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1.  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
2.  A comparison of open and minimally invasive surgery for hepatic and pancreatic resections using the nationwide inpatient sample 
Surgery  2014;156(3):538-547.
Background
The use of minimally invasive surgery (MIS) techniques for pancreatic and liver operations remains ill defined. We sought to compare inpatient outcomes among patients undergoing open versus MIS pancreas and liver operations using a nationally representative cohort.
Methods
We queried the Nationwide Inpatient Sample database for all major pancreatic and hepatic resections performed between 2000 and 2011. Appropriate International Classification of Diseases, 9th Revision (ICD-9) coding modifiers for laparoscopy and robotic assist were used to categorize procedures as MIS. Demographics, comorbidities, and inpatient outcomes were compared between the open and MIS groups.
Results
A total of 65,033 resections were identified (pancreas, n = 36,195 [55.7%]; liver, n = 28,035 [43.1%]; combined pancreas and liver, n = 803 [1.2%]). The overwhelming majority of operations were performed open (n = 62,192, 95.6%), whereas 4.4% (n = 2,841) were MIS. The overall use of MIS increased from 2.3% in 2000 to 7.5% in 2011. Compared with patients undergoing an open operation, MIS patients were older and had a greater incidence of multiple comorbid conditions. After operation, the incidence of complications for MIS (pancreas, 35.4%; liver, 29.5%) was lower than for open (pancreas, 41.6%; liver, 33%) procedures (all P < .05) resulting in a shorter median length of stay (8 vs 7 days; P = .001) as well as a lower in-hospital mortality (5.1% vs 2.8%; P = .001).
Conclusion
During the last decade, the number of MIS pancreatic and hepatic operations has increased, with nearly 1 in 13 HPB cases now being performed via an MIS approach. Despite MIS patients tending to have more preoperative medical comorbidities, postoperative morbidity, mortality, and duration of stay compared favorably with open surgery.
doi:10.1016/j.surg.2014.03.046
PMCID: PMC4316739  PMID: 25017135
3.  INTEGRIN β1 IS CRITICAL FOR GASTRIN-RELEASING PEPTIDE RECEPTOR-MEDIATED NEUROBLASTOMA CELL MIGRATION AND INVASION 
Surgery  2013;154(2):369-375.
Background
Gastrin-releasing peptide (GRP) and its receptor, GRP-R, are critically involved in neuroblastoma tumorigenesis; however, the molecular mechanisms and signaling pathways that are responsible for GRP/GRP-R-induced cell migration and invasion remain unclear. Here, we sought to determine the cell signals involved in GRP/GRP-R-mediated neuroblastoma cell migration and invasion.
Methods
Human neuroblastoma cell lines, SK-N-SH, LAN-1 and IMR-32, were used for our study. Transwell migration and invasion assays were performed after GRP (10−7 M) stimulation. cDNA GEArray® Microarray kit was used to determine GRP-R-induced gene expression changes. Protein and membrane expression of integrin subunits were confirmed by Western blotting and flow cytometry analysis. siRNA transfection was performed using Lipofectamine 2000. For scratch assay, a confluent monolayer of cells in 6-well plate were wounded with micropipette tip and observed microscopically at 24 to 72 h.
Results
GRP increased neuroblastoma cell migration and expressions of MMP-2 while TIMP-1 level decreased. GRP-R overexpression stimulated SK-N-SH cell migration, and upregulated integrin α2, α3, and β1 protein as well as mRNA expression. Targeted silencing of integrin β1 inhibited cell migration.
Conclusions
GRP/GRP-R signaling contributes to neuroblastoma cell migration and invasion. Moreover, integrin β1 subunit critically regulates GRP-R-mediated neuroblastoma cell migration and invasion.
doi:10.1016/j.surg.2013.04.067
PMCID: PMC4313735  PMID: 23889963
Integrin; GRP-R; Migration; Neuroblastoma
4.  Proteome and system ontology of hemorrhagic shock: Exploring early constitutive changes in postshock mesenteric lymph 
Surgery  2009;146(2):347-357.
Background
Postshock mesenteric lymph (PSML) is the mechanistic link between splanchnic ischemia reperfusion (IR) and remote organ injury. We hypothesize that an unbiased inspection of the proteome of PSML will reveal previously unrecognized aberrations in systems biology provoked by hemorrhage-induced mesenteric IR injury in vivo.
Methods
Shock was induced in male Sprague-Dawley rats by controlled hemorrhage, and the mesenteric duct was cannulated for lymph collection. Preshock and postshock lymph were collected for differential in-gel electrophoresis (DIGE)-based proteomics. Proteins that increased or decreased in relative concentration ≥1.5-fold were selected for trypsin digestion and analysis by mass spectrometry (MS).
Results
Evidence of tissue injury was detected by an increase in cell/tissue proteins in PSML. Components of coagulation were depleted, whereas products of hemolysis were increased. Haptoglobin was decreased, which supports an early postshock hemolytic process. Interestingly, several protective protease inhibitors were decreased in PSML. The unexpected findings were an increase in α-enolase (a key glycolitic enzyme and cell-surface plasminogen binding receptor, +2.4-fold change) and increased major urinary protein (MUP, a sex-specific lipid-binding protein, +17.1-fold change) in PSML.
