Antipsychotic drugs are primarily efficacious in treating positive symptoms by blocking the dopamine D2 receptor, but they fail to substantially improve negative symptoms and cognitive deficits. The limited efficacy may be attributed to the fact that the pathophysiology of psychosis involves multiple neurotransmitter systems. In patients with chronic schizophrenia, memantine, a non-competitive glutamatergic NMDA receptor antagonist, shows promise for ameliorating negative symptoms and improving cognition. Yet, it is unknown how memantine modulates glutamate levels, and memantine has not been investigated in patients with first-episode psychosis.This investigator-initiated double-blinded randomized controlled trial is designed to (1) test the clinical effects on negative symptoms of add-on memantine to antipsychotic medication, and (2) neurobiologically characterize the responders to add-on memantine.Antipsychotic-naïve patients with first-episode psychosis will be randomized to 12 weeks treatment with [amisulpride + memantine] or [amisulpride + placebo]. We aim for a minimum of 18 patients in each treatment arm to complete the trial. Brain mapping will be performed before and after 12 weeks focusing on glutamate and neuromelanin in predefined regions. Regional glutamate levels will be probed with proton magnetic resonance spectroscopy (MRS), while neuromelanin signal will be mapped with neuromelanin-sensitive magnetic resonance imaging (MRI). We will also perform structural and diffusion weighted, whole-brain MRI. MRS and MRI will be performed at an ultra-high field strength (7 Tesla). Alongside, participants undergo clinical and neuropsychological assessments. Twenty matched healthy controls will undergo similar baseline- and 12-week examinations, but without receiving treatment.The primary endpoint is negative symptom severity. Secondary outcomes comprise: (i) clinical endpoints related to cognition, psychotic symptoms, side effects, and (ii) neurobiological endpoints related to regional glutamate- and neuromelanin levels, and structural brain changes.We hypothesize that add-on memantine to amisulpride will be superior to amisulpride monotherapy in reducing negative symptoms, and that this effect will correlate with thalamic glutamate levels. Moreover, we anticipate that add-on memantine will restore regional white matter integrity and improve cognitive functioning.By combining two licensed, off-patent drugs, AMEND aims to optimize treatment of psychosis while investigating the memantine response. Alongside, AMEND will provide neurobiological insights to effects of dual receptor modulation, which may enable future stratification of patients with first-episode psychosis before initial antipsychotic treatment.ClinicalTrials.gov], identifier [NCT04789915].[ Antipsychotic medication (AP) is primarily effective in treating positive psychotic symptoms such as delusions, hallucinations, and disorganized thinking, which are cardinal symptoms of schizophrenia. However, AP does not ameliorate the accompanying negative symptoms , and cognitive deficits, which are highly disabling and predictive of patients’ long-term prognosis –3. PersiThe pathophysiology of psychosis is complex and involves multiple neurotransmitters, e.g., serotoninergic- , GABAergUsing 3T magnetic resonance spectroscopy (MRS), we recently reported increased thalamic glutamate levels in antipsychotic-naïve patients with first episode psychosis (FEP) compared to healthy controls (HC). Importantly, high thalamic glutamate levels predicted poor treatment response . Other sCutting-edge 7T MRS can non-invasively determine brain metabolite levels of e.g., γ-aminobutyric acid (GABA), N-acetylaspartate, N-acetylaspartyl and importantly, 7T allows for discrimination of glutamate concentrations from glutathione and glutamine , 30, 31.Regarding brain structure, the use of structural 7T sequences offers increased sensitivity to quantify neurodegenerative processes such as volume loss e.g., by hippocampal subfield segmentation .in vivo-investigating dopamine in neuropsychiatric illness has been developed. Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates in the SN. NM may be regarded as a proxy of structural and functional integrity of dopaminergic cells in SN  . Recentlls in SN . Findingls in SN .NMDA-receptor modulation has been investigated in several preclinical studies –40. InteAgainst this background, modulation of glutamatergic NMDAR has been investigated as a potential treatment target in patients with schizophrenia or other psychotic disorders. Memantine is a non-competitive NMDAR antagonist used for treatment of Alzheimer’s disease. Two recent meta-analyses , 43 and Memantine has been theorized to ameliorate progression of negative symptoms by counteracting excitotoxicity correlated to high glutamate levels in early stages of psychosis , but thiClinicaltrials.gov, ID: NCT04789915), where antipsychotic-naïve patients with first-episode psychosis will be randomly allocated to treatment with first-line antipsychotic compound with addition of memantine or placebo. Patients will be matched with HCs and all participants will undergo baseline and 12-weeks examinations . Phase I, known medicine (memantine) tested for new indication (treatment of negative symptoms in psychosis).We will include antipsychotic-naïve people with schizophrenia spectrum first-episode psychosis. Patients will be recruited from psychiatric hospitals and outpatient psychiatric centers in the Capital Region and in Region Zealand of Denmark. Doctor or nursing staff will inform potentially relevant patients about the project, and if he/she accepts, contact the AMEND project medical doctor. Present State Examination (PSE), will be performed by the project medical doctor, to confirm a psychosis diagnosis. Included ICD-10 diagnosis are shown in Patients will receive no economical compensation for participation as remuneration is not allowed according to Danish regulations. The medication will be provided free of charge and transportations costs will be covered.1 Healthy controls will receive a taxable disadvantage allowance of DKK 1,000 for completion of the baseline visit and DKK 2,000 for the end of trial visit.Twenty healthy controls (HC) matched 1:2 on age, sex, ethnicity and parental socioeconomic status will be recruited through online advertisement per website.In- and exclusion criteria are shown in At baseline in the antipsychotic-naïve state as well as after 12 weeks of treatment, patients will undergo detailed examination program including: (1) clinical ratings and assessments, (2) neurocognitive testing, and (3) Magnetic Resonance Imaging (MRI) scans. Between week 0 and week 12 regular clinical examinations will be undertaken, see examination program Symptom severity will be assessed by the Positive and Negative Syndrome Scale (PANSS) . MoreoveBased on previous studies in similar patient populations we expect the mean PANSS negative symptom score to reside around 20, eg. , 55 and In order to retain comparability to other studies, e.g.,–44 we opSpecific cognitive functions will be examined using selected tasks from The Cambridge Neuropsychological Test Automated Battery (CANTAB) –60 and TFrom CANTAB we will include Spatial Working Memory (SWM) to assess visual working memory, Paired Associated Learning (PAL) to assess visual learning, and Rapid Visual Information Processing (RVP) to assess sustained attention. BACS will be used to assess verbal learning, verbal working memory, processing speed, planning and verbal fluency. Finally, premorbid intelligence (IQ) will be estimated using the Danish version of the National Adult Reading Test (DART)  adapted.Magnetic resonance imaging scans will be performed at the Danish Research Centre for Magnetic Resonance (DRCMR), Copenhagen University Hospital Amager and Hvidovre, on a whole-body 7 Tesla (7T) MR scanner  using a 2-channel volume transmit head-coil and 32-channel receiver array . MRS will be used to assess glutamate levels pre – and post treatment in five preselected regions of interest: anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), thalamus, hippocampus, and the basal ganglia. In addition, T1- and T2 weighted structural images and diffusion sensitive sequences will be performed to explore cortical and subcortical brain structures, and the integrity of white matter tracts. Quantitative Susceptibility Mapping (QSM) will be used to estimate regional iron accumulation, and measurement of the neuromelanin (NM) concentration will be performed in substantia nigra (SN) as a proxy for structural and functional integrity of dopaminergic cells .Our group has established a robust 7T protocol for glutamate MRS at our 7T MR system and validated the protocol in a cohort on healthy individuals in a study on normal cognitive aging , 72.We will apply this optimized MR protocol in the AMEND study on a Philips 7T whole body MR scanner (Philips) using a dual transmit coil and a 32-channel receive head coil . We will use a sLASER sequence  with a TFor structural MRI, we will use a tailored acquisition protocol which we have successfully applied to map the SN and LC at high resolution and signal-to-noise ratio in a cohort of patients with Parkinson’s disease and age-matched controls. The neuroimaging results regarding the Locus coeruleus have been recently published . In addiamisulpride is a second-generation antipsychotic and a first-line, generic drug against psychosis and schizophrenia in Denmark (Tablet  Denmark . Amisulp Denmark . In AMENmemantine is approved for treatment of Alzheimer’s Disease (AD) showing benefits on the main domains of AD i.e.,. cognition, function, behavior, and clinical global change  according to GCP-guidelines; marked with trial reference number, trial subject reference, dosage, administration route, storage and expiration date.The Hospital Pharmacy will be responsible for randomization, which will be conducted 1:1. Randomization will be stratified by PANSS negative sub-score, categorizing patients in either [Low PANSS negative baseline <20] or [High PANSS negative baseline ≥20].The randomization will use permuted blocs in sizes of 4,6 and 8 to ensure an even distribution among the two groups. The number of patients in each group will not be restricted. In need of unblinding of a patient’s treatment, the pharmacy can be contacted at any time.Intolerable side-effects or clinical worsening  will result in discontinuation of study treatment and study exclusion. Patients will be consulted with the senior consultant psychiatrist associated to the research project and further treatment will be initiated according to general treatment guidelines respecting the patients’ autonomy and requests.All tablets are provided to patients free of charge. Tablets will be administered with regular time intervals by a research nurse at the hospital or at home visits . CompliaThe primary endpoint will be reduction in negative symptoms as measured with the negative symptom score from the Positive and Negative Syndrome Scale (PANSS) . Reductia priori selected regions of interest mentioned above. Additionally, dopamine function in substantia nigra will be explored using NM-MRI techniques , PANSS positive and total-scores, other clinical measures, level of functioning, adverse effects, and glutamate levels in the five chniques .Exploratory endpoints include associations between clinical data, quality of life, brain metabolites in other regions, e.g., ACC , 34, strHomogeneity of variance between the two groups will be assessed using Levene’s test. Parametric data will be evaluated using parametric testing. Non-normally distributed data or data that exhibit unequal variances will be tested using non-parametric tests as appropriate. Fisher’s or χ2 exact tests will be used for group comparisons between categorical data. The Benjamini-Hochberg procedure will be used to control the type I error rate.t-tests for continuous variables and Chi-square tests for nominal and ordinal variables. Primary and secondary outcomes will be tested using repeated measures (rm)ANOVA.Data analyses on the primary outcome and most of the secondary outcomes will be performed before un-blinding and according to the per-protocol principle. Analyses of adverse events will be performed according to the intention-to-treat principle. Demographic variables and clinical characteristics will be reported in frequency for categorical data, and in mean values (with standard deviations and range) for normally distributed, continuous variables. Group comparisons for demographic data will be performed using independent N = 40) reported a reduction in PANSS negative of −2.8 (SD 1.6) with memantine compared to −0.8 (SD 0.9) with placebo (a priori Student t-test (two-sided) with significance level α of 0.05 and a desired power (1-α) of 80%, shows that 16 completed patients in each arm is needed.The power calculation is based on the primary outcome. We used the most representative clinical study we could identify and attempted to modify to the current setting. An 8-week RCT using risperidone plus memantine in stable schizophrenia patients ] . Based oBy rational combination of two licensed, off-patent drugs, amisulpride and memantine, AMEND aims to optimize treatment of psychosis, especially the accompanying negative and cognitive symptoms, alongside with unraveling the signature of memantine response. If successful, AMEND will provide pivotal neurobiological evidence for future stratification of patients with first-episode psychosis before initial antipsychotic treatment.There are few potential risks related to participating in the AMEND study. Side effects of memantine are relatively mild