Isocitrate-dehydrogenase-mutant lower grade glioma in elderly patients: treatment and outcome in a molecularly characterized contemporary cohort.

PURPOSE: Lower-grade glioma (LGG) is rare among patients above the age of 60 ("elderly"). Previous studies reported poor outcome, likely due to the inclusion of isocitrate dehydrogenase (IDH) wildtype astrocytomas and advocated defensive surgical and adjuvant treatment. This study set out to question this paradigm analyzing a contemporary cohort of patients with IDH mutant astrocytoma and oligodendroglioma WHO grade 2 and 3. METHODS: Elderly patients treated in our department for a supratentorial, hemispheric LGG between 2009 and 2019 were retrospectively analyzed for patient-, tumor- and treatment-related factors and progression-free survival (PFS) and compared to patients aged under 60. Inclusion required the availability of subtype-defining molecular data and pre- and post-operative tumor volumes. RESULTS: 207 patients were included, among those 21 elderlies (10%). PFS was comparable between elderly and younger patients (46 vs. 54 months; p = 0.634). Oligodendroglioma was more common in the elderly (76% vs. 46%; p = 0.011). Most patients underwent tumor resection (elderly: 81% vs. younger: 91%; p = 0.246) yielding comparable residual tumor volumes (elderly: 7.8 cm3; younger: 4.1 cm3; p = 0.137). Adjuvant treatment was administered in 76% of elderly and 61% of younger patients (p = 0.163). Uni- and multi-variate survival analyses identified a tumor crossing the midline, surgical strategy, and pre- and post-operative tumor volumes as prognostic factors. CONCLUSION: Elderly patients constitute a small fraction of molecularly characterized LGGs. In contrast to previous reports, favorable surgical and survival outcomes were achieved in our series comparable to those of younger patients. Thus, intensified treatment including maximal safe resection should be advocated in elderly patients whenever feasible.

Integrated molecular characterization of IDH-mutant glioblastomas.

AIMS: Mutations of isocitrate dehydrogenase (IDH)1/2 affect almost all astrocytomas of WHO grade II and III. A subset of IDH-mutant astrocytic tumours progresses to IDH-mutant glioblastoma or presents with the histology of a glioblastoma at first presentation. We set out here to assess the molecular spectrum of IDH-mutant glioblastomas. METHODS: We performed an integrated molecular analysis of a mono-centric cohort (n = 97); assessed through genome-wide DNA methylation analysis, copy-number profiling and targeted next generation sequencing using a neurooncology-tailored gene panel. RESULTS: Of these 97 IDH-mutant glioblastomas, 68 had a glioblastoma at first presentation ('de novo' IDH-mutant glioblastoma) and 29 emerged from a prior low-grade lesion ('evolved' IDH-mutant glioblastoma). Unsupervised hierarchical clustering of DNA methylation data disclosed that IDH-mutant glioblastoma ('de novo' and 'evolved') formed a distinct group separate from other diffuse glioma subtypes. Homozygous deletions of CDKN2A/B were found to be associated with shorter survival. CONCLUSIONS: This study demonstrates DNA methylation patterns in IDH-mutant glioblastoma to be distinct from lower-grade astrocytic counterparts but homogeneous within de novo and evolved IDH-mutant glioblastomas, and identifies CDKN2A as a marker for possible genetic sub-stratification.

WHO 2016 classification: changes and advancements in the diagnosis of miscellaneous primary CNS tumours.

This short review highlights significant changes and recent findings incorporated to varying extent in the WHO 2016 definition of a variety of tumours, including peripheral nerve sheath tumours, meningiomas, mesenchymal nonmeningothelial tumours, melanocytic tumours, lymphomas and histiocytic tumours, germ cell tumours and non-neuroendocrine pituitary tumours. Most notable classification changes include: adding 'hybrid nerve sheath tumours' to the spectrum of benign nerve sheath tumours; an updated definition of atypical meningioma (WHO grade II), including cases with brain invasion; recognizing dural solitary fibrous tumour (SFT) and haemangiopericytoma (HPC) as a single tumour entity characterized by NAB2 and STAT6 gene fusions for which the term SFT/HPC was chosen; recognizing that pituitary granular cell tumour, spindle cell oncocytoma, and pituicytoma all share nuclear expression of TTF-1, possibly representing a spectrum of a single nosological entity derived from posterior pituitary glial cells. The most significant diagnostic markers which have emerged include: inactivation of NF1, CDKN2A, and PRC2 components, SUZ12 and EED in MPNST, leading to neurofibromin and H3K27me3 expression loss; GNAQ and GNA11 mutations in CNS primary melanocytic tumours; BRAFV600E mutation in histiocytic tumours (Langerhans cell histiocytosis and Erdheim-Chester disease) and papillary craniopharyngioma, which provides both a diagnostic marker in the appropriate pathological setting and a therapeutic target. The WHO 2016 Classification has balanced cutting-edge knowledge on the molecular characteristics of the miscellaneous CNS tumours reviewed here with a practical approach for their daily diagnostic work-up. Much more progress can be expected in the classification of these neoplasms in the near future.

Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma.

Background: Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy. Patients and methods: We used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.D579del) as potentially druggable target in this patient and carried out cancer hotspot panel sequencing to detect secondary resistance-conferring mutations in KIT. Furthermore, as a step towards clinical exploitation of the recently described signatures of mutational processes in cancer genomes, we established and applied a novel bioinformatics algorithm that enables supervised analysis of the mutational catalogs of individual tumors. Results: Molecularly guided treatment with imatinib in analogy to the management of gastrointestinal stromal tumor (GIST) resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. KIT dependency was further validated by a secondary KIT exon 17 mutation (c.2459_2462delATTCinsG, p.D820_S821delinsG) that was detected upon tumor progression after 10 months of imatinib treatment and provided a rationale for salvage therapy with regorafenib, which has activity against KIT exon 11/17 mutant GIST. Conclusions: These observations highlight the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscore that KIT exon 11 mutations represent tractable therapeutic targets across different histologies.

BRAF V600E expression and distribution in desmoplastic infantile astrocytoma/ganglioglioma.

AIMS: Desmoplastic infantile astrocytoma/ganglioglioma (DIA/DIG) is a rare primary neuroepithelial brain tumour typically affecting paediatric patients younger than 24 months. Knowledge about genetic alterations in DIA/DIG is limited. However, a previous study on BRAF V600E mutation in paediatric glioma revealed a BRAF mutation in one of two tested DIAs/DIGs. The limited number of cases in that study did not allow any conclusion about mutation frequency of BRAF in this tumour entity. METHODS: We collected a series of 18 DIAs/DIGs for testing BRAF V600E mutational status by BRAF V600E immunohistochemistry (clone VE1). Cases with sufficient DNA were tested for BRAF V600E mutation by pyrosequencing. RESULTS: Three out of 18 DIAs/DIGs presented with VE1 binding. A considerable proportion of BRAF V600E mutated tumour cells was detected in the cortical tumour component, whereas the pronounced leptomeningeal tumoural stroma was predominantly negative for VE1 binding. Pyrosequencing confirmed BRAF V600E mutation in two of three VE1-positive cases. CONCLUSION: BRAF V600E mutation affects a subset of DIAs/DIGs and offers new therapeutic opportunities.

TRAIL-mediated apoptosis in malignant glioma cells is augmented by celecoxib through proteasomal degradation of survivin.

Celecoxib is a cyclooxygenase 2-selective nonsteroidal anti-inflammatory drug (NSAID) that exhibited therapeutic activity in cancer. In this study three malignant glioma, U87-MG, U251 and A172, were treated with celecoxib, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of both. Single treatment with celecoxib (25-100muM) for 24h resulted in a concentration-dependant decrease of cellular viability in U87-MG, U251 and A172. Combining subtoxic concentrations of celecoxib with TRAIL strongly increased cell death in human malignant glioma cells. After 8h treatment with celecoxib we found down-regulation of the inhibitor of apoptosis protein survivin that was mediated by proteasomal degradation. In addition, over-expression of survivin not only attenuated celecoxib-induced cytotoxicity but also cytotoxicity induced by the combination of celecoxib and TRAIL. Taken together, in malignant glioma survivin is a key regulator in celecoxib- and TRAIL-celecoxib-mediated cell death.

Biomarkers for malignant peripheral nerve sheath tumours.

BACKGROUND: Malignant peripheral nerve sheath tumour (MPNST) is a highly aggressive soft tissue sarcoma affecting predominantly patients with neurofibromatosis type I. The appearance of MPNST varies considerably and discrimination from other high-grade soft tissue tumours as well as cellular variants of benign nerve sheath tumours may be difficult. Therefore, there is great interest in defining biological markers for MPNST. OBJECTIVE: This review summarises research on the pathogenesis and progress in diagnostics of MPNST. METHODS: The literature on MPNST focusing on pathogenesis and potential biomarkers was reviewed. CONCLUSION: Recent molecular analyses contributed significantly to our understanding of MPNST. Candidate markers and expression signatures await further validation for their feasibility in guiding diagnostic and therapeutic decisions.

Methylation analysis of the neurofibromatosis type 1 (NF1) promoter in peripheral nerve sheath tumours.

