bluuebunny/crossref_metadata_2025 huggingface dataset:
P14.58 Extending adjuvant temozolomide longer than six cycles doesn’t add any benefit to glioblastoma patients according to the randomized GEINO-014 TRIAL
Authors: Balana C , Sepulveda J , Pineda E , Vaz M , Mesia C , Fuster J , Girones R , Muñoz-Langa J , Navarro M , Alonso M , Gil Gil M , Herrero A , Estival A , Gallego O , Peralta S , Olier C , Pérez-Segura P , Covela M , Martinez García M , Domenech M , Carrato C , Sanz C , Velarde J , Berrocal A , Luque R , De las Peñas R , Del Barco S
Published: September 2019

BACKGROUND

Standard treatment of glioblastoma (GBM) is focal radiation with concomitant and adjuvant temozolomide (TMZ) for 6 cycles. The GEINO-14-01 trial (NCT02209948) investigated the role of extending adjuvant TMZ to 12 cycles in a randomized multicenter study.

MATERIAL AND METHODS

Between Aug/2014 and Nov/2018, 166 patients (p) were screened and 159 randomized to extend (80p) or not (79p) TMZ treatment to 12 cycles after proving stable disease in the MRI performed before inclusion. The trial was stratified by MGMT status and presence or absence of residual disease (defined as a residual enhancement larger than 1cm on the MRI). The primary endpoint was differences in 6monthsPFS, secondary endpoints were differences in PFS, OS, toxicity, between arms and per stratification factors.

RESULTS

Median age was 60.4 (range 29–83), 97p (61%) were methylated and 83 p (52.2%) were reported with residual disease. Median (m) PFS was 7.9 months (95%CI: 6.1–9.8) and mOS: 20.9 (95%CI: 17.6–24.1). A methylated status was a factor of better PFS (HR=0.29, 95% CI 0.46–0.95; p=0.029) and better OS (HR= 0.43: 95% CI 0.28–0.66; p=0.000) as well as the absence of residual disease (PFS: HR = 0.84: 95% CI =0.71–1.01; p=0.068; OS: HR=0.77, 95%CI 0.63–0.96; p=0.019). We didn’t find any difference in PFS (HR=1.02, 95%CI 0.85–1.21; p=0.82), or OS (HR=0.90; 0.73–1.11; p=0.34) on extending treatment with temozolomide longer than 6 cycles.

CONCLUSION

There is no benefit of continuing TMZ treatment for more than 6 cycles in the adjuvant treatment of glioblastoma. Final data will be presented at the congress. Supported by a Grant of the ISCIII: PI13/01751
P14.60 FET PET response upon radiochemotherapy followed by Tumor Treating Fields (TTFields) in a patient with progressive high-grade glioma
Authors: Keßler A F , Weiland J , Linsenmann T , Ernestus R , Hagemann C , Löhr M
Published: September 2019

BACKGROUND

The addition of Tumor Treating Fields (TTFields) to the first-line therapy in glioblastoma (GBM) demonstrated significantly improved progression free survival, overall survival and longterm survival rates in the EF-14 phase 3 trial. However, responder analysis of patients with recurrent GBM (rGBM) treated with TTFields monotherapy (in the EF-11 trial) revealed delayed response monitored by MRI analysis. More recent data suggests that O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET may add valuable information for monitoring therapy response of glioblastoma patients treated with TTFields. Here, we report on FET PET response in a patient with progressive anaplastic astrocytoma WHO grade III (AA) treated with TTFields in combination with temozolomide (TMZ) chemotherapy.

METHODS

We present a 38-year old patient with an initial diagnosis of a diffuse astrocytoma WHO grade II in 2011, and malignisation to an AA on progression. The treatment regimen included initially radio-chemotherapy (RCT) with TMZ. On further progression of the AA in 2017, TTFields were added to another 6 cycles of TMZ. Several FET PET scans for differentiation of tumor progression from treatment-related changes were performed over time. The definitive diagnosis (tumor progression and grading) was confirmed by histopathology after stereotactic biopsy (SB).

RESULTS

In 2012, the patient was first diagnosed with a low grade astrocytoma WHO grade II of the right frontal, temporal and parietal lobe including infiltration of thalamus and corpus was confirmed by SB, followed by irradiation. On progression in 2015, a FET PET Scan showed FET avidity in all tumor affected regions of the brain. SB confirmed an AA, while FET PET scans showed only a mild response in the temporoparietal region after 6 cycles of TMZ. In 2017, the next progression without further malignisation was confirmed by SB and treated RCT with 41.4 Gy and TMZ chemotherapy, followed by application of TTFields with an average usage rate of 85.7 % over 6 months. Thus, the TTFields adherence was well above the independent prognostic threshold of 75 %. No additional adverse events due to the combined therapy of TTFields and TMZ were observed. Due to a new contrast enhancing lesion in the right frontal lobe (10x7mm), another FET PET scan was performed 1.5 years later. In this scan, obtained after combined TTFields and RCT therapy a strong response regarding FET avidity was observed.

CONCLUSION

In summary, FET PET is able to add important additional information for evaluation of treatment response in high grade glioma patients, in particular for TTFields treated patients, while adding TTFields to radiochemotherapy might even enhance treatment response of high grade glioma. Further studies might elucidate the role of FET PET imaging for therapy monitoring in high grade glioma patients treated with TTFields.
P14.76 Characteristics of anaplastic oligodendrogliomas short-term survivors: a POLA network study
Authors: Garnier L , Dehais C , Curtit E , Tabouret E , Ramirez C , Vauleon E , Bourg V , Boone M , Figarella-Branger D , Ducray F
Published: September 2019

BACKGROUND

Although patients with 1p/19q codeleted anaplastic oligodendrogliomas (AO) usually have a prolonged survival, some patients have a poorer outcome. The aim of the present study was to analyze their characteristics.

MATERIAL AND METHODS

The characteristics of AO patients with a survival < 5 years included in the POLA network were analyzed and compared to those of AO patients with a survival > 5 years.

RESULTS

In January 2019, among the 519 patients AO patients included in the POLA network, 55 patients were short-term survivors and 146 patients had a survival > 5 years. Among the 55 AO short-term survivors, 44 patients (80%) died from tumor progression and 11 patients (20%) from another cause (suicide n=2, toxicity n=2, intercurrent disease n=6, other n=1). Compared to > 5 years survivors, short-term survivors were older (57 years vs 48 years, p<0.001) and less frequently presented with isolated seizures (9% vs 33%, p=0.0017). They presented with tumors that more frequently involved multiple lobes (66% vs 47%, p=0.03), had a higher rate of nuclear atypia (80% vs 48%, p<0.001), a higher proliferative index (Ki67, 26% vs 18%, p<0.001), a higher level of p53 expression (10.8% vs 3.9% p<0.001), and had a higher rate of chromosomal abnormalities (91% vs 71% p=0.008). Compared to > 5 years survivors, short-term survivors less frequently underwent a surgical resection (64% vs 89% p<0.001) and their initial treatment more frequently consisted in temozolomide chemotherapy alone (41% vs 20% p=0.008).

CONCLUSION

AO short-term survivors are associated with distinct clinical, radiological, histological and molecular characteristics at diagnosis.
P14.85 Brain metastasis from Hodgkin’s Lymphoma: case report and literature review
Authors: Bruno F , Pronello E , Bortolani S , Palmiero R , Melcarne A , Chiappella A , Mantovani C , Soffietti R , Rudà R
Published: September 2019

BACKGROUND

Central nervous system (CNS) metastases from Hodgkin’s Lymphoma (HL) are very rare, occurring in 0.02–0.5% of cases. They are usually associated to systemic relapse of the disease. Treatment options for HL brain metastases include surgery, radiotherapy, and systemic chemotherapy.

CASE REPORT

A 54 year-old woman presented with thoracic pain and dyspnea. Chest CT showed a thoracic bulky mass larger than 10 cm. Biopsy confirmed HL stage IIA, nodular sclerosing variant. No typical B symptoms, such as fever, night sweats or weight loss, were observed. The patient underwent chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD scheme), followed by 30Gy mediastinic radiotherapy (RT), which led to complete remission in September 2017. After 3 months, she presented with headache and rapidly progressing gait disorder. MRI showed a contrast-enhanced lesion in the right occipital lobe, with central necrosis and massive edema. Total-body CT scan and FDG-PET ruled out either the presence of new solid tumors or systemic relapses of HL. Gross total resection of the brain lesion was carried out, and HL histology was confirmed. CSF analysis from lumbar puncture was normal. Afterwards, the patient underwent 2 cycles of high dose cytarabine, but she rapidly progressed, and received salvage RT (30 Gy). Nevertheless, further systemic progression occurred: the patient developed headache, diplopia and dysphagia and, unfortunately, she died 6 months after the diagnosis of brain metastasis.

DISCUSSION

Thus far, only 45 cases of CNS HL have been reported from 2000 to 2018. Whole brain radiotherapy, with or without chemotherapy, was the most common treatment. In our patient, we chose surgical resection for the solitary brain metastasis followed by chemotherapy, delaying RT at recurrence. In the literature, median overall survival of patients diagnosed with brain metastases from HL is 18 months (1–273): 17 patients (38%) showed a progression (local / systemic: 12/17 - 71%), while 28 (62%) showed complete remission after a median follow-up of 20 months (6–273).

CONCLUSION

Intracranial localisation of Hodgkin’s Lymphoma is a rare entity but still has to be taken into account. Advanced brain imaging could be of help in case of uncertain radiological presentation. A multidisciplinary approach is needed as there is no consensus on the best treatment to choose: surgery, radiotherapy and chemotherapy should be considered on individual basis.
P14.92 Study of Glutaminergic and Glutamatergic Metabolism in 1H-MRS Monovoxel in the Most Aggressive Part of 62 Glioblastoma Before and After 18 months Treatment
Authors: Heintz A , Chombar J , Boussida S , Saidak Z , Lefranc M , Deleval N , Coutte A , Chauffert B , Boone M , Constans J
Published: September 2019

BACKGROUND

To study the relationships between glutaminergic metabolism (Glx/tCr), tumor proliferation (tCho/tCr) and other metabolic activities in patients with glioblastoma (GBM).

MATERIAL AND METHODS

Patients: 62 patients with glioblastoma, all having a STUPP Protocol (radiotherapy and concomitant chemotherapy), were selected and separated into 2 groups: Biopsies (30) and resections (32). In total, 269 NMR spectra (PRESS at GE 1.5T and 3T; multi-TEs TE=35ms and TE=144ms) were acquired. Processing: MRS data were processed with jMRUI software and quantitated using HLSVD and QUEST algorithms. Statistical analysis of longitudinal MRS data (every 3 months)

RESULTS

Glx/tCr and Lac/tCr ratios are correlated with the tumoral proliferation (tCho/tCr) before the beginning of treatment. This correlations decreases over time in biopsied and resected patients. In biopsied patients, the evolution of lactate (Lac/tCr) and Glx (Glx/tCr) ratios is similar along the follow-up with a progressive decrease in tumor proliferation (tCho/tCr). However, in resected patients, the evolution of lactate (Lac/tCr) and Glx (Glx/tCr) ratios is similar until 6 months and differ above: a progressive decrease of Lac/tCr and Glx/tCr until 18 months with a higher level of Glx/tCr.

CONCLUSION

Despite the difficulties to separate glutamine from glutamate (post-processing improvement is ongoing), spectroscopic measurements of Glx changes before clinical deterioration. The increase of Glx is longer (in time) than the Lactate increase after 6 months of treatment in the resected patients could be predictive of the observed increase of tumor proliferation at 12 months of treatment.The study of glutaminergic metabolism in the GBM could be used to evaluate the response to treatment. Being able to predict the increase of tumor proliferation in resected patients could allow a faster treatment adaptation.
P14.94 Mitochondrial DNA copy number in new onset and recurrent glioblastoma and its effect on radiation resistance and patient survival
Authors: Sravya P , Nimbalkar V P , Kanuri N N , Rao S , Arivazhagan A , Somanna S , Kondaiah P , Santosh V
Published: September 2019

BACKGROUND

Recent evidence shows that mitochondrial DNA (mtDNA) content is responsible for radiation resistance in various cancers, but not evaluated in glioblastoma(GBM).Hence,we studied the role of mtDNA content in GBM pathogenesis and treatment response.

MATERIAL AND METHODS

Archived FFPE tissues of newly diagnosed GBM(n=130), recurrent GBM (n=32 pairs) and non-neoplastic control brain(n=30) with available clinical details were utilized for the study. Immunohistochemistry, Sanger’s sequencing, methylation specific PCR and fluorescent in-situ hybridization were used to study IDH, ATRX and TERT promoter mutations, MGMT promoter methylation and EGFR amplification. mtDNA content was analyzed using quantitative real time PCR (relative quantification) and was calculated using the formula 2- ΔΔCTx100. Malignant glioma cell lines U87 and LN229 were used to study the difference in mtDNA content following radiation exposure.LN229 cell line was subjected to mtDNA depletion by incubation with ethidium bromide for 4 days.The parent and mtDNA depleted LN229 cell lines were then assessed for sensitivity to radiation and Temozolomide(TMZ) therapy using MTT assay.

RESULTS

mtDNA content was lower than control brain tissue(mean mtDNA content 19.6) in all cases studied,with significantly lower content in older patients(p=0.04).Lower mean mtDNA content was seen in IDH wild type, MGMT unmethylated and EGFR amplified tumors when compared to their counterparts(p=1.06).Survival analysis using Cox regression showed that lower mtDNA copy number is associated with higher risk and hence poorer prognosis(p=0.047).Paired tumor analysis was performed in 32 patients with recurrence of whom only 19 had received radiation therapy (RT).The mean mtDNA content was higher at recurrence as compared to the primary tumor in those who received RT(mean at diagnosis 20.1; mean at recurrence 49.3, p=0.02) while no significant difference was observed in those who did not receive RT. U87 and LN229 cell lines exposed to radiation (0, 2, 4 and 6Gy) showed an increase of 8% and 25% in mtDNA content, respectively, after 6Gy radiation exposure.LN229 parent cells showed a radiation dose dependent decline in cell viability(86% at 2Gy, 68% at 4Gy and 50% at 6Gy).The mtDNA depleted LN229 cells were 100% viable at 0, 2 and 4 Gy and 82% viable at 6Gy.The IC50 of TMZ in parent LN229 cells was 69.3 µM while in the mtDNA depleted cells,it was 100.8 µM. Conclusion:Our study shows that lower mtDNA content is associated with poorer survival in GBM.RT increased the mtDNA content in both patient samples and malignant glioma cell lines.mtDNA depleted LN229 lines are more radio-chemo resistant than parent LN229 lines,thus showing that lower mtDNA content leads to treatment resistance.Hence,we establish the significant role of mtDNA content in the pathogenesis and treatment resistance of GBM.
P14.107 Rapid early progression of glioblastoma is not related to cortical/neural stem cells regions
Authors: Jancalek R , Kazda T , Belanova R , Pospisil P , Burkon P , Hynkova L , Slampa P , Lakomy R
Published: September 2019

BACKGROUND

Rapid early progression (REP) of glioblastoma after surgery is quite often observed on pre-radiotherapy MR scan. Clinical and molecular biomarkers indicating increased risk of this REP may be of high clinical need. Subventricular brain zone (SVZ) and hippocampal regions are supposed to harbor astrocyte-like neural stem cells with tumors arising from these transformed SVZ stem cells dreaded to be of higher risk of REP. Lim′s et al classification of initial glioblastoma location related to these neural stem cells regions was predictive for invasive and multifocal tumor phenotype. The aim of this retrospective single-institutional study is to evaluate the relations of this Lim classification on REP in unselected cohort of glioblastoma patients.

MATERIAL AND METHODS

Patients treated by radiotherapy between 2014–2017 were grouped as follows: Lim1 (SVZ+⋯SVZ/hippocampal involvement and Cortex+⋯cortex involvement), Lim2 (SVZ+ and Cortex-), Lim3 (SVZ- and Cortex+) and Lim4 (SVZ- and Cortex-). Some patients were indicated to Stupp regimen. REP was defined on pre-radiotherapy MR as new distant lesion, progression of residuum, or new enhancement in postsurgery cavity.

