Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer.

Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood-brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.

Cellular senescence in glioma.

INTRODUCTION: Glioma is the most common primary brain tumor and is often associated with treatment resistance and poor prognosis. Standard treatment typically involves radiotherapy and temozolomide-based chemotherapy, both of which induce cellular senescence-a tumor suppression mechanism. DISCUSSION: Gliomas employ various mechanisms to bypass or escape senescence and remain in a proliferative state. Importantly, senescent cells remain viable and secrete a large number of factors collectively known as the senescence-associated secretory phenotype (SASP) that, paradoxically, also have pro-tumorigenic effects. Furthermore, senescent cells may represent one form of tumor dormancy and play a role in glioma recurrence and progression. CONCLUSION: In this article, we delineate an overview of senescence in the context of gliomas, including the mechanisms that lead to senescence induction, bypass, and escape. Furthermore, we examine the role of senescent cells in the tumor microenvironment and their role in tumor progression and recurrence. Additionally, we highlight potential therapeutic opportunities for targeting senescence in glioma.

Concurrence of Hyperhidrosis and Hypohidrosis in Ross Syndrome.

Ross Syndrome is a rare disorder characterized by tonic pupils, hyporeflexia, and abnormal segmental sweating. The pathophysiology of the disease remains unclear, with either hypohidrosis or hyperhidrosis reported in individual patients. We present the case of a man, aged 57 years, who presented with hyperhidrosis in his right extremities, anhidrosis in the left extremities, and changes in his pupils. The disease was not associated with markers of autoimmune disease, which supports recent research findings on the role of neurodegeneration. The patient's son was exhibiting similar symptoms, which implicates genetic inheritance in the process. A multidisciplinary approach is crucial for the diagnosis and ultimate management of patients with Ross Syndrome.

Repurposing autophagy regulators in brain tumors.

Malignant brain tumors, such as glioblastoma multiforme (GBM) and brain metastases, continue to be an unmet medical challenge. Despite advances in cancer diagnostics and therapeutics, tumor cell colonization in the central nervous system renders most treatment options ineffective. This is primarily due to the selective permeability of the blood-brain barrier (BBB), which hinders the crossing of targeting agents into the brain. As such, repositioning medications that demonstrate anticancer effects and possess the ability to cross the BBB can be a promising option. Antidepressants, which are BBB-permeable, have been reported to exhibit cytotoxicity against tumor cells. Autophagy, specifically, has been identified as one of the common key mediators of antidepressant's antitumor effects. In this work, we provide a comprehensive overview of US Food and Drug Administration (FDA)-approved antidepressants with reported cytotoxic activities in different tumor models, where autophagy dysregulation was demonstrated to play the main part. As such, imipramine, maprotiline, fluoxetine and escitalopram were shown to induce autophagy, whereas nortriptyline, clomipramine and paroxetine were identified as autophagy inhibitors. Sertraline and desipramine, depending on the neoplastic context, were demonstrated to either induce or inhibit autophagy. Collectively, these medications were associated with favorable therapeutic outcomes in a variety of cancer cell models, including brain tumors.

Emerging principles of brain immunology and immune checkpoint blockade in brain metastases.

Brain metastases are the most common type of brain tumours, harbouring an immune microenvironment that can in principle be targeted via immunotherapy. Elucidating some of the immunological intricacies of brain metastases has opened a therapeutic window to explore the potential of immune checkpoint inhibitors in this globally lethal disease. Multiple lines of evidence suggest that tumour cells hijack the immune regulatory mechanisms in the brain for the benefit of their own survival and progression. Nonetheless, the role of the immune checkpoint in the complex interplays between cancers cells and T cells and in conferring resistance to therapy remains under investigation. Meanwhile, early phase trials with immune checkpoint inhibitors have reported clinical benefit in patients with brain metastases from melanoma and non-small cell lung cancer. In this review, we explore the workings of the immune system in the brain, the immunology of brain metastases, and the current status of immune checkpoint inhibitors in the treatment of brain metastases.

Augmented and virtual reality usage in awake craniotomy: a systematic review.

Augmented and virtual reality (AR, VR) are becoming promising tools in neurosurgery. AR and VR can reduce challenges associated with conventional approaches via the simulation and mimicry of specific environments of choice for surgeons. Awake craniotomy (AC) enables the resection of lesions from eloquent brain areas while monitoring higher cortical and subcortical functions. Evidence suggests that both surgeons and patients benefit from the various applications of AR and VR in AC. This paper investigates the application of AR and VR in AC and assesses its prospective utility in neurosurgery. A systematic review of the literature was performed using PubMed, Scopus, and Web of Science databases in accordance with the PRISMA guidelines. Our search results yielded 220 articles. A total of six articles consisting of 118 patients have been included in this review. VR was used in four papers, and the other two used AR. Tumour was the most common pathology in 108 patients, followed by vascular lesions in eight patients. VR was used for intraoperative mapping of language, vision, and social cognition, while AR was incorporated in preoperative training of white matter dissection and intraoperative visualisation and navigation. Overall, patients and surgeons were satisfied with the applications of AR and VR in their cases. AR and VR can be safely incorporated during AC to supplement, augment, or even replace conventional approaches in neurosurgery. Future investigations are required to assess the feasibility of AR and VR in various phases of AC.

Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial.

BACKGROUND: Malignant glioma is the most common and lethal primary brain tumour, with dismal survival rates and no effective treatment. We examined the safety and activity of NSC-CRAd-S-pk7, an engineered oncolytic adenovirus delivered by neural stem cells (NSCs), in patients with newly diagnosed high-grade glioma. METHODS: This was a first-in-human, open-label, phase 1, dose-escalation trial done to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3 + 3 design. Patients with newly diagnosed, histologically confirmed, high-grade gliomas (WHO grade III or IV) were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. The first patient cohort received a dose starting at 6·25 × 1010 viral particles administered by 5·00 × 107 NSCs, the second cohort a dose of 1·25 × 1011 viral particles administered by 1·00 × 108 NSCs, and the third cohort a dose of 1·875 × 1011 viral particles administered by 1·50 × 108 NSCs. No further dose escalation was planned. Within 10-14 days, treatment with temozolomide and radiotherapy was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase 2 trial. All analyses were done in all patients who were included in the trial and received the study treatment and were not excluded from the study. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT03072134. FINDINGS: Between April 24, 2017, and Nov 13, 2019, 12 patients with newly diagnosed, malignant gliomas were recruited and included in the safety analysis. Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) of 12 patients with anaplastic astrocytoma. The median follow-up was 18 months (IQR 14-22). One patient receiving 1·50 × 108 NSCs loading 1·875 × 1011 viral particles developed viral meningitis (grade 3) due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. Otherwise, treatment was safe as no formal dose-limiting toxicity was reached, so 1·50 × 108 NSCs loading 1·875 × 1011 viral particles was recommended as a phase 2 trial dose. There were no treatment-related deaths. The median progression-free survival was 9·1 months (95% CI 8·5-not reached) and median overall survival was 18·4 months (15·7-not reached). INTERPRETATION: NSC-CRAd-S-pk7 treatment was feasible and safe. Our immunological and histopathological findings support continued investigation of NSC-CRAd-S-pk7 in a phase 2/3 clinical trial. FUNDING: US National Institutes of Health.

Clinical Presentation and Outcomes of Pregnant Women With Coronavirus Disease 2019: A Systematic Review and Meta-analysis.

BACKGROUND: Descriptions of coronavirus disease 2019 (COVID-19) have focused on the nonpregnant adult population. This study aims to describe the clinical characteristics and perinatal outcomes of COVID-19 in pregnancy. METHODS: We searched databases from December 2019 to 30 April 2020. Eligible studies reported clinical characteristics, radiological findings, and/or laboratory testing of pregnant women during infection. Data were pooled across studies using a random-effects model. RESULTS: Twenty-four studies (136 women) were included. The most common symptoms were fever (62.9%) and cough (36.8%). Laboratory findings included elevated C-reactive protein (57%) and lymphocytopenia (50%). Ground-glass opacity was the most common radiological finding (81.7%). Preterm birth rate was 37.7% and cesarean delivery rate was 76%. There was 1 maternal death. There were 2 fetal COVID-19 cases. CONCLUSIONS: The clinical picture in pregnant women with COVID-19 did not differ from the nonpregnant population; however, the rate of preterm birth and cesarean delivery are considerably higher than international averages.

Sever's Disease of the Pediatric Population: Clinical, Pathologic, and Therapeutic Considerations.

Sever's disease is an underreported prevalent pediatric condition that causes heel pain in children worldwide. It is often described as an overuse injury that can present with either unilateral or bilateral heel pain. Even though the exact mechanism of injury is unknown, it is often thought it involves repetitive stress and pressure on the calcaneal growth plate. Diagnosing Sever's disease mainly relies on a thorough clinical investigation and physical examination, with a positive squeeze test usually sufficient to establish diagnosis. Nevertheless, radiographic imaging can help exclude other differential diagnoses. Therapeutic options of Sever's disease are mostly conservative, and these include rest, physical therapy, kinesiotherapy, and orthoses. Educating parents and coaches on the symptomatology and presentation of Sever's disease is pivotal for the establishment of efficient preventive interventions and earlier diagnoses. This study presents a case of a pediatric patient with Sever's disease and offers medical insight into the diagnostic, clinical, pathologic, and therapeutic characteristics of this condition, in light of the current existing literature.

Clinical Presentation and Management of Severe Acute Renal Failure in McArdle Disease.

McArdle disease, also known as glycogen storage disease type V, is an autosomal recessive disease due to the absence of myophosphorylase activity, leading to the complete disruption of glycogen breakdown in muscles. We present a rare case of a Caucasian male, aged 26 years, who developed rhabdomyolysis-induced acute renal failure and uremic encephalopathy. Neurological examination and histopathological studies supported the diagnosis of McArdle disease. The severity of his symptoms necessitated urgent hemodialysis, upon which the patient reported improvement in status. Acute renal failure in McArdle disease usually resolves with supportive treatment and maintenance of regular physical activity. Nevertheless, in more severe cases, intensive care with urgent hemodialysis may be needed. A multidisciplinary approach is necessary for the adequate management of similar cases.

Landscape of combination therapy trials in breast cancer brain metastasis.

Combination therapy has become a cornerstone in cancer treatment to potentiate therapeutic effectiveness and overcome drug resistance and metastasis. In this work, we explore combination trials in breast cancer brain metastasis (BCBM), highlighting deficiencies in trial design and underlining promising combination strategies. On October 31, 2019, we examined ClinicalTrials.gov for interventional and therapeutic clinical trials involving combination therapy for BCBM, without limiting for date or location. Information on trial characteristics was collected. Combination therapies used in trials were analyzed and explored in line with evidence from the medical literature. Sixty-five combination therapy trials were selected (n = 65), constituting less than 0.7% of all breast cancer trials. Most trials (62%) combined ≥2 chemotherapeutic agents. Chemotherapy with radiation was main-stay in 23% of trials. Trastuzumab was mostly used in combination (31%), followed by lapatinib (20%) and capecitabine (15%). Common strategies involved combining tyrosine kinase inhibitors with thymidylate synthase inhibitors (6 trials), dual HER-dimerization inhibitors (3 trials), microtubule inhibitors and tyrosine kinase inhibitors (3 trials), and HER-dimerization inhibitors and tyrosine kinase inhibitors (3 trials). The combination of tucatinib and capecitabine yielded the highest objective response rate (83%) in early phase trials. The triple combination of trastuzumab, tucatinib and capecitabine lowered the risk of disease progression or death by 52% in patients with HER2-positive BCBM. Combining therapeutic agents based on biological mechanisms is necessary to increase the effectiveness of available anti-cancer regimens. Significant survival benefit has yet to be achieved in future combination therapy trials. Enhancing drug delivery through blood-brain barrier permeable agents may potentiate the overall therapeutic outcomes.

GCN2 is essential for CD8+ T cell survival and function in murine models of malignant glioma.

Amino acid deprivation is a strategy that malignancies utilize to blunt anti-tumor T-cell immune responses. It has been proposed that amino acid insufficiency in T-cells is detected by GCN2 kinase, which through phosphorylation of EIF2α, shuts down global protein synthesis leading to T-cell arrest. The role of this amino acid stress sensor in the context of malignant brain tumors has not yet been studied, and may elucidate important insights into the mechanisms of T-cell survival in this harsh environment. Using animal models of glioblastoma and animals with deficiency in GCN2, we explored the importance of this pathway in T-cell function within brain tumors. Our results show that GCN2 deficiency limited CD8+ T-cell activation and expression of cytotoxic markers in two separate murine models of glioblastoma in vivo. Importantly, adoptive transfer of antigen-specific T-cells from GCN2 KO mice did not control tumor burden as well as wild-type CD8+ T-cells. Our in vitro and in vivo data demonstrated that reduction in amino acid availability caused GCN2 deficient CD8+ T-cells to become rapidly necrotic. Mechanistically, reduced CD8+ T-cell activation and necrosis was due to a disruption in TCR signaling, as we observed reductions in PKCθ and phoshpo-PKCθ on CD8+ T-cells from GCN2 KO mice in the absence of tryptophan. Validating these observations, treatment of wild-type CD8+ T-cells with a downstream inhibitor of GCN2 activation also triggered necrosis of CD8+ T-cells in the absence of tryptophan. In conclusion, our data demonstrate the vital importance of intact GCN2 signaling on CD8+ T-cell function and survival in glioblastoma.

Peroneal neuropathy and bariatric surgery: untying the knot.

Purpose: Peroneal neuropathy is a neurological complication of bariatric surgery (BS) that can impair the functional capacity of the presenting patient and reduce quality of life. The aim of this paper is to explore and offer medical insight into the presentation, etiologies, and therapeutic modalities of peroneal neuropathy following BS.Methods: We explored PubMed/Medline for cases involving peroneal neuropathy as a complication of BS. The search included all articles published from database inception until April 25, 2019. Only articles published in English were included. Clinical information and demographics extracted from the reported studies were analyzed and assessed.Results: Only 9 studies met our criteria, with a total of 21 cases (n = 21). Females dominated in 14 cases (67%). Ages ranged from 12 to 53 years with mean age being 36. All cases reported pain, numbness and weakness in their lower limb. Gastric bypass was the most common procedure with 9 cases (43%). All cases witnessed loss of a large amount of weight following BS. Amount of weight lost per month ranged from 2.7 kg/month to 19 kg/month. Electrodiagnostic studies were used in 18 cases (86%). Of all the cases presented, 12 (57%) underwent surgical treatment, 7 (33%) underwent conservative treatment, and 2 (10%) resolved spontaneously. All patients reported improvement of symptoms.Conclusion: Better knowledge of the demographics and clinical characteristics of peroneal neuropathy following BS will help in achieving earlier diagnosis and avoiding invasive therapeutic modalities. Guidance with respect to weight reduction is pivotal in deterring similar neurological complications.

Acute Kidney Injury Following Dermatomyositis.

Renal involvement in patients with inflammatory myopathies, like dermatomyositis, is rare. We present the case of a woman, aged 66 years, who arrived at the hospital with acute renal failure. She had a diffuse erythematous rash, severe muscle weakness and decreased motor capacity. Inflammatory features of the skin/muscle biopsy along with the dramatic improvement in symptomatology upon the intake of steroids pointed towards dermatomyositis. Recognition of this pattern of events, adopting a multidisciplinary approach, early diagnosis and steroid treatment are necessary for better patient outcomes.

Neurogenesis in the adult hippocampus: history, regulation, and prospective roles.

BACKGROUND: The hippocampus is one of the sites in the mammalian brain that is capable of continuously generating controversy. Adult neurogenesis is a remarkable process, and yet an intensely debatable topic in contemporary neuroscience due to its distinctiveness and conceivable impact on neural activity. The belief that neurogenesis continues through adulthood has provoked remarkable efforts to describe how newborn neurons differentiate and incorporate into the adult brain. It has also encouraged studies that investigate the consequences of inadequate neurogenesis in neuropsychiatric and neurodegenerative diseases and explore the potential role of neural progenitor cells in brain repair. The adult nervous system is not static; it is subjected to morphological and physiological alterations at various levels. This plastic mechanism guarantees that the behavioral regulation of the adult nervous system is adaptable in response to varying environmental stimuli. Three regions of the adult brain, the olfactory bulb, the hypothalamus, and the hippocampal dentate gyrus, contain new-born neurons that exhibit an essential role in the natural functional circuitry of the adult brain. Purpose/Aim: This article explores current advancements in adult hippocampal neurogenesis by presenting its history and evolution and studying its association with neural plasticity. The article also discusses the prospective roles of adult hippocampal neurogenesis and describes the intracellular, extracellular, pathological, and environmental factors involved in its regulation. Abbreviations AHN Adult hippocampal neurogenesis AKT Protein kinase B BMP Bone Morphogenic Protein BrdU Bromodeoxyuridine CNS Central nervous system DG Dentate gyrus DISC1 Disrupted-in-schizophrenia 1 FGF-2 Fibroblast Growth Factor 2 GABA Gamma-aminobutyric acid Mbd1 Methyl-CpG-binding domain protein 1 Mecp2 Methyl-CpG-binding protein 2 mTOR Mammalian target of rapamycin NSCs Neural stem cells OB Olfactory bulb; P21: cyclin-dependent kinase inhibitor 1 RBPj Recombination Signal Binding protein for Immunoglobulin Kappa J Region RMS Rostral migratory Stream SGZ Subgranular zone Shh Sonic hedgehog SOX2 SRY (sex determining region Y)-box 2 SVZ Subventricular zone Wnt3 Wingless-type mouse mammary tumor virus.

Deciphering glycomics and neuroproteomic alterations in experimental traumatic brain injury: Comparative analysis of aspirin and clopidogrel treatment.

As populations age, the number of patients sustaining traumatic brain injury (TBI) and concomitantly receiving preinjury antiplatelet therapy such as aspirin (ASA) and clopidogrel (CLOP) is rising. These drugs have been linked with unfavorable clinical outcomes following TBI, where the exact mechanism(s) involved are still unknown. In this novel work, we aimed to identify and compare the altered proteome profile imposed by ASA and CLOP when administered alone or in combination, prior to experimental TBI. Furthermore, we assessed differential glycosylation PTM patterns following experimental controlled cortical impact model of TBI, ASA, CLOP, and ASA + CLOP. Ipsilateral cortical brain tissues were harvested 48 h postinjury and were analyzed using an advanced neuroproteomics LC-MS/MS platform to assess proteomic and glycoproteins alterations. Of interest, differential proteins pertaining to each group (22 in TBI, 41 in TBI + ASA, 44 in TBI + CLOP, and 34 in TBI + ASA + CLOP) were revealed. Advanced bioinformatics/systems biology and clustering analyses were performed to evaluate biological networks and protein interaction maps illustrating molecular pathways involved in the experimental conditions. Results have indicated that proteins involved in neuroprotective cellular pathways were upregulated in the ASA and CLOP groups when given separately. However, ASA + CLOP administration revealed enrichment in biological pathways relevant to inflammation and proinjury mechanisms. Moreover, results showed differential upregulation of glycoproteins levels in the sialylated N-glycans PTMs that can be implicated in pathological changes. Omics data obtained have provided molecular insights of the underlying mechanisms that can be translated into clinical bedside settings.

NEURAL FIBROLIPOMA OF THE MEDIAN NERVE.

We report a rare case of neural fibrolipoma (lipofibromatous hamartoma) of the median nerve of the hand. An 18-year-old male complaining of progressive and chronic macrodactyly of his thumb of the left hand, with neurological complains, was admitted to the hospital. Magnetic resonance (MR) evaluation revealed fibro-fatty infiltration of the median nerve at the level of the carpal tunnel, and the terminal branches of the median nerve in the thumb and index. The pathological examination of excised tissue confirmed the diagnosis of neural fibrolipoma of the terminal branch of the median nerve in his thumb. Imaging is recommended; MR studies on morphological abnormalities must be done in similar cases.

Head and facial injuries due to cluster munitions.

Cluster munitions are weapons that scatter smaller sub-munitions intended to kill or mutilate on impact. They have been used by the Israeli army in the south of Lebanon and are now scattered over wide rural areas affecting its inhabitants. Because of their easily "pickable" nature, sub-munitions can inflict injuries to the head and face regions. In this study, we aimed to explore the head and face injuries along with their clinical features in a group of Lebanese patients who suffered from such injuries due to a sub-munition's detonation. The study included all the cases reported between 14 August 2006 and 15 February 2013, with head and face injuries related to cluster bombs. Injuries were classified into brain, eye, otologic and auditory impairments, oral and maxillofacial, and skin and soft-tissue injuries. Psychological effects of these patients were also examined as for post-traumatic stress disorder, major depressive disorder, generalized anxiety disorder and acute stress syndrome. During the study period, there were 417 casualties as a result of cluster munitions' blasts. Out of the total number of victims, 29 (7 %) were injured in the head and the face region. The convention on cluster munitions of 2008 should be adhered to, as these inhumane weapons indiscriminately and disproportionately harm innocent civilians, thereby violating the well-established international principles governing conflict and war today.

Molecular diversity in isocitrate dehydrogenase-wild-type glioblastoma.

In the dynamic landscape of glioblastoma, the 2021 World Health Organization Classification of Central Nervous System tumours endeavoured to establish biological homogeneity, yet isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma persists as a tapestry of clinical and molecular diversity. Intertumoural heterogeneity in IDH-wt glioblastoma presents a formidable challenge in treatment strategies. Recent strides in genetics and molecular biology have enhanced diagnostic precision, revealing distinct subtypes and invasive patterns that influence survival in patients with IDH-wt glioblastoma. Genetic and molecular biomarkers, such as the overexpression of neurofibromin 1, phosphatase and tensin homolog and/or cyclin-dependent kinase inhibitor 2A, along with specific immune cell abundance and neurotransmitters, correlate with favourable outcomes. Conversely, increased expression of epidermal growth factor receptor tyrosine kinase, platelet-derived growth factor receptor alpha and/or vascular endothelial growth factor receptor, coupled with the prevalence of glioma stem cells, tumour-associated myeloid cells, regulatory T cells and exhausted effector cells, signifies an unfavourable prognosis. The methylation status of O6-methylguanine-DNA methyltransferase and the influence of microenvironmental factors and neurotransmitters further shape treatment responses. Understanding intertumoural heterogeneity is complemented by insights into intratumoural dynamics and cellular interactions within the tumour microenvironment. Glioma stem cells and immune cell composition significantly impact progression and outcomes, emphasizing the need for personalized therapies targeting pro-tumoural signalling pathways and resistance mechanisms. A successful glioblastoma management demands biomarker identification, combination therapies and a nuanced approach considering intratumoural variability. These advancements herald a transformative era in glioblastoma comprehension and treatment.