PhaseⅠstudy of chlorogenic acid injection for recurrent high-grade glioma with long-term follow-up

Objective:This study was aimed at analyzing the efficacy and safety of an injectable form of chlorogenic acid(CGA)in patients with recurrent high-grade glioma after standard of care treatments,through a first-in-human,open-label,dose-escalation phase I trial.Methods:A total of 26 eligible patients were enrolled,received intramuscular CGA injections at 5 dose levels,and were followed up for 5 years.CGA was well tolerated,and the maximum tolerated dose was 5.5 mg/kg.Results:The most common treatment-related adverse events occurred at the sites of injection.No grade 3 or 4 adverse events(e.g.,drug allergy)were reported for these patients except for induration at the injection sites.A clinical pharmacokinetic study showed that CGA was rapidly eliminated from the plasma,with a t_(1/2)of 0.95–1.27 h on day 1 and 1.19–1.39 h on day 30,and no detectable CGA was observed on days 9,11,13,23,25,27,and 29 before CGA administration.After the first treatment cycle,52.2%of patients(12 of 23)achieved stable disease.Long-term follow-up indicated an estimated median overall survival of 11.3 months for all 23 evaluable patients.Of the 18 patients with grade 3 glioma,the median overall survival was 9.5 months.Two patients remained alive at the cutoff day.Conclusions:This phase I study demonstrated that CGA has a favorable safety profile(with no severe toxicity),and provides preliminary clinical benefits for patients with high grade glioma relapsing after prior standard therapies,thus shedding light on the potential clinical application of CGA for recurrent grade 4 glioma.

Drug clinical trials on high-grade gliomas: challenges and hopes

Gliomas are the most common group of malignant central nervous system tumors across all ages and have high heterogeneity.According to histopathologic criteria and molecular pathology,gliomas are classified as grades 1–4.High-grade gliomas(HGG),including the most aggressive subtype,glioblastoma(GBM),belong to grade 3 or 4.Although a standard therapy comprising surgical resection,chemotherapy,and radiation is available,almost all patients with HGG experience recurrence within several months and a dismal prognosis1.

Re-irradiation for high-grade gliomas:Has anything changed?

Optimal management after recurrence or progression of high-grade gliomas is still undefined and remains a challenge for neuro-oncology multidisciplinary teams.Improved radiation therapy techniques,new imaging methods,published experience,and a better radiobiological knowledge of brain tissue have positioned re-irradiation(re-RT)as an option for many of these patients.Decisions must be individualized,taking into account the pattern of relapse,previous treatment,and functional status,as well as the patient’s preferences and expected quality of life.Many questions remain unanswered with respect to re-RT:Who is the most appropriate candidate,which dose and fractionation are most effective,how to define the target volume,which imaging technique is best for planning,and what is the optimal timing?This review will focus on describing the most relevant studies that include re-RT as salvage therapy,with the aim of simplifying decision-making and designing the best available therapeutic strategy.

Relationship between FGF12 expression in high-grade gliomas and clinical features

Objective:gliomas are the most common intracranial tumors.Fibroblast growth factor-12(FGF12),which belongs to the fibroblast growth factor(FGFs)family,plays an important role in cell mitosis,as well as in other life functions,such as embryo development,tissue repair,cell proliferation,and tumor growth and invasion.The purpose of this study was to explore the potential value of FGF12 in high-grade gliomas and to predict its drug sensitivity.To provide a possible therapeutic target for glioma.Methods:high-grade glioma gene expression data and clinical information were downloaded from the gene expression omnibus(GEO)database,using the R language“impute”and“survival”survival analysis package.The FGF12 genes closely related to survival were screened,a survival curve was drawn,and clinical correlation analysis was conducted.The differentially expressed genes(DEGs)were defined as |logFC|>1,adj.PVal<0.05 as the standard.We used the David for Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis,and constructed the protein-protein interactions(PPI)network.Then we used the Connectivity Map(CMAP)database for drug location,and the validation group was verified by the Chinese Glioma Genome Atlas(CGGA)database in the same way.Results:we found that high FGF12 expression was associated with a higher survival rate.The same validation was performed in the validation group through the CGGA database,and the survival curve showed the same trend.The expression level of FGF12 is an independent factor that affects the life time and status of the samples,and it is a low risk factor.GO enrichment analysis showed that differential genes were enriched in matrix transmembrane transporter activity,ion channels and calcium ion active channels.KEGG showed that DEGs were enriched in the phosphatidylinositol 3-kinase(PI3K)-protein kinase B(Akt)signaling pathway,dopaminergic synapse and cyclic adenosine monophosphate(cAMP)signaling pathway.Four seed genes,GRIA2,COLLA2,GRIA4 and HES6,were obtained by PPI network analysis.The cAMP was used to analyze and obtained 7 small molecule drugs,such as merbromin,naloxone,AH-2384&ticarcillin,vincamine,amoxicillin,azacyclonol,which may be helpful in the prognosis of high-grade gliomas.Conclusion:FGF12 and its pathway may serve as a biomarker or therapeutic target for high-grade gliomas.

