To investigate the clinical characteristics, surgical experience, and surgical outcomes of external auditory canal cholesteatoma (EACC) surgery under endoscopic otolaryngoscopy.  A retrospective analysis of 85 EACC cases admitted to the Department of Otolaryngology, Renji Hospital, Shanghai Jiaotong University School of Medicine, from January 2016 to February 2021 was performed, followed by retrospective analysis of clinical data to explore the feasibility and clinical characteristics of all-oral endoscopic EACC surgery. A total of 85 EACC patients (90 ears) with a mean age of 49.93 ± 14.87 years were included in the study. According to Udayabhanu staging, 43 ears (47.78%) were stage I, 40 ears (44.44%) were stage II, and 7 ears (7.78%) were stage III. All patients underwent transendoscopic surgery.  79 ears (87.78%) underwent endoscopic EACC resection alone , 9 ears (10%) underwent endoscopic EACC resection+tympanostomy+tympanoplasty, 1 ear (1.11%) underwent endoscopic EACC resection+tympanoplasty, and 2 ears (2.22%) underwent EACC resection+otolaryngotomy+tympanoplasty+auditory chain reconstruction endoscopically. Of these, 7 ears (7.78%) underwent auricular cartilage-chondroplasty and 2 ears (2.22%) underwent auricular cartilage membrane repair. All patients were reviewed at 1 week, 2 weeks, 1 month, 3 months, 6 months, and 1 year postoperatively. One patient with stage II external auditory atresia had a recurrence after 6 months and underwent endoscopic ear surgery (ESS) again. One patient with stage 2 atresia recurred after 1 year and again underwent endoscopic ear surgery. The rest of the patients recovered well after the surgery, and the grafts healed well.  EACC surgery through the external ear canal under a dedicated endoscope is a safe, reliable, and effective method. Patients with stage I and II external auditory canal cholesteatoma surgery under endoscopy have a rapid postoperative recovery with significant hearing improvement, and stage IIIA patients can also achieve good results under strict evaluation of indications. External auditory canal cholesteatoma (EACC) is a cystic mass of skin debris and cholesterol crystals that obstructs the external auditory canal and is not a true tumor with osteoplastic properties. It is an uncommon, benign disease of unclear etiology and pathogenesis. EACC has been reported as a result of external ear canal trauma, chronic inflammation, narrowing of the ear canal, or spontaneous occurrence , 2. PatiThe initial presentation of EACC relies on simple examinations such as frontoscopy and endoscopy, which do not reveal the full extent of the disease , 8. HighThe principles of treatment for EACC are to completely remove the lesion, maintain normal structure and function, restore the normal epithelial migration ability of the external auditory canal, and maintain the integrity of the tympanic membrane and auditory chain as much as possible. The specific surgical approach should be determined by the extent of the lesion and the specific intraoperative situation. Shin's staging not only evaluates the preoperative site and extent of EACC invasion but also provides a basis for the operator to choose the appropriate surgical approach. Due to the physiological curvature of the external auditory canal or scar stenosis, some relatively hidden lesions  are not clearly identified during microscopic surgery, and there are certain blind spots in the field of view. In contrast, microscopic surgery, in order to remove the hidden lesions present in a wide range of lesions and to preserve important structures, is inevitably achieved at the cost of destroying more bony structures; however, this cost, although we now have many reconstruction methods to repair the relevant structures, is still fraught with difficulties, and the repair does not guarantee the integrity of the original anatomical structures , 14.Based on this, this paper retrospectively analyzed 85 cases of EACC admitted to the Department of Otolaryngology, School of Otolaryngology, Shanghai Jiao Tong University, from January 2016 to February 2021, followed by a retrospective analysis of clinical data to investigate the feasibility and clinical characteristics of total oral endoscopic EACC surgery. A total of 85 EACC patients (90 ears) with a mean age of 49.93 ± 14.87 years were included in the study. According to Udayabhanu staging, 43 ears (47.78%) were stage I, 40 ears (44.44%) were stage II, and 7 ears (7.78%) were stage III. All patients underwent transendoscopic surgery, to explore the different stages of endoscopic otolaryngoscopy surgical approach and efficacy of EACC.General data of cases: a total of 85 (90 ears) EACC cases were included in this study. There were 31 males and 54 females, aged 14-93 years, with age of 50 ± 15 years. The distribution was more concentrated in the two age groups of 14~33 years and 53~71 years. The disease course ranged from 1 week to 30 years, with an average of 31 ± 13 months. Among them, 80 had monaural disease and 5 had binaural disease. 52 ears were left and 38 ears were right. 83 ears (92%) were acquired primary and 7 ears (8%) were secondary. It was secondary to an external auditory canal mass in 2 ears, secondary to external auditory canal atresia in 1 ear, and secondary to radiotherapy for nasopharyngeal carcinoma in 4 ears. The chief complaints were ear stuffiness in 54 patients, earache in 48 patients, hearing loss in 55 patients, tinnitus in 12 patients, ear discharge in 15 patients, ear bleeding in 5 patients, ear itching in 6 patients, and mouth opening pain in 4 patients. None of the patients had vertigo or facial paralysis. 53 patients had experienced one or more external auditory canal irrigations in the outpatient clinic. Otoendoscopy showed granulation in the external auditory canal in 17 cases and a mass in the external auditory canal in 2 cases. All patients underwent middle ear and mastoid CT, and 29 patients (32 ears) underwent pure tone threshold audiometry before surgery. Hearing subjects were normal in 5 ears, conductive deafness in 10 ears, mixed deafness in 12 ears, and sensorineural deafness in 5 ears.The same skilled otosurgeon performed all the procedures on the study subjects. The hospital medical ethics committee has approved this clinical study, and all patients and their families have given informed consent and signed the informed consent form.(1) Medical history is consistent with the clinical presentation of external auditory cholesteatoma. (2) Age is 18-60 years. (3) There is no previous history of otitis media surgery. (4) On examination, visual or endoscopic examination showed white, gray, or brown soft tissue masses and granules in the external auditory canal. (5) On ancillary examination, high-resolution CT of the temporal bone showed soft tissue masses in the external auditory canal with or without destruction of the external auditory canal wall and/or mastoid, destruction of the tympanic chamber, and destruction of the bone wall mainly in the external auditory canal. (6) On audiometry, pure tone audiometry showed conductive deafness or mixed deafness. (7) Pathological diagnosis is external auditory canal cholesteatoma.Exclusion criteria are as follows: (1) significant narrowing and malformation of the external auditory canal; (2) benign and malignant tumors and tuberculosis of the external auditory canal; (3) mental disorders, cognitive and consciousness disorders; (4) serious underlying diseases with poor control ; (5) pregnant or preparing for pregnancy, lactating; and (6) unable to cooperate with the evaluation.All patients underwent otoendoscopy, CT of the middle ear and mastoid, and otoendoscopic surgical treatment. According to the extent of lesion invasion in EACC, Udayabhanu staging was adopted . Stage IAll patients underwent ESS under local or general anesthesia. Among them, 64 patients (67 ears) underwent local anesthesia surgery  and 21 patients (23 ears) underwent general anesthesia surgery . Intraoperative diagnosis combined with CT and intraoperative findings showed destruction of the bone wall of the external auditory canal in 47 ears (40 ears in stage II and 7 ears in stage IIIA). Among them, 31 had destruction of the posterior wall of the ear, 28 had destruction of the inferior wall of the ear, 26 had destruction of the anterior wall of the ear, and 19 had destruction of the parietal wall of the ear. There were 19 ears with annular destruction of the bone wall of the external auditory canal, 29 ears with thin invagination of the tympanic membrane, 10 ears with perforation of the tympanic membrane, and 4 ears with destruction of the ossicular chain. It involved the horizontal and vertical segments of the facial nerve canal in 1 ear, the temporomandibular joint in 5 ears, and the mastoid process in 1 ear. 74 ears underwent exclusively otoendoscopic resection of EACC, 2 ears underwent otoendoscopic resection of EACC+resection of external auditory canal mass, 3 ears underwent otoendoscopic resection of EACC+tympanoplasty, 9 ears underwent otoendoscopic resection of EACC+tympanoplasty+tympanoplasty, 1 ear underwent otoendoscopic resection of EACC+tympanoplasty, and 2 ears underwent otoendoscopic resection of EACC+atticotomy+tympanoplasty+ossicular chain reconstruction .Among them, 7 ears were repaired with tragus cartilage-perichondrium and 2 ears were repaired with tragus perichondrium.Local anesthesia and preoperative preparation: patients with local block anesthesia of the external auditory canal combined with external auditory canal mass underwent tumor resectionExploration and resection of cholesteatoma: for impacted significant cholesteatoma, the volume was first reduced from the center of the lesion and then the dissection was performed between the cholesteatoma capsule and the external auditory canal skin until the pocket was completely removedThorough cleaning of the epithelium: sequential cleaning of the epithelium at the “pit” of bone destruction, the epithelium around the tympanic ring, and the epithelium and granulation on the surface of the tympanic membrane. The tympanic membrane was checked for integrity. There was pinpoint perforation or small perforation of the tympanic membrane with exudation, and preoperative CT showed no significant abnormality of the tympanum, which was not repaired at the same time. Tympanic exploration was performed while moderate or large perforation of the tympanic membrane or preoperative CT revealed tympanic soft tissue shadowsExploration of the tympanum: an external auditory canal skin tympanic membrane flap was done and the exploration tympanum was lifted. If there was cholesteatoma epithelium in the tympanic cavity, incision and exploration of the lateral wall of the attic were performed. If the ossicular chain is interrupted/destroyed, the