bluuebunny/crossref_metadata_2025_split huggingface dataset:
P14.126 radiation-induced optic neuropathy
Authors: Thomas A , Birzu C , Feuvret L , Noël G , Hoang-Xuan K , Savatosky J , Ricard D , Psimaras D 
Published: September 2019

Abstract

BACKGROUND
Optic neuropathy is an inflammation of the optic nerve leading to a rapidly progressive visual loss. Most frequent etiologies are multiple sclerosis, vasculitides, and infections. In the context of tumorous pathology, optic neuropathy can occur due to meningeal infiltration, tumoral compression, or antitumor therapeutics (radiation therapy, some targeted cancer therapies, and checkpoint inhibitors). In the current study, we examine radiation-induced optic neuropathy (RION), which is the most frequent among optic neuropathies caused by antitumor therapeutics.

MATERIAL AND METHODS
We present the cases of 3 patients who experienced RION. For each patient, we collected data on age, type of tumor, date and modalities of radiation-therapy, starting date of visual loss, ophthalmologic description, MRI images, treatment, and clinical and radiological evolution.

RESULTS
The three patients were aged 57 to 68 years old at the time of NORI. They had irradiation between 2013 and 2018. Two patients had proton therapy and one had whole brain irradiation. The visual loss occurred between seven and twelve months after the end of radiation therapy. In all patients the symptoms were bilateral and the loss of vision was rapidly worsened until culminating in almost total blindness. The MRI abnormalities were consistent with retrobulbar optic neuritis. The visual loss remained severe despite the treatment administered. High dose steroids had no clinical effect. Bevacizumab enabled a discrete subjective visual improvement in one patient, but a worsening of visual loss in another. Hyperbaric oxygen therapy had no clinical effect but was undertaken three months after the starting date of visual loss which is probably too late for efficiency. Interestingly one patient was treated with an anti-IL6 antibody (tocilizumab). It was administered in order to avoid fibrosis formation, which is the ultimate condition of the inflammatory process. The rationale is that radiation-induced opening of the bood-brain-barrier and destruction of endothelial and glial cells lead to reparation process through microglia activation. In-vitro studies showed an increased secretion of IL-6 (and other pro-inflammatory cytokines) by the activated microglia. Our patient could not experience benefit from tocilizumab, but the treatment was administered four months after the starting date of visual loss and fibrosis was probably already formed.

CONCLUSION
These cases are consistent with existing literature. The risk is mostly due to the total dose and dose per fraction of the irradiation and the prognosis is very poor with no efficient treatment at the present time. Anti-IL6 antibody could be an interesting treatment if administered at an early stage, but a future prospective clinical trial would be needed to clinically validate this hypothesis.
Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells
Authors: Echizenya Smile , Ishii Yukiko , Kitazawa Satoshi , Tanaka Tadashi , Matsuda Shun , Watanabe Eriko , Umekawa Masao , Terasaka Shunsuke , Houkin Kiyohiro , Hatta Tomohisa , Natsume Tohru , Maeda Yoshimasa , Watanabe Shin-Ichi , Hagiwara Shinji , Kondo Toru 
Published: September 2019

Abstract

Background
Glioblastoma-initiating cells (GICs) comprise a tumorigenic subpopulation of cells that are resistant to radio- and chemotherapies and are responsible for cancer recurrence. The aim of this study was to identify novel compounds that specifically eradicate GICs using a high throughput drug screening approach.

Methods
We performed a cell proliferation/death-based drug screening using 10 560 independent compounds. We identified dihydroorotate dehydrogenase (DHODH) as a target protein of hit compound 10580 using ligand-fishing and mass spectrometry analysis. The medical efficacy of 10580 was investigated by in vitro cell proliferation/death and differentiation and in vivo tumorigenic assays.

Results
Among the effective compounds, we identified 10580, which induced cell cycle arrest, decreased the expression of stem cell factors in GICs, and prevented tumorigenesis upon oral administration without any visible side effects. Mechanistic studies revealed that 10580 decreased pyrimidine nucleotide levels and enhanced sex determining region Y–box 2 nuclear export by antagonizing the enzyme activity of DHODH, an essential enzyme for the de novo pyrimidine synthesis.

