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Diffuse astrocytic gliomas and their most common and aggressive representation, glioblastoma (GBM), which as per the 2021 World Health Organization (WHO) guidelines is an isocitrate dehydrogenase (IDH) wildtype without alteration in histone 3 and has glomeruloid vascular proliferation, tumor necrosis, telomerase reverse transcriptase (TERT) promoter mutation, epidermal growth factor receptor (EGFR) gene amplification, or +7/-10 chromosome copy-number changes, are fast-growing tumors with a dismal patient prognosis. Herein, we present cases of a 63-year-old male who, despite no evidence of tumor growth, developed a 6-cm tumor, histologically verified as GBM, WHO CNS grade 4, within eight months, and a 74-year-old female in whom a 1.5-cm tumor grew to 43 mm within 28 days, once again histologically confirmed as GBM, WHO CNS grade 4. Other studies using previous WHO guidelines and including up to 106 cases have shown that these tumors have a daily growth rate of 1.4% and can double their size in a period varying from two weeks to 49.6 days. These growth rates further underline the need for extensive surgical resection as disease progression is rapid, with studies reporting that resection of more than 85% of the tumor volume determined on neuroradiology improves survival compared to biopsy or limited resection and resection of more than 98% of the tumor volume statistically improves patient survival.

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Introductions Immuno-oncology is a rapidly developing field wherein tumor-immune system interactions can be harnessed for diagnostics. Herein, we set out to establish the role of the immune system response, as measured by preoperative neutrophil, platelet, and monocyte to lymphocyte ratios (NLR, PLR, and MLR) as prognostic markers for patient survival based on the newly defined criteria for glioblastoma (GBM). Materials and methods The study included patients diagnosed with GBM at a four-year interval. Exclusion criteria were patients subject to reoperation in the time period; tumors in more than one system; a history of hematological and autoimmune diseases; and cases with infectious or other inflammatory conditions. Data regarding patient demographics and preoperative blood counts were pulled from patient records and compared to postoperative survival. Results A total of 22 patients fit the established criteria, with a male to female ratio of 2.14:1, a mean age of 66.23 years, and a mean survival of 255.72 days (8.04 months, range 24-801 days). Eight patients had an elevation of NLR and five of PLR, with no statistical correlation to survival. Six patients had an increase in MLR with a statistically significant (p=0.0044) shorter postoperative survival. Synergic increases in NLR and PLR did not show significance, while synergic increases with MLR showed no added benefit. Conclusion Preoperative MLR, but not NLR or PLR, is a promising independent biomarker for patient survival in GBM. It is suggested that elevations in these ratios directly correlate to tumor biological potential.

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INTRODUCTION: Glioblastoma (GBM) is the most aggressive central nervous system (CNS) tumor with astrocytic differentiation. The growth pattern of GBM mimics that of the precursor cell migration during the fetal development of the brain. Diaphanous homolog (Diaph3) has been established to play a role in both CNS maturation and cancer progression as it is required both for cell migration and division. Furthermore, Diaph3 has been shown to play a role in malignant disease progression through hyperactivation of the EGFR/MEK/ERK in loss of expression and its overexpression correlating to hyperactivity of the mTOR pathway, both of which are with a well-established role in GBM. Herein, we aimed at establishing the diagnostic role of Diaph3 immunohistochemistry expression patterns in GBM and their possible implications for molecular response to different therapies. MATERIALS AND METHODS: The study utilized a retrospective nonclinical approach. Results of Diaph3 immunohistochemical expression were compared to healthy controls and reactive gliosis and statistically analyzed for correlation with neuroradiological tumor parameters and patient survival. RESULTS: Healthy controls showed individual weakly positive cells, while reactive gliosis controls showed a strong expression in astrocytic projections. GBM samples showed a heterogeneous positive reaction to Diaph3, mean number of positive cells 62.66%, median 61.5, range 12-96%. Areas of migrating cells showed a strong diffuse cytoplasmic reaction. Cells located in the tumor core and those in areas of submeningeal aggregation had no antibody expression. Statistical analysis revealed no correlation with tumor size or patient survival. CONCLUSION: The different expression pattern of Diaph3 in healthy controls, reactive gliosis and GBM shows promise as a clinical differentiating marker. Despite Diaph3 expression not correlating with survival and tumor size in GBM, there is an accumulating body of evidence that Diaph3 correlates with mTOR activity and can thus be used as a predictor for response to rapamycin and taxanes, clinical studies of which have shown promising, if mixed results in GBM.