corresponding reconstruction is performed. For patients with attic incision, the tragus cartilage-perichondrium was used to repair the residual tympanic membrane, while for patients with tympanic membrane perforation, the tragus perichondrium was used to repair the residual tympanic membraneReconstruction of the ossicular chain: there was ossicular chain destruction for corresponding artificial ossicular chain reconstructionAll patients in this study had no statistical differences in general data indicators such as age of onset, side, and gender and were balanced and comparable, and the clinical characteristics are shown in Udayabhanu proposed the following staging criteria for EACC: stage I lesions are limited to the external auditory canal without bone destruction, stage II lesions are those with bone destruction with or without middle ear involvement but without the involvement of adjacent structures , stage IIIA lesions are those with bone destruction and involvement of adjacent structures without complications, and stage IIIB lesions are those with a combination of other complications . Unlike The clinical incidence of EACC is low, and the first diagnosis in the outpatient clinic is less confirmed. In this study, 53 patients (62%) experienced at least one outpatient irrigation treatment with impacted cerumen as the first diagnosis, which may be related to cerumen accumulation on the keratinocyte surface in some patients with cholesteatoma. The maximum number of rinses was 5, which may be related to insufficient experience in diagnosis and treatment in lower community hospitals. Given the different incidence ratio between men and women, reports vary in the literature. There were 31 males (36%) and 54 females (64%) in this study. Both the age of onset and the course of the disease present a polarization. There were more adolescent patients and elderly patients and more patients with disease duration of less than 1 month and more than 10 years. It may be due to the narrower external auditory canal in younger patients and decreased epithelial migration and poor hygiene in older patients. 45 (53%) patients had an onset time of no more than 1 month and were mostly accompanied by ear stuffy ear pain, which was associated with acute infection or periostitis of the external auditory canal caused after irrigation stimulation. Nine (11%) patients had an onset time of more than 10 years, which was considered to be related to the fact that the patients did not return after anti-infective treatment in the acute phase and their willingness to seek treatment decreased. Acquired primary in 83 ears (92%), secondary in 7 ears (8%), secondary to external auditory canal mass in 2 ears, secondary to external auditory canal atresia in 1 ear, and secondary to nasopharyngeal carcinoma after radiotherapy in 4 ears. The relationship between a history of radiotherapy for NPC and the incidence of EACC has rarely been mentioned in previous literature. In fact, we found that EACC patients with a history of radiotherapy for nasopharyngeal carcinoma were mostly associated with secretory otitis media, which was associated with radiation damage to the cilia of the middle ear mucosal epithelium and decreased self-cleaning ability of the external auditory canal skin; see CT of EACC showed soft tissue shadows in the external auditory canal with/without bone destruction, with/without middle ear involvement. It has been reported in the literature that its growth direction shows an “inward roll” property characterized by outside-in, which is distinguished from inside-out of middle ear cholesteatoma. EACC may involve the attic and tympanic sinuses inward or the mastoid posteriorly. In this study, the posterior wall was the most destroyed in statistics, which is more consistent with literature reports.There are two main directions of external auditory canal cholesteatoma invasion. The tympanic membrane is compressed inward, resulting in thin, invaginated, loss of elasticity, and even perforation of the tympanic membrane. If some patients have repeated irrigation or coinfection, it can also cause acute inflammation or even perforation of the tympanic membrane. In this study, 10 ears (12%) had perforation. The cholesteatoma epithelium enters the attic and tympanic sinuses through perforation and destroys structures such as the ossicular chain, which can involve the horizontal segment of the facial nerve canal. The other is the mastoid posteriorly, involving the vertical segment of facial nerve canal; see For middle ear cholesteatoma, the facial nerve is most commonly involved in the horizontal and conical segments. For EACC, the most commonly affected facial nerve is the vertical segment, as it can invade the mastoid process. Four ears had secretory otitis media in this study. After EACC destroys the external auditory canal, the wall will block the mastoid air cells, poor drainage causes mastoid effusion, and nasopharyngeal carcinoma radiotherapy complicated by secretory otitis media is much common. Endoscopic surgery does not involve bone grinding in the mastoid region and cannot expose the entire course of the facial nerve canal, so endoscopic surgery should pay attention to avoid injury in patients with EACC involving the mastoid process, especially those with bone destruction in the mastoid segment of the facial nerve canal suggested by preoperative CT.64 patients  were operated on with local anesthesia. 21 patients  were operated on with general anesthesia. In this study, we found that stage I and II can be completely operated with local anesthesia, while some stage II and IIIA patients involving attic chiseling were recommended for general anesthesia surgery. For patients with external auditory canal cholesteatoma, the effect of local block anesthesia of the external auditory canal was inferior to that of tympanic membrane repair under local anesthesia because they have experienced repeated ear canal irrigation, combined otitis externa, and external auditory canal periostitis in the outpatient clinic. Most of the patients with tympanic membrane repair under local anesthesia had no pain. In external auditory canal cholesteatoma surgery under local anesthesia, about 20% of patients complain of pain during surgery, which was mostly tolerable. Only one 91-year-old female patient complained of intolerable ear pain. For such patients, in addition to local block anesthesia of the external auditory canal, local block anesthesia of the posterior auricular sulcus and temporomandibular joint fossa can be added, and attention should be paid to the direction and depth of needle insertion to implement injection to avoid causing transient facial paralysis [In stage I patients with EACC, otoendoscopic resection of external auditory canal cholesteatoma was performed, and those with external auditory canal tumors also underwent resection of external auditory canal tumors. Patients with EACC stage II and secretory otitis media underwent otoendoscopic resection of external auditory canal cholesteatoma+tympanic membrane. There are not many reports on this in the previous literature, considering that the patients with personal history of nasopharyngeal carcinoma in this study were caused by decreased epithelial self-cleaning ability due to radiotherapy. For patients with EACC stage II~III, otoendoscopic resection of external auditory canal cholesteatoma+tympanic exploration+tympanoplasty (+ossicular chain reconstruction) was performed.In EACC stage III, even if mastoid was involved, most were cholesteatoma invasion and obstructive inflammation. Mastoid inflammation can improve spontaneously after thorough epithelial cleaning and unobstructed drainage. Not many cases of this have been reported. There are a large number of domestic reports on EACC , especiaThere were a total of 2 patients with recurrence in this study.One of the patients with recurrence had atresia of the external auditory canal, and the first operation was performed under otoendoscope to chisel the atretic bone, clean the external auditory canal and tympanic cholesteatoma epithelium, and perform tympanoplasty. The patient's own ear canal was narrow and recurred again after surgery; thus, epithelial debridement under local anesthesia was performed. The principle of surgical treatment of EACC is complete removal of the lesion, followed by reconstruction of the external auditory canal structure to restore epithelial self-cleaning ability. Patients with recurrent cholesteatoma in the literature are mostly associated with external auditory canal stenosis or atresia, and microscopic external auditory meatoplasty is recommended. If some narrow lesions of the external auditory canal are present for more than 1/2 week, external auditory canal skin grafting is considered . TherefoFor stage I and II EACC patients with invasion of the external auditory canal bone and tympanic membrane, endoscopic surgery is the best choice, and with the increasing use of endoscopy in middle ear surgery, it has the advantages of aesthetics, faster postoperative recovery, smaller visual field blindness, and more direct surgical access compared to traditional microsurgery with posterior or internal ear incisions . In the In conclusion, patients with stage I and II external auditory canal cholesteatoma recovered quickly after endoscopic surgery and had significantly improved hearing, and the air-bone conduction difference was significantly reduced or disappeared, while stage IIIA patients could also achieve good results under strict evaluation of indications, but should be prepared to change microscopic surgery at any time. However, the sample size of this study was small, a more comprehensive understanding of the use of endoscopy in patients with stage III external auditory canal cholesteatoma is lacking, and a larger sample is needed to evaluate the effectiveness of staged treatment.Although it is a nongenuine tumor, it is biologically aggressive, easily destroying bone and eroding adjacent structures. The preoperative imaging  is an important clinical guide for otologists to assess the extent of lesion destruction, diagnose EACC, guide clinical staging, and select the appropriate surgical approach. Patients with stage I and II EACC can be completely managed endoscopically, and most patients can even tolerate local anesthesia, and patients with disrupted auditory chain can undergo simultaneous or two-stage reconstruction. Some stage IIIA EACC patients can be operated endoscopically and require simultaneous tympanoplasty+tympanoplasty (+auditory chain reconstruction). Some stage IIIA and IIIB cases require microscopic management or combined surgery with laparoscopy. ESS has limitations in cases with external auditory canal stenosis, and microscopic external auditory meatoplasty is recommended.