Conclusion
In this study, we identified 10580 as a promising new drug against GICs. Given that normal tissue cells, in particular brain cells, tend to use the alternative salvage pathway for pyrimidine synthesis, our findings suggest that 10580 can be used for glioblastoma therapy without side effects.
Key Points
1.  Chemical screening identified 10580 as a novel GIC-eliminating drug that targets DHODH, an essential enzyme for the de novo pyrimidine synthesis pathway.
2. Compound 10580 induced cell cycle arrest, apoptosis, and differentiation in GICs.
Risk factors for the development of epilepsy in patients with brain metastases
Authors: Wolpert Fabian , Lareida Anna , Terziev Robert , Grossenbacher Bettina , Neidert Marian C , Roth Patrick , Poryazova Rositsa , Imbach Lukas L , Le Rhun Emilie , Weller Michael 
Published: September 2019

Abstract

Background
Current guidelines do not recommend primary prophylactic anti-epileptic drug (AED) therapy for patients with brain metastases (BM). Yet, subgroups of patients at high seizure risk might still benefit from prophylaxis.

Methods
We identified 799 patients diagnosed with BM by retrospective screening of our electronic chart system. Candidate risk factors for the development of epilepsy were tested by univariate and multivariate Cox regression models.

Results
Epilepsy was diagnosed in 226 of 799 patients (28%). Risk factors for epilepsy in non-operated patients were single BM (P = 0.002, hazard ratio [HR] 3.2, 95% CI: 1.5–6.6) and detection of tumoral hemorrhage (P = 0.008, HR 2.5, 95% CI: 1.3–4.9). Preoperative seizures occurred predominantly in patients with supratentorial BM (P = 0.003, HR 20.78, 95% CI: 2.8–153.4) and lung cancer (P = 0.022; HR 2.0, 95% CI: 1.1–3.6). Postoperative seizures were associated with supratentorial localization (P = 0.017, HR 5.8, 95% CI: 1.4–24.3), incomplete resection (P = 0.005, HR 4.6, 95% CI: 1.6–13.1), and by trend for multiple brain surgeries (P = 0.095, HR 1.9, 95% CI: 0.9–4.0). These risk factors were integrated into a predictive score model for postoperative epilepsy (score sum 0–8). A gradual increase of seizure rates along with higher sum score was confirmed post hoc (score 0 = no seizures; score 8 = 48% seizures). Receiver operating characteristic analysis supported diagnostic accuracy (P = 0.00001, area under the curve = 0.75).

Conclusions
Here we have defined risk profiles for the development of BM-related epilepsy and derived a score which might help to estimate the risk of postoperative seizures and identify individuals at risk who might benefit from primary prophylactic AED therapy.
The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma
Authors: Neirinckx Virginie , Hau Ann-Christin , Schuster Anne , Fritah Sabrina , Tiemann Katja , Klein Eliane , Nazarov Petr V , Matagne André , Szpakowska Martyna , Meyrath Max , Chevigné Andy , Schmidt Mirko H H , Niclou Simone P 
Published: September 2019

Abstract

Background
Targeted approaches for inhibiting epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in glioblastoma (GBM) have led to therapeutic resistance and little clinical benefit, raising the need for the development of alternative strategies. Endogenous LRIG1 (Leucine-rich Repeats and ImmunoGlobulin-like domains protein 1) is an RTK inhibitory protein required for stem cell maintenance, and we previously demonstrated the soluble ectodomain of LRIG1 (sLRIG1) to potently inhibit GBM growth in vitro and in vivo.

Methods
Here, we generated a recombinant protein of the ectodomain of LRIG1 (sLRIG1) and determined its activity in various cellular GBM models including patient-derived stem-like cells and patient organoids. We used proliferation, adhesion, and invasion assays, and performed gene and protein expression studies. Proximity ligation assay and NanoBiT complementation technology were applied to assess protein–protein interactions.

Results
We show that recombinant sLRIG1 downregulates EGFRvIII but not EGFR, and reduces proliferation in GBM cells, irrespective of their EGFR expression status. We find that sLRIG1 targets and downregulates a wide range of RTKs, including AXL, and alters GBM cell adhesion. Mechanistically, we demonstrate that LRIG1 interferes with AXL but not with EGFR dimerization.

