Colorectal Cancer-Associated Myofibroblasts Exhibit Enhanced Angiogenin Expression and Signaling via the PLXNB2 Receptor.

INTRODUCTION: Dynamic cell-cell interactions shape the tumor microenvironment to regulate tumor growth and invasiveness. Myofibroblasts are gastrointestinal stromal cells that are upregulated in the setting of colorectal cancer (CRC) and may play an important role in tumor-stromal cell communication. Angiogenin is a 14-kDa ribonuclease that regulates myofibroblast function and has been implicated in myofibroblast-CRC cell communication in mouse models. However, its role in human patients has not been well established. METHODS: Open access, annotated single-cell RNA sequencing data of paired normal human colon and CRC tissue were available in the National Center for Biotechnology Information Gene Expression Omnibus Database. We supplemented and verified these data by analyzing scRNA-seq data from an independent set of paired normal human colon and CRC tissue. CellChat was used to quantitatively infer biologically meaningful cell-cell communication networks from scRNA-seq data. PLXNB2 and α-2 actin (ACTA2) are cell surface angiogenin receptors that regulate angiogenin signaling. Ligand-receptor interactions involving angiogenin, PLXNB2, and ACTA2 were analyzed between cell populations in each sample. RESULTS: We found no difference in overall angiogenin expression comparing normal colon and CRC tissue. In normal colon tissue, myofibroblasts do not express angiogenin or the PLXNB2 receptor. In the presence of CRC, there was a striking increase in the number of myofibroblast cells within the surrounding stroma. CRC-associated myofibroblasts were characterized by a significant upregulation of both angiogenin and PLXNB2 receptor expression (P < 0.05), while no difference was seen in ACTA2. CRC cells not only use angiogenin for autocrine signaling but also communicate with myofibroblasts via the PLXNB2 receptor. CONCLUSIONS: Compared to normal human colon tissue, CRC tissue is associated with an enrichment of myofibroblasts that exhibit upregulated expression of angiogenin and the angiogenin receptor PLXNB2. CRC cells engage in autocrine signaling via angiogenin and paracrine signaling with myofibroblasts via PLXNB2. Angiogenin appears to be directly involved in tumor-stromal cell communication in human CRC tissue and may play an important role in disease progression.

Remaining microtia tissue as a source for 3D bioprinted elastic cartilage tissue constructs, potential use for surgical microtia reconstruction.

The absence of ears in children is a global problem. An implant made of costal cartilage is the standard procedure for ear reconstruction; however, side effects such as pneumothorax, loss of thoracic cage shape, and respiratory complications have been documented. Three-dimensional (3D) printing allows the generation of biocompatible scaffolds that mimic the shape, mechanical strength, and architecture of the native extracellular matrix necessary to promote new elastic cartilage formation. We report the potential use of a 3D-bioprinted poly-ε-caprolactone (3D-PCL) auricle-shaped framework seeded with remaining human microtia chondrocytes for the development of elastic cartilage for autologous microtia ear reconstruction. An in vivo assay of the neo-tissue formed revealed the generation of a 3D pinna-shaped neo-tissue, and confirmed the formation of elastic cartilage by the presence of type II collagen and elastin with histological features and a protein composition consistent with normal elastic cartilage. According to our results, a combination of 3D-PCL auricle frameworks and autologous microtia remnant tissue generates a suitable pinna structure for autologous ear reconstruction.

The correlation between rheological properties and extrusion-based printability in bioink artifact quantification.

Bioinks for cell-based bioprinting face availability limitations. Furthermore, the bioink development process needs comprehensive printability assessment methods and a thorough understanding of rheological factors' influence on printing outcomes. To bridge this gap, our study aimed to investigate the relationship between rheological properties and printing outcomes. We developed a specialized bioink artifact specifically designed to improve the quantification of printability assessment. This bioink artifact adhered to established criteria from extrusion-based bioprinting approaches. Seven hydrogel-based bioinks were selected and tested using the bioink artifact and rheological measurement. Rheological analysis revealed that the high-performing bioinks exhibited notable characteristics such as high storage modulus, low tan(δ), high shear-thinning capabilities, high yield stress, and fast, near-complete recovery abilities. Although rheological data alone cannot fully explain printing outcomes, certain metrics like storage modulus and tan(δ) correlated well (R2 > 0.9) with specific printing outcomes, such as gap-spanning capability and turn accuracy. This study provides a comprehensive examination of bioink shape fidelity across a wide range of bioinks, rheological measures, and printing outcomes. The results highlight the importance of considering the holistic view of bioink's rheological properties and directly measuring printing outcomes. These findings underscore the need to enhance bioink availability and establish standardized methods for assessing printability.

