Titanium Biohybrid Middle Ear Prostheses: A Preliminary In Vitro Study.

Ossiculoplasty is a surgical operation performed to restore auditory transmission through the reconstruction of the ossicular chain using prosthetics. Tissue bioengineering has assumed a pivotal role in implementing alternatives to conventional ossicular middle ear replacement prostheses, to overcome extrusion while preserving acoustic properties. This in vitro study aims to explore, for the first time in current literature, the feasibility of a biohybrid middle ear prosthesis, composed of titanium surrounded by a bone extracellular matrix as bio-coating. We have hereby studied the adhesion and proliferation of human adipose-derived mesenchymal stem cells (hASC) on titanium scaffolds in vitro. Moreover, we identified the osteogenic differentiation of hASC using an immunofluorescence assay to analyze osteoblasts' gene expression profiles (Alp, Runx2, Col1a1, Osx, and Bglap), and we counted the presence of collagen as a marker of hASC's ability to secrete an extracellular matrix. We utilized scanning electron microscopy to evaluate the presence of an extracellular matrix on the scaffolds. Our preliminary data demonstrated the titanium's ability to support human adipose-derived mesenchymal stem cell colonization, proliferation, and osteoblastic differentiation, in order to obtain a biohybrid device. Our experience seems encouraging; thus, we advocate for further in vivo research to corroborate our results regarding bone transplantation.

Extrusion and Dislocation in Titanium Middle Ear Prostheses: A Literature Review.

Titanium middle ear (ME) prostheses are widely used in surgical practice due to their acoustic properties. However, they present a significant drawback shared by all synthetic materials currently in use for ME reconstruction: they can be rejected by the organism of the host. In this study, we aim to review the current literature on titanium partial ossicular replacement prostheses (PORPs) and total ossicular replacement prostheses (TORPs) extrusion and dislocation. Eighty articles were analysed after a full article review based on the inclusion and exclusion criteria. The most common indication for reconstruction was chronic otitis media with cholesteatoma. The average extrusion or dislocation rate was 5.2%, ranging from 0 to 35%. The average improvements in the air-bone gap were 12.1 dB (1.6 dB to 25.1 dB) and 13.8 (-0.5 dB to 22.7 dB) for the PORP and TORP groups, respectively. The data reported on this topic are highly variable, demonstrating that functional outcomes are difficult to predict in clinical practice. We believe that the current limitations could be overcome with technological developments, including bioengineering research focused on promoting prosthesis adaptation to the ME environment.

The Role of PEMFs on Bone Healing: An In Vitro Study.

Bone responses to pulsed electromagnetic fields (PEMFs) have been extensively studied by using devices that expose bone cells to PEMFs to stimulate extracellular matrix (ECM) synthesis for bone and cartilage repair. The aim of this work was to highlight in which bone healing phase PEMFs exert their action. Specifically, we evaluated the effects of PEMFs both on human adipose mesenchymal stem cells (hASCs) and on primary human osteoblasts (hOBs) by testing gene and protein expression of early bone markers (on hASCs) and the synthesis of late bone-specific proteins (on hOBs) as markers of bone remodeling. Our results indicate that PEMFs seem to exert their action on bone formation, acting on osteogenic precursors (hASCs) and inducing the commitment towards the differentiation pathways, unlike mature and terminally differentiated cells (hOBs), which are known to resist homeostasis perturbation more and seem to be much less responsive than mesenchymal stem cells. Understanding the role of PEMFs on bone regenerative processes provides important details for their clinical application.

Detection of SARS-CoV-2 in Cancellous Bone of Patients with COVID-19 Disease Undergoing Orthopedic Surgery: Laboratory Findings and Clinical Applications.

