O Joe Hines

University of California, Los Angeles, Los Ángeles, California, United States

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Publications (233)1158.36 Total impact

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    ABSTRACT: In-hospital cardiopulmonary arrest can contribute significantly to publicly reported mortality rates. Systems to improve mortality are being implemented across all specialties. A review was conducted for all surgical patients >18 years of age who experienced a “Code Blue” event between January 1, 2013 and March 9, 2014 at a university hospital. A previously validated Modified Early Warning Score (MEWS) using routine vital signs and neurologic status was calculated at regular intervals preceding the event. In 62 patients, the most common causes of arrest included respiratory failure, arrhythmia, sepsis, hemorrhage, and airway obstruction, but remained unknown in 27 per cent of cases. A total of 56.5 per cent of patients died before hospital discharge. In-hospital death was associated with American Society of Anesthesiologists status (P = 0.039) and acute versus elective admission (P = 0.003). Increasing MEWS on admission, 24 hours before the event, the event-day, and a maximum MEWS score on the day of the event increased the odds of death. Max MEWS remained associated with death after multivariate analysis (odds ratio 1.39, P = 0.025). Simple and easy to implement warning scores such as MEWS can identify surgical patients at risk of death after arrest. Such recognition may provide an opportunity for clinical intervention resulting in improved patient outcomes and hospital mortality rates.
    The American surgeon 10/2015; 81(10). · 0.82 Impact Factor
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    ABSTRACT: Obesity, a known risk factor for pancreatic cancer, is associated with inflammation and insulin resistance. Pro-inflammatory PGE2, and elevated IGF-1 related to insulin resistance, are both shown to play critical roles in pancreatic cancer progression. We aimed at exploring a potential crosstalk between the PGE2 signaling and IGF-1/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In PANC-1 human pancreatic cancer cells, we showed that PGE2 stimulated mTORC1 activity independently of Akt, as evaluated by downstream signaling events. Subsequently using pharmacological and genetic approaches, we demonstrated that PGE2-induced mTORC1 activation is mediated by EP4/cAMP/PKA, as well as an EP1/Ca(2+)-dependent pathway. The cooperative roles of the two pathways were supported by the maximal inhibition achieved with the combined pharmacological blockade, and the co-existence of highly expressed EP1 (mediating Ca(2+) response) and EP2 or 4 (mediating cAMP/PKA pathway) in PANC-1 and a prostate cancer line PC-3, which also robustly exhibited PGE2-induced mTORC1 activation, as identified from a screen in various cancer cell lines. Importantly, we showed a reinforcing interaction between PGE2 and IGF-1 on mTORC1 signaling, with an increased IL-23 production as a cellular outcome. Together, our data reveal a previously unrecognized mechanism of PGE2-stimulated mTORC1 activation mediated by EP4/cAMP/PKA and EP1/Ca(2+) signaling, which may be of great importance in elucidating the promoting effects of obesity in pancreatic cancer. Ultimately, a precise understanding of these molecular links may provide novel targets for efficacious interventions devoid of adverse effects. Copyright © 2015, American Journal of Physiology - Cell Physiology.
    AJP Cell Physiology 08/2015; 75(15 Supplement):ajpcell.00417.2014. DOI:10.1152/ajpcell.00417.2014 · 3.78 Impact Factor
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    ABSTRACT: The epithelial-mesenchymal transition (EMT) is critical in the development of invasive epithelial malignancies. EMT is accelerated by inflammation and results in decreased E-cadherin expression. Diet-induced obesity is an inflammatory state that accelerates pancreatic carcinogenesis; its effect on EMT and E-cadherin expression in the development of pancreatic ductal adenocarcinoma is unclear. Conditional Kras(G12D) mice were fed a control diet or a high-fat, high-calorie diet for 3 or 9 months (n = 10 each). Immunohistochemistry with anti-E-cadherin antibody was performed. E-cadherin expression was characterized by staining intensity, location, and proportion of positive cells. In vitro expression of E-cadherin and Slug in primary pancreatic intraepithelial neoplasia (PanIN) and cancer cells was determined by Western blot. The HFCD led to increased weight gain in both 3- (15.8 vs 5.6 g, P < .001) and 9-month (19.8 vs 12.9 g, P = .007) mice. No differences in E-cadherin expression among various stages of preinvasive PanIN lesions were found-regardless of age or diet. In invasive cancer, E-cadherin expression was aberrant, with loss of membranous staining and prominent cytoplasmic staining, associated with strong, cytoplasmic expression of β-catenin. In vitro expression of E-cadherin was greatest in primary PanIN cells, accompanied by absent Slug expression. Cancer cell lines demonstrated significantly decreased E-cadherin expression in the presence of upregulated Slug. Despite increased pancreatic inflammation and accelerated carcinogenesis, the high-fat, high-calorie diet did not induce changes in E-cadherin expression in PanIN lesions of all stages. Invasive lesions demonstrated aberrant cytoplasmic E-cadherin staining. Loss of normal membranous localization may reflect a functional loss of E-cadherin. Copyright © 2015 Elsevier Inc. All rights reserved.