Asunto(s)

Neoplasias Encefálicas , Glioblastoma , Línea Celular Tumoral , Movimiento Celular , Forminas , Glioblastoma/metabolismo , Gliosis , Humanos , Estudios Retrospectivos , Serina-Treonina Quinasas TOR

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Introduction The 2021 World Health Organization (WHO) classification of tumors of the central nervous system (CNS) has introduced significant changes to tumor taxonomy. One of the most significant changes in the isolation of isocitrate dehydrogenase (IDH) mutant forms of glioblastoma multiforme (GBM) into separate entities, as well as no longer allowing for entries to be classified as not otherwise specified (NOS). As a result, this entity now includes only the most aggressive adult-type tumors. As such, established prognostic factors no longer apply, as they now form the criteria of different disease entries or have been established based on a mixed cohort. Herein, we aimed to reclassify glioblastoma cases diagnosed per the 2016 WHO tumors of the CNS classification into the 2021 WHO tumors of the CNS classification and establish a patient survival pattern based on age, gender, tumor location, and size as well as tumor O-6-methylguanine-DNA methyltransferase (MGMT) mutation. Materials and methods A retrospective, non-clinical approach was utilized. Biopsy specimens of adults diagnosed with GBM, WHO grade 4, NOS in the period February 2018-February 2021 were reevaluated. The data regarding the patient's gender and age were withdrawn from the medical documentation. Immunohistochemistry was performed with mouse monoclonal anti-IDH R132H and rabbit polyclonal anti-MGMT. Radiology data on tumor location and size were pulled from the radiology repository. Data were statistically analyzed for significance, using Kaplan-Meier survival analysis, with a 95% confidence interval and p<0.05 defined as significant. Results A total of 58 cases fit the set criteria, with eight of them (13.7%) harboring an IDH R132H mutation and were hence reclassified as diffuse astrocytoma IDH-mutant, WHO CNS grade 4. The cases that retained their GBM classification included n=28 males and n=22 females, a male to female ratio of 1.27:1, and a mean age of 65.3 years (range 43-86 years). The MGMT mutational status revealed a total of n=17 positive cases (35%), while the remaining cases were negative. No hemispheric predilection could be established. Lobar predilection was as follows: temporal (37.78%), parietal (28.89%), frontal (24.44%), and occipital (8.89%). The mean tumor size measured on neuroradiology across the cohort was 50.51 mm (range 20-76 mm). The median survival across cases was 255.96 days (8.41 months), with a range of 18-1150 days (0.59-37.78 months). No statistical correlation could be established between patient survival and gender, hemispheric location, lobar location, and tumor size. A significant difference in survival was established only when comparing the 41-50 age groups to the 71-80 and 81-90 age groups and MGMT positive versus negative tumors (p=0.0001). Conclusion From a practical standpoint, the changes implemented in the new classification of CNS tumors define GBM as the most aggressive adult type of tumor. Based on their significantly more favorable prognosis, the reclassification of IDH mutant forms of astrocytomas has had little epidemiological impact on this relatively common malignancy but has significantly underlined the dismal prognosis. The changes have also led to MGMT promoter methylation status being the only significant prognostic factor for patient survival in clinical use, based on its prediction for response to temozolomide therapy in this nosological unit clinically presenting when it has already reached immense size.

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Since the novel coronavirus (COVID-19) pandemic started, children and young adults have seldom been placed in high-risk groups, despite reports that they are at increased risk of severe forms of the disease and death in the presence of comorbidities. Herein we report an autopsy case of an 18-year-old female with a history of cerebral palsy (CP), recurrent respiratory infections, and newly diagnosed COVID-19, and who expired 22 days after presenting with symptoms of the disease. Gross findings were concurrent with CP-significant hypotrophy, with deep and wide brain sulci. The lungs grossly were with increased weight and blood-filled. Histopathology of the respiratory system showed the well-established COVID-19-associated alveolar multinucleated cells, type two pneumocyte hyperplasia, and vascular changes. Furthermore, foci of groups of enlarged cells with foamy cytoplasm were identified in the pulmonary interstitium. Similar changes were also seen in the spleen, liver, and central nervous system, concurrent with an unrecognized lipid storage disease. The clinically unrecognized neurolipidosis, corresponding morphologically and clinically to Niemann-Pick disease type B, leading to interstitial lung disease and recurrent respiratory infections, inevitably played a role in the severity and progression of COVID-19 in our case, despite the age.