Novel therapeutic modalities using medical devices have the potential to deliver effective treatment against the most aggressive form of primary brain tumour, Glioblastoma, for which there is currently no cure. These devices not only offer methods to enhance the effect of currently available therapies but also aim to provide innovative ways to deliver better therapeutic outcomes for this deadly disease. This review highlights recent innovations in this promising, growing field, and is intended to serve as a primer for clinicians, engineers and scientists interested in translating such technologies for the improvement of patient outcomes.Despite decades of research and the growing emergence of new treatment modalities, Glioblastoma (GBM) frustratingly remains an incurable brain cancer with largely stagnant 5-year survival outcomes of around 5%. Historically, a significant challenge has been the effective delivery of anti-cancer treatment. This review aims to summarize key innovations in the field of medical devices, developed either to improve the delivery of existing treatments, for example that of chemo-radiotherapy, or provide novel treatments using devices, such as sonodynamic therapy, thermotherapy and electric field therapy. It will highlight current as well as emerging device technologies, non-invasive versus invasive approaches, and by doing so provide a detailed summary of evidence from clinical studies and trials undertaken to date. Potential limitations and current challenges are discussed whilst also highlighting the exciting potential of this developing field. It is hoped that this review will serve as a useful primer for clinicians, scientists, and engineers in the field, united by a shared goal to translate medical device innovations to help improve treatment outcomes for patients with this devastating disease. Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumour, accounting for more than 60% of all brain tumours in adults . The gloThe aggressiveness of GBM is characterized by its extensive tumour infiltration, microvascular proliferation, and high genomic instability. Histological characteristics of GBM include marked hypercellularity, microvascular proliferation and necrosis with pseudo-palisading features . The hypThe current standard of care for GBM includes surgery, followed by radiotherapy and chemotherapy . There iThis review aims to provide a comprehensive overview of the clinical applications of current and emerging medical devices that directly deliver or augment therapy for GBM. Notably, we recognize that there have been recent advances in the development of intra-operative technologies to improve resection outcomes, such as the use of fluorescence guided resection . and hanBroadly, therapeutic medical devices can be classed into two categories (1) Medical devices used to enhance current therapeutic modalities and (2) Medical devices that deliver novel therapeutic modality against tumour cells . We shalMedical devices that enhance current therapeutic strategies mainly work by disrupting/circumventing the BBB, such as convection-enhanced delivery (CED) and ultrasound-mediated BBB opening (BBBO) aim to deliver higher therapeutic drug concentrations in the brain and minimizing off-target adverse toxicity associated with systemic drug delivery  28]. . 28]. The BBB is a protective barrier composed of a continuous layer of endothelial cells connected by tight junctions that separates the systemic circulation from central nervous system (CNS) tissues . It playDelivery of therapeutic agents into the brain to treat GBM has been an ongoing challenge for many years due to the presence of the BBB, which greatly limits the entry of therapeutics into the brain parenchyma . CED is Since its inception, CED has been explored clinically with the use of a variety of therapeutic candidates and here we review noteworthy clinical trials using different agents including chemotherapeutic agents, viral vectors, and monoclonal antibodies .In 2020 Wang et al., reported the first clinical trial that demonstrate the feasibility and safety of CED of carboplatin in 10 patients with recurrent high-grade gliomas . The autLikewise in the same year Upadhyayula et al., reported a long term follow up from a single institutional experience of a Phase 1B clinical trial investigating the use of Topotecan (TPT) CED in 10 GBM and 6 anaplastic astrocytoma patients ,47. TheyOncolytic viruses have emerged as a novel therapeutic approach to GBM treatment, which utilizes native or genetically modified viruses that selectively replicate within tumour cells . In 2014In a recent study, van Putten et al., demonstrated the safety of Delta24-RGD (DNX-2401) administered by CED in a phase 1 trial on 20 patients with recurrent GBM . Delta-2Antibody therapies are also being explored for CED applications such as OS2966, which is a humanized and de-immunized monoclonal antibody that targets the CD29/β1integrin, which is highly expressed in GBM and implicated in several hallmarks of cancer including growth, proliferation, invasion, angiogenesis, and drug resistance ,55. OS29Nwagwu et al., have proposed the first in-human clinical trial investigating the use of CED to deliver OS2966 to treat high-grade gliomas . Prior tOverall, clinical studies have demonstrated the feasibility and favorable safety profile of CED. However, there are various challenges that need to be addressed before CED can fully realize its therapeutic potential. From a technical perspective, it is important to determine the type and design of catheter to optimize delivery, reduce infusate reflux, and achieve accurate catheter placement . From a One of the most promising technologies in recent years for BBBO is focused ultrasound (FUS) B. FUS deA non-invasive approach for BBBO is the ExAblate system, which is an extracorporeal fixed stereotactic frame-based MRI-guided device used to deliver FUS to the CNS. This transcranial system couples a hemispheric transducer array to MRI, enabling intraoperative imaging and real-time acoustic feedback determining the sonication parameters . The first clinical trial investigating BBBO using the ExAblate system in patients with malignant brain tumours was reported by Mainprize et al., in 2019 . They dePark et al., investigated the therapeutic effect of BBBD with the ExAblate system on GBM patients during standard adjuvant TMZ chemotherapy . They reOne practical limitation with the ExAblate system may be to do with the longevity of effect of FUS BBBD; whilst varying FUS parameters can generate a greater effect of BBBD, a study by Samiotaki and Konofagu found the maximum length of BBBD effect of their tested FUS parameters to be 72 hrs, with a mean of 8 hrs . Whilst SonoCloud is an implantable ultrasound device that can be inserted within the skull bone during surgical resection and can be repeatedly activated using a transcutaneous needle connection system prior to chemotherapy administration. The first phase 1/2a clinical trial using the SonoCloud technology was performed by Carpentier et al., in patients with recurrent GBM treated with intravenous carboplatin . The autp = 0.03), and 0.49 (p = 0.09) for survival. Therefore, this suggests a potentially greater efficacy of carboplatin when used in combination with ultrasound-induced disruption of the BBB. In a subsequent study, Idbaih et al., reported an increase in both median PFS and OS of 4.11 and 12.94 months, respectively, in GBM patients with BBBD, which is markedly higher than 2.73 months and 8.64 months in patients without BBBD ,70. The NaviFUS is a novel frameless device that involves the use of a neuronavigational system to steer in real-time the transcranial ultrasound energy precisely and repeatedly toward targeted CNS regions . NaviFUSIn 2021, Chen et al., reported the first-in-human, prospective, open-label, phase 1 clinical trial investigating the feasibility and safety of NaviFUS treatment in patients with recurrent GBM . The autThe effect of FUS technology on BBBO and its efficacy and safety upon chronic application is still in its early stages. This needs to be studied further in future clinical trials, with greater attention to optimisation of various parameters related to volume of BBBO achieved which could play a major role in diffuse tumours such as GBM, and the target drugs that are going to be used . Medical devices that deliver anti-tumour therapeutic modality can be classed into two categories based on the need for surgical intervention 1) Non-invasive medical devices—such as Sonodynamic therapies (SDT), Magnetic hyperthermia-mediated cancer therapy (MHCT), high-frequency focused ultrasound (HIFU) and Electric field therapy (EFT) and 2) Invasive medical devices- such as Carmustine wafers, brachytherapy, Laser interstitial thermal therapy (LITT), Photodynamic therapy (PDT) and implantable EFT.The following medical devices do not require surgical intervention to provide their treatment .Sonodynamic therapy (SDT) is an emerging modality for non-invasive treatment, which combines ultrasound with sonosensitizers to produce a localized cytotoxic effect via generation of reactive oxygen species  Figure A. SonoseAminolevulinic acid hydrochloride (5-ALA) is a precursor of protoporphyrin (PPIX), which selectively accumulates in and sensitizes malignant glioma cells. The compound itself is non-toxic but can induce apoptosis of cancer cells when activated by ultrasound waves . To dateOther than 5-ALA induced PPIX, fluorescein (FL) is another sonosensitizer that is used for SDT. It is a biosafe xanthene dye with fluorescent properties, selective accumulation in brain lesions, and rapid washing out from vessels and healthy tissues ,81. ThesA significant step forward has been made in 2021 by Raspagliesi et al., who reported the first intracranial MRI-guided SDT with FL and 5-ALA induced PPIX in a large animal model using the ExAblate system . The porWhile clinical evidence of SDT in treatment of gliomas remains limited, two clinical trials are currently underway to investigate the use of intravenous 5-ALA (NCT 04559685) and oral 5-ALA (NCT 04845919) in combination with FUS in GBM patients [Magnetic hyperthermia therapy (MHT) builds upon the principles of localized HT where temperature in a local region of the body is elevated above baseline by involving injection of magnetic nanoparticles (MNP) into the tumour and subsequent application of an alternating magnetic field (AMF), resulting in an increased intratumoural temperature and thermal ablation of tumour cells B. MagForce Nanotechnologies  has developed a MHT system, NanoTherm, which consists of an aqueous deposition of superparamagnetic iron oxide nanoparticles (SPIONs) with an iron concentration of 112 mg/mL. These biocompatible nanoparticles are injected directly into the tumour site and are subsequently exposed to an alternating magnetic field to generate heat for ablation of tumour cells. The treatment area of the AMF applicator (NanoActivator) has a diameter of 20 cm, a magnetic field strength of up to 18 