Beware the Jaccard: the choice of similarity measure is important and non-trivial in genomic colocalisation analysis.

The generation and systematic collection of genome-wide data is ever-increasing. This vast amount of data has enabled researchers to study relations between a variety of genomic and epigenomic features, including genetic variation, gene regulation and phenotypic traits. Such relations are typically investigated by comparatively assessing genomic co-occurrence. Technically, this corresponds to assessing the similarity of pairs of genome-wide binary vectors. A variety of similarity measures have been proposed for this problem in other fields like ecology. However, while several of these measures have been employed for assessing genomic co-occurrence, their appropriateness for the genomic setting has never been investigated. We show that the choice of similarity measure may strongly influence results and propose two alternative modelling assumptions that can be used to guide this choice. On both simulated and real genomic data, the Jaccard index is strongly altered by dataset size and should be used with caution. The Forbes coefficient (fold change) and tetrachoric correlation are less influenced by dataset size, but one should be aware of increased variance for small datasets. All results on simulated and real data can be inspected and reproduced at https://hyperbrowser.uio.no/sim-measure.

JASPAR 2020: update of the open-access database of transcription factor binding profiles.

JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) for TFs across multiple species in six taxonomic groups. In this 8th release of JASPAR, the CORE collection has been expanded with 245 new PFMs (169 for vertebrates, 42 for plants, 17 for nematodes, 10 for insects, and 7 for fungi), and 156 PFMs were updated (125 for vertebrates, 28 for plants and 3 for insects). These new profiles represent an 18% expansion compared to the previous release. JASPAR 2020 comes with a novel collection of unvalidated TF-binding profiles for which our curators did not find orthogonal supporting evidence in the literature. This collection has a dedicated web form to engage the community in the curation of unvalidated TF-binding profiles. Moreover, we created a Q&A forum to ease the communication between the user community and JASPAR curators. Finally, we updated the genomic tracks, inference tool, and TF-binding profile similarity clusters. All the data is available through the JASPAR website, its associated RESTful API, and through the JASPAR2020 R/Bioconductor package.

A map of direct TF-DNA interactions in the human genome.

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is the most popular assay to identify genomic regions, called ChIP-seq peaks, that are bound in vivo by transcription factors (TFs). These regions are derived from direct TF-DNA interactions, indirect binding of the TF to the DNA (through a co-binding partner), nonspecific binding to the DNA, and noise/bias/artifacts. Delineating the bona fide direct TF-DNA interactions within the ChIP-seq peaks remains challenging. We developed a dedicated software, ChIP-eat, that combines computational TF binding models and ChIP-seq peaks to automatically predict direct TF-DNA interactions. Our work culminated with predicted interactions covering >4% of the human genome, obtained by uniformly processing 1983 ChIP-seq peak data sets from the ReMap database for 232 unique TFs. The predictions were a posteriori assessed using protein binding microarray and ChIP-exo data, and were predominantly found in high quality ChIP-seq peaks. The set of predicted direct TF-DNA interactions suggested that high-occupancy target regions are likely not derived from direct binding of the TFs to the DNA. Our predictions derived co-binding TFs supported by protein-protein interaction data and defined cis-regulatory modules enriched for disease- and trait-associated SNPs. We provide this collection of direct TF-DNA interactions and cis-regulatory modules through the UniBind web-interface (http://unibind.uio.no).

ReMap 2018: an updated atlas of regulatory regions from an integrative analysis of DNA-binding ChIP-seq experiments.

With this latest release of ReMap (http://remap.cisreg.eu), we present a unique collection of regulatory regions in human, as a result of a large-scale integrative analysis of ChIP-seq experiments for hundreds of transcriptional regulators (TRs) such as transcription factors, transcriptional co-activators and chromatin regulators. In 2015, we introduced the ReMap database to capture the genome regulatory space by integrating public ChIP-seq datasets, covering 237 TRs across 13 million (M) peaks. In this release, we have extended this catalog to constitute a unique collection of regulatory regions. Specifically, we have collected, analyzed and retained after quality control a total of 2829 ChIP-seq datasets available from public sources, covering a total of 485 TRs with a catalog of 80M peaks. Additionally, the updated database includes new search features for TR names as well as aliases, including cell line names and the ability to navigate the data directly within genome browsers via public track hubs. Finally, full access to this catalog is available online together with a TR binding enrichment analysis tool. ReMap 2018 provides a significant update of the ReMap database, providing an in depth view of the complexity of the regulatory landscape in human.

JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework.

JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) and TF flexible models (TFFMs) for TFs across multiple species in six taxonomic groups. In the 2018 release of JASPAR, the CORE collection has been expanded with 322 new PFMs (60 for vertebrates and 262 for plants) and 33 PFMs were updated (24 for vertebrates, 8 for plants and 1 for insects). These new profiles represent a 30% expansion compared to the 2016 release. In addition, we have introduced 316 TFFMs (95 for vertebrates, 218 for plants and 3 for insects). This release incorporates clusters of similar PFMs in each taxon and each TF class per taxon. The JASPAR 2018 CORE vertebrate collection of PFMs was used to predict TF-binding sites in the human genome. The predictions are made available to the scientific community through a UCSC Genome Browser track data hub. Finally, this update comes with a new web framework with an interactive and responsive user-interface, along with new features. All the underlying data can be retrieved programmatically using a RESTful API and through the JASPAR 2018 R/Bioconductor package.

Major aging-associated RNA expressions change at two distinct age-positions.

BACKGROUND: Genome-wide expression profiles are altered during biological aging and can describe molecular regulation of tissue degeneration. Age-regulated mRNA expression trends from cross-sectional studies could describe how aging progresses. We developed a novel statistical methodology to identify age-regulated expression trends in cross-sectional datasets. RESULTS: We studied six cross-sectional RNA expression profiles from different human tissues. Our methodology, capable of overcoming technical and genetic background differences, identified an age-regulation in four of the tissues. For the identification of expression trends, five regression models were compared and the quadratic model was found as the most suitable for this study. After k-means clustering of the age-associated probes, expression trends were found to change at two major age-positions in brain cortex and in Vastus lateralis muscles. The first age-position was found to occur during the fifth decade and a later one during the eighth decade. In kidney cortex, however, only one age-position was identified correlating with a late age-position. Functional mapping of genes at each age-position suggests that calcium homeostasis and lipid metabolisms are initially affected and subsequently, in elderly mitochondria, apoptosis and hormonal signaling pathways are affected. CONCLUSIONS: Our results suggest that age-associated temporal changes in human tissues progress at distinct age-positions, which differ between tissues and in their molecular composition.

A 3D cone beam computed tomography study of the styloid process of the temporal bone.

BACKGROUND: To investigate the length and three-dimensional orientation and to detail the morphological variations of the styloid process. MATERIALS AND METHODS: Forty-four patients undergoing temporal bone evaluation for different reasons were randomly selected and included in the present study. The length, angulation in the coronal and sagittal planes, as well as morphological variations of the styloid processes were assessed using conebeam computer tomography. Pearson's correlation coefficient was used to test possible associations between the length of styloid process and angulations, as well as between angulations. Student's t-test was used to compare the differences between the sample mean length and angulations in normal and elongated styloid process groups. RESULTS: The sagittal angle showed weak positive correlations with the styloid process length and the transverse angle (r = 0.24, p = 0.02, n = 88). A medium positive correlation was found between the sagittal and transverse angulations in the elongated styloid process group (r = 0.49, p = 0.0015, n = 38). There was a statistical significant difference between the mean sagittal angulation in elongated styloid and normal styloid process groups (p = 0.015). The styloid process morphology also varied in terms of shape, number, and degree of ossification. CONCLUSIONS: The morphometric and morphologic variations of the styloid process may be important factors to be taken into account not only from the viewpoint of styloid syndromes, but also in preoperatory planning and during surgery.

Astrocytes - friends or foes in neurodegenerative disorders.

Astrocytes (AS) are the most abundant glial cells in the central nervous system (CNS). They have various morphologies and numerous (50-60) branching prolongations, with roles in the maintenance of the CNS function and homeostasis. AS in the optic nerve head (ONH) have specific distribution and function and are involved in the pathogenesis of glaucoma and other neural diseases, modify their morphologies, location, immune phenotype, and ultrastructure, thus being the key players in the active remodeling processes of the ONH.

Chronic Diarrhea Caused by Vasoactive Intestinal Peptide-Secreting Tumor.