Radiotherapy of high-grade gliomas: current standards and new concepts, innovations in imaging and radiotherapy, and new therapeutic approaches

The current standards in radiotherapy of high-grade gliomas(HGG) are based on anatomic imaging techniques, usually computed tomography(CT) scanning and magnetic resonance imaging(MRI). The guidelines vary depending on whether the HGG is a histological grade 3 anaplastic glioma(AG) or a grade 4 glioblastoma multiforme(GBM). For AG, T2-weighted MRI sequences plus the region of contrast enhancement in T1 are considered for the delineation of the gross tumor volume(GTV), and an isotropic expansion of 15 to 20 mm is recommended for the clinical target volume(CTV). For GBM, the Radiation Therapy Oncology Group favors a two-step technique, with an initial phase(CTV1) including any T2 hyperintensity area(edema) plus a 20 mm margin treated with up to 46 Gy in 23 fractions, followed by a reduction in CTV2 to the contrast enhancement region in T1 with an additional 25 mm margin. The European Organisation of Research and Treatment of Cancer recommends a single-phase technique with a unique GTV, which comprises the T1 contrast enhancement region plus a margin of 20 to 30 mm. A total dose of 60 Gy in 30 fractions is usually delivered for GBM, and a dose of 59.4 Gy in 33 fractions is typically given for AG. As more than 85% of HGGs recur in field, dose-escalation studies have shown that 70 to 75 Gy can be delivered in 6 weeks with relevant toxicities developing in < 10% of the patients. However, the only randomized dose-escalation trial, in which the boost dose was guided by conventional MRI, did not show any survival advantage of this treatment over the reference arm. HGGs are amongst the most infiltrative and heterogeneous tumors, and it was hypothesized that the most highly aggressive areas were missed; thus, better visualization of these high-risk regions for radiation boost could decrease the recurrence rate. Innovations in imaging and linear accelerators(LINAC) could help deliver the right doses of radiation to the right subvolumes according to the dose-painting concept. Advanced imaging techniques provide functional information on cellular density(diffusion MRI), angiogenesis(perfusion MRI), metabolic activity and cellular proliferation [positron emission tomography(PET) and magnetic resonance spectroscopy(MRS)]. All of these non-invasive techniques demonstrated good association between the images and histology, with up to 40% of HGGs functionally presenting a high activity within the non- contrast-enhanced areas in T1. New LINAC technologies, such as intensity-modulated and stereotactic radiotherapy, help to deliver a simultaneous integrated boost(SIB) > 60 Gy. Trials delivering a SIB into a biological GTV showed the feasibility of this treatment, but the final results, in terms of clinical benefits for HGG patients, are still pending. Many issues have been identified: the variety of MRI and PET machines(and amino-acid tracers), the heterogeneity of the protocols used for image acquisition and post-treatment, the geometric distortion and the unreliable algorithms for co-registration of brain anatomy with functional maps, and the semi-quiescent but highly invasive HGG cells. These issues could be solved by the homogenization of the protocols and software applications, the simultaneous acquisition of anatomic and functional images(PET-MRI machines), the combination of complementary imaging tools(perfusion and diffusion MRI), and the concomitant addition of some ad hoc targeted drugs against angiogenesis and invasiveness to chemoradiotherapy. The integration of these hybrid data will construct new synthetic metrics for fully individualized treatments.

