A machine learning analysis of a "normal-like" IDH-WT diffuse glioma transcriptomic subgroup associated with prolonged survival reveals novel immune and neurotransmitter-related actionable targets.

BACKGROUND: Classification of primary central nervous system tumors according to the World Health Organization guidelines follows the integration of histologic interpretation with molecular information and aims at providing the most precise prognosis and optimal patient management. According to the cIMPACT-NOW update 3, diffuse isocitrate dehydrogenase-wild type (IDH-WT) gliomas should be graded as grade IV glioblastomas (GBM) if they possess one or more of the following molecular markers that predict aggressive clinical course: EGFR amplification, TERT promoter mutation, and whole-chromosome 7 gain combined with chromosome 10 loss. METHODS: The Cancer Genome Atlas (TCGA) glioma expression datasets were reanalyzed in order to identify novel tumor subcategories which would be considered as GBM-equivalents with the current diagnostic algorithm. Unsupervised clustering allowed the identification of previously unrecognized transcriptomic subcategories. A supervised machine learning algorithm (k-nearest neighbor model) was also used to identify gene signatures specific to some of these subcategories. RESULTS: We identified 14 IDH-WT infiltrating gliomas displaying a "normal-like" (NL) transcriptomic profile associated with a longer survival. Genes such as C5AR1 (complement receptor), SLC32A1 (vesicular gamma-aminobutyric acid transporter), MSR1 (or CD204, scavenger receptor A), and SYT5 (synaptotagmin 5) were differentially expressed and comprised in gene signatures specific to NL IDH-WT gliomas which were validated further using the Chinese Glioma Genome Atlas datasets. These gene signatures showed high discriminative power and correlation with survival. CONCLUSION: NL IDH-WT gliomas represent an infiltrating glioma subcategory with a superior prognosis which can only be detected using genome-wide analysis. Differential expression of genes potentially involved in immune checkpoint and amino acid signaling pathways is providing insight into mechanisms of gliomagenesis and could pave the way to novel treatment targets for infiltrating gliomas.

The posterior cervical transdural approach for retro-odontoid mass pseudotumor resection: report of three cases and discussion of the current literature.

OBJECTIVE: The treatment of a retro-odontoid pseudotumor mass associated with severe spinal cord compression is challenging due to the complex regional anatomy. Here, we present an attractive treatment option involving a single-stage posterior transdural microsurgical resection followed by instrumented cervical reconstruction. METHODS: We describe three patients presenting with clinical signs of cervical myelopathy and an imaging finding of mucoid and fibrous soft or semi-soft retro-odontoid pseudotumor mass with significant spinal cord compression at the C1/C2 level. Given the severity of the symptoms, surgical decompression was planned and fusion was necessitated by the severe degenerative osteoarthritis seen at the C1/C2 level with signs of instability. Using a standard posterior approach to the spine, a suboccipital decompression by craniectomy and laminectomy of C1, C2 and C3 was performed. The masses were visualized and confirmed with ultrasound imaging, and intraoperative neurosurgical monitoring was applied. The dura was then opened from the level of C0-C2. Exiting C2-C3 nerve roots were identified and protected throughout the procedure, and the dentate ligament was cut to facilitate access. Incision of the anterior dura provided easy access to the lesion for resection without any spinal cord retraction. Multiple intraoperative samples were sent to pathology for tissue diagnosis. The dura was closed with sutures and an overlay of fibrin sealant with collagen matrix sponge. The fusion procedures were performed using a standard occipital cervical plate and screws technique with contoured titanium rods. CONCLUSIONS: The posterior cervical transdural approach is a safe alternative procedure for mucoid and fibrous soft or semi-soft retro-odontoid pseudotumor mass removal. Preoperative CT scan can evaluate tissue characteristics and distinguish between a soft or ossified mass in front of the spinal cord. Local anatomical conditions facilitate less bleeding and adhesions, together with less spinal cord traction, in the intradural space. Cranio-cervical and suboccipital stabilization can be easily and safely performed with this exposure.