Conclusion
A proteomic evaluation of PSML revealed evidence of several shock-associated processes: protein release from tissue injury, depletion of coagulation factors and evidence of hemolysis, depletion of protective protease inhibitors, and an increase in abundance of lipid carriers. These results suggest that constitutive changes in the proteome of PSML may provide novel insights into the complex pathophysiology of postshock systems biology.
doi:10.1016/j.surg.2009.02.022
PMCID: PMC4313876  PMID: 19628095
5.  Impact of adjuvant external beam radiotherapy on survival in surgically resected gallbladder adenocarcinoma: A propensity score–matched Surveillance, Epidemiology, and End Results analysis 
Surgery  2013;155(1):85-93.
Background
We sought to define the utilization and effect of adjuvant external-beam radiotherapy (XRT) on patients having undergone curative-intent resection for gallbladder cancer (GBC).
Methods
Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 5,011 patients with GBC who underwent resection between 1988 and 2009. The impact of XRT on survival was analyzed by the use of propensity-score matching by comparing clinicopathologic factors between patients who received resection only versus resection plus XRT.
Results
Median age was 72 years, and most patients were female (73.4%); 66.2% patients had intermediate to poorly differentiated tumors, and 19.1% had lymph node metastasis. The majority (75.0%) had “localized” disease by Surveillance, Epidemiology, and End Results classification. A total of 899 patients (17.9%) received XRT whereas 4,112 patients did not. Factors associated with receipt of XRT were younger age (odds ratio [OR] 5.33), tumor extension beyond the serosa (OR 1.55), intermediate- to poorly differentiated tumors (OR 1.56), and lymph node metastasis (OR 2.59) (all P <.05). Median and 1-year survival were 15 months and 59.0%, respectively. On propensity-matched multivariate model, despite having more advanced tumors, XRT was independently associated with better long-term survival at 1 year (hazard ratio 0.45; P < .001), but not 5 years (hazard ratio 1.06; P = .50).
Conclusion
A total of 18% of patients with GBC received XRT after curative intent surgery. The use of adjuvant XRT was associated with a short-term survival benefit, but the benefit dissipated over time.
doi:10.1016/j.surg.2013.06.001
PMCID: PMC3979596  PMID: 23876364
6.  Impact and Timing of Bilateral Adrenalectomy for Refractory ACTH-Dependent Cushing’s Syndrome 
Surgery  2013;154(6):1174-1184.
Introduction
In patients with refractory ACTH-dependent Cushing’s syndrome (CS), we evaluated steroidogenesis inhibition (SI) and bilateral adrenalectomy (BA) to predict which patients might benefit most from each treatment modality.
Methods
Clinical data from patients treated 1970-2012 were retrospectively reviewed by treatment group (SI or SI+BA). Validated severity scales were used to calculate metabolic (M) score (hypokalemia, hyperglycemia, hypertension, proximal muscle weakness) and adverse events (AE) score (thrombosis, fracture, infection).
Results
65 patients (16 pituitary, 49 ectopic) were treated with SI+BA (n=21,32%) or SI alone (n=44,68%). Presenting M scores and source of ACTH excess (ectopic vs. pituitary) were similar. Both groups improved metabolically after treatment. 39% of AEs in the SI+BA group occurred within 12 months of presentation. 24(55%) SI patients died (median survival 24.0 months); steroid excess contributed to 71%. Six SI+BA patients died (29%), including all 3 patients with recurrent CS after BA. Minor perioperative complications occurred in 7 patients (33%).
Conclusions
Post-treatment M and AE scores improved for all patients and 70% of AEs occurred in SI+BA patients within 12 months of presentation, emphasizing the importance of early surgical intervention. These data argue for the safety and efficacy of early BA in selected patients with uncontrollable CS.
PMCID: PMC4271839  PMID: 24383115
7.  Novel In Vitro Model for Studying Hepatic Ischemia-Reperfusion Injury Using Liver Cubes 
Surgery  2012;152(2):247-253.
Background
While inflow occlusion techniques have given surgeons the ability to carry out increasingly complex liver resections, ischemia-reperfusion (IR) injury continues to be a source of morbidity. Efforts to ameliorate IR injury have been hindered in absence of adequate pre-clinical models. The goal of the present study was to develop a simple, efficient, and cost-effective means of studying hepatic IR injury.
Methods
Liver cubes were procured from normal (C57BL/6) mice. Following hepatectomy, 4 mm punch biopsies were taken for individual placement in culture wells containing hepatocyte media. Experimental cubes underwent hypoxia for 60 minutes, while controls remained normoxic. Supernatants were collected from individual wells following 0, 6 and 12 hours of rediffusion for transaminase and cytokine measurement. Histologic examination was performed on individual cubes.