kA/m, and a field frequency of 100 kHz . NanoTheSeveral clinical trials have demonstrated the efficacy and safety of intratumoural thermotherapy using aminosilane-coated SPIONs (NanoTherm) in GBM patients. In a phase 1 study, Maier-Hauff et al., demonstrated the feasibility of thermotherapy using MNP in 14 patients with recurrent GBM . SPIONs In a subsequent phase 2 study, the authors investigated the combination of MNP and external bean radiotherapy in 59 recurrent glioblastoma (rGBM) patients . The AMFMore recently, Grauer et al., investigated the tolerability and efficacy of the intracavitary thermotherapy using SPIONs combined with radiotherapy in 6 rGBM patients . The autMagForce has reported that one course of NanoTherm costs roughly €23,000 per patient. However, there are no studies in the literature examining its cost-effectiveness due to a lack of efficacy data, making direct comparisons of NanoTherm to other medical device treatments impossible . Moving forward, it is imperative to optimize MHT parameters, including ensuring accurate intratumoural heating and precise temperature control at the tumour site as well as minimize perifocal oedema. One practical consideration in the use of MNP may be their potential to generate interference in MRI imaging; if the particles persist within region of the tumour resection cavity, MRI artefacts generated by the very large difference in magnetic susceptibility between tissue and the MNPs would likely obscure large volumes of the surrounding tissue (including the tumour resection margins) on imaging. If MHT were to be used to treat newly diagnosed GBM, clinicians may be concerned that such interference could limit their ability to detect and monitor tumour recurrence and thereby impact decision making in ongoing patient care. In the event of a truly efficacious MHT therapy, such a practical consideration is likely to be forgiven. However, if survival outcomes for MHT are only equivalent to other emerging treatment modalities, it may factor into the decision making of clinicians over which therapy to pursue. 2) through the skull, which can increase tissue temperature up to approximately 65 °C, thereby inducing precise thermal ablation at target tumour sites with minimal effect on surrounding tissues [High-intensity focused ultrasound (HIFU) is a therapy where under MRI guidance a stereotactic device is used to distribute high intensity energy  thermal ablation . They shIn 2010, McDannold et al., reported on a Phase 1 clinical trial in 3 GBM patients, which demonstrated for the first time that ultrasound beams can be focused noninvasively through the intact skull and heating was visualized using real time MR temperature imaging (ExAblate 3000 system) . The patIn a more recent study, Coluccia et al., reported brain tumour ablation with transcranial MR-guided FUS in a 63-year-old patient with centrally located recurrent GBM . ThermalOverall, HIFU appears to be a promising technology for brain tumour ablation. However, as the clinical experience of HIFU is currently limited to small case series, further clinical trials are required to evaluate the safety and efficacy of HIFU for thermal ablation of brain tumours. Currently, two trials (NCT01473485 and NCT00147056) are underway on 10 patients each, looking at the safety and feasibility of MRgHIFU thermal ablation using the ExAblate transcranial system with results expected at the end of 2022 which hopefully will provide further insight regarding the feasibility of HIFU. Potential drawbacks of the ExAblate system on patient through-flow in MRI suites discussed previously would also apply here.EFT, variously also known as Tumour Treatment Fields (TTF) or Intratumoural Modulation Therapy (IMT), is a recent treatment modality that has shown efficacy both in preclinical studies and clinical trials of GBM patients  98,99,1,102,103.EFT has received widespread attention due to its remarkable ability to specifically influence the fate of proliferating cells, whilst leaving non proliferating cells unaffected. Although the exact mechanism by which EFT exerts anti-tumour effects is not fully understood, an anti-mitotic effect has been proposed whereby they are thought to alter the tumour cell polarity, ultimately disrupting normal polarization and depolarization of mitotic spindle microtubules, causing dielectrophoretic dislocation of intracellular macromolecules and organelles during cytokinesis. This leads to miotic and cell membrane disruption and ultimately to apoptosis ,105,108.To date, a single EFT device, Optune , has received regulatory approval for the treatment of supratentorial GBM in adults aged 22 or over ,104. IniOptune consists of a portable electric field generator, carried in a backpack or satchel, connected via cables to non-invasive insulated transducer arrays affixed to the scalp. Alternating electrical fields at frequency of 200kHz are passed sequentially between paired sets of these transducer arrays on opposite sides of the head to generate an electrical field intensity of at least 1V/cm throughout the tumour to the supratentorial brain regions with a recommended treatment duration of 18 h per day. Parameters including intensity of the electric field and frequency are pre-set and are software controlled . n = 120) with recurrent GBM tumours compared to physicians’ choice chemotherapy alone (n = 117). Findings revealed no significant difference in OS or PFS in patients receiving EFT vs. chemotherapy. Therefore, it was concluded that using EFT was just as effective as using chemotherapy in recurrent GBM treatment, but with fewer side effects and overall improvement of quality of life [Clinical trials have demonstrated the safety and efficacy of Optune in the treatment of GBM. The first pilot trial (EF-07) began in 2004 using the Novo-TTF-100a system (forerunner to Optune) in 10 patients with recurrent GBM and the effectiveness of the treatment was compared to recurrent GBM historical controls. This was the inaugural instance of EFT being used as a strategy to treat GBM . These f of life . Based o of life . n = 466) vs. TMZ alone (n = 229) in newly diagnosed GBM (ndGBM) patients [p < 0.001) and OS was 20.9 months vs. 16.0 months (p < 0.001). The 5-year survival rate for patients receiving EFT plus TMZ was 13% vs. 5% for TMZ alone (p < 0.001). One of the major limitations of the conclusion of the EF-14 trial may be that only patients that were progression free at the completion of chemoradiation were enrolled in the study, thereby removing the poor prognosis patients from the study [Subsequently, a multicenter randomized phase 3 clinical trial (EF-14) assessed the efficacy of Optune plus adjuvant TMZ (patients . All pathe study . Questiohe study . An aspen = 7) of patients undergoing Optune therapy, Olubajo et al., reported disruption of daily activities including showering, cooking, going out in the rain and sleep [In the EF-14 trial, systemic adverse events were commonly related to chemotherapy use and were mostly absent in the EFT arm, suggesting the safety of electrical fields as a treatment modality . The mosnd sleep . These lnd sleep . Following EF-14′s positive results, FDA approval was achieved for concomitant use of chemotherapy and EFT for ndGBM patients. Despite this, the adoption of Optune within the neuro-oncology community has been somewhat limited—in the first full year (2016) following its FDA approval for ndGBM, Optune received 2344 prescriptions in North America (predominantly the USA), by 2018 this had quickly grown to 3741 patients (~15% of new GBM cases in the USA). Optune has since received national reimbursement in Japan, Israel, Sweden and Germany . HoweverDue to the entirely novel nature of EFT as a treatment modality, there are many outstanding questions regarding how its clinical application can be optimised. At the forefront of these is limited understanding of the possible synergistic effects between EFT and other treatment modalities, including Chemo-/Radio- therapy and some of the other technologies discussed in this review. An initial pilot trial demonstrated the safety and efficacy of the concurrent use of EFT, TMZ and radiotherapy in patients with ndGBM . This haAnother area that requires investigation in order to optimise the efficacy of EFT is in dosing compliance; strong correlation between dose of EFT delivered and OS has been suggested by the EF-14 trial data, with patients receiving >22 h of daily EFT presenting a median OS of 28.7 months and 5 years survival rate of 29.3% . This suOne hypothesis would be that all other factors being equal, the greatest survival benefit of EFT would be achieved through continuous 24-h a day treatment. However, the external design of Optune makes achieving 24-h therapy in a significant number of patients unlikely due to the need to daily affix electrodes, regular head shaving along with other considerations in patient lives such as bathing. One approach to address this issue would be through an implantable EFT device, which would theoretically enable continuous therapy whilst also bypassing the possible patient quality of life impacts of skin irritation and the conspicuous design of Optune.The following medical devices require a minor or major surgical intervention to provide treatment and usually require the placement within the tumour bulk, or in the cavity left after surgical intervention .Intracranially implanted local chemotherapy using alkylating agent Carmustine -1-nitrosurea (BCNU)), have been approved by FDA for recurrent high grade gliomas since 1996 and for new high grade gliomas since 2003 . GLIADELSince its first use in the late 1990’s, various clinical trials have been carried out using Gliadel wafers for both ndGBMs and recurrent GBM. Westphal et al., in a phase 3 trial with BCNU wafers on high grade glioma (HGG) patients demonstrated an improved OS (13.9 vs. 11.6 months) with no change in PFS, when compared to placebo treated control . A propensity matched French multicentre study by Pallud et al., in 2015, demonstrated that carmustine wafers implantation in combination with SOC demonstrated both an improved median PFS (12 vs. 10 months) and median OS (20.4 vs. 18 months) when compared to standard group . Carmustine wafers have different reported costs in various markets. In the UK, carmustine wafers were assessed for recommendation by the National Institute for Health and Care Excellence (NICE) for use in the National Health Service (NHS). The assessment by NICE priced carmustine wafers at £6105 for 8 wafers, plus the additional cost of managing potential adverse effects whilst determining that the addition-al QALY  was equal to 0.107 (5.6 weeks). This placed the final ICER  value at £57,000 per QALY. NICE deemed carmustine wafers to lack evidence of cost-effectiveness, as the cost per QALY was far higher than its typical £30,000 per QALY threshold . However, complications arising from these wafers have been a hindrance in their uptake and use within the clinical setting A study by Bregy et al., using data from 19 studies