    Surgery 08/2015; DOI:10.1016/j.surg.2015.07.023 · 3.38 Impact Factor
  • Greg D Sacks · Elise H Lawson · Areti Tillou · O Joe Hines ·

    Annals of surgery 08/2015; 262(2):228-229. DOI:10.1097/SLA.0000000000001268 · 8.33 Impact Factor
  • Mu Xu · O Joe Hines ·

    JAMA SURGERY 06/2015; 150(8). DOI:10.1001/jamasurg.2015.0702 · 3.94 Impact Factor
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    ABSTRACT: Lymph node (LN) involvement is a well-known poor prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC). However, there have been conflicting results on the significance of the mechanism of LN involvement, "direct" tumor invasion versus "metastatic," disease on patient survival. Clinicopathologic records from all patients who underwent resection for PDAC from 1990 to 2014 at a single-institution were reviewed. Of the 385 total patients, there was tumor invasion outside of the pancreas in 289 (75.1%) patients. Overall, 239 (62.1%) had node-positive disease: 220 (92.0%) by "metastatic" involvement, 14 (5.9%) by "direct" tumor extension, and five (2.1%) by a mix of "metastatic" and "direct". There were no significant differences in clinicopathologic factors associated with PDAC survival between "metastatic" and "direct" LN patients. The median overall survival for the whole cohort was 31.1 months. Compared to overall survival in patients with LN-negative disease (median 40.7 months), those with LNs involved by "metastatic" spread was significantly shorter (median 25.7 months, P < 0.001), yet "direct" LN extension was similar (median 48.1 months, P = 0.719). The mechanism of LN involvement affects PDAC prognosis. Patients with LNs involved by direct extension have similar survival to those with node-negative disease. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Gastroenterology 04/2015; 148(4):S-1163. DOI:10.1016/S0016-5085(15)33971-8 · 16.72 Impact Factor
  • Alexander Stark · O Joe Hines ·
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    ABSTRACT: Malignant biliary obstruction, duodenal, and gastric outlet obstruction, and tumor-related pain are the complications of unresectable pancreatic adenocarcinoma that most frequently require palliative intervention. Surgery involving biliary bypass with or without gastrojejunostomy was once the mainstay of treatment in these patients. However, advances in non-operative techniques-most notably the widespread availability of endoscopic biliary and duodenal stents-have shifted the paradigm of treatment away from traditional surgical management. Questions regarding the efficacy and durability of endoscopic stents for biliary and gastric outlet obstruction are reviewed and demonstrate high rates of therapeutic success, low rates of morbidity, and decreased cost. Surgery remains an effective treatment modality, and still produces the most durable relief in appropriately selected patients. Copyright © 2015 Elsevier Inc. All rights reserved.
    Seminars in Oncology 02/2015; 42(1):163-176. DOI:10.1053/j.seminoncol.2014.12.014 · 3.90 Impact Factor
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    ABSTRACT: Autologous islet transplantation is an elegant and effective method for preserving euglycemia in patients undergoing near-total or total pancreatectomy for severe chronic pancreatitis. However, few centers worldwide perform this complex procedure, which requires interdisciplinary coordination and access to a sophisticated Food and Drug Administration-licensed islet-isolating facility. To investigate outcomes from a single institutional case series of near-total or total pancreatectomy and autologous islet transplantation using remote islet isolation. Retrospective cohort study between March 1, 2007, and December 31, 2013, at tertiary academic referral centers among 9 patients (age range, 13-47 years) with chronic pancreatitis and reduced quality of life after failed medical management. Pancreas resection, followed by transport to a remote facility for islet isolation using a modified Ricordi technique, with immediate transplantation via portal vein infusion. Islet yield, pain assessment, insulin requirement, costs, and transport time. Eight of nine patients had successful islet isolation after near-total or total pancreatectomy. Four of six patients with total pancreatectomy had islet yields exceeding 5000 islet equivalents per kilogram of body weight. At 2 months after surgery, all 9 patients had significantly reduced pain or were pain free. Of these patients, 2 did not require insulin, and 1 required low doses. The mean transport cost was $16 527, and the mean transport time was 3½ hours. Pancreatic resection with autologous islet transplantation for severe chronic pancreatitis is a safe and effective final alternative to ameliorate debilitating pain and to help prevent the development of surgical diabetes. Because many centers lack access to an islet-isolating facility, we describe our experience using a regional 2-center collaboration as a successful model to remotely isolate cells, with outcomes similar to those of larger case series.
