Microarchitecture of medication-related osteonecrosis of the jaw (MRONJ); a retrospective micro-CT and morphometric analysis

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive (AR) drugs such as bisphosphonates (BP) and denosumab (Dmab). Although several risk factors are described, the etiology of MRONJ is still not fully elucidated. Bone-strengthening is the primary aim of antiresorptive therapy; however, overly increased bone mass and microcrack accumulation are also discussed in MRONJ etiologies. The aim of this study is to evaluate the microarchitecture of jaw bones with micro?computed tomography (micro-CT) in AR-treated patients with or without MRONJ.Human jaw bone samples of AR-treated patients were separated into 11 groups by AR treatment bisphosphonate (BP), denosumab (Dmab), both (M) and control groups. Subgroups were divided according to the clinical localization as AR-exposed vital jaw bone (BP_exp, Dmab_exp, M_exp), osteonecrosis–margin of a sequestrum (BPO_mar, DmabO_mar, MO_mar) and osteonecrosis–sequestrum (BPO_seq, DmabO_seq, MO_seq). Healthy jaw bone (C_HB) and osteoporotic jaw bone (C_OP) represent control groups. Samples underwent retrospective micro-CT and morphometric analysis in representative units by bone volume fraction (BV/TV), bone surface density (BS/BV), trabecular thickness (Tr.Th.), trabecular number (Tr.N.), trabecular space (Tr.Sp.), Euler characteristic for bone connectivity, bone mineral density (BMD) and tissue mineral density (TMD).A total of 141 samples from 78 patients were analyzed. BV/TV of M_exp group (mean: 0.46 ± 0.27) was significantly higher than in the C_OP group (mean: 0.14 ± 0.05; p = 0.0053). Tr.Th. differed significantly between the BP_exp group (mean: 0.32 ± 0.15) and the M_exp group (mean: 0.57 ± 0.20; p = 0.0452) as well as between the BPO_seq group (mean: 0.25 ± 0.10) and the MO_seq group (mean: 0.39 ± 0.18; p = 0.0417). Signs of trabecular thickening and unorganized trabecular microarchitecture from AR-exposed- to sequestrum groups, were analyzed in 3D reconstructions. However, BS/BV, Tr.N., and Tr.Sp. showed no significant differences. Euler characteristic of the BPO_seq group (median: 7.46) doubled compared to that of the BP_exp group (median: 14.97; p = 0.0064). Mineralization parameters BMD and TMD were similar in all groups.Findings show evidence of enhanced bone mass and suspect microarchitecture in some AR-treated jaw bone compared to osteoporotic jaw bone. Despite increased bone mass, some MRONJ samples showed decreased trabecular connectivity by Euler characteristic compared to AR-treated jaw bone. These samples may indicate extensive ossification and ineffective bone mass with superficially higher bone mass without existing or even reduced mechanical stability, indicated by connectivity loss. This result might also suggest a high risk to microcrack accumulation. At some point, possibly some kind of over-ossification could lead to under-nourishment and microarchitectural weakness, creating instability, subsequently increasing vulnerability to MRONJ.     

Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma,and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity

Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.     

Predictive molecular markers in metastases to the central nervous system: recent advances and future avenues

Metastases to the central nervous system (CNS) are common in several cancer types. For most primary tumors that commonly metastasize to the CNS, molecular biomarker analyses are recommended in the clinical setting for selection of appropriate targeted therapies. Therapeutic efficacy of some of these agents has been documented in patients with brain metastases, and molecular testing of CNS metastases should be considered in the clinical setting. Here, we summarize the clinically relevant biomarker tests that should be considered in neurosurgical specimens based on the current recommendations of the European Society of Medical Oncology (ESMO) or the National Comprehensive Cancer Network (NCCN) for the most relevant primary tumor types: lung cancer (EGFR mutations, ALK rearrangement, BRAF mutations), breast cancer (HER2 amplification, steroid receptor overexpression), melanoma (BRAF mutations), and colorectal cancer (RAS mutations). Furthermore, we discuss emerging therapeutic targets including novel oncogenic alterations (ROS1 rearrangements, FGFR1 amplifications, CMET amplifications, and others) and molecular features of the tumor microenvironment (including immune-checkpoint molecules such as CTLA4 and PD-1/PD-L1). We also discuss the potential role of advanced biomarker tests such as next-generation sequencing and “liquid biopsies” for patients with CNS metastases.     

Prognostic value of histamine H1 receptor expression in oral squamous cell carcinoma

Objectives

Overexpression of the histamine H1 receptor (H1R) has been described in a variety of tumor models, but experience in oral squamous cell carcinomas (OSCC) is not available. Current adjuvant treatment options for OSCC can be improved by the identification of new targets of therapy. Herein, we evaluated H1R expression in a large patient cohort of OSCC.

Materials and methods

H1R immunoexpression was evaluated in 191 cases of OSCC and two OSCC cell lines BICR56 and BICR3. Scanned images were digitally analyzed using ImageJ and the immunomembrane plug-in. The combined score of computer-assisted semiquantitative analysis was correlated with manually counted percentages of tumor cells by Kendall’s tau (т) correlation coefficient. Disease-free survival times were estimated using the Kaplan–Meier method and were compared by using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards model.

Results

H1R was rarely expressed in OSCC but significantly related with advanced tumor stages (n?=?21/191, mean expression 63.5 % of cancer cells in positive tumor samples, 95 % confidence interval of the mean 53.5 to 73.6 %, p?=?0.006). Following univariate analysis, patients with H1R expression showed a significant poorer prognosis (p?=?0.0004). Multivariate analysis revealed H1R expression as an independent prognostic factor (p?=?0.0164). Expression of H1R in cancer cell lines was confirmed by specific staining of OSCC cell lines BICR56 and BICR3.

Conclusion

This is the first study focusing on H1R expression showing a significant poorer DFS rate in the H1R+ patient cohort. Based on these data, H1R activation may promote carcinogenesis in OSCC.

Clinical relevance

Investigation of H1R regulation and its antagonists shows a clear rationale for future supportive anticancer therapies in OSCCs.     

Focal epilepsy in Glucose transporter type 1 (Glut1) defects: case reports and a review of literature

Mutations in SLC2A1, encoding the glucose transporter type 1 (Glut1), cause a wide range of neurological disorders: (1) classical Glut1 deficiency syndrome (Glut1-DS) with an early onset epileptic encephalopathy including a severe epilepsy, psychomotor delay, ataxia and microcephaly, (2) paroxysmal exercise-induced dyskinesia (PED) and (3) various forms of idiopathic/genetic generalized epilepsies such as different forms of absence epilepsies. Up to now, focal epilepsy was not associated with SLC2A1 mutations. Here, we describe four cases in which focal seizures present the main or at least initial category of seizures. Two patients suffered from a classical Glut1-DS, whereas two individuals presented with focal epilepsy related to PED. We identified three novel SLC2A1 mutations in these unrelated individuals. Our study underscores that focal epilepsy can be caused by SLC2A1 mutations or that focal seizures may present the main type of seizures. Patients with focal epilepsy and PED should undergo genetic testing and can benefit from a ketogenic diet. But also individuals with pharmaco-resistant focal epilepsy and cognitive impairment might be candidates for genetic testing in SLC2A1.     

Clinical presentation of young people (10–24 years old) with brain tumors: results from the international MOBI-Kids study

Journal of Neuro-Oncology - We used data from MOBI-Kids, a 14-country international collaborative case–control study of brain tumors (BTs), to study clinical characteristics of the tumors in...     

Reliability and validity of Quality of Life assessed by the Short-Form 36 and the Modular System for Quality of Life in patients with schizophrenia and patients with depression

Reliability and validity of the Quality of Life (QoL) construct were investigated in healthy controls (N=346), patients with depression (N=114) and patients with schizophrenia (N=91) using two different QoL instruments: the Short-Form 36 (SF-36), a well-established generic instrument measuring eight dimensions; and the Modular System for Quality of Life (MSQoL), a recently developed instrument measuring seven core dimensions and four specific modules (objective data, partnership, family, occupation). The MSQoL and the SF-36 were administered at three intervals (hospital admission, discharge and 4-month follow-up). Reliability, group profiles (clinical specificity), responsiveness, discriminant validity (with regard to sociodemographic, psychopathological, clinical and state variables) and convergent validity were tested. At admission, patients with depression had the lowest QoL level, patients with schizophrenia had an intermediate level, and controls had the highest QoL level. At discharge and follow-up, the two patient groups did not differ from each other, but still had lower levels than controls. Both patient groups improved significantly in QoL from admission to discharge. This improvement was confounded by improvement in depressive symptoms, but not in positive or negative symptoms. Current mood state influenced QoL assessments in all three samples substantially. In conclusion, QoL can be measured reliably and with sufficient responsiveness by the MSQoL and the SF-36 in psychiatric and non-clinical populations, although discriminant validity with regard to depression and current mood is questionable.     

Transformation of MALT lymphoma to pure plasma cell histology following treatment with the anti-CD20 antibody rituximab

Mucosa associated lymphoid tissue (MALT) lymphoma is a relatively common lymphoma arising from marginal-zone B-cells which are closely related to plasma cells. As opposed to the large majority of plasma cells, MALT lymphoma cells express CD20, and the anti-CD20 antibody rituximab has been reported as active treatment in patients with MALT lymphoma. We present a patient with MALT lymphoma involving stomach and lung which transformed to a pure plasma cell tumor after therapy with rituximab. This observation again supports the close association between the cell of origin of MALT lymphoma and plasma cells, suggesting that “plasmacytoma of the GI-tract” as anecdotally reported may in fact be a MALT lymphoma with extreme plasmacytic differentiation. In addition, our findings suggest that MALT lymphomas with plasmacytic differentiation might have a different 18F-FDG uptake as compared to classical MALT lymphoma.