Deep-Learning Convolutional Neural Networks Accurately Classify Genetic Mutations in Gliomas.

BACKGROUND AND PURPOSE: The World Health Organization has recently placed new emphasis on the integration of genetic information for gliomas. While tissue sampling remains the criterion standard, noninvasive imaging techniques may provide complimentary insight into clinically relevant genetic mutations. Our aim was to train a convolutional neural network to independently predict underlying molecular genetic mutation status in gliomas with high accuracy and identify the most predictive imaging features for each mutation. MATERIALS AND METHODS: MR imaging data and molecular information were retrospectively obtained from The Cancer Imaging Archives for 259 patients with either low- or high-grade gliomas. A convolutional neural network was trained to classify isocitrate dehydrogenase 1 (IDH1) mutation status, 1p/19q codeletion, and O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status. Principal component analysis of the final convolutional neural network layer was used to extract the key imaging features critical for successful classification. RESULTS: Classification had high accuracy: IDH1 mutation status, 94%; 1p/19q codeletion, 92%; and MGMT promotor methylation status, 83%. Each genetic category was also associated with distinctive imaging features such as definition of tumor margins, T1 and FLAIR suppression, extent of edema, extent of necrosis, and textural features. CONCLUSIONS: Our results indicate that for The Cancer Imaging Archives dataset, machine-learning approaches allow classification of individual genetic mutations of both low- and high-grade gliomas. We show that relevant MR imaging features acquired from an added dimensionality-reduction technique demonstrate that neural networks are capable of learning key imaging components without prior feature selection or human-directed training.

TRIM11 is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth.

TRIM11 (tripartite motif-containing protein 11), an E3 ubiquitin ligase, is known to be involved in the development of the central nervous system. However, very little is known regarding the role of TRIM11 in cancer biology. Here, we examined the expression profile of TRIM11, along with two stem cell markers CD133 and nestin, in multiple glioma patient specimens, glioma primary cultures derived from tumors taken at surgery and normal neural stem/progenitor cells (NSCs). The oncogenic function of TRIM11 in glioma biology was investigated by knockdown and/or overexpression in vitro and in vivo experiments. Our results showed that TRIM11 expression levels were upregulated in malignant glioma specimens and in high-grade glioma-derived primary cultures, whereas remaining low in glioblastoma multiforme (GBM) stable cell lines, low-grade glioma-derived primary cultures and NSCs. The expression pattern of TRIM11 strongly correlated with that of CD133 and nestin and differentiation status of malignant glioma cells. Knock down of TRIM11 inhibited proliferation, migration and invasion of GBM cells, significantly decreased epidermal growth factor receptor (EGFR) levels and mitogen-activated protein kinase activity, and downregulated HB-EGF (heparin-binding EGF-like growth factor) mRNA levels. Meanwhile, TRIM11 overexpression promoted a stem-like phenotype in vitro (tumorsphere formation) and enhanced glial tumor growth in immunocompromised mice. These findings suggest that TRIM11 might be an indicator of glioma malignancy and has an oncogenic function mediated through the EGFR signaling pathway. TRIM11 overexpression potentially leads to a more aggressive glioma phenotype, along with increased malignant tumor growth and poor survival. Taken together, clarification of the biological function of TRIM11 and pathways it affects may provide novel therapeutic strategies for treating malignant glioma patients.

SU-E-J-108: Quantitative Analysis of Longitudinal Cognitive Impairment Due to Radiation Therapy Based on Automatic Segmentation of Hippocampus and Subcortical Structure.

