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1.  Utility of Thyroglobulin Measurements Following Prophylactic Thyroidectomy in Patients with Hereditary Medullary Thyroid Cancer 
Surgery  2014;156(2):394-398.
Introduction
Prophylactic thyroidectomy can be curative for patients with hereditary medullary thyroid cancer (MTC) caused by RET proto-oncogene mutations. Calcitonin is a sensitive tumor marker used to follow patients. We suggest that thyroglobulin (Tg) levels should also be monitored postoperatively in these patients.
Methods
We reviewed patients with RET mutations who underwent prophylactic thyroidectomy between 1981 and 2011 at an academic endocrine surgery center. Patients were excluded if they had no postoperative Tg levels.
Results
Of the 22 patients who underwent prophylactic thyroidectomy, 14 were included in final analysis. The average age at thyroidectomy was 9.8 years (range 4 to 29). Tg levels were detectable 1.5 months to 31 years postoperatively in 11 patients (79%), all of whom were younger than 15 years-old at thyroidectomy. Median TSH was 2.5 mIU/L and 13.4 mIU/L in patients with undetectable and detectable Tg, respectively. Of those with detectable Tg, five had neck ultrasounds: Two showed no residual tissue in the thyroid bed, and three showed remnant thyroid tissue.
Conclusions
Tg levels can identify patients with remnant thyroid tissue after prophylactic thyroidectomy. Ultrasound can determine if thyroid tissue remains posterolaterally and is at risk of MTC recurrence. Maintaining normal TSH may prevent growth of remaining thyroid follicular cells.
doi:10.1016/j.surg.2014.03.037
PMCID: PMC4099273  PMID: 24882762
2.  Trajectory of Care and Use of Multimodality Therapy in Older Patients with Pancreatic Adenocarcinoma* 
Surgery  2014;156(2):280-289.
INTRODUCTION
Multimodality therapy with chemotherapy and surgical resection is recommended for patients with locoregional pancreatic cancer, but is not received by many patients.
OBJECTIVE
To evaluate patterns in the use and timing of chemotherapy and resection and factors associated with receipt of multimodality therapy in older patients with locoregional pancreatic cancer.
METHODS
We used Surveillance, Epidemiology, and End Results (SEER)-linked Medicare data (1992–2007) to identify patients with locoregional pancreatic adenocarcinoma. Multimodality therapy was defined as receipt of both chemotherapy and pancreatic resection. Logistic regression was used to determine factors independently associated with receipt of multimodality therapy. Log-rank tests were used to identify differences in survival for patients stratified by type and timing of treatment.
RESULTS
We identified 10,505 patients with pancreatic adenocarcinoma. 5,358 patients (51.0%) received either chemotherapy or surgery, with 1,166 patients (11.1%) receiving both modalities. Resection alone was performed in 1,138 patients (10.8%) and chemotherapy alone was given to 3,054 (29.1%) patients. In patients undergoing resection as the initial treatment modality, 49.4% never received chemotherapy. 97.4% of patients who underwent chemotherapy as the initial treatment modality never underwent resection. The use of multimodality therapy increased from 7.4% of patients in 1992–1995 to 13.8% of patients in 2004–2007 (p<0.0001). 2-year survival was 41.0% for patients receiving multimodality therapy, 25.1% with resection alone, and 12.5% with chemotherapy alone (p<0.0001). Of the patients receiving multimodality therapy, chemotherapy was delivered in the adjuvant setting in 93.1% and in the neoadjuvant setting in 6.9%, with similar 2-year survival with either approach (neoadjuvant vs. adjuvant, 46.9% vs. 40.6%, p=0.16). Year of diagnosis, white race, less comorbidity, and no vascular invasion were independently associated with receipt of multimodality therapy.
CONCLUSION
Only half of older patients with locoregional pancreatic cancer receive any treatment, and less than a quarter of treated patients receive multimodality therapy. Nearly all patients receiving chemotherapy as the initial treatment modality did not undergo resection, while half of those undergoing resection first received chemotherapy. When multimodality therapy is used, the vast majority of patients had chemotherapy in the adjuvant setting and survival was similar regardless of approach.
doi:10.1016/j.surg.2014.03.001
PMCID: PMC4099282  PMID: 24851723
neoadjuvant therapy; adjuvant therapy; survival; pancreatic cancer
3.  The Role of Enteral Fat as a Modulator of Body Composition Following Small Bowel Resection 
Surgery  2014;156(2):412-418.
Background
Following massive small bowel resection (SBR), a postoperative diet that is high in fat is associated with enhanced villus growth. The purpose of this study was to further elucidate the quantity and composition of enteral fat in structural and metabolic changes after SBR.
Methods
C57/Bl6 mice underwent a 50% proximal SBR. Mice were then randomized to receive a low fat diet (LFD- 12% kcal fat), medium fat diet (MFD-44% kcal fat), or high fat diet (HFD-71% kcal fat) ad lib. In a separate experiment, mice underwent 50% proximal SBR and then randomized to liquid diets of 42% kcal of fat in which the fat was composed of menhaden oil, milk fat, or olive oil. After 2 weeks, mice underwent body composition analysis and the small intestine harvested.
Results
Mice that ingested the greatest amount of enteral fat (HFD) had the highest percent lean mass. When the effects of the different kinds of enteral fat were analyzed, mice that consumed menhaden oil had the greatest percent lean mass with the greatest overall retention of preoperative weight.
Conclusions
These findings suggest that enteral fat enriched in omega-3 fatty acids may offer significant metabolic advantages for patients with short gut syndrome.
doi:10.1016/j.surg.2014.03.013
PMCID: PMC4099283  PMID: 24713095
small bowel resection; high fat diet; body composition; adaptation
4.  Morbidity and Mortality in Patients with Esophageal Atresia 
Surgery  2014;156(2):483-491.