    12/2014; 150(2). DOI:10.1001/jamasurg.2014.932
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    ABSTRACT: Background: The 2012 Sendai Criteria recommend that patients with 3 cm or larger branch duct intraductal papillary mucinous neoplasms (BD-IPMN) without any additional "worrisome features" or "high-risk stigmata" may undergo close observation. Furthermore, endoscopic ultrasound (EUS) is not recommended for BD-IPMN <2 cm. These changes have generated concern among physicians treating patients with pancreatic diseases. The purposes of this study were to (i) apply the new Sendai guidelines to our institution's surgically resected BD-IPMN and (ii) reevaluate cyst size cutoffs in identifying patients with lesions harboring high-grade dysplasia or invasive cancer. Methods: We retrospectively reviewed 150 patients at a university medical center with preoperatively diagnosed and pathologically confirmed IPMNs. Sixty-six patients had BD-IPMN. Pathologic grade was dichotomized into low-grade (low or intermediate grade dysplasia) or high-grade/invasive (high-grade dysplasia or invasive cancers). Fisher's exact test, chi-square test, student's t test, linear regression, and receiver operating characteristic (ROC) analyses were performed. Results: The median BD-IPMN size on imaging was 2.4 cm (interquartile range 1.5-3.0). Fifty-one (77 %) low-grade and 15 (23 %) high-grade/invasive BD-IPMN were identified. ROC analysis demonstrated that cyst size on preoperative imaging is a reasonable predictor of grade with an area under the curve of 0.691. Two-thirds of high-grade/invasive BD-IPMN were <3 cm (n = 10). Compared to a cutoff of 3, 2 cm was associated with higher sensitivity (73.3 vs. 33.3 %) and negative predictive value (83.3 vs. 80 %, NPV) for high-grade/invasive BD-IPMN. Mural nodules on endoscopic ultrasound (EUS) or atypical cells on endoscopic ultrasound-fine needle aspiration (EUS-FNA) were identified in all cysts <2 and only 50 % of those <3 cm. Forty percent of cysts >3 cm were removed based on size alone. Discussion/conclusions: Our results suggest that "larger" size on noninvasive imaging can indicate high-grade/invasive cysts, and EUS-FNA may help identify "smaller" cysts with high-grade/invasive pathology.
    Journal of Gastrointestinal Surgery 11/2014; 19(2). DOI:10.1007/s11605-014-2693-z · 2.80 Impact Factor
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    ABSTRACT: Objective To satisfy trainees’ operative competency requirements while improving feedback validity and timeliness using a mobile Web-based platform. Design The Southern Illinois University Operative Performance Rating Scale (OPRS) was embedded into a website formatted for mobile devices. From March 2013 to February 2014, faculty members were instructed to complete the OPRS form while providing verbal feedback to the operating resident at the conclusion of each procedure. Submitted data were compiled automatically within a secure Web-based spreadsheet. Conventional end-of-rotation performance (CERP) evaluations filed 2006 to 2013 and OPRS performance scores were compared by year of training using serial and independent-samples t tests. The mean CERP scores and OPRS overall resident operative performance scores were directly compared using a linear regression model. OPRS mobile site analytics were reviewed using a Web-based reporting program. Setting Large university-based general surgery residency program. Participants General Surgery faculty used the mobile Web OPRS system to rate resident performance. Residents and the program director reviewed evaluations semiannually. Results Over the study period, 18 faculty members and 37 residents logged 176 operations using the mobile OPRS system. There were 334 total OPRS website visits. Median time to complete an evaluation was 45 minutes from the end of the operation, and faculty spent an average of 134 seconds on the site to enter 1 assessment. In the 38,506 CERP evaluations reviewed, mean performance scores showed a positive linear trend of 2% change per year of training (p = 0.001). OPRS overall resident operative performance scores showed a significant linear (p = 0.001), quadratic (p = 0.001), and cubic (p = 0.003) trend of change per year of clinical training, reflecting the resident operative experience in our training program. Differences between postgraduate year-1 and postgraduate year-5 overall performance scores were greater with the OPRS (mean = 0.96, CI: 0.55-1.38) than with CERP measures (mean = 0.37, CI: 0.34-0.41). Additionally, there were consistent increases in each of the OPRS subcategories. Conclusions In contrast to CERPs, the OPRS fully satisfies the Accreditation Council for Graduate Medical Education and American Board of Surgery operative assessment requirements. The mobile Web platform provides a convenient interface, broad accessibility, automatic data compilation, and compatibility with common database and statistical software. Our mobile OPRS system encourages candid feedback dialog and generates a comprehensive review of individual and group-wide operative proficiency in real time.
