Elena M. Paulus

Blunt cerebrovascular injury screening with 64-channel multidetector computed tomography: more slices finally cut it.

BACKGROUND Aggressive screening to diagnose blunt cerebrovascular injury (BCVI) results in early treatment, leading to improved outcomes and reduced stroke rates. While computed tomographic angiography (CTA) has been widely adopted for BCVI screening, evidence of its diagnostic sensitivity is marginal. Previous work from our institution using 32-channel multidetector CTA in 684 patients demonstrated an inadequate sensitivity of 51% (Ann Surg. 2011,253: 444–450). Digital subtraction angiography (DSA) continues to be the reference standard of diagnosis but has significant drawbacks of invasiveness and resource demands. There have been continued advances in CT technology, and this is the first report of an extensive experience with 64-channel multidetector CTA. METHODS Patients screened for BCVI using CTA and DSA (reference) at a Level 1 trauma center during the 12-month period ending in May 2012 were identified. Results of CTA and DSA, complications, and strokes were retrospectively reviewed and compared. RESULTS A total of 594 patients met criteria for BCVI screening and underwent both CTA and DSA. One hundred twenty-eight patients (22% of those screened) had 163 injured vessels: 99 (61%) carotid artery injuries and 64 (39%) vertebral artery injuries. Sixty-four–channel CTA demonstrated an overall sensitivity per vessel of 68% and specificity of 92%. The 52 false-negative findings on CTA were composed of 34 carotid artery injuries and 18 vertebral artery injuries; 32 (62%) were Grade I injuries. Overall, positive predictive value was 36.2%, and negative predictive value was 97.5%. Six procedure-related complications (1%) occurred with DSA, including two iatrogenic dissections and one stroke. CONCLUSION Sixty-four–channel CTA demonstrated a significantly improved sensitivity of 68% versus the 51% previously reported for the 32-channel CTA (p = 0.0075). Sixty-two percent of the false-negative findings occurred with low-grade injuries. Considering complications, cost, and resource demand associated with DSA, this study suggests that 64-channel CTA may replace DSA as the primary screening tool for BCVI. LEVEL OF EVIDENCE Diagnostic study, level III.

MicroRNA-21 Promotes Glioblastoma Tumorigenesis by Down-regulating Insulin-like Growth Factor-binding Protein-3 (IGFBP3)

Background: miR-21 is overexpressed in many human cancers, including glioblastoma. Results: Insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) is a novel miR-21 target gene and inhibits gliomagenesis in vitro and in vivo. Conclusion: miR-21 down-regulates IGFBP3, which acts as a tumor suppressor in human glioblastoma. Significance: IGFBP3 may have promise as a therapeutic target and prognostic marker for glioblastoma. Despite advances in surgery, imaging, chemotherapy, and radiation, patients with glioblastoma multiforme (GBM), the most common histological subtype of glioma, have an especially dismal prognosis; >70% of GBM patients die within 2 years of diagnosis. In many human cancers, the microRNA miR-21 is overexpressed, and accumulating evidence indicates that it functions as an oncogene. Here, we report that miR-21 is overexpressed in human GBM cell lines and tumor tissue. Moreover, miR-21 expression in GBM patient samples is inversely correlated with patient survival. Knockdown of miR-21 in GBM cells inhibited cell proliferation in vitro and markedly inhibited tumor formation in vivo. A number of known miR-21 targets have been identified previously. By microarray analysis, we identified and validated insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) as a novel miR-21 target gene. Overexpression of IGFBP3 in glioma cells inhibited cell proliferation in vitro and inhibited tumor formation of glioma xenografts in vivo. The critical role that IGFBP3 plays in miR-21-mediated actions was demonstrated by a rescue experiment, in which IGFBP3 knockdown in miR-21KD glioblastoma cells restored tumorigenesis. Examination of tumors from GBM patients showed that there was an inverse relationship between IGFBP3 and miR-21 expression and that increased IGFBP3 expression correlated with better patient survival. Our results identify IGFBP3 as a novel miR-21 target gene in glioblastoma and suggest that the oncogenic miRNA miR-21 down-regulates the expression of IGFBP3, which acts as a tumor suppressor in human glioblastoma.