Background
This study reports national estimates of population characteristics and outcomes for patients with EA/TEF and evaluates relationships between hospital volume and outcomes.
Methods
Patients admitted within 30 days of life who had ICD-9-CM diagnosis and procedure codes relevant to EA/TEF during 1999–2012 were identified using the Pediatric Health Information System database. Baseline demographics, comorbidities, and post-operative outcomes, including predictors of in-hospital mortality, were examined up to 2 years following EA/TEF repair.
Results
We identified 3479 patients with EA/TEF treated at 43 children’s hospitals; 37% were premature and 83.5% had ≥1additional congenital anomaly, with cardiac anomalies (69.6%) being the most prevalent. Within two years of discharge, 54.7% were readmitted, 5.2% had a repeat TEF ligation, 11.4% had a repeat operation for their esophageal reconstruction, and 11.7% underwent fundoplication. In-hospital mortality was 5.4%. Independent predictors of mortality included lower birth weight, congenital heart disease, other congenital anomalies, and preoperative mechanical ventilation. There was no significant relationship between hospital volume and mortality or repeat TEF ligation.
Conclusions
This study describes population characteristics and outcomes, including predictors of in-hospital mortality, in EA/TEF patients treated at children’s hospitals across the United States. Across these hospitals, rates of mortality or repeat TEF ligation were not dependent on hospital volume.
doi:10.1016/j.surg.2014.03.016
PMCID: PMC4099299  PMID: 24947650
5.  Oncolytic Immunotherapy Using Recombinant Vaccinia Virus GLV-1h68 Efficiently Kills Sorafenib-Resistant Hepatocellular Carcinoma 
Surgery  2014;156(2):263-269.
Background
Sorafenib is the standard systemic therapy for un-resectable or recurrent hepatocellular carcinoma (HCC) with minimal increase in survival. Therefore, there is a great need to develop novel therapies for advanced or recurrent HCC. One emerging field of cancer treatment involves oncolytic viruses that specifically infect, replicate within, and kill cancer cells. In this study we look at the ability of GLV-1h68, a recombinant vaccinia virus derived from the vaccine strain that was used to eradicate smallpox, to kill sorafenib-resistant HCC.
Methods
Four sorafenib-resistant HCC cell lines were generated by repeated passage in the presence of sorafenib. Median inhibitory concentration was determined for all cell lines. The infectivity, viral replication and cytotoxicity of GLV-1h68 were assayed for both parental and sorafenib-resistant HCC cells.
Results
Infectivity increased in a time and concentration dependent manner in all cell lines. All cell lines supported efficient replication of virus. No significant difference between the rates of cell death between the parental and sorafenib-resistant cell lines was observed.
Conclusions
Our results demonstrate that oncolytic vaccinia virus GLV-1h68 efficiently kills both parental and sorafenib-resistant HCC cell lines. This study indicates that patients who have failed treatment with sorafenib remain viable candidates for oncolytic therapy.
doi:10.1016/j.surg.2014.03.031
PMCID: PMC4216725  PMID: 24957667
Oncolytic Virus; Immunotherapy; Vaccinia; Sorafenib-resistance; Hepatocellular Carcinoma
6.  Selective Histone Deacetylase-6 Inhibition Attenuates Stress Responses and Prevents Immune Organ Atrophy in a Lethal Septic Model 
Surgery  2014;156(2):235-242.
Background
An overproduction of corticosterone during severe sepsis results in increased apoptosis of immune cells, which may result in relative immunosuppression and an impaired ability to fight infections. We have previously demonstrated that administration of Tubastatin A, a selective inhibitor of histone deacetylase-6 (HDAC6), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice. The purpose of this study was to characterize the effects of this treatment on sepsis-induced stress responses and immune function.
Methods
C57BL/6J mice were subjected to CLP, and 1 hour later given an intraperitoneal injection of either Tubastatin A dissolved in dimethyl sulfoxide (DMSO), or DMSO only. Blood samples were collected to measure the levels of circulating corticosterone and adrenocorticotropic hormone (ACTH). Thymus, and long bones (femur and tibia) were subjected to H&E staining, and immunohistochemistry was utilized to detect cleaved-caspase 3 in the splenic follicles as a measure of cellular apoptosis.
Results
All vehicle-treated CLP animals died within 3 days, and displayed increased corticosterone and decreased ACTH levels compared to the sham-operated group. These animals also developed atrophy of thymic cortex with a marked depletion of thymocytes. Tubastatin A treatment significantly attenuated the stress hormone abnormalities. Treated animals also had significantly lower percentages of thymic atrophy (95.0±5.0 vs. 42.5±25.3, p=0.0366), bone marrow depletion and atrophy (58.3±6.5 vs. 25.0±14.4%, p=0.0449), and cellular apoptosis in the splenic follicles (41.2±3.7 vs. 28.5±4.3 per 40× field, p=0.0354).
Conclusions
Selective inhibition of HDAC6 in this lethal septic model was associated with a significant blunting of the stress responses, with attenuated thymic and bone marrow atrophy, and decreased splenic apoptosis. Our findings identify a novel mechanism behind the survival advantage seen with Tubastatin A treatment.
doi:10.1016/j.surg.2014.03.033
PMCID: PMC4267495  PMID: 24947640
7.  Histone Deacetylase Inhibitor Treatment Attenuates Coagulation Imbalance in a Lethal Sepsis Model 
Surgery  2014;156(2):214-220.
Background
Sepsis has a profound impact on the inflammatory and hemostatic systems. In addition to systemic inflammation, it can produce disseminated intravascular coagulation, microvascular thrombosis, consumptive coagulopathy, and multiple organ failure. We have shown that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice. However, its effect on coagulation remains unknown. The goal of this study was to quantify the impact of SAHA treatment on coagulopathy in sepsis.