Focal Leptomeningeal Disease with Perivascular Invasion in EGFR-Mutant Non-Small-Cell Lung Cancer.

We report a previously undescribed pattern of brain metastases in patients with epidermal growth factor receptor-mutated non-small-cell lung cancer treated with tyrosine kinase inhibitors and radiation therapy. These highly distinct lesions appear to spread focally within the leptomeninges, with invasion along the perivascular spaces (FLIP). The survival of patients with FLIP was significantly better compared with patients with classic leptomeningeal disease (median survival, 21 versus 3 months; P = .003). It is unclear whether this pattern of growth is unique to epidermal growth factor receptor-mutated non-small-cell lung cancer.

Echocardiograms during six hours of bedrest at head-down and head-up tilt and during space flight.

Left ventricular end-diastolic volume increased after 4 1/2 to 6 hours of space flight, but was significantly decreased after 5 to 6 days of space flight. To determine the role of acute gravitational effects in this phenomenon, responses to a 6-hour bedrest model of 0 gravity (G; 5 degrees head-down tilt) were compared with those of fractional gravity loads of 1/6 G, 1/3 G, and 2/3 G by using head-up tilts of 10 degrees, 20 degrees, and 42 degrees, respectively. On 4 different days, six healthy male subjects were tilted at one of the four angles for 6 hours. Cardiac dimensions and volumes were determined from two-dimensional and M-mode echocardiograms in the left lateral decubitus position at control (0), 2, 4, and 6 hours. Stroke volume decreased with time (P < .05) for all tilt angles when compared with control. Ejection fraction (EF) at -5 degrees was greater than at +20 degrees and +42 degrees (not significant); EF at +10 degrees was greater than at +42 degrees (not significant). For the tilt angles of -5 degrees, +10 degrees, and +20 degrees, mean heart rate decreased during the first 2 hours, and returned to control or was slightly elevated above control (+20 degrees) by 6 hours (not significant). At the +42 degrees angle of tilt, heart rate was increased above control at hours 2, 4, and 6. There were no significant differences in cardiac output at any time point for any tilt angle.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and intermediate cardiovascular responses to zero gravity and to fractional gravity levels induced by head-down or head-up tilt.

Determination of early cardiovascular responses to simulated gravity levels between 0 and 1 G will add knowledge of cardiovascular responses to space flight. Cardiovascular responses to 6 hours in a -5 degrees head-down bedrest model of weightlessness (0 G) were compared to those in head-up tilts of +10 degrees, +20 degrees, and +42 degrees (1/6, 1/3, and 2/3 G, respectively). Six healthy young adult males experienced the four angles on separate days. Impedance cardiography was used to measure thoracic fluid index, cardiac output, stroke volume, and peak flow. Although much intersubject variation occurred, the mean thoracic fluid content at -5 degrees decreased during the first hour and remained decreased; 6-hour values were similar to +10 degrees and +20 degrees. Heart rate decreased the first 2 hours for all angles, then increased, converging at 3-4 hours, and reached control by hour 6. Stroke volume decreased for the first 3 hours at -5 degrees, +10 degrees, +20 degrees; values at all four angles converged at hour 3 and increased in unison thereafter. Cardiac output and peak aortic flow reflected the angle at start of tilt; values at all angles converged by the second hour, decreased through the third hour, and increased thereafter. Pulse pressure decreased for the first 3 hours for angles -5 degrees, +10 degrees, and +20 degrees, converged at the fourth hour, and returned to control. Peak flow at +42 degrees was constant for the first 3 hours and increased thereafter. Blood pressure decreased for the first 2 hours, although the greatest decrease occurred at -5 degrees and +42 degrees; thereafter, values at all angles increased in unison and converged at the fourth hour. Total peripheral resistance increased during the first hour at -5 degrees and +20 degrees and decreased from hour 3 to hours 5-6 at the +42 degrees angle. Cardiovascular values were related to tilt angle for the first 2 hours of tilt, but after hour 3 values at all four angles began to converge, suggesting that cardiovascular homeostatic mechanisms seek a common adapted state regardless of effective gravity level (tilt angle) up to 2/3 G.

