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Background: Intraoperative neuromonitoring is crucial for facial nerve preservation in cerebellopontine angle (CPA) surgery. Among the available techniques, the role of intraoperative corticobulbar facial motor evoked potentials (FMEPs) is unclear. Objective: To evaluate the significance of intraoperative FMEPs as indicators for early and late postoperative facial nerve function (FNF) in CPA tumor resection and the feasibility of their integration with standard monitoring techniques. Methods: An institutional series of 83 patients who underwent surgery under intraoperative monitoring for CPA extra-axial tumor resection was reported. A pair of needle electrodes was used to record FMEP from orbicularis oculi (OOc) and orbicularis oris (OOr) muscles at baseline, at the end of surgery and minimum values recorded. From FMEP amplitudes, minimum-to-baseline amplitude ratio (MBR), final-to-baseline amplitude ratio (FBR), and recovery value, intended as FBR minus MBR, were calculated. These indices were correlated with early and late postoperative FNF. Results: Our analysis demonstrated that higher FBR (both from OOc and OOr) and MBR (from OOr only) were associated with a good early and late FNF; a higher MBR from OOc was significantly associated with a good late FNF. The most accurate index in predicting early FNF was FBR measured from OOr with a cutoff of 35.56%, whereas the most accurate index in predicting late FNF was FBR as measured from OOc with a cutoff of 14.29%. Conclusion: Our study confirmed that FMEPs are reliable predictors of early and late postoperative FNF in CPA surgery and could be easily integrated with standard intraoperative neuromonitoring techniques.

Five-year event-free survival in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) currently exceeds 80–85%. However, 15–20% of patients still experience a relapsed/refractory disease. From 1 January 2015 to 31 December 2020, thirty-nine patients, 0–21 years old with r/r BCP-ALL were treated with blinatumomab with the aim of inducing remission (n = 13) or reducing MRD levels (n = 26) in the frame of different multiagent chemotherapy schedules, in seven AIEOP centers. Patients were treated in compassionate and/or off-label settings and were not enrolled in any controlled clinical trials. Treatment was well tolerated; 22 (56.4%) patients reported adverse events (AE) on a total of 46 events registered, of which 27 (58.7%) were ≤2 grade according to CTCAE. Neurological AEs were 18 (39.1%); only two patients required transient blinatumomab discontinuation. Complete remission (CR) rate was 46% for the 13 patients treated with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with blasts < 5%. Median relapse-free survival was 33.4 months (95% CI; 7.5–59.3); median overall survival was not reached over a mean follow-up of 16 months. In our study, as in other real-life experiences, blinatumomab proved to be effective and well-tolerated, able to induce a high rate of CR and MRD negativity.

The cerebellopontine angle (CPA) is a highly complex anatomical compartment consisting of numerous nervous and vascular structures that present mutual and intricate spatial relationships. CPA surgery represents, therefore, a constant challenge for neurosurgeons. Over the years, neurosurgeons have developed and refined several solutions with the aim of maximizing the surgical treatment effects while minimizing the invasiveness and risks for the patient. In this paper, we present our integrated approach to CPA surgery, describing its advantages in treating pathologies in this anatomical district. Our approach incorporates the use of technology, such as neuronavigation, along with advanced and multimodal intraoperative neuromonitoring (IONM) techniques, with the final goal of making this surgery safe and effective.

Background: The exoscope has been proposed as a valid tool in 5-aminolevulinic acid–guided resection of high-grade gliomas. However, it is not clear if, beyond ergonomics, the exoscope provides a real benefit over the optical microscope (OM). The aim of this study was to compare the exoscope with the OM in terms of surgical visualization and workflow in 5-aminolevulinic acid–guided brain surgery. Methods: Surgical videos of patients diagnosed with histopathologically confirmed, Shinoda stage I, high-grade gliomas who underwent surgery in from January to April 2022 were studied. Visualization under a 5-aminolevulinic acid blue filter for vessels, parenchyma, surgical instruments, and fluorescence was categorized for both superficial and deep fields. The following data were also recorded: median number of switches between white light and blue filter, average duration per switch, and amount of work under blue filter. Results: There were 5 surgeries performed under OM guidance and 5 performed under exoscope guidance. Under a blue filter, the exoscope was significantly better than the OM in visualizing vessels, parenchyma, and surgical instruments for both superficial and deep surgical fields. The median number of switches between blue and white light was lower compared with the OM. Both median switch duration and percentage of work under the blue filter were superior when using the exoscope. Conclusions: Within the limitations of a preliminary analysis, use of the exoscope in fluorescence-guided surgery for high-grade gliomas provided significant advantages in terms of visualization of the surgical field under a blue filter and linearity of surgical flow.

