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A practical and succinct guide to neurophysiological monitoring for safer brain tumor surgery The surgical treatment of infiltrating brain tumors is an extremely challenging and often highly rewarding facet of neurosurgery. The decision-making process involves deeply human interconnections with patients and relatives, cutting-edge neuroscience, and fascinating technology. Video Atlas of Neurophysiological Monitoring in Surgery of Infiltrating Brain Tumors by renowned oncological neurosurgeon Michael Sabel and esteemed contributors demonstrates the practical applications of neurophysiological monitoring to achieve safe removal of infiltrating brain tumors in asleep and awake settings. Organized in three primary parts, the book starts with an introduction including a discussion of the impact and challenges posed by infiltrating gliomas and cerebral metastases and the philosophy behind supramarginal resection. The second part covers critical theoretical components including relevant anatomy, nervous system electricity and fields, transcranial monitoring methods and principles, and direct cortical and subcortical mapping including awake brain surgery. The final part provides insightful, practical guidance on decision making, monitoring set-up, planning of surgical cases, and a summary of accompanying videos. Key Highlights * Discussion of impacted anatomy, physiology of the neural pathways monitored in brain tumor surgery, and key neurophysiological techniques for monitoring and testing during resection * Instructive illustrations coupled with concise explanations enhance knowledge and facilitate understanding of techniques * Fifteen videos covering real-life intraoperative cases provide in-depth insights on applying IONM principles to infiltrating brain tumors This is an essential resource for any neurosurgeon involved or interested in brain tumor surgery, from residents and fellows to board-certified neurosurgeons not yet trained in this field.

A fundamental question in cancer biology is whether cells with tumorigenic potential are common or rare within human cancers. Studies on diverse cancers, including melanoma, have indicated that only rare human cancer cells (0.1–0.0001%) form tumours when transplanted into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. However, the extent to which NOD/SCID mice underestimate the frequency of tumorigenic human cancer cells has been uncertain. Here we show that modified xenotransplantation assay conditions, including the use of more highly immunocompromised NOD/SCID interleukin-2 receptor gamma chain null ( Il2rg -/- ) mice, can increase the detection of tumorigenic melanoma cells by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients, including cells from primary and metastatic melanomas obtained directly from patients, formed tumours under these more permissive conditions. In single-cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumours. Modifications to xenotransplantation assays can therefore dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers. Tumorigenic potential: A common attribute of human melanoma cells Cancer stem cells in human tumours have been defined in functional experiments as cells that are tumorigenic and self-renew when transplanted into immunocompromised mice. It has been shown for a number of tumour types that such cells are relatively rare. This has informed some approaches to therapy based on a 'cancer stem cell model', which targets these stem cells, rather than a whole tumour or cell population. New work suggests that for human melanomas at least, the cancer stem cell model may not apply. Rather, tumorigenic potential is a common attribute of melanoma cells. The experiments took melanoma cells from twelve patients, and using a xenotransplantation assay, found that about a quarter of the melanoma cells were tumour producing in mice. This suggests that a broad spectrum of cancer cells has the potential to contribute to tumour progression, and raises doubts over therapies specifically directed against small 'cancer stem cell' populations. The cover image depicts melanoma cells and tumours formed from such cells. Cancer stem cells in human tumours have been defined as cells that are tumourigenic and self-renew when transplanted into immunocompromised mice. It has been shown in a number of tumour types that such cancer stem cells exist at relatively low frequencies. This paper now shows that in human melanomas at least, there is a high proportion of tumourigenic cells when the conditions for such transplanation experiments are modified, casting doubt on the generality of the cancer stem cell model.