compared to antipsychotic medication. In previous memantine add-on RCTs in schizophrenia patients, the reported side effects did not differ from placebo  and chroMagnetic resonance imaging procedures have not been associated with any health risk, however, the examination might cause discomfort for people with claustrophobia and anxiety. Participants will be followed carefully during the project and any potential discomfort will be attempted minimized by research staff. Great care will be taken by the research group to ensure that all examinations are carried out as smoothly and efficiently as possible, including breaks when needed. Scanning will be discontinued in cases of discomfort or anxiety, and communication between staff and participants will be possible during the whole scan.Participants with head/neck tattoos or permanent make-up might experience warming and soreness of the painted area, and scanning will be interrupted should these symptoms arise. Incidental findings on MRI scans might lead to worrying and further clinical work-up. Blood samplings might cause discomfort for some people but will be taken by trained personal and under hygienic circumstances.Participants can withdraw from the study at any time without explanation, and without any consequences for the following treatment.Regarding the statistics, our power calculation and number of participants are not sized for all exploratory analyses, but our RCT design and previous pilot data, justify the rationale for conducting these tests. Admittedly, a mean 2-point reduction in PANSS negative symptoms may only represent a modest clinical improvement for the individual patient participating in this study. However, the RCT design in combination with 7T MRS data will provide strong neuroscientific evidence on how NMDARs may mediate effects on unresolved symptom domains. If successful, the combined clinical and neurobiological insights from AMEND will provide an important steppingstone, which will have major impact for further research, for stakeholders in the pharmaceutical industry, and for future patients with psychosis.With the ambitious goal of moving clinical psychiatry toward pre-treatment stratification based on pathophysiological markers, AMEND will provide evidence for rational drug repurposing to optimize treatment outcome for patients with psychosis.ClinicalTrials.gov (NCT04789915). The trial can be subjected to quality audit. Research data and results (positive and negative), will be presented at national and international scientific meetings and conferences. Articles will be submitted to peer-reviewed journals. Authorships will adhere to the International Committee of Medical Journal Editors statement (ICMJE).2The trial has been approved by the Danish Health and Medicines Authority, the National Committee on Health Research Ethics, Danish National Committee on Biomedical Research, and the Danish Data Protection Agency. Trial participation presupposes oral and written informed consent of all participants. Memantine will be used off-label, and tolerability and clinical symptoms will be monitored closely. Personal integrity and privacy concerning participants will be protected by the Danish Law of Health. The study will be conducted in accordance with the Helsinki Declaration II and monitored according to Good Clinical Practice principles (ICH-GCP). AMEND is registered at EudraCT nr: 2021-001061-20 and The studies involving human participants were reviewed and approved by Danish Health and Medicines Authority, the National Committee on Health Research Ethics, Danish National Committee on Biomedical Research, and the Danish Data Protection Agency. The patients/participants provided their written informed consent to participate in this study.BE conceived the study. KB, MN, BF, BG, and HS contributed to the study design was adjusted in discussions. AM, CL, VB, HL, DS, MS, AL, WS, and CP refined the clinical- and neuropsychiatric examination programs with respect to their respective fields of expertise. KS, OB, and BE drafted the manuscript. All authors approved the submitted version of the manuscript.BE was part of the Advisory Board of Eli Lilly Denmark A/S, Janssen-Cilag, Lundbeck Pharma A/S, and Takeda Pharmaceutical Company Ltd; and has received lecture fees from Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, Eli Lilly Company, and Lundbeck Pharma A/S. HS has received honoraria as speaker from Sanofi Genzyme, Denmark and Novartis, Denmark, as consultant from Sanofi Genzyme, Denmark, and Lundbeck AS, Denmark, and as editor-in-chief  and senior editor (NeuroImage) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as book editor from Springer Publishers, Stuttgart, Germany and from Gyldendal Publishers, Copenhagen, Denmark. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Antibody-mediated immunity is an essential part of the immune system in vertebrates. The ability to specifically bind to antigens allows antibodies to be widely used in the therapy of cancers and other critical diseases. A key step in antibody therapeutics is the experimental identification of antibody-antigen interactions, which is generally time-consuming, costly, and laborious. Although some computational methods have been proposed to screen potential antibodies, the dependence on 3D structures still limits the application of these methods.Here, we developed a deep learning-assisted prediction method  for fast identification of antibody-antigen interactions that only relies on amino acid sequences. A Siamese-like convolutional neural network architecture was established with the amino acid composition encoding scheme for both antigens and antibodies.http://www.zzdlab.com/AbAgIntPre.The generic model of AbAgIntPre achieved satisfactory performance with the Area Under Curve (AUC) of 0.82 on a high-quality generic independent test dataset. Besides, this approach also showed competitive performance on the more specific SARS-CoV dataset. We expect that AbAgIntPre can serve as an important complement to traditional experimental methods for antibody screening and effectively reduce the workload of antibody design. The web server of AbAgIntPre is freely available at  Antibody-mediated immunity is an essential part of the immune system in vertebrates. Antibodies are a special class of proteins with Y shape. One key responsibility of these proteins is the specific recognition and neutralization of foreign agents. The root of the specificity of antibodies to a particular antigen can be traced to the diversity of each tip of antibodies’ Y-shaped structures . This biOne latest application of MAbs is for the treatment of coronavirus disease 2019 (COVID-19). The COVID-19 pandemic has placed a heavy burden on society. Currently, there are a variety of vaccine strategies, such as inactivated vaccines, nucleic acid-based vaccines, and vector vaccines, to provide protection against COVID-19 . All theGiven the importance of identifying the antibody-antigen recognition specificity, radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) methods have been widely applied to identify the affinity and specificity of antibody-antigen interactions , 13. DueOn the other hand, the increasing availability of experimental data of antibody-antigen interaction provides valuable guidance for the development of computational approaches. The International ImmunoGeneTics (IMGT) information system is the most well-known immunity-related database that integrates sequence, genome, and structure immunogenetic data . Other sThanks to the increasingly available experimental data, several computational approaches for computational antibody design have been developed. Molecular docking is a classical method for predicting antibody-antigen binding mode and relative positions. However, molecular docking is often computationally expensive, especially when dealing with flexible molecules such as antibodies . The emeStill, the aforementioned computational methods have issues to be improved: (i) Most of them require the structural information of antigens or antibodies which are hard to obtain; (ii) These methods are often implemented for one specific antigen, and therefore are not widely applicable; (iii) The published algorithms or tools did not have a user-friendly interface for non-specialists to use. To this end, we proposed AbAgIntPre, an online tool to predict the interactions between antibodies and antigens based only on the sequence features. AbAgIntPre combines the composition of k-spaced amino acid pairs (CKSAAP) encoding and CNN deep learning framework for an efficient prediction of antibody-antigen interactions. AbAgIntPre enables general antigen-antibody interaction prediction by capturing various types of antigens. We also established a specific interaction prediction model for coronavirus, including severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2. For the convenience of the community, we have implemented AbAgIntPre as a web server with a friendly interface. Users can freely select the generic model and SARS-CoV-specific model to meet their needs.Many structures of antibodies and corresponding antigens are collected in the SAbDab database . We seleWe also collected antibodies binding to SARS-CoV and trained a SARS-CoV-specific predictor. SARS-CoV antibody data were collected from CoV-AbDab  and screThe previous literature has shown that the sequence compositions can effectively reflect the properties of antibodies such as specificity, stability, viscosity and immunogenicity. For example, Hebditch et al. predicted the solubility of antibodies by using a linear model with amino acid compositions and several other sequence features . Liaw etk = 0,1,2,3. Therefore, each protein is represented as a 1600-dimensional vector.In this study, we used CKSAAP as the preferred sequence composition-based encoding strategy. CKSAAP summarizes the frequency of k-spaced amino acid pairs normalized by all possible 400 kinds of pair combinations , 39, whiWe also compared the performance of CKSAAP encoding with those of the alternative encodings, including:One-hot encoding is a typical sequence coding strategy in machine learning (ML). In one-hot encoding, we used a 20-bit vector of ‘0’ or ‘1’ to represent 20 kinds of amino acids, ‘1’ at each position denotes a specific amino acid, and ‘0’ for the rest of bits .In PSSM profiles, each residue in query protein is encoded as a 20-dimensional vector, in which each element reflects the conservation of 20 kinds of amino acids at corresponding position among a set of homologous sequences , 42. We DPC encoding uses a 400-dimensional vector to capture the character of the protein sequence . Each digenism of the python package. Each sequence was divided into several k-mers, and each k-mer was represented by a 64-dimensional embedding vector. In this study, we set k to 3 and set the window size to 4 to capture the context information.In natural language processing, word2vec has been widely used to obtain the distributed representation of words , 46. TheIn this study, we used a Siamese-like CNN as the deep learning classifier to infer whether the query antigen and antibody can interact (sklearn (https://scikit-learn.org/) of the python package.We also compared the performance of our deep learning framework with those of several traditional ML models, including RF, SVM, Adaboost (ADA), logistic regression (LR), and multilayer perceptron (MLP). All the traditional ML models were implemented through the In this study, we used receiver operating characteristic (ROC) and precision-recall (PR) curves to measure the performance of the predictors. ROC and PR curves reflect the overall relationship between sensitivity and specificity and the overall relationship between precision and recall when different thresholds are applied. The definitions of sensitivity , specificity, and precision are as follows:where TP, TN, FP, and FN denote the number of true positive, true negative, false positive, and false negative samples, respectively. The larger the area under the curve (AUC), the higher the prediction performance.In addition, to test whether antigen-antibody binding could be simply determined by sequence similarity, we also compared our models with the well-established PSI-BLAST method on the independent test set. First, testing samples were aligned to training samples by PSI-BLAST . Then, wAbRank and AgRank denote the ranking of E-value in PSI-BLAST results. The more similar the query antigen or antibody is to known sequences, the higher the prediction score.where By collecting various antigens and their corresponding antibodies in SAbDab, we have established a generic prediction model of antigen-antibody interaction. First, 918 high-quality antibody-antigen complexes were collected after data cleaning and redundancy removal. Then the 918 pairs of complexes were clustered into 408 subgroups. The high-quality positive and negative antibody-antigen pairs can be assigned based on this grouping, following the principle that similar antibodies bind similar antigens  and CoV-AbDab (http://opig.stats.ox.ac.uk/webapps/covabdab/). The processed datasets and source code of AbAgIntPre are available at: https://github.com/emersON106/AbAgIntPre. The web server of AbAgIntPre is available at http://www.zzdlab.com/AbAgIntPre.Publicly available datasets were analyzed in this study. This data can be found here: The original data are available at public database SAbDab (YZ and ZZ designed and supervised the study. YH performed the analysis, built the model and webserver, and drafted the manuscript. YZ and ZZ revised the manuscript. All authors contributed to the article and approved the submitted version.


