Total Pelvic Exenteration for Gynecologic Malignancies

Total pelvic exenteration (PE) is a radical operation, involving en bloc resection of pelvic organs, including reproductive structures, bladder, and rectosigmoid. In gynecologic oncology, it is most commonly indicated for the treatment of advanced primary or locally recurrent cancer. Careful patient selection and counseling are of paramount importance when considering someone for PE. Part of the evaluation process includes comprehensive assessment to exclude unresectable or metastatic disease. PE can be curative for carefully selected patients with gynecologic cancers. Major complications can be seen in as many as 50% of patients undergoing PE, underscoring the need to carefully discuss risks and benefits of this procedure with patients considering exenterative surgery

Indomethacin promotes survival of new neurons in the adult murine hippocampus accompanied by anti-inflammatory effects following MPTP-induced dopamine depletion

Abstract Background Parkinson’s disease (PD) is characterized by dopaminergic cell loss and inflammation in the substantia nigra (SN) leading to motor deficits but also to hippocampus-associated non-motor symptoms such as spatial learning and memory deficits. The cognitive decline is correlated with impaired adult hippocampal neurogenesis resulting from dopamine deficit and inflammation, represented in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) mouse model of PD. In the inflammatory tissue, cyclooxygenase (COX) is upregulated leading to an ongoing inflammatory process such as prostaglandin-mediated increased cytokine levels. Therefore, inhibition of COX by indomethacin may prevent the inflammatory response and the impairment of adult hippocampal neurogenesis. Methods Wildtype C57Bl/6 and transgenic Nestin-GFP mice were treated with MPTP followed by short-term or long-term indomethacin treatment. Then, aspects of inflammation and neurogenesis were evaluated by cell counts using immunofluorescence and immunohistochemical stainings in the SN and dentate gyrus (DG). Furthermore, hippocampal mRNA expression of neurogenesis-related genes of the Notch, Wnt, and sonic hedgehog signaling pathways and neurogenic factors were assessed, and protein levels of serum cytokines were measured. Results Indomethacin restored the reduction of the survival rate of new mature neurons and reduced the amount of amoeboid CD68+ cells in the DG after MPTP treatment. Indomethacin downregulated genes of the Wnt and Notch signaling pathways and increased neuroD6 expression. In the SN, indomethacin reduced the pro-inflammatory cellular response without reversing dopaminergic cell loss. Conclusion Indomethacin has a pro-neurogenic and thereby restorative effect and an anti-inflammatory effect on the cellular level in the DG following MPTP treatment. Therefore, COX inhibitors such as indomethacin may represent a therapeutic option to restore adult neurogenesis in PD

Dopaminergic Neurodegeneration in the Mouse Is Associated with Decrease of Viscoelasticity of Substantia Nigra Tissue.

The biomechanical properties of brain tissue are altered by histopathological changes due to neurodegenerative diseases like Parkinson's disease (PD). Such alterations can be measured by magnetic resonance elastography (MRE) as a non-invasive technique to determine viscoelastic parameters of the brain. Until now, the correlation between histopathological mechanisms and observed alterations in tissue viscoelasticity in neurodegenerative diseases is still not completely understood. Thus, the objective of this study was to evaluate (1) the validity of MRE to detect viscoelastic changes in small and specific brain regions: the substantia nigra (SN), midbrain and hippocampus in a mouse model of PD, and (2) if the induced dopaminergic neurodegeneration and inflammation in the SN is reflected by local changes in viscoelasticity. Therefore, MRE measurements of the SN, midbrain and hippocampus were performed in adult female mice before and at five time points after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin hydrochloride (MPTP) treatment specifically lesioning dopaminergic neurons in the SN. At each time point, additional mice were utilized for histological analysis of the SN. After treatment cessation, we observed opposed viscoelastic changes in the midbrain, hippocampus and SN with the midbrain showing a gradual rise and the hippocampus a distinct transient increase of viscous and elastic parameters, while viscosity and-to a lesser extent-elasticity in the SN decreased over time. The decrease in viscosity and elasticity in the SN was paralleled by a reduced number of neurons due to the MPTP-induced neurodegeneration. In conclusion, MRE is highly sensitive to detect local viscoelastic changes in specific and even small brain regions. Moreover, we confirmed that neuronal cells likely constitute the backbone of the adult brain mainly accounting for its viscoelasticity. Therefore, MRE could be established as a new potential instrument for clinical evaluation and diagnostics of neurodegenerative diseases

