UDP-6-glucose dehydrogenase in hormonally responsive breast cancers.

Survival for metastatic breast cancer is low and thus, continued efforts to treat and prevent metastatic progression are critical. Estrogen is shown to promote aggressive phenotypes in multiple cancer models irrespective of estrogen receptor (ER) status. Similarly, UDP-Glucose 6-dehydrogenase (UGDH) a ubiquitously expressed enzyme involved in extracellular matrix precursors, as well as hormone processing increases migratory and invasive properties in cancer models. While the role of UGDH in cellular migration is defined, how it intersects with and impacts hormone signaling pathways associated with tumor progression in metastatic breast cancer has not been explored. Here we demonstrate that UGDH knockdown blunts estrogen-induced tumorigenic phenotypes (migration and colony formation) in ER+ and ER- breast cancer in vitro. Knockdown of UGDH also inhibits extravasation of ER- breast cancer ex vivo, primary tumor growth and animal survival in vivo in both ER+ and ER- breast cancer. We also use single cell RNA-sequencing to demonstrate that our findings translate to a human breast cancer clinical specimen. Our findings support the role of estrogen and UGDH in breast cancer progression provide a foundation for future studies to evaluate the role of UGDH in therapeutic resistance to improve outcomes and survival for breast cancer patients.

Single-cell RNA sequencing comparison of the human metastatic prostate spine tumor microenvironment.

Spinal column tumors can be difficult to process for single-cell omic studies, given the heterogeneity in tissue. Here, we present a protocol for operating room-to-benchtop single-cell processing of clinical specimens from a prostate cancer patient. We describe steps for sample homogenization, red blood cell lysis, cryopreservation, and single-cell sequencing analysis. This protocol can be used to identify prognostic markers and therapeutic targets for patients with osseous spine metastases and better inform eligibility for clinical trials.

Association Between Urbanicity and Outcomes Among Patients with Spinal Cord Ependymomas in the United States.

BACKGROUND: Spinal cord ependymomas (SCEs) represent the most common intramedullary spinal cord tumors among adults. Research shows that access to neurosurgical care and patient outcomes can be greatly influenced by patient location. This study investigates the association between the outcomes of patients with SCE in metropolitan and nonmetropolitan areas. METHODS: Cases of SCE between 2004 and 2019 were identified within the Central Brain Tumor Registry of the United States, a combined dataset including the Centers for Disease Control and Prevention's National Program of Cancer Registries and National Cancer Institute's Surveillance, Epidemiology, and End Results Program data. Multivariable logistic regression models were constructed to evaluate the association between urbanicity and SCE treatment, adjusted for age at diagnosis, sex, race and ethnicity. Survival data was available from 42 National Program of Cancer Registries (excluding Kansas and Minnesota, for which county data are unavailable), and Cox proportional hazard models were used to understand the effect of surgical treatment, county urbanicity, age at diagnosis, and the interaction effect between age at diagnosis and surgery, on the survival time of patients. RESULTS: Overall, 7577 patients were identified, with 6454 (85%) residing in metropolitan and 1223 (15%) in nonmetropolitan counties. Metropolitan and nonmetropolitan counties had different age, sex, and race/ethnicity compositions; however, demographics were not associated with differences in the type of surgery received when stratified by urbanicity. Irrespective of metropolitan status, individuals who were American Indian/Alaska Native non-Hispanic and Hispanic (all races) were associated with reduced odds of receiving surgery. Individuals who were Black non-Hispanic and Hispanic were associated with increased odds of receiving comprehensive treatment. Diagnosis of SCE at later ages was linked with elevated mortality (hazard ratio = 4.85, P < 0.001). Gross total resection was associated with reduced risk of death (hazard ratio = 0.37, P = 0.004), and age did not interact with gross total resection to influence risk of death. CONCLUSIONS: The relationship between patients' residential location and access to neurosurgical care is critical to ensuring equitable distribution of care. This study represents an important step in delineating areas of existing disparities.

Prophylactic Muscle Flaps Decrease Wound Complication Rates in Patients with Oncologic Spine Disease.