Primary large B-cell lymphoma of immune-privileged sites (IP-LBCL) is a rare malignant hematological neoplasm. Involvement of the cerebellum is even rarer and its diagnosis is often difficult to make due to its non-specific clinical and radiological presentation. Methods: We reported 3 cases of cerebellar IP-LBCL followed at our hospital and reviewed the medical literature to unravel the peculiarities of this poorly studied entity. Outcomes: Analyzing our cases and reviewing the literature, we could collect and study 26 cases of cerebellar IP-LBCL. To the best of our knowledge, this is the largest cohort of such patients currently published. Conclusion: Cerebellar IP-LBCL presents more often in adult females with cerebellum-related focal neurological signs such as ataxia, headache, and nausea. Histological confirmation is mandatory for a correct diagnosis and treatment and all cases feature diffuse large B-cell lymphoma histopathology. Compared to other encephalic IP-LBCL, cerebellar cases seem to include a higher number of cases with germinal center B-cell phenotype and better survival. These differences may be related to a different immune microenvironment and especially immunoregulation that distinguishes the cerebellum from other areas of the CNS. According to the 5th edition of the WHO classification of lymphoid neoplasms, primary large B-cell lymphoma of immune privileged sites (IP-LBCL) is a rare B-cell lymphoma that arises in the central nervous system (CNS), vitreoretinal tissues, and testis of immunocompetent patients in their fifth to seventh decade. They roughly account for 3% of non-Hodgkin lymphoma (NHL) and 2–3% of all brain tumors ,2,3. FroFrom a histopathological point of view, CNS IP-LBCL is diffuse large B-cell lymphomas (DLBCL) that display diffusely growing tumors with perivascular aggregates of medium-sized to large, atypical cells with nuclear pleomorphism and often prominent nucleoli and more or less extensive necrosis. The tumor proliferation elicits an intense astrocytic and microglial activation as well as a different degree of T-cell mediated response. The immunophenotype is that of a B-cell proliferation  with immunoglobulin light chain restriction. Most cases (>90%) are CD10-negative and mostly display a non-germinal center B-cell phenotype (nGC) with positivity to Bcl6 and MUM1 in the vast majority of cases. Of interest, CD10 positivity should lead to suspect of a CNS spread of a systemic DLBCL. Mitotic figures are brisk and the proliferation index (Ki67/Mib1) is often as high as 80% [Another characteristic feature of IP-LBCL is their restricted homing to IP sites upon relapse. This may be also related to the lack of HLA proteins that protect neoplastic cells from immune activation against them. The prognosis is poor, and worse compared to other DLBCLs, with a median overall survival (OS) of 36 months. The treatment of choice in high-dose methotrexate-based polychemotherapy. Despite improving the outcome, the use of adjuvant whole-brain irradiation bears a high risk of neurotoxicity, especially in elderly patients. The rarity of IP-LBCL together with their non-specific even though potentially severe symptomatology may induce a delay in the final diagnosis [Recently, regional heterogeneity in CNS immunity has been acknowledged. Specifically, the cerebellum seems to be different from other structures of the CNS in terms of blood–brain barrier permeability, cell trafficking, and immune responses . We, theA 76-year-old Caucasian man presented with frontal headaches, dizziness, nausea, and vomiting. Magnetic resonance imaging (MRI) showed a mass in the left cerebellar hemisphere that while perfusion-weighted imaging underlined an elevated and abnormal blood flow in the cerebellar mass and a proton magnetic resonance spectroscopy (H-MRSI) confirmed a raise in the choline signal. In the suspicion of a high-grade malignancy of possible glial origin, a complete cerebellar tumor excision under general anesthesia via posterior craniotomy was performed with a surgical microscope by neuronavigation. The histological diagnosis was of a diffuse large B-cell lymphoma (DLBCL). The complete clinical-radiographical staging was negative, as well as a bone marrow biopsy. Therefore, the patient underwent chemotherapy with 4 cycles of methotrexate (MTX) and 3 of high-dose cytosine arabinoside (ARA-C). After two cycles, the patient achieved complete remission (CR). Four months after he was discharged with a diagnosis of cognitive impairment due to chemotherapy. Seventy-two months after the diagnosis, the patient is still in CR.A 65-year-old Caucasian woman with a history of dyslipidemia, alcoholism, heavy smoking, and two spontaneous miscarriages, came to our attention after she performed a CT scan showing a single lesion in the posterior cranial fossa. MRI could identify two separated lesions: one in the right hemisphere with a mass effect on the fourth ventricle and a second one in the left cerebellar peduncle. A posterior craniotomy with partial cerebellar tumor excision was performed for diagnostic porpoises. The histological analysis rendered a diagnosis of DLBCL. The patient received 4 cycles of R-MTX plus high-dose ARA-C and achieved a CR after two months. Three more months later, conditioning chemotherapy and auto-transplant of hematopoietic stem cells were successfully performed. At his last follow-up, 17 months after the diagnosis, the patient was still in CR.A 65-year-old Caucasian woman with a previous diagnosis of meningioma, treated with surgery presented with long-standing headache and nausea. A CT and MRI scan showed an expansive lesion located in the right cerebellar hemisphere close to the dentate nucleus, suspicious of malignancy. A stereotactic biopsy was performed, after a cycle of steroids, and was conclusive for a DLBCL. The staging was completely negative. The patients, therefore, underwent chemoimmunotherapy according to the MATRix scheme  followed by conditioning chemotherapy and auto-transplant of autologous stem cells. Eighteen months after her diagnosis, the patient is still alive, in CR.The radiological and histopathological features of our three patients are further depicted in To comprehensively review the literature on cerebellar IP-LBCL we searched PubMed, Google Scholar, Scopus, and Cochrane Library databases for articles having the following keywords in their title, abstract, or keywords: “Cerebellar”, “lymphoma”, “B-cell”, “primitive”. The last search was performed in November 2022 and the data collection and analysis were performed according to PRISMA guidelines .p-values < 0.05 were considered statistically significant. Statistical analysis was performed using GraphPad Prism software .We analyzed the data gathered from the literature together with those from our patient series. We described the data in percentages based on the total number of records for each. Overall survival (OS) was calculated as the time between diagnosis and death or last follow-up and was estimated by Kaplan–Meier product-limit method. Two-sided From the first literature search, we collected 884 hits. After the exclusion of duplicates and non-relevant reports, we included in the study 14 articles spanning from 1968 to 2022, describing 23 patients .Counting our patients, we collected the data from 26 patients with cerebellar IP-LBCL. Of these 14 were females . The median age at diagnosis was of 57 years (ranging from 22 to 78 years). The median time from symptoms to diagnosis was 30 days.p = 0.03, Most patients reported at least one symptom related to cerebellar localization . Interestingly, intracranial hypertension was diagnosed in five patients and was associated with a significant worsening in patients’ survival at statistical analysis . We could analyze the Hans algorithm in only six cases, being in five cases (83%) germinal center B-cell phenotype lymphomas. Furthermore, in 5/6 tested cases CD10 was reported as positive and none of these patients died, despite lacking a significant prognostic advantage compared to other cases C. Bcl6 wHistopathology reports described a monomorphic to polymorphic population of medium to large-sized lymphoid cells with scant cytoplasm, prominent nucleoli, and brisk mitotic figures. Immunostaining showed invariably a B-cell phenotype. We could analyze the Hans algorithm in only three cases. However, in 5/6 tested cases (83%) CD10 was reported as positive, suggesting a number of GC cases higher than expected in IP-LBCL. Furthermore, none of the CD10+ cases died, despite lacking a significant prognostic advantage compared to other cases . Bcl6 waMost patients were treated with chemotherapy (78%), more commonly with methotrexate and/or cytarabine, followed by the combination of chemotherapy and radiotherapy (43%). Only two patients showed a local recurrence. Seven patients (30%) died of disease with a median time to death of 6 months, while 5 (26%) achieved a complete remission (CR). The median follow-up was of 6 months and the 5-year OS was 38% A.CNS IP-LBCL is infrequent and it represents only around 3% of all newly diagnosed primary brain tumors and up to 6% of all extranodal lymphomas ,9. The fThe epidemiology of cerebellar and other CNS-IP-LBCL is superimposable. Both are disorders arising in people in their sixties. However, while other CNS-IP-LBCL is slightly more frequent in males, cerebellar cases are more often seen in females.Their clinical presentation includes a raise in intracranial hypertension  and focal neurological deficits. Obviously, cerebellar cases generally display symptoms such as ataxia, and gait disturbances which may suggest their specific localization. Interestingly, we demonstrate that a diagnosis of intracranial hypertension in cerebellar IP-LBCL is associated with inferior survival. Moreover, the only two cases presenting with B-symptoms were associated with liquor analysis positive for neoplastic lymphocytes suggesting a possible systemic release of inflammatory cytokines.The more common clinical suspicion was metastasis, followed by lymphoma, glial tumors, infection, and ictus. At CT scan the neoplasm appears as isodense or hyperdense masses and enhances on contrast as observed in our cases. Still, MRI is the elective and most sensitive technique for detecting IP-LBCL and most lesions are hypointense on T1-weighted images, isointense or hyperintense on T2-weighted images, and enhance moderately to markedly post contrast administration ,14. SomeThe gold standard to diagnose IP-LBCL is the stereotaxic biopsy. Cerebellar IP-LBCL were histologically diagnosed as DLBCL in all cases, as in the majority of other CNS IP-LBCL . HistoloFrom a systematic point of view, IP-LBCL is conceptually included in both the current classifications of lymphoid neoplasms ) . The onlAt clinical and radiological staging  all the studied cases were negative for disease spread, as observed virtually in all CNS IP-LBCL cases . This waCNS IP-LBCL is considered an aggressive tumor with a high recurrence rate following treatments and a 5-year OS of 30%. Nevertheless, cerebellar cases seem to pursue a slightly less aggressive behavior, and have a higher OS , as we demonstrate, in statistical analysis .p > 0.05).The current therapy management for all CNS IP-LBCL consists of induction and consolidation therapy . Still, in a variable number of cases, patients receive steroids before the biopsy. This may constitute a relevant diagnostic pitfall for lymphoma , as observed in two cases included in our review ,25. EvenThe differences we highlight in our present work should be considered within some recent advances in the regional immunity of the CNS. In fact, in the last years, a growing number of papers demonstrated that the cerebellum is immunologically distinct with respect to the other CNS parts . The CNSEven though the physiological reasons are currently unknown, it has been demonstrated that the above-mentioned mechanism of immune protection of the CNS, differs among the CNS regions. Specifically, the cerebellum has a higher permeability of the blood–brain barrier of this organ as well as a higher vulnerability to inflammatory processes and different mechanisms of leukocyte trafficking given its lower expression of tight junction components such as claudin-1 and higher expression of adhesion molecules such as VCAM-1 and ICAM ,28. ThesIn this work, we describe a series of cerebellar IP-LBCL and collected and analyzed the medical literature on this rare lymphoma. Doing so we highlighted many interesting epidemiological, biological, and prognostic differences between cerebellar cases and those involving other CNS structures. Indeed, cerebellar IP-LBCL is a neoplasm that affects more frequently females in their sixties and presents with symptoms related to cerebellar involvement such as ataxia or gait disturbances. All cases displayed a DLBCL morphology, possibly with a higher fraction of cases with a germinal center B-cell phenotype compared with other IP-LBCL. Finally, cerebellar IP-LBCL showed better OS survival.All these features need to be validated in further studies on larger cohorts of patients and possibly in the context of a multi-institutional effort. Moreover, it should be determined whether and how the immunological peculiarities of the cerebellum contribute to the pathogenesis of this intriguing subset of lymphoma. This may further contribute to the understanding of the biological links between regional immunity and lymphomagenesis.


The adverse effects of anticancer therapy in patients with malignancies and cardiovascular diseases are complicated. Oxaliplatin is one of the most commonly used chemotherapy drugs for gastric and colorectal cancers, and oxaliplatin-induced cardiotoxicity has rarely been reported.We report a 76-year-old man with adenocarcinoma of the esophagogastric junction and a 40-day history of non-ST-elevation myocardial infarction who exhibited a new third-degree atrioventricular block after oxaliplatin administration. We immediately withdrew oxaliplatin treatment and, to avoid future episodes, we implanted a permanent pacemaker for safety and added diltiazem hydrochloride. The third-degree atrioventricular block disappeared after oxaliplatin withdrawal. We detected no recurrence of the third-degree atrioventricular block in future chemotherapies.This is the first reported oxaliplatin-induced third-degree atrioventricular block, likely mediated by coronary artery spasm. Cancer patients with acute coronary syndrome are a unique and vulnerable population, whom physicians should carefully evaluate and monitor during anticancer treatment. Remarkably, even the most common chemotherapy drugs can cause life-threatening cardiac adverse events. Malignancies and cardiovascular diseases have the highest mortality . With trOxaliplatin is widely used in treating gastric and colorectal cancers, and effectively prevent DNA replication by forming platinum-DNA adducts, stopping the cell cycle, and ultimately leading to mitotic cell apoptosis. Neurotoxicity is its most unique adverse reaction , while cA 76-year-old man visited our outpatient clinic complaining of abdominal discomfort with no history of drug allergy. Gastroscopy detected an ulcerated 2-cm diameter mass in the cardia, lying within 1.5 cm of the dentate line. The pathology revealed moderately to poorly differentiated adenocarcinoma, partly mucinous adenocarcinoma, with a mixed type in Laurén's classification. Chest and abdominal enhanced computed tomography suggested possible lymph node metastasis of the hepatogastric ligament without distant metastasis. According to the Union for International Cancer Control/American Joint Committee on Cancer tumor–node–metastasis staging system , the clinical stage was stage IIIB (T3N2M0).Hospitalized in the surgical department, the patient suddenly developed precordial pain with heavy sweat. The electrocardiogram (ECG) suggested dynamic lead II, III, aVF ST-segment depression of 0.1 mv with T-wave inversion . The carUpon admission to the medical oncology department, the patient reported no chest discomfort with a negative troponin level. He had a temperature of 36.4°C, pulse rate of 72 bpm, breathing rate of 17 breaths per minute, and blood pressure of 125/71 mmHg. Physical examination was unremarkable. We implemented a chemotherapy course consisting of oxaliplatin and tegafur/gimeracil/oteracil and he received oxaliplatin (150 mg) infusion over 1 h. After 1 h of infusion, the patient suddenly complained of shortness of breath, palpitation, and diaphoresis. The patient was alert and oriented. Physical examination revealed a heart rate of 37 bpm, breathing rate of 26 breaths per minute, and blood pressure of 110/50 mmHg. The patient was afebrile. His face was pale and no rash was seen. Cardiovascular examination was notable for a bradycardic rhythm. The ECG identified a new third-degree atrioventricular block . At thatIn the present case, a 76-year-old patient with adenocarcinoma of the esophagogastric junction underwent cancer therapy and suffered from acute non-ST segment elevation myocardial infarction before surgery. Because he was unable to undergo surgery or radiotherapy, we implemented tailored chemotherapy with oxaliplatin and tegafur/gimeracil/oteracil. Unexpectedly, he developed a third-degree atrioventricular block during oxaliplatin infusion, with newly elevated troponin levels. Having suspected coronary spasms triggered by oxaliplatin, we administered diltiazem to prevent future onsets and implanted a permanent pacemaker. The patient reported no discomfort during future chemotherapies, and the pacemaker programming detected no third-degree atrioventricular blocks.Anti-cancer therapies, particularly chemotherapy, can account for increased risks of cardiovascular disease and mortalities . HoweverWe used the Naranjo adverse drug reaction probability scale  to evaluOxaliplatin is a third-generation platinum-based drug, and it is one of the most commonly used chemotherapy drugs for gastric and colorectal cancers . The advRegarding the possible pathophysiology of our case, because prior coronary angiography ruled out the possibility of acute coronary occlusion, the most likely etiology of the spontaneously resolved third-degree atrioventricular block and mildly elevated troponin was coronary artery spasm. Coronary artery spasm, also known as Primzmetal angina or variant angina, was first described in 1959 . Its mecA possible pathophysiology of oxaliplatin-induced coronary spasms may be through hyperexcitable voltage-gated Na+ channels , 13; anoTreatment of coronary artery spasms includes avoiding predisposing factors (such as smoking or vasoactive drugs) and long-acting calcium channel blockers or nitrates. However, their interventions, such as balloon angioplasty, coronary artery bypass surgery, or drug-eluting coronary stent implantation, are ineffective . TherefoTo the best of our knowledge, this is the first reported case of an oxaliplatin-induced third-degree atrioventricular block. Our patient provided us the opportunity to understand that cancer patients with acute coronary syndrome comprise a unique and vulnerable population who often receive suboptimal anti-cancer and cardiovascular treatment. Therefore, the baseline cardiac status of these patients must be thoroughly evaluated before chemotherapy to avoid unnecessary iatrogenic harm. Moreover, monitoring during treatment and close follow-ups are necessary to ensure immediate and long-term safety. Finally, the management experience for this population was limited to observational studies, as patients with acute coronary syndrome are often excluded from randomized controlled trials. Therefore, we urgently need more clinical experience and research data to assist when formulating treatment plans. However, there are some limitations to this article. The patient refused a cardiac magnetic resonance imaging and further electrophysiological examination or coronary angiography to further confirm the cause, due to financial reasons. This oxaliplatin adverse event needs to be further explored in future work.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.Conceptualization: XC, HW, ZZ, and XAn. Data curation: XC, YX, and XAi. Writing—original draft: XC. Writing—review and editing: LL. All authors contributed to the article and approved the submitted version.CAMS Innovation Fund for Medical Sciences (2021-12M-1-012) financed this study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Inflammation and metabolic alterations are two significant contributors to retinal degenerative disorders (RD) including diabetic retinopathy (DR), retinopathy of prematurity (ROP), glaucoma, and age-related macular degeneration (AMD). To facilitate research on new potential therapeutic targets, in this Research Topic we highlighted the role of inflammation and metabolism, as well as their interaction in disease progression.Goit et al. showed that anti-inflammatory α-melanocyte-stimulating hormone (α-MSH) alleviated I/R-induced retinal damage in diabetic mice under hyperglycemic condition. A follow-up study in non-diabetic conditions is warranted to better understand the mechanism, and local vs. systemic effects α-MSH should be clarified.DR and AMD are leading causes of vision loss in working-age adults and seniors, respectively  can infiltrate into the subretinal space. The accumulation of MPs is likely meant to be a defense mechanism resulting in low-grade inflammation, called para-inflammation, maintaining tissue homeostasis. However, if the normal inflammation resolution mechanism fails, for instance, due to abnormal complement function, inflammation can shift from beneficial para- to detrimental pro-inflammatory state. Accordingly, MP factors that maintain the adaptive para-inflammation in aging RPE vs. those that trigger an overt pro-inflammatory response is a promising strategy for developing therapies to slow vision loss in AMD. Certain complement pathway inhibitors have slowed down dry AMD-associated geographic atrophy progression in Phase II trials. However, the clinical risk-to-benefit profile of these approaches requires close monitoring -dependent necroptosis in RD. Accumulating data from experimental models suggest that RIPK inhibition can reduce inflammation and necroptosis, phenomena that enhances each other, in various types of RD, including dry AMD. More research is needed to understand whether RIPK-dependent necroptosis could be a feasible drug target in AMD and/or other types of RD.The degeneration of retinal pigment epithelium (RPE) cells results in the death of photoreceptors and to the loss of central vision in AMD  enhanced inflammation and disturbed glycolysis and mitochondrial morphology in primary human RPE cells, suggesting an interaction between inflammation and metabolism. They also showed that the pre-treatment of RPE cells with dimethyl fumarate (DMF) prevented TNF-α-induced mitochondrial dysfunction and morphological abnormalities. In an animal model of Parkinson's disease, DMF protected the brain by activating autophagy and modulating neuroinflammation  contribute to retinal abnormalities including retinal vessel regression and proliferation , described the diversity of animal models, and compared their strengths and limitations. These models have revealed the roles of retinal hypoxia, inflammation, lipid metabolism, von Hippel–Lindau (VHL)–hypoxia-inducible factor (HIF) pathway, and retinoblastoma tumor suppressor (Rb)–E2F cell cycle pathway in the development of MNV3.The increasing recognition that animals develop retinal diseases with similar traits to humans has provided a means for testing possible treatments and successful gene therapy trials. These animal models provided much insight into the underlying pathological mechanisms. Collectively, this Research Topic includes original research and review articles regarding the contribution of inflammation and metabolic alterations to retinal disorders. Improved understanding of the disease mechanisms is indispensable to the exploration of new potential therapeutictargets.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was supported by NIH R01EY032492, NIH R01EY017017, Boston Children's Hospital , Mass Lions Eye Foundation 77426 (ZF), Academy of Finland Grant 346295, Business Finland Grant 1689-31-2022, the Eye and Tissue Bank Foundation (Finland), Retina Registered Association (Finland), Sokeain Ystävät/De Blindas Vänner Registered Association (HL), and Foundation Fighting Blindness U.S. Career Development Award. CD-RM-0821-0806-UHN (BB).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Despite the theoretical benefits of biodegradable polymer drug-eluting stents (BP-DES), clinical benefits of BP-DES over durable polymer DES (DP-DES) have not been clearly demonstrated. Using data from a large-volume nationwide cohort, we compared long-term clinical outcomes between BP-DES- and DP-DES-treated patients.A retrospective cohort study that enrolled all patients who underwent percutaneous coronary intervention (PCI) with new-generation DES between 2010 and 2016 in Korea was conducted by using the National Health Insurance Service database. The outcomes of interest were all-cause death, cardiovascular death, and myocardial infarction (MI).n = 19,521) at 5 years after PCI , while showing no statistically significant difference at 2 years after PCI . Similarly, use of BP-DES was associated with a lower incidence of cardiovascular death , and MI  at 5 years after PCI. There was no statistically significant difference of cardiovascular death  and MI  at 2 years after PCI.A total of 127,731 patients treated with new-generation DES with thin struts (<90 μm) were enrolled for this analysis. After stabilized inverse probability of treatment weighting, the incidence of all-cause death was significantly lower in patients treated with BP-DES (Implantation of BP-DES was associated with a lower risk of all-cause death, cardiovascular death, and MI compared with DP-DES implantation. This difference was clearly apparent at 5 years after DES implantation.ClinicalTrial.gov, NCT04715594. Compared with first-generation drug-eluting stents (DES) that harbored the risk of stent thrombosis, new-generation DES with durable polymers (DP-DES) have successfully lowered the risk of stent thrombosis while maintaining the lower rate of in-stent restenosis, compared with bare-metal stents , 2. In aClinicalTrial.gov (NCT04715594).This study was a retrospective analysis of the national health claims database established by the National Health Insurance Service (NHIS) of Korea. This database contains claimed medical cost, detailed information of prescribed drugs including the number of pills and drug dosage, and medical history presented as International Classification of Diseases, Tenth Revision (ICD-10) codes. Most of the Korean population (97.1%) are forced to subscribe to the NHIS, which is a sole insurer managed by the Korean government. Given that NHIS also covers information for the remaining population (2.9%) categorized as medical aid subjects, this cohort is considered to represent the entire Korean population . We weren = 69,316); those who had a prior history of PCI or coronary artery bypass surgery  because clinical events during follow-up cannot be discriminated whether those were caused by a prior PCI (coronary artery bypass surgery) or index PCI; those who died within 7 days after index PCI  because these early death might be not due to different DESs but to clinical characteristic of the patients; those with four or more stents implanted (n = 936); those who were implanted with both types of DES ; and those with missing medical information . Therefore, 177,792 patients who were treated with new-generation DES remained. Among these patients, those implanted with new-generation DES with thick struts (≥90 μm thickness)  or struts not commonly used worldwide  were further excluded. Consequently, the remaining 127,731 patients who were treated with new-generation DES with thin struts  were finally included in the analysis of this study  who were treated with DES between January 2005 and December 2016 in Korea (CONNECT DES cohort registry). First-generation DES implantation was more frequently performed between 2005 and 2009. New-generation DESs were more frequently implanted between 2010 and 2016. According to the stringent policy of the NHIS database to protect personal information, type of polymer, generation of DES, strut thickness and type of eluted drugs were only provided without the DES product names. is study . The lisvia emergency department, or (3) performance of cardiac biomarker testing more than 4 times. Additionally, we included baseline comorbidities and drug prescription status before PCI for the propensity score calculation, and inverse probability treatment of weighting (IPTW) was used to account for differences in baseline characteristics, medical history and confounding bias  and R version 3.6 .Continuous variables are reported as mean and standard deviation, while dichotomous variables are presented as frequencies and their percentages. To minimize the effect of confounding bias, we calculated the inverse probability of treatment weights (IPTW) by the propensity score, which was calculated by logistic regression with covariates including age, sex, history of comorbidities and medications, and year of PCI . We alsop < 0.001; p = 0.238). Statistical significance of reduced all-cause death was achieved in the BP-DES group at 3 years after index PCI . Similarly, use of BP-DES was associated with a lower incidence of cardiovascular death . The incidence and relative hazards for the outcomes of interest between the two groups before stabilized IPTW are presented in p < 0.001; p < 0.001; p < 0.001; Baseline clinical characteristics and medical history of the whole cohort population before and after stabilized IPTW are presented in To the best of our knowledge, the results of our analyses were derived from a nationwide cohort with the largest study population ever published. Of note, a major strength of our study was inclusion of all patients treated with thin-strut DESs that are commonly used world-wide in daily clinical practice. Therefore, very-high-risk patients who were usually excluded in prior randomized studies were entirely included in this study. In addition, there was completeness in monitoring for demographic characteristics, comorbidities, medication history, occurrence of clinical events requiring hospitalization, and prescription status of essential cardiac medications such as anti-platelet agents during 5-year follow-up after index PCI. Through analysis of the death certificates provided by the National Statistical Office, we could discriminate cardiovascular death from all-cause death. Therefore, we could investigate the impact of remnant polymer in new-generation DES on cardiovascular death. The principal findings of our study are as follows: (1) In the early term period, the rates for the clinical outcomes of interest were not significantly different between BP- and DP-DES-treated patients; however, (2) the cumulative incidence of clinical events was gradually different between the two groups as time passed after index PCI. Favorable results for the clinical outcomes of interest were distinctly apparent at 5 years after index PCI in BP-DES-treated patients.per se and their polymer carriers in the coronary arterial bed continuously evoke chronic vascular inflammation  over the durable polymer everolimus-eluting stents (n = 450 patients) by reducing 1-year incidence rate of target-lesion failure  and sirolimus-eluting stents  vs. durable polymer zotarolimus-eluting stents  . Itn = 1,063 patients) vs. durable polymer everolimus-eluting stent   vs. durable polymer everolimus-eluting stents (n = 652 patients) (Neoatherosclerosis is one of the main mechanisms of very late stent thrombosis after DES implantation . Persistatients) . The ISAatients) . These satients) , 24. TheThis study has several limitations. First, the findings from this observational study cannot be applied to establish causal relationships and persistent residual confounding factors should be considered in the interpretation of our results, although we tried to minimize the bias through IPTW. Furthermore, as the NHIS database does not contain laboratory parameters or clinical information except for the diagnostic codes, unmeasured variables could have affected the results of our analyses. Second, because this database does not include angiographic or procedural information, including the extent and complexity of coronary artery disease, the impact of high-risk procedural characteristics was not fully considered in the interpretation of our analyses. Furthermore, since the result of electrocardiography was not available in this database, the impact of clinical presentation such as ST-elevation MI or non-ST elevation MI was not considered in statistical analyses. Third, to protect patients' personal information and avoid unnecessary conflict with the device manufacturer, the NHIS database provides information of DESs after sufficient encryption work, which includes DES generation, polymer degradability, and strut thickness. Finally, the temporal difference between the groups still remained even after IPTW-adjustment. Thus, care should be taken in interpretation of our result, although we adjusted the temporal difference in all regression analyses. Therefore, further analyses such as impact of the eluted drug or stent material was not performed, which should be carried out through following research.In this nationwide cohort of all patients treated with new-generation DES in Korea, BP-DES implantation was associated with a lower risk of all-cause death, cardiovascular death or MI. This difference appeared around 3 years after DES implantation and became more distinct with time.mkhong61@yuhs.ac.The data analyzed in this study is subject to the following licenses/restrictions: the datasets generated for the analyses are not publicly available because of strict government restrictions. Requests to access these datasets should be directed to M-KH, The studies involving human participants were reviewed and approved by Severance Hospital Institutional Review Board. The Ethics Committee waived the requirement of written informed consent for participation.S-JL, D-WC, C-MN, and M-KH contributed to the conception and design and verified the data and conducted all analyses. S-JL and M-KH wrote the study protocol. D-WC and C-MN performed the programming to extract the data from the NHIS database. M-KH had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. YS, S-JH, C-MA, J-SK, B-KK, Y-GK, DC, E-CP, and YJ provided a critical review of manuscript. All authors read and approved on the final publication.This work was supported by the Cardiovascular Research Center, Seoul, South Korea.