Clinical roles of EGFR amplification in diffuse gliomas: a real-world study using the 2021 WHO classification of CNS tumors.

Background: The 2021 World Health Organization Classification of Central Nervous System Tumors updates glioma subtyping and grading system, and incorporates EGFR amplification (Amp) as one of diagnostic markers for glioblastoma (GBM). Purpose: This study aimed to describe the frequency, clinical value and molecular correlation of EGFR Amp in diffuse gliomas based on the latest classification. Methods: We reviewed glioma patients between 2011 and 2022 at our hospital, and included 187 adult glioma patients with available tumor tissue for detection of EGFR Amp and other 59 molecular markers of interest. Clinical, radiological and pathological data was analyzed based on the status of EGFR Amp in different glioma subtypes. Results: 163 gliomas were classified as adult-type diffuse gliomas, and the number of astrocytoma, oligodendroglioma and GBM was 41, 46, and 76. EGFR Amp was more common in IDH-wildtype diffuse gliomas (66.0%) and GBM (85.5%) than IDH-mutant diffuse gliomas (32.2%) and its subtypes (astrocytoma, 29.3%; oligodendroglioma, 34.8%). EGFR Amp did not stratify overall survival (OS) in IDH-mutant diffuse gliomas and astrocytoma, while was significantly associated with poorer OS in IDH-wildtype diffuse gliomas, histologic grade 2 and 3 IDH-wildtype diffuse astrocytic gliomas and GBM. Conclusion: Our study validated EGFR Amp as a diagnostic marker for GBM and still a useful predictor for shortened OS in this group.

A prognostic model for overall survival in recurrent glioma patients treated with bevacizumab-containing therapy.

Predictive markers and prognostic models are useful for the individualization of cancer treatment. In this study, we sought to identify clinical and molecular factors to predict overall survival in recurrent glioma patients receiving bevacizumab-containing regimens. A cohort of 102 patients was retrospectively collected from June 2011 to January 2022 at our institution. A nomogram was generated by Cox regression and feature selection algorithms based on 19 clinicopathological and 60 molecular variables. The model's performance was internally evaluated by bootstrapping in terms of discrimination and calibration. The median overall survival from the initiation of bevacizumab administration to death or last follow-up was 11.6 months (95% CI: 9.2-13.8 months) for all 102 patients, 10.2 months (95% CI: 6.4-13.3 months) for 66 patients with grade 4 tumors, and 13.8 months (lower limit of 95% CI: 11.5 months) for 36 patients with tumors of grade lower or not available. In the final model, a lower WHO 2021 grade (Grade lower or not available vs. Grade 4, HR: 0.398, 95% CI: 0.223-0.708, p = 0.00172), having received adjuvant radiochemotherapy (Yes vs. No, HR: 0.488, 95% CI: 0.268-0.888, p = 0.0189), and wildtype EGFR (Wildtype vs. Altered, HR: 0.193, 95% CI: 0.0506-0.733, p = 0.0157; Not available vs. Altered, HR: 0.386, 95% CI: 0.184-0.810, p = 0.0118) were significantly associated with longer overall survival in multivariate Cox regression. The overall concordance index was 0.652 (95% CI: 0.566-0.714), and the areas under the time-dependent curves for 6-, 12-, and 18-month overall survival were 0.677 (95% CI: 0.516-0.816), 0.654 (95% CI: 0.470-0.823), and 0.675 (95% CI: 0.491-0.860), respectively. A prognostic model for overall survival in recurrent glioma patients treated with bevacizumab-based therapy was established and internally validated. It could serve as a reference tool for clinicians to assess the extent the patients may benefit from bevacizumab and stratify their treatment response.

Molecular Determinants of Neurocognitive Deficits in Glioma: Based on 2021 WHO Classification.

Cognitive impairment is a common feature among patients with diffuse glioma. The objective of the study is to investigate the relationship between preoperative cognitive function and clinical as well as molecular factors, firstly based on the new 2021 World Health Organization's updated classification of central nervous system tumors. A total of 110 diffuse glioma patients enrolled underwent preoperative cognitive assessments using the Mini-Mental State Examination and Montreal Cognitive Assessment. Clinical information was collected from medical records, and gene sequencing was performed to analyze the 18 most influenced genes. The differences in cognitive function between patients with and without glioblastoma were compared under both the 2016 and 2021 WHO classification of tumors of the central nervous system to assess their effect of differentiation on cognition. The study found that age, tumor location, and glioblastoma had significant differences in cognitive function. Several genetic alterations were significantly correlated with cognition. Especially, IDH, CIC, and ATRX are positively correlated with several cognitive domains, while most other genes are negatively correlated. For most focused genes, patients with a low number of genetic alterations tended to have better cognitive function. Our study suggested that, in addition to clinical characteristics such as age, histological type, and tumor location, molecular characteristics play a crucial role in cognitive function. Further research into the mechanisms by which tumors affect brain function is expected to enhance the quality of life for glioma patients. This study highlights the importance of considering both clinical and molecular factors in the management of glioma patients to improve cognitive outcomes.