PURPOSE: In this study, we developed a quantitative analysis tool based on patient's longitudinal MR images to 1) measure the radiation dose received by each subcortical structure, 2) follow the change of volume and shape of each structure longitudinally. This tool provides a systematic approach to study the radiation therapy (and subsequent chemotherapy) associated with cognitive impairments. METHODS: MRI scans of one patient taken before and after radiation therapy are demonstrated in this study. 3D Conformal radiation therapy was performed on RapidArc™. An open source MRI analysis tool, FMRIB's Integrated Registration and Segmentation Tool (FIRST), was used for segmentation. The images are registered to a standard template with expert-defined labeling for all sub-cortical structures, and the labeling of each structure is mapped back to the individual MRI space for segmentation. After the segmentation, the radiation dose map was coregistered to the MRI space to calculate the dose received by each structure. RESULTS: For the structure that is contained within the radiation zone, we can calculate the total dose based on the volumetric distribution of radiation dose. For the structure that is outside the radiation field, we can calculate the distance from the radiation zone. We have demonstrated in this work that the analysis can be done for all segmented sub-cortical structures. The change of volume before and after radiation treatment can be analyzed, and the results can be correlated with the change of cognitive performance over time. CONCLUSIONS: We presented an automated tool for efficient, quantitative and user-independent measurements of radiation dose in subcortical structures. The obtained results can be correlated with the cognitive test score and the clinical outcome to evaluate radiation and the subsequent chemotherapy induced changes in brain structures and functions.

Potential risk factors for infection with Candida spp. in critically ill patients.

The incidence, risk factors and prognostic factors for candidal infection were determined in a prospective study of 280 infected patients. Thirty-one (11%) patients were infected with Candida spp., sub-divided into 18 (58%) with C. albicans, and 13 (42%) with non-albicans spp. (six C. glabrata, three C. parapsilosis, and one each of C. krusei, C. tropicalis, C. guilliermondii and C. lusitaniae). Infection with Candida spp. was always associated with concurrent bacterial infection. By univariate logistic regression analysis, the degree of morbidity and the duration of mechanical ventilation were independent predictive factors for death, but infection with Candida spp., was not. Factors associated with Candida spp. infection were the degree of morbidity, intensive care unit length of stay, alterations of immune response, and the number of medical devices involved. By multivariate logistic regression analysis, the only independent risk factor for candidal infection was intensive care unit length of stay.

Epidemiology and outcome in renal failure.

Acute renal failure (ARF) in the ICU patient usually occurs as part of a wider multiple organ dysfunction, and is associated with mortality rates of around 50%. Differences in definitions make comparing study populations difficult and moves are being made to improve uniformity, and to recognize that ARF is not a single event but a continuous process from mild renal dysfunction through to complete organ failure requiring renal replacement therapy. In this review we will discuss the epidemiology of ARF within the limitations imposed by comparing studies that use different definitions and focus on different patient populations.

Serial evaluation of the SOFA score to predict outcome in critically ill patients.

CONTEXT: Evaluation of trends in organ dysfunction in critically ill patients may help predict outcome. OBJECTIVE: To determine the usefulness of repeated measurement the Sequential Organ Failure Assessment (SOFA) score for prediction of mortality in intensive care unit (ICU) patients. DESIGN: Prospective, observational cohort study conducted from April 1 to July 31, 1999. SETTING: A 31-bed medicosurgical ICU at a university hospital in Belgium. PATIENTS: Three hundred fifty-two consecutive patients (mean age, 59 years) admitted to the ICU for more than 24 hours for whom the SOFA score was calculated on admission and every 48 hours until discharge. MAIN OUTCOME MEASURES: Initial SOFA score (0-24), Delta-SOFA scores (differences between subsequent scores), and the highest and mean SOFA scores obtained during the ICU stay and their correlations with mortality. RESULTS: The initial, highest, and mean SOFA scores correlated well with mortality. Initial and highest scores of more than 11 or mean scores of more than 5 corresponded to mortality of more than 80%. The predictive value of the mean score was independent of the length of ICU stay. In univariate analysis, mean and highest SOFA scores had the strongest correlation with mortality, followed by Delta-SOFA and initial SOFA scores. The area under the receiver operating characteristic curve was largest for highest scores (0.90; SE, 0.02; P<.001 vs initial score). When analyzing trends in the SOFA score during the first 96 hours, regardless of the initial score, the mortality rate was at least 50% when the score increased, 27% to 35% when it remained unchanged, and less than 27% when it decreased. Differences in mortality were better predicted in the first 48 hours than in the subsequent 48 hours. There was no significant difference in the length of stay among these groups. Except for initial scores of more than 11 (mortality rate >90%), a decreasing score during the first 48 hours was associated with a mortality rate of less than 6%, while an unchanged or increasing score was associated with a mortality rate of 37% when the initial score was 2 to 7 and 60% when the initial score was 8 to 11. CONCLUSIONS: Sequential assessment of organ dysfunction during the first few days of ICU admission is a good indicator of prognosis. Both the mean and highest SOFA scores are particularly useful predictors of outcome. Independent of the initial score, an increase in SOFA score during the first 48 hours in the ICU predicts a mortality rate of at least 50%.