on 795 BCNU wafer patients reported a mean OS of 16.2 months and a staggering complication rate of 42.7%, prompting them to recommend not using the agent . FurtherCurrently, the mainstay of GBM therapy is a multimodal strategy of surgical resection followed by administration of adjuvant radiotherapy 4–8 weeks after the initial surgery ,136. AltBrachytherapy, the implantation of interstitial radioactive isotopes in close proximity to the target tissue, has emerged as an attractive treatment option in this context, as it can be performed intraoperatively directly after tumour resection, allowing irradiation to begin immediately. In recent years, cesium-131 (131Cs) has emerged as a promising isotope for brachytherapy for GBM ,143,144.Several studies over the past few years have evaluated 131Cs brachytherapy tiles for the treatment of brain cancers ,71,72. TMore recently, a permanently implantable device consisting of 131Cs radiation emitting seeds embedded within a resorbable collagen-based carrier tile  has received FDA clearance to treat brain tumours. As a form of surgically targeted radiation therapy (STaRT), GammaTile (GT) delivers a large dose of radiation to the tumour bed upon implantation, while sparing the surrounding tissue. Each tile measures 2 cm × 2 cm × 0.4 cm and contains four 131Cs radioactive seeds with a half-life of 9.7 days and photon energy of 30.4 KeV . The lowGessler et al., reported the first clinical series of the use of GT in treatment of recurrent GBM patients since its FDA clearance in late 2018 . The stuAnother study by Budnick et al., involving seven patients with recurrent gliomas (2/7 with rGBM) reported that none of the enrolled patients have shown signs of radiation necrosis on surveillance imaging whilst receiving adequate radiation coverage , therebyHowever, there are some practical limitations to GT. It has been found that tumour cells more than 5–8 mm distant to the resection cavity where GT is implanted are less likely to benefit from this therapy , which rLaser interstitial thermal therapy (LITT) is a novel thermal ablation treatment which uses a stereotactically guided laser-tip probe to deliver controlled thermal energy to tumour bulk. Real-time magnetic resonance imaging (MRI) thermometry is also used for continuous monitoring of the ablation zone . This prThe first clinical trials of LITT on GBM patients were performed in 1994, which demonstrated a decrease of total lesion size (15–87%), highlighting the feasibility of LITT for the treatment of brain tumours . CurrentSeveral studies have demonstrated the feasibility and safety of LITT in the treatment of patients with both ndGBM and rGBM. In 2013, the first-in-human Phase 1 study using NeuroBlate to assess the safety and efficacy of LITT in rGBM at 3 thermal dose levels was published . The medn = 9) had complete resolution of deficits and 7.1% (n = 1) had partial resolution of symptoms within 1 month, 14.3% (n = 2) had not had resolution of deficits at the most recent follow-up, and 14.3% (n = 2) died as a result of progression without resolution of deficits. For the 10 patients who had resolution of deficits, the authors found that their neurological symptoms were caused by the postoperative edema in the ablation bed, which resolved with steroids. In the 2 patients who died, 1 lesion was relatively large and the other was located within the midbrain and pons. Rapid development of malignant edema in both patients caused the global neurological decline. This shows that LITT, although minimally invasive, should be used with caution as thermal damage to critical and eloquent structures can lead to serious complications. In a recent study, Kamath et al., reported a median OS of 11.5 months and median PFS of 6.6 months following LITT treatment of 54 patients with GBM (41 of whom has recurrent disease) who were not candidates for open surgical resection [In a subsequent study, Patel et al., reported their single-center experience of 102 patients with a variety of intracranial tumours, the largest series to date . The autesection . They weesection ,170,171.esection . The autBeaumont et al., demonstrated that treatment with LITT in 15 patients with GBM of the corpus callosum achieved a PFS and survival post-LITT (SPL) of 3.4 and 7.2 months, respectively, and OS of 18.2 months . This is3. Notably, a considerable number of post-LITT complications in large tumours have been reported, including malignant oedema, and increased intracranial pressure, necessitating urgent craniectomy and debulking of the tumour [Many studies have suggested that LITT is best suited for tumours with diameters less than 3 cm, which corresponds to a tumour volume of approximately 14.1 cme tumour ,174. Nevertheless, these studies have altogether shown that LITT is a feasible and minimally invasive treatment for GBM and can be used as an alternative in patients in whom aggressive surgery is not an option. As LITT is becoming part of the neurosurgical armamentarium, it is important to consider the benefits and risks of this technology. The risks of LITT can be placed in 2 main categories: (1) laser insertion, in which haemorrhage is a known complication, and (2) thermal ablation, which could result in unintended thermal damage to surrounding structures, and is particularly problematic for ablation targets that lie close to critical neural structures . We hopeThere are also several benefits to LITT. Aside from the minimal invasiveness of the approach, real-time monitoring of both thermal distribution and damage allows for a high degree of therapy control . CompareHowever, the current literature consists mainly of pilot trials, phase 1 trials and retrospective analysis. Larger prospective series are required to evaluate the efficacy of this technique. Efforts are also currently underway to standardize and optimize the LITT procedure as well as to identify patient populations and tumour characteristics (location and volume) that would benefit most from this minimally invasive approach. Photodynamic therapy (PDT) is a treatment modality that works through photoactivation of a light sensitive dye—photosensitizer (PS) that is incorporated into neoplastic cells. Once a photosensitizer accumulates within neoplastic cells, in the presence of oxygen, it can be excited by photo-irradiation using visible light of appropriate wavelength, which causes the PS to convert molecular oxygen into either a singlet state or triplet state ,178,179.The use of PDT as a therapeutic option against cancer dates to late 1970s with report on the effect of Hematoporphyrin derivative (HPD) plus light on bladder carcinoma . The firInterstitial PDT (iPDT)—This is a minimally invasive procedure and performed on patients whose tumours are present in eloquent areas or on fragile patients who cannot undergo a craniotomy and (2) Intracavitary PDT—Brain tumours that can undergo complete or partial resection, PDT can be performed within the tumour cavity at the end of the surgical procedure  rocedure D.Interstitial PDT—The use of iPDT within glioma patients is usually performed via placement of multiple optical fibers with a diffuser within tumours using stereotactic coordinates [rdinates . Multiplrdinates . One of rdinates . Howeverrdinates .To achieve optimal therapeutic effect of PDT, ‘advanced photobleaching’ of the PS is necessary. By definition, advanced photobleaching is achieved when ≥95% of PS undergoes photobleaching. To this end advanced dosimetric modelling of PS used should therefore be taken into consideration before and during surgical planning. A recent systematic review by Leroy H-A et al., on the use of iPDT against GBM over the last 3 decades demonstrates that overall the technique was safe and effective . The stuThe median progression-free survival (PFS) was 14.5 months for de novo GBM and 14 months for recurrent GBM. The overall survival (OS) was 19 months for de novo GBM and 8 months for recurrent GBM. The discrepancy between PFS and OS for rGBM was due to the heterogeneity between the studies and not all studies reporting PFS and OS . A recent single-center retrospective study on the use of iPDT as a salvage treatment for local recurrent malignant gliomas demonstrated promising outcomes with a time-to-treatment failure of 7.1 months and with a 2- and 5-year post-recurrence survival at 25% and 4.5%, respectively, . Althoug3 and (e) Strong tumour PPIX uptake [The systematic review by Leroy H-A et al., did point to specific criteria for prolonged survival (>2 years): (a) Preoperative Karnofsky PS > 70, (b) Complete response on early brain imaging (c) Well limited/spherical lesion (d) Tumour volume <5 cmX uptake .3, with Kaneko et al., determining that a tumour volume of less than 5 cm3 was required to achieve complete response without persistent neurological deficits [3, in which 41% (5 out of 12) of GBM patients developed permanent neurological deficit [Of all these criteria, tumour volume is an extremely important factor in determining not only efficacy but also safety of iPDT. The median tumour volume from the 12 studies were found to be 12 cmdeficits ,189. Lar deficit . Intracavitary PDT—Intracavitary PDT or post resection PDT is performed after the maximal safe tumour resection has been undertaken in the operating room or in the post-operative recovery room. Cavitary PDT is usually performed by placing a balloon filled with diffusing liquid within the resection cavity with an external light source within it. The balloon is inflated to conform to the resection cavity thereby diffusing the light to all margins of the tumour resection cavity [n cavity . 