Background Several hypotheses proposed to explain the worse prognosis for older melanoma patients include different tumor biology and diminished host response. If the latter were true, then biologic frailty, and not age, should be an independent prognostic factor in melanoma. Methods Our prospective institutional review board (IRB)-approved database was queried for stage III patients with computed tomography (CT) scans at time of lymph node dissection (LND). Psoas area (PA) and density (PD) were determined in semi-automated fashion. Kaplan–Meier (K–M) survival estimates and Cox proportional-hazard models were used to determine PA and PD impact on survival and surgical complications. Results Among 101 stage III patients, PD was significantly associated with both disease-free survival (DFS) ( P  = 0.04) and distant disease-free survival (DDFS) ( P  = 0.0002). Cox multivariate modeling incorporating thickness, age, ulceration, and N stage showed highly significant association with PD and both DFS and DDFS. DDFS was significantly associated with Breslow thickness ( P  = 0.04), number of positive nodes ( P  = 0.001), ulceration ( P  = 0.04), and decreasing muscle density ( P  = 0.01), with hazard ratio of 0.55 [95% confidence interval (CI) 0.35–0.87]. PD also correlated with surgical complications, with odds ratio (OR) of 1.081 [95% CI 1.016–1.150, P  = 0.01]. Conclusions Decreased psoas muscle density on CT, an objective measure of frailty, was as important a predictor of outcome as tumor factors in a cohort of stage III melanoma patients. On multivariate analysis, frailty, not age, was associated with decreased disease-free survival and distant disease-free survival, and higher rate of surgical complications.

Breast cancer is the second-leading cause of cancer-related deaths in women, but the details of how it begins remain elusive. Increasing evidence supports the association of aggressive triple-negative (TN) breast cancer with heightened expression of the Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2) and increased tumor-initiating cells (TICs). However, mechanistic links between EZH2 and TICs are unclear, and direct demonstration of a tumorigenic function of EZH2 in vivo is lacking. Here, we identify an unrecognized EZH2/NOTCH1 axis that controls breast TICs in TN breast carcinomas. EZH2 overexpression increases NOTCH1 expression and signaling, and inhibition of NOTCH1 activity prevents EZH2-mediated stem cell expansion in nontumorigenic breast cells. We uncover a unique role of EZH2 in activating, rather than repressing, NOTCH1 signaling through binding to the NOTCH1 promoter in TN breast cancer cells. EZH2 binding is independent of its catalytic histone H3 lysine 27 methyltransferase activity and of the Polycomb Repressive Complex 2 but corresponds instead to transcriptional activation marks. In vivo, EZH2 knockdown decreases the onset and volume of xenografts derived from TN breast TICs. Conversely, transgenic EZH2 overexpression accelerates mammary tumor initiation and increases NOTCH1 activation in mouse mammary tumor virus-neu mice. Consonant with these findings, in clinical samples, high levels of EZH2 are significantly associated with activated NOTCH1 protein and increased TICs in TN invasive carcinomas. These data reveal a functional and mechanistic link between EZH2 levels, NOTCH1 signaling activation, and TICs, and provide previously unidentified evidence that EZH2 enhances breast cancer initiation.

Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m2 temozolomide, given on days 1–7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6–7 weeks in 30 fractions of 1·8–2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3–10·2) in the temozolomide group versus 9·6 months (8·2–10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84–1·42, pnon-inferiority=0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2–4·1] vs 4·7 [4·2–5·2]; HR 1·15, 95% CI 0·92–1·43, pnon-inferiority=0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0–10·0]; HR 0·62, 95% CI 0·42–0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5–11·7] vs 4·6 [4·2–5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0–3·5] vs 4·6 months [3·7–6·3]). The most frequent grade 3–4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. Merck Sharp & Dohme.