An emerging issue for orthopedic surgeons is how to manage patients with active or previous COVID-19 disease, avoiding any major risks for the surgeons and the O.R. personnel. This monocentric prospective observational study aims to assess the prevalence of SARS-CoV-2 viral RT-PCR RNA in cancellous bone samples in patients with active or previous COVID-19 disease. We collected data about 30 consecutive patients from our institution from January 2021 to March 2021 with active or previous COVID-19 disease. The presence of SARS-CoV-2 in the samples was determined using two different PCR-based assays. Eighteen of the thirty patients included in the study had a positive nasopharyngeal swab at the time of surgery. Twelve patients had a negative nasopharyngeal swab with a mean days since negativization of 138 ± 104 days, ranging from 23 to 331 days. Mean days of positivity to the nasal swab were 17 ± 17. Twenty-nine out of thirty (96.7%) samples were negative for the presence of SARS-CoV-2 RNA. In one sample, low SARS-CoV-2 load (Cycle threshold (Ct) 36.6.) was detected but not confirmed using an additional confirmatory assay. The conducted study demonstrates the absence of the viral genome within the analyzed cancellous bone. We think that the use of personal protection equipment (PPE) to only protect from aerosol produced during surgery, both in active and recovered patients, is not strictly necessary. We think that the use of PPE should not be employed by surgeons and the O.R. personnel to protect themselves from aerosols produced from the respiratory tract. Moreover, we think that our results could represent a valid basis for further studies related to the possibility of bone donation in patients that suffered and recovered from COVID-19.

Fast Functional Rehabilitation Protocol versus Plaster Cast Immobilization Protocol after Achilles Tendon Tenorrhaphy: Is It Different? Clinical, Ultrasonographic, and Elastographic Comparison.

BACKGROUND: the incidence of Achilles tendon (AT) rupture is rising; however, there is no clear consensus regarding the optimal treatment. The aim of this retrospective study was to compare instrumental and patient-reported outcome scores after fast functional rehabilitation (group A) versus plaster cast immobilization (group B) programs in patients who underwent AT tenorrhaphy. METHODS: 33 patients, with similar clinical and demographic features, underwent open AT tenorrhaphy between January and July 2018. Of these, 15 patients were treated with fast functional rehabilitation program (group A), and 18 patients were treated with plaster cast immobilization protocol (group B). Sural triceps hypotrophy and functional scores (American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score, and Achilles tendon Total Rupture Score (ATRS)) were recorded at a 12-month follow-up. Ultrasonography (US) and elastosonography (ES) were used to compare the characteristics of the tendons after surgery. RESULTS: At 12 months, no significant differences in any of the patient-reported outcomes or the instrumental measurement tests were seen between the two groups. CONCLUSIONS: fast functional rehabilitation after AT surgical repair is safe, effective, and may be the first choice of treatment, especially in young, collaborative, and active patients.

Haemophilic Pelvic Pseudotumour: A New Surgical Option.

BACKGROUND: Haemophilia is an inherited coagulopathy caused by the absence or dysfunction of clotting factor VIII or IX. Clinical manifestations are generally secondary to recurrent bleeding episodes mainly in the musculoskeletal system. Bleeding symptoms appear early in life and, when the disease is severe (when plasma factor VIII or IX activity is <1% of normal), joint and muscle bleeding may occur spontaneously. A pseudotumour is a recurrent, chronic, encapsulated, slowly expanding, muscle hematoma. Haemophilic pseudotumour is a rare complication of haemophilia which occurs, as a condition either from repeated spontaneous bleeding or coming from a traumatic origin, in 1-2% of haemophilic patients. CASE REPORT: A 32-year-old man with severe haemophilia A referred to our Clinic with a massive right iliac wing pseudotumour complicated by Staphylococcus aureus superinfection and skin fistulisation. In this report we describe the medical management and surgical treatment by the adoption of a novel surgical technique which involves the use of a pedicle-screw and rod system (PSRS), a polyglycolic acid MESH and bone cement in order to build up an artificial ilium-like bony mass. This case report highlights the importance of interdisciplinary approach and the efficacy of eradicating surgery as treatment, especially in the case of large and long-lasting lesions.

Pulsed Electromagnetic Fields in Bone Healing: Molecular Pathways and Clinical Applications.

In this article, we provide an extensive review of the recent literature of the signaling pathways modulated by Pulsed Electromagnetic Fields (PEMFs) and PEMFs clinical application. A review of the literature was performed on two medical electronic databases (PubMed and Embase) from 3 to 5 March 2021. Three authors performed the evaluation of the studies and the data extraction. All studies for this review were selected following these inclusion criteria: studies written in English, studies available in full text and studies published in peer-reviewed journal. Molecular biology, identifying cell membrane receptors and pathways involved in bone healing, and studying PEMFs target of action are giving a solid basis for clinical applications of PEMFs. However, further biology studies and clinical trials with clear and standardized parameters (intensity, frequency, dose, duration, type of coil) are required to clarify the precise dose-response relationship and to understand the real applications in clinical practice of PEMFs.

