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Objective: To evaluate the role and possible complications of tumor resection in the management of glioblastoma (GBM) in a series of patients 80 years of age and older with review of literature., Methods: The authors retrospectively analyzed cases involving patients 80 years or older who underwent biopsy or initial resection of GBM at their hospital between 2007 and 2018. A total of 117 patients (mean age 82 years) met the inclusion criteria; 57 had resection (group A) and 60 had biopsy (group B). Functional outcomes and survival at follow-up were analyzed., Results: Group A differed significantly from group B at baseline in having better WHO performance status, better ASA scores, more right-sided tumors, and no basal ganglia or "butterfly" gliomas. Nevertheless, 56% of group A patients had an ASA score of 3. Median survival was 9.5 months (95% CI 8-17 months) in group A, 4 months (95% CI 3.5-6 months) in group B, and 17.5 months (95% CI 12-24 months) in the 56% of group A patients treated with resection and Stupp protocol. Rates of postoperative neurologic and medical complications were almost identical in the 2 groups, but the rate of surgical site complications was substantially greater in group A (12% vs 5%). There was no significant difference in mean preoperative and postoperative KPS scores (group A)., Conclusions: In selected patients 80 years or older, radical removal of GBM was associated with acceptable survival and a low perioperative complication rate which is comparable to that of a biopsy. Although the median survival of the whole group was lower than reported for younger patients, a subgroup amenable to radical surgery and Stupp protocol achieved a median survival of 17.5 months., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, AT part of Springer Nature.)

Objective: The purpose of this study was to investigate the possible benefit of repeat surgery on overall survival for patients with recurrent glioblastoma multiforme (GBM)., Methods: We performed a retrospective analysis of data from patients who presented with recurrent GBM over a 5-year period ( n = 157), comparing baseline characteristics and survival for patients who had at least 1 new tumor resection followed by chemotherapy (reoperation group, n = 59) and those who received medical treatment only (no-reoperation group, n = 98) for recurrence., Results: The baseline characteristics of the two groups differed in terms of WHO performance status (better in the reoperation group), mean age (60 years in the reoperation group vs. 65 years in the no-reoperation group), mean interval to recurrence (3 months later in the reoperation group than in the no-reoperation group) and more gross total resections in the reoperation group. Nevertheless, the patients in the reoperation group had a higher rate [32.8%] of sensorimotor deficits than those of the no-reoperation group [14.2]. There was no significant difference in sex; tumor localization, side, or extent; MGMT status; MIB-1 labeling index; or Karnofsky Performance Status [KPS] score. After adjustment for age, the WHO performance status, interval of recurrence, and extent of resection at the first operation, multivariate analysis showed that median survival was significantly better in the reoperation group than in the no-reoperation group (22.9 vs. 14.61 months, P < 0.05). After a total of 69 repeat operations in 59 patients (10 had 2 repeat surgeries), we noted 13 temporary and 20 permanent adverse postoperative events, yielding a permanent complication rate of 28.99% (20/69). There was also a statistically significant ( P = 0.029, Student's t -test) decrease in the mean KPS score after reoperation (mean preoperative KPS score of 89.34 vs. mean postoperative score of 84.91)., Conclusion: Our retrospective study suggests that repeat surgery may be beneficial for patients with GBM recurrence who have good functional status (WHO performance status 0 and 1), although the potential benefits must be weighed against the risk of permanent complications, which occurred in almost 30% of the patients who underwent repeat resection in this series., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Asian Journal of Neurosurgery.)