VIPomas are a type of neuroendocrine tumor that independently produces vasoactive intestinal peptide (VIP). VIPomas causing watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome are not frequently observed in adult patients without pancreatic ailments. However, in children, the occurrence of a VIPoma originating in the pancreas is exceedingly uncommon. Instead, WDHA syndrome is more commonly associated with neurogenic tumors that secrete VIP, often located in the retroperitoneum or mediastinum. Among infants, chronic diarrhea is a prevalent issue that often necessitates the attention of pediatric gastroenterologists. The underlying causes are diverse, and delays in arriving at a definitive diagnosis can give rise to complications affecting the overall well-being of the child. The authors present the case of an infant with chronic watery diarrhea, subocclusion manifestations, mild hypokalemia, and metabolic hyperchloremic acidosis secondary to a VIPoma in the retroperitoneum that was diagnosed via abdominal ultrasound and tomography. The laboratory results revealed lowered potassium levels and an excessive secretion of VIP. Following the surgical removal of the tumor, the diarrhea resolved, and both electrolyte levels and the imbalanced hormone levels returned to normal. Immunohistochemical examination confirmed the diagnosis of ganglioneuroblastoma, with N-MYC negative on molecular biology tests. We present the clinical and histo-genetic aspects of this rare clinical entity, with a literature review.

Case report: Clinical profile, molecular genetics, and neuroimaging findings presenting in a patient with Kearns-Sayre syndrome associated with inherited thrombophilia.

Background: Kearns-Sayre syndrome (KSS) is classified as one of the mitochondrial DNA (mtDNA) deletion syndromes with multisystemic involvement. Additionally, the negative prognosis is associated with inherited thrombophilia, which includes the presence of homozygous Factor V G1691A Leiden mutation, MTHFR gene polymorphisms C677T and A1298C, and PAI-1 675 homozygous genotype 5G/5G. Case presentation: This case report presents a 48-year-old man with chronic progressive external ophthalmoplegia, bilateral ptosis, cerebellar ataxia, cardiovascular signs (syncope, dilated cardiomyopathy, and cardiac arrest) with electrocardiographic abnormalities (first-degree atrioventricular block and major right bundle branch block), endocrine dysfunction (short stature, growth hormone insufficiency, primary gonadal insufficiency, hypothyroidism, and secondary hyperparathyroidism), molecular genetic tests (MT-TL2 gene), and abnormal MRI brain images, thus leading to the diagnosis of KSS. The patient came back 4 weeks after the diagnosis to the emergency department with massive bilateral pulmonary embolism with syncope at onset, acute cardiorespiratory failure, deep left femoral-popliteal vein thrombophlebitis, and altered neurological status. In the intensive care unit, he received mechanical ventilation through intubation. Significant improvement was seen after 2 weeks. The patient tested positive for inherited thrombophilia and was discharged in stable conditions on a new treatment with Rivaroxaban 20 mg/day. At 6 months of follow-up, ECG-Holter monitoring and MRI brain images remained unchanged. However, after 3 months, the patient died suddenly while sleeping at home. Conclusion: The genetic tests performed on KSS patients should also include those for inherited thrombophilia. By detecting these mutations, we can prevent major complications such as cerebral venous sinus thrombosis, coronary accidents, or sudden death.

Placental pathology in early-onset fetal growth restriction: insights into fetal growth restriction mechanisms.

BACKGROUND: Early-onset fetal growth restriction (FGR), an identifiable variant of FGR, exhibits divergences in its severity, management, and placental pathologies when juxtaposed with late-onset FGR. The objective of this cross-sectional investigation was to scrutinize placental pathologies in pregnancies afflicted by early-onset FGR, emphasizing a comparative analysis between cohorts with and without preeclampsia (PE). PATIENTS, MATERIALS AND METHODS: The study encompassed a cohort of 85 expectant mothers who received a diagnosis of early-onset FGR. Rigorous histopathological (HP) and immunohistochemical (IHC) assessments were conducted on the placentas. Comparative analyses were performed, distinguishing between individuals diagnosed with both PE and early-onset FGR, and those presenting normotensive early-onset FGR. RESULTS: HP analysis unveiled a multitude of shared placental lesions, encompassing retroplacental hemorrhage, expedited villous maturation, infarctions, and calcification-associated fibrin deposits. IHC investigations displayed affirmative immunoreactivity for anti-hypoxia-inducible factor (HIF) and anti-vascular endothelial growth factor (VEGF) antibodies within the placental infarcted villitis. Moreover, noteworthy variances in placental measurements and distinctive lesions were discerned when comparing the PE and early-onset FGR cohort with the normotensive group. CONCLUSIONS: Maternal malperfusion emerged as a pivotal determinant linked to placental lesions in pregnancies affected by early-onset FGR. Remarkably, the occurrence of infarctions, specifically delayed infarctions, exhibited a noteworthy correlation with PE. These findings accentuate the significance of pursuing additional research endeavors aimed at unraveling the intricate mechanisms governing maternal malperfusion and its consequential influence on placental health in the context of early-onset FGR, with particular attention to the interplay with PE.