Conclusions
These results identify AXL as a novel sLRIG1 target and show that LRIG1-mediated RTK downregulation depends on direct protein interaction. The pan-RTK inhibitory activity of sLRIG1 warrants further investigation for new GBM treatment approaches.
Photosynthesis Regulation in Response to Fluctuating Light in the Secondary Endosymbiont Alga Nannochloropsis gaditana
Authors: Bellan Alessandra , Bucci Francesca , Perin Giorgio , Alboresi Alessandro , Morosinotto Tomas 
Published: September 2019

Abstract
In nature, photosynthetic organisms are exposed to highly dynamic environmental conditions where the excitation energy and electron flow in the photosynthetic apparatus need to be continuously modulated. Fluctuations in incident light are particularly challenging because they drive oversaturation of photosynthesis with consequent oxidative stress and photoinhibition. Plants and algae have evolved several mechanisms to modulate their photosynthetic machinery to cope with light dynamics, such as thermal dissipation of excited chlorophyll states (non-photochemical quenching, NPQ) and regulation of electron transport. The regulatory mechanisms involved in the response to light dynamics have adapted during evolution, and exploring biodiversity is a valuable strategy for expanding our understanding of their biological roles. In this work, we investigated the response to fluctuating light in Nannochloropsis gaditana, a eukaryotic microalga of the phylum Heterokonta originating from a secondary endosymbiotic event. Nannochloropsis gaditana is negatively affected by light fluctuations, leading to large reductions in growth and photosynthetic electron transport. Exposure to light fluctuations specifically damages photosystem I, likely because of the ineffective regulation of electron transport in this species. The role of NPQ, also assessed using a mutant strain specifically depleted of this response, was instead found to be minor, especially in responding to the fastest light fluctuations.
Pregnancy and undifferentiated connective tissue disease: outcome and risk of flare in 100 pregnancies
Authors: Zucchi Dina , Tani Chiara , Monacci Francesca , Elefante Elena , Carli Linda , Parma Alice , Stagnaro Chiara , Ferro Francesco , Gori Sabrina , Strigini Francesca Anna Letizia , Mosca Marta 
Published: September 2019

AbstractObjectiveUCTD is a systemic autoimmune condition that fails to fulfil the criteria for a definite CTD. Given that there are a lack of studies on links between pregnancy and UCTD, the purpose of this study was to evaluate the risk of disease flares or development of CTD in addition to the risk of adverse pregnancy outcomes in patients with UCTD.MethodsThis is a retrospective study using prospectively collected data for 100 pregnancies in 81 incidences of UCTD treated in a single referral centre.ResultsA total of 11 pregnancies (11%) ended in miscarriage in the first trimester and the remaining 89 (89%) ended with a live birth. Thirteen patients (13%) flared during pregnancy or puerperium and three (3%) suffered major flares that led to the development of SLE with renal involvement. Obstetric complications occurred in 26 of the 89 successful pregnancies (29%), including 1 case (1%) of pre-eclampsia; in some cases, a single pregnancy was affected by more than one complication. There was a significant link between disease flare and both anti-dsDNA-positive antibodies at baseline (P &lt; 0.01) and disease activity at the beginning of pregnancy (P &lt; 0.01).ConclusionThe impact on pregnancy in the study’s cohort appears to be less serious in UCTD than in other CTDs. Nevertheless, disease flares and obstetric complications can represent a clinical challenge and clinical and serological disease activity would appear to represent important determinants of pregnancy outcomes. Pre-pregnancy counselling and planning as well as close monitoring during pregnancy is therefore essential.
The Effect of an Educational and Interactive Informed Consent Process on Patients With Cervical Spondylotic Myelopathy Caused by Ossification of the Posterior Longitudinal Ligament
Authors: Lee Young-Seok , Cho Dae-Chul , Sung Joo-Kyung , Han Inbo , Kim Chi Heon , Kim Ji-Yoon , Kim Kyoung-Tae 
Published: September 2019

Study Design.
Prospective observational cohort study.

Objective.
In this study, an educational and interactive informed consent (EIC) program was proposed for patients with cervical spondylotic myelopathy caused by ossification of the posterior longitudinal ligament (OPLL-CSM) to improve their comprehension level during the informed consent process.

