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Objective: To compare measured and perceived taste function before and after surgery of patients with chronic otitis media with cholesteatoma (OMCC) to patients without cholesteatoma (patients with chronic suppurative otitis media [CSOM] and patients with lateral skull base lesions [LSB]). Methods: This prospective cohort study included 29 patients undergoing surgery for unilateral OMCC. The chorda tympani nerve (CTN) was resected in 8 of these patients. Fourteen patients undergoing surgery for unilateral CSOM and 5 patients undergoing surgery for unilateral LSB (with CTN resection) served as the comparison group. Taste function was measured using taste strips on both sides of the tongue before surgery, 2 weeks postoperatively and 3 months postoperatively. The affected side of the tongue was compared to the unaffected side. A questionnaire on taste perception was completed at each visit. Results: Preoperatively, cholesteatoma patients showed higher taste strip scores than non-cholesteatoma patients, indicating a larger difference between the healthy and affected sides of the tongue. Despite this difference in measured taste function few cholesteatoma patients reported taste alteration before surgery (3/29 [10.3%]). Postoperatively, patients with CTN resection (OMCC patients with CTN resection and LSB patients) showed a decreased measured taste function. Subjectively, only approximately 20% of these patients reported taste alteration 3 months postoperatively. Conclusions: Before surgery, cholesteatoma patients displayed an impaired measured taste function compared to patients without cholesteatoma (CSOM, LSB). Subjectively this was often unnoticed. After surgery, despite removal of the CTN and consequent reduction of measured taste function, few patients reported taste alteration and subjective taste perception was seen to be improving. In regards to middle ear surgery, perceived taste function does not seem to reflect measured gustatory function. [ABSTRACT FROM AUTHOR]

Wilms's tumor gene (WT1) is overexpressed in a variety of hematologic malignancies and solid tumors. Recently, WT1 protein has been considered as a molecular target of cancer immunotherapy for several solid tumors and as a tool for monitoring minimal residual disease in leukemia patients. There are only few investigations on WT1 expression in central nervous system neoplasms, which suggest that the WT1 gene may play an important role in tumorigenesis of primary astrocytic tumors and that high-grade tumors express high levels of WT1 proteins. We examined 50 low-grade and high-grade gliomas using tissue microarray and immunohistochemical methods to identify WT1 protein, P53, Ki-67, GFAP, NFP, EGFR, nestin, and Neu-N expression. WT1 and nestin shared overlapping expression in all gliomas and were increased in high-grade examples, highlighting their potential use as diagnostic and prognostic tumor markers. Our results support the combined role of WT1 and nestin in glial tumorigenesis and progression. [ABSTRACT FROM AUTHOR]

Objective: Recent studies indicate that WT1 and Bcl2 protein are detected in melanocytic lesions of the skin. We examined, for the first time, WT1 and Bcl2 expression in a variety of conjunctival melanocytic lesions to evaluate their diagnostic utility compared with other melanocytic markers. Methods: Protein expression and localization of WT1 and Bcl2 were studied by means of immunolabeling and semiquantification in 123 conjunctival melanocytic lesions (71 benign nevi, 21 atypical nevi, 11 primary acquired melanosis, and 20 malignant melanomas). Ancillary immunohistochemical studies were performed with Bcl2, S100, HMB45, and Melan A antibodies. Results: WT1 showed a graded increase in expression in lesions with increasing atypia. Higher mean numbers of WT1-positive cells correlated with increasing atypia in melanocytes. In all cases, Bcl2 expression was positive and more robust than was S100, HMB45, or Melan A expression. WT1 and HMB45 frequently showed diffuse and strong staining in atypical nevi, primary acquired melanosis with atypia, and malignant melanomas compared with benign lesions. Conclusions: Bcl2 is a highly sensitive immunohistochemical marker for melanocytic tumors of the conjunctiva; HMB45 and WT1 staining distinguishes benign from malignant lesions. Clinical Relevance: Our results show that HMB45 and WT1 immunolabeling is helpful in the evaluation of conjunctival melanocytic lesions. Accordingly, we recommend the development of an immunohistochemical panel to classify these lesions. [ABSTRACT FROM AUTHOR]