Do standards of care and early outcomes of periprosthetic fractures change during the COVID-19 pandemic? A multicentre study.

BACKGROUND: Periprosthetic fractures (PPFs) are a growing matter for orthopaedic surgeons, and patients with PPFs may represent a frail target in the case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The purpose of this study is to investigate whether hospital reorganisations during the most severe phase of the SARS-CoV-2 pandemic affected standards of care and early outcomes of patients treated for PPFs in Northern Italy. MATERIALS AND METHODS: Data were retrieved from a multicentre retrospective orthopaedics and traumatology database, including 14 hospitals. The following parameters were studied: demographics, results of nasopharyngeal swabs, prevalence of coronavirus disease 2019 (COVID-19), comorbidities, general health status (EQ-5D-5L Score), frailty (Clinical Frailty Scale, CFS), pain (visual analogue scale, VAS), anaesthesiologic risk (American Society of Anaesthesiology Score, ASA Score), classification (unified classification system, UCS), type of operation and anaesthesia, in-hospital and early complications (Clavien-Dindo Classification, CDC), and length of stay (LOS). Data were analysed by means of descriptive statistics. Out of 1390 patients treated for any reason, 38 PPFs were included. RESULTS: Median age was 81 years (range 70-96 years). Twenty-three patients (60.5%) were swabbed on admission, and two of them (5.3%) tested positive; in three patients (7.9%), the diagnosis of COVID-19 was established on a clinical and radiological basis. Two more patients tested positive post-operatively, and one of them died due to COVID-19. Thirty-three patients (86.8%) presented a proximal femoral PPF. Median ASA Score was 3 (range, 1-4), median VAS score on admission was 3 (range, 0-6), median CFS was 4 (range, 1-8), median EQ-5D-5L Score was 3 in each one of the categories (range, 1-5). Twenty-three patients (60.5%) developed post-operative complications, and median CDC grade was 3 (range, 1-5). The median LOS was 12.8 days (range 2-36 days), and 21 patients (55.3%) were discharged home. CONCLUSIONS: The incidence of PPFs did not seem to change during the lockdown. Patients were mainly elderly with comorbidities, and complications were frequently recorded post-operatively. Despite the difficult period for the healthcare system, hospitals were able to provide effective conventional surgical treatments for PPFs, which were not negatively influenced by the reorganisation. Continued efforts are required to optimise the treatment of these frail patients in the period of the pandemic, minimising the risk of contamination, and to limit the incidence of PPFs in the future. LEVEL OF EVIDENCE: IV.

Operating procedures for electrochemotherapy in bone metastases: Results from a multicenter prospective study on 102 patients.

INTRODUCTION: Bone metastases are frequent in patients with cancer. Electrochemotherapy (ECT) is a minimally invasive treatment. Preclinical and clinical studies supported the use of ECT in patients with metastatic bone disease (MBD). The purposes of this multicentre study are to confirm the safety and efficacy of ECT, and to identify appropriate operating procedures in different MBD conditions. MATERIALS AND METHODS: 102 patients were treated in 11 Centres and recorded in the REINBONE registry (a shared database protected by security passwords): clinical and radiological information, ECT session, adverse events, response, quality of life indicators and duration of follow-up were registered. RESULTS: 105 ECT sessions were performed (one ECT session in 99 patients, two ECT sessions in 3 patients). 24 patients (23.5%) received a programmed intramedullary nail after ECT, during the same surgical procedure. Mean follow-up was 5.9 ± 5.1 months (range 1.5-52). The response to treatment by RECIST criteria was 40.4% objective responses, 50.6% stable disease and 9% progressive disease. According to PERCIST criteria the response was: 31.4% OR; 51.7% SD, 16.9% PD with no significant differences between the 2 criteria. Diagnosis of breast cancer and ECOG values 0-1 were significantly associated to objective response. A significant decrease in pain intensity and significant better quality of life was observed after ECT session at follow-up. CONCLUSION: The results are encouraging on pain and tumour local control. ECT proved to be an effective and safe treatment for MBD and it should be considered as an alternative treatment as well as in combination with radiation therapy.

Association between preoperative evaluation with lung ultrasound and outcome in frail elderly patients undergoing orthopedic surgery for hip fractures: study protocol for an Italian multicenter observational prospective study (LUSHIP).