    Journal of Surgical Education 11/2014; 71(6). DOI:10.1016/j.jsurg.2014.06.008 · 1.38 Impact Factor
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    ABSTRACT: Surgical resection is recommended for all mucinous cystic neoplasms (MCNs) of the pancreas as a result of: 1) lack of an accurate tumor marker for invasive cancer; 2) young age at diagnosis; and 3) historical studies revealing 36 per cent incidence of malignancy in resected lesions. This study compares the clinicopathologic and prognostic features of our series of resected MCNs to recent studies using the current International Association of Pancreatology (IAP) system. Thirty-eight resected MCNs were identified. Almost all patients were female (97.4%); median age at diagnosis was 53.5 years (interquartile range [IQR], 41.3 to 61.0). The majority occurred in the body/tail of the pancreas (86.8%); median size on computed tomography/magnetic resonance imaging was 5.0 cm (IQR, 3 to 8.8). Comparison of the five high-grade (HG, 13.2%) and 33 low-grade (86.8%) MCNs revealed that 1) patients were similar in age (55.0 vs 52.0 years, respectively) and 2) HG lesions were significantly larger on preoperative imaging (9.9 vs 3.5 cm) and final pathology (10.9 vs 3.5 cm). These data, taken together with five recent studies that adhere to the 2012 IAP criteria (385 total MCNs), reveal that a cutoff of less than 3 cm without mural nodules would have only missed one (0.26%) HG lesion. Surveillance of these lesions may be appropriate for some patients.
    The American surgeon 10/2014; 80(10). · 0.82 Impact Factor
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    ABSTRACT: Importance General surgical residency continues to experience attrition. To date, work hour amendments have not changed the annual rate of attrition.Objective To determine how often categorical general surgery residents seriously consider leaving residency.Design, Setting, and Participants At 13 residency programs, an anonymous survey of 371 categorical general surgery residents and 10-year attrition rates for each program. Responses from those who seriously considered leaving surgical residency were compared with those who did not.Main Outcomes and Measures Factors associated with the desire to leave residency.Results The survey response rate was 77.6%. Overall, 58.0% seriously considered leaving training. The most frequent reasons for wanting to leave were sleep deprivation on a specific rotation (50.0%), an undesirable future lifestyle (47.0%), and excessive work hours on a specific rotation (41.4%). Factors most often cited that kept residents from leaving were support from family or significant others (65.0%), support from other residents (63.5%), and perception of being better rested (58.9%). On univariate analysis, older age, female sex, postgraduate year, training in a university program, the presence of a faculty mentor, and lack of Alpha Omega Alpha status were associated with serious thoughts of leaving surgical residency. On multivariate analysis, only female sex was significantly associated with serious thoughts of leaving residency (odds ratio, 1.2; 95% CI, 1.1-1.3; P = .003). Eighty-six respondents were from historically high-attrition programs, and 202 respondents were from historically low-attrition programs (27.8% vs 8.4% 10-year attrition rate, P = .04). Residents from high-attrition programs were more likely to seriously consider leaving residency (odds ratio, 1.8; 95% CI, 1.0-3.0; P = .03).Conclusions and Relevance A majority of categorical general surgery residents seriously consider leaving residency. Female residents are more likely to consider leaving. Thoughts of leaving seem to be associated with work conditions on specific rotations rather than with overall work hours and are more prevalent among programs with historically high attrition rates.