Orthostatic function during a stand test before and after head-up or head-down bedrest.

Astronauts may exhibit orthostatic dysfunction upon returning to 1 g after space flight. Understanding cardiovascular changes at 0 G will provide insights into the mechanisms of the loss of orthostatic tolerance, whether due to space flight or bedrest. Bedrest is one model used to produce cardiovascular changes that are associated with space flight. In the current study, young male adults were placed at -5 degrees, +10, +20, or +42 degrees bedrest (0, 1/6, 1/3, and 2/3g, respectively) for 6 hours on 4 different days. This was preceded and followed by a stand test: 5 minutes in the supine position, and then 5 minutes in the standing position, with the feet 9 inches apart and 6 inches from the wall. Cardiovascular values were measured at 1-minute intervals. Systolic and diastolic pressures were measured using an automated blood pressure device; mean arterial pressure (MAP; mm Hg) was calculated. Heart rate (bpm) and cardiac parameters were measured with a thoracic impedance device. Minute 3, 4, and 5 values were used to determine whether there were time or angle effects. Of six subjects, one reported nausea upon 3 minutes of standing after 6 hours of bedrest at -5 degrees. The same subject was lightheaded in the first minute of standing after 6 hours of bedrest at +10 degrees. Mean heart rate pre-bedrest in the supine position was 63 and increased by 24 bpm on standing. Heart rate post-bedrest in the supine position was 65 and increased by 35 bpm on standing; standing heart rate increased 11 bpm after -5 degrees bedrest. The increases after +10 degrees, +20 degrees, and +42 degrees tilts were 4, 3, and 4 bpm, respectively. Changes in the mean arterial blood pressure were minimal. Results from the stand test pre- and post- 6 hours of bedrest at -5 degrees but not at +10 degrees, +20 degrees, or +42 degrees are similar to those after space flight.

Immunofluorometric quantitation and histochemical localisation of kallikrein 6 protein in ovarian cancer tissue: a new independent unfavourable prognostic biomarker.

Human kallikrein 6 protein is a newly discovered human kallikrein. We determined the amount of human kallikrein 6 in extracts of 182 ovarian tumours and correlated specific activity (ng hK6 mg(-1) total protein) with clinicopathological variables documented at the time of surgical excision and with outcome (progression free survival, overall survival) monitored over a median interval of 62 months. Thirty per cent of the tumours were positive for human kallikrein 6 (>35 ng hK6 mg(-1) total protein). Human kallikrein 6-specific immunohistochemical staining of four ovarian tissues that included benign, borderline and malignant lesions indicated a cytoplasmic location of human kallikrein 6 in tumour cells of epithelial origin, although the intensity of staining was variable. Tumour human kallikrein 6 (ng hK6 mg(-1) total protein) was higher in late stage disease, serous histotype, residual tumour >1 cm and suboptimal debulking (>1 cm) (P<0.05). Univariate analysis revealed that patients with tumour human kallikrein 6 positive specific activity were more likely to suffer progressive disease and to die (hazard ratio 1.71 (P=0.015) and 1.88 (P=0.022), respectively). Survival curves demonstrated the same (P=0.013 and 0.019, respectively). Multivariate analysis revealed that human kallikrein 6 positivity was retained as an independent prognostic variable in several subgroups of patients, namely those with (low) grade I and II tumours (hazard ratio progression free survival 4.3 (P=0.027) and overall survival 4.1 (P=0.023)) and those with optimal debulking (hazard ratio progression free survival 3.8 (P=0.019) and overall survival 5.6 (P=0.011)). We conclude that tumour kallikrein 6 protein levels have utility as an independent adverse prognostic marker in a subgroup of ovarian cancer patients with otherwise apparently good prognosis.