Protein degradation in mitochondria: implications for oxidative stress, aging and disease: a novel etiological classification of mitochondrial proteolytic disorders.

The mitochondrial genome encodes just a small number of subunits of the respiratory chain. All the other mitochondrial proteins are encoded in the nucleus and produced in the cytosol. Various enzymes participate in the activation and intramitochondrial transport of imported proteins. To finally take their place in the various mitochondrial compartments, the targeting signals of imported proteins have to be cleaved by mitochondrial processing peptidases. Mitochondria must also be able to eliminate peptides that are internally synthesized in excess, as well as those that are improperly assembled, and those with abnormal conformation caused by mutation or oxidative damage. Damaged mitochondrial proteins can be removed in two ways: either through lysosomal autophagy, that can account for at most 25-30% of the biochemically estimated rates of average mitochondrial catabolism; or through an intramitochondrial proteinolytic pathway. Mitochondrial proteases have been extensively studied in yeast, but evidence in recent years has demonstrated the existence of similar systems in mammalian cells, and has pointed to the possible importance of mitochondrial proteolytic enzymes in human diseases and ageing. A number of mitochondrial diseases have been identified whose mechanisms involve proteolytic dysfunction. Similar mechanisms probably play a role in diminished resistance to oxidative stress, and in the aging process. In this paper we review current knowledge of mammalian mitochondrial proteolysis, under normal conditions and in several disease states, and we propose an etiological classification of human diseases characterized by a decline or loss of function of mitochondrial proteolytic enzymes.

Cutting edge: identification of the orphan receptor G-protein-coupled receptor 2 as CCR10, a specific receptor for the chemokine ESkine.

A number of orphan G-protein coupled receptors (GPR) have been reported as putative chemokine receptors. One previously reported orphan receptor is an incomplete PCR clone, called GPR2. Here we report the cloning of full-length human (h)GPR2 and mouse (m)GPR2 cDNAs, and the identification of GPR2 as a receptor for a novel CC chemokine called ESkine. hGPR2 is expressed at high levels in testis and small intestine, and at lower levels in other tissues. mGPR2 was expressed at high levels in small intestine, colon, lymph nodes, and Peyer's patches and at lower levels in thymus and spleen. Stimulation of L1.2/hGPR2 transfectants with hESkine induced their migration and resulted in intracellular calcium mobilization. These results provide evidence that GPR2 is a specific receptor for ESkine. We propose that GPR2 be renamed as CCR10. The expression pattern of mGPR2/CCR10 suggests that it may play a role in the homing/trafficking of leukocytes within intestinal and lymphoid environments.

Structure and function of the murine chemokine receptor CXCR3.

