MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma

Glioblastomas (GBMs) diffusely infiltrate the brain, making complete removal by surgical resection impossible. The mixture of neoplastic and nonneoplastic cells that remain after surgery form the biological context for adjuvant therapeutic intervention and recurrence. We performed RNA-sequencing (RNA-seq) and histological analysis on radiographically guided biopsies taken from different regions of GBM and showed that the tissue contained within the contrast-enhancing (CE) core of tumors have different cellular and molecular compositions compared with tissue from the nonenhancing (NE) margins of tumors. Comparisons with the The Cancer Genome Atlas dataset showed that the samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM, whereas the samples from the NE regions predominantly resembled the neural subtype. Computational deconvolution of the RNA-seq data revealed that contributions from nonneoplastic brain cells significantly influence the expression pattern in the NE samples. Gene ontology analysis showed that the cell type-specific expression patterns were functionally distinct and highly enriched in genes associated with the corresponding cell phenotypes. Comparing the RNA-seq data from the GBM samples to that of nonneoplastic brain revealed that the differentially expressed genes are distributed across multiple cell types. Notably, the patterns of cell type-specific alterations varied between the different GBM subtypes: the NE regions of proneural tumors were enriched in oligodendrocyte progenitor genes, whereas the NE regions of mesenchymal GBM were enriched in astrocytic and microglial genes. These subtype-specific patterns provide new insights into molecular and cellular composition of the infiltrative margins of GBM.Glioma cells diffusely infiltrate the brain and intermingle with neural cells in the surrounding brain tissue, resulting in a complex mixture that includes variable proportions of glioma cells, neurons, and various lineages of reactive or recruited glia. At the infiltrative margins of glioblastoma (GBM), the nonneoplastic brain cells can far outnumber the glioma cells and, therefore, will have a significant effect on the molecular features of the tissue. Expression profiling and whole genome sequencing from hundreds of GBM specimens by The Cancer Genome Atlas (TCGA) has revealed a broad spectrum of genetic alterations and discrete expression signatures or subtypes that stratify the majority of patients (1, 2). These studies analyzed tumor samples that were removed during surgery, but were not radiographically localized and, therefore, do not address the question of how the molecular signature may vary across different regions of a tumor. Recent studies have sampled multiple regions within a GBM and shown that more than one molecular subtype can coexist within a single tumor (3). However, the effect of varying cellular composition on GBM subtype, particularly the contribution of nonneoplastic cells, has not been addressed.GBM typically appears as a contrast-enhancing mass, which represents the highly cellular core of the tumor with vascular proliferation and blood–brain barrier breakdown. This contrast-enhancing (CE) region is typically surrounded by a diffuse, nonenhancing (NE) region of abnormal T2/FLAIR signal, which represents edematous brain tissue with varying numbers of infiltrating glioma cells. The primary treatment of GBM is surgical resection, during which the surgeon removes as much of the CE mass as possible. Thus, molecular and genetic profiling of GBM, including the TCGA effort, has predominantly used samples from the CE regions of tumor. However, it is the NE regions of glioma that are left behind after surgery, which neurooncologists must treat and which inevitably give rise to recurrence. Thus, there is immense prognostic and therapeutic significance to understanding the cellular and molecular features of the NE regions of tumor, yet often these areas are not resected and, therefore, have not been directly studied.There are two major obstacles to this goal. The first is the surgical challenge of radiographically localized sampling of the NE tumor margins. The second is the issue of the complex cellular composition that characterizes these regions of diffuse infiltration. In this study, we have addressed both challenges, and associated distinct molecular and cellular features of the NE regions of GBM with the molecular subtype, as defined by the resected CE regions of the tumor.     

Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re-induction chemotherapy

Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials were used to test the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients. The bone marrow samples were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts. We found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies.     

Pharmacist involvement in clinical assessment and laboratory testing for heparin-induced thrombocytopenia

Journal of Thrombosis and Thrombolysis - Heparin-induced thrombocytopenia (HIT) is a rare adverse drug reaction. The anti-PF4 antibody assay (ELISA) is utilized to assist in the clinical evaluation...     

Epidural catheters are associated with an increased risk of venous thromboembolism in trauma

Journal of Thrombosis and Thrombolysis - Little is known about the association between epidural catheters (EC) and venous thromboembolism (VTE) in trauma. We sought to study this association and...     

The cerebral palsy transition clinic: administrative chore,clinical responsibility,or opportunity for audit and clinical research?

Purpose

The majority of children with orthopaedic conditions in childhood survive to adult life, and there is a need for many of them to transition to adult services. This includes children with disorders such as club foot or developmental dislocation of the hip as well as those with complex syndromic conditions, bone dysplasias or neuromuscular disorders such as cerebral palsy and myelomeningocele. In many tertiary paediatric centres, transition has become a formal process in which clinicians document and communicate the status of patients who have been under their care to ensure a smooth transfer to adult services. The purpose of this report is to support the need for clear communication when children with cerebral palsy transition to adult services and to suggest that this transition represents a significant opportunity for audit and clinical research.

Methods

Some of the factors to be considered in developing a minimum data sheet for the transfer or transition of children with cerebral palsy to adult services are described.

Conclusion

Using the model of adolescents with cerebral palsy transitioning to adult services, orthopaedic surgeons can be encouraged to develop similar methodology and documentation for many other conditions for the purposes of communication, facilitation of transition, audit and clinical research.     

Pathologie odontogener Kieferhöhlenerkrankungen

The differential diagnosis of odontogenic lesions of the maxillary sinus may cause significant problems; however an adequate therapy is based on the correct histopathological diagnosis determining whether the surgical treatment consists of a simple minimally invasive procedure or a complex resection with safety margins and perhaps also lymph node dissection. Only an integrated approach considering all clinical, radiological and histopathological information can allow for an adequate treatment of an individual case. This overview discusses the most relevant entities which can be differentiated by histopathological criteria with respect to their clinical impact.     

Beliefs about abortion risks in women returning to the clinic after their abortions: a pilot study

Background

Misinformation regarding the risks of abortion is prevalent and commonly includes medical inaccuracies about health, depression, infertility and breast cancer. This pilot study sought to assess misinformation among abortion clients as well as the origin(s) of their abortion knowledge.

Study Design

Women who presented to the Mount Sinai School of Medicine Family Planning Division for postabortion follow-up were recruited for participation. Participants completed a researcher-administered survey regarding knowledge and beliefs about abortion.

Results

Sixty-seven women completed the survey between 1/11/10 and 8/6/12. Common sources of abortion information included clinicians (79.1%), Web sites (70.1%), friends (50.7%) and family (40.3%). Over two thirds of women (77.6%) overestimated the health risks, and close to half (43.3%) overestimated the risk of depression after a first trimester abortion.

Conclusions

Misperceptions about the health risks of abortion were prevalent among this sample. Education tools should be developed to provide accurate information about the risks of abortion.