, Dominah G, Lobel G, Obungu A, Lynes J, Sanchez V, Adamstein N, Wang X, Edwards NA, Wu T, Maric D, Giles AJ, Gilbert MR, Quezado M, Nduom EK. Programmed Death Ligand 1 Is a Negative Prognostic Marker in Recurrent Isocitrate Dehydrogenase-Wildtype Glioblastoma. Neurosurgery. 2018 Jul 12. doi: 10.1093/neuros/nyy268. [Epub ahead of print] PubMed PMID: 30011045.
3)

Jan CI, Tsai WC, Harn HJ, Shyu WC, Liu MC, Lu HM, Chiu SC, Cho DY. Predictors of Response to Autologous Dendritic Cell Therapy in Glioblastoma Multiforme. Front Immunol. 2018 May 29;9:727. doi: 10.3389/fimmu.2018.00727. eCollection 2018. PubMed PMID: 29910795; PubMed Central PMCID: PMC5992384.
4)

Lee KS, Lee K, Yun S, Moon S, Park Y, Han JH, Kim CY, Lee HS, Choe G. Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma. J Neurooncol. 2018 Feb;136(3):453-461. doi: 10.1007/s11060-017-2675-6. Epub 2017 Nov 16. PubMed PMID: 29147863.
5)

Heiland DH, Haaker G, Delev D, Mercas B, Masalha W, Heynckes S, Gäbelein A, Pfeifer D, Carro MS, Weyerbrock A, Prinz M, Schnell O. Comprehensive analysis of PD-L1 expression in glioblastoma multiforme. Oncotarget. 2017 Feb 2. doi: 10.18632/oncotarget.15031. [Epub ahead of print] PubMed PMID: 28178682.
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