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The preauricular sinus (PAuS) is a congenital foramen, opening or invagination, usually located on the crus of the auricular helix and is considered a congenital malformation and component of multiple syndromes. The structure can be present unilaterally or bilaterally, with the possibility of more than one fistula present on one ear, predominantly on the auricular tags. As a well-defined and established clinical entry, PAuS has a very strictly laid-out history. However, different works of art give us a glimpse into the structure before its first true clinical description, showing that the PAuS was known to man long before it was first clinically described, such as those of Hieronymous Bosch, with the first medical descriptions being attributed to Heusinger and Virchow. In modern times, the condition is considered both an individual malformation and a component of several genetic syndromes.

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Pontocerebellar hypoplasia (PCH) is a diverse group of autosomal recessive genetic conditions presenting with hypoplastic changes in the brainstem, cerebellum, and spinal cord. It clinically manifests with neurological symptoms, respiratory failure, and often in a combination with other malformations of the internal organs and musculoskeletal system. In this report, we present an autopsy case report of a two-month-old female patient with blood-relative parents. The patient presented clinically with neonatal-onset respiratory failure, mild neurological symptoms, facial dysmorphism, and developmental delay. On autopsy, the cerebellum and brainstem were severely hypoplastic, and the diagnosis of PCH was established grossly. The central nervous system (CNS) revealed specific hypoplastic changes in the structures, with a decreased neuronal count, stratification disturbances of the cortex of the cerebellum, and cellular misarrangement. The morphological findings in the CNS and their associated parenchymal organ changes, even in the absence of a genetic test, were specific enough to identify PCH type 1B as the main condition.

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Acute necrotizing encephalitis (ANE) is a rare complication of viral respiratory tract infections, with specific histological changes. The condition is most commonly described in the pediatric population, however, it can also develop in the elderly, with some genetic factors being described as contributory. Herein, we report the autopsy finding of a patient with a viral respiratory tract infection, complicated with ANE. The patient was a 77-year-old female with multiple comorbidities living in a social home. For the two months prior, she had been hospitalized with cerebral infarction, respiratory tract infection, and exacerbation of chronic cardiac failure and concomitant hypertension and type 2 diabetes. On gross examination, the brain was edematous, with ground-glass opacity meninges a focus of encephalomalacia in the right cerebral hemisphere and multiple petechial hemorrhages. Histology revealed diffuse foci of encephalitis, with large areas of neuronal necrosis (coagulative-like necrosis) around the blood vessels and a sharp border with the surrounding healthy parenchyma - ANE. The patients tested negative for coronavirus disease 2019 (COVID-19).

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Pathophysiology is a medical science whose subject is the change in regulatory mechanisms related to the onset, development, and outcome of diseases. The first lectures on pathophysiology were held in 1790 at the University of Erfurt, Germany, by Professor Augustus Hecker, who in 1791 also published the first work on the discipline - "Grundriss der Physiologia pathologica" in 770 pages. The teaching of pathophysiology as an independent discipline was introduced by academician Viktor Pashutin at the University of Kazan, Russia in 1874. Academician Pashutin called this new discipline "Pathological Physiology and Experimental Medicine." Despite the persuasiveness of Pashutin that pathological anatomy and pathophysiology are inseparable parts of a whole, his students, academician Nikolay Anichkov and Prof. Semyon Khalatov, implemented the so-called "divorce" due to the different, though complementary, approaches and methodologies of the two ideological fields. By Royal Decree on November 29, 1917, in the Bulgarian State Gazette, amendments were published in the law on the national education, which introduced new university "disciplines and departments". Under number nine in the law is the discipline of "Pathological Physiology and Experimental Medicine". Due to various factors, the Pathological Physiology and Experimental Medicine department was the only one of the first 25 departments not to be established. The beginning of the training for pathophysiology in Bulgaria was laid by Prof. Vassil Mollov and Assoc. Prof. Minko Dobrev, however due to their untimely deaths, the course lasted only three years (1936-1939) and was not continued in the next academic year. At the beginning of the academic year 1946/47, two assistants in pathophysiology were enrolled in the Department of Pathological Anatomy at Sofia University. The following year a separate department was formed at the newly founded Plovdiv University and shortly after at Sofia University. For the 100 years since its legislative establishment, 82 years since its unofficial start and 71 years since its academic establishment pathophysiology in Bulgaria has distinguished itself by scientific, administrative and clinical contributions. In its 57 years in Varna, Bulgaria pathophysiology has widely carried out that tradition with immense contributions.