    07/2014; 149(9). DOI:10.1001/jamasurg.2014.935
  • O Joe Hines ·

    Surgery 06/2014; 156(2). DOI:10.1016/j.surg.2014.04.032 · 3.38 Impact Factor
  • K.M. Hertzer · A. Moro · D.W. Dawson · G. Eibl · O.J. Hines ·

    Journal of Surgical Research 02/2014; 186(2):635. DOI:10.1016/j.jss.2013.11.650 · 1.94 Impact Factor
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    ABSTRACT: IMPORTANCE Treatment of patients with locally advanced/borderline resectable (LA/BR) pancreatic ductal adenocarcinoma (PDAC) is not standardized. OBJECTIVE To (1) perform a detailed survival analysis of our institution's experience with patients with LA/BR PDAC who were downstaged and underwent surgical resection and (2) identify prognostic biomarkers that may help to guide a decision for the use of adjuvant therapy in this patient subgroup. DESIGN, SETTING, AND PARTICIPANTS Retrospective observational study of 49 consecutive patients from a single institution during 1992-2011 with American Joint Committee on Cancer stage III LA/BR PDAC who were initially unresectable, as determined by staging computed tomography and/or surgical exploration, and who were treated and then surgically resected. MAIN OUTCOMES AND MEASURES Clinicopathologic variables and prognostic biomarkers SMAD4, S100A2, and microRNA-21 were correlated with survival by univariate and multivariate Cox proportional hazard modeling. RESULTS All 49 patients were deemed initially unresectable owing to vascular involvement. After completing preoperative chemotherapy for a median of 7.1 months (range, 5.4-9.6 months), most (75.5%) underwent a pylorus-preserving Whipple operation; 3 patients (6.1%) had a vascular resection. Strikingly, 37 of 49 patients were lymph-node (LN) negative (75.5%) and 42 (85.7%) had negative margins; 45.8% of evaluable patients achieved a complete histopathologic (HP) response. The median overall survival (OS) was 40.1 months (range, 22.7-65.9 months). A univariate analysis of HP prognostic biomarkers revealed that perineural invasion (hazard ratio, 5.5; P = .007) and HP treatment response (hazard ratio, 9.0; P = .009) were most significant. Lymph-node involvement, as a marker of systemic disease, was also significant on univariate analysis (P = .05). Patients with no LN involvement had longer OS (44.4 vs 23.2 months, P = .04) than LN-positive patients. The candidate prognostic biomarkers, SMAD4 protein loss (P = .01) in tumor cells and microRNA-21 expression in the stroma (P = .05), also correlated with OS. On multivariate Cox proportional hazard modeling of HP and prognostic biomarkers, only SMAD4 protein loss was significant (hazard ratio, 9.3; P = .004). CONCLUSIONS AND RELEVANCE Our approach to patients with LA/BR PDAC, which includes prolonged preoperative chemotherapy, is associated with a high incidence of LN-negative disease and excellent OS. After surgical resection, HP treatment response, perineural invasion, and SMAD4 status should help determine who should receive adjuvant therapy in this select subset of patients.
    JAMA SURGERY 12/2013; 149(2). DOI:10.1001/jamasurg.2013.2690 · 3.94 Impact Factor
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    ABSTRACT: The objective of this study was to summarize all clinical studies evaluating the prognostic role of gemcitabine (GEM) metabolic genes in pancreaticobiliary (PB) cancer patients receiving GEM therapy in the neoadjuvant, adjuvant, or palliative settings. Meta-analyses were performed to calculate the pooled hazard ratios for each gene by each clinical outcome (overall survival [OS], disease-free survival [DFS], and progression-free survival) using a random-effects approach. The search strategy identified 16 eligible studies, composed of 632 PB patients total, with moderate quality. Compared with low expression, pooled hazard ratios for OS of hENT1, dCK, RRM1, RRM2, and DPD were 0.37 (95% confidence interval [CI], 0.28-0.47), 0.40 (95% CI, 0.20-0.80), 2.21 (95% CI, 1.12-4.36), 2.13 (95% CI, 1.00-4.52), and 1.91 (95% CI, 1.16-3.17), respectively. A similar trend was observed for each of these biomarkers in DFS and progression-free survival prognostication. Subgroup analyses for hENT1 showed a comparable survival correlation in the adjuvant and palliative settings. High expression of hENT1 in PB cancer patients receiving GEM-based adjuvant therapy is associated with improved OS and DFS and may be the best examined prognostic marker to date. Evidence for other biomarkers is limited by a small number of publications investigating these markers.