BACKGROUND: Hip fracture is one of the most common orthopedic causes of hospital admission in frail elderly patients. Hip fracture fixation in this class of patients is considered a high-risk procedure. Preoperative physical examination, plasma natriuretic peptide levels (BNP, Pro-BNP), and cardiovascular scoring systems (ASA-PS, RCRI, NSQIP-MICA) have all been demonstrated to underestimate the risk of postoperative complications. We designed a prospective multicenter observational study to assess whether preoperative lung ultrasound examination can predict better postoperative events thanks to the additional information they provide in the form of "indirect" and "direct" cardiac and pulmonary lung ultrasound signs. METHODS: LUSHIP is an Italian multicenter prospective observational study. Patients will be recruited on a nation-wide scale in the 12 participating centers. Patients aged > 65 years undergoing spinal anesthesia for hip fracture fixation will be enrolled. A lung ultrasound score (LUS) will be generated based on the examination of six areas of each lung and ascribing to each area one of the four recognized aeration patterns-each of which is assigned a subscore of 0, 1, 2, or 3. Thus, the total score will have the potential to range from a minimum of 0 to a maximum of 36. The association between 30-day postoperative complications of cardiac and/or pulmonary origin and the overall mortality will be studied. Considering the fact that cardiac complications in patients undergoing hip surgery occur in approx. 30% of cases, to achieve 80% statistical power, we will need a sample size of 877 patients considering a relative risk of 1.5. CONCLUSIONS: Lung ultrasound (LU), as a tool within the anesthesiologist's armamentarium, is becoming increasingly widespread, and its use in the preoperative setting is also starting to become more common. Should the study demonstrate the ability of LU to predict postoperative cardiac and pulmonary complications in hip fracture patients, a randomized clinical trial will be designed with the scope of improving patient outcome. Trial registration ClinicalTrials.gov, NCT04074876. Registered on August 30, 2019.

Early mortality in hip fracture patients admitted during first wave of the COVID-19 pandemic in Northern Italy: a multicentre study.

BACKGROUND: Treatment of hip fractures during the coronavirus disease 2019 (COVID-19) pandemic has posed unique challenges for the management of COVID-19-infected patients and the maintenance of standards of care. The primary endpoint of this study is to compare the mortality rate at 1 month after surgery in symptomatic COVID-positive patients with that of asymptomatic patients. A secondary endpoint of the study is to evaluate, in the two groups of patients, mortality at 1 month on the basis of type of fracture and type of surgical treatment. MATERIALS AND METHODS: For this retrospective multicentre study, we reviewed the medical records of patients hospitalised for proximal femur fracture at 14 hospitals in Northern Italy. Two groups were formed: COVID-19-positive patients (C+ group) presented symptoms, had a positive swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and received treatment for COVID-19; COVID-19-negative patients (C- group) were asymptomatic and tested negative for SARS-CoV-2. The two groups were compared for differences in time to surgery, survival rate and complications rate. The follow-up period was 1 month. RESULTS: Of the 1390 patients admitted for acute care for any reason, 477 had a proximal femur fracture; 53 were C+ but only 12/53 were diagnosed as such at admission. The mean age was > 80 years, and the mean American Society of Anesthesiologists (ASA) score was 3 in both groups. There was no substantial difference in time to surgery (on average, 2.3 days for the C+ group and 2.8 for the C- group). As expected, a higher mortality rate was recorded for the C+ group but not associated with the type of hip fracture or treatment. No correlation was found between early treatment (< 48 h to surgery) and better outcome in the C+ group. CONCLUSIONS: Hip fracture in COVID-19-positive patients accounted for 11% of the total. On average, the time to surgery was > 48 h, which reflects the difficulty of maintaining normal workflow during a medical emergency such as the present pandemic and notwithstanding the suspension of non-urgent procedures. Hip fracture was associated with a higher 30-day mortality rate in COVID-19-positive patients than in COVID-19-negative patients. This fact should be considered when communicating with patients and/or their family. Our data suggest no substantial difference in hip fracture management between patients with or without COVID-19 infection. In this sample, the COVID-19-positive patients were generally asymptomatic at admission; therefore, routine screening is recommended. LEVEL OF EVIDENCE: Therapeutic study, level 4.

