Morbidity and Mortality of Total Pelvic Exenteration for Malignancy in the US.

BACKGROUND: Total pelvic exenterations (TPEs) for malignancies are complex operations often performed by multidisciplinary teams. The differences among primary cancer for TPE and multicentered results are not well described. We aimed to describe TPE outcomes for different malignant origins in a national multicentered sample. METHODS: Patients from the National Surgical Quality Improvement Program (NSQIP) database who underwent TPE between 2005 and 2016 for all malignant indications (colorectal, gynecologic, urologic, or other) were included. Chi square and Kruskal-Wallis tests were used to compare patient characteristics by primary malignancy. Multivariate logistic and linear regression models were used to determine factors associated with any 30-day Clavien-Dindo grade 3 or higher complication, length of hospital stay (LOS; days), 30-day wound infection, and 30-day mortality. RESULTS: Overall, 2305 patients underwent TPE. Indications for surgery included 33% (749) colorectal, 15% (335) gynecologic, 9% (196) other, and 45% (1025) urologic malignancies. Median LOS decreased from 10 to 8 days during the study period (p < 0.001), 36% were males, and 50% required blood transfusion. High-grade complications occurred in 15% of patients and were associated with bowel diversion [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.1-2.4], disseminated cancer (OR 1.8, 95% CI 1.4-2.3), and gynecologic cancers (OR 2.9, 95% CI 1.8-4.7). Mortality was 2% and was associated with disseminated cancer (OR 2.2, 95% CI 1.1-4.3) and male sex (OR 2.4, 95% CI 1.3-4.4). CONCLUSIONS: TPE is associated with high rates of complications, however mortality rates remain low. Preoperative and perioperative outcomes differ depending on the origin of the primary malignancy.

WNT2 is necessary for normal prostate gland cyto-differentiation and modulates prostate growth in an FGF10 dependent manner.

Wnt proteins are highly conserved secreted morphogens that function in organ development across species. This study investigates the role(s) of Wnt2 during prostate gland development. Wnt2 mRNA ontogeny in the rat ventral prostate rapidly declines in expression from peak value at post-natal day (pnd) 1 to nadir levels sustained through adulthood. Wnt2 mRNA is expressed in prostate mesenchymal cells and Wnt2 protein localizes to both mesenchymal and epithelial cells. Sustained expression of Wnt2 by adenoviral expression during rat postnatal prostate gland development resulted in significant reduction in gland size confirming its necessary decline to permit normal development. Wnt2 overexpression in a murine embryonic urogenital sinus mesenchyme cell line, UGSM2 revealed Wnt2 modulated several growth factors including significant down-regulation of Fgf10, an essential stimulator of normal prostate gland branching morphogenesis. Growth inhibitory effects of Wnt2 were reversed by exogenous Fgf10 addition to developing rat ventral prostates. Renal grafts of Wnt2-/- male urogenital sinus revealed that Wnt2-/- grafts had a disruption in normal lateral polarity, disruption in cell to cell adhesion, and a reduction in the differentiated luminal cell marker, cytokeratin 8/18. Our results demonstrate that the growth inhibiting effects of sustained Wnt2 during prostate development are mediated, in part, by reduction in Fgf10 expression by mesenchymal cells and Wnt2 plays a role in normal prostate luminal cell differentiation and cell to cell integrity. These findings add to the body of work that highlights the unique roles of individual Wnts during prostate development and suggest that their deregulation may be implicated in prostate pathology.

Motor activity affects dopaminergic and noradrenergic systems of the dorsal horn of the rat lumbar spinal cord.

Dopamine (DA) and noradrenaline (NA) modulate responses to nociceptive stimuli, within the dorsal horn of the spinal cord. Both neurotransmitters may play a role in supraspinal regulation in response to proprioceptive afferences to the dorsal horn. However, direct evidence of changes in neurotransmitter release within the dorsal horn due to non-noxious stimuli is lacking. The present study was designed to determine, whether non-nociceptive exercise produces changes in release of DA and NA within the dorsal horn, and whether these changes are associated with long-lasting inhibition after the exercise stops. Microdialysis probes, implanted in layers 2-5 of Rexed, in combination with high-performance liquid chromatography coupled to electrochemical detection (HPLC-EC) were used to measure concentrations of DA and NA metabolite (MHPG) in lumbar spinal cords of rats. Microdialysate was sampled before, during, and after a treadmill exercise of one hour. Results indicate that DA and NA releases are inhibited during non-nociceptive motor activity. At rest, DA concentration was 204 ± 10.5 pg/10 µl and was significantly decreased during exercise to -11.4% (P ≤ 0.05). Greater decrease occurred after 30 min of exercise and was of -31.4% (P ≤ 0.05). Similarly, MHPG was significantly decreased of -18% during exercise (P ≤ 0.05). When exercise stopped, both systems showed long-lasting inhibition. Exercise post-release lasted 30 min for DA and 90 min for MHPG. MHPG greatest decrease of -47.8% occurred 30 min after stopping the exercise (P ≤ 0.001). Thus, DA and NA systems seem to respond to exercise-induced proprioceptive afferent stimuli to the dorsal horn.

Estrogen-initiated transformation of prostate epithelium derived from normal human prostate stem-progenitor cells.

The present study sought to determine whether estrogens with testosterone support are sufficient to transform the normal human prostate epithelium and promote progression to invasive adenocarcinoma using a novel chimeric prostate model. Adult prostate stem/early progenitor cells were isolated from normal human prostates through prostasphere formation in three-dimensional culture. The stem/early progenitor cell status and clonality of prostasphere cells was confirmed by immunocytochemistry and Hoechst staining. Normal prostate progenitor cells were found to express estrogen receptor α, estrogen receptor ß, and G protein-coupled receptor 30 mRNA and protein and were responsive to 1 nm estradiol-17ß with increased numbers and prostasphere size, implicating them as direct estrogen targets. Recombinants of human prostate progenitor cells with rat urogenital sinus mesenchyme formed chimeric prostate tissue in vivo under the renal capsule of nude mice. Cytodifferentiation of human prostate progenitor cells in chimeric tissues was confirmed by immunohistochemistry using epithelial cell markers (p63, cytokeratin 8/18, and androgen receptor), whereas human origin and functional differentiation were confirmed by expression of human nuclear antigen and prostate-specific antigen, respectively. Once mature tissues formed, the hosts were exposed to elevated testosterone and estradiol-17ß for 1-4 months, and prostate pathology was longitudinally monitored. Induction of prostate cancer in the human stem/progenitor cell-generated prostatic tissue was observed over time, progressing from normal histology to epithelial hyperplasia, prostate intraepithelial neoplasia, and prostate cancer with local renal invasion. These findings provide the first direct evidence that human prostate progenitor cells are estrogen targets and that estradiol in an androgen-supported milieu is a carcinogen for human prostate epithelium.

Combination strategies for repair, plasticity, and regeneration using regulation of gene expression during the chronic phase after spinal cord injury.

Although recovery after spinal cord injury (SCI) is rare in humans, recent literature indicates that some patients do recover sensorimotor function years after the trauma. This study seeks to elucidate the genetic underpinnings of SCI repair through the investigation of neurodegenerative and regenerative associated genes involved in the response to SCI during the chronic phase in adult rats. Intervention on the level of gene regulation focused on enhancing naturally attempting SCI regenerative genes has the potential to promote SCI repair. Our aim was to analyze gene expression characteristics of candidate genes involved in the neuro-degenerative and -regenerative processes following various animal models of SCI. We compiled data showing gene expression changes after SCI in adult rats and created a chronological time-line of candidate genes differentially expressed during the chronic phase of SCI. Compiled data showed that SCI induced a transient upregulation of endogenous neuro-regenerative genes not only within a few hours but also within a few days, weeks, and months after SCI. For example, gene controlling growth-associated protein-43 (GAP-43), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and others, showed significant changes in mRNA accumulation in SCI animals, from 48 hours to 12 weeks after SCI. Similarly, inhibitory genes, such as RhoA, LINGO-1, and others, were upregulated as late as 4 to 14 days after injury. This indicates that gene specific regulation changes, corresponding to repair and regenerative attempts, are naturally orchestrated over time after injury. These delayed changes after SCI give ample time for therapeutic gene modulation through upregulation or silencing of specific genes responsible for the synthesis of the corresponding biogenic proteins. By following the examination of differential gene regulation during the chronic phase, we have determined times, successions, co-activations, interferences, and dosages for potential therapeutic synchronized interventions. Finally, local cellular specificities and their neuropathophysiologies have been taken into account in the elaboration of the combination treatment strategy we propose. The interventions we propose suggest the delivery of exogenous therapeutic agents to upregulate or downregulate chosen genes or the expression of the downstream proteins to revert the post-traumatic stage of SCI during the chronic phase. The proposed combination and schedule of local cell-specific treatment should enhance intrinsic regenerative machinery and provide a promising strategy for treating patients sustaining chronic SCI.