BACKGROUND: Patients with oncologic spine disease face a high systemic illness burden and often require surgical intervention to alleviate pain and maintain spine stability. Wound healing complications are the most common reason for reoperation in this population and are known to impact quality of life and initiation of adjuvant therapy. Prophylactic muscle flap (MF) closure is known to reduce wound healing complications in high-risk patients; however, the efficacy in oncologic spine patients is not well established. METHODS: A collaboration at our institution presented an opportunity to study the outcomes of prophylactic MF closure. The authors performed a retrospective cohort study of patients who underwent MF closure versus a cohort who underwent non-MF closure in the preceding time. Demographic and baseline health data were collected, as were postoperative wound complication data. RESULTS: A total of 166 patients were enrolled, including 83 patients in the MF cohort and 83 control patients. Patients in the MF group were more likely to smoke ( P = 0.005) and had a higher incidence of prior spine irradiation ( P = 0.002). Postoperatively, five patients (6%) in the MF group developed wound complications, compared with 14 patients (17%) in the control group ( P = 0.028). The most common overall complication was wound dehiscence requiring conservative therapy, which occurred in six control patients (7%) and one MF patient (1%) ( P = 0.053). CONCLUSIONS: Prophylactic MF closure during oncologic spine surgery significantly reduces the wound complication rate. Future studies should examine the precise patient population that stands to benefit most from this intervention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

UDP-glucose dehydrogenase (UGDH) in clinical oncology and cancer biology.

UDP-glucose-6-dehydrogenase (UGDH) is a cytosolic, hexameric enzyme that converts UDP-glucose to UDP-glucuronic acid (UDP-GlcUA), a key reaction in hormone and xenobiotic metabolism and in the production of extracellular matrix precursors. In this review, we classify UGDH as a molecular indicator of tumor progression in multiple cancer types, describe its involvement in key canonical cancer signaling pathways, and identify methods to inhibit UGDH, its substrates, and its downstream products. As such, we position UGDH as an enzyme to be exploited as a potential prognostication marker in oncology and a therapeutic target in cancer biology.

The Association Between Sociodemographic Factors, Social Determinants of Health, and Spine Surgical Patient Portal Utilization.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To examine patient portal use among the surgical spine patient population across different sociodemographic groups and assess the impact of patient portal use on clinical outcomes. SUMMARY OF BACKGROUND DATA: Patient portals (PP) have been shown to improve outcomes and quality of care. Engaging them requires internet access, technological literacy, and dexterity, which may serve as access barriers. METHODS: After exclusion criteria were applied, the study included data for 9211 encounters from 7955 patients. PP utilization was defined as having activated and used the Duke University Medical Center patient portal system, MyChart, at least once. Sociodemographic characteristics included urbanicity, age, race, ethnicity, language, employment, and primary insurer. Clinical outcomes included the length of hospital stay during the procedure, 30-day return to the emergency department, 30-day readmission, and being discharged somewhere other than home. RESULTS: Being older than 65, non-White, unemployed, non-English-speaking, male, not-partnered, uninsured or publicly insured (Medicaid, Medicare and under 65 years of age, or other government insurance), and living in a rural environment were all risk factors for decreased PP utilization among surgical spine patients. A one-risk factor decrease in the number of social risk factors was associated with a 78% increase in the odds of PP utilization [odds ratio (OR): 1.78; 95% Confidence interval (CI): 1.69-1.87; P <0.001]. Patients not utilizing the portal at the time of their procedure had higher odds of 30-day readmission (OR: 1.59; 95% CI: 1.26-2.00), discharge somewhere other than home (OR: 2.41, 95% CI: 1.95-2.99), and an increased length of hospital stay (geometric mean ratio: 1.21; 95% CI: 1.12-1.30) compared with those who utilized it. CONCLUSIONS: In patients undergoing spine procedures, PPs are not equally utilized among different sociodemographic groups. PP utilization is also associated with better outcomes. Interventions aimed at increasing PP uptake may improve care for certain patients.

Muscle Flap Closures in Spine Surgery: Predictors of Usage Patterns and Factors Associated With Postoperative Complications From the NSQIP Database.