RESULTS

In total, 144 patients were analyzed (94 men, mean age 59 years). 47 patients (30.5%) were treated according to Stupp regimen. Lim1 classification was presented in 74 (48%) patients, Lim2 in 22 (14.3%), Lim3 in 50 (32.5%) and Lim4 in 8 (5.2%) patients. Cortical structures (Lim1 and Lim3) were involved in 124 (80.5%) patients. Median overall survival was significantly better in patients treated according to Stupp regimen (23.3 vs. 8.6 months, p<0.001) and in those without REP (18.5 vs. 10.2 months, p=0.001). REP was presented in 52% of 95 evaluable patients who underwent both post-surgery and pre-radiotherapy MR scans and there was no significant impact of time to start of radiotherapy. No significant relation between REP and Lim classification was observed (REP in 23/47 Lim1, in 8/13 Lim2, in 16/31 Lim3 and in 2/4 Lim4 patients).

CONCLUSION

Initial location of enhancing glioblastoma is not predictive for REP. Patients experiencing REP have significantly worse overall survival and modification of their management represents urgent unmet clinical need. Molecular and clinical biomarkers indicating increased risk of REP are needed. Supported by Ministry of Health of the Czech Republic, grant No. 18-03-00469.
P14.123 Neurological complications related to checkpoints inhibitors
Authors: Esparragosa I , Valenti-Azcarate R , Moreno-Ajona D , Gallego Perez de Larraya J
Published: September 2019

BACKGROUND

Currently, immunotherapy is part of the therapeutic arsenal for oncological treatment. Indeed, the need for new medications has led to the development of immune checkpoint inhibitors. Despite favourable oncological outcomes, these treatments have been associated with immune-related adverse events. Although infrequent, neurological toxicities have been reported. Early recognition is crucial for improvement of functional outcome and requires a multidisciplinary approach.

OBJECTIVE

To describe a case series of patients with neurological complications related to checkpoint inhibitors.

PATIENTS AND METHODS

We identified six oncological patients who presented immunomediated neurological complications, derived from the use of checkpoints inhibitors. Five cases were men. Ages ranged from 58 to 73 years. Nivolumab, alone or combined, was the most commonly associated drug (4/6). Underlying diseases included lung carcinoma (2/6), melanoma (2/6), renal carcinoma (1/6) and ovarian adenocarcinoma (1/6). An acute demyelinating sensory-motor polyneuropathy and an acute axonal sensory polyneuropathy were documented in two and one case, respectively. In these, the cerebrospinal fluid analysis revealed albuminocytologic dissociation. All three cases improved after treatment with intravenous immunoglobulins (0.4 g/Kg a day for five days). The latter and another case were diagnosed of aseptic meningitis after cerebrospinal fluid lymphocytic pleocytosis was found. High fever was also associated with lower extremities areflexia, weakness and ataxia. Methylprednisolone (1g/day for five days) was administered. One case of necrotizing inflammatory myositis with high levels of creatine kinasa, confirmed by muscular biopsy, involving cervical weakness and ptosis, was effectively treated with Methylprednisolone (1g/day for five days) follow by oral prednisone tapering. An anti-Yo related pancerebellar syndrome was the only case with a fatal outcome despite treatment.

CONCLUSION

The increasingly frequent use of immunotherapy in the treatment of cancer may lead to an increase in neurological complications. These include a broad spectrum of syndromes with peripheral nervous system predominantly susceptible. Early identification of these and appropriate management of drug-related toxicity are required. Immune-modulating therapies are particularly beneficial.
P14.124 EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with standard temozolomide-based radiochemotherapy versus standard temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma
Authors: Roth P , Reijneveld J , Gorlia T , Dhermain F , De Vos F , Vanlancker M , O’Callaghan C , Le Rhun E , van den Bent M , Mason W , Weller M
Published: September 2019

BACKGROUND

The standard of care for patients with newly diagnosed glioblastoma includes maximal debulking surgery followed by radiotherapy (RT), and concomitant as well as maintenance therapy with the alkylating agent, temozolomide (TMZ). However, the prognosis remains poor and novel treatment strategies are urgently needed. Targeting the proteasome has been considered a promising anti-cancer approach for several years. Marizomib is a novel, irreversible and pan-proteasome inhibitor, which crosses the blood-brain barrier and has been assessed in phase I trials in patients with newly diagnosed or recurrent glioblastoma.

MATERIAL AND METHODS

EORTC 1709/CCTG CE.8 is a randomized, controlled, open label phase III superiority trial. Patients with histologically confirmed newly diagnosed glioblastoma and a performance status >70 are eligible. Patients are randomized in a 1:1 ratio to receive standard of care (TMZ/RT→TMZ) alone or TMZ/RT→TMZ plus marizomib. The study aims at enrolling 750 patients. Stratification factors include study site, age, performance status and extent of resection. The primary objective of this trial is to compare overall survival in patients receiving marizomib in addition to standard of care with those receiving standard treatment only. The testing strategy specifies the determination of this objective in the intent-to-treat population as well as the subgroup of patients with MGMT-unmethylated tumors. Secondary endpoints include progression-free survival, safety, neurocognitive function and quality of life. A translational research program has been set up. The study will be activated at approximately 50 EORTC sites across Europe, 25 sites in Canada and additional sites in the US. Patient recruitment started in June 2018 and as of April 29, 2019, a total of 164 patients have been randomized. An update on the enrolment status will be provided at the EANO meeting. ClinicalTrials.gov Identifier: NCT03345095
P14.127 From next generation sequencing and comparative genomic hybridization to personalised medicine for adult primary brain tumors: the profiler trial
Authors: Bonneville-levard A , Frappaz D , Pissaloux D , Wang Q , Perol D , Blay J , Meyronet D
Published: September 2019

BACKGROUND

Personalized anti-tumoral therapies may currently be proposed on the basis of immuno-histochemistry, but also next-generation sequencing and comparative genomic hybridization. ProfiLER trial explored the feasibility, efficacy and the impact of molecular profiling for patients with solid or hematological advanced cancers including brain tumors.