Results
Extensive histologic injury was seen in the experimental cubes compared to controls with greater staining for activated caspase-3 and TUNEL at 6 and 24 hours, respectively. Changes consistent with ischemic injury occurred more centrally in liver cubes whereas markers for rediffusion injury were appreciated along the periphery. Transaminases were significantly higher at 6 hours following rediffusion in experimental cubes compared to controls, p = 0.02. TNF-α and IL-1β were significantly higher in the media of experimental cubes compared to controls at 12 hours rediffusion, p = 0.05 and 0.03 respectively.
Conclusions
In vitro IR of cubes produces a significant injury whose pattern is reflective of hepatic lobular architecture. This novel technique may open new avenues for uncoupling the mechanisms of IR while facilitating rapid screening of potential therapies.
doi:10.1016/j.surg.2012.02.012
PMCID: PMC4258692  PMID: 22698934
8.  Radioguided Parathyroidectomy for Hyperparathyroidism in the Reoperative Neck 
Surgery  2009;146(4):592-599.
Background
The purpose of this study was to determine if radioguided parathyroidectomy (RGP) is effective for hyperparathyroidism (HPT) in the reoperative neck.
Methods
We retrospectively reviewed all patients with HPT and a history of neck surgery who underwent RGP over a 7-year period. Data are reported as mean ± SEM.
Results
We identified 110 patients with primary (n=94), secondary (n=7), or tertiary (n=9) HPT who underwent 138 previous neck operations. The average hospital stay was 0.6 ± 0.1 days. The in and ex vivo counts obtained with the gamma probe were 310 ± 26 and 130 ± 13, respectively. The ex vivo percentage of background was 69 ± 9%, and virtually all resected parathyroids had ex vivo counts ≥ 20%. Following RGP, 96% of patients were cured, and 4.5% experienced complications (all transient). Cure rates after RGP significantly decreased as the number of previous neck surgeries increased (P=0.002). Additionally, reoperative neck patients with single adenomas were more likely to experience cure than patients with hyperplasia (P=0.02).
Conclusions
These results illustrate that RGP is valuable adjunct in the reoperative neck. In addition, RGP allows similar lengths of stay, efficacy, and complication rates as those reported for patients undergoing initial parathyroidectomy.
doi:10.1016/j.surg.2009.06.031
PMCID: PMC4254908  PMID: 19789017
9.  THE EFFECT OF CINACALCET (SENSIPAR®) ON INTRAOPERATIVE FINDINGS IN TERTIARY HYPERPARATHYROIDISM PATIENTS UNDERGOING PARATHYROIDECTOMY 
Surgery  2014;156(6):1308-1314.
Introduction
Tertiary hyperparathyroidism (3HPTH) patients who undergo parathyroidectomy are often managed with calcium lowering medications such as cinacalcet (Sensipar®) preceding surgery. Here, we assess how cinacalcet (Sensipar®) treatment influences intraoperative PTH (IOPTH) kinetics and surgical findings in 3HPTH patients undergoing parathyroidectomy.
Methods
116 retrospectively reviewed 3HPTH patients underwent, parathyroidectomy of which 14 were on cinacalcet and 112 were on no drug. IOPTH levels fitted to linear curves vs. time were used to evaluate the role of cinacalcet.
Results
Cinacalcet did not significantly correlate with rates of cure (p=0.41) or recurrence (p=0.54). Patients on cinacalcet experienced a significantly steeper decline in IOPTH compared to those not on medication (p=0.005). Cinacalcet treatment was associated with a significant increase in rate of hungry bones (p=0.04). Weights of the heaviest glands resected (p=0.02) and preoperative PTH levels (p=0.0004) were significantly higher among patients on cinacalcet.
Conclusions
Perioperative cinacalcet treatment in 3HPTH patients alters IOPTH kinetics by causing a steeper IOPTH decline, but does not require modifying standard IOPTH protocol. Although cinacalcet use does not adversely affect cure rates, it is associated with higher preoperative PTH and an increased incidence of hungry bones, hence serving as an indicator of more severe disease. Cinacalcet does not need to be held prior to surgery.
doi:10.1016/j.surg.2014.08.003
PMCID: PMC4254721  PMID: 25456900
10.  Is Central Lymph Node Dissection Necessary for Parathyroid Carcinoma? 
Surgery  2014;156(6):1336-1341.
Background
Parathyroid carcinoma is a rare cancer. Unlike other more common malignancies, the significance of lymph node (LN) status remains controversial. The purpose of this study was to determine the relative importance of LN metastases in disease-specific survival (DSS).
Methods
A retrospective review of the Surveillance, Epidemiology, and End Result (SEER) database was performed on parathyroid carcinoma cases diagnosed between 1988 and 2010.
Results
405 parathyroid carcinoma patients were identified. Among 114 patients with LNs examined at surgery, only 12 (10.5%) had positive LNs. Sensitivity analysis found that a tumor size threshold of 3 cm best divided the cohort by DSS. Only tumors ≥3 cm and distant metastasis but not LN metastases were independent prognostic factors on multivariate analysis. When examining factors associated with LN status, only tumors ≥3 cm predicted LN metastasis. LN metastases were 7.5 times more likely in patients with tumors ≥3 cm than those with tumors <3 cm.