Preservation of facial nerve function (FNF) during neurosurgery for cerebellopontine angle (CPA) tumors is paramount in elderly patients. Corticobulbar facial motor evoked potentials (FMEPs) allow assessment intraoperatively of the functional integrity of facial motor pathways, thus improving safety. We aimed to evaluate the significance of intraoperative FMEPs in patients 65 years and older. A retrospective cohort of 35 patients undergoing CPA tumors resection was reported; outcomes of patients aged 65–69 years vs. ≥70 years were compared. FMEPs were registered both from upper and lower face muscles, and amplitude ratios (minimum-to-baseline, MBR; final-to-baseline, FBR; and recovery value, FBR minus MBR) were calculated. Overall, 78.8% of patients had a good late (at 1 year) FNF, with no differences between age groups. In patients aged ≥70 years, MBR significantly correlated with late FNF. At receiver operating characteristics (ROC) analysis, in patients aged 65–69 years, FBR (with 50% cut-off value) could reliably predict late FNF. By contrast, in patients aged ≥70 years, the most accurate predictor of late FNF was MBR, with 12.5% cut-off. Thus, FMEPs are a valuable tool for improving safety in CPA surgery in elderly patients as well. Considering literature data, we noticed higher cut-off values for FBR and a role for MBR, which suggests an increased vulnerability of facial nerves in elderly patients compared to younger ones.

Letter to the Editor

In recent years, research on brain cancers has turned towards the study of the interplay between the tumor and its host, the normal brain. Starting from the establishment of a parallelism between neurogenesis and gliomagenesis, the influence of neuronal activity on the development of brain tumors, particularly gliomas, has been partially unveiled. Notably, direct electrochemical synapses between neurons and glioma cells have been identified, paving the way for new approaches for the cure of brain cancers. Since this novel field of study has been defined “cancer neuroscience”, anticancer therapeutic approaches exploiting these discoveries can be referred to as “cancer neuromodulation”. In the present review, we provide an up-to-date description of the novel findings and of the therapeutic neuromodulation perspectives in cancer neuroscience. We focus both on more traditional oncologic approaches, aimed at modulating the major pathways involved in cancer neuroscience through drugs or genetic engineering techniques, and on electric stimulation proposals; the latter is at the cutting-edge of neuro-oncology.

Objective: Ability to thrive after invasive and intensive treatment is an important parameter to assess in patients with glioblastoma multiforme (GBM). Karnofsky Performance Status (KPS) is used to identify those patients suitable for postoperative radiochemotherapy. The aim of the present study is to investigate whether machine learning (ML)-based models can reliably predict patients' KPS 6 months after surgery. Methods: A cohort of 416 patients undergoing surgery for a histopathologically confirmed GBM were collected from a multicentric database and split into a training and hold-out test set in an 80:20 ratio. Worsening of KPS at 6 months after surgery (compared with preoperative KPS) occurred in 138 patients (33.2%). Relevant preoperative, intraoperative, and immediately postoperative variables were selected by a recursive features selection algorithm (Boruta) and used to build 2 ML-based predictive models. Results: A random forest classifier and a random forest regressor were trained to predict 6 months postoperative KPS as a categorical (worsening vs. stable/improving) and continuous variables; they achieved, respectively, an area under the curve of 0.81 (95% confidence interval, 0.76–0.84) and a mean absolute error of 4.4 (95% confidence interval, 4.0–4.7). Leveraging the predictive value resulting from the combination of independent variables, the random forest classifier outperformed conventional statistics (area under the curve improvement of +21%). Conclusions: Two robust ML-based prediction models were successfully trained and internally validated. Considerable effort remains to improve the interpretation of the results when these predictions are used in a patient-centered care context.

Microvascular decompression (MVD) is the only etiological technique for the treatment of trigeminal neuralgia (TN). Whilst there is a consensus MVD is likely effective regardless of age, the elderly population is thought to be more prone to have a higher rate of surgical complication, morbidity, and mortality. The main objective of our single-center, retrospective study was to analyze the surgical and clinical outcomes of MVD in TN elderly patients. From a surgical series of patients with TN who had undergone MVD from April 2018 to April 2022, 76 patients who matched the inclusion criteria were divided into two groups: twenty-five (32.9%) patients were older than 65 years and included in the elderly group, while the remaining fifty-one (61.1%) patients were below 65 years included in the non-elderly one. There were no differences between the groups in terms of acute pain relief (APR), Barrow Neurological Index (BNI) at follow-up, complications, and recurrence rate. In multivariate analysis (Cox proportional hazards regression analysis) the presence of an offending artery with nerve root distortion/indentation emerged as the only independent prognostic factor for pain-free survival (p = 0.0001). Our data endorse MVD as a safe and effective surgical procedure also for elderly patients with TN.

