Molecular Genetics of Intracranial Meningiomas with Emphasis on Canonical Wnt Signalling.

Research over the last decade recognized the importance of novel molecular pathways in pathogenesis of intracranial meningiomas. In this review, we focus on human brain tumours meningiomas and the involvement of Wnt signalling pathway genes and proteins in this common brain tumour, describing their known functional effects. Meningiomas originate from the meningeal layers of the brain and the spinal cord. Most meningiomas have benign clinical behaviour and are classified as grade I by World Health Organization (WHO). However, up to 20% histologically classified as atypical (grade II) or anaplastic (grade III) are associated with higher recurrent rate and have overall less favourable clinical outcome. Recently, there is emerging evidence that multiple signalling pathways including Wnt pathway contribute to the formation and growth of meningiomas. In the review we present the synopsis on meningioma histopathology and genetics and discuss our research regarding Wnt in meningioma. Epithelial-to-mesenchymal transition, a process in which Wnt signalling plays an important role, is shortly discussed

A rare case of centronuclear myopathy with DNM2 mutation: genotype–phenotype correlation

Centronuclear myopathy (CNM) is a group of rare genetic muscle disorders characterized by muscle fibers with centrally located nuclei. The most common forms of CNM have been attributed to X-linked recessive mutations in the MTM1 gene; autosomal-dominant mutations in the DNM2 gene-encoding dynamin-2, the BIN1 gene; and autosomal-recessive mutations in BIN1, RYR1, and TTN genes. Dominant CNM due to DNM2 mutations usually follows a mild clinical course with the onset in adolescence. Currently, around 35 mutations of the DNM2 gene have been identified in CNM; however, the underlying molecular mechanism of DNM2 mutation in the pathology of CNM remains elusive, and the standard clinical characteristics have not yet been defined. Here, we describe the case of a 17-year-old female who presented with proximal muscle weakness along with congenital anomalous pulmonary venous connection (which has not been described in previous cases of CNM), scoliosis, and lung disease without a significant family history. Her creatine kinase level was normal. Histology, special stains, and electron microscope findings on her skeletal muscle biopsy showed CNM with the characteristic features of a DNM2 mutation, which was later confirmed by next-generation sequencing. This case expands the known clinical and pathological findings of CNM with DNM2 gene mutatio

Abnormal white matter tracts resembling pencil fibers involving prefrontal cortex (Brodmann area 47) in autism: a case report.

BackgroundAutism is not correlated with any neuropathological hallmark as the brain of autistic individuals lack defined lesions. However, previous investigations have reported cortical heterotopias and local distortion of the cytoarchitecture of the neocortex in some cases of autism.Case presentationOur patient was a 40-year-old white woman diagnosed at an early age with autism and mental retardation. Pencil fibers were present within the prefrontal cortex (Brodmann area 47) and its composition resembled that of the underlying white matter region. Pencil fibers encompassed most of the extent of the cortical grey matter and were populated by oligodendrocytes, astrocytes, and microglial cells, but not by neurons.ConclusionsHere we report a new cytoarchitectural abnormality that has not been previously described in autism. Future pathological examinations should keep in mind the potential presence of pencil fibers within the prefrontal cortex of cases with autism

Chondroblastoma of the Clivus: Case Report and Review.

Background and Importance Chondroblastoma is a benign primary bone tumor that typically develops in the epiphyses of long bones. Chondroblastoma of the craniofacial skeleton is extremely rare, with most cases occurring in the squamosal portion of the temporal bone. In this report, we describe the first case of chondroblastoma of the clivus presenting with cranial neuropathy that was treated with endoscopic endonasal resection. We review the literature on craniofacial chondroblastomas with particular emphasis on extratemporal lesions. Case Presentation A 27-year-old woman presented with severe headache, left facial dysesthesias, and diplopia. Physical examination revealed hypesthesia in the left maxillary nerve dermatome, and complete left abducens nerve palsy. Imaging demonstrated an expansile intraosseous mass originating in the upper clivus with extension superiorly into the sella turcica and laterally to involve the medial wall of the left cavernous sinus. The tumor was completely resected via an endoscopic endonasal approach, with postoperative improvement in lateral gaze palsy. Histopathology was consistent with chondroblastoma. Conclusion Chondroblastoma is a rare tumor of the craniofacial skeleton that should be included in the differential diagnosis of an osteolytic lesion of the clivus. Complete surgical resection remains the mainstay of treatment

A rare case of centronuclear myopathy with DNM2 mutation: genotype–phenotype correlation