STUDY DESIGN: Retrospective cohort study using the National Surgical Quality Improvement Program. OBJECTIVE: The objective of this study was to identify preoperative factors that impact the decision to perform prophylactic muscle flap closure and assess risk factors for wound healing complications in patients undergoing spinal procedures with and without muscle flap closure. SUMMARY OF BACKGROUND DATA: Prior studies suggest that muscle flap closure following complex spine surgery results in a lower risk of wound healing complications. However, these studies have been limited to single institutions and/or surgeons. METHODS: The National Surgical Quality Improvement Program database was queried for all patients undergoing spine surgery between 2005 and 2017 with and without concomitant muscle flaps. Preoperative and perioperative variables were extracted. Univariate and multivariate analyses were performed to assess risk factors influencing surgical site infection (SSI) and wound disruption, as well as to delineate which preoperative factors increased the likelihood of patients receiving flap closures a priori. RESULTS: Concomitant muscle flaps were performed on 758 patients; 301,670 patients did not receive a flap. Overall 29 (3.83%) patients in the flap group experienced SSI compared to 5154 (1.71%) in the nonflap group (P<0.0001). Preoperative steroid use [odds ratio (OR) 0.5; P<0.0001], wound infection (OR 0.24; P<0.0001), elevated white blood cell count (OR 1.034; P<0.0001), low hematocrit (OR 0.94; P<0.0001), preoperative transfusion (OR 0.22; P=0.0068) were significantly associated with utilization of muscle flaps. Perioperative factors including a contaminated wound (OR 4.72; P<0.0001), the American Society of Anesthesiologists classification of severe disease (OR 1.92; P=0.024), and longer operative time (OR 1.001; P=0.0024) were significantly associated with postoperative wound disruption. In addition, after propensity score matching for these factors that increase risk of wound complications, there was no difference in the rates of SSI between the flap and nonflap group. CONCLUSION: Our results suggest that patients with a higher burden of illness preoperatively are more likely to receive prophylactic paraspinal flaps which can reduce the rates of wound-related complications.

Risk factors for prolonged length of stay in patients undergoing surgery for intramedullary spinal cord tumors.

Primary spine tumors are rare neoplasms that affect about 0.62 per 100,000 individuals in the US. Intramedullary spinal cord tumors (IMSCTs) are the rarest of all primary tumors involving the spine and can cause pain, imbalance, urinary dysfunction and neurological deficits. These types of tumors oftentimes necessitate surgical treatment, yet there is a lack of data on hospital length of stay and complication rates following treatment. Given that treatment candidacy, quality of life, and outcomes are tied so closely to potential for prolonged length of stay and postoperative complications, it is important to better understand the factors that increase the risk of these outcomes in patients with IMSCTs. METHODS: The National Surgical Quality Improvement Program (NSQIP) database was queried for all patients undergoing surgery for treatment of intramedullary spinal cord tumors between 2005 and 2017. Univariate and multivariate analysis were performed to assess patient risk factors influencing prolonged length of stay and post-op complications. RESULTS: A total of 638 patients were included in the analysis. Pre-operative American Society of Anesthesiology (ASA) physical status classification of 3 and above (OR 1.89; p = 0.0005), dependent functional status (OR 2.76; p = 0.0035) and transfer from facilities other than home (OR 8.12; p <0.0001) were independent predictors of prolonged length of stay (>5 days). The most commonly reported complications were pneumonia (5.7%), urinary tract infection (9.4%), septic shock (3.8%), superficial incisional infection (5.7%), organ or space infection (5.7%), pulmonary embolism (11.3%), DVT requiring therapy (15.1%) and wound dehiscence (5.7%). CONCLUSION: Our study demonstrated the significant influence of clinical variables on prolonged hospitalization of IMSCT patients. This should be factored into clinical and surgical decision making and when counseling patients of their expected outcomes.

Animal Models of Metastatic Lesions to the Spine: A Focus on Epidural Spinal Cord Compression.

Epidural spinal cord compression (ESCC) secondary to spine metastases is one of the most devastating sequelae of primary cancer as it may lead to muscle weakness, paresthesia, pain, and paralysis. Spine metastases occur through a multistep process that can result in eventual ESCC; however, the lack of a preclinical model to effectively recapitulate each step of this metastatic cascade and the symptom burden of ESCC has limited our understanding of this disease process. In this review, we discuss animal models that best recapitulate ESCC. We start with a broad discussion of commonly used models of bone metastasis and end with a focused discussion of models used to specifically study ESCC. Orthotopic models offer the most authentic recapitulation of metastasis development; however, they rarely result in symptomatic ESCC and are challenging to replicate. Conversely, models that involve injection of tumor cells directly into the bloodstream or bone better mimic the symptoms of ESCC; however, they provide limited insight into the epithelial to mesenchymal transition and natural hematogenous spread of tumor cells. Therefore, until an ideal model is created, it is critical to select an animal model that is specifically designed to answer the scientific question of interest.

Interhospital transfer status for spinal metastasis patients in the United States is associated with more severe clinical presentations and higher rates of inpatient complications.

