Аспекты формирования энцефалопатии и миокардиопатии при сепсисе

Relevance. The severe brain damage in most cases leads the patient to a long-term chronic critical condition (CCS). Regardless of the underlying  disease that led to CCS, patients will have a certain imbalance of neurohumoral regulation and characteristic cognitive, muscle-reflex disorders.  This cohort of patients is characterized not only by a cascade of typical pathological processes in the brain, but also by the consistent involvement of  the cardiovascular system, respiratory organs, digestive organs, water metabolism, hormonal regulation, immunity, the addition of infectious-septic  complications closes the circle of pathological processes, which often leads to death. Materials and methods. The search for domestic publications was carried out in the database on the RSCI website, foreign – in the PubMed, Google  Scholar databases in the period 2000–2023. When analyzing the PubMed database, the query «sepsis neuroinflammation» found 5272 links. We  also studied works on the following keywords: «neurotransmitters and sepsis». Publications describing the clinical picture, diagnosis, and sepsis  were analyzed. A total of 40 articles were analyzed Such systems as immune, nervous and endocrine are interconnected due to regulatory peptides. Stable functioning of the central nervous system  (CNS), or rather adequate secretion of neuropeptides are necessary for a normal immune response. Neuronal anti-inflammatory regulation of tissue  macrophages is characterized by a local, rapid response to the pathogen through neuromediators.Confirmation of the neuropeptide theory of immunity regulation is the verification of neuropeptide receptors on peripheral blood lymphocytes and  monocytes. These results indicate a possible mechanism of a «vicious» circle that occurs in infectious-septic complications and leads to damage to  vital organs.To date, there are no widely available means for accurate monitoring of brain function at the patient’s bedside. There is no evidence or recommendations  to support monitoring of cerebral perfusion or function in sepsis patients. At the same time, modern research on the phenotyping of patients taking  into account brain dysfunction (sepsis associated encephalopathy) is based on the basic postulates of the pathophysiology and biochemistry of  sepsis, but does not offer any methods of instrumental diagnosis of this condition, except for the use of validated delirium, coma scales (Glasgow  coma scale, FOUR, CAM-ICU, etc.). Despite the described pathogenesis, there is currently no single definition of cardiac cardiomyopathy. However, most authors describe the fundamental  features of this pathology: acute reversible one- or two-ventricular systolic or diastolic dysfunction with reduced contractility, not due to coronary  heart disease. Primary cellular myocardial dysfunction in sepsis can manifest in several ways, including impaired function of the left and/or right  ventricles during systole or diastole, as well as with insufficient cardiac output (CO) and oxygen delivery. To explain the changes in myocardial  contractility associated with sepsis, several mechanisms have been proposed taking into account the host response. Since most of the parameters  of the echo signal depend on the conditions of the volemic status, the evaluation of the echo signal should be repeated at several time points and  supplemented with the definition of cardiac biomarkers. Conclusion. Analyzing the literature data on sepsis-associated encephalopathy and septic cardiomyopathy, it is possible to judge the interconnectedness  of these events indirectly through damage to neurons during infectious-septic complications. Especially neuro-humoral mechanisms of regulation of  the response to an infectious agent should be evaluated in patients with CCS, not only relying on laboratory diagnostics, but also using instrumental  methods of visualization of brain, heart, and kidney damage. Such methods include magnetic resonance imaging (MRI), electroencephalogram  (EEG), cerebral oximetry (CMRO2), echocardiography, ultrasound examination of the kidneys, etcАктуальность. Тяжелое