Novel insight into histological and molecular astrocytoma, IDH-mutant, Grade 4 by the updated WHO classification of central nervous system tumors.

BACKGROUND: The latest fifth edition of the World Health Organization (WHO) classification of the central nervous system (CNS) tumors (WHO CNS 5 classification) released in 2021 defined astrocytoma, IDH-mutant, Grade 4. However, the understanding of this subtype is still limited. We conducted this study to describe the features of astrocytoma, IDH-mutant, Grade 4 and explored the similarities and differences between histological and molecular subtypes. METHODS: Patients who underwent surgery from January 2011 to January 2022, classified as astrocytoma, IDH-mutant, Grade 4 were included in this study. Clinical, radiological, histopathological, molecular pathological, and survival data were collected for analysis. RESULTS: Altogether 33 patients with astrocytoma, IDH-mutant, Grade 4 were selected, including 20 with histological and 13 with molecular WHO Grade 4 astrocytoma. Tumor enhancement, intratumoral-necrosis like presentation, larger peritumoral edema, and more explicit tumor margins were frequently observed in histological WHO Grade 4 astrocytoma. Additionally, molecular WHO Grade 4 astrocytoma showed a tendency for relatively longer overall survival, while a statistical significance was not reached (47 vs. 25 months, p = 0.22). TP53, CDK6, and PIK3CA alteration was commonly observed, while PIK3R1 (p = 0.033), Notch1 (p = 0.027), and Mycn (p = 0.027) alterations may affect the overall survival of molecular WHO Grade 4 astrocytomas. CONCLUSIONS: Our study scrutinized IDH-mutant, Grade 4 astrocytoma. Therefore, further classification should be considered as the prognosis varied between histological and molecular WHO Grade 4 astrocytomas. Notably, therapies aiming at PIK3R1, Notch 1, and Mycn may be beneficial.

Histological and molecular glioblastoma, IDH-wildtype: a real-world landscape using the 2021 WHO classification of central nervous system tumors.

Introduction: Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors. This study aimed to characterize the clinical, radiological, molecular, and survival features of GBM under the current classification scheme and explore survival determinants. Methods: We re-examined the genetic alterations of IDH-wildtype diffuse gliomas at our institute from 2011 to 2022, and enrolled GBMs for analysis after re-classification. Univariable and multivariable analyses were used to identify survival determinants. Results: Among 209 IDH-wildtype gliomas, 191 were GBMs, including 146 hist-GBMs (76%) and 45 mol-GBMs (24%). Patients with mol-GBMs were younger, less likely to develop preoperative motor dysfunction, and more likely to develop epilepsy than hist-GBMs. Mol-GBMs exhibited lower radiographic incidences of contrast enhancement and intratumoral necrosis. Common molecular features included copy-number changes in chromosomes 1, 7, 9, 10, and 19, as well as alterations in EGFR, TERT, CDKN2A/B, and PTEN, with distinct patterns observed between the two subtypes. The median overall survival (mOS) of GMB was 12.6 months. Mol-GBMs had a higher mOS than hist-GBMs, although not statistically significant (15.6 vs. 11.4 months, p=0.17). Older age, male sex, tumor involvement of deep brain structure or functional area, and genetic alterations in CDK4, CDK6, CIC, FGFR3, KMT5B, and MYB were predictors for a worse prognosis, while MGMT promoter methylation, maximal tumor resection, and treatment based on the Stupp protocol were predictive for better survival. Conclusion: The definition of GBM and its clinical, radiological, molecular, and prognostic characteristics have been altered under the current classification.

Spotlights on adult patients with pediatric-type diffuse gliomas in accordance with the 2021 WHO classification of CNS tumors.