Conclusions
Tumors ≥3 cm were associated with LN metastases in parathyroid carcinoma but positive LN status was not associated with DSS. Tumor size can potentially risk stratify patients by their risk of LN metastases.
doi:10.1016/j.surg.2014.08.005
PMCID: PMC4254726  PMID: 25456903
11.  Efferent vagal nerve stimulation attenuates acute lung injury following burn: The importance of the gut-lung axis 
Surgery  2011;150(3):379-389.
Background
The purpose of this study was to assess acute lung injury when protection to the gut mucosal barrier offered by vagus nerve stimulation is eliminated by an abdominal vagotomy.
Methods
Male balb/c mice were subjected to 30% total body surface area steam burn with and without electrical stimulation to the right cervical vagus nerve. A cohort of animals were subjected to abdominal vagotomy. Lung histology, myeloperoxidase and ICAM-1 immune staining, myeloperoxidase enzymatic assay, and tissue KC levels were analyzed 24 hours after burn. Additionally, lung IkB-α, NF-kB immunoblots, and NF-kB-DNA binding measured by photon emission analysis using NF-kB-luc transgenic mice were performed.
Results
Six hours post burn, phosphorylation of both NF-kB p65 and IkB-α were observed. Increased photon emission signal was seen in the lungs of NF-kB-luc transgenic animals. Vagal nerve stimulation blunted NF-kB activation similar to sham animals whereas abdominal vagotomy eliminated the anti-inflammatory effect. After burn, MPO positive cells and ICAM-1 expression in the lung endothelium was increased, and lung histology demonstrated significant injury at 24 hours. Vagal nerve stimulation markedly decreased neutrophil infiltration as demonstrated by MPO immune staining and enzyme activity. Vagal stimulation also markedly attenuated acute lung injury at 24 hours. The protective effects of vagal nerve stimulation were reversed by performing an abdominal vagotomy.
Conclusion
Vagal nerve stimulation is an effective strategy to protect against acute lung injury following burn. Moreover, the protective effects of vagal nerve stimulation in the prevention of acute lung injury are eliminated by performing an abdominal vagotomy. These results establish the importance of the gut-lung axis after burn in the genesis of acute lung injury.
doi:10.1016/j.surg.2011.06.008
PMCID: PMC4251587  PMID: 21783215
12.  Targeting the gut barrier: Identification of a homing peptide sequence for delivery into the injured intestinal epithelial cell 
Surgery  2009;146(2):206-212.
Background
Severe injury results in intestinal barrier dysfunction that may be responsible for significant morbidity and mortality. We postulated that mining a peptide library that was displayed on phage would identify peptide sequences that bind and internalize into the gut epithelium following injury.
Methods
We utilized a severe full thickness burn in mice as a model of severe injury. Candidate peptides were identified by screening 1012 phage displaying unique peptide sequences. In vivo assessment was performed by injecting targeted phage into the lumen of a segment of distal ileum following burn injury, then analyzed for uptake of peptide sequence using quantitative polymerase chain reaction (PCR), DNA sequencing, and confocal microscopy of the peptide bound to quantum dots (Qdots).
Results
Phage screening identified the peptide sequence T18 (LTHPQDSPPASA) as an optimal candidate for in vivo testing. PCR of intestinal cells following injury showed a higher level of T18 sequence when compared to untargeted phage. Confocal microscopy of the peptide sequence bound to Qdots showed internalization into gut mucosa following injury.
Conclusion
We have identified a peptide sequence that targets the injured intestinal epithelium and may allow for the development of targeted therapies to attenuate inflammation, or other pathologic conditions of the small bowel.
doi:10.1016/j.surg.2009.05.007
PMCID: PMC4251594  PMID: 19628075
13.  Oncolytic Vesicular Stomatitis Virus as a Treatment for Neuroendocrine Tumors 
Surgery  2013;154(6):10.1016/j.surg.2013.04.050.
Background
Therapeutic goals for neuroendocrine tumors (NETs) not amenable to surgical cure are limited to relieving symptoms and slowing progression. However, many cancers acquire defective antiviral responses as they undergo unregulated proliferation. Therefore, we explored the abilities of recombinant wild-type vesicular stomatitis virus (rwt-VSV) and an attenuated Matrix protein mutant (M51R-VSV) to exploit defective antiviral pathways in NETs.
Methods
Viral infectivity and lethality were evaluated in a panel of human NET cell lines H727, UMC-11, and CNDT2.5. We evaluated β-interferon pathways in these cells to define the acquired defect. Murine xenografts were treated with a single intratumoral injection of M51RVSV to study viral efficacy in vivo.
Results
VSV infected >99% of cells within 24 hours and killed >95% within 72 hours. NET cells did not produce significant amounts of β-interferon after infection, but exogenous β-interferon protected cells from oncolysis. Treatment with M51R-VSV resulted in significantly suppressed tumor growth compared with mock-infected xenografts for H727 (87±72% vs. 2197±335%, p<0.001), UMC-11 (12±59% vs. 1471±324%, p<0.001), and CNDT2.5 (81±121% vs. 1576±349%, p=0.001).