Methods
C57BL/6J mice were subjected to CLP, and 1 hour later given intraperitoneally either SAHA dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Sham-operated animals were handled in similar manner without CLP. Blood samples were collected by cardiac puncture and evaluated using the TEG® 5000 Thrombelastograph® Hemostasis Analyzer System.
Results
Compared to the sham group, all animals in DMSO vehicle group died within 72 hrs, and developed coagulopathy that manifested as prolonged initial fibrin formation and fibrin cross-linkage time, and decreased clot formation speed, platelet function and clot rigidity. SAHA treatment significantly improved survival and was also associated with improvement in fibrin cross-linkage, clot formation, as well as platelet function and clot rigidity, without a significant impact on the clot initiation parameters.
Conclusions
SAHA treatment enhances survival and attenuates sepsis-associated coagulopathy by improving fibrin cross-linkage, rate of clot formation, platelet function and clot strength. HDACI may represent a novel therapeutic strategy for correcting sepsis-associated coagulopathy.
doi:10.1016/j.surg.2014.04.022
PMCID: PMC4267526  PMID: 24957668
8.  Citrullinated Histone H3 – A Novel Target for Treatment of Sepsis 
Surgery  2014;156(2):229-234.
INTRODUCTION
We have recently demonstrated that in a rodent model of lipopolysaccharide (LPS)-induced shock, an increase in circulating citrullinated histone H3 (Cit H3) is associated with lethality of sepsis, and treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor (HDACI), significantly improves survival. However, the role of Cit H3 in pathogenesis and therapeutics of sepsis are largely unknown. The present study was designed to test whether treatment with HDACI could inhibit cellular Cit H3 production, and inhibition of peptidyalarginine deiminase (PAD, an enzyme producing Cit H3) with Cl-amidine (PAD inhibitor) or neutralization of blood Cit H3 with anti-Cit H3 antibody could improve survival in a clinically relevant mouse model of cecal ligation and puncture (CLP) induced septic shock.
METHODS
Three experiments were carried out. In experiment I, HL-60 neutrophilic cells grown on a coverslip were treated with LPS (100 ng/ml) in the presence or absence of SAHA (5 µmol) for 3 h, and subjected to immuno-staining with anti-Cit H3 antibody to assess effect of SAHA on Cit H3 production under a fluorescence microscope. The ratio of Cit H3 positive cells was calculated as mean ± SD (n=3). In experiment II, male C57BL/6J mice were subjected to CLP, and 1 hour later randomly divided into three groups for intraperitoneal injection as follows: (1) dimethyl sulfoxide (DMSO), (2) SAHA (50 mg/kg) in DMSO, and (3) Cl-amidine (80 mg/kg) in DMSO (n=10/group). In experiment III, male C57BL/6J mice were divided into control and treatment groups, and subjected to CLP. Two hours later, immunoglobulin (IgG) and Cit H3 antibody (20 mg/kg iv; n=5/group) were injected into the control and treatment groups, respectively. Survival was monitored for up to 10 days.
RESULTS
In experiment I, LPS induced Cit H3 production in the HL-60 cells, while SAHA treatment inhibited H3 citrullination significantly (p<0.05). In experiment II, all vehicle injected mice died within 3 days with increased circulating Cit H3 levels, whereas treatment with HDACI or Cl-amidine notably improved long-term survival (p< 0.01). In experiment III, administration of IgG did not improve survival, but a single treatment with Cit H3 specific antibody significantly improved survival (p<0.014).
CONCLUSIONS
Inhibition of HDAC or PAD significantly suppresses Cit H3 production in vitro, and improves survival in vivo. Neutralization of Cit H3 significantly improves survival in septic mice. Collectively, our findings indicate for the first time that Cit H3 could not only serve as a potential biomarker but also a novel therapeutic target in sepsis.
doi:10.1016/j.surg.2014.04.009
PMCID: PMC4267527  PMID: 24957671
sepsis; citrullinated histone H3; suberoylanilide hydroxamic acid; peptidyl arginine deiminase inhibitor; Cl-amidine; anti-Cit H3 antibody
9.  Procedure-specific venous thromboembolism prophylaxis: A paradigm from colectomy surgery 
Surgery  2012;152(4):528-536.
Background
Colectomy patients are at high-risk for venous thromboembolism (VTE), but associated risk factors and best prophylaxis in this defined population are only generalized.
Methods
Fifteen hospitals prospectively collected pre-, peri-, and postoperative variables related to VTE and prophylaxis, in addition to the variables defined by the National Surgical Quality Improvement Program between 2008 and 2009 concerning open and laparoscopic colectomy patients with 30-day outcomes. Symptomatic VTE was the primary outcome, and risk factors were tested for association with VTE using multiple logistic regression.
Results
The cohort included 3,464 patients with a mean age of 65; 53% were female. Overall, the 30d incidence of VTE was 2.2%. VTE prophylaxis included sequential compression devices (SCDs, 11%) alone; pharmacologic prophylaxis alone (15%); and both SCDs and pharmacologic prophylaxis (combined prophylaxis, 74%). VTE was associated with each additional year of age (OR, 1.05; 95% CI 1.02–1.06, P < .001); increased body mass index (OR 1.03; CI 1.01–1.05; P = .02); preoperative anemia (OR 2.4; CI 1.2–4.8; P = .011); contaminated wound (OR 3.4; CI 1.6–7.3; P < .01); postoperative surgical site infection (OR 2.5; CI 1.2–5.2; P < .011); and postoperative sepsis/pneumonia (OR 3.6; CI 1.9–6.7; P < .01). Postoperative factors alone accounted for 32% of VTE risk. When controlling for all other factors, only combination prophylaxis was protective against VTE (OR 0.48; CI 0.27–0.9; P = .02). Operative time, presence of disseminated malignancy, anastomotic leak, transfusion, urinary tract infection, and laparoscopic procedure were not significantly associated with VTE. Propensity matching showed that unfractionated heparin was equivalent to low molecular weight heparin, and the transfusion rate was not increased with pharmacologic prophylaxis compared to SCDs alone.