    Pancreas 11/2013; 42(8):1303-10. DOI:10.1097/MPA.0b013e3182a23ae4 · 2.96 Impact Factor
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    ABSTRACT: The optimal surgical management of small nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) remains controversial. We sought to identify (1) clinicopathologic factors associated with survival in NF-PNETs and (2) preoperative tumor characteristics that can be used to determine which lesions require resection and lymph node (LN) harvest. The records of all 116 patients who underwent resection for NF-PNETs between 1989 and 2012 were reviewed retrospectively. Preoperative factors, operative data, pathology, surgical morbidity, and survival were analyzed. The overall 5- and 10-year survival rates were 83.9 and 72.8 %, respectively. Negative LNs (p = 0.005), G1 or G2 histology (p = 0.033), and age <60 years (p = 0.002) correlated with better survival on multivariate analysis. The 10-year survival rate was 86.6 % for LN-negative patients (n = 73) and 34.1 % for LN-positive patients (n = 32). Tumor size ≥2 cm on preoperative imaging predicted nodal positivity with a sensitivity of 93.8 %. Positive LNs were found in 38.5 % of tumors ≥2 cm compared to only 7.4 % of tumors <2 cm. LN status, a marker of systemic disease, was a highly significant predictor of survival in this series. Tumor size on preoperative imaging was predictive of nodal disease. Thus, it is reasonable to consider parenchyma-sparing resection or even close observation for NF-PNETs <2 cm.
    Journal of Gastrointestinal Surgery 10/2013; 17(12). DOI:10.1007/s11605-013-2360-9 · 2.80 Impact Factor
  • Graham Donald · Dharma Sunjaya · Timothy Donahue · O Joe Hines ·
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    ABSTRACT: The association between gallbladder polyps (GBP) and gallbladder cancer (GBC) is unclear. We sought to determine the association between preoperative diagnosis of GBP on imaging and GBC. A retrospective review of patients over 9 years was conducted using International Classification of Diseases, 9th Revision codes for GBP and GBC who underwent cholecystectomy at our institution. Demographics, imaging findings, and pathology results were recorded. A total of 2416 patients underwent cholecystectomy during the study period. Twenty-seven had an operation for GBP either as a result of concern for size or symptoms. Polyp sizes were categorized as less than 1 cm, 1 to 2 cm, or 2 cm or greater. Twenty-four patients in this group (88.9%) had no evidence of high-grade dysplasia or cancer and all of these benign polyps were 2 cm or less on imaging. One patient with a 2.4-cm polyp had high-grade dysplasia, and two patients with polyps over 3 cm had adenocarcinoma. During the same period, 20 patients had an operation for GBC with two patients common to the polyp group. The group of patients with noncancerous polyps was significantly younger than the cancer group (polyps and no polyps). The cancer group was more likely to be symptomatic. Therefore, polyps over 2 cm should be removed given the risk of high-grade dysplasia and cancer above this size. Polyps less than 2 cm were not associated with high-grade dysplasia or cancer and thus surgery may not be required. Intermediate- and small-sized polyps can be monitored with serial ultrasound, especially in younger, asymptomatic patients in whom the risk of malignancy is low.