There is a lack of knowledge about the factors associated with the recurrence of hemifacial spam (HFS) following an initially successful microvascular decompression (MVD) surgery. The aim of the present study was to systematically review the pertinent literature and carry out a meta-analysis of factors linked to HFS recurrence in patients undergoing initially successful MVD treatment. An online literature search was launched on the PubMed/Medline and Scopus databases. The following data were collected: sex, age at surgery, affected side, reported improvement after surgery, presence of post-operatory facial weakness, symptom duration, offender vessels, and data obtained from intraoperative neurophysiological monitoring. Upon full-text review, eight articles were included, studying 1105 patients, of which 64 (5.7%) reported recurrence after MVD surgery for hemifacial spasm. There was a statistically significant increased incidence of HFS recurrence in patients with the persistence of lateral spread response (LSR after surgery (OR 9.44 (95% CI 1.69– 52.58) p 0.01), while those patients experiencing a shorter disease duration before going to surgery were significantly less prone to experiencing disease recurrence (OR 0.11 (95% CI 0.03–0.46) p 0.002). The remaining examined factors did not result as significantly associated with the risk of recurrence. The funnel plots were largely symmetrical for each variable studied. Taken together, the results of our meta-analysis seem to suggest that short-term symptom duration is a protective factor against HFS recurrence after MVD surgery, while LSR persistence is a negative prognostic factor. Well-designed randomized controlled clinical trials with a long follow-up are expected to further explore therapeutic alternatives for HFS recurrence.

Background: Mild traumatic brain injury (TBI) in anticoagulated patients is a common challenge for emergency departments because of lack of appropriate epidemiological data and huge management variability for those under oral anticoagulation therapy. Given the discrepancies between guidelines, the aim of the present study was to quantify the association between oral anticoagulant therapy (either vitamin K antagonist (VKA) or direct oral anticoagulant (DOAC)) and the post-traumatic intracranial hemorrhage worsening compared to admission CT scan. Methods: We included all consecutive records of patients admitted to our emergency department for mild TBI as chief complaint and with a positive admission CT scan. After statistical univariate comparison, cause-specific hazard ratio (HR) and 95% confidence interval (CI) were determined with the use of Cox proportional hazard model. Results: In the study period, 4667 patients had a CT scan for mild TBI; 439 (9.4%) were found to have intracranial hemorrhage. Among these patients, 299 (68.1%) were prescribed observation and control CT: 46 (15.38%) were on anticoagulant therapy, 23 (50%) on VKA, and 23 (50%) on DOAC. In multivariate analysis, only oral anticoagulation therapy was significantly associated to an increased risk of intracranial hemorrhage progression (HR 2.58; 95% CI 1.411–4.703; p =.002 and HR 1.9; 95% CI 1.004–3.735; p =.0048 for VKA and DOAC, respectively). Surgery was due to isolated subdural hematoma in 87.5% of cases, to subdural hematoma associated with intraparenchymal hemorrhage in 9.38% and to intraparenchymal hemorrhage only in 3.12%; 13 cases (4.35%) deceased in intensive care unit. Conclusions: In our series, anticoagulation was associated to a significant increase in intracranial progression, leaving the question open as to what this implies in current clinical practice; subdural hematoma was the major finding associated to evolution and surgery. Against this background, further studies are needed to c

Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of S. aureus and vancomycin resistance in 40% of E. faecium. Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant S. aureus was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs.

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Allogeneic hematopoietic stem cell transplantation is the treatment of choice for autosomal recessive osteopetrosis caused by defects in the TCIRG1 gene. Despite recent progress in conditioning, a relevant number of patients are not eligible for allogeneic stem cell transplantation because of the severity of the disease and significant transplant-related morbidity. We exploited peripheral CD34+ cells, known to circulate at high frequency in the peripheral blood of TCIRG1-deficient patients, as a novel cell source for autologous transplantation of gene corrected cells. Detailed phenotypical analysis showed that circulating CD34+ cells have a cellular composition that resembles bone marrow, supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPCs). To overcome the limit of bone marrow harvest/ HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex-vivo expansion of HSPCs coupled with lentiviral gene transfer. Circulating CD34+ cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector (LV) expressing TCIRG1 under the control of phosphoglycerate promoter and expanded ex vivo. Expanded cells maintained long-term engraftment capacity and multi-lineage repopulating potential when transplanted in vivo both in primary and secondary NSG recipients. Moreover, when CD34+ cells were differentiated in vitro, genetically corrected osteoclasts resorbed the bone efficiently. Overall, we provide evidence that expansion of circulating HSPCs coupled to gene therapy can overcome the limit of stem cell harvest in osteopetrotic patients, thus opening the way to future gene-based treatment of skeletal diseases caused by bone marrow fibrosis.