MATERIAL AND METHODS

Patients with primary brain tumors, pre-treated with at least one line of anti-cancer treatment, could be included in this multicentric prospective trial. A molecular profile (next-generation sequencing and comparative genomic hydridization) was established on fresh or archived sample. Weekly molecular tumor board analysed results to propose as far as possible a molecular targeted therapy.

RESULTS

between February 2013 and December 2015, 141 patients with primary brain tumor were enrolled. One hundred five samples were further analyzed as 30 samples were excluded, and 6 are on-going. The rate of screen failure was 16/33 for stereotactic biopsy (49%) versus 11/104 (11%) for removal. The main representative histologic type of tumors were glioblastoma (n=46, 43,8%), low grade glioma (n=26, 24,8%), high grade glioma (n=12, 11,4%) and atypical and anaplastic meningioma (n=8, 7,6%). Median delay between the diagnostic of the primitive tumor and the inclusion in ProfiLER study was 2.7 years (0.2 - 29 years). Median delay between the consent and the results of the multidisciplinary meeting was 2.8 months (1–7.1 months). Forty-three patients (41%) presented at least one “druggable molecular alteration”. The most frequently altered genes were CDKN2A (n=18, 29%), EGFR (n=12, 20%), PDGFRa (n=8, 13%), PTEN (n=8, 13%), CDK4 (n=7, 11%), KIT (n=6, 10%), PIK3CA (n=5, 8%), MDM2 (n=3, 5%). Sixteen patients could not have a proposition of specific treatment due to death before MBT (n=5, 31.3%), lack of available clinical trials (n=9, 56%), or ambiguous results (n=2, 12.5%). Among the 27 patients (26%) for whom a specific therapy has been proposed, only six patients ultimately received a medical targeted therapy (everolimus n=3, erlotinib n=1, ruloxitinib n=1, sorafenib n=1). Four patients discontinued the treatment for toxicity, the 2 others for clinical progression.

CONCLUSION

routine high-throughput sequencing is feasible for brain tumors but delays should be reduced to be able to propose targeted therapies to patients fit enough to benefit from experimental treatment. Macroscopic surgery is the best way to obtain workable samples. Specific panel genes for neurologic tumors should be developed, as well as change of practices concerning exclusion criteria in clinical trials.
P14.129 Predicting glioblastoma invasion using multiparametric MRI and a bi-level machine learning approach
Authors: Li C , Liu P , Wei Y , Li Y , Schönlieb C , Price S J
Published: September 2019

BACKGROUND

Glioblastoma is characterized by its extensive infiltration into the brain parenchyma, which poses challenges to accurate treatment volume targeting. Current treatment planning is based on the contrast-enhancing images. Tumor invasion, however, is well known beyond the contrast enhancement. Although deep learning shows potential in delineating tumor invasion based on multiparametric MRI, it requires large amount of training data. Image inpainting may reconstruct the lost image information based on image structure and requires less training data. The purpose of this study is to investigate whether a bi-level deep learning approach could integrate conventional neural network (CNN) and image inpainting to delineate tumor invasion based on the multiparametric MRI.

MATERIAL AND METHODS

A total of 115 patients (mean age 59.3 yrs, range 22 - 76 yrs, 87 males) with supratentorial de novo glioblastoma were recruited for maximal safe tumor resection. Post-operative temozolomide chemoradiotherapy was performed following the Stupp protocol. The Response Assessment in Neuro-oncology criteria was used to evaluate patient response. All MRI sequences were pre-operatively acquired using a 3T scanner, including T2-weighted, post-contrast T1-weighted, FLAIR, dynamic susceptibility contrast (DSC) and diffusion tensor imaging (DTI). The isotropic (p) and anisotropic (q) maps were generated from DTI. The relative cerebral blood volume (rCBV), mean transit time (MTT) and relative cerebral blood flow (rCBF) were generated from the DSC images after the leakage correction. All images were coregistered to post-contrast T1W images. Contrast-enhancing (CE) and non-enhancing (NE) regions were semi-automatically segmented and validated by an experienced neuro-radiologist. A tissue segmentation was performed using the FAST (FMRIB’s Automated Segmentation Tool) to segment the normal-appearing brain excluding the above both tumor regions and were classified into three tissue types (grey matter, white matter and CSF). A CNN model was applied to build a classification function between the CE region and the three normal-appearing tissue types based on the multi-parametric MRI. A bespoke inpainting scheme was then applied to predict the tumor invasion area in the NE region. Kaplan-Meier and Cox proportional regression were used to evaluate the significance of the predicted volume.

RESULTS

The volumes of the contrast-enhancing tumor is 53.6 ± 33.8 cm3. The predicted invasive volume in the non-enhancing region is 31.0 ± 17.7 cm3.The multivariate model shows that the predicted volume was significantly associated with OS (HR = 0.97, P= 0.006). The patient subgroup with a higher predicted volume showed significantly better OS (P= 0.009) and PFS (P= 0.021).

CONCLUSION

The proposed bi-level deep learning approach may effectively integrate multiparametric MRI for predicting tumor invasio.
High-resolution MRI demonstrates that more than 90% of small intracranial melanoma metastases develop in close relationship to the leptomeninges
Authors: Lasocki Arian , Khoo Chloe , Lau Peter K H , Kok David L , Mcarthur Grant A
Published: September 2019

Background

Despite classic teaching that intracranial metastases typically arise at the gray–white matter junction, small intracranial melanoma metastases (IMM) are frequently observed at the interface between the cortex and leptomeninges (ie, “corticomeningeal interface”), suggesting possible leptomeningeal origin.