OBJECTIVE: In patients with metastatic spinal disease (MSD), interhospital transfer can potentially impact clinical outcomes as the possible benefits of transferring a patient to a higher level of care must be weighed against the negative effects associated with potential delays in treatment. While the association of clinical outcomes and transfer status has been examined in other specialties, the relationship between transfer status, complications, and risk of mortality in patients with MSD has yet to be explored. The purpose of this study was to examine the impact of transfer status on in-hospital mortality and clinical outcomes in patients diagnosed with MSD. METHODS: The National (Nationwide) Inpatient Sample (NIS) database was retrospectively queried for adult patients diagnosed with vertebral pathological fracture and/or spinal cord compression in the setting of metastatic disease between 2012 and 2014. Demographics, baseline characteristics (e.g., metastatic spinal cord compression [MSCC] and paralysis), comorbidities, type of intervention, and relevant patient outcomes were controlled in a multivariable logistic regression model to analyze the association of transfer status with patient outcomes. RESULTS: Within the 10,360 patients meeting the inclusion and exclusion criteria, higher rates of MSCC (50.2% vs 35.9%, p < 0.001) and paralysis (17.3% vs 8.4%, p < 0.001) were observed in patients transferred between hospitals compared to those directly admitted. In univariable analysis, a higher percentage of transferred patients underwent surgical intervention (p < 0.001) when compared with directly admitted patients. After controlling for significant covariates and surgical intervention, transferred patients were more likely to develop in-hospital complications (OR 1.34, 95% CI 1.18-1.52, p < 0.001), experience prolonged length of stay (OR 1.33, 95% CI 1.16-1.52, p < 0.001), and have a discharge disposition other than home (OR 1.70, 95% CI 1.46-1.98, p < 0.001), with no significant difference in inpatient mortality rates. CONCLUSIONS: Patients with MSD who were transferred between hospitals demonstrated more severe clinical presentations and higher rates of inpatient complications compared to directly admitted patients, despite demonstrating no difference in in-hospital mortality rates.

Gender disparities in clinical presentation, treatment, and outcomes in metastatic spine disease.

BACKGROUND: The incidence of metastatic spine disease (MSD) is increasing among cancer patients. Given the poor outcomes and high rates of morbidity associated with MSD, it is important to determine demographic factors that could impact interventions and outcomes for this patient population. The objectives of this study were to compare in-hospital mortality and complication rates, clinical presentation, and interventions between female and male patients diagnosed with MSD. METHODS: Patient data were collected from the United States National Inpatient Sample (NIS) database from the years 2012-2014. Descriptive statistics were used to compare data from 51,800 cases; subsequently, multivariable logistic regression analyses were conducted to assess the effect of gender on outcomes. RESULTS: Males had significantly higher rates of in-hospital mortality (OR 1.30; 95 % CI 1.09-1.56, p = 0.004) and were more likely to have received surgical intervention than females (OR 1.34; 95 % CI 1.16-1.55, p < 0.001). Additionally, female patients were more likely to present with vertebral compression fracture (p < 0.001), while metastatic spinal cord compression (MSCC) and paralysis were more common in male patients (p < 0.001). There was no significant difference in rates of in-hospital complications between female and male patients. CONCLUSION: Given the significant differences in mortality, disease course, treatment, and in-hospital complications between female and male patients diagnosed with MSD, additional prospective studies are necessary to understand how to meaningfully incorporate these differences into clinical care and prognostication going forward.

A Need for More Molecular Profiling in Brain Metastases.

As local disease control improves, the public health impact of brain metastases (BrM) continues to grow. Molecular features are frequently different between primary and metastatic tumors as a result of clonal evolution during neoplasm migration, selective pressures imposed by systemic treatments, and differences in the local microenvironment. However, biomarker information in BrM is not routinely obtained despite emerging evidence of its clinical value. We review evidence of discordance in clinically actionable biomarkers between primary tumors, extracranial metastases, and BrM. Although BrM biopsy/resection imposes clinical risks, these risks must be weighed against the potential benefits of assessing biomarkers in BrM. First, new treatment targets unique to a patient's BrM may be identified. Second, as BrM may occur late in a patient's disease course, resistance to initial targeted therapies and/or loss of previously identified biomarkers can occur by the time of occult BrM, rendering initial and other targeted therapies ineffective. Thus, current biomarker data can inform real-time treatment options. Third, biomarker information in BrM may provide useful prognostic information for patients. Appreciating the importance of biomarker analyses in BrM tissue, including how it may identify specific drivers of BrM, is critical for the development of more effective treatment strategies to improve outcomes for this growing patient population.