Conclusion
Regardless of preoperative factors, VTE prophylaxis using a combination of SCDs and chemoprophylaxis was associated with significant reduction in VTE and should be standard care for patients after colectomy.
doi:10.1016/j.surg.2012.07.012
PMCID: PMC4496155  PMID: 23021132
10.  Effects of Poloxamer 188 on human PMN cells 
Surgery  2008;144(2):198-203.
Poloxamer 188 (P188), a nonionic block copolymer chemical surfactant known to have cytoprotective, rheologic, anti-inflammatory, and anti-thrombotic activity, has shown promise in the management of selected trauma patients. We studied human PMN oxidative burst and adhesion molecule expression when exposed to P188.
After RBC lysis of whole blood samples, WBC components were primed with PAF, primed and activated with fMLP, primed and activated with PMA, or left unstimulated. Each group was treated with vehicle or P188 (0.005 – 15 mg/ml concentrations). Flow cytometry quantified: 1) PMN superoxide anion production and 2) PMN marker expression of CD11b and L-selectin.
Among non-PMA activated PMNs, P188 increased superoxide anion production. PMA-activated PMNs decreased superoxide anion production, proportional to P188 dose. Among fMLP-activated PMNs, the highest P188 dose increased the expression of CD11b. Among PMA-activated PMNs, decreased CD11b expression was seen for the mid-range doses.
PMN’s altered their oxidative burst and marker expression after exposure to P188. When used at lower doses, P188 may increase the oxidative burst response and, when used at very high doses, increase CD11b expression. However, if PMNs are in a maximally activated state, a higher dose of P188 may decrease the oxidative burst response and decrease CD11b expression.
doi:10.1016/j.surg.2008.05.001
PMCID: PMC4477269  PMID: 18656626
11.  Development of a calcium-sensing receptor molecular imaging agent 
Surgery  2013;154(6):1378-1384.
Background
Calcium-sensing receptor (CaSR) is expressed by parathyroid cells and thyroid C-cells (from which medullary thyroid carcinoma [MTC] is derived). A molecular imaging agent localizing to the CaSR could improve the detection of parathyroids and MTC preoperatively or intraoperatively. We synthesized a novel compound containing a fluorine residue for potential future labeling and demonstrated that the compound inhibited CaSR function in vitro.
Methods
We synthesized compound M, a derivative of a known calcilytic compound, Calhex-231. Human embryonic kidney cells transfected with green-fluorescent protein-tagged CaSR or control vector were preincubated with compound M before the addition of calcium. Immunoblotting for total mitogen-activated protein kinase (MAPK: ERK1/2), activated MAPK (phosphorylated ERK1/2), and glyceraldehyde 3-phosphate dehydrogenase was performed.
Results
Synthesis of compound M was confirmed by mass spectrometry. Inhibition of the MAPK signaling pathway by compound M was demonstrated in a dose-dependent manner by a decrease in phosphorylated ERK1/2 with no change in total ERK1/2 levels. Compound M inhibited MAPK signaling slightly better than the parent compound.
Conclusion
We have developed a novel molecule which demonstrates functional inhibition of CaSR and has a favorable structure for labeling. This compound appears to be appropriate for further development as a molecular imaging tool to enhance the surgical treatment of parathyroid disease and MTC.
doi:10.1016/j.surg.2013.06.044
PMCID: PMC4477839  PMID: 24238055
12.  Heparin-binding EGF-like Growth Factor Restores Wnt/β-catenin Signaling in Intestinal Stem Cells Exposed to Ischemia/Reperfusion Injury 
Surgery  2014;155(6):1069-1080.
Background
We have previously demonstrated that heparin-binding EGF-like growth factor (HB-EGF) protects the intestines from injury in several different experimental animal models. In the current study, we investigated whether the ability of HB-EGF to protect the intestines from ischemia/reperfusion (I/R) injury was related to its effects on Wnt/β-catenin signaling in intestinal stem cells (ISC).
Methods
LGR5-EGFP transgenic (TG) mice with fluorescently labeled ISC, as well as the same mice treated with intraluminal HB-EGF or genetically engineered to overexpress HB-EGF, were exposed to segmental mesenteric artery occlusion (sMAO) to the terminal ilium. Wnt/β-catenin signaling was evaluated using immunofluorescent staining and Western blotting.
Results
LGR5 expression and Wnt/β-catenin signaling in the ISC of the terminal ilium of LGR5-EGFP TG mice was significantly reduced 24 h post sMAO. Intraluminal administration of HB-EGF or HB-EGF overexpression in these mice led to preservation of LGR5 expression and Wnt/β-catenin signaling.
Conclusion
These data show that HB-EGF preserves Wnt/β-catenin signaling in ISC after I/R injury.
doi:10.1016/j.surg.2014.01.013
PMCID: PMC4034135  PMID: 24856127
13.  For-Profit Hospital Ownership Status and Use of Brachytherapy after Breast-Conserving Surgery 
Surgery  2013;155(5):776-788.
BACKGROUND
Little is known about the relation between surgical care for breast cancer at for-profit hospitals and subsequent use of adjuvant radiation therapy (RT). Among Medicare beneficiaries, we examined whether hospital ownership status is associated with the use of breast brachytherapy – a newer and more expensive modality – as well as overall RT.
METHODS
We conducted a retrospective study of female Medicare beneficiaries receiving breast-conserving surgery for invasive breast cancer in 2008 and 2009. We assessed the relationship between hospital ownership and receipt of brachytherapy or overall RT using hierarchical generalized linear models.