We report a skull chondromyxoid fibroma with symptomatic intracranial extension causing initial misdiagnosis as a psychiatric disorder in a 14-year-old child. CT performed for work-up of the patient’s “stuffy nose” revealed a large calcified frontal bone mass with extensive intracranial growth. We present this child with the diagnosis of intracranial chondromyxoid fibroma with detailed neuroimaging and neuropathology correlations. [ABSTRACT FROM AUTHOR]

Abstract We studied the microscopic features of 137 cases of human cerebral infarct. In each case, the age of the lesion was determined by measuring the time elapsed between initial clinical presentation and date of surgery or death. Multiple microscopic variables were analyzed on hematoxylin and eosin-stained sections. There were 104 (76%) male and 33 (24%) female patients with a median age of 64 years. The location of the infarcts included 129 cerebral, 5 cerebellar, and 1 each in the pons, midbrain and medulla. The age of the lesions ranged from 1 day to 53 years. All lesions were single and varied from lacunes to large infarcts in the distribution of one or more cerebral arteries. Key histologic features of the proposed classification are as follows: (1) phase of acute neuronal injury (11 cases studied), age 1-2 days, characterized by the presence of neuronal changes, and spongiosis of the neuropil and absence of neuronal ferrugination, chronic inflammation, macrophages, neo-vascularization and cavitation; (2) phase of organization subdivided into: (a) phase of acute inflammation (31 cases), age 3-37 days, characterized by coagulative necrosis, and frequent acute inflammation, and (b) phase of chronic inflammation (57 cases), age 10 days-53 years, characterized by the presence or absence of coagulative necrosis, neuronal injury, red neurons, macrophages, mononuclear inflammatory cells, perivascular cuffing, cavitation, gliosis, spheroids; absence of neutrophils; and (3) phase of resorption (38 cases), age 26 days-23 years, characterized by absence of an inflammatory response. Neuronophagia is not a feature of cerebral infarcts. [ABSTRACT FROM AUTHOR]

Aims: Low‐grade non‐intestinal‐type sinonasal adenocarcinoma (LGSNAC) is a rare heterogeneous and poorly characterised group of tumours, distinct from intestinal‐ and salivary‐type neoplasms. Therefore, further characterisation is needed for clearer biological understanding and classification. Methods and results: Clinical, histological and molecular characterisation of four cases of biphasic, low‐grade adenocarcinomas of the sinonasal tract was performed. All patients were male, aged between 48 and 78 years, who presented with polypoid masses in the nasal cavity. Microscopically, virtually all tumours were dominated by tubulo‐glandular biphasic patterns, microcystic, focal (micro)papillary, oncocytic or basaloid features. Immunohistochemical staining confirmed biphasic differentiation with an outer layer of myoepithelial cells. Molecular profiling revealed HRAS (p.G13R, p.Q61R) mutations, and concomitant AKT1 (p.E17K, p.Q79R) mutations in two cases. Two cases showed potential in‐situ/precursor lesions adjacent to the tumour. Follow‐up periods ranged from 1 to 30 months, with one case relapsing locally after 12 and > 20 years. Conclusion: This study further corroborates a distinct biphasic low‐grade neoplasm of the sinonasal tract with seromucinous differentiation. Although morphological and molecular features overlap with salivary gland epithelial–myoepithelial carcinoma, several arguments favour categorising these tumours within the spectrum of LGSNAC. [ABSTRACT FROM AUTHOR]

Background and purpose: Venous thromboembolic events (VTEs) are a major complication in cancer patients, and therefore, also in brain cancer patients, anticoagulants are considered appropriate in the treatment of VTEs. Methods: Frequency, risk factors, and treatment of VTEs, as well as associated complications, were assessed in a population‐based cohort of glioblastoma patients in the Canton of Zurich, Switzerland. Correlations between clinical data and survival were retrospectively analyzed using the log‐rank test and Cox regression models. Results: Four hundred fourteen glioblastoma patients with isocitrate dehydrogenase wild‐type status were identified. VTEs were documented in 65 patients (15.7%). Median time from tumor diagnosis to the occurrence of a VTE was 1.8 months, and 27 patients were diagnosed with VTEs postoperatively (within 35 days; 42.2%). History of a prior VTE was more common in patients who developed VTEs than in those who did not (p = 0.004). Bevacizumab treatment at any time during the disease course was not associated with occurrence of VTEs (p = 0.593). Most patients with VTEs (n = 61, 93.8%) were treated with therapeutic anticoagulation. Complications occurred in 14 patients (23.0%), mainly intracranial hemorrhages (n = 7, 11.5%). Overall survival did not differ between patients diagnosed with VTEs and those who had no VTE (p = 0.139). Tumor progression was the major cause of death (n = 283, 90.7%), and only three patients (1.0%) died in association with acute VTEs. Conclusions: Venous thromboembolic events occurred early in the disease course, suggesting that the implementation of primary venous thromboembolism prophylaxis during first‐line chemoradiotherapy could be explored in a randomized setting. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 49-year-old woman complaining for increasing neck pain accompanied by hoarseness and dysphagia. The patient underwent into angioembolization of the supratentorial tumor and diagnosed with myopericytoma. The article also discusses histological differential diagnosis of myopericytoma, gene expression, and neoplasm.

Summary The microenvironment shapes cell behavior and determines metastatic outcomes of tumors. We addressed how microenvironmental cues control tumor cell invasion in pediatric medulloblastoma (MB). We show that bFGF promotes MB tumor cell invasion through FGF receptor (FGFR) in vitro and that blockade of FGFR represses brain tissue infiltration in vivo . TGF-β regulates pro-migratory bFGF function in a context-dependent manner. Under low bFGF, the non-canonical TGF-β pathway causes ROCK activation and cortical translocation of ERK1/2, which antagonizes FGFR signaling by inactivating FGFR substrate 2 (FRS2), and promotes a contractile, non-motile phenotype. Under high bFGF, negative-feedback regulation of FRS2 by bFGF-induced ERK1/2 causes repression of the FGFR pathway. Under these conditions, TGF-β counters inactivation of FRS2 and restores pro-migratory signaling. These findings pinpoint coincidence detection of bFGF and TGF-β signaling by FRS2 as a mechanism that controls tumor cell invasion. Thus, targeting FRS2 represents an emerging strategy to abrogate aberrant FGFR signaling. [ABSTRACT FROM AUTHOR]

Predicting tumor behavior in meningiomas based on morphologic features alone remains difficult. A recent study showed that cytoplasmic localization of p63, a member of the p53 protein family, was correlated with poor patient survival in lung adenocarcinoma. The present study assesses the potential correlation between the sub-cellular localization of p63 expression and histological grade in benign, atypical, and malignant meningiomas. According to the 2000 WHO criteria, 37 archival intracranial meningiomas were classified into 19 grade 1 (benign), 14 grade II (atypical), and 4 grade III (malignant) meningiomas. Nuclear and cytoplasmic patterns of p63 expression were evaluated by means of immunohistochemistry. Staining was scored semiquantitatively based on nuclear and/or cytoplasmic distribution within neoplastic cells as follows: 0, no staining; 1, 50% or less of the cells; 2, more than 50% of the cells. Of grade I meningiomas, 95% (18/19) lacked nuclear p63 expression; a single case showed nuclear expression in greater than 50% of cells. None of the grade I tumors exhibited cytoplasmic staining. Overall, 86% of grade II tumors showed nuclear expression: 43% (6/14) exhibited nuclear expression in greater than 50% of cells and 43% (6/14) in less than 50% of cells; 14% (2/14) lacked nuclear expression; 14% (2/14) showed cytoplasmic expression. Grade 111 tumors showed an overall nuclear expression of 75% (3/4) with 75% also exhibiting cytoplasmic staining (one case lacked both nuclear and cytoplasmic p63 expression). Our results indicate that in meningiomas, a good correlation exists between histological grading and p63 protein expression, suggesting that p63 expression might be correlated with progression and clinical outcome of meningomas. [ABSTRACT FROM AUTHOR]

Children diagnosed with diffuse midline gliomas (DMG) have an extremely poor overall survival: 9–12 months from diagnosis with currently no curative treatment options. Given DMG molecular heterogeneity, surgical biopsies are needed for molecular profiling and as part of enrolment into molecular-based and precision medicine type clinical interventions. In this study, we describe the results of real time profiling and drug testing at the diffuse intrinsic pontine glioma/DMG Research Centre at University Children's Hospital Zurich. Biopsies were taken using a frame based stereotactic robot system (NeuroMate®, Renishaw) at University Children's Hospital Zurich. Tissue samples were evaluated to confirm diagnosis by H3K27M and H3K27 trimethylation loss. Genomic analyses were done using a variety of platforms (INFORM, Oncomine, UCSF500 gene panel). Cell lines were developed by mechanical tissue dissociation and verified by either sequencing or immunofluorescence staining confirming H3K27M mutation and used afterwards for drug testing. Twenty-five robot-assisted primary biopsies were successfully performed. Median hospital stay was 2 days (range 1–4 days). Nine low-passage patient-derived cells were developed, whereas 8 cell lines were used to inform response to clinically relevant drugs. Genome and RNA expression were used to further guide treatment strategies with targeted agents such as dual PI3K/mTOR inhibitor paxalisib. We established a systematic workflow for safe, robot-assisted brainstem biopsies and in-house tissue processing, followed by real-time drug testing. This provides valuable insights into tumour prognostic and individual treatment strategies targeting relevant vulnerabilities in these tumours in a clinically meaningful time frame. • Robot-assisted brainstem biopsy for pontine diffuse midline gliomas (DMG) is feasible and safe. • Real-time drug testing on patient-derived DMG cells define individualised treatments. • Targeted agents as paxalisib can be successfully integrated into the care of DMG. [ABSTRACT FROM AUTHOR]

The cover image is based on the article Expanding the spectrum of low‐grade sinonasal adenocarcinoma with biphasic seromucinous differentiation and activating HRAS/AKT1 mutations by Viktoria S. Hadnagy et al., https://doi.org/10.1111/his.15251..By Viktoria S Hadnagy; Meike Körner; Matthias Rössle; Patrick Dubach; Gunther Pabst; Alexandra Kotulova; Stefan Weder; Robert Seifert; Elisabeth J Rushing; David Holzmann; Martin Hüllner; Sandra N Freiberger and Niels J RuppReported by Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)–wild-type glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter–methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma. MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH–wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302). In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter–unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07–2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter–methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes. Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter–methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH–wild-type glioblastoma. • MGMT and TERT status do not interact prognostically in IDH-wild-type glioblastoma. • TERT mutation is not linked to benefit from TMZ in IDH-wildtype glioblastoma. • C228T and C250T TERT promoter-mutant glioblastoma show similar outcome. • TERT status is not required for prognostic stratification in clinical trials. [ABSTRACT FROM AUTHOR]

The article offers information on Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. It mentions that Microglia control small vessel calcification via TREM2, along with discusses the role of microglia in the biology of the neurovascular unit (NVU).

Abstract: The presence of inflammation and demyelination in a central nervous system (CNS) biopsy points towards a limited, yet heterogeneous group of pathologies, of which multiple sclerosis (MS) represents one of the principal considerations. Inflammatory demyelination has also been reported in patients with clinically suspected primary central nervous system lymphoma (PCNSL), especially when steroids had been administered prior to biopsy acquisition. The histopathological changes induced by corticosteroid treatment can range from mild reduction to complete disappearance of lymphoma cells. It has been proposed that in the absence of neoplastic B cells, these biopsies are indistinguishable from MS, yet despite the clinical relevance, no histological studies have specifically compared the two entities. In this work, we analyzed CNS biopsies from eight patients with inflammatory demyelination in whom PCNSL was later histologically confirmed, and compared them with nine well defined early active multiple sclerosis lesions. In the patients with steroid‐treated PCNSL (ST‐PCNSL) the interval between first and second biopsy ranged from 3 to 32 weeks; all of the patients had received corticosteroids before the first, but not the second biopsy. ST‐PCNSL patients were older than MS patients (mean age: ST‐PCNSL: 62 ± 4 years, MS: 30 ± 2 years), and histological analysis revealed numerous apoptoses, patchy and incomplete rather than confluent and complete demyelination and a fuzzy lesion edge. The loss of Luxol fast blue histochemistry was more profound than that of myelin proteins in immunohistochemistry, and T cell infiltration in ST‐PCNSL exceeded that in MS by around fivefold (P = 0.005). Our data indicate that in the presence of extensive inflammation and incomplete, inhomogeneous demyelination, the neuropathologist should refrain from primarily considering autoimmune inflammatory demyelination and, even in the absence of lymphoma cells, instigate close clinical follow‐up of the patient to detect recurrent lymphoma. [ABSTRACT FROM AUTHOR]