повреждение головного мозга в большинстве случаев приводит пациента к длительному хроническому критическому  состоянию (ХКС). Вне зависимости от основного заболевания, приведшего к ХКС, у больных будет отмечаться определенный дисбаланс  нейрогуморальной регуляции и характерные когнитивные, мышечно-рефлекторные нарушения. Данная группа пациентов характеризуется  не только типовыми патологическими процессами в головном мозге, но и последовательным вовлечением сердечно-сосудистой системы,  органов дыхания, пищеварения, водного обмена, гормональной регуляции, иммунитета. Замыкает круг патологических процессов присоединение инфекционно-септических осложнений, что приводит к летальному исходу.Материалы и методы. Поиск отечественных публикаций проводился в базе данных на сайте РИНЦ, зарубежных – в базах PubMed, Google  Scholar в период 2000–2023 гг. При анализе базы данных PubMed запрос «sepsis neuroinflammation» обнаружил 5272 ссылки. Также изучались  работы по следующим ключевым словам: «neurotransmitters and sepsis». Были проанализированы публикации, описывающие клиническую  картину, диагностику при сепсисе. Всего было проанализировано 40 статей. Такие системы, как иммунная, нервная и эндокринная, связаны между собой благодаря регуляторным пептидам. Для нормального иммунного  ответа необходимо стабильное функционирование центральной нервной системы (ЦНС), а точнее, адекватная секреция нейропептидов.  Нейрональная противовоспалительная регуляция тканевых макрофагов характеризуется локальным, быстрым ответом на возбудителя  через нейромедиаторы. Подтверждением нейропептидной теории регуляции иммунитета является верификация нейропептидных рецепторов на лимфоцитах и  моноцитах периферической крови. Эти результаты указывают на возможный механизм «порочного» круга, возникающий при инфекционно-септических осложнениях и приводящий к поражению «ключевых», жизненно важных органов. На сегодняшний день в широком доступе отсутствуют средства для точного мониторинга функции головного мозга у постели больного.  Также нет никаких доказательств или рекомендаций в поддержку мониторинга церебральной перфузии у пациентов с сепсисом. В то же  время современное исследование по фенотипированию больных с учетом дисфункции головного мозга (сепсис-ассоциированной энцефалопатии) опирается на базовые постулаты патофизиологии и биохимии сепсиса, но не предлагает никаких методов инструментальной  диагностики данного состояния за исключением использования валидированных шкал делирия, комы (ШКГ, FOUR, CAM-ICU и т. д.). Несмотря на описанный патогенез, единого определения септической кардиомиопатии на данный момент нет. Однако большинство авторов  характеризует особенности данной патологии как острую обратимую одно- или двухжелудочковую систолическую или диастолическую  дисфункцию со сниженной сократительной способностью, не обусловленную ишемической болезнью сердца. Первичная клеточная дисфункция миокарда при сепсисе может проявляться несколькими способами, включая нарушение функции левого и/или правого желудочков во время систолы или диастолы, а также с недостаточным сердечным выбросом и доставкой кислорода. Для объяснения изменений  сократительной способности миокарда, связанных с сепсисом, было предложено несколько механизмов с учетом хост-ответа. Поскольку  большинство параметров эхо-сигнала зависят от условий волемического статуса, оценку эхо-сигнала следует повторять в нескольких  временных точках и дополнять определением сердечных биомаркеров. Заключение. Анализируя полученные литературные данные о сепсис-ассоциируемой энцефалопатии и септической кардиомиопатии,  можно судить о взаимосвязанности этих событий опосредованно через повреждение нейронов во время инфекционно-септического осложнения. Особенно нейрогуморальные механизмы регуляции ответа на инфекционный агент стоит оценивать у пациентов в ХКС, опираясь  не только на лабораторную диагностику, но и используя инструментальные методы визуализации повреждения головного мозга, сердца,  почек. К таким методам относятся магнитно-резонансная томография (МРТ), электроэнцефалограмма (ЭЭГ), церебральная оксиметрия  (CMRO2 ), ЭХО-кардиография, ультразвуковое исследование (УЗИ) почек и др