RESULTS
The sample consisted of 35,118 women, 8.0% of whom had surgery at for-profit hospitals. Among patients who received RT, those who underwent surgery at for-profit hospitals were significantly more likely to receive brachytherapy (20.2%) than patients treated at not-for-profit hospitals (15.2%; OR for for-profit vs. not-for-profit: 1.50; 95%CI: 1.23–1.84; p<0.001). Among women aged 66–79, there was no relation between hospital ownership status and overall RT use. Among women aged 80–94 years old – the group least likely to benefit from RT due to shorter life expectancy – receipt of surgery at a for-profit hospital was significantly associated with higher overall RT use (OR: 1.22; 95%CI: 1.03–1.45, p=0.03) and brachytherapy use (OR: 1.66; 95%CI: 1.18–2.34, p=0.003).
CONCLUSIONS
Surgical care at for-profit hospitals was associated with increased use of the newer and more expensive RT modality, brachytherapy. Among the oldest women, who are least likely to benefit from RT, surgical care at a for-profit hospital was associated with higher overall RT use, with this difference largely driven by the use of brachytherapy.
doi:10.1016/j.surg.2013.12.009
PMCID: PMC4008843  PMID: 24787104
14.  Hospital-based, acute care following ambulatory surgery center discharge 
Surgery  2013;155(5):743-753.
Background
As a measure of quality, ambulatory surgery centers have begun reporting rates of hospital transfer at discharge. However, this may underestimate patient’s acute care needs after care. We conducted this study to determine rates and evaluate variation in hospital transfer and hospital-based, acute care within 7 days among patients discharged from ambulatory surgery centers.
Methods
Using data from the Healthcare Cost and Utilization Project, we identified adult patients who underwent a medical or surgical procedure between July 2008 and September 2009 at ambulatory surgery centers in California, Florida, and Nebraska. The primary outcomes were hospital transfer at the time of discharge and hospital-based, acute care (emergency department visits or hospital admissions) within 7-days expressed as the rate per 1,000 discharges. At the ambulatory surgery center level, rates were adjusted for age, sex, and procedure-mix.
Results
We studied 3,821,670 patients treated at 1,295 ambulatory surgery centers. At discharge, the hospital transfer rate was 1.1/1,000 discharges (95% CI, 1.1–1.1). Among patients discharged home, the hospital-based, acute care rate was 31.8/1,000 discharges (95% CI, 31.6–32.0). Across ambulatory surgery centers, there was little variation in adjusted hospital transfer rates (median=1.0/1,000 discharges [25th–75th percentile=1.0–2.0]), while substantial variation existed in adjusted hospital-based, acute care rates (28.0/1,000 [21.0–39.0]).
Conclusions
Among adult patients undergoing ambulatory surgery center care, hospital transfer at discharge is a rare event. In contrast, the hospital-based, acute care rate is nearly 30-fold higher, varies across centers, and may be a more meaningful measure for discriminating quality.
doi:10.1016/j.surg.2013.12.008
PMCID: PMC4114736  PMID: 24787100
15.  A qualitative analysis of acute care surgery in the United States: It’s more than just “a competent surgeon with a sharp knife and a willing attitude” 
Surgery  2013;155(5):809-825.
Background
Since acute care surgery (ACS) was conceptualized a decade ago, the specialty has been adopted widely; however, little is known about the structure and function of ACS teams.
Methods
We conducted 18 open-ended interviews with ACS leaders (representing geographic [New England, Northeast, Mid-Atlantic, South, West, Midwest] and practice [Public/Charity, Community, University] diversity). Two independent reviewers analyzed transcribed interviews using an inductive approach (NVivo qualitative analysis software).
Results
All respondents described ACS as a specialty treating “time-sensitive surgical disease” including trauma, emergency general surgery (EGS), and surgical critical care (SCC); 11 of 18 combined trauma and EGS into a single clinical team; 9 of 18 included elective general surgery. Emergency orthopedics, emergency neurosurgery, and surgical subspecialty triage were rare (1/18 each). Eight of 18 ACS teams had scheduled EGS operating room time. All had a core group of trauma and SCC surgeons; 13 of 18 shared EGS due to volume, human resources, or competition for revenue. Only 12 of 18 had formal signout rounds; only 2 of 18 had prospective EGS data registries. Streamlined access to EGS, evidence-based protocols, and improved education were considered strengths of ACS. ACS was described as the “last great surgical service” reinvigorated to provide “timely,” cost-effective EGS by experts in “resuscitation and critical care” and to attract “young, talented, eager surgeons” to trauma/SCC; however, there was concern that ACS might become the “wastebasket for everything that happens at inconvenient times.”
Conclusion
Despite rapid adoption of ACS, its implementation varies widely. Standardization of scope of practice, continuity of care, and registry development may improve EGS outcomes and allow the specialty to thrive. (Surgery 2014;155:809-25.)
doi:10.1016/j.surg.2013.12.012
PMCID: PMC4207259  PMID: 24787108
16.  User-centered design of quality of life reports for clinical care of patients with prostate cancer 
Surgery  2013;155(5):789-796.
Background
Primary treatment of localized prostate cancer can result in bothersome urinary, sexual, and bowel symptoms. Yet clinical application of health-related quality-of-life (HRQOL) questionnaires is rare. We employed user-centered design to develop graphic dashboards of questionnaire responses from patients with prostate cancer to facilitate clinical integration of HRQOL measurement.
Methods
We interviewed 50 prostate cancer patients and 50 providers, assessed literacy with validated instruments (Rapid Estimate of Adult Literacy in Medicine short form, Subjective Numeracy Scale, Graphical Literacy Scale), and presented participants with prototype dashboards that display prostate cancer-specific HRQOL with graphic elements derived from patient focus groups. We assessed dashboard comprehension and preferences in table, bar, line, and pictograph formats with patient scores contextualized with HRQOL scores of similar patients serving as a comparison group.