2 at the balloon wall ensured the deposition of at least 25 J/cm2, which had been determined to be an optimal dose in preclinical studies [A pilot feasibility and safety study by Vermandel et al.,  on 10 ndGBM patients was conducted in 2018 (NCT 03048240). Patients underwent maximal tumour resection guided by 5-ALA Fluorescence Guided Surgery (FGS) followed by intraoperative PDT. Postoperatively patients underwent adjuvant therapy (Stupp protocol). The interim analysis showed an actuarial 12-months progression-free survival (PFS) rate of 60% (median 17.1 months), and the actuarial 12-months OS rate was 80% (median 23.1 months). They also noted that a dose deposit of 200 J/cm studies . No unac studies ,192. When applying PDT outside the operating room, a balloon diffuser is placed in the resection cavity and filled with a radio-opaque lipid emulsion until the cavity is filled. The PDT is then applied in the recovery room for a total of 5 treatments (one per day), after which the balloon diffuser is deflated and removed in the recovery room. 2 applied per session) for 5 days during the post-operative period. The control arm underwent FGS for tumour resection without PDT. The mean survival of patients in the PDT and surgery only groups was 52.8 weeks and 24.2 weeks, respectively (p < 0.001) [Eljamel et al., conducted a single-center, randomized controlled phase III trial to evaluate porfimer sodium mediated PDT after 5-ALA FGS for ndGBMs. In the study, 13 patients underwent FGS followed by intracavitary placement of a balloon diffuser to provide repetitive PDT  ,193. Various complications related to PDT have been reported over the years. The majority of them relate to the PS and the systemic administration of it. Although this varies depending on the type of PS used, one of the most common risks related to all PS is that of retinal and cutaneous photosensitivity. This photosensitivity can last from several days to a few weeks depending on the PS used and during this time exposure to direct sunlight is harmful to the patient . Apart fAlthough various studies have pointed towards favorable outcomes when using PDT (both iPDT and intracavitary PDT), there remains a large dearth in concrete data on the length of the outcome. The lack of large RCT’s with a dedicated PS and dosing regimen as well as towards a standard control group makes interpretation difficult ,184.TM as described above, has shown convincing survival benefit compared to SOC, through a series of sequential, large randomized controlled trials over the past decade in recurrent and ndGBM. Of the treatment modalities reviewed, it has demonstrated the biggest gain in survival metrics for GBM patients, with a 5-year survival of 13% compared to 3% in patients treated with SOC [External EFT in the form of Optunewith SOC . DespiteAn implanted approach may be able to overcome the limitations of the current device especially relating to issues of dosing compliance and potential quality of life concerns. It is also likely to provide significant advantages in terms of delivering the therapy directly to where it is needed to enable better local disease control E. Pre-clGenerally, modern medicine trends toward the use of minimally invasive therapy over the use of implantable medical devices admittedly due to the risks associated with surgical procedures. However, surgical resection very much remains a key component of the standard of care for GBM and delivering an implant during an existing cytoreductive surgical procedure may mitigate such concerns. There will of course be patients who will be unable to undergo surgical resection due to tumour location, age, or comorbidity, for which such a strategy may not be possible. In which case externally applied EFT therapy or approaches such as LITT remain viable alternatives following SOC treatment. Despite the promise of these studies and the potential benefits of an implantable EFT approach, considerable technical challenges remain to be solved to enable this form of therapy to be translated clinically. These include how to generate sufficient coverage of an effective electrical field through the tumour volume/surrounding brain, how to power an implantable system and how to implant a system safely surgically. Proposed solutions to some of these design challenges have included using ultrasound to power a stimulator  or usingDespite decades of research to improve patient outcomes, GBM remains a challenging disease to treat. Its molecular and cellular heterogeneity, critical location, and the BBB are critical constraints which limit the efficacy of current treatment options. In recent years, a range of novel device technologies have exhibited significant potential for the treatment of this aggressive cancer. While promising, many of these studies are limited by low enrolment numbers, limited follow-up, and potentially confounded by varying adjuvant therapies. Therefore, additional studies are necessary to investigate efficacy, establish optimal patient selection criteria, standardized surgical technique and treatment parameters of many of these technologies. More knowledge of the toxicity profiles, long-term stability, and safety data of these novel therapies are also necessary before widespread adoption by the clinical community is likely to occur.For many of these devices, a greater understanding of the structure, physiology, and barrier properties of the BBB will allow optimisation of these device technologies in order to enhance the delivery of anticancer therapeutics. In conjunction, careful patient selection by clinicians will be key. For example, highly vascularized tumours might benefit more from FUS, as this technique requires systemic administration of microbubbles and drugs. Furthermore, FUS was found to suppress efflux transporters, which could potentially increase the accumulation of anticancer drugs within tumour tissue . In contEFT has arguably shown the most promise to date of all the technologies highlighted in this review, with regard to increasing the OS of patients with this deadly disease. Nevertheless, ongoing studies to further understand the underlying mechanisms of EFT, particularly when used in conjunction with various emerging pharmacotherapies could help establish it as a key component in the standard of care patients receive . PotentiFinally, with the concurrent emergence of various medical device technologies as highlighted in this review, there may soon come a point in time where clinicians and healthcare payers will be faced with a difficult choice between various novel technologies, all of which have study outcomes reporting efficacy to varying degrees. It is therefore important going forward that a concerted and considered effort is made to undertake studies which attempt to identify what might be the best technology to use in combination with SOC as well as importantly, emerging molecular and immune-mediated therapies. Furthermore, stratifying future study patients in line with the recently updated 2021 WHO classifications which add further weight to the molecular underpinnings of disease such as isocitrate dehydrogenase (IDH) status, will be equally important [


Cognitive decline, the primary clinical phenotype of Alzheimer’s disease (AD), is currently attributed mainly to amyloid and tau protein deposits. However, a growing body of evidence is converging on brain lipids, and blood–brain barrier (BBB) dysfunction, as crucial players involved in AD development. The critical role of lipids metabolism in the brain and its vascular barrier, and its constant modifications particularly throughout AD development, warrants investigation of brain lipid metabolism as a high value therapeutic target. Yet, there is limited knowledge on the biochemical and structural roles of lipids in BBB functionality in AD. Within this framework, we hypothesize that the ApoE4 genotype, strongly linked to AD risk and progression, may be related to altered fatty acids composition in the BBB. Interestingly, alpha linolenic acid (ALA), the precursor of the majoritarian brain component docosahexaenoic acid (DHA), emerges as a potential novel brain savior, acting via BBB functional improvements, and this may be primarily relevant to ApoE4 carriers. Transport of lipids to the brain is mediated by the major facilitator superfamily domain containing 2A (Mfsd2a) lining the BBB .The BBB is a selective interphase between systemic blood and brain parenchyma with brain endothelial cells as its principal cellular component. Its structural and functional stability is critical to keep a healthy brain. The brain blood capillaries are different from peripheral blood vessels due to the presence of tight junctions, lack of fenestrations, high number of mitochondria, restricted endocytosis and presence of unique transporters . PericytThe capillaries in brain provide the largest endothelial surface for molecular interchange between blood and brain . Even thGrowing evidence points to brain DHA reduced levels ,32 in phNeuroimaging studies in individuals with early AD as well as histological images of postmortem tissue have shown BBB breakdown in different brain areas . IncreasEssential fatty acids (EFA) LA and ALA are precursors of the important brain components arachidonic acid  and DHA (n-3), respectively, through processes of desaturation and elongation. The genes encoding the enzymes involved in those pathways are highly expressed in liver and brain ,43. ImpoAA has been shown to have neurotoxic effects . AA is aDHA is notoriously decreased in the AD human brain , and so The essential ALA n-3 and LA n-6 FA, source of the metabolic PUFA DHA and AA, respectively, come from the diet. The brain is highly enriched in long-chain DHA and AA as structural components of neuronal membranes. These FA are precursors of lipid-derived prostaglandins and resolvins. When derived from DHA, they contribute to reverse inflammatory and other neurodegenerative processes . Neural The conversion of essential ALA and LA to PUFA occurs via the same elongase and Δ6 desaturase enzymes in the metabolic pathway. Higher ALA levels usually overcome the LA substrate competition, allowing for the production of higher n-3 than n-6 PUFA metabolites . ImportaDHA supplementation has shown inconclusive results of both positive and negative effects related to BBB integrity  and imprSaturated FA conversion into MUFA is regulated by ∆9 desaturase activity (SCD1 gene). Curiously, MUFA have been found, in some studies, to be elevated in AD patients brain, and to correlate with cognitive impairment, although the underlying mechanisms beyond this association are unknown . Our recIn addition to the peripheral hepatic EFA metabolism and consequent brain transport, astrocytes have been suggested to be the central neural system providers of PUFA ,65. SurpThe early detection of AD-related brain lipid changes should be considered as a critical point related to the role of nutritional lipids in the prevention/restoration of the BBB during AD development. Based on our previous studies in C57Bl6/J mice , early aDue to the BBB inherent impermeability, brain and peripheral cholesterol synthesis are separated . Brain cApolipoprotein E4 (ApoE4) allele carriers are at increased risk to develop AD compared with those carrying the ApoE3 or E2 alleles . The ApoWe predict that the link between ApoE4 genotype and AD evolution towards cognitive decline emerges, at least for some extent, from the BBB deterioration due to altered nutritional and biochemical FA processes leading to ineffective brain lipid accretion though the BBB.The strong impact of ALA dietary enrichment on hepatic n-3 FA metabolism, may lead to restoration of DHA brain levels, by rescuing BBB disruption through membrane remodeling in brain endothelial cells. We envision that further research will unravel the mechanisms through which ALA enrichment improves BBB functionality, not only by repairing lipid transport, but also by enhancing brain ALA metabolism. In doing so, n-3 PUFA enrichment would comprise whole brain lipid homeostasis supporting restored cognitive functioning. This innovative concept opens the path for exciting prospects on ALA properties related to BBB in various brain diseases. Understanding the role and evolution of lipid modifications from early to old age, specifically in high risk ApoE4 carriers, would promote the discovery of novel nutritional strategies for the prevention, delay or restoration of cognitive decline.