Methods

MRI brain examinations of melanoma patients treated at a specialist oncology center from July 2015 to June 2017 were retrospectively reviewed. The MRI examination on which IMM were first visible was identified, utilizing 1 mm volumetric postcontrast imaging prior to local therapy. Individual metastases (up to 10 per patient) were assessed for the presence of leptomeningeal contact, as well as their number, size, and morphology. Lesions ≥10 mm in long axis were excluded, in order to examine early metastatic disease.

Results

Seventy-five patients had evidence of IMM. Fifteen patients had only lesion(s) measuring ≥10 mm at diagnosis, leaving 60 patients. One hundred ninety-two individual metastases were examined (median 2 per patient; interquartile range, 1–4), 174 (91%) demonstrating leptomeningeal contact. A nodular morphology was observed in 154 of 192 (82%), 32 (17%) were ovoid but elongated along the cortex, and 6 (3%) were linear. Only 3 patients (5%) also exhibited a “classic” linear leptomeningeal disease appearance.

Conclusions

Most IMM measuring between 2 and 9 mm in diameter are corticomeningeal nodules. These data raise the hypothesis that deeper parenchymal extension of IMM occurs secondarily. If the leptomeninges provide a preferential site for establishment of IMM, further investigation of the underlying biology of this phenomenon may provide opportunities for novel therapeutic strategies for patients with IMM.

Key Points

1. Most small IMM develop at the corticomeningeal interface, rather than the gray‒white junction.

2. This suggests that the pia mater provides a preferential site for establishment of IMM.

3. Deeper brain parenchymal extension may occur secondarily.
Proton pump inhibitors and histamine-2 receptor antagonists on the risk of pancreatic cancer: a systematic review and meta-analysis
Authors: Laoveeravat P , Thavaraputta S , Vutthikraivit W , Suchartlikitwong S , Mingbunjerdsuk T , Motes A , Nugent K , Rakvit A , Islam E , Islam S
Published: September 2019

Background

Proton pump inhibitors (PPI) and histamine-2 receptor antagonists (H2RA) have been widely used for multiple purposes. Recent studies have suggested an association between these medications and the risk of pancreatic cancer. However, the results have been inconclusive.

Aim

We, therefore, conducted a study to assess the risk of developing pancreatic cancer in patients who used PPI and H2RA.

Design

A systematic review and meta-analysis.

Methods

A literature search was performed using MEDLINE and EMBASE databases from inception through February 2019. Studies that reported risk ratio comparing the risk of pancreatic cancer in patients who received PPI or H2RA versus those who did not receive treatments were included. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effect generic inverse variance method. Sensitivity analysis, excluding one study at a time, was performed.

Results

After screening abstracts from the searching methods, seven studies (six case–control studies and one cohort study) were included in the analysis with total 546 199 participants. Compared to patients who did not take medications, the pooled RR of developing pancreatic cancer in patients receiving PPI and H2RA were 1.73 (95% CI: 1.16–2.57) and 1.26 (95% CI: 1.02–1.57), respectively. However, the sensitivity analysis of PPI changed the pooled RR to 1.87 (95% CI: 1.00–3.51) after a study was dropped out. Likewise, H2RA sensitivity analysis also resulted in non-significant pooled RR.

Conclusions

This meta-analysis did not find the strong evidence for the associations between the use of PPI and H2RA and pancreatic cancer.
Is axial psoriatic arthritis distinct from ankylosing spondylitis with and without concomitant psoriasis?
Authors: Feld Joy , Ye Justine Yang , Chandran Vinod , Inman Robert D , Haroon Nigil , Cook Richard , Gladman Dafna D
Published: September 2019

Objective

The aim of this study was to compare patients with ankylosing spondylitis with psoriasis (ASP) and without psoriasis (AS), to axial PsA (axPsA) patients.

Methods

Two adult cohorts were recruited from the AS clinic: ASP and AS. These two cohorts were compared with two adult cohorts recruited from the PsA clinic: axPsA (radiographic sacroiliitis: ⩾bilateral grade 2 or unilateral grade 3 or 4); and Peripheral PsA. All patients were followed prospectively according to the same protocol. The demographic, clinical and radiographic variables were compared. Adjusted means were used to account for varying intervals between visits. A logistic regression was performed and adjusted for follow-up duration.

Results

There were 477 axPsA patients, 826 peripheral PsA, 675 AS and 91 ASP patients included. AS patients were younger (P < 0.001), more male and HLA-B*27 positive (76%, 72% vs 64%, P ⩽ 0.001, 82%, 75%, vs 19%, P = 0.001). They had more back pain at presentation (90%, 92% vs 19%, P = 0.001), worse axial disease activity scores (bath ankylosing spondylitis disease activity index: 4.1, 3.9 vs 3.5 P = 0.017), worse back metrology (bath ankylosing spondylitis metrology index: 2.9, 2.2 vs 1.8, P < 0.001), worse physician global assessments (2.4, 2.2 vs 2.1, P < 0.001), were treated more with biologics (29%, 21% vs 7%, P = 0.001) and had a higher grade of sacroiliitis (90%, 84% vs 51%, P < 0.001). Similar differences were detected in the comparison of ASP to axPsA and in a regression model.