Modular tapered conical revision stem in hip revision surgery: mid- term results.

BACKGROUND: The aim of this paper is to evaluate the clinical and radiological outcomes of a fluted tapered modular distal-fixation stem at medium to long-term follow-up. The hypothesis of this investigation was to verify if the use of this implant design may have provided potential advantages in femoral revisions and post-traumatic instances where the restoration of the anatomy was the prime concern. METHODS: We retrospectively reviewed 62 cases of femoral revision surgeries, performed in Paprosky type IIIA and IIIB bone defects between January 2001 and December 2011 with a mean follow-up of 8.5 ± 1.5 years (range 5.1-15.9 years) where a modular fluted stem was used. The clinical assessment was performed with the Harris Hip Score (HHS), and the radiographic evaluation was carried in order to assess the stability of the femoral component. Intra-operative and postoperative complications were recorded, and the rates of complications and revisions for any cause were determined. RESULTS: Mean HHS improved 35.4 points from the preoperative assessment. Radiographic evaluation showed a stable stem anchorage in 90.3% of the cases at the last follow-up. Five (8%) implants required additional surgery. Neither breakage of the stem nor loosening of the taper junction were recorded. Kaplan-Meier survivorship was 89.4% (CI: 88.8-90%) for any complication and 92.3% (CI: 91.8-92.7%) according to revision for any causes at 81 months follow-up. CONCLUSIONS: Our findings suggest that this stem design is a reliable option in cases of complex femoral bone defects, as well as in cases with high functional deficiencies, with promising survivorship.

Unique immunological profile in patients with COVID-19.

The relationship between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host immunity is poorly understood. We performed an extensive analysis of immune responses in 32 patients with severe COVID-19, some of whom succumbed. A control population of healthy subjects was included. Patients with COVID-19 had an altered distribution of peripheral blood lymphocytes, with an increased proportion of mature natural killer (NK) cells and low T-cell numbers. NK cells and CD8+ T cells overexpressed T-cell immunoglobulin and mucin domain-3 (TIM-3) and CD69. NK cell exhaustion was attested by increased frequencies of programmed cell death protein 1 (PD-1) positive cells and reduced frequencies of natural killer group 2 member D (NKG2D)-, DNAX accessory molecule-1 (DNAM-1)- and sialic acid-binding Ig-like lectin 7 (Siglec-7)-expressing NK cells, associated with a reduced ability to secrete interferon (IFN)γ. Patients with poor outcome showed a contraction of immature CD56bright and an expansion of mature CD57+ FcεRIγneg adaptive NK cells compared to survivors. Increased serum levels of IL-6 were also more frequently identified in deceased patients compared to survivors. Of note, monocytes secreted abundant quantities of IL-6, IL-8, and IL-1ß which persisted at lower levels several weeks after recovery with concomitant normalization of CD69, PD-1 and TIM-3 expression and restoration of CD8+ T cell numbers. A hyperactivated/exhausted immune response dominate in severe SARS-CoV-2 infection, probably driven by an uncontrolled secretion of inflammatory cytokines by monocytes. These findings unveil a unique immunological profile in COVID-19 patients that will help to design effective stage-specific treatments for this potentially deadly disease.

Osteogenic potential of human adipose derived stem cells (hASCs) seeded on titanium trabecular spinal cages.

Spine degenerative conditions are becoming increasingly prevalent, affecting about 5.7% of the population in Europe, resulting in a significant reduction of life's quality. Up to now, many materials have been used in manufacturing cage implants, used as graft substitutes, to achieve immediate and long-term spinal fixation. Particularly, titanium and its alloys are emerging as valuable candidates to develop new types of cages. The aim of this in vitro study was to evaluate the adhesion, proliferation and osteogenic differentiation of adipose derived mesenchymal stem cells (ASCs) seeded on trabecular titanium cages. ASCs adhered, proliferated and produced an abundant extracellular matrix during the 3 weeks of culture. In the presence of osteogenic medium, ASCs differentiated into osteoblast-like cells: the expression of typical bone genes, as well as the alkaline phosphatase activity, was statistically higher than in controls. Furthermore, the dispersive spectrometry microanalysis showed a marked increase of calcium level in cells grown in osteogenic medium. Plus, our preliminary data about osteoinduction suggest that this titanium implant has the potential to induce the ASCs to produce a secretome able to trigger a shift in the ASCs phenotype, possibly towards the osteogenic differentiation, as illustrated by the qRT-PCR and ALP biochemical assay results. The trabecular porous organization of these cages is rather similar to the cancellous bone structure, thus allowing the bone matrix to colonize it efficiently; for these reasons we can conclude that the architecture of this cage may play a role in modulating the osteoinductive capabilities of the implant, thus encouraging its engagement in in vivo studies for the treatment of spinal deformities and diseases.