Solid Organ Bioprinting: Strategies to Achieve Organ Function.

The field of tissue engineering has advanced over the past decade, but the largest impact on human health should be achieved with the transition of engineered solid organs to the clinic. The number of patients suffering from solid organ disease continues to increase, with over 100 000 patients on the U.S. national waitlist and approximately 730 000 deaths in the United States resulting from end-stage organ disease annually. While flat, tubular, and hollow nontubular engineered organs have already been implanted in patients, in vitro formation of a fully functional solid organ at a translatable scale has not yet been achieved. Thus, one major goal is to bioengineer complex, solid organs for transplantation, composed of patient-specific cells. Among the myriad of approaches attempted to engineer solid organs, 3D bioprinting offers unmatched potential. This review highlights the structural complexity which must be engineered at nano-, micro-, and mesostructural scales to enable organ function. We showcase key advances in bioprinting solid organs with complex vascular networks and functioning microstructures, advances in biomaterials science that have enabled this progress, the regulatory hurdles the field has yet to overcome, and cutting edge technologies that bring us closer to the promise of engineered solid organs.

The Role of the Microenvironment in Controlling the Fate of Bioprinted Stem Cells.

The field of tissue engineering and regenerative medicine has made numerous advances in recent years in the arena of fabricating multifunctional, three-dimensional (3D) tissue constructs. This can be attributed to novel approaches in the bioprinting of stem cells. There are expansive options in bioprinting technology that have become more refined and specialized over the years, and stem cells address many limitations in cell source, expansion, and development of bioengineered tissue constructs. While bioprinted stem cells present an opportunity to replicate physiological microenvironments with precision, the future of this practice relies heavily on the optimization of the cellular microenvironment. To fabricate tissue constructs that are useful in replicating physiological conditions in laboratory settings, or in preparation for transplantation to a living host, the microenvironment must mimic conditions that allow bioprinted stem cells to proliferate, differentiate, and migrate. The advances of bioprinting stem cells and directing cell fate have the potential to provide feasible and translatable approach to creating complex tissues and organs. This review will examine the methods through which bioprinted stem cells are differentiated into desired cell lineages through biochemical, biological, and biomechanical techniques.

Release Kinetics and In Vitro Characterization of Sodium Percarbonate and Calcium Peroxide to Oxygenate Bioprinted Tissue Models.

Oxygen-generating materials have been used in several tissue engineering applications; however, their application as in situ oxygen supply within bioprinted constructs has not been deeply studied. In this study, two oxygen-generating materials, sodium percarbonate (SPO) and calcium peroxide (CPO), were studied for their oxygen release kinetics under a 0.1% O2 condition. In addition, a novel cell-culture-insert setup was used to evaluate the effects of SPO and CPO on the viability of skeletal muscle cells under the same hypoxic condition. Results showed that SPO had a burst oxygen release, while CPO had a more stable oxygen release than SPO. Both SPO and CPO reduced cell viability when used alone. The addition of catalase in SPO and CPO increased the oxygen release rate, as well as improving the viability of skeletal muscle cells; however, CPO still showed cytotoxicity with catalase. Additionally, the utilization of 1 mg/mL SPO and 20 U catalase in a hydrogel for bioprinting significantly enhanced the cell viability under the hypoxic condition. Moreover, bioprinted muscle constructs could further differentiate into elongated myotubes when transferring back to the normoxic condition. This work provides an excellent in vitro model to test oxygen-generating materials and further discover their applications in bioprinting, where they represent promising avenues to overcome the challenge of oxygen shortage in bioprinted constructs before their complete vascularization.

Enhanced method to select human oogonial stem cells for fertility research.

Alternative methods to obtain mature oocytes are still needed for women with premature ovarian failure (POF). Oogonial stem cells (OSCs), found in adult ovaries, have provided insight into potential paths to treating infertility. Previously, the DDX4 antibody marker alone was utilized to isolate OSCs; however, extensive debate over its location in OSCs versus resulting oocytes (transmembrane or intracytoplasmic) has raised doubt about the identity of these cells. Separate groups, however, have efficiently isolated OSCs using another antibody marker Ifitm3 which is consistently recognized to be transmembrane in location. We hypothesized that by using anti-DDX4 and anti-IFITM3 antibodies, in combination, with MACS, we would improve the yield of isolated OSCs versus using anti-DDX4 antibodies alone. Our study supports earlier findings of OSCs in ovaries during the entire female lifespan: from reproductive age through post-menopausal age. MACS sorting ovarian cells using a the two-marker combination yielded a ~ twofold higher percentage of OSCs from a given mass of ovarian tissue compared to existing single marker methods while minimizing the debate surrounding germline marker selection. During in vitro culture, isolated cells retained the germline phenotype expression of DDX4 and IFITM3 as confirmed by gene expression analysis, demonstrated characteristic germline stem cell self-assembly into embryoid bodies, and formed > 40 µm "oocyte-like" structures that expressed the early oocyte markers GDF9, DAZL, and ZP1. This enhanced and novel method is clinically significant as it could be utilized in the future to more efficiently produce mature, secondary oocytes, for use with IVF/ICSI to treat POF patients.

Optimized culture system to maximize ovarian cell growth and functionality in vitro.

Ovaries are the primary physiological source of female sex hormones, which play a crucial role in maintaining ovarian cycle, determining secondary sexual characteristics and preparing the endometrium for implantation. In vitro follicle engineering has been used to investigate follicle development, including ovarian hormone production and gamete maturation. To engineer functional follicles, culture and expansion of the primary ovarian cells are essential. However, the phenotypic and functional characteristics of primary ovarian cells are often lost during culture. The objective of this study is to develop an optimized culture system for maintaining ovarian cell growth and functionality. Granulosa cells (GCs) and theca cells (TCs) were isolated from female rats. The addition of follicle-stimulating hormone (FSH) or luteinizing hormone (LH) to the basal culture media significantly enhanced the secretion of estradiol from GCs and androstenedione from TCs. Serum concentrations of 5% and 10% had a similar role in promoting ovarian cell expansion and secretion of estradiol and androstenedione hormones from both types of cells. Growth differentiation factor 9 (GDF9), bone morphogenic protein 15 (BMP15), BMP7 and basic fibroblast growth factor (bFGF) enhanced GC proliferation and estradiol production, respectively. Among them, the effect of bFGF was most significant. bFGF also enhanced TC proliferation. When GCs and TCs were cultured in 5% serum, gonadotropin and bFGF-containing medium, they proliferated exponentially throughout the culture period of up to 40 days while maintaining their functional characteristics. Taken together, these results indicate that our medium formula is optimal for maximizing proliferation of functionally differentiated ovarian cells.

Analysis of Electronic Residency Application Service (ERAS) Data Can Improve House Staff Diversity.

BACKGROUND: Training diverse house staff, including those who are underrepresented in medicine, is vital to provide high-quality patient care for the communities that we serve. In 2018, the Accreditation Council for Graduate Medical Education announced new common program requirements for systematic efforts to recruit and retain a diverse workforce. However, questions remain about how to implement such efforts. MATERIALS AND METHODS: Electronic Residency Application Service (ERAS) data from eight residency programs spanning two recruitment cycles (2017-2018, 2018-2019) was reviewed. The number of candidates at each stage in the process (applicant, invited to interview, interviewed, and matched) was examined by self-identified race or ethnicity. These data were presented to residency program directors at our Graduate Medical Education committee meeting before the next recruitment cycle. Data were analyzed following the 2019-20 residency match. Odds ratios and Pearson's chi-squared test were used to assess statistical significance. RESULTS: A total of 10,445 and 10,982 medical students applied to our 8 core residency programs in 2017 and 2018, respectively. Medical students who applied and self-identified as Asian, Black or African American, and Hispanic or Latino or Spanish origin had lower odds of being invited to interview than those who self-identified as White. After data presentation, the odds of inviting Black or African American applicants to interview increased significantly. The odds of attending an interview once invited were the same across groups. CONCLUSIONS: Sharing ERAS data patterns with residency program directors was associated with a significant year over year change in interviewee diversity. Structured analysis of institutional ERAS data can provide insight into the resident selection process and may be a useful tool to improve house staff diversity.