The Oncogenic MicroRNA-21 Inhibits the Tumor Suppressive Activity of FBXO11 to Promote Tumorigenesis

Background: miR-21 is overexpressed in many human cancers. Results: FBXO11 (a member of the F-box subfamily lacking a distinct unifying domain) is a novel miR-21 target gene, and inhibits tumorigenesis. Conclusion: miR-21 down-regulates FBXO11 which acts as a tumor suppressor in melanoma, prostate cancer and glioblastoma. Significance: FBXO11 may have promise as a therapeutic target, and as a diagnostic and prognostic marker in cancer. The microRNA miR-21 is overexpressed in most human cancers and accumulating evidence indicates that it functions as an oncogene. Since miRNAs suppress the expression of their target genes, we hypothesized that some miR-21 targets may act as tumor suppressors, and thus their expression would be anticipated to be reduced by the high miR-21 levels observed in various human cancers. By microarray analysis and quantitative PCR we identified and validated FBXO11 (a member of the F-box subfamily lacking a distinct unifying domain) as a miR-21 target gene. FBXO11 is a component of the SKP1-CUL1-F-box ubiquitin ligase complex that targets proteins for ubiquitination and proteosomal degradation. By loss of function and gain of function studies, we show that FBXO11 acts as a tumor suppressor, promotes apoptosis and mediates the degradation of the oncogenic protein BCL6. The critical role that FBXO11 plays in miR-21-mediated tumorigenesis was demonstrated by a rescue experiment, in which silencing FBXO11 in miR-21KD cancer cells restored their high tumorigenicity. Expression of miR-21 and FBXO11 are inversely correlated in tumor tissue, and their expression correlates with patient survival and tumor grade. High FBXO11 expression correlates with better patient survival and lower tumor grade consistent with its tumor suppressor activity. In contrast high miR-21 expression, which correlates with poor patient survival and higher tumor grade, is consistent with its oncogenic activity. Our results identify FBXO11 as a novel miR-21 target gene, and demonstrate that the oncogenic miRNA miR-21 decreases the expression of FBXO11, which normally acts as a tumor suppressor, and thereby promotes tumorigenesis.

Routine peritoneal drainage of the surgical bed after elective distal pancreatectomy: is it necessary?

BACKGROUND Recent literature suggests that peritoneal drainage (PD) is not helpful after elective pancreatectomy and may be detrimental. Data specific to distal pancreatectomy (DP) have not received prior evaluation. METHODS We performed a retrospective review of patients who underwent DP. Factors examined included postoperative morbidity and the need for therapeutic intervention. RESULTS Sixty-nine patients had DP, 30 without PD. Thirty-four patients suffered 45 complications, most were intra-abdominal in nature. Twelve, 19, and 3 patients required radiologic drainage, reoperation, or both, respectively. There was no difference between groups relative to intra-abdominal complications or the need for therapeutic intervention. Of 39 patients undergoing PD, 19 had abdominal morbidity. The drain was useful in identifying and/or treating the complication in 3 patients. CONCLUSIONS First, PD after DP does not confer a reduction in morbidity or the need for therapeutic intervention versus patients with no drains. Second, the presence of a drain infrequently was helpful in detecting complications. Third, a multi-institutional, randomized study is recommended.

Emergency general surgery outcomes at safety net hospitals

BACKGROUND The United States hospital safety net is defined by the Agency for Healthcare Research and Quality as the top decile of hospitals, which see the greatest proportion of uninsured patients. These hospitals provide important access to health care for uninsured patients but are commonly believed to have worse outcomes. The aim of this study was to compare the outcomes of emergency general surgery procedures performed at safety net and nonsafety net hospitals. MATERIAL AND METHODS The Healthcare Cost and Utilization Project Nationwide Inpatient Sample from 2008-2010 was used to create a cohort of inpatients who underwent emergency appendectomy, cholecystectomy, or herniorrhaphy. Outcomes measured included length of stay, charge, cost, death in hospital, complications, and failure to rescue (FTR). Univariate and logistic regression analysis was performed to associate variables with outcomes. RESULTS A total of 187,913 emergency general surgery cases were identified, 11.5% of which were performed at safety net hospitals. The safety net cohort had increased length of stay but lower mean charge and cost. Age, comorbidity score, black race, male gender, and Medicaid and Medicare insurance were associated with mortality, complication, and FTR. Lower socioeconomic status was associated with mortality and complication. Safety net status was positively associated with complication but not mortality or FTR. CONCLUSIONS Safety net hospitals had higher complication rates but no difference in FTR or mortality. This may mean that the hospitals are able to effectively recognize and treat patient complications and do so without increased cost.

Diagnostic laparoscopy after anterior abdominal stab wounds: Worth another look?

BACKGROUND The National Institute of Medicine’s report Hospital-Based Emergency Care: At the Breaking Point highlighted the critical issue of emergency department overcrowding. At our institution, patients with anterior abdominal stab wounds (AASW) have been managed with a protocol that uses diagnostic laparoscopy (DL) after positive result on local wound exploration. Patients with negative DL result are eligible for discharge directly from the recovery room. The purpose of this study was to evaluate the use of DL for AASWs in light of the recommendations that suggested serial abdominal examination (SAE) is preferred to determine the need for laparotomy. METHODS Patients admitted to a Level 1 trauma center from January 2010 through August 2012 with AASWs were included (contemporary period to Western Trauma Association study). Information regarding baseline characteristics, diagnostic workup, injury management, and outcomes were retrospectively reviewed and compared with the SAE AASW algorithm. RESULTS A total of 158 patients with AASWs were evaluated using our institutional algorithm. Thirty-eight patients (24%) went directly to the operating room for peritonitis, shock, or evisceration; 120 underwent local wound exploration; 99 had positive result (82%). Twenty-eight patients had immediate laparotomy owing to worsening clinical examination findings. Seventy had DL, and 19 of these patients were discharged home from the recovery room, with a mean length of stay of 6.4 hours. When comparing patients managed using the DL algorithm to those managed using the SAE-based algorithm, the nontherapeutic laparotomy rate was lower, although not statistically significant. However, the DL algorithm produced a significantly higher percentage of patients discharged directly home following local wound exploration. CONCLUSION With some trauma centers suffering from emergency department overcrowding and constrained resources, DL may offer an alternative to SAE to efficiently use available resources. Both SAE and DL are safe and offer similar therapeutic laparotomy rates. The method used to evaluate patients after AASW should be tailored to institutional needs and resources. LEVEL OF EVIDENCE Therapeutic/care management, level IV.

Crystalloid administration during trauma resuscitation: does less really equal more?

BACKGROUND Current direction in trauma resuscitation includes emphasis on minimizing crystalloid, along with early transfusion of blood products. Although evidence suggests that higher crystalloid volume during the first 24 hours is associated with negative outcomes, the effect of crystalloid administration during initial resuscitation remains unclear. The purpose of this study was to evaluate the impact of the ratio of crystalloid to packed red blood cells (C/PRBCs) infused during initial emergency department resuscitation on pulmonary morbidity and mortality. METHODS Over 6.5 years at a Level 1 trauma center, prospective data were collected on patients that received more than 1 PRBC unit in the resuscitation room. C/PRBC was defined as the ratio of crystalloid infused in liters to the units of PRBCs transfused in the resuscitation room. Patients were stratified by high ratio (>0.75) versus low ratio (<0.75). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were determined for the association between C/PRBC group and outcomes, namely, adult respiratory distress syndrome (ARDS), 24-hour mortality, and in-hospital mortality. RESULTS A total of 383 patients met study criteria: 192 (50%) in the high-ratio and 191 (50%) in the low-ratio group. Variables associated with in-hospital mortality were Injury Severity Score (ISS) (OR, 1.05; 95% CI, 1.03–1.07), admission base excess (OR, 0.94; 95% CI, 0.90–0.98), and time in the resuscitation room (OR, 1.01; 95% CI, 1.00–1.03). Variables associated with 24-hour mortality were ISS (OR, 1.04; 95% CI, 1.02–1.06) and base excess (OR, 0.95; 95% CI, 0.91–1.00). Only ISS (OR, 1.05; 95% CI, 1.02–1.07) was associated with ARDS. ARDS (OR, 1.43; 95% CI, 0.75–2.73), 24-hour mortality (OR, 0.89; 95% CI, 0.49–1.63), and in-hospital mortality (OR, 0.89; 95% CI, 0.52–1.53) were not associated with C/PRBC. CONCLUSION In this cohort of patients receiving PRBC in the resuscitation room, factors related primarily to injury severity were associated with pulmonary morbidity and mortality, but C/PRBC was not. Pertaining to initial resuscitation, the purported benefit of crystalloid limitation was not observed. LEVEL OF EVIDENCE Therapeutic study, level IV; prognostic study, level III.

Cytotoxicity of Hypo-osmolar Lavage Fluid on Ovarian Cancer Cells In vitro

Objective: Ovarian cancer is difficult to diagnose early and many patients present with advanced disease. The presence of exfoliated ovarian cancer cells in the peritoneal cavity after debulking surgery is a poor prognostic indicator. Sterilization of the peritoneum during surgery may have clinical benefit in reducing tumor burden. Several studies have evaluated osmotic cytotoxicity in gastrointestinal and genitourinary cancers with varied results. We studied the cytotoxic effect of lavage fluids of differing osmolarities against multiple ovarian cancer cell lines (SKOV3, OV90, and OVCAR3) in vitro. Methods: Cells were treated for either 10 minutes or 30 minutes with water, or 5 mOsm, 10 mOsm, 50 mOsm, 100 mOsm, 200 mOsm, 280 mOsm NaCl (dilutions in water), and PBS. After 24 hours, surviving cells were enumerated in a Coulter Counter. Results: All 3 ovarian cancer cell lines were lysed progressively as lavage osmolarity was reduced (p<0.01). For the OVCAR3 ovarian cancer cells, lavage for 30 min resulted in greater cell cytotoxicity for lavage with the water, 5, 10, 50, and 200 mOsm saline when compared to lavage for 10 min. For the OV90 cancer cell line, lavage for 30 min resulted in greater cell cytotoxicity for the water, 5, and 10 mOsm saline lavages. In the SKOV3 ovarian cancer cell line, only lavage for the 30 min water had cytotoxicity. Conclusions: Since ovarian cancer uniquely resides in the peritoneal cavity, this anatomic feature allows concentrated washing to directly target these cancer cells residing in the peritoneal cavity. Hypo-osmolar treatment was found to be most effective in lysing ovarian cancer cell lines in vitro.

Abstract P4-14-07: Understanding disparities in breast cancer care in Memphis, Tennessee

Although significant progress has been made in improving breast cancer survival, disparities among racial, ethnic, and underserved groups still exist. The goal of this investigation is to quantify racial disparities in the context of breast cancer care, examining the outcomes of recurrence and mortality in the city of Memphis. Patients with a biopsy-proven diagnosis of breast cancer from January 1, 2002, through December 31, 2012, were obtained from the tumor registry. Black patients were more likely to have advanced (II, III, or IV) clinical stage of breast cancer at diagnosis versus white patients. Black breast cancer patients had a two times higher odds of recurrence (95% confidence interval: 1.4, 3.0) after adjusting for race and clinical stage. Black breast cancer patients were 1.5 times more likely to die (95% confidence interval: 1.2, 1.8), after adjusting for race; age at diagnosis; clinical stage; ER, PR, HER2 status; and recurrence. Black women with stages 0, I, II, and III breast cancer all had a statistically significant longer median time from diagnosis to surgery than white women. Black patients were more likely to have advanced clinical stages of breast cancer at diagnosis versus white patients on a citywide level in Memphis. Black breast cancer patients have higher odds of recurrence and mortality when compared with white breast cancer patients, after adjusting for appropriate demographic and clinical attributes. More work is needed to develop, evaluate, and disseminate interventions to decrease inequities in timeliness of care for breast cancer patients.