The glioblastoma microenvironment plays a substantial role in glioma biology. However, few studies have investigated its spatial heterogeneity. Exploiting 5-ALA Fluorescence Guided Surgery (FGS), we were able to distinguish between the tumor core (ALA+), infiltrating area (ALAPALE) and healthy tissue (ALA-) of the glioblastoma, based on the level of accumulated fluorescence. The aim of this study was to investigate the properties of the microenvironments associated with these regions. For this purpose, we isolated glioma-associated stem cells (GASC), resident in the glioma microenvironment, from ALA+, ALA-PALE and ALA-samples and compared them in terms of growth kinetic, phenotype and for the expression of 84 genes associated with cancer inflammation and immunity. Differentially expressed genes were correlated with transcriptomic datasets from TCGA/GTEX. Our results show that GASC derived from the three distinct regions, despite a similar phenotype, were characterized by different transcriptomic profiles. Moreover, we identified a GASC-based genetic signature predictive of overall survival and disease-free survival. This signature, highly expressed in ALA+ GASC, was also well represented in ALA PALE GASC. 5-ALA FGS allowed to underline the heterogeneity of the glioma microenvironments. Deepening knowledge of these differences can contribute to develop new adjuvant therapies targeting the crosstalk between tumor and its supporting microenvironment.

Background: One of the most valuable innovations in high-grade glioma surgery is 5-aminolevulinic acid (5-ALA). Fluorescence is a specific and sensitive indicator of metabolically active tumor tissue. In the published literature, the main focus has been placed on false-negative cases, with only a few articles addressing false positivity. The aim of the article was to highlight settings in which 5-ALA fluorescence does not necessarily mean tumor and to point out conditions in which intraoperative 5-ALA fluorescence has to be critically interpreted. Methods: Using PubMed, a review of pertinent literature was done to specifically investigate all conditions, including non-neoplastic and other metabolically active lesions, that can mimic high-grade gliomas and cause a misleading intraoperative diagnosis. In addition, an institutional case characterized by strong 5-ALA fluorescence in radionecrosis is presented. Results: Literature results were grouped in 2 main categories according to the field of application: oncologic setting (9 articles and 1 institutional case) and nononcologic settings (5 articles). Conclusions: As reported, 5-ALA-induced fluorescence is not limited to glioma but is also evident in nonglioma and non-neoplastic conditions. Critical interpretation of intraoperative fluorescence is therefore mandatory in recurrences and in atypical cases that might hinder alternative diagnoses.

In children with acute myeloid leukaemia (AML), assessment of initial treatment response is an essential prognostic factor; methods more sensitive than morphology are still under evaluation. We report on the measurement of minimal residual disease (MRD), by multicolour flow-cytometry in one centralized laboratory, in 142 children with newly diagnosed AML enrolled in the Associazione Italiana di EmatoOncologia Pediatrica-AML 2002/01 trial. At the end of the first induction course, MRD was <0·1% in 69, 0·1–1% in 16 and >1% in 51 patients. The 8-year disease-free survival (DFS) of 125 children in morphological complete remission and with MRD <0·1%, 0·1–1% and ≥1% was 73·1 ± 5·6%, 37·8 ± 12·1% and 34·1 ± 8·8%, respectively (P < 0·01). MRD was also available after the second induction course in 92/142 patients. MRD was ≥0·1% at the end of the first induction course in 36 patients; 13 reached an MRD <0·1% after the second one and their DFS was 45·4 ± 16·7% vs. 22·8 ± 8·9% in patients with persisting MRD ≥0·1% (P = 0·037). Multivariate analysis demonstrated that MRD ≥0·1% after first induction course was, together with a monosomal karyotype, an independent adverse prognostic factor for DFS. Our results show that MRD detected by flow-cytometry after induction therapy predicts outcome in patients with childhood AML and can help stratifying post-remission treatment.

Introduction: Advances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry. Materials and methods: CCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs). Results: Among 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86–88) and at 45 years was 81% (95% CI: 77–84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7–12), corresponding to an AER of 48 (95% CI: 45–51). Mortality decreased by 60% for survivors treated most recently (1990–1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death. Conclusions: This study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs.