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Revisiting the Role of Surgical Resection for Brain Metastasis.

Brain metastasis (BM) is the most common type of brain tumor in adults. The contemporary management of BM remains challenging. Advancements in systemic cancer treatment have increased the survival of patients with cancer. Although the treatment of BM is still complicated, advances in radiotherapy, including stereotactic radiosurgery and chemotherapy, have improved treatment outcomes. Surgical resection is the traditional treatment for BM and its role in the surgical resection of BM has been well established. However, refinement of the surgical resection technique and strategy for BM is needed. Herein, we discuss the evolving role of surgery in patients with BM and the future of BM treatment.

Transcription factor ZBTB42 is a novel prognostic factor associated with immune cell infiltration in glioma.

Molecular subtypes predict the preferential site of distant metastasis in advanced breast cancer a nationwide retrospective study.

This study aimed to explore possible associations between molecular subtypes and site of distant metastasis in advanced breast cancer (ABC). 3577 ABC patients were selected from 21 hospitals of seven geographic regions in China from 2012-2014. A questionnaire was designed to collect medical information regarding demographic characteristics, risk factors, molecular subtype, recurrencemetastasis information, and disease-free survival (DFS). The cancers were classified into Luminal A, Luminal B, HER2-enriched and Triple Negative subtypes. Chi-square test and multivariate Cox proportional hazard models were performed to explore the associations between molecular subtypes and distant metastasis sites. A total of 2393 cases with molecular subtypes information were finally examined. Patients with Luminal A (51.1%) and Luminal B (44.7%) were most prone to bone metastasis, whereas liver metastasis was more frequently observed in HER2-enriched ABC patients (29.1%).The cumulative recurrence and metastasis rates of ABC patients at 36 months of DFS were the most significant within molecular types, of which Triple Negative was the highest (82.7%), while that of Luminal A was the lowest (58.4%). In the adjusted Cox regression analysis, Luminal B, HER2-enriched and Triple Negative subtypes increased the risk of visceral metastasis by 23%, 46% and 87% respectively. In addition, Triple Negative patients had a higher probability of brain metastasis (HR 3.07, 95% CI 1.04-9.07). Molecular subtypes can predict the preferential sites of distant metastasis, emphasizing that these associations were of great help in choices for surveillance, developing appropriate screening and cancer management strategies for follow-up and personalized therapy in ABC patients.

When tissue is not the only issue Poorly differentiated lung squamous-cell carcinoma with adrenal, costochondral, and cardiac metastases - case report.

Nonmelanoma skin cancer is the most common cancer in the world, and lung cancer is the leading cause of death from cancer. Histologically, squamous cell carcinoma (SCC) is the second most prevalent type of both skin and lung cancers. We report the case of a 38-year-old female with metastatic, poorly differentiated lung SCC detected on chest X-ray after she presented to the hospital with cough and dyspnea. She had had a 7.5 cm moderately differentiated well-circumscribed posterior scalp SCC completely excised eight years earlier. CT scan showed a large right lung mass, nodular filling defect in the left atrium (LA), and metastases to the adrenal glands and the first rib. Her pulmonary tumor extends to the LA

Rapid progression of subcutaneous glioblastoma A case report and literature review.

Extra-neural spread of glioblastoma (GBM) is extremely rare. We report a case of postoperative intracranial GBM spreading to the subcutaneous tissue

Spatial distribution of supratentorial diffuse gliomas A retrospective study of 990 cases.

Gliomas distribute unevenly in the supratentorial brain space. Many factors were linked to tumor locations. This study aims to describe a more detailed distributing pattern of these tumors with age and pathological factors concerned. A consecutive series of 990 adult patients with newly-diagnosed supratentorial diffuse gliomas who underwent resection in Beijing Tiantan Hospital between January 2013 and January 2017 were retrospectively reviewed. For each patient, the anatomic locations were identified by the preoperative MRI, and the pathological subtypes were reviewed for histological grade and molecular status (if any) from his medical record. The MNI template was manually segmented to measure each anatomic locations volume, and its invaded ratio was then adjusted by the volume to calculate the frequency density. Factors of age and pathological subtypes were also compared among locations. The insulae, hippocampi, and corpus callosum were locations of the densest frequencies. The frequency density decreased from the anterior to posterior (frontal - motor region - sensory region - parietal - occipital), while the grade (p < 0.0001) and the proportion of IDH-wt (p < 0.0001) increased. More tumors invading the right basal ganglion were MGMT-mt (p 0.0007), and more of those invading the left frontal were TERT-wt (p 0.0256). Age varied among locations and pathological subtypes. This study demonstrated more detailed spatial disproportions of supratentorial gliomas. There are potential interactions among age, pathological subtypes, and tumor locations.

Integrative analysis of single-cell transcriptomics reveals age-associated immune landscape of glioblastoma.

Glioblastoma (GBM) is the most malignant tumor in center nervous system. Clinical statistics revealed that senior GBM patients had a worse overall survival (OS) comparing with that of patients in other ages, which is mainly related with tumor microenvironment including tumor-associated immune cells in particular. However, the immune heterogeneity and age-related prognosis in GBM are under studied. Here we developed a machine learning-based method to integrate public large-scale single-cell RNA sequencing (scRNA-seq) datasets to establish a comprehensive atlas of immune cells infiltrating in cross-age GBM. We found that the compositions of the immune cells are remarkably different across ages. Brain-resident microglia constitute the majority of glioblastoma-associated macrophages (GAMs) in patients, whereas dramatic elevation of extracranial monocyte-derived macrophages (MDMs) is observed in GAMs of senior patients, which contributes to the worse prognosis of aged patients. Further analysis suggests that the increased MDMs arisen from excessive recruitment and proliferation of peripheral monocytes not only lead to the T cell function inhibition in GBM, but also stimulate tumor cells proliferation

Errata Brain tumor IDH, 1p19q, and MGMT molecular classification using MRI-based deep learning an initial study on the effect of motion and motion correction.

This corrects the article DOI 10.11171.JMI.9.1.016001..

Incidental screening of descending colon carcinoma by 18F-FDG PETMR imaging in a patient with endometrial carcinoma A case report of Lynch syndrome.

Lynch syndrome (LS) is associated with the early onset of carcinoma and the development of numerous types of carcinoma, particularly endometrial and colon carcinomas. LS-associated endometrial carcinoma (EC) has been widely noted by gynecologists. However, there is still a lack of a non-invasive and reliable tool for early screening for LS in patients with EC. There are a few reports of PET and MR images revealing EC associated with LS. A 63-year-old female patient presented with postmenopausal intermittent vaginal bleeding. Transvaginal ultrasonography showed a small amount of bleeding in the uterine cavity and no thickening of the endometrium. The levels of relevant tumor markers were all within normal ranges. The endometrial cytology examination hint to possible endometrial adenocarcinoma. The hybrid 18F-fluorodeoxyglucose (18F-FDG) positron emission tomographymagnetic resonance (PETMR) images showed a polypoid mass in the lower uterine segment and unexpectedly found a mass in the descending colon. A colonoscopy confirmed that there was a colon adenocarcinoma in the same place as the PETMR images. Thus, LS was suspected even though this patient did not match the clinical diagnostic criteria. The gene analysis of both tumors was performed to identify microsatellite instability (MSI) for the diagnosis of Lynch syndrome. Postoperative adjuvant therapy and follow-up protocol customized for patients with Lynch syndrome. This case highlights that hybrid 18F-FDG PETMR imaging could play a key role in the screening for Lynch syndrome in EC patients.

Microenvironment and the progress of immunotherapy in clinical practice of NSCLC brain metastasis.

One of the most frequent distant metastases of lung cancer occurs in the brain. The average natural survival duration for patients with lung cancer who have brain metastases is about 1 to 2 months. Knowledge about brain metastases is currently restricted since they are more difficult to acquire than other metastases. This review begins with an analysis of the immune microenvironment of brain metastases focuses primarily on the functions of microglia, astrocytes, neurons, and tumor-infiltrating lymphocytes in the microenvironment of brain metastases and offers an atlas of the immune microenvironment of brain metastases involving significant cells. In an effort to give researchers new research ideas, the study also briefly covers how immunotherapy for non-small cell lung cancer with brain metastases is currently faring.

Clinical utility of serum glial fibrillary acidic protein in glial neoplasm.

Glial fibrillary acidic protein (GFAP) is a member of the cytoskeletal protein family and is widely expressed in astroglial and neural stem cells, also in glial tumors such as astrocytoma and Glioblastoma (GBM). Increased GFAP expression and disruption of the blood-brain barrier are the characteristic features of GBM. Higher serum GFAP levels can help differentiate GBM from GBM mimics (such as primary central nervous system lymphoma, metastasis, or demyelinating lesions). This prospective study was carried out in a tertiary care center in the department of neurosurgery on newly diagnosed glioma patients who underwent surgery from January 2018 to July 2019, excluded patients with history of the previous surgery for glioma, traumatic brain injury, and ischemic or hemorrhagic stroke. The blood sample was obtained at admission before undergoing invasive procedure. Pathological examination of the tumor biopsy sample was carried out using classical hematoxylin-eosin and immunohistochemical staining. All statistical analyses were performed using SPSS version 24.0. The mean preoperative tumor volume was 40 cm Increasing serum GFAP levels in the preoperative period correlate with higher tumor grade, especially grade III and grade IV tumors. The serum GFAP levels showed relation to tumor volume, both before and after surgery.

The efficacy and safety of quinagolide in hyperprolactinemia treatment A systematic review and meta-analysis.

Three dopamine agonists bromocriptine, cabergoline, and quinagolide (CV) have been used for hyperprolactinemia treatment for decades. Several studies have reviewed the efficacy and safety of bromocriptine and cabergoline. However, no systematic review or meta-analysis has discussed the efficacy and safety of CV in hyperprolactinemia and prolactinoma treatment. Five medical databases (PubMed, Web of Science, Embase, Scopus, and Cochrane Library) were searched up to 9 May 2022 to identify studies related to CV and hyperprolactinemia. A meta-analysis was implemented by using a forest plot, funnel plot, sensitivity analysis, meta-regression, and Eggers test A total of 1,211 studies were retrieved from the five medical databases, and 33 studies consisting of 827 patients were finally included in the analysis. The pooled proportions of patients with prolactin concentration normalization and tumor reduction (>50%) under CV treatment were 69% and 20%, respectively, with 95% confidence intervals of 61%-76% and 15%-28%, respectively. The pooled proportion of adverse effects was 13%, with a 95% confidence interval of 11%-16%. Our study showed that CV is not less effective than cabergoline and bromocriptine in treating hyperprolactinemia, and the side effects were not significant. Hence, this drug could be considered an alternative first-line or rescue treatment in treating hyperprolactinemia in the future. httpswww.crd.york.ac.ukPROSPERO, identifier CRD42022347750.

Transcranial near-infrared laser improves postoperative neurocognitive disorder in aged mice

Postoperative neurocognitive disorder (PND) is a common central nervous system (CNS) complication that might increase the morbidity and mortality of elderly patients after anesthesiasurgery. Neuroinflammation, oxidative stress, and synaptic dysfunction are closely related to cognitive dysfunction, an important clinical feature of PND. Transcranial near-infrared laser (TNIL) is regarded as an effective treatment for cognitive-related diseases by improving mitochondrial function and alleviating neuroinflammation and oxidative stress damage. Aged male C57BL6 mice underwent a carotid artery exposure procedure under isoflurane anesthesia. We treated PND-aged mice for three consecutive days (4 h post-operation, 1-laser) with 810 nm continuous wave (CW) laser 18 Jcm The results demonstrated that TNIL improved PND and the levels of synaptic function-associated proteins such as post-synaptic density protein 95 (PSD95), synaptophysin (SYP), and brain-derived neurotrophic factor (BDNF). Besides, neuroinflammatory cytokine levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β as well as microglia activation and oxidative stress damage were attenuated after TNIL treatment in aged mice with PND. Further investigation suggested that TNIL relieved oxidative stress response by activating the SIRT3AMPKNrf2 pathway. Transcranial near-infrared laser improved cognitive impairment in aged mice with PND, which may be a promising therapeutic for PND.

Clinical characteristics, surgical management, and prognostic factors for supratentorial hemangioblastoma A retrospective study.

Supratentorial hemangioblastoma is an extremely rare neoplasm. The aim of this study is to delineate the clinical features among cystic and solid supratentorial hemangioblastoma patients and evaluate the risk factors for progression-free survival (PFS). We conducted a literature search in PubMed for histopathologically identified supratentorial hemangioblastoma between 1947 and 2021 and extracted and collected the clinical features of patients treated at our own institute. The rate of PFS was determined using Kaplan-Meier analysis. Differences in categorical factors, such as the location of tumor and diagnosis of von Hippel-Lindau disease, were analyzed using the Pearson A total of 237 cases of supratentorial hemangioblastoma were identified from 169 studies. A survival analysis found that patients with cystic tumors had a significantly better prognosis than those with solid tumors (log-rank, Cystic hemangioblastoma vs. solid hemangioblastoma may be two tumoral statuses with different clinical features, and a specific treatment strategy should be considered.

Neuroprotective Efficacy of Europinidin in Streptozotocin-Induced Memory Impairment by Modulation of Oxidative Stress, Inflammatory Mediators, and Cholinesterase Activity in Rats.

Oral acute toxicity studies were performed to evaluate the toxicological effects of europinidin in animals. In this study, four different animal groups ( The rats in the europinidin-treated group exhibited a significant restoration of body weight and blood glucose level as compared with the streptozotocin control group. Furthermore, europinidin significantly modulated the spatial and working memory in rats, when assessed through behavioural paradigms. Streptozotocin caused a significant alteration in biochemical, neuronal enzymatic, and neuroinflammatory parameters, which were significantly restored to normal levels by europinidin. The present study attributed the neuroprotective efficacy of europinidin in experimental animal models by subsiding the several biomarkers of oxidative stress, neuroinflammation, and neuronal enzymatic activities.

Lipocalin 2 induces visual impairment by promoting ferroptosis in retinal ischemia-reperfusion injury.

Retinal ischemia-reperfusion (RIR) is a common pathological condition that can lead to retinal ganglion cell (RGC) death and visual impairment. However, the pathogenesis of RGC loss and visual impairment caused by retinal ischemia remains unclear. A mouse model of elevated intraocular pressure (IOP)-induced RIR injury was used. Flash visual evoked potentials (FVEPs) and electroretinography (ERG) recordings were performed to assess visual function. The structural integrity of the retina and the number of RGC were assessed using hematoxylin and eosin (HE) staining and retinal flat mounts. Ferroptosis was evaluated by testing the levels of glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase (GPX4), and ferritin light chains (FTL) in the retina of wild-type (WT) and lipocalin-2 transgenic ( We found that LCN2 was mainly expressed in the RGC layer in the retina of wild-type mice and remarkably upregulated after RIR injury. Compared with wild-type mice, aggravated RGC death and visual impairment were exhibited in Our study provides important insights linking upregulated LCN2-mediated promotion of ferroptosis to RGC death and visual function impairment in the pathogenesis of ischemic retinopathy.

Evolving indications for pediatric neurointerventional radiology A single institutional 25-year experience in infants less than one year of age and a brief historical review.

Pediatric neurointerventional radiology is an evolving subspecialty with growing indications and technological advancement such as miniaturization of devices and decreased radiation dose. The ability to perform these procedures is continuously balanced with necessity given the inherently higher risks of radiation and cerebrovascular injury in infants. The purpose of this study is to review our institutions neurointerventional experience in infants less than one year of age to elucidate trends in this patient population. We retrospectively identified 132 patients from a neurointerventional database spanning 25 years (1997-2022) who underwent 226 procedures. Treatment type, indication, and location as well as patient demographics were extracted from the medical record. Neurointerventional procedures were performed as early as day of life 0 in a patient with an arteriovenous shunting malformation. Average age of intervention in the first year of life is 5.9 months. Thirty-eight of 226 procedures were completed in neonates. Intra-arterial chemotherapy (IAC) for the treatment of retinoblastoma comprised 36% of neurointerventional procedures completed in infants less than one year of age followed by low flow vascular malformations (21.2%), vein of Galen malformations (11.5%), and dural arteriovenous fistulas (AVF) (9.3%). Less frequent indications include non-Galenic pial AVF (4.4%) and tumor embolization (3.0%). The total number of interventions has increased secondary to the onset of retinoblastoma treatment in 2010 at our institution. The introduction of IAC for the treatment of retinoblastoma in the last decade is the primary driver for the increased trend in neurointerventional procedures completed in infants from 1997 to 2022.

Radiation-Triggered Selenium-Engineered Mesoporous Silica Nanocapsules for RNAi Therapy in Radiotherapy-Resistant Glioblastoma.

Radiotherapy-resistant glioblastoma (rrGBM) remains a significant clinical challenge because of high infiltrative growth characterized by activation of antiapoptotic signal transduction. Herein, we describe an efficiently biodegradable selenium-engineered mesoporous silica nanocapsule, initiated by high-energy X-ray irradiation and employed for at-site RNA interference (RNAi) to inhibit rrGBM invasion and achieve maximum therapeutic benefit. Our radiation-triggered RNAi nanocapsule showed high physiological stability, good blood-brain barrier transcytosis, and potent rrGBM accumulation. An intratumoral RNAi nanocapsule permitted low-dose X-ray radiation-triggered dissociation for cofilin-1 knockdown, inhibiting rrGBM infiltration. More importantly, tumor suppression was further amplified by electron-affinity aminoimidazole products converted from metronidazole polymers under X-ray radiation-exacerbated hypoxia, which sensitized cell apoptosis to ionizing radiation by fixing reactive oxygen species-induced DNA lesions. In vivo experiments confirmed that our RNAi nanocapsule reduced tumor growth and invasion, prolonging survival in an orthotopic rrGBM model. Generally, we present a promising radiosensitizer that would effectively improve rrGBM-patient outcomes with low-dose X-ray irradiation.

Common molecular features of H3K27M DMGs and PFA ependymomas map to hindbrain developmental pathways.

Globally decreased histone 3, lysine 27 tri-methylation (H3K27me3) is a hallmark of H3K27-altered diffuse midline gliomas (DMGs) and group-A posterior fossa ependymomas (PFAs). H3K27-altered DMGs are largely characterized by lysine-to-methionine mutations in histone 3 at position 27 (H3K27M). Most PFAs overexpress EZH inhibitory protein (EZHIP), which possesses a region of similarity to the mutant H3K27M. Both H3K27M and EZHIP inhibit the function of the polycomb repressive complex 2 (PRC2) responsible for H3K27me3 deposition. These tumors often arise in neighboring regions of the brainstem and posterior fossa. In rare cases PFAs harbor H3K27M mutations, and DMGs overexpress EZHIP. These findings together raise the possibility that certain cell populations in the developing hindbrainposterior fossa are especially sensitive to modulation of H3K27me3 states. We identified shared molecular features by comparing genomic, bulk transcriptomic, chromatin-based profiles, and single-cell RNA-sequencing (scRNA-seq) data from the two tumor classes. Our approach demonstrated that 1q gain, a key biomarker in PFAs, is prognostic in H3.1K27M, but not H3.3K27M gliomas. Conversely, Activin A Receptor Type 1 (ACVR1), which is associated with mutations in H3.1K27M gliomas, is overexpressed in a subset of PFAs with poor outcome. Despite diffuse H3K27me3 reduction, previous work shows that both tumors maintain genomic H3K27me3 deposition at select sites. We demonstrate heterogeneity in shared patterns of residual H3K27me3 for both tumors that largely segregated with inferred anatomic tumor origins and progenitor populations of tumor cells. In contrast, analysis of genes linked to H3K27 acetylation (H3K27ac)-marked enhancers showed higher expression in astrocytic-like tumor cells. Finally, common H3K27me3-marked genes mapped closely to expression patterns in the human developing hindbrain. Overall, our data demonstrate developmentally relevant molecular similarities between PFAs and H3K27M DMGs and support the overall hypothesis that deregulated mechanisms of hindbrain development are central to the biology of both tumors.

Intraoperative hypovolemia as a possible precipitating factor for pituitary apoplexy a case report.

Pituitary apoplexy is acute infarction with or without hemorrhage of the pituitary gland. It is a rare but potentially life-threatening emergency that most commonly occurs in the setting of pituitary adenoma. The mechanisms underlying pituitary apoplexy are not well understood, but are proposed to include factors of both hemodynamic supply and adenoma demand. In the case of patients with known pituitary macroadenomas undergoing major surgery for other indications, there is a theoretically increased risk of apoplexy in the setting of surgical stress. However, risk stratification of patients with nonfunctioning pituitary adenomas prior to major surgery is challenging because the precipitating factors for pituitary apoplexy are not completely understood. Here we present a case in which intraoperative hypovolemia is a possible mechanistic precipitating factor for pituitary apoplexy. A 76-year-old patient with a known hypofunctioning pituitary macroadenoma underwent nephrectomy for renal cell carcinoma, during which there was significant intraoperative blood loss. He became symptomatic with ophthalmoplegia on the second postoperative day, and was diagnosed with pituitary apoplexy. He was managed conservatively with cortisol replacement therapy, and underwent therapeutic anticoagulation 2 months after pituitary apoplexy for deep vein thrombosis. His ophthalmoplegia slowly resolved over months of follow-up. Pituitary apoplexy did not recur with therapeutic anticoagulation. When considering the risk of surgery in patients with a known pituitary macroadenoma, an operation with possible high-volume intraoperative blood loss may have increased risk of pituitary apoplexy because intraoperative hypovolemia may precipitate ischemia, infarction, and subsequent hemorrhage. This may be particularly relevant in the cases of elective surgery. Additionally, we found that we were able to therapeutically anticoagulate a patient 2 months after pituitary apoplexy for the management of deep vein thrombosis without recurrence of pituitary apoplexy.

Pan-cancer analysis predictive role of TAP1 in cancer prognosis and response to immunotherapy.

Transporter associated with antigen processing 1 (TAP1) is a molecule involved in processing and presentation of major histocompatibility complex class I restricted antigens, including tumor-associated antigens. TAP1 participates in tumor immunity, and is aberrantly expressed in multiple cancer types METHODS Transcriptome profiles were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression databases. Genetic alterations, protein distribution, and interaction information for TAP1 were downloaded from cBioPortal, Human Protein Atlas and Compartmentalized Protein-Protein Interaction, respectively. Single-cell analyses of TAP1 across cancers were conducted via the Tumor Immune Single-cell Hub website. Gene set enrichment analysis was employed to investigate TAP1-associated functional mechanisms and processes. Immune cell infiltration was explored using Tumor Immune Estimation Resource 2.0. Pan-cancer correlations between TAP1 expression and immunotherapy biomarkers were explored using the Spearmans correlation test. Associations with immunotherapy responses were also investigated using clinicopathological and prognostic information from cohorts of patients with cancer receiving immune checkpoint inhibitors. TAP1 expression was elevated in most cancer types and exhibited distinct prognostic value. Immune cells expressed more TAP1 than malignant cells within most tumors. TAP1 expression was significantly correlated with immune-related pathways, T-lymphocyte infiltration, and immunotherapeutic biomarkers. Clinical cohort validation revealed a significant correlation with immune therapeutic effects and verified the prognostic role of TAP1 in immunotherapy. Western blot assay indicated that TAP1 is upregulated in glioblastoma compared with adjacent normal brain tissues. TAP1 is a robust tumor prognostic biomarker and a novel predictor of clinical prognosis and immunotherapeutic responses in various cancer types.

The phosphorylation of PHF5A by TrkA-ERK12-ABL1 cascade regulates centrosome separation.

During interphase, the newly duplicated pairs of centrosomes are held together by a centrosome linker, and the centrosome separation needs the disruption of this linker to induce the duplicated centrosomes separating into two distinct microtubule organization centers. The mechanism of regulating centrosome separation is however poorly understood. Here, we demonstrated that the phosphorylation of PHF5A at Y36 by the TrkA-ERK12-ABL1 cascade plays a critical role in regulating centrosome separation. PHF5A, a well-characterized spliceosome component, is enriched in the centrosome. The pY36-PHF5A promotes the interaction between CEP250 and Nek2A in a spliceosomal-independent manner, which leads to premature centrosome separation. Furthermore, the unmatured centrosome remodels the microtubule and subsequently regulates cell proliferation and migration. Importantly, we found that the phosphorylation cascade of TrkA-ERK12-ABL1-PHF5A is hyper-regulated in medulloblastoma. The inhibition of this cascade can induce senescence and restrict the proliferation of medulloblastoma. Our findings on this phosphorylation cascade in regulating centrosome separation could provide a series of potential targets for restricting the progress of medulloblastoma.

FGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells.

Although tissue-resident memory T (T

Initial experience with Scepter Mini dual lumen balloon for embolization of cerebrovascular diseases.

Endovascular treatment of cerebrovascular diseases is often challenging due to small caliber, tortuous distal vessels. Several devices and techniques have evolved to overcome these challenges. Recently, a low profile dual lumen microballoon catheter, specifically designed for distal navigation is employed for neurovascular procedures. Due to its recent advent, scarce data is available on clinical utility and safety of Scepter Mini. The aim of this case series is to report our initial experience with Scepter Mini in the management of various cerebrovascular diseases. All interventional neurovascular cases performed using Scepter Mini between January 2020 till April 2021 were included. Data regarding patient demographics, procedural details and complications was retrospectively collected from patients electronic medical record and procedure reports. Total twelve embolization procedures were performed in eleven patients, including six brain arteriovenous malformation, two dural arteriovenous fistula, one vein of Galen malformation and three hyper-vascular glomus tumor embolizations. All procedures were successfully performed with adequate penetration of the embolic agent. Complete embolization was performed in six procedures, while intended partial embolization was performed in the rest of procedures. Scepter Mini was solely used in ten procedures, however in the other two embolization procedures it was used as an additional conjunct tool to complete the intended embolization. No balloon related complication was observed in any procedure. Scepter Mini dual lumen microballoon catheter is safe and feasible for delivery of liquid embolic agents for cerebrovascular embolization procedures.

IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM.

The immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression of IL15 is one attractive strategy to modulate the TME. However, at present, it is unclear if IL15 could be used to directly target myeloid-derived suppressor cells (MDSCs), a major cellular component of the GBM TME. Here, we explored if MDSC express IL15Rα and the feasibility of exploiting its expression as an immunotherapeutic target. RNA-seq, RT-qPCR, and flow cytometry were used to determine IL15Rα expression in paired peripheral and tumor-infiltrating immune cells of GBM patients and two syngeneic murine GBM models. We generated murine T cells expressing IL13Rα2-CARs and secretory IL15 (CAR.IL15s) or IL13Rα2-CARs in which IL15 was fused to the CAR to serve as an IL15Rα-targeting moiety (CAR.IL15f), and characterized their effector function in vitro and in syngeneic IL13Rα2glioma models. IL15Rα was preferentially expressed in myeloid, B, and dendritic cells in patients and syngeneic GBMs. In vitro, CAR.IL15s and CAR.IL15f T cells depleted MDSC and decreased their secretion of immunosuppressive molecules with CAR.IL15f T cells being more efficacious. Similarly, CAR.IL15f T cells significantly improved the survival of mice in two GBM models. TME analysis showed that treatment with CAR.IL15f T cells resulted in higher frequencies of CD8T cells, NK, and B cells, but a decrease in CD11bcells in tumors compared with therapy with CAR T cells. We demonstrate that MDSC of the glioma TME express IL15Ra and that these cells can be targeted with secretory IL15 or an IL15Rα-targeting moiety incorporated into the CAR. Thus, IL15-modified CAR T cells act as a dual targeting agent against tumor cells and MDSC in GBM, warranting their future evaluation in early-phase clinical studies.

Single-Cell Analysis of Unidirectional Migration of Glioblastoma Cells Using a Fiber-Based Scaffold.

Glioblastoma (GBM) is a malignant incurable brain tumor in which immature neoplastic cells infiltrate brain tissue by spreading along nerve fibers. The aim of the study was to compare the migration abilities of glioma cells with those of other cancer cells and elucidate the migratory profiles underlying the differential migration of glioma cells using a fiber-based quantitative migration assay. Here, wound healing and transwell assays were used to assess cell mobility in four cell lines U87-MG glioblastoma cells, MDA-MB-231 breast cancer cells, HCT116 colorectal cancer cells, and MKN45 gastric cancer cells. We also assessed cell mobility using a fiber model that mimics nerve fibers. Time-lapse video microscopy was used to observe cell migration and morphology. The cytoskeleton arrangement was assessed in the fiber model and compared with that in the conventional cell culture model. The conventional evaluation of cell migration ability revealed that the migration ability of breast cancer and glioblastoma cell lines was higher than that of colon cancer and gastric cancer cell lines. The fiber model confirmed that the glioblastoma cell line had a significantly higher migration ability than other cell lines. Tubulin levels were significantly higher in the glioblastoma cells than in other cell lines. In conclusion, the developed fiber-based culture model revealed the specific migratory profile of GBM cells during invasion.

A method for non-destructive microwave focusing for deep brain and tissue stimulation.

Non-invasive stimulation of biological tissue is highly desirable for several biomedical applications. Of specific interest are methods for tumor treatment, endometrial ablation, and neuro-modulation. In traditional neuro-modulation, single- and multi-coil transcranial stimulation techniques in low oscillation frequencies are utilized to non-invasively penetrate the skull and elicit action potentials in cortical neurons. Although these methods have been proven effective, tightly focusing these signals to localized regions is difficult. In recent years, microwave (MW) methods have seen an increase usage as a minimally invasive treatment modality for ablation and neuro-stimulation. Unlike low frequency signals, MW signals can be focused to localized sub-centimeter regions. In this work we demonstrate that a three-dimensional array of MW antennas can be used to tightly focus signals to a localized region in space within the human body with MW frequencies. Assuming an array of small MW loop antennas are placed around the body, the optimal amplitude and phase of each array element can be accurately determined to match an arbitrary desired field profile. The major innovation of the presented method is that the fields that penetrate the biological region are determined via computing numerical Greens functions (NGF) that are then used to drive an optimization algorithm. Using simplified models of regions in the human body, it is shown that the MW fields at 1 GHz can be focused to sub-centimeter sized hot spots at depths of several centimeters. The algorithm can be easily extended to more realistic models of the human body or for non-biological applications.

Immunostaining protocol for infiltrating brain cancer spheroids for light-sheet imaging.

Glioblastoma tumors form in brains white matter and are fast-growing and aggressive. Poor prognosis is the result of therapeutic resistance and infiltrating growth into the surrounding brain. Here we present a protocol for the detection of the cytoskeleton intermediate filament, vimentin, in cells at the proliferating spheroid surface. By combining a classical invasion assay with immunofluorescence and light-sheet imaging, we find that it is exactly these cytoskeleton-reinforcing cells on the spheroids surface that will start the infiltration. We anticipate our results to be the starting point of more sophisticated investigation of anti-cancer drug effects on cytoskeleton reorganisation.

Structural and Molecular Fusion MRI Nanoprobe for Differential Diagnosis of Malignant Tumors and Follow-Up Chemodynamic Therapy.

Enhanced imaging techniques using contrast agents enable high-resolution structural imaging to reveal space-occupying lesions but rarely provide detailed molecular information. To this end, we report a structural and molecular fusion magnetic resonance imaging (MRI) nanoprobe for differential diagnosis between benign and malignant tumors. This fusion nanoprobe, termed FFT NPs, follows a working mechanism involving a

Do animal models of brain tumors replicate human peritumoral edema a systematic literature search.

Brain tumors cause morbidity and mortality in part through peritumoral brain edema. The current main treatment for peritumoral brain edema are corticosteroids. Due to the increased recognition of their side-effect profile, there is growing interest in finding alternatives to steroids but there is little formal study of animal models of peritumoral brain edema. This study aims to summarize the available literature. A systematic search was undertaken of 5 literature databases (Medline, Embase, CINAHL, PubMed and the Cochrane Library). The generic strategy was to search for various terms associated with brain tumors, brain edema and animal models. We identified 603 reports, of which 112 were identified as relevant for full text analysis that studied 114 peritumoral brain edema animal models. We found significant heterogeneity in the species and strain of tumor-bearing animals, tumor implantation method and edema assessment. Most models did not produce appreciable brain edema and did not test for observable manifestations thereof. No animal model currently exists that enable the investigation of novel candidates for the treatment of peritumoral brain edema. With current interest in alternative treatments for peritumoral brain edema, there is an unmet need for clinically relevant animal models.

Modeling brain and neural crest neoplasms with human pluripotent stem cells.

Pluripotent stem cells offer unique avenues to study human-specific aspects of disease and are a highly versatile tool in cancer research. Oncogenic processes and developmental programs often share overlapping transcriptomic and epigenetic signatures, which can be reactivated in induced pluripotent stem cells. With the emergence of brain organoids, the ability to recapitulate brain development and structure has vastly improved, making in vitro models more realistic and hence more suitable for biomedical modeling. This review highlights recent research and current challenges in human pluripotent stem cell modeling of brain and neural crest neoplasms, and concludes with a call for more rigorous quality control and for the development of models for rare tumor subtypes.

Efficient detection and monitoring of pediatric brain malignancies with liquid biopsy based on patient-specific somatic mutation screening.

Brain cancer is the leading cause of cancer-related death in children. Early detection and serial monitoring are essential for better therapeutic outcomes. Liquid biopsy has recently emerged as a promising approach for detecting these tumors by screening body fluids for the presence of circulating tumor DNA (ctDNA). Here we tested the limits of liquid biopsy using patient-specific somatic mutations to detect and monitor primary and metastatic pediatric brain cancer. Somatic mutations were identified in 3 ependymoma, 1 embryonal tumor with multilayered rosettes, 1 central nervous system neuroblastoma and 7 medulloblastoma patients. The mutations were used as liquid biomarkers for serial assessment of cerebrospinal fluid (CSF) samples using a droplet digital PCR (ddPCR) system. The findings were correlated to the imaging data and clinical assessment to evaluate the utility of the approach for clinical translation. We developed personalized somatic mutation ddPCR assays which we show are highly specific, sensitive and efficient in detection and monitoring of ctDNA, with a positive correlation between presence of ctDNA, disease course and clinical outcomes in the majority of patients. We demonstrate the feasibility and clinical utility of personalized mutation-based liquid biopsy for the surveillance of brain cancer in children. However, even with this specific and sensitive approach, we identified some potential false negative analyses. Overall, our results indicate that changes in ctDNA profiles over time demonstrate the great potential of our specific approach for predicting tumor progression, burden, and response to treatment.

Application of ethmoid artery pedicled septal floor mucosa flap in repair of postoperative cerebrospinal fluid leak after transsphenoidal pituitary surgery.

Multi-organ carcinogenicity by inhalation exposure to 2-Bromopropane in rats.

The purpose of this study was to investigate the carcinogenicity of 2-bromopropane (2-BP) in rats. Male and female F344 rats were exposed by whole body inhalation to 2-BP vapor at concentrations of 0, 67, 200, and 600 ppm for 6 hday, 5 daysweek for 2 years. All rats of both sexes exposed to 600 ppm died or became moribund within 85 weeks. Deathmoribundity was caused by 2-BP induced tumors. In males, significantly increased tumors were malignant Zymbals gland tumors sebaceous adenoma and basal cell carcinoma of the skinappendage adenocarcinoma of the smalllarge intestine follicular cell adenoma of the thyroid fibroma of the subcutis, and malignant lymphoma of the lymph node. In addition, an increased trend in tumor incidence was found in the preputial gland, lung, forestomach, pancreas islet, brain, and spleen. In females, significantly increased tumors were adenocarcinoma and fibroadenoma of the mammary gland, squamous cell papilloma of the vagina, and large granular lymphocytic leukemia of the spleen. In addition, an increased trend in tumor incidence was found in Zymbals gland, the clitoral gland, skin, large intestine, pancreas islet, uterus, and subcutis. Particularly, malignant Zymbals gland tumors were induced even in males exposed to the lowest concentration, 67 ppm. Two-year inhalation exposure to 2-BP resulted in multi-organ carcinogenicity in rats. Based on sufficient evidence of carcinogenicity in this study, 2-BP has the potential to be a human carcinogen.

Prognostic Factors of Gliosarcoma in the Real World A Retrospective Cohort Study.

Gliosarcoma is a histopathological variant of glioblastoma, which is characterized by a biphasic growth pattern consisting of glial and sarcoma components. Owing to its scarcity, data regarding the impact of available treatments on the clinical outcomes of gliosarcoma are inadequate. The purpose of this retrospective cohort study was to analyze the prognostic factors of gliosarcoma. By screening the clinical database of neurosurgical cases at a single center, patients with gliosarcoma diagnosed histologically from 2013 to 2021 were identified. Clinical, pathological, and molecular data were gathered founded on medical records and follow-up interviews. Prognostic factors were derived using the Cox proportional hazards model with backward stepwise regression analysis. Forty-five GSM patients were included. Median overall survival was 25.6 months (95% CI 8.0-43.1), and median relapse-free survival was 15.2 months (95% CI 9.7-20.8). In multivariable analysis, total resection ( This single-center retrospective study with a limited cohort size has demonstrated the treatment of gross total resection and low expression of Ki-67 which are beneficial for patients with GSM, while radiotherapy or temozolomide is not.

Rapid disease progression on immune checkpoint inhibitors in young patients with stage IV melanoma.

Immune checkpoint inhibitors (ICIs) are the standard of care for metastatic cutaneous melanoma (mCM) patients, but their efficacy in young adults aged less than 40 years remains unclear. We retrospectively analyzed 303 stage IV melanoma patients of different ages treated with nivolumab, pembrolizumab, or ipilimumab plus nivolumab combination therapy. Clinical data and blood values such as LDH, CRP, and absolute immune cell counts were retrieved from the medical records. Pre-treatment serum concentrations of soluble immune checkpoint proteins were measured using ELISA. In addition, information on frequencies of various T cell subsets in the peripheral blood was collected from a previously reported study (ELEKTRA). Patient characteristics and clinical information was correlated with PFS and OS using univariate and multivariate cox regression analysis. Of 303 patients, 33 (11%) were ≤ 40 years old. The older patients had a median age of 64 (95% CI 61-66). Concerning prognostic parameters, there was no difference between the age groups, e.g., in gender, LDH, or the existence of brain or liver metastases. Patients aged ≤ 40 years Young patients with stage IV melanoma may experience shorter progression-free survival upon ICI treatment compared to patients above 40 years and are characterized by fewer basophils and memory T cells in the blood.

Epidemiology and survival of patients with central nervous system solitary fibrous tumors A population-based analysis.

The objective of this study was to determine population-based estimates of the epidemiology and prognosis of central nervous system solitary fibrous tumors (cSFTs). We extracted the data of patients diagnosed with cSFTs between 2004 and 2018 from the Surveillance, Epidemiology, and End Results database. We analyzed the distribution of patients according to their demographic and clinical characteristics. Binary logistic regression analysis was performed to predict which patients would be diagnosed with malignant cSFT. Possible prognostic indicators were analyzed by multivariable Cox proportional hazards models. A total of 650 cases were included. The majority of patients were diagnosed at 50-59 years old, and the median age at diagnosis was 55 years. A total of 13.4% of the tumors were located in the spinal canal, and 24% of the tumors were benign. Most of the tumors were larger than 3 cm, but distant metastasis was rare. Tumor resection was the first choice of treatment for these patients, and total resection was achieved in 51.1%. Radiation therapy after surgery was also administered to 42.3% of the patients. The median survival was 57 months. Intracranial tumors and tumors with distant metastasis tended to be malignant. The results of the log-rank test showed that the patients who underwent total resection had better overall survival (OS), but the effect of radiation therapy after surgery was not significant. cSFT is a rare and aggressive type of tumor. Tumor resection is the first choice for treatment, and radiation therapy after surgery does not improve OS. Patients older than 60 years of age who are diagnosed with intracranial tumors, malignant tumors and distant metastasis have worse OS outcomes than their counterparts.

Multiscale reconstruction of bronchus and cancer cells in human lung adenocarcinoma.

While previous studies primarily focused on the structure of the normal whole mouse lung, the whole bronchus and cytoarchitectural details of the mouse intact lung lobe have been discovered at single-cell resolution. Revealing the sophisticated lung adenocarcinoma structure at three-dimensional (3D) and single-cell level remains a fundamental and critical challenge for the pathological mechanism research of lung adenocarcinoma (LA). Fluorescence micro-optical Sectioning Tomography (fMOST) combined with PI staining were used to obtain the 3D imaging of the human LA tissue at single-cell resolution. With a spatial resolution of 0.32 × 0.32 × 1.0 μm Based on the human LA tissue dataset obtained by fMOST and PI staining, the bronchi and cells were reconstructed and visualized. This work provides a technical roadmap for studying the bronchus and cytoarchitectural structure and their spatial relationship in LA tissue, which may help with the understanding of the main histological structure of LA among pathologists.

Exosome-transmitted circCABIN1 promotes temozolomide resistance in glioblastoma via sustaining ErbB downstream signaling.

Although temozolomide (TMZ) provides significant clinical benefit for glioblastoma (GBM), responses are limited by the emergence of acquired resistance. Here, we demonstrate that exosomal circCABIN1 secreted from TMZ-resistant cells was packaged into exosomes and then disseminated TMZ resistance of receipt cells. CircCABIN1 could be cyclized by eukaryotic translation initiation factor 4A3 (EIF4A3) and is highly expressed in GBM tissues and glioma stem cells (GSCs). CircCABIN1 is required for the self-renewal maintenance of GSCs to initiate acquired resistance. Mechanistically, circCABIN1 regulated the expression of olfactomedin-like 3 (OLFML3) by sponging miR-637. Moreover, upregulation of OLFML3 activating the ErbB signaling pathway and ultimately contributing to stemness reprogramming and TMZ resistance. Treatment of GBM orthotopic mice xenografts with engineered exosomes targeting circCABIN1 and OLFML3 provided prominent targetability and had significantly improved antitumor activity of TMZ. In summary, our work proposed a novel mechanism for drug resistance transmission in GBM and provided evidence that engineered exosomes are a promising clinical tool for cancer prevention and therapy.

Effect of one-lung ventilation on the correlation between left and right cerebral saturation.

To investigate if the correlation between left and right cerebral tissue oxygen saturation (SctO Patients who underwent surgery for lung cancer were enrolled. Left and right SctO Left-right SctO The correlation between left and right SctO This study was a secondary analysis of a cohort study approved by the Clinical Research Review Board of Peking University First Hospital (2017-1378) and was registered in the Chinese Clinical Trial Registry on 10092017 ( httpwww.chictr.org.cn , ChiCTR-ROC-17012627).

Keratin-positive fibrotic extraskeletal myxoid chondrosarcoma a close mimic of myoepithelial tumor.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare form of adult sarcoma with distinct histology and NR4A3 gene fusion. Immunohistochemically, EMCs are variably positive for S100 protein and neuroendocrine markers. Unlike histologically similar soft-tissue myoepithelial tumors, keratin expression is rare. Prompted by two recent EMC cases with diffuse keratin expression, we investigated the expression of epithelial markers in a molecularly confirmed cohort of EMC and identified two additional similar cases. Four keratin-positive EMCs occurred in one man and three women aged 46-59 years. All tumors displayed non-classic histology with prominent stromal fibrosis, and keratin AE1AE3 was expressed either diffusely (N 2) or focally (N 2). In one tumor, keratin expression was limited to the sclerotic area. All tumors co-expressed epithelial membrane antigen and two additionally expressed S100 protein or glial fibrillary acidic protein. All tumors harbored NR4A3 fusions including TAF15NR4A3 (N 1) and EWSR1NR4A3 (N 3). Two cases were initially considered as most consistent with myoepithelial tumors based on widespread stromal fibrosis and keratin expression. DNA methylation analysis classified two tumors tested as EMCs. We identified a small subset of EMCs characterized by keratin expression and prominent stromal fibrosis. This histological pattern must be recognized in the differential diagnosis of myoepithelial tumors because misclassification may lead to the erroneous prediction of tumor behavior and may alter patient management. NR4A3 genetic analysis should be considered even in the face of keratin expression and prominent stromal fibrosis.

Association of Employment Status With Symptom Burden and Health-Related Quality of Life in People Living With Primary CNS Tumors.

Financial toxicity significantly impacts many patients, especially cancer survivors. We evaluated the association of unemployment as a major contributor to financial toxicity with patient-reported outcomes (PROs) assessing multiple illness experience domains in a primary CNS tumor (PCNST) cohort. Patient and disease characteristics and PROs measuring symptom burden, interference, psychologic distress, functional impairment, and health-related quality of life (HRQOL) from participants enrolled an IRB-approved observational study at the US National Institutes of Healths Neuro-Oncology Branch were collected between 92016-122019. Descriptive statistics, tests of association, and comparison of group means were used to describe and evaluate PROs. Of the 277 participants diagnosed with a PCNST, 57% were male and 43% were female. Participants reported their race as White, non-Hispanic (78%) White, HispanicLatino (9%) Asian (7%) Black (4%) Native HawaiianPacific Islander (1%) other (2%) with 8% missing. The median age of the overall cohort was 45 years (range 18-74). Hispanic participants in the overall sample were 2.3 times more likely, and in the brain tumor group 3.2 times more likely, to report unemployment ( Being unemployed due to a PCNST strongly correlated with high symptom burden, functional impairment, psychological distress and reduced HRQOL which may be impediments to returning to work that warrant intervention. Lack of employer-based health insurance and reduced earnings are financial sequelae of unemployment superimposed on the physical, social, and cognitive effects of living with a PCNST. Innovations to screen for and address financial toxicity and its contributing factors are needed.

Astrocytoma (CNS WHO grade 4), IDH-mutant with co-occurrence of BRAF p.V600E mutation, and homozygous loss of CDKN2A.

Molecular alterations nowadays play a crucial role in the diagnosis of brain tumors. Some of these alterations are associated with outcome andor response to treatment, including sequence variants of isocitrate dehydrogenase (IDH) at position p.R132 or p.R172. Such IDH variants have so far been described in histone H3-wildtype primary brain tumors only in adult-type diffuse gliomas and are associated with a better outcome compared to their IDH-wildtype counterpart, the glioblastoma. Moreover, homozygous loss of CDKN2A andor CDKN2B in IDH-mutant astrocytomas shortens the median overall survival regardless of histological features of malignancy. Such tumors are therefore considered to be aggressive and graded as WHO central nervous system (CNS) grade 4 lesions. The coexistence of an IDH-sequence variation and a BRAF p.V600E alteration has only rarely been described in diffuse astrocytomas. Due to the small number of cases, little is known about such neoplasms in terms of clinical behavior and response to treatment. Herein we describe the first case, to our knowledge, of an astrocytoma (CNS WHO grade 4), IDH-mutant, and BRAF p.V600E-mutant with homozygous deletion of CDKN2A. Pathologists should be aware that such an expression profile does exist even in WHO CNS grade 4 astrocytomas, IDH-mutant, and are encouraged to test for the BRAF p.V600E sequence variant as such an alteration may provide additional treatment options.

Schwann cell-derived CXCL2 contributes to cancer pain by modulating macrophage infiltration in a mouse breast cancer model.

Pain is one of the most severe complications affecting the quality of life of cancer patients. Although substantial progress has been made in the diagnosis and treatment of cancer, the neurobiological mechanism of cancer pain is still unclear. In the present study, we identified the critical role of CXC chemokine 2 (CXCL2), released by Schwann cells after being activated by cancer cells, in maintaining cancer-induced macrophage infiltration and the resulting mechanical hypersensitivity and persistent spontaneous nociception. In vitro, Schwann cells cocultured with breast cancer cells exhibited a significant increase in CXCL2 expression in addition, conditioned medium from Schwann cells activated by breast cancer cells had a similar effect to recombinant CXCL2 in terms of inducing macrophage migration. Targeting CXCL2 signaling by both CXC chemokine receptor 2 (CXCR2) antagonist pharmacological blockade and anti-CXCL2 mAb immunological blockade robustly prevented conditioned medium-induced macrophage migration. In vivo, both application of recombinant CXCL2 and perineural breast cancer cell implantation resulted in mechanical hypersensitivity and persistent spontaneous nociception in mice, along with increased macrophage infiltration into the sciatic nerves. Similar to the in vitro results, inhibition of CXCL2CXCR2 signaling or conditional knockdown of CXCL2 in sciatic nerve Schwann cells effectively attenuated breast cancer cell-induced mechanical hypersensitivity, persistent spontaneous nociception, and macrophage recruitment in the sciatic nerve. Mechanistically, we found that redox effector factor-1 (Ref-1) secreted by breast cancer cells activated hypoxia inducible factor-1α (HIF-1α) expression and inhibited reactive oxygen species (ROS) production in Schwann cells, ultimately inducing CXCL2 expression in Schwann cells. In brief, the present study expands new insights into cancer pain mechanisms from promising animal models to provide new strategies for the control of cancer pain.

CB2R activation ameliorates late adolescent chronic alcohol exposure-induced anxiety-like behaviors during withdrawal by preventing morphological changes and suppressing NLRP3 inflammasome activation in the microglia of the prefrontal cortex in mice.

Chronic alcohol exposure (CAE) during late adolescence increases the risk of anxiety development. Alcohol-induced prefrontal cortex (PFC) microglial activation, characterized by morphological changes and increased associations with neurons, plays a critical role in the pathogenesis of anxiety. Alcohol exposure increases NLRP3 inflammasome expression, increasing cytokine secretion by activated microglia. Cannabinoid type 2 receptor (CB2R), an essential receptor of the endocannabinoid system, regulates microglial activation and neuroinflammatory reactions. We aimed to investigate the role of CB2R activation in ameliorating late adolescent CAE-induced anxiety-like behaviors and microglial activation in C57BL6J mice. Six-week-old C57BL6J mice were acclimated for 7 days and then were administered alcohol by gavage (4 gkg, 25% wv) for 28 days. The mice were intraperitoneally injected with the specific CB2R agonist AM1241 one hour before alcohol treatment. Anxiety-like behaviors during withdrawal were assessed by the open field test and elevated plus maze test 24 hours after the last alcohol administration. Microglial activation, microglia-neuron interactions, and CB2R and NLRP3 inflammasome-related molecule expression in the PFC were measured using immunofluorescence, immunohistochemical, qPCR, and Western blotting assays. Microglial morphology was evaluated by Sholl analysis and the cell body-to-total cell size index. Additionally, N9 microglia were activated by LPS in vitro, and the effects of AM1241 on NLRP3 and N9 microglial activation were investigated. After CAE, mice exhibited severe anxiety-like behaviors during withdrawal. CAE induced obvious microglia-neuron associations, and increased expression of microglial activation markers, CB2R, and NLRP3 inflammasome-related molecules in the PFC. Microglia also showed marked filament retraction and reduction and cell body enlargement after CAE. AM1241 treatment ameliorated anxiety-like behaviors in CAE model mice, and it prevented microglial morphological changes, reduced microglial activation marker expression, and suppressed the microglial NLRP3 inflammasome activation and proinflammatory cytokine secretion induced by CAE. AM1241 suppressed the LPS-induced increase in NLRP3 inflammasome-related molecules, IL-1β release, and M1 phenotype markers (iNOS and CD86) in N9 cell, which was reversed by CB2R antagonist treatment. CAE caused anxiety-like behaviors in late adolescent mice at least partly by inducing microglial activation and increasing microglia-neuron associations in the PFC. CB2R activation ameliorated these effects by preventing morphological changes and suppressing NLRP3 inflammasome activation in PFC microglia.

Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET.

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial tumors with variable recurrence rate. Currently, the recurrence prediction is unsatisfying and can be improved by understanding the cellular origins and differentiation status. Here, to comprehensively reveal the origin of PitNET, we perform comparative analysis of single-cell RNA sequencing data from 3 anterior pituitary glands and 21 PitNETs. We identify distinct genes representing major subtypes of well and poorly differentiated PitNETs in each lineage. To further verify the predictive value of differentiation biomarkers, we include an independent cohort of 800 patients with an average follow-up of 7.2 years. In both PIT1 and TPIT lineages, poorly differentiated groups show significantly higher recurrence rates while well-differentiated groups show higher recurrence rates in SF1 lineage. Our findings reveal the possible origin and differentiation status of PitNET based on which new differentiation classification is proposed and verified to predict tumor recurrence.

Cesium-131 brachytherapy for the treatment of brain metastases Current status and future perspectives.

Adjuvant radiotherapy is often necessary following surgical resection of brain metastases to improve local tumor control and survival. Brachytherapy using cesium-131 offers a novel method for loco-regional radiotherapy. We reviewed the current literature reporting the use of cesium-131 brachytherapy for the treatment of brain metastases. Published studies and ongoing trials were reviewed to identify treatment protocols and clinical outcomes of cesium-131 brachytherapy for brain metastases. Cesium-131 brachytherapy was further compared to current outcomes for iodine-125 brachytherapy and stereotactic radiosurgery. Intraoperative brachytherapy allows patients to receive two treatment modalities in one setting while minimizing tumor cell repopulation. After initial interest, the use of iodine-125 brachytherapy has declined due to unfavorable rates of radiation necrosis without survival improvement. Recent data on intracavitary cesium-131 brachytherapy in brain metastases have demonstrated improved locoregional tumor control with low risks of radiation necrosis, with associated improvements in patients compliance and satisfaction. Cesium-131 isotope has a short half-life, delivers 90% of its dose within a month, shortens the time to initiation of systemic therapy compared to iodine-125 or external radiotherapy, and has an excellent radiation safety profile. Further analyses have demonstrated superior cost-effectiveness and quality-of-life improvement ratios of cesium-131 brachytherapy than adjuvant stereotactic radiosurgery. Cesium-131 brachytherapy is a safe and effective post-surgical treatment option for brain metastases with associated clinical and cost-effectiveness benefits in appropriately selected patients.

Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models.

D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-ITαCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8

Anti-seed PNAs targeting multiple oncomiRs for brain tumor therapy.

Glioblastoma (GBM) is one of the most lethal malignancies with poor survival and high recurrence rates. Here, we aimed to simultaneously target oncomiRs 10b and 21, reported to drive GBM progression and invasiveness. We designed short (8-mer) γ-modified peptide nucleic acids (sγPNAs), targeting the seed region of oncomiRs 10b and 21. We entrapped these anti-miR sγPNAs in nanoparticles (NPs) formed from a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG). The surface of the NPs was functionalized with aldehydes to produce bioadhesive NPs (BNPs) with superior transfection efficiency and tropism for tumor cells. When combined with temozolomide, sγPNA BNPs administered via convection-enhanced delivery (CED) markedly increased the survival (>120 days) of two orthotopic (intracranial) mouse models of GBM. Hence, we established that BNPs loaded with anti-seed sγPNAs targeting multiple oncomiRs are a promising approach to improve the treatment of GBM, with a potential to personalize treatment based on tumor-specific oncomiRs.

Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study.

Use of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR-mutant advanced NSCLC however, the efficacy of these agents in patients with brain metastases remains unclear. To investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases. This open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR-sensitive mutated NSCLC were enrolled. The eligible patients were randomly assigned (11) to receive gefitinib plus chemotherapy or gefitinib alone. The primary end point was intracranial PFS secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed. A total of 161 patients (87 54.0% women mean SD age, 55 9.8 years range, 26-80 years) were enrolled and randomized to receive gefitinib (n 81) or gefitinib plus chemotherapy (n 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36 95% CI, 0.25-0.53 P < .001). Similarly, the median PFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16.3 95% CI, 14.4-18.2 months vs 9.5 95% CI, 8.3-10.8 months P < .001). Gefitinib plus chemotherapy had a better intracranial objective response rate (85.0% 95% CI, 77.0%-93.0% vs 63.0% 95% CI, 52.2%-73.7% P .002) and overall objective response rate (80.0% 95% CI, 71.0%-89.0% vs 64.2% 95% CI, 53.5%-74.9% P .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months hazard ratio, 0.65 95% CI, 0.43-0.99 P .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable. In this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases and could be an optional first-line treatment for these patients. ClinicalTrials.gov Identifier NCT01951469.

Stimuli-Responsive Gene Delivery Nanocarriers for Cancer Therapy.

Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects. Currently, the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy. For this purpose, stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection, prolonged blood circulation, specific tumor accumulation, and controlled release profile of nucleic acid drugs. Besides, synergistic therapy could be achieved when combined with other therapeutic regimens. This review summarizes recent advances in various stimuli-responsive nanocarriers for gene delivery. Particularly, the nanocarriers responding to endogenous stimuli including pH, reactive oxygen species, glutathione, and enzyme, etc., and exogenous stimuli including light, thermo, ultrasound, magnetic field, etc., are introduced. Finally, the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed. The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.

Association of Postoperative Drift in Hemoglobin With Mortality After Brain Tumor Craniotomy.

Postoperative downward drift in hemoglobin (Hb) concentration may be associated with complications and death, even if nadir Hb remains more than the red blood cell transfusion threshold of 7 gdL. To assess whether postoperative Hb drift in patients undergoing brain tumor craniotomy influences mortality in the immediate perioperative period. This retrospective cohort study included patients undergoing craniotomy for brain tumors. We defined no postoperative Hb decrease, mild decrease, moderate decrease, and severe decrease as postoperative Hb drift of ≤25%, 26% to 50%, 51% to 75%, and >75%, respectively. The primary outcome was 30-day mortality after craniotomy. This study included 8159 patients who underwent a craniotomy for brain tumors. Compared with patients with no postoperative Hb drift, the odds of postoperative mortality at 30 days increased in patients with mild postoperative Hb drift (adjusted odds ratio OR 2.47, 95% CI 1.72-3.56), moderate drift (adjusted OR 6.56, 95% CI 3.42-12.59), and severe drift (adjusted OR 12.33, 95% CI 3.48-43.62). When postoperative Hb drift was analyzed as a continuous variable, for each 10% increase in Hb drift, the adjusted OR of postoperative mortality at 30 days was 1.46 (95% CI 1.31-1.63). In patients undergoing brain tumor craniotomy, a small postoperative Hb drift was associated with increased odds of postoperative mortality at 30 days, even if the nadir Hb level remained greater than the red blood cell transfusion threshold of 7 gdL. Future randomized clinical trials of perioperative transfusion practices may examine the effect of both nadir Hb and Hb drift.

The Role of Ketogenic Diet in the Treatment of Neuroblastoma.

The ketogenic diet (KD) was initially used in 1920 for drug-resistant epileptic patients. From this point onward, ketogenic diets became a pivotal part of nutritional therapy research. To date, KD has shown therapeutic potential in many pathologies such as Alzheimers disease, Parkinsons disease, autism, brain cancers, and multiple sclerosis. Although KD is now an adjuvant therapy for certain diseases, its effectiveness as an antitumor nutritional therapy is still an ongoing debate, especially in Neuroblastoma. Neuroblastoma is the most common extra-cranial solid tumor in children and is metastatic at initial presentation in more than half of the cases. Although Neuroblastoma can be managed by surgery, chemotherapy, immunotherapy, and radiotherapy, its 5-year survival rate in children remains below 40%. Earlier studies have proposed the ketogenic diet as a possible adjuvant therapy for patients undergoing treatment for Neuroblastoma. In this study, we seek to review the possible roles of KD in the treatment of Neuroblastoma.

Inhibiting tau protein improves the recovery of spinal cord injury in rats by alleviating neuroinflammation and oxidative stress.

After spinal cord injury, the concentrations of total and hyperphosphorylated tau in cerebrospinal fluid increase, and levels of both correlate with injury severity. Tau inhibition is considered effective therapy for many central nervous system diseases, including traumatic brain injury and Alzheimers disease. However, whether it can play a role in the treatment of spinal cord injury remains unclear. In this study, the therapeutic effects of tau inhibition were investigated in a rat model of transection spinal cord injury by injecting the rats with a lentivirus encoding tau siRNA that inhibits tau expression. We found that tau inhibition after spinal cord injury down-regulated the levels of inflammatory mediators, including tumor necrosis factor-α, interleukin-6 and interleukin-1β. It also led to a shift of activated microglial polarization from the M1 pro-inflammatory phenotype to the M2 anti-inflammatory phenotype, and reduced the amount of reactive oxygen species in the acute phase. Furthermore, the survival of residual neural cells around the injury epicenter, and neuronal and axonal regeneration were also markedly enhanced, which promoted locomotor recovery in the model rats. Collectively, our findings support the conclusion that tau inhibition can attenuate neuroinflammation, alleviate oxidative stress, protect residual cells, facilitate neurogenesis, and improve the functional recovery after spinal cord injury, and thus suggest that tau could be a good molecular target for spinal cord injury therapy.

Sphingosine 1-phosphate receptor 1 regulates blood-brain barrier permeability in epileptic mice.

Destruction of the blood-brain barrier is a critical component of epilepsy pathology. Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity. However, its effect on blood-brain barrier permeability in epileptic mice remains unclear. In this study, we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL6 mice. S1P1 expression was increased in the hippocampus after status epilepticus, whereas tight junction protein expression was decreased in epileptic mice compared with controls. Intraperitoneal injection of SEW2871, a specific agonist of sphingosine-1-phosphate receptor 1, decreased the level of tight junction protein in the hippocampus of epileptic mice, increased blood-brain barrier leakage, and aggravated the severity of seizures compared with the control. W146, a specific antagonist of sphingosine-1-phosphate receptor 1, increased the level of tight junction protein, attenuated blood-brain barrier disruption, and reduced seizure severity compared with the control. Furthermore, sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1β and tumor necrosis factor-α and caused astrocytosis. Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline, a neuroinflammation inhibitor. Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors. Additionally, specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage, seizure severity, and epilepsy-associated depression-like behaviors. Taken together, our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.

Immortalized hippocampal astrocytes from 3xTg-AD mice, a new model to study disease-related astrocytic dysfunction a comparative review.

Alzheimers disease (AD) is characterized by complex etiology, long-lasting pathogenesis, and cell-type-specific alterations. Currently, there is no cure for AD, emphasizing the urgent need for a comprehensive understanding of cell-specific pathology. Astrocytes, principal homeostatic cells of the central nervous system, are key players in the pathogenesis of neurodegenerative diseases, including AD. Cellular models greatly facilitate the investigation of cell-specific pathological alterations and the dissection of molecular mechanisms and pathways. Tumor-derived and immortalized astrocytic cell lines, alongside the emerging technology of adult induced pluripotent stem cells, are widely used to study cellular dysfunction in AD. Surprisingly, no stable cell lines were available from genetic mouse AD models. Recently, we established immortalized hippocampal astroglial cell lines from amyloid-β precursor proteinpresenilin-1Tau triple-transgenic (3xTg)-AD mice (denominated as wild type (WT)- and 3Tg-iAstro cells) using retrovirus-mediated transduction of simian virus 40 large T-antigen and propagation without clonal selection, thereby maintaining natural heterogeneity of primary cultures. Several groups have successfully used 3Tg-iAstro cells for single-cell and omics approaches to study astrocytic AD-related alterations of calcium signaling, mitochondrial dysfunctions, disproteostasis, altered homeostatic and signaling support to neurons, and blood-brain barrier models. Here we provide a comparative overview of the most used models to study astrocytes in vitro, such as primary culture, tumor-derived cell lines, immortalized astroglial cell lines, and induced pluripotent stem cell-derived astrocytes. We conclude that immortalized WT- and 3Tg-iAstro cells provide a non-competitive but complementary, low-cost, easy-to-handle, and versatile cellular model for dissection of astrocyte-specific AD-related alterations and preclinical drug discovery.

Tandem chimeric antigen receptor (CAR) T cells targeting EGFRvIII and IL-13Rα2 are effective against heterogeneous glioblastoma.

Chimeric antigen receptor (CAR) T cells have achieved remarkable responses in patients with hematological malignancies however, the potential of this therapeutic platform for solid tumors like glioblastoma (GBM) has been limited, due in large part to the targeting of single antigens in a heterogeneous disease. Strategies that allow CAR T cells to engage multiple antigens concomitantly may broaden therapeutic responses and mitigate the effects of immune escape. Here we have developed a novel, dual-specific, tandem CAR T (TanCART) cell with the ability to simultaneously target both EGFRvIII and IL-13Rα2, two well-characterized tumor antigens that are frequently found on the surface of GBM cells but completely absent from normal brain tissues. We employed both standard immunological assays and multiple orthotopic preclinical models including patient-derived xenograft to demonstrate efficacy of this approach against heterogeneous tumors. Tandem CAR T cells displayed enhanced cytotoxicity We demonstrate that TanCART is effective against heterogeneous tumors in the brain. These data lend further credence to the development of multi-specific CAR T cells in the treatment of GBM and other cancers.

Management dilemma in a rare case of pituitary apoplexy with akinetic mutism in the setting of ruptured junctional brain aneurysm A case report and literature review.

Pituitary apoplexy is associated with stroke, head injury, and brain tumors. Still, its presentation due to the ruptured aneurysm is rare and its presentation with akinetic mutism has not been reported. The patient in the present study is 21-year-old female who presented in our emergency department in an altered sensorium with Glasgow comma score (GCS) E2V1M1. She was intubated and resuscitated. Routine blood investigations, lipid profile, and hormonal studies were normal. Initial noncontrast computed tomography (NCCT) head revealed subarachnoid hemorrhage in the interhemispheric fissure and evidence of bleeding in the pituitary gland. Magnetic resonance imaging (MRI) brain was soon done, which showed an infarct and hemorrhage in the pituitary gland there was an evidence of an infarct in the bilateral medial frontal gyrus, basal ganglia, and supplementary motor area. MR arteriography revealed an aneurysm at the left A1-anterior communicating artery (Acom) junction directed superomedially with diffuse spasm in a bilateral anterior cerebral artery. Pterional craniotomy was done with clipping of the aneurysm and evacuation of blood clots from the interhemispheric fissure and pituitary gland. Histopathology features suggestive of the non-functioning pituitary tumor with interspersed hemorrhagic necrosis. Intraarterial vasodilation with microcatheter injection was given, but vasospasm did not improve. Postoperatively, Levodopa was started. She used to track objects in front of her eye and started nodding her head in yes and no fashion, with power in limbs improved to 35 at 6 months of follow-up. Pituitary apoplexy with ruptured A1-Acom junction aneurysm with nonfunctioning pituitary macroadenoma is rare, and its presentation with akinetic mutism has not been reported. As there is scarce literature suggesting an association between pituitary apoplexy and ruptured aneurysm, it is challenging to comment regarding its pathogenesis. Although akinetic mutism generally has a poor prognosis, it may respond to Levodopa with a better outcome.

Glioblastoma multiforme at internal auditory canal.

Glioblastomas are the most common adult primary brain tumor present supratentorially. The presence of true extra-axial GBM infratentorially, especially in the internal auditory canal, is extremely rare with only three cases reported previously in the literature. We report the fourth case of primary internal auditory canalcerebellopontine angle (CPA) glioblastoma which initially mimicked vestibular schwannoma on the basis of its location and presentation. A 65-year-old male presented with headache, vertigo, and progressive right ear deafness for 5 months. His preoperative magnetic resonance imaging findings were consistent with vestibular schwannoma. Maximum safe resection (near total) was done. The final histopathology report showed glioblastoma multiforme. As per our knowledge, this is the fourth reported case of an extra-axial VIII cranial nerve glioblastoma located in internal auditory canal. Hence, despite being very rare, they should be considered as a differential in tumors at CPA.

Ileal signet-ring cell carcinoma with brain metastases A case report.

Signet-ring cell carcinoma (SRCC) is a rare subtype of adenocarcinoma that frequently originates in the stomach. Uncommonly, this tumor can lead to brain metastases an event rarely reported in the literature. A 76-year-old man with a history of cognitive impairment was diagnosed with two brain space-occupying lesions. A whole-body 18F-FDG PETcomputed tomography scan revealed a hypermetabolic lesion in a segment of the ileum corresponding to mural thickening and an ulcerated lesion detected on colonoscopy. A brain biopsy, using an immunohistochemistry protocol, showed signet-ring cells with a pattern that suggested an intestinal origin. The diagnosis of SRCC brain metastases with an ileal origin was made, and a treatment protocol was designed. However, the patient rapidly deteriorated, and passed away shortly afterward. To the best of our knowledge, this is the first case report of an ileal SRCC with brain metastases.

Correlation of Brain Metastasis Shrinking and Deviation During 10-Fraction Stereotactic Radiosurgery With Late Sequela Suggesting Dose Ramification Between Tumor Eradication and Symptomatic Radionecrosis.

Stereotactic radiosurgery (SRS) with >5 fraction (fr) has been increasingly adopted for brain metastases (BMs), given the current awareness of limited brain tolerance for ≤5 fr. The target volumeconfiguration change andor deviation within the cranium during fractionated SRS can be unpredictable and critical uncertainties affecting treatment accuracy, plus the effect of these events on the long-term outcome remains uncertain. Herein, we describe a case of two challenging BMs treated by 10 fr SRS with a unique dose-gradient optimization strategy, in which the large cystic tumor revealed an intriguing correlation of such inter-fractional change with late radiographic sequela, suggesting a dose threshold for attaining long-term local tumor control and being immune to symptomatic brain necrosis. A 63-year-old man presented with two cystic lesions located in the left parietal lobe (19.9 cm

Expression of the P53 Protein and Morphological Changes in Neurons in the Pyramidal Layer of the Hippocampus After Simulation of Surgical Interventions in the Nasal Cavity in Rats.

To determine the role of surgical stress on the formation of p53-positive and dark neurons (DN) in the hippocampus, and to examine the parallelism of their formation in the pyramidal layer of the hippocampus. Simulated septoplasty was performed on 20 Wistar rats. The hippocampus and dentate gyrus (DG) were examined, in which the number of DN and p53-positive neurons was determined at 2, 4 and 6 days after surgery. In each rat, 10 brain slices were stained with antibodies to p53 protein with Meyers haematoxylin and 10 slices were stained with Nissl toluidine blue. Hippocampal subfields CA1, CA2, CA3 and DG were studied. In the pyramidal subfield layer, the absolute number of neurons that were nuclear antibody-positive to p53 protein was counted, as well as the number of dark neurons. The counting area in each subfield was 20934±1260 µm2. Neurons are counted using the Aperio ImageScope program. For the histological specimen analysis, the ImageJ software was used. The data obtained using cell counting methods were presented as mean ± SE. Then, they were compared between both groups using a t-test SPSS 21software. Compared with the control group (n 5), the number of DN and p53-positive neurons increased in experimental animals at all periods. A direct relationship was obtained between the increase in the number of DN and p53-positive neurons in the hippocampal formation. Septoplasty simulation in rats results in the pathogenetic cascades onset, which, in its turn, changes the morpho-functional properties of neurons of the pyramidal layer of the hippocampus and contributes to their neuroplasticity. Activation of NMDS receptors of neurons during stress apparently, initiates two ways of neuron life - the beginning of p53 protein expression and the DN formation. Both ways can finally lead to apoptosis. The formation of dark neurons and the expression of the p53 protein in them are most likely to be interconnected and can probably provide neuroprotective mechanisms.

Genomic profiling and prognostic factors of H3 K27M-mutant spinal cord diffuse glioma.

H3 K27-altered diffuse midline glioma is a highly lethal pediatric-type tumor without efficacious treatments. Recent findings have highlighted the heterogeneity among diffuse midline gliomas with different locations and ages. Compared to tumors located in the brain stem and thalamus, the molecular and clinicopathological features of H3 K27-altered spinal cord glioma are still largely elusive, thus hindering the accurate management of patients. Here we aimed to characterize the clinicopathological and molecular features of H3 K27M-mutant spinal cord glioma in 77 consecutive cases. We found that the H3 K27M-mutant spinal cord glioma, with a median age of 35 years old, had a significantly better prognosis than H3 K27M-mutant brain tumors. We noticed a molecular heterogeneity of H3 K27M-mutant spinal cord astrocytoma via targeted sequencing with 34 cases. TP53 mutation which occurred in 58.8% of cases is mutually exclusive with PPM1D (26%) and NF1 (44%) mutations. The TP53-mutant cases had a significantly higher number of copy number variants (CNV) and a marginally higher proportion of pediatric patients (age at diagnosis <18 years old, p 0.056). Cox regression and Kaplan-Meier curve analysis showed that the higher number of CNV events (≥3), chromosome (Chr) 9p deletion, Chr 10p deletion, ATRX mutation, CDK6 amplification, and retinoblastoma protein (RB) pathway alteration are associated with worse survival. Cox regression analysis with clinicopathological features showed that glioblastoma histological type and a high Ki-67 index (>10%) are associated with a worse prognosis. Interestingly, the histological type, an independent prognostic factor in multivariate Cox regression, can also stratify molecular features of H3 K27M-mutant spinal cord glioma, including the RB pathway, KRASPI3K pathway, and chromosome arms CNV. In conclusion, although all H3 K27M-mutant spinal cord diffuse glioma were diagnosed as WHO Grade 4, the histological type, molecular features representing chromatin instability, and molecular alterations associated with accelerated cell proliferative activity should not be ignored in clinical management.

Brain metastases in Japanese NSCLC patients prognostic assessment and the use of osimertinib and immune checkpoint inhibitors-retrospective study.

The Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and the factors impacting survival need to be assessed. We retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results. The median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, and 2.5‒3.0) were 3.2, 11.0, and 16.0 months (p 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS 34.2 and 17.6 months with and without osimertinib, respectively (p 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months). We confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patients with BM, and ICI was effective in patients with high PD-L1 expressions.

Research on the mechanism of prednisone in the treatment of ITP via VIPPACAP-mediated intestinal immune dysfunction.

Immune thrombocytopenia (ITP) is thought to be a result of immune dysfunction, which is treated by glucocorticoids such as prednisone. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) have immunomodulatory properties, but their role in intestinal immune control is unclear. The major goal of this study was to look at the effects of prednisone on platelet, VIP, and PACAP levels in ITP mice, as well as the regulatory system that controls intestinal immunity. Eighteen BALBc mice were randomly divided into three groups blank control group, model control group, and prednisone group, with six mice in each group. The ITP animal model control group and the prednisone group were injected with anti-platelet serum (APS) to replicate the ITP animal model. The prednisone group began prednisone intervention on the 8th day. Platelet count was dynamically measured before APS injection, on the 4th day of injection, on the 1st day of administration, on the 4th day of administration, and at the end of the experiment. After the experiment, the expression of p53 protein in mouse mesenteric lymph node lymphocytes was detected by immunohistochemistry. The changes in lymphocyte apoptosis rate in mouse mesenteric lymph nodes were detected by in situ terminal transferase labeling (TUNEL). The contents of VIP and PACAP in the mouse brain, colon, and serum were detected by enzyme-linked immunosorbent assay (ELISA). The contents of IFN-γ, IL-4, IL-10, IL-17A in the mouse spleen were detected by ELISA. ①Changes of peripheral platelet count there was no significant difference in platelet count among the three groups before modeling on the 4th day, the platelet count decreased in the model control group and prednisone group on the 8th day, the number of platelets in model control group and prednisone group was at the lowest level on the 12th day, the platelet count in prednisone group recovered significantly on the 15th day, the platelet count in prednisone group continued to rise. ②Changes of VIP, PACAP compared with the blank control group, VIP and PACAP in the model control group decreased significantly in the brain, colon, and serum. Compared with the model control group, the levels of VIP and PACAP in the brain, colon, and serum in the prednisone group were increased except for serum PACAP. ③Changes of mesenteric lymphocytes the expression of p53 protein in the mesenteric lymph nodes of model control group mice was significantly higher than that of blank control group mice. After prednisone intervention, the expression of p53 protein decreased significantly.④Changes of cytokines in spleen compared with blank control group, IFN- γ, IL-17A increased and IL-4 and IL-10 decreased in model control group. After prednisone intervention, IFN- γ, IL-17A was down-regulated and IL-4 and IL-10 were upregulated. Prednisone-upregulated VIP and PACAP levels decreased P53 protein expression and apoptosis rate in mesenteric lymph node lymphocytes and affected cytokine expression in ITP model mice. Therefore, we speculate that the regulation of intestinal immune function may be a potential mechanism of prednisone in treating ITP.

Identification and gene expression profiling of human gonadotrophic pituitary adenoma stem cells.

Gonadotrophic pituitary adenoma is a major subtype of pituitary adenoma in the sellar region, but it is rarely involved in the hypersecretion of hormones into blood thus, it is commonly regarded as non-functioning. Its tumorigenic mechanisms remain unknown. The aim of this study was to identify human gonadotrophic pituitary adenoma stem cells (hPASCs) and explore the underlying gene expression profiles. In addition, the potential candidate genes involved in the invasive properties of pituitary adenoma were examined. The hPASCs from 14 human gonadotrophic pituitary adenoma clinical samples were cultured and verified via immunohistochemistry. Genetic profiling of hPASCs and the matched tumor cells was performed through RNA-sequencing and subjected to enrichment analysis. By aligning the results with public databases, the candidate genes were screened and examined in invasive and non-invasive gonadotrophic pituitary adenomas using Real-time polymerase chain reaction. The hPASCs were successfully isolated and cultured from gonadotrophic pituitary adenoma in vitro, which were identified as positive for generic stem cell markers (Sox2, Oct4, Nestin and CD133) via immunohistochemical staining. The hPASCs could differentiate into the tumor cells expressing follicle-stimulating hormone in the presence of fetal bovine serum in the culture medium. Through RNA-sequencing, 1352 differentially expressed genes were screened and identified significantly enriched in various gene ontologies and important pathways. The expression levels of ANXA2, PMAIP1, SPRY2, C2CD4A, APOD, FGF14 and FKBP10 were significantly upregulated while FNDC5 and MAP3K4 were downregulated in the invasive gonadotrophic pituitary adenomas compared to the non-invasive ones. Genetic profiling of hPASCs may explain the tumorigenesis and invasiveness of gonadotrophic pituitary adenoma. ANXA2 may serve as a potential therapeutic target for the treatment of gonadotrophic pituitary adenoma.

Radiosurgery of limited brain metastases from primary solid tumor results of the randomized phase III trial (NCT02355613) comparing treatments executed with a specialized or a C-arm linac-based platform.

Comparative prospective data regarding different radiosurgery (SRS) modalities for treating brain metastases (BMs) from solid tumors are not available. To investigate with a single institute phase III randomized trial whether SRS executed with linac (Arm-B) is superior to a dedicated multi-source gamma-ray stereotactic platform (Arm-A). Adults patients with 1-4 BMs from solid tumors up to 30 mm in maximum diameter were randomly assigned to arms A and B. The primary endpoint was cumulative incidence of symptomatic (grade 2-3) radionecrosis (CIRN). Secondary endpoints were local progression cumulative incidence (CILP), distant brain failure, disease-free survival (DFS), and overall survival (OS). A total of 251 patients were randomly assigned to Arm-A (121) or Arm-B (130). The 1-year RN cumulative incidence was 6.7% in whole cohort, 3.8% (95% CI 1.9-7.4%) in Arm-B, and 9.3% (95% CI 6.2-13.8%) in the Arm-A (p 0.43). CIRN was influenced by target volume irradiated only for the Arm-A (p << 0.001 HR 1.36 95% CI 1.25-1.48). Symptomatic RN occurred in 56 cases at a median time of 10.3 months (range 1.15-54.8 months), 27 in the Arm-B at a median time of 15.9 months (range 4.9-54.8 months), and 29 in the Arm-A at a median time of 6.9 months (1.2-32.3 months), without statistically significant differences between the two arms. No statistically significant differences were recorded between the two arms in CILP, BDF, DFS or OS. The mean beam-on time to deliver SRS was 49.0 ± 36.2 min in Arm-A, and 3.1 ± 1.6 min in Arm-B. Given the technical differences between the treatment platforms investigated in this single-institution study, linac-based SRS (Arm-B) did not lead to significantly lower grade 2-3 RN rates versus the multi-source gamma-ray system (Arm-A) in a population of patients with limited brain metastases of small volume. No significant difference in local control was observed between both arms. For Arm-B, the treatment delivery time was significantly lower than for Arm-A. ClinicalTrials.gov Identifier NCT02355613.

A case report about a child with drug-resistant tuberculous meningitis.

Hematogenous disseminated tuberculosis predisposes to concurrent tuberculous meningitis (TBM), the most devastating and disabling form of tuberculosis. However, children often have atypical clinical symptoms, difficulty in specimen collection, low specimen content, and an increasing incidence of drug-resistant tuberculosis. Thus, the accurate diagnosis and timely treatment of childhood tuberculosis face monumental challenges. The 14-year-old female presented to the hospital with intermittent fever, headache, and blurred vision. Her cerebrospinal fluid (CSF) showed a lymphocytic pleocytosis, an elevated protein level, and a decreased chloride level. And her CSF tested positive for TB-RNA. Xpert MTBRIF detected Mycobacterium tuberculosis in her CSF, but the rifampin resistance test was unknown. Subsequently, her CSF culture was positive for Mycobacterium tuberculosis. The drug sensitivity test (DST) revealed resistance to isoniazid, rifampin, and fluoroquinolones. A computed tomography (CT) of the chest showed diffuse miliary nodules in both lungs. Intracranial enhanced magnetic resonance imaging (MRI) showed multiple intensified images of the brain parenchyma, cisterns, and part of the meninges. The final diagnosis is miliary pulmonary tuberculosis and pre-extensive drug-resistant TBM. After 19 months of an oral, individualized antituberculosis treatment, she recovered with no significant neurological sequelae. For patients with miliary pulmonary tuberculosis, especially children, even if there are no typical clinical symptoms, it is necessary to know whether there is TBM and other conditions. Always look for the relevant aetiological basis to clarify whether it is drug-resistant tuberculosis. Only a rapid and accurate diagnosis and timely and effective treatment can improve the prognosis and reduce mortality and disability rates.

The impact of brain lesions on health-related quality of life in patients with WHO CNS grade 3 or 4 glioma a lesion-function and resting-state fMRI analysis.

In glioma patients, tumor development and multimodality therapy are associated with changes in health-related quality of life (HRQoL). It is largely unknown how different types and locations of tumor- and treatment-related brain lesions, as well as their relationship to white matter tracts and functional brain networks, affect HRQoL. In 121 patients with pretreated gliomas of WHO CNS grades 3 or 4, structural MRI, O-(2- Right hemisphere gliomas were associated with significantly less favorable outcomes in physical, role, emotional and social functioning, compared with left-sided tumors. Most functional HRQoL scores correlated significantly with right-sided white-matter tracts involvement by T2FLAIR hyperintensities and with loss of within-network functional connectivity of right-sided nodes. Tumors of the left hemisphere caused significantly more communication deficits. In pretreated high-grade gliomas, right hemisphere lesions are associated with reduced HRQoL scores in most functional domains except communication ability, compared to tumors of the left hemisphere. These relationships are mainly observed for T2FLAIR lesions involving structural and functional networks in the right hemisphere. The data suggest that sparing the right hemisphere from treatment-related tissue damage may improve HRQoL in glioma patients.

RARE CASE OF PHYLLODES TUMOUR OF BREAST WITH CARDIAC AND PANCREATIC METASTASES. FINDINGS ON FDG PET-CT.

Phyllodes tumors (PTs) represents a rare breast tumor arising from its stromal component rather than epithelium. Metastatic spread occurs hematogenous with lung, bone, brain and liver being the most common sites. We hereby present 18F-FDG PET-CT scan of one such case of phyllodes tumor showing cardiac and pancreatic metastases which is extremely rare occurrence.

Oral IRAK-4 inhibitor CA-4948 is blood-brain barrier penetrant and has single-agent activity against CNS lymphoma and melanoma brain metastases.

An ongoing challenge in cancer is the management of primary and metastatic brain malignancies. This is partly due to restrictions of the blood-brain barrier (BBB) and their unique microenvironment. These challenges are most evident in cancers such as lymphoma and melanoma, which are typically responsive to treatment in systemic locations but resistant when established in the brain. We propose IRAK-4 as a potential target across these diseases and describe the activity and mechanism of oral IRAK-4 inhibitor CA-4948. Human primary central nervous system lymphoma (PCNSL) and melanoma brain metastases (MBM) samples were analyzed for expression of IRAK-4 and downstream transcription pathways. We next determined the CNS applicability of CA-4948 in naïve and tumor-bearing mice using models of PCNSL and MBM. The mechanistic effect on tumors and the tumor microenvironment was then analyzed. Human PCNSL and MBM have high expression of IRAK-4, IRAK-1, and NF-κB. This increase in inflammation results in reflexive inhibitory signaling. Similar profiles are observed in immunocompetent murine models. Treatment of tumor-bearing animals with CA-4948 results in the downregulation of ERK and MAPK signaling in addition to decreased NF-κB. These intracellular changes are associated with a survival advantage. IRAK-4 is an attractive target in PCNSL and MBM. The inhibition of IRAK-4 with CA-4948 downregulates the expression of important transcription factors involved in tumor growth and proliferation. CA-4948 is currently being investigated in clinical trials for relapsed and refractory lymphoma and warrants further translation into PCNSL and MBM.

Cytohesin-4 Upregulation in Glioma-Associated M2 Macrophages Is Correlated with Pyroptosis and Poor Prognosis.

Cytohesin-4 (CYTH4) is a member of the PSCD family. Members of this family appear to mediate the regulation of protein sorting and membrane trafficking. In previous studies, CYTH4 has been linked with multiple brain diseases, but not glioma, the most common type of brain tumor. We utilized multiple glioma single-cell RNA sequencing datasets and bulk data from the TCGA and CGGA and conducted GSEA and KEGG and GO analyses. Biomarker potential was tested via ROC curve analysis. Radar plots were used to study TMB and MSI correlations. Immune cell studies were conducted using CIBERSORT. All statistical analyses were performed in R software and GraphPad Prism 9. CYTH4 was overexpressed in the glioma macrophage population in several single-cell RNA sequencing datasets and was most correlated with M2 macrophages. CYTH4 expression was higher in tumor tissues and was correlated with survival and WHO grade. ROC curves suggested CYTH4 overexpression to be a potential glioma biomarker. GSEA results indicated a relationship between CYTH4 and apoptosis, and PPI analysis supported a pyroptosis correlation. KEGG and GO analysis results linked CYTH4 with antigen processing and presentation and neutrophil activities. In summary, the study identified a CYTH4pyroptosisM2 macrophage axis. CYTH4 was upregulated in M2 macrophages in glioma and affected pyroptosis. CYTH4 overexpression is a potential biomarker predicting a poor prognosis.

Molecular subgroup of medulloblastoma evaluation of contribution to CSF diversion following tumour resection.

Medulloblastoma is the commonest malignant brain tumour in children. Pre-operative hydrocephalus is present in up to 90% of these patients at presentation. Following posterior fossa surgery, despite resolution of fourth ventricular obstruction, a proportion of these children will still require cerebrospinal fluid (CSF) diversion for management of persistent or new hydrocephalus. Various scoring systems have been developed to predict the risk for CSF diversion following posterior fossa surgery. However, no accurate tool exists regarding which pathological subset or group of medulloblastoma patients will require a shunt post-operatively. In this study we investigated the impact of molecular subgroup of medulloblastoma on shunt dependency post-operatively in paediatric patients. We undertook a retrospective multi-centre study of children with medulloblastoma who underwent tumour resection. Those with available molecular subgroup were identified. Demographic data and clinical parameters including age, sex, presence of pre-operative hydrocephalus, extent of surgical resection, evidence of metastasisleptomeningeal disease and need for CSF diversion post-operatively were further analysed. Sixty-nine children with medulloblastoma with available molecular data were identified during the study period with male to female ratio of 1.51 (42M27F). Twelve patients (17.4%) belonged to SHH, 10 (14.5%) Wnt, 19 (27.5%) Group 3 and 15 (21.7%) Group 4 13 (18.8%) were non-specified Group 3 or 4. A total of 18 (26%) patients had evidence of leptomeningeal disease at presentation (20% of Wnt, 42% of Group 3, 33% of group 4, 23% of group 34, and 0% of SHH). Fifteen patients (22%) underwent post-operative ventriculoperitoneal (VP) shunt insertion. No patient in the Wnt group required ventriculoperitoneal (VP) shunt post-operatively in this cohort. Need for shunt was associated with pre-operative hydrocephalus, leptomeningeal disease, with molecular group 3 or 4 demonstrating higher rate of leptomeningeal disease, and pre-operative hydrocephalus. Age, extent of resection and pre-operative EVD were not associated with need for shunt in this cohort. Regression analysis identified only pre-operative hydrocephalus and leptomeningeal disease as independent predictors of need for shunt post-resection in this cohort. All patients requiring permanent post-operative VP shunt belonged to non-Wnt groups, particularly group 3 and 4. Although medulloblastoma subgroup does not independently predict need for post-operative shunt, presence of leptomeningeal disease and pre-operative hydrocephalus, and their higher prevalence in group 3 and 4, likely account for observed higher rate of shunting in these groups.

WNT-pathway medulloblastoma what constitutes low-risk and how low can one go

Novel biological insights have established that medulloblastoma is a heterogenous disease comprising four broad molecular subgroups - WNT, SHH, Group 3, and Group 4 respectively, resulting in the incorporation of moleculargenetic information in 5th edition of WHO classification and contemporary risk-stratification. Concerns regarding therapy-related late toxicity in long-term survivors have led to systematic attempts at treatment de-intensification in good-risk medulloblastoma. Given the excellent survival (>90%) of WNT-pathway medulloblastoma, prospective clinical trials have focused on optimization of therapy to balance survival versus quality of survival. The currently accepted definition of low-risk WNT-pathway medulloblastoma includes children <16 years of age with residual tumour <1.5 cm

Imaging and pathological diagnosis of primary intracranial malignant melanoma A case report and literature review.

Primary intracranial malignant melanoma (PIMM) is a rare malignant tumor that lacks specific clinical manifestations. Preoperative diagnosis is difficult to differentiate from meningiomas on computed tomography (CT) scans. Magnetic resonance imaging (MRI) usually shows typical characteristics with high signal intensity on T1WI and low signal intensity on T2WI. PIMM is highly invasive, insensitive to chemoradiotherapy, and has a poor prognosis. A 27-year-old woman was admitted to the hospital with a headache for 10 days. She did not experience nausea, vomiting, dizziness, or any other discomfort. A computerized tomography (CT) scan demonstrated a high-density mass in the left cerebellum with patchy calcification at the posterior edge, and heterogeneous enhancement was observed on a contrast-enhanced scan. MRI revealed typical characteristics of high signal intensity on T1WI and low signal intensity on T2WI. The signal characteristics of FLAIR were similar to those of T2WI, and diffusion-weighted imaging (DWI) sequence showed limited diffusion of the tumor. Magnetic resonance spectroscopy revealed increased choline (Cho) and decreased creatine (Cr) and N-acetyl aspartate (Naa) in the tumor. The patient underwent tumor resection and postoperative chemoradiotherapy and immunotherapy. Histological and Immunohistochemistry (IHC) tests confirmed the diagnosis of PIMM. In addition, genetic testing revealed GNAQ gene variation. No recurrence or complications were observed during the follow-up for 6 months. PIMM is rare, and its pathological diagnosis should be closely combined with clinical and medical history. GNAQ is a common variant of PIMM and is expected to be a therapeutic target.

Sequential Control of Cellular Interactions Using Dynamic DNA Displacement.

Intercellular interactions play a significant role in various complex biological processes, and their dysregulation promotes disease progression. To reveal the mechanisms of intercellular interactions without destroying basic life processes, it is necessary to mimic multicellular behaviors

Postradiosurgery cystic degeneration in brain metastases causing delayed and potentially severe sequelae systematic review and illustrative cases.

Cystic postradiation degeneration has previously been described in the literature as a rare but potentially severe complication after central nervous system (CNS) irradiation for vascular malformations. Limited cases have been reported in the setting of brain metastases. Thirty-six total cases, including three reported here, of cystic postradiation degeneration are identified. Of 35 cases with complete clinical information, 34 (97.25%) of 35 were symptomatic from cystic changes at diagnosis. The average time between initial radiation dose and cyst development was 7.61 years (range 2-31 years). Although most patients were initially treated conservatively with medication, including steroids, 32 (88.9%) of 36 ultimately required surgical intervention. The most common interventions were craniotomy for cyst fenestration or resection (25 of 36 69.4%) and Ommaya placement (8 of 36). After intervention, clinical improvement was seen in 10 (67%) of 15 cases, with persistent or worsening deficit or death seen in 5 (33%) of 15. Cysts were decompressed or obliterated on postoperative imaging in 20 (83.3%) of 24 cases, and recurrence was seen in 4 (16.7%) of 24. Cystic degeneration is a rare and delayed sequela after radiation for brain metastases. This entity has the potential to cause significant and permanent neurological deficit if not properly recognized and addressed. Durable control can be achieved with a variety of surgical treatments, including cyst fenestration and Ommaya placement.

DNA methylation profiling of a lipomatous meningioma illustrative case.

Lipomatous meningiomas are an extremely rare, benign meningioma subtype subcategorized under metaplastic meningioma in the most recent 2021 update to the World Health Organization classification. They make up less than 0.3% of all meningiomas and, to date, less than 70 cases have been reported in the literature, none of which have undergone molecular profiling. This study aims to promote the utility of molecular profiling to better diagnose these rare tumors. The authors present the first case of a lipomatous meningioma with DNA methylation profiling that both confirmed its benign biology and uncovered unique cytogenetic changes. Molecular characterization of a lipomatous meningioma confirmed its diagnosis as a distinct, benign meningioma subtype and revealed several copy number variations on chromosome 8 and in NF2 and SMARCB1. Here we discuss some of the radiological and histopathological features of lipomatous meningiomas, how they can be used to distinguish from other meningiomas and other similarly presenting tumors, and a brief literature review discussing the pathophysiology and presentation of this rare tumor. This study provides evidence supporting the use of molecular profiling to diagnose lipomatous meningiomas and guide their clinical management more accurately.

Do young adults with cancer receive information about treatment-related impact on sex life Results from a population-based study.

Sexual dysfunction is common following a cancer diagnosis in young adulthood (18-39 years) and problems related to sex life are ranked among the core concerns in this age group. Yet, few studies have investigated to what extent adults younger than 40, receive information from healthcare providers about the potential impact of cancer and its treatment on their sex life. A population-based cross-sectional survey study was conducted with 1010 young adults 1.5 years after being diagnosed with cancer (response rate 67%). Patients with breast, cervical, ovarian and testicular cancer, lymphoma, and brain tumors were identified in national quality registries. Sociodemographic and clinical factors associated with receiving information were examined using multivariable binary logistic regression. Men to a higher extent than women reported having received information about potential cancer-related impact on their sex life (68% vs. 54%, p < 0.001). Receipt of information varied across diagnoses in separate regression models, using lymphoma as reference, both women and men with brain tumors were less likely to receive information (women OR 0.10, CI 0.03-0.30 men OR 0.37, CI 0.16-0.85). More intensive treatment was associated with higher odds of receiving information in both women (OR 1.89 CI 1.28-2.79) and men (OR 2.08 CI 1.09-3.94). None of the sociodemographic factors were associated with receipt of information. To improve sexual health communication to young adults with cancer, we recommend diagnosis-specific routines that clarify when in the disease trajectory to discuss these issues with patients and what to address in these conversations.

Active Immunotherapy for Glioblastoma Treatment A Systematic Review and Meta-Analysis.

Glioblastoma multiforme (GBM) makes 60-70% of gliomas and 15% of primary brain tumors. Despite the availability of standard multimodal therapy, 2 years, 3 years, and 5 years survival rate of GBM are still low. Active immunotherapy is a relatively new treatment option for GBM that seems promising. An electronic database search on PubMed, Cochrane, Scopus, and clinicaltrials.gov was performed to include all relevant studies. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Reported parameters are OS, PFS, AEs, post treatment KPS, and 2 year mortality. Active immunotherapy provided better OS (HR .85 95% CI .71-1.01 Active immunotherapy might be beneficial in terms of survival rate in patients with GBM although not statistically significant. It could be a treatment option for GBM in the future.

Cholesterol-Amino-Phosphate (CAP) Derived Lipid Nanoparticles for Delivery of Self-Amplifying RNA and Restoration of Spermatogenesis in Infertile Mice.

Male infertility caused by genetic mutations is an important type of infertility. Currently, there is no reliable method in the clinic to address this medical need. The emergence of mRNA therapy provides a possible strategy for restoring mutant genes in the reproductive system. However, effective delivery of mRNA to spermatocytes remains a formidable challenge. Here a series of cholesterol-amino-phosphate (CAP) lipids are reported by integrating three bioactive moieties into a geometric structure, which is favorable for mRNA delivery. The results demonstrate that CAP-derived lipid nanoparticles (CAP LNPs) can deliver RNA including traditional mRNA and self-amplifying RNA (saRNA) encoding DNA Meiotic Recombinase 1 (Dmc1) protein in spermatocytes and treat male infertility caused by the Dmc1 gene mutation. Notably, the delivery efficiency of CAP LNPs is significantly higher than that of the MC3 and ALC-0315 LNPs, which is consistent with the design of CAP molecules. More importantly, a single injection of CAP LNPs-saRNA can produce Dmc1 protein for an extended period, which restores the spermatogenesis in the Dmc1 gene knockout mouse model. Overall, this study proves the concept of LNPs for the delivery of mRNA to spermatocytes, which provides a unique method to probe male infertility caused by the genetic mutation.

Cardiac metastasis of ependymoma report of a case.

报道1例椎管内室管膜瘤转移至心脏的病例。患者男，65岁。入院后发现右心房占位性病变，以“黏液瘤”行肿块切除。镜下观察：肿瘤细胞排列呈片状，可见室管膜腔隙，肿瘤细胞立方形或多角形，细胞核卵圆形，胞质丰富嗜酸性。患者3年后再次入院，CT发现全身多处静脉内瘤栓及骨质多发转移。行髂骨穿刺活检见大量血管周围假菊形团。两次标本免疫组织化学均胶质纤维酸性蛋白、S-100蛋白阳性，上皮细胞膜抗原核旁点状阳性，N-MYC基因未见扩增。患者第二次入院穿刺确诊后行化疗1个周期，出院后4个月死亡。.

The introduction of pediatric-type diffuse high-grade gliomas in 2021 WHO classification of tumors of the central nervous system (5th edition).

2021年WHO第5版中枢神经系统肿瘤分类将常见于儿童的胶质瘤分为儿童型弥漫性低级别胶质瘤和高级别胶质瘤。其中儿童型高级别胶质瘤根据分子病理学改变及全基因组DNA甲基化谱聚类分析分为以下4类：弥漫性中线胶质瘤，H3K27变异型；弥漫性半球胶质瘤，H3G34突变型；弥漫性儿童型高级别胶质瘤，H3和IDH野生型；婴儿型半球胶质瘤。本文对其进行详细的解读。.

Medulloblastoma Development in a Patient with a Constitutional Balanced t(522)(q35.1q11.2) Involving the

Neurofibromatosis type 2 (NF2) is a brain tumor predisposing syndrome caused by inactivating alterations of the

Prefrontal cortical protease TACEADAM17 is involved in neuroinflammation and stress-related eating alterations.

Childhood traumatic stress profoundly affects prefrontal cortical networks regulating top-down control of eating and body weight. However, the neurobiological mechanisms contributing to trauma-induced aberrant eating behaviors remain largely unknown. Traumatic stress influences brain immune responses, which may, in turn, disrupt prefrontal cortical networks and behaviors. The tumor necrosis factor alpha-converting enzyme a disintegrin and metalloproteinase 17 (TACEADAM17) is a sheddase with essential functions in brain maturation, behavior, and neuroinflammation. This study aimed to determine the role of TACEADAM17 on traumatic stress-induced disruption of eating patterns. We demonstrate a novel mechanistic connection between prefrontal cortical TACEADAM17 and trauma-induced eating behaviors. Fifty-two (52) adolescent Lewis rats (postnatal day, PND, 15) were injected intracerebrally either with a novel Accell™ SMARTpool ADAM17 siRNA or a corresponding siRNA vehicle. The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Observation cages were used to monitor ethological behaviors in a more naturalistic environment over long periods. We found that traumatic stress blunts startle reactivity and alter eating behaviors (increased intake and disrupted eating patterns). We also found that the rats that received prefrontal cortical TACEADAM17 siRNA administration exhibited decreased eating and increased grooming behaviors compared to controls. These changes were associated with decreased AIF-1 expression (a typical marker of microglia and neuroinflammation). This study demonstrates that prefrontal cortical TACEADAM17 is involved in neuroinflammation and may play essential roles in regulating feeding patterns under stress conditions. TACEADAM17 represents a promising target to ameliorate inflammation-induced brain and behavior alterations.

L3MBTL3 is induced by HIF-1α and fine tunes the HIF-1α degradation under hypoxia in vitro.

HIF-1α plays a crucial part in hypoxia response by transcriptionally upregulating genes to adapt the hypoxic condition. HIF-1α is under severe cellular control as its exceptional activation is always associated with tumorigenesis and tumor progression. Here, we report L3MBTL3 serves as a novel negative regulator of HIF-1α. It is upregulated during hypoxia and acts as a transcriptional target of HIF-1α. In the nuclei, L3MBTL3 makes an interaction with HIF-1α and promotes its ubiquitination and degradation. These findings indicate L3MBTL3 forms a negative feedback loop with HIF-1α in vitro to dampen the hypoxic response.

Assessment of artificial intelligence (AI) reporting methodology in glioma MRI studies using the Checklist for AI in Medical Imaging (CLAIM).

The Checklist for Artificial Intelligence in Medical Imaging (CLAIM) is a recently released guideline designed for the optimal reporting methodology of artificial intelligence (AI) studies. Gliomas are the most common form of primary malignant brain tumour and numerous outcomes derived from AI algorithms such as grading, survival, treatment-related effects and molecular status have been reported. The aim of the study is to evaluate the AI reporting methodology for outcomes relating to gliomas in magnetic resonance imaging (MRI) using the CLAIM criteria. A literature search was performed on three databases pertaining to AI augmentation of glioma MRI, published between the start of 2018 and the end of 2021 RESULTS A total of 4308 articles were identified and 138 articles remained after screening. These articles were categorised into four main AI tasks grading (n 44), predicting molecular status (n 50), predicting survival (n 25) and distinguishing true tumour progression from treatment-related effects (n 10). The average CLAIM score was 2042 (range 10-31). Studies most consistently reported the scientific background and clinical role of their AI approach. Areas of improvement were identified in the reporting of data collection, data management, ground truth and validation of AI performance. AI may be a means of producing high-accuracy results for certain tasks in glioma MRI however, there remain issues with reporting quality. AI reporting guidelines may aid in a more reproducible and standardised approach to reporting and will aid in clinical integration.

Complement inhibition alleviates donor brain death-induced liver injury and post-transplant cascade injury by regulating PI3K signaling.

Brain death (BD) donors are the primary source of donor organs for liver transplantation. However, the effects of BD on donor livers and outcomes after liver transplantation remain unclear. Here, we explored the role of complement and the therapeutic effect of complement inhibition in BD-induced liver injury and post-transplantation injury in mouse BD model and liver transplantation model. For complement inhibition, we used CR2-Crry, a murine inhibitor of C3 activation that specifically targets sites of complement activation. In the mouse model, BD resulted in complement activation and liver injury in donor livers and a cascade liver injury post-transplantation, mediated in part through C3a-C3aR signaling pathway, which was ameliorated by treatment with CR2-Crry. Treatment of BD donors with CR2-Crry improved graft survival, which was further improved when recipients received an additional dose of CR2-Crry post-transplantation. Mechanistically, we determined that complement inhibition alleviated donor brain death-induced liver injury and post-transplant cascade injury by regulating PI3K signaling pathways. Together, the data indicate that BD induced donor liver injury and cascade injury post-transplantation is mediated by complement activation products acting on PI3K signaling pathways. Our study provides an experimental basis for developing strategies to improve the survival of BD donor grafts in liver transplantation.

Cutting Off H

Cancer stem cells (CSCs) are associated with the invasion and metastatic relapse of various cancers. However, current cancer therapies are limited to targeting the bulk of primary tumor cells while remaining the CSCs untouched. Here, we report a new proton (H

Spautin-1 Protects Against Mild TBI-Induced Anxiety-Like Behavior in Mice via Immunologically Silent Apoptosis.

Anxiety is reportedly one of the most common mental changes after traumatic brain injury (TBI). Perineuronal nets (PNNs) produced by astrocytes in the lateral hypothalamus (LHA) that surround gamma-aminobutyric acid-ergic (GABAergic) neurons have been associated with anxiety. The potent anti-tumor effects of Spautin-1, a novel autophagy inhibitor, have been documented in malignant melanoma moreover, the inhibition of autophagy is reported to mitigate anxiety disorders. However, little is known about the ability of spautin-1 to alleviate anxiety. In this study, we sought to investigate whether spautin-1 could alleviate anxiety-like behaviors post-TBI by reducing the loss of PNNs in the LHA. A mild TBI was established in mice through Feeneys weight-drop model. Then, Spautin-1 (20 mmol2 μl) was immediately administered into the left lateral ventricle. Behavioral and pathological changes were assessed at 24 h, 7 days, 30 days, 31 days and 32 days after TBI by the neurological severity scores (NSS), open field test (OFT), elevated plus-maze (EPM) test, western blot, immunofluorescence assays and electron microscopy. Spautin-1 significantly reversed TBI-induced decreased time in the central zone during OFT and in the open-arm during the EPM test. Spautin-1 also increased PNNs around GABAergic neurons indicated by WFA- plus GAD2- positive A2-type astrocytes and attenuated M1-type microglia in the LHA 32 days after TBI compared to TBI alone. Moreover, compared to mice that only underwent TBI, spautin-1 downregulated autophagic vacuoles, abnormal organelles, the expression of Beclin 1, USP13, phospho-TBK1, and phospho-IRF3 and upregulated the levels of cleaved caspase-3, -7 and -9, but failed to increase TUNEL-positive cells in the LHA at 24 h. Spautin-1 alleviated anxiety-like behavior in mice exposed to mild TBI this protective mechanism may be associated with decreased PNNs loss around GABAergic neurons via immunologically silent apoptosis induced by the caspase cascade.

p53 inhibits the Urea cycle and represses polyamine biosynthesis in glioma cell lines.

Glioma is the most common malignant tumor of the central nervous system. The urea cycle (UC) is an essential pathway to convert excess nitrogen and ammonia into the less toxic urea in humans. However, less is known about the functional significance of the urea cycle in glioma. p53 functions as a tumor suppressor and modulates several cellular functions and disease processes. In the present study, we aimed to explore whether p53 influences glioma progression by regulating the urea cycle. Here, we demonstrated the inhibitory impact of p53 on the expression of urea cycle enzymes and urea genesis in glioma cells. The level of polyamine, a urea cycle metabolite, was also regulated by p53 in glioma cells. Carbamoyl phosphate synthetase-1 (CPS1) is the first key enzyme involved in the urea cycle. Functionally, we demonstrated that CPS1 knockdown suppressed glioma cell proliferation, migration and invasion. Mechanistically, we demonstrated that the expression of ornithine decarboxylase (ODC), which determines the generation of polyamine, was regulated by CPS1. In addition, the impacts of p53 knockdown on ODC expression, glioma cell growth and aggressive phenotypes were significantly reversed by CPS1 inhibition. In conclusion, these results demonstrated that p53 inhibits polyamine metabolism by suppressing the urea cycle, which inhibits glioma progression.

Impact of Anesthetic Exposures on the Neurocognitive Profiles of Pediatric Brain Tumor Survivors A New Direction for Research and Multidisciplinary Collaboration.

Primary brain tumors are the most commonly diagnosed solid tumors in children, and pediatric brain tumor survivors experience lasting, pervasive deficits of neurocognitive functioning. Repeated exposure to anesthetic drugs is a necessary component not only of surgical resection but also of multimodal cancer care for the youngest patients with brain tumors. The potential for anesthetic neurotoxicity to worsen neurocognitive outcomes in this vulnerable group, therefore, warrants our attention and further study through multi-disciplinary collaboration. This review discusses neurocognitive functioning in pediatric brain tumor survivors, highlighting the findings of a recent study of children with tumors of the posterior fossa which identified treatment-related risk factors for neurocognitive difficulties, with those undergoing multimodal therapies (eg, chemotherapy and irradiation) experiencing the greatest deficits compared with healthy controls. The role of anesthetic neurotoxicity in long-term outcomes among pediatric brain tumor survivors is also reviewed.

Fiber Density and Structural Brain Connectome in Glioblastoma Are Correlated With Glioma Cell Infiltration.

Glioblastoma (GBM) preferred to infiltrate into white matter (WM) beyond the recognizable tumor margin. To investigate whether fiber density (FD) and structural brain connectome can provide meaningful information about WM destruction and glioma cell infiltration. GBM cases were collected based on inclusion criteria, and baseline information and preoperative MRI results were obtained. GBM lesions were automatically segmented into necrosis, contrast-enhanced tumor, and edema areas. We obtained the FD map to compute the FD and lnFD values in each subarea and reconstructed the structural brain connectome to obtain the topological metrics in each subarea. We also divided the edema area into a nonenhanced tumor (NET) area and a normal WM area based on the contralesional lnFD value in the edema area, and computed the NET ratio. Twenty-five GBM cases were included in this retrospective study. The FDlnFD value and topological metrics (aCp, aLp, aEg, aEloc, and ar) were significantly correlated with GBM subareas, which represented the extent of WM destruction and glioma cell infiltration. The FDlnFD values and topological parameters were correlated with the NET ratio. In particular, the lnFD value in the edema area was correlated with the NET ratio (coefficient, 0.92). Therefore, a larger lnFD value indicates more severe glioma infiltration in the edema area and suggests an extended resection for better clinical outcomes. The FD and structural brain connectome in this study provide a new insight into glioma infiltration and a different consideration of their clinical application in neuro-oncology.

Neurocognitive development after pediatric brain tumor - a longitudinal, retrospective cohort study.

Survivors of Pediatric Brain Tumors (PBTs) treated with cranial radiation therapy (CRT) often experience a decline in neurocognitive test scores. Less is known about the neurocognitive development of non-irradiated survivors of PBTs. The aim of this study was to statistically model neurocognitive development after PBT in both irradiated and non-irradiated survivors and to find clinical variables associated with the rate of decline in neurocognitive scores. A total of 151 survivors were included in the study. Inclusion criteria Diagnosis of PBT between 2001 and 2013 or earlier diagnosis of PBT and turning 18 years of age between 2006 and 2013. Exclusion criteria Death within a year from diagnosis, neurocutaneous syndromes, severe intellectual disability. Clinical neurocognitive data were collected retrospectively from medical records. Multilevel linear modeling was used to evaluate the rate of decline in neurocognitive measures and factors associated with the same. A decline was found in most measures for both irradiated and non-irradiated survivors. Ventriculo-peritoneal (VP) shunting and treatment with whole-brain radiation therapy (WBRT) were associated with a faster decline in neurocognitive scores. Male sex and supratentorial lateral tumor were associated with lower scores. Verbal learning measures were either stable or improving. Survivors of PBTs show a pattern of decline in neurocognitive scores irrespective of treatment received, which suggests the need for routine screening for neurocognitive rehabilitation. However, survivors treated with WBRT andor a VP shunt declined at a faster rate and appear to be at the highest risk of negative neurocognitive outcomes and to have the greatest need for neurocognitive rehabilitation.

H3K27-altered diffuse midline glioma a paradigm shifting opportunity in direct delivery of targeted therapeutics.

Despite much progress, the prognosis for H3K27-altered diffuse midline glioma (DMG), previously known as diffuse intrinsic pontine glioma when located in the brainstem, remains dark and dismal. A wealth of research over the past decade has revolutionized our understanding of the molecular basis of DMG, revealing potential targetable vulnerabilities for treatment of this lethal childhood cancer. However, obstacles to successful clinical implementation of novel therapies remain, including effective delivery across the blood-brain barrier (BBB) to the tumor site. Here, we review relevant literature and clinical trials and discuss direct drug delivery via convection-enhanced delivery (CED) as a promising treatment modality for DMG. We outline a comprehensive molecular, pharmacological, and procedural approach that may offer hope for afflicted patients and their families. Challenges remain in successful drug delivery to DMG. While CED and other techniques offer a chance to bypass the BBB, the variables influencing successful intratumoral targeting are numerous and complex. We discuss these variables and potential solutions that could lead to the successful clinical implementation of preclinically promising therapeutic agents.

The new oncogene transmembrane protein 60 is a potential therapeutic target in glioma.

Glioma is a malignant tumor with a high fatality rate, originating in the central nervous system. Even after standard treatment, the prognosis remains unsatisfactory, probably due to the lack of effective therapeutic targets. The family of transmembrane proteins (TMEM) is a large family of genes that encode proteins closely related to the malicious behavior of tumors. Thus, it is necessary to explore the molecular and clinical characteristics of newly identified oncogenes, such as transmembrane protein 60 (TMEM60), to develop effective treating options for glioma. We used bioinformatic methods and basic experiments to verify the expression of transmembrane protein 60 in gliomas and its relationship with 1p and 19q (1p19q) status, isocitrate dehydrogenase (IDH) status, patient prognosis, and immune cell infiltration using public databases and clinical samples. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to detect co-expressed genes. Thus, we inhibited the expression of transmembrane protein 60 to observe the proliferation and activity of glioma LN229 cells. We found transmembrane protein 60 was significantly upregulated in glioma compared with that in normal brain tissue at the mRNA. In the subgroups of World Health Organization high grade, isocitrate dehydrogenase wildtype, 1p and 19q non-codeletion, or isocitrate dehydrogenase wild combined with 1p and 19q non-codeletion, the expression of transmembrane protein 60 increased, and the prognosis of glioma patients worsened. In the transmembrane protein 60 high expression group, infiltration of immune cells and stromal cells in the tumor microenvironment increased, tumor purity decreased, and immune cells and pathways were activated. The immune cells mainly included regulatory T-cell, gamma delta T-cell, macrophages M0, neutrophils, and CD8

Quality of life, out-of-pocket expenditures, and indirect costs among patients with the central nervous system tumors in Thailand.

The aim of this study was to investigate out-of-pocket (OOP) expenditures, indirect costs, and health-related quality of life (HRQoL) associated with the central nervous system (CNS) tumors in Thailand. A prospective study of CNS tumor patients who underwent first tumor resection at a tertiary care institution in Thailand was conducted. Patients were interviewed during hospitalization for undergoing first surgery. Within 6 months, they were interviewed once more if the disease continued to progress. Costs collected from a patient perspective and converted to 2019 US dollars. For dealing with these skewed data, a generalized linear model was used to investigate the effects of disease severity (malignancy, progressive disease, Karnofsky performance status score, and histology) and other factors on costs (OOP, informal care, productivity loss, and total costs). Among a total of 123 intracranial CNS tumor patients, there were 83 and 40 patients classified into benign and malignant, respectively. In the first brain surgery, there was no statistical difference in HRQoL between patients with benign and malignant tumors ( Although there was no statistical difference in HRQoL and costs between patients with benign and malignant tumor, the total costs accounted for more than half of the reported income in malignant tumor patients. The primary cause of significant increases in all costs categories was disease progression.

Cerebral tissue oxygenation response to brain irradiation measured during clinical radiotherapy.

Cancer therapy treatments produce extensive changes in the physiological and morphological properties of tissues, which are also individual dependent. Currently, a key challenge involves developing more tailored cancer therapy, and consequently, individual biological response measurement during therapy, such as tumor hypoxia, is of high interest. This is the first time human cerebral haemodynamics and cerebral tissue oxygenation index (TOI) changes were measured during the irradiation in clinical radiotherapy and functional near-infrared spectroscopy (fNIRS) technique was demonstrated as a feasible technique for clinical use in radiotherapy, based on 34 online patient measurements. Our aim is to develop predictive biomarkers and noninvasive real-time methods to establish the effect of radiotherapy during treatment as well as to optimize radiotherapy dose planning for individual patients. In particular, fNIRS-based technique could offer an effective and clinically feasible online technique for continuous monitoring of brain tissue hypoxia and responses to chemo- and radiotherapy, which involves modulating tumor oxygenation to increase or decrease tumor hypoxia. We aim to show that fNIRS is feasible for repeatability measuring in patient radiotherapy, the temporal alterations of tissue oxygenation induced by radiation. Fiber optics setup using multiwavelength fNIRS was built and combined with a medical linear accelerator to measure cerebral tissue oxygenation changes during the whole-brain radiotherapy treatment, where the radiation dose is given in whole brain area only preventing dosage to eyes. Correlation of temporal alterations in cerebral haemodynamics and TOI response to brain irradiation was quantified. Online fNIRS patient measurement of cerebral haemodynamics during clinical brain radiotherapy is feasible in clinical environment, and results based on 34 patient measurements show strong temporal alterations in cerebral haemodynamics and decrease in TOI during brain irradiation and confirmed the repeatability. Our proof-of-concept study shows evidently that irradiation causes characteristic immediate changes in brain tissue oxygenation. In particular, TOI seems to be a sensitive parameter to observe the tissue effects of radiotherapy. Monitoring the real-time interactions between the subjected radiation dose and corresponding haemodynamic effects may provide important tool for the researchers and clinicians in the field of radiotherapy. Eventually, presented fNIRS technique could be used for improving dose planning and safety control for individual patients.

Local recurrence of submucosal invasive colorectal cancer after endoscopic submucosal dissection revealed by copy number variation.

We report a case in which analysis of copy number variation revealed local recurrence of submucosal invasive colorectal cancer after curative endoscopic submucosal dissection (ESD). An 86-year-old man with a history of abdominoperineal resection of the rectum for rectal cancer underwent resection with ESD for early-stage sigmoid cancer 5 cm away from the stoma opening. At the same time, ileocecal resection was performed for advanced cecal cancer. Twelve months after ESD, advanced cancer occurred in the area of the ESD lesion. It was unclear if the cancer was a local recurrence after ESD, implantation of cecal cancer, or a new lesion. Copy number variation analysis performed for the three lesions revealed that the new lesion originated from residual tumor cells from ESD and was unlikely to be cecal cancer.

Mononeuropathy multiplex as a first manifestation of renal cell carcinoma a case report.

The neurologic symptoms that appear due to paraneoplastic syndrome may give manifestations of undiagnosed tumor, and give an opportunity for early detection and treatment of it. Here the authors present a case of a 54-year-old woman who suffered from rapidly progressive muscle weakness, accompanied by right third cranial nerve palsy. The nerve conduction study consistent with multiple mononeuropathy, and laboratories revealed undiagnosed diabetes mellitus but elevated erythrocyte sedimentation rate and the rapid progression prompted for additional investigations. Brain MRI, repetitive nerve stimulation, lumbar puncture, and paraneoplastic panel were all negative. Computed tomography scan with contrast for the abdomen showed a right renal mass consistent with renal cell carcinoma. The tumor was removed and steroids and intravenous immunoglobulin was started but without any clinical improvement because of the late presentation. Patients with renal cell carcinoma can present with paraneoplastic syndromes but multiple mononeuropathy are extremely rare. It is crucial to investigate for all possible causes of neuropathy and not attributing it to a new discovered diabetes in the presence of clinical and laboratory red flags such as rapid progression and elevated erythrocyte sedimentation rate.