Conclusion

AS patients, with or without psoriasis, seem to be different demographically, genetically, clinically and radiographically from axPsA patients. axPsA seems to be a distinct entity.
Out of Sight, Out of Mind: Post-return Monitoring – A Missing Link in the International Protection of Refugees?
Authors: Pirjola Jari
Published: September 2019

Post-return monitoring of rejected asylum-seekers is the missing link in the protection chain for rejected asylum-seekers. In the European Union, for example, the rights of rejected asylum-seekers are well guaranteed and monitored in the pre-return and return phases. Systematic monitoring of forced returns stops when the deportee arrives at the airport of his or her country of origin. The sending countries do not know what happens to rejected asylum-seekers and irregular migrants upon return. International human rights organisations have started to pay attention to this gap in the international protection system. Ignorance by States in this regard deprives them of important insights from the viewpoint of human rights protection and return policies. This article explores what comprises post-return monitoring, what kinds of post-return monitoring projects have been carried out so far and how post-return monitoring could be implemented in the future. The article also discusses the role of post-return monitoring in the refugee determination procedure. It is argued that post-return monitoring could both strengthen the protection of refugees and asylum-seekers and assist States in creating effective, transparent, and morally responsible return policies.
Neural signatures of cooperation enforcement and violation: a coordinate-based meta-analysis
Authors: Yang Zhong , Zheng Ya , Yang Guochun , Li Qi , Liu Xun
Published: September 2019

The social norms of fairness and reciprocity are fundamental to cooperation and constitute core behavioral principles. Warm glow theory suggests that cooperative behavior is driven by positive emotions, whereas inequity aversion theory proposes that cooperative behavior is necessary to avoid negative feelings. However, the precise characteristics underlying the enforcement (fairness or reciprocity) and violation (unfairness or betrayal) of cooperation remain elusive. Moreover, whether the neural mechanism of cooperation as a partner or a spectator is the same remains unclear. To resolve the above issues, we summarized the findings of human cooperation neuroimaging studies through a meta-analysis. Based on our results, cooperation enforcement activates reward-related brain areas, such as the striatum and orbitofrontal cortex, only during other-cooperation. In contrast, cooperation violation is associated with the negative emotion-related insula in both self- and other-noncooperation. Thus, people expect others to cooperate rather than themselves; however, people are disgusted when cooperation is violated by themselves or others. Taken together, cooperative behavior might be mainly driven by a process designed to avoid negative emotion, which supports the inequity aversion theory but not the warm glow theory, thereby improving our understanding of cooperation theory.
Spinal Lengthening With Magnetically Controlled Growing Rods
Authors: Rushton Paul R.P. , Smith Simon L. , Kandemir Göksu , Forbes Liam , Fender David , Bowey Andrew J. , Gibson Michael J. , Joyce Thomas J.
Published: September 2019

Study Design.

Laboratory analysis of explanted MAGnetic Expansion Control (MAGEC) rods.

Objective.

The aim of this study was to identify the in vivo lengthening of MAGEC rods.

Summary of Background Data.

Little data is available regarding the lengthening achieved by MAGEC rods.

Methods.

Cases were identified from the largest series of independently analyzed explanted MAGEC rods. The in vivo growth of rods was determined by the distance between the first “growth mark” and the actuator. The instrumented spinal lengthening was calculated for each construct. Constructs were considered functional if all rods could lengthen with external remote controller activation and no rods were “telescoping”.

Results.

Fifty-five MAGEC constructs (99 rods) from 53 patients treated at 10 centers were included. The mean age at insertion was 8.5 years with rods implanted a mean of 35 months. Sixty rods were suitable for analysis with mean lengthening 21.7 mm, 8.9 mm/year. Of these 60 rods, three were maximally distracted. Mean instrumented spinal lengthening for 38 suitable cases was 22.1 mm, 8.4 mm/year. This was positively correlated with the duration of implantation (r = 0.34, P = 0.04) but negatively with patient age at insertion (r = −0.35, P = 0.03). The rate of instrumented spinal lengthening was negatively correlated with duration of implantation (r = −0.47, P = 0.004). Of 55 constructs, 34 were nonfunctional at time of removal with nine functional and 12 indeterminate. Functional constructs had been implanted significantly less time (20.0 vs. 39.7 months, P < 0.001) and lengthened less than those nonfunctional (12.3 mm vs. 23.3 mm, P = 0.04).

Conclusion.

This multicenter explant study represents the largest cohort managed with MAGEC rods reported. Rods are very rarely removed having fully lengthened with mean instrumented spinal growth of 22 mm over the implant's life. This may be explained by a high rate of lengthening mechanism failure in received rods after around 3 years in vivo. Our findings question the effectiveness of the MAGEC system and mandate urgent comparative clinical studies.

Level of Evidence: 4
Diagnostic Efficacy, Sensitivity, and Specificity of Xpert MTB/RIF Assay for Spinal Tuberculosis and Rifampicin Resistance
Authors: Patel Jwalant , Upadhyay Mihir , Kundnani Vishal , Merchant Zahir , Jain Sanyam , Kire Neil
Published: September 2019

Study Design.

A cross-sectional observational study.

Objective.

This study aims to determine the diagnostic accuracy, sensitivity, and specificity of the Xpert MTB/RIF assay (Mycobacterium Tuberculosis/Rifampicin resistance) for the detection of spinal Tuberculosis (TB) and rifampicin (RIF) resistance.

Summary of Background Data.

The Spinal TB is often a paucibacillary extra pulmonary tuberculosis which gives a major challenge in early diagnosis and initializing the correct anti-tubercular treatment (ATT). Due to its rapidity and sensitivity, the dependence and reliability on the Xpert MTB/RIF assay has increased in the last few years. The studies describing accuracy of the Xpert MTB/RIF assay in spinal TB are scanty.

Methods.

This institutional review board-approved study included 360 diagnosed spinal TB patients. To determine the accuracy of the Xpert MTB/RIF assay, it was compared with other diagnostic tests like histopathology, acid fast bacilli (AFB) smear, culture, and drug sensitivity testing (DST).