High-grade gliomas: reality and hopes

In this issue of the Chinese Journal of Cancer, European experts review current standards, trends, and future prospects in the difficult domain of high-grade glioma. In all fields covered by the different authors, the progress has been impressive. For example, discoveries at the molecular level have already impacted imaging, surgery, radiotherapy, and systemic therapies, and they are expected to play an increasing role in the management of these cancers. The European Organization for Research and Treatment of Cancer(EORTC) has pioneered new treatment strategies and contributed to new standards. The articles in this issue will cover basic molecular biological principles applicable today, novel surgical approaches, innovations in radiotherapy planning and delivery, evidence-based standards for radiotherapy alone or combined with chemotherapy, current standards and novel approaches for systemic treatments, and the important but often neglected field of health-related quality of life. Despite the advances described in these articles, the overall prognosis of high-grade glioma, especially glioblastoma, remains poor, and more research is needed to address this problem.

Molecular biology of high-grade gliomas: what should the clinician know?

The current World Health Organization classification system of primary brain tumors is solely based on morphologic criteria. However, there is accumulating evidence that tumors with similar histology have distinct molecular signatures that significantly impact treatment response and survival. Recent practice-changing clinical trials have defined a role for routine assessment of O-6-methylguanine-DNA methyltransferase(MGMT) promoter methylation in glioblastoma patients, especially in the elderly, and 1p and 19q codeletions in patients with anaplastic glial tumors. Recently discovered molecular alterations including mutations in IDH-1/2, epidermal growth factor receptor(EGFR), and BRAF also have the potential to become targets for future drug development. This article aims to summarize current knowledge on the molecular biology of high-grade gliomas relevant to daily practice.

A Phase II Study of Antineoplastons A10 and AS2-1 in Children with High-Grade Glioma. Final Report (Protocol BT-06), and Review of Recent Trials

Standard treatment for high-grade glioma involves surgical resection followed by radiation therapy and temozolomide. Unfortunately, there are no standard treatment recommendations after recurrence and new therapies are needed for patients whose tumor recurs after first-line treatment. This single-arm, two-stage, interventional Phase II study evaluated the efficacy and safety of a combination of antineoplastons A10 and AS2-1. Nineteen patients were enrolled in the study (safety population), but fifteen patients with a median age of 9.4 years who met eligibility criteria were evaluated. The majority of subjects (12/15) were Caucasian and 8/15 (53%) were female. More than half (53%) of patients were diagnosed with glioblastoma and 33% with anaplastic astrocytoma. All patients had failed standard therapy including surgery, radiation, and chemotherapy. Antineoplastons were administered intravenously every four hours (median dose of A10 6.9 g/kg/d and AS2-1 0.30 g/kg/d) until objective response was documented and thereafter for a further 8 months. Clinical evaluations were performed every 8 weeks. All patients enrolled in the study were included in the safety analysis but only patients fulfilling the inclusion criteria were included in the efficacy evaluation. The duration of treatment with antineoplastons ranged from 2 weeks to 120 weeks. A complete response was documented in 2/15 (13%), partial response in 2/15 (13%), stable disease in 3/15 (20%). Progression-free survival at six months was 47% and overall survival (OS) at one year was 33.3%. One patient (6.7%) survived 10 years from treatment start. A small group of patients suffered reversible Grade 3 and 4 toxicities including hypernatremia 2/19 (11%) and decrease of neutrophils 1/19 (5%). There were no chronic toxicities. There was improvement of quality of life in patients who had objective response. It is concluded that antineoplastons show efficacy with an acceptable profile in this cohort of patients with recurrent high-grade glioma.