Introduction: The fifth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors released in 2021 formally defines pediatric-type diffuse gliomas. However, there is still little understanding of pediatric-type diffuse gliomas, and even less attention has been paid to adult patients. Therefore, this study describes the clinical radiological, survival, and molecular features of adult patients with pediatric-type glioma. Methods: Adult patients who underwent surgery from January 2011 to January 2022, classified as pediatric-type glioma, were included in this study. Clinical, radiological, histopathological, molecular pathological, and survival data were collected for analysis. Results: Among 596 adult patients, 20 patients with pediatric-type glioma were screened, including 6 with diffuse astrocytoma, MYB- or MYBL1-altered, 2 with diffuse midline glioma, H3 K27-altered, and 12 with diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. Pediatric high-grade glioma (pHGG) frequently showed tumor enhancement, peritumoral edema, and intratumoral necrosis. Adult patients with pHGG showed a longer life expectancy than adult patients with glioblastoma. Common molecular alterations included chromosome alterations and CDKN2A/B, PIK3CA, and PTEN, while altered KMT5B and MET were found to affect the overall survival. Conclusion: Our study demonstrated adult patients with pediatric-type glioma. Notably, our research aims to expand the current understanding of adult patients with pediatric-type diffuse gliomas. Furthermore, personalized therapies consisting of targeted molecular inhibitors for MET and VEGFA may exhibit beneficial effects in the corresponding population.

Recent advances and future challenges of tumor vaccination therapy for recurrent glioblastoma.

Glioblastoma (GBM) is the most malignant CNS tumor with a highest incidence rate, and most patients would undergo a recurrence. Recurrent GBM (rGBM) shows an increasing resistance to chemotherapy and radiotherapy, leading to a significantly poorer prognosis and the urgent need for novel treatments. Immunotherapy, a rapidly developing anti-tumor therapy in recent years, has shown its potential value in rGBM. Recent studies on PD-1 immunotherapy and CAR-T therapy have shown some efficacy, but the outcome was not as expected. Tumor vaccination is the oldest approach of immunotherapies, which has returned to the research focus because of the failure of other strategies and subversive understanding of CNS. The isolation effect of blood brain barrier and the immunosuppressive cell infiltration could lead to resistance existing in all phases of the anti-tumor immune response, where novel tumor vaccines have been designed to overcome these problems through new tumor antigenic targets and regulatory of the systematic immune response. In this review, the immunological characteristics of CNS and GBM would be discussed and summarized, as well as the mechanism of each novel tumor vaccine for rGBM. And through the review of completed early-phase studies and ongoing large-scale phase III clinical trials, evaluation could be conducted for potential immune response, biosecurity and initial clinical outcome, which further draw a panorama of this vital research field and provide some deep thoughts for the prospective tendency of vaccination strategy. Video Abstract.

Clinical updates on gliomas and implications of the 5th edition of the WHO classification of central nervous system tumors.

Background: The 5th edition of the World Health Organization (WHO) classification of central nervous system tumors incorporated specific molecular alterations into the categorization of gliomas. The major revision of the classification scheme effectuates significant changes in the diagnosis and management of glioma. This study aimed to depict the clinical, molecular, and prognostic characteristics of glioma and its subtypes according to the current WHO classification. Methods: Patients who underwent surgery for glioma at Peking Union Medical College Hospital during 11 years were re-examined for tumor genetic alterations using next-generation sequencing, polymerase chain reaction-based assay, and fluorescence in situ hybridization methods and enrolled in the analysis. Results: The enrolled 452 gliomas were reclassified into adult-type diffuse glioma (ntotal=373; astrocytoma, n=78; oligodendroglioma, n=104; glioblastoma, n=191), pediatric-type diffuse glioma (ntotal=23; low-grade, n=8; high-grade, n=15), circumscribed astrocytic glioma (n=20), and glioneuronal and neuronal tumor (n=36). The composition, definition, and incidence of adult- and pediatric-type gliomas changed significantly between the 4th and the 5th editions of the classification. The clinical, radiological, molecular, and survival characteristics of each subtype of glioma were identified. Alterations in CDK4/6, CIC, FGFR2/3/4, FUBP1, KIT, MET, NF1, PEG3, RB1, and NTRK2 were additional factors correlated with the survival of different subtypes of gliomas. Conclusions: The updated WHO classification based on histology and molecular alterations has updated our understanding of the clinical, radiological, molecular, survival, and prognostic characteristics of varied subtypes of gliomas and provided accurate guidance for diagnosis and potential prognosis for patients.

Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy.

Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.

Assessment of the Health-Related Quality of Life in Neurocysticercosis Patients in Hot Spot Areas - China, 2017-2018.