Key Points: We performed a prospective electrostimulation study of the motor homunculus in 100 patients without motor deficit or brain lesion in the precentral gyrus in order to acquire accurate Montreal Neurological Institute (MNI) coordinates of the functional areas. The analysis of 248 body coordinates in the precentral gyrus showed rare inter-individual variations in the medial-to-lateral somatotopic movement organization with quite similar intensity thresholds. Electrostimulation only induced basic and stereotyped movements. We detected a relative medial-to-lateral somatotopy of the wrist/hand/global/individual fingers, with sometimes different sites for an individual muscle or movement. We found some similarities to, but also substantial differences from, the seminal work of Penfield and colleagues. We propose an updated version of the human motor homunculus and of its correlation with the somatosensory homunculus, previously defined in MNI space with a similar brain mapping technique., Abstract: In this prospective electrostimulation study, based on 100 operated patients without motor deficit or brain lesion in the precentral gyrus, we acquired coordinates of the functional areas of the motor homunculus and normalized them to standard MNI space. Among 608 sites stimulated in the precentral gyrus (and 1937 in gyri nearby), 248 positive points (40%) for motor response were detected - 245 in the precentral gyrus. Positive stimulations were detected through the 'on/off' outbreak effect, and only basic movements were detected. We found no significant difference in mean intensity threshold between the motor representations of the fingers (1.94 mA), tongue and lower limbs (both 2.0 mA), or face (2.25 mA). In the precentral gyrus, the evoked body movements displayed a medial-to-lateral somatotopy in very small (often <10 mm 2 ) areas. The hand region displayed multiple areas for a specific movement, with areas inducing either global or single-finger movement (with a relative medial-to-lateral somatotopy). Among these tested patients, the somatotopic organization of the intact motor cortex showed little inter-individual variations. Unlike Penfield and collaborators, we evoked no sensations such as sense of movement or desire to move, and only 2% of motor responses outside the precentral gyrus. We propose a rationalization of the standard drawing of the motor homunculus according to MNI space. We found a somatotopic correlation perpendicular to the central sulcus when matching our motor data to those previously obtained for the somatosensory homunculus., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Objectives: Establishing an overall survival prognosis for resected glioblastoma during routine postoperative management remains a challenge. The aim of our single-center study was to assess the usefulness of basing survival analyses on preradiotherapy MRI (PRMR) rather than on postoperative MRI (POMR)., Patients and Methods: A retrospective review was undertaken of 75 patients with glioblastoma treated at our institute. We collected overall survival and MRI volumetric data. We analyzed two types of volumetric data: residual tumor volume and extent of resection. Overall survival rates were compared according to these two types of volumetric data, calculated on either POMR or PRMR and according to the presence or absence of residual enhancement., Results: Analysis of volumetric data revealed progression of some residual tumors between POMR and PRMR. Kaplan-Meier analysis of the correlations between extent of resection, residual tumor volume, and overall survival revealed significant differences between POMR and PRMR data. Both MRI scans indicated a difference between the complete resection subgroup and the incomplete resection subgroup, as median overall survival was longer in patients with complete resection. However, differences were significant for PRMR (25.3 vs. 15.5, p =  0.012), but not for POMR (21.3 vs. 15.8 months, p =  0.145). With a residual tumor volume cut-off value of 3 cm 3 , Kaplan-Meier survival analysis revealed non-significant differences on POMR (p =  0.323) compared with PRMR (p =  0.007)., Conclusion: Survival in patients with resected glioblastoma was more accurately predicted by volumetric data acquired with PRMR. Differences in predicted survival between the POMR and PRMR groups can be attributed to changes in tumor behavior before adjuvant therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Pure traumatic spinal cord injury (without associated bone lesion) are encountered in pediatric accidentology, the most typical being spinal cord injury without radiological abnormality (SCIWORA). The present study reports a multicenter series of under-18-year-olds admitted for traumatic medullary lesion. The objectives were: (1) to describe the causes of pure spinal cord injuries in children in France and their clinical presentation; (2) to identify any prognostic factors; and (3) to describe their medical management in France., Patients and Method: A multicenter retrospective study was conducted in 3 pediatric spine pathology reference centers. Files of 37 patients with confirmed spinal cord injury between January 1988 and June 2017 were analyzed: SCIWORA (n=30), myelopathy associated with severe cranial trauma (n=2), and obstetric trauma (n=5). Accident causes, associated lesions, initial Frankel grade, level of clinical spinal cord injury, initial MRI findings, type of treatment and neurology results at last follow-up were collated. The main endpoint was neurologic recovery, defined by improvement of at least 1 Frankel grade., Results: Causes comprised 17 road accidents, 11 sports accidents, 5 obstetric lesions and 4 falls. Mean follow-up was 502 days. The rate of at least partial neurologic recovery was 20/30 in SCIWORA, 0/5 in obstetric trauma, and 0/4 in case of associated intracranial lesion. In SCIWORA, factors associated with recovery comprised age, accident type, and absence of initial MRI lesion., Discussion: We report a large series of pediatric spinal cord injury without associated bone lesion. This is a potentially serious pathology, in which prognosis is mainly related to age and trauma mechanism., Level of Evidence: IV, case series., (Copyright © 2019. Published by Elsevier Masson SAS.)

Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach.

Activating mutations in the platelet-derived growth factor (PDGF) receptor alpha (PDGFRA) have been described in patients with gastrointestinal stromal tumors or myeloid malignancies associated with hypereosinophilia. These patients respond well to imatinib mesylate, raising the question as to whether patients with a PDGF receptor mutation in other tumor types should receive a tyrosine kinase inhibitor treatment. We characterized 10 novel somatic point mutations in PDGFRA that have been reported in isolated cases of glioblastoma, melanoma, acute myeloid leukemia, peripheral nerve sheath tumors and neuroendocrine carcinoma. The PDGFRA transmembrane domain mutation V536E stimulated Ba/F3 cell growth and signaling via ERK and STAT5 in the absence of ligand. This mutant, identified in glioblastoma, was strongly inhibited by imatinib. Modeling suggested that the mutation modulates the packing of the transmembrane domain helices in the receptor dimer. By contrast, two mutations in highly conserved residues affected the receptor traffic to the cell surface or kinase activity, thereby preventing the response to PDGF. The other mutations had no significant impact on the receptor activity. This functional analysis matched the predictions of SIFT and PolyPhen for only five mutations and these algorithms do not discriminate gain from loss of function. Finally, an E996K variant that had been identified in a melanoma cell line was not expressed in these cells. Altogether, several newly identified PDGFRA mutations do not activate the receptor and may therefore represent passenger mutations. Our results also underline the importance of characterizing novel kinase alterations in cancer patients.