The Association Between Sex and Survival for Anal Squamous Cell Carcinoma.

BACKGROUND: The incidence of anal squamous cell carcinoma (SCC) is rising, despite the introduction of a vaccine against human papillomavirus (HPV), the most common etiology of anal SCC. The rate of anal SCC is higher among women and sex-based survival differences may exist. We aimed to examine the association between sex and survival for stage I-IV anal SCC. MATERIALS AND METHODS: The National Cancer Database was used to identify patients with stage I-IV anal SCC from 2004-2016. Outcomes were assessed utilizing log rank tests, Kaplan-Meier statistics, and Cox proportional-hazard modeling. Subgroup analyses by disease stage and by HPV status were performed. Outcomes of interest were median, 1-, and 5-year survival by sex. RESULTS: There were 31,185 patients with stage I-IV anal SCC. 10,714 (34.3%) were male and 20,471 (65.6%) were female. 1- and 5- year survival was 90.2% (95% CI 89.8 - 90.7) and 67.7% (95% CI 66.9 - 68.5) for females compared to 85.8% (95% CI 85.1 - 86.5) and 55.9% (95% CI 54.7 - 57.0) for males. In subgroup analysis, females demonstrated improved unadjusted and adjusted survival for all stages of disease. Female sex was an independent predictor of improved survival (HR 0.68, 95% CI 0.65 - 0.71, P < 0.001). CONCLUSIONS: We demonstrate better overall survival for females compared to males for stage I-IV anal SCC. It is not clear why women have a survival advantage over men, though exposure to prominent risk factors may play a role. High-risk men may warrant routine screening for anal cancer.

Methods to generate tissue-derived constructs for regenerative medicine applications.

The shortage of donor organs for transplantation remains a continued problem for patients with irreversible end-stage organ failure. Tissue engineering and regenerative medicine aims to develop therapies to provide viable solutions for these patients. Use of decellularized tissue scaffolds has emerged as an attractive approach to generate tissue constructs that mimic native tissue architecture and vascular networks. The process of decellularization which involves the removal of resident cellular components from donor tissues has been successfully translated to the clinic for applications in patients. However, transplantation of bioengineered solid organs using this approach remains a challenge as the process requires repopulating target cells to achieve functioning organs. This article presents a comprehensive overview of the methods used to achieve decellularization, the types of decellularizing agents, and the potential cell sources that could be used to achieve tissue function. Understanding the mechanism of action of the decellularizing agent and the processing methods will provide the optimal results for applications.

A novel decellularized skeletal muscle-derived ECM scaffolding system for in situ muscle regeneration.

The cell-based tissue engineering strategies have gained attention in restoring normal tissue function after skeletal muscle injuries; however, these approaches require a donor tissue biopsy and extensive cell expansion process prior to implantation. In order to avoid this limitation, we developed a novel cell-free muscle-specific scaffolding system that consisted of a skeletal muscle-derived decellularized extracellular matrix (dECM) and a myogenic factor, insulin growth factor-1 (IGF-1). Rheological, morphological, and biological properties of this muscle-specific scaffold (IGF-1/dECM) as well as collagen and dECM scaffolds were examined. The cell viability in all scaffolds had over 90% at 1, 3, and 7 days in culture. The cell proliferation in the IGF-1/dECM was significantly increased when compared with other groups. More importantly, the IGF-1/dECM strongly supported the myogenic differentiation in the scaffold as confirmed by myosin heavy chain (MHC) immunofluorescence. We also investigated the feasibility in a rabbit tibialis anterior (TA) muscle defect model. The IGF-1/dECM had a significantly greater number of myofibers when compared to both collagen and dECM groups at 1 and 2 months after implantation. We demonstrated that this novel muscle-specific scaffolding system could effectively promote the muscle tissue regeneration in situ.

Bonding methods for chip integration with Parylene devices.

Flexible electronics require more compact interconnects for next-generation devices. Polymer devices can be bonded to integrated circuit chips, but combining flexible and rigid substrates poses unique technical challenges. Existing technologies either cannot achieve the density required for modern chips or employ specialized equipment and complex processes to do so. Here, we adapt several approaches to achieve fine-pitch bonding between rigid and flexible substrates including epoxy, ultrasonic wire, and anisotropic conductive film bonding and also introduce a novel technique called polymer ultrasonic on bump (PUB) bonding. Using Parylene C devices and various rigid substrates as our model testbed systems, we investigate these four methods across a range of bond pad size and pitch by measuring yield and resistance and by subjecting devices to thermomechanical reliability tests. We demonstrate that all methods are capable of bonding fine pitch interconnects (100 µm) at low temperature (<100 °C). Additionally, we focus on PUB bonding and join a packaged chip and a bare die to Parylene devices.

Angiogenin regulates PKD activation and COX-2 expression induced by TNF-α and bradykinin in the colonic myofibroblast.

INTRODUCTION: The myofibroblast is a gastrointestinal stromal cell that is a target of tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine strongly implicated in colitis-associated cancer. Crosstalk between TNF-α and other pro-inflammatory mediators amplify inflammatory signaling but the mechanism is unknown. Angiogenin (ANG) is a 14-kDa angiogenesis protein that is regulated in patients with inflammatory bowel disease. However, the role of ANG on inflammatory mediator crosstalk in the myofibroblast is unknown. METHODS: The human colonic myofibroblast cell line 18Co, as well as primary mouse and human colonic myofibroblasts, were exposed to TNF-α (10 ng/ml) and bradykinin (BK, 100 nM). ANG was quantified by ELISA. The expression of cyclo-oxygenase-2 (COX-2) and phosphorylation of PKD was assessed by Western Blot. RESULTS: Primary mouse and human colonic myofibroblasts exposed to TNF-α/BK led to enhanced PKD phosphorylation and synergistic COX-2 expression. 18Co cells secrete high levels of ANG (24h, 265 ± 5 pg/ml). The monoclonal antibody 26-2F, which neutralizes ANG, inhibited TNF-α/BK-mediated PKD phosphorylation and synergistic COX-2 expression in primary human myofibroblasts. Likewise, in primary mouse myofibroblasts that do not express ANG (ANG-KO), TNF-α/BK failed to enhance PKD phosphorylation and COX-2 expression. CONCLUSIONS: TNF-α/BK enhance PKD phosphorylation and COX-2 expression in primary mouse and human colonic myofibroblasts. Angiogenin is produced by the myofibroblast, and inhibition of ANG signaling, either by its absence (ANG-KO) or by pharmacologic inhibition, blocks enhanced PKD phosphorylation and synergistic COX-2 expression induced by TNF-α/BK. ANG mediates crosstalk signaling between TNF-α/BK in the regulation of stroma-derived COX-2 and may be a novel therapeutic target for the management of colitis-associated cancer.

Dynamic Changes in Erectile Function and Histological Architecture After Intracorporal Injection of Human Placental Stem Cells in a Pelvic Neurovascular Injury Rat Model.