Diagnosis and Management of Cerebral Venous Thrombosis Due to Polycythemia Vera and Genetic Thrombophilia: Case Report and Literature Review.

(1) Background: Cerebral venous and dural sinus thrombosis (CVT) rarely appears in the adult population. It is difficult to diagnosis because of its variable clinical presentation and the overlapping signal intensities of thrombosis and venous flow on conventional MR images and MR venograms. (2) Case presentation: A 41-year-old male patient presented with an acute isolated intracranial hypertension syndrome. The diagnosis of acute thrombosis of the left lateral sinus (both transverse and sigmoid portions), the torcular Herophili, and the bulb of the left internal jugular vein was established by neuroimaging data from head-computed tomography, magnetic resonance imaging (including Contrast-enhanced 3D T1-MPRAGE sequence), and magnetic resonance venography (2D-TOF MR venography). We detected different risk factors (polycythemia vera-PV with JAK2 V617F mutation and inherited low-risk thrombophilia). He was successfully treated with low-molecular-weight heparin, followed by oral anticoagulation. (3) Conclusions: In the case of our patient, polycythemia vera represented a predisposing risk factor for CVT, and the identification of JAK2 V617F mutation was mandatory for the etiology of the disease. Contrast-enhanced 3D T1-MPRAGE sequence proved superior to 2D-TOF MR venography and to conventional SE MR imaging in the diagnosis of acute intracranial dural sinus thrombosis.

The T Cell Epitope Landscape of SARS-CoV-2 Variants of Concern.

During the COVID-19 pandemic, several SARS-CoV-2 variants of concern (VOC) emerged, bringing with them varying degrees of health and socioeconomic burdens. In particular, the Omicron VOC displayed distinct features of increased transmissibility accompanied by antigenic drift in the spike protein that partially circumvented the ability of pre-existing antibody responses in the global population to neutralize the virus. However, T cell immunity has remained robust throughout all the different VOC transmission waves and has emerged as a critically important correlate of protection against SARS-CoV-2 and its VOCs, in both vaccinated and infected individuals. Therefore, as SARS-CoV-2 VOCs continue to evolve, it is crucial that we characterize the correlates of protection and the potential for immune escape for both B cell and T cell human immunity in the population. Generating the insights necessary to understand T cell immunity, experimentally, for the global human population is at present a critical but a time consuming, expensive, and laborious process. Further, it is not feasible to generate global or universal insights into T cell immunity in an actionable time frame for potential future emerging VOCs. However, using computational means we can expedite and provide early insights into the correlates of T cell protection. In this study, we generated and revealed insights on the T cell epitope landscape for the five main SARS-CoV-2 VOCs observed to date. We demonstrated using a unique AI prediction platform, a significant conservation of presentable T cell epitopes across all mutated peptides for each VOC. This was modeled using the most frequent HLA alleles in the human population and covers the most common HLA haplotypes in the human population. The AI resource generated through this computational study and associated insights may guide the development of T cell vaccines and diagnostics that are even more robust against current and future VOCs, and their emerging subvariants.

Aphasic Syndromes in Cerebral Venous and Dural Sinuses Thrombosis-A Review of the Literature.