Magnetic Resonance Perfusion Imaging in the Diagnosis of High-Grade Glioma Progression and Treatment-Related Changes: A Systematic Review

In patients with high grade gliomas (HGGs), progression after treatment can be difficult to diagnose due to treatment-related effects, which overlap in appearance with tumour progression on conventional magnetic resonance imaging (MRI) sequences. Specialised imaging methods have been studied for this purpose, though most institutions currently use histopathology or clinicoradiological follow-up for diagnosis. This publication aims to review the evidence for perfusion MRI techniques. The databases of Pubmed, MEDLINE, EMBASE and Scopus were searched using combinations of the subject headings high grade glioma and MRI perfusion. 41 articles fulfilled the inclusion criteria. Dynamic Susceptibility Contrast (DSC) MRI was the most extensively studied, with several studies achieving high sensitivities and specificities. Other techniques exhibiting potential include Dynamic Contrast Enhanced (DCE) MRI, Arterial Spin Labelling (ASL). However, these techniques are not widely used or available for clinical practice. Composite measures combining results from multiple techniques tended to achieve higher accuracies. Some publications compared processing software used or looked at machine learning with relative success. An issue common to the literature is the lack of standardisation in the reference standard and acquisition/processing methods. Furthermore, many had small sample sizes, and further consideration needs to be given with regards to timing of imaging, and treatment regimens received in such studies.

Health-related quality of life in high-grade glioma patients

Gliomas are malignant primary brain tumors and yet incurable. Palliation and the maintenance or improvement of the patient's quality of life is therefore of main importance. For that reason, health-related quality of life(HRQoL) has become an important outcome measure in clinical trials, next to traditional outcome measures such as overall and progression-free survivals, and radiological response to treatment. HRQoL is a multidimensional concept covering physical, psychological, and social domains, as well as symptoms induced by the disease and its treatment. HRQoL is assessed by using self-reported, validated questionnaires. Various generic HRQoL questionnaires, which can be supplemented with a brain tumor- specific module, are available. Both the tumor and its treatment can have a negative effect on HRQoL. However, treatment with surgery, radiotherapy, chemotherapy, and supportive treatment may also improve patients' HRQoL, in addition to extending survival. It is expected that the impact of HRQoL measurements in both clinical trials and clinical practice will increase. Hence, it is important that HRQoL data are collected, analyzed, and interpreted correctly. Methodological issues such as selection bias and missing data may hamper the interpretation of HRQoL data and should therefore be accounted. In clinical trials, HRQoL can be used to assess the benefits of a new treatment strategy, which should be weighed carefully against the adverse effects of that treatment. In daily clinical practice, HRQoL assessments of an individual patient can be used to inform physicians about the impact of a specific treatment strategy, and it may facilitate the communication between the physicians and the patients.

A study on the relationship between long non-coding RNA H19 and high-grade glioma temozolomide resistance and their related mechanism

Objective:To investigate the expression level of long chain non coding RNAH19 in advanced gliomas and its relationship with glioma cell temozolomide (TMZ) resistance, and make a preliminary study on their related mechanism.Methods:Tissue samples of normal brain tissue, early onset and recurrence of high grade gliomas were collected, and the expression of LNC H19 was detected by reverse transcription polymerase chain reaction (RT-PCR). The construction of Resistant U251 TMZ Resistant (U251-TR) Cell Lines were completed by intermittent concentration gradient increments and verified by MTT method. The changes in the expression of LncRNA H19 was detected by RT-PCR, lovirus transfection was used to construct U251-TR cell line with stable interference with LNC H19 (U251-TRsiLNC H19), and MTT assay was used to observe the changes of TMZ half-maximal inhibitory concentration (IC50). Western Blot and RT-PCR were used to detect the changes of O6-methylguanine DNA methyltransferase (MGMT) in U251, U251-TR and U251-TRsiLNC H19.Results: The results of RT-PCR showed that the expression of LNC H19 in high-grade glioma was significantly higher than that in primary glioma tissue and normal brain tissue. The IC50 value and drug resistance index of U251-TR cell line were significantly increased, the expression of LncRNA H19 in U251-TR cell line was significantly higher than that in U251 cells and the expression of MGMT were also increased. We succeeded in interfering with the expression of LNC H19 in the U251-TR cell line, and found that the IC50 value and drug resistance index of U251-TR cell line were decreased significantly and the expression of MGMT were also decreased.Conclusion:LNC H19 is highly expressed in recurrent high-grade gliomas, which may increase the level of MGMT, leading to the occurrence of glioma cell TMZ resistance. LNC H19 is a key factor in the occurrence of TMZ resistance in glioma cells.

Resection of high-grade glioma involving language areas assisted by multimodal techniques under general anesthesia:a retrospective study

Background Multimodal techniques-assisted resection of glioma under general anesthesia(GA)has been shown to achieve similar clinical outcomes as awake craniotomy(AC)in some studies.In this study,we aim to validate the use of multimodal techniques can achieve the maximal safe resection of high-grade glioma involving language areas(HGILAs)under GA.Methods HGILAs cases were reviewed and collected between January 2009 and December 2020 in our center.Patients were separated into multimodal group(using neuronavigation,intraoperative MRI combined with direct electrical stimulation[DES]and neuromonitoring[IONM])and conventional group(neuronavigation alone)and clinical outcomes were compared between groups.Studies of HGILAs were reviewed systematically and the meta-analysis results of previous(GA or AC)studies were compared with our results.Results Finally,there were 263 patients in multimodal group and 137 patients in conventional group.Compared to the conventional group,the multimodal group achieved the higher median EOR(100%versus 94.32%,P<0.001)and rate of gross total resection(GTR)(73.8%versus 36.5%,P<0.001)and the lower incidence of permanent language deficit(PLD)(9.5%versus 19.7%,P=0.004).The multimodal group achieved the longer median PFS(16.8 versus 10.3 months,P<0.001)and OS(23.7 versus 15.7 months,P<0.001)than the conventional group.The multimodal group achieved a higher rate of GTR than the cohorts in previous multimodal studies under GA and AC(73.8%versus 55.7%[95%CI 32.0-79.3%]versus 53.4%[35.5-71.2%]).The multimodal group had a lower incidence of PLD than the cohorts in previous multimodal studies under GA(9.5%versus 14.0%[5.8-22.1%])and our incidence of PLD was a little higher than that of previous multimodal studies under AC(9.5%versus 7.5%[3.7-11.2%]).Our multimodal group also achieved a relative longer survival than previous studies.Conclusions Surgery assisted by multimodal techniques can achieve maximal safe resection for HGILAs under GA.Further prospective studies are needed to compare GA with AC for HGILAs.

High-grade pancreatic intraepithelial neoplasia diagnosed based on changes in magnetic resonance cholangiopancreatography findings:A case report

BACKGROUND High-grade pancreatic intraepithelial neoplasia(PanIN)exhibits no mass and is not detected by any examination modalities.However,it can be diagnosed by pancreatic juice cytology from indirect findings.Most previous cases were diagnosed based on findings of a focal stricture of the main pancreatic duct(MPD)and caudal MPD dilatation and subsequent pancreatic juice cytology using endoscopic retrograde cholangiopancreatography(ERCP).We experienced a case of high-grade PanIN with an unclear MPD over a 20-mm range,but without caudal MPD dilatation on magnetic resonance cholangiopancreatography(MRCP).CASE SUMMARY A 60-year-old female patient underwent computed tomography for a follow-up of uterine cancer post-excision,which revealed pancreatic cysts.MRCP revealed an unclear MPD of the pancreatic body at a 20-mm length without caudal MPD dilatation.Thus,course observation was performed.After 24 mo,MRCP revealed an increased caudal MPD caliber and a larger pancreatic cyst.We performed ERCP and detected atypical cells suspected of adenocarcinoma by serial pancreatic juice aspiration cytology examination.We performed a distal pancreatectomy and obtained a histopathological diagnosis of high-grade PanIN.Pancreatic parenchyma invasion was not observed,and curative resection was achieved.CONCLUSION High-grade Pan-IN may cause MPD narrowing in a long range without caudal MPD dilatation.

Management of retroperitoneal high-grade serous carcinoma of unknown origin:A case report

BACKGROUND Retroperitoneal high-grade serous carcinoma(HGSC)of unknown origin is a sporadic tumor that can originate from ovarian cancer.Herein,we report the case of a woman with retroperitoneal HGSC of unknown origin and describe how she was diagnosed and treated.CASE SUMMARY A 71-year-old female presented with the tumor marker CA125 elevated to 1041.9 U/mL upon a regular health examination.Computed tomography revealed retroperitoneal lymph node enlargement.Subsequently,positron emission tomography scanning revealed lesions with increased F-18 fluorodeoxyglucose uptake at the nodes.As a result,she underwent laparoscopic lymph node resection,and pathology revealed metastatic adenocarcinoma with CK7(+),PAX8(+),WT1(+),PR(-),and p53 mutational loss of expression,indicating that the origin may be from the adnexa.The patient was admitted to our ward and underwent laparoscopic staging;however,the pathological results were negative.Under the suspicion of retroperitoneal HGSC of unknown origin,chemotherapy and targeted therapy were initiated.Tumor marker levels decreased after treatment.CONCLUSION We present a case of HGSC of unknown origin managed using retroperitoneal lymphadenectomy,staging surgery,chemotherapy,and targeted therapy.

High-grade serous carcinoma of the fallopian tube in a young woman with chromosomal 4q abnormality:A case report

BACKGROUND Few studies have reported an association between an increased risk of acquiring cancers and survival in patients with 4q deletion syndrome.This study presents a rare association between chromosome 4q abnormalities and fallopian tube highgrade serous carcinoma(HGSC)in a young woman.CASE SUMMARY A 35-year-old woman presented with acute dull abdominal pain and a known chromosomal abnormality involving 4q13.3 duplication and 4q23q24 deletion.Upon arrival at the emergency room,her abdomen appeared ovoid and distended with palpable shifting dullness.Ascites were identified through abdominal ultrasound,and computed tomography revealed an omentum cake and an enlarged bilateral adnexa.Blood tests showed elevated CA-125 levels.Paracentesis was conducted,and immunohistochemistry indicated that the cancer cells favored an ovarian origin,making us suspect ovarian cancer.The patient underwent debulking surgery,which led to a diagnosis of stage IIIC HGSC of the fallopian tube.Subsequently,the patient received adjuvant chemotherapy with carboplatin and paclitaxel,resulting in stable current condition.CONCLUSION This study demonstrates a rare correlation between a chromosome 4q abnormality and HGSC.UBE2D3 may affect crucial cancer-related pathways,including P53,BRCA,cyclin D,and tyrosine kinase receptors,thereby possibly contributing to cancer development.In addition,ADH1 and DDIT4 may be potential influencers of both carcinogenic and therapeutic responses.

Transformation of marginal zone lymphoma into high-grade B-cell lymphoma expressing terminal deoxynucleotidyl transferase:A case report

BACKGROUND High-grade B-cell lymphoma(HGBL)is an unusual malignancy that includes myelocytomatosis viral oncogene(MYC),B-cell lymphoma-2(BCL-2),and/or BCL-6 rearrangements,termed double-hit or triple-hit lymphomas,and HGBL-not otherwise specific(HGBL-NOS),which are morphologically characteristic of HGBL but lack MYC,BCL-2,or BCL-6 rearrangements.HGBL is partially transformed by follicular lymphoma and other indolent lymphoma,with few cases of marginal zone lymphoma(MZL)transformation.HGBL often has a poor prognosis and intensive therapy is currently mainly advocated,but there is no good treatment for these patients who cannot tolerate chemotherapy.CASE SUMMARY We reported a case of MZL transformed into HGBL-NOS with TP53 mutation and terminal deoxynucleotidyl transferase expression.Gene analysis revealed the gene expression profile was identical in the pre-and post-transformed tissues,suggesting that the two diseases are homologous,not secondary tumors.The chemotherapy was ineffective and the side effect was severe,so we tried combination therapy including venetoclax and obinutuzumab.The patient tolerated treatment well,and reached partial response.The patient had recurrence of hepatocellular carcinoma and died of multifunctional organ failure.He survived for 12 months after diagnosis.CONCLUSION Venetoclax combined with obinutuzumab might improve the survival in some HGBL patients,who are unsuitable for chemotherapy.

Long-term adjuvant administration of temozolomide impacts serum ions concentration in high-grade glioma

Background:Adjuvant temozolomide(TMZ)chemotherapy with standard regimen remarkably improves survival in patients with high-grade glioma(HGG).However,the influence of long-term TMZ chemotherapy on serum ions concentration is unclear.Methods:One hundred and thirty-eight patients with HGG were included.Their blood samples were collected for blood biochemistry and routine test.The alteration in serum ions concentration,total protein,albumin,globin,and blood cells counts were used to identify the impact of long-term TMZ chemotherapy.Results:Through the comparation of quantitative value of diverse parameters among different chemotherapy cycles,we identified that serum potassium concentration had a downward trend after TMZ administration(1st vs.6th,p<0.001;1st vs.12th,p<0.001).Additionally,the correlation analysis showed that platelets was negatively correlated with chemotherapy cycles(r=−0.649,p=0.023).The hematological adverse events mainly centered on grade 1 to 2.Conclusion:Long-term administration of TMZ may lead to serum ions disturbance.Besides the myelosuppression,we should pay attention to the alteration in serum ions concentration,and give patients proper symptomatic treatment when necessary.

Comparison of biological behavior of lacrimal gland adenoid cystic carcinoma with high-grade transformation cells

AIM:To evaluate the differences between human lacrimal gland adenoid cystic carcinoma with high-grade transformation(LACC-HGT)primar y cells cultured by high-grade transformation tissue and non-high-grade transformation(non-HGT)primary cells cultured by non-highgrade transformation tissue in proliferation,metastasis,drug susceptibility,and genes.METHODS:LACC-HGT primary cells were established by tissue block culture,and the 4^(th)to 10^(th)generation primary cells were selected as research objects.The cells were preliminarily identified by immunofluorescent staining.The differences between non-HGT and LACC-HGT primary cells in terms of proliferation,metastasis,and drug susceptibility were compared by cell counting kit-8(CCK-8)assay,wound healing,and drug sensitivity experiments.Differentially expressed genes were screened using mRNA array.Gene expression was analyzed using real-time quantitative polymerase chain reaction(RT-qPCR).RESULTS:LACC-HGT primary cells were successfully cultured by tissue block culture.Immunofluorescence staining results showed that cytokeratin(CK)and CK7 expression levels were positive in LACC-HGT primary cells.CCK-8 results showed that the proliferation ability of LACCHGT cells was significantly higher than that of non-HGT cells.Wound healing experiment showed that the migration ability of LACC-HGT cells was significantly higher than that of non-HGT cells.LACC-HGT cells were also less sensitive to cisplatin and paclitaxel than non-HGT cells.Compared with non-HGT cells,9566 differentially expressed genes were found in LACC-HGT primary cells,of which 5162 were upregulated and 4404 were down-regulated.The expression of N-acetylneuraminate pyruvate lyase(NPL),MARVEL domain containing 3(MARVELD3),syntabulin(SYBU),and allograft inflammatory factor 1(AIF1)was higher in LACCHGT cells than in non-HGT cells,whereas that of periostin(POSTN)was lower.CONCLUSION:LACC-HGT primary cells have faster proliferation,stronger migration ability,and poorer sensitivity to chemotherapy drugs than non-HGT primary cells.The expression of mRNAs in non-HGT and LACC-HGT primary cells are significantly different.These features are speculated to be the reasons why high-grade transformation tissues exhibit higher malignant degree and poorer prognosis than their counterparts.