What is already known about this topic?: Neurocysticercosis is the most severe form of infection caused by ingesting cysticerci, the larval cysts of the pork tapeworm, Taenia solium. Approximately 50 million people worldwide have neurocysticercosis, which is the leading cause of acquired epilepsy in many endemic countries. What is added by this report?: The health of neurocysticercosis patients can be seriously impaired, including through loss of mobility, inability to do self-care, impairment of usual activities, pain/discomfort, anxiety/depression, and impaired cognition. Cognitive impairment is the major consequence of neurocysticercosis and significant contributor to decreased health-related quality of life. Our study made the first estimate of disability weight from neurocysticercosis as a key parameter for disease burden assessment in China. What are the implications for public health practice?: To prevent severe health outcomes from neurocysticercosis in China, it is necessary to improve public awareness of neurocysticercosis and relevant health behaviors.

Comparative efficacy and safety of therapeutics for elderly glioblastoma patients: A Bayesian network analysis.

Optimal management strategies for elderly glioblastoma (GBM) patients remain elusive. Overall survival (OS) and progression-free survival (PFS) in elderly newly diagnosed GBM (ndGBM) patients were analyzed with random-effects Bayesian network meta-analysis with the estimated hazard ratio (HR) with a 95% confidence interval (95% CrI). In addition, OS, PFS and adverse event (AE) data on ndGBM and recurrent GBM (rGBM) were assessed. Seventeen eligible trials with 12 on ndGBM and 5 on rGBM were identified. For the improvements it induced in the OS of elderly ndGBM patients, tumor treating field (TTF) + temozolomide (TMZ) (HR: 0.11, 95% CrI: 0.02-0.67 vs. supportive care (SPC)) ranked first, followed by TMZ + hyperfractionated radiotherapy (HFRT) (HR: 0.17, 95% CrI: 0.03-0.95 vs. SPC). For the improvements it induced in the PFS of elderly ndGBM patients, bevacizumab (BEV) + HFRT ranked first, followed by TMZ + HFRT. TMZ was observed to be more effective in O6-methylguanine-DNA-methyltransferase (MGMT) promoter-methylated ndGBM patients than HFRT and standard radiotherapy (STRT). For elderly rGBM patients, the treatments included were comparable. The rates of other neurological symptoms (16.1%) and lymphocytopenia (10.4%) were higher in ndGBM patients; lymphocytopenia (10.3%) and infection (8.1%) were higher in rGBM patients among the ≥ 3 grade AEs. TMZ-related AEs should be further considered. In conclusion, TTF + adjuvant TMZ and TMZ + HFRT are most likely to be recommended for elderly ndGBM patients. No best treatment for rGBM in elderly patients is illustrated. TMZ is identified to be more effective in elderly ndGBM patients with methylated MGMT status; however, AEs associated with TMZ-related therapy should be well considered and managed.

Spatio-temporal distribution characteristics of cysticercosis from 2000 to 2014 in Dali, Yunnan province, China.

Cysticercosis remains a public health problem in China, with disease prevalence attributed to poor socio-economic and public health conditions. This parasitic food-borne disease was prioritized for effective control following implementation of the national surveys on parasitic diseases carried out in China. We predicted the cysticercosis distribution in Dali, Yunnan Province by assessing spatio-temporal distribution characteristics between 2000 and 2014 to better understand the trend of the disease incidence. A database of cysticercosis cases was provided by the clinical department at the Dali Prefectural Institute of Research and Control of Schistosomiasis. Describing the epidemiological features of cysticercosis and analyzing its spatiotemporal distribution of cases using mapping, scanning and spatial autocorrelation analysis, our findings found a total of 3,347 patients with cysticercosis infection, neurocysticercosis in particular. Cysticercosis prevalence was the highest among young and middle-aged male farmers, and also predominant among the Bai nationality. Three aggregation areas were identified during the period 2000-2014. Hotspot analysis implicated Dali City, Eryuan County and Yangbi County between 2000 and 2007, with areas gradually shifting towards the western and northern parts of the province. The hotspot map indicated that Eryuan County was a constant problem with respect to cysticercosis. The results indicated three cysticercosis clusters in Dali that could be attributed to environmental factors and unhealthy lifestyles. Multi-sectoral control initiatives are, therefore, recommended in these areas to effectively control and prevent cysticercosis among the population.

Extensive disseminated cysticercosis: a case report in Yunnan province, China.

BACKGROUND: Cysticercosis is spreading all over the world and it is a major health problem in most countries of Latin America, Africa, and Asia. Extensive disseminated cysticercosis is relatively rare and fewer than 120 case have been reported in the worldwide. We reported a rare case of extensive disseminated cysticercosis in Yunan province, China. CASE PRESENTATION: A rare case of extensive disseminated cysticercosis, in a 61-year-old male Chinese was detected from Yunnan province in 2018. Clinical and etiological examination was performed, as well as the epidemiological investigation. CONCLUSION: The life cycle of T. solium in the area where the case came from is complete. We expect this case could raise the attentions to the control of Taenia solium infection and subsequent cysticercosis there.