Ten-year outcomes of a nitrided Ti-6Al-4V titanium alloy fixed-bearing total knee replacement with a highly crosslinked polyethylene-bearing in patients with metal allergy.

BACKGROUND: Metal hypersensitivity in patients with a total knee arthroplasty (TKA) is a rare condition and a very controversial topic. Despite the lack of data concerning the real effective impact of allergy on TKA failures, most of the manufactures offer the choice of 'non-allergenic' implants both for primary and revision TKA, some of which provide the same designs and surgical techniques as the conventional ones. Only a few studies are available on outcomes on these 'hypersensitivity-friendly' implants and even fewer specifically on allergic patients with a mid- to long-term follow-up. METHODS: Between 2007 and 2015, we enrolled 72 patients (57 females, 15 males), who underwent TKA treated with a non-allergenic posterior-stabilized (PS) total knee implant for a declared and proven metal allergy. Patients were followed clinically and radiographically for a mean 10 years of follow-up. RESULTS: With revision as an endpoint the Kaplan-Meier survival estimate showed a survival rate of 97.2% at five years and 95.1% at 10 years. Significant improvements in range of motion (ROM), Knee Society Scoring (KSS) and Hospital for Special Surgery (HSS) knee scores were registered at final follow-up (P < 0.0001). At final follow-up validated Patient-Reported Outcome Measures (PROMs) showed the following scores: Oxford Knee Score (OKS) 42.1, EQ5D 0.80, EQ VAS 80.1, Forgotten Joint Score 71.2. CONCLUSIONS: This nitrided Ti-6Al-4V titanium alloy fixed-bearing total knee replacement with a highly crosslinked polyethylene-bearing showed interesting results and survival rates in patients with metal allergy at mid- to long-term follow-up.

Innovative therapies for malignant brain tumors: the road to a tailored cure.

BACKGROUND: Immune tolerance, immune escape, neoangiogenesis, phenotypic changes, and glioma stem cells are all responsible for the resistance of malignant brain tumors to current therapies and persistent recurrence. The present study provides a panoramic view of innovative therapies for malignant brain tumors, especially glioblastoma, aimed at achieving a tailored approach. METHODS: PubMed/Medline and ClinicalTrials.gov were the main sources of an extensive literature review in which "Regenerative Medicine," "Cell-Based Therapy," "Chemotherapy," "Vaccine," "Cell Engineering," "Immunotherapy, Active," "Immunotherapy, Adoptive," "Stem Cells," "Gene Therapy," "Target Therapy," "Brain Cancer," "Glioblastoma," and "Malignant Brain Tumor" were the search terms. Only articles in English published in the last 5 years were included. A further selection was made according to the quality of the studies and level of evidence. RESULTS: Cell-based and targeted therapies represent the newest frontiers of brain cancer treatment. Active and adoptive immunotherapies, stem cell therapies, and gene therapies represent a tremendous evolution in recent years due to many preclinical and clinical studies. Clinical trials have validated the effectiveness of antibody-based immunotherapies, including an in-depth study of bevacizumab, in combination with standard of care. Preclinical data highlights the role of vaccines, stem cells, and gene therapies to prevent recurrence. CONCLUSION: Monoclonal antibodies strengthen the first-line therapy for high grade gliomas. Vaccines, engineered cells, stem cells, and gene and targeted therapies are good candidates for second-line treatment of both newly diagnosed and recurrent gliomas. Further data are necessary to validate this tailored approach at the bedside.

Gene therapies for high-grade gliomas: from the bench to the bedside.