Современные подходы к визуализации головного мозга при наркомании (обзор литературы)

Background. Brain neuroimaging studies provided information about the neurobiological effects of narcotic substances, and established the mechanisms of their systematic use, as well as provided important information about the subjective experience and behavior of people with drug addiction, including their struggle for recovery. Until recently, five main methods of brain neuroimaging were considered – structural magnetic resonance imaging (MRI), functional MRI (fMRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET) and single-photon emission computed tomography (SPECT). These methods allow us to identify various aspects of the structure or function of the brain. Microwave thermometry (MR thermometry) is also used as a neuroimaging method of the brain, which allows us to study the temperature homeostasis of the brain in various human conditions.Materials and methods. The search for domestic publications was carried out in the database on the RSCI website, foreign – in the PubMed, Google Scholar databases in the period 1990–2022. When analyzing the PubMed database, the query «neuroimaging drug addiction» found 16066 links. We also studied works on the following keywords: «neurotransmitters and drug abuse». Publications describing the clinical picture, diagnosis, and poisoning with psychoactive substances were analyzed. A total of 45 articles were analyzed.Conclusion. The obtained results strongly confirm that drug addiction is a brain disease that causes important disorders in many areas, including pathways affecting encouragement and cognition. Neuroimaging methods allow researchers to observe the effect of drug substances on the brain and compare the structure, functions and metabolism of the brain in people who abuse and do not abuse drug’s substances. MR thermometry allows measuring the temperature of the brain, which is a reflection of the metabolism of the brain and allows assessing the effect of various substances on the brain. However, nowadays, there is not enough information about the change in cerebral temperature when using psychoactive substances.Актуальность. Исследования нейровизуализации мозга предоставили информацию о нейробиологических эффектах наркотических веществ и установили механизмы возникновения систематического их употребления, а также позволили получить важные сведения о субъективном опыте и поведении людей с наркозависимостью, включая их борьбу за выздоровление. До недавнего времени рассматривалось 5 основных методов нейровизуализации мозга – структурная магнитно-резонансная томография (МРТ), функциональная МРТ (фМРТ), магнитно-резонансная спектроскопия (МРС), позитронно-эмиссионная томография (ПЭТ) и однофотонная эмиссионная компьютерная томография (ОФЭКТ). Данные методы позволяют выявить различные аспекты структуры или функции мозга. Также в качестве нейровизуализационного метода головного мозга используется микроволновая термометрия (МР-термометрия), которая позволяет изучить температурный гомеостаз головного мозга при различных состояниях человека.Материалы и методы. Поиск отечественных публикаций проводился в базе данных на сайте РИНЦ, зарубежных – в базах PubMed, Google Scholar в период 1990–2022 гг. При анализе базы данных PubMed запрос «neuroimaging drug addiction» обнаружил 16066 ссылок. Также изучали работы по ключевым словам «neurotransmitters and drug abuse». Были проанализированы публикации, описывающие клиническую картину, диагностику при отравлении психоактивными веществами. Всего было проанализировано 45 статей.Заключение. Полученные на сегодняшний день результаты твердо подтверждают, что наркомания – это болезнь мозга, вызывающая важные нарушения во многих областях, включая пути, влияющие на поощрение и познание. Методы нейровизуализации позволяют исследователям наблюдать за действием наркотических веществ на мозг и сравнивать структуру, функции и метаболизм головного мозга у людей, злоупотребляющих и не злоупотребляющих наркотическими веществами. МР-термометрия позволяет измерить температуру головного мозга, что является отображением его метаболизма и позволяет оценить влияние различных веществ на головной мозг. Однако на данный момент нет достаточно информации об изменении церебральной температуры при употреблении психоактивных веществ

Therapeutic implications of improved molecular diagnostics for rare CNS-embryonal tumor entities: results of an international, retrospective study

BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS-embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumor with multi-layered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n=307). Additional cases (n=66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n=292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58(19%) cases as ETMR, 57(19%) as HGG, 36(12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63%±7%, OS: 85%±5%, n=63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18%±6% and 22%±7%, and 5-year OS of 24%±6% and 25%±7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk-CSI based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments

Применение синтетического аналога простагландина Е1 для подготовки шейки матки и индукции родов

A clinical prospective examination of 90 women with complete pregnancy and indications for labor induction because of unsatisfactory maturity of uterus cervix has been made. The aim was to create a comparative analysis of efficiency of intravaginal introduction of prostaglandin synthetic analogue E1 misoprostol («Sytotec») and intracervical introduction of prostaglandin E2 dinoprostone («Prepidil» gel) for uterus cervix preparation and labor induction at complete pregnancy. Misoprostol in a dose of 25 mkg has been introduced to pregnant women of the 1 group (n=44), every 4 hours not more than 3 times. In case of discharge of waters or labor activity the second introduction has not been done. Dinoprostone has been introduced intracervically in a single dose to pregnant women of the 2 group (n=46). The use of misoprostol has been accompanied by spontaneous beginning of labor activity by 2 times more often than the use of dinoprostone. The quantity of vaginal births within 12 and 24 hours of observation has been surely greater and the duration of time between the beginning of introduction and labor has been surely smaller in the group of women received misoprostol as compared to the one received dinoprostone. It has not been revealed any differences between examined groups by the frequency of uterus hyperstimulation symptom development, labor duration, frequency of abdominal and vaginal labor, as well as perinatal outcomes.С целью сравнительного анализа эффективности интравагинального введения синтетического аналога простагландина Е1 мизопростола («Сайтотек») и интрацервикального введения простагландина Е2 динопростона (гель «Препидил») для подготовки шейки матки и индукции родов при доношенной беременности проведено клиническое проспективное исследование 90 женщин с доношенной беременностью, имеющих показания для родовозбуждения при неудовлетворительной зрелости шейки матки. Беременным 1-й группы (n = 44) интравагинально вводили мизопростол в дозе 25 мкг через каждые 4 ч не более 3 раз. Повторное введение препарата не проводили в случае отхождения вод или развития родовой деятельности. Беременным 2-й группы (n = 46) однократно интрацервикально вводили динопростон. Применение мизопростола в 2 раза чаще сопровождалось самостоятельным началом родовой деятельности, чем при использовании динопростона. Количество влагалищных родов в течение 12 и 24 ч наблюдения было достоверно больше, а продолжительность времени от начала введения препарата до родоразрешения достоверно меньше в группе женщин, получавших мизопростол, по сравнению с группой пациенток, получавших динопростон. Не было выявлено различий между исследуемыми группами в частоте развития симптомов гиперстимуляции матки, продолжительности родов, частоте абдоминального и влагалищного родоразрешений, а также перинатальных исходах