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Research in sickle cell anemia (SCA) has used, with limited race-matched control data, binary categorization of patients according to the presence or absence of silent cerebral infarction (SCI). SCI have primarily been identified using low-resolution MRI, with radiological definitions varying in lesion length and the requirement for abnormality on both fluid attenuated inversion recovery (FLAIR) and T1-weighted images. We aimed to assess the effect of published SCI definitions on global, regional, and lobar lesion metrics and their value in predicting cognition. One hundred and six patients with SCA and 48 controls aged 8–30 years underwent 3T MRI with a high-resolution FLAIR sequence and Wechsler cognitive assessment. Prevalence, number, and volume of lesions were calculated using a semi-automated pipeline for SCI defined as: (1) Liberal: any length (L-SCI); (2) Traditional: >3 mm in greatest dimension (T-SCI); (3) Restrictive; >3 mm in greatest dimension with a corresponding T1-weighted hypo-intensity (R-SCI). Globally, as hypothesized, there were large effects of SCI definition on lesion metrics in patients and controls, with prevalence varying from 24–42% in patients, and 4–23% in controls. However, contrary to hypotheses, there was no effect of any global metric on cognition. Regionally, there was a consistent distribution of SCI in frontal and parietal deep and juxta-cortical regions across definitions and metrics in patients, but no consistent distribution in controls. Effects of regional SCI metrics on cognitive performance were of small magnitude; some were paradoxical. These findings expose the challenges associated with the widespread use of SCI presence as a biomarker of white-matter injury and cognitive dysfunction in cross-sectional high-resolution MRI studies in patients with SCA. The findings indicate that with high-resolution MRI: (1) radiological definitions have a large effect on resulting lesion groups, numbers, and volumes; (2) there is a non-negligible prevalence of lesions in young healthy controls; and (3) at the group-level, there is no cross-sectional association between global lesion metrics and general cognitive impairment irrespective of lesion definition and metric. With high-resolution multi-modal MRI, the dichotomy of presence or absence of SCI does not appear to be a sensitive biomarker for the detection of functionally significant pathology; the search for appropriate endpoints for clinical treatment trials should continue. People with sickle cell anemia (SCA) are at risk of silent cerebral infarction (SCI) . Traditi0 thalassemia should undergo MRI to detect SCI  , based oDiscrepancies in prevalence and association with cognition may relate to differences in the precise definition of SCI, clinical care, sample characteristics including age and cognitive range, and advances in technology . StudiesThere are relatively few data on the prevalence of SCI or any association with cognition in age- and race- matched controls and it is unclear whether the combination of increased lesion detectability and more liberal criteria improves or disrupts the ability to predict cognitive outcomes based on SCI presence alone in SCA. Greater detection of SCI in patients may include those with associated impairment, but smaller WMHs, also reported in children without SCA , and assn = 7) or more widely distributed (n = 18) lesions  identifying significantly greater lesion burden. We also hypothesized that global lesion metrics based on the L-SCI definition would best predict general cognitive performance. In addition, we explored regional and lobar lesion metrics based on different SCI definitions and their value in predicting general cognition.0-thalassemia were recruited to three on-going and concurrent studies at UCL Great Ormond Street Institute of Child Health between 2015 and 2019: the Sleep and Asthma Cohort follow-up (SAC) (People with homozygous SCA (HbSS) or HbSßup (SAC) , the Preup (SAC)  and a stup (SAC) . ControlIQ was estimated using the two-subtest Wechsler Abbreviated Scale of Intelligence  , the Wec2) was recorded at rest using a single fingertip pulse oximeter (Masimo Pronto) reading for at least 3 min on the day of MRI (SAC) or the closest trial visit (POMS). For patients with SCA, use of disease-modifying treatments  and blood counts were collected from medical records using the closest scheduled routine clinic visit to date of MRI.Peripheral oxygen saturation  with 80 mT/m gradients and a 64-channel receive head coil. The protocol included coronal high-resolution 3D FLAIR , axial 2D T2-w turbo spin echo , T1-w magnetization-prepared rapid acquisition gradient echo  and 3D time-of-flight MRA sequences .https://horosproject.org), lesions were then manually measured on the coronal FLAIR, counted, and considered against three definitions;The full pipeline for definition, quantification, and classification of SCI in participants without focal neurological symptoms is shown in (1) L-SCI: any length , 29.: at least 3 mm in greatest dimension  (2) T-SCI T-SCI: a: at least 3 mm in greatest dimension with a corresponding hypo-intensity on T1w MRI ((3) R-SCI T1w MRI .http://surfer.nmr.mgh.harvard.edu/). Regions of interest (ROIs) were then manually drawn around the identified lesions on native FLAIR images, before FLAIR and T1w images were bias-corrected using SPM , and linearly affine-aligned using FSL . Based on a previously published SCA-specific pipeline , cortical reconstruction and volumetric segmentation were performed on T1-w images using Freesurfer . We had also experimented with the 10th percentile of white matter for the distance from ventricles mask, and the 85th percentile of voxels for the distance from cortex mask. For the 10th percentile periventricular threshold, 1 lesion that was classed as periventricular by the neuroradiologist fell in the deep regional mask. Similarly, for the 85th percentile juxta-cortical threshold, 1 lesion that was classed as deep by the neuroradiologist fell in the juxta-cortical mask.To classify lesions as periventricular, deep, or juxtacortical, FSL was used to create participant-specific maps quantifying distances from the ventricle and cortex masks from Freesurfer. Although established absolute distance rules for classification of lesions exist from work with adult non-SCA samples, we elected not to apply these given the younger age range of our sample. Instead, for each participant's “distance from ventricle” map, an upper threshold corresponding to the 5th percentile of voxels in white matter was used to create a periventricular region mask . Voxels N = 3 cases). For the volume of lesions, the number of voxels within each regional mask was used, allowing for within-lesion overlap between regions. A simplified “bulls-eye” representation of lesion burden , and Mann-Whitney U tests. Effect sizes were estimated using maximum-corrected measure of effect size , Cohens d (d), and correlation coefficients (r), and interpreted using Cohen's conventions   .For each SCI definition, regression models estimating IQ, WMI, PSI, and cognitive impairment from an increasingly complex combination of global lesion metrics were computed . Models To explore potential effects of SCA status on the effect of SCI metric, where distributions allowed, models were also computed with interaction terms composed of [mean-centered SCA status] X [lesion metric]  or lobar  lesion presence, were compared to corresponding models including indicator variables alongside continuous quantifiers denoting SCI number or volume. Models were also computed with a predictor based on the total number of regional-lobar zones with lesion voxels. Previous reports indicate a significantly unequal regional and lobar distribution of lesions in patients with SCA . Therefop < 0.05 was considered statistically significant, and model assumptions and variance inflation factors (VIF) were assessed. If there was significant multi-collinearity  between binary indicator or continuous quantifier variables, binary indicator variables were dropped from models. The predictive value of definitions was assessed by comparing beta-values and semi-partial correlation coefficients for any significant lesion predictors between the models. Based on prior literature  and 48 race- and age- matched controls  were included in the final sample , and 4 IQ points . 11.3% of people with SCA (12/106) were identified as having cognitive impairment  compared with 4.2% (2/48) of controls  and 11 controls  had lesions that met the L-SCI definition and survived the semi-automated pipeline. Cochran's Q tests revealed significant effects of SCI definition on lesion prevalence in both patients and controls; the L-SCI definition identified three more patients (7%) and six more controls (120%) with lesions compared to the T-SCI definition, and 20 more patients (80%) and nine more controls (450%) compared to the R-SCI definition (ps > 0.05).T-SCI were detected in controls with sickle cell trait as young as 9 years of age, and in those with HbAA/AC as young as 12 years of age. A non-significantly greater proportion of controls with HbAS were identified as having SCI , irrespective of the definition (p < 0.05) and PSI  were observed  radiological definitions have a large effect on resulting lesion groups, numbers, and volumes; (2) there is a non-negligible prevalence of lesions also in healthy controls; and (3) at the group-level, there is no association between global lesion metrics and general cognitive outcome irrespective of lesion definition and metric.We observed large effects of SCI definition on global lesion metrics, with the resulting lesion subgroups varying widely, particularly in controls. Estimates of SCI prevalence based on the L-SCI and T-SCI definitions in patients were in broad agreement , and were broadly comparable with prior SCA studies employing higher field-strength MRI . The totWhile radiological SCI definitions that include minimum length criteria may be justifiable in studies employing lower-resolution sequences where reliability may be a concern, there is less justification in higher resolution studies unless increased sensitivity to a specific pathology and/or outcome can be demonstrated. For prediction of cognitive performance, the present study indicated little utility of the length requirement of the T-SCI definition, or the additional T1 hypo-intensity requirement of the R-SCI definition, though both definitions had significant effects on resulting lesion groups, numbers, and volumes. These findings demonstrate the need for a standardized definition and quantification approach that is reliable and replicable for further exploration in high-resolution MRI studies. Ideally, future studies should also take into account the definitions used in studies of cerebral small vessel disease (CSVD) in adults –46.For comparability with studies in CSVD, and to avoid excluding smaller lesions before attempting to explore and understand the features of such lesions, it may be useful to consider the greatest dimension and T1-intensity not as criteria for inclusion, but as features worthy of further exploration alongside other imaging features. Future studies should therefore consider employing L-SCI definitions and semi-automated segmentation techniques. Although substantial progress has been made in the development of automated segmentation techniques in other populations , the senGlobally, our results indicate greater variation in cognition within than between lesion groups, with no observable dose-dependent effect of the total lesion burden or the lesion burden for age, in patients or controls. These findings align with those of several recent high-resolution MRI studies that have failed to detect an effect of the presence of T-SCI on cognition in patients with SCA , 16, 48 Of 11 studies conducted at 3T examining effects of SCI on cognitive outcome, the only study to detect an effect used a sequence with a 5 mm slice thickness , while 1This interpretation raises the possibility that there may be a tipping point beyond which lesions become large and prominent and begin to have an effect. It is also possible that the inclusion of young adults in our sample reduced our sensitivity to potential age-dependent effects of SCI across specific domains. Although we excluded participants >30 years, used cognitive scores that were scaled for age, included age as a covariate in our regression models, and observed no relationships between age and global lesion metrics, we cannot exclude the possibility of age-dependent effects of the global presence and burden of lesions on individual cognitive trajectories in specific domains.Discrepancies in the literature may also be accounted for by differences in sample characteristics between prior and more recent studies. The lesions observed at 1.5T MRI in the majority of prior studies are likely to have met the traditional or restrictive criteria . These sOur regional analyses yielded several interesting findings. We detected a consistent regional distribution of lesions across metrics and definitions in patients, but not controls. Whilst lesions in patients were similarly prevalent in deep and juxta-cortical frontal and parietal zones, lesions in deep frontal and parietal zones were greater in number and size, echoing prior SCA studies , 63, 64.It is possible that the paradoxical effects we observed using the R-SCI definition were related to our operationalization of the visual definition of a T1-hypointensity , which wThese possibilities could also account for the paradoxical univariate association observed between higher volume and larger number of R-SCI and higher, rather than lower, IQ in children with SCA <16 years. Another possibility is that in the child's brain, adaptive physiology which may enable brain growth and development, e.g., higher cerebral blood flow (CBF), might eventually favor the development of SCI in the borderzone regions , 65 relap-values. Given the high number of models computed, these effects would not have survived correction for multiple comparisons, irrespective of method. In line with prior studies [e.g.,  for unknown and likely variable durations. These limitations may have decreased the sensitivity of our regression models, but given the raw data, are unlikely to have had a major impact on the results. Unlike prior studies , we alson = 4; A further limitation is that we did not include further multi-modal analyses on the etiology or consequences of SCI in this manuscript. It is however worth noting that although the name “SCI” implies infarction, white matter hyperintensities on FLAIR are non-specific, and other underlying pathologies are possible, both in patients and controls. Although the pathophysiology is unknown, the distinction between periventricular, deep, and juxta-cortical lesions is thought to be etiologically meaningful . The anaUsing quantitative multi-modal methods to explore the haemodynamic, susceptibility, and microstructural characteristics of lesions, and of normal-appearing white-matter in anatomical regions “at-risk” of haemodynamic compromise , 67–69, In parallel with quantification of SCI, documenting the effect of reduced arterial oxygen content secondary to anemia and hypoxia on cerebral blood flow  and oxygFuture quantitative multi-modal approaches may also help overcome another major challenge, which is that lesions are not detected at the time they occur. As a result, there is no way to determine the presence or absence of transient focal neurological symptoms at the time of insult. Elegant work has demonstrated a high prevalence of lesions on diffusion-weighted imaging in acutely anemic, as well as in steady-state  patientsIn conclusion, our results highlight the challenges surrounding SCI definition and quantification and suggest limited utility of SCI metrics as biomarkers of cognitive dysfunction in cross-sectional high-resolution MRI studies in patients with SCA. We have demonstrated that with high-resolution MRI: (1) radiological definitions have a large effect on resulting lesion groups, numbers, and volumes; (2) there is a non-negligible prevalence of lesions in young healthy race-matched controls; and (3) at the group-level, there is no cross-sectional association between global lesion metrics and general cognitive outcome irrespective of lesion definition and metric. As high-resolution multi-modal MRI is more widely available, the dichotomy of presence or absence of T-SCI does not appear to be a sensitive biomarker for detection of functionally significant pathology. There is therefore a need to move beyond the focus on the SCI dichotomy, with further standardization regarding definitions and methods, toward a better understanding of the broader underlying pathology. As such, the search should continue for appropriate endpoints for clinical treatment trials, including brief cognitive assessments in domains important for school and work performance, such as processing speed and executive function  as well The data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by West London NHS , Yorkshire NHS, , and University College London (community recruitment 14475/001) research Ethics Committees. Written informed consent to participate in this study was provided by participants or their legal guardian/next of kin.HS: conceptualization, data curation, investigation, methodology, formal analysis, visualization, and writing—original draft. JK: conceptualization, investigation, methodology, and writing—review and editing. JC: resources, methodology, formal analysis, validation, and writing—review and editing. DS: investigation, and writing—review and editing. AH: resources, methodology, and writing—review and editing. MK: data curation, investigation, and writing—review and editing. SS: data curation, investigation, and project administration. DR, OW, ML, MP, BI, JH, and SC: investigation and writing—review and editing. CC: supervision and writing—review and editing. FK: conceptualization, investigation, supervision, funding acquisition, methodology, and writing—review and editing. All authors contributed to the article and approved the submitted version.HS and MK were funded by Action Medical Research (GN2509) and JK by Great Ormond Street Children's Charity (V4615). AH was supported by an NIH grant (1F32HL143915). The National Institute for Health Research (PB-PG-1112-29099) and NIH (R01HL079937) provided funding for patient recruitment. The work was supported by the National Institute for Health Research Biomedical Research Centre (IS-BRC-1215-20012) at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.FK was grantholder for GN2509, V4615, PB-PG-1112-29099 and R01HL079937 and has received honoraria from Global Blood Therapeutics, Bluebird Bio, Novartis, BIAL, Shire and Johnson and Johnson. JH received research funding from Bluebird Bio, and payments in relation to work as an advisory board member from IMR, Novartis, Global Blood Therapeutics, Novo Nordisk, Forma therapeutics, Agios, Add Medica, and Terumo, and also received a travel grant from Novartis and payments relating to work as a panel speaker from Novartis and Global Blood Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


It also outperforms two one-view-two-side models that achieve AUC of 0.724 ± 0.013 (CC view) and 0.769 ± 0.036 (MLO view), respectively. The study demonstrates the potential of using transformers to develop high-performing computer-aided diagnosis schemes that combine four mammograms.Deep convolutional neural networks (CNNs) have been widely used in various medical imaging tasks. However, due to the intrinsic locality of convolution operations, CNNs generally cannot model long-range dependencies well, which are important for accurately identifying or mapping corresponding breast lesion features computed from unregistered multiple mammograms. This motivated us to leverage the architecture of Multi-view Vision Transformers to capture long-range relationships of multiple mammograms from the same patient in one examination. For this purpose, we employed local transformer blocks to separately learn patch relationships within four mammograms acquired from two-view (CC/MLO) of two-side (right/left) breasts. The outputs from different views and sides were concatenated and fed into global transformer blocks, to jointly learn patch relationships between four images representing two different views of the left and right breasts. To evaluate the proposed model, we retrospectively assembled a dataset involving 949 sets of mammograms, which included 470 malignant cases and 479 normal or benign cases. We trained and evaluated the model using a five-fold cross-validation method. Without any arduous preprocessing steps , our four-image (two-view-two-side) transformer-based model achieves case classification performance with an area under ROC curve (AUC = 0.818 ± 0.039), which significantly outperforms AUC = 0.784 ± 0.016 achieved by the state-of-the-art multi-view CNNs ( Breast cancer is one of the most common cancers diagnosed in women . MammogrResNet-22 models. One ResNet-22 takes two CC images as input and concatenates the LCC and RCC feature representations for malignancy prediction, while the other model is used to process LMLO and RMLO images. The proposed approach made separate predictions for CC and MLO view images, and the predictions were averaged during inference.With the help of machine learning technologies, different types of CAD schemes of mammography have been developed over the last two decades ,8,9. Sinself-attention mechanism [The methods introduced above are based on CNNs. In the most recent literature, vision transformers  are beinechanism . It can echanism . Enabledwithin-mammogram dependency refers to pixel/patch relationships in a mammogram. For example, an image patch that contains a suspicious mass is likely to receive more attention than other patches, due to differences in mammographic density, shape, texture, etc. Meanwhile, this patch may be more closely related to its surrounding patches than the image patches at a far distance. These different kinds of patch relationships within a mammogram can be learned by transformers to identify suspicious patches and predict more accurately the likelihood of the case being malignant. As for the inter-mammogram dependency, it focuses on the pixel/patch relationships between mammograms of different sides or views. Accordingly, inter-mammogram dependencies can be further divided into two categories. On the one hand, bilateral feature difference between the left and right mammograms  of the same view can be learned, which is important because in clinical practice, it is common to see that either one breast shows malignancy, or both breasts are benign/negative, whereas the situation that both the left and right breasts are malignant rarely occurs. Especially for a malignant case, the left and right mammograms tend to exhibit different characteristics in terms of mammographic density, mass presence, etc. Such bilateral feature difference has been shown to be useful in delivering more accurate results for near-term breast cancer risk prediction [For multi-view mammograms, two types of dependencies are important: within-mammogram dependency and inter-mammogram dependency. The ediction ,26,27 anediction . On the Despite transformers’ great potential in modeling long-range dependencies, their applications in multi-view mammogram analysis remain largely unexplored. At the time of writing, only one study so far has partially leveraged transformers for this purpose . The autFrom an existing de-identified retrospective full-field digital mammography (FFDM) image database pre-assembled in our medical imaging research laboratory, we assembled a dataset that contains 3796 mammograms acquired from 949 patients for this study. Specifically, each patient has four mammograms acquired from CC and MLO view of the left and right breasts, which are named as LCC, RCC, LMLO, and RMLO view images, respectively. All mammograms were acquired using Hologic Selenia digital mammography machines , which have a fixed pixel size of 70 μm. Depending on breast sizes, the acquired mammograms have two sizes of either 2558 × 3327 or 3327 × 4091 pixels.Among all the patients, 349 were diagnosed as screening negative or benign (BIRAD 1 or 2) by radiologists, and the rest were recalled and recommended to do biopsy due to the detection of suspicious soft-tissue masses. Based on the histopathological reports of tissue biopsy, 130 and 470 cases were confirmed to be benign and malignant, respectively. To perform binary classification using transformers, we grouped all screening negative cases and benign lesion cases into one class of benign (or cancer-free), while the cases confirmed having malignant lesions were grouped into another class of cancer or malignant cases. Since in this study, we only focused on predicting the likelihood of the mammographic case being malignant, the original FFDM images were subsampled via a pixel averaging method using a kernel size of 5 × 5 pixels. As a result, the sizes of two types of original FFDM images were reduced to 512 × 666 and 666 × 819 pixels, respectively, with a pixel size of 0.35 mm. More detailed information of the FFDM image database was reported in our previous studies  individually. In comparison, the global transformer blocks process information from the four view mammograms jointly. The local and global transformer blocks share the same design, and their key components include self-attention, multi-head attention and multi-layer perceptron. We first introduce these components in the following subsections. After that, we describe our model’s inputs  and provide more details about local and transformer blocks.Self-attention (SA)query and key of dimension value of dimension When processing a patch at a certain position, the SA mechanism simultaneously determines how much focus to place on patches at other positions. For each image patch embedding To speed up the computation for a sequence of image patch embeddings tention” , as showGiven a query (one row of Multi-head self-attention (MSA)heads) to perform h self-attention operations in parallel. As shown in h times. Then, the projections of heads and MSA can be expressed as Equations (3) and (4).At the core of transformers is the MSA mechanism ,23. UnliMulti-layer perceptron (MLP)In each transformer block a, followPatch and position embeddingpatch embeddings. Meanwhile, a classification token Patch embedding  aims at positional embeddings are performed to preserve such spatial information. Learnable 1D position embeddings  and small (21.7 M parameters) DeiTs without distillation  were finAll the experiments were performed using a single NVIDIA GeForce RTX 2080 Ti GPU with 11 GB VRAM. Five-fold cross-validation was used to train and evaluate models. For the transformers based on tiny DeiT, training a single-view-two-side (2-image), two-view-two-side (4-image) model took 10.1 h and 19.5 h, respectively. For the two-view-two-side (4-image) model based on small DeiT, the training time was 22.4 h.Performance evaluationhttp://metz-roc.uchicago.edu/MetzROC/software 29 May 2022) to generate ROC curves. The corresponding AUC value along with the standard deviation (STD) is computed as an index to evaluate model performance to classify between malignant and benign cases. The significant differences  between AUC values are also computed for comparing classification performance  of different models. Second, since the model has two outcome nodes representing the two classes of the case being malignant or benign, a testing case is assigned to the malignant class if the probability score of malignancy is greater than the probability score of benign or vice versa. After case assignment, we build a confusion matrix to record true-positive (TM), false-positive (FP), true-negative (TN), and false-negative (FN) classification results. Then, for each model, we compute and report the average of validation accuracies from the five folds and their standard deviations using Equations (9) and (10).In summary, the new model is applied to process four view mammograms of one study case together and generate one prediction score that represents the probability or likelihood of the case depicting malignant lesion. The model-generated prediction scores are compared with biopsy-confirmed ground-truth to determine model detection and classification accuracy. In this study, we take two steps of data analysis methods to evaluate and compare model performance. First, we perform a standard receiver operating characteristic (ROC) type data analysis using a maximum likelihood-based ROC curve fitting program .First, the model (Single-view DeiT-tiny) has the smallest number of parameters that need to be finetuned using mammograms. As a result, it can not only improve model training or finetuning efficiency, but also help increase model robustness by reducing the risk of overfitting using relatively small medical image datasets.p < 0.05) with smaller standard deviations, which indicates that fusion of useful features computed from four images can help reduce image feature noise and irrelevance to the malignancy prediction task.Second, comparing with the use of only either CC or MLO view images, fusion of the four mammograms of both CC and MLO view as input simultaneously to finetune the model, yields significantly higher malignancy classification accuracy and/or AUC value , features extracted and computed from different view images are often quite different and may contain complementary lesion detection or classification information. However, developing multi-view image-based CAD schemes has not been successful to date due to the many remaining technical challenges including difficulty of reliable image registration. In this paper, we present a novel study to develop the multi-view image CAD scheme by directly applying to unregistered four mammograms. The study has several unique characteristics and has generated several new observations.First, we recognize that within-mammogram dependencies and inter-mammogram dependencies are important for accurately predicting the likelihood of the mammographic case depicting malignant lesions. We also recognize that unlike human eyes that can easily identify and register lesions depicting on ipsilateral (CC and MLO) views and bilateral tissue asymmetry between left and right breast images, applying CAD schemes to register mammograms or lesions is very difficult due to the lack of reliable fiducials in mammograms. Thus, one of the significant advantages of this study is that we developed and tested a new CAD scheme that does not require image registration. Four mammograms are fed into the MVT model “as is” directly. Due to the intrinsic capability in modeling long-range relationships of the input sequence, we exploit transformers to capture different kinds of mammogram dependencies and/or associated features extracted from different images. We use local transformer blocks to model patch relationships within each of the LCC, RCC, LMLO, RMLO mammograms individually and global transformer blocks to capture patch relationships among these four mammograms jointly. Skipping the traditional image registration step does not only increase the efficiency of developing multi-view image-based CAD schemes, but also enhances the robustness of the CAD schemes due to avoiding the impact of image registration errors.Second, to verify the effectiveness of our proposed new method , we compThird, the state-of-the-art performance of CNNs for multi-view mammogram analysis has been strongly reliant on several key factors, such as cropping off background areas, using high-resolution images  , and obtFourth, our multi-image transformer-based model is basically a pure transformer model, except that one convolutional layer is used for image patch embedding, and it also uses and combines multi-layer local and global transformer blocks. Thus, our new model is very different from a recently reported study  that onlVision transformers have been quickly emerging as powerful architectures for learning long-range dependencies over the last two years. However, their potential in the field of multi-view mammogram analysis remains largely unleashed to date. In this study, we propose using local and global transformer blocks to model within-mammogram and inter-mammogram dependencies, respectively. The model was successfully applied to process four view mammograms simultaneously. By comparing with other state-of-the-art multi-view image-based CAD schemes, our new model yielded higher malignancy classification performance with small variance (or standard deviation). Therefore, the promising results demonstrate that Multi-view Vision Transformers (MVTs) are a strong or better alternative to CNNs toward building high-performing and robust multi-view image-based CAD schemes of FFDM images. The reported study results should be further validated using new large and diverse image datasets in the future studies.