This clinical review presents what is known about the antiviral features of humic substances (HS) to the benefit of the clinical healthcare provider using available data in humeomics, the study of the soil humeome. It provides the reader with a working framework of historical studies and includes clinically relevant data with the goal of providing a broad appreciation of the antiviral potential of humic substances while also preparing for a translational leap into the clinical application of humic acid. Inonotus obliquus), though this iteration contains almost no nitrogen in contrast to primary reservoirs of humic substances , though often without distinguishing between the relative contribution of humic acid versus fulvic acid to the net clinical effect , Herpes Simplex Virus Types 1 and 2 (HSV-1 and HSV-2), Epstein Barr Virus (EBV), Varicella Zoster Virus (VZV), Influenza A, Influenza B, Respiratory Syncytial Virus (RSV), human Cytomegalovirus (hCMV), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and other virus dynamics through an extracellular mechanism of action. Other studies have illuminated an intracellular antiviral contribution, particularly with HBV, HIV and influenza A  completed a comparative study that examined the relative antiviral activity of humic acid in vitro . The datin vitro research on humic substances. Though studies performed since 2002 have taken advantage of technological developments to provide more precise comparative data regarding the antiviral potential of humic substances, the NIH work is notable for its breadth of study, the quality of its data, and the lessons learned based on its conclusions. Subsequent work by others has verified specific conclusions of this study  studies that sought to validate the CPE data by quantifying the intensity of neutral red absorbed by surviving cells. In the final study, natural (and synthetic) humates that were regarded as active by CPE inhibition and confirmed by the NR assay were retested using the CPE method. These samples were then assessed for a reduction of virus yield (VY) relative to a positive control by assaying viral titers in the presence of susceptible cells. Development of CPE in the susceptible cell population was an indication of the presence of infectious virus and an ineffective natural humate.Contrary to the data generated for the Herpesviridae study summarized in The antiviral mechanism of humic acid is divided into a dominant extracellular component and a secondary cadre of intracellular mechanisms. In the extracellular framework, negatively charged carboxylated polyanions bind to positively charged viral envelop glycoproteins. Using HIV as a model, humic acid interacts with the positively charged V3 loop of the HIV-1 glycoprotein (gp120) or the glycoprotein 41 (gp41) complex . With SAin vitro to provide back door insight regarding humic acid’s mechanism(s) of action. In the absence of cytotoxicity, other rationales to explain the antiviral findings in vitro would advance to the forefront. Using a combination of toxicity and cell proliferation assays, the NIH’s 2002 study established that humic acid was not cytotoxic at levels at least as high as 100mcg/mL across a variety of cell lines  inhibits HBV-induced cell proliferation and autophagy via inhibition of HBx protein expression; (3) inhibits HBV DNA and HBsAg, and (4) inhibits HBV-induced autophagosome formation  during primary infection and (2) downstream of the replication cycle during viral shedding. Though the primary nexus for humic acid as an antiviral is extracellular, discreet observations have been reported for multiple intracellular activities. In studies evaluating Hepatits B virus, ormation . The infin vivo may be the subject of further study.In 2000, Lüscher-Mattli noted that in their capacity as antiviral agents, anionic polymers such as humic acid inhibit syncytium formation between HIV-infected and normal CD4 T lymphocytes, which mirrored Meerbach’s parallel observation for a selection of 12 synthetic phenolic polymers (polyhydroxycarboxylates) . Given fvia the suppression of tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX-2) expression in human monocyte culture is also potentially clinically relevant  and Krezel (2016) conclude that humic acid behaves as an ionophore to facilitate the intracellular transport of zinc ions, which relevant ; as is iecretion .in vitro into clinical practice has been slow to mature. In the wake of SARS-CoV-2, the need for adjuvant antiviral therapies that are oral, deployable, and indifferent to viral antigenic shift is relevant. Translating the in vitro antiviral characteristics of humic acid into clinical practice would add to the clinician’s toolbox and the dialog within public health circles.Humic substances have numerous potential clinical applications; however, the translation of what is known Pre-clinical studies have established two inflection points with humic substances. The first is that humic acid’s antiviral potential supersedes any contribution from fulvic acid, which in turn dwarfs the antiviral activity of shilajit. The second is that the translation of what is known regarding humic acid’s antiviral portfolio from pre-clinical studies to clinical application has been marred by concerns about efficacy, safety and tolerability.in vitro, humic acid needs to be isolated from its sister molecule, fulvic acid. In the absence of this purity, fulvic acid competitively inhibits the binding sites of the humic acid polyanion, rendering it less effective as an antiviral .Subsequent to this clinical review, clinical experience with a purified and further enhanced iteration of humic acid that has been used to mitigate SARS-CoV-2 infection will be presented in tandem with data regarding significant TNF-α suppression, CD4via a serum protein-humic substance aggregate, unremarkable data on protime (PT) and partial thromboplastin time (PTT) will also be presented and contrasted with expectations based on thromboelastography studies (The clinical data to be presented further intends to balance clinical experience with humic acid’s potential disadvantages as a source of heavy metal toxicity, mineral chelation, and pro-coagulant potential. The data yields that individuals using 500 mg of a purified and further enhanced humic acid iteration for a minimum of 6 months exhibit no abnormalities of serum lead levels or clinically abnormal levels of calcium, iron, magnesium or zinc. Further, regardless of humic acid’s potential influence on the coagulation cascade, specifically Factors IIa, VIIa and Xa  studies .in vitro studies have chronicled the broad-spectrum antiviral capacity of humic substances against enveloped RNA and DNA viruses while also acknowledging their relative indifference to viral antigenic shift, among other features. These same studies established that humic substances, or polyanionic carboxylates, inhibit viral fusion to target cell membrane receptors as their primary mode of action, though other intracellular and broader indirect influence on the immune system and host viral response have also been reported. This being said, the translation of this body of in vitro research into clinical practice has been underwhelming based on concerns about bioavailability, a short plasma half-life and side effects. Future presentations will share insight regarding the successful deployment of humic acid as an antiviral in clinical practice and the basis for the pivot from pre-clinical studies into clinical practice.Humic substances, including humic acid, have been the subject of scientific inquiry since the early 1930s . As a mo


Aerobic glycolysis is a metabolic mode of tumor cells different from normal cells that plays an important role in tumor proliferation and distant metastasis. Radiotherapy has now become a routine and effective treatment for many malignancies, however, resistance to radiotherapy remains a major challenge in the treatment of malignant tumors. Recent studies have found that the abnormal activity of the aerobic glycolysis process in tumor cells is most likely involved in regulating chemoresistance and radiation therapy resistance in malignant tumors. However, research on the functions and mechanisms of aerobic glycolysis in the molecular mechanisms of resistance to radiotherapy in malignant tumors is still in its early stages. This review collects recent studies on the effects of aerobic glycolysis and radiation therapy resistance in malignant tumors, to further understand the progress in this area. This research may more effectively guide the clinical development of more powerful treatment plans for radiation therapy resistant subtypes of cancer patients, and take an important step to improve the disease control rate of radiation therapy resistant subtypes of cancer patients. Professor Otto Warburg first demonstrated in 1927 that proliferating cancer cells can consume glucose to produce lactate even under aerobic conditions. This phenomenon is referred to as the Warburg effect or aerobic glycolysis . ResearcRadiation therapy is an important treatment modality for many cancers, and 50% of cancer patients achieve remission or are cured with radiation therapy . The maiThe literature cited in the text is based on the authors’ personal choice to reliably describe the methods described in the text. Searches were conducted in the Google Scholar, PubMed, and Wanfang databases to select appropriate references as examples. Different keywords that were appropriate for the search were used for each analyzed case. The final selection of references included studies on the relationship between the Warburg effect and resistance to radiotherapy in different malignancies.via mitochondrial pyruvate carriers (MPCs) or via monocarboxylate transporters (MCTs) after conversion to acetyl CoA; it undergoes oxidative phosphorylation through the tricarboxylic acid cycle and electron transport chain to generate ATP, specifically, 32–34 ATP for each glucose molecule  chain is encoded by the LDHA gene, and the H-type (heart) is encoded by the LDHB gene. Five isozymes, LDH1 to LDH5, can be produced by five different combinations of M and H chains. LDH-1 (H4) consists of four H subunits, while LDH-5 (M4) consists of four M subunits. LDH-2, LDH-3, and LDH-4 correspond to the MH3, M2H2, and M3H combinations respectively. The higher the number of M subunits in the LDH molecule, the stronger is its ability to catalyze the conversion of pyruvate to lactate. In contrast, H-dominant isozymes catalyze the reverse conversion of lactate to pyruvate . The mosvia DNA damage caused by the ionizing effect of radiation. A study of AT-101 monotherapy in 23 men with metastatic desmoplastic-resistant prostate cancer showed that a dose of 20 mg/day was well tolerated and resulted in more than 50% decrease in PSA in 9% of the patients , and then transported to the liver to be utilized as a substrate for gluconeogenesis or taken up by neighboring slow oxidizing fibers via MCT1 as a precursor to glucose to replenish energy stores. A similar mechanism has been observed in tumor cells  may induce or enhance resistance to radiation and may lead to chemoresistance (Ionizing radiation and some chemotherapeutic drugs kill cancer cells by inducing oxidative stress in target cells and stimulating the overproduction of ROS, thus leading to DNA and RNA damage, lipid peroxidation, and genomic instability. Moreover, ROS is necessary for the repair of radiation-induced DNA damage. sistance . A prospsistance . It has sistance . These fvia MCT4 and subsequently enters oxygen-rich cancer cells via MCT1, where it is used by cancer cells as an alternative feedstock for energy production (In vitro experiments on the treatment of oral squamous cell carcinoma cell lines with MCT1/MCT4 inhibitors combined with radiotherapy showed that the proliferation, migration, and cladogenesis of the cancer cells were significantly reduced; thus, these findings demonstrate that MCT1/MCT4 inhibitors and radiotherapy have a synergistic anti-tumor effect (Tumor survival is dependent on the shuttling of lactate between cells, and the transporters mediating this process are MCT1 and MCT4. Therefore, these two MCTs are potential targets for enhancing the efficacy of radiotherapy. MCT is a class of plasma membrane transporters that carry lactate and pyruvate across biological membranes during glycolysis. Tumors with a high degree of malignancy rely primarily on glycolytic processes for anabolic metabolism and, therefore, require MCT transporter proteins to transport lactate from cancer cells to the extracellular tumor microenvironment and protect tumor cells from acidosis induced by excessive lactate accumulation; these processes promote tumor progression by regulating various parameters in the tumor microenvironment, including cell invasion, angiogenesis, survival signaling, metastatic development, and evasion of immune surveillance . Accordioduction . Aerobicoduction . In vitrr effect . Furtherr effect . These fr effect .Taken together, the findings of the reviewed studies suggest that aerobic glycolysis has an important role in resistance to radiation therapy in malignant tumors. Specifically, the metabolic conversion of tumor cells by aerobic glycolysis to produce intermediates that increase cell growth and division is a very early oncogenic event. Further, lactate, an important product of aerobic glycolysis, promotes tumor growth, in addition to being a source of energy. Elevated lactate levels and lactate-mediated downstream pathways have been found to cause changes in transcription , tumor iIn conclusion, energy metabolic conversions caused by aerobic glycolysis in cancer cells not only represent promising molecular markers for monitoring sensitivity to radiotherapy in malignancies, but also provide new targets for the development of new cancer treatment strategies. Importantly, these findings open an exciting new chapter of research in the field of resistance to radiotherapy in malignancies.