Results
Health literacy (mean score, 6.8/7) and numeracy (mean score, 4.5/6) of patient participants was high. Patients favored the bar chart (mean rank, 1.8 [P = .12] vs line graph [P <.01] vs table and pictograph); providers demonstrated similar preference for table, bar, and line formats (ranked first by 30%, 34%, and 34% of providers, respectively). Providers expressed unsolicited concerns over presentation of comparison group scores (n = 19; 38%) and impact on clinic efficiency (n = 16; 32%).
Conclusion
Based on preferences of prostate cancer patients and providers, we developed the design concept of a dynamic HRQOL dashboard that permits a base patient-centered report in bar chart format that can be toggled to other formats and include error bars that frame comparison group scores. Inclusion of lower literacy patients may yield different preferences.
doi:10.1016/j.surg.2013.12.007
PMCID: PMC4237217  PMID: 24787105
17.  The effect of complications on the patient-surgeon relationship after colorectal cancer surgery 
Surgery  2013;155(5):841-850.
Background
Trust in physicians is an essential part of therapeutic relationships. Complications are common after colorectal cancer procedures, but little is known of their effect on patient-surgeon relationships. We hypothesized that unexpected complications impair trust and communication between patients and surgeons.
Methods
We performed a population-based survey of surgically diagnosed stage III colorectal cancer patients in the Surveillance Epidemiology and End Results registries for Georgia and Metropolitan Detroit between August 2011 and October 2012. Using published survey instruments, we queried subjects about trust in and communication with their surgeon. The primary predictor was the occurrence of an operative complication. We examined patient factors associated with trust and communication then compared the relationship between operative complications and patient-reported trust and communication with their surgeons.
Results
Among 622 preliminary respondents (54% response rate), 25% experienced postoperative complications. Those with complications were less likely to report high trust (73% vs 81%, P = .04) and high-quality communication (80% vs 95%, P < .001). Complications reduced trust among only 4% of patient-surgeon dyads with high-quality communication, whereas complications diminished patients’ trust in 50% with poorer communication (P < .001). After controlling for communication ratings, we found there was no residual effect of complications on trust (P = .96).
Conclusion
Most respondents described trust in and communication with their surgeons as high. Complications were common and were associated with lower trust and poorer communication. However, the relationship between complications and trust was modified by communication. Trust remained high, even in the presence of complications, among respondents who reported high levels of patient-centered communication with their surgeons.
doi:10.1016/j.surg.2013.12.011
PMCID: PMC4254758  PMID: 24787111
18.  A critical analysis of the American Joint Committee on Cancer (AJCC) staging system for differentiated thyroid carcinoma in young patients on the basis of the Surveillance, Epidemiology, and End Results (SEER) registry 
Surgery  2012;152(2):145-151.
Background
Differentiated thyroid carcinomas (DTC) are the only tumors for which age is a determinant of stage in the American Joint Committee on Cancer’s (AJCC) staging protocol. In this study, we re-examined the relationship between age, extent of disease, and prognosis by using a large dataset with longer follow-up times.
Methods
We examined the Surveillance, Epidemiology, and End Results (SEER) registry data 1973 to 2005 for patients with DTC as their only known malignancy. We used Cox multivariate analyses to generate mortality hazard ratios, controlling for several variables, to evaluate the effects of age and disease extent.
Results
We identified 55,402 patients with DTC. Of these, 49,240 had sufficient data to generate a TNM stage on the basis of AJCC guidelines. Within stage II, younger patients (<45 years) have worse outcomes than older patients (P <.001). Younger patients had an 11-fold increase in mortality between stages I and II, whereas there was no difference for older patients. When we uniformly applied the 45-and-older staging protocol to all patients, we found that stages III–IVc had a significantly greater risk of mortality for all patients compared with stage I.
Conclusion
The presence of regional and metastatic thyroid cancer bears prognostic significance for all ages. Under current AJCC guidelines, young patients with metastatic thyroid cancer may be understaged.
doi:10.1016/j.surg.2012.02.015
PMCID: PMC4416476  PMID: 22503316
19.  Chemokines and chemokine receptors: Update on utility and challenges for the clinician 
Surgery  2014;155(6):961-973.
doi:10.1016/j.surg.2014.02.006
PMCID: PMC4390364  PMID: 24856117
20.  Peri-anal implantation of bioengineered human internal anal sphincter constructs intrinsically innervated with human neural progenitor cells 
Surgery  2013;155(4):668-674.
Background
The internal anal sphincter (IAS) is a major contributing factor to anal canal pressure and is required for maintenance of rectoanal continence. IAS damage or weakening results in fecal incontinence. We have demonstrated that bioengineered intrinsically innervated human IAS tissue replacements possess key aspects of IAS physiology, like generation of spontaneous basal tone and contraction/relaxation in response to neurotransmitters. The objective of this study is to demonstrate the feasibility of implantation of bioengineered IAS constructs in the peri-anal region of athymic rodents.
Methods
Human IAS tissue constructs were bioengineered from isolated human IAS circular smooth muscle cells and human enteric neuronal progenitor cells. Upon maturation of the bioengineered constructs in culture, they were implanted surgically into the perianal region of athymic rats. Growth factor was delivered to the implanted constructs through a microosmotic pump. Implanted constructs were retrieved from the animals 4 weeks post-implantation.
Results
Animals tolerated the implantation well, and there were no early postoperative complications. Normal stooling was observed during the implantation period. Upon harvest, implanted constructs were adherent to the perirectal rat tissue, and appeared healthy and pink. Immunohistochemical analysis revealed neovascularization. Implanted smooth muscle cells maintained contractile phenotype. Bioengineered constructs responded to neuronally evoked relaxation in response to electrical field stimulation and vasoactive intestinal peptide, indicating the preservation of neuronal networks.
Conclusions
Our results indicate that bioengineered innervated IAS constructs can be used to augment IAS function in an animal model. This is a regenerative medicine based therapy for fecal incontinence that would directly address the dysfunction of the IAS muscle.
doi:10.1016/j.surg.2013.12.023
PMCID: PMC4017655  PMID: 24582493
21.  Viscoelastic clot strength predicts coagulation-related mortality within 15 minutes 
Surgery  2011;151(1):48-54.