Peripheral nerve sheath tumours are hallmarks of neurofibromatosis type 1 (NF1). Development of plexiform neurofibromas to malignant peripheral nerve sheath tumours (MPNST) is common. The NF1 gene promoter harbours a hypomethylated CpG island. Thus, methylation changes may be involved in the development of different types of neurofibromas and malignant transformation. We investigated NF1-associated dermal (n=9) and plexiform neurofibromas (n=7), MPNST (n=5) and non-NF1 leucocyte samples (n=20) for their methylation pattern by bisulphite genomic sequencing. We could not find global hypermethylation in the NF1 promoter in our series. Nevertheless, site-specific methylation, involving transcription factor binding sites for SP1, CRE (-10), and AP-2, was observed. One region of the 5'-UTR (untranslated region) overlapping with a putative AP-2 binding site was methylated at 30-100% in 4/20 control samples. In conclusion, we did not find hypermethylation in NF1-associated tumours. Instead, low level methylation could parallel a global genomic hypomethylation in malignancy.

Will quality management paradigms of the 1990s survive into the next century?

This article offers four views of the future importance of quality management. First, a pathologist author describes current controversies surrounding the viability of established schools of practice. A vice president at the Joint Commission on Accreditation of Healthcare Organizations outlines the continued need for some form of total quality management and continuous quality improvement from the accreditation stance. A laboratory director from a university medical center discusses the economic changes that are fueling the continued emphasis on quality management. And, a laboratory manager from a community hospital focuses on the impact of quality management, pointing out what is required for quality management to be successful at the operational level in a laboratory. These four independent view-points reveal a clear consensus that the practice of quality management will continue to be important in our laboratories into the 21st century.

Effects of dexamethasone on chemotactic activity and inflammatory mediators in tracheobronchial aspirates of preterm infants at risk for chronic lung disease.

To evaluate the effects of dexamethasone on pulmonary inflammation and permeability in preterm infants at high risk for chronic lung disease (birth weight < 1200 gm), we assessed tracheobronchial aspirate fluid for chemotactic activity and concentrations of mediators of inflammation. In a prospective study, 21 infants still undergoing mechanical ventilation at day 10 of postnatal age who required a fraction of inspired oxygen > or = 0.3, a peak inspiratory pressure > or = 16 cm H2O, or both were randomly assigned to treatment with dexamethasone at day 10 (early treatment group, n = 10) or day 16 (late treatment group, n = 11). The groups were compared with respect to all measurements on day 15; the late treatment group served as a control group. Additionally, the effects of dexamethasone within both groups were evaluated. In the early treatment group, the chemotactic response of peripheral blood neutrophils exposed to tracheobronchial aspirate fluid was significantly reduced 5 days after initiation of dexamethasone treatment compared with pretreatment values of the late treatment group (median (25th to 75th percentile): migratory distance before dexamethasone, 149 microns (140 to 173 microns); after dexamethasone, 81 microns (68 to 114 microns); p < 0.01). In addition, the following values were decreased after dexamethasone therapy in the early treatment group: number of neutrophils in tracheobronchial aspirate fluid (p < 0.05), and concentrations of leukotriene B4 (p < 0.01), interleukin-1 (p < 0.01), elastase-alpha 1-proteinase inhibitor (p < 0.01), and albumin (p < 0.01). Free elastase activity was found in only two infants; detectable activity of protective alpha 1-proteinase inhibitor was present in the others. Analysis of dexamethasone effects within the groups showed that all measurements were significantly decreased after both the early and the late treatment regimens, with the exception of leukotriene B4 and interleukin-1, which declined only after early dexamethasone treatment. Our results indicate that the pulmonary inflammatory response and microvascular permeability are decreased by dexamethasone, which affects the release of inflammatory mediators and neutrophil influx into the airways of preterm infants who require mechanical ventilation.

Interferometric temperature measurements of a flame in a cylindrical tube using holography.

Double-exposure holographic interferometry was used to determine, at one instant, the entire temperature distribution of an axisymmetric flame propagating through a 51-mm i.d. cylindrical tube. The algorithm used to reconstruct the 2-D temperature distribution included a numerical form of the Abel inversion and a ray-tracing routine to correct for light-ray refraction by the quartz tube. Errors due to flame refraction were minimized by observing the interferogram in the image of the tube center line. The precision of the technique was determined by comparing radial temperature distributions from five separate experiments. The sources of the imprecision and inaccuracies observed in the data are discussed.

Effects of refraction on axisymmetric flame temperatures measured by holographic interferometry.

Neglect of refraction can produce errors when temperature distributions in axisymmetric flames are reconstructed by Abel inversion of interferometric fringe data. This study quantifies these errors and their reduction by imaging during interferogram readout. Rays were traced through analytic temperature distributions characteristic of real flames at different equivalence ratios to determine the fringe patterns that would be observed interferometrically with and without imaging. The Abel inversion was applied to each computed fringe pattern to reconstruct the temperature distribution. Reconstructed and analytic distributions were compared to determine the error caused by using the Abel inversion. Our results indicate that proper imaging will generally be necessary to reduce reconstruction errors to below 5% in real axisymmetric flames.