    The American surgeon 10/2013; 79(10):1005-8. · 0.82 Impact Factor
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    ABSTRACT: Small non-coding RNAs, microRNAs (miRNA), inhibit the translation or accelerate the degradation of message RNA (mRNA) by targeting the 3'-untranslated region (3'-UTR) in regulating growth and survival through gene suppression. Deregulated miRNA expression contributes to disease progression in several cancers types, including pancreatic cancers (PaCa). PaCa tissues and cells exhibit decreased miRNA, elevated cyclooxygenase (COX)-2 and increased prostaglandin E2 (PGE2) resulting in increased cancer growth and metastases. Human PaCa cell lines were used to demonstrate that restoration of miRNA-143 (miR-143) regulates COX-2 and inhibits cell proliferation. miR-143 were detected at fold levels of 0.41 ± 0.06 in AsPC-1, 0.20 ± 0.05 in Capan-2 and 0.10 ± 0.02 in MIA PaCa-2. miR-143 was not detected in BxPC-3, HPAF-II and Panc-1 which correlated with elevated mitogen-activated kinase (MAPK) and MAPK kinase (MEK) activation. Treatment with 10 μM of MEK inhibitor U0126 or PD98059 increased miR-143, respectively, by 187 ± 18 and 152 ± 26 fold in BxPC-3 and 182 ± 7 and 136 ± 9 fold in HPAF-II. miR-143 transfection diminished COX-2 mRNA stability at 60 min by 2.6 ± 0.3 fold in BxPC-3 and 2.5 ± 0.2 fold in HPAF-II. COX-2 expression and cellular proliferation in BxPC-3 and HPAF-II inversely correlated with increasing miR-143. PGE2 levels decreased by 39.3 ± 5.0 % in BxPC-3 and 48.0 ± 3.0 % in HPAF-II transfected with miR-143. Restoration of miR-143 in PaCa cells suppressed of COX-2, PGE2, cellular proliferation and MEK/MAPK activation, implicating this pathway in regulating miR-143 expression.
    Biochemical and Biophysical Research Communications 08/2013; 439(1). DOI:10.1016/j.bbrc.2013.08.042 · 2.30 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) patients demonstrate highly variable survival within each stage of the American Joint Committee on Cancer (AJCC) staging system. We hypothesize that tumor grade is partly responsible for this variation. Recently our group developed a novel tumor, node, metastasis, grade (TNMG) classification system utilizing Surveillance Epidemiology and End Results (SEER) data in which the presence of high tumor grade results in advancement to the next higher AJCC stage. This study's objective was to validate this TNMG staging system utilizing single-institution data. All patients with PDAC who underwent resection at UCLA between 1990 and 2009 were identified. Clinicopathologic data reviewed included age, sex, node status, tumor size, grade, and stage. Grade was redefined as a dichotomous variable. The impact of grade on survival was assessed by Cox regression analysis. Disease was restaged into the TNMG system and compared to the AJCC staging system. We identified 256 patients who underwent resection for PDAC. Patients with low-grade tumors experienced a 13-month improvement in median survival compared to those with high-grade tumors. On multivariate analysis, tumor grade was the strongest predictor of survival with a hazard ratio of 2.02 (p = 0.0005). Restaging disease according to the novel TNMG staging system resulted in improved survival discrimination between stages compared to the current AJCC system. We were able to demonstrate that grade is one of the strongest independent prognostic factors in PDAC. Restaging with our novel TNMG system demonstrated improved prognostication. This system offers an effective and convenient way of adding grade to the current AJCC staging system.
    Annals of Surgical Oncology 08/2013; 20(13). DOI:10.1245/s10434-013-3159-3 · 3.93 Impact Factor

Publication Stats

5k Citations
1,158.36 Total Impact Points


  • 1994-2015
    • University of California, Los Angeles
      • • Department of Surgery
      • • Division of General Surgery
      Los Ángeles, California, United States
  • 1996-2014
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 1995-2014
    • Harbor-UCLA Medical Center
      Torrance, California, United States
    • University of Cincinnati
      • Department of Surgery
      Cincinnati, Ohio, United States
  • 2011
    • University of Nebraska Medical Center
      • Department of Pathology and Microbiology
      Omaha, Nebraska, United States
  • 2010
    • Mahidol University
      • Department of Pathology
      Krung Thep, Bangkok, Thailand
  • 2007-2010
    • CSU Mentor
      Long Beach, California, United States
  • 2009
    • Technische Universität München
      München, Bavaria, Germany
  • 2006
    • John Wayne Cancer Institute
      Santa Monica, California, United States
  • 2003-2006
    • Universität Heidelberg
      • • Institute of Pathology (Mannheim)
      • • Department of Spine Surgery
      Heidelburg, Baden-Württemberg, Germany
    • University of Miami Miller School of Medicine
      Miami, Florida, United States
    • Heidelberg University
      Tiffin, Ohio, United States
  • 2004
    • University of Southern California
      • Keck School of Medicine
      Los Ángeles, California, United States
  • 2001
    • Freie Universität Berlin
      • Institute of Social and Cultural Anthropology
      Berlín, Berlin, Germany
  • 2000
    • Albert Einstein College of Medicine
      • Department of Surgery
      New York, New York, United States