Summary of Background Data.
OPLL-CSM is a slow progressive disease, and it is difficult for patients to understand the disease. Few studies have evaluated very specific programs to improve the informed consent process for these patients.

Methods.
This prospective study evaluated patients with OPLL-CSM who either underwent the proposed EIC process (n = 63) or the standard consent process (n = 124). The standard consent process only included a physician–patient interview. During the EIC process, information was provided regarding OPLL-CSM through information booklets, a video, verbal information, and initial and second physician–patient interviews. After the second physician–patient interview, the patient was requested to answer 14 medical questions to assess their knowledge about OPLL-CSM. The proposed EIC process took approximately 90 minutes. They were asked to report the most useful educational method and the most effective method of reinforcing verbal communication.

Results.
The mean questionnaire scores were higher in the EIC group than in the control group (P < 0.001). Video was selected by 50/63 patients (79.4%) as the most useful EIC process method, and the most effective method of reinforcing verbal communication was video (n = 61; 96.8%). Patients in the EIC group reported having higher satisfaction with surgery (P = 0.024) than did those in the control group.

Conclusion.
The proposed EIC process was shown to result in good patient comprehension and recall regarding OPLL-CSM. Using a video was the most informative and effective reinforcement of verbal communication. The enhanced educational group had better knowledge and improved satisfaction following surgery. The EIC process might help physicians educate and counsel patients regarding OPLL-CSM and its treatment.

Level of Evidence: 2
A Study of Critical Events That Lead to Spinal Cord Injury and the Importance of Rapid Reversal of Surgical Steps in Improving Neurological Outcomes
Authors: Sarwahi Vishal , Galina Jesse , Thornhill Beverly , Legatt Alan , Pawar Abhijit , Moguilevich Marina , Amaral Terry D. 
Published: September 2019

Study Design.
Porcine model.

Objective.
To quantify critical vascular and mechanical events that occur before and during an evolving spinal cord injury.

Summary of Background Data.
Spinal cord injuries are one of the most devastating complications in spine surgery. Intraoperative neuromonitoring changes can occur as a secondary event of spinal cord compression and decrease in spinal cord blood flow (SCBF). Laser Doppler flowmetry has been well validated for measuring blood flow.

Methods.
Seventeen pigs were studied, 14 of which completed the experiment. Multilevel, midthoracic laminectomies were performed. Laser Doppler flowmetry electrodes were placed on the dura to measure SCBF. Spinal cord injury was induced by incremental balloon inflation in the epidural space. The animals were separated into two groups. After motor-evoked potential (MEP) loss, group A underwent medical interventions and then balloon decompression approximately 20 minutes later. Group B underwent immediate balloon decompression followed by medical interventions. After interventions, wake-up test was performed and computed tomography scan measured thoracic spinal canal volume.

Results.
Median SCBF changes were seen 15.8 (5.4–25.1) minutes before MEP loss. However, the 20% threshold interval was often reached before. At the 20% threshold, median pressure was 7 psi, balloon volume was 0.5 cm3, and 50% of the spinal canal was compromised. In group A, no pigs moved and all had pathology indicating ischemia. In group B, 9 of 10 were found to be moving their hind legs with 7 indicating ischemia.

Conclusion.
Compression spinal cord injury is the end of a cascade involving increasing intracanal pressure, decreasing canal volume, and hypoperfusion. Rapid relief of compression leads to MEP return. SCBF monitoring can detect ischemia preinjury, giving surgeons an opportunity for early intervention.

Level of Evidence: 4
Solid Organ Transplant Is Associated With Increased Morbidity and Mortality in Patients Undergoing One or Two-level Anterior Cervical Decompression and Fusion
Authors: Labaran Lawal A. , Harris Andrew B. , Puvanesarajah Varun , Amin Raj , Raad Micheal , Jain Amit , Hassanzadeh Hamid 
Published: September 2019

Study Design.
Retrospective database review

Objective.
The aim of this study was to analyze the implications of solid organ transplant (SOT) on postoperative outcomes following elective one or two-level anterior cervical discectomy and fusion (ACDF).

Summary of Background Data.
Although SOTs have been associated with increased morbidity, postoperative outcomes in SOT recipients undergoing cervical spinal surgery are not well studied.