Enhanced Adult Neurogenesis Increases Brain Stiffness: <i>In Vivo</i> Magnetic Resonance Elastography in a Mouse Model of Dopamine Depletion

<div><p>The mechanical network of the brain is a major contributor to neural health and has been recognized by in vivo magnetic resonance elastography (MRE) to be highly responsive to diseases. However, until now only brain softening was observed and no mechanism was known that reverses the common decrement of neural elasticity during aging or disease. We used MRE in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) mouse model for dopaminergic neurodegeneration as observed in Parkinson’s disease (PD) to study the mechanical response of the brain on adult hippocampal neurogenesis as a robust correlate of neuronal plasticity in healthy and injured brain. We observed a steep transient rise in elasticity within the hippocampal region of up to over 50% six days after MPTP treatment correlating with increased neuronal density in the dentate gyrus, which could not be detected in healthy controls. Our results provide the first indication that new neurons reactively generated following neurodegeneration substantially contribute to the mechanical scaffold of the brain. Diagnostic neuroimaging may thus target on regions of the brain displaying symptomatically elevated elasticity values for the detection of neuronal plasticity following neurodegeneration.</p></div

Results of cell counts in the DG.

<p>Fluorescence- and DAB-stained brain sections of MPTP-treated and CTR mice at the different time-points of MRE assessment, showing the total number of a) GCL/SGZ cells (DAPI), b) newborn cells (BrdU+), c) new precursor cells (BrdU+/Nestin/GFP+), d) new neuronal cells (BrdU+/NeuN+), and f) microglia and macrophages (Iba1+) in the GCL/SGZ, ML and hilus (mean±SEM). *p<0.05, **p<0.01.</p

Representative confocal images of doublelabeled BrdU+/Nestin/GFP+ and BrdU+/NeuN+ cells.

<p>Mouse brain sections (40 μm) fluorescently stained with BrdU (red), NeuN (blue) and Nestin/GFP (green), showing the granular cell layer of the dentate gyrus with a Nestin/GFP-expressing precursor cell that is also positive for BrdU (a, 200×magnification and b, 630×magnification; arrow) and BrdU-positive cells coexpressing the neuronal marker NeuN (c, 400×magnification and d, 630×magnification; arrows).</p

Variation of MRE parameters due to MPTP in the hippocampus of mice and results of cell counts in the DG.

<p>MPTP induced a transient increase of brain elasticity and viscosity (a, b and c) at 6 dpi, while the phase angle φ (d) remained unchanged (mean±SEM). Histologically, a transient MPTP-induced increase of new precursor cells (BrdU+/Nestin/GFP+) at 3 dpi (e) and of new neurons (BrdU+/NeuN+) at 6 dpi (f) as percentage of all newborn cells (BrdU+) was found (mean±SEM). *p<0.05, **p<0.01.</p

Representative images of the magnitude MRE signal, shear waves and the magnitude complex modulus (|G*|) in a mouse.

<p>The green line demarcates the chosen region of interest in the hippocampus.</p

Representative images of MRI signal and complex modulus map of G' and G''.

<p>Regions of interest: substantia nigra (red line), midbrain (blue line) and hippocampus (yellow line) were marked in T1w-MRI.</p

Results of MRE measurement and histological cell count in the hippocampus.

<p>MPTP induced a transient increase of elasticity (a) and viscosity (b) in the hippocampus at 6dpi (mean±SEM, n(-3,3,6,10,14,18dpi = 5). Quantification of DAPI-stained cells showed an elevated amount at 6dpi (mean±SEM, n(-3,3,6,10,14,18dpi) = 2, no statistical analysis). * vs. -3dpi, **p≤0.01, ***p≤0.001.</p