Novel 3D-printed prosthetic composite for reconstruction of massive bone defects in lower extremities after malignant tumor resection.

OBJECTIVE: To introduce a novel 3D-printed prosthetic composite for reconstruction of massive bone defects after resection for bone malignancy of lower extremities. The design concept, surgical technique, and the preliminary outcomes were elaborated. METHODS: Patients with primary malignant tumors of lower extremities requiring tumor resection and reconstruction were recruited between Jun 2015 and Nov 2018. Patient-specific 3D-printed prostheses were designed according to preoperative imaging data. After tumor resection, reconstruction was performed with composites consisting of 3D- printed prosthesis, beta-tricalcium phosphate (ß-TCP) bioceramics and/or vascularized fibula. All patients underwent regular follow-up postoperatively. The functional outcomes were assessed by the Musculoskeletal Tumor Society score (MSTS). Oncological outcomes, imaging results, and complications were recorded and analyzed. RESULTS: Ten cases averaging 12.90 years of age participated in this study. There were five femur and five tibia reconstructions. The mean follow-up period was 16.90 months. At last follow-up, all patients were alive without tumor recurrence. Average MSTS functional score was 80.33 ± 11.05%. All prostheses were intact and stable without failure or systemic breakage. No serious complications occurred after the operation. Postoperative X-ray, computed tomography (CT) and single-photon emission computed tomography (SPECT) showed an ideal integration between the bone and the prosthetic composite. Moreover, vascularized fibula and implanted ß-TCP bioceramics indicated relatively high metabolic activity in vivo. CONCLUSIONS: Patient-specific 3D-printed prostheses combined with ß-TCP bioceramics and/or vascularized fibula provide an excellent option for reconstruction of massive bone defects after lower extremity malignant tumor extirpation. Short-term follow up showed promising clinical results in recovering lower limb function, promoting osseointegration and reducing complications.

[Construction of antisense recombinant adenoviral vector for c-myc and its antiproliferative effect on rat lymphocytes].

AIM: To observe the antiproliferative effect of antisense recombinant adenoviral vector for c-myc on rat thymus lymphocytes. METHODS: Antisense and sense bacterial plasmids for c-myc were constructed. Bacterial plasmids and El detected adenoviral plasmid were cotransfected into 293 cells. Recombinant adenoviral vectors were obtained after cotransfection. The antiproliferative effects were assayed by MTS. The expression of c-myc mRNA was detected by RT-PCR. RESULTS: The results showed that antisense recombinant adenoviral vector for c-myc could inhibit rat thymus lymphocytes proliferation. The expression of c-myc mRNA was decreased after antisense recombinant adenoviral vector for c-myc was transfected into cells. CONCLUSION: Recombinant antisense adenoviral vector for c-myc could inhibit rat thymus lymphocytes proliferation.

[NF-kappaB expression in lung tissue of acute lung injury rat model and the influence by antioxidant N-acetylcysteine].

AIM: To observe the NF-kappaB expression in the lung tissue of LPS-induced acute lung injury(ALI) rat model and the influence of N-acetylcysteine (NAC) on NF-kappaB expression. METHODS: The expression of NF-kappaB in lung tissue in ALI rat model and the influence of NAC on NF-kappaB expression were detected by immunohistochemical (ABC) staining and Western blot. RESULTS: There were a small amount of sporadic NF-kappaB cells in airway epithelium and interstitium in normal control group. In contrast, nuclear NF-kappaB expression-positive cells increased obviously in airway mucosa, lung interestium, alveolar cavity and vascular wall of ALI rats. NF-kappaB(+) cells were mainly airway mucosa epithelial cells, infiltrating inflammatory cells, alveolar epithelial cells, and vascular endothelial cells. The NF-kappaB expression-positive cells in NAC therapy group notably decreased compared with ALI group and control group(P<0.01). Western blot analysis showed that the expression of NF-kappaB was different at various time points, reaching the peak at 3 h and then decreased (P<0.01) after LPS induced lung injury. CONCLUSION: In LPS induced acute lung injury rat model, the NF-kappaB nuclear expression increased obviously in airway mucosa, lung interestium and alveolar cavity. Most cells in lung tissue participated in the activation of NF-kappaB. NAC could alleviate inflammation by inhibiting activation of NF-kappaB.