Conclusions
VSV infects and kills human NETs by exploiting their inability to produce a type I antiviral response. Therefore, M51R-VSV is an excellent candidate for the treatment of advanced NETs.
doi:10.1016/j.surg.2013.04.050
PMCID: PMC3833953  PMID: 23973113
14.  Prospective Screening in Familial Non-medullary Thyroid Cancer 
Surgery  2013;154(6):10.1016/j.surg.2013.06.019.
Background
Approximately 8% of non-medullary thyroid cancers are familial. The optimal age for screening in familial non-medullary thyroid cancer (FNMTC) is unknown.
Method
Kindreds with FNMTC (2 or more first-degree relatives affected) were prospectively screened by thyroid ultrasound.
Results
Fifteen kindreds showed an overall prevalence of thyroid nodule(s) ≥ 5 mm of 44.4% at screening; 19.2% in the second generation, and 90% in the generation anterior to the index case. The youngest age of detection was 10 years for thyroid nodules and 18 years for thyroid cancer. Thyroid nodule microcalcification at screening was associated with a higher risk of cancer (p < 0.05). Family members diagnosed with thyroid cancer by ultrasound screening were diagnosed at a younger age and had a lower rate of extrathyroidal invasion (p < 0.05).
Conclusions
In FNMTC, first-degree relatives 10 years or older, including the generation anterior to the index case, should have thyroid ultrasound screening. This may result in earlier diagnosis.
doi:10.1016/j.surg.2013.06.019
PMCID: PMC3857607  PMID: 23978593
Familial non-medullary thyroid cancer; screening; thyroid nodule
15.  Timing of Symptom Improvement After Parathyroidectomy for Primary Hyperparathyroidism 
Surgery  2013;154(6):10.1016/j.surg.2013.09.005.
Background
The timing of symptom improvement after parathyroidectomy for primary hyperparathyroidism (PHPT) has not been well characterized.
Methods
This prospective study involved administering a questionnaire to patients with PHPT who underwent curative parathyroidectomy over an 11-month period. The questionnaire evaluated the frequency of 18 symptoms of PHPT on a 5-point Likert scale, and was administered pre-operatively, and 1 week, 6 weeks, and 6 months postoperatively.
Results
Of 197 eligible patients, 132 (67%) participated in the study. The questionnaires were completed at a rate of 91%, 92%, and 86% at 1 week, 6 weeks, and 6 months post-operatively, respectively. The most commonly reported pre-operative symptoms were fatigue (98%), muscle aches (89%), and bone/joint pain (87%). Improvement in symptom severity occurred across all symptoms and was separated into three categories based on the timing of improvement. Fatigue and bone/joint pain demonstrated ‘Immediate Improvement’ (>50% of patients reporting improvement by post-operative week 1), whereas the majority of symptoms showed peak improvement at 6 weeks (‘Delayed Improvement’). Symptoms categorized as ‘Continuous Improvement’ were those showing progressive improvement up to 6 months post-operatively (polydipsia, headaches, and nausea/vomiting).
Conclusions
Symptom improvement was most prominent 6 weeks post-parathyroidectomy, though some symptoms showed continued improvement at 6 months.
doi:10.1016/j.surg.2013.09.005
PMCID: PMC3860985  PMID: 24238059
16.  Potential role of 5- aza-2’-deoxycytidine induced MAGE-A4 expression in immunotherapy for anaplastic thyroid cancer 
Surgery  2013;154(6):10.1016/j.surg.2013.07.009.
Background
MAGEA4, a member of the cancer testis antigen (CTA) family has been reported in various cancers including melanoma, bladder, head and neck, oral, lung, and is a potential target for T cell receptor (TCR) based immunotherapy. Baseline expression levels of the MAGEA4 gene in thyroid cancer cell lines have not been previously thoroughly studied.
Method
Human thyroid cancer cell lines (8505c, HTh7, BCPAP and TPC-1) were treated with either 10μM 5’-azacytidine (Aza), 10μM 5-aza-2’deoxycytidine (DAC) and evaluated for various MAGEA gene expression. Later melanoma cell line, A375 and 8505c were treated with PLX4720 in combination with DAC and evaluated for MAGEA4 expression.
Results
Only BCPAP cells expressed moderate levels of MAGEA3 and A6 at baseline. Treatment with DAC/ Aza induced the expression of MAGEA4 and A1 in 8505c cells. PLX4720 treatment did not affect MAGEA4 expression in 8505c cells but increased its expression in A375 cells. However, addition of PLX4720 to DAC treated 8505c cells decreased the previously induced MAGEA4 expression by DAC in these cells. Similar dampening of MAGEA4 expression by DAC was also seen in 8505cBRAF−/− cells. While DAC treatment resulted in demethylation of the MAGEA4 promoter in two CpG sites, PLX addition to DAC did not affect the demethylation status.
Conclusion
Demethylating agents increased the MAGE's expression in thyroid cancer cells. The effect of BRAFV600E inhibitors on MAGEA4 expression suggest the role of downstream MEK/BRAF signaling in its expression apart from promoter demethylation being the sole requirement. Expression of MAGEA4 may make immunotherapeutic intervention possible in selected thyroid cancer patients.
doi:10.1016/j.surg.2013.07.009
PMCID: PMC3863391  PMID: 24238058
Cancer-testis antigens; MAGE; thyroid cancer; melanoma; demethylation agents; BRAFV600E inhibitor
17.  MiR-34a and miR-483-5p are candidate serum biomarkers for adrenocortical tumors 
Surgery  2013;154(6):10.1016/j.surg.2013.06.022.
Background
Nonfunctioning adrenal incidentalomas are common and many patients undergo adrenalectomy to exclude adrenocortical carcinoma (ACC). Recent studies have shown dysregulated microRNA expression in ACC. The objective of this study was to determine the feasibility and diagnostic accuracy of measuring serum microRNAs in patients with benign and malignant adrenocortical tumors.
Method
Five microRNAs were selected from microRNA profiling studies in ACC (miR-let-7d, -34a, -195, -214, and 483-5p). Total microRNA was extracted from serum samples in patients with malignant and benign adrenal neoplasms. MicroRNAs levels were measured by quantitative RT-PCR and normalized to miR-16. To determine if microRNAs were secreted from ACC cells, we measured microRNA levels in culture.
Results
Serum samples from 22 patients with cortical adenomas and 17 patients with ACC were analyzed and all 5 microRNAs were detected. We found higher levels of miR-34a(p=0.001) and miR-483-5p(p=0.011) in patients with ACC. The AUC was 0.81 for miR-34a and 0.74 for miR-438-5p. MiR-34a and miR-483-5p levels in ACC cells were higher in the supernatant at 48 hours as compared to intracellular levels.
Conclusions
We show dysregulated microRNAs in ACC are detectable in human serum samples. MiR-34a and miR-483-5p are candidate serum biomarkers for distinguishing between benign and malignant adrenocortical tumors.
doi:10.1016/j.surg.2013.06.022
PMCID: PMC3874721  PMID: 24238045
adrenocortical carcinoma; microRNA; serum; diagnosis; biomarker
18.  Gastric inhibitory polypeptide receptor (GIPR) is a promising target for imaging and therapy in neuroendocrine tumors 
Surgery  2013;154(6):10.1016/j.surg.2013.04.052.
Background
Ligands binding the somatostatin receptor type 2 (SSTR2) are useful for imaging and treatment of neuroendocrine tumors (NETs), but not all tumors express high levels of these receptors. The aim of this study was to evaluate gene expression of new therapeutic targets in NETs relative to SSTR2.
Methods
RNA was extracted from 103 primary small bowel (SBNET) and pancreatic neuroendocrine tumors (PNET), matched normal tissue, and 123 metastases. Expression of 12 candidate genes was measured by quantitative PCR normalized to internal controls; candidate gene expression was compared to SSTR2.
Results
Relative to normal tissue, primary NET expression of SSTR2, GPR98, BRS3, GIPR, GRM1, and OPRK1 were increased by 3, 8, 13, 13, 17, and 20-fold, respectively. Similar changes were found in metastases. While most candidate genes showed lower absolute expression than SSTR2, absolute GIPR expression was closest to SSTR2 (mean dCT 3.6 vs. 2.7, p=0.01). Absolute OPRK1 and OXTR expression varied significantly by primary tumor type and was close to SSTR2 in SBNETs but not PNETs.
Conclusions
Compared to the current treatment standard SSTR2, GIPR has only somewhat lower absolute gene expression in tumor tissue but much lower expression in normal tissue, making it a promising new target for NET imaging and therapy.
doi:10.1016/j.surg.2013.04.052
PMCID: PMC3881364  PMID: 24238043
19.  A novel optical approach to intraoperative detection of parathyroid glands 
Surgery  2013;154(6):1371-1377.
Background
Inadvertent removal of parathyroid glands is a challenge in endocrine operations. There is a critical need for a diagnostic tool that provides sensitive, real-time parathyroid detection during procedures. We have developed an intraoperative technique using near-infrared (NIR) fluorescence for in vivo, real-time detection of the parathyroid regardless of its pathologic state.
Methods
NIR fluorescence was measured intraoperatively from 45 patients undergoing parathyroidectomy and thyroidectomy. Spectra were measured from the parathyroid and surrounding neck tissues during the operation with the use of a portable, probe-based fluorescence system at 785-nm excitation. Accuracy was evaluated by comparison with histology or visual recognition by the surgeon.
Results
NIR fluorescence detected the parathyroid in 100% of patients. Parathyroid fluorescence was stronger (1.2–18 times) than that of the thyroid with peak fluorescence at 822 nm. Surrounding tissues showed no auto-fluorescence. Disease state did not affect the ability to discriminate parathyroid glands but may account for signal variability.
Conclusions
NIR fluorescence spectroscopy can detect intraoperatively the parathyroid regardless of tissue pathology. The signal may be caused by calcium-sensing receptors present in the parathyroid. The signal strength and consistency indicates the simplicity and effectiveness of this method. Its implementation may limit operative time, decrease costs, and improve operative success rates.
doi:10.1016/j.surg.2013.06.046
PMCID: PMC3898879  PMID: 24238054
20.  PTTG1 Over-expression in Adrenocortical Cancer is Associated with Poor Survival and Represents a Potential Therapeutic Target 
Surgery  2013;154(6):1405-1416.
Background
Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data for prognostic biomarkers and therapeutic targets.
Methods
44 ACC and 4 normal adrenals were profiled on Affymetrix U133 Plus 2 expression microarrays. Pathway and transcriptional enrichment analysis was performed. Protein levels were determined by western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed for validation.
Results
Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Over-expression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average beta-actin <-3.04 ) was 1.8 years compared to 9.0 years if tumors expressed lower levels of PTTG1 (P<0.0001). Analysis of a previously published data set confirmed the association of high PTTG1 expression with a poor prognosis. Treatment of two ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (IC50s of 1.69 uM and 0.891 uM, for SW-13 and H295R, respectively).
Conclusion
Over-expression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target.
doi:10.1016/j.surg.2013.06.058
PMCID: PMC4054940  PMID: 24238056
21.  Recalcitrant Hypocalcemia after Thyroidectomy in Patients with Previous Roux-en-Y Gastric Bypass 
Surgery  2013;154(6):1300-1306.
Background
Hypocalcemia is a potential complication after thyroidectomy. Patients with previous roux-en-Y gastric bypass (RYGBP) may be at increased risk for recalcitrant symptomatic hypocalcemia after thyroidectomy. This complication is poorly described and there is no current consensus on optimal management in this unique population.
Methods
All patients from 2000-2012 who underwent thyroidectomy with history of preceding RYGBP were identified retrospectively. Each of the 19 patients meeting inclusion criteria were matched 2:1 for age, gender, and BMI to a cohort who underwent thyroidectomy without previous RYGBP. The study cohort and matched controls were compared for incidence of symptomatic post-operative hypocalcemia, requirement of intravenous (IV) calcium supplementation, and length of hospital stay (LOS).
Results
Age, proportion of female patients, and BMI were equivalent between cases (n=19) and controls (n=38). Comparison of primary outcomes demonstrated that the study group had a significantly higher incidence of symptomatic hypocalcemia (42% vs. 0%, p<0.01), administration of IV calcium (21% vs. 0%, p<0.01), and LOS (2.2 vs. 1.2 days, p=0.02).
Conclusions
Patients with previous RYGBP have higher incidence of recalcitrant symptomatic hypocalcemia after thyroidectomy resulting in prolonged LOS. In this patient population calcium levels should be closely monitored and early calcium and vitamin D supplementation preemptively initiated.
doi:10.1016/j.surg.2013.04.031
PMCID: PMC4063313  PMID: 23978591
22.  CLINICAL AND THERAPEUTIC IMPLICATIONS OF SPROUTY2 FEEDBACK DYSREGULATION IN BRAF V600E MUTATION POSITIVE PAPILLARY THYROID CANCER 
Surgery  2013;154(6):1239-1245.
Background
The BRAF V600E (BRAF+) mutation activates the MAPK/ERK pathway and may confer an aggressive phenotype in papillary thyroid cancer (PTC). However, clinically BRAF+PTC behavior varies from indolent to aggressive. SPRY2 is a negative feedback regulator of the MAPK/ERK pathway. We hypothesize that the level of SPRY2 expression contributes to MAPK/ERK pathway output and accounts for BRAF+ clinical heterogeneity.
Methods
A tissue microarray with BRAF+PTCs was constructed and analyzed for SPRY2 expression and MAPK/ERK output. Data were studied in the context of clinicopathologic factors to develop a risk stratification system predictive of tumor biology. SPRY2 function was studied by silencing SPRY2 in BRAF+PTC cells. These cells were treated with MAPK/ERK pathway inhibitors and assessed for growth effects.
Results
BRAF+PTCs with an intact MAPK/ERK feedback pathway, do not exhibit lymph node metastases. BRAF+PTCs with dysregulated feedback pathways have nodal metastasis. When SPRY2 is silenced the BRAF+PTC cells are significantly more sensitive to MAPK/ERK inhibition.
Conclusions
PTC behavior likely is dependent on both the driver of the MAPK/ERK pathway and its regulatory feedback. When the feedback pathway is intact the tumor phenotype seems to be less aggressive. This has a direct and important clinical implication and may alter our treatment strategies.
doi:10.1016/j.surg.2013.06.024
PMCID: PMC4100696  PMID: 24094449
23.  CLINICAL UTILITY OF IMMUNOHISTOCHEMISTRY FOR THE DETECTION OF THE BRAF V600E MUTATION IN PAPILLARY THYROID CARCINOMA 
Surgery  2013;154(6):1199-1205.
Background
BRAF V600E mutation is the most common genetic alteration in papillary thyroid cancer (PTC). We utilized a mutation-specific antibody for immunohistochemical (IHC) detection of the BRAF V600E mutation and correlated expression with clinicopathological features. The study was designed to validate the accuracy and determine the significance of IHC detection of the BRAF V600E mutation in PTC.
Methods
Direct sequencing and IHC for BRAF V600E mutation was performed in 37 consecutive PTCs. IHC was scored on an intensity, proportion scale. IHC positive tumors were stratified into intensity categories. The categories were assessed for clinicopathologic variables including age, extrathyroidal extension, lymphovascular invasion, and lymph node metastases.
Results
25 PTCs were BRAF V600E positive and 12 were BRAF mutation negative on IHC. The BRAF V600E mutation-specific antibody showed a sensitivity of 89% and specificity of 100% for detecting the mutation. Tumors with high intensity staining were significantly more likely to have extrathyroidal extension.
Conclusions
IHC is an accurate method for the detection of the BRAF V600E mutation in PTC and its ability to quantify the mutation expression may serve as a better predictor of tumor behavior than molecular sequencing. It provides a potentially rapid, easily applicable and economical alternative to current techniques.
doi:10.1016/j.surg.2013.06.020
PMCID: PMC4100700  PMID: 23931769
24.  Previous percutaneous coronary intervention increases morbidity after coronary artery bypass grafting 
Surgery  2012;152(1):5-11.
Background
We hypothesized that the incidence of previous percutaneous coronary intervention (PCI) is increasing and that prior PCI influences patient morbidity and mortality after coronary artery bypass grafting (CABG).
Methods
A total of 34,316 patients underwent isolated CABG operations at 16 different statewide, institutions from 2001 to 2008. Patients were stratified into prior PCI (n = 4346; 12.7%) and no prior PCI (n = 29,970). Patient risk factors, intraoperative variables, and outcomes were compared by univariate and multivariate analyses.
Results
The incidence of prior PCI in CABG has risen from <1% to 22.0% from 2001 to 2008 (P < .001). Prior PCI patients were younger (P < .001) and more commonly had previous myocardial infarction (P < .001), but less commonly had heart failure (P < .001). The operative mortality was similar between groups (2.3% vs 1.9%; P = .13). Prior PCI patients had more major complications (15.0% vs 12.0%; P < .001), longer hospitalization (P = .01), and higher readmission rates (P = .01). Importantly, by multivariate analyses, prior PCI was not associated with mortality, but was an independent predictor of major complications after CABG (odds ratio, 1.15; P = .01).
Conclusion
The incidence of prior PCI in patients undergoing CABG is increasing. Previous PCI is associated with a higher risk of major complications, greater hospital length of stay, and higher readmission rates after CABG.
doi:10.1016/j.surg.2012.02.013
PMCID: PMC4218734  PMID: 22503323
25.  The protective role of MnTBAP in Oxidant-mediated injury and inflammation following Lung Contusion 
Surgery  2013;154(5):10.1016/j.surg.2013.05.023.
Background
Lung contusion (LC) is a unique direct and focal insult that is considered a major risk factor for initiation of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). We have recently shown that consumption of Nitric oxide (NO)(due to excess superoxide) resulting in peroxynitrite formation leads to diminished vascular reactivity after LC. Here, we set to determine if superoxide scavenger Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) plays a protective role in alleviating acute inflammatory response and injury in LC.
Methods
Non-lethal closed-chest bilateral lung contusion was induced in a rodent model. Administration of superoxide dismutase (SOD) mimetic-MnTBAP, concurrently with LC in rats was performed and bronchoalveolar lavage (BAL) and lung samples were analyzed for degree of injury and inflammation at 5 and 24 h following the insult. The extent of injury was assessed by the measurement of cells and albumin with cytokine levels in the BAL and lungs. Lung samples were subjected to H&E and superoxide staining with dihydro-ethidium (DHE). Protein-bound dityrosine and nitrotyrosine levels were quantified in lung tissue by tandem mass spectrometry.
Results
The degree of lung injury after LC as determined by BAL albumin levels were significantly reduced in the MnTBAP administered rats at all the time points, when compared to the corresponding controls. The release of pro-inflammatory cytokines and BAL neutrophils were significantly lower in the MnTBAP administered rats after LC. Pathological examination revealed that administration of MnTBAP reduced tissue damage with decreased necrosis and neutrophil-rich exudate at the 24 h time point. Staining for superoxide anions showed significantly higher intensity in the lung samples from LC group compared to LC+ MnTBAP. Liquid chromatography/tandem mass spectrometry [HPLC/MS/MS] revealed that MnTBAP treatment significantly attenuated dityrosine and nitrotyrosine levels consistent with reduced oxidant injury.
Conclusion
SOD mimetic-MnTBAP reduced permeability and oxidative injury in LC and may have a therapeutic role in diminishing inflammation in LC.
doi:10.1016/j.surg.2013.05.023
PMCID: PMC3855248  PMID: 24139490

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