Most cancer cells use anaerobic-like glycolysis to generate energy instead of oxidative phosphorylation. They also avoid recognition by CTLs, which occurs primarily through decreasing the level of MHC class I (MHC-I) at the cell surface. We find that the two phenomena are linked; culture conditions that force respiration in leukemia cells upregulate MHC-I transcription and protein levels at the cell surface, whereas these decrease in cells forced to perform fermentation as well as in leukemia cells lacking a functional mitochondrial respiratory chain. Forced respiration leads to increased expression of the MAPK ERK5, which activates MHC-I gene promoters, and ERK5 accumulation in mitochondria. Respiration-induced MHC-I upregulation is reversed upon short hairpin RNA-mediated ERK5 downregulation and by inactive mutants of ERK5. Moreover, short hairpin RNA for ERK5 leukemia cells do not tolerate forced respiration. Thus, the expression of ERK5 and MHC-I is linked to cell metabolism and notably diminished by the metabolic adaptations found in tumor cells.

Tumor cell-based vaccines are currently used in clinical trails, but they are in general poorly immunogenic because they are composed of cell extracts or apoptotic cells. Live tumor cells should be much better Ags provided that they are properly processed by the host immune system. We show herein that stable expression of a small hairpin RNA for ERK5 (shERK5) decreases ERK5 levels in human and mouse leukemic cells and leads to their elimination by NK cells in vivo. The shERK5 cells show down-regulation of MHC class I expression at the plasma membrane. Accordingly, ectopic activation of the ERK5 pathway induces MHC class I gene expression. Coinjection of shERK5-expressing cells into the peritoneum diminishes survival of engrafted wild-type tumor cells. Moreover, s.c. injection of shERK5-expressing cells strongly diminishes tumor development by wild-type cells. Our results show that shERK5 expression in leukemia cells effectively attenuates their tumor activity and allows their use as a tumor cell-based vaccine.

The cancer immunosurveillance hypothesis has found strong experimental support in recent years. It is believed that cytotoxic lymphocytes are important effectors in this process. PKCtheta plays an essential role in proliferation, activation and survival of these cells, but also proliferation and survival of leukemic T cells. In light of this, we tested the role of PKCtheta in T cell leukemia progression by inducing this disease in wild-type (wt) and PKCtheta-deficient mice with moloney-murine leukemia virus (M-MuLV). Leukemic PKCtheta(-/-) and wild-type (wt) mice showed the same profile of leukemic cell types, similar spleen and thymus sizes and comparable hematocrits. In contrast, disease incidence was higher and disease onset more rapid in PKCtheta(-/-) mice. Transfer of leukemic T cells from wt donors into PKCtheta-deficient and wt recipients induced leukemia in 100% and 40% of the mice, respectively. Interestingly, leukemic cells from PKCtheta(-/-) donors induced the disease in only 50% of the PKCtheta-deficient and 10% of the wt recipients. Intravenous injection of low numbers of EL4 cells induced tumors earlier in PKCtheta(-/-) mice. Taken together, our results show that PKCtheta is essential for the immune response to leukemia in mice and raise questions about the chronic treatment of humans with PKCtheta inhibitors.

The AP-1 family member JunB is a critical regulator of T cell function. JunB is a transcriptional activator of various cytokine genes, such as IL-2, IL-4, and IL-10; however, the post-translational modifications that regulate JunB activity in T cells are poorly characterized. We show here that JunB is conjugated with small ubiquitin-like modifier (SUMO) on lysine 237 in resting and activated primary T cells and T cell lines. Sumoylated JunB associated with the chromatin-containing insoluble fraction of cells, whereas nonsumoylated JunB was also in the soluble fraction. Blocking JunB sumoylation by mutation or use of a dominant-negative form of the SUMO-E2 Ubc-9 diminished its ability to transactivate IL-2 and IL-4 reporter genes. In contrast, nonsumoylable JunB mutants showed unimpaired activity with reporter genes controlled by either synthetic 12-O-tetradecanoylphorbol-13-acetate response elements or NF-AT/AP-1 and CD28RE sites derived from the IL-2 promoter. Ectopic expression of JunB in activated human primary CD4(+) T cells induced activation of the endogenous IL-2 promoter, whereas the nonsumoylable JunB mutant did not. Thus, our work demonstrates that sumoylation of JunB regulates its ability to induce cytokine gene transcription and likely plays a critical role in T cell activation.