Methods.
A retrospective database review of Medicare patients younger than 85 years who underwent an elective one to two-level ACDF from 2006-2013 was conducted. Following our exclusion criteria, patients were then divided into the following groups: those with a prior history of kidney, liver, heart or lung transplant (SOT group) and non-SOT patients. Both groups were compared for hospital length of stay, 90-day major medical complications, 90-day hospital readmission, 1-year surgical site infection (SSI), 1-year revision ACDF, and 1-year mortality.

Results.
A total of 992 (0.5%) SOT recipients (1,144 organs) were identified out of 199,288 ACDF patients. SOT recipients had a significantly longer length of stay (2.32 vs. 5.22 days, p<0.001), higher rate of major medical complications (8.2% vs. 4.5%; OR 1.85, 95% CI 1.45-2.33, p<0.001) and hospital readmission (19.5% vs. 7.5%, OR 2.05, 95% CI 1.74-2.41, p<0.001). In addition, SOT patients had increased mortality within one year of surgery (5.8% vs. 1.3%; OR 3.01, 95% CI 2.26-3.94, p<0.001) compared to non-SOT patients. SOT was not independently associated with SSI (OR 1.25, 95% CI 0.85-1.75, p=0.230), and there was no significant difference in revision rate (0.9% vs. 0.5%; OR 1.54, 95% CI 0.73-2.82, p=0.202) between both groups.

Conclusion.
SOT is independently associated with longer hospital stay, increased rate of major medical complications, hospital readmission and mortality. Spine surgeons should be aware of the higher rates of morbidity and mortality in these patients and take it into consideration when developing patient-specific treatment plans.

Level of Evidence: 3
Are Outcomes of Anterior Cervical Discectomy and Fusion Influenced by Presurgical Depression Symptoms on the Mental Component Score of the Short Form-12 Survey?
Authors: Divi Srikanth N. , Goyal Dhruv K.C. , Mangan John J. , Galetta Matthew S. , Nicholson Kristen J. , Fang Taolin , Goyal Sourabh , Booth Thomas J. , Tarazona Daniel , Lucasti Christopher , Kaye I. David , Kurd Mark F. , Woods Barrett I. , Radcliff Kris E. , Rihn Jeffery A. , Anderson D. Greg , Hilibrand Alan S. , Kepler Christopher K. , Vaccaro Alexander R. , Schroeder Gregory D. 
Published: September 2019

Study Design.
Retrospective comparative study.

Objective.
The purpose of this study was to investigate whether preoperative depressive symptoms, measured by mental component score of the Short Form-12 survey (MCS-12), influence patient-reported outcome measurements (PROMs) following an anterior cervical discectomy and fusion (ACDF) surgery for cervical degeneration.

Summary of Background Data.
There is a paucity of literature regarding preoperative depression and PROMs following ACDF surgery for cervical degenerative disease.

Methods.
Patients who underwent an ACDF for degenerative cervical pathology were identified. A score of 45.6 on the MCS-12 was used as the threshold for depression symptoms, and patients were divided into two groups based on this value: depression (MCS-12 ≤45.6) and nondepression (MCS-12 >45.6) groups. Outcomes including Neck Disability Index (NDI), physical component score of the Short Form-12 survey (PCS-12), and Visual Analogue Scale Neck (VAS Neck), and Arm (VAS Arm) pain scores were evaluated using independent sample t test, recovery ratios, percentage of patients reaching the minimum clinically important difference, and multiple linear regression – controlling for factors such as age, sex, and BMI.

Results.
The depression group was found to have significantly worse baseline pain and disability than the nondepression group in NDI (P < 0.001), VAS Neck pain (P < 0.001), and VAS Arm pain (P < 0.001) scores. Postoperatively, both groups improved to a similar amount with surgery based on the recovery ratio analysis. The depression group continued to have worse scores than the nondepression group in NDI (P = 0.010), PCS-12 (P = 0.026), and VAS Arm pain (P = 0.001) scores. Depression was not a significant predictor of change in any PROMs based on regression analysis.

Conclusion.
Patients who presented with preoperative depression reported more pain and disability symptoms preoperatively and postoperatively; however, both groups achieved similar degrees of improvement.

Level of Evidence: 3