Background
Predicting refractory coagulopathy early in resuscitation of injured patients may decrease a leading cause of preventable death. We hypothesized that clot strength (G) measured by point-of-care rapid thrombelastography (r-TEG) on arrival in the emergency department can predict massive transfusion (MT) and coagulation-related mortality (MT-death).
Methods
Trauma alerts/activations from May 2008 to September 2010 were reviewed. The variables included the following: age, sex, injury severity score (ISS), systolic blood pressure (SBP), base deficit (BD), traditional coagulation tests (international normalized ratio ([INR], partial thromboplastin time [PTT]), TEG-derived G, and blood products transfused within the first 6 hours. Independent predictors of 2 outcomes (MT [≥10 packed red blood cells units/6 h] and MT-related death) were identified using logistic regression. The individual predictive values of BD, INR, PTT, and G were assessed comparing the areas under the receiver operating characteristic curves (AUC ROC), while adjusting for age, ISS, and SBP.
Results
Among the 80 study patients, 48% required MT, and 21% died of MT-related complications. INR, ISS, and G were independent predictors of MT, whereas age, ISS, SBP, and G were independently associated with MT-death. The predictive power for outcome MT did not differ among INR (adjusted AUC ROC = 0.92), PTT (AUC ROC = 0.90, P = .41), or G (AUC ROC = 0.89, P = .39). For outcome MT-death, G had the greatest adjusted AUC ROC (0.93) compared with the AUC ROC for BD (0.87, P = .05), INR (0.88, P = .11), and PTT (0.89; P = .19).
Conclusion
These data suggest that the point-of-care TEG parameter clot strength (G) provides consistent, independent prediction of MT and MT-death early in the resuscitation of injured patients.
doi:10.1016/j.surg.2011.06.023
PMCID: PMC4364997  PMID: 21899867
22.  Novel Pharmacological Treatment Attenuates Septic Shock and Improves Long-Term Survival 
Surgery  2013;154(2):206-213.
Background
We have previously demonstrated that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lipopolysaccharide (LPS)-induced lethal endotoxemia model. The goal of this study was to investigate the impact of SAHA on survival in a more clinically relevant cecal ligation and puncture (CLP)-induced septic shock model, and to elucidate changes in cytokine responses and organ injury.
Methods
C57BL/6J mice were subjected to CLP, and 1 hour later given either SAHA dissolved in dimethyl sulfoxide (DMSO) or DMSO only, intra-peritoneal. Survival was monitored for 10 days. In a second study, livers were harvested for evaluation of acute liver injury, and peritoneal fluid and blood samples were collected for cytokine assays. In addition, RAW264.7 and bone marrow-derived macrophages (BMMs) were utilized to assess effects of SAHA on cytokine responses.
Results
SAHA treated animals displayed a significant improvement in survival. In addition, SAHA also significantly attenuated cytokine levels in blood and peritoneal fluid compared to vehicle animals, as well as in culture supernatant of macrophages stimulated with bacterial components (LPS or Pam3CSK4). Moreover, SAHA treated animals showed a significant decrease in acute liver injury.
Conclusions
SAHA treatment improves survival, reduces “cytokine storm”, and prevents distant organ damage in a lethal septic model.
doi:10.1016/j.surg.2013.04.003
PMCID: PMC4361041  PMID: 23889949
23.  Two-stage brachial-basilic transposition fistula provides superior patency rates for dialysis access in a safety-net population 
Surgery  2010;148(4):687-694.
Background
Guidelines of the National Kidney Foundation recommending aggressive pursuit of autogenous fistulae for dialysis access in lieu of prosthetic arteriovenous grafts have stimulated a renewed interest in transposed brachial-basilic fistulae as an alternative technique for upper arm access in patients who may not be candidates for a lower arm radial-cephalic or forearm brachial-cephalic fistula. We hypothesized that in our safety-net population, where radial-cephalic and brachial-cephalic often are not possible, brachial-basilic would provide patency rates superior to arteriovenous grafts and equivalent to radial-cephalic and brachial-cephalic fistulae.
Methods
We analyzed retrospectively our most recent 2.5-year experience with dialysis access procedures at our metropolitan safety-net hospital. Procedures were grouped as follows: radial-cephalic, brachial-cephalic, brachial-basilic, and arteriovenous grafts. The access outcomes measured were primary failure, time to use, need for intervention, and primary as well as secondary patency. Differences in age, sex, race, renal function (Modification of Diet in Renal Disease), baseline diagnoses (diabetes mellitus, hypertension, coronary artery disease, and peripheral vascular disease), as well as the number of previous accesses, were adjusted in the analysis. Logistic regression was used to identify independent predictors of primary failure, and Kaplan-Meier plots assessed differences in primary patency rates. A log of the time variables was used to approximate normal distribution.
Results
In all, 193 patients were included in this study as follows: radial-cephalic, 75 (39%) patients; brachial-cephalic, 35 (18%) patients; brachial-basilic, 33 (17%) patients; and arteriovenous grafts, 50 (26%) patients. Primary patency means differed marginally between groups (P = .08), and when grafts were excluded from the analysis, no difference was found between primary patency in all autogenous fistula techniques (P = .88). Kaplan-Meier plots showed that when analyzing the first 35 weeks, a significantly lower primary patency among graft recipients early after the procedure was noted, and a higher performance of BB after 20 weeks was noted (log-rank P = .05,Wilcoxon P = .004). Furthermore, secondary patency did not vary significantly between groups (P = .62). Radial-cephalic were more likely to fail primarily when compared with the other access groups (P = .03), and in a univariate analysis, underlying hypertension was associated with a lower risk of primary failure (P = .01) compared with other diagnoses. A logistic regression stepwise selection showed that the underlying diagnoses of peripheral vascular disease, diabetes mellitus, or coronary artery disease were associated with a greater risk of primary failure compared with those with HTN (P = .001; odds ratio, 4.05; 95%confidence interval, 1.71–9.59), as well as the presence of a previously failed access (P = .04; odds ratio, 2.39; 95% confidence interval, 1.08–5.67).