Crimean-Congo hemorrhagic fever (CCHF) was detected in 2 refugees living in a refugee settlement in Kikuube district, Uganda. Investigations revealed a CCHF IgG seroprevalence of 71.3% (37/52) in goats within the refugee settlement. This finding highlights the need for a multisectoral approach to controlling CCHF in humans and animals in Uganda. Hyalomma species. Humans are typically infected through contact with body fluids of infected livestock or through bites from infected ticks; human-to-human transmission of CCHFV has been documented (Crimean-Congo hemorrhagic fever (CCHF) is caused by CCHF virus (CCHFV). CCHF is a zoonotic disease that infects mainly livestock, and CCHFV is transmitted by ticks, primarily Uganda first reported a case of CCHF in 2013 in Agago district; subsequent sporadic cases have been detected throughout the country, especially within the cattle corridor  living in Kyangwali Refugee Settlement, Kikuube district, Uganda , sought On April 30, 2021, a 13-year-old boy (patient 2) from the same village was seen at the same health facility; symptoms were a 2-day history of fever that progressed into hemoptysis and epistaxis. The patient tested positive for malaria and received malaria treatment the day of symptom onset, but his condition did not improve. A blood sample was transported to Uganda Virus Research Institute and tested positive for CCHFV by rRT-PCR; CCHFV IgM and IgG were detected.Both patients were managed clinically with supportive care, including intravenous fluids and paracetamol; they clinically recovered and were discharged. Next-generation sequencing analysis of nucleic acids extracted from a blood sample from patient 1 indicated the circulating virus grouped within the African 2 lineage, closely matching the virus from a case detected in the same area in 2019 , 2. SequBoth CCHF patients were from the same village, attended the same church, and were refugees of Congolese origin; however, we did not identify any close contact or epidemiologic link suggestive of human-to-human transmission between them. Patient 1 had previously herded 15 goats that were housed in a barn adjacent to the family’s house and had not recently used tick control measures on the goats. Patient 2 lived near the goat pen of a neighbor in the camp. These goats, together with all livestock herds from the refugee settlement, grazed on communal land that was located <1 km away from the homes of the 2 confirmed patients, enabling easy mixing and transmission of pathogens.Rhipicephalus appendiculatus) from the sampled goats; all tested negative for CCHFV by rRT-PCR.We collected blood samples from 52 goats in the communal grazing land, including the 15 goats owned by patient 1’s family, and tested them by CCHFV rRT-PCR and CCHFV IgG ELISA. All 52 goats were rRT-PCR-negative, but 37/52 (71.3%) goats had detectable IgG. We also collected 14 ticks ; these infections cannot be differentiated without diagnostic testing. Improved diagnostic capability for multipathogen detection could also improve early identification and patient outcomes, as well as limiting the potential for transmission. Both patients sought care after developing hemorrhagic signs, which usually develop late in illness (Both patients were living in close proximity to goats; the livestock were located in the same compound for patient 1 and in a nearby goat pen for patient 2. Both patients reported close interaction with goats by way of grazing and tethering them. This close interaction with livestock increases the chance of zoonotic disease transmission. Livestock act as reservoirs for pathogens such as Rift Valley fever virus, CCHF, tuberculosis, and brucellosis and should be housed separately because they can act as carriers of infections to humans. The presence of ticks on the sampled goats demonstrates limited tick control in the herd. Tickborne diseases affect not only the health of humans but also livestock production. Vector control strategies coupled with improved management practices would improve these challenges, because communal grazing increases risk for pathogen transmission among animals from different herds.This investigation of 2 confirmed CCHF cases highlights the rapid identification and intervention by healthcare workers and response from the Kikuube District health team and partners, such as the United Nations High Commission for Refugees, Prime Minister’s office, Medical Teams International, to successfully mitigate onward transmission of CCHFV in this vulnerable community. These efforts are particularly notable given the concurrent burden on the healthcare system and associated disease surveillance challenges from the COVID-19 pandemic.


Optical neural networks (ONN) have become the most promising solution to replacing electronic neural networks, which have the advantages of large bandwidth, low energy consumption, strong parallel processing ability, and super high speed. Silicon-based micro-nano integrated photonic platforms have demonstrated good compatibility with complementary metal oxide semiconductor (CMOS) processing. Therefore, without completely changing the existing silicon-based fabrication technology, optoelectronic hybrid devices or all-optical devices of better performance can be achieved on such platforms. To meet the requirements of smaller size and higher integration for silicon photonic computing, the topology of a four-channel coarse wavelength division multiplexer (CWDM) and an optical scattering unit (OSU) are inversely designed and optimized by Lumerical software. Due to the random optical power splitting ratio and incoherency, the intensities of different input signals from CWDM can be weighted and summed directly by the subsequent OSU to accomplish arbitrary multiply–accumulate (MAC) operations, therefore supplying the core foundation for scattering ONN architecture.  With the widespread use of deep learning techniques, artificial intelligence (AI) has achieved great success in machine vision, autonomous driving, and clinical diagnosis. However, the growth of the computational capability of integrated circuit (IC) chips as a carrier for training and executing AI models is gradually slowing down and failing to meet the demand of artificial neural network (ANN). The IC chip based on the von Neumann architecture has a structural defect that cannot be avoided, as it separates the program from the data when executing operations, resulting in tidal data loads between the memory and the computational unit, which decreases the computational rate and increases the computational power consumption . ResearcANN based on optical devices, the so-called optical neural network (ONN), can overcome the aforementioned defects. Compared with the electronics counterpart, optical transmission inherently has the advantages of high speed, large bandwidth, low delay, high parallelism, low energy consumption, and immunity to electro-magnetic interference (EMI) . Therefo2NN) consisting of multiple layers of diffractive surfaces that could perform computational tasks at the speed of light. The training of D2NN was completed by computer. After completing the training, a 3D model of each diffraction layer was established by Poisson surface reconstruction method. Then, the diffraction surface was printed by a 3D printer to classify handwritten digits and images of fashionable items. In 2020, Qu et al. [−4 and 97.1% recognition accuracy on the classical image classification dataset MNIST. In 2021, Zhang et al. [In 2017, Shen et al.  successfu et al.  proposedBased on a silicon-on-insulator (SOI) processing platform, we propose a four-channel coarse wavelength division multiplexer (CWDM) and an optical scattering unit (OSU) chip architecture, to inversely design their inner topologies, to forwardly verify such basic metastructure elements, and finally to export mask patterns for fabrication. In this paper, CWDM is used to decompose the input broadband optical signal into four channels with different wavelengths and input them to OSU. The metastructure cascades the CWDM and OSU to implement the arbitrary multiply–accumulate (MAC) operations, realizing the core functionality of ONN.In silicon photonics, a CMOS-compatible SOI platform illustrated in s 400 nm . The CWDFor optoelectronic devices, the traditional forward design cycles  involve LumOpt as a python module. LumOpt comes in two different approaches—shape and topology optimization [While in Lumerical FDTD software  this paradigm shift is implemented using mization . Rather mization ,17, we oOnce the optimization is running it proceeds in two or three steps. First comes the greyscale phase where the parameters vary continuously between the core and cladding index. Next, a binarization phase is run to force the mesh cells to take either the core or cladding index. Finally, an optional design for manufacturing (DFM) step is implemented. In this step a penalty function is added to the figure-of-merit (FOM). The magnitude of the penalty function is determined by the degree to which the minimum feature size constraint is violated. Typically, the minimum feature size is set about 500 nm, the finest resolution of mask aligner.WDM unit combines a series of different wavelength optical signals into one channel as multiplexer (MUX) and splits them into each wavelength vice versa as demultiplexer (DEMUX). CWDM distinguishes from dense wavelength division multiplexer (DWDM) by broader wavelength channel separation, typically 10–20 nm, loosens the requirements for fine tunability of light source and wavelength division, and therefore could be used simply and cost-effectively.A four-channel wavelength DEMUX working around a 1550 nm window is depicted in We set FOMs as monitors for the four output ports demonstrating the wavelength division equality, which decrease and converge to a constant value as the iteration number increases, as shown in To verify the functionality and performance of the inversely designed DEMUX, the optical transmission characteristics  and fielThe inversely designed and subsequently forward-validated metastructure tends to create features that break process design rules. To ensure DFM, Lumerical IDE supplies ways of explicitly enforcing specific minimum feature size constraints . The maiI1(λ1), I2(λ2), I3(λ3)and I4(λ4) accordingly. Through the OSU, i.e., the MIMO system, we obtain the mixed and redistributed optical signal at output ports with the intensity of Io1, Io2, Io3and Io4 The relationship between the input optical intensity inI and output optical intensity outI is given by Equations (1) and (2). Due to the light source incoherency and scattering behavior, the intensities of different input signals can be weighted and summed directly so that the OSU perfectly fulfills the specific MAC computation represented by the stochastic matrix P defined in Equation (3). Thus, arbitrary MAC operations based on random optical power splitting ratio and summation could be accomplished by OSU.Based on inverse design methodology, we conceive an initial guess of OSU metastructure with multi-input–multi-output (MIMO) on SOI, which has four input ports and four output ports as an instance, illustrated in The FOMs of the OSU can converge when the iteration number reaches 800 as λ1 is almost equally routing to the four output ports as the relative electric intensity curve at certain output port indicates in 2 is equally routing to the output port 2, 3, and 4 as the relative electric intensity curve indicates in 3 is equally routing to the output port 3 and 4 as 4 is directly routing to the fourth output port shown in Moreover, we can detail each optical signal propagation characteristics as follows. The optical signal For the sake of DFM rule, as with CWDM-DEMUX, we export the OSU layout illustrated in In the end, as depicted in Furthermore, metastructures over four channels, such as one by nine CWDM and nine by nine OSU, could fulfill nine optical signals’ weighting and summation operation by the stochastic matrix implemented on the random optical power splitting ratio and incoherency.To tackle the obstacles confronted by electronics in AI and meanwhile meet the requirements of smaller size and higher integration for silicon photonic computing, the topologies of four-channel CWDM and OSU are inversely designed and optimized in the state-of-the-art Lumerical IDE, based on which, the scattering metastructures are constructed. Due to the random optical power splitting ratio and incoherency, the intensities of different input signals from CWDM can be weighted and summed directly by the cascaded OSU to accomplish arbitrary MAC operations, therefore supplying the core foundation for scattering ONN architecture. The ongoing research will focus on the optical performance and feasibility of the fabrication on conventional silicon material and universal photolithography/etching process to exploit the potential application of handwritten digit classification in ONN.