The gene encoding the murine homologue of human CXCR3 exists in a single copy consisting of two exons with an intron interrupting the coding sequence between nucleotides 10 and 11. The deduced amino acid sequence is 86% identical to the predicted human sequence. Murine CXCR3 mRNA is detectable in bone marrow cells cultured in the presence of IL-2 but not unstimulated cells. It is also detectable at low abundance in normal mouse spleen, lymph node, mammary gland, and thymus. Transfection of murine CXCR3 in murine pre-B lymphocyte line (CXCR3++/L1.2) conferred binding of the ligands IP10, ITAC and Mig with K(D)'s of 1.35 +/- 0.56, 1.41 +/- 0.20, and 11.65 +/- 0.90 nM, respectively. Lower affinity binding was observed for several beta or CC chemokines (eotaxin, MCP-3, MIP3alpha and SLC/6Ckine/Exodus 2). ITAC, IP10 and Mig induced chemotaxis with an order of potency ITAC > IP10 = Mig. The chemokines also increased intracellular calcium concentration and were variably desensitized to repeated agonist stimulation. The hierarchy for cross- desensitization was ITAC > Mig > IP10. Thus, while Mig, ITAC and IP10 all act on the same receptor for binding and agonist stimulation, they may interact with different receptor conformational isoforms to produce divergent responses.

Hepaticojejunostomy without suture.

Common bile duct (CBD) surgery sometimes demands performing 'a la Roux' hepaticojejunal anastomosis. This kind of stoma is technically easy to perform on a biliary stump of sufficient width (> 8 mm), sufficient length (> 0.5 cm) and with a resilient wall so that stitches will not cut off. In some cases, however, the anatomical conditions are poor: short or thin biliary stump. This situation is especially encountered in iatrogenic lesions of the main biliary channel, but it can infrequently be found in some malignant lesions of the CBD. The authors present their procedure of hepaticojejunal anastomosis without suture, which is adequate for the treatment of benign or even malignant stenosis of the CBD. The method realizes anastomosis of the segments without using sutures by simply keeping them in apposition with continuous traction exerted via a Foley-type balloon catheter which stents the anastomosis in an axial manner. The balloon is then inflated and traction is exerted on the catheter, enabling the two segments of the anastomosis to remain in place until complete healing (10 days average). We performed the procedure in 7 cases: 4 for neoplastic stenosis, and 3 for an accidental lesion of the CBD. There was no perioperative morbidity and 1 fatal outcome. The results prompt further evaluation of the method.

[The therapeutic options in central hydatid cysts of the right hepatic lobe]. / Optiuni terapeutice în chisturile hidatice centrale ale lobului hepatic drept.

The authors of the article propose a method that is highly efficient and presents minimal risks in the treatment of hepatic hydatid cysts located in the central area of the right lobe. This "dangerous area" of the VIIIth segment generates the most delicate problems for the surgical treatment, due to limitation of therapeutic solutions and the highest rate of postoperative complications. The technique presented is that of external extraperitoneal transligamentous drainage introduced by D. Burlui in 1968. This technique should be considered as an alternative to lobectomies or wedge resections or to the direct external drainage of the remaining cavity, the latter being responsible for numerous complications. Considering the figures covering the past 35 years at Caritas Hospital, the authors note the decrease of corrective reinterventions from 27% to 10% after 1968. By associating cholecystectomy after 1983 they dropped to only 4%. The authors do not claim that the method should be universally applied but consider it obviously the choice in the treatment of hydatid cysts in the "dangerous area" in which other therapeutic methods are inappropriate (pericysto-digestive anastomosis) or excessive (right lobe resection), avoiding the problems of direct drainage.

[Stenosing hypertrophic antromyopathy]. / Antromiopatia hipertrofica stenozanta.

The authors describe a case of insufficiency of gastric evacuation, due to the a very rare injury of the antrum which they called:--"hypertrophic and stenosing antromiopathiae". By similarity with the pilor hypertrophy, but without altering the pilor which is intact, the hypertrophy involves especially the gastric antrum, the muscular tunic--mainly the circular fibres in the absence of any acute or chronic inflammatory process. In the interstice between the muscular fibres, there appear collagen fibres in spiral disposition, probably in a contraction. Due to the similitude of the clinical syndrome, the described disease could be ranged among the stenosant diseases of the pyloric pole of the stomach. Out of these, more frequently pointed out, although very rare too, seems to be the pilor hypertrophy at adults. Mention must be made that the two diseases are completely different, because in the "Hypertrophic and stenosing antromiopathiae", the pilor is macroscopic and at the same time normal from the histopathologic aspect point of view.