INTRODUCTION: The human placenta provides a bountiful and noncontroversial source of stem cells which have the potential for regeneration of injured tissue. These cells may restore erectile function after neurovascular tissue injury such as that seen in radical pelvic surgeries and pelvic trauma. AIM: To determine the effect of human placenta-derived stem cells on erectile function recovery and histological changes at various time points in a cavernous nerve injury rat model and to study the fate of injected stem cells throughout the regenerative process. METHODS: Human placental stem cells (PSCs) were dual labeled with monomeric Katushka far red fluorescent protein (mKATE)-renLUC using a lentivirus vector. A pelvic neurovascular injury-induced erectile dysfunction model was established in male, athymic rats by crushing the cavernous nerves and ligating the internal pudendal neurovascular bundles, bilaterally. At the time of defect creation, nonlabeled PSCs were injected into the corpus cavernosum at a concentration of 2.5 × 106 cells/0.2 mL. The phosphate-buffered saline-treated group served as the negative control group, and age-matched rats (age-matched controls) were used as the control group. Erectile function, histomorphological analyses, and Western blot were assessed at 1, 6, and 12 weeks after model creation. The distribution of implanted, dual-labeled PSCs was monitored using an in vivo imaging system (IVIS). Implanted cells were further tracked by detection of mKATE fluorescence in histological sections. MAIN OUTCOME MEASURE: The main outcome measure includes intracavernous pressure/mean arterial pressure ratio, neural, endothelial, smooth muscle cell regeneration, mKATE fluorescence, and IVIS imaging. RESULTS: The ratio of intracavernous pressure to mean arterial pressure significantly increased in PSC-injected rats compared with phosphate-buffered saline controls (P < 0.05) at the 6- and 12-week time points, reaching 72% and 68% of the age-matched control group, respectively. Immunofluorescence staining and Western blot analysis showed significant increases in markers of neurons (84.3%), endothelial cells (70.2%), and smooth muscle cells (70.3%) by 6 weeks in treatment groups compared with negative controls. These results were maintained through 12 weeks. IVIS analysis showed luminescence of implanted PSCs in the injected corpora immediately after injection and migration of cells to the sites of injury, including the incision site and periprostatic vasculature by day 1. mKATE fluorescence data revealed the presence of PSCs in the penile corpora and major pelvic ganglion at 1 and 3 days postoperatively. At 7 days, immunofluorescence of penile PSCs had disappeared and was diminished in the major pelvic ganglion. CLINICAL IMPLICATIONS: Placenta-derived stem cells may represent a future "off-the-shelf" treatment to mitigate against development of erectile dysfunction after radical prostatectomy or other forms of pelvic injury. STRENGTH & LIMITATIONS: Single dose injection of PSCs after injury resulted in maximal functional recovery and tissue regeneration at 6 weeks, and the results were maintained through 12 weeks. Strategies to optimize adult stem cell therapy might achieve more effective outcomes for human clinical trials. CONCLUSION: Human PSC therapy effectively restores the erectile tissue and function in this animal model. Thus, PSC therapy may provide an attractive modality to lessen the incidence of erectile dysfunction after pelvic neurovascular injury. Further improvement in tissue regeneration and functional recovery may be possible using multiple injections or systemic introduction of stem cells. Gu X, Thakker PU, Matz EL, et al. Dynamic Changes in Erectile Function and Histological Architecture After Intracorporal Injection of Human Placental Stem Cells in a Pelvic Neurovascular Injury Rat Model. J Sex Med 2020;17:400-411.

Kidney regeneration approaches for translation.

The increase in the incidence of chronic kidney diseases that progress to end-stage renal disease has become a significant health problem worldwide. While dialysis can maintain and prolong survival, the only definitive treatment that can restore renal function is transplantation. Unfortunately, many of these patients die waiting for transplantable kidneys due to the severe shortage of donor organs. Tissue engineering and regenerative medicine approaches have been applied in recent years to develop viable therapies that could provide solutions to these patients. Cell-based and cell-free approaches have been proposed to address the challenges associated with chronic kidney diseases. Strategies and progress toward developing alternative therapeutic options will be reviewed.

Treatment of stage I-III rectal cancer: Who is refusing surgery?

BACKGROUND AND OBJECTIVES: Surgical resection is a cornerstone in the management of patients with rectal cancer. Patients may refuse surgical treatment for several reasons although the rate of refusal is currently unknown. METHODS: The National Cancer Database was utilized to identify patients with stage I-III rectal cancer. Patients who refused surgical resection were compared to patients who underwent curative resection. RESULTS: A total of 509 (2.6%) patients with stage I and 2082 (3.5%) patients with stage II/III rectal cancer refused surgery. In multivariable analysis for stage I disease, older age, Black race, and Medicaid/no insurance were independent predictors of surgery refusal. Patients were less likely to refuse surgery if they had a higher income or lived further distances from the treatment facility. In multivariable analysis for stage II/III disease, older age, Black race, insurance other than private, and rural county were independent predictors of surgery refusal. Patients were less likely to refuse surgery if they had higher Charlson comorbidity scores, lived further distances from the treatment facility, or underwent chemoradiation. There was a significant decrease in survival for patients refusing surgery compared to patients undergoing recommended surgery. CONCLUSIONS: A small proportion of patients refuse surgery for rectal cancer, and this treatment decision significantly affects survival.

Sociodemographic predictors of surgery refusal in patients with stage I-III colon cancer.

BACKGROUND AND OBJECTIVES: Over 104 000 cases of colon cancer are estimated to be diagnosed in 2020. Surgical resection is a critical part of colon cancer treatment and adequate resection impacts prognosis. However, some patients refuse potentially curative surgery. We aimed to identify the rate and predictors of surgery refusal among patients with colon cancer. METHODS: The National Cancer Database (2004-2015) was queried for patients diagnosed with stage I-III colonic adenocarcinoma. Sociodemographic factors, clinical features, and treatment facility characteristics were collected. Patients who underwent surgery with curative intent were compared to those who refused surgery. Multivariable analysis was used to identify factors associated with surgery refusal. Adjusted survival analysis was performed on propensity-matched cohorts. RESULTS: A total of 151 020 patients were included and 1071 (0.71%) refused surgery. In multivariable analysis older age, Black race, higher Charlson comorbidity score, Medicaid, Medicare, or lack of insurance were predictive of refusing surgery. After propensity matching, there was a significant difference in 5-year survival for patients who refused surgery vs those who underwent surgery (P < .001). CONCLUSIONS: There are racial and socioeconomic disparities in the refusal of surgery for colon cancer. Further studies are needed to better understand the drivers behind differences in refusing curative surgery for colon cancer.

Surgical resection improves overall survival of patients with small bowel leiomyosarcoma.

PURPOSE: Small bowel leiomyosarcoma (SB LMS) is a rare disease with few studies characterizing its outcomes. This study aims to evaluate surgical outcomes for patients with SB LMS. METHODS: The National Cancer Database was queried from 2004 to 2016 to identify patients with SB LMS who underwent surgical resection. The primary outcome was overall survival. RESULTS: A total of 288 patients with SB LMS who had undergone surgical resection were identified. The median age was 63, and the majority of patients were female (56%), White (82%), and had a Charlson comorbidity score of zero (76%). Eighty-one percent of patients had negative margins following surgical resection. Fourteen percent of patients had metastatic disease at the time of diagnosis. Nineteen percent of patients received chemotherapy and 3% of patients received radiation. One-year overall survival was 77% (95% CI: 72-82%) and 5-year overall survival was 43% (95% CI: 36-49%). Higher grade (HR: 1.98, 95% CI: 1.10-3.55, p = 0.02) and metastatic disease at diagnosis (HR: 2.57, 95% CI: 1.45-4.55, p = 0.001) were independently associated with higher risk of death. CONCLUSION: SB LMS is a rare disease entity, with treatment centering on complete surgical resection. Our results demonstrate that overall survival is higher than previously thought. Timely diagnosis to allow for complete surgical resection is key, and investigation into the possible role of chemotherapy or radiation therapy is needed.

Long-term therapeutic effect of cell therapy on improvement in erectile function in a rat model with pelvic neurovascular injury.

OBJECTIVE: To determine the long-term therapeutic effect amongst three human cell types on erectile function recovery in a rat model of dual neurovascular-injury erectile dysfunction (NVED). MATERIALS AND METHODS: A dual NVED model was established in athymic rats by crushing the bilateral cavernous nerves and ligating the bilateral internal pudendal neurovascular bundles. At the time of defect creation, three different types of human cell populations (2.5 × 106  cells/0.2 mL: umbilical vein endothelial cells, adipose-derived stem cells, and amniotic fluid-derived stem cells) were injected intracavernously into the penile tissue. Saline injection (0.2 mL) served as a control group. Erectile function and histomorphological analyses of penile tissues were assessed 12 weeks after defect creation and cell or saline injection. RESULTS: The ratio of intracavernous pressure to mean arterial pressure (functional indicator) was significantly higher in the cell therapy groups compared to the saline-injected control group (P < 0.05). Immunofluorescence staining showed more cells expressing biomarkers of endothelial, smooth muscle, and nerve cells within the penile tissue in the cell therapy groups when compared to the control group. CONCLUSIONS: Cell therapy enhanced erectile function and ameliorated the histological changes 12 weeks after pelvic neurovascular injury in vivo, indicating that cell therapy may improve the long-term outcomes in neurogenic, myogenic and vascular tissue regeneration in the treatment of NVED.