Conclusion
In a safety-net population, our results suggest that 2-stage brachial-basilic transposition fistulae provide patency rates equivalent to brachial-cephalic and radial-cephalic fistulae and superior to grafts. Although 2 procedures are required, brachial-basilic fistulae provide a reliable access and should be considered the next choice when radial-cephalic and/or brachial-cephalic are not possible.
doi:10.1016/j.surg.2010.07.033
PMCID: PMC4358877  PMID: 20723958
24.  Laparoscopy is safe among patients with congestive heart failure undergoing general surgery procedures 
Surgery  2014;156(2):371-378.
Background
Over the past 2 decades, laparoscopy has been established as a superior technique in many general surgery procedures. Few studies, however, have examined the impact of the use of a laparoscopic approach in patients with symptomatic congestive heart failure (CHF). Because pneumoperitoneum has known effects on cardiopulmonary physiology, patients with CHF may be at increased risk. This study examines current trends in approaches to patients with CHF and effects on perioperative outcomes.
Methods
The 2005–2011 National Surgical Quality Improvement Program Participant User File was used to identify patients who underwent the following general surgery procedures: Appendectomy, segmental colectomy, small bowel resection, ventral hernia repair, and splenectomy. Included for analysis were those with newly diagnosed CHF or chronic CHF with new signs or symptoms. Trends of use of laparoscopy were assessed across procedure types. The primary endpoint was 30-day mortality. The independent effect of laparoscopy in CHF was estimated with a multiple logistic regression model.
Results
A total of 265,198 patients were included for analysis, of whom 2,219 were identified as having new or recently worsened CHF. Of these patients, there were 1,300 (58.6%) colectomies, 486 (21.9%) small bowel resections, 216 (9.7%) ventral hernia repairs, 141 (6.4%) appendectomies, and 76 (3.4%) splenectomies. Laparoscopy was used less frequently in patients with CHF compared with their non-CHF counterparts, particularly for nonelective procedures. Baseline characteristics were similar for laparoscopy versus open procedures with the notable exception of urgent/emergent case status (36.4% vs 71.3%; P < .001). After multivariable adjustment, laparoscopy seemed to have a protective effect against mortality (adjusted odds ratio, 0.45; P = .04), but no differences in other secondary endpoints.
Conclusion
For patients with CHF, an open operative approach seems to be utilized more frequently in general surgery procedures, particularly in urgent/emergent cases. Despite these patterns and apparent preferences, laparoscopy seems to offer a safe alternative in appropriately selected patients. Because morbidity and mortality were considerable regardless of approach, further understanding of appropriate management in this population is necessary.
doi:10.1016/j.surg.2014.03.003
PMCID: PMC4346558  PMID: 24947641
25.  Assessing the experience in complex hepatopancreatobiliary surgery among graduating chief residents: Is the operative experience enough? 
Surgery  2014;156(2):385-393.
Introduction
Resident operative autonomy and case volume is associated with posttraining confidence and practice plans. Accreditation Council for Graduate Medical Education requirements for graduating general surgery residents are four liver and three pancreas cases. We sought to evaluate trends in resident experience and autonomy for complex hepatopancreatobiliary (HPB) surgery over time.
Methods
We queried the Accreditation Council for Graduate Medical Education General Surgery Case Log (2003–2012) for all cases performed by graduating chief residents (GCR) relating to liver, pancreas, and the biliary tract (HPB); simple cholecystectomy was excluded. Mean (±SD), median [10th–90th percentiles] and maximum case volumes were compared from 2003 to 2012 using R2 for all trends.
Results
A total of 252,977 complex HPB cases (36% liver, 43% pancreas, 21% biliary) were performed by 10,288 GCR during the 10-year period examined (Mean = 24.6 per GCR). Of these, 57% were performed during the chief year, whereas 43% were performed as postgraduate year 1–4. Only 52% of liver cases were anatomic resections, whereas 71% of pancreas cases were major resections. Total number of cases increased from 22,516 (mean = 23.0) in 2003 to 27,191 (mean = 24.9) in 2012. During this same time period, the percentage of HPB cases that were performed during the chief year decreased by 7% (liver: 13%, pancreas 8%, biliary 4%). There was an increasing trend in the mean number of operations (mean ± SD) logged by GCR on the pancreas (9.1 ± 5.9 to 11.3 ± 4.3; R2 = .85) and liver (8.0 ± 5.9 to 9.4 ± 3.4; R2 = .91), whereas those for the biliary tract decreased (5.9 ± 2.5 to 3.8 ± 2.1; R2 = .96). Although the median number of cases [10th:90th percentile] increased slightly for both pancreas (7.0 [4.0:15] to 8.0 [4:20]) and liver (7.0 [4:13] to 8.0 [5:14]), the maximum number of cases preformed by any given GCR remained stable for pancreas (51 to 53; R2 = .18), but increased for liver (38 to 45; R2 = .32). The median number of HPB cases that GCR performed as teaching assistants (TAs) remained at zero during this time period. The 90th percentile of cases performed as TA was less than two for both pancreas and liver.
Conclusion
Roughly one-half of GCR have performed fewer than 10 cases in each of the liver, pancreas, or biliary categories at time of completion of residency. Although the mean number of complex liver and pancreatic operations performed by GCR increased slightly, the median number remained low, and the number of TA cases was virtually zero. Most GCR are unlikely to be prepared to perform complex HPB operations.
doi:10.1016/j.surg.2014.03.006
PMCID: PMC4316664  PMID: 24953270

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