Application of convolutional neural network-based endoscopic imaging in esophageal cancer or high-grade dysplasia: A systematic review and meta-analysis

BACKGROUND Esophageal cancer is the seventh-most common cancer type worldwide,accounting for 5%of death from malignancy.Development of novel diagnostic techniques has facilitated screening,early detection,and improved prognosis.Convolutional neural network(CNN)-based image analysis promises great potential for diagnosing and determining the prognosis of esophageal cancer,enabling even early detection of dysplasia.METHODS PubMed,EMBASE,Web of Science and Cochrane Library databases were searched for articles published up to November 30,2022.We evaluated the diagnostic accuracy of using the CNN model with still image-based analysis and with video-based analysis for esophageal cancer or HGD,as well as for the invasion depth of esophageal cancer.The pooled sensitivity,pooled specificity,positive likelihood ratio(PLR),negative likelihood ratio(NLR),diagnostic odds ratio(DOR)and area under the curve(AUC)were estimated,together with the 95%confidence intervals(CI).A bivariate method and hierarchical summary receiver operating characteristic method were used to calculate the diagnostic test accuracy of the CNN model.Meta-regression and subgroup analyses were used to identify sources of hetero-geneity.RESULTS A total of 28 studies were included in this systematic review and meta-analysis.Using still image-based analysis for the diagnosis of esophageal cancer or HGD provided a pooled sensitivity of 0.95(95%CI:0.92-0.97),pooled specificity of 0.92(0.89-0.94),PLR of 11.5(8.3-16.0),NLR of 0.06(0.04-0.09),DOR of 205(115-365),and AUC of 0.98(0.96-0.99).When video-based analysis was used,a pooled sensitivity of 0.85(0.77-0.91),pooled specificity of 0.73(0.59-0.83),PLR of 3.1(1.9-5.0),NLR of 0.20(0.12-0.34),DOR of 15(6-38)and AUC of 0.87(0.84-0.90)were found.Prediction of invasion depth resulted in a pooled sensitivity of 0.90(0.87-0.92),pooled specificity of 0.83(95%CI:0.76-0.88),PLR of 7.8(1.9-32.0),NLR of 0.10(0.41-0.25),DOR of 118(11-1305),and AUC of 0.95(0.92-0.96).CONCLUSION CNN-based image analysis in diagnosing esophageal cancer and HGD is an excellent diagnostic method with high sensitivity and specificity that merits further investigation in large,multicenter clinical trials.

Features and therapeutic potential of T-cell receptors in high-grade glioma

Background: Previous studies have shown that endogenous T cells play an important role in the prolonged survival time of highgrade glioma (HGG) patients. Our objectives were to investigate the features of T-cell receptor (TCR) repertoires in HGG patients and to elucidate any potential therapeutic value. Methods: During November 2011 and December 2018, tumor tissues and blood samples of 35 patients with HGG who underwent surgery at Beijing Tiantan Hospital or Beijing Shijitan Hospital were selected after surgery. After isolating DNA from samples, multiple rounds of PCR were performed to establish a DNA immune repertoire (IR). Then, the sequences and frequencies of the complementarity-determining 3 (CDR3) region in TCR beta chain (TRB) were identified by high-throughput sequencing and IR analysis. A survival follow-up was conducted monthly thereafter until December 2018. Finally, the t test and Mann-Whitney test were used to compare statistical differences between two sets of data. Results: The Shannon diversity index (SHDI) of TRB sequences of HGG patients was significantly lower than that of healthy individuals (7.34 vs. 8.45, P = 0.001). The SHDI of TRB sequences of glioblastoma (GBM) patients with more than 16 months survival time was much higher than that of GBM patients with shorter survival times in both tumor tissues (3.48 ± 0.31 vs. 6.21 ± 0.33, t =-5.49, P = 0.002) and blood cells (6.02 ± 0.66 vs. 7.44 ± 0.32, t =-2.20, P = 0.036). In addition, patients achieved a distinctly higher proportion compared to that of healthy individuals in the proportion of TRBV9 and TRBV5 functional regions (9.83% vs. 6.83%, P = 0.001). Surgical tissue from patients who survived more than 16 months yielded a much higher proportion of TRBV4 and TRBV9 regions (7.14% vs. 3.28%, t = 3.18, P = 0.019). In surgical tissues from two GBM patients who survived for longer than 46 months, we found a potentially therapeutic TCR sequence. Conclusions: HGG patients have less species diversity of TCR repertoires compared with that of healthy individuals. TRBV9 regions in TCRs may be protective factors for long-term survival of GBM patients.