Results.

The Xpert MTB/RIF assay showed 86.3% sensitivity and 85.3% specificity when compared with culture for the diagnosis of Spinal TB and showed 75.86% sensitivity, 96.12% specificity for RIF resistance when compared to DST. Four cases were false positive and 11 cases were false negative for RIF resistance on the Xpert MTB/RIF assay.

Conclusion.

The Xpert MTB/RIF assay is an efficient technique for the rapid diagnosis of spinal TB; however, a clinician should not solely rely on it for starting ATT. As there are false results also with this test which should be read cautiously and be well correlated with culture and DST pattern to guide the start of sensitive drug regimen only. The purpose is to prevent exposure of the second line drugs to false cases found on the Xpert MTB/RIF assay and avoid emergence of new acquired drug resistance.

Level of Evidence: 4
The Influence of Preoperative Mental Health on PROMIS Physical Function Outcomes Following Minimally Invasive Transforaminal Lumbar Interbody Fusion
Authors: Yoo Joon S. , Hrynewycz Nadia M. , Brundage Thomas S. , Mogilevsky Franchesca A. , Shah Holly C. , Mehraban Nasima , Singh Kern
Published: September 2019

Study Design.

Retrospective.

Objective.

To demonstrate whether preoperative mental health status can be predictive of postoperative functional outcomes as measured by Patient-Reported Outcome Measurement Information System Physical Function (PROMIS PF) following minimally invasive transforaminal lumbar interbody fusion (MIS TLIF).

Summary of Background Data.

There is a paucity of scientific investigations into the association between preoperative mental health as evaluated by a validated questionnaire such as the Short Form-12 Mental Health Composite Score (SF-12 MCS) and postoperative outcomes following MIS TLIF.

Methods.

Patients undergoing a primary MIS TLIF were retrospectively reviewed and stratified into cohorts based on preoperative SF-12 MCS scores. The Physical Function scores of PROMIS, of which there are other domains including Pain Interference, Sexual Function, and Cognitive Function, were compared between the cohorts. In addition, the improvement in PROMIS scores based on preoperative SF-12 MCS scores following MIS TLIF was analyzed using multivariate linear regression.

Results.

One hundred seventy-two patients were included: 85 patients (49.4%) had a preoperative SF-12 MCS score <50 and 87 (50.6%) had a preoperative SF-12 MCS score ≥50. Patients with poorer mental health demonstrated significantly worse PROMIS PF scores preoperatively (33.8 vs. 36.5, P < 0.001), as well as at all postoperative timepoints: 6-weeks (35.1 vs. 38.4, P < 0.001), 3-months (38.9 vs. 42.9, P < 0.001), 6-months (41.4 vs. 45.5, P < 0.001), and 1-year (42.4 vs. 47.6, P < 0.001). However, at the 1-year timepoint, patients with worse mental health reported experiencing significantly less improvement from baseline (postoperative change of 8.6 vs. 11.1, P = 0.002).

Conclusion.

Patients with worse preoperative mental health not only demonstrated worse preoperative PROMIS PF scores, but also continued to have significantly worse postoperative outcomes. However, the postoperative improvement experienced by patients was similar in the short-term following surgery regardless of preoperative mental health status. Patients with poor mental health experienced significantly less postoperative improvement only at the 1-year timepoint.

Level of Evidence: 3
A Case Study of Toxic Epidermal Necrolysis
Authors: Wedel Lisa , Rash Diane
Published: September 2019

Toxic epidermal necrolysis is a rare, life-threatening, drug-induced disease that was first described by a Scottish dermatologist named Dr. Alan Lyell in 1958. After nearly 60 years, the mortality rate remains at approximately 30%. Stevens–Johnson syndrome and toxic epidermal necrolysis are differentiated by the percentage of skin involvement, with greater than 30% being classified as toxic epidermal necrolysis. Patients with Stevens–Johnson syndrome and toxic epidermal necrolysis should be managed in a burn or intensive care unit. Prompt identification is crucial to the effective management and treatment of the disease. This article presents a case study of a 10-year-old boy diagnosed with toxic epidermal necrolysis with 94% skin involvement who was effectively treated and discharged without major complications or infections.
Validation of the NeuroImaging Radiological Interpretation System for Acute Traumatic Brain Injury
Authors: Zhou Bo , Ding Victoria Y. , Li Ying , Ball Robyn L. , Jiang Bin , Zhu Guangming , Boothroyd Derek , Zeineh Michael , Gean Alisa , Wintermark Max
Published: September 2019

Purpose

The aim of the study was to refine and validate the NeuroImaging Radiological Interpretation System (NIRIS), which was developed to predict management and clinical outcome based on noncontrast head computerized tomography findings in patients suspected of acute traumatic brain injury (TBI).

Methods

We assessed the performance of the NIRIS score in a prospective, single-center cohort of patients suspected of TBI (n = 648) and compared the performance of NIRIS with that of the Marshall and Rotterdam scoring systems. We also revised components of the NIRIS scoring system using decision tree methodologies implemented on pooled data from the retrospective and prospective studies (N = 1190).

Results

The NIRIS performed similarly to the Marshall and Rotterdam scoring systems in predicting mortality and markedly better in terms of predicting more granular elements of disposition and management of TBI patients, such as admission, follow-up imaging, intensive care unit stay, and neurosurgical procedures. The revised NIRIS classification correctly predicted disposition and outcome in 91.2% (331/363) after excluding patients with other major extracranial traumatic injuries or intracranial nontraumatic injuries.

Conclusions

The present study further demonstrates the predictive value of NIRIS in guiding standardized clinical management and decision-making regarding treatment options for TBI patients.