BACKGROUND: Gene therapy is the most attractive therapeutic approach against high-grade gliomas (HGGs). This is because of its theoretical capability to rework gene makeup in order to yield oncolytic effects. However, some factors still limit the upgrade of these therapies at a clinical level of evidence. We report an overview of glioblastoma gene therapies, mainly focused on the rationale, classification, advances and translational challenges. METHODS: An extensive review of the online literature on gene therapy for HGGs was carried out. The PubMed/MEDLINE and ClinicalTrials.gov websites were the main sources. Articles in English published in the last five years were sorted according to the best match with the multiple relevant keywords chosen. A descriptive analysis of the clinical trials was also reported. RESULTS: A total of 85 articles and 45 clinical trials were selected. The main types of gene therapies are the suicide gene, tumor suppressor gene, immunomodulatory gene and oncolytic therapies (virotherapies). The transfer of genetic material entails replication-deficient and replication-competent oncolytic viruses and nanoparticles, such as liposomes and cationic polymers, each of them having advantages and drawbacks. Forty-eight clinical trials were collected, mostly phase I/II. CONCLUSION: Gene therapies constitute a promising approach against HGGs. The selection of new and more effective target genes, the implementation of gene-delivery vectors capable of greater and safer spreading capacity, and the optimization of the administration routes constitute the main translational challenges of this approach.

The impact of stem cells in neuro-oncology: applications, evidence, limitations and challenges.

BACKGROUND: Stem cells (SCs) represent a recent and attractive therapeutic option for neuro-oncology, as well as for treating degenerative, ischemic and traumatic pathologies of the central nervous system. This is mainly because of their homing capacity, which makes them capable of reaching the inaccessible SC niches of the tumor, therefore, acting as living drugs. The target of the study is a comprehensive overview of the SC-based therapies in neuro-oncology, also highlighting the current translational challenges of this type of approach. METHODS: An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites, restricting it to the most pertinent keywords regarding the systematization of the SCs and their therapeutic use for malignant brain tumors. A large part of the search was dedicated to clinical trials. Only preclinical and clinical data belonging to the last 5 years were shortlisted. A further sorting was implemented based on the best match and relevance. RESULTS: The results consisted in 96 relevant articles and 31 trials. Systematization involves a distinction between human embryonic, fetal and adult, but also totipotent, pluripotent or multipotent SCs. Mesenchymal and neuronal SCs were the most studied for neuro-oncological illnesses. 30% and 50% of the trials were phase I and II, respectively. CONCLUSION: Mesenchymal and neuronal SCs are ideal candidates for SCs-based therapy of malignant brain tumors. The spectrum of their possible applications is vast and is mainly based on the homing capacity toward the tumor microenvironment. Availability, delivery route, oncogenicity and ethical issues are the main translational challenges concerning the use of SCs in neuro-oncology.

Adoptive immunotherapies in neuro-oncology: classification, recent advances, and translational challenges.

BACKGROUND: Adoptive immunotherapies are among the pillars of ongoing biological breakthroughs in neuro-oncology, as their potential applications are tremendously wide. The present literature review comprehensively classified adoptive immunotherapies in neuro-oncology, provides an update, and overviews the main translational challenges of this approach. METHODS: The PubMed/MEDLINE platform, Medical Subject Heading (MeSH) database, and ClinicalTrials.gov website were the sources. The MeSH terms "Immunotherapy, Adoptive," "Cell- and Tissue-Based Therapy," "Tissue Engineering," and "Cell Engineering" were combined with "Central Nervous System," and "Brain." "Brain tumors" and "adoptive immunotherapy" were used for a further unrestricted search. Only articles published in the last 5 years were selected and further sorted based on the best match and relevance. The search terms "Central Nervous System Tumor," "Malignant Brain Tumor," "Brain Cancer," "Brain Neoplasms," and "Brain Tumor" were used on the ClinicalTrials.gov website. RESULTS: A total of 79 relevant articles and 16 trials were selected. T therapies include chimeric antigen receptor T (CAR T) cell therapy and T cell receptor (TCR) transgenic therapy. Natural killer (NK) cell-based therapies are another approach; combinations are also possible. Trials in phase 1 and 2 comprised 69% and 31% of the studies, respectively, 8 of which were concluded. CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) was demonstrated to reduce the recurrence rate of glioblastoma after standard-of-care treatment. CONCLUSION: Adoptive immunotherapies can be classified as T, NK, and NKT cell-based. CAR T cell therapy redirected against EGFRvIII has been shown to be the most promising treatment for glioblastoma. Overcoming immune tolerance and immune escape are the main translational challenges in the near future of neuro-oncology.