Centronuclear myopathy (CNM) is a group of rare genetic muscle disorders characterized by muscle fibers with centrally located nuclei. The most common forms of CNM have been attributed to X-linked recessive mutations in the MTM1 gene; autosomal-dominant mutations in the DNM2 gene-encoding dynamin-2, the BIN1 gene; and autosomal-recessive mutations in BIN1, RYR1, and TTN genes. Dominant CNM due to DNM2 mutations usually follows a mild clinical course with the onset in adolescence. Currently, around 35 mutations of the DNM2 gene have been identified in CNM; however, the underlying molecular mechanism of DNM2 mutation in the pathology of CNM remains elusive, and the standard clinical characteristics have not yet been defined. Here, we describe the case of a 17-year-old female who presented with proximal muscle weakness along with congenital anomalous pulmonary venous connection (which has not been described in previous cases of CNM), scoliosis, and lung disease without a significant family history. Her creatine kinase level was normal. Histology, special stains, and electron microscope findings on her skeletal muscle biopsy showed CNM with the characteristic features of a DNM2 mutation, which was later confirmed by next-generation sequencing. This case expands the known clinical and pathological findings of CNM with DNM2 gene mutatio

An extremely rare case of concurrent BRAF V600E mutation driven hairy cell leukemia and melanoma: case report and review of literature

BRAF protein is a serine/threonine kinase with 766 amino acids. Approximately 15% of human cancers harbor BRAF mutations as well as other BRAF anomalies (amplifications, fusions). Somatic mutations mainly occur in the catalytic kinase domain (CR3), and the predominant mutation is p.V600E which is the substitution of glutamic acid (E) for valine (V) as result of a mutation at codon 600 of the kinase domain. To our knowledge, the vast majority of the cancers have non-germline BRAF mutations. Here we describe a case of a 60-year-old female with a history of hairy cell leukemia (HCL) who presented with aphasia and forgetfulness. A follow-up Brain CT scan showed three distinct brain lesions which were found to be diagnostic of melanoma (confirmed by immunohistochemistry) with no evidence of a concurrent brain involvement by a B-cell neoplasm. Molecular studies confirmed the same BRAF p.V600E mutation in both malignancies (hairy cell leukemia and melanoma). Thereafter the patient was started on BRAF inhibitor treatment and is now symptom-free after one year of follow up. Having two concurrent malignancies with a shared BRAF mutation is extremely rare and makes this an excellent example of a genomic marker-driven treatment in two histologically and immunophenotypically distinct tumor

Microscopy with ultraviolet surface excitation for rapid slide-free histology.

Histologic examination of tissues is central to the diagnosis and management of neoplasms and many other diseases, and is a foundational technique for preclinical and basic research. However, commonly used bright-field microscopy requires prior preparation of micrometre-thick tissue sections mounted on glass slides, a process that can require hours or days, that contributes to cost, and that delays access to critical information. Here, we introduce a simple, non-destructive slide-free technique that within minutes provides high-resolution diagnostic histological images resembling those obtained from conventional haematoxylin-and-eosin-histology. The approach, which we named microscopy with ultraviolet surface excitation (MUSE), can also generate shape and colour-contrast information. MUSE relies on ~280-nm ultraviolet light to restrict the excitation of conventional fluorescent stains to tissue surfaces, and it has no significant effects on downstream molecular assays (including fluorescence in situ hybridization and RNA-seq). MUSE promises to improve the speed and efficiency of patient care in both state-of-the-art and low-resource settings, and to provide opportunities for rapid histology in research

Concomitant occurrence of FXTAS and clinically defined sporadic inclusion body myositis: report of two cases.

This report describes unique presentations of inclusion body myositis (IBM) in two unrelated patients, one male and one female, with genetically and histologically confirmed fragile X-associated tremor/ataxia syndrome (FXTAS). We summarize overlapping symptoms between two disorders, clinical course, and histopathological analyses of the two patients with FXTAS and sporadic IBM, clinically defined per diagnostic criteria of the European Neuromuscular Centre. In case 1, a post-mortem analysis of available brain and muscle tissues is also described. Histopathological features (rimmed vacuoles) consistent with clinically defined IBM were detected in both presented cases. Postmortem testing in case 1 revealed the presence of an FMR1 premutation allele of 60 CGG repeats in both brain and skeletal muscle samples. Case 2 was a premutation carrier with 71 CGG repeats who had a son with FXS. Given that FXTAS is associated with immune-mediated disorders among premutation carriers, it is likely that the pathogeneses of IBM and FXTAS are linked. This is, to our knowledge, the first report of these two conditions presenting together, which expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS. Following detection of a premutation allele of the FMR1 gene, FXTAS patients with severe muscle pain should be assessed for IBM

An extremely rare case of concurrent BRAF V600E mutation driven hairy cell leukemia and melanoma: case report and review of literature

BRAF protein is a serine/threonine kinase with 766 amino acids. Approximately 15% of human cancers harbor BRAF mutations as well as other BRAF anomalies (amplifications, fusions). Somatic mutations mainly occur in the catalytic kinase domain (CR3), and the predominant mutation is p.V600E which is the substitution of glutamic acid (E) for valine (V) as result of a mutation at codon 600 of the kinase domain. To our knowledge, the vast majority of the cancers have non-germline BRAF mutations. Here we describe a case of a 60-year-old female with a history of hairy cell leukemia (HCL) who presented with aphasia and forgetfulness. A follow-up Brain CT scan showed three distinct brain lesions which were found to be diagnostic of melanoma (confirmed by immunohistochemistry) with no evidence of a concurrent brain involvement by a B-cell neoplasm. Molecular studies confirmed the same BRAF p.V600E mutation in both malignancies (hairy cell leukemia and melanoma). Thereafter the patient was started on BRAF inhibitor treatment and is now symptom-free after one year of follow up. Having two concurrent malignancies with a shared BRAF mutation is extremely rare and makes this an excellent example of a genomic marker-driven treatment in two histologically and immunophenotypically distinct tumor

Mogući utjecaji rata u Hrvatskoj (1990.-1995.) na epidemiologiju raka štitne žlijezde

A Thyroid Cancer Registry containing data of patients treated at our department during a 20-year period (1980-1999) has been established. The aim of the study was to analyze the possible effects of the 1990-1995 war in Croatia on the prevalence, type, and age and sex distribution of thyroid carcinoma. Three different 2-year periods were analyzed: distant prewar (1980-1981), immediate prewar (1989-1990) and postwar (1998-1999) period. There was no statistically significant difference in age at diagnosis and sex ratio among the three study periods. The incidence of follicular cancer was at the upper limit for countries with normal iodine uptake when the 20-year period was analyzed, however, in the 1980-1981 period follicular cancer accounted for 34.9%, and in 1998-99 for only 2.8% of all cases. Papillary cancer was diagnosed in less advanced stages than others. Five-year survival for papillary, follicular and anaplastic cancer was 100%, 100% and 0%, respectively. Analysis of the 2-year periods for all cancer types except anaplastic cancer showed the mean age at onset to be on a decrease. In the 1998-1999 period, papillary cancer was diagnosed in a more advanced stage. The number of follicular cancer cases decreased from 22 in 1980-1981 to 3 in 19891990 and 2 in 1998-1999. Analysis of the epidemiology of thyroid cancer in the pre- and post-Chernobyl period did not reveal any increase in the number of papillary cancer in younger patients. It was concluded that in the postwar period, patients presented in more advanced stages of the disease. However, the effects of war on the epidemiology of thyroid carcinoma and other malignant tumors should be further investigated.Na našoj Klinici uspostavljeni Registar raka štitne žlijezde sadrži podatke o svim bolesnicima obrađenim u Klinici u 20godišnjem razdoblju (1980.-1999.). Cilj ovoga istraživanja bio je utvrditi moguće učinke rata u Hrvatskoj na učestalost, histološki tip te spolnu i dobnu raspodjelu bolesnika sa zloćudnim tumorom štitne žlijezde. Analizom su obuhvaćena 3dvogodišnja razdoblja uključujući vrijeme znatno prije rata (1980.-1981.), neposredno prije rata (1989.-1990.) i nakon rata(1998.-1999.). Nije utvrđena statistički značajna razlika u starosti i spolnoj raspodjeli tumora između tri navedena razdoblja. Učestalost folikularnog raka bila je na gornjoj granici učestalosti za zemlje bez gušavosti, s tim da je u razdoblju 1980.-1981. bilo ukupno 34,9%, a u razdoblju 1998.-1999. samo 2,8% folikularnog karcinoma. Petogodišnje preživljenje bilo je 100%, 100% odnosno 0% za papilarni, folikularni i anaplastični rak. U uspoređivanim razdobljima prosječna starost bolesnika se snižavala, ali se rak dijagnosticirao u sve uznapredovalijem stadiju. Analiza populacije prije i nakon Černobila nije pokazala povećan broj mladih bolesnika s papilarnim karcinomom. Na temelju rezultata ovoga istraživanja zaključeno je da nije bilo povećanja učestalosti karcinoma štitnjače u poratnom razdoblju, međutim, bolesnici su se javljali s uznapredovalijim stadijima tumora. Ovaj i moguće druge učinke rata na karcinom štitnjače, kao i na druge zloćudne tumore, valja dalje istraživati