Aphasia is an acquired central disorder of language that affects a person's ability to understand and/or produce spoken and written language, caused by lesions situated usually in the dominant (left) cerebral hemisphere. On one hand aphasia has a prevalence of 25-30% in acute ischemic stroke, especially in arterial infarcts. On the other hand, cerebral venous and dural sinuses thrombosis (CVT) remains a less common and underdiagnosed cause of ischemic stroke (0.5-1% of all strokes). Aphasia has been observed in almost 20% of patients who suffered CVT. The presence of aphasia is considered a negative predictive factor in patients with stroke, severe language disorders corresponding to arduous recovery. Taking into consideration data from the literature, aphasia is also considered a predictive factor for patients with CVT; its absences, together with the absence of worsening after admission, are determinants of complete recovery after CVT. This review has as the principal role of gathering current information from the literature (PubMed database 2012-2022) regarding the clinical features of aphasic syndromes and its incidence in patients with CVT. The main conclusion of this review was that aphasic syndromes are not usually the consequence of isolated thrombosis of dural sinuses or cerebral veins thrombosis. The most frequent form of CVT that determines aphasia is represented by the left transverse sinus thrombosis associated with a posterior left temporal lesion (due to left temporal cortical veins thrombosis), followed by the superior sagittal sinus thrombosis associated with a left frontal lesion (due to left frontal cortical veins thrombosis). Only a few cases are presenting isolated cortical veins thrombosis and left thalamus lesions due to deep cerebral vein thrombosis. We also concluded that the most important demographic factor was the gender of the patients, women being more affected than men, due to their postpartum condition.

An Integrated Approach on the Diagnosis of Cerebral Veins and Dural Sinuses Thrombosis (a Narrative Review).

(1) Objective: This review paper aims to discuss multiple aspects of cerebral venous thrombosis (CVT), including epidemiology, etiology, pathophysiology, and clinical presentation. Different neuroimaging methods for diagnosis of CVT, such as computer tomography CT/CT Venography (CTV), and Magnetic Resonance Imaging (MRI)/MR Venography (MRV) will be presented. (2) Methods: A literature analysis using PubMed and the MEDLINE sub-engine was done using the terms: cerebral venous thrombosis, thrombophilia, and imaging. Different studies concerning risk factors, clinical picture, and imaging signs of patients with CVT were examined. (3) Results: At least one risk factor can be identified in 85% of CVT cases. Searching for a thrombophilic state should be realized for patients with CVT who present a high pretest probability of severe thrombophilia. Two pathophysiological mechanisms contribute to their highly variable clinical presentation: augmentation of venular and capillary pressure, and diminution of cerebrospinal fluid absorption. The clinical spectrum of CVT is frequently non-specific and presents a high level of clinical suspicion. Four major syndromes have been described: isolated intracranial hypertension, seizures, focal neurological abnormalities, and encephalopathy. Cavernous sinus thrombosis is the single CVT that presents a characteristic clinical syndrome. Non-enhanced CT (NECT) of the Head is the most frequently performed imaging study in the emergency department. Features of CVT on NECT can be divided into direct signs (demonstration of dense venous clot within a cerebral vein or a cerebral venous sinus), and more frequently indirect signs (such as cerebral edema, or cerebral venous infarct). CVT diagnosis is confirmed with CTV, directly detecting the venous clot as a filling defect, or MRI/MRV, which also realizes a better description of parenchymal abnormalities. (4) Conclusions: CVT is a relatively rare disorder in the general population and is frequently misdiagnosed upon initial examination. The knowledge of wide clinical aspects and imaging signs will be essential in providing a timely diagnosis.

Analysis of the relationship between placental histopathological aspects of preterm and term birth.

OBJECTIVES: This study aims to establish a correlation between placental histopathological and immunohistochemical (IHC) changes and preterm birth with fetal growth restriction (FGR, formerly called intrauterine growth restriction - IUGR). PATIENTS, MATERIALS, AND METHODS: This prospective study was performed on a group of 30 parturients, with singleton gestation, of which 15 patients gave birth at term, and the other 15 patients gave birth prematurely. After the statistical correlation of the clinical and demographic data with premature birth (PB) and term birth (TB), we performed histological and IHC research on the respective placentae. To observe normal and pathological microscopic placental structures, we used the Hematoxylin-Eosin (HE) and Periodic Acid Schiff-Hematoxylin (PAS-H) classical stainings, but also special immunostaining with anti-cluster of differentiation 34 (CD34) and anti-vascular endothelial growth factor (VEGF) antibodies. RESULTS: We found a statistically significant difference between the TB∕PB categories and the age of the patients, their antepartum weight, the weight of the newborns, and the placenta according to the sex of the newborn. Histological analysis revealed in the case of TB, small areas of perivillous amyloid deposition, with the significant extension of these areas both intravillous and perivillous in the case of PB. Massive intravillous calcifications, syncytial knots, and intravillous vascular thrombosis were also frequently present in PB. With PAS-H staining were highlighted the intra∕extravillous vascular basement membranes, but especially the massive fibrin deposits rich in glycosaminoglycans. By the IHC technique with the anti-CD34 antibody, we noticed the numerical vascular density, higher in the case of TB, but in the case of PB, there were large areas of placental infarction, with a lack of immunostaining in these areas. Through the anti-VEGF antibody, we observed the presence of signal proteins that determined and stimulated the formation of neoformation vessels in the areas affected by the lack of post-infarction placental vascularization. We observed a highly significant difference between placental vascular density between TB∕PB and newborn weight, sex, or placental weight. CONCLUSIONS: Any direct proportional link between the clinical maternal-fetal and histological elements yet studied must be considered. Thus, establishing an antepartum risk group can prevent a poor pregnancy outcome.

Ultrasound Technologies and the Diagnosis of Giant Cell Arteritis.

Giant cell arteritis (GCA) is a primary autoimmune vasculitis that specifically affects medium-sized extracranial arteries, like superficial temporal arteries (TAs). The most important data to be considered for the ultrasound (US) diagnosis of temporal arteritis are stenosis, acute occlusions and "dark halo" sign, which represent the edema of the vascular wall. The vessel wall thickening of large vessels in GCA can be recognized by the US, which has high sensitivity and is facile to use. Ocular complications of GCA are common and consist especially of anterior arterial ischemic optic neuropathies or central retinal artery occlusion with sudden, painless, and sharp loss of vision in the affected eye. Color Doppler imaging of the orbital vessels (showing low-end diastolic velocities and a high resistance index) is essential to quickly differentiate the mechanism of ocular involvement (arteritic versus non-arteritic), since the characteristics of TAs on US do not correspond with ocular involvement on GCA. GCA should be cured immediately with systemic corticosteroids to avoid further visual loss of the eyes.

Brain metastases originating in breast cancer: clinical-pathological analysis and immunohistochemical profile.

The incidence of brain metastases (BMs) originating in breast cancer (BC) is increasing due to advances in imaging techniques, which can detect such events early, and due to new therapies that can ensure longer survival. We performed a retrospective study on patients with BMs originating in BC and receiving surgical treatment in Neurosurgery Clinics of Prof. Dr. Nicolae Oblu Emergency Clinical Hospital, Iasi, Romania, from January 2018 to December 2019. We identified 10 consecutive patients who underwent a craniotomy for a BMs originating in a BC (either for diagnostic purpose or with therapeutic intent). Clinicopathological data were collected from the electronic medical record and included the patient demographics (age at diagnosis of their BM), morphological characteristics of BM [location, cytopathological features, histopathological (HP) subtype, and immunohistochemical features, i.e., cytokeratin 5∕6 (CK5∕6), mammaglobin, estrogen receptor (ER), progesterone receptor (PR), and Ki67 labeling index (LI)], and time from BC diagnosis to BM diagnosis. Ninety percent of patients were in their sixth and seventh decades of life, with a median age of 57.9 years (47-65 years). Median time from BC diagnosis to BM was 34.42 months. Fifty percent of BMs were located in the parietal lobes, and 70% of all cases have multiple (≥2) BMs. All cases (100%) had a cytopathological examination, showing a hypercellular pattern, with poorly cohesive clusters of mild or pleomorphic cells, with nuclei with homogeneously distributed fine granular chromatin membrane, and with small or enlarged and irregular nucleoli. The dominant histopathology was invasive breast carcinoma of no special type (IBC-NST) (70%), but we also identified specific subtypes, i.e., tubular carcinoma (TC) (20%) and invasive micropapillary carcinoma (IMPC) (10%). Correlating location with HP subtypes of BMs from BC, IBC-NST and IMPC were located mostly in parietal lobes, and TC developed only in the occipital lobe. We found three patterns of immunostaining: (i) CK5∕6 +∕-, mammaglobin+, ER+, PR-, which was much more characteristic for IBC-NST; (ii) CK5∕6-, mammaglobin+, ER-, PR-, being identified in tubular breast carcinoma; (iii) CK5∕6 +∕-, mammaglobin-, ER-, PR-, which were revealed by invasive micropapillary breast carcinoma. Our study revealed the fact that BMs originating in BC show heterogeneity of hormone receptor status, although morphologically there is not so much diversity. We also found a very variable Ki67 LI, which correlated especially with the morphological subtype.