This report identifies oncogenic fusions in individuals with breast cancer involving the genes encoding NOTCH and MAST, recurring in approximately 5–7% of studied cases. The fusions show growth-promoting properties that suggest that they may represent targetable events in a subset of people with breast cancer. Breast cancer is a heterogeneous disease that has a wide range of molecular aberrations and clinical outcomes. Here we used paired-end transcriptome sequencing to explore the landscape of gene fusions in a panel of breast cancer cell lines and tissues. We observed that individual breast cancers have a variety of expressed gene fusions. We identified two classes of recurrent gene rearrangements involving genes encoding microtubule-associated serine-threonine kinase (MAST) and members of the Notch family. Both MAST and Notch-family gene fusions have substantial phenotypic effects in breast epithelial cells. Breast cancer cell lines harboring Notch gene rearrangements are uniquely sensitive to inhibition of Notch signaling, and overexpression of MAST1 or MAST2 gene fusions has a proliferative effect both in vitro and in vivo. These findings show that recurrent gene rearrangements have key roles in subsets of carcinomas and suggest that transcriptome sequencing could identify individuals with rare, targetable gene fusions.

Background Excessive opioid prescribing is common in surgical oncology, with 72% of prescribed opioids going unused after curative-intent surgery. In this study, we sought to reduce opioid prescribing after breast and melanoma procedures by designing and implementing an intervention focused on education and prescribing guidelines, and then evaluating the impact of this intervention. Methods In this single-institution study, we designed and implemented an intervention targeting key factors identified in qualitative interviews. This included mandatory education for prescribers, evidence-based prescribing guidelines, and standardized patient instructions. After the intervention, interrupted time-series analysis was used to compare the mean quantity of opioid prescribed before and after the intervention (July 2016–September 2017). We also evaluated the frequency of opioid prescription refills. Results During the study, 847 patients underwent breast or melanoma procedures and received an opioid prescription. For mastectomy or wide local excision for melanoma, the mean quantity of opioid prescribed immediately decreased by 37% after the intervention ( p  = 0.03), equivalent to 13 tablets of oxycodone 5 mg. For lumpectomy or breast biopsy, the mean quantity of opioid prescribed decreased by 42%, or 12 tablets of oxycodone 5 mg ( p  = 0.07). Furthermore, opioid prescription refills did not significantly change for mastectomy/wide local excision (13% vs. 14%, p  = 0.8), or lumpectomy/breast biopsy (4% vs. 5%, p  = 0.7). Conclusion Education and prescribing guidelines reduced opioid prescribing for breast and melanoma procedures without increasing the need for refills. This suggests further reductions in opioid prescribing may be possible, and provides rationale for implementing similar interventions for other procedures and practice settings.

Purpose Multimodal therapies have significantly improved prognosis in glioma. However, in particular radiotherapy may induce long-term neurotoxicity compromising patients’ neurocognition and quality of life. The present prospective multicenter study aimed to evaluate associations of multimodal treatment with neurocognition with a particular focus on hippocampal irradiation. Methods Seventy-one glioma patients (WHO grade 1–4) were serially evaluated with neurocognitive testing and quality of life questionnaires. Prior to (baseline) and following further treatment (median 7.1 years [range 4.6–11.0] after baseline) a standardized computerized neurocognitive test battery (NeuroCog FX) was applied to gauge psychomotor speed and inhibition, verbal short-term memory, working memory, verbal and non-verbal memory as well as verbal fluency. Mean ipsilateral hippocampal radiation dose was determined in a subgroup of 27 patients who received radiotherapy according to radiotherapy plans to evaluate its association with neurocognition. Results Between baseline and follow-up mean performance in none of the cognitive domains significantly declined in any treatment modality (radiotherapy, chemotherapy, combined radio-chemotherapy, watchful-waiting), except for selective attention in patients receiving chemotherapy alone. Apart from one subtest (inhibition), mean ipsilateral hippocampal radiation dose > 50 Gy (Dmean) as compared to < 10 Gy showed no associations with long-term cognitive functioning. However, patients with Dmean < 10 Gy showed stable or improved performance in all cognitive domains, while patients with > 50 Gy numerically deteriorated in 4/8 domains. Conclusions Multimodal glioma therapy seems to affect neurocognition less than generally assumed. Even patients with unilateral hippocampal irradiation with > 50 Gy showed no profound cognitive decline in this series.

Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) mutation, 1p/19q co-deletion and telomerase reverse transcriptase ( TERT ) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (−10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/−10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.