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

Cellular Proteins in Influenza Virus Particles

Virions are thought to contain all the essential proteins that govern virus egress from the host cell and initiation of replication in the target cell. It has been known for some time that influenza virions contain nine viral proteins; however, analyses of other enveloped viruses have revealed that proteins from the host cell can also be detected in virions. To address whether the same is true for influenza virus, we used two complementary mass spectrometry approaches to perform a comprehensive proteomic analysis of purified influenza virus particles. In addition to the aforementioned nine virus-encoded proteins, we detected the presence of 36 host-encoded proteins. These include both cytoplasmic and membrane-bound proteins that can be grouped into several functional categories, such as cytoskeletal proteins, annexins, glycolytic enzymes, and tetraspanins. Interestingly, a significant number of these have also been reported to be present in virions of other virus families. Protease treatment of virions combined with immunoblot analysis was used to verify the presence of the cellular protein and also to determine whether it is located in the core of the influenza virus particle. Immunogold labeling confirmed the presence of membrane-bound host proteins on the influenza virus envelope. The identification of cellular constituents of influenza virions has important implications for understanding the interactions of influenza virus with its host and brings us a step closer to defining the cellular requirements for influenza virus replication. While not all of the host proteins are necessarily incorporated specifically, those that are and are found to have an essential role represent novel targets for antiviral drugs and for attenuation of viruses for vaccine purposes

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. FINDINGS: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. INTERPRETATION: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. FUNDING: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario

Peculiarities of the influenza viruses circulation and their properties during 2018-2019 epidemic season in Russia and countries of the Northern Hemisphere

Objective. To identify the drift variability of influenza viruses during the period of epidemic rise in the incidence of acute respiratory viral infections in the period 2018-2019. The biological and molecular-genetic properties of epidemic strains isolated in certain territories of the Russian Federation were studied and compared with data from the countries of the Northern Hemisphere. Materials and methods. A range of laboratory diagnostic methods has been applied, including immune fluorescence, RT-PCR, sequencing, methods for determining sensitivity to influenza drugs and receptor specificity. Results and discussion. The proportion of influenza viruses was as follows: A (H1N1) pdm09 - 53 %, A (H3N2) - 46 %, B - about 1 %. Cases of severe acute respiratory infections have most often been associated with influenza A(H1N1) pdm09 virus. According to antigenic properties, isolated strains corresponded to the properties of vaccine viruses (A/Michigan/45/2015 - by 99.6 % and A/Singapore INFIMH-16-0019/2016 - by 86 %). The heterogeneity of influenza A virus strains population was revealed as regards individual mutations in hemaglutinin. The influenza B virus population was equally represented by both evolutionary lines (B/Victoria and B/Yamagata-like). Receptor specificity was favorable for the course and outcome of the disease. Among 70 studied epidemic strains, no strains resistant to anti-neuraminidase drugs, oseltamivir and zanamivir, were detected. The article presents WHO recommendations on the composition of influenza vaccines for the countries of the Northern Hemisphere for 2019-2020, provides data on cases of human infection with avian influenza viruses A(H